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Comprehensive Organic Functional

Group Transformations, Volume 3


Elsevier, 2003

Editors-in-Chief: Alan R. Katritzky, Otho Meth-Cohn, and Charles W. Rees

Synthesis: Carbon with One Heteroatom Attached by a


Multiple Bond

Part I: Tricoordinated Carbon Functions, R2C=Y


3.01 Aldehydes: Alkyl Aldehydes, Pages 1-52, Kevin E. B. Parkes and Stewart
K. Richardson
3.02 Aldehydes: α,β-Unsaturated Aldehydes, Pages 53-79, Warren J. Ebenezer
and Paul Wight
3.03 Aldehydes: Aryl and Heteroaryl Aldehydes, Pages 81-109, Gregory J.
Hollingworth
3.04 Ketones: Dialkyl Ketones, Pages 111-204, Kevin E. B. Parkes and Stewart
K. Richardson
3.05 Ketones: α,β-Unsaturated Ketones, Pages 205-276, Warren J. Ebenezer
and Paul Wight
3.06 Ketones Bearing an α,β-Aryl or -Hetaryl Substituent, Pages 277-312,
Daryl S. Walter
3.07 Aldehyde and Ketone Functions Further Substituted on Oxygen, Pages
313-327, Donald A. Whiting
3.08 Thioaldehydes and Thioketones, Pages 329-380, William G. Whittingham

3.09 Seleno- and Telluroaldehydes and -ketones, Pages 381-401, Frank S.


Guziec and Lynn J. Guziec
3.10 Imines and Their N-Substituted Derivatives: NH, NR and N-Haloimines,
Pages 403-423, Graeme M. Robertson
3.11 Imines and their N-Substituted Derivatives: Oximes and their O-R
Substituted Analogues, Pages 425-441, Graeme M. Robertson
3.12 Imines and Their N-Substituted Derivatives: Hydrazones and Other =NN
Derivatives Including Diazo Compounds, Pages 443-490, J. Stephen Clark
3.13 Synthesis of P, As, Sb and Bi Ylides (R3P=CR2, etc.), Pages 491-500, by kmno4
Éamonn J. Coyne and Declan G. Gilheany
3.14 Doubly Bonded Metalloid Functions (Si, Ge, B), Pages 501-505, Tao Ye
and M. Anthony McKervey
3.15 Doubly Bonded Metal Functions, Pages 507-523, Tao Ye and M. Anthony
McKervey

Part II: Dicoordinated Carbon Functions, R2C=C=Y

3.16 Ketenes, their Cumulene Analogues and their S, Se and Te Analogues,


Pages 525-554, David C. Harrowven and Shelagh T. Dennison
3.17 Ketenimines and Their P, As, Sb, and Bi Analogues, Pages 555-610,
Joseph P. Michael and Charles B. De Koning

Part III: Dicoordinated Carbon Functions, R C Z

3.18 Nitriles: General Methods and Aliphatic Nitriles, Pages 611-640, Michael
North
3.19 α,β-Unsaturated and Aryl Nitriles, Pages 641-676, Milton J. Kiefel

3.20 N-Substituted Nitriles and Other Heteroanalogues of Nitriles of the Type


RCZ, Pages 677-692, R. Michael Paton

Part IV: Monocoordinated Carbon Functions

3.21 Isocyanides and their Heteroanalogues (RZC), Pages 693-726,


Ian A. O’Neil
3.22 References to Volume 3, Pages 727-856
by kmno4
3.01
Aldehydes: Alkyl Aldehydes
KEVIN E. B. PARKES
Roche Products Ltd., Welwyn Garden City, UK

and

STEWART K. RICHARDSON
University of Notre Dame, IN, USA
2[90[0 SATURATED UNSUBSTITUTED ALDEHYDES 1
2[90[0[0 From Alkanes 1
2[90[0[1 From Alkenes 1
2[90[0[2 From Alkynes 2
2[90[0[3 From Halides 2
2[90[0[4 From Alcohols and their Derivatives 2
2[90[0[4[0 By oxidation of primary alcohols 2
2[90[0[4[1 From diols 6
2[90[0[4[2 Oxidation of alcohol derivatives 7
2[90[0[4[3 Rearran`ement of allylic alcohols 7
2[90[0[5 From Epoxides 8
2[90[0[6 From Acetals\ Enol Ethers and Enol Esters 8
2[90[0[7 From Aldehydes or Ketones 09
2[90[0[7[0 From saturated aldehydes or ketones 09
2[90[0[7[1 From unsaturated aldehydes 01
2[90[0[7[2 From a!functionalized aldehydes 01
2[90[0[8 From Carboxylic Acids and their Derivatives 02
2[90[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives 02
2[90[0[8[1 Formylation reactions 03
2[90[0[8[2 Other preparations from acids and acid derivatives 04
2[90[0[09 From Sulfur!containin` or Other Lower!Chalco`en!Containin` Precursors 04
2[90[0[00 From Nitro`en!containin` Precursors 06
2[90[0[00[0 From amines 06
2[90[0[00[1 From oximes\ hydrazones and their derivatives 07
2[90[0[00[2 From nitroalkanes 07
2[90[0[01 From Or`anosilanes 07
2[90[0[02 From Or`anoboranes 08
2[90[0[03 Methods Involvin` Umpolun` 08
2[90[0[03[0 Formyl anion equivalents 19
2[90[0[03[1 Other anion equivalents 19

2[90[1 b AND MORE REMOTELY UNSATURATED ALDEHYDES 10


2[90[1[0 Alkyl Aldehydes with One Double Bond 10
2[90[1[0[0 From aldehydes 10
2[90[1[0[1 Preparations involvin` rearran`ements 10
2[90[1[0[2 Other preparations 12
2[90[1[1 Alkyl Aldehydes with More than One Double Bond 13
2[90[1[2 Alkyl Aldehydes with Aryl or Hetaryl Substituents 13
2[90[1[2[0 From aldehydes 13
2[90[1[2[1 Other preparations 13

0
1 Alkyl Aldehydes
2[90[1[3 Alkynyl!Substituted Alkyl Aldehydes 14
2[90[1[3[0 Fra`mentation reactions 14
2[90[2 HALOALKYL ALDEHYDES "a\ b AND MORE REMOTE HALOGEN# 15
2[90[2[0 Introduction 15
2[90[2[1 From Stable Enol Derivatives and Enamines 15
2[90[2[2 From Aldehydes 15
2[90[2[3 Miscellaneous Preparations 16
2[90[2[3[0 Functional `roup transformations 16
2[90[2[3[1 Carbon0carbon bond!formin` methods 16
2[90[3 ALDEHYDES BEARING AN OXYGEN FUNCTION 17
2[90[3[0 OH!functionalized Aldehydes 17
2[90[3[0[0 a!OH!functionalized aldehydes 17
2[90[3[0[1 b! and more remotely functionalized OH aldehydes 20
2[90[3[1 OR!functionalized Aldehydes 20
2[90[3[2 OX!functionalized Aldehydes 22
2[90[4 ALDEHYDES BEARING A SULFUR FUNCTION 23
2[90[4[0 SH! and SR!functionalized Aldehydes 23
2[90[4[1 Hi`her!coordinated Sulfur!functionalized Aldehydes 26
2[90[5 ALDEHYDES BEARING A SELENIUM OR TELLURIUM FUNCTION 26
2[90[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Aldehydes 26
2[90[6 ALDEHYDES BEARING A NITROGEN FUNCTION 28
2[90[6[0 NH1!\ NHR! and NR1!functionalized Aldehydes 28
2[90[6[0[0 a!NH1!\ NHR! and NR1!functionalized aldehydes 28
2[90[6[0[1 b! and more remotely NH1!\ NHR! and NR1!functionalized aldehydes 33
2[90[6[1 NHX! and NX1!functionalized Aldehydes 35
2[90[6[2 NY!functionalized Aldehydes 35
2[90[7 ALDEHYDES BEARING A PHOSPHORUS\ ARSENIC\ ANTIMONY OR
BISMUTH FUNCTION 37
2[90[7[0 XR1\ X¦R2!functionalized Aldehydes 37
2[90[7[1 Hi`her!coordinated Phosphorus!\ Arsenic!\ Antimony! or Bismuth!functionalized Aldehydes 38
2[90[8 ALDEHYDES BEARING A METALLOID FUNCTION 40
2[90[8[0 Silicon!functionalized Aldehydes*a!silyl Aldehydes 40
2[90[8[0[0 From alcohols 40
2[90[8[0[1 From aldehydes or ketones 40
2[90[8[1 b!Silyl Aldehydes 41

2[90[0 SATURATED UNSUBSTITUTED ALDEHYDES

2[90[0[0 From Alkanes


No synthetically useful methods of oxidizing totally unactivated methyl groups to aldehydes have
been reported\ although in view of the relatively high reactivity of aldehydes under oxidizing
conditions this is perhaps not surprising[

2[90[0[1 From Alkenes


Although many oxidants will cleave alkenes to aldehydes\ relatively few do so cleanly or in high
yield\ the most important and well!established exception being ozone ðB!58MI 290!90Ł[ In cases where
ozone is not employed\ the conversion is generally achieved via the 0\1!diol by osmium"VIII# oxide!
mediated hydroxylation\ followed by periodate\ or lead"IV# acetate\ cleavage[ Isolation of the diol
intermediate is not necessary\ and hydroxylation and cleavage can be achieved in a single pot by a
mixture of osmium"VIII# oxide and sodium periodate ð45JOC367Ł[ The cleavage can also be achieved
using potassium manganate"VIII# under phase transfer conditions with careful control of pH
ð68CL332Ł[
Several methods have been developed for the homologative conversion of alkenes into aldehydes[
Probably the most important of these methods\ and certainly the most important industrially\ is the
hydroformylation\ or OXO reaction\ in which the alkene is treated with a mixture of hydrogen and
Saturated Unsubstituted 2
carbon monoxide in the presence of a cobalt\ rhodium or ruthenium catalyst ð80COMC!I"3#802Ł[ In
general\ the order of reactivity is terminal alkene×straight chain internal alkene×branched alkene\
with the formyl group being delivered to the least hindered end\ although with highly polarized
alkenes\ formylation occurs at the more electron!de_cient carbon atom[ The reaction tolerates most
functional groups\ although halides usually interfere[ Recent developments include low!temperature
hydroformylation catalysts "½49>C# ð67BCJ2905Ł\ polymer!bound ruthenium hydroformylation
catalysts ð70JOC0890Ł\ and asymmetric versions of the reaction\ which in favourable cases give
enantiomeric excesses of over 79) "Equation "0## ð76JA6011Ł[
H
CHO
H2, CO, SnCl2
(1)
60% conversion

78% ee

2[90[0[2 From Alkynes


Alkynes may be converted into aldehydes by hydroboration and oxidation of intermediate
vinylboranes[ Although diborane and many simple mono! and dialkylboranes give very poor
regioselectivity in the hydroboration\ excellent results can be obtained with either dimesitylborane
ð72TL0322Ł or the thexyliodoboraneÐdimethyl sul_de complex ð82TL4002Ł\ followed by a con!
ventional basic hydrogen peroxide workup "Equation "1##[

i, BHI•Me2S O O
Bun + (2)
ii, H2O2, OH– Bun Bun
99.0 : 1.0

2[90[0[3 From Halides


Primary alkyl halides may be oxidized to aldehydes by treatment with N!oxides or sulfoxides at
high temperatures in a reaction initially developed by Kornblum\ and which involves a nucleophilic
displacement of the halide as a _rst step[ Most subsequent work has concentrated on developing
modi_ed oxide reagents which may be used under less vigorous conditions^ reagents include
3!dimethylaminopyridine N!oxide in the presence of 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu#
ð70BCJ1110Ł\ a variety of pyridone N!oxide reagents ð68JCS"P0#1382Ł\ and DMSO in the presence of
sodium hydrogen carbonate and sodium iodide ð75SC0232Ł "Equation "2##[ The conversion may also
be achieved with more conventional oxidizing agents including tetrabutylammonium periodate
ð75SC32Ł\ tetrabutylammonium dichromate ð68CI"L#102Ł and iodine penta~uoride ð66S308Ł[
0!Haloalkenes may be hydrolysed to aldehydes using mercury"II# acetate in formic acid ð65BSF0830Ł[
Ph Ph
DMSO, NaI
O O (3)
Br O
O 60% O

2[90[0[4 From Alcohols and their Derivatives

2[90[0[4[0 By oxidation of primary alcohols


A mild\ versatile\ selective and practically convenient reagent for the conversion of primary
alcohols to aldehydes has been a long!standing objective of many research groups[ The available
methods will be discussed in six categories] "i# metal reagents\ particularly chromium and ruthenium
salts^ "ii# activated DMSO reagents^ "iii# halogen!based oxidants^ "iv# Oppenauer!type oxidations^
"v# electrochemical and photochemical oxidations^ and "vi# miscellaneous methods[
3 Alkyl Aldehydes
Recent research on oxidation methods has often been directed to developing low!cost methods
with increased environmental acceptability[ Thus catalytic methods\ particularly those using hydro!
gen peroxide or t!butylhydroperoxide as the ultimate oxidant\ have received considerable attention[
Also of interest from this point of view are solid!supported oxidants\ which allow the reaction to
be simply worked up by _ltration[ Such oxidants\ which often vary in selectivity and reactivity when
compared with the unsupported parent reagent\ have been the subject of a review ð68S390Ł[

"i# Usin` metal ion!based oxidants


"a# Chromium rea`ents[ Most traditional chromium!based oxidants have been found to be less
than satisfactory reagents for aldehyde preparation[ They are often unstable or hazardous to
prepare\ show little selectivity\ and need to be used in quite large excesses[ In addition\ the major
product is quite often not the aldehyde but a dimeric ester formed by preferential oxidation of the
hemiacetal derived from the product aldehyde and starting material[ This discouraging picture has
been transformed by a number of new reagents\ of which perhaps the pre!eminent is pyridinium
chlorochromate "pcc#\ and which has been the subject of a review ð71S134Ł[ Despite its now estab!
lished position\ occasional variations or improvements on the original method are still being
published\ and of particular note is an improved preparation of the reagent which is not only higher!
yielding but also less hazardous ð89T3306Ł[ An important group of modi_cations is aimed at
simplifying the workup\ which can be complicated by di.culties separating the product from tarry
chromium!containing residues[ These modi_ed reagents include polyvinylpyridinium chloro!
chromate\ a polymeric analogue of pcc ð67S423\ 70JOC0617Ł\ a variety of polymer!bound quaternary
ammonium chlorochromates ð75JOC3905Ł\ and 1\1?!bipyridinium chlorochromate\ which apparently
gives more tractable residues ð79S580Ł[ A wide range of other supported forms of chromic acid have
also been described\ including chromic acid adsorbed on silica gel ð67S423\ 68T0678Ł\ and chromate
ion bound to an anion exchange resin ð65JA5626Ł or to a poly"vinylpyridine# resin ð67JOC1507Ł[
One of the few disadvantages of pcc is its mildly acidic character\ which makes it unsuitable for
the oxidation of some sensitive substrates[ Several modi_ed reagents which reduce or overcome this
problem have been reported\ the most important of which is probably pyridinium dichromate "pdc#
in dichloromethane ð68TL288Ł\ and which\ like pcc\ is available in a resin!supported form ð78SC0206Ł[
Other reagents with reduced acidity include pyridinium ~uorochromate ð71S477Ł\ pcc absorbed onto
alumina\ which will oxidize citronellol to citronellal in 89) yield\ whereas pcc gives pulegone
ð79S112Ł\ and trimethylsilyl chlorochromate\ which is prepared in situ from chromium trioxide and
chlorotrimethylsilane and allows oxidations to be performed under strictly neutral and anhydrous
conditions ð72TL3256\ 74T1892Ł[ In addition\ the use of ultrasound in oxidations with silica gel!
supported pcc\ leading to a signi_cant reduction in the length of time and the amount of reagent
required\ has been described ð78JOC4276Ł\ and molecular sieves have been found to assist the
oxidations of a variety of alcohols including carbohydrates and nucleosides ð71JCS"P0#0856Ł[
Trimethylammonium chlorochromate has also been proposed as an alternative to pcc ð89S016Ł[
Several neutral organic soluble dichromate oxidants have been developed\ and o}er a number of
advantages in comparison to pdc\ in particular allowing the oxidation of sensitive substrates\
and short reaction times[ These include the 1! and 3!benzylpyridinium dichromates ð80SC308Ł\
bis"benzyltriethylammonium#dichromate ð71S0980Ł and tetrakispyridinocobalt"II# dichromate
ð81SC0380Ł[ Bisphosphonium dichromate ð75TL0664Ł and 2!carboxypyridine dichromate "sometimes
referred to as nicotinium dichromate\ NDC# ð76T2852Ł\ although insoluble in organic solvents\ also
appear to have advantages over pdc for some oxidations[ Lastly\ zinc dichromate has been reported
to display an unusual selectivity\ and e.ciently oxidizes primary alcohols while leaving the normally
more reactive allylic alcohols una}ected ð75S174Ł[ This reagent is also known in a polymer!supported
form ð80SC1966Ł[
Relatively little has been published on phase transfer!catalysed chromate oxidations\ although
the method seems to have considerable potential[ Although the earliest methods were only applicable
to acid!stable substrates ð67TL0590Ł\ more modern methods are considerably milder ð68S023\
79TL3542Ł\ and examples containing quite acid!sensitive functionalities\ such as an isoxazole ring are
known ð72SC706Ł[ High yields of aldehydes can also be obtained in oxidations with preformed
quaternary ammonium chromates ð68S245Ł[
An important early oxidant was Collins reagent\ a solution of chromium trioxide in pyridine[
The reagent is still occasionally of value\ although its preparation can be hazardous\ and a number
of variants are now known\ including solutions of chromium trioxide in DMSO ð81SC656Ł or
hexamethylphosphoramide "HMPA# ð65S283Ł[ A rather di}erent way of modulating the reactivity
Saturated Unsubstituted 4
of chromium trioxide is by suspending it on Celite ð68S704Ł\ which has the additional advantage of
simplifying the workup[
Peroxychromium species such as CrO4 = C4H4N ð66TL2638Ł\ and CrO6 ð75T608Ł\ and a number of
chromium"V# complexes ð79TL0472Ł have been used as reagents for primary alcohol oxidation\
although despite some advantages\ in particular being neutral\ they have not achieved widespread
use[
Lastly\ it is worth mentioning that\ despite the industrial and economic importance of the goal\
relatively little progress has so far been reported in developing catalytic chromium systems for the
oxidation of alcohols[ This area is clearly receiving some attention although\ unfortunately\ the
methods reported so far do not appear to be applicable to the oxidation of primary alcohols to
aldehydes[
"b# Man`anese rea`ents[ Simple manganate"VI# or manganate"VII# salts are very powerful and
unselective oxidants\ which even in simple cases are of little synthetic use for the oxidation of
primary alcohols to aldehydes since\ except in strongly basic solutions\ further oxidation to the
carboxylic acid is faster than the initial oxidation to the aldehyde[ Although a range of modi_ed
manganese reagents is now available\ which are useful for the preparation of conjugated unsaturated
aldehydes and ketones\ only occasional examples of their use for the preparation of saturated
aldehydes have been reported ð72BCJ803\ 89T5758Ł[
"c# Ruthenium rea`ents[ As with chromium and manganese reagents\ the challenge for chemists
wanting to develop oxidants of this class has been to moderate the reactivity and improve the
selectivity of simple ruthenium reagents[ In an interesting contrast to the other metal oxidants\
where modi_ed stoichiometric reagents have been developed\ the most successful approach has been
the development of catalytic systems[ Two distinct systems have been found to be useful[
The _rst\ and less widely used\ of these employs bis"triphenylphosphine#ruthenium"II# chloride\
which appears to have some potential as a stoichiometric\ as well as a catalytic\ oxidant of primary
alcohols[ It was _rst reported with N!methylmorpholine N!oxide as a cooxidant ð65TL1492Ł\ although
more recent publications have used bis"trimethylsilyl#peroxide ð77BCJ2596Ł\ phenyliodosodiacetate
ð70TL1250Ł or m!iodosylbenzoic acid ð72HCA0689Ł as the cooxidant[ The stoichiometric version of
the reaction is of interest since it allows the oxidation of primary alcohols in the presence of
secondary ones ð70TL0594Ł[
Unquestionably the most important ruthenium oxidants\ and one of the most important recent
developments in oxidation methodology generally\ are the tetraalkylammonium perruthenates
developed by Gri.th and by Ley[ These use a catalytic tetraalkylammonium perruthenate\ generally
tetrapropylammonium perruthenate "TPAP#\ in the presence of 3A nm molecular sieves with
N!methylmorpholine N!oxide as a regenerating oxidant to achieve the oxidation under very mild\
neutral conditions[ The reagent is notable for the wide range of functionalities tolerated\ including
THP and silyl ethers\ alkenes\ epoxides and esters "Equation "3##\ and the fact that chiral centres a
to the newly formed carbonyl group are not epimerized ð76CC0514Ł[ The reagent has also been the
subject of a review ð89MI 290!90Ł[

OH O

TPAP
O O (4)
70%
O-TBDPS O-TBDPS

TBDPS = t-butyldiphenylsilyl

"d# Miscellaneous metal oxidants[ Although catalytic molybdenum! and tungsten!based systems
are well established for the oxidations of secondary alcohols\ primary alcohols are generally una}ec!
ted[ However\ two molybdenum peroxy complexes\ "0# ð79TL3732Ł and "1# ð76JOC4356Ł\ which are
both used stoichiometrically\ do oxidize primary alcohols to aldehydes[ Osmium tetroxide in ether
has the unusual selectivity of oxidizing primary alcohols in the presence of secondary alcohols\
although the high reactivity of the reagent to other functionalities limits the application of the
reaction ð73S844Ł[ Nickel"II# bromide catalyses the oxidation by benzoyl peroxide of primary
alcohols to aldehydes in high yield ð68JOC1844Ł[
A number of catalytic palladium systems for alcohol oxidation are known\ and the scope of the
method has been examined ð72JOC0175Ł[ The optimal conditions employ 0Ð2 mol) of either a
palladium"9# or palladium"II# catalyst with bromobenzene as a reoxidant[ The oxidation can
also be performed under phase transfer conditions with iodobenzene as a reoxidant ð74TL5146Ł[
5 Alkyl Aldehydes
O
O O
Mo
Ph O O O O
N O O O
Mo
O N
Ph O O

(1) (2)

Ytterbium"III# nitrate will catalyse the oxidation of alcohols by iodosobenzene[ Like osmium
tetroxide this reagent shows the unusual selectivity of oxidizing primary alcohols in preference to
secondary alcohols ð82CL460Ł[

"ii# Usin` DMSO rea`ents


Since P_tzner and Mo}at|s serendipitous discovery in 0852 that alcohols were oxidized at room
temperature by DMSO in the presence of dicyclohexylcarbodiimide and phosphoric acid ð52JA2916Ł\
oxidations of alcohols by activated DMSO have become established as one of the mildest and most
general methods for the oxidation of alcohols\ although today the most commonly used variant is
that developed by Swern and co!workers which uses oxalyl chloride as the activating agent
ð67JOC1379\ 67T0540Ł[ The method is of particular value for aldehyde preparations because of its
exceptionally mild nature and the fact that over!oxidation does not occur[
The area is well served by several good reviews[ The literature up to 0879 is covered in a classic
review by Manusco and Swern ð70S054Ł[ This has been updated to 0878 by Tidwell ð89S746Ł\ who
has also written an Or`anic Reactions article on the subject\ which includes extensive tabulations of
examples\ and a good discussion of the scope of the oxidation and of potential side reactions
ð89OR"28#186Ł[ Relatively little can be added to the coverage provided by these reviews\ although
bis"trichloromethyl#carbonate "triphosgene# recently has been reported to be a good activating
reagent\ and\ being a crystalline solid\ avoids the handling and scale!up problems associated with
the relatively toxic and corrosive reagents generally used ð80JOC4837Ł[
N!Chlorosuccinimide and diisopropyl sul_de will oxidize alcohols in a reaction which is probably
mechanistically very closely related to the SwernÐMo}att oxidation ð73CC651Ł[ The method shows
the curious\ and unexplained\ feature that at 9>C primary alcohols are oxidized in preference to
secondary alcohols while at −67>C the opposite selectivity is found[

"iii# Usin` halo`en!based oxidants


Many electrophilic halogen"I# reagents can oxidize primary alcohols to aldehydes\ and some\
such as trichloroisocyanuric acid ð81SC0478Ł and N!iodosuccinimide ð70S283Ł\ do so cleanly and in
good yield[ However\ more important as oxidants are the iodine"V# reagents\ and in particular
periodinane "2#\ which was _rst reported as an oxidant for alcohols by Dess and Martin in 0872
ð72JOC3044Ł[ An improved preparation has been described ð82JOC1788Ł[ The oxidation occurs under
very mild conditions and is compatible with a wide range of other functionalities including secondary
amides\ sul_des\ alkenes\ furans and vinyl ethers ð80JA6166Ł[ The related alkoxyaryltri~uoro!
periodinane "3# has also been reported to oxidize alcohols to aldehydes in moderate to high yields
ð68JA4183Ł[

AcO OAc F F
I OAc I F
O O

O
(3) (4)
Saturated Unsubstituted 6
"iv# Oppenauer and related oxidations
The oxidation of secondary alcohols by an aluminum alkoxide!catalysed hydrogen transfer to an
acceptor ketone\ present in excess to drive the equilibrium in the desired direction\ was _rst reported
by Oppenauer ð26RTC026Ł[ The method was quite widely used in the older literature\ particularly
for the oxidation of steroidal alcohols\ and was the subject of an early review ð40OR"5#196Ł[ Unfor!
tunately\ the method\ despite the mild conditions\ cannot be directly applied to the oxidation of
primary alcohols to aldehydes since the product aldehydes condense with the excess ketone present
as a hydrogen acceptor\ and until recently there was no general solution to this problem[ However\
new catalysts which do not catalyse the aldol side reaction are now becoming available[ These include
bis"cyclopentadienyl#zirconium hydride ð75JOC139\ 75S663Ł\ zirconium oxide with benzophenone as
the hydrogen acceptor ð80BCJ201Ł\ and a variety of lanthanide alkoxides ð73JOC1934Ł^ they make
the method an attractive option for the oxidation of sensitive substrates with the added bene_t of
avoiding any risk of overoxidation[

"v# Electrochemical and photochemical oxidations


Since an alcohol will not lose an electron at experimentally achievable electrode potentials\ the
direct electrochemical oxidation of alcohols is an impossibility[ However\ a number of systems are
known which use an intermediary species\ often referred to as an {electron carrier|\ which can oxidize
the alcohol chemically\ the resulting reduced form of the electron carrier being reoxidized at the
anode to complete the cycle[ These include a number of traditional electron carriers such as iodonium
reagents ð68TL054Ł\ sulfur species ð68TL2750\ 79TL0756Ł\ molecular oxygen ð78S392Ł and nitroxyls
ð72JA3381Ł\ as well as established oxidants for alcohols such as ruthenium salts ð89SC288Ł\ in what
are e}ectively electrocatalytic versions of these oxidations[ Two!stage systems in which the oxidant
is not reoxidized directly at the anode but via an electron carrier are also possible ð80BCJ685Ł[
The photochemical oxidation of alcohols to aldehydes is a very underexplored area of meth!
odology\ although it is known that irradiation of an alcohol in the presence of a copper"II#\ iron"III#
or silver"I# salt ð68JOC027Ł or platinum on titanium dioxide ð73TL2252Ł can give high yields of
aldehydes[

"vi# Miscellaneous oxidations


Dimesityl diselenide catalyses the oxidation of alcohols to aldehydes by t!butyl hydroperoxide[
The method is extremely mild and is even compatible with the presence of phenylthio or phenylseleno
groups ð71JOC726Ł[ The oxaminium salt "4# "XOMe# has been found to be an e.cient oxidant
which shows selectivity for primary over secondary alcohols ð74JOC0221Ł[ Variants of the reaction
in which the reagent is used catalytically with sodium hypochlorite ð76JOC1448Ł\ sodium bromite
ð89JOC351Ł or calcium hypochlorite ð89JOC351Ł as a cooxidant are also known[ A similar oxidation
can be achieved with the oxaminium salt "4# "XH# and sodium hypochlorite as the cooxidant\
and leads to less overoxidation to the corresponding carboxylic acid ð89TL1066Ł[ Another useful
oxidant is 0\0?!"azodicarbonyl#dipiperidine\ which provides a very mild method of oxidizing alcohols
via their bromomagnesium salts ð66BCJ1662Ł[
X

+
N Br–
O
(5)

2[90[0[4[1 From diols


Probably the most important route to aldehydes from 0\1!diols is by oxidative cleavage[ Many
oxidants\ particularly metal!based reagents\ will cleave vicinal diols\ although the major products
7 Alkyl Aldehydes
are often carboxylic acids[ However\ consistently high yields can be obtained with periodate\ lead"IV#
acetate or bismuth reagents ðB!54MI 290!90\ B!58MI 290!91\ 70CC0121Ł[ Silica gel!supported sodium
periodate has been found to be particularly convenient for the cleavage of 0\1!diols to aldehydes
ð78S53Ł[ Most glycol cleavages proceed by mechanisms that involve cyclic intermediates and there!
fore cannot be used for the cleavage of trans!diols[ However\ cleavages with iodine"III# or iodine"I#
acetates appear to be radical in nature and proceed equally well with cis! or trans!diols
ð67JCS"P0#0372Ł[ Diols protected as their dibutylstannylene derivatives can also be cleaved with either
periodate or lead"IV# acetate ð70TL1774Ł[

2[90[0[4[2 Oxidation of alcohol derivatives

"i# Ethers
A wide range of alkyl and silyl ethers of primary alcohols react with hydride!abstracting reagents
to give an oxonium ion which is hydrolysed to give the aldehyde on workup[ Thus\ methyl ethers
of primary alcohols are cleaved oxidatively by nitronium tetra~uoroborate ð66JOC2986Ł\ or uran!
ium"VI# ~uoride ð67JA4285Ł\ and O!trimethylsilyl derivatives of primary alcohols can be oxidized
with trityl tetra~uoroborate ð65JOC0368Ł[ Similarly\ sodium bromate\ in the presence of a catalytic
amount of cerium"IV# ammonium nitrate\ will oxidize a wide range of ether derivatives\ including
methyl\ benzyl\ trimethylsilyl and t!butyldimethylsilyl ð79S786Ł[
Trimethylsilyl ethers can be oxidized using DMSO:oxalyl chloride\ although the conditions
"−29>C for 29Ð34 minutes# are appreciably more vigorous than are normally required for alcohol
oxidations ð76JCS"P0#0110Ł[ t!Butyldimethylsilyl ethers are inert to the reaction conditions\ and
hindered or secondary trimethylsilyl ethers react appreciably less rapidly\ allowing some interesting
selective oxidations to be achieved "Equation "4## ð78S839Ł[ The oxidative deprotection and stability
under alcohol oxidative conditions of silyl ethers has been the subject of a very comprehensive
review\ which includes some useful tabulations of the reactivities observed ð82S00Ł[

O O

O DMSO, (COCl)2 O
(5)
O-TMS 62% O

OSiEt3 OSiEt3

"ii# Esters
Aldehydes may be prepared under strictly neutral conditions by the photolysis of the pyruvate
esters of primary alcohols ð65JOC2929\ 65SC170Ł\ and the reaction has been applied to good e}ect in
the preparation of a number of delicate carbohydrate aldehydes ð66JOC0105Ł[ Alkyl nitrites are
oxidized in a Kornblum!type reaction by DMSO ð75T3022Ł\ and alcohols can be oxidized via their
aci!nitro esters in a reaction that is probably mechanistically related ð68CC292\ 70TL1184Ł[

2[90[0[4[3 Rearrangement of allylic alcohols


A variety of primary allylic alcohols can be isomerized to aldehydes on treatment with
N!lithioethylenediamine or N!lithioaminopropylamine in the amine as the solvent ð74CC701Ł[ The
reaction is somewhat capricious although in favourable cases very good yields of the expected
aldehyde are obtained "Equation "5##[ The main alternative to these strongly basic conditions is a
ruthenium"II#!catalysed rearrangement[ Although the optimal conditions are substrate!dependent\
Saturated Unsubstituted 8
good yields are frequently attainable\ and isolated double bonds and alcohols are una}ected
ð80TL2928Ł[

OH O

LiNHCH2CH2NH2
(6)
74%

2[90[0[5 From Epoxides


The treatment of epoxides with Lewis acids can give respectable yields of aldehydes\ although the
identity of the carbonyl compound formed appears to depend both on the direction of ring opening
and the migratory aptitude of the substituents[ Thus\ mono! and 0\0!disubstituted epoxides generally
give aldehydes\ but with 0\1!disubstituted and trisubstituted epoxides both the exact structure of
the substrate and the conditions used are important[ For instance\ treatment of 0\1!disubstituted
epoxides with lithium bromide on alumina ð77S283Ł\ or trisubstituted epoxides with methylaluminum
bis"3!bromo!1\5!di!t!butylphenoxide# ð80SL380Ł\ gives aldehydes selectively[ The subject is discussed
in greater depth in a review of epoxide chemistry ð73S518Ł[

2[90[0[6 From Acetals\ Enol Ethers and Enol Esters


The chief importance of acetals in organic synthesis is as protecting groups for carbonyl
compounds[ As well as simple dialkylacetals\ 0\2!dioxanes and 0\2!dioxolanes\ many more complex
acetals have been used as protecting groups\ and allow the preparation and deprotection of aldehydes
under a remarkably wide range of conditions[ Readers particularly interested in these aspects
should refer to one of the specialist works on protecting groups such as that by Greene and Wuts
ðB!80MI 290!90Ł\ since the following discussion is only intended to highlight some of the more
important approaches to preparing aldehydes from simple acetals[
Traditional methods of aldehyde preparations from acetals are variants on the theme of acid!
catalysed hydrolysis\ and these have now been extended to use supported or heterogeneous acids
such as Amberlyst!04 ð73S0910Ł\ or wet silica gel ð67S52Ł\ which permit the reaction to be worked
up more easily[ However\ a more important objective of research in this area has been to develop
less strongly acidic conditions for the reaction\ and to _nd methods that allow highly selective
deprotections to be performed[ One important approach to the former goal is to use trans!
acetalizations which are catalysed by very mild reagents such as pyridinium tosylate ð68S613Ł\
and palladium"II# bis"acetonitrile# dichloride ð74TL694Ł\ although actual hydrolyses with neutral
reagents\ such as aqueous DMSO ð78CL890Ł\ are also possible[
A relatively recent discovery is the ability of a number of reagents to e}ect the {hydrolysis| of
acetals under strictly nonaqueous conditions[ These methods appear to involve an electrophilic
attack on one of the acetal oxygens leading to an oxonium ion which is cleaved to the aldehyde by
nucleophilic attack on the alkyl group[ The proposed mechanism is illustrated in Scheme 0 for the
case of iodotrimethylsilane ð66TL3064Ł[ Another reagent which appears to work in this way is a
mixture of acetyl chloride and zinc chloride\ and has the advantage of allowing the cleavage of
dimethyl and diethyl acetals derived from aldehydes in the presence of ketone!derived acetals\ silyl
ethers and dioxolanes "Equation "6## ð81SC0106Ł[

I–
I– O
TMS-I O-TMS O-TMS
O O O O+ +O + I
TMS
R
R R R

Scheme 1
09 Alkyl Aldehydes

O O O O
AcCl, ZnCl2
DMSO
MeO O (7)
O 63% O
OMe

Enol esters and silyl enol ethers are most often prepared from aldehydes as intermediates in
other reactions[ They are\ in general\ relatively labile compounds hydrolytically\ making their
transformations back to aldehydes relatively straightforward should it be required[ Tributyltin
~uoride has been recommended for the hydrolysis of more stable silyl enol ethers ð72JA4692Ł[

2[90[0[7 From Aldehydes or Ketones

2[90[0[7[0 From saturated aldehydes or ketones


"i# Alkylation
Although\ in principle\ aldehyde alkylations provide a powerful way of elaborating aldehydes\
simple alkylations of metal enolates su}er from a number of drawbacks which limit their use[ These
include poor or no diastereomeric and enantiomeric control\ the occurrence of O! as well as
C!alkylation\ and a propensity to give a mixture of singly and polyalkylated products[ However\ a
range of alternative methods are now available which o}er solutions to all these problems[
The fundamental problem underlying the polyalkylation of sodium and potassium enolates is the
fact that alkylation and proton transfer proceed at similar rates[ In contrast\ lithium enolates\
probably because of the more covalent nature of the lithiumÐoxygen bond\ undergo proton transfer
far less rapidly and allow monoalkylations to be performed[ The alkylation of metal enolates\ in
particular alkylations involving preformed metal enolates which have the advantage of giving less
aldol by!product than base!catalysed conditions\ has been well reviewed by Caine ðB!68MI 290!90Ł[
Several important methods of aldehyde alkylation involve nitrogen derivatives of the aldehyde\
of which the _rst to be introduced were enamines ð43JA1918Ł\ quickly followed by metallated imines
ð52AG"E#572Ł\ and\ lastly\ metallated hydrazones ð65TL2Ł[ The alkylation of aldehydes via their
nitrogen derivatives has been the subject of a Synthesis review ð72S406Ł[ One particularly important
application of these methods is for the enantioselective alkylation of ketones\ with probably the
best established method being that developed by Enders ðB!72MI 290!90Ł[ This employs hydrazones
derived from "S#!"−#! or "R#!"¦#!0!amino!1!methoxymethylpyrrolidine "abbreviated to SAMP and
RAMP\ respectively# and gives reliably high enantioselectivities of predictable sense\ making it the
method of choice for most chiral alkylations "Scheme 1# ðB!73MI 290!90Ł[ Good enantioselectivities
can also be obtained with metallated imines derived from suitable homochiral primary amines
ð68TL2818Ł[
O
i, base
N ii, MeI N H3O+
N N
79% 80%
OMe OMe
Ph

Ph Ph

Scheme 2

Although the reaction of silyl enol ethers derived from ketones with tertiary alkylating agents
under Lewis acid catalysis to give\ after workup\ good yields of alkylated ketone is well established\
examples with aldehyde!derived silyl enol ethers are uncommon ð71AG"E#85Ł[ The reaction is impor!
tant in that it complements enolate chemistry both in using acidic rather than basic conditions and\
most importantly\ by allowing the introduction of tertiary alkyl groups[

"ii# Homolo`ation
Although any preparation of functionalized aldehydes involving carbon0carbon bond formation
and starting from a ketone or aldehyde can be thought of as a homologation\ this section will only
Saturated Unsubstituted 00
deal with reactions which increase the number of carbon atoms without any increase in the functional
group complexity of the molecule[
Homologation of aldehydes generally involves alkenation to give a functionalized alkene which
can be converted into the required aldehyde in a second step "Scheme 2 and Table 0#[ The reagents
can often also be applied to the preparation of aldehydes from ketones\ and use a wide range of
alkenation methodologies\ including Wittig and related phosphorus chemistry\ and Peterson reac!
tions[ A variety of enol ether and enamine precursors to homologated aldehydes can also be prepared
via the diazoalkene derivative resulting from the reaction of an aldehyde or ketone with dimethyl
diazomethylphosphonate "Scheme 3# ð72JOC337Ł[
R O X O
R R
Scheme 3

Table 0 Preparation of aldehydes by the homologation of aldehydes to ketones[


Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
X Rea`ent Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
OMe Ph1P"O#CH1OMe 68JCS"P0#2988
Ph2P1CHOMe 79TL2424
Me2SiCH1OMe 68CC711
O!MEM "EtO#1P"O#CH1O!MEM 67TL2518
O!THP "EtO#1P"O#CH1O!THP 68JOC3736
OSiEt2 "Me1N#1P"O#CH1OSiEt2 68JA260
OBn BnOCH1CO1H 68S277
OCH1CH1!TMS Ph2P1CHOCH1CH1SiEt2 72TL462
Morpholine Ph1P"O#CH1!morpholine 68TL1322
NMePh Ph1P"O#CH1NMePh 79TL1560
SMe Ph2P1CHSMe 66CI"M#728
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

N2
OMe
O •

(MeO)2P(O)CHN2

KOBut, MeOH 53%

Scheme 4

Corey et al[ have developed a variant of the Peterson strategy in which the carbon atom is
introduced by cyanohydrin formation\ which\ although employing several steps\ is useful for the
preparation of aldehydes from very hindered ketones ð79JA0631Ł[ A very di}erent homologative
approach to aldehydes\ which also introduces the carbon atom at the acid oxidation level\ uses the
dithiolane containing WadsworthÐEmmons reagent "5# and involves the borohydride reduction of
a ketene thioacetal intermediate "Scheme 4# ð76S68Ł[

O
S S
HBF4

+ (MeO)2P(O)
100%
S S
(6)

CHO

S NaBH4 S HgO, HBF4 (aq.)


+

S 98% S 90%
BF4–

Scheme 5
01 Alkyl Aldehydes
2[90[0[7[1 From unsaturated aldehydes

"i# Conju`ate reduction


Conjugate reduction of the carbon0carbon double bond of an a\b!enal is inherently more di.cult
than of an enone because of the greater reactivity of the aldehyde group\ and the range of reagents
available is therefore more limited[ The conjugate reduction of enones to saturated ketones has
traditionally been achieved with dissolving metal reagents\ particularly lithium in liquid ammonia\
and\ although the number of examples is rather small\ this does also appear to work for enals
ð65OR"12#0Ł[ An alternative dissolving metal method employing aluminum powder in the presence
of nickel"II# chloride has also been reported ð80T7476Ł[
Relatively little success has been reported in developing modi_ed hydride reagents with reasonable
0\3! versus 0\1!selectivity in the reduction of a\b!unsaturated aldehydes[ One reagent with the
required selectivity is the copper hydride cluster ð"PPh2#CuHŁ5\ all six hydrides of which are trans!
ferable ð77JA180\ 77TL2638\ 78TL4566Ł[ Rhodium!catalysed hydrosilation and hydrolysis of the result!
ing silyl enol ether ð61TL4924Ł\ triethylborane!catalysed triphenylsilane reduction ð80BCJ1474Ł\ and
transfer catalytic hydrogenation ð67JOC2874Ł have also been used for the saturation of conjugated
enals[

"ii# Conju`ate additions of carbon nucleophiles


a\b!Unsaturated aldehydes are ambident electrophiles which can react with carbon nucleophiles
in both a 0\1! and a 0\3!sense[ The outcome is partly determined by the electronic nature of the
reagent\ with soft\ polarizable species tending to give predominantly the 0\3!product[ Unfortunately\
steric factors do play a signi_cant role and account for the conjugate addition to enals being
appreciably more di.cult than to enones[ Conjugate additions to b\b!disubstituted enals are par!
ticularly problematic[
Easily the best established class of reagents for conjugate additions is the organocuprates\ which\
since they have been the subject of a considerable number of reviews\ will not be discussed in detail
here[ The early literature has been described by Posner\ one of the pioneers in the area\ in an Or`anic
Reactions article ð61OR"08#0Ł\ and the coverage has been updated by Lipshutz\ whose research
group has also made major contributions to cuprate chemistry ð81OR"30#024Ł[ Speci_c aspects of
organocuprate chemistry such as copper!catalysed reactions of Grignard and organolithium reagents
ð73T530Ł\ and organocopper conjugate additionÐenolate trapping reactions ð74S253Ł\ have also been
the subject of reviews[ Dialkyl zinc reagents in the presence of catalytic Ni"acac#1 have been found
to be particularly useful for conjugate additions to b\b!disubstituted enals ð74JOC4650\ 74TL718Ł[

2[90[0[7[2 From a!functionalized aldehydes


Because of the ready reducibility of the aldehyde functional group the selective reductive cleavage
of any a!functionality is di.cult\ and no general methods have been reported[ However\ 0\2!
dimethyl!1!phenylbenzimidazole "6# "XH# will reduce a!haloaldehydes in high yield ð75JOC4399Ł\
and multistep a!dehalogenations via a!haloaldimines and 1!aza!0\2!dienes are also possible and give
quite respectable overall yields ð81JOC4650Ł[

Me
N Ph

N X
Me
(7)
Saturated Unsubstituted 02
2[90[0[8 From Carboxylic Acids and their Derivatives

2[90[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives


The high reactivity of an aldehyde under reducing conditions makes the development of reagents
which can selectively reduce a carboxylic acid or carboxylic acid derivative to an aldehyde\ without
over!reduction to the primary alcohol\ a challenging undertaking[ Indeed\ the reliability of modern
oxidants\ in particular the SwernÐMo}at oxidation\ for the selective oxidation of primary alcohols
to aldehydes makes a two!step conversion via full reduction to the primary alcohol the favoured
option for many chemists\ particularly since the reactions can be performed in a single pot ð68S693Ł[
Nevertheless\ a number of very successful methods for the single!step reduction of carboxylic acid
or carboxylic acid derivatives to aldehydes are known[
Probably the oldest of these methods is the Rosenmund reduction in which an acid chloride is
reduced catalytically with a poisoned palladium catalyst and which overcomes the problems of
selectivity by combining a very reactive substrate with very mild reducing conditions ð37OR"3#251Ł[
Modern approaches to this transformation have tended to concentrate on borohydride!derived
reagents[ In fact\ even sodium borohydride can be used provided pyridine ð71SC728Ł or cadmium"II#
chloride ð79JCS"P0#16Ł is included in the reaction mixture and appropriate care is taken during the
workup\ although appreciable amounts of primary alcohol are also formed[ More selective are the
copper"I# borohydride complexes developed by the groups of Fleet ð67TL0326Ł and Sorrell
ð79JOC2338Ł\ although they have the dual disadvantages of being very high molecular weight sources
of a single hydride\ and requiring the presence of two equivalents of phosphine from which the
product must eventually be separated[ The latter drawback can be avoided by the use of
bis"triphenylphosphine#copper"I# cyanoborohydride ð79TL702Ł[ Acid chlorides can also be reduced
to aldehydes with tributyltin hydride under palladium"9# catalysis ð70JOC3328Ł\ or with 0\2!dimethyl!
1!phenylbenzimidazole "6# "XH#[ The latter is of particular value in allowing the preparation of
deuterated aldehydes with "6# "XD# ð75JOC4399Ł[
The reduction of simple esters to aldehydes is a particularly useful transformation because of their
considerable importance as functional groups[ Fortunately\ diisobutylaluminum hydride "dibal!H#
at low temperature "−69>C# has been found to achieve the transformation very successfully\
tolerating a wide range of other functionalities\ and even allows the selective reduction of methyl
or ethyl esters in the presence of t!butyl esters ð64S506Ł[ Diisobutylaluminum deuteride "dibal!D#
can be used for the preparation of deutero aldehydes ð73T2276Ł[ Thiol esters can also be reduced to
aldehydes\ most traditionally with Raney nickel deactivated by boiling in acetone ð43OR"7#107Ł\ but
also with triethylsilane in the presence of palladium on carbon ð89JA6949Ł[
The reduction of simple amides to aldehydes is a particularly challenging transformation because
of their low reactivity to nucleophilic reducing agents[ However\ the preparation of aldehydes from
primary carboxamides by treatment with lithium tris"diethylamino#aluminum hydride ð80TL5892Ł\
and from tertiary N\N!dimethylamides with lithium tri!s!butylborohydride "L!selectride# in the
presence of an alkyl tri~ate ð89JCS"P0#646Ł have been reported[ The latter reaction\ which probably
proceeds via an imidate intermediate\ is compatible with ester\ alkene and nitrile functionalities
"Equation "7##[ A number of aldehyde preparations use speci_c amide precursors\ of which the most
important are probably the N!methoxy!N!methyl "Weinreb# amides\ which may be reduced with
excess lithium aluminum hydride or dibal!H to give good yields of the required aldehyde[ Little
overreduction occurs because the N!methoxy group stabilizes the tetrahedral intermediate by
internal coordination ð70TL2704Ł[ The preparation of aldehydes by the dibal!H reduction of acyl
imidazoles ð68CC68Ł\ and acyl thiazolidine derivatives "7# ð68BCJ444Ł\ has also been reported[ Nitriles
can be reduced with dibal!H to imines\ which are hydrolysed to aldehydes on workup ð64S506Ł\ and
also\ via nitrilium salts\ with triethylsilane ð70JOC591Ł[

O O O O
EtOTf, L-selectride
(8)
MeO NMe2 69% MeO

Perhaps surprisingly\ carboxylic acids themselves may be directly reduced to aldehydes with
a variety of reagents[ These include the thexyl chloroboraneÐdimethyl sul_de complex\ which is
incompatible with alkene functionality ð76JOC4399Ł\ and the thexyl bromoboraneÐdimethyl sul_de
complex\ which although compatible with alkenes requires dimethyl sul_de as the solvent ð76JOC4929\
76TL1278Ł[ In neither case is the workup particularly straightforward[ Probably more convenient is
bis"N!methylpiperazinyl#aluminum hydride\ which may be prepared as a stock solution in THF\
03 Alkyl Aldehydes
O S

R N S

(8)

and e}ects the reduction in high yield ð73JOC1168Ł[ The pentavalent silane "8# has also been used
for this reduction ð76TL2830Ł[ Despite this range of reagents\ in practice carboxylic acids are most
often reduced to aldehydes in multistep sequences\ either via the primary alcohol or a heterocyclic
derivative such as a benzimidazoles "Scheme 5# ð70S292Ł[
Ph H
Si H
NMe2

(9)

N
O NH2 i, NaOEt
polyphosphoric acid ii, MeI
OH
+ N O
70% iii, NaBH4
O NH2 H 89%

Me
N HCl O
O
66%
N O
Me

Scheme 6

2[90[0[8[1 Formylation reactions


Tertiary formamides such as DMF have long been known to give aldehydes on reaction with
Grignard reagents\ although it is necessary to control the reaction temperature carefully and avoid
any excess of the Grignard reagent if satisfactory results are to be obtained ð73S117Ł[ The reaction
has been the subject of a study which compared a number of tertiary formamides and found that
less secondary alcohol by!product is formed if the electrophile contains an additional chelating
group ð72TL0032Ł[ The preferred reagent was N!"N!formyl!N!methylamino#piperidine "09#[ The
preparation and formylation of the organometallic species can also be achieved in a single step by
the ultrasonication of an alkyl halide in the presence of lithium metal and DMF ð71TL2250Ł[
O
Me
N
N

(10)

Probably the most widely used formylating reagent for Grignard reagents after DMF is triethyl
orthoformate\ although comparative studies suggest that higher yields are obtained if the cyclic
orthoester "00# is used ð79JCS"P0#645Ł[ Other formates have not been widely exploited as formylating
agents\ although both methyl formate and sodium or lithium formates can be used to formylate
Saturated Unsubstituted 04
organometallic reagents[ The former reagent requires very low temperatures "−009>C# if secondary
alcohol formation is to be avoided in its reaction with alkyllithium reagents ð75JOC840Ł\ whereas
the latter requires elevated temperatures if a reasonable rate of reaction with Grignard reagents is
to be obtained ð73TL0732Ł[

O
O
O O OMe

(11)

Several procedures are available in which the formyl group derives ultimately from carbon
monoxide[ The carbon monoxide can either be gaseous\ as in the reaction of tetraalkylstannanes
with carbon monoxide under palladium"II# catalysis ð68TL1590Ł\ or in the form of a metal carbonyl
as in the protonation of acyl ferrates prepared from the reaction of Grignard reagents with pen!
tacarbonyliron ð71BCJ0552Ł[ The latter method may be used to prepare 0!deuteroaldehydes if deut!
eroacetic acid is used to decompose the intermediate[ 0\2!Benzodithiolium tetra~uoroborate "01#
has also been reported as a useful synthon for the preparation of deutereoaldehydes ð71BCJ1178Ł[

S
+
D
S

(12)

2[90[0[8[2 Other preparations from acids and acid derivatives


A simple one!carbon homologative preparation of aldehydes from esters involves the treatment
of the ester with bromomethyllithium to form the lithium ynolate\ which is reduced with cyclo!
hexadiene to give the lithium enolate of the aldehyde with one extra carbon atom "Scheme 6#
ð75JA0214Ł[

i, LiTMP, CH2Br2
OMe ii, BunLi OMe OLi
CO2Me

i, TMS-Cl
OMe ii, H3O+ OMe
OLi 61% CHO

Scheme 7

2[90[0[09 From Sulfur!containing or Other Lower!Chalcogen!Containing Precursors


The hydrolyses of thioacetals and vinyl sul_des are closely related processes which involve a
common sulfenium ion intermediate "Scheme 7#[ The mechanism is analogous to that of the closely
related hydrolysis of acetals and vinyl ethers\ although the reaction di}ers since the equilibrium in
this case lies predominantly towards the thioacetal rather than the carbonyl compound[ For this
reason it is necessary to drive the hydrolysis to completion by removing the thiol produced\ and a
number of methods have been developed for doing this\ the most important of which are the
formation of an insoluble transition metal thiolate\ and oxidation of the thiol to a higher oxidation
05 Alkyl Aldehydes
state of sulfur[ References to a selection of methods are contained in Table 1\ and the subject has
been discussed in rather more detail by Grobel and Seebach ð66S246Ł[ Thioacetals have an important
application as protecting groups\ and a useful discussion of this aspect may be found in Greene and
Wuts ðB!80MI 290!90Ł[

SR1
R2 +SR1
SR1 –R1S– H2O O
R2 R2
SR1 +H+
R2

Scheme 8

Table 1 Preparation of aldehydes from thioacetals[


Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Rea`ent Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Transition metal reagents
HgO\ HBF3 70S40
PbO1\ BF2 = Et1O 71S479
Alkylating reagents
MeOSO1F 61S450
Oxidizing reagents
Tl"NO2#2 68SC290
Electrochemical 89TL1488
mcpba 76S002
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

The Pummerer reaction allows the preparation of an a!functionalized sul_de from a sulfoxide
bearing at least one a hydrogen atom\ in an internal redox process that results in the reduction of
the sulfoxide with concomitant oxidation of a neighbouring carbon atom from the alcohol to the
aldehyde oxidation state ð80OR"39#046Ł[ The reaction provides an important approach to aldehydes
from alkyl aryl sul_des since the product a!functionalized sul_des can be readily hydrolysed to the
aldehydes "Scheme 8# ð67S770Ł[ a!Silyl sulfoxides\ prepared by silylation of sulfoxide!stabilized
anions\ spontaneously undergo a Pummerer rearrangement at room temperature to give a!silyloxy
sul_des\ which can be hydrolysed to the required aldehyde under very mild conditions ð64TL1906Ł[
Related aldehyde precursors\ a!chlorosul_des\ can be prepared by NCS chlorination of sul_des\
and are hydrolysed in the presence of mercury"II# or cadmium"II# salts ð65SC464Ł[ The chlorination
and hydrolysis can alternatively be achieved in the same pot by sequential treatment of a sul_de
with sulfuryl chloride and silica gel ð72JOC2460Ł[

OTf O
TFAA NaHCO3
BnO BnO BnO
SOPh 2,6-lutidine SPh 53%

TFAA = trifluoroacetic anhydride

Scheme 9

Anions of sulfones can be oxidized directly to aldehydes with bis"trimethylsilyl#peroxide


ð72JOC3321Ł\ or alternatively by boration of the anion with dimethyl chloroborate followed by
treatment with the sodium salt of mcpba "Scheme 09# ð74TL1222Ł[ Both reactions proceed via an
a!oxygenated sulfone which immediately eliminates benzenesul_nic acid[
The cleavage of selenoacetals has been the subject of a systematic study which found that
mercury"II# chloride in wet acetonitrile\ and hydrogen peroxide or benzeneseleninic anhydride in
THF\ gave good results ð68S766Ł[
Saturated Unsubstituted 06
B(OMe)2
i, BunLi Na salt of mcpba
SO2Ph SO2Ph
ii, ClB(OMe)2 72%

Scheme 10

2[90[0[00 From Nitrogen!containing Precursors

2[90[0[00[0 From amines


Although the conversion of an amine into a carbonyl compound is a relatively common biological
transformation\ which can occur by ~avin!\ NADP! or pyridoxyl!mediated processes\ it is only
rarely performed chemically[ Despite this there is a range of methods for achieving an oxidative
deamination\ including methods involving a pyridoxal!like prototropic rearrangement of an imine
"Scheme 00# ð71JA3335Ł[ The imine tautomerization may also be achieved via a base!induced
fragmentation of an oxaziridine\ prepared by peracid oxidation of a Schi} base ð68TL2190Ł[ The
direct oxidation of an amine to an imine is also possible with an arylsulfonyl peroxide in the presence
of strong base\ and can be followed by hydrolysis to the aldehyde ð73JOC3900Ł[ Alternatively\ the
oxidation and hydrolysis can be achieved in a single pot by nitroxyl!mediated electrooxidation
ð72JA5621Ł[ Anodic methoxylation of carbamates also provides a simple route to aldehydes via their
dimethylacetals ð72JOC2227Ł[

+ + dbu
Bun NH2 + Me N CHO Me N
PhSO2– N
Bun

+
Me N H3O+
BunCHO
N 84%
Bun

Scheme 11

Although the ease of hydrolysis of imines makes them a particularly attractive intermediate in an
amine to aldehyde conversion\ a recent method which involves the oxidation of a metallated
silylamine with dry air to give an oxime appears attractive[ The oxime intermediate is hydrolysed
to the required aldehyde during ~ash chromatographic puri_cation\ and the conditions are com!
patible with phosphine\ thioether and tertiary amine functionalities "Scheme 01# ð77TL5690Ł[

OLi
TMS TMS O O
HN N N
i, BunLi

ii, dry air

OH
N O

SiO2, H2O

87%

Scheme 12
07 Alkyl Aldehydes
2[90[0[00[1 From oximes\ hydrazones and their derivatives
Probably because they are relatively stable derivatives of aldehydes\ and have the reputation of
only being hydrolysed under fairly vigorous conditions\ oximes and hydrazones are relatively
infrequently considered as potential precursors or protecting groups\ despite the very sizeable body
of literature describing methods of achieving this sort of transformation[
Classical oxime and hydrazone hydrolyses use fairly vigorous acidic conditions^ however\ the
transformation can be achieved with milder heterogeneous acid catalysts such as Amberlyst!04 resin
for tosylhydrazones\ dinitrophenylhydrazones and semicarbazones ð77JCS"P0#1452Ł or Dowex!49
resin for oximes and semicarbazones ð77JOC767Ł[ Dimethylhydrazones may also be hydrolysed by
a Lewis acid!catalysed transfer of the hydrazine to acetone ð65S345Ł[ One important method of
facilitating the C1N hydrolysis of hydrazones is by metal complexation of the nitrogen to activate
the carbon atom to attack by water[ The metal ion most commonly used for this purpose is
copper"II#\ which also has the advantage of driving the reaction to completion by scavaging the
liberated hydrazine derivative ð65TL2556Ł[
Probably the largest group of methods for preparing carbonyl compounds from C1N derivatives
are those employing oxidizing agents[ These include nitrosating reagents\ which\ like the copper"II#
complexation\ work by activating the carbon atom to attack by water by removing electrons from
nitrogen[ An example of this type of method is the hydrolysis of oximes mediated by a mixture of
sodium nitrite and chlorotrimethylsilane which provides an in situ source of nitrosyl chloride
ð89TL5566Ł[ Active oxygen reagents can also be used[ For instance\ aryl hydrazones have been
cleaved with basic hydrogen peroxide ð67S808Ł\ and the recently introduced magnesium mon!
operoxyphthalate has been found to be particularly valuable in cleaving hydrazones without a}ect!
ing the stereochemical integrity of a chiral centre a to the aldehyde product ð89SL614Ł[
Dimethylhydrazones have also been regenerated with bu}ered periodic acid ð65TL2Ł[
Conventional high!valent metal oxidants can also be employed in the preparation of aldehydes
from oximes or hydrazones[ Thus\ bis"trimethylsilyl#chromate has been found valuable for the
preparation of aldehydes from oximes ð81SC1314Ł\ and thallium"III# acetate can be used to regenerate
aldehyde tosyl hydrazones ð68TL3472Ł[ Benzeneseleninic anhydride will also cleave a range of
C1N derivatives\ including oximes\ aryl and tosyl hydrazones\ and semicarbazones\ but not N\N!
dimethylhydrazones or O!methyl oximes[ The reagent appears to be particularly e}ective for the
regeneration of hindered substrates ð79JCS"P0#0101Ł[
Although the majority of new publications describe the use of oxidative reagents\ it is also possible
to achieve the transformation under reducing conditions^ for example\ both Raney nickelÐsodium
hypophosphite ð75SC792Ł and vanadium"II# chloride ð79S119Ł can be used for deoximation[ Despite
the variety in types of reducing agent used\ they all appear to involve an initial reduction to an
imine\ which is hydrolysed under either the reaction or workup conditions[
Lastly\ it has recently been reported that both oximes ð80JCS"P0#1945Ł and hydrazones ð80TL1546Ł
can be cleaved enzymatically with baker|s yeast[ The hydrolysis\ which is greatly aided by sonication\
gives near!quantitative yields of the aldehyde[

2[90[0[00[2 From nitroalkanes


The preparation of a carbonyl compound from a primary or secondary nitroalkane is usually
known as the Nef reaction[ The conversion was originally achieved by treatment of the nitronate
salt derived from a nitroalkane with a strong acid\ but the extremely vigorous nature of these
conditions\ and the occurrence of a number of side reactions\ has led to the development of a wide
range of alternative conditions[ These methods have been comprehensively reviewed in a volume of
Or`anic Reactions ð89OR"27#544Ł[

2[90[0[01 From Organosilanes


Probably the most important organosilane precursors of unsubstituted aldehydes are vinyl silanes[
Provided that the silicon bears an electronegative substituent\ such as alkoxy\ these can be oxidized
directly to the aldehyde with hydrogen peroxide ð73TL210Ł[ More generally the conversion can be
achieved by epoxidation followed by boron tri~uoride etherate!catalysed rearrangement to give the
aldehyde silyl enol ether ð73JCS"P0#008Ł\ or by mineral acid treatment to give the aldehyde directly
ð60JA1979Ł[ Both methods result in formation of the aldehyde at the silicon!bearing carbon atom[
Saturated Unsubstituted 08
Vicinal hydroxylation of a vinylsilane followed by acid treatment yields aldehydes by a silapinacol
rearrangement "Equation "8## ð75TL3158Ł[ Because of the preferential migration of the silicon group\
good control of the product distribution from an unsymmetrical diol is observed[

HO OH O
TFA
(9)
TBDMS 86% TBDMS

Aldehydes have also been prepared by the catalytic hydrogenation of acyl silanes containing a
phenyl group bound to silicon ð80TL346Ł[ Remarkably\ the reaction can be performed in the presence
of other hydrogenolizable functionalities\ such as benzyl and benzyloxymethyl ethers\ and acid!
sensitive groups such as t!butyldimethylsilyl and methoxymethyl ethers "Equation "09##[

O H2, Pd (cat.) O
O O
PhMe2Si (10)
82%
O OBn O OBn

2[90[0[02 From Organoboranes


Hydroboration reactions are most often worked up with alkaline hydrogen peroxide to give an
alcohol[ In cases where an aldehyde is required it is generally obtained in a second oxidation step\
although it is also possible to achieve the transformation in a single step by using pyridinium
chlorochromate as the oxidant ð72TL520Ł[
Trialkylboranes can be carbonylated with carbon monoxide to give aldehydes after oxidative
work up with hydrogen peroxide "Scheme 02# ð68S690Ł[ Two!carbon homologations can be achieved
by reaction with dimethoxyethenyllithium to give an ate complex\ which can be rearranged to the
aldehyde by treatment with Lewis acid and a hydrolytic workup "Scheme 03# ð72SC0038Ł[

CO, KBH(OPri)3 H2O2, pH 7


n-C6H13 B n-C6H13 B
87%

OH

n-C6H13 O

Scheme 13

– i, BF3•OEt2
Br i, BunLi
Bu3B ii, H3O+ Bu

MeO OMe ii, Bu3B MeO OMe 82% O

Scheme 14

2[90[0[03 Methods Involving Umpolung


Although reactions involving polarity reversal\ such as the benzoin condensation\ have been
known since the earliest days of organic chemistry\ it is only since the mid!0859s that the concept
has really played an important role in synthetic chemistry[ Much of the early development of the
area and the nomenclature used in this review are due to Seebach ð68AG"E#128Ł[ Although a vast
range of umpolung synthons have been developed for aldehyde preparation\ by far the most
important are the d0 "formyl anion# reagents\ and the d2 "homoenolate# equivalents[
19 Alkyl Aldehydes
2[90[0[03[0 Formyl anion equivalents
An enormous number of d0 synthons have been described which vary in importance from widely
used reagents to mechanistic curiosities[ A compilation of synthons reported up to the early 0879s
is available and includes useful detail on the types of electrophiles used and reactivities seen "e[g[\
0\1!versus 0\3!addition to an a\b!unsaturated system# ð70MI 290!90Ł[ The general topic of nucleophilic
acylation has also been reviewed ð65T0832Ł[
The large number of formyl anion synthons available can actually be divided into quite a small
number of reagent types\ of which easily the largest group are those reagents based on sulfur[ This
includes one of the earliest\ and still one of the most important\ formyl anion synthons\ 1!lithio!
0\2!dithiane\ which itself has been the subject of several reviews ð66S246\ 78T6532Ł[ Although the
majority of sulfur!based formyl anion synthons contain sulfur"II#\ reagents containing sulfur"VI#\
such as "02# ð80SL490Ł\ are also valuable[ The major drawback of the sulfur reagents is the di.culty
of their hydrolysis\ which\ despite the considerable amount of attention the problem has received\
can still present problems[ One solution has been the development of reagents such as "03# which
contain both sulfur and silicon\ and which can be deprotected very easily by oxidation to the
sulfoxide and sila!Pummerer rearrangement ð79TL0448\ 79TL0566Ł[ The chemistry of silicon!
containing carbonyl equivalents has been reviewed ð71CSR382Ł[

ButO SO2Ph PhS TMS


(13) (14)

The largest remaining group of d0 formyl synthons used for simple alkyl aldehyde preparations
are those based on nucleophilic metal carbonyl derivatives[ The best known example of these is the
Collman reagent Na1Fe"CO#3\ which reacts with primary and secondary halides and sulfonates to
give an alkyl iron complex which rearranges to the acyl complex in the presence of carbon monoxide
or a phosphine[ Treatment of the acyl complex with mineral acid then liberates the aldehyde
"Equation "00##[ The reagent tolerates ketone\ ester or nitrile functionalities\ but has the drawback
of being somewhat basic\ causing elimination of some substrates\ in particular tertiary halides and
sulfonates ð64ACR231Ł[ A number of related ionic iron carbonyl complexes ð78TL5260Ł\ including
polymer!supported variants ð67JOC0487Ł\ can also be used[ A quite remarkable formylation of an
alkyl acetate involves its treatment with octacarbonyldicobalt in the presence of a trialkylsilane[
The immediate product is a silyl enol ether which can either be isolated\ or hydrolysed with potassium
~uoride in methanol "Scheme 04# ð72JA0269Ł[
i, Na2Fe(CO)4, THF, CO
ii, HOAc
Br CHO (11)
Cl Cl
82%

MeEt2SiH, Co2(CO)8
OAc
CO, 200 °C OSiEt2Me KF

63% 100%
But But

But

Scheme 15

The d0 reactivity of cyanohydrins that underlies the benzoin condensation has also inspired a
number of formyl anion synthons such as the N\N!diethylaminoacetonitrile anion "Et1NCHCN#\
which\ after alkylation\ is hydrolysed with oxalic acid in aqueous THF to give the required aldehyde
ð67TL4064Ł[

2[90[0[03[1 Other anion equivalents


Although homoenolates of nonenolizable carbonyl compounds can be formed with very strong
bases\ the chemistry is of limited synthetic generality\ and d2 synthons are generally preferred[ The
b and More Remotely Unsaturated 10
majority of homoenolate equivalents are substituted allyl anion species\ and consequently can su}er
problems controlling the selectivity of the alkylation to the required g position[ A useful introduction
to the chemistry of both homoenolates and their equivalents has been provided by Werstiuk
ð72T194Ł[

2[90[1 b AND MORE REMOTELY UNSATURATED ALDEHYDES


The unconjugated alkene functionality is relatively unreactive\ and many of the methods described
in Section 2[90[0 can be used for the preparation of remotely unsaturated aldehydes simply by
using an appropriately unsaturated precursor[ One very signi_cant restriction to this generalization
concerns b\g!unsaturated aldehydes\ where the ease with which the double bond can migrate into
conjugation restricts the choice of reagents[ This section describes methods in which the unsaturation
is a necessary or integral part of the chemistry[ The reactions consequently have no direct analogies
with the preparation of saturated aldehydes[ Indeed\ some of the methods\ with the inclusion of a
_nal hydrogenation step\ can become powerful approaches to saturated aldehydes[

2[90[1[0 Alkyl Aldehydes with One Double Bond

2[90[1[0[0 From aldehydes


"i# Allylation of saturated aldehydes
Since allyl halides are highly reactive alkylating agents\ conventional base!catalysed and metal
enolate!based alkylation methods may be employed for the allylation of aldehydes\ although with
the usual attendant problems of polyalkylation and poor regiocontrol "see Section 2[90[0[7[0#[
Potassium enolates of aldehydes in tetrahydrofuran have been reported to give clean C!alkylation
with primary allyl halides ð67TL380Ł[

2[90[1[0[1 Preparations involving rearrangements

"i# Claisen rearran`ements


The Claisen rearrangement\ the ð2\2Ł sigmatropic rearrangement of an allyl vinyl ether can be a
useful route to g\d!unsaturated aldehydes ð64OR"11#0\ 66S478Ł[ The chief di.culty of the reaction lies
in the preparation of the allyl vinyl ether substrate\ which is normally achieved by a mercury"II#!
catalysed vinyl ether exchange reaction "Scheme 05#\ although a number of alternatives have been
reported[ These include the palladium on charcoal catalysed prototropic rearrangement of diallyl
ethers "Equation "01## ð71TL1962Ł\ and the cohalogenation of alkenes in ethylene oxide\ a reaction
which appears to be relatively general "Scheme 06# ð82S288Ł[ Claisen rearrangements have also been
used in tandem with Cope rearrangements to prepare aldehydes with both b\g! and o\z!unsaturation
"Equation "02## ð71JA6070Ł[ Thio and aza analogues of the Claisen rearrangement which give vinyl
sulphide ð62JA1582Ł or imine ð77JOC3378Ł precursors of aldehydes are also known\ and o}er some
advantages in terms of ease of preparation of the precursors[

Hg(OAc)2, ethyl vinyl ether


200 °C
85%
HO O
CHO

Scheme 16
11 Alkyl Aldehydes

O O

Pd-C, ∆
(12)
58%

O O

Br
Br2, oxirane, –80 °C ButOK, 18-crown-6 190 °C
O O
81% 93% 77%
Br
O
Scheme 17

O

(13)
O

"ii# Oxy!Cope rearran`ements


The oxy!Cope rearrangement is a ð2\2Ł sigmatropic rearrangement of a hexa!0\4!dien!2!ol system
to form a d\o!unsaturated ketone\ and is generally performed under thermal conditions "×199>C#
"Equation "03## ð64OR"11#0Ł[ Oxy!Cope rearrangements of tertiary dienols\ which yield ketonic
products\ are greatly accelerated by the formation of an alkali metal\ particularly potassium\ salt of
the starting dienol[ These conditions have greatly extended the scope and application of the reaction
for ketone preparations "see Section 2[92[1[0[2"ii##\ but have only infrequently been applied to the
rearrangement of secondary dienols to prepare aldehydes\ although examples are known ð66TL1448Ł[

O
OH
220 °C
(14)
90%

The preparation of the appropriate starting material for an oxy!Cope rearrangement is not always
trivial[ One particularly ingenious way of overcoming this problem is to use a tandem ð1\2Ł WittigÐ
oxy!Cope rearrangement of a diallyl ether ð71CL0238Ł[ Unfortunately\ studies of this chemistry with
chiral cyclohexenyl systems have shown that the ð0\1Ł Wittig rearrangement\ which leads to the
enantiomeric product\ competes to a minor extent with the ð1\2Ł rearrangement "Scheme 07#
ð71TL2820Ł[

OH OH
O
BunLi BunLi

[1,2]Wittig [2,3]Wittig

KH, 18-crown-6 KH, 18-crown-6


oxy-Cope oxy-Cope

O O

minor major

Scheme 18
b and More Remotely Unsaturated 12
2[90[1[0[2 Other preparations

"i# Formylation reactions


A useful hydroformylation approach to g\d!unsaturated aldehydes involves the addition of a
zirconium hydride complex to a 0\2!diene[ The hydrozirconation is speci_cally 0\1 in orientation
and shows good selectivity for the less hindered double bond of an unsymmetrical diene[ The
reaction of the unsaturated zirconium derivative with carbon monoxide gives the aldehyde "Scheme
08# ð65JA151Ł[ Allylic halides can also be formylated at their less substituted terminus with carbon
monoxide and tributyltin hydride in the presence of a palladium"9# catalyst ð75JA341Ł[

i, CO
ZrCp2HCl ii, H3O+ O
Zr
80–90% Cl 98%

Scheme 19

Nucleophilic formylation of unsaturated electrophiles can be achieved with many of the d0


synthons discussed in Section 2[90[0[03[0[ In addition\ methods have been developed for the for!
mylation of allylic halides at their more hindered termini[ These involve the ð1\2Ł sigmatropic
rearrangement of a sulfur ð79CC0985Ł or nitrogen ð65BSF0334\ 73TL2346Ł ylide formed by the treatment
of an initially formed allyl sulfonium or allyl ammonium salt with a base "Scheme 19#[
b\g!Unsaturated aldehydes have also been prepared by the electrophilic formylation of allyl
Grignard reagents with 3\3!dimethyl!1!oxazolines ð65BSF0764Ł[
CN
Me2NCH2CN CN AgNO3, H2O CHO
K2CO3, DMF NMe2 Et2O, THF
+
Br NMe2

Scheme 20

"ii# Miscellaneous preparations


A novel approach to g\d!unsaturated aldehydes involves the oxidation of a!trimethylstannyl zinc
reagents with dry air at −09>C\ a reaction which is thought to proceed by insertion of oxygen into
the carbon to zinc bond[ The complete sequence\ including the preparation of the a!trimethylstannyl
zinc reagents by trimethylstannylation of the product from the reaction of an allylzinc bromide with
a vinyl Grignard reagent\ is depicted in Scheme 10 ð77TL5586Ł[

Me3SnCl
MgBr + ZnBr
n-C6H11 MgBr
n-C6H11
ZnBr

dry air, TMS-Cl


SnMe3 SnMe3 87% O
n-C6H11 n-C6H11 n-C6H 11
ZnBr O
O-TMS

Scheme 21
13 Alkyl Aldehydes
2[90[1[1 Alkyl Aldehydes with More than One Double Bond
Aldehydes containing more than one nonconjugated double bond are generally prepared by
methods that are directly analogous to those used for the preparation of saturated aldehydes "see
Section 2[90[0# or aldehydes with a single nonconjugated double bond "see Section 2[90[1[0#[
The oxy!Cope rearrangement\ a powerful approach to d\o!unsaturated aldehydes and ketones
"see Sections 2[90[1[0[1 and 2[92[1[0[1#\ has been extended by several workers to give compounds
with two or more double bonds[ So far these variants have been applied only to unsaturated
ketone preparations "see Section 2[92[1[1#\ although in view of the success of the basic oxy!Cope
rearrangement for the preparation of aldehydes\ there seems to be no obvious chemical reason for
this limitation[

2[90[1[2 Alkyl Aldehydes with Aryl or Hetaryl Substituents

2[90[1[2[0 From aldehydes


"i# Arylation of saturated aldehydes
Far less attention has been given to the arylation of aldehydes than of ketones\ and very few
general methods are available[ One approach involves the FriedelÐCrafts!type reaction of an arene
with an a!chloroaldimine in the presence of aluminum chloride\ followed by the hydrolysis of the
imine\ although proton loss from the presumed a!imidoylcarbenium ion intermediate to give the
unsaturated imine is a yield!limiting side reaction "Scheme 11# ð71TL1742Ł[

N
CHO

N AlCl3, ∆ 6N HCl Et
+ Et
40%
Cl
Et
Scheme 22

"ii# Conju`ate addition of aryl nucleophiles to a\b!unsaturated aldehydes


The conjugate addition of benzyl groups to a\b!unsaturated aldehydes is complicated by the
tendency of benzyl halides to undergo Wurtz coupling during the formation of an organometallic
derivative\ and by the poor thermal stability of benzylic cuprates[ However\ with careful control of
the conditions\ counterion and Lewis acid additive\ very good results have been obtained in the
conjugate addition of benzylmagnesium chloride!derived copper reagents to enals "Equation "04##
ð81TL1272Ł[
BnMgCl, CuI
O TMS-Cl, HMPA, THF O
Ph Ph + Ph OH (15)
62%
Ph Ph
16 : 1

2[90[1[2[1 Other preparations


The well!established use of palladium chemistry for the formation of aryl to carbon bonds
has been exploited in several syntheses of aryl!substituted aldehydes[ For example\ palladium"9#!
catalysed cross!couplings of aryl halides with 1!ethoxyvinylboranes ð71JOC1006Ł\ or with acrylamide
ð80S428Ł\ gives functionalized styrene derivatives which can be converted to the required aldehyde
by hydrolysis\ or by Hofmann rearrangement and hydrolysis\ respectively "Schemes 12 and 13#[
b and More Remotely Unsaturated 14
More remotely aryl!substituted aldehydes can be prepared by the palladium"II#!catalysed coupling
of aryl halides with terminal alkenols in the presence of a mild base[ The reaction\ which involves
the palladium!catalysed double bond migration of an initial styrene product\ is successful even with
undecen!00!ol\ although the regioselectivity of the initial carbonÐcarbon bond!forming reaction is
only moderate "Equation "05## ð78TL5518Ł[ Chiral 1!aryl aldehydes of modest to fair enantiomeric
excess have been prepared by the alkylation of cinnamyl ethers prepared from the atrolactic acid
derived\ and recoverable\ chiral auxiliary "04# "Scheme 14# ð71CL0526Ł[

O O O

B Pd(PPh3)4 H3O+
+ OEt
3 96%
Br OEt O

Scheme 23

Cl Cl O Cl
I H2CCHCONH2 i, NaOCl, MeOH O
Pd0, NaOAc, 100 °C NH2 ii, H3O+

87% 38%
Cl Cl Cl

Scheme 24

I
10 Pd0
+ 1 OH
11 91%

11 1 10 1 O
O
+ (16)

88 : 12

Ph Ph i, KNPri2, Et2O
OMe NaH, cinnamyl bromide OMe ii, BunI

90% 65%
OH O Ph
(15)

Ph
OMe Bun
HClO4
+ (15)
O Bun O Ph
75% ee
Ph

Scheme 25

2[90[1[3 Alkynyl!Substituted Alkyl Aldehydes

2[90[1[3[0 Fragmentation reactions


The fragmentation of an a\b!epoxy ketone on reaction with tosyl hydrazide to give an alky!
nylketone was _rst described by Eschenmoser|s group\ and is now generally referred to as an
Eschenmoser fragmentation ð56HCA697Ł[ The reaction is not particularly satisfactory for the prep!
aration of aldehydes\ although mesitylenesulfonyl hydrazide has been found to give signi_cantly
better results "Equation "06## ð70S165Ł[ N!Aminoaziridine hydrazone derivatives of epoxy ketones
15 Alkyl Aldehydes
fragment in a similar manner on heating and give good yields of aldehydes "Equation "07##
ð61HCA0165Ł[

O + (17)
42% CHO

SO2NHNH2

Ph

N Ph
N

140 °C
O (18)
61% CHO

2[90[2 HALOALKYL ALDEHYDES "a\ b AND MORE REMOTE HALOGEN#

2[90[2[0 Introduction
The literature to mid!0875 on the synthesis and chemistry of a!halo aldehydes containing one or
two halogen atoms has been the subject of an excellent chapter by De Kimpe and Verhe in one of
the Updates to the Chemistry of the Functional Groups monographs edited by Patai and Rappoport
ðB!77MI 290!90Ł[
a!Halo aldehydes are considerably more reactive than are a!halo ketones\ and satisfactory general
methods for their preparation have only become available since the mid!0859|s[ Their isolation and
use can also be di.cult because of the frequently high stability of many of their hydrates\ and the
ease with which they can oligomerize[ One recently reported solution to the problem involves the
preparation of an aldehydeÐLewis acid complex by treatment of the oligomer with methylaluminum
bis"1\5!diphenylphenoxide#[ The resulting complex can then be employed directly in reactions with
nucleophiles ð82JA2832Ł[ Because of these di.culties\ the literature is considerably more sparse than
for a!halo ketones\ and this discussion is arranged by starting material rather than by halogen[
More remotely substituted halo aldehydes are generally prepared by methods typical of unfunc!
tionalized aldehydes or halo compounds\ and few general methods speci_cally aimed at this class
of compounds have been reported[

2[90[2[1 From Stable Enol Derivatives and Enamines


Although the control of regioselectivity\ which constitutes the major advantage of preparing
a!halo ketones from enol derivatives\ is irrelevant to the preparation of a!halo aldehydes\ the
reactions of halogens with enol silanes has proved to be a very successful route to a!chloro and
a!bromo aldehydes ð63JOC0674Ł[ Impressively\ the reaction can also performed with 4) ~uorine in
nitrogen to give a!~uoro aldehydes\ although the products were found to be unstable both to
attempted distillation and on standing "Equation "08## ð75TL1604Ł[

F
O-TMS O
F2/N2, CFCl3, –78 °C
(19)
72%

2[90[2[2 From Aldehydes


The direct halogenation of aldehydes\ although free of the regiochemical problems that plague
the halogenation of ketones\ is in fact rather less satisfactory due to the higher reactivity of the
Haloalkyl 16
aldehyde function\ and the possibility of other side reactions\ such as acid halide formation[
Fortunately\ a number of reagents for both chlorination and bromination are known[ For example\
the bromination of aldehydes can be achieved in very high yields by treatment with bromo!
trimethylsilane ð75JCR"S#315Ł\ or t!butyl bromide in DMSO ð73T1924Ł[ The reaction can also be
performed with chlorotrimethylsilane to give a!chloro aldehydes\ although the yields are con!
siderably worse[ Brominations of aldehydes have also been reported with the related brominating
agents dibromobarbituric acid "05# ð74CB3177Ł and dibromo!Meldrum|s acid "06# ð67S039Ł[
O O
H
Br N Br O
O
Br N Br O
H
O O
(16) (17)

The literature on the preparation of a!iodo aldehydes is particularly sparse\ although several very
satisfactory synthetic approaches have been described[ These include iodination of aldehydes by
iodine in the presence of mercury"II# chloride ð75S567Ł\ of aldehyde enolates with iodine ð68TL1706Ł\
and the halogen exchange of a!chloroaldehydes with sodium iodide in dry acetonitrile ð75OPP68Ł[
a\a!Dihalo aldehydes can be prepared from aldehydes by reaction with either chlorine or bromine
in the presence of pyrrolidine hydrohalide salt as a catalyst ð74SC866Ł[

2[90[2[3 Miscellaneous Preparations

2[90[2[3[0 Functional group transformations


a!Fluoro and a\a!di~uoro aldehydes have been prepared from bromo~uoroalkanes by a route
that involves nucleophilic introduction of sulfur and Pummerer rearrangement[ The authors rec!
ommend that the product aldehydes\ which are unstable to storage at ordinary temperatures\ only
be released from the stable acetoxy sul_de precursor when they are actually required "Scheme 15#
ð89T3150Ł[
F F
PhSNa i, mcpba
Br SPh
n-C8H17 89% n-C8H17 ii, Ac2O, NaOAc
46%

F F
SPh dibal-H O
n-C8H17 n-C8H17
92%
OAc
dibal-H = diisobutylaluminum hydride

Scheme 26

The preparation of a\a!dichloro aldehydes from primary alcohols with chlorine in a dimethyl!
formamideÐchloroformÐmagnesium chloride system has been reported to give better results than
previously described conditions ð77BSB414Ł[
a!Bromo aldehydes can be prepared by the haloboration of terminal alkynes[ The reaction\ which
is compatible with halide ester and alkene functionalities\ involves a modi_ed alkaline peroxide
oxidative workup designed to reduce the base!catalysed elimination of hydrogen bromide from the
product "Scheme 16# ð74S395Ł[

2[90[2[3[1 Carbon0carbon bond!forming methods


Halooxazines "07# can be metallated with butyllithium to give a ~uoroacetaldehyde ð89TL068Ł or
chloroacetaldehyde ð63JOC507Ł enolate equivalent which will react with a range of electrophiles
including alkyl halides[ Unmasking the aldehyde is achieved in two steps by reduction and acid
hydrolysis "Scheme 17#[ Both a!chloro and a!bromo aldehydes can be prepared by the reaction of
17 Alkyl Aldehydes
i, pH 5 buffer
ii, KOAc
Br iii, H2O2
BBr3
BBr2
60%

Br
O

Scheme 27

a dihalomethyllithium with a ketone[ The reaction\ which involves an a!halo epoxide intermediate\
appears to be fairly general for cyclic ketones and can be applied to quite sensitive structures\ such
as protected sugars "Equation "19## ð80CL0358\ 82JOC4382Ł[ a!Chloro and a!bromo aldehydes can
also be prepared by the formylation of the related a!haloalkyllithium reagents\ which are prepared
by metal halogen exchange of 0\0!dihaloalkanes at −099>C\ with methyl formate "Equation "10##
ð79S533Ł[

i, BunLi i, NaBH4 O
N ii, RBr N ii, H3O+ R
X X
O O X
(18) R
X = F, Cl

Scheme 28

O i, Cl2CHLi O
O ii, NaOAc, 15-crown-5 O
O O O O (20)
77%
Cl
O O O
O

i, LDA, –100 °C
Br ii, HCO2Me
Br
Bun Bun (21)
Br 73% CHO

2[90[3 ALDEHYDES BEARING AN OXYGEN FUNCTION

2[90[3[0 OH!functionalized Aldehydes


Although many methods exist for the preparation of hydroxy aldehydes\ the isolation of the
products is not always straightforward due to competing dimerization\ polymerization or elim!
ination reactions[ Thus\ many methods for the synthesis of hydroxy aldehydes are designed to
incorporate a protecting group on the hydroxyl or carbonyl groups[

2[90[3[0[0 a!OH!functionalized aldehydes


Perhaps the most common method for the synthesis of an a!hydroxy aldehyde is the addition of
a heteroatom!stabilized formyl anion equivalent to an aldehyde or ketone having one less carbon
atom[ The success of the method depends on the e.ciency of the addition and the ability to unmask
the formyl group without causing side reactions\ such as elimination[ A comprehensive account of
much of the early work in this area has already appeared ðB!76MI 290!90Ł\ and there has also been a
Bearin` an Oxy`en 18
review on the use of 0\2!dithiane ð78T6532Ł[ In other developments since that time\ Katritzky and
co!workers have reported that the benzotriazole "08# gives\ on treatment with BunLi\ an anion which
reacts with aldehydes and ketones[ The adducts can be hydrolysed in situ to the hydroxy aldehydes\
which are isolated as the corresponding hydrazones ð80JOC1032Ł[ This paper has an extensive list of
references for other formyl anion equivalents[ Dondoni and co!workers\ and others\ have dem!
onstrated that a thiazole ring can be equivalent to a formyl group[ 1!Lithiothiazoles react even with
sterically hindered or highly enolizable aldehydes and ketones[ Quaternization at nitrogen and
reduction gives the thiazoline\ from which the aldehyde should be available by hydrolysis "Scheme 18#
ð77BCJ2526Ł[ 1!TMS!thiazole will also directly attack aldehydes[ Several features are notable about
this sequence[ First\ the reaction occurs without the need for anion formation by a strong base[
Second\ the reaction with alkoxy aldehydes can be highly stereoselective\ giving rise to the anti
adducts\ whilst stereoselectivity for amino aldehydes depends on the protecting groups "Scheme 29#[
Finally\ this reagent can be used in an iterative manner to prepare long!chain\ polyoxygenated
aldehydes ðB!81MI 290!90Ł[ 1!Lithiothiazole will attack amino acid esters^ subsequent reduction under
nonchelation controlled conditions then gives the syn adducts ð81TL6148Ł[

N
N
N
N

(19)

S i, BunLi, –78 °C S OH i, MeI, DMF, heat S OH


R1 R1
N ii, R1R2CO, –78 °C N R2 ii, NaBH4, EtOH N R2
Me

Scheme 29

S
TMS + O NBOC O NBOC
85%, de 92%
N S
CHO
HO N

S NHBOC BOCNH S
TMS + BnO BnO
60%, de 80% N
N CHO
OH
Scheme 30

Very few methods are available for the asymmetric addition of formyl anions to achiral aldehydes\
but one successful approach uses the enolate derived from the racemic iron complex "19#[ The
copper enolate gives predominantly the RRS "SSR# adduct\ whereas the aluminum enolate is
selective\ at least 3 ] 0\ for the RRR "SSS# isomer "Equation "11##[ In an attempt to obtain homochiral
materials\ the menthyl complexes were prepared\ and the two diastereoisomers readily separated by
column chromatography[ The "R# isomer "10#\ via its aluminum enolate\ reacts with iso!
butyraldehyde to give preferentially the "RRR# adduct in a 04 ] 0 excess[ Under the same conditions
the "S# enantiomer gives a complex mixture of all four diastereoisomers\ indicating\ in this case\ a
mismatched stereochemical in~uence ð78TL1860Ł[ Epoxy sulfones\ for example "11#\ prepared via a
Darzens reaction between a chlorosulfone and a ketone\ undergo base!catalysed ring opening to
hydroxy aldehydes[ A list of references for much of the early work on the preparation of oxygenated
aldehydes has been published in this same paper ð73JOC0267Ł[
29 Alkyl Aldehydes
Ph Ph
OC
P
Fe

O OBn

(20)

Ph Ph
OC i, BunLi, –78 °C OBn
P ii, Et2AlCl, –40 °C
Fe R (22)
OBn
iii, RCHO, –100 °C
iv, Br2, BnOH OH
O OBn

O
Ph Ph
OC SO2Ph
P
Fe

O O-menthyl
THP-O
(21) (22)

Oxidative and reductive transformations can be used to prepare a!hydroxy aldehydes[ O!Silyl!
protected cyanohydrins can be reduced to a!hydroxy aldehydes using dibal ð80SL368Ł\ and optically
active hydroxy aldehydes ð83T1710Ł are available from the corresponding optically active cyano!
hydrins ð82SL796Ł[ A complementary reduction which gives carbonyl!protected hydroxy aldehydes
is the baker|s yeast!mediated reduction of cyclic and acyclic acyl dithioacetals to give\ usually\ the
"S#!alcohols in high enantiomeric excess ð89S0\ 80CRV38Ł[ In fact\ baker|s yeast!mediated reductions
can be used to establish a range of remote hydroxy carbonyl relationships\ although usually only
one enantiomer is available directly[ Both epimers of the same alcohol\ however\ can be prepared
from the stereocomplementary reduction of a ketone using the same chiral auxiliary "Equation "12##
ð81CL1062Ł[

S S S (23)
O O + O
O OH OH

Zn(BH4)2 99 : 1
NaBH4/YCl3 3 : 97

Nucleophilic attack of vinyl anions to carbonyl groups\ followed by ozonolysis of the alkene\
is a well!established method for the synthesis of a!hydroxy aldehydes\ and developments have
demonstrated that this method can be used to prepare homochiral products[ Addition of 0\1!
propadienyltributylstannane to aldehydes in the presence of a chiral borane has been shown to
occur with ×88) ee[ Protection of the alcohol and ozonolysis of the allene gives enantiomerically
pure products ð80TL4602Ł[ Alternatively\ optically pure acyl diene iron tricarbonyl complexes "12#
have been shown to give a single diastereoisomer of a tertiary alcohol on treatment with organo!
lithium reagents[ Exhaustive ozonolysis then gives the desired products "Scheme 20# ð89SL530Ł[
Terminal 0\1!diols can be oxidized selectively using catalytic Cp1ZrH1 at 049>C to give a!hydroxy
aldehydes ð75S663Ł[

O
R1 R1 i, H2O2, NaOH
R2Li, –78 °C R1
R2
O OH ii, O3, MeOH R2
OH
(CO)3Fe (CO)3Fe
(23)
Scheme 31
Bearin` an Oxy`en 20
2[90[3[0[1 b! and more remotely functionalized OH aldehydes
A well!established method for the synthesis of b!hydroxy aldehydes relies on the addition of allyl
organometallics to aldehydes\ followed by cleavage of the alkene with ozone[ A wide variety of
metals has been shown to promote the allylation\ and the high chemoselectivity and increasing ability
to predict and control the relative and absolute stereochemistry during the addition ð82CRV1196Ł has
allowed this to become a very powerful procedure for the synthesis of b!oxygenated aldehydes[ The
use of chiral catalysts with achiral aldehydes and ketones has been shown to give homoallylic alcohols
in excellent enantiomeric excess ð82JA6990\ 82JA7356\ 82JOC5432Ł[ Many formyl anion equivalents will
successfully attack epoxides to give b!hydroxy aldehydes\ and this method has been highlighted in
several reviews ðB!76MI 290!90\ 78T6532Ł[
Apparently few methods exist for the oxidation of 0\2!diols to 2!hydroxy aldehydes\ perhaps
due to the facile dehydration of the product[ However\ one method which is successful uses
N!oxoammonium salts ð89JOC351Ł\ and the yields are very high[ In the oxidation of 0\3! and 0\4!
diols the intermediate hydroxy aldehydes often undergo further in situ oxidation to the cor!
responding lactones[ As might be expected\ more remote hydroxy aldehydes can be successfully
isolated ð78JOC1869Ł[
The selective reduction of ketones in the presence of aldehydes is di.cult without a prior
protection step[ However\ the greater reactivity of the latter can be exploited using speci_c
conditions\ where protection occurs in situ[ Among the conditions developed to achieve this are
NaBH3:CeCl2 ð70TL3966Ł and LiAl"OBut#2H:ButNH1 ð71T0716Ł[
Homoenolate anions derived from protected aldehydes can add to other carbonyl groups to give
hydroxy aldehydes[ The reagents that have been developed for this purpose include "13#\ which
reacts with aldehydes\ ketones and a!silyloxy ketones leading to hydroxy or dihydroxy aldehydes
ð81JOC649\ 82T3812Ł\ "14#\ prepared from reductive lithiation of the corresponding sul_des ð81JOC5Ł\
and "15# ð83T2326Ł[ The development of other nucleophilic three!carbon homologating agents\
including homoenolate anions\ has been covered in an early review ð73CRV398Ł[
Li R2
Li
O O Li
OEt
O O R1
(24) (25) (26)

2[90[3[1 OR!functionalized Aldehydes


Many O!alkyl or O!acyl a!hydroxy aldehydes are interchangeable with the corresponding hydroxy
aldehydes "see Section 2[90[3[0[0# via protectionÐdeprotection sequences on suitable intermediates[
In fact\ the well!known instability of hydroxy aldehydes due to isomerization\ oxidation or dimer!
ization means that it may be bene_cial to isolate them in protected form[ For example\ many of
the nucleophilic formylation procedures proceed via protected hydroxy aldehydes[ In additional
examples\ phenylsulfonylmethyl t!butyl ether acts as a formyl anion in its reaction with aldehydes\
and the resulting alcohol can be acylated prior to release of the carbonyl ð80SL490Ł\ and methyl!
thiomethyl p!toluene sulfone can be used in a similar manner ð75TL2554Ł[ Allylic ethers\ which are
easily prepared from the corresponding alcohols\ undergo ozonolysis to a!oxygenated aldehydes
ð89JOC4947Ł[ An oxidative cleavage used to prepare b!oxygenated aldehydes is shown in Equation
"13# ð80TL256Ł[

R CHO
NaIO4, MeOH O
O (24)
75–85% CHO
O R
O

Direct oxidation of aldehydes or their enol derivatives to the corresponding a!oxygenated deriva!
tives is less facile than for the corresponding ketones\ at least in part because of the greater reactivity
of aldehyde enolates[ However\ some methods have been applied to this transformation\ including
the use of mcpba ð64JOC2316Ł and lead tetraacetate ð72T750Ł to give a!acyloxy aldehydes\ and SAMP
21 Alkyl Aldehydes
or RAMP hydrazones to give a!alkoxy aldehydes ð77TL1326Ł[ The oxidative transformation of a
sulfoxide to an aldehyde\ via a Pummerer rearrangement\ has been known for many years ð67S770Ł\
and the mild conditions allow it to be used for the synthesis of functionalized aldehydes "Scheme
21# ð82CC873Ł[ A method for the synthesis of a!alkoxy aldehydes which could have wide applicability
is shown in Scheme 22[ Thus\ diastereospeci_c hydroxylation of an Evans imide\ followed by amide
exchange\ protection and reduction\ gives the product in high overall yield ð81JA8323Ł[ b!Alkoxy
imides\ generated by an Evans aldol approach\ can be reduced to b!alkoxy aldehydes via a similar
procedure ð81JOC0956Ł[ The enolate formed from 1!acetylthiazole undergoes aldol reactions with a
range of aldehydes[ Reduction of the ketone\ protection of the resulting alcohol and unmasking of
the aldehyde gives anti 1\3!dioxygenated aldehydes ð78TL5952Ł[
OBn O OBn OBn
TFAA, pyridine CuCl, K2CO3
S S
Ar Ar CHO
F F OCOCF3 F
TFAA = trifluoroacetic anhydride

Scheme 32

O O O O
i, ii MeO iii, iv
O N N
80% 78%
Me OH PMB-O
Bn
i, NaHMDS, 2-(phenylsulfonyl)-3-phenyloxaziridine, –78 °C; ii, AlMe3, MeONHMe•HCl, 45 °C;
iii, NaH, p-MeOC6H4CH2Br, 0 °C; iv, dibal, –78 °C

Scheme 33

Nucleophilic displacement of the halide from a!halo aldimines or a!halo aldehydes by oxygen
nucleophiles is not always a predictable reaction whose outcome depends on the substrate and
the conditions used "for a review\ see ðB!77MI 290!90Ł#[ Alkoxides are frequently the least useful
nucleophiles\ but carboxylate salts can be used more successfully ð71JOC0090Ł[ A novel\ ~exible and
iterative procedure for the synthesis of polyhydroxy aldehydes involves electrochemical oxidation
of alkoxysilanes "Scheme 23# ð81JOC0210Ł[
OMe OMe v, vi
i, ii iii, iv
HO MeO2CO MeO2CO TMS
TMS OMe vii, viii

OH
BnO TMS

OMe

i, anodic oxidation, Et4NOTs, MeOH; ii, ClCO2Me, C5H5N; iii, H3O+; iv, Br2CH-TMS, CrCl2; v, LiAlH4;
vi, (+)-diisopropyl tartrate, Ti(OPri)4, ButO2H; vii, NaH, BnBr; viii, BF3•Et2O, MeOH

Scheme 34

Low!molecular!weight\ optically active\ polyoxygenated aldehydes\ which are excellent building


blocks for organic synthesis\ are available via the modi_cation of naturally occurring materials "for
reviews\ see ðB!72MI 290!91Ł and ðB!81MI 290!91Ł#[ Optically active a!alkoxypropanals have been
prepared from the reduction of lactic acid esters ð72JOC4079Ł or amides ð78BCJ2927Ł without race!
mization[ The enzymatic resolution of 1!acyloxy 2!heterosubstituted propenals has been reported
by Wong and co!workers[ Aldehydes having N2\ RO and halogens at C!2 gave excellent enanti!
oselectivities\ with both enantiomers being available by the same route "Scheme 24#[ In the case of
compounds with a b halogen\ treatment with a base gives an epoxide "Scheme 24# which is ideally
functionalized for the introduction of other substituents at C!1 or C!2[ In addition\ both thiiranes
and aziridines were available from appropriate intermediates "Equations "14# and "15## ð89JOC3786Ł[
Bearin` an Oxy`en 22
Similar aldehydes can also be resolved using a transketolase "Equation "16##\ although in this case
only one enantiomer is available directly ð81TL4046Ł[
OAc OH OAc
LP-80-lipase, pH 7
Cl OEt Cl OEt + Cl OEt
50% conversion
OEt OEt OEt
>98% ee >98% ee

KOH, EtOH KOH, EtOH


95% 92%

O O
OEt OEt

OEt OEt

Scheme 35

O S
thiourea
OEt OEt (25)
100%
OEt OEt

H
OH N
PPh3
N3 OEt OEt (26)
40%
OEt OEt

OH O OH OH O
R1 OH transketolase R1 R1 OH
CHO + LiO C CHO + (27)
2
OH
R1 = SH, R2S, R3O, F, CN, Me 52–78%, >98% ee 72–82%

2[90[3[2 OX!functionalized Aldehydes


Transition metal!catalysed carbonyl insertion reactions are proving extremely useful\ and they
are widely used for the introduction of one additional carbon atom[ In one example\ aldehydes were
converted into a!silyloxy aldehydes via a silylformylation[ Aromatic and aliphatic aldehydes act as
substrates\ and the aldehyde group in the product does not undergo further reaction ð82JA1948Ł[
Reduction of O!TMS or O!TBDMS cyanohydrins can be used to prepare racemic or optically active
a!silyloxy cyanohydrins ð80SL368\ 83T1710Ł[
A number of reagents are known to exploit the di}erential stability of trialkyl silyl ethers to the
extent that TMS or triethylsilyl "TES# ethers undergo in situ deprotective oxidation in the presence
of TBDMS ethers to give remote silyloxy aldehydes[ Alternatively\ in polyols where all hydroxyl
groups are derivatized with the same silyl group\ the primary group can be selectively oxidized due
to steric and:or electronic e}ects[ This whole area of selective oxidations has been the subject of a
review ð82S00Ł[ Some of the methods outlined in Section 2[90[3[0[0 for the synthesis of a!hydroxy
aldehydes either proceed via silyloxy aldehydes ð80TL4602Ł or could be used for their preparation[
In addition\ in isolated cases\ the oxidation of silyl enol ethers with dimethyldioxirane "see Section
2[93[3[0[0# has been applied to the synthesis of a!silyloxy aldehydes ð78JOC3138Ł[ Optically active a!
"silyloxy#propenals have also been prepared from the reduction of lactic acid derivatives ð72JOC4079Ł[
The carbonylative ring opening of epoxides to give b!oxygenated aldehydes has been limited by the
requirement for a large excess of epoxide in order to prevent side reactions[ It now appears that the
use of rhodiumÐamine catalysts is crucial to the success of this reaction\ and\ under
a carbon monoxide atmosphere\ cyclohexene oxide gives predominantly trans!1!"trialkyl!
silyloxy#cyclohexane carboxaldehyde in 71) yield[ Nonsymmetrical epoxides are cleaved pref!
erentially at the least substituted position ð82JOC3076Ł[ The Lewis acid!catalysed rearrangement of
23 Alkyl Aldehydes
epoxy silyl ethers appears to be a very useful method for the synthesis of highly functionalized b!
silyloxy aldehydes[ As the substrates can be prepared in homochiral form from the Sharpless
oxidation of allylic alcohols\ and the rearrangement is concerted\ with the silyloxy alkyl group
approaching anti to the epoxide\ then the products are also enantiomerically pure "Equation
"17##[ Of the Lewis acids tried\ the sterically hindered methyl aluminum bis"3!bromo!1\5!di!t!
butylphenoxide# was the most successful[ The substitution pattern on the substrate is crucial to the
success of the reaction[ Thus\ g\g!dialkyl\ g!aryl and g!alkenyl epoxides behave as expected\ but
g!monoalkyl epoxides do not rearrange under these conditions ð80T5872Ł[ A related rearrangement\
involving proton transfer\ has been reported "Equation "18## ð82JA0197Ł[ Using the strongly basic
LDA:KOBut mixture\ epoxy ethers\ "16#\ undergo a selective deprotonation at the a carbon to give
vinyl ethers[ These can be silylated and hydrolysed to give b!silyloxy aldehydes ð81SL792Ł[ In a
reaction that invokes participation of a common solvent\ the SAMP and RAMP hydrazones of
aldehydes attack THF in the presence of TMS!OTf to introduce a 3!silyloxybutyl group at the a
position[ The aldehyde group can be deprotected using ozone without loss of the silyl group to give
5!trimethylsiloxy aldehydes ð82S0981Ł[

O-TBDMS
O (28)
CHO
Ph O-TBDMS 75–87%, 98% ee
Ph

OH O-TES
TES-OTf
O (29)
Ph Ph CHO
collidine
80%

α
Bun Me
O O
O
(27)

2[90[4 ALDEHYDES BEARING A SULFUR FUNCTION

2[90[4[0 SH! and SR!functionalized Aldehydes


The chemistry of a!thiol aldehydes is restricted by their existence as the cyclic dimers "17# which
can be puri_ed but are insoluble in some organic solvents[ Under basic conditions there is an
equilibrium between cyclic and acyclic forms[ They can be prepared from the corresponding bromo
aldehyde or acetal using sodium hydrogen sul_de\ but an excess of sul_de is required in order to
prevent formation of "18# "Scheme 25# ð64JOC0183Ł[ More recently\ the same compounds have been
prepared by reduction of "29# ð72CJC0761Ł[ b!Thiol aldehydes can be prepared from the hydrolysis
of the corresponding thioacetates "20#\ although their isolation cannot be readily achieved
ð66JOC1012Ł[ The synthesis of thiol aldehydes has been part of a previous review ð66HOU"6:1C#1206Ł[

R S OH O O O O
HS NaSH Br NaSH S

HO S R R R R R
(28) (29)

Scheme 36

R CHO
O
AcS
S

(30) (31)
Bearin` a Sulfur 24
Direct sulfenylation of aldehydes or their derivatives is\ perhaps\ the most useful preparation of
a!sulfenyl aldehydes\ and a number of procedures have been developed to achieve this[ The lithium
enolates of alkyl aldehydes\ generated from the treatment of a silyl enol ether with methyl lithium\
react with sulfenyl chlorides to give the desired products in fair yield ð62TL4002Ł\ while potassium
enolates react with dialkyl or diaryl disul_des ð68TL1706Ł[ The latter method works best for aldehydes
with only one a proton[ Metalloenamines also undergo reaction with disul_des to give similar
products ð63TL2844Ł[ Enamines derived from a chiral amine lead to enantiomerically enriched a!
sulfenyl ketones ð76S048Ł[ Other papers have shown that enol ethers ð74T3338Ł and silyl enol ethers
ð80JCS"P0#340Ł react with phenyl sulfenyl chloride in the absence of organometallic reagents to give
a!sulfenyl aldehydes directly[ Despite the reactive nature of the electrophile\ dioxolanes\ ethers and
THP ethers have been shown to survive the sulfenylating conditions[ Hydrocinnamaldehyde reacts
directly with "methoxycarbonyl#sulfenyl chloride in the absence of a base to give a!"methoxy!
carbonylsulfenyl#hydrocinnamaldehyde "21# in 51) yield[ Under the reaction conditions\ elim!
ination does not appear to be a problem\ and the experimental procedure is very simple ð81JOC0942Ł[

CHO
Ph
S
CO2Me

(32)

As a contrast to these methods which require electrophilic sulfenylating agents\ nucleophilic


attack by thiolate anions at a!halo aldehydes can also be used to prepare a!sulfenyl aldehydes or
acetals ð79TL3060\ 71TL0554\ 73S35\ 76S548\ 83T2238Ł or a\a!disulfenyl aldehydes ð73S35Ł[ The di.culty
in preparing a!halo aldehydes means that it is often more e.cient to use a!halo acid derivatives
and adjust the oxidation state after sulfenylation ð66JCS"P0#0020\ 66JCS"P0#1152Ł[ A review on the
displacement of halogens by sul_des from a!halo aldehydes has been published ðB!77MI 290!90Ł[
A combination of nucleophilic displacement and enolate alkylation has been used by Enders and
co!workers in an asymmetric synthesis of a!sulphenyl aldehydes[ The diethyl acetal of bromo!
acetaldehyde reacts with a range of thiols to give the corresponding sul_de\ which can then be
converted into the SAMP or RAMP hydrazones[ Either of these undergo e.cient reaction with
alkyl halides\ and\ under carefully controlled conditions\ the hydrazone can be cleaved to the
aldehyde without oxidation at sulfur "Scheme 26#[ Epimerization at the a position does not appear
to be a problem throughout the sequence and the enantiomeric excesses obtained are high ð83T2238Ł[

O
OEt R1SNa then LDA, R2X
N R1S
Br N
OEt SAMP then O3
65–90% R1S OMe 45–80% R2

LDA = lithium diisopropylamide


SAMP = (S)-(–)-1-amino-2-methoxymethylpyrrolidine

Scheme 37

The reaction of the formyl anion equivalent "22# with ketones results in an adduct which can
undergo rearrangement to an a!sulfenyl aldehyde on treatment with SOCl1 "Scheme 27# ð70TL776\
76RTC378Ł[ Although "22# will also add to aldehydes\ subsequent rearrangement does not proceed
smoothly unless SOCl1 is replaced by methanesulfonyl chloride ð77JA4198Ł[ This reaction is thought
to proceed via a 0\1!rearrangement of the phenylsulfenyl group\ and a similar mechanism must also
be involved in the bromination and hydrolysis of vinyl thioethers "Equation "29## ð63LA1974Ł[
Formylation of the anion derived from the boronate ester "23# with ethyl formate gives\ following
cleavage of the carbon0boron bond by hydrolysis\ a!sulfenyl aldehydes[ In a subsequent reaction\
a!sulfenyl aldehydes can undergo alkylation at the a position with reactive benzyl or allyl halides
ð71JOC1368Ł[ Stereocomplementary reduction of the oxazolidine "24# under chelation! or non!
chelation!controlled conditions can lead to either enantiomer of the corresponding hydroxy!
oxazolidine[ Thiolysis of each of these leads to enantiomerically pure a!"arylsulfenyl#propanal
ð82JOC2054Ł[
25 Alkyl Aldehydes
OH SPh
PhS OMe R1 R1
R1R2CO OMe SOCl2 O
R2 R2
Li
(33) SPh

Scheme 38

R1 SPh Br2 then H2O


R1 O
PhS (30)
R2 R2

Ts
R1 O
N
B O
PhS O H O Ph

(34) (35)

The use of electrolytic methods for the interconversion of functional groups is attractive because
of the absence of expensive reagents and the reduced environmental hazards associated with the
disposal of by!products[ As part of the continuing search to exploit such procedures\ terminal
alkenyl sul_des ð70CC152\ 77CC0357Ł and alkenyl silanes ð82T1900Ł can be oxidized to a!phenylsulfenyl
aldehydes in the presence of thiophenol and O1[ For both substrates\ the same transformation can
be achieved without using electrolysis\ although the reaction is much slower[ For alkenylsilanes\
isolated alcohols and ketones can survive the reaction conditions[ Terminal alkenyl sulfoxides are
also intermediates to a!sulfenyl aldehydes[ The reaction involves treatment of a b!aryl or b\b!dialkyl
sulfoxide with NaOAc and Tf1O\ and proceeds via the acylals "Scheme 28# ð80TL5862Ł[ In a procedure
that has been widely adopted for the synthesis of a!heterosubstituted carbonyl compounds\ PhSNa
adds to a\b!epoxy sulfoxides\ for example "25#\ at the b position to give a!sulfenyl aldehydes after
elimination of phenylsulfenic acid ð74BCJ1738\ 81SL344Ł[ Amines\ THP ethers and alkyl chlorides are
some of the groups that remain una}ected[ The epoxy sulfoxides are easily prepared via a Darzens
reaction between the anion of a 0\0!chlorosulfoxide and a ketone[ Apparently\ fewer methods are
known for the synthesis of more remote sulfenyl!substituted aldehydes[ The addition of thiophenol
to acrolein has been reported\ but the product was only isolated after protection of the aldehyde
group with propane 0\2!dithiol ð68TL2056Ł[

Ar i, NaOAc, Ac2O, Tf2O


PhS OAc K2CO3, MeOH PhS O

ii, NaHCO3 Ar OAc 60–65%


SOPh Ar
20–85%

Scheme 39

Li
O
O-THP O NR2
PhOS
O
(36) (37)

Silyl enol ethers derived from aldehydes react with chloroalkyl sul_des to give b!sulfenyl alde!
hydes ð68TL1068\ 77T3196Ł[ Many homenolate anions derived from aldehydes have been developed
ðB!76MI 290!91Ł\ and some of these\ for example "26#\ have been shown to react with electrophilic
sulfenylating agents at the g position to give protected b!sulfenyl aldehydes ð63JA4459\ 70AG"E#016Ł[
The silyl enol ether derived from isobutyraldehyde reacts with trimethylthio orthoformate in the
presence of SnCl3 to give 1\1!dimethyl!2\2!bis"methylthio#propanal ð74TL5402Ł "for reactions of
enolate donors with thionium ions to give g!sulfenyl ketones\ see Section 2[92[4[0#[
5!"Phenylsulfenyl#hexanal can be prepared in good yield by the photolytic cleavage of 1!"phenyl!
sulfenyl#cyclohexanol[ The application of this method to other ring sizes or more highly substituted
Bearin` a Selenium or Tellurium 26
systems would enhance its usefulness\ as the sulfenyl alcohols can be readily prepared from the
corresponding alkenes via the epoxides ð89TL52Ł[ The synthesis of a!sulphenyl aldehydes and ketones
has been part of a previous review ð66HOU"6:1C#1206Ł[

2[90[4[1 Higher!coordinated Sulfur!functionalized Aldehydes


Hydrazones derived from aldehydes undergo metallation and trapping with menthyl p!toluene!
sul_nate to give enantiomerically enriched a!sul_nyl hydrazones\ although attempts to remove
the protecting group were unsuccessful ð71S718Ł[ a!Sulfonyl aldehydes can be prepared from the
formylation of lithiomethyl phenyl sulfone ð65S395Ł\ and oxidation of allylic sulfones gives b!
sulfonyl enals "Scheme 39# ð74JOM"179#158Ł[ a\b!Epoxy sulfoxides have been shown to be useful
intermediates to a!sulfenyl aldehydes "see Section 2[90[4[0#\ but for the corresponding sulfones a
0\1!migration of the sulfonyl group leads to a!sulfonyl enamines "Equation "20## ð72S517Ł[

hν, PdII, O2 SO2Ph SO2Ph


SO2Ph +
OH O
pcc

pcc = pyridinium chlorochromate


Scheme 40

Ar O i, BF3•Et2O Ar
NR1R2 (31)
SO2Ar ii, R1R2NH ArO2S

2[90[5 ALDEHYDES BEARING A SELENIUM OR TELLURIUM FUNCTION

2[90[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Aldehydes


The primary interest in the synthesis of a!alkylselenyl or arylselenyl aldehydes and ketones lies
in their ready oxidation to the corresponding selenoxides and subsequent elimination of a selenic
acid to give the corresponding a\b!unsaturated carbonyl compounds[ This usually occurs under
mild conditions\ often spontaneously at room temperature\ to result in a transformation for which
there are relatively few attractive alternatives[ The success of this overall procedure is attested to
by the numerous examples that can be found in the literature "for reviews\ see ð67T0938\ 74T3616\
B!75MI 290!90Ł and ðB!76MI 290!91Ł#[ As already demonstrated\ however\ in Sections 2[90[3 and 2[90[4
on a!oxygenated and a!sulfenylated aldehydes\ respectively\ and Sections 2[92[3 and 2[92[4 on
ketones\ there is usually a paucity of methods to prepare otherwise identical aldehydes compared
to ketones[
The most widely used method for the synthesis of a!selenyl aldehydes is the reaction between an
aldehyde or derivative and a selenium"II# reagent\ of which a number are available[ In fact\ the _rst
reported procedure for the phenylselenylation of aldehydes used neutral or mildly acidic conditions
in which aldehydes react directly in the presence of esters ð62JA5026Ł[ Presumably\ this re~ects the
ability of aldehydes to exist in the enol form to at least some extent under the reaction conditions[
This enolization can be enhanced\ in di.cult cases\ by the presence of a catalytic amount of acid or
by using higher temperatures[ Chemoselectivity is very high and elimination can occur without
oxidation "Equation "21## ð70JA613Ł[ Phenylselenyl chloride is the most frequently used selenylating
agent under these conditions[ Elimination of a 1!pyridylselenyl group has been reported to occur
under milder conditions and give higher yields than using a phenylselenyl group[ The selenoxide is
available from the selenide\ which is introduced using 1!pyridylselenyl bromide despite the fact that
PhSeBr can act primarily as a brominating agent under comparable reaction conditions ð73JOC2685Ł[
A useful chemoselective introduction of a phenylselenyl group has been developed using selenamides
"Equation "22##[ Selenylation occurs at room temperature in the absence of a base\ and introduces
the phenylselenyl group a to an aldehyde in the presence of malonate ester or ketone groups
ð70TL2450Ł[ Normally\ diselenides are insu.ciently electrophilic to react with aldehydes without
prior enolate formation[ However\ on treatment with SeO1\ a more reactive selenylating agent is
27 Alkyl Aldehydes
generated in situ which will react directly with aldehydes[ The requirement for the presence of a
catalytic amount of acid\ H1SO3\ may limit the types of functional groups which will survive the
reaction conditions ð71TL3702Ł[ N!"Phenylselenyl#phthalimide also acts as a selenylating agent in
the presence of one equivalent of p!TsOH ð82TL6644Ł[ b!Keto aldehydes react from the central
carbon atom with PhSeCl in the presence of pyridine ð70JOC1819Ł[

H
OHC O OHC O
PhSeCl, 60 °C
O O (32)
AcO AcO
H
OAc OAc

O O SePh
PhSeNEt2, CH2Cl2
(33)
CHO 72% CHO

A number of aldehyde derivatives have been used as enolate donors during phenylselenylation
reactions[ For example\ enamines react directly with PhSeCl at −009>C ð79TL3306Ł or with selen!
amides to give mono! or bis!a!selenyl aldehydes ð71TL0446Ł\ and enol ethers react with PhSeBr
ð68HCA0395Ł or PhSeCl ð68S871Ł to give a!phenylselenyl aldehydes[ In the latter case there are some
interesting examples of chemoselectivity as\ at low temperatures\ silyl ethers\ isolated alkenes and
dioxolanes survive the reaction conditions "Equation "23##\ whereas at room temperature cyclic
acetals give selenylated products "Equation "24##[ Dihydropyran undergoes a regioselective addition
using PhSeCl in water to give a 1!hydroxy!2!"phenylselenyl#tetrahydropyran ð71TL1396Ł\ and silyl
enol ethers ð66S763Ł or silyl dienol ethers "Equation "25## ð67SC100Ł can be derivatized in the same
way[ Further examples of the selenylation of aldehydes can be found in the excellent review by Back
ðB!76MI 290!92Ł[

O PhSeCl, –78 °C O CHO


(34)
O OMe 88% O SePh

SePh
O PhSeCl, RT O
(35)
O 70% O

O
TMS-O PhSeCl
(36)
67%
SePh

Terminal alkenes can undergo oxyselenylation to give a!phenylselenyl aldehydes and:or a!phenyl!
selenyl ketones\ depending on the regiospeci_city of the addition[ As might be expected\ the latter
generally predominate\ although the ratio can be as low as 0 ] 0 ð70BCJ2099Ł[ The directing e}ect of
the oxygen atom in allylic ethers or silyl ethers results in regiochemically controlled addition to give
b!oxygenated a!phenylselenyl aldehydes "Equation "26## ð70BCJ2409Ł[ This directing e}ect of the
oxygen is strongly dependent on distance\ as the corresponding homoallylic ethers give no better
than a 2 ] 0 mixture of selenyl aldehyde to selenyl ketone ð70BCJ2409Ł[ The presence of a heteroatom
on the alkene can also control the regiochemistry of the addition "Equation "27## ð79CC840Ł[

TBDMS-O TBDMS-O O
Ph2Se2, (PhSeO)2O
(37)
Ph Ph
81%
SePh
TBDMS = t-butyldimethylsilyl

(PhSeO)2O n-C9H19 CHO


n-C9H19 (38)
SeMe 78% SeMe
Bearin` a Nitro`en 28
The p!toluenesulfonyl hydrazones of a!bromo aldehydes undergo direct substitution of the halide
with PhSeH at −67>C[ For the hydrazones derived from ketones the carbonyl group can be
regenerated using BF2 = Et1O ð71JCS"P0#1608Ł[ Bromoacetaldehyde diethyl acetal reacts with Na1Se1
to give\ following hydrolysis\ bis"1!oxoethyl#diselenide ð73CC78Ł[ In general\ nucleophilic dis!
placement of halides by selenate ions is compatible with a range of functional groups\ although not
lactones\ esters or epoxides\ and so this approach should be applicable to more complex systems[
In a complementary approach\ selenium!stabilized carbanions\ prepared via Se:Li halogen exchange
in diselenoacetals\ react with DMF to give a!selenyl aldehydes directly ð65TL342\ 89SL044Ł[
The conjugate addition of selenates to a\b!unsaturated aldehydes is potentially the most direct
synthesis of b!selenyl aldehydes\ and it can be achieved using a number of di}erent conditions[
Benzeneselenol adds even to sterically hindered b\b!disubstituted aldehydes in the presence of acetic
acid ð79S553Ł\ whilst potassium phenyl selenate\ generated from PhSe!TMS and KF\ will also
function in this way ð67TL4976Ł[ Other papers have appeared that describe the use of PPh2 or TMS!
I for activating PhSe!TMS towards conjugate addition ð67TL4980\ 68TL3078Ł[ Sodium hydrogen
selenide adds to cinnamaldehyde to give the product of 0\3!addition[ There appears to be no way
of preventing a second addition to give the observed product "27# ð80SC840Ł[ The use of selenium!
stabilized carbocations has lead to an e}ective synthesis of b\b!diselenyl aldehydes via the reaction
of silyl enol ethers with trimethylseleno or triphenylseleno orthoformate in the presence of a Lewis
acid ð74TL5402Ł[

Se
OHC CHO
Ph Ph

(38)

Diisobutylaluminum phenyltellurolate\ which can be easily prepared by the reduction of diphenyl


ditelluride with diisobutylaluminum hydride\ delivers a phenyltelluro group to the b position of
acrolein to give 2!"phenyltelluro#propanal[ This compound is somewhat sensitive to air\ but can be
isolated following treatment of the reaction mixture with degassed HCl ð78CL596Ł[

2[90[6 ALDEHYDES BEARING A NITROGEN FUNCTION

2[90[6[0 NH1!\ NHR! and NR1!functionalized Aldehydes


The synthesis and reactions of amino!substituted aldehydes is an area of active research and one
which cannot be completely covered in the available space[ Excellent reviews dealing with the
synthesis and reactions of amino aldehydes have appeared which incorporate additional material
ð78CRV038\ 89OPP288\ 80AG"E#0420Ł[

2[90[6[0[0 a!NH1!\ NHR! and NR1!functionalized aldehydes


There has been an increase in activity in the synthesis and reactions of a!amino!substituted
aldehydes\ attributable\ in part\ to their role as mimics of the tetrahedral intermediates found in
many enzyme!catalysed reactions[ For example\ a!amino aldehydes undergo a ready hydration
which may be simulated in vivo\ using an enzyme!bound serine residue[ Alternatively\ treatment of
an a!amino aldehyde with an organometallic reagent gives a chiral 0\1!amino alcohol which can
mimic the transition state of some proteolytic enzymes ðB!89MI 290!90Ł[ Amino aldehydes are\ in
fact\ excellent intermediates to a whole range of polyfunctional compounds\ but their value is
compromised by their con_gurational and chemical instability[ Usually\ speci_c e}ort must be
directed to stop epimerization at the a position\ and the products are normally isolated in partially
protected form to minimize dimerization[
The ready availability of the naturally occurring homochiral a!amino acids and their derivatives
would indicate that these represent ideal starting materials for the synthesis of amino aldehydes\
requiring only a reduction step[ This can be achieved in a number of ways[ The most readily
available amino acid derivatives are the carboxylic acid esters\ and these can be reduced to N!
protected a!amino aldehydes using dibal!H ð71JCS"P0#296\ 76T2952Ł[ In many cases\ however\ variable
amounts of the corresponding alcohol are produced due to overreduction[ a!Amino acid
39 Alkyl Aldehydes
chlorides can be selectively reduced to aldehydes using Bu2SnH in the presence of a palladium"9#
catalyst ð83TL0070Ł and mixed anhydrides with LiAl"ButO#2H ð83HCA464Ł[ Perhaps the best
methods\ however\ employ the reduction of the easily prepared N!a!protected cyclic or acyclic
hydroxamates with LiAlH3[ Under these conditions\ neither racemization at the a position nor
alcohol formation is usually a problem "Scheme 30# ð76JA125\ 89S342Ł[ Racemization in general is
minimized by the use of the 8!"8!phenyl~uorenyl# protecting group on the a nitrogen ð76JA125Ł[
Other heterocycles have been used to activate acids towards selective reduction including imidazoles\
for example "28# ð65JOC2206Ł\ and pyrazoles\ for example "39# ð71TL414Ł[ Only in the _rst of these
examples was any alcohol detected[ A method has been reported which may compete with the best
known methods for this conversion[ It involves the reduction of the easily prepared thiol ester with
Et2SiH ð89JA6949\ 82JOC1202Ł\ and the reaction shown in Equation "28# has been performed on a
39 g scale with no racemization[
O O O
R2HN Me LiAlH4, 0 °C R2HN LiAlH4, 0 °C R2HN
N N O
R1 = Pri, 70% R1 = Me, 90%
R1 OMe R1 R1

Scheme 41

O O

Ph N N
NHZ NHZ N
N

(39) (40)

O O O OMe
i, Et3SiH, Pd on C
(39)
MeO SEt ii, CSA, MeOH MeO OMe
95%, 100% ee
t-BOCHN t-BOCHN

t-BOC = t-butoxycarbonyl
LSA = camphorsulfonic acid

In cases where the chemoselectivity for the reduction is low\ that is\ appreciable alcohol formation
results\ it may be more favourable to use excess reducing agent and then oxidize the resulting alcohol
back to the aldehyde[ Many reagents have been reported for the reduction\ including LiAlH3 ð80SC0Ł\
borohydrides ð82JOC2457Ł and sodium metal ð83TL0666Ł^ whilst for the subsequent oxidation the
ParikhÐDoering conditions "DMSO\ SO2 = py# often result in the least racemization\ although many
other useful procedures are known ð76AG"E#0030\ 89OPP288\ 83JA0205Ł[ 0\1! or 0\2!Amino alcohols
prepared using other methods can be oxidized in the same way to a! or b!amino aldehydes ð81T3120Ł[
Dipeptides containing serine can be prepared by the oxidative cleavage of a glucosamine amide
in which the sugar acts as the source of the serine residue "Scheme 31# ð81AG"E#0280Ł[ As might be
expected from this\ the oxidative cleavage of alkenes ð73TL0960Ł or 0\1!diols ð68CC764\ 75JOC4183\
78TL5658Ł having proximal amino groups has been used to prepare amino aldehydes[
The methods described above are ideal for the synthesis of N!protected a!amino aldehydes but
are less suitable if the requirement is for carbonyl!protected derivatives[ These can be made in a
complementary approach involving adjustment of the oxidation state at the amino terminus\ and
this is an ideal method for making low!molecular!weight building blocks in racemic or homochiral
form[ In one early example\ it was demonstrated that diethoxy acetonitrile was susceptible to
successive nucleophilic attack by organometallics to give a!disubstituted amino acetals "Scheme 32#
ð79S778Ł[ Glyoxal is an ideal starting material for a!amino aldehyde synthesis due to its low cost\
but methods for the selective functionalization of one of the aldehyde groups have not been widely
available[ However\ it has been demonstrated that the monoacetal of glyoxal can be prepared using
a number of di}erent alcohols in a very simple but high!yielding procedure[ The remaining aldehyde
group was subjected to a reductive amination\ using primary amines or ammonia\ also in high yield
"Scheme 33# ð77BSF84Ł[ As a logical extension of this work\ a number of groups have investigated
the use of chiral auxiliaries as a way of generating optically active amino aldehydes[ Chastrette and
Bearin` a Nitro`en 30
OH OH R
O H
NH3Cl i, ii
N iii, iv
O ZHN O NHZ
+ OH
HO 60–72% HO O 80–90%
OH R OH
OH OH
R O
H
N
ZHN
O
OH

i, NaOMe, DMF; ii, dicyclohexylcarbodiimide, hydroxybenzotriazole; iii, NaBH4, EtOH; iv, NaIO4, H2O

Scheme 42

co!workers have prepared a number of hydrazino acetals using di}erent diols "Scheme 34# and
determined that the acetals "30# and "31# give the best results\ with the addition of BunLi or MeLi
to "30# or "31# giving at least 73) diastereomeric excess[ Reduction of the hydrazine group then
gives the free amino acetal[ The enantiomer of the diol leading to "30# is available\ and so both
enantiomers of the amino acetal might be prepared using this approach ð89TL0318\ 81BSF050Ł[
Coordination of the nucleophile to the chiral auxiliary accounts for the transfer of chirality and this
can also be achieved using a chiral hydrazine[

EtO EtO NMgBr i, BunLi, RT EtO NH2


PhMgBr, RT
CN Bun
ii, H3O+
EtO EtO Ph EtO Ph
90%

Scheme 43

R1OH, Lewis acid or R 1O NH3 or R2NH2 R1O


OHC–CHO NH2(NHR2)
Brønsted acids R1 O CHO H2, 90–100 bar, Ni R1O

Scheme 44

Ph

MeO H2NNMe2 MeO HO OH O


Ph
90% NNMe2 p-TsOH NNMe2
MeO CHO MeO 95% O

Scheme 45

OTr MeO OMe

O NNMe2 MeO O NNMe2


O
O O

(41) (42)

The addition of Grignard or organolithium reagents to "32# in the presence of CeCl2 gives in most
cases at least 69) diastereomeric excess[ The N!protected amino aldehyde can be unmasked as
shown in Scheme 35\ with some observable loss of stereochemical integrity during the _nal step
ð82SL248Ł[ Using "S#!0!phenylethylamine as the chiral auxiliary\ the acetal of alanine can be prepared
in high chemical and stereochemical yield "Scheme 36#\ although the method works less well for
other amino aldehydes ð78S597Ł[ Alexakis and co!workers have used a C!1 symmetrical diamine as
31 Alkyl Aldehydes
the chiral auxiliary and achieved excellent yields of stereocomplementary products[ The addition of
organolithium reagents to the aminal "33# gives\ generally as a single diastereoisomer\ the adduct
"34# "Scheme 37#\ arising from the approach of the nucleophile from the bottom face of the
hydrazone ð80TL0060Ł[ Under identical reaction conditions Grignard reagents do not react^ however\
in a less polar solvent\ nucleophilic attack occurs from the opposite face with good selectivity
ð81JOC3452Ł[ The amino aldehydes can be unmasked under mild conditions and the chiral diamine
recovered\ if required[ Katritzky and co!workers have extended their elegant work using the chem!
istry of benzotriazole to the synthesis of amino aldehydes in excellent yields ð89S0062\ 80T1572Ł[
Primary and secondary amines can be introduced in this manner\ and variation of the group at the
a position is possible using the appropriate organometallic reagent "Scheme 38#[
OMe OMe CO2Bui
OMe N N
SAMP MeO N i, BuiMgCl, CeCl3 MeO N i, Li, NH3

MeO CHO ii, BuiOCOCl But ii, TMS-I


92%, 88% de 92%, 86% ee
OMe OMe
(43)
H
OHC N OBui

Bui O

Scheme 46

OMe
OMe
(S)-1-(phenyl)ethylamine H2, 5 bar, Ni on Al
OMe
OMe
p-TsOH 92%, 90% de
Ph N
O

OMe
OMe
HCO2NH4, Pd on C
OMe
Ph NH 96%, 92% ee OMe
NH2

Scheme 47

Ph Me Ph Me Ph Me
N Bun BunMgBr, PhMe, THF N BunLi, Et2O N Bun

N 95%, >99% de N 60%, >99% de N


Ph N NMe2 Ph NNMe2 Ph N NMe2
Me H Me Me H
(44) (45)

Scheme 48

N OHCCH(OEt)2 N i, R3MgX R3
N N
N R1R2NH N ii, HCl R1R2N CHO
H 70–80% OEt 60–90%

R1R2N
OEt

Scheme 49

Several research groups have used the thiazole moiety as an equivalent of the formyl anion and
demonstrated its ability to attack carbonyl compounds to give a!hydroxy aldehydes "see Section
Bearin` a Nitro`en 32
2[90[3[0#[ Dondoni and co!workers have studied its reaction with C1N systems and found an
excellent spectrum of reactivity with nitrones[ With nitrones derived from alkoxy aldehydes\ anti
addition is preferred and the initial products can be further elaborated to the desired systems
"Scheme 49# ð81TL3110Ł[ 0\2!Dithiane reacts with disubstituted imines to give amino aldehydes
ð63BSF220Ł or with nitriles to give the enamine "35#\ and reduction of this compound with diborane
gives the protected amino aldehyde "36# ð76CC664Ł[ Relatively few other formyl anion equivalents
are reactive enough to add to simple imines\ although those that do are included in an earlier review
ðB!76MI 290!90Ł[

O O– 2-lithiothiazole O N 3 steps O
O O O
N+ Ph 62%, 93% de S CHO

N Ph NHBOC
HO

Scheme 50

S NH2 S NH2

S Ph S Ph
(46) (47)

A number of papers have demonstrated the 0\1!migration of an amino group as part of a synthesis
of a!amino aldehydes[ The anodic oxidation of n!tosylamines generates the corresponding imine\
which rearranges to the enamine[ This enamine is su.ciently electron!rich to react with a positive
bromine species\ generated in situ\ and following aziridine formation the desired product is isolated
in reasonable yield "Scheme 40#[ The conversion is independent of steric factors\ as isolated yields are
similar for a!unsubstituted\ monosubstituted or disubstituted amino aldehydes ð75TL5972\ 89JA1257Ł[
Similar products are obtained from the treatment of enol ethers with N!halo amides ð67CJC008Ł[
N\N!Dialkyl enamines demonstrate a preference for the migration of the more electron!rich amino
group "Scheme 41# ð68AG"E#822Ł[

R1 R1 R1
–2 e– Br+/MeOH R2
NHTs NHTs NHTs
R2 R2 Br
OMe

R1 Ts R1
N R2
OMe
R2 50–60% TsHN
OMe OMe

Scheme 51

+ O
p-TsNHCl NHTs NR1R2 H3O+
NR1R2 Cl
NR1R2 R1R2N
NHTs

Scheme 52

The outcome of the reaction between ammonia or amines and a!halo aldehydes is strongly
dependent on the speci_c reagents\ but frequently fails to give the desired a!amino aldehydes[
Displacement with ammonia cannot be controlled in such a way as to prevent dimerization or
pyrazine formation\ whilst for primary amines the ambident reactivity\ carbonyl addition versus
halide displacement\ of the halo aldehyde tends to result in mixtures of products[ Using secondary
amines the initial products\ "37#\ can give rise to isomeric amino ketones "38# via an intramolecular
33 Alkyl Aldehydes
rearrangement "Scheme 42#\ although by careful control of the reaction conditions either product
can be obtained selectively[ Some of the problems associated with this transformation can be over!
come by protection of the aldehyde group as the acetal or imine prior to aminolysis ðB!77MI 290!90\
89JOC301Ł[

O O O
R2R3NH
R1 R1 NR2R3
R1
X NR2R3
(48) (49)

Scheme 53

The addition of heteroatom nucleophiles to a\b!epoxy sulfoxides is directed to the b position\


with a subsequent 0\0!elimination generating an a!substituted ketone[ The use of appropriate
nucleophiles has led to the synthesis of a!oxygenated\ a!sulfenylated and a!aminated aldehydes
ð81SL344Ł[ Aliphatic and aromatic amines can be introduced in this way\ and the method is applicable
even to a\a!disubstituted aldehydes "Equation "39##[

O SOPh piperidine
N (40)
78%
CHO

2[90[6[0[1 b! and more remotely NH1!\ NHR! and NR1!functionalized aldehydes


Many of the methods outlined in the previous section for the synthesis of protected a!amino
aldehydes are potentially applicable to the synthesis of more remote positional isomers[ Thus\
procedures involving oxidation\ reduction using the Rosenmund reaction ð89HCA394Ł or LiAlH3
ð89TL6208Ł\ halide displacement\ nucleophilic addition and oxidative cleavage are all appropriate
for the synthesis of a variety of amino aldehydes[
The reductive amination of aldehydes or ketones is often done using conditions where acid!
sensitive groups do not survive[ Using Ti"OPri#3 as a Lewis acid catalyst and NaBH2CN as the
reducing agent\ cyclic and acyclic acetals remain intact\ demonstrating the usefulness of this pro!
cedure for the synthesis of a wide range of carbonyl!protected amino carbonyl compounds
ð89JOC1441Ł[
The conjugate addition of amines to a\b!unsaturated aldehydes has rarely been reported as a
useful route to b!amino aldehydes\ presumably due to the competing decomposition of the highly
reactive anionic intermediates[ However\ Marko and co!workers have developed a set of conditions
that allow for the formation of the desired products in good yield[ The key to the transformation is
the use of THF as the solvent and a catalytic amount of dbu[ Without either of these a rapid
polymerization takes place[ Using these conditions\ secondary amines add in a 0\3!manner in good
yield\ even using weakly nucleophilic amines such as N!methylaniline[ Although the amino aldehydes
cannot be isolated without polymerization\ they can be subjected to further derivatization in situ\
to give isolable products "Scheme 43# ð89SC2056\ 81SL164Ł[ Benzophenone imine has been used as an
ammonia equivalent in the Michael addition to a\b!unsaturated carbonyl compounds[ In one
example it was shown to add to acrolein\ although no attempt was made to remove the diphenyl!
methyl protecting group ð78S248Ł[
The SAMP or RAMP hydrazones derived from a monoacetal of malondialdehyde show ×64)
diastereoselectivity\ which is raised to ×84) diastereomeric excess by chromatography\ on reaction
with alkyl\ allyl or aryl organolithium reagents[ The protected amino acetals can be released without
racemization by treatment with Li:NH2 "Scheme 44# ð82SL115Ł[ Hydroboration of propargylic
amines\ for example "49#\ proceeds as expected to give predominantly the terminal vinyl borane[
Oxidation under bu}ered conditions then liberates the free aldehyde group in good overall yield
ð89SC1980Ł[
The creation of acyclic molecules from cyclic ones can be a powerful method to establish relative
stereochemistry\ but it may also serve as a means of protecting reactive combinations of functionality
until a _nal deprotection step[ In this regard\ the cycloaddition of 0\2!dipoles to alkenes can represent
Bearin` a Nitro`en 34
OH

N N OH

MgBr NaBH4
O 78%
86%
N LDA
Ph3PCHCO2Me methyl crotonate

85% 67%
OH
CO2Me CO2Me
N N

Scheme 54

N i, EtMgBr, CeCl3, –100 °C to RT MeO2C N Li, NH3, –33 °C


O N O N
OMe ii, MeOCOCl, RT, 18 h OMe 92%, 95% ee
O 88%, 79% de O

O HN OMe

Scheme 55

Me
(EtO)2PO N

(50)

a useful method for the preparation of 0\2!bisheterosubstituted alkanes[ For example\ the reaction
of alkenes with nitrile oxides or nitrones leads to cyclic products which contain a masked b!amino
alcohol "Scheme 45#[ This can be released by reduction and:or ring cleavage "for reviews on 0\2!
dipolar cycloaddition reactions\ see ð80COS"3#0958Ł and ð80COS"3#0000Ł#[ In order to form the desired
amino aldehyde an additional oxidation step is required\ but this can be avoided by the use of an
enol ether rather than an alkene "Scheme 46# ð73JA4487Ł[

R4 R4
N R1 R5 N+ N
R3 R3 N O– O– R5
O O
R2
R1 R2 R1 R2

Scheme 56

The Mannich reaction to prepare b!amino carbonyl compounds is one of the best known reactions
for the preparation of amino ketones "see Section 2[92[6[0"ii##\ but it has rarely been applied to the
synthesis of amino aldehydes\ perhaps because under classical Mannich reaction conditions the
aldehyde undergoes rapid self!condensation[ The dimethylaminomethyl group can\ however\ be
introduced using an in situ!formed iminium salt and a silyl enol ether in DMSO "Equation "30##
ð79CL0102\ 71BCJ423Ł or an iminium salt and an enolate anion at lower temperature in THF ð66JA833Ł[
35 Alkyl Aldehydes

O O OMe
O O HCl, MeOH, H2, Pd(OH)2
OEt
O
93%
H H
+ O– 74%
N N NH2
Ph
O OH
Ph
OEt

Scheme 57

O-TMS NMe2
CHO
Me2NCH2NMe2
(41)
ClCH2I
71%

2[90[6[1 NHX! and NX1!functionalized Aldehydes


The reduction of nitro groups to hydroxylamines can be achieved in neutral conditions using
SmI1[ Diethyl acetals and dioxolanes adjacent to\ for example "40#\ or more remote from the
nitro group remain una}ected\ allowing this method to be used for the synthesis of protected
hydroxylamino aldehydes ð80TL0588Ł[

OEt
NO2
EtO

(51)

2[90[6[2 NY!functionalized Aldehydes


Although nitro aldehydes themselves appear to be poorly reported compounds\ a number of
routes are available for the preparation of their corresponding acetals "for a review\ see ð89OPP696Ł#[
For example\ the diethyl acetal of nitroacetaldehyde was prepared from triethyl orthoformate and
nitromethane ð70S767Ł\ and other acetals can be prepared from this by acetal exchange ð73T1088Ł[
The presence of an alkyl substituent adjacent to the nitro group results in only low isolated yields\
and so an alternative procedure has been developed which involves conjugate addition of an alkoxide
anion to a b!chloro! or b!phenylsulfenylnitroalkene "Equation "31## ð67BSB582\ 89S583Ł[ The addition
of formaldehyde dimethylhydrazone to a nitroalkene results in a spontaneous Michael addition
without the need for acid or base catalysis[ The hydrazone can be cleaved to release the aldehyde
group in excellent overall yield\ even for multifunctional systems "Scheme 47# ð81TL2580Ł[ The b!
nitroaldehyde acetals "41# can be prepared from the corresponding bromides using NaNO1 and a
cationic resin ð71JOC3939\ 76S421Ł[ Their lithium or potassium nitronate salts react with acyl imi!
dazoles to give a variety of more complex systems "Equation "32##[ In fact\ the acetals "41# act as a
typical nitronate anion in the nitro aldol reaction with aldehydes[ The resulting 1!nitro alcohol can
be oxidized to the a!nitro ketone ð73T2798Ł[ The parent aldehyde 2!nitropropanal can be formed
from the acid!catalysed conjugate addition of nitrite to acrolein[ It can be isolated and stored for
several weeks without decomposition and converted as required into a variety of carbonyl!protected
derivatives ð75S424Ł[ Nitro groups have been demonstrated to be stable to a number of oxidative
cleavage conditions "Equations "33# and "34##\ and\ hence\ such methods are appropriate for the
synthesis of nitro aldehydes ð74TL5158\ 75JOC143Ł[
Bearin` a Nitro`en 36
NO2
PhS Et EtO–, THF BnO (42)
NO2 77%
OBn

NMe2
N
NMe2 OAc OAc OAc OAc
i, O3
N H + AcO NO2 AcO NO2
91% ii, Me2S
H OAc OAc OAc OAc 85%
enantiomeric selectivity 3.6 : 1

OAc OAc CHO


AcO NO2

OAc OAc

Scheme 58

OR1 i, LiOEt NO2 OR1


(43)
ii, O
O2N OR1 EtO2C OR1
EtO N N
(52)
91%

NO2 O OMe
i, O3, Me2S TBDPS-O
(44)
TBDPS-O
ii, MeOH, H+
76%
O2N
OH

O CHO
OH O
O2N NaIO4
CHO (45)
92% O2N
BnO OH
OBn

The conjugate addition of any nucleophile to an a\b!unsaturated aldehyde is complicated by the


instability of the enal and a ready polymerization driven by the intermediate aldehyde enolate[ This
situation is compounded for primary nitronate anions by the possibility of the addition of a second
molecule of the enal to the initial adduct[ Because of this\ there has been considerable interest in
the development of new procedures for the controlled Michael addition of nitroalkanes to enals[
One procedure which works well\ even for acrolein\ is done in the absence of solvent ð75S126\
75S0913Ł[ An aldehyde enolate has been shown to attack a nitro enamine in a conjugate additionÐ
elimination procedure "Equation "35##[ The intermediate nitroalkene was relatively unstable and so
was reduced immediately with the Hantzsch ester ð76S618Ł[ This reduction of oxonitroalkenes has
been shown to be generally applicable ð77BCJ3918Ł[

CHO
CHO NO2
N i, LDA, –78 °C to 0 °C NO2
+ (46)
O ii, reduction
55%

Among the more unusual nitrogen!substituted aldehydes that have been prepared\ a\a!
disubstituted aldehydes react\ via their silyl enol ethers\ with NOCl to give a!nitroso aldehydes[ The
products are stable at 9>C but dimerize at higher temperatures and decompose on silica gel
ð63JOC1447Ł[
Diazoacetaldehyde dimethyl acetal can be prepared from the corresponding amino compound
ð56CB0380Ł[ A more general procedure\ and one which gives the free diazo aldehyde\ involves the
reaction between a b!amino a!substituted enal and p!TsN2\ which may proceed via the intermediate
37 Alkyl Aldehydes
triazoline "Scheme 48# ð69CCC2507\ 60OPP116Ł[ The chemistry of diazo compounds has been the
subject of a monograph ðB!75MI 290!91Ł[

R2R3N R1
CHO p-TsN3 CHO R1 CHO
R2R3N
R1 N N N2
Ts N

Scheme 59

The addition of nucleophiles to a\b!epoxy sulfoxides to generate a!amino aldehydes has already
been mentioned "see Equation "39##\ and a similar approach using NaN2 and a\b!epoxy sulfones
has been used to introduce an azide group at the a position ð67JOC1955Ł[ Oxidative cleavage of
alkenes and 0\1!diols are well!known routes to aldehydes\ and the azide group has been shown to
survive both transformations ð80JOC2738\ 82TL392Ł[ Azide is\ in fact\ a relatively powerful nucleophile
which attacks enals at the b position to give b!azido aldehydes or b!azido acetals "Equation "36##
ð40JA4137\ 78JA2813\ 80JOC2480Ł[
O OH
CHO NaN3, AcOH
BzO
(47)
BzO
OH 95%
N3

2[90[7 ALDEHYDES BEARING A PHOSPHORUS\ ARSENIC\ ANTIMONY OR BISMUTH


FUNCTION

2[90[7[0 XR1\ X¦R2!functionalized Aldehydes


The use of phosphonium salts for the construction of alkenes\ via the Wittig reaction\ explains
the vast amount of literature dealing with the synthesis and reactions of these species and their
derived ylides[ Such a body of literature cannot be covered comprehensively here\ but other reviews
are available ð77CSR0\ 78CRV752\ 80COS"5#060\ B!83MI 290!90Ł[ The most common methods for the
synthesis of formyl!substituted phosphonium salts\ or compounds in which the formyl group is
protected as an acetal\ are the treatment of the appropriate halides with trialkyl phosphines\ and
the formylation of phosphonium ylides[
Phosphonium salts are not the only species which participate in Wittig!type reactions\ as arsonium
ylides have attracted some attention[ A number of factors are responsible for this interest[ Arsonium
ylides are\ in many cases\ more reactive than the corresponding phosphonium ylides for the for!
mation of double bonds\ and can be used to generate alkenes where phosphonium ylides fail[ Also\
depending on the nature of the arsonium ylide\ the predominant product may be an epoxide "42#\
an outcome that is only rarely observed using phosphonium ylides\ or an alkene "43# "Scheme 59#[
In general\ stabilized arsonium ylides give alkenes whereas nonstabilized ones give epoxides\ the
products being predominantly or exclusively trans in each case[ For semistabilized ylides\ the choice
of solvent and base dictates the product ratio[ The nonvolatile nature of arsonium salts and their
ylides means that extreme precautions during their handling and use are not essential\ although if
their preparation involves the use of arsines then these should be considered as extremely hazardous[
R2CHO + R2CHO O
R1 Ar3As R1 R1
R2 R2
R1 = CO2Et R1 = alkyl

(54) (53)

Scheme 60

The preparation of simple arsonium salts is the same as for phosphonium salts involving dis!
placement of a halide by an arsine[ Thus\ triphenylarsonium acetaldehyde "44# has been prepared
in 89) yield from the reaction between triphenylarsine and bromoacetaldehyde ð74TL5336\ 77TL2838Ł\
and the arsines "45# and "46# are also known ð75TL3472\ 78TL068Ł[ Arsonium ylides stabilized by two
Bearin` a P\ As\ Sb or Si 38
carbonyl groups\ "i[e[\ "47## can be prepared directly from the condensation of an arsine oxide with
a 0\2!dicarbonyl compound[ Reviews on arsonium ylides have been published ð76CSR34\ B!89MI 290!
91Ł[

O O
+ + +
Ph3As CHO Ar3As CHO Ar3As OPri –
R R
+
OPri AsPh3
(55) (56) (57) (58)

2[90[7[1 Higher!coordinated Phosphorus!\ Arsenic!\ Antimony! or Bismuth!functionalized Aldehydes


The synthesis of formyl!substituted phosphonates has not attracted as much attention as the
corresponding keto phosphonates^ nevertheless\ a number of methods have been developed for their
synthesis "for an early review\ see ð62RCR427Ł#[ The most direct and attractive method may be the
formylation of alkyl phosphonate anions with HCO1Et ð76TL394Ł or DMF[ The latter has been
used for the synthesis of a variety of derivatives "Scheme 50#\ least successfully for a!unsubstituted
compounds "R0 H#\ but more so using mono! or disubstituted phosphonates[ The intermediate
alkoxide is stabilized by chelation\ and\ in one case\ the enamine "48#\ arising from dehydration\ has
been isolated ð72S523\ 73JOM"153#8\ 78TL3676Ł[ Enamines derived from formyl phosphonates can be
prepared directly by phosphonylation of the t!butylimine of acetaldehyde using diethyl chloro!
phosphate "Equation "37## ð67JOC2677Ł or by condensation of a formyl phosphonate with an amine[
In the latter case\ further methylation or benzylation of the magnesium salt occurs exclusively on
carbon "Scheme 51# ð58JCS"C#359Ł[ The parent compound for this class\ formylmethyl phosphonic
acid "59#\ is a known compound ð58JOC644Ł[
Li
O O O O
BunLi then DMF H3O+
P R1 P P CHO
R2O R2O NMe2 50–90% R2O
R 2O R2O R1
2
R O R1

Scheme 61

O
P
PriO NMe2
i
Pr O
(59)

O
i, LDA, –78 °C
P (48)
NBut EtO NHBut
ii, (EtO)2POCl EtO

O O O
cyclohexylamine i, EtMgBr
P CHO P c-C6H11 P c-C6H11
EtO EtO N EtO N
75% ii, MeI
EtO EtO EtO
H 40% H

Scheme 62

O
P CHO
HO
HO
(60)
49 Alkyl Aldehydes
The attack of phosphorus"III# nucleophiles at imines or halides has been used to prepare formyl!
substituted phosphonates[ Addition to the former "Equation "38## has been demonstrated to give
high yields of adducts\ and to occur chemoselectively in the presence of aldehydes and ketones
ð89T6064Ł[ In the latter\ the substitution occurs with bromoacetaldehyde diethyl acetal and also with
2!bromopropionaldehyde diethyl acetal\ where substitution at the a or b positions of the acetal is
tolerated[ Additional substituents can then be introduced by alkylation adjacent to the phosphonate
group "Equation "49## ð70T0266Ł or by a Mannich reaction to give intermediates to a range of
heterocycles "Equation "40## ð74T316Ł[ The Arbuzov reaction of trialkyl phosphites with a!halo
aldehydes cannot be used as a method for the preparation of formyl phosphonates due to the
predominance of two competing reactions "Scheme 52# ðB!77MI 290!90Ł[

PO(Ph)OBu
BuO(Ph)PO-TMS
EtO Bn EtO Bn (49)
N N
81%
OEt OEt H

O O
i, BunLi
P OEt P OEt (50)
EtO EtO
EtO ii, EtI EtO
OEt 70% Et OEt

O O
P CHO DMF, heat P CHO
EtO EtO (51)
EtO EtO
NMe2

O-TMS
P(O-TMS)3 R1 CHO P(OR2)3
R1 R1
PO(O-TMS)2 OPO(OR2)2
X
X

Scheme 63

In a reaction related to that shown in Scheme 50\ the b!keto esters "50# undergo a further
formylation via their a\g!dianions to give "51# ð81SC108Ł[ Aldehyde enolates react from the a position
with diethyl chlorophosphite\ and exposure of the adducts to air gives the phosphonates "Scheme 53#
ð80JOC4445Ł[

O O O O
P R2 P CHO
EtO EtO
EtO EtO
R1 R1 R2
(61) (62)

O OK O
KH i, ClP(OEt)2

ii, air
41% PO(OEt)2

Scheme 64

Treatment of the vinylphosphonium salts "52# with ethoxide had been postulated to give the
ylides "53#\ but a re!examination of the evidence has lead to the reassignment of the products as the
phosphine oxides "54# "Scheme 54# ð81TL750Ł whilst similar products can be made from the addition
of phosphorus halides to ethyl vinyl ether ð76JGU192Ł[ The presence of a chlorine on the epoxide
"55# directs nucleophilic attack by trialkyl phosphites to the b position[ A carbonyl group is formed
by a 0\0!elimination of chloride\ which then proceeds to promote an Arbuzov reaction to give "56#
ð71CB590Ł[
Bearin` a Metalloid 40
R1 +PPh
3 P(O)Ph2
OEt NaOEt NaOEt
Ph3P R1 R1
OEt OEt OEt
(64) (63) (65)

Scheme 65

O Cl R1 CHO

R1 PO(OEt)2
(66) (67)

Among the methods that have been developed to deliver a phosphorus nucleophile to the b
position of an enone "see Section 2[92[7[1"ii##\ very few have been reported as being e}ective for
enals\ and those that are tend to give 0\1 adducts also[ One approach that does work involves simple
mixing of diethyl methyl phosphinate with an enal to give "57# ð77JOC3958Ł[

O
EtO P
Me
EtO OEt
R2 R1
(68)

2[90[8 ALDEHYDES BEARING A METALLOID FUNCTION

2[90[8[0 Silicon!functionalized Aldehydes*a!silyl Aldehydes

2[90[8[0[0 From alcohols


b!Hydroxy silanes\ which may be conveniently prepared by the reaction of an organocopper
reagent with an a!epoxy silane ð82TL2584Ł\ can be oxidized to a!silyl aldehydes with tetra!
kis"triphenylphosphine#rhodium hydride in the presence of an enone as a hydrogen acceptor
ð74TL3118Ł\ or using Swern conditions ð82TL2584Ł[ The TFA!mediated silapinacol rearrangement of
a\b!dihydroxy silanes has been found to provide a general route to a!t!butyldimethylsilyl aldehydes[
Because of the stabilization of cations b to silicon and the good migratory aptitude of silyl groups\
the reaction is both regiospeci_c and high!yielding "Equation "41## ð75TL3158Ł[

HO OH TBDMS
TFA
(52)
86%
n-C6H13
TBDMS n-C6H13
O

2[90[8[0[1 From aldehydes or ketones


Homochiral trialkylsilyl aldehydes can be prepared by the reaction of metallated "S#!"−#! or "R#!
"¦#!0!amino!1!methoxymethylpyrrolidine!derived aldehyde hydrazones with t!butyldimethylsilyl
tri~ate\ followed by hydrolysis[ Although the overall yields of the sequence are quite modest\ the
enantiomeric excesses of the products are excellent "Scheme 55# ð76AG"E#240Ł[
41 Alkyl Aldehydes

O O3 O
N i, LDA N
SAMP Ph
OMe N OMe
N 42% overall, >96% ee
ii, TBDMS-OTf TBDMS
Ph TBDMS
Ph Ph

Scheme 66

2[90[8[1 b!Silyl Aldehydes


b!Trialkylsilyl aldehydes can be prepared by the conjugate addition of trialkylsilyl cuprates to
enals\ although relatively few examples have been reported[ Conjugate additionÐenolate trapping is
also possible and proceeds with high diastereoselectivity "Equation "42## ð73CC17Ł[
O i, (PhMe2Si)2CuLi PhMe2Si O PhMe2Si O
ii, MeI
+ (53)
Ph 74%
Ph Ph

92 : 8

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.02
Aldehydes: a,b-Unsaturated
Aldehydes
WARREN J. EBENEZER and PAUL WIGHT
ZENECA Specialties, Manchester, UK
2[91[0 ALDEHYDES BEARING AN a\b!ALKENIC BOND 43
2[91[0[0 a\b!Unsaturated Aldehydes Without Further Unsaturation 43
2[91[0[0[0 By elimination reactions 43
2[91[0[0[1 By oxidations of alcohols and their equivalents 46
2[91[0[0[2 Oxidation of allylic methyl `roups 47
2[91[0[0[3 By formylations of alkenes 47
2[91[0[0[4 By rearran`ements of a!acetylenic alcohols 48
2[91[0[0[5 By displacements of b!leavin` `roups 48
2[91[0[0[6 By aldol condensation reactions 48
2[91[0[0[7 By Witti` reactions 59
2[91[0[0[8 By DielsÐAlder reactions 50
2[91[0[0[09 By isomerisations 50
2[91[0[0[00 By reductions 50
2[91[0[0[01 From epoxides 51
2[91[0[0[02 Miscellaneous methods 51
2[91[0[1 a\b!Unsaturated Aldehydes With Further Unsaturation 51
2[91[0[1[0 By elimination reactions 51
2[91[0[1[1 By formylations of dienes 53
2[91[0[1[2 By oxidations of alcohols and reductions of acids 53
2[91[0[1[3 By rin` openin` reactions of pyrilium salts and furans 53
2[91[0[1[4 By Witti` reactions 54
2[91[0[1[5 From cyclopropanes 54
2[91[0[1[6 Miscellaneous reactions 55
2[91[0[2 Halo`enated a\b!Unsaturated Aldehydes 55
2[91[0[2[0 1!Halo`enated a\b!unsaturated aldehydes 55
2[91[0[2[1 2!Halo`enated a\b!unsaturated aldehydes 57
2[91[0[3 Oxy`en Substituted a\b!Unsaturated Aldehydes 60
2[91[0[3[0 1!Oxy`en substitution 60
2[91[0[3[1 2!Oxy`en substitution 60
2[91[0[4 a\b!Alkenic Aldehydes with Sulfur Substituents 61
2[91[0[4[0 1!Thio a\b!unsaturated aldehydes 61
2[91[0[4[1 2!Thio a\b!unsaturated aldehydes 61
2[91[0[5 Selenium Substituted a\b!Unsaturated Aldehydes 63
2[91[0[6 Nitro`en!Substituted a\b!Unsaturated Aldehydes 63
2[91[0[6[0 a!Nitro`en substituted a\b!unsaturated aldehydes 63
2[91[0[6[1 b!Nitro`en substituted a\b!unsaturated aldehydes 64
2[91[0[7 a\b!Alkenic Aldehydes with P\ As\ Sb\ or Bi!based Substituents 66
2[91[0[8 a\b!Alkenic Aldehydes with Si!based Substituents 66
2[91[0[09 a\b!Alkenic Aldehydes with Metal Substituents 67
2[91[1 ALDEHYDES BEARING AN a\b!TRIPLE BOND 67

42
43 a\b!Unsaturated Aldehydes
2[91[0 ALDEHYDES BEARING AN a\b!ALKENIC BOND

2[91[0[0 a\b!Unsaturated Aldehydes Without Further Unsaturation

2[91[0[0[0 By elimination reactions

"i# By oxidative elimination of H1


Aldehydes can be oxidised to a\b!unsaturated aldehydes in a palladium promoted dehydro!
genation "Equation "0## ð72CL0196Ł[ The conditions in this reaction are such that ketones are not
a}ected[ Silyl enol ethers of aldehydes can be oxidised to enals with lead tetraacetate ð72T750Ł\ and
enols can be oxidised to a\b!unsaturated aldehydes by 1\2!dichloro!4\5!dicyano!0\3!benzoquinone
"ddq# ð55TL3002\ 56CRV042Ł[

PdCl2(PhCN)2
N-methyl morpholine
O AgOTf, THF O
O O (1)
62%

"ii# By elimination of halide from a!halo aldehydes


a!Halo aldehydes give a\b!unsaturated aldehydes when treated with base[ The a!halo aldehydes
themselves are often made by halogenation of the aldehyde "Equation "1## ð38JCS626Ł[ The reaction
works best in cases where over halogenation is not possible*i[e[\ where only one a!hydrogen is
present\ but even in these cases side reactions can lower the yield in the elimination step[ "For further
examples see ð46JA345\ 52MI 291!90Ł[# A more convenient procedure seems to be to _rst convert the
aldehyde to its imine\ then chlorinate\ eliminate and hydrolyse to give the product "without isolation#
ð89BSB30Ł[ Alternatively\ the enol acetate can be brominated and undergoes elimination to give
good yields of the enal ""E# stereochemistry# "Equation "2## ð68S496Ł[ a\b!Unsaturated aldehydes
can be prepared from ketones in a 0!carbon homologation\ the _nal step of which is elimination of
HCl from an a!chloro aldehyde "Equation "3## ð62TL1354\ 89JCS"P0#0890Ł[

O O
i, Br2, CaCO3, CHCl3
ii, PhNEt2, 100 °C
(2)
77%

i, NBS, CCl4 O
ii, NaOH, MeOH
OAc (3)
n-C5H11 n-C4H9
86%

i, THF, -95 °C
Cl ii, LiClO4, CaCO3, 130 °C
+ Li O (4)
O Cl 74%

"iii# By elimination from alkoxy enol ethers and thioenol ethers


Corey et al[ have developed a synthesis of a\b!unsaturated aldehydes which involves\ e}ectively\
the hydrolysis and elimination of thioether groups from "a#\ which are themselves prepared from
bismethylthio allyl anion "Scheme 0# ð60JA0613Ł[ Julia and co!workers have used the facile hydrolysis
of allylic alkoxy thioenol ethers in a synthesis of a\b!unsaturated aldehydes ð72TL3714Ł\ whereas
Trost has used the hydrolysis of allylic thioenol alcohols "Equation "4## in a scheme that e}ects a
1!carbon homologation of ketones ð64JA3907Ł[ "For related examples see ð64S616\ 68TL1798\
71TL3720Ł[# The starting materials for this scheme can also be made by the addition of thiophenol to
a\b!Alkenic Bond 44
propargylic alcohol "Equation "5## ð73TL078Ł[ The corresponding enol ethers can also be hydrolysed
"Equation "6## ð66CL234\ 72TL3718\ 78JOC1668Ł[

SMe
Li+ HgCl2, MeOH, H2O O
n-C5H11Br + – n-C5H11
MeS SMe 84% n-C5H11
SMe
(a)

Scheme 1

HgCl2
HO (5)
66%
SPh O

i, PhSH
ii, H+ O
HO (6)
60%

SPh
i, HCl, H2O, MeCN
ii, HgCl2, HCl O
Ph (7)
98% Ph
OMe

"iv# By elimination from b!hydroxy and alkoxy aldehydes


Many methods have been described for e}ecting the elimination to unsaturated aldehydes from
alkoxy and hydroxy aldehydes\ often with the aldehyde group _rst being protected as an acetal[
Direct methods include the use of acid catalysts\ for example\ H2PO3 "Equation "7## ð48CB0453Ł\ or
base\ for example\ 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# "Equation "8## ð60JOC255Ł[ Acids such
as formic acid or 1) HCl have often been used to simultaneously eliminate and remove the
acetal "Equation "09## ð38JA2357\ 70S026Ł[ For related reactions see ð51CR"144#0016\ 62CC008Ł[ The
transformation of b!ketoaldehydes to a\b!unsaturated aldehydes can be performed by _rst protecting
the aldehyde group as an enol ether\ then reducing the ketone to a hydroxy\ followed by an
eliminationÐdeprotection step to give the product\ for example\ Equation "00# ð40HCA617\ 75TL1460\
77HCA057Ł[ Elimination from b!hydroxy substituted aldehydes made from epoxides is also known
"Equation "01## ð67TL4064Ł[ Parsons has described the synthesis of enals as outlined in Scheme 1
ð70TL1910Ł\ which involves a rearrangement and hydrolysis reaction\ i[e[\ an allylic elimination[
Formation of a mesylate from a b!hydroxy aldehyde\ followed by elimination using dbu has also
been used ð70JA3486Ł[

O O

OH H3PO4
(8)
89%

H H
OH OH

OAc
dbu EtO
EtO O (9)
O
77% EtO
EtO
dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene
45 a\b!Unsaturated Aldehydes
OEt
HCO2H, HCO2Na, H2O, 100 °C
EtO O (10)
82%
EtO

i, TMS-Cl, Et3N Ph
O OH ii, PhCH2MgCl O
iii, p-TsA, pyr
(11)
65%

i, LDA, HMPA
O ii, (CO2H)2
+ Et2N CN n-C5H11 O (12)
n-C5H11 50%
LDA = lithium diisopropylamide
HMPA = hexamethylphosphoramide

TMS TMS O
i, PhSCl, Et3N
OH LiAlH4 OH ii, AgNO3, H2O

68%

Scheme 2

"v# By elimination of selenoxides


The a!selenation of aldehydes\ followed by oxidation to the selenoxide and elimination is less well
known than with ketones\ but can be a useful route to a\b!unsaturated aldehydes\ especially where
the aldehyde is already a!substituted "Equation "02## ð71JOC0507\ 78JOC3234Ł[ The aldehyde can be
formed by a sigmatropic rearrangement of an allylic selenium compound as in Equation "03#
ð71JOC0507Ł[

O O O O
H i, PhSeCl, pyr
ii, H2O2
(13)
100%
H H

i, LDA, THF
ii, ketone
iii, H2O2
+ OH (14)
PhSe SePh
77% O
O

"vi# By elimination of sulfones


Elimination of b!sulfonyl aldehydes can give excellent yields of a\b!unsaturated aldehydes "Equa!
tion "04## ð64BSF0252Ł[ The sulfone can be made by oxidation of the sul_de with NaIO3 ð68TL1068Ł\
or ozone\ in which case the aldehyde group can be made simultaneously by ozonolysis of a double
bond "Equation "05## ð71JA3886\ 71TL1288Ł[ For an example of alkylation a to the sulfone of a
b!sulfonyl acetal\ followed by elimination and deprotection see ð64TL0996Ł[
a\b!Alkenic Bond 46
PhSO2 O Na2CO3, EtOH n-C6H13 O
(15)
n-C6H13 99%

i, O3, –78 °C
O SPh ii, Me2S
O
iii, CCl4, 70 °C
O (16)
66%

"vii# Miscellaneous reactions


a!Epoxy aldehydes undergo an elimination type reaction to a\b!unsaturated aldehydes "Equation
"06## ð76TL1988\ 78TL2582Ł[ The a!epoxy aldehydes can be made from the reaction of an arsonium
ylide with a carbonyl compound "Equation "07## ð78TL068Ł[ See ð71JOC4906Ł for an example of
elimination of nitrous acid from a b!nitro aldehyde\ and ð70ACS"B#532\ 73TL4244Ł for ring opening
and elimination from isoxazolidines leading to enals[

OH i, (COCl)2, DMSO O
ii, Et3N
iii, Ac2O, pyr
(17)
O 70%
AcO AcO OAc
H

O OH
OEt O
+ – + (18)
Ph3As OEt 58%

2[91[0[0[1 By oxidations of alcohols and their equivalents


The oxidation of primary allylic alcohols to a\b!unsaturated aldehydes is one of the commonest
methods of preparing this functional group[ There are a very large number of reagents with varying
selectivities[ One of the mildest is manganese dioxide "e[g[\ Equation 08#\ ð57JA4505\ 64S142\ 65S022Ł[
Other reagents include pyridinium chlorochromate "pcc# ð64TL1536Ł\ sodium dichromate ð68JA6020Ł\
oxalyl chloride:DMSO "Swern oxidation# ð75OS"53#053Ł\ pyridinium sulfonate:DMSO ð56JA4494Ł\
silver carbonate:celite ð64JCS"P0#0346Ł\ and use of nitroso compounds ð30HCA0928\ 75CL1924Ł[ Various
transition metal catalysed systems have also been described\ for example\ Cp1ZrH1 ð70JOC139Ł\ and
RuH1"PPh2#3 ð75TL0794Ł[ For a list of reagents see ðB!78MI 291!90Ł[ The oxidation of allylic tertiary
alcohols can lead to a\b!unsaturated aldehydes\ although generally a mixture of "E#:"Z# isomers is
obtained "e[g[\ Equation "19## ð66JOC571\ 66JOC702\ 68S245Ł[ Nef reactions of allylic nitro compounds
to give a\b!unsaturated aldehydes have been reported "Equation "10## ð67AG"E#347\ 76S068Ł[ The
oxidation of allylic thioamides by deprotonation\ capture of the anion with a sulfur electrophile
and deprotection has been used to give "E#!a\b!unsaturated aldehydes "Equation "11## ð63TL2514\
66TL1314Ł[ The Pummerer rearrangement can be used to prepare enals ð77SC0894Ł[ Allylic iodides
can be oxidised to a\b!unsaturated aldehydes with DMSO:base "the Kornblum reaction# "Equation
"12## ð61TL1632\ 68CJC534\ 73S597Ł[ Allylic halides can also be oxidised with other reagents\ notably
potassium dichromate ð65CC089Ł\ N!ethyl morpholine oxide ð75BCJ2176Ł and nitrocyclohexane
ð48JGU2814Ł[ See also ð71CL0876\ 72TL666Ł for oxidations of other allylic compounds[

MnO2, hexane, 0 °C
(19)
OH 97%
O
47 a\b!Unsaturated Aldehydes

OH pcc, 25 °C
(20)
90% O
pcc = pyridinium chlorochromate

i, 3M NaOH
ii, H2SO4
NO2 O (21)
68%

i, LDA, THF
ii, Me2S2
S iii, HgCl2, H2O
n-C5H11 O (22)
n-C5H11 S NMe2 78%

DMSO, NaHCO3, 130 °C


Ph I Ph O (23)

2[91[0[0[2 Oxidation of allylic methyl groups


Selenium dioxide can give good yields of enals from the corresponding methyl alkene ð78CI"L#422Ł[
The reaction gives the "E#!enal "Equation "13## ð60JA4200Ł\ and the most electron!rich double bond
is usually that which is oxidised allylically ð76T3370Ł[

SeO2, EtOH, 50 °C
MeO2C MeO2C O (24)
48%

2[91[0[0[3 By formylations of alkenes


Vinyl silanes can be formylated with dichloromethyl methyl ether "Equation "14## ð67CL748Ł\
usually with TiCl3 as the catalyst[ The reaction proceeds with retention of con_guration but the
products isomerise to the "E#!enals under the reaction conditions ð66S610\ 66TL2206\ 73S880Ł[ Vinyl
lithium or magnesium species undergo formylation to enals with electrophiles such as DMF
ð74JCS"P0#336\ 75RTC55Ł\ methyl formate ð70TL0326Ł and N!methyl!N!formyl!1!aminopyridine "Equa!
tion "15## ð67S392Ł[ Vinyl lithium species have been formed in situ by a Shapiro reaction\ and can
then be trapped by DMF "Equation "16## ð68S33\ 70JOC0204Ł[ Vinyl iodides can be formylated with
carbon monoxide to give good yields of enals\ using a palladium catalyst\ followed by a reduction
"one!pot# "Equation "17## ð72JA6064Ł[
i, TiCl4, CH2Cl2, –78 °C
Cl ii, H2O
+ MeO (25)
79% O
TMS Cl

HCl, 0 °C O
MgBr + Me (26)
Ph N N 70% Ph
CHO

Pri Pri
i, BusLi
O2S ii, DMF
O (27)
N Pri 56%
N H

i, Pd(PPh3)4
O ii, Bu3SnH, toluene O
+ CO (28)
I 83% CHO
a\b!Alkenic Bond 48
2[91[0[0[4 By rearrangements of a!acetylenic alcohols
Although a!acetylenic alcohols would normally rearrange to a\b!unsaturated ketones with acid
catalysts "see Section 2[94[0[0[6#\ alternative conditions have been found that give a\b!unsaturated
aldehydes[ This is e}ectively the anti!Markovnikov hydration of the alkyne[ The commonest reagent
is "Ph2SiO#VO and the reaction is proposed to go through a vanadate ester\ as in Scheme 2 ð65S14Ł[
For other examples see ð74TL4474\ 89TL6410Ł[

OSiPh3
OH Ph3SiO V
O
O
O
H (Ph3SiO)3VO, 146 °C
O
91% H
H H
O H H
O

O
H

H H
O

Scheme 3

2[91[0[0[5 By displacements of b!leaving groups


b!Alkoxy ð74SC260Ł\ silyloxy ð75CB0626Ł\ and dialkylamino ð75TL1460Ł enals can be treated with
nucleophiles to give carbon substituted a\b!unsaturated aldehydes\ for example\ Equation "18#
ð76S0Ł[ The chlorine of b!chloroenals can be removed with a Zn:EtOH reduction ð61CPB298Ł[

i, BuLi S
EtO O + (29)
S S O
ii, H+ S

2[91[0[0[6 By aldol condensation reactions


Probably the most important and versatile route to a\b!unsaturated aldehydes is the aldol con!
densation^ the reaction of the enol or enolate of an aldehyde with a second activated carbonyl\
followed by dehydration of the resulting adduct[ This is commonly observed intramolecularly with
0\5!dialdehyde systems to yield cyclopentenals "Equation "29## ð77JOC0512Ł "also see ð38JA2209\
42JA273\ 70HCA0039Ł#\ the 0\5!dialdehyde often being generated by the oxidation of a diene or cyclic
alkene ð65CL18\ 70TL0910\ 77S586Ł[ 0\6!Dialdehydes behave similarly ð62TL1298\ 76TL0782\ 78TL4250Ł[
The regioselectivity of the intramolecular aldol reaction can be controlled by the conditions used
"Equation "20## ð70CPB655\ 73JA3447Ł or by the use of an enamine or similar group ð76HCA334Ł[

CHO CHO

OHC O piperidinium acetate


PhH, 80 °C
(30)
77%

H H
59 a\b!Unsaturated Aldehydes
CHO
TiCl4, PhNH2Me•O2CCF3
(31)
50% O
O O CHO

Intermolecular aldol condensations are equally facile occurring under a range of conditions
"Equation "21## ð40HCA0371\ 57JOC664\ 64JCS"P0#0416\ 66JOC1012Ł[ The control of the regio chemistry
for unsymmetrical condensations can be achieved by the use of enol ethers and enamines ð66JA6254\
76JOC3677\ 77TL3606Ł or a!lithioimines and a!lithiohydrazones ð58JOC0011\ 65TL6\ 67JOC2677Ł[ The
Mannich reaction\ followed by elimination of the b!amino group from the intermediate Mannich
base\ is closely related to the aldol condensation and is often used to prepare a!methylene!aldehydes
ð32CB0379\ 72TL0060\ 78CL0172Ł[

C5H11
H2BO2, m-xylene, 138 °C
C6H13CHO C6H13 (32)
100% CHO

2[91[0[0[7 By Wittig reactions


The Wittig reaction is also a well used reaction in the synthesis of a\b!unsaturated aldehydes[ The
major route to these systems involves the reaction of a formyl phosphorane with an aldehyde and
generally leads to the "E#!isomer stereoselectively "Equation "22## ð81TL3942Ł^ see also ð63JCS"P0#26\
68S155\ 73JA159\ 77SC0802Ł[ The corresponding stabilised arsonium ylides have also been investigated
ð76JOC2447Ł[ An analogous WadsworthÐEmmons type Wittig reaction can be achieved using the
phosphonate "0#^ this has the added advantage of allowing reaction with ketones which are too
stable to react with a!formyl phosphoranes "Equation "23## ð57TL3248\ 76JOC3936Ł[ The use of the
phosphorane "1# also leads cleanly to a\b!unsaturated aldehydes after hydrolysis of the enol ether
"Equation "24## ð66TL2764Ł[ The Peterson alkenation is a related reaction enabling the preparation
of a\b!unsaturated aldehydes from lithiated a!silylimines and aldehydes "Equation "25## ð74TL1280\
78TL4124Ł[

Ph3P CHO PhH, reflux


CHO + CHO (33)
O 55% O

i, NaH CHO
O H O ii, H3O+
N 25 °C
(OEt)2P + (34)
86%

(1)

+ Ph CHO O
Ph3P OMe Ph (35)
(2)

TES i, THF, –20 °C


TBDMS-O Li TBDMS-O
N ii, TFA, 0 °C
+ (36)
MeO iii, H2O, 0 °C MeO
CHO CHO

TBDMS = t-butyldimethylsilyl
a\b!Alkenic Bond 50
2[91[0[0[8 By DielsÐAlder reactions
The DielsÐAlder reaction enables the synthesis of cyclic a\b!unsaturated aldehydes via the use of
formyl substituted diene systems ð71TL1700\ 78CB474Ł or alkynic aldehydes "Equation "26## ð70TL514\
72AG"E#309\ 76JOC3024Ł[

OAc OAc

70 °C
CHO + (37)
89%
OHC
OAc OAc

2[91[0[0[09 By isomerisations
The isomerisation of bg!unsaturated aldehydes also furnishes a\b!unsaturated aldehydes and can
occur under acidic ð68S021\ 76JCR"S#185Ł or basic conditions ð79HCA0554Ł[ The isomerisation of
propargylic ethers to allenic ethers followed by hydrolysis similarly furnishes a\b!unsaturated alde!
hydes "Equation "27## ð54RTC20\ 61TL0704Ł[ g!Hydroxy!a\b!unsaturated aldehydes can be prepared
by the deprotection and hydroxy!rearrangement of tertiary carbinols such as "2# "Equation "28##
ð67TL0294\ 76SC044Ł[
CHO
i, NaNH2, NH3, –33 °C
OEt ii, 5N H2SO4, 70 °C
(38)
70%

S CHO
HgO, HBF4
HO S H2O, THF, reflux
(39)
84%
OH

(3)

2[91[0[0[00 By reductions
a\b!Unsaturated aldehydes can be prepared by the diisobutylaluminum hydride "dibal!H#
reduction of a\b!unsaturated nitriles ð70JOC3706\ 70TL0068Ł or the reduction of a\b!unsaturated
acid chlorides using poor hydride donor reducing agents such as NaBH"OMe#2 "Equation "39##
ð47CB1341Ł[ In a similar fashion oxazines have been used as protected carboxylic acid equivalents
and can be reduced and hydrolysed to the aldehyde using sodium borohydride "Equation "30##
ð62JOC25\ 63JOC512Ł[ Benzoisothiazoles have been used in an analogous fashion in the synthesis of
a\b!unsaturated aldehydes\ acting as a formyl anion equivalent ð67TL4Ł[
OAc OAc
AcO NaBH(OMe)3 AcO
(40)

AcO COCl AcO CHO

OHC
CHO i, BunLi, –78 °C
ii, NaBH4, EtOH, –40 °C
iii, H3O+
O + (41)
53 °C
N
51 a\b!Unsaturated Aldehydes
2[91[0[0[01 From epoxides
Epoxides are useful intermediates in the synthesis of a\b!unsaturated aldehydes[ Thus the
DarzensÐClaisen reaction was used by Isler et al[ in the _rst synthesis of vitamin A "Scheme 3#
ð36HCA0800Ł "also see ð47JOC046Ł#[ Related reactions involve the acid catalysed rearrangement of
a!epoxy sulfoxides\ ð66TL0266\ 78JA6493Ł\ a!epoxy nitriles ð52JIC003Ł and a!epoxy silanes ð71CL0886Ł
yielding a\b!unsaturated aldehydes[ The pinacol type rearrangement of an a!hydroxy epoxide
similarly leads to an unsaturated aldehyde ð62JOC0279Ł as does the oxidation of a terminal epoxide
using sulfuryl chloride ð76TL1064Ł "Equation "31##[

O
O
NaOEt, –10 °C CO2Et 15% NaOH, MeOH, 5 °C
+ Cl CO2Et
80% overall

steps
CHO Vitamin A

Scheme 4

O O O O
H H H H
SO2Cl2, CH2Cl2, 39 °C
(42)
90% CHO
O
H CO2Me H CO2Me

2[91[0[0[02 Miscellaneous methods


The oxidative ring opening of furans with a variety of oxidising agents leads to unsaturated
aldehydes ð64JHC0214\ 68TL1186\ 74TL1758\ 75TL1646\ 75TL3872\ 78IJC"B#2\ 78JOC4075Ł as does the careful
ozonolysis of various dienes "Equation "32## ð62TL1306\ 64S670\ 77JA3624\ 89S0922\ 89TL4468Ł[ The use of
oxy!substituted cyclopropanes in the synthesis of a\b!unsaturated aldehydes has also been reported
ð67TL2936\ 67TL2940\ 74TL2502Ł[

O3, Na2CO3, MeOH, CH2Cl2, –78 °C CHO


(43)
71%
CO2Me

2[91[0[1 a\b!Unsaturated Aldehydes With Further Unsaturation

2[91[0[1[0 By elimination reactions


Eliminations of hydroxy or alkoxy groups b or d to an aldehyde\ usually under acidic conditions\
can give dienals[ For example\ reaction of lithium acetylide "Equation "33## with an enone furnishes
a tertiary propargylic alcohol[ Removal of the thioenol ether protecting group gives the aldehyde
function\ and under the acidic conditions the b!hydroxy group eliminates to give the mainly
"E#!unsaturated enal ð68TL1798Ł[ This reaction also works if the ketone is reduced to a secondary
alcohol with LiAlH3 "58) yield#[ Similarly\ partial reduction of an alkoxy alkyne "Equation
"34## followed by deprotection and elimination gave the "E\E#!trienal ð37RTC862Ł[ The hydroxy
compound can be made in situ from an a\b!unsaturated aldehyde and a b!lithio enol ether ð35JCS826\
70JOC2630Ł[ The elimination of a b!alkoxy group has also been used ð45HCA138Ł[ Formation of a
mesylate and elimination under weakly basic conditions has often been used\ especially in the _eld
of leukotriene chemistry "Equation "35## ð79JA0325\ 72TL3788Ł[
a\b!Alkenic Bond 52

i, Li
O ii, H2SO4
(44)
Ph
Ph SBut 98%

EtO O
OH
i, H2/Pd-BaSO4
ii, HCl
(45)
85%

O i, BuLi O
O OEt ii, MsCl, Et3N O
+ Bu3Sn (46)
iii, NaHCO3
H H H H

d!Hydroxy groups can be eliminated from a\b!unsaturated aldehyde as part of a similar procedure
that a}ords a 3!carbon homologation "Equation "36## ð89SC1872Ł[ "1"E#\3"E##!Isomers are exclus!
ively formed from aldehydes in this reaction\ whereas use of unsymmetrical ketones gives mixtures
of "1"E#\3"E## and "1"E#\3"Z##!isomers[ The 3!lithioalkoxydiene can also be made by hydro!
stannylation of an alkoxyenyne\ followed by tin:lithium exchange ð67TL606Ł[ Alternatively\ the
alkoxyenyne can be used directly "Equation "37##\ with the alkyne then being partly reduced with
LiAlH3\ followed by acid!catalysed hydrolysis and elimination ð45JCS3971Ł[ See ð47JOC0479Ł for a
similar example\ and also note ð76HCA0399Ł for an example of d!OH elimination using basic
conditions "NaHCO2:THF#[ d!Methoxy groups are often eliminated under basic conditions\ for
example\ dbu ð64CL0190\ 66BCJ0050Ł\ or NaOMe ð61CC752Ł[

TMS-O i, ButLi
ii, Aldehyde
O iii, HCl
+ Ph O (47)
Ph 72%
Br

O Li
i, aldehyde
ii, LiAlH4
iii, H2SO4
+ (48)
52%

OMe OMe

OMe

Elimination of b!sulfoxides ð67CC813Ł and sulfones ð89JCS"P0#086Ł is known\ as is elimination of


d!sulfoxides "Equation "38## ð70TL3026Ł[

Ph
S O
O O toluene/reflux
(49)
85%
53 a\b!Unsaturated Aldehydes
2[91[0[1[1 By formylations of dienes
Direct Vilsmeier formylation of dienes and trienes is possible\ especially if they are electronically
activated or electron rich\ "Equation "49## ð66TL1018Ł[ Cycloheptatriene reacts similarly ð67CL30Ł\
as do dihydropyridines "Equation "40## ð89JOC181Ł^ see ð55CB1368\ 55CB2946Ł for other examples[
The b!methyl enone in Equation "41# is formylated under similar conditions to give a good yield of
a chlorodienal ð65RTC297Ł[ Lithio dienes can also be used as the nucleophile ð65ZN"B#0543Ł[ A
vinylogous formylation a}ording a 2!carbon homologation can be achieved using b!dimethyl!
aminopropenal ð89TL0254Ł or triformylmethane ð61CB0704Ł[ Takahashi and co!workers have inves!
tigated the use of a Rh3"CO#01 catalyst to hydroformylate enynes\ producing dienals ð75TL3386\
77BCJ3242Ł[

Me POCl3, 25 °C
+
+ N (50)
Me Cl 80%

O
SiPri3
SiPri3
DMF, POCl3, CH2Cl2
(51)
Ph N 97%
Ph N
CO2Ph
CO2Ph

O Cl
DMF, POCl3, 80 °C
(52)
80%
O

2[91[0[1[2 By oxidations of alcohols and reductions of acids


Oxidation of dien!0!ols to dienals proceeds in much the same way as the oxidation to
a\b!unsaturated aldehydes without further unsaturation "see Section 2[91[0[0[1#[ Common reagents
include MnO1 ð40JCS1576\ 78JCS"P0#0828Ł\ pyridinium dichromate "pdc# "Equation "42## ð71LA0105Ł\
and DessMartin periodinane "a very mild hypervalent iodine species# ð76TL1810Ł[ Matsumoto has
used a RuCl1"PPh2#2 catalyst in the presence of O1 ð70CC896Ł[
O
HO
pdc, CH2Cl2, 20 °C
(53)
86%

Ried has investigated reduction of dienoic acids\ via the acid chlorides\ which are reacted with
2\4!dimethylpyrazole\ and subsequently reduced with LiAlH3 "Equation "43## ð48LA"511#26Ł*this
also works for vitamin A acid[
i, 3,5-dimethylpyrazole
O ii, LiAlH4 O
(54)
Cl 74%

2[91[0[1[3 By ring opening reactions of pyrilium salts and furans


Taylor and co!workers have investigated the ring opening of pyrilium salts with nucleophiles\ for
example\ Equation "44# ð56G286\ 80S219Ł[ The reaction also gives the "1"E#\3"Z## stereochemistry
a\b!Alkenic Bond 54
with phenyl acetylide and phenyl lithium ð74CC671\ 78JCS"P0#572Ł[ 1!Monosubstituted furans can ring
open to dienals when a!deprotonated "Equation "45## ð67JOC3124\ 70TL3376Ł[

Li THF, –78 °C
+ (55)
+
O 69%

i, LDA, THF
ii, NH4Cl
NHCOPh O NHCOPh (56)
O 95%

2[91[0[1[4 By Wittig reactions


The Wittig reaction provides a facile route to a\b!unsaturated aldehydes possessing further
unsaturation[ This can be achieved by the reaction of an aldehyde with two equivalents of
formylphosphorane ð70TL868Ł or by reaction of an aldehyde with the corresponding vinylogous
phosphorane "3#\ which yields a mixture of cis\trans and trans\trans products "Equation "46##
ð71TL056Ł[ The corresponding arsonium ylide has also been described ð75TL3472Ł[ The reaction of
a protected formyl phosphonium ylide with an unsaturated aldehyde followed by deprotection is
similarly known ð77SC40Ł[ The use of the more reactive WadsworthÐEmmons methodology requires
the protection of the aldehyde function on the phosphonate\ and conversion of the carbonyl to its
imine ð77ACS458Ł or acetal ð89TL2018Ł has been reported "Equation "47##[
H
H O
O CO2Me
CH2Cl2, 25 °C
OHC CO2Me + OHC (57)
PPh3
73% H
H (4)
OHC
(E),(Z):(E),(E) 4:1

O i, ButOK, THF
ii, H3O+
O O + OHC (58)
78% OHC
P(OEt)2

2[91[0[1[5 From cyclopropanes


The reaction of a!ketocarbenes with furans followed by in situ electrocyclic ring!opening of the
intermediate cyclopropane\ yields doubly unsaturated aldehyde systems\ predominantly\ as the
cis\trans isomers\ in high yield "Equation "48## ð54TL710\ 62TL1764\ 70CC09\ 72TL4074\ 73TL24\
89JCS"P0#78Ł[ The thermolysis of the isolated cyclopropanes\ giving rise to the same products\ has
also been reported ð52LA"557#08\ 62TL0524Ł[ This reaction has also been observed intramolecularly
"Equation "59## ð63TL1144\ 76HCA0318Ł\ and yields an ynenal if the carbene generated is a to the
furan system "Equation "50## ð63JOC1828\ 67JA6816\ 67JA6823\ 68JA0292Ł[

CHO
N2
S
Rh2(OAc)4, 0 °C S
N + (59)
O O 100% N
CO2CHPh2 O
CO2CHPh2
55 a\b!Unsaturated Aldehydes
N2
O
O Rh2(OAc)4, CH2Cl2, 20 °C
(60)
95%
O CHO

CO2Et CH2Cl2 OHC


O (61)
100%
N2 CO2Et

2[91[0[1[6 Miscellaneous reactions


There are relatively few examples of aldol condensations in the synthesis of a\b!unsaturated
aldehydes with further unsaturation\ probably due to problems associated with controlling the
regiochemistry ð79S787Ł[ The reaction of a!cyclocitral with benzaldehyde occurs via a vinylogous
aldolisation and leads to the aldehyde "4# in 77) yield "Equation "51## ð70JHC438Ł[ The hydrolytic
ring opening of pyridinium salts is a useful route to dienal systems such as "5# "Equation "52##
ð52AG"E#279\ 57LA"604#095\ 70T1264Ł[ Closely related reactions include the ring opening of pyridines
with thiophosgene ð63JCS"P0#0430\ 72CC63Ł and the Fujiwara reaction ð70JOC2064Ł[ Other ring opening
reactions yielding dienals as products are mainly oxidative ð66JCS"P0#0235Ł "Equation "53## ð45CB1113\
50TL619\ 56CB2061\ 68TL0596\ 71TL762Ł[ Propargylic aldehydes are reported to react with b!amino!
acrylates to give d!aminodienals\ in the same way as propargylic ketones "Equation "54## ð46CB1154Ł[
Allylic propargylic tertiary alcohols can isomerise to dienals under acidic conditions ð45JOC527Ł[

CHO
CHO PhCHO, 37% HCl, 20 °C
(62)
88%

Ph
(5)

O2N NO2

+ H
N N
HO–
NO2 (63)
73%

NO2 OHC
(6)

mcpba, PhH, 20 °C CHO


(64)
32% OHC
O

CO2Et EtO2C
O EtOH, 78 °C
+ (65)
90% O
H 2N NH2

2[91[0[2 Halogenated a\b!Unsaturated Aldehydes

2[91[0[2[0 1!Halogenated a\b!unsaturated aldehydes


Alkoxychloro~uorocyclopropanes can be obtained in good yield from the reaction of enol ethers\
dichloro~uoromethane and aqueous potassium hydroxide[ The resulting cyclopropane system then
a\b!Alkenic Bond 56
undergoes clean ring opening at re~ux temperature in an aqueous medium to give the 1!~uoro!1!
alkenals usually as a mixture of "E# and "Z# stereoisomers "Scheme 4# ð66HCA0628\ 74S643Ł[ The
addition of dihalocarbenes to silyl enol ethers has also been investigated and gives a!chloro and
a!bromo alkenals in high yields ð65S085Ł[
Cl F
OMe CHO

HCCl2F, KOH, H2O OMe RSO3Na, H2O F


66% 70%

Scheme 5

A second general method for the preparation of 1!~uoro!1!alkenals involves the reduction and
subsequent rearrangement of 0\0\1!tri~uoro!2!hydroxy alkenes[ Thus 0\0\1!tri~uoro!2!hydroxy!0!
alkenes "6# are prepared in good yield by the addition of tri~uorovinyllithium to carbonyl
compounds[ Nucleophilic replacement of one ~uorine atom by hydride is achieved using lithium
aluminum hydride in ether and the resulting di~uorovinyl alcohols "7# undergo rearrangement in
85) sulfuric acid at low temperature to give the ~uoro aldehyde product "8# generally as a mixture
of stereoisomers "Scheme 5# ð67S017Ł[ The use of 0!chloro!1\1!di~uorovinyl lithium in place of
tri~uorovinyl lithium in an analogous reaction yields the corresponding 1!chloro!1!alkenals in very
good overall yield ð67S347Ł[
F F
F F R1
R1 LiAlH4, Et2O 98% H2SO4
F Li R1 F R1 CHO
O
THF, Et2O R2 76–82% R2 40–69%
R2
R2 MO F MO F F
(7) (8) (9)

Scheme 6

The use of 0!bromo!1!methoxyvinyl lithium as a synthon for the bromoacetaldehyde anion


enables the synthesis of several 1!bromo!alkenals[ Thus reaction of 0!bromo!1!methoxyvinyl lithium
with acetone followed by in situ allylic rearrangement of the intermediate alcohol gave a 36) yield
of the bromo!aldehyde "09#\ "Equation "55## ð72JOC1984Ł[
MeO Li
i,
Br
CHO
ii, H3O+
O (66)
47% Br
(10)

1!Iodo!1!alkenals "00# can be prepared under mild conditions in a one!pot procedure from
acetylenic alcohols "01# using a pdc oxidation of the derived iodine complex "Equation "56##[ Yields
are good and unsymmetrical aldehydes yield a single geometric isomer as the product ð70TL0930Ł[
i, I2, RT
R1 R1 CHO
ii, pdc, RT
R2 (67)
HO 30–66% R2 I
(12) (11)

pdc = pyridinium dichromate

The substitution of a!hydrogen for a halogen in a\b!unsaturated aldehydes can be achieved by


several means[ Common reagents include molecular halogen\ via an addition elimination mechanism
for molecules where a hydrogen b to the carbonyl is the most acidic "Equation "57## ð34OS"14#81\
44OSC"2#620Ł[ Alternatively\ hypohalous acid can be used for less b!acidic cases "Equation "58##
57 a\b!Unsaturated Aldehydes
ð42OS"22#04Ł[ a!Bromination has also been noted to occur with thionyl bromide "Equation "69##\
and a radical mechanism has been proposed ð70JPR562Ł[

CHO i, Br2 CHO


ii, Na2CO3
(68)
85% Br

O O
Cl2, H2O Cl
(69)

O O
SOBr2
(70)
85%
Br

The Wittig reaction has been used to prepare a!halo alkenals ð51CB2992Ł[ The formyl methylene!
phosphorane "02# is _rst halogenated with molecular halogen to give the haloformyl methylene
phosphorane "03#[ This reacts with aldehydes in the normal manner to give the desired 1!haloalkenals
"Scheme 6#[ Preparation of the "Z#!1!bromo!alkenal "04# can be achieved stereospeci_cally from the
readily available "E#!bromoacetal "05# by formolysis accompanied by concomitant "E# to "Z#!
isomerisation in 66) yield "Equation "60## ð66S531Ł[ 1!Chloro!1\3!pentadienal "06# was formed by
the thermolysis in quinoline of the pyran "07#\ which is easily prepared from 1\2!dihydrofuran
"Equation "61## ð53T1980Ł[

X2
X PhCHO X
O
Ph3P O Ph O
X = Br, Cl Ph3P X = Br, 34%
X = Cl, 52%
(13) (14)

Scheme 7

MeO OMe i, HCO2H


ii, H2O Br
MeO2C (71)
MeO2C 77% CHO
Br
(16) (15)

Cl Cl
quinoline, 120 °C
(72)
44%
O Cl O
(18) (17)

2[91[0[2[1 2!Halogenated a\b!unsaturated aldehydes


b!Halo acroleins are not inde_nitely stable and decompose\ sometimes suddenly\ even when
refrigerated\ giving hydrogen halide and a tar[

"i# By VilsmeierÐHaackÐArnold reaction with carbonyl compounds


The VilsmeierÐHaackÐArnold reaction is the most important and widely used reaction for making
b!halo substituted a\b!unsaturated aldehydes[ The starting material is an enolisable carbonyl com!
pound which is formylated and halogenated according to the mechanism in Scheme 7 ð48CCC1267\
77CB888Ł[ Unsymmetrical carbonyl compounds possessing two enolisable sites introduce a regio!
chemistry problem ð72JOC0810Ł[ Mixtures of regioisomers are usually produced in such cases[ In
a\b!Alkenic Bond 58
addition\ mixtures of "E# and "Z# stereoisomers are often possible\ although this does not appear
to have been discussed much ð69JCS"C#1373Ł[ The simplest cases are for symmetrical\ and:or cyclic
ketones\ for example\ Equation "62# in which only a single regio! and stereoisomer is possible
ð59CB1632Ł[ Regiochemistry problems can be circumvented by introducing a nonenolisable site[
However\ in one example Katritzky et al[ have shown that SN1? attack by hydroxide can lead to
signi_cant quantities of allylic alcohols as by products "Equation "63## ð77CB888Ł[ Aromatic ketones
also react extremely well\ producing mixtures of stereoisomers "Equations "64# and "65## ð48CCC1274\
79T1014Ł[ The regiochemistry has also been shown to be strongly in~uenced by steric factors\ for
example\ in Equation "66# the ratio of product "a# ] "b# increases from 59 ] 39 for the cyclopentanone
to 099 ] 9 for the cyclooctanone ð72JOC0810Ł[ Single regioisomers can result if one of the intermediate
enols is produced preferentially "Equation "67## ð89JHC654Ł[ Phosphorus oxybromide has also been
used to make the bromo analogues*a single regioisomer in this case "Equation "68## ð66T1916Ł[
b!Dimethylamino a\b!unsaturated carbonyl compounds have also been used^ these are formal
intermediates in the VilsmeierÐHaackÐArnold reaction[ Thus\ Arnold prepared the b!chloroacrolein
"08# by halogenation and hydrolysis of "19# "Equation "79## ð48CCC1267Ł[ Alkoxy acroleins have
also been shown to react with thionyl chloride to give the b!halo unsaturated aldehydes\ with allyl
chloromethyl ether compounds "10# being the proposed intermediates "Scheme 8# ð53JGU098Ł[

Me + Me Me + Me
N N
O
R1 O O
R2 +
R1 R1
R2 R2

Me + Me
N

O Cl
Cl–, H2O
R1 R1
R2 R2

Me + CHO
N
Me

Scheme 8

CHO
DMF, POCl3
(73)
O 83%
Cl

O N Cl Cl
CHO OHC
+ (74)
POCl3
OH

O Cl
POCl3, DMF
(75)
91%
CHO

POCl3 Cl
(76)
50%
N O N CHO
69 a\b!Unsaturated Aldehydes
O Cl Cl
POCl3, DMF OHC
+ (77)
CHO
( )n ( )n ( )n
(a) (b)
n (a) (b)
1 60 : 40
2 90 : 10
3 95 : 5
4 100 : 0

Cl
O
POCl3, DMF CHO
(78)
84%

POBr3, DMF CHO


(79)
85%
O Br

O
i, ClCOCl
ii, H2O
Cl (80)
84%
NMe2 CHO

(20) (19)

O Cl Cl
SOCl2 H2O

57% overall
OMe Cl OMe O
(21)

Scheme 9

"ii# Miscellaneous
Dialkyl alkynes can be chloroformylated with dichloromethyl ether and boron trichloride
"alkenes\ however\ add twice to this reagent under these conditions# "Equation "70## ð77CB080Ł[
Again\ a mixture of "E# and "Z# stereoisomers results from this reaction[ No nonsymmetric alkynes
were considered in this paper so the regiochemistry of this reaction is unknown[ Treatment of the
trichloromethyl substituted cyclohexadienol "11# with 09) sulfuric acid at room temperature yields
the b\b!dichloroalkenal "12# in 89) yield\ "Equation "71## ð45JOC527Ł[

Cl Cl
OMe
Cl
(81)
BCl3
51%
O
a\b!Alkenic Bond 60

Cl3C

10% H2SO4
(82)
Cl
HO
Cl O
(22) (23)

2[91[0[3 Oxygen Substituted a\b!Unsaturated Aldehydes

2[91[0[3[0 1!Oxygen substitution


Few routes to a!alkoxyacroleins are known[ Williams et al[ have devised a route starting from
alcohols such as "13# via a Swern oxidation and b!elimination "Equation "72## ð76S897Ł[ The
oxidation of 1!alkoxy substituted allylic alcohols is also known ð62LA1967Ł[ Other methods include
the reaction of a dimethoxy vinyl lithium species with an aldehyde "Equation "73## ð65SC008Ł\ or
the rearrangement of propargylic esters ð89CL0694Ł[

OH
i, DMSO, (ClCO)2 O
Br O ii, Et3N
Br O (83)
79%
S
(24)

i, BunLi
ii, PhCHO
Br O
iii, HCl, H2O
(84)
MeO OMe 76% Ph OMe

2[91[0[3[1 2!Oxygen substitution


The uses of b!alkoxyacroleins in organic synthesis has been reviewed ð66S0Ł[ They are generally
prepared from enol ethers by a b!formylation reaction[ This can be achieved using Vilsmeier type
conditions\ i[e[\ POCl2:DMF "Equation "74## ð53TL622\ 60JOC599Ł or with triethyl ortho!formate:BF2
ð48HCA733\ 60CB554Ł[ Dihydropyran has been formylated by a ð1¦0Ł cycloaddition\ followed by
ring expansion and contraction reactions "Scheme 09# ð69JOC2199Ł[ Similar compounds have been
prepared by a cycloaddition reaction of vinyl ethers and malonaldehyde derivatives "Equation "75##
ð53CB0848\ 71TL0036\ 77TL1750Ł[

O
i, DMF, POCl3
ii, 5% NaOH
(85)
O Ph 58%
O Ph

O
Cl3CCO2Et Cl Cl
ButO– H+

O EtO– O Cl O OBut
O

Scheme 10
61 a\b!Unsaturated Aldehydes
Bun O Bun O

+ (86)
EtO 63%
O EtO O

The addition of alcohols to propargylic esters\ followed by reduction to the allylic alcohols
and subsequent oxidation constitutes a useful and stereoselective synthesis of 2!alkoxy acroleins
"Equation "76## ð72TL4198Ł[ 2!Alkoxy substituted allylic alcohols have also been oxidised by other
reagents\ for example\ pcc ð66CC797\ 53CB0848Ł[ Other methods reported for the synthesis of 2!oxygen
substituted acroleins are] the reaction of the corresponding 2!halo "or ammonium# acroleins with
alcohols ð66JPR0931\ 89CB288Ł and Pd catalysed oxidation of a!silyl substituted allylic tosylates
ð74TL728Ł[
i, MeOH
ii, dibal-H
iii, MnO2 O
CO2Me (87)
70% MeO

2[91[0[4 a\b!Alkenic Aldehydes with Sulfur Substituents

2[91[0[4[0 1!Thio a\b!unsaturated aldehydes


The 1!thio!1!alkenal "14# was prepared in good yield via the hydrolytic ring opening of the
alkoxybromothiocyclopropane "15# derived in turn from the dibromoalkoxycyclopropane "16#
"Scheme 00# ð67TL2936Ł[ The enol ether "17# has been cleaved under mild nonacidic conditions to
give the a!thioalkenal "18# in quantitative yield "Equation "77## ð79TL2848Ł\ whereas tri~uoroacetic
acid in chloroform was used to produce the a!sulfonyl!alkenal "29# from the enol ether "20# "Equation
"78## ð76TL878Ł[
Br Br Br SPh i, EtOH, K2CO3
i, BunLi ii, H3O+
O
ii, PhSSPh 74% overall SPh
OEt OEt
(27) (26) (25)

Scheme 11

i, NaI, MeCN
SPh ii, TMS-Cl
SPh (88)
100%
MeO CHO
(28) (29)

Ph OH Ph
TFA, CHCl3
(89)
OMe 83%
PhSO2 OHC SO2Ph
(31) (30)

2[91[0[4[1 2!Thio a\b!unsaturated aldehydes


The displacement of a halogen leaving group from an activated 2!chloro!1!alkenal by a sulfur
nucleophile has been used to prepare b!thio!alkenals in very high yields[ Thus\ Gallagher et al[
treated 2\2!dichloropropenal "21# with propane!0\2!dithiol "22# to give the aldehyde "23# in 83)
yield "Equation "89## ð78JCS"P0#0682Ł[ Similarly the thiophene precursor "24# was prepared by
treatment of the chloroenal "25# with sodium sul_de and subsequent alkylation with an a!bromoester
"Equation "80## ð64CR"170#24Ł[ The thiapyran "26# was prepared by treating 2!chloro!1!methyl!but!
a\b!Alkenic Bond 62
1!enal "27# with sodium sul_de and proceeded via an intermediate mercaptovinylaldehyde "Equation
"81## ð61T4086Ł[ An analogous procedure utilising a nitrogen leaving group led to the aldehyde "28#
in high yield "Equation "82## ð66JPR0931Ł[

Cl HS NaOH, H2O, Et2O, 0 °C S


+ (90)
Cl O HS 94% S O
(32) (33) (34)

O O
i, Na2S
ii, PhCHBrCO2Et
Ph (91)
85%
Cl S CO2Et
(36) (35)

O Na2S, H2O, MeOH


S (92)
92%
Cl
O
(38) (37)

SH S O
H2O, NaOH
+ O NMe3+ ClO4– (93)
CO2Me 90%
CO2Me
(39)

The aldehyde "39# was prepared in 71) yield via a simple Wittig condensation with glyoxal
at room temperature\ using triethylamine to generate the requisite ylide in situ "Equation "83##
ð69JCS"C#1301Ł[

S i, TEA, THF S
S ii, glyoxal, H2O
S O
PPh3+ BF4– (94)
S 82% S
S S
(40)

The 0\1!dithiole "30# has been prepared by ring opening of the thiopyran "31# and subsequent
intramolecular oxidative coupling "Equation "84## ð58CC355\ 61T4086Ł[ Other routes to these
2!acylmethylene!2H!0\1!dithioles are also available ð47CB0113\ 52JA2133\ 55JOC2378\ 57JCS"C#1432\
61BSF3465Ł[

O
i, NaOH, H2O, DMF CHO
ii, K3Fe(CN)6
(95)
77% S
Ph S
Ph S
(42) (41)

A Vilsmeier formylation of an activated alkene or heterocycle has also been used to prepare
b!thioalkenals[ Thus the diene "32# was formylated at 9>C to yield the unsymmetrical aldehyde "33#
"Equation "85## ð78TL4178Ł\ and the 0\3!benzooxathiin "34# was formylated at room temperature to
give the corresponding aldehyde "35# "Equation "86## ð59JOC42Ł[ Formylation of the 0\3!benzodithiin
"36# provides the a\b!dithioalkenal "37# in moderate yield "Equation "87## ð42JA0536\ 43JA0957Ł[
Similarly formylation of tetrathiafulvalenyl lithium "38# with dimethylformamide produced the
corresponding aldehyde "49# "Equation "88## ð68JOC0365Ł[
63 a\b!Unsaturated Aldehydes
MeO2C S MeO2C S CHO
S CO2Me (COCl)2, DMF, 0 °C S CO2Me
S S (96)
MeO2C 75% MeO2C
S CO2Me S CO2Me
(43) (44)

S S
POCl3, DMF
(97)
27%
O O CHO
(45) (46)

S S
POCl3, PhNMeCHO
(98)
54%
S S CHO
(47) (48)

S S Li S S CHO
DMF, –70 °C to –20 °C, Et2O
(99)
44%
S S S S
(49) (50)

2[91[0[5 Selenium Substituted a\b!Unsaturated Aldehydes


a!Selenium substituted enals can be made by the reaction of enals with morpholino!
benzoselenamide "Equation "099## ð73TL0876Ł[ Alternatively\ vinyl selenides can be transmetallated
and formylated as shown in Equation "090# ð71TL2300Ł[ A rearrangement reaction starting from an
allylic alcohol has also been reported ð68TL2350Ł[ b!Selenium substituted enals have been made by
nucleophilic displacement of chlorine from a b!chloroenal with a selenol ð62JHC156Ł[ Other routes
include hydroselenation of propynal ð62JHC156Ł\ and oxidation of selenium substituted allylic
alcohols ð70TL1072Ł[

O
O PhSe N O
(100)
65%
SePh

i, BuLi
O
ii,
O
SeMe
n-C10H21 NHMe
n-C10H21 (101)
SeMe
SeMe

2[91[0[6 Nitrogen!Substituted a\b!Unsaturated Aldehydes

2[91[0[6[0 a!Nitrogen substituted a\b!unsaturated aldehydes


Substitution by nitrogen at the a!position of a\b!unsaturated aldehydes is not widely reported\
although they have been prepared by a VilsmeierÐHaackÐArnold reaction[ For example\ the ene!
diamine "40# reacts with "COCl#1 and POCl2 ð62CCC0057Ł to give the a\b!diaminoacrolein "41#\ which
can be selectively hydrolysed further to the a!amino!b!hydroxy acrolein "42# "Scheme 01#[ Similarly\
the dipiperidino compound "43# yields the asymmetrically substituted diaminoacrolein "44# in DMF
"Equation "091## ð62AG"E#212Ł[ a!Amino substituted ketones can also undergo a VilsmeierÐHaackÐ
a\b!Alkenic Bond 64
Arnold reaction\ and give the corresponding a!amino substituted a\b!unsaturated aldehydes "45#
"Equation "092## ð60BSF2874\ 77CCC0408Ł[

i, (COCl)2 or POCl3, DMF, CHCl3 O O


NMe2 ii, K2CO3, 60–70 °C NaOH
Me2N Me2N HO
65%
NMe2 NMe2
(51) (52) (53)

Scheme 12

i, (COCl)2, DMF, CHCl3


ii, K2CO3, 60–70 °C
N N (102)
N
20%
Me2N CHO
(54) (55)

O Cl
i, POCl3, DMF CHO
MeO ii, H2O MeO
(103)
N SO2Me 25% N SO2Me
MeO MeO
(56)

Propynol undergoes oxidative aminomercuration with secondary amines to give bis"1\2!N!alkyl!


amino#!propenals "46# "Equation "093## ð75CC0079Ł[

Me O
NHMe i, Hg(OAc)2, Et3N N
OH ii, NaBH4 Ph
+ (104)
54% Me
N
Ph
(57)

2[91[0[6[1 b!Nitrogen substituted a\b!unsaturated aldehydes


The reaction of 0\2!dicarbonyl compounds\ in particular malonaldehyde derivatives\ with nitrogen
nucleophiles a}ords b!amino!a\b!unsaturated aldehydes[ Thus acetamide "or amines# react with the
symmetric malonaldehyde derivative "47# to give the enaminoacrolein "48# "Equation "094##
ð78CB72Ł[ Anilines "59# also react "Equation "095## ð73LA538Ł[ Alkoxy acroleins are also known to
undergo aminolysis to b!aminoacroleins "Equation "096## ð76S0\ 89JCS"P0#0348Ł[

O
O OH H
O toluene, Na2SO4 O N
+ (105)
NH2 60%
CO2Me
CO2Me
(58) (59)
(E):(Z) 95:5
65 a\b!Unsaturated Aldehydes
NO2
NH2
O O H
O N
20 °C
+ (106)
40%

NO2
(60)

NaOMe, MeOH H
O MeO2C N (107)
CHO MeO2C NH3 + CHO

b!Nitrogen substituted acroleins can also be prepared by a VilsmeierÐHaackÐArnold reaction


with amides[ Thus the azapine "50# reacts with DMF:POCl2 in moderate yield to give the formylated
product "51# "Equation "097## ð78JCS"P0#1984Ł[ Diformylation of "50# is also possible in 54) yield[
Similarly the benzazepine!1!one "52# gives the b!amino substituted a\b!unsaturated aldehyde "53#
"Equation "098## ð61CPB0214Ł[ In an analogous manner\ vinyl ethers can undergo an aminomethyl!
eneation reaction\ followed by partial hydrolysis to the b!amino acroleins[ For example\ the methyl
vinyl ether "54# reacts cleanly to give the amino acrolein "55# in good yield "Equation "009## ð62TL2868\
73LA538Ł[

i, POCl3, DMF, CH2Cl2 CHO


ii, NaOAc
N N (108)
Cl O 35% Cl Cl

Ph Ph
(61) (62)

POCl3, DMF CHO


(109)
N 23% N
O Cl
H H
(63) (64)

i, POCl3, DMF O
OMe ii, K2CO3
NMe2 (110)
71%

(65) (66)

A related method involves reacting the lithium salts of alkanoic acids with an aminomethyl!
eneating reagent\ preferably N\N!dimethylmethoxymethaneiminium methyl sulfate "56#\ to give the
amino compounds "57# via a decarboxylative double formylation "Equation "000## ð73JOC0177Ł[ "Z#!
b!Aminoacroleins have been prepared from b!lithioenamines\ which are themselves prepared by
metal halogen exchange[ Thus in Scheme 02\ the enamine "58# is _rst halogenated and then the
halogen is exchanged for lithium to give the stereochemically pure "Z#!b!lithioenamine[ This can
then be reacted with DMF to a}ord the enaminoaldehyde "69# ð72JCR"S#111Ł[

O
MeO
LDA (2 equiv.)
CO2H + Ph
Ph + (111)
N 35%
Me Me
NMe2
(67) (68)

Oxidative addition of amines to propargylic alcohols in the presence of activated MnO1 has been
reported\ and gives moderate to good yields of b!amino!acroleins "Equation "001## ð60ZOR1019Ł[
Alternatively\ alcohols can be added to 2!amino!propynals[ Thus 2!N\N!dimethylaminopropynal
a\b!Alkenic Bond 66
But But But
Br CHO
i, Br2 i, BunLi
N N N
ii, Et3N ii, DMF

O O O
(69) (70)

Scheme 13

"60# reacts smoothly with methanol "or ethanol# to give the enaminal "61# "Equation "002##
ð57AG"E#359\ 58HCA1530Ł[

H O
N MnO2
OH
+ N (112)
86%

O
O MeOH MeO
(113)
Me2N 92%
Me2N
(71) (72)

Photolysis of isoxazilines such as "62# "Equation "003## has been shown to lead to the formation
of b!nitrogen substituted a\b!unsaturated aldehydes "63# ð62TL1172\ 64T0262\ 66H"5#0448\ 73JCS"P0#1092\
75CCC1056Ł[

Ph Ph Ph Ph
hν, MeCN
(114)
N 86% NH2
O O
(73) (74)

Sodium azide reacts with the chlorinated cycloalkenal "64# to give the azidocycloalkenal "65#
without cyclisation to the isoxazole as expected "Equation "004## ð77SC0364Ł[
CHO CHO
NaN3, DMSO
(115)
80%
Cl N3
(75) (76)

2[91[0[7 a\b!Alkenic Aldehydes with P\ As\ Sb\ or Bi!based Substituents


As of mid!0884\ no compounds of this type have been reported[

2[91[0[8 a\b!Alkenic Aldehydes with Si!based Substituents


2!Silyl!1!alkenals can be obtained by the formal silylformylation of alkynes in the presence of
Rh3"CO#01 as the catalyst[ Thus reaction of an alkyne with dimethylphenylsilane and trimethylamine
under carbon monoxide gas gives an excellent yield of the aldehyde\ the stereochemistry of which
was dependant on the substitution of the starting alkyne "Equation "005## ð78JA1221\ 89JA5019Ł[ A
similar concept involves the selective hydroformylation of a silylalkyne[ This occurs in two steps]
"i# initial nickel"9# catalysed hydrocyanation of the silylalkyne\ followed by^ "ii# dibal!H reduction
ð76S0922Ł[ A novel synthetic method yielding b!trimethylsilyl!a\b!unsaturated aldehydes was
reported in 0874 utilising the allylic sul_de "66# as a homoenolate dianion equivalent\ which
67 a\b!Unsaturated Aldehydes
is unmasked by treatment with aqueous sodium periodate in dioxane ð74TL1566Ł[ Pyridinium
chlorochromate can be used to oxidise the allylic alcohol "67# to give the silyl aldehyde "68# "Equation
"006## ð68T510Ł[

CO, Rh4(CO)12 R1 R2 R2 R1
R1 R2 + (116)
PhH, Et3N, 100 °C
OHC SiMe2Ph OHC SiMe2Ph

PhS OMe

TMS
(77)

pcc
HO TMS TMS
OHC (117)
CH2Cl2
67%
(78) (79)

2[91[0[09 a\b!Alkenic Aldehydes with Metal Substituents


Alkynyl aldehydes can be hydrostannylated using hexamethyldistannane in the presence of a
palladium"9# catalyst to give the corresponding "Z#!2!"trimethyl!stannyl#!prop!1!enal "79#\ stereo!
selectively and in high yield[ The reaction is successful in the presence of a number of di}erent
functional groups ð78JCS"P0#1013Ł "Equation "007##[ HMn"CO#4 also adds to alkynl aldehydes in a
trans fashion to give the adduct "70# in low yield "Equation "008## ð66IC2013Ł[

Me3Sn CHO
(Me3Sn)2, Pd(Ph3P)4, THF
R1 CHO (118)
R1
(80)

(CO)5Mn CHO
CHO + HMn(CO)5 (119)

(81)

2[91[1 ALDEHYDES BEARING AN a\b!TRIPLE BOND


Oxidations of propargylic alcohols to propargylic aldehydes can be performed in much the same
way as for allylic alcohols "see section 2[91[0[0[1#^ however propargylic aldehydes are very reactive
and decompose easily[ As expected manganese dioxide can be used "Equation "019## ð62CB1644Ł\
and chromium trioxide:pyridine has been reported as useful by several authors ð46JCS1656\ 51OS"30#702\
62TL3388Ł[ Atkinson et al[ have investigated the use of NiO1 ð58JCS1062Ł and Ni1O2 ð56CC607Ł
"Equation "010##[ Propynal has been made by the oxidative deamination of a propargylamine using
bisdiphenylphosphorinylperoxide "Equation "011## ð77S896Ł[

OH MnO2, 20 °C O
(120)
S S 65% S S

OH Ni2O3, 20 °C O
(121)
Ph 70% Ph

O
i, Ph2P O
2 O
N ii, H+
(122)
H 59%
a\b!Triple Bond 68
Alkynals can be prepared simply by the formylation of acetylide anions\ and this has been
reported using a formate ester or DMF ð47JCS0943\ 67S296Ł[ Terminal alkynes can also be formylated
under acidic conditions using an ortho!ester in the presence of a Lewis acid catalyst at high
temperature "Equation "012## ð52OSC"3#790Ł[ Eliminations of HBr from 1\2!dibromoaldehydes lead
to alkynals in moderate yield ð34OS"14#81Ł\ as does the reaction of formyl phosphorane with acid
chlorides followed by elimination of triphenylphosphine oxide ð74S048Ł[
i, ZnI2, 214 °C
ii, 7% H2SO4, 100 °C
Ph + HC(OEt)3 Ph CHO (123)
64%

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
OFA038

3.03
Aldehydes: Aryl and Heteroaryl
Aldehydes
GREGORY J. HOLLINGWORTH
University of Nottingham, UK
2[92[0 GENERAL METHODS FOR THE SYNTHESIS OF ARYL ALDEHYDES 71
2[92[0[0 Reduction of Aromatic Carboxylic Acids and Their Derivatives 71
2[92[0[0[0 Reduction of benzoic acids 71
2[92[0[0[1 Reduction of benzoyl halides 72
2[92[0[0[2 Reduction of aromatic esters 73
2[92[0[0[3 Reduction of anhydrides 73
2[92[0[0[4 Reduction of thiol esters 74
2[92[0[0[5 Reduction of amides 74
2[92[0[0[6 Reduction of aromatic nitriles 75
2[92[0[1 Oxidation of Aromatic Methyl Groups and Benzyl Alcohols\ Halides and Amines 75
2[92[0[1[0 Oxidation of toluenes to benzaldehydes 75
2[92[0[1[1 Oxidation of aryl ethylenes 76
2[92[0[1[2 Oxidation of benzylic alcohols 76
2[92[0[1[3 Oxidation of benzyl halides 77
2[92[0[1[4 Oxidation of benzylamines 78
2[92[0[2 Synthesis of Benzaldehydes from Aryl Or`anometallic Rea`ents 78
2[92[0[2[0 Aryl palladium rea`ents 78
2[92[0[2[1 Aryl lithium rea`ents and aryl Gri`nard rea`ents 89
2[92[0[3 Other Formylation Reactions of Arenes 80
2[92[0[3[0 The Duff reaction 80
2[92[0[3[1 The ReimerÐTiemann reaction 80
2[92[0[3[2 The VilsmeierÐHaack reaction 80
2[92[0[3[3 The GattermannÐKoch reaction 81
2[92[0[3[4 The Gattermann reaction 81
2[92[0[3[5 Dichloromethyl methyl ether as formylation rea`ent 81
2[92[0[3[6 Miscellaneous formylations 82

2[92[1 BENZALDEHYDE AND SUBSTITUTED BENZALDEHYDES 82


2[92[1[0 Benzaldehyde 82
2[92[1[1 Alkyl Benzaldehydes 82
2[92[1[2 Halobenzaldehydes 83
2[92[1[3 Oxy`en!substituted Benzaldehydes 85
2[92[1[4 Sulfur!substituted Benzaldehydes 87
2[92[1[5 Nitro`en!substituted Benzaldehydes 87

2[92[2 POLYAROMATIC ALDEHYDES 88

2[92[3 HETEROCYCLIC ARYL ALDEHYDES 091


2[92[3[0 O!Heterocyclic Aldehydes 091
2[92[3[0[0 Furan and benzofuran carboxaldehydes 091
2[92[3[1 S\ Se and Te Heterocyclic Aldehydes 093
2[92[3[1[0 Thiophene and benzothiophene carboxaldehydes 093
2[92[3[1[1 Se and Te heterocyclic aldehydes 095
2[92[3[2 N!Heterocyclic Aldehydes 095

70
71 Aryl and Heteroaryl Aldehydes
2[92[3[2[0 Pyrrole and indole carboxaldehydes 095
2[92[3[2[1 Pyridine and quinoline carboxaldehydes 096
2[92[3[3 Miscellaneous Heterocycles] Oxazoles\ Thiazoles and Imidazoles 098

2[92[0 GENERAL METHODS FOR THE SYNTHESIS OF ARYL ALDEHYDES


The vast majority of methods for the synthesis of aromatic aldehydes fall into one of four main
categories] "i# reductions of carboxylic acids and their derivatives^ "ii# oxidations of alcohols\ halides
or activated alkyl groups^ "iii# reactions of an organometallic reagent with a formylating reagent\
and "iv# {classical| formylations by electrophilic!substitution reactions of arenes[ It is in these broad
sections that the synthetic methods towards aromatic aldehydes are presented[ For a review of
aromatic aldehydes\ see ð68COC"4#0094Ł[

2[92[0[0 Reduction of Aromatic Carboxylic Acids and Their Derivatives


Many methods are available for the direct partial reduction of aromatic acids and derivatives to
aldehydes[ The vast majority of these methods use metal hydride reducing agents\ and this area has
been reviewed ð78OPP340\ 80COS"7#148Ł[ There is\ however\ a selection of other methods which have
also been reviewed ð43OR"7#107\ 80COS"7#172Ł[

2[92[0[0[0 Reduction of benzoic acids


Reductions of aromatic acids to the corresponding aldehydes are less general than for aliphatic
acids[ For example\ treatment of an aromatic acid with lithium metal in ethyl! or methylamine is
inapplicable due to concurrent reduction of the aromatic ring under the reaction conditions
ð52JOC1807\ 69JA4663Ł[
Many metal hydride reagents\ however\ may react to give aromatic aldehydes although the
reactions tend to be sluggish compared to those with aliphatic acids[ This feature reduces the scope
of the reaction since other reducible groups may react preferentially[ Therefore\ only relatively
simple benzaldehydes with substituents such as halo\ nitro\ amino and alkoxy groups have been
prepared in this manner[ A whole host of borane reagents have been developed\ mainly by Brown
and Cha\ and yields on the whole are moderate to good[ Reagents which have been utilised include
boraneÐdimethyl sul_de complex\ then pyridinium chlorochromate "pcc# "the latter to oxidise
the intermediate trialkoxyboroxine# ð68S693Ł\ t!thexylborane ð61JOC1831Ł and t!hexylhaloboraneÐ
dimethyl sul_de complexes "Equation "0## ð73JA7990\ 75JOC4153\ 76JOC4929\ 76JOC4399\ 76MI 292!90\
76TL1278\ 77MI 292!90Ł[ Reactions of aromatic acids with 8!borabicycloð2[2[0Łnonyl "8!BBN!H# give
acyloxy!8!borabicycloð2[2[0Łnonanes which have been reduced with a number of reagents such
as ButLi:8!BBN!H ð76TL5120Ł\ lithium!8!boratabicycloð2[2[0Łnonane ð76TL3464Ł\ LiAlH3:pyridine
ð89MI 292!90Ł and lithium tris"diethylamino# aluminum hydride ð81OPP216Ł[ Acid salts are reduced
to aldehydes by 8!BBN!H alone ð77H"16#0484Ł[

CO2H CHO
t-hexBHBr•SMe2
(1)
90%
H2N H 2N

Since diisobutylaluminum hydride "dibal!H# was _rst observed to reduce acids to aldehydes
ð53ZOB0918Ł\ a variety of aluminum!based reagents have been used for this transformation[ Benzoic
acid itself has been reduced by bis"N!methylpiperazinyl# aluminum hydride in 75) yield ð63CL0336\
73JOC1168Ł[ Other suitable reducing agents include lithium tris"dialkylamino# aluminum hydrides
ð81MI 292!90Ł and bis"dialkylamino# aluminum dihydrides ð83MI 292!90Ł[
Treatment of simple benzoic acids with certain hypervalent silicon species leads to a silyl carboxy!
late\ which on pyrolysis gives aldehydes in moderate to good yields "49Ð85)# "Equation "1##
ð76TL2830Ł[ Sato|s titanium!catalysed Grignard reagent method tends to over!reduce aromatic acids
ð70S760Ł[ Aromatic acids also react with oxalyl chloride:DMF to form carboxymethylene iminium
chlorides\ which can then be reduced in situ with LiAlH"OBut#2 and a CuI catalyst to aldehydes in
moderate yield "Scheme 0# ð72TL0432Ł[
General Methods 72
Ph NMe2
SiH2

i,
CO2H CHO
ii, heat
(2)
F 94% F

O
CO2H CHO
(COCl)2 + Me LiAlH(OBut)3
O N
DMF CuI
O2N Me O2N
O 2N

Scheme 1

Other less widely used reducing methods include the use of sodium amalgam ð35JA1491Ł and
electrochemical reduction ð61JOC0402\ 83CPB093Ł[
An indirect method of reduction involves treatment of the carboxylic acid with a dithiaborinane
reagent ð76JOC1003\ 76PAC0994\ 76TL0802Ł^ the product dithioacetals are then readily hydrolysed to
the corresponding aldehydes[

2[92[0[0[1 Reduction of benzoyl halides


For many years\ the main method of reducing acyl chlorides to aldehydes was by catalytic partial
hydrogenation\ using the Rosenmund procedure ð37OR"3#251\ 75JA1597Ł[ The reaction has various
modi_cations but requires forcing conditions with aromatic acyl chlorides ð65S656Ł[ As a conse!
quence\ hydride!based methods have now almost totally replaced the Rosenmund procedure[ The
most widely used hydride reagent is lithium tri"t!butoxy#aluminum hydride ð45JA141\ 47JA4266Ł which
reduces meta! and para!substituted aromatic acyl chlorides to aldehydes in moderate yields\ and
ortho!substituted acyl chlorides in somewhat lower yields[ Tolerated groups include halo\ alkoxy\
nitro and cyano functions[ Much improved yields\ however\ have been reported using sodium
tri"t!butoxy# aluminum hydride as reducing agent "Equation "2## ð82JOC3621Ł[ Another aluminum
hydride\ sodium diethyldihydroaluminate in the presence of piperidine has also been reported to
e}ect the transformation ð82SC0664Ł[ Sodium borohydride with a variety of additives ð79JCS"P0#16\
70TL00\ 71SC728Ł\ and complex copper borohydrides ð67TL0326\ 67TL1362\ 79TL702Ł also reduces aro!
matic acyl chlorides to aldehydes in moderate yields\ but normally these methods also give small
amounts of over!reduced products[

COCl CHO
NaAlH(OBut)3
(3)
88%
OMe OMe

Benzoyl bromide may be cleanly reduced to benzaldehyde by tributylstannane ð55JA460Ł\ but this
reducing agent works well for chlorides only if a palladium catalyst\ normally Pd"PPh2#3\ is present
giving high yields of simple benzaldehydes "Equation "3## ð79CC321\ 70JOC3328Ł^ tributyl!
germane:Pd"PPh2#3 has also been used ð78JOM"265#30Ł[ Triethylsilane may act as a reducing agent
in the presence of a palladium ð58JOC0866Ł\ platinum ð69CC0692\ 64JCS"D#1535Ł or a rhodium catalyst
ð64JCS"D#1359Ł[ The former procedure requires the least harsh reaction conditions\ whilst the latter
tends to produce signi_cant quantities of diaryl ketones in addition to the desired product[ Excellent
yields have been obtained using hypervalent silicon hydrides ð77TL0160Ł[ Some iron complexes
reduce aromatic acyl halides to aldehydes\ such as Collmans reagent\ Na1Fe"CO#3 ð60BCJ1458Ł and
the hydridoiron tetracarbonyl anion HFe"CO#3− ð66TL670\ 89CRV0930Ł[ Various other transition
metal complex reducing agents have also been used for this transformation ð73OM0590\
74JOM"181#114Ł[ Finally\ yields of over 79) for the reductions of aromatic acyl chlorides have
been reported using the heterocyclic hydride donor 0\2!dimethyl!1!phenyl benzimidazoline "DMBI#
"Equation "4## ð75JOC4399Ł[
73 Aryl and Heteroaryl Aldehydes
COCl CHO
Bu3SnH, Pd(PPh3)4
(4)
92%

Me
N
Ph
N
COCl Me CHO
MeCN, AcOH
(5)
85%
MeO MeO

2[92[0[0[2 Reduction of aromatic esters


The best!known reagent for the reduction of aromatic esters to aldehydes is dibal!H "for example\
as shown in Equation "5## ð51TL508Ł[ The yields\ however\ are generally lower for aromatic esters
than for aliphatic ones\ and for this reason much fewer examples have been reported[ Sodium
aluminum hydride has also been used but again aromatic esters give lower yields ð52TL1976Ł^ a
similar outcome is found with sodium di!isobutyl aluminum dihydride ð51TL508Ł[ The known
reduction of phenyl esters by lithium tri!t!butoxy aluminum hydride fails for those derived from
aromatic carboxylic acids ð61S106Ł[

CO2Et CHO
dibal-H
(6)
70%
MeO MeO

Moderate yields with simple benzoate esters have been achieved\ however\ with bis"3!methyl!0!
piperazinyl# aluminum hydride "BMPA# ð64CL104Ł[ Another reagent\ Red!Al "NaAlH1
"OC1H3OCH2#1#\ reduces aromatic esters in low yield ð69MI 292!90Ł\ but when an equivalent of
N!methylpiperazine is added to the Red!Al prior to the ester\ the modi_ed reagent produces benz!
aldehyde in 74) yield ð65S415Ł "isolated as its 1\3!dinitrophenylhydrazine "DNP##[ Two promising
reducing agents reported in the early 0889s\ for this transformation are sodium diethylpiperidino
aluminum hydride ð80MI 292!90Ł and lithium tris"diethylamino# aluminum hydride ð81OPP224Ł[

2[92[0[0[3 Reduction of anhydrides


Anhydrides of aromatic acids may be reduced to aldehydes by disodium tetracarbonylferrate in
moderate yields ð62TL2424\ 64BCJ1389Ł[ Benzoic anhydride gave 62) benzaldehyde using this reagent
and phthalic anhydride gave 1!formyl benzoic acid via the acylcarbonylferrate intermediate "0#
shown in Scheme 1[

O O
– CHO
Na2Fe(CO)4 Fe(CO)4
O 2Na+
O–
CO2H
O O

(1)

Scheme 2

Mixed aryl and alkyl anhydrides show little selectivity as to which C0O bond is cleaved[ Related
aromatic carboxylic ethyl carbonic anhydrides\ however\ react to give moderate yields of simple
benzaldehydes ð64TL0952Ł[
Triphenylacetic benzoic anhydride on treatment with lithium metal gave complete selectivity\
with benzaldehyde being the only aldehyde product ð81TL2626Ł[ A similar result was observed for
the same substrate when the C0O bond was cleaved photochemically ð82JA71Ł[
General Methods 74
2[92[0[0[4 Reduction of thiol esters
Aromatic carboxylic acids have been converted into aldehydes in two steps via their thiol esters[
Hydrogenolysis of thiol esters in the presence of Raney nickel then produces the corresponding
aldehydes in moderate yields ð48CB429\ 43OR"7#107Ł[ The 1!thiazoline!1!thiol ester of benzoic acid
has been reduced to benzaldehyde in 82) yield by dibal!H ð67CC229Ł[ Other reducing agents for
aromatic thiol esters are lithium metal ð81TL2626Ł\ and triethylsilane in the presence of a catalytic
amount of palladium on carbon ð89JA6949Ł[ The latter method appears to tolerate a wide range of
functional groups including esters\ amides\ acetals and sul_des\ and has been used in many natural
product syntheses\ although the vast majority of reported cases are for aliphatic thiolesters[

2[92[0[0[5 Reduction of amides


A wide variety of N\N!disubstituted carboxylic amides have been partially reduced to their
aldehydes[ For a list of amide types and reagents\ see ðB!78MI 292!90Ł[ Almost invariably the reducing
agent is an aluminum hydride reagent[ One exception is the use of disiamyl borane which reduces
N\N!dimethylbenzamide to benzaldehyde in 78) yield ð69JA6050Ł[ Of the remaining methods\ many
give only moderate yields when applied to aromatic amides^ those methods giving high yields are
discussed below[ A good general method is the reduction of aromatic N\N!dimethylamides with
lithium di! or triethoxy aluminum hydrides ð53JA0978Ł[ Chloro!\ methoxy! and nitrobenzylamides
are reduced in 59Ð89) yield[ N\N!Dimethylamides are also reduced in good yield by NaAlH3
ð58T4444Ł[ Similar yields are observed for the reductions of 0!acyl imidazoles with LiAlH3
ð51AG"E#240Ł[ Benzaldehyde itself is produced in 89) yield from its 0!acyl!2[4!dimethyl pyrazole
"1# derivative using LiAlH3 ð47AG054Ł[

N
N

(2)

Reductions of 2!acyl thiazolidine!1!thiones "2# with either dibal!H or lithium tri"t!butoxy# alumi!
num hydride give greater than 79) yield for benzaldehyde and p!chloro! and p!nitrobenzaldehydes
ð68BCJ444Ł\ and dibal!H also reduces the Weinreb amide N!methyl!N!methoxybenzamide "3# to
benzaldehyde in 60) yield ð70TL2704Ł[ Newer hydride reagents which reduce primary carboxamides
in good yield include lithium n!butyl diisobutyl aluminum hydride ð73JOC0606Ł and lithium tris!
"diethylamino# aluminum hydride ð80TL5892Ł[ The reduction of tertiary amides has also been
accomplished using ethyl tri~ate and L!selectride ð89JCS"P0#646Ł[

O S O
OMe
N N
S
Me

(3) (4)

For aromatic aldehyde syntheses some of the older methods are still amongst the best[ These
earlier methods have been reviewed ð43OR"7#107Ł[ 0!Aroyl!1!cyano!0\1!dihydroquinolines "or Reis!
sert compounds "4## are readily formed from acyl chlorides\ and may be hydrolysed under acidic
conditions to give good yields of benzaldehydes[ The McFadyen and Stevens procedure is a good
method for the preparation of benzaldehydes containing hydroxy\ alkoxy\ alkyl and halo substitu!
ents\ by basic decomposition of 0!acyl!1!arylsulfonylhydrazines "5#[ Alkoxy and alkyl benzaldehydes
have been prepared by the method of Sonn and Muller in moderate to good yields from
N!phenylaromatic amides in a three!step sequence via an imido chloride and Schi}s base[
75 Aryl and Heteroaryl Aldehydes

O
H
N CN N
Ar N SO2Ar
H
O Ar
(5) (6)

2[92[0[0[6 Reduction of aromatic nitriles


One of the older methods for converting aromatic nitriles into aldehydes is that devised by
Stephen ð14JCS0763Ł[ Treatment of the nitrile with HCl and SnCl1 gives the corresponding crystalline
aldimine stannichloride salt "6#\ which can then be readily hydrolysed to the aldehyde[ Various
alkyl\ alkoxy and halo substituents are tolerated ð28JA1137\ 43OR"7#107\ 44OSC"2#515\ 45JCS0575Ł\ and
yields are generally good^ notable exceptions include 1!methylbenzaldehyde and 0!naphthaldehyde[
NH•HCl•SnCl4
Ar
(7)

Inevitably newer methods have been developed using metal hydride reagents[ Dibal!H\ LiAlH3
and NaAlH3 reduce benzonitrile to benzaldehyde in 26)\ 81) and 89) yields respectively
ð48JOC516\ 53JA0968\ 82JOC3616Ł\ but a more general method uses Li"EtO#2AlH ð48TL8\ 53JA0974Ł[
Again alkyl\ alkoxy and halo substituents are tolerated[ More modern hydride reagents that have
been used for this transformation in high yield include t!hexylbromoboraneÐdimethyl sul_de com!
plex ð76MI 292!91Ł\ sodium diethylpiperidino hydroaluminate "SDPA# "Equation "6## ð82JOC0830Ł
and lithium tris"dihexylamino# aluminum hydride ð81MI 292!91\ 81OPP220Ł[ This latter reagent is
reported to leave aliphatic nitriles untouched[
O
CHO
Me SDPA
N (7)
99%
Me

A relatively mild two!step procedure which converts aromatic nitriles into benzaldehydes involves
alkylation of the nitrogen of the CN bond to _rst form the activated N!alkylnitrilium ion "7#\ which
is then reduced in good yield by triethylsilane to the N!alkylaldimine^ hydrolysis _nally gives the
aldehyde[ Alkylation of the nitrile can be accomplished with either triethyloxonium tetra!
~uoroborate\ or with isopropyl chloride in the presence of FeCl2 ð63CC34\ 70JOC591Ł[ Alkyl\ alkoxy\
halo and notably nitro and carbethoxy substituents are tolerated[
+
Ar N R
(8)

Aromatic aldehydes have also been produced by reactions of nitriles with Raney nickel in
re~uxing aqueous HCO1H ð54JCS4664Ł and\ in 0878\ in excellent yields\ by wet Raney nickel using
triethylammonium hypophosphite hydrate as a hydrogen source[ Under these controlled conditions
hydrogenation of the nitrile is facile\ but hydrolysis of the product imine predominates over
hydrogenation\ thus leading to the aldehydes with little or no over!reduction ð78JOC838Ł[

2[92[0[1 Oxidation of Aromatic Methyl Groups and Benzyl Alcohols\ Halides and Amines

2[92[0[1[0 Oxidation of toluenes to benzaldehydes


A whole host of reagents have been utilised for the oxidation of toluenes to benzaldehydes[
Originally Etard used chromyl chloride "CrO1Cl1# ð47CRV0Ł as oxidant\ but in the 0889s other
reagents are preferred[ Of these\ one of the most popular is the use of cerium"IV# ion as oxidant in
an acidic medium\ for example\ cerium ammonium nitrate "can# which will oxidise toluene to
benzaldehyde in 81) yield[ Substituents which are tolerated include halo\ nitro\ and N!acetylamino
General Methods 76
groups ð55TL3382Ł[ This oxidant has been used for oxidation of the aromatic methyl group of
steroidal compounds "Equation "7## ð57JCS"C#1804Ł[

O O

can, AcOH, H2O CHO


H H (8)
70%
H H H H
MeO MeO

Other oxidants which give this transformation include 1\2!dichloro!4\5!dicyano!0\3!benzo!


quinone "ddq# ð68S033\ 73TL1890Ł\ bromine ð42JA623Ł\ silver"II# oxide ð56TL3082Ł\ potassium per!
manganate:triethylamine ð78S182Ł and dioxygen with a copper catalyst ð89TL1596Ł[

2[92[0[1[1 Oxidation of aryl ethylenes


The oxidative cleavage of styrenes or 0\1!diols derived from styrenes is very facile using a number
of reagents\ notably ozone or OsO3:NaIO3[ A particularly unusual example was used by Bremner
and co!worker in the key step to a functionalised 2!azað8Ł meta!cyclophane system "Equation "8##
ð80AJC024Ł[

MeO
MeO
CN
CN i, O3 N
N MeO CHO (9)
MeO
ii, Me2S

Perhaps a more synthetically useful procedure than oxidative cleavage of simple styrenes is the
ozonolysis of benzofurans to 1!hydroxy benzaldehydes ð82CPB0055Ł[ This strategy was used by
Gammill and co!worker\ who treated khellin with OsO3:NaIO3 and produced the hydroxy benz!
aldehyde in 62) yield\ which was then used in the synthesis of various khellin analogues "Equation
"09## ð73TL1842\ 75JOC2005Ł[

OMe O OMe O
OHC
OsO4, NaIO4, THF, 50 °C
(10)
O O HO O
OMe OMe

2[92[0[1[2 Oxidation of benzylic alcohols


The oxidations of benzylic alcohols are very facile[ Like allylic alcohols\ they are {activated| with
respect to saturated alcohols and therefore are generally oxidised more readily[ There are very many
reagents for carrying out the oxidations of alcohols to aldehydes and\ due to the reactivity of
benzylic alcohols\ most are applicable "for a list of reagents and references see ðB!78MI 292!90Ł#\
however\ caution must be exercised in some cases to avoid over!oxidation[ The most popular
methods of alcohol oxidation and their applicability to benzyl alcohols are discussed in this section[
In addition\ some mild oxidants\ capable of chemoselectively oxidising benzyl alcohols in the
presence of other alcohol functions are presented[
Probably the most popular and mild method for the oxidation of benzylic alcohols is the use of
activated manganese dioxide ð65S54Ł[ This reagent oxidises benzylic alcohols much faster than
aliphatic ones and has been used extensively\ for example\ Equation "00# ð50JOC1862\ 57JOC2985\
63JA824Ł[
77 Aryl and Heteroaryl Aldehydes
OMe
OMe
O MnO2, 6 h, RT, CHCl3
O (11)
O
O CHO
OH

Other manganese oxidants such as potassium permanganate:triethylamine ð78S182Ł and


cetyltrimethyl ammonium permanganate ð73CL1020Ł also work for this transformation\ and yields
are generally good[ Various chromium reagents ð77OPP422Ł including pyridinium dichromate
"pdc#:TMS!Cl ð75CJC114Ł\ pyridinium chlorochromate "pcc# ð71S1348\ 76JOC2894Ł and pyridinium
~uorochromate ð71S477Ł have been applied to the general oxidation of benzyl alcohols[ Other
chromium reagents\ however\ have been shown to be useful for selective oxidations[ 3!"Dimethyl!
amino# pyridinium chlorochromate has been used for the oxidation of various simple primary
benzyl alcohols in good yield\ but also shows remarkable selectivity for benzyl alcohols over aliphatic
alcohols "Equation "01## ð71JOC0676Ł^ the product shown in the equation contained ³1) of the
dialdehyde[
+
Me2N NH ClCrO3– CHO
OH
(12)
HO 62% HO

Bis"tetrabutylammonium# dichromate ð79SC64Ł\ bis"benzyltriethylammonium# dichromate


ð71S0980Ł\ and tetrabutylammonium chlorochromate ð72S638Ł also show quite good selectivity for
benzyl alcohols\ and give good yields of benzaldehydes[
Of the general methods for the oxidation of alcohols using activated DMSO\ most would appear
applicable to benzyl alcohols\ although relatively few examples have been reported presumably due
to the e.ciency of other methods[ However\ benzyl alcohol itself has been oxidised to benzaldehyde
by DMSO:tri~uoroacetic anhydride and by DMSO:oxalyl chloride in 79) and 87) yields respec!
tively ð70S054Ł^ see also ð56CRV136\ 78TL1926Ł for the oxidation of a naphthyl derivative[
Other oxidants which have been successfully applied for the selective oxidation of benzylic
alcohols include potassium ferrate ð67CL0286\ 73S755Ł and\ in good yields\ silver ferrate ð75SC100Ł\
air and a catalytic amount of can ð72TL1288Ł\ silver"II# oxide ð56TL3082Ł\ benzeneseleninic anhydride
ð67CC841Ł and oxygen using a catalytic mixture of CuCl and 1\1\5\5!tetramethyl piperidinyl!0!oxy
"TEMPO# ð73JA2263Ł[
Two new methods giving excellent yields from simple benzyl alcohols\ use as oxidant chro!
mium"VI# trioxide in the presence of wet alumina ð89BCJ1322Ł and t!butylhydroperoxide with either
a titanium or zirconium catalyst ð89CB0246Ł[

2[92[0[1[3 Oxidation of benzyl halides


Benzaldehydes may be produced in moderate to good yields "49Ð79)# from benzyl halides using
the Sommelet reaction\ by treatment with hexamethylenetetramine "HMT#^ this reaction has been
reviewed ð43OR"7#086Ł[ The reaction proceeds via a hexaminium salt to the benzylamine\ which then
reacts with more HMT at mildly acidic pH to give the aldehyde[ Tolerated groups include halo\
nitro\ alkyl\ alkoxy and ester[ 1!Substituted benzyl halides give lower yields due to steric hindrance\
and 1\5!disubstituted benzyl halides fail completely[ Accumulation of electron!withdrawing groups
hinders the reaction\ and the procedure is not general for phenols\ although some examples are
known[ For the preparation of aromatic dialdehydes see ð49JA1881Ł[ The related Krohnke procedure
which involves formation of a pyridinium salt\ treatment with 3!nitrosodimethylaminobenzene and
hydrolysis has been used but it is less general than the Sommelet reaction ð28CB339Ł[
Benzyl halides react with the sodium salt of 1!nitropropane in ethanol giving moderate to good
yields "57Ð66)# of simple 3!substituted benzaldehydes containing substituents such as alkyl\ halo\
keto\ cyano\ ester and tri~uoromethyl groups "Equation "02## ð38JA0656\ 52OSC"3#821Ł[ The use of
DMSO as co!solvent has extended the scope of this reaction ð55JOC1507\ 57JOC2166Ł[ One of the most
popular methods for the oxidation of benzyl halides to benzaldehydes is that reported by Kornblum
using DMSO as oxidant "sometimes after _rst converting them to their tosylates using silver tosylate#
ð48JA3002\ 56CRV136Ł[ It has been found that addition of a silver salt to the DMSO solution of the
General Methods 78
halide facilitates direct conversion into the aldehyde in good yield^ for examples see "Equation "03##
ð73S493\ 82TL2408Ł[ Other oxidants used in Kornblum!type oxidations include bis"3!methoxyphenyl#
selenoxide ð73CL780Ł and either dimethyl selenoxide or potassium benzene selenite in the presence
of potassium hydrogen phosphate ð73S636Ł[ Excellent yields are reported for a wide range of
polysubstituted benzyl halides[

CHO
Br [Me2CNO2]– Na+
(13)
Br 75%
Br

DMSO, AgNO3, NaHCO3


Br (14)
CHO
OMe OMe

Other reagents which have been used for the oxidation of benzyl halides to benzaldehydes include
various amine oxides\ particularly pyridine N!oxide ð46JOC0024Ł\ dimethylaminopyridine N!oxide
ð70BCJ1110Ł and N!methylmorpholine N!oxide ð81SC0856Ł[ McKillop et al[ have reported the reac!
tion between various benzyl bromides and mercury"I# nitrate which leads to nitrate esters\ which
then decompose to benzaldehydes on treatment with aqueous ethanolic alkali\ for example\ Equation
"04# ð63SC34Ł[ Finally\ a whole host of chromium!based oxidants e}ect the transformation ð65CC089\
65TL2874\ 78BSB110\ 81SC0380\ 82BSB188Ł^ see also ð67S508Ł[

Cl Cl
i, Hg2(ONO2)2, DME
ii, NaOH (aq.), EtOH CHO
Br (15)
71%
Cl Cl

2[92[0[1[4 Oxidation of benzylamines


Many of the oxidants mentioned for the oxidation of benzyl halides to benzaldehydes also oxidise
benzyl amines^ for example the Sommelet reaction "which actually proceeds via the amine#[ Because
the halides are more readily available\ the oxidations of amines will not be discussed in detail
here[ Occasional publications however concentrate on the latter\ for example by DMSO oxidation
ð89BSB234Ł or oxidation via sul_namide intermediates ð70JOC3506Ł[

2[92[0[2 Synthesis of Benzaldehydes from Aryl Organometallic Reagents

2[92[0[2[0 Aryl palladium reagents


An excellent synthesis of benzaldehydes reported by Stille may be accomplished from aryl iodides
by reaction with carbon monoxide and tributylstannane in the presence of a palladium catalyst
ð72JA6064\ 75AG"E#497\ 75JA341Ł[ The reaction proceeds by CO insertion into the aryl palladium bond
of the initial complex\ followed by hydrideÐhalo exchange with the tin hydride\ and _nally reductive
elimination of the aldehyde product[ Iodides react much more e.ciently than other halides\ so
selective reactions of dihaloarenes can be achieved[ Many functional groups are tolerated\ for
example ester\ CF2\ Br\ Cl\ CH1OH\ MeO[ If electron!donating groups are present\ the reaction
usually occurs at 0 atm CO pressure^ for electron!withdrawing groups slightly higher CO pressures
are required to minimise the competitive reduction reaction[ Even so\ low yields are found for nitro
derivatives[ Otherwise yields are often ×74)\ for example\ Equation "05#\ but slightly lower for
1!substituted halides\ presumably due to steric hindrance[

I CHO
CO, Bu3SnH, THF, Pd(PPh3)4 (cat.)
(16)
91%
MeO2C MeO2C
89 Aryl and Heteroaryl Aldehydes
Aryl halides have been converted into their aldehydes in similar palladium!catalysed reactions
using dihydrogen to reduce the intermediate acyl palladium complex[ However\ the shortfall of this
method is the high pressure required for reaction "7[2 MPa "0199 psi## ð63JA6650Ł[ Use of poly
"methylhydrosiloxane# as hydrogen donor allows the reaction to be carried out under the reduced
pressure of 49 psi ð73JOC3998Ł\ but the practical ease of the Stille procedure makes it more generally
useful[ Various other palladium!catalysed formylations are known ð65BCJ0570\ 73JOM"169#172\
78CC0705Ł\ with some starting from aryl diazonium salts[
Carbonylations of aryl halides under radical conditions have also been accomplished\ although
once again high pressures of CO are required ð89TL5776Ł[

2[92[0[2[1 Aryl lithium reagents and aryl Grignard reagents


A vast number of benzaldehydes have been made from reactions of aryl lithium reagents or aryl
Grignard reagents with various formylating agents\ and this remains one of the most popular
methods for their synthesis[
The organometallic reagents may be made either by halogenÐmetal exchange from aryl halides
or by ring deprotonation of activated arenes "i[e[\ those with ortho!directing groups# with strong
bases[
The most common early method was the formylation of a Grignard reagent with DMF\ for
example\ ð50JOC1114\ 66JOC2297Ł^ for a later improved procedure see ð73S117Ł[ The reaction is not
reported to be as e}ective using aryl lithium reagents\ although good examples exist ð69JCS"C#116Ł
and later good yields were achieved for the preparation of benzaldehyde from bromobenzene\
lithium metal and DMF under ultrasonic irradiation "Equation "06## ð75TL0680Ł[ Other formylating
reagents which give good yields of benzaldehydes from either aryl lithium or Grignard reagents
after hydrolysis include N!formylpiperidine ð70AG"E#767\ 75AG"E#0915Ł\ lithium "or sodium# formate
ð73TL0732Ł\ 1!"N!methyl!N!formyl# amino pyridine ð67S392Ł\ the related imidazolidinium salt "8#
ð68CC006Ł and oxazolinium salt "09# ð69JA5565\ 63OS"43#31Ł[ A more direct method to aldehydes is
the reaction of Fe"CO#4 with organolithium reagents ð53BCJ230Ł or Grignard reagents ð71BCJ0552Ł[
The latter gives higher yields of benzaldehyde but few examples of this reaction have been reported
up to 0884[

Br CHO
Li, DMF, ultrasound, THF
(17)
81%

+ O
Me Ac
N N
N+ I–
I–
Me
(9) (10)

Various arenes may be deprotonated adjacent to certain existing functionality capable of sta!
bilising the anion formed\ that is\ directed metallation groups "DMGs#[ The resulting aryl lithium
reagents can then be formylated using one of the agents described above\ normally DMF[ The
products are thus 1!substituted benzaldehydes[ There are a vast number of DMGs "for excellent
reviews see ð68OR"15#0\ 77BSF56Ł# and an {order of metallation| has been established for these groups[
Most appear applicable to the synthesis of benzaldehydes especially the alkoxy function\ for example\
Equation "07# ð68S895Ł[ For a later example see ð82T0310Ł[

O OMe O OMe
i, BunLi
(18)
ii, DMF CHO
OMe OMe

Other important DMGs that have been applied to the synthesis of benzaldehydes include t!butyl
sulfonyl ð78JOC13Ł\ tertiary amido ð71ACR295Ł\ and ~uoro groups ð81TL6388Ł[
General Methods 80
2[92[0[3 Other Formylation Reactions of Arenes

2[92[0[3[0 The Duff reaction


Treatment of activated arenes such as phenols with hexamethylenetetramine "HMT# in an acidic
medium gives\ after hydrolysis of the imine intermediate\ substituted benzaldehydes[ The original
Du} reaction was carried out in acetic acid\ then later in glycerol:glyceroboric acid medium
ð30JCS436Ł\ and formylates ortho to the activating group\ "or para if this position is blocked# although
yields do tend to be low[ A much improved procedure was later employed using TFA ð61JOC2861Ł\
giving much higher yields\ for example\ Equation "08#[ The new conditions allow even simple alkyl
benzenes to be formylated\ and tend to give para!substitution^ they also tolerate more functionality\
including halogen\ ester and amine substituents[ For other examples see ð76IJC"B#803\ 77CPB863\
81CL890\ 81S0110Ł[

CHO
HMT, TFA, reflux, 12 h
(19)
HO 95% HO

2[92[0[3[1 The ReimerÐTiemann reaction


Treatment of phenols with chloroform and hydroxide ion leading to ortho!hydroxy benzaldehydes
is called the ReimerÐTiemann reaction ð71OR"17#0Ł[ Unfortunately yields are generally less than 49)
although the use of ultrasound ð89SC598Ł has improved these yields somewhat[ Ortho!formylation
generally predominates and is enhanced by phase transfer catalysts ð68TL2642Ł[ Various modi!
_cations can make the reaction para!selective ð49JCS656\ 75S458Ł\ although the formation of mixtures
is common[ Halo\ alkoxy and carboxylic acid substituents are amongst those tolerated^ an example
is given in Equation "19# ð66IJC"B#0945Ł[

NaOH, CHCl3 N
N (20)
HO O
HO O 40%
CHO

2[92[0[3[2 The VilsmeierÐHaack reaction


Active aromatic substrates containing electron!donating substituents\ for example amino\
hydroxy\ alkylthio and alkoxy groups\ react with electrophilic chloromethylene iminium salts\ which
are then readily hydrolysed to the corresponding aldehydes\ thus achieving overall formylations[
This is the most common method for the formylation of aromatic rings\ and is known as the
VilsmeierÐHaack reaction^ for reviews see ðB!53MI 292!90\ 62MI 292!90Ł[
The chloromethylene iminium intermediates are formed by reaction of a dialkylformamide\
normally DMF with an acid chloride\ normally phosphorus oxychloride "POCl2#\ for example
Equation "10# ð63JCS"P0#0242Ł^ see also ð44BSF0483\ 52OSC"3#220Ł[ N!methylformanilide "MFA# has
also been used in place of DMF\ for example\ Equation "11# ð78M654Ł[ Yields are often high and
formylation occurs at a position ortho or para to an activating substituent[

MeO OMe POCl3, DMF MeO OMe


(21)
83%
CHO

O O
MFA, POCl3
O O (22)
63% CHO
OMe OMe
81 Aryl and Heteroaryl Aldehydes
Other acid chlorides have also been used\ including thionyl chloride\ oxalyl chloride\ phosgene\
phosphorus pentoxide\ phosphorus tribromide\ phosphorus pentachloride and pyrophosphoryl
chloride[ In the last example a more reactive electrophilic species serves as formylating agent\ and
higher yields and regioselectivity than normal have been observed "Equation "12## ð81SL66\ 82T3904Ł[
OMe OMe
P2O3Cl4, DMF OHC
(23)
100%
OMe OMe

Another modi_cation\ which leads to improved yields for less active substrates\ makes use of the
reactive iminium salt produced from tri~uoromethane sulfonic anhydride and DMF ð89CC0460Ł[
An indirect method for the preparation of benzaldehydes under Vilsmeier conditions has
been developed using aryl trialkylstannanes[ Thus treatment of trimethylphenylstannane with
POCl2:DMF at room temperature gives 45) benzaldehyde via electrophilic ipso!substitution with
loss of a stannyl cation ð78T840Ł[

2[92[0[3[3 The GattermannÐKoch reaction


The GattermannÐKoch reaction converts benzene and simple alkyl and halobenzenes into alde!
hydes in moderate to good yield ð38OR"4#189Ł[ Formylation takes place using hydrochloric acid and
a FriedelÐCrafts catalyst\ normally AlCl2 or AlBr2 under high pressures of CO\ or atmospheric CO
pressure if CuCl is used as a promoter[ The reaction fails for hydroxy\ alkoxy and amino benzenes
and polyaromatics^ see also ð79JOM"083#110Ł[ Good para!selectivity is observed for monoalkyl ben!
zene formylations[

2[92[0[3[4 The Gattermann reaction


The Gattermann reaction is a commonly used method for the formylation of phenols and phenol
ethers by treatment with HCN and HCl in the presence of aluminum chloride\ or more commonly\
in a modi_ed procedure using HCl and zinc cyanide ð46OR"8#26Ł[ Formylation generally occurs para
to an activating substituent[ For examples\ see Equation "13# ð68JHC688Ł and also ð37JCS1072\
75OPP098Ł[

OHC
Zn(CN)2, HCl, Et2O
O (24)
HO HO O
87%
OMe OMe

2[92[0[3[5 Dichloromethyl methyl ether as formylation reagent


Perhaps the most general formylation procedure for arenes\ and certainly the most popular in
recent times\ is formylation using dichloromethyl methyl ether in the presence of SnCl3\ or more
usually TiCl3 in CH1Cl1 ð52CB297\ 67OPP190Ł[ The procedure is practically very simple\ gives high
yields and is normally complete within an hour at room temperature or below[ Formylations occur
ortho or para to an activating substituent\ but nonactivated arenes also react[ Yields are normally
good\ and a wide variety of substituents are tolerated including halo\ alkoxy\ amido and carboxylic
acid groups[ Many examples have been reported\ for example\ Equation "14# ð80JOC0581Ł^ for more
examples see ð67AJC0422\ 70JCS"PI#0326\ 76TL1362\ 89SC1454Ł[

MeO Cl OMe
MeO
Br , CH2Cl2, SnCl4 Br
Cl
N OHC N (25)
82%
OMe OMe
O O
Benzaldehyde and Substituted Benzaldehydes 82
2[92[0[3[6 Miscellaneous formylations
Various miscellaneous formylations of arenes are known[ Of these\ among the more important
are the formylations of simple nonactivated arenes with formyl ~uoride ð59JA1279\ 76CRV560Ł in a
FriedelÐCrafts type reaction[ Similar\ simple arenes have also been formylated with CO\ catalysed
by super acids\ where yields are moderate ð76CRV560\ 80CC0440\ 81JOC1566Ł[ For a detailed discussion
of formylation reactions in general\ see ðB!53MI 292!90Ł[
The formation of benzaldehydes directly by pericyclic reactions is rare and is not discussed in this
chapter[

2[92[1 BENZALDEHYDE AND SUBSTITUTED BENZALDEHYDES

2[92[1[0 Benzaldehyde
Although\ virtually all of the reductive\ oxidative and organometallic routes mentioned in Section
2[92[0 give good yields of benzaldehyde\ not all of the formylation methods are generally applicable
since most require activating electron!donating substituents on the substrate[ The RiemerÐTiemann
reaction is not applicable and the VilsmeierÐHaack reaction also fails for benzene[ The Gattermann
reaction\ Du} reaction and reaction of benzene with dichloromethyl methyl ether:AlCl2 all give
poor yields of benzaldehyde[ Formylation of benzene using formyl ~uoride with boron tri~uoride as
catalyst proceeds in modest yield "45)# ð76CRV560Ł[ Best results are obtained using the GattermannÐ
Koch procedure with AlBr2 as catalyst "89) yield of benzaldehyde# ðB!53MI 292!90Ł[
An industrially viable route to benzaldehyde involves the oxidation of toluene using chlorine
followed by hydrolysis of the benzal chloride intermediate\ although some ring chlorination products
are also observed[ An alternative\ cleaner method is oxidation of toluene using manganese dioxide
in the presence of acetic anhydride[ In this case the intermediate is benzal diacetate which is also
readily hydrolysed to benzaldehyde ðB!78MI 292!91Ł[

2[92[1[1 Alkyl Benzaldehydes


Because alkyl substituents are inert to most conditions\ the majority of general methods are also
applicable to the synthesis of alkyl benzaldehydes[ For reductive procedures\ the carbon that will
become the formyl carbon is already in place so only one positional isomer is possible\ and electronic
e}ects of alkyl substituents have little e}ect[ Such reactions therefore appear applicable to mono!\
di!\ or polyalkyl benzoic acids and their derivatives\ assuming the starting materials are available\
although relatively few examples containing more than one alkyl group have been reported[
3!Methylbenzoic acid derivatives have often been used as model compounds[ Some of the best yields
of aldehyde are from reduction of 3!methylbenzoyl chloride with sodium tri"t!butoxy# aluminum
hydride "76)#\ ð82JOC3621Ł\ or cadmium moderated borohydride "78)# ð79JCS"P0#16Ł\ or by
reduction of 3!methylbenzonitrile with potassium 8!sec!amyl!8!boratabicycloð2[2[0Łnonane "72)#
ð78TL2566Ł[ Steric hindrance may be an important consideration when making 1!alkylbenzaldehydes
by reductions of their acid derivatives[ Of the few examples where comparisons have been made
between 1!\ 2! and 3!alkyl substituted compounds\ 1!substituted benzaldehydes tend to be produced
in lower yield[ Simple 1!methyl benzaldehydes can nevertheless be produced in good yield\ for
example\ Equation "15# ð53JOC0974Ł[

CN CHO
Li(OEt)3AlH, Et2O
(26)
87%

Oxidations of polyalkyl benzenes to alkyl benzaldehydes might be expected to be problematic


since more than one benzylic C0H bond exists[ However\ various selective oxidations have shown
this to be a synthetically viable method[ For instance\ can will oxidise 0\1!\ 0\2!\ and 0\3!dimethyl
benzenes selectively at just one carbon to produce 1!\ 2!\ and 3!methylbenzaldehydes respectively\
all in quantitative yield "Equation "16## ð55TL3382Ł[
83 Aryl and Heteroaryl Aldehydes
CHO
can, 100 °C, 50% AcOH
(27)
R3 R1 R3 R1
R2 R2
R1 = Me; R2, R3 = H, 100%
R2 = Me; R1, R3 = H, 100%
R3 = Me; R1, R2 = H, 100%

Virtually all of the methods listed for the oxidations of benzyl alcohols\ halides and amines to
benzaldehydes appear to tolerate alkyl substituents on the benzene ring\ and they are used exten!
sively[ The same applies to the organometallic methods[ The palladium!catalysed formylation of
aryl iodides is reported to give lower yields for the formation of 1!substituted benzaldehydes than
for 2! or 3!substituted analogues\ presumably due to steric hindrance ð75JA341Ł[ This may be true
for other methods\ but few comparative studies have been reported[
Alkyl benzenes are signi_cantly more reactive towards formylation than benzene itself[ Of the
formylation methods\ the GattermannÐKoch reaction of alkyl benzenes is suitable for the formation
of para!substituted benzaldehydes ðB!53MI 292!90Ł[ Only modest yields result\ but the reaction does
give almost exclusively the one isomer[ Formyl ~uoride formylations also give high paraÐortho
ratios and better yields "×69)# for alkyl and polyalkyl benzenes\ for example\ Equation "17#
ð76CRV560Ł[

CHO

HCOF, BF3
(28)
72%

The modi_ed Du} reaction gives moderate yields of alkyl benzaldehydes\ although mixtures of
ortho! and para! products are generally observed[ However\ in some cases where steric hindrance
plays a role\ good yields of a single product may be achieved\ for example\ t!butyl benzene gives a
64) yield of 3!t!butyl benzaldehyde ð61JOC2861Ł[ The Gattermann synthesis works best for very
activated aryls but also works for alkylbenzenes at elevated temperatures[ Yields are often good[
An example by a modi_ed procedure using s!triazine instead of zinc cyanide is shown in Equation
"18# ð58AP"291#717\ 60AP"293#251Ł^ para! or ortho!substitution is observed[

N CHO

N N , HCl
(29)
89%

Dichloromethyl alkyl ethers may also be used for the synthesis of alkyl benzaldehydes\ although
the regioselectivity is not as good as for many other formylations\ so this method is most useful if
one position is blocked[

2[92[1[2 Halobenzaldehydes
The hydrogenolysis of organic halides\ including aryl halides is a well!documented reaction
ð79S314Ł\ and hence caution should be exercised when synthesising halobenzaldehydes by reductions
of corresponding halo benzoic acid derivatives\ especially since the presence of the electron!with!
drawing acyl group makes this process more facile[ Nevertheless\ many of the reductive methods
are applicable\ notably those using borane reagents and certain aluminum hydrides[ Some examples
giving good yields of halobenzaldehydes are the reduction of halobenzoic acids with NaAlH"ButO#2
ð82JOC3621Ł and t!thexylbromoborane!DMS complex ð76JOC4929Ł\ reduction of halo!substituted
benzoyl chlorides with complex borohydrides ð67TL1362Ł\ and the reduction of halobenzonitriles
with LiAlH"EtO#2 "Equation "29## ð53JA0974Ł[
Benzaldehyde and Substituted Benzaldehydes 84
CN CHO
LiAlH(OEt)3
(30)
84%
Cl Cl

Palladium!catalysed reactions of tributylstannane with 3!bromobenzoyl chloride give very little


"³4)# hydrogenolysis of the C0Br bond\ and 67) of the desired aldehyde ð70JOC3328Ł[ Good
results are also obtained using tributylgermane:Pd"PPh2#3 "Equation "20## ð78JOM"265#30Ł[
COCl CHO
Bu3GeH, Pd(PPh3)4, HMPA, 80–100 °C
(31)
85%
Cl Cl Cl Cl

Fluorine!substituted benzaldehydes have been obtained by the reduction of the corresponding


acids with hypervalent silicon species "Equation "21## ð76TL2830Ł[
Ph
SiH2 NMe2

CO2H CHO
(32)
96%
F F

A halo!substituent appears to be inert to virtually all the methods of oxidising benzyl alcohols\
halides and amines\ thus making it an excellent method for the synthesis of halobenzaldehydes[
Furthermore\ the slight electron!withdrawing e}ect exhibited by these substituents helps prevent
over!oxidation[ Similarly\ halotoluenes can be oxidised e.ciently to benzaldehydes by the methods
described in Section 2[92[0[1[0[ For examples see Equation "22# ð89BSB234Ł\ Equation "23# ð78S182Ł
and Equation "24# ð63SC34Ł[
CHO
NH2•HBr Me2SO, 100 °C
(33)
Cl 87%
Cl

i, KMnO4, Et3N, CHCl3, H2O CHO


ii, H2SO4
(34)
Cl 89%
Cl

CHO
Br i, Hg2(ONO2)2, DME
(35)
Br ii, NaOH
Br

Of the organometallic!based methods for the synthesis of benzaldehydes\ many utilise haloarenes
as starting materials[ The e.ciency of metalÐhalogen exchange varies in the order I×Br×Cl×F\
and thus selective formylations of dihaloarenes are possible[ This strategy has been utilised suc!
cessfully for the synthesis of Br!\ Cl! and F!substituted benzaldehydes[ Methods which have been
used include Grignard reagent additions to imidazolidinium salts "Equation "25## ð68CC006Ł\ pal!
ladium!catalysed formylations with CO and either Bu2SnH "Equation "26## ð75JA341Ł or poly"methyl
hydrosiloxane# "PMHS# "Equation "27## ð73JOC3998Ł[
Me +
N
N Ac
i, I–
MgBr CHO
ii, H2O
(36)
90%
Cl Cl

I CHO
CO (3 atm), Bu3SnH, Pd(PPh3)4, THF
(37)
78%
Cl Cl
85 Aryl and Heteroaryl Aldehydes
I CHO
CO (50 atm), PMHS, Pd(PPh3)4
(38)
95%
Br Br

1!Fluorobenzaldehydes may be synthesised selectively from ~uoroarenes by an ortho!lithiation


procedure using ~uoride as an ortho!directing group[ 1!Fluorobenzaldehydes with a variety of other
substituents have been prepared in this manner\ for example\ Equation "28# ð81TL6388Ł[

Cl Cl
i, LDA
I ii, DMF I CHO
(39)
97%
F F

Classical formylations of simple haloarenes to give halobenzaldehydes are not widely used since
halo substituents deactivate the ring towards electrophilic substitution[ However\ if other activating
groups are present\ halo groups are tolerated in many cases[

2[92[1[3 Oxygen!substituted Benzaldehydes


There are many hundreds of syntheses of benzaldehydes containing either hydroxy or ether
substituents directly attached to the aromatic ring[ Of those papers reporting general routes to
benzaldehydes by reduction of carboxylic acid derivatives\ almost all have examples containing an
alkoxy substituent or occasionally more than one "see Section 2[92[0[0#[ Yields range from moderate
to excellent^ for an example see Equation "39# ð67TL0326Ł[

COCl CHO
(Ph3P)2CuBH4, PPh3, Me2CO
(40)
MeO 86% MeO
OMe OMe

By contrast\ hardly any examples have been reported for reductions of benzoic acids containing
a free hydroxy group[ One method that has been used\ however\ is reduction by sodium amalgam
"Equation "30## ð35JA1491Ł[

CO2H CHO
Na-Hg
(41)
OH 57% OH
F F

Most oxidative methods also tolerate alkoxy groups\ and more examples containing free hydroxy
groups are found using these reactions^ see Equation "31# ð68S033Ł\ Equation "32# ð82TL2408Ł and
Equation "33# ð73S636Ł[

OHC
ddq, dioxan
(42)
O 70% O

OMe O OMe O

Ag2CO3, DMSO, 90 °C
(43)
O Ph 80% O Ph
CHO
OMe Br O OMe O
Benzaldehyde and Substituted Benzaldehydes 86
OH CHO
Me2SeO, PhH, 80 °C OH
OH (44)
92%
OH CHO

Aryl Grignard reagents containing alkoxy substituents have been formylated using reagents
such as DMF "Equation "34## ð66JOC2297Ł\ lithium formate ð73TL0732Ł and N!3\3!trimethyl!1!
oxazolinium iodide ð69JA5565\ 63OS"43#31Ł\ and Stille!type formylations of methoxy!substituted iodo!
benzenes have also been accomplished ð75JA341Ł[

Br CHO
i, Mg
(45)
ii, DMF
MeO MeO

Oxygen is one of the most widely used atoms for directed ortho!metallations[ This method has
been utilised extensively for the selective conversion of oxygen substituted arenes into ortho!oxygen
substituted benzaldehydes[ Some examples are shown in Equation "35# ð82T0310Ł and Equation "36#
ð80SC056Ł[ Selective ortho!formylations of phenols may be realised by reaction of the corresponding
aryloxymagnesium halides with formaldehyde in the presence of HMPA "Equation "37##
ð67JCS"P0#207Ł[ For other less direct methods for overall exclusive ortho!formylation of phenols\
see ð63TL2352Ł[ RiemerÐTiemann\ Vilsmeier\ Gattermann and Lewis acid mediated reactions of
dichloromethyl ethers are all particularly well suited to substrates containing electron!donating
substituents such as hydroxyl and alkoxy groups\ and they have been used extensively "see Section
2[92[0[3#[ Some further examples containing various other functional groups are shown in Equation
"38# ð89SC598Ł\ Equation "49# ð76TL1362Ł and Equation "40# ð72CPB0640Ł[
i, BunLi
O
O ii, DMF
iii, H+
(46)
72% O O-THP
O O-THP
CHO

i, BunLi
MeO O-TIPS MeO OH
ii, DMF
iii, H+
(47)
85% OHC
OMe OMe

OMgBr i, HMPA, PhH, para HCO2H


OH
ii, 10% HCl OHC
(48)
90%

OH OH
NaOH, CHCl3, H2O, ultrasound
(49)
84%
Cl Cl CHO

O Cl O
OMe
Cl
MeO N MeO N (50)
TiCl4, CH2Cl2
O O
MeO MeO CHO

OH OH
MeO2C MeO2C CHO
HMT, MeSO3H, HCl, H2O
(51)
77%

Cl Cl
87 Aryl and Heteroaryl Aldehydes
An alternative formylation procedure for arenes containing oxygen substituents is by reaction
with tris"phenylthio#methane in the presence of dimethyl"methylthio#sulfonium tetra~uoroborate
"dmtsf#[ The intermediate dithioacetals formed in these reactions are readily hydrolysed to produce
the corresponding benzaldehydes\ for example\ Scheme 2 ð73S055Ł[

OMe OMe
OMe
DMTSF, (PhS)3CH DMTSF, H2O

OMe 70%
OMe
OMe
PhS SPh CHO

Scheme 3

2[92[1[4 Sulfur!substituted Benzaldehydes


There are fewer examples of benzaldehydes containing sulfur substituents than those containing
oxygen substituents[ This may re~ect the fact that the sulfur centre itself may react under certain
reducing and:or oxidising conditions[ Nevertheless\ some examples have been reported^ for instance\
a benzyl bromide containing a thioether may be oxidised selectively at the benzylic position with
dimethylselenoxide "Equation "41## ð73S636Ł\ and under certain conditions manganese dioxide
oxidises benzylic alcohols to benzaldehydes in the presence of a thioether ð66JOC2403Ł[

SMe SMe
Me2SeO, ClCH2CH2Cl, KHPO4
(52)
Br 97%
CHO

Sulfur substituents in general tend to be excellent at directing ortho!metallations[ Quenching with


DMF is then an excellent route to ortho!S!substituted benzaldehydes\ for example\ Equation "42#
ð78JOC13Ł and Equation "43# ð75JOC1722Ł[

i, BunLi SO2But
SO2But ii, DMF
(53)
90%
CHO

i, BunLi SO3Et
SO3Et
ii, DMF
(54)
74%
CHO

Very few methods have been reported for the formylation of aryl alkyl thioethers by classical
formylation techniques[ Vilsmeier reaction of methyl phenyl sul_de does give 3!methyl!
thiobenzaldehyde but the yield is reported to be poor ð44BSF0483Ł[

2[92[1[5 Nitrogen!substituted Benzaldehydes


Many reagents will reduce benzoic acids and their derivatives containing a nitro substituent and
yields are very often high "×79)#[ A notable exception is the reaction of p!nitrobenzoyl chloride
with hydridoiron tetracarbonyl anion which fails because the nitro group is reduced simultaneously
under the conditions[
A selection of methods giving excellent yields of simple nitrobenzaldehydes are reductions of the
acyl chlorides with either sodium tri"t!butoxy# aluminum hydride "Equation "44## ð82JOC3621Ł\
hypervalent silicon hydrides ð77TL0160Ł\ tributylstannane under palladium catalysis ð70JOC3328Ł or
0\2!dimethyl!1!phenylbenzimidazole ð75JOC4399Ł[
Polyaromatic Aldehydes 88
COCl CHO
NaAlH(OBut)3
(55)
O2N 89%
O2N

Fewer examples of reductive approaches to amino benzaldehydes are reported\ although good
yields have been found for the reductions of nitrobenzoic acids by t!thexylbromoborane!DMS
complex ð76JOC4929Ł\ or ButLi:8!BBN!H ð76TL5120Ł[
The nitro substituent appears to tolerate most oxidation procedures\ with excellent yields being
obtained for the oxidation of 3!nitrobenzyl bromide with dimethyl selenoxide "099)# ð73S636Ł\ or
the oxidation of 3!nitrobenzyl alcohol with tetrakis"pyridino# cobalt"II# dichromate "84)#
ð81SC0380Ł^ see also ð89BCJ1322Ł[ Free amino substituents do not appear to tolerate many oxidants\
although amino toluenes have been oxidised by 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#
if the amino group is sterically hindered "Equation "45## ð73TL1890Ł[
CHO
ddq, dioxan
(56)
H 2N 49% H2N

1! and 3!Methyl!N!acetylanilines have been oxidised successfully to 1! and 3!N!acetylamino


benzaldehydes respectively\ in ×89) yield using can ð55TL3382Ł[
Of the organometallic routes to benzaldehydes\ few examples have been reported for N!substituted
derivatives[ The synthesis of p!nitrobenzaldehyde has been reported by the Stille procedure\ but in
poor yield[
Formylations of nitroarenes by electrophilic aromatic substitution are not very viable since the
reactions are disfavoured by the electron!withdrawing nature of the nitro group[ A few examples
are known however\ where other activating groups are present to counteract this e}ect\ for example\
Equation "46# ð59CB77Ł[
O2N O2N CHO
AlCl3, Cl2CHOMe
(57)
62%
OMe OMe

The strong electron!withdrawing nature of the nitro group actually makes nitroarenes susceptible
to nucleophilic substitution\ and direct formylations have been achieved by reactions with the CCl2−
anion followed by hydrolysis of the intermediate "Scheme 3# ð76TL2910Ł[
Cl
Cl Cl CHO
ButOK, CHCl3 Cl H+, H2O
Cl
94% 66%
NO2 NO2
NO2

Scheme 4

Formylations of N!alkyl and N\N!dialkyl amines are best achieved using the Vilsmeier reaction\
although yields are very variable^ the formylations occur para to the amine substituent ð52OSC"3#220\
B!53MI 292!90\ 82T3904Ł[
Finally a simple direct route to 3!aminobenzaldehydes has been achieved by reaction of simple
anilines with the DMSO!HCl reagent in the presence of copper"II# chloride\ where yields are good
to excellent\ for example\ Equation "47# ð81JCS"P0#1124Ł[
Br Br
Br DMSO-HCl, CuCl2 Br CHO
(58)
84%
H2N H 2N

2[92[2 POLYAROMATIC ALDEHYDES


Just as benzaldehyde has been extensively used as the model product for methodology towards
simple aryl aldehydes\ naphthaldehyde has correspondingly been used for routes to polycyclic aryl
099 Aryl and Heteroaryl Aldehydes
aldehydes[ Both 0! and 1!naphthaldehydes have been made by numerous reductive methods from
various naphthoic acid derivatives[ Yields in many cases are excellent[ High yielding syntheses of
1!naphthaldehyde include reduction of 1!naphthoyl chloride either by Rosenmund reaction "70)#
ð44OSC"2#516Ł\ or with NaAlH"ButO#2 "70)# ð82JOC3621Ł\ reduction of 1!N\N!dimethylnaphthamide
with LiAlH"EtO2# "70)# ð53JA0978Ł\ or reduction of the corresponding nitrile by Stephen|s method
"80)# ð28JA1137Ł[ Good yields of 0!naphthaldehyde are also reported from the reduction of the
corresponding acid with bis"N!methylpiperazinyl# aluminum hydride "84)# ð73JOC1168Ł\ and the
nitrile via reduction of its nitrilium ion with triethylsilane "73)# ð63CC34Ł\ amongst others "see
Section 2[92[0[0#^ interestingly the Stephen reaction gives very poor yields in this case[
Few examples of multifunctionalised naphthaldehydes or aldehydes of other polyaromatic systems
have been made by the newer reductive methods\ although they have much potential[ For older
methods such as the McFadyenÐStevens procedure some more interesting examples have been
documented\ for example\ Equation "48# ð36JA0887Ł[

OMe
OMe OMe
Na2CO3
OMe (59)
O 79%

PhSO2 N OHC
N

A greater variety of polyaromatic aldehydes have been made by oxidative routes[ Oxidants
that have been used include barium manganate "Equation "59## ð67TL728Ł\ ddq "Equation "50##
ð77JOC3476Ł and N!cyclohexylbenzene sul_namide "Equation "51## ð70JOC3506Ł[
CHO
OH BaMnO4, CH2Cl2
(60)
OH 87%
CHO

ddq, AcOH, H2O


(61)
90%
CHO

Br Br
NaH CHO
Br (62)
O
S Ph
N
H

Reaction of 4!bromo methyl!0\ 0H!benzo"a#~uoren!0\0!one with silver nitrate followed by base


decomposition of the intermediate\ the nitrate ester\ gave the corresponding aldehyde in 75) yield
"Equation "52## ð50JA082Ł[
O
O
i, AgNO3
ii, KOH
(63)
86%

Br CHO

Certain polyaromatic compounds on treatment with strong oxidants can be cleaved selectively at
one position to give aldehyde products\ for example\ Equation "53# ð59JOC0785Ł[

i, OsO4
ii, NaIO4
(64)
78% CHO
CHO
Polyaromatic Aldehydes 090
Naphthyl lithium and naphthyl magnesium halide reagents can be formylated by dialkyl!
formamides\ or by other formylating agents mentioned in Section 2[92[0[2^ see for example ð67S392\
70AG"E#767\ 73S117\ 73TL0732Ł^ yields are generally high[
Many polyaromatic aldehydes have been made by classical electrophilic!substitution reactions of
activated arenes with formyl cation equivalents[ In these reactions regioselectivity is an important
factor[ Formylation of naphthalene generally occurs at the 0!position\ as is the case using dichloro!
methyl methyl ether:SnCl3[ The yield in this case is 79) ð59CB77Ł[ Anthracene gives an 73) yield
of 8!formyl anthracene in the Vilsmeier reaction "Equation "54## ð44OSC"2#87Ł[

CHO
PhMeNCHO, POCl3
(65)
84%

Anthracene itself has also been formylated in nearly quantitative yield by a modi_ed Vilsmeier
reaction using the formylation complex derived from tri~uoromethane sulfonic anhydride and DMF
ð89CC0460Ł[ Naphthalenes with electron!donating substituents in the 1!position formylate in the
0!position of the same ring as the activating substituent "Equation "55# ð61JCS"P0#781Ł and Equation
"56# ð52CB297Ł#^ similar substituents on anthracenes alter the position of formylation "Equation
"57## ð45MI 292!90\ 63BCJ0576Ł[
CHO
Zn(CN)2, AlCl3, HCl
(66)
89%

Cl
CHO
OH OMe, TiCl4
Cl OH
(67)
82%

CHO
OH
Zn(CN)2, HCl, Et2O, H2O OH
(68)

The formylation of naphthalenes with various combinations of alkoxy substituents by malonic


acid in the presence of manganese"III# gives modest yields of the corresponding aldehydes
ð78BCJ434Ł[ Reactions of 0! and 1!methoxynaphthalenes with DMF and pyro!phosphoryl chloride
lead to formylation at the 3! and 0!positions respectively\ in yields over 85) ð82T3904Ł[ Equation
"58# shows an example where the Du} formylation has been used in a synthesis of 0\3\7!trimethoxy!
1!naphthaldehyde[ Interestingly\ attempted reaction under Vilsmeier conditions gave mainly
O!formylation[ Treatment of the trimethoxy derivative under the same conditions gave the 4!formyl
product "00# ð78BCJ1625Ł[
OMe OH OMe OH
CHO
HMT, AcOH, TsOH
(69)
61%

OMe OMe

OMe OMe

CHO OMe
(11)
091 Aryl and Heteroaryl Aldehydes
2[92[3 HETEROCYCLIC ARYL ALDEHYDES

2[92[3[0 O!Heterocyclic Aldehydes

2[92[3[0[0 Furan and benzofuran carboxaldehydes


Both 1! and 2!furoic acids and various derivatives have been reduced to the corresponding
furan carboxaldehydes using numerous reducing agents[ 1!Furoic acid itself may be reduced with
hypervalent silicon hydrides ð76TL2830Ł\ or reaction with N\N!dimethyl chloromethyleniminium
chloride followed by reduction of the intermediate with LiAlH"ButO#2 ð72TL0432Ł\ to give the
aldehyde in 65) and 69) yields respectively[ Better yields are obtained by reduction of the
corresponding acyl chloride with complex borohydrides "71)# ð67TL1362Ł\ hypervalent silanes
"76)# ð77TL0160Ł\ or the hydridoiron tetracarbonyl anion "89)# ð66TL670Ł[
Furan 2!carboxaldehyde has been produced in 51) yield from 2!furoic acid by reduction using
bis"N!methylpiperazinyl# aluminum hydride ð73JOC1168Ł[
Reductions of cyano furans with dibal!H has been used to make various substituted furan
carboxyaldehydes\ for example\ Equation "69#\ as well as all the possible regioisomeric furan
dicarboxyaldehydes "from the dicyano derivatives# in good yield ð69BSF0334Ł^ see also ð53JOC2935Ł[
CN CHO
dibal-H (2 equiv.), PhH
(70)
CN 65% CHO
O O

Furans and benzofurans appear to tolerate many oxidative conditions and these methods have
proved popular for the synthesis of a variety of O!hetaryl aldehydes[ Oxidants that have been used
include MnO1 "Equation "60## ð60AJC0772Ł\ silver carbonate "Equation "61## ð65JHC414Ł\ or barium
ferrate "Equation "62## ð77BCJ1074Ł for the oxidation of hydroxymethyl furans[ Oxidations under
Swern conditions have been carried out in the presence of a phenythio methyl group in good yield
"Equation "63## ð81JA2809Ł[
OMe OMe
OH MnO2, CCl4
(71)
87% CHO
O O

Ag2CO3, PhH
OH (72)
O 80% O CHO

HO OH OHC CHO
BaFeO4, H2O, PhH
(73)
Ph Ph 80%
O Ph O Ph

CO2Me CO2Me
i, (COCl)2, DMSO
HO SPh SPh (74)
ii, Et3N OHC
O O

Furans containing halomethyl substituents have been oxidised to the corresponding aldehydes
by\ amongst others\ the Sommelet reaction\ for example\ Equation "64# ð69BSF0334Ł\ or by oxidation
with the sodium salt of 1!nitropropane\ for example\ Equation "65# ð57JHC84Ł[

Br i, HMT, CHCl3 CHO


ii, H2O
(75)
CO2Me 54% CO2Me
O O

CO2Et CO2Et
NaOEt, PriNO2, EtOH
Br (76)
CF3 71% OHC CF3
O O
Heterocyclic Aryl Aldehydes 092
Other oxidative methods leading to furan carboxaldehydes include oxidative decarboxylation of
a benzofuran!2!acetic acid using pyridine N!oxide "Equation "66## ð81IJC"B#415Ł\ and a!sulfuration
of a phenylthiomethyl group followed by silver perchlorate promoted hydrolysis of the intermediate
dithioacetal "Equation "67## ð81JA2809Ł[ This latter example has been used in studies towards the
total synthesis of furanocembranolides[ A _nal oxidative procedure involves cleavage of a diol using
an oxidant such as NaIO3\ for example\ Equation "68#[ The substrate in this case is readily available
by condensation of glucose with acetylacetone ð34JCS005Ł[

+
N O–
CO2H CHO
Ac2O, PhH
(77)
90%
O O

CO2Me CO2Me

CHO
SPh
O i, KHMDS, then PhSO2SPh O
(78)
ii, AgClO4, H2O, PhH
O O
OSiButPh2 OSiButPh2
O H O H

OH OH O
HO O
NaIO4
(79)
OH O
OHC O

Lithiations of furans and benzofurans occur preferentially at the 1!position[ This strategy has
been used in the synthesis of the corresponding 1!formyl derivatives by quenching the anions
with DMF\ for example\ Equation "79# ð66BSF031Ł^ see also ð67HCA329\ 72TL0666Ł[ MetalÐhalogen
exchange reactions followed by quenching with DMF have also been used for the synthesis of
both 1! and 2!furan carboxaldehydes\ for example\ ð69BSF0727Ł[ Preferential metallation of
1\2!dibromofuran occurs at the 1!position "Equation "70##[

BunLi, DMF
CHO (80)
O 70% O

Br Br
BunLi, DMF
(81)
O Br O CHO

Palladium!catalysed formylation of 2!iodofuran with CO and Bu2SnH occurs under Stille con!
ditions in 59) yield ð75JA341Ł[ Classical formylations of furans and benzofurans have been
accomplished using either Lewis acid mediated reactions with dichloromethyl methyl ether or by
Gattermann reactions[ The most popular method however is by use of the Vilsmeier reaction
ðB!53MI 292!90Ł[
Furans undergo formylation at the 1! or 4!positions\ and benzofurans at the 1!position pref!
erentially[ Formylation at other positions may occur if the favoured positions are blocked however\
although yields tend to be lower[ For benzofurans where the 1!position is blocked formylation in
the benzene ring may compete\ particularly if electron!donating substituents are present[ Selected
examples are presented in Equation "71# ð73JOC1404Ł\ Equation "72# ð42JIC092Ł and Equation "73#
ð81T0928Ł[ In the last example\ concomitant removal of the acetate function has been observed[

POCl3, DMF
(82)
96% CHO
O O
093 Aryl and Heteroaryl Aldehydes

ZnCl2, HCN, HCl, Et2O


(83)
85%
CHO
MeO O MeO O

O CHO

O Zn(CN)2, HCl, KCl, Et2O HO


(84)
O 50% O

OMe OMe

Lastly\ 2!formyl benzofuran has been synthesised by an intramolecular cyclisation reaction of an


aryl radical onto a pendant propargyloxy group followed by a radical trapping reaction with
TEMPO[ Acid!catalysed elimination of amine from the initially formed O!vinylhydroxylamine then
furnishes the aldehyde "Scheme 4# ð70CC484Ł[

NR2 H+
+ N O•
CHO
N2 O
H+
Me2CO
O H O
BF4–
O

Scheme 5

2[92[3[1 S\ Se and Te Heterocyclic Aldehydes

2[92[3[1[0 Thiophene and benzothiophene carboxaldehydes


Thiophene is classed as a relatively electron!rich aromatic compound with a resonance energy
larger than furan and about half that of benzene ðB!74MI 292!90Ł[ Its similarity to benzene is
highlighted by the fact that many of the methods used for the synthesis of formyl thiophenes parallel
those for benzaldehydes\ and most start with the thiophene ring already in place[ Like furan\
classical formylations using the Vilsmeier reaction or similar procedures occur preferentially at the
1! or 4!position of thiophene[ Deprotonation with strong bases occurs at the same position\ thus
making the synthesis of 2! and 3!substituted derivatives more di.cult[ Both 1! and 2!formyl
thiophene derivatives have\ however\ been synthesised by reduction of the corresponding cyano
compounds ð58BSF1400Ł[ Thiophene!1!carboxylic acid and its acyl chloride have also been reduced
to 1!formyl thiophene by hypervalent silicon hydrides ð76TL2830\ 77TL0160Ł in 77) and 79)
yields respectively[ The Sommelet oxidation of 1! and 2!halomethylthiophenes has produced 1! and
2!formylthiophenes in 63) and 61) yields respectively\ for example\ Equation "74# ð42JCS0631\
52OSC"3#807Ł[

i, HMT, 50% AcOH


ii, conc. HCl
Cl (85)
S 74% S CHO

An interesting route to certain 2!formylthiophenes involves dibromination of 2!methylthiophenes


followed by hydrolysis "Scheme 5# ð64TL3694Ł[ Slow addition of bromine to a light!irradiated
Heterocyclic Aryl Aldehydes 094
solution of the substrate in the presence of AIBN promotes this reaction and suppresses the normal
rapid ring bromination of thiophenes[

Br
CHO
Br2, AIBN, hν, CCl4 Br Na2CO3, py

Cl 85% 70% Cl
S Cl S
S

Scheme 6

Probably the most popular method for the synthesis of formyl thiophenes is by treatment of an
appropriate lithiated thiophene with a dialkyl formamide[ 1!Lithio thiophenes can be formed directly
from deprotonation of the parent thiophene or by haloÐlithium exchange from a 1!halothiophene\
for example\ ð42JA2586\ 65BSF154\ 77S205Ł[ The selective formation of 2!formyl thiophenes has also
been accomplished by haloÐlithium exchange of 2!bromothiophenes\ followed by addition of DMF\
for example\ Equation "75# ð56BSF1384\ 75CB2087Ł[

Br S i, BunLi CHO S
ii, DMF
(86)
99%
S S

Treatment of 2!bromothiophene with two equivalents of butyllithium leads to 1\2!dilithio!


thiophene by simultaneous haloÐmetal exchange and deprotonation[ Addition of DMF then a}ords
the corresponding dialdehyde in moderate yield\ "Equation "76## ð56BSF1384Ł^ see also ð58BSF1400Ł
for the synthesis of di! and triformyl thiophenes[
Br i, BuLi (2 equiv.) OHC
ii, DMF
(87)
40% OHC
S S

Thiophene\ like furan is more reactive towards electrophiles than benzene[ Because of its
relatively high aromatic character\ substitution products predominate over addition products^ thus
thiophene is an excellent candidate for formylation by the Vilsmeier reaction ð49JA0311\ 52OSC"3#804\
B!53MI 292!90\ 79S022Ł[ Finally\ 1!nitrothiophene undergoes nucleophilic substitution with CCl2−
anion to give\ after hydrolysis\ the 2!formyl derivative ð76TL2910Ł[
The preparations of formyl benzothiophenes may be accomplished in many cases by analogous
procedures to those used for formyl thiophenes[ Lithiation occurs preferentially at the 1!position
and 2!formyl derivatives may be made by lithiation of the corresponding bromides\ for example\
Equation "77# ð60JCS"C#071Ł[ It should be noted however that 2!lithio benzofurans need to be kept
at low temperature to avoid ring cleavage occurring[

Br i, BuLi, –70 °C CHO


ii, DMF
(88)
85%
S S

Benzothiophene is slightly less reactive towards electrophiles than thiophene itself\ but still
undergoes Vilsmeier formylation[ The 2!position is more activated than the 1!position\ unlike
thiophene and benzofuran\ although mixtures are often produced[ If one position is blocked single
products can be obtained\ for example\ Equation "78# ð56JCS"C#668Ł[ If the benzene ring contains
electron!donating substituents "or the heterocyclic ring contains electron!withdrawing substituents#\
then formylation may occur preferentially in the six!membered ring\ for example\ Equation "89#
ð56JCS668Ł[

OMe OMe
MFA, POCl3
(89)
50% CHO
S S
095 Aryl and Heteroaryl Aldehydes
OMe
OMe
MFA, POCl3
(90)
70% S
S
CHO

2[92[3[1[1 Se and Te heterocyclic aldehydes


Various formyl selenophenes and tellurophenes have been made\ normally by analogous methods
to those used for the preparation of formyl thiophenes[ Tellurophene is more reactive to electrophilic
attack than selenophene\ which is more reactive than thiophene[ All are less reactive than furan[
For a comparison of the formylation reactions of these heterocycles see ð60CC0330Ł[ For other
examples of formyl selenophenes see ð58BSF1400\ 65BSF154Ł[

2[92[3[2 N!Heterocyclic Aldehydes

2[92[3[2[0 Pyrrole and indole carboxaldehydes


Many of the general procedures used for the synthesis of benzaldehydes may be applied to the
synthesis of pyrrole and indole carboxaldehydes\ and due to their importance in the nature of the
pyrrole subunit "for instance in porphyrins# many examples are to be found in the literature[
Conversions of acyl pyrroles into the corresponding aldehydes have been accomplished by Raney
nickel reduction of a corresponding 2!"thiolester# pyrrole in good yield "Equation "80## ð55CJC0996Ł[
The most common method for converting 1!acyl pyrroles into 1!formyl pyrroles appears to be
treatment of the carboxylic acid with trimethylorthoformate and tri~uoroacetic acid ð61AJC0868Ł[
This reaction is actually a decarboxylation formylation sequence but gives the same overall trans!
formation as reduction[ Battersby and co!workers have used such a procedure\ for example\ in a
synthesis of an isobacteriochlorin macrocycle "Equation "81## ð70CC686Ł[
O
EtO2C CHO
EtO2C SEt Raney Ni, Me2CO, MeOH
(91)
85% EtO2C N
EtO2C N H
H

CO2Me CO2Me
MeO2C MeO2C

CO2But (MeO)3CH, TFA CHO


N N (92)
H 86% H
NH NH

O O

Pyrrole and indole carboxaldehydes have been made from oxidations of their methyl analogues\
for example\ N!protected 2!methylindoles have been oxidised to the 2!carboxaldehydes by selenium
dioxide ð72TL3462Ł\ and 1!methylpyrroles have been oxidised by sulfuryl chloride ð63JOC1761Ł[ For
examples of the oxidation of 1!hydroxymethyl indoles to aldehydes by MnO1\ see ð73JOC2084\
76JCS"P0#820Ł^ the same reagent has also been used for the partial oxidation of 3!hydroxymethyl
indole ð79JOC2249Ł[ The Sommelet oxidation can be applied to indole systems ð41JA4009Ł\ and
N!protected pyrroles and indoles both metallate preferentially at the 1!position^ the anions may
then be quenched by DMF to give the aldehyde products ð71SC120\ 81H"23#0184Ł[
Probably the most frequently used way of making pyrrole or indole carboxaldehydes is by classical
formylation procedures[ The Vilsmeier reaction of pyrrole is a very important reaction and occurs
at the 1!position in good yield ð52OSC"3#720Ł[ If both of the 1! and 4!positions are blocked\ the other
positions often still undergo formylation ð52JOC2941Ł[ With electron!withdrawing groups in the
Heterocyclic Aryl Aldehydes 096
1!position\ formylation tends to occur at the 3!position[ However\ di}erent methods may give
di}erent selectivities[ For the reaction shown in Equation "82#\ the Vilsmeier procedure gave a
mixture of isomers in moderate yield\ whereas formylation with dichloromethyl methyl ether proved
far superior ð67JOC3738Ł[ If electron!donating groups are present in the 1!position 4!formyl deriva!
tives are generally observed[

OHC
OMe AlCl3, Cl2CHOMe
OMe (93)
N
O 89% N
Me O
Me

Indole\ unlike pyrrole\ but similar to benzothiophene undergoes preferential formylation at the
2!position[ Under Vilsmeier conditions 2!indole aldehyde itself is produced in 86) yield from indole
ð52OSC"3#428Ł[ If the 2!position is blocked\ 1!formylation is sometimes successful as shown in
Equation "83# ð74TL1044Ł[ If the nitrogen centre is not protected N!formylation tends to occur[

F F

POCl3, DMF
(94)
86%
CHO
N N
Me Me

When positions 1 and 2 are both blocked\ formylation can occur in the six!membered ring[ A
very elegant example of this is shown in Equation "84# where the Du} reaction proved to be the
method of choice for the regioselective formylation of ellipticine ð81S0110Ł[

OHC

N HMT, TFA
N (95)
N 97%
H N
H

2[92[3[2[1 Pyridine and quinoline carboxaldehydes


Pyridine is very deactivated towards electrophilic substitution with respect to benzene[ For this
reason classical formylation\ using methods such as the Gattermann or Vilsmeier reactions\ are not
generally successful[ The best ways of making substituted pyridines tend to be by ring synthesis
using a suitably functionalised precursor ðB!74MI 292!90Ł\ however few methods give formyl pyridines
directly[ It is therefore important to be able to transform other functional groups on the pyridine
ring into aldehyde groups[
Reductions of pyridines containing carboxylic acid substituents or their derivatives are commonly
used procedures for the synthesis of pyridine carboxaldehydes[ This feature is demonstrated by the
following examples] "i# 1!formyl pyridines have been made by reduction of the corresponding acyl
chlorides with sodium diethyldihydroaluminate ð82SC0664Ł\ or with hypervalent silicon hydrides
ð76TL2830\ 77TL0160Ł^ "ii# 2!formyl derivatives have been produced from the cyano pyridines using
triethoxy aluminum hydride ð45AG327Ł\ or by a modi_ed Stephen reduction ð40JOC0010Ł "in the
latter the semithiocarbazone was isolated#\ from the acyl chloride by palladium!catalysed reduction
with tributylstannane ð70JOC3328Ł\ or reduction of the acid using dimethylchloro methyleneiminium
chloride:lithium tri"t!butoxy# aluminum hydride ð72TL0432Ł\ or bis"3!methylpiperazinyl# aluminum
hydride "Equation "85## ð63CL0336Ł[ The latter reagent has also been used for 3!formyl pyridine
synthesis by reduction of the corresponding methyl ester ð64CL104Ł[ For ester reduction using
dibal!H\ see ð57BSF3006Ł[ Electrochemical reduction of acid derivatives has also been achieved
ð52ACS1214Ł[
097 Aryl and Heteroaryl Aldehydes

HAl N N Me (2 equiv.)
CO2H CHO
2
(96)
75%
N N

The synthesis of formyl pyridines from oxidation of a methyl substituent has been achieved using
selenium dioxide "Equation "86## ð57CPB786\ 73CPB3803Ł or iodine:DMSO ð69JOC730Ł[ The most
popular method for oxidation of hydroxymethyl pyridines is by use of manganese dioxide\ for
example\ Equation "87# ð73JA529Ł[
O O O O
EtO EtO
OEt SeO2 OEt
(97)
N N 69% OHC N N

O O
MnO2, CH2Cl2
NH NH (98)
HO N 75% N
N OHC N

For an example where MnO1 selectively oxidises a 3!hydroxymethyl substituent over a


2!hydroxymethyl substituent\ see ð37JA2323Ł[ Silver carbonate has been used to oxidise 1!\ 2! and
3!hydroxymethylpyridines to the aldehydes ð65JHC414Ł[ The Sommelet reaction ð42JCS0639Ł and the
Kornblum oxidation ð73S636Ł have also been employed for the synthesis of pyridine carbox!
aldehydes[ For a comparison of methods that have been used to synthesise 2!formyl pyridines\ see
ð65HCA100Ł[ Various routes proceeding via pyridyl organometallic reagents are known\ for example\
2!formyl pyridine has been made from the 2!bromo derivative by palladium!catalysed formylation
under pressure of CO[
Probably the most popular method used for the preparation of substituted formyl pyridines is by
reaction of a metallated pyridine with a dialkylformamide[ Metallation is not always easy since
alkyllithium reagents sometimes undergo nucleophilic addition to pyridines[ Lithiation is\ however\
often successful if directed metallation groups are present or if hindered bases such as LDA are
used[ For selected examples see Equation "88# ð72TL2180Ł\ Equation "099# ð71CPB0146Ł\ Equation
"090# ð67TL116Ł and Equation "091# ð74CL0792Ł[
CHO
i, LDA
ii, DMF
(99)
Br N 73%
Br N

O But O But
i, BunLi OHC
ii, DMF
MeO NH MeO NH (100)
73%

N N

N i, MeLi N CHO
ii, DMF
O O (101)
52%
N N

i, Mg, EtMgBr
ii, DMF
(102)
O N Br 94% O N CHO
Heterocyclic Aryl Aldehydes 098
Many of the methods which have been used for the preparation of pyridine carboxaldehydes are
equally applicable to the synthesis of quinoline carboxaldehydes[ For example\ methyl quinolines
have been oxidised to the corresponding aldehydes using selenium dioxide ð30JA1543\ 65BSF678Ł\
quinoline esters have been reduced to aldehydes using dibal!H ð65BSF678Ł\ and certain quinolines
have been metallated and reacted with DMF or MFA to produce the formyl derivatives\ for
example\ Equation "092# ð63T3042Ł[
OMe OMe
i, BunLi
ii, MFA CHO
(103)
68%
N OMe N OMe

2[92[3[3 Miscellaneous Heterocycles] Oxazoles\ Thiazoles and Imidazoles


Oxazoles\ thiazoles and imidazoles all react preferentially at the 1!position with strong lithium
bases[ The standard method of synthesis of 1!formyl derivatives is therefore by metallation at this
centre\ by deprotonation or haloÐmetal exchange\ followed by quenching the resulting anion with
a suitable electrophile\ such as DMF[ For an example of this strategy applied to 1!formyloxazole\
see ð80JOC338Ł[ In fact\ the same organometallic reagent\ 1!lithiooxazole\ can be used for the
synthesis of the 3!formyl derivative\ since it is an ambident nucleophile and reacts with aldehydes
at the 3!position[ Choice of a suitable aldehyde\ such as "01#\ a}ords the alcohol "02# which may be
deprotected and the resulting triol then cleaved oxidatively to produce 3!formyl oxazole "Scheme
6# ð80JOC338Ł[
O
O
OH
N OHC N
O i, DOWEX
Li O N
O (12) ii, NaIO4
O
O O
(13)

Scheme 7

In the case of thiazoles all three isomeric formyl derivatives have been produced using selective
lithiation procedures\ and quenching the resulting anions with a formamide ð76S887Ł[ Likewise\
formyl imidazoles may be made using analogous metallation reactions ð77TL2396\ 80JOC3185Ł[ Classi!
cal formylations of these heterocycles are di.cult\ and therefore not generally applicable[ Oxidative
methods appear to be applicable if the required starting materials are available[ For instance\ both
1!formylimidazoles and 1!formylthiazoles have been produced from selenium dioxide oxidation of
the corresponding alcohols ð55ACS1538Ł[

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.04
Ketones: Dialkyl Ketones
KEVIN E. B. PARKES
Roche Products Ltd., Welwyn Garden City, UK

and

STEWART K. RICHARDSON
University of Notre Dame, IN, USA
2[93[0 SATURATED UNSUBSTITUTED KETONES 001
2[93[0[0 From Alkanes 001
2[93[0[1 From Alkenes 002
2[93[0[2 From Alkynes 003
2[93[0[3 From Halides 003
2[93[0[4 From Alcohols and Their Derivatives 003
2[93[0[4[0 By oxidation of secondary alcohols 003
2[93[0[4[1 From diols 010
2[93[0[4[2 By oxidation of derivatives of alcohols 010
2[93[0[4[3 Rearran`ement of allylic alcohols 011
2[93[0[5 From Epoxides 011
2[93[0[6 From Acetals\ Enol Ethers and Enol Esters 012
2[93[0[7 From Aldehydes or Ketones 012
2[93[0[7[0 From saturated aldehydes or ketones 012
2[93[0[7[1 From unsaturated ketones 016
2[93[0[7[2 From a!functionalized ketones 017
2[93[0[8 From Carboxylic Acids and Their Derivatives 018
2[93[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives 018
2[93[0[8[1 Other preparations from acids and acid derivatives 020
2[93[0[09 From Sulfur or Other Lower Chalco`en!containin` Precursors 020
2[93[0[00 From Nitro`en!containin` Precursors 021
2[93[0[00[0 From amines 021
2[93[0[00[1 From oximes\ hydrazones and their derivatives 022
2[93[0[00[2 From nitroalkanes 023
2[93[0[00[3 From nitriles 023
2[93[0[01 From Or`anosilanes 023
2[93[0[02 From Or`anoboranes 023
2[93[0[03 Methods Involvin` Umpolun` 024
2[93[0[03[0 Acyl anions and their equivalents 025
2[93[0[03[1 Other anion equivalents 026
2[93[1 BETA!UNSATURATED AND MORE REMOTELY UNSATURATED KETONES 027
2[93[1[0 Dialkyl Ketones with One Double Bond 027
2[93[1[0[0 From ketones 027
2[93[1[0[1 From carboxylic acid and carboxylic acid derivatives 039
2[93[1[0[2 Preparations involvin` rearran`ements 030
2[93[1[0[3 Miscellaneous preparations 031
2[93[1[1 Dialkyl Ketones with More Than One Double Bond 033
2[93[1[2 Dialkyl Ketones with Aryl or Heteroaryl Substituents 033
2[93[1[2[0 From ketones 033
2[93[1[2[1 From carboxylic acids and carboxylic acid derivatives 035

000
001 Dialkyl Ketones
2[93[1[2[2 Other preparations 035
2[93[1[3 Alkynyl!substituted Dialkyl Ketones 035
2[93[1[3[0 From ketones 035
2[93[1[3[1 Fra`mentation reactions 036

2[93[2 HALO!SUBSTITUTED DIALKYL KETONES "a!\ b! AND MORE REMOTE HALOGENS# 037
2[93[2[0 Introduction 037
2[93[2[1 Fluoroaliphatic Ketones 037
2[93[2[1[0 a!Fluoroaliphatic ketones 037
2[93[2[1[1 b!Fluoroaliphatic ketones 049
2[93[2[2 Chloroaliphatic Ketones 040
2[93[2[2[0 a!Chloroaliphatic ketones 040
2[93[2[2[1 b!Chloroaliphatic Ketones 042
2[93[2[3 Bromoaliphatic Ketones 042
2[93[2[3[0 a!Bromoaliphatic ketones 042
2[93[2[4 Iodoaliphatic Ketones 044
2[93[2[4[0 a!Iodoaliphatic ketones 044
2[93[2[4[1 b!Iodoaliphatic ketones 045
2[93[3 KETONES BEARING AN OXYGEN FUNCTION 045
2[93[3[0 OH!functionalized Ketones 045
2[93[3[0[0 a!OH!functionalized ketones 045
2[93[3[0[1 b!OH!functionalized ketones 048
2[93[3[0[2 g!Functionalized and more remotely OH!functionalized ketones 050
2[93[3[1 OR!functionalized Ketones 051
2[93[3[2 OX!functionalized Ketones 052

2[93[4 KETONES BEARING A SULFUR FUNCTION 053


2[93[4[0 SH! and SR!functionalized Ketones 053
2[93[4[0[0 a!SH! and SR!functionalized ketones 053
2[93[4[0[1 b!Functionalized and more remotely substituted SH! and SR!functionalized ketones 057
2[93[4[1 Hi`her!coordinated Sulfur!functionalized Ketones 069

2[93[5 KETONES BEARING A Se or Te FUNCTION 062


2[93[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Ketones 062
2[93[5[1 Hi`her!coordinated Se! or Te!functionalized Ketones 066
2[93[6 KETONES BEARING A NITROGEN FUNCTION 067
2[93[6[0 NH1\ NHR and NR1!functionalized Ketones 067
2[93[6[0[0 a!NH1\ NHR and NR1!functionalized ketones 067
2[93[6[0[1 b!Functionalized and more remotely NH1\ NHR and NR1!functionalized ketones 073
2[93[6[1 NHX and NX1!functionalized Ketones 078
2[93[6[2 NY!functionalized Ketones 089
2[93[6[3 NZ!functionalized Ketones 083
2[93[7 KETONES BEARING A P\ As\ Sb OR Bi FUNCTION 084
2[93[7[0 XR1 and X¦R2!functionalized Ketones 084
2[93[7[1 Hi`her!coordinated P\ As\ Sb or Bi!functionalized Ketones 085
2[93[7[1[0 a!Hi`her!coordinated P\ As\ Sb or Bi!functionalized ketones 085
2[93[7[1[1 g!Coordinated and more remotely hi`her coordinated P\ As\ Sb or Bi!functionalized ketones 199

2[93[8 KETONES BEARING A METALLOID FUNCTION 191


2[93[8[0 Silicon!functionalized Ketones 191
2[93[8[0[0 a!Silyl ketones 191
2[93[8[0[1 b!Silyl ketones 192
2[93[8[1 Germanium!functionalized Ketones 192
2[93[8[2 Boron!functionalized Ketones 192

2[93[09 KETONES BEARING A METAL FUNCTION 193


2[93[09[0 Tin!functionalized Ketones 193

2[93[0 SATURATED UNSUBSTITUTED KETONES

2[93[0[0 From Alkanes


Although the oxidation of activated methylene groups next to unsaturated or aromatic groups is
a well established method for the synthesis of unsaturated and aromatic carbonyl compounds\ no
Saturated Unsubstituted 002
equivalent methodology exists for the oxidation of unactivated methylene groups[ The area is\
however\ one of active interest in a number of groups\ notably those of Barton ðB!80MI 293!90Ł\
Sawyer ð89JA0825Ł and Murahashi ð82TL0188Ł[ So far the most promising results have been obtained
in the metal!mediated peroxide oxidations of highly symmetrical alkanes\ which can give modest
yields of ketones at partial completion[
A somewhat unusual methylene activating group is the cyclopropyl ring\ and oxidations of
cyclopropylmethyl groups with ruthenium tetroxide\ generated in a catalytic ruthenium trichlorideÐ
sodium periodate system ð74CL0274Ł\ with the complex of chromium trioxide with 2\4!dimethyl!
pyrazole "Equation "0## ð82CC843Ł\ or with ozone adsorbed onto silica gel ð65AG"E#650Ł give good
yields of cyclopropyl ketones\ particularly for doubly activated examples[

O
80%
(1)

2[93[0[1 From Alkenes


The Wacker oxidation of ethylene to acetaldehyde by oxygen in the presence of a palladium"II#
catalyst and a copper salt as cooxidant has been an important industrial process since it was _rst
developed in 0847[ The reaction was slow to be adopted as a synthetic method because of the
aqueous hydrochloric acid!containing medium used and the chlorinated by!products seen with
higher alkenes[ However\ it is now known that an appropriate choice of solvent "particularly
2!methylsulfolane or N!methyl!1!pyrrolidone# and cooxidant allows a wide variety of terminal
alkenes to be oxidized in high yield to the corresponding methyl ketones[ Tsuji has discussed the
organic synthetic potential of the reaction in a useful review which also includes some unpublished
material from the author|s own laboratory ð73S258Ł[ Recent publications have extended the method
to use electrochemistry to regenerate the oxidant ð76TL2572Ł\ and a palladium"II#\ hydroquinone\
iron phthalocyanine catalyst system which\ being chloride free\ avoids the problem of chlorinated
by!products ð77TL1774Ł[ The same transformation can also be achieved using the Jones reagent in
the presence of mercury"II# salts as catalyst ð64JOC2466Ł[ The oxidation of disubstituted alkenes to
a!diketones has been reported with potassium permanganate in the presence of copper sulfate
ð78JOC4071Ł[
Although a number of oxidants will cleave alkenes\ relatively few do so cleanly or in high yield\
the most important and well established exception being ozone ðB!58MI 293!90Ł[ In cases where ozone
is not employed\ the conversion is generally achieved via the corresponding 0\1!diol by osmium"VIII#
oxide!mediated hydroxylation\ followed by periodate or lead"IV# acetate cleavage[ Isolation of the
diol intermediate is not necessary and hydroxylation and cleavage can be achieved in a single pot
by a mixture of osmium"VIII# oxide and sodium periodate ð45JOC367Ł[ Cleavage of alkenes can
also be achieved by oxygen in the presence of rhodium catalysts ð72HCA066Ł\ and by catalytic
triphenylbismuth and N!bromosuccinimide "NBS# in bu}ered aqueous acetonitrile ð75T4516Ł[
Despite the importance of hydroformylation as a route to aldehydes\ the analagous hydro!
acylation transformation is virtually unknown\ although both the silver!catalysed addition of an
aldehyde ð68TL2Ł\ and rhodium"I#!catalysed addition of an aldimine ð68JA378Ł to an alkene have
been reported[ The intramolecular version of this transformation is slightly better studied\ and
3!pentenals are known to give cyclopentanones both on treatment with tin"IV# chloride ð68CC034Ł\
and with rhodium"I# catalysts ð73TL850Ł[ The latter reaction clearly has considerable potential since
2!substituted cyclopentanones of high optical purity can be prepared using chiral rhodium catalysts
"Equation "1## ð81TL5220Ł[

O
O
Rh[(S)-BINAP]ClO4
(2)
87%, 99% ee
But
But
(S)-BINAP = (S)-2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl
003 Dialkyl Ketones
2[93[0[2 From Alkynes
Mercury"II#!catalysed acid hydration of terminal alkynes is a well established method for the
synthesis of methyl ketones[ The transformation has also been reported using a gold"II# catalyst\
which has the advantage of requiring neutral conditions and can be performed on substrates
containing an alkene\ hydroxy or acetate functionality ð80JOC2618Ł[ Variants using mercury!impreg!
nated Na_on!H ð67S560Ł\ phenylmercuric hydroxide ð71JOC2220Ł\ or p!methoxybenzenetellurinic
anhydride have also been reported ð75TL5988Ł[
Alkynes may also be converted into ketones by hydroboration and oxidation of the intermediate
vinylborane[ Diborane and simple mono! and dialkylboranes give very poor regioselectivity in the
hydroboration^ however\ excellent results can be obtained either with dimesitylborane ð72TL0322Ł
or with thexyliodoboraneÐdimethylsul_de complex ð82TL4002Ł\ followed by a conventional basic
hydrogen peroxide workup "Equation "2##[

Prn O
Prn + (3)
Prn
O
1.0% 99.0%

The cobalt!catalysed combination of an alkene\ an alkyne and carbon monoxide is known as the
PausonÐKhand reaction\ and normally gives a cyclopentenone product[ However\ it has recently
been found that if the reaction is performed under nitrogen with the reagents adsorbed on silica in
the absence of solvent\ the saturated cyclopentanone is formed instead "Scheme 0# ð82TL1976Ł[
Co2(CO)6

AcN Co2(CO)8 ∆
AcN AcN O
76% 94%

Scheme 1

2[93[0[3 From Halides


The Kornblum oxidation\ in which a primary alkyl halide is heated with an N!oxide or sulfoxide\
is most often used for the preparation of aldehydes\ but can also be used for the preparation of
ketones from secondary halides[ Most recent work has been aimed at developing modi_ed conditions
and reagents which allow the reaction to be performed under less vigorous conditions[ New reagents
include 3!dimethylaminopyridine N!oxide in the presence of diazobicycloundecane ð70BCJ1110Ł\ a
variety of pyridone N!oxide reagents ð68JCS"P0#1382Ł\ and DMSO in the presence of sodium hydrogen
carbonate and sodium iodide ð75SC0232Ł[ The conversion may also be achieved with more
conventional oxidizing agents\ including tetrabutylammonium periodate ð75SC32Ł\ tetra!
butylammonium dichromate ð68CI"L#102Ł\ and iodine penta~uoride ð66S308Ł[
The dehydrohalogenation of halohydrins can be achieved with potassium carbonate in the
presence of catalytic palladium"II# acetate ð71TL2974Ł[ A slightly less general reaction is catalysed
by the cobalt complex chlorotris"triphenylphosphine#cobalt"I# ""Ph2P#2CoCl#\ which\ in the presence
of a tertiary amine as hydrogen bromide scavenger\ e}ects the dehydrobromination of bromohydrins
to give ketones[ The reaction is suggested to involve a b!hydroxyalkylcobalt intermediate
ð66BSF0830Ł[ In the special cases of halohydrins derived from terminal alkenes\ or some cyclic
alkenes\ dehydrohalogenation can be achieved photochemically ð81TL1348Ł[
Vinyl halides may be hydrolysed to ketones using mercury"II# acetate either in tri~uoroacetic acid
or in acetic acid containing boron tri~uoride etherate ð67TL0832Ł[

2[93[0[4 From Alcohols and Their Derivatives

2[93[0[4[0 By oxidation of secondary alcohols


Although the greater oxidative stability of ketones compared to aldehydes makes the preparation
of ketones by oxidation of secondary alcohols a relatively easier process\ the same or similar reagents
Saturated Unsubstituted 004
are generally used for both oxidations[ As with aldehydes "Chapter 2[90#\ the reagents may be
conveniently discussed in six classes] "i# metal!based oxidants\ particularly chromium\ magnesium\
and ruthenium salts^ "ii# activated dimethyl sulfoxide reagents^ "iii# halogen!based oxidants^ "iv#
Oppenauer and related oxidations^ "v# electrochemical and photochemical oxidations^ and "vi#
miscellaneous[
Recent research in oxidation methods has often been directed towards developing low!cost
methods with increased environmental acceptability[ Thus\ catalytic methods\ particularly those
using hydrogen peroxide or t!butyl hydroperoxide as ultimate oxidant\ have received considerable
attention[ Also of interest from this point of view are solid!supported oxidants\ which allow a
simpli_ed workup by _ltration[ Such oxidants\ which also often vary in selectivity and reactivity
when compared with the unsupported parent reagent\ have been the subject of a review ð68S390Ł[

"i# Usin` metal!based oxidants


"a# Chromium rea`ents[ High!valent chromium reagents are probably the most important group
of oxidants for alcohol oxidation[ However\ as evidenced by its use for cleaning glassware\ chromic
acid is a very powerful oxidant and the challenge is to develop reagents that have improved
selectivity\ work under near!neutral conditions\ and allow a simple workup[ The earliest reagents
to achieve some success were the Jones "chromic acidÐacetone# and Collins "chromium trioxideÐ
pyridine# reagents[ Although not without their drawbacks\ they are still used today\ with the Collins
reagent in particular showing advantages for some sensitive substrates such as b!hydroxyketones
ð70S456Ł[
A number of other reagents based on chromium trioxide are now known[ These include several
modi_ed versions of the Collins reagent in which the pyridine is replaced by phenanthroline
ð79TL0472Ł or benzatriazole ð89SC2248Ł[ Although these amines have the advantage of giving stable\
isolable complexes\ the actual oxidation chemistry seems very similar[ A rather di}erent way of
modulating the reactivity of chromium trioxide is by suspending it on celite ð68S704Ł\ or on {wet|
aluminum oxide ð80BCJ1746Ł^ such reagents have the distinct advantage of greatly simplifying the
workup\ which is by _ltration[
The Jones reagent was the _rst of an enormous range of chromate! or dichromate!based oxidants\
of which the most important is pyridinium chlorochromate "pcc#[ This is probably the most suc!
cessful and versatile chromium oxidant\ and certainly the single most popular oxidant for alcohols
today ð71S134Ł[ Despite the established position of the reagent\ modi_cations and improvements of
the original method are still being published\ the most important of which is an improved and safer
procedure for its preparation ð89T3306Ł[ An important group of modi_cations is aimed at simplifying
the workup\ which can be complicated by di.culties in separating the product from tarry chromium!
containing residues[ These include poly"vinylpyridinium# "chlorochromate#\ a polymeric analogue
of pcc ð67JOC1507\ 70JOC0617Ł\ a variety of polymer!bound quaternary ammonium chlorochromates
ð75JOC3905Ł\ and 1\1?!bipyridinium chlorochromate\ which apparently gives more tractable residues
ð79S580Ł[
One of the few disadvantages of pcc is its mildly acidic character\ which makes it unsuitable for
the oxidation of some sensitive substrates[ Several modi_ed reagents which reduce or overcome this
problem have been reported\ including pyridinium ~uorochromate ð71S477Ł\ pcc adsorbed onto
alumina ð79S112Ł\ and trimethylsilyl chlorochromate\ which is prepared in situ from chromium
trioxide and chlorotrimethylsilane and allows oxidations to be performed under strictly neutral and
anhydrous conditions ð72TL3256\ 74T1892Ł[ In addition\ the use of ultrasound in oxidations with
silica!gel!supported pcc\ leading to a signi_cant reduction in the length of time and the amount of
reagent required\ has been described ð78JOC4276Ł\ and molecular sieves have been found to assist
the oxidations of a variety of alcohols including carbohydrate and nucleoside derivatives
ð71JCS"P0#0856Ł[
A wide range of other supported forms of chromic acid have been described\ testifying to the
considerable interest there is in simplifying the workup of chromium oxidations[ Examples include
chromic acid adsorbed on silica gel ð67S423\ 68T0678Ł\ and chromate ion bound to an anion exchange
resin ð65JA5626Ł or to a poly"vinylpyridine# resin ð67JOC1507Ł[ High yields of ketones can also be
obtained in oxidations with preformed quaternary ammonium chromates ð68S245Ł[
After pcc the most widely used chromate oxidant for alcohols is pyridinium dichromate in
dichloromethane\ which has the advantage of being appreciably less acidic ð68TL288Ł and\ like pcc\
of being available in a resin supported form ð68TL0390Ł[ Several other neutral\ organic!soluble\
005 Dialkyl Ketones
dichromate oxidants have been developed and o}er a number of advantages\ in particular allowing
the oxidation of very sensitive substrates and short reaction times[ These include the 1! and
3!benzylpyridinium dichromates ð80SC308Ł\ bis"benzyltriethylammonium# dichromate ð71S0980Ł\
and tetrakis"pyridino#cobalt"II# dichromate ð81SC0380Ł[ Bis"phosphonium#dichromate ð75TL0664Ł
and 2!carboxypyridine dichromate "sometimes referred to as nicotinium dichromate\ ndc# ð76T2852Ł
have also been found to have advantages for some oxidations[ The use of potassium dichromate
under phase transfer conditions is also very e}ective and has the advantage of simplifying the
workup and product isolation\ although the method is unfortunately only applicable to acid!stable
substrates ð67TL0590Ł[
One of the most interesting recent developments is the use of the chromate ester "0# as a catalytic
oxidant for alcohols[ The reagent is used with a peracid as co!oxidant\ is compatible with acid!
sensitive functionalities like tetrahydropyranyl ethers\ and oxidizes primary alcohols only very
slowly\ allowing selective oxidations to be performed ð74TL4744Ł[ Other catalytic chromium systems
include chromia!pillared montmorillonite clay ð89TL4674Ł\ or chromium"III# bound to a per!
~uorinated resin sulfonic acid support ð73TL2206Ł\ both used with t!butyl hydroperoxide as
cooxidant[

O O
Cr
O O
(1)

Peroxychromium species such as CrO4 = C4H4N ð66TL2638Ł\ and CrO6 ð75T608Ł and a number of
chromium"V# complexes ð79TL0472Ł have been used as reagents for secondary alcohol oxidation[
Although they do have advantages in some situations\ in particular in being neutral\ they have not
achieved widespread use[
"b# Man`anese rea`ents[ Simple manganate"VI# or manganate"VII# reagents are very powerful
and unselective oxidants with little application in organic synthesis\ although a variety of modi_ed
and more useful reagents are now available[ Probably the most important of these reagents for the
preparation of saturated ketones is copper manganate"VII# ð71JOC1689Ł\ which is generally used in
the form of a solid mixture of potassium manganate"VII# and copper sulfate ð68JOC2335Ł[ This
reagent appears to be a very mild as well as high!yielding oxidant and is compatible with functionality
as sensitive as an N!nitroso group "Equation "3## ð78SC104Ł\ although the reaction is inhibited by
remote unsaturation in the substrate ð72JA2077Ł[ Barium manganate"VII# has also been reported to
be an e}ective oxidant for secondary alcohols and a!hydroxyketones\ and has the advantage of not
only being more selective but also of having greater heat and light stability than earlier manga!
nate"VII#!based reagents[ Other potentially useful reagents include benzyltriethylammonium
manganate"VII# ð70AG"E#093Ł and solid potassium manganate"VII#\ which gives much improved
results under the in~uence of ultrasonic irradiation ð72CL268Ł[

OH NO O NO
N N (4)
92%

Less work has been done with manganate"VI# reagents^ however\ a mixture of potassium manga!
nate"VI#\ copper sulfate and alumina has been reported to selectively oxidize secondary and benzylic
alcohols in the presence of primary of allylic alcohols "Equation "4## ð78TL1448Ł[

OH OH O OH
(5)
65%

"c# Ruthenium rea`ents[ As with chromium and manganese reagents\ the challenge for chemists
wanting to develop oxidants of this class has been to moderate the reactivity and improve the
selectivity of simple ruthenium reagents[ In an interesting contrast to the other metal oxidants\
where modi_ed stoichiometric reagents have been developed\ the most successful approach towards
Saturated Unsubstituted 006
ruthenium!based oxidants has been the development of catalytic systems\ and three distinct systems
have been found to be useful[
Although not very widely used\ bis"triphenylphosphine#ruthenium"II# chloride appears to have
some potential as a catalytic oxidant of secondary alcohols[ It was _rst reported in combination
with N!methylmorpholine!N!oxide ð65TL1492Ł\ although more recent publications have used
bis"trimethylsilyl#peroxide ð77BCJ2596Ł\ or iodosylbenzene ð70TL1250Ł\ as cooxidant[
Rather more valuable are the oxidations in which the active species is ruthenium tetroxide[ These
are generally performed in a two!phase system with the substrate in an organic phase\ normally tri!
or tetrachloromethane\ and an aqueous cooxidant phase[ A careful study with octan!1!ol as substrate
and sodium bromate as cooxidant has de_ned the optimal conditions to be a pH of between 4 and
7 and a stirrer speed su.cient to break up the boundary between the phases ð77JOC0092Ł[ The
authors also emphasize that it is important to use the {hydrated| form of the oxide\ which actually
has a hydroxide structure\ since the anhydrous oxide is very insoluble and does not form the active
tetroxide under the reaction conditions[ Variants on this procedure use sodium bromate in a
phosphate bu}er with ruthenium trichloride as precursor of the tetroxide ð74TL1096Ł\ or use sodium
periodate ð76JOC0038Ł or hydrogen peroxide with didecyldimethylammonium bromide phase trans!
fer catalyst ð77JOC2442Ł as cooxidant[
Unquestionably the most important ruthenium oxidants\ and one of the most important recent
developments in oxidation methodology generally\ are the tetraalkylammonium perruthenates
developed by Gri.th and by Ley[ These use a catalytic tetraalkylammonium perruthenate\ generally
tetrapropylammonium perruthenate "TPAP#\ in the presence of 9[3 nm "3 A ý # molecular sieves with
N!methylmorpholine!N!oxide as regenerating oxidant to achieve the oxidation under very mild\
neutral conditions[ The reagent is notable for the wide range of functionality tolerated\ including
THP and silyl ethers\ alkenes\ epoxides and esters "Equation "5##\ and the fact that chiral centres a
to the newly formed carbonyl group are not epimerized ð76CC0514Ł[ The reagent has been the subject
of a review ð89MI 293!90Ł[

O O
(6)
73%
OH O

"d# Miscellaneous metal oxidants[ Despite their importance in epoxidation chemistry\ vanadyl
species have seen very little use in alcohol oxidation reactions\ although they are known to o}er a
high degree of selectivity for secondary over primary alcohols ð72TL4998Ł[
A wide range of molybdenum and tungsten salts can catalyse the oxidation of alcohols by
hydrogen peroxide or t!butyl hydroperoxide[ The research group of Ishii has been particularly active
in this area\ publishing a series of papers on a number of variants of which the tris"cetylpyridinium#
01!tungstophosphateÐhydrogen peroxide system appears to be optimal ð77JOC2476\ 77SC758Ł\
although Venturello et al[ recommend the related trioctylmethylammonium tungstophosphateÐ
hydrogen peroxide system ð80JOC4813Ł[ Benzyltrimethylammonium tetrabromooxomolybdate
"BnMe2N¦ MoOBr3−# ð73TL3306Ł\ and ammonium molybdate ð73TL062Ł\ are also known to catalyse
the hydrogen peroxide oxidation of alcohols[ Two molybdenum peroxy complexes\ "1# ð79TL3732Ł
and "2# ð76JOC4356Ł\ have also been reported as stoichiometric oxidants for alcohols\ although "2#
can also be used catalytically with hydrogen peroxide as cooxidant ð68JOC810Ł[

O
O O
Mo
Ph O O O
N O O
Mo O O
O O
Ph N
O

(2) (3)

A number of ferrates have been examined as potential oxidants for alcohols[ In one valuable
comparative study\ barium ferrate was found to show a very similar reactivity to barium manganate
007 Dialkyl Ketones
ð75SC612Ł[ Silver ferrate ð75SC100Ł\ and a mixture of potassium ferrate\ alumina\ and copper sulfate
ð75TL1764Ł\ have also been found to be potentially useful oxidants[
Iridium pentahydride catalyses the dehydrogenation of alcohols in a remarkable reaction that
requires no cooxidant or hydrogen acceptor but actually evolves gaseous hydrogen ð76TL2004Ł[
Raney nickel can also be used to dehydrogenate secondary alcohols\ although in this case 0!octene
is required as a hydrogen acceptor ð75JOC4371Ł[
A number of catalytic palladium systems for alcohol oxidation are known\ and the scope of the
method has been examined ð72JOC0175Ł[ The optimal conditions found employ 0Ð2 mol) of either
a palladium"9# or palladium"II# catalyst with bromobenzene as reoxidant[ The oxidation can also
be performed with tetrachloromethane or bromotrichloromethane as reoxidant ð74T4534Ł\ and
under phase transfer conditions with iodobenzene as reoxidant ð74TL5146Ł[
Copper"II# or zinc"II# nitrate supported on silica gel ð78JOC0420Ł\ and iron"III# nitrate supported
on clay ð79S738Ł\ have all been reported to oxidize secondary alcohols to ketones in good yield[
Primary and secondary benzylic alcohols are also oxidized\ although unactivated primary alcohols
are una}ected[ The complex of copper"II# bromide and lithium t!butoxide oxidizes secondary
alcohols in high yield ð81CL0074Ł[
Barton|s group have examined a range of pentavalent bismuth reagents for oxidizing secondary
alcohols and recommend triphenylbismuth carbonate ð68CC694Ł[ The reagent is of interest since
some normally sensitive functionalities\ such as pyrroles and indoles\ are una}ected[
Lanthanide reagents have received relatively little attention as potential oxidants for alcohols[
The most important exception is the cerium"IV#!catalysed oxidation of alcohols by sodium bromate
ð71TL428Ł\ which may also be performed with a polymer!supported catalyst using cerium"IV#
impregnated on Na_on resin ð78BCJ408Ł[ Ytterbium"III# nitrate is also known to catalyse the
oxidation of alcohols by iodosobenzene and has the unusual selectivity of oxidizing primary in
preference to secondary alcohols\ although good yields of ketones can be obtained with longer
reaction times ð82CL460Ł[

"ii# Usin` dimethylsulfoxide rea`ents


Since P_tzner and Mo}at|s serendipitous discovery in 0852 that alcohols were oxidized at room
temperature by dimethyl sulfoxide in the presence of dicyclohexylcarbodiimide and phosphoric acid
ð52JA2916Ł\ oxidations by activated DMSO have become established as one of the mildest and most
general methods for the oxidation of alcohols[ Today the most commonly used variant is that
developed by Swern and co!workers\ which uses oxalyl chloride to activate the DMSO ð67JOC1379\
67T0540Ł[
The area is well served by several good reviews[ Literature up to 0879 is covered in a classic review
by Mancuso and Swern ð70S054Ł\ which has been updated to the end of 0878 by Tidwell ð89S746Ł[
Tidwell has also published an Or`anic Reactions chapter on the subject which includes extensive
tabulations of examples\ and a good discussion of the scope of the oxidation and of potential side
reactions ð89OR"28#186Ł[ Relatively little can be added to the coverage provided by these reviews[
However\ bis"trichloromethyl# carbonate "triphosgene# has recently been reported to be a good
activating reagent and\ being a crystalline solid\ avoids the handling and scale!up problems associ!
ated with the relatively toxic and corrosive reagents generally used ð80JOC4837Ł[
Alcohols can also be oxidized by a mixture of N!chlorosuccinimide and diisopropyl sul_de
ð73CC651Ł[ The reaction is probably mechanistically closely related to the SwernÐMo}att oxidation
and shows the curious and unexplained feature that at 9>C primary alcohols are oxidized in
preference to secondary\ while at −67>C the opposite selectivity is found[

"iii# Usin` halo`en!based oxidants


Although clearly the reactions are of limited generality\ under suitable conditions both elemental
chlorine and bromine may be used for the oxidation of alcohols to ketones[ For example\ chlorine
in hexamethylphosphoramide ð65S700Ł and bromine in the presence of nickel"II# benzoate ð79SC770Ł\
or a hexaalkyldistannoxane ð65BCJ0545\ 65TL3486Ł\ have been used to prepare ketones from alcohols[
In fact these elemental halogen oxidations are merely examples of a much larger class of electrophilic
halogen"I# reagents which can oxidize secondary alcohols to ketones\ and of which the most
important members are the hypohalites[ Good results have been reported with sodium hypochlorite
Saturated Unsubstituted 008
under phase transfer conditions ð65TL0530\ 77S757Ł\ and with the easily stored calcium hypochlorite
ð71TL24Ł[ Calcium hypochlorite can also be used in a nonaqueous system which uses the hypochlorite
form of the ion exchange resin IRA 899 as catalyst and permits a simple workup by _ltration
ð71JOC253Ł[ In acetic acid solution\ sodium hypochlorite oxidations are selective for secondary over
primary alcohols\ and appear not to be prone to epimerizing sensitive ketone products ð79JOC1929\
71TL3536Ł[ The reaction may well involve an acetyl hypohalite as the actual oxidant\ as is the most
likely case in oxidations using peracetic acid and sodium bromide ð76BCJ3032Ł or benzyltrimethyl!
ammonium tribromide ð78BCJ1474Ł[ Other electrophilic halogen reagents reported as oxidants for
alcohols include trichloroisocyanuric acid ð81SC0478Ł\ bisquinuclidine bromine ð81JOC0599Ł\ and
N!iodosuccinimide ð70S283Ł[
A number of higher oxidation state halogen reagents are important oxidants for alcohols\ in
particular periodinane "3#\ which was _rst reported as an oxidant for alcohols by Dess and Martin in
0872 ð72JOC3044Ł[ An improved preparation has recently been described ð82JOC1788Ł[ The oxidation
occurs under very mild conditions and is compatible with a wide range of other functionalities\
including secondary amides\ sul_des\ alkenes\ furans and vinyl ethers ð80JA6166Ł[ The related
alkoxyaryltri~uoroperiodinane "4# has also been reported to oxidize alcohols to ketones in moderate
to high yields ð68JA4183Ł[ Lastly in this section\ sodium bromite in acetic acid ð72S704Ł\ or in the
presence of aluminum oxide ð77JCS"P0#1312Ł\ is known to be an e}ective oxidant for alcohols[

AcO OAc
F F
I OAc
I F
O
O

O
(4) (5)

"iv# Oppenauer and related oxidations


The oxidation of secondary alcohols by an aluminum alkoxide!catalysed hydrogen transfer to an
acceptor ketone\ present in excess to drive the equilibrium in the desired direction\ was _rst reported
by Oppenauer ð26RTC026Ł[ The method was quite widely used in the older literature\ particularly
for the oxidation of steroidal alcohols\ and was the subject of a review ð40OR"5#196Ł[ Very recently
there has been a resurgence of interest in the method\ mainly centred on the development of new
catalysts which can be used for the oxidation of primary alcohols to aldehydes\ although
ruthenium"II# halides ð81CC226Ł and lanthanide alkoxides ð73JOC1934Ł have been found to be useful
alternative catalysts for the oxidation of secondary alcohols[
An interesting extension of the reaction couples carbon!to!carbon bond formation with the
oxidation[ Thus\ addition of a solution of a Grignard reagent in an acyclic ether to an aldehyde
forms a new carbon!to!carbon bond\ and the resulting halomagnesium alkoxide can be oxidized\ in
the same pot\ by addition of benzaldehyde as hydrogen acceptor[ Alternatively\ the halomagnesium
alkoxide can be prepared directly from an alcohol and ethylmagnesium bromide\ although in
both cases the majority of reported examples are preparations of unsaturated ketones "Scheme 1#
ð76TL658Ł[ Snider et al[ have also coupled the diethylaluminum chloride!catalysed sequential ene
reactions of exocyclic alkenes with acrolein "which lead to cyclohexanols# with an Oppenauer
oxidation which occurs in the presence of excess acrolein\ to give an attractive one!pot cyclohexanone
ring annelation "Scheme 2# ð75T1840Ł[

O PhCHO
MgBr +
OMgBr 69% O

Scheme 2

Possibly related to the Oppenauer oxidation is the highly selective oxidation of secondary alcohols
on alumina using trichloroacetaldehyde as oxidant ð65TL2388Ł[ The method has been particularly
recommended for cyclobutanone preparations ð66S444Ł[
019 Dialkyl Ketones

+ AlMe2Cl
O+ HO
– AlMe2Cl
acrolein, AlMe2Cl

OAlMeCl O

acrolein

Scheme 3

"v# Electrochemical and photochemical oxidations


Since an alcohol will not lose an electron at experimentally achievable electrode potentials\
the direct electrochemical oxidation of alcohols is impossible[ However a number of systems are
known which use an intermediary species\ often referred to as an {electron carrier|\ which can oxidize
the alcohol chemically\ the resulting reduced form of the electron carrier being reoxidized at the
anode to complete the process[ These include several traditional electron carriers such as iodonium
reagents ð68TL054Ł\ sulfur species ð68TL2750\ 79TL0756Ł\ molecular oxygen ð78S392Ł\ nitrate
ð79TL3584Ł\ and hydroxyphthalimide ð72CC368Ł\ as well as established oxidants for alcohols like
ruthenium salts ð75JOC044\ 89SC288Ł\ in what are e}ectively electrocatalytic versions of the oxidations[
Two!stage systems in which the oxidant is not reoxidized directly at the anode but via an electron
carrier are also possible ð80BCJ685Ł[
Photochemical oxidations of alcohols to form ketones is a largely unexplored area\ although it is
known that irradiation of an alcohol in the presence of a copper"II#\ iron"III# or silver"I# salt
ð68JOC027Ł or platinum on titanium dioxide ð73TL2252Ł can give high yields of ketones[

"vi# Miscellaneous other oxidations


Dimesityl diselenide catalyses the oxidation of alcohols to ketones by t!butylhydroperoxide[ The
method is extremely mild and is even compatible with the presence of phenylthio or phenylseleno
groups ð71JOC726Ł[ Under suitable conditions many peroxy reagents\ including mcpba in the pres!
ence of dry hydrogen chloride ð89SC526Ł\ and Oxone "a mixed persulfate reagent# in the presence of
hydrated aluminum oxide ð80BCJ0935Ł\ are capable of oxidizing alcohols to ketones[ Perhaps more
useful is methyl"tri~uoromethyl#dioxirane\ which not only achieves the conversion remarkably
rapidly "1Ð19 min#\ but is also compatible with acid!labile functionalities such as epoxides "Equation
"6## ð80JA1194Ł[ Good results have also been reported with the per~uorodialkyloxaziridine "5#
ð81TL6134Ł[
F3C O
H H
O H3C O O
(7)
94%
OH O

O
N C3F7
C4F9
F
(6)

Other miscellaneous oxidants include trityl tetra~uoroborate ð67TL1660Ł\ and 0\0?!azo!


dicarbonylpiperidine\ which provides an attractive method of oxidizing alcohols via their bromo!
magnesium salts ð66CL646Ł[
Saturated Unsubstituted 010
2[93[0[4[1 From diols
Probably the most important route to ketones from 0\1!diols is by oxidative cleavage[ Many
alcohol oxidants\ particularly metal!based oxidants\ will cleave vicinal diols\ and this can be a
serious side reaction in attempts to prepare 0\1!diones[ However\ since few of these reagents give
consistently high yields of ketones\ the majority of glycol cleavages are performed with either
periodate\ lead"IV# acetate\ or occasionally bismuth reagents ðB!54MI 293!90\ B!58MI 293!91\ 70CC0121Ł[
In all three cases the mechanism appears to involve cyclic species\ explaining why the cleavage of
rigid trans diols is generally unsuccessful[ Diols protected as their dibutylstannylene derivatives can
also be cleaved with either periodate or lead"IV# acetate ð70TL1774Ł[
The preparation of ketones from 0\1!diols by pinacol rearrangement ð59QR246Ł\ and by rho!
dium"III#!catalysed dehydration of 0\2!diols ð65CL120Ł is possible\ although problems of regio!
control limit the application of both these reactions in syntheses where no additional directing
functionality is present[

2[93[0[4[2 By oxidation of derivatives of alcohols

"i# Ethers
A wide range of alkyl and silyl ethers react with hydride!abstracting reagents to give an oxonium
ion which hydrolyses to a ketone on workup[ Thus methyl ethers of secondary alcohols are oxi!
datively cleaved by nitronium tetra~uoroborate ð66JOC2986Ł\ or uranium"VI# ~uoride ð67JA4285Ł\
and O!trimethylsilyl derivatives can be oxidized with trityl tetra~uoroborate ð65JOC0368Ł or with
nitrosonium tetra~uoroborate\ which will also oxidized stannyl ethers ð65S598Ł[ Sodium bromate\
in the presence of cerium"IV# ammonium nitrate ð79S786Ł or polymer!supported cerium"IV# or
chromium"III# catalysts ð78BCJ408Ł will oxidize a wide range of ether derivatives including methyl\
benzyl\ trimethylsilyl and t!butyldimethylsilyl\ with selectivity for secondary over primary deriva!
tives[ Alkyl ethers can be oxidized by copper"II# or zinc"II# nitrates suspended on silica ð78JOC2990Ł[
Silyl ethers can also be oxidized under rather milder conditions[ For example\ trimethylsilyl ethers
are oxidized using dimethyl sulfoxideÐoxalyl chloride\ although the conditions "−29>C for 29Ð34
min# are appreciably more vigorous than are normally required for alcohol oxidations
ð76JCS"P0#0110Ł[ t!Butyldimethylsilyl ethers are inert to the reaction conditions and hindered
trimethylsilyl ethers react appreciably less rapidly\ allowing some interesting selective oxidations to
be achieved "Equation "7##[ The Jones reagent will also oxidize trimethylsilyl ethers ð72S461Ł and\
in the presence of potassium ~uoride\ t!butyldimethylsilyl ethers to ketones in yields that compare
well with a conventional two!pot deprotectionÐoxidation sequence ð74SC648Ł[ t!Butyldiphenylsilyl
ethers are una}ected\ again allowing some interesting selective transformations to be achieved
"Equation "8##[ The oxidative deprotection and stability under alcohol oxidative conditions of silyl
ethers has been the subject of a very comprehensive review\ which includes extensive tabulations of
the reactivities observed ð82S00Ł[ Lastly in this section\ tributylstannyl ethers can be oxidized to
ketones by a combination of lithium bromide and copper"II# bromide ð81CL312Ł[
O O
TMS-O HO

(8)
74%

TMS-O O

(9)
TBDMS-O OSiPh2But 90% O OSiPh2But
TBDMS = t-butyldimethylsilyl

"ii# Esters
Ketones may be prepared under strictly neutral conditions by the photolysis of the pyruvate
esters of alcohols ð65JOC2929\ 65SC170Ł\ and the reaction has been applied to good e}ect in the
011 Dialkyl Ketones
preparation of a number of delicate carbohydrate ketones ð66JOC0105Ł[ Nitrite esters are oxidized
to ketones by dimethyl sulfoxide ð75T3022Ł\ and alcohols may be oxidized via their aci!nitro esters
ð68CC292\ 70TL1184Ł[ Both reactions can be regarded as variants of the Kornblum oxidation[

"iii# Carbonates
Treatment of alkyl allyl carbonates with palladium catalysts in the absence of phosphine ligands
gives good yields of ketones "Equation "09## ð73TL1680Ł[

O
O
O O
PdII
(10)
77%

2[93[0[4[3 Rearrangement of allylic alcohols


Allylic alcohols can be isomerized to ketones by treatment with rhodium"I# ð79JOC1158Ł or
ruthenium"II# catalysts ð80TL2928\ 82TL4348Ł[ Although the optimal conditions are substrate depen!
dent\ good yields are frequently attainable\ and isolated double bonds and alcohols are una}ected[
In the special case of 3!keto allylic alcohols\ acid!catalysed rearrangement to the 0\3!dione is possible
"Equation "00## ð74JOC1549Ł[

HBr
(11)
O 93% O
H
OH O

2[93[0[5 From Epoxides


Treatment of epoxides with Lewis acids can give respectable yields of carbonyl compounds\
although the identity of the product formed appears to depend on both the direction of ring opening
and the migratory aptitude of the substituents[ Thus mono! and 0\0!disubstituted epoxides generally
give aldehydes\ but with 0\1!disubstituted and trisubstituted epoxides both the exact structure of
the substrate and the conditions used are important[ For instance\ treatment of trisubstituted
epoxides with antimony"V# ~uoride ð80SL380Ł gives ketones selectively[ However\ even in 0\0!
disubstituted epoxides\ the selectivity can be a}ected by small changes in the substrate\ as is the case
in the lithium bromide!mediated rearrangement of the epoxide "6#\ which normally gives "7#\ the
electronically preferred product\ but when R is an oxygen functional group a chelation!controlled
migration leads to the formation of "8# as the sole product "Equation "01## ð74CL0326Ł[ This area
has been discussed in rather greater depth in a review of epoxide chemistry ð73S518Ł[

H H H
LiBr, HMPA
+ (12)
O
R O R O R
(7) (9) (8)
HMPA = hexamethylphosphoramide
Saturated Unsubstituted 012
2[93[0[6 From Acetals\ Enol Ethers and Enol Esters
The chief importance of acetals in organic synthesis is as protecting groups for carbonyl
compounds[ As well as simple dialkylacetals\ 0\2!dioxanes\ and 0\2!dioxolanes\ many more complex
acetals have been used as protecting groups and allow the preparation and deprotection of ketones
under a remarkably wide range of conditions[ Readers interested in these aspects should refer to
one of the specialist works on protecting groups such as that by Greene and Wuts ðB!80MI 293!91Ł\
since the following discussion is only intended to highlight some of the more important approaches
to preparing ketones from simple acetals[
Traditional methods of ketone preparation from acetals are variants on the theme of acid!
catalysed hydrolysis\ and these have now been extended to use supported or heterogeneous acids
such as Amberlyst!04 ð73S0910Ł or wet silica gel ð67S52Ł\ which permit a much simpler reaction
workup[ However\ a more important objective of research in this area has been to develop less
strongly acidic conditions for acetal hydrolysis and to _nd methods that allow highly selective
deprotections to be performed[ One approach to the former goal is to use transacetalizations
which are catalysed by very mild reagents such as pyridinium tosylate ð68S613Ł\ and palladium"II#
bis"acetonitrile# dichloride ð74TL694Ł\ although hydrolyses with neutral reagents\ such as aqueous
DMSO ð78CL890Ł\ are also possible[ The use of aqueous DMSO is of particular note since it allows
dimethyl acetals to be hydrolysed in the presence of other\ more sensitive\ functionalities\ including
acetal!based alcohol protection such as methoxymethyl "MOM# or THP[ A number of procedures\
including silica!supported iron"III# chloride ð76S26Ł and samarium"III# chloride in the presence of
chlorotrimethylsilane ð78CL0512Ł\ allow acetals derived from ketones to be cleaved preferentially in
the presence of those derived from aldehydes[
A relatively recent discovery is the ability of a number of reagents to e}ect the {hydrolysis| of
acetals under strictly nonaqueous conditions[ These methods appear to involve an electrophilic
attack on one of the acetal oxygens leading to an oxonium ion which is cleaved to the ketone by
nucleophilic attack on the alkyl group[ The mechanism is illustrated in Scheme 3 for the case of
iodotrimethylsilane ð66TL3064Ł[ Other reagents which work in this way include diiododimethylsilane
ð89JOC1816Ł and phenyldichlorophosphate in the presence of sodium iodide ð75SC0246Ł[

I– I–
TMS-I O-TMS
O O + +O
O O
TMS
R1 R2
R1 R2 R1 R2

O
+ O-TMS
I
R1 R2

Scheme 4

Enol esters and silyl enol ethers are most often prepared from ketones as intermediates in other
reactions[ They are\ in general\ hydrolytically labile compounds\ making their transformation back
to ketones relatively straightforward should it be required[ Tributyltin ~uoride with palladium
catalysis has been recommended for the hydrolysis of more stable silyl enol ethers ð72JA4692Ł[

2[93[0[7 From Aldehydes or Ketones

2[93[0[7[0 From saturated aldehydes or ketones


"i# Alkylation
Although in principle ketone alkylations provide a powerful way of elaborating ketones\ simple
base!catalysed alkylations su}er from a number of drawbacks which limit their use[ These include
poor or no regio!\ diastereo! or enantiocontrol\ the occurrence of O! as well as C!alkylation\ and a
propensity to give over!alkylated and aldol products[ Methods which o}er solutions to all these
problems are now available and are described in this section\ although the coverage is necessarily
brief[
013 Dialkyl Ketones
The fundamental problem underlying the problems of both poor regioselectivity and poly!
alkylation of sodium and potassium enolates is the fact that alkylation and proton transfer from
alkylated product to unreacted enolate proceed at similar rates\ although\ for reasons that are
unclear\ tri~ate alkylating agents appear to be an exception and give good yields of monoalkylated
products with potassium enolates ð82JOC3358Ł[ Probably the earliest approach to controlling ketone
alkylation involved the introduction of a directing group such as an ester\ thiolester or arylsulfonyl
group which is removed after alkylation[ The decarboxyalkylation of keto!ester intermediates can
be achieved by basic hydrolysis and acidi_cation\ and more conveniently with hot DMSO ð71S794Ł[
Allyl esters can also be removed by treatment with palladium"9# ð74JOC2305Ł and thiol esters with
Raney nickel ð68TL3010Ł[ Today\ however\ alkylations of metal enolates are more likely to be
performed with the lithium species which\ because of the greater covalent character of the lithium
oxygen bond\ undergo proton transfer far less rapidly and allow regioselective monoalkylation[
Particularly low levels of polyalkylation have been reported to occur with manganese enolates
ð82TL6284Ł[ The alkylation of metal enolates\ in particular those involving preformed metal enolates
which avoid the aldol by!products often obtained under base!catalysed conditions\ has been well
reviewed by Caine ðB!68MI 293!90Ł\ and the speci_c topics of regiospeci_c enolate generation by
d|Angelo ð65T1868Ł and of stereoselective alkylation of chiral enolates by Evans ðB!73MI 293!90Ł[
The poor diastereo! and enantiocontrol of the alkylation of metal enolates is less easily overcome\
although the sense of any diastereoselection can be predicted using Houk|s rule\ an electrophilic
analogue of Cram|s rule which predicts the transition state depicted as "09# to be favoured[ This has
been tested quite extensively for the methylation and protonation of enolates and found to hold in
the vast majority of cases\ although the diastereoselectivity is frequently quite modest ð74CC038Ł[
Enantioselective alkylations of ketone enolates are proving to be a particularly challenging objective\
and are receiving quite extensive attention\ as are the enantioselective protonations of enolates\ a
process that provides a complementary approach to a!chiral ketones ð80TA0Ł[

E+

M
S
L
(10)

Several important methods of ketone alkylation involve nitrogen derivatives of the ketone\ of
which the _rst to be introduced were enamines ð43JA1918Ł\ followed by metallated imines ð52JA1067Ł\
and lastly metallated hydrazones ð65TL2Ł[ The alkylation of ketones via their nitrogen derivatives
has been the subject of a Synthesis review ð72S406Ł[ One particularly important application of
these methods is for the enantioselective alkylation of ketones ð70JA2970\ 68CPB1659\ B!72MI 293!90Ł[
Probably the best established of these methods is that developed by Enders\ which employs hydra!
zones derived from "S#!"−#! or "R#!"¦#!0!amino!1!methoxymethylpyrrolidine "abbreviated to
SAMP and RAMP\ respectively# and gives reliably high enantioselectivities of predictable sense
"Scheme 4# ðB!73MI 293!91Ł[
Some stable enolate species\ such as silyl enol ethers\ will react with alkylating agents and\ after
workup\ allow the isolation of good yields of alkylated ketones[ In the case of silyl enol ethers the
reaction is Lewis acid!catalysed and involves the electrophilic attack of a carbocation on the enol
ether[ This mechanistic pathway also rationalizes the major limitation of the method\ which is
restricted to tertiary alkylating agents and is thus complementary to metal enolate methods which
do not allow alkylations with tertiary halides[ The other major advantage of the method is that
it allows one to harness the well!developed techniques for preparing either the kinetic or the
thermodynamic silyl enol ether with high speci_city to be used to control the regioselectivity of the
alkylation[ Early work in the area has been reviewed ð71AG"E#85Ł[ Further research has been directed
to trying to extend the bene_ts of this good regiocontrol to a wider variety of alkylating agents[
One approach has been to use an a!phenylthio halide to introduce an a!phenylthio alkyl group from
which the phenylthio substituent is removed in a subsequent reduction "Scheme 5# ð77T3196Ł[
Silver"I# tri~uoroacetate has been found to activate primary alkyl halides to nucleophilic attack by
silyl enol ethers\ although primary alkyl bromides and secondary alkyl iodides are unreactive
ð81TL0744Ł[ Lastly\ intramolecular alkylations are an important route to cyclohexanones and cyclo!
heptanones ð67JOC699Ł\ but not cyclopentanones\ in accord with Baldwin|s rules ð66CC122Ł[
Saturated Unsubstituted 014

O
i–iv
N
N OMe 70%
SAMP
O 87% >95% ee
RAMP

87% O
i–iv
N
N OMe 70%

>95% ee

i, LDA; ii, Br ; iii, MeI; iv, HCl

LDA = lithium diisopropylamide


SAMP = (S)-(–)-1-amino-2-methoxymethylpyrrolidine
RAMP = (R)-(+)-1-amino-2-methoxymethylpyrrolidine

Scheme 5

O-TMS i, TiCl4 O O
ii, PhSCH2Cl Raney Ni
SPh
87% 99%
LDA, TMS-Cl
O 97%

Et3N, TMS-Cl
83%

O-TMS i, TiCl4 O O
ii, PhSCH2Cl Raney Ni
PhS
71% 98%

LDA = lithium diisopropylamide

Scheme 6

"ii# Homologation
Although any preparation of functionalized ketones involving carbon!to!carbon bond formation
and starting from a ketone can be thought of as a homologation\ this section will deal only with
those reactions which increase the number of carbon atoms without any increase in the functional
complexity of the molecule[ Homologations of this sort\ particularly by one carbon atom\ have
proved particularly important for the synthesis of medium!ring ketones by the ring expansion of
more accessible\ normal ring ketones[
One important and well established reagent for ketone homologation is diazomethane
ð43OR"7#253Ł\ although trimethylsilyldiazomethane has been recommended as a safer alternative
ð71CPB008\ 71CPB2279Ł[ Epoxide formation can be a signi_cant\ or even dominant\ side reaction
although good results are generally obtained with cyclic ketones[ One alternative which does
not appear to share this drawback is dibromomethyllithium\ which adds to a ketone to give a
dibromomethylcarbinol[ This rearranges to the homologated ketone on further treatment with
butyllithium in a reaction which is proposed to proceed by a carbenoid mechanism and which allows
the regioselective homologation of unsymmetrical ketones "Scheme 6# ð66BCJ0481Ł[ The reaction of
a ketone with phenylselenoalkyllithium gives a hydroxyselenide which may also be rearranged to
the homologated ketone "Scheme 7# ð89BSF570Ł[ Both the selenium and dibromomethyllithium
chemistry have been extended to allow the introduction of an RCH unit ð68S857Ł[
Dowd et al[ have developed a very versatile\ free!radical!mediated ring expansion of b!keto esters[
015 Dialkyl Ketones
Br O
O
Br OH

LiCHBr2 BunLi

78% 79%

Scheme 7

PhSe O
O
HO AgBF4
+ SePh
70% 85%
Li

Scheme 8

The method allows homologation by one ð80TL454Ł\ three or four carbons "Equation "02## ð78T66Ł\
and appears to be quite tolerant of other functionality[

O
O O
CO2Et Bu3SnH, AIBN CO2Et
+ (13)
I

CO2Et
71% 25%

AIBN = 2,2'-azobisisobutyronitrile

"iii# Transposition
0\1!Carbonyl transpositions regularly prove to be valuable in organic synthesis and\ fortunately\
are the subject of a very comprehensive review ð72T234Ł[ Three chief groups of methods\ involving
sulfur\ silicon or boron chemistry\ can be distinguished\ all of which have variants allowing for the
introduction of an alkyl group at the original ketonic carbon[
The sulfur methods generally involve the preparation of an a!thioketone\ which is subsequently
converted into a vinyl sul_de and hydrolysed to give the transposed ketone "Scheme 8# ð68TL420Ł[
Transpositions during which an additional alkyl group is introduced are also possible ð73BCJ097Ł[
The boron!based transpositions involve the addition of a Grignard reagent to the ketone and
dehydration of the resulting carbinol to give an alkene which is then hydroborated and oxidized to
give the transposed\ alkylated ketone "Scheme 09# ð50JA1840Ł[
The silicon!based methods involve the initial preparation of a vinylsilane followed by transposition
via an a!silyl epoxide "Scheme 00# ð79JOC2917Ł[

O NHTs NHTs
N N
TsNHNH2 i, BunLi, TMEDA BunLi
SMe
ii, MeSSMe

SMe O
HgCl2, MeCN, H2O

Scheme 9
Saturated Unsubstituted 016
O R OH R R
RMgX –H2O i, B2H6 O
ii, chromic acid

Scheme 10

O i, PhSO2NHNH2 TMS TMS


O
ii, BunLi, TMEDA mcpba LAH

iii, TMS-Cl

TMS
O
OH chromic acid

Scheme 11

"iv# Oxidative addition to aldehydes


Although the addition of an organometallic reagent to an aldehyde followed by oxidation of the
resulting secondary alcohol is a standard method for the two!step preparation of ketones\ their
combination in a single pot is uncommon[ However\ organovanadium dichlorides\ which are
prepared by the reaction of vanadium"III# chloride with a Grignard or an organolithium reagent
ð74JA6068Ł\ and boronÐWittig reagents ð78TL4532Ł do react chemoselectively with aldehydes to give
saturated ketones in a high!yielding\ one!pot process[ The less general conversion of an aldehyde to
a methyl ketone can also be achieved with "1\5!di!t!butoxy!3!methylphenoxy#dimethylaluminum
ð89TL212Ł[

2[93[0[7[1 From unsaturated ketones

"i# Conju`ate reduction


The conjugate reduction of enones to saturated ketones has traditionally been achieved with
dissolving metal reagents\ particularly lithium in liquid ammonia ð65OR"12#0Ł[ Variants which
employ ultrasound to promote the reduction by nickel"II# chloride activated zinc dust ð76TL1236Ł
or use aluminum powder in the presence of nickel"II# chloride have also been reported ð80T7476Ł[
Catalytic hydrogenation is also a well established method for the reduction of the carbonÐcarbon
double bond of enones[ The reduction can be achieved both by transfer hydrogenation ð67JOC2874Ł
and using homogeneous catalysts ð78SC562Ł[ The latter technique has been extended by the use of
BINAPÐRu"II# catalysts to allow the enantioselective reduction of 1!alkylidinecyclopentanones
with high enantiomeric excess ð81TL524Ł[
Recent research on conjugate reduction has mainly been devoted to developing modi_ed hydride
reducing agents with improved 0\3! versus 0\1!selectivity[ Aluminum!based reagents have generally
proved less satisfactory\ although good results have been reported for diisobutylaluminum hydride
"dibal!H# in the presence of the hindered Lewis acid methylaluminum bis"1\5!di!t!butyl!3!methyl!
phenoxide# ð77BCJ1130Ł\ for a variety of aluminum hydride reagents in the presence of copper"I#
salts ð65JOC0828\ 66JOC2079Ł\ and for bis"diisopropylamino#aluminum hydride ð65TL2754Ł[
The development of conjugate reducing agents based on borane or borohydride derivatives has
been rather more successful[ Probably the best!established reagent of this class is potassium tri!s!
butylborohydride "K!Selectride#\ although reasonable selectivity is only observed with cyclic ketones
ð65JOC1083Ł[ This limitation is not shared by the softer potassium triphenylborohydride which\ in a
recent and careful study\ has been shown to be generally the superior reagent for this application
ð77SC78Ł[ Catchecol borane has also been found to give very high 0\3!selectivity and is notable for
being equally successful in the conjugate reduction of b\b!disubstituted enones ð89JOC4567Ł[ Because
of the requirement that the enone must adopt an s!cis conformation\ the reaction fails for cyclic
017 Dialkyl Ketones
ketones\ a limitation that is shared by the otherwise very successful molybdenum carbonyl!catalysed
conjugate reduction with phenylsilane ð76JOC1465Ł[
Other attractive metal hydride reagents for the conjugate reduction of a\b!unsaturated ketones
include the copper hydride cluster ð"PPh2#CuHŁ5\ all six hydrides of which are transferable ð77JA180\
77TL2638Ł\ triphenylsilane in the presence of catalytic triethylborane ð80BCJ1474Ł\ and a mixture of
Collman|s reagent "Na1Fe"CO#3# and iron pentacarbonyl\ conditions which have the advantage of
being compatible with a wide range of other functionalities including epoxides\ aldehydes\ halides
and isolated double bonds ð64ACR231Ł[ Alternatively organic hydride donors\ such as 0\2!dimethyl!
1!phenylbenzimidazole "00#\ which can also be used to introduce deuterium speci_cally at either the
a or b position may be used ð75BCJ0636Ł[ Sodium dithionite under phase transfer conditions will
also selectively reduce the carbon!to!carbon double bond ð75T3592Ł[
Me
N
Ph
N
Me
(11)

"ii# Conju`ate additions of carbon nucleophiles


a\b!Unsaturated ketones are ambident electrophiles which can react with carbon nucleophiles in
both a 0\1! and a 0\3! fashion[ The outcome is largely determined by the electronic nature of the
reagent\ with soft\ polarizable species tending to give predominantly the 0\3!product\ although steric
factors do play a role and make conjugate addition to b\b!disubstituted enones appreciably more
di.cult[
Easily the best!established class of reagents for conjugate additions are the organocuprates which\
since they have been the subject of a considerable number of reviews\ will not be discussed in detail
here[ The early literature has been described by Posner\ one of the pioneers in the area\ ð61OR"08#0Ł\
and the coverage has recently been updated by Lipshutz et al[\ whose group has also made major
contributions to cuprate chemistry ð81OR"30#024Ł[ Speci_c aspects of organocuprate chemistry such
as higher!order cuprate chemistry ð73T4994Ł\ copper!catalysed reactions of Grignard and organo!
lithium reagents ð73T530Ł and organocopper conjugate additionÐenolate trapping reactions ð74S253Ł
have also been the subject of reviews[
The conjugate addition of cuprate reagents to enones is still a very active area of research\ with
one important objective being the development of reagents which add enantioselectively[ At present
the enantiomeric excesses being reported are quite variable\ although some results reported for
amidocuprates\ which contain a chiral amine ligand\ appear very promising ð89TL3094\ 82T854Ł\ as
do the results of Grignard additions catalysed by chiral copper"I# thiolate complexes ð82TL6614Ł[
Another interesting development is the preparation of organocopper reagents directly from an alkyl
halide by reaction with a zero!valent copper species formed by the lithium naphthalenide reduction
of "thienyl#Cu"CN#Li[ The method has the considerable advantage of permitting the preparation
of organocopper reagents containing functional groups such as ester or chloro which would be
incompatible with a Grignard or organolithium intermediate\ and should signi_cantly increase the
scope of the chemistry ð81JOC1382Ł[
Although the majority of conjugate additions of alkyl groups are achieved by copper!based
methods\ some alternatives are available[ Triorganozincates are one such option and appear to be
superior with respect to solubility and thermal stability[ They can be prepared by the reaction of
Grignard ð75JOC2882Ł or lithium ð75TL0326Ł reagents with zinc chloride\ or from Grignard reagents
and dimethylzinc[ The latter method gives a mixed triorganozincate in which methyl acts as a
{dummy| ligand and is not transferred ð77JOC3022Ł[ Dialkylzinc reagents in the presence of catalytic
Ni"acac#1 have been found to be particularly useful for conjugate additions to b\b!disubstituted
enones ð74JOC4650Ł[

2[93[0[7[2 From a!functionalized ketones


Although a wide range of reducing agents is capable of e}ecting the reductive a!defunc!
tionalization of particular classes of a!functionalized ketones\ samarium"II# iodide has attracted
Saturated Unsubstituted 018
considerable popularity because of the very good results obtained with many of these substrates\
including a!halo\ a!acetoxy\ a!silyloxy\ a!tosyloxy\ a!phenylthio and a!phenylsulfonyl ketones[ How!
ever a!hydroxyketones are not reduced and poor results can be obtained with substrates with
hindered a!centres ð75JOC0024Ł[
a!Haloketones are probably the most frequently studied substrates for reductive a!cleavage\ and
many classes of reducing agent are known to e}ect the transformation[ Thus\ a number of one!
electron reductants including samarium"II# or cerium"III# iodides may be used ð68SC130Ł\ as may
some mild hydride donors such as 0\2!dimethyl!1!phenylbenzimidazole "00# ð75JOC4399Ł or phenyl!
silane in the presence of a molybdenum"9# catalyst and triphenylphosphine ð76JOC4469Ł[ Dehalo!
genation with soft nucleophilic reagents such as sodium iodide ð75S469Ł\ sodium hydrogen telluride
ð75S469Ł and sodium formaldehyde sulfoxylate "HOCH1SO1−Na¦# ð76SC0476Ł\ or with some metal
carbonyls ð68JOC1457\ 68JOC530Ł\ is also possible[
a\a?!Dihaloketones give oxyallyl species on dehalogenation with low!valent metal reagents which
will react with alkenes or dienes in a ð2¦1Ł or ð2¦3Ł sense to give cyclopentanones or cyclo!
heptanones[ The reaction provides a very ~exible route to odd!membered ring systems of importance
in natural product chemistry "Equation "03## ð74T4768Ł[ This chemistry has been reviewed as part
of a much more general chapter on the reductive dehalogenation of polyhaloketones in Or`anic
Reviews ð72OR"18#052Ł[

O O
i, Fe2(CO)4
O ii, Zn/Cu
Br Br + (14)
63% O
Br Br

Hydroxide is a relatively poor leaving group and consequently many of the single!electron
reductants that are very e}ective for a!dehalogenation work poorly on a!hydroxyketones[ It is
therefore often preferable to activate the acyloin _rst\ by acylation or sulfonation\ and then reduce
with samarium"II# iodide ð75JOC0024Ł or the vanadium"II#ÐTHF complex ðV1Cl2"THF#5ŁðZn1Cl5Ł
ð81CL0784Ł[ However\ a!hydroxyketones can be reduced directly with lithium diphenylphosphide\
which presumably adds 0\1! to the ketone and then undergoes a Wittig type reaction ð75JOC1267Ł\
and with trimethylsilyl iodide ð68SC554Ł\ in which it is most likely the a!trimethylsilyloxy derivative
which undergoes the reduction[
Relatively few alternatives to the standard reductive desulfonation of a!sulfonylketones with
aluminum amalgam are available ð53JA0528Ł[ However\ the reduction can be achieved with sam!
arium"II# iodide ð75JOC0024Ł and photochemically in the presence of a rhodium"II# sensitizer and a
Hantzch ester as ultimate reducing agent ð75CL76Ł[
a!Diazoketones are very versatile intermediates from which a wide range of derivatives may be
prepared[ The two most important reactions from the point of view of this chapter are cyclo!
propanation and the intramolecular insertion into C0H bonds\ generally to give cyclopentanones[
Both processes are mediated by copper"II# and rhodium"II# catalysts and have been the subject of
a review ð80T0654Ł[ The insertion reaction can occasionally provide a very elegant cyclopentanone
ring synthesis\ the major drawback being the poor regiospeci_city[ Several strategies for improving
the selectivity are known\ including suitable placement of electron!withdrawing groups\ such as
esters\ which protect C0H bonds a and b to them from attack ð77TL1172Ł\ using rhodium catalysts
with bulky ligands to favour methylene insertion over methine insertion ð81TL1698Ł\ or placing
double bonds to harness the preference for allylic over nonallylic insertion ð80T6392Ł[ Enantio!
selective versions of the reaction are also known ð72JA4824Ł[

2[93[0[8 From Carboxylic Acids and Their Derivatives

2[93[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives


The preparation of ketones by the reaction of an acid chloride with an organometallic reagent has
been attempted with an enormous range of organometallic reagents[ Unfortunately\ few alkylmetal
species show su.cient selectivity for reaction with the starting acid chloride over reaction with the
product ketone to make the reaction synthetically viable[ Probably the _rst successful approach
used Grignard reagents\ although an inverse addition of the Grignard reagent to an excess of acid
chloride at low temperature is required if reasonable yields are to be obtained ð43OR"7#17Ł[ Improved
029 Dialkyl Ketones
results are obtained if THF rather than ether is used as solvent ð68TL3292Ł or if the reaction is
performed in the presence of tris"acetylacetonato#iron"III# ð76TL1942Ł[ The latter conditions are
interesting in being compatible with a wide range of other functional groups including ester and
nitrile[ The other two reagents traditionally used for converting acid halides into ketones are
organozinc and organocadmium halides ð43OR"7#17Ł[ The latter\ which are prepared from an alkyl!
lithium or Grignard reagent and cadmium"II# chloride\ are now little used\ for toxicological and
environmental reasons[
Today the transformation is most often undertaken with an organocuprate\ an organozinc halide
or an organomanganese halide[ The disadvantages of the organozinc halides are their relatively low
reactivity\ even with acid chlorides\ and di.culty of preparation[ However\ the reaction has been
found to be greatly facilitated both by palladium catalysis ð72TL4070Ł and by copper"I# salts
ð80JOC0334Ł and\ with the improved methods of preparation available ð74TL4418Ł\ must now con!
stitute a very attractive preparation of ketones\ particularly in view of the toleration of sensitive
functionality like "8!~uorenyl#methoxycarbonyl "Fmoc# and phthalimide "Equation "04## ð89SL624Ł[

i, Zn/Cu, ultrasound
NH-t-BOC ii, PdII, AcOCH2COCl NH-t-BOC
I AcO (15)
CO2Me 64% O CO2Me
t-BOC = t-butoxycarbonyl

As well as the zinc!derived cuprates\ a wide range of other organocopper species have been used
to prepare ketones from acid chlorides[ When an unfunctionalized primary alkyl group is to be
coupled\ simple lower!order cuprates work well and are compatible with acid chlorides containing
ester\ nitrile and iodo groups ð61JA4095Ł\ although for more hindered cases higher!order cuprates
give better results ð77OSC"5#137Ł[ It is even possible to prepare suitable organocopper species direct
from the alkyl halides containing ester\ nitrile and chloro groups by reaction with the copper"9#
complex obtained by treating lithium 1!thienyl cyanocuprate with lithium naphthalenide ð78SC0722Ł[
The acylation of organomanganese halides\ which are prepared from a Grignard or alkyllithium
reagent and manganese"II# halide\ has been the subject of a detailed study ð73T572Ł[ Organo!
manganese couplings can also be performed catalytically by adding a Grignard reagent to a solution
of the acid halide and 2 mol) of MnCl3Li1 ð81TL3328Ł[ Other reagents that\ although less widely
used or studied\ appear to have considerable potential for preparing ketones from acid chlorides
include organothallium ð89JOC2257Ł\ and organovanadium ð75TL818Ł reagents[
Although many of the methods described above for preparing ketones from acid halides also
work with acid anhydrides\ the reaction is somewhat limited by the fact that only half of the acid is
incorporated into the product[ This drawback can be avoided if mixed anhydrides are used and the
idea has been shown to be practical for both Grignard reagents ð67SC48Ł\ and organomanganese
reagents ð68SC528Ł\ although few applications have been reported[
The preparation of a ketone by the reaction of a simple ester with an organometallic reagent
appears to be a particularly di.cult transformation which is only successful if special precautions
are taken to prevent further reaction of the ketone product[ This can be achieved by performing the
reaction with an alkyllithium reagent at low temperature "−009>C# in the presence of chloro!
trimethylsilane\ which presumably traps the tetrahedral intermediate ð75JOC840Ł\ or with a Grignard
reagent in the presence of triethylamine ð79S766Ł or lithium diisopropylamide ð76HCA0634Ł\ which
protects the ketone by enolization[ The introduction of a bulky silyl substituent at the a position of
the ester also very e}ectively prevents the reaction proceeding beyond the ketone stage ð74JOC4159Ł\
and cyclic ketones can be prepared in high yields by the samarium"II# iodide!mediated cyclization
of v!iodo esters\ a reaction which appears to involve the addition of an alkylsamarium nucleophile
to the ester "Equation "05## ð82JOC6105Ł[

MeO2C
I SmI2, THF
O (16)
93%

A number of ketone preparations from activated esters have been reported which\ despite the
requirement to prepare the particular ester\ do appear to have some advantages[ For example\ both
selenoesters ð72TL3244Ł and 1!pyridyl esters ð72JOC1597Ł react with organocuprates to give high
Saturated Unsubstituted 020
yields of ketones[ The latter reaction has the distinct advantage over the analogous reaction of an
acid chloride with a dialkylcuprate of using both alkyl groups from the organometallic reagent[
Perhaps surprisingly\ tertiary amides can be converted directly into ketones by reaction with an
alkyllanthanum tri~ate ð76TL3280Ł[ However\ most ketone preparations from amides use particularly
reactive derivatives\ such as acyl imidazoles ð89SC1572Ł\ or acyl aziridines ð73TL700Ł\ and N!methoxy!
N!methyl "Weinreb# amides[ The latter\ in which internal chelation stabilizes the tetrahedral inter!
mediate and prevents overreaction\ are rapidly becoming one of the preferred acid derivatives for
ketone preparation[ The idea has been generalized to N\N?!dimethoxy!N\N?!dimethylurea\ which
has been found to react with a wide range of organometallic reagents to give N!methoxy!N!methyl
amides\ which can then be coupled with a second organometallic reagent to give an unsymmetrical
ketone ð80JOC1800Ł[
The preparation of ketones by the reaction of Grignard reagents with nitriles has a long history\
although the conditions are quite critical\ with aromatic solvents being required for good results
ð79TL044Ł[ The reaction is also catalysed by the addition of copper"I# salts\ which allow the reaction
to be used for the preparation of quite hindered ketones ð76JOC2890Ł[
The reaction of a carboxylic acid with two equivalents of an alkyllithium reagent is a well
established preparation of ketones which works because the dianionic tetrahedral intermediate does
not break down under the reaction conditions to liberate the ketone\ which is therefore unavailable
for overreaction to the tertiary alcohol[ In practice\ obtaining good yields of ketone\ free from
carbinol\ depends heavily on good experimental technique\ both in the addition of the alkyllithium
and in the hydrolysis of the tetrahedral intermediate ð69OR"07#0Ł[ Improved workups in which the
reaction is quenched with aniline ð70JOC2817Ł\ gaseous formaldehyde ð70JOC2817Ł or\ for the speci_c
case of methyl ketone preparation\ with chlorotrimethylsilane ð72JOC0449Ł have been described\ and
the addition of cerium"III# chloride to the reaction mixture has been found to be highly bene_cial
ð83TL192Ł[ It is also possible to generate the lithium salt of the carboxylic acid from an alkyllithium
and carbon dioxide and react it in situ with a second equivalent of a di}erent alkyllithium to give
an unsymmetrical ketone ð81AG"E#0924Ł[

2[93[0[8[1 Other preparations from acids and acid derivatives


The ready accessibility of b!keto esters by Claisen and Dieckmann condensations makes them
important precursors of ketones[ Although the preparation of a ketone from a b!keto ester was
traditionally achieved by basic hydrolysis followed by acidi_cation and decarboxylation\ the reaction
is frequently performed today with the salt:DMSO conditions _rst developed by Krapcho ð71S794Ł[
The initial condensation can also be combined with the decarboxylation by using either acid dianions
ð66JOC0078Ł or silyl ester enolates ð67TL2602Ł as one partner in the initial condensation[ In both
cases the aqueous workup gives a b!keto acid which decarboxylates in situ[ a!Hydroxy acids can be
cleaved by a variety of reagents\ including N!iodosuccinimide ð71JOC2995Ł\ and the benzoazolium
salt "01# ð67CL38Ł\ to carbon dioxide and a ketone[

Et
N+
Cl BF4–
O
(12)

2[93[0[09 From Sulfur or Other Lower Chalcogen!containing Precursors


The hydrolyses of thioacetals and vinyl sul_des are closely related processes which involve a
common sulfenium ion intermediate "Scheme 01#[ The mechanism is analagous to that of the closely
related hydrolysis of acetals and vinyl ethers\ although it di}ers in the important respect that the
equilibrium is strongly towards the thioacetal rather than the carbonyl compound[ For this reason
it is necessary to drive the hydrolysis to completion by removing the thiol produced\ and a number
of methods have been developed for doing so\ the most important of which are the formation of an
insoluble transition metal thiolate\ alkylation of the thiol\ and oxidation of the thiol to a higher
oxidation state of sulfur[ References to a selection of methods are contained in Table 0\ and the
021 Dialkyl Ketones
subject has been discussed in rather more detail by Grobel and Seebach ð66S246Ł[ Thioacetals have
an important application as protecting groups and a useful discussion of this aspect may be found
in Greene and Wuts ðB!80MI 293!91Ł[ The cleavage of selenoacetals has been the subject of a
systematic study which found that mercury"II# chloride in wet acetonitrile\ basic copper"II# chloride
in aqueous acetone\ and hydrogen peroxide or benzeneseleninic anhydride in THF all gave good
results ð68S766Ł[

SR3 –R3S–
SR3
R1
R2
+ O
SR3 H2O
R1 R1
R2 R2
SR3 +H+
R1
R2

Scheme 12

Table 0 Preparation of ketones from thioacetals[


Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Rea`ent Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Transition metal reagents
HgO\ HBF3 70S40
PbO1\ BF2 = Et1O 71S479
Alkylating reagents
MeOSO1F 61S450
Et2O = BF3 70S024
Oxidizing reagents
Tl"NO2#2 68SC290
Electrochemical 89TL1488
Ceric ammonium nitrate 70SC312
"PhSeO#1O 79JCS"P0#0543
PhIO 71TL846
mcpba 76S0002
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

Anions of sulfones can be oxidized to ketones by either bis"trimethylsilyl#peroxide ð72JOC3321Ł


or the molybdenum peroxide reagent MoO4 = pyridine = HMPA "MoOPH# ð79TL2228Ł[ In both cases
an a!hydroxy sulfone is the presumed intermediate[

2[93[0[00 From Nitrogen!containing Precursors

2[93[0[00[0 From amines


Although the conversion of an amine into a carbonyl compound is a relatively common biological
transformation\ which can occur by ~avin!\ NADP! or pyridoxyl!mediated processes\ it is only
rarely performed chemically[ Despite this there is a range of methods for achieving the trans!
formation\ including some involving a pyridoxal!like prototropic rearrangement of an imine
"Scheme 02# ð71JA3335Ł[
Direct oxidation of an amine to an imine is possible using an arylsulfonyl peroxide under strongly
basic conditions\ followed by hydrolysis to the ketone ð73JOC3900Ł[ Alternatively the oxidation and
hydrolysis can be achieved in a single pot by nitroxyl!mediated electro!oxidation ð72JA5621Ł[ Anodic
methoxylation of carbamates also provides a simple route to ketones via their dimethylacetals
ð72JOC2227Ł[
Although the ease of hydrolysis of imines makes them a particularly attractive intermediate in an
amine!to!ketone conversion\ a recent method which involves the oxidation of a metallated silylamine
with dry air to give an oxime also appears attractive[ The oxime intermediate is hydrolysed to the
required ketone during ~ash chromatographic puri_cation\ and the conditions are compatible with
phosphine\ thioether and tertiary amine functionality "Scheme 03# ð77TL5690Ł[
Saturated Unsubstituted 022
NH2
+
+ Me N dbu
+ Me N CHO
N

+
Me N H3O+
O
N 91%

dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene

Scheme 13

OLi
TMS O
HN TMS O N
i, BunLi N

ii, dry air

OH O
N
SiO2, H2O

87%

Scheme 14

2[93[0[00[1 From oximes\ hydrazones and their derivatives


Probably because they are relatively stable derivatives of ketones\ and have the reputation of only
being hydrolysed under fairly vigorous conditions\ oximes and hydrazones are relatively infrequently
considered as potential precursors or protecting groups\ despite the very sizeable body of literature
describing methods of achieving this sort of transformation[
Classical oxime and hydrazone hydrolyses use fairly vigorous acidic conditions[ However\ the
transformation can be achieved with milder heterogeneous acid catalysts such as Amberlyst!04 resin
for tosylhydrazones\ dinitrophenylhydrazones and semicarbazones ð77JCS"P0#1452Ł\ or Dowex!49
resin for oximes and semicarbazones ð77JOC767Ł[ Dowex!49 is particularly useful since it will allow
the selective hydrolysis of semicarbazones derived from ketones in the presence of those derived
from aldehydes[ Dimethylhydrazones may also be hydrolysed by a Lewis acid!catalysed transfer of
the hydrazine to acetone ð65S345Ł\ or by addition of water to the complex of the hydrazone with
boron tri~uoride etherate ð71SC04Ł[ A milder approach to the hydrolysis of hydrazones uses metal
complexation of nitrogen to help polarize the carbonÐnitrogen double bond and facilitate attack by
water[ The metal ion most commonly used for this purpose is copper"II#\ which has the advantage of
also driving the reaction to completion by scavenging the liberated hydrazine derivative ð65TL2556Ł[
Probably the largest group of methods for preparing carbonyl compounds from C1N derivatives
comprises those employing oxidizing agents[ These include a number of nitrosating reagents which\
like copper"II# complexation\ activate the carbon atom to attack by water by electrophilic attack at
the nitrogen atom[ Examples of this type of method include the hydrolysis of oximes by nitrosyl
chloride ð66CI"L#343Ł or a mixture of sodium nitrite and chlorotrimethylsilane which provides an in
situ source of nitrosyl chloride ð89TL5566Ł^ the hydrolysis of tosyl hydrazones mediated by sodium
nitrite in tri~uoroacetic acid ð68S196Ł^ and hydrolysis of both oximes and N\N!dimethylhydrazones
with either nitronium or nitrosonium tetra~uoroborate ð65S509Ł[ Active oxygen reagents can also
be used[ For instance\ aryl hydrazones can be cleaved with basic hydrogen peroxide ð67S808Ł\ oximes
with dimethyldioxirane ð82SL316Ł\ tosylhydrazones with sodium percarbonate ð81SC1476Ł\ and
dimethylhydrazones with sodium periodate ð65TL2Ł[ The recently introduced magnesium mono!
peroxyphthalate has been found to be particularly valuable in cleaving hydrazones without a}ect!
023 Dialkyl Ketones
ing the stereochemical integrity of a chiral centre a to the ketone product ð89SL614Ł\ an advantage
also o}ered by the N!bromosuccinimide!mediated cleavage of tosyl hydrazones ð66JOC2194Ł[
Conventional high!valency metal oxidants can also be employed for preparing ketones from
oximes or hydrazones[ Thus\ bis"trimethylsilyl# chromate ð81SC1314Ł\ and pcc in the presence of
hydrogen peroxide ð79S014Ł\ have both been found valuable for the preparation of ketones from
oximes^ thallium"III# acetate can be used to regenerate ketone tosylhydrazones ð68TL3472Ł^ and
cetyltrimethylammonium permanganate will convert arylhydrazones to ketones ð75JOC2952Ł[ Ben!
zeneseleninic anhydride will also cleave a range of C1N derivatives\ including oximes\ aryl! and
tosylhydrazones and semicarbazones\ but not N\N!dimethylhydrazones or O!methyl oximes[ The
reagent appears to be particularly e}ective for the regeneration of hindered ketones ð79JCS"P0#0101Ł[
Although the majority of new methods involve the use of oxidative reagents\ it is also possible to
achieve the transformation under reducing conditions[ For example\ both Raney nickelÐsodium
hypophosphite ð75SC792Ł and vanadium"II# chloride ð79S119Ł can be used for deoximation\ and
titanium"III# chloride can be used to liberate ketones from tosylhydrazones\ oximes\ semicarbazones\
and thiosemicarbazones ð66CI"L#631Ł[ Despite the variety in the types of reducing agent used\ they
all appear to involve an initial reduction to an imine\ which is hydrolysed under either the reaction
or workup conditions[
Lastly\ it has recently been reported that both oximes ð80JCS"P0#1945Ł and hydrazones ð80TL1546Ł
can be cleaved enzymatically with baker|s yeast[ The hydrolysis\ which is greatly aided by sonication\
gives near quantitative yields of the ketone[

2[93[0[00[2 From nitroalkanes


The preparation of a carbonyl compound from a primary or secondary nitroalkane is usually
known as the Nef reaction[ The conversion was originally achieved by treatment of the nitronate
salt of a nitroalkane with strong acid\ but the extremely vigorous nature of these conditions\ and
the occurrence of a number of side reactions\ has lead to the development of a wide range of
alternative conditions[ These methods have been reviewed comprehensively in a recent volume of
Or`anic Reactions ð89OR"27#544Ł[

2[93[0[00[3 From nitriles


A study of a number of methods for achieving the oxidative decyanation of secondary nitriles
found that the best results were obtained by preparing the a!hydroperoxy nitriles by direct oxy!
genation of the anion and subsequent reductive hydrolysis with tin"II# chloride followed by sodium
hydroxide ð72JOC3976Ł[

2[93[0[01 From Organosilanes


Probably the most important organosilane precursors of unsubstituted ketones are vinylsilanes\
which can be oxidized directly to the corresponding ketone with molecular oxygen ð78CL1122Ł\
although the conversion is most often achieved by epoxidation followed by acid!catalysed rearrange!
ment ð63JA2572Ł[ Both methods result in formation of the ketone at the silicon!bearing carbon atom[

2[93[0[02 From Organoboranes


Hydroboration reactions are most often worked up with alkaline hydrogen peroxide to give an
alcohol[ In cases where a ketone is required\ it is generally obtained by oxidation of the alcohol in
a second step\ although it is also possible to achieve the transformation in a single pot by using
pyridinium chlorochromate rather than alkaline hydrogen peroxide to oxidize the borane inter!
mediate ð89SC2154Ł[
Organoboranes are valuable precursors of ketones\ particularly symmetrical ones\ through a
number of carbon!to!carbon bond forming reactions in which alkyl groups on boron become bound
to the ketone carbon atom[ The earliest examples of this involved the reaction of a thexyl!
dialkylborane with either carbon monoxide or cyanide and have recently been combined with
Saturated Unsubstituted 024
enantioselective hydroboration methodology to give quite complex ketones of very high optical
purity ð77JA0418Ł[ The thexyl group is important since\ being nonmigrating\ overreaction to give a
tertiary carbinol is not possible[
Ketones can also be prepared by reaction of an organoborane with a carbanion bearing three
leaving groups and\ for reasons of both reaction selectivity and reagent toxicity\ this chemistry is
now normally preferred[ Thus\ good yields of ketones can be obtained by treatment of tri!
alkylboranes with the anion derived from 3\3!dimethyl!1!oxazoline ð72SC256Ł or tris"phenyl!
thio#methane ð70CC0038Ł\ in which tertiary carbinol formation is apparently not a problem[
Overreaction can also be prevented by using an alkoxyborane\ the alkoxy group\ like thexyl\ being
nonmigrating[ Such boranes have been used in a number of recent approaches to homochiral
ketones by the reaction of lithium dichloromethyl methyl ether with the products of enantioselective
hydroborations "Scheme 04# ð71JA5733\ 73T0214\ 76JA4319Ł[ An ingenious variation on this theme uses
"phenyldimethylsilyl#dichloromethyllithium to give an a!hydroxy silane which can be oxidized to
the required ketone with the Jones reagent "Scheme 05# ð79SC702Ł[

BH2
i, trans-2-butene MeCHO
B
ii, 1-pentene

i, Cl2CHOMe, ButOLi
ii, H2O2, HO–
B
EtO 66%, 70% ee O

Scheme 15

i, thexylborane n-C8H17 i, PhMe2SiCCl2Li


B
ii, 1-octene ii, H2O2, HO–

O
Jones
n-C8H17
51%
PhMe2Si n-C8H17
OH

Scheme 16

A number of attractive boron!based routes to ketones involve the preparation of an alkenylborane


which\ on treatment with basic hydrogen peroxide\ gives the ketone directly[ These preparations
bene_t from the impressive range of methods which are now available for the synthesis of alken!
ylboranes and which complement the simple hydroboration of alkynes[ These include an alkylative
hydration of an alkyne in which chlorotributyltin is used to induce the migration of a primary alkyl
group to the adjacent acetylenic carbon of a lithiumÐ0!alkynyltrialkylborate complex "Scheme 06#
ð73JOC4064Ł[ A similar borane!based transformation of a 0!bromoalkyne is also known ð71JOC643\
71JOC2797Ł\ as are sequences involving 0\1!dimethoxyethenylborates "Scheme 07# ð70CL0948Ł[

2[93[0[03 Methods Involving Umpolung


Although reactions involving polarity reversal\ such as the benzoin condensation\ have been
known since the earliest days of organic chemistry\ it is only over the last 29 years that the concept
has really played an important role in synthetic chemistry[ Much of the early development of the
area and the nomenclature used in this section are due to Seebach ð68AG"E#128Ł[ A vast range of
umpolung synthons are now available\ with by far the most important for ketone preparation being
the d0 "formyl dianion and acyl anion# reagents\ and the d2 "homoenolate# equivalents[
025 Dialkyl Ketones

Bun

Li Bun n-C6H13 Bu3SnCl


n-C6H13 B
B

n-C6H13 Bun
H2O2, HO– O
B SnBu3 62% n-C6H13 n-C5H11

Scheme 17


Br i, BunLi Bu3B O
i, EtOSO2F
Et
MeO OMe ii, Bu3B MeO OMe ii, H3O+ Bu

Scheme 18

2[93[0[03[0 Acyl anions and their equivalents


Although their synthetic value is perhaps rather limited\ a number of acylmetal reagents can be
prepared\ and some reports\ most notably from the group of Seyferth\ of their use in preparative
chemistry have appeared[ Acyllithium reagents can be prepared by the addition of an alkyllithium
to a saturated solution of carbon monoxide in a tetrahydrofuranÐetherÐpentane solvent mixture at
−009>C ð74JOC0874Ł or more conveniently\ in cases where the method is applicable\ by lithiumÐ
tellurium exchange of a telluroester having no acidic a!protons ð89JA344Ł[ Although the extreme
basicity and low stability of these reagents limits their synthetic applications\ acylcuprates\ which
are prepared in an analogous way from carbon monoxide and a dialkylcyanocuprate\ appear to be
more useful and will add to both cyclic and acyclic enones and to enals in very respectable yields
ð75TL0362Ł[
Acyl radicals have received a considerable amount of attention over the last few years and\ like
the acyl anion species\ o}er the possibility of achieving transformations that would be impossible
according to {normal| criteria of reactivity[ Acyl radicals are usually generated by treatment of an
acyl selenide with tributyltin hydride and have been trapped with alkenes\ either intermolecularly
ð78JOC066Ł or intramolecularly to give cyclohexanes ð89JCS"P0#1764Ł or large ring systems ð89JA3997Ł[
Interestingly\ 05!membered ring lactones are formed even when competing 5!exo or 6!endo!tri`
cyclization modes are also possible\ although macrocyclization and 4!exo!tri` cyclization occur at
similar rates "Equation "06##[ The generation of acyl radicals from acylgermanes ð89JOC4451Ł\ from
"S#!acylxanthates ð77CC297Ł\ and from acylcobalt precursors ð89JCS"P0#1610Ł has also been reported[
O

O O
Bu3SnH, AIBN
O (17)
SePh 70%

O O
AIBN = 2,2'-azobisisobutyronitrile

Many d0 synthons that have been described and can be classi_ed either as formyl dianion
equivalents\ in which the two carbonyl substituents are introduced in successive alkylating steps\ or
as acyl anion equivalents\ in which one of these substituents is already present[ A compilation of
acyl anion equivalents reported up to the early 0879s is available and includes details of the
electrophiles used ð71MI 293!90Ł[ The general topic of nucleophilic acylation has been the subject of
a review ð65T0832Ł\ as has the chemistry of silicon!containing carbonyl equivalents ð71CSR382Ł[
Saturated Unsubstituted 026
It should also be noted that many of the formyl anion equivalents discussed in Chapter 2[90[0[03[0
can be doubly alkylated and are thus also formyl dianion equivalents[
A large proportion of formyl anion and dianion equivalents are based on sulfur[ This group
includes one of the earliest and still one of the most important synthons\ 1!lithio!0\2!dithiane\
which has been the subject of several reviews ð66S246\ 78T6532Ł[ Formyl anion synthons containing
sulfur"VI#\ such as "02# ð73CC375Ł\ are also known[


PhSO2 TMS
(13)

d0!Formyl anion and dianion synthons based on nucleophilic metal carbonyl derivatives can be
very useful reagents for ketone synthesis[ The best!known example is the Collman reagent\
Na1Fe"CO#3\ which reacts with primary and secondary halides and sulfonates to give an alkyl iron
complex which can be alkylated a second time to liberate the required ketone "Equation "07##[ The
reagent tolerates ketone\ ester or nitrile functionality\ but has the drawback of being somewhat
basic\ causing elimination of some substrates\ in particular of tertiary halides and sulfonates\ and
being restricted to quite reactive alkylating agents "generally primary iodides# in the second step
ð64ACR231Ł[ A number of related ionic iron carbonyl complexes ð68CL210\ 78BCJ1617Ł have also been
used[

i, Na2Fe(CO)4
ii, EtI CO2Et
Br
CO2Et (18)
74% O

Acyl anion equivalents\ which already contain one of the carbonyl substituents\ are also important
ketone precursors[ Two principal groups can be identi_ed] those based on vinyl anions\ and those
using protected cyanohydrins or related species[ The latter\ which are extensions of the benzoin
condensation\ have been the subject of a review ð72T2196Ł[ One particularly important class of these
synthons is the dialkylaminonitriles which\ since they are prepared by the Strecker reaction of an
aldehyde\ allow a fairly direct preparation of ketones from aldehydes[ Lastly\ a wide variety of
metallated vinyl compounds have been prepared and used as acyl anion equivalents[ Examples
include lithium and Grignard derivatives of vinyl silanes ð71CSR382Ł\ and lithiated derivatives
of vinyl sul_des ð73BCJ0752Ł\ vinyl esters ð70T2886Ł\ vinyl carbamates ð89JOC4579Ł and enamines
ð70CC0010Ł[

2[93[0[03[1 Other anion equivalents


Although homoenolates of nonenolizable ketones can be formed with very strong bases\ the
chemistry is of limited synthetic generality and d2 synthons are generally preferred[ The majority of
homoenolate equivalents are substituted allyl anion species and consequently have the limitation
that the selectivity for alkylation at the required g!position can be modest[ A useful introduction to
the chemistry of both homoenolates and their equivalents has been provided by Wertiuk ð72T194Ł[
b!Functionalization of ketones can also be achieved via b!keto radical intermediates[ These are
available by the manganese"III# oxidation of cyclopropanols and allow the rapid elaboration of
substituted medium!ring ketone systems "Equation "08## ð82CL434Ł[

O
HO
MnIII, Bu3SnH H
(19)
75%

H
027 Dialkyl Ketones
Lastly\ a number of a1 synthons are known\ although they have most often been reported reacting
with fairly stabilized anions such as enolates or keto esters[ However\ the sulfur!substituted allyl
acetate "03# will couple with a lithium dialkylcuprate and thus acts as an a!keto cation equivalent
"Scheme 08# ð68JA3302Ł[
SPh SPh O
Bu2CuLi HgCl2
OAc Bun Bun
89%

(14)
Scheme 19

2[93[1 BETA!UNSATURATED AND MORE REMOTELY UNSATURATED KETONES


The unconjugated alkene functionality is relatively unreactive and many of the methods described
in Section 2[93[0 can therefore be used for the preparation of remotely unsaturated ketones simply by
using an appropriately unsaturated precursor[ One very signi_cant restriction to this generalization
concerns b\g!unsaturated ketones where the ease with which the double bond can migrate into
conjugation can restrict the choice of reagents[
This section describes methods in which the unsaturation is a necessary\ or integral\ part of the
chemistry[ The reactions consequently have no direct analogues for the preparation of saturated
ketones^ indeed some of the methods\ with the addition of a _nal hydrogenation step\ can form
powerful approaches to saturated ketones[

2[93[1[0 Dialkyl Ketones with One Double Bond

2[93[1[0[0 From ketones


"i# Vinylation of saturated ketones
Although the direct base!catalysed vinylation of a ketone with a 0!bromoalkene is not possible\
the transformation can be achieved using one of a number of vinyl cation equivalents[ Most of these
reagents employ transition metal chemistry\ as in the palladium!catalysed vinylation of lithium
enolates with alkenes ð79JA3862Ł and of tin enolates by 0!bromoalkenes ð72CL728Ł[ Lithium enolates
can also be vinylated with h1!ethoxyethene complexes of iron ð79JA4829Ł[ This chemistry has been
extended both to allow isopropenylation of enolates ð70JOC3092Ł and\ with 0\1!dimethoxyethene
complexes\ to give a 0\1!ethene dication equivalent[ By variation of the reaction conditions\ the
latter complex allows the preparation of both "E#! and "Z#! alkenylated ketones "Scheme 19#
ð73JA6153Ł[ Enol silanes can be ethenylated intramolecularly by alkynes with mercury"II# catalysis\
via a postulated transient a!mercury ketone intermediate[ The initially formed vinylmercury product
is normally protonated "or deuterated# in the workup\ but can also be trapped with other elec!
trophiles "Equation "19## ð74JA0615Ł[ Ethenylation of zinc enolates can also be achieved with
phenylselenoacetaldehyde "Scheme 10# ð71JOC0521Ł[

MeO OMe OMe OMe


i, Me2CuLi RT, 30 min
Fe+ Fe+ Fe+
CO ii, HBF4 CO CO
CO CO CO
OLi
OLi

CO O
CO O O
O Fe ∆ ∆

52% 38% Fe
CO
CO

Scheme 20
b! and More Remotely Unsaturated 028

O-TMS i, HgCl2 O
ii, HCl
(20)
83%

O(1/2Zn) O OH O
PhSeCH2CHO MsCl, Et3N

95% 82%
SePh

Scheme 21

"ii# Allylation of saturated ketones


Since allyl halides are highly reactive alkylating agents\ conventional base!catalysed and metal
enolate!based alkylation methods may be employed for the allylation of ketones\ although with the
usual attendant problems of polyalkylation and poor regiocontrol "Section 2[93[0[7[0#[
The palladium!catalysed allylation of stabilized anions\ such as those derived from b!ketoesters\
with allyl acetates is\ by now\ a well established reaction which has been studied in considerable
detail ð66T1504Ł[ More recent work has shown the reaction to be successful with nucleophiles such
as enol stannanes ð79TL1480Ł\ enol silanes ð72CL0214\ 75CL0998Ł\ enol acetates ð72TL3602Ł and even
lithium ð70CC0048Ł or zinc ð72JOC3987Ł enolates\ thus allowing the preparation of a variety of simple
unsaturated ketones[ The allylation is also reported to be catalysed by rhodium"I# to give products
with inversion rather than retention of allyl con_guration ð73TL4046Ł\ and by cobalt"II# under
neutral rather than mildly basic conditions ð82TL5290Ł[ Considerable variation is also possible in
the allyl component of the reaction^ for example\ allyl isoureas ð73CL0116Ł or allyl carbonates
ð74JOC0412Ł can be substituted for the more usual allylic acetate[
One particularly interesting development of the palladium!catalysed allylation chemistry is the
decarboxylative allylation where an allyl b!ketoester undergoes a formal extrusion of carbon dioxide
on treatment with either a palladium"9# ð79JA5270Ł or a palladium"II# ð79TL2088\ 72TL0682Ł catalyst
"Equation "10##[ Decarboxylative allylations of b!ketoacids with allylic acetates are also possible
ð75JOC310Ł[ Considerable e}ort is also being devoted to the development of enantioselective versions
of the reaction\ although largely with ketoester and malonate nucleophiles[ However the
palladium"9#!catalysed intramolecular allylation of proline!derived enamines has been shown to
proceed with very high enantiomeric excess\ although the chemical yields are quite modest "Equation
"11## ð75CC358Ł[

O
Pd0 O
O (21)
96%
O

O
O
O H
N Pd0
H (22)
47%, 100% ee

Allyl halides\ because of their high SN0 reactivity\ are e}ective electrophiles in the Lewis acid!
catalysed alkylation of silyl enol ethers ð68TL0408\ 68TL3860Ł[ The reaction is discussed in more detail
in Section 2[93[0[7[0[
039 Dialkyl Ketones
"iii# Conju`ate addition of unsaturated nucleophiles to a\b!unsaturated ketones
Although the methodology used for the conjugate addition of carbon nucleophiles is broadly
similar\ irrespective of whether or not the nucleophile contains carbonÐcarbon double bonds\ the
rather di}erent character and generation of vinyl! and allylmetal reagents justi_es some additional
discussion beyond that of Section 2[93[0[7[1[
Hydrometallation of alkynes is an attractive way of preparing alkenylmetal reagents[ For example\
hydroalumination of an alkyne gives an alkenylaluminum reagent which can either be used as a
precursor of a cuprate ð89JOC0314Ł or treated with methyllithium to form an ate complex which will
add 0\3! to an enone ð68JOC0327Ł[ Alkenylzirconium reagents\ prepared analogously by hydro!
zirconation of an alkyne\ can also be used as cuprate precursors ð89JA6339\ 89JA6330Ł or alternatively
can be activated towards conjugate addition\ even to hindered enones\ by Ni"acac#1\ or Ni"acac#1
prereduced with dibal!H ð79JA0222Ł[ Alkenylboranes\ prepared by the reaction of an alkyne with 8!
borabicycloð2[2[0Łnonane "8!BBN!H#\ also undergo e.cient conjugate addition to acyclic enones
ð65JA6721Ł[
Allylsilanes add 0\3 to enones in the presence of titanium"IV# chloride ð66JA0562Ł\ or trityl
perchlorate ð76CL178Ł catalysts[ Impressively\ the reaction is equally successful with b\b!dis!
ubstituted enones "Equation "12##\ and the resulting enolate intermediate can be trapped with
carbon electrophiles ð68CL134Ł[ Allylstannanes undergo 0\3!addition to enones in the presence of
trimethylsilyl tri~ate\ to give the product in which the allylstannane has coupled at its more hindered
position "Equation "13## ð80SC14Ł[ Allylsilanes do not react under these conditions and the reaction
fails for b\b!disubstituted enones[ The reaction can also be performed photochemically^ under these
conditions couplings with b\b!disubstituted enones are successful\ although products from both a!
and g!attack are also seen ð80CL0902Ł[

TiCl4
+ TMS (23)
85% O
O

O O-TBDMS

TBDMS-OTf
+ Bu3Sn (24)
88%

2[93[1[0[1 From carboxylic acid and carboxylic acid derivatives


b\g!Unsaturated ketones can be prepared by the aluminum chloride!catalysed electrophilic acyl!
ation of allylsilanes ð68JOC2286Ł\ or by the reaction of allylmercury"II# iodides with acid chlorides
ð82JOC1736Ł[ The Lewis acid!catalysed reactions can also be performed with allylstannanes
ð80CL0070Ł\ which also react with transition metal catalysis ð66JOM"018#25Ł[ In all three systems the
reaction proceeds by an E1? mechanism with allylic rearrangement[ A related reaction is the
aluminum chloride!catalysed acylation of 0!trimethylsilyl!1!methylcyclopropane\ which provides
b\g!unsaturated ketones in a regio! and stereospeci_c manner "Equation "14## ð70TL1772Ł[ b\g!
Unsaturated ketones have also been prepared by the acylation of h2!allylnickel complexes with
pyridine!1!carboxylates ð68CL0372Ł\ and by the zincÐsilver couple!mediated reaction of allyl halides
with nitriles ð70TL538Ł[

O
TMS PriCOCl, AlCl3
(25)
75%
b! and More Remotely Unsaturated 030
2[93[1[0[2 Preparations involving rearrangements

"i# Claisen rearran`ements


The Claisen rearrangement\ the ð2\2Ł sigmatropic rearrangement of an allyl vinyl ether\ can be a
useful route to g\d!unsaturated ketones ð64OR"11#0\ 66S478Ł[ The chief di.culty with the reaction lies
in the preparation of the allyl vinyl ether substrate[ This is normally achieved by a mercury"II#!
catalysed vinyl ether exchange reaction "Equation "15##\ although a number of alternatives have
been reported\ including the Bronsted acid!catalysed reaction of an allylic alcohol with a ketone
acetal ð71JOC632Ł and the reaction of an allylic alcohol with a b!chloroacrylic acid to give a
b!allyloxyacrylic acid which rearranges and decarboxylates in situ "Scheme 11# ð74JOC3553Ł[ An aza
analogue of the Claisen rearrangement is also known and o}ers some advantages in terms of ease
of preparation of the precursors ð77JOC3378Ł[ Finally\ Claisen rearrangements of allyloxyketone!
derived enol silanes have been used to prepare b\g!unsaturated ketones "Scheme 12# ð75JOC0282Ł[

Hg(OAc)2, ethyl vinyl ether


(26)
85%
HO
O

O
i, NaH
Cl O i, NaH (2 equiv.) OH ii, 200–215 °C O
+ O
OH OH ii, H3O+ 78%

Scheme 22

O-TMS O
O
TMS-Cl, Et3N O HIO4
O
84% 72%

Scheme 23

"ii# Oxy!Cope rearran`ements


The oxy!Cope rearrangement is a ð2\2Ł sigmatropic rearrangement of a hexa!0\4!dien!2!ol system
to form a d\o!unsaturated ketone[ Early studies of the rearrangement were performed using thermal
conditions which\ because of the temperatures required "×199>C#\ are of limited synthetic utility
ð64OR"11#0Ł[ However\ formation of the potassium salt of the starting dienol has been found to lead
to an enormous increase in the rate of the reaction\ allowing it to be run at room temperature[ This
discovery has greatly extended the scope of the reaction by permitting the use of substrates containing
more sensitive functionality and allowing further elaboration of the product by trapping of the
potassium enolate in situ ð89AG"E#598Ł[ One of the few drawbacks of the anionic conditions is that
the yields can vary considerably depending on the batch of potassium hydride used\ although the
problem can be avoided by pretreatment of the hydride with 09 mol) of iodine ð75JOC0013Ł[ The
rearrangement can also be promoted by catalytic mercury"II# tri~uoroacetate ð71TL3152Ł or by
formation of a trimethylsilyl ether derivative ð71CC717Ł[ The reaction has proved to be particularly
valuable for the preparation of macrocyclic ketones by four!carbon ring expansion of more accessible
031 Dialkyl Ketones
cyclic ketones[ Such a strategy requires the a!ethenylation of the starting ketone\ a far from simple
transformation for which a number of elegant solutions have been developed "Scheme 13# ð79BCJ1847\
71JOC1157Ł[

O OMgCl
MgCl O MgCl
Cl Cl 70 °C

OH O
200 °C

Scheme 24

"iii# Other rearran`ements


Since the migratory aptitude of vinyl groups is greater than that of alkyl or hydrogen groups in
a pinacol rearrangement\ the reaction has considerable potential for the preparation of b\g!unsatu!
rated ketones[ This has been nicely illustrated by an asymmetric synthesis of a!vinyl ketones by the
triethylaluminum!promoted rearrangement of homochiral vicinal hydroxymesylates "Equation "16##
ð72TL3886Ł[ Vinyl cycloalkanones can be prepared from cycloalkenes in a four!step sequence which
involves the alkoxide!induced rearrangement of an a\a!dichlorocyclobutanone formed by addition
of dichloroketene to the alkene "Scheme 14# ð82TL7046Ł[

R OH O
Et3Al
(27)
MsO H H R

R = Ph, 86%, >99% ee


R = vinyl, 75%, >99% ee

Cl
• O Cl
Cl Cl NaOMe dibal-H
CO2Me
75% 83%
O OMe

OH i, MsCl, pyridine
ii, HClO4

63%
OMe O

Scheme 25

2[93[1[0[3 Miscellaneous preparations


The reaction of nitrile oxides with allylsilanes has been used to prepare b\g!unsaturated ketones
in a sequence which uses a Peterson elimination to form the double bond "Scheme 15# ð75S201Ł[
b\g!Unsaturated ketones can also be prepared from allyl halides by reaction with acyl stannanes
ð76CL0260Ł[ One remarkable approach to b\g!unsaturated ketones involves the fragmentation of
bis"homoallylic# potassium alkoxides[ Thus addition of an excess of an allylic Grignard reagent to
a carboxylic ester gives the corresponding tertiary alcohol\ which on warming with potassium
b! and More Remotely Unsaturated 032
hydride looses one allyl group to form the unsaturated ketone\ often in high yield and with relatively
little migration of the double bond into conjugation "Scheme 16# ð76HCA0747Ł[
O
TMS
+ N H2, Raney Ni
But N O– + TMS
81% 85%
But

O OH BF3•Et2O O
TMS
But 77% But

Scheme 26

MgCl Bun OH i, KH, HMPA


BunCO2Me +
ii, NH4Cl (aq.)

O O
+
Bun Bun
5:1
HMPA = hexamethylphosphoramide

Scheme 27

g\d!Unsaturated ketones can be prepared by the aluminum chloride!catalysed reaction of an


allylsilane with a nitroalkene to give a nitronate which is readily converted into the unsaturated
ketone with a Nef reaction "Equation "17## ð70TL0004Ł^ d\o!unsaturated ketones can be prepared by
the silver ~uoride!mediated reaction of allyl chlorides with trimethylsiloxycyclopropanes\ a reaction
in which a b!silver ketone species is the postulated intermediate "Equation "18## ð77TL5026Ł[

i, AlCl3
NO2 ii, TiCl3
TMS n-C10H21
+ O (28)
74% n-C10H21

O
AgF
Cl + (29)
TMS-O
53%

The free!radical fragmentation of b!trialkylstannyl alkoxy radicals has been employed in several
preparations of remotely unsaturated ketones[ In the most direct approach\ the alkoxy radical is
generated by treatment of the corresponding alcohol with lead"IV# acetate ð73TL4224Ł or with
iodosobenzene boron tri~uoride etherate and dicyclohexylcarbodiimide ð73CC0996Ł and gives a
product whose double!bond geometry is determined by the stereochemistry of the starting material[
Alternatively\ the required oxygen radical can be produced by the intramolecular addition to a
ketone of an alkyl radical generated by tin hydride reduction of a halide\ providing a ~exible and
elegant ring expansion methodology "Equation "29## ð77CC0393Ł[ Similar products have also been
prepared via the Wharton fragmentation of monosulfonates of 0\2!diols ð74JOC064Ł[
O
O
SePh Bu3SnH (cat.), AIBN
(30)
89%
SnBu3
AIBN = 2,2'-azobisisobutyronitrile
033 Dialkyl Ketones
2[93[1[1 Dialkyl Ketones with More Than One Double Bond
Ketones containing more than one nonconjugated double bond are generally prepared by methods
that are directly analogous to those used for the preparation of saturated ketones "Section 2[93[0#
or ketones with a single nonconjugated double bond "Section 2[93[1[0#[
The oxy!Cope rearrangement\ a powerful approach to d\o!unsaturated ketones "Section
2[93[1[0[1#\ has been extended by several workers to give multiply unsaturated ketones[ For example\
2\4!hexadienones can be prepared by replacing one of the double bonds in the 0\4!hexadiene unit
with an alkyne "Equation "20## ð73S0909Ł or an allene "Equation "21## ð82JOC4371Ł[ In both cases
the rearrangement products contain additional b\g unsaturation but di}er in placing the double
bond endo or exo to the ring[ The acetylenic rearrangement is also catalysed by silver"I# salts
ð75T0222Ł[

CO2Et CO2Et
NaH
(31)
45%
OH O

CO2Et CO2Et
NaOEt
(32)
• 80%
OH O

Wender|s group has developed a double oxy!Cope rearrangement which allows the preparation
of triply unsaturated cyclic ketones\ which are ring!expanded by eight carbon atoms[ One of the
challenges of this chemistry has been the preparation of the a!butadienyl ketone precursors required\
and several approaches which are of general interest for unsaturated ketone preparation have been
developed "Scheme 17# ð70T2856\ 70TL1360\ 73CC423Ł[

i, MeS SMe
Li i, Ph3P=CH2
ii, Ac2O OAc ii, LAH
iii, HgCl2 iii, CrO3•pyridine
O
73% O 64%

O OH O
Li KH

70% 90%

Scheme 28

2[93[1[2 Dialkyl Ketones with Aryl or Heteroaryl Substituents

2[93[1[2[0 From ketones


"i# Arylation of saturated ketones
The a!arylation of ketones\ although infrequently used\ can be a very e.cient reaction and
provide rapid access to an otherwise inaccessible molecule[ Two e}ective\ and related\ ketone
arylation procedures involve the dichlorobis"tri!o!tolylphosphine#palladium"II#!catalysed reaction
of an a!stannyl ketone or enol stannane intermediate with an aryl bromide[ The reactive tin species
can be generated either from an enol acetate with trimethyltin methoxide ð71CL828\ 73BCJ131Ł or
from an enol silane with tributylstannyl ~uoride ð71JA5720Ł[ Both reactions give respectable results
with a wide range of substrates[ The photochemical arylation of ketone enolates also appears to
have quite a wide scope ð65JOC0691Ł and has recently been extended to the intramolecular arylation of
enol silanes "Equation "22## ð82TL5520Ł[ A photosensitized electron transfer mechanism is suggested[
Other useful arylation procedures include the electrophilic arylation of enol silanes with arene
b! and More Remotely Unsaturated 034
diazonium salts ð74CC0434Ł\ the nickel"II#!catalysed coupling of a!bromoenol silanes with aryl
Grignard reagents ð65CL0128Ł\ and the reaction of cyclic a\a?!dibromoketones with diphenylcopper
lithium which\ surprisingly\ gives monophenylated products "Equation "23## ð75TL3560Ł[ Ketones
can be perphenylated by reaction of their enolates with triphenylbismuth carbonate ð74JCS"P0#1556Ł[

MeO
MeO O-TBDMS

(33)
74% MeO
MeO
O

Br
O
O Ph2CuLi
(34)
81%
Ph
Br

"ii# Benzylation of saturated ketones


Because of their high reactivity\ benzyl halides can be used successfully for the benzylation of
ketones using conventional enolate\ imine anion\ or enamine chemistry[ In addition\ secondary
benzylic halides react under Lewis acid!catalysed conditions with enol silanes to give mono!
benzylated products regiospeci_cally and in high yield ð68TL0408\ 68TL3860Ł[ Silver tri~ate has also
been found to catalyse the reaction of enol silanes with the secondary benzylic sul_de "04# ð89TL154Ł
and with both primary and secondary benzylic chloroformates ð81TL840Ł[ p!Acetoxybenzylation of
diketones can be achieved with p!acetoxybenzyl acetate in the presence of caesium carbonate in a
reaction which probably involves a quinone methide intermediate "Equation "24## ð81TL4176Ł[

N N
N
S N
Ph

(15)

O O

O O AcO
+ (35)
65%
OAc

OAc

"iii# Conju`ate reduction of aryl!containin` a\b!unsaturated ketones


b!Phenyl a\b!unsaturated ketones can be reduced with many of the reagents available for the
conjugate reduction of a\b!unsaturated ketones[ In addition\ their very mild reduction to the
saturated carbonyl compound with the related\ and unlikely\ mixtures of t!butyl chloride and water
ð76BCJ2310Ł and of chlorotrimethylsilane\ sodium iodide and water ð76BCJ0952Ł have been reported[

"iv# Conju`ate addition of aryl nucleophiles to a\b!unsaturated ketones


The conjugate addition of aryl groups to a\b!unsaturated ketones is generally achieved by the
same sorts of methods used for the introduction of alkyl substituents "Section 2[93[0[7[1"ii##\
although some variations not applicable to the alkyl case are known[ For example\ diarylzinc
reagents\ which are conveniently prepared by the sonication of a mixture of the aryl bromide\
lithium wire and zinc bromide in an ether solvent\ have been found to add to a\b!unsaturated
ketones in the presence of catalytic nickel acetylacetonate ð72JOC2726Ł[ Alternatively\ the coupling
035 Dialkyl Ketones
can be achieved by a palladium"II#!catalysed Heck!type reaction of an aryl iodide and an
a\b!unsaturated ketone in formic acid containing triethylamine ð72JOC3125Ł[
The conjugate addition of benzyl groups to a\b!unsaturated ketones is complicated by the
tendency of benzyl halides to undergo Wurtz coupling during the formation of an organometallic
derivative\ and by the poor thermal stability of benzylic cuprates[ However\ with careful control of
the reaction conditions and choice of counterion and Lewis acid additive\ very good results can be
obtained ð81TL1272Ł[

2[93[1[2[1 From carboxylic acids and carboxylic acid derivatives


The tendency for preparations of benzylmetal reagents to give Wurtz!coupled products com!
plicates the use of such species for coupling with carboxylic acid derivatives\ as it does their conjugate
addition chemistry[ Fortunately\ a number of methods have been developed for generating a
nucleophilic benzyl species in the presence of an acid chloride or anhydride which can react before
dimerization occurs[ Thus electroreduction of benzylic halides in the presence of acid chlorides
ð66CL0910Ł\ or anhydrides ð75TL3064Ł gives moderate to good yields of alkyl benzyl ketones[ The
coupling can also be achieved chemically with metallic nickel ð72TL1340Ł\ or with zinc and 4 mol)
Pd"PPh2#1Cl1 in DME ð70CL0024Ł[

2[93[1[2[2 Other preparations


Several methods have been developed for the homologation of aryl ketones to benzyl ketones[
For example\ addition of phenylselenylmethyllithium to an aromatic ketone gives a tertiary alcohol
which\ after oxidation to the selenoxide\ undergoes rearrangement to the homologated ketone in
reasonable yield "Equation "25## ð89JCS"P0#0586Ł[ The analogous homologation of cyclic arylalkyl
ketones can be achieved by Wittig alkenation to the exo!methylene derivative and oxidative
rearrangement with thallium"III# nitrate ð66TL0716Ł[ Tolyl methylthiomethyl sulfone has also been
used to prepare benzylic ketones from aromatic aldehydes "Scheme 18# ð75CL0486Ł[
i, PhSeCH2Li
O ii, mcpba O
Ph Ph Ph (36)
Ph 83%

SMe SMe SMe i, MeI, NaH


K2CO3 NaBH4 ii, HCl
PhCHO +
SO2Tol 85% Ph SO2Tol 97% Ph SO2Tol 96%

O
Ph

Scheme 29

Although pinacol rearrangements are generally of rather limited synthetic utility\ the high
migratory aptitude of aryl substituents allows the regio! and stereospeci_c rearrangement of chiral
vic!diol monosulfonates to a!aryl ketones of high optical purity "Equation "16## ð72TL3886Ł[

2[93[1[3 Alkynyl!substituted Dialkyl Ketones

2[93[1[3[0 From ketones


"i# Ethynylation of saturated ketones
Ethynylation of ketone enolates has received far less attention than ethenylation or arylation\
although tertiary enolates are known to react with dichloroethyne ð71TL1262Ł[
b! and More Remotely Unsaturated 036
"ii# Propargylation of saturated ketones
Although propargyl halides are good alkylating agents which can be used for enolate alkylations\
they tend to give mixtures of allenic and propargylic products[ This di.culty can be avoided by the
use of cobalt!stabilized propargyl cations which react with ketones\ enol silanes and enol acetates
to give pure acetylenic products after decomplexation ð79JA1497Ł[

"iii# Conju`ate addition of unsaturated nucleophiles to a\b!unsaturated ketones


The conjugate addition of alkynyl groups to enones is limited by the reluctance of either alkyn!
ylcuprates or alkynylzinc reagents to undergo such reactions\ although alkynylzinc reagents will
react with b!monosubstituted enones in the presence of trialkylsilyl tri~ates ð89TL6516Ł[ Fortunately\
the transformation can be achieved with a variety of other reagents including alkynylboranes which
react with "E#!acyclic enones and a!methylene ketones ð66JA844\ 81CL584Ł\ and mixed tetra!
organothallium ate complexes which deliver alkynyl preferentially over methyl to cyclic ketones
ð81TL0652Ł[ Alkynylalanes in the presence of a nickel catalyst will add in a conjugate fashion to
enones with either an s!cis or s!trans conformation ð79JOC2942Ł[

2[93[1[3[1 Fragmentation reactions


The fragmentation of an a\b!epoxy ketone on treatment with tosyl hydrazone to give an alkynyl
ketone was _rst described by Eschenmoser|s group\ and is now generally referred to as an Eschen!
moser fragmentation "Equation "26## ð56HCA697Ł[ N!Aminoaziridine derivatives of epoxy ketones
fragment in a similar manner on heating "Scheme 29# ð61HCA0165Ł\ as do the tosyl hydrazones of
a\b!unsaturated ketones on treatment with N!bromosuccinimide ð68HCA1544Ł[ Cyclic 2!hydroxy!
vinylselenones fragment under basic conditions to give alkynyl ketones\ although in this case the
scission is between the a and b rather than the b and g carbons of the precursor enone "Equation
"27## ð70JOC4135Ł[

O
TsNHNH2 O
(37)
O 80%

Ph
Ph
O
N N
H2N Ph N Ph 110 °C
O
O 68%
O

Scheme 30

HO Bun O
NaH
Bun (38)
84%
SeO2Ph
037 Dialkyl Ketones
2[93[2 HALO!SUBSTITUTED DIALKYL KETONES "a!\ b! AND MORE REMOTE
HALOGENS#

2[93[2[0 Introduction
Although there is a considerable body of information on haloketones scattered throughout the
literature\ few attempts have been made to gather and collate the data[ One notable exception to
this is a _ne chapter by DeKimpe and Verhe on the synthesis and chemistry of a!haloketones in one
of the Updates from the Chemistry of the Functional Groups monographs edited by Patai and
Rappoport ðB!77MI 293!90Ł[

2[93[2[1 Fluoroaliphatic Ketones

2[93[2[1[0 a!Fluoroaliphatic ketones


The synthesis of a!~uoro ketones has been reviewed by Rozen and Filler ð74T0000Ł\ and that of
tri~uoromethyl ketones and related ~uoromethyl ketones by Begue and Bonnet!Delpon ð80T2196Ł[

"i# From alcohols


The oxidation of b!~uoro alcohols appears to be a fairly di.cult transformation which fails with
the majority of conventional alcohol oxidants[ Good results\ however\ are reported for the Dess!
Martin periodinane reagent "3# ð78JOC550Ł\ for which an improved preparation has recently been
reported ð82JOC1788Ł[

"ii# From epoxides


Treatment of a!chloro epoxides with silver tetra~uoroborate gives a!~uoro ketones containing
only small quantities of a!chloro ketone by!product ð70CB0747Ł[ The analogous reaction of 0!~uoro!
1!chloro epoxides can be used to prepare a\a!di~uoro ketones "Equation "28## ð72CB1530Ł[ a!Fluoro
ketones have also been prepared from functionalized a!trimethylsilyl epoxides "Equation "39##
ð78JFC"31#324Ł[ The reaction involves initial ~uoride!induced Peterson elimination to give an allene
oxide which reacts further with ~uoride to give the _nal product[

O O
Cl AgBF4
(39)
F 90%
F F

O O
O O
F3C
Bu4NF F
TMS (40)
70%

"iii# From stable enol derivatives and enamines


Although in the early literature elemental ~uorine was reported to be unsatisfactory for the a!
~uorination of ketone derivatives\ the treatment of enol silanes at low temperatures with 4) ~uorine
in nitrogen and with Freon 00 as solvent does give good yields of a!~uoro ketones[ In some cases\
however\ over!~uorination is a problem\ particularly with enol silanes derived from methyl ketones
ð75TL1604Ł[ A range of N!~uoropyridinium salts of varying reactivity have been developed for
electrophilic ~uorination of enol silanes[ Fluorinations can be achieved with these reagents in the
Halo!substituted 038
presence of enol acetates\ ethers and double bonds\ and some remarkably selective transformations
have been reported "Equation "30## ð89JA7452Ł[ Steroidal enol silanes have also been ~uorinated
with p!iodotoluene di~uoride ð71TL0054Ł\ and both steroidal enol silanes and enol acetates with the
stable electrophilic ~uorine source 0!"chloromethyl#!3!~uoro!0\3!diazabicycloð1[1[1Łoctane
bis"tetra~uoroborate# "05# ð82JOC1680Ł[ The ~uorination of enol acetates in the presence of ketones
by N!~uoropyridinium pyridine hepta~uorodiborate ð80JOC4851Ł\ of enol silanes with tri~uoro!
methyl hypo~uorite ð79JA3734Ł and of cyclic enamines with di~uorodiimide ð66TL1686Ł has also
been reported[

O-TMS O
TMS-O + O
N
–OTf
F
(41)
51%
F
TMS-O O
H H

F
+
N
(BF4–)2
+
N

Cl
(16)

"iv# From ketones


One important traditional approach to a!~uoro ketones which still _nds applications today is by
the halide exchange of a!chloro\ or preferably\ a!bromo ketones[ The transformation is most
commonly achieved with a heavy!metal ~uoride such as mercury"II# ~uoride ð66JOC2416Ł or silver
tetra~uoroborate ð68TL2246Ł\ which drives the reaction to completion by the formation of a less!
soluble halide salt[
Although a number of reagents have become available over the last few years for the electrophilic
~uorination of enol acetates and silanes\ no comparably general methods for the ~uorination of
ketones are available[ However 0\2!diketones can be mono! or di~uorinated with N!~uoro!
bis"tri~uoromethylsulfonyl#imide "06# ð80CC068Ł^ benzylic ketones can be ~uorinated by anodic
oxidation in acetonitrile and triethylamine trihydro~uoride ð76TL1248Ł^ and alkyl aryl ketone enol!
ates can be ~uorinated with N!~uorosultam "07# ð80TL0668Ł[ The sultam chemistry has been extended
by the use of the chiral camphor!derived N!~uorosultam "08# to allow the enantioselective ~uo!
rination of the lithium enolates of b!keto esters and alkyl aryl ketones\ although both the chemical
yields and enantiomeric excesses reported are quite modest "Equation "31## ð82TL2860Ł[

Cl
F3CSO2
N F N F Cl
F3CSO2 S
O N
O S F
O
O
(17) (18) (19)

O– Na+ O
(–)-(19)
(42)
F
40%, 75% ee
049 Dialkyl Ketones
"v# From acids or esters
The preparation of more highly ~uorinated ketones is often approached by the assembly of
appropriately ~uorinated building blocks using carbon!to!carbon bond forming reactions[ For
example\ the reaction of ethyl tri~uoroacetate with Grignard reagents ð76JOC4915Ł\ of ethyl
per~uoroalkanoates with phosphorus ylides ð81JOC2796Ł\ and of esters with per~uoroalkyllithium
reagents ð76CL0042Ł have all been used to prepare alkyl per~uoroalkyl ketones[ Ketenes derived
from primary\ but not secondary\ acid chlorides can be trapped with tri~uoroacetic anhydride to
give tri~uoromethyl ketones after hydrolysis and decarboxylation "Equation "32## ð81TL0174Ł[

O O

Cl CF3
i, pyridine
AcO AcO
ii, TFAA
(43)
67%

AcO OAc AcO OAc


H H
TFAA = trifluoroacetic anhydride

"vi# Miscellaneous other preparations


Homochiral a!~uoro ketones\ for which relatively few syntheses are available\ have been prepared
from a!~uoro esters using sulfoxide chemistry "Scheme 20# ð77CC107Ł[ The synthesis of a\a!di~uoro
ketones has given rise to some interesting chemistry] for example\ Percy et al[ have developed a
number of equivalents of the di~uoroacetaldehyde anion such as the vinyllithium "19# ð81CC0366\
81SL372Ł^ and the Claisen rearrangement of allyl di~uorovinyl ethers to a\a!di~uoroketones has been
found to proceed under unusually mild conditions ð74TL1750Ł[

F i, NaI
i, LDA ii, Raney Ni
S F ii, Me2CH(CH2)2Br
S 69%
O O O O
:

Scheme 31

O NEt2
F
Li
F
(20)

2[93[2[1[1 b!Fluoroaliphatic ketones


Relatively little work has been reported on the preparation of speci_cally b!~uorinated ketones[
However\ both silyl enol ethers and enamines can be tri~uoromethylated electrophilically with
Halo!substituted 040
"tri~uoromethyl#dibenzothiophenium tri~ate "10# ð89TL2468Ł\ and homologous per~uoroalkyl
ketones have been prepared by the ðCpFe"CO#1Ł1!catalysed addition of per~uoroalkyl iodides to the
b position of enol ethers ð80CC75Ł[

+
S
–OTf
CF3
(21)

2[93[2[2 Chloroaliphatic Ketones

2[93[2[2[0 a!Chloroaliphatic ketones


"i# From alkenes or alkynes
The preparation of a!chloro ketones by the oxidation of disubstituted alkenes with a variety of
chromium!based oxidants\ in particular Etard|s reagent "CrO1Cl1#\ has been known for many years\
and a recent study of the reaction recommends cyanopyridinium chlorochromate as the preferred
reagent for the conversion ð77TL5696Ł[ Photooxidation of disubstituted alkenes in the presence of
iron"III# chloride also gives modest yields of a!chloro ketones\ although carbon!to!carbon bond
cleavage reactions occur with tri! or tetrasubstituted alkenes ð70JOC498Ł[ Neither method allows the
regioselective oxychlorination of unsymmetrical alkenes[
The preparation of a\a!dichlorocyclobutanones by the ð1¦1Ł cycloaddition of dichloroketene
and an alkene has been widely exploited because of the synthetic versatility of the products[ The
reaction\ which is promoted by ultrasound ð74SC880Ł\ has been reviewed in a recent article on
haloketene chemistry ð70T1838Ł[ Dichloromethyl ketones can be prepared by the treatment of
terminal alkynes with Oxone "1KHSO4 = KHSO3 = K1SO3# in the presence of hydrogen chloride
"Equation "33## ð81CL592Ł[

O
Oxone, HCl
Cl
n-C6H13 n-C6H13 (44)
71%
Cl

"ii# From epoxides


Epoxides can be smoothly converted into a!chloro ketones by treatment with a chlorosulfonium
chloride "e[g[\ Me1S = Cl1# ð68TL2542Ł[ Trisubstituted epoxides react regiospeci_cally placing the
chlorine on the more!substituted carbon atom ð66CL884Ł[ Alternatively\ dimethylchlorosulfonium
chloride can be generated in situ from DMSO and oxalyl chloride and allows the conversion to be
achieved under very mild and low!temperature "−59>C# conditions ð81TL5910Ł[ The method is
compatible with ester and alkene functionality\ and proceeds with high\ although not readily
rationalized\ regioselectivity "Equation "34##[
O
O DMSO, (COCl)2
OAc Cl OAc (45)
90%

"iii# From alcohols or their derivatives


The oxidation of chlorohydrins is less problematical than that of ~uorohydrins\ and mono!\ di!
and trichloromethyl ketones can be prepared by the chromium trioxide oxidation of the appropriate
chlorohydrin or b!chloroalkyl methyl ether precursors ð71TL0598Ł[ The oxidation has been suc!
041 Dialkyl Ketones
cessfully applied to the preparation of quite highly functionalized\ and unracemized\ peptide ana!
logues "Equation "35## ð78S355Ł[

Ph Ph
O OH O O
H chromic acid H
N N (46)
N CCl3 83% N CCl3
H H
O O

"iv# From stable enol derivatives and enamines


Oxidation of a wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or with
lead"IV# salts ð71S0910Ł\ in the presence of chloride leads smoothly and regiospeci_cally to the
a!chloro ketone[ Enol silanes can also be chlorinated by treatment with copper"II# or iron"III#
chlorides in DMF ð79JOC1911Ł or by sulfuryl chloride ~uoride or sulfuryl chloride ð73JOC1921Ł[
Hexachloroacetone has been recommended as a convenient and mild source of electrophilic
chlorine for the chlorination of enamines ð66JA5561Ł\ although high yields can also be obtained with
elemental chlorine itself ð68CB0569Ł[

"v# From ketones


The direct chlorination of ketones not only su}ers from problems of regioselectivity but is also
complicated by the formation of over!chlorinated by!products[ The considerable body of knowledge
of the e}ect on the reaction of variations in the substrate and conditions "particularly the solvent#
has been well summarized by DeKimpe and Verhe ðB!77MI 293!90Ł[ Alternatively\ a methoxycarbonyl
group can be used to direct the chlorination to the required position\ and is easily removed afterwards
by acid hydrolysis ð76S077\ 89S484Ł[ Ketones can also be chlorinated via their lithium enolates using
NCS ð73JOC687Ł[

"vi# From acids or esters


a!Chloro acid chlorides react with organomanganese reagents to provide a convenient preparation
of a!chloro ketones ð73S26Ł[ The reaction may also be performed with Grignard reagents\ although
in this case the temperature must be kept below −67>C ð73S623Ł[ A related\ and conceptually very
attractive\ approach to chloromethyl ketones is by the addition of chloromethyllithium to an ester[
Although the reagent is fairly unstable\ it can be prepared by the metalÐhalogen exchange of
bromochloromethane at low temperature "−009>C#\ and it reacts smoothly with esters "Equation
"36## ð73TL724Ł[ Barluenga|s research group has reported extensively on the analogous preparation
of dichloromethyl and bromochloromethyl ketones by the reaction of esters with a dihalomethyl!
lithium\ which is generated in situ by the addition of lithium dicyclohexylamide to a mixture of the
dihalomethane and carboxylic ester at −67>C ð80TL0668Ł[ The preparation of a\a?!dihalo ketones
and a\a\a?!trihalo ketones from a!halo esters using this chemistry has also been described ð89S0992Ł\
as has its extension\ by the use of a!chloroalkyllithium reagents\ to the preparation of higher
a!chloroalkyl ketones ð70S57Ł[ These products can also be prepared by treatment of the initial
bromochloromethyllithium adduct with an alkyl cuprate "Equation "37## ð80JCS"P0#1789Ł[

O ClCH2Li O
Cl (47)
C6H13 OEt 62% C6H13

i, BrClCHLi
ii, (Bun)2CuLi O
O iii, H3O+ Bun
Prn (48)
Prn OEt 87%
Cl

Trichloromethyl ketones have been prepared both by the reaction of trichloroacetyl chloride
Halo!substituted 042
with organozinc reagents\ and by the addition of trichloromethyl anions\ generated by the facile
decarboxylation of sodium trichloroacetate\ to aldehydes\ followed by oxidation of the resulting
alcohols with chromic acid ð81TL2324Ł[

"vii# Miscellaneous preparations


An interesting approach to a!chloro ketones involves the reaction of lithio chloromethyl phenyl
sulfoxide with an aldehyde[ The resulting a!chloro!b!hydroxy sulfoxide can be converted into the
_nal product either by thermolysis ð66TL0114Ł or in two steps by Swern oxidation followed by
desul_nation with ethylmagnesium bromide "Scheme 21# ð81BCJ1799Ł[

O O O O
i, LDA, n-C9H19CHO EtMgBr
S Prn S Prn
Ph Ph n-C9H19 n-C9H19
ii, Swern oxidation
X X Prn X
X = Cl, Br

Scheme 32

2[93[2[2[1 b!Chloroaliphatic ketones


b!Chloro ketones can be prepared by the treatment of cyclopropyl ketones with pyridine hydro!
chloride in pyridine "Equation "38## ð67S116Ł[

O pyridine•HCl O
(49)
70%

Cl

2[93[2[3 Bromoaliphatic Ketones

2[93[2[3[0 a!Bromoaliphatic ketones


"i# From alkenes
The oxidative hydrolysis of vinyl bromides with NBS in aqueous acetonitrile provides an e.cient
and regiospeci_c synthesis of a!bromo ketones which is compatible with ester\ amide\ ketone and
tosylate functionality "Equation "49## ð82TL3370Ł[

Br O
NBS (aq.)
Br (50)
85%
O O

"ii# From epoxides


Epoxides can be converted smoothly\ but not regioselectively\ into a!bromo ketones by treatment
with the complex of dimethyl sul_de with bromine ð68TL2542Ł or by reaction with bromo!
trimethylsilane and Jones oxidation ð70TL0318Ł[ Bromomethyl ketones can be prepared by the
photocatalytic bromination of epoxides derived from terminal alkenes ð67S028Ł[
043 Dialkyl Ketones
"iii# From stable enol derivatives and enamines
Oxidation of a wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or with
lead"IV# salts ð71S0910Ł\ in the presence of bromide leads smoothly and regiospeci_cally to the
a!bromo ketone[ Elemental bromine has been used to prepare a!bromo ketones from both enol
silanes ð65S083Ł\ and in near!quantitative yield from enamines ð68CB0569Ł[

"iv# From ketones


The a!bromination of ketones has been a particularly active area of research\ with a large number
of electrophilic brominating reagents being developed for this purpose[ For example\ 4\4!dibromo
Meldrum|s acid "11# ð67S039Ł\ and 3!"dimethylamino#pyridine bromide perbromide ð73SC828Ł will
monobrominate ketones in high yield[ Perhaps more interesting is the combination of t!butyl
bromide and DMSO ð73T1924Ł which\ like the photobromination of ketones in the presence of
cyclohexene oxide ð66JCS"P0#490Ł\ has been shown to brominate the more highly substituted
a!carbon of an unsymmetrical ketone with very high selectivity[

O
Br O

Br O
O
(22)

"v# From acids or esters


Barluenga|s research group has reported on the preparation of dibromomethyl ketones by the
reaction of esters with dibromomethyllithium\ which is generated in situ by the addition of lithium
diisopropylamide to a mixture of the dibromomethane and a carboxylic ester at −67>C ð80TL0668Ł[
The preparation of a\a?!dihalo ketones and a\a\a?!trihalo ketones from a!halo esters using this
chemistry has also been described "Equation "40## ð89S0992Ł\ as has its generalization by the use of
a!bromoalkyllithium reagents to prepare higher a!bromoalkyl ketones ð70S57Ł[ Although the
method does not appear to be extendable to the preparation of bromomethyl ketones from esters
and bromomethyllithium\ bromomethyl ketones can be prepared from dibromomethyl ketones by
metalÐhalogen exchange with n!butyllithium to give an a!bromo ketone enolate which is protonated
during the workup ð74JOC4039Ł[

Br
O Li O
Br Br
OEt (51)
67%
Cl Cl Br

"vi# Miscellaneous preparations


An interesting approach to a!bromo ketones involves the reaction of lithio bromomethyl phenyl
sulfoxide with an aldehyde[ The resulting a!bromo!b!hydroxy sulfoxide can be converted into the
_nal product either by thermolysis ð68CL198Ł or in two steps by Swern oxidation followed by
desul_nation with ethylmagnesium bromide "Scheme 21# ð81BCJ1799Ł[
Halo!substituted 044
2[93[2[4 Iodoaliphatic Ketones

2[93[2[4[0 a!Iodoaliphatic ketones


"i# From alkenes
a!Iodo ketones can be very conveniently prepared by the treatment of alkenes with silver chromate
and iodine^ with terminal alkenes\ iodomethyl ketones are formed with high selectivity ð66JOC3157Ł[
Cyclic a!iodo ketones can be synthesized by the related oxidation of alkeneÐiodine complexes with
pyridinium dichromate ð79TL3410Ł\ and bis"sym!collidine#iodine"I# tetra~uoroborate in dimethyl
sulfoxide will oxidize alkenes to a!iodo ketones\ although in neither case is much regioselectivity
observed in the reaction of unsymmetrical substrates ð75S616Ł[

"ii# From epoxides


Epoxides are considerably less important precursors of a!iodo ketones than of a!chloro or
a!bromo ketones\ although a simple regiospeci_c preparation of a!iodo ketones by the nucleophilic
addition of iodide to an a!nitro epoxide\ followed by elimination of nitrite\ has been reported
"Equation "41## ð78CL0130Ł[ The conversion can also be achieved nonregioselectively by reaction
with iodotrimethylsilane and Jones oxidation ð70TL0318Ł[

O
O DMSO, BF3•Et2O, NaI
(52)
75%
NO2 I

"iii# From stable enol derivatives and enamines


As well as having the advantage of regiospeci_city\ preparations of a!iodo ketones from enol
acetates or enol silanes are frequently both very e.cient and very general[ These methods thus often
provide the method of choice for the preparation of a!iodo ketones[ For example\ the oxidation of
a wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or with lead"IV# salts ð71S0910Ł\
in the presence of iodide leads smoothly and regiospeci_cally to the a!iodo ketone[ The iodination
of enol silanes can be accomplished in high yields by treatment with iodine and silver acetate
ð68JOC0620Ł\ with N!iodosuccinimide\ conveniently prepared in situ from sodium iodide and
N!chlorosuccinimide ð73TL122Ł\ and by reaction with sodium iodide and mcpba in the presence of
hexamethyldisilazane ð76JOC2808Ł[ Enol acetates can be iodinated with iodine and thallium"III#
acetate ð67JCS"P0#015Ł\ and both types of substrate can be iodinated with iodine in the presence of
copper"II# nitrate ð80JOC5697Ł[

"iv# From ketones


Traditionally a!iodo ketones have been prepared from ketones by treatment with iodine in the
presence of strong base or by the halogen exchange of a!chloro or a!bromo ketones\ although
neither method was particularly satisfactory ðB!77MI 293!90Ł[ More recently developed iodinations
of ketones with iodine in the presence of copper"I# iodide ð70S201Ł\ ceric ammonium nitrate ð77CL20Ł
or\ for acyclic ketones\ mercury"II# chloride ð75S567Ł are much more satisfactory and give good
yields of a!iodo ketones[ The conditions for all three methods are mildly acidic\ and with the latter
two reagents the iodination of unsymmetrical ketones occurs preferentially at the more!substituted
a!carbon "Equation "42##[

O O
O can, I2, MeOH
+ (53)
83%
I I
96 : 4
can = ceric ammonium nitrate
045 Dialkyl Ketones
2[93[2[4[1 b!Iodoaliphatic ketones
Relatively little literature is available on the preparation of b!iodo ketones\ although they can be
prepared by the conjugate addition of iodotrimethylsilane to enones\ followed by hydrolysis of the
intermediate enol silane ð68JOC0327Ł[

2[93[3 KETONES BEARING AN OXYGEN FUNCTION

2[93[3[0 OH!functionalized Ketones

2[93[3[0[0 a!OH!functionalized ketones


One of the earliest procedures for the direct oxidation of ketones to a!hydroxy ketones used
molecular oxygen ð57JOC2183Ł\ and the method was ideally suited to oxidation at a hindered\ tertiary
a position[ In fact\ under these conditions\ less highly substituted a!hydroxy ketones undergo an in
situ decomposition[ Applications of this method can be found in the recent literature ð78JOC3465Ł[
The problems associated with the use of oxygen have lead to the development of other methods for
enolate hydroxylation ð80COS040Ł[ One of the most frequently used\ MoO4 = Py = HMPA "MoOPH#
was originally developed by Vedejs and co!workers ð67JOC077Ł\ and recently a derivative of this
which avoids the use of HMPA was prepared and demonstrated to be equally e}ective ð89SL096\
81CEN1Ł[ Ketones with only one alpha C0H group or hindered ketones can be oxidized directly to
a!hydroxy ketones with "PhSeO#1O[ Furans\ acetates and dioxolanes survive the reaction conditions
ð70T362Ł[
Independent work by several groups "e[g[\ ð64JOC2316Ł# has demonstrated that the oxidation of
enol silanes with mcpba gives a!oxygenated ketones\ and this procedure has been used extensively[
In the majority of cases regiospeci_c enol silane formation allows regiospeci_c ketone hydroxylation[
This reaction was hypothesized to proceed via a silyloxy epoxide "12#\ although the detection of this
intermediate has proved elusive in all but a few cases[ More recently\ however\ dimethyl dioxirane
and methyl tri~uoromethyl dioxirane\ oxidants which produce no acidic by!products\ have been
applied to the oxidation of silyl enol ethers\ and\ in many cases\ the intermediate epoxides are stable
enough to be isolated or observed by 0H NMR ð78JOC3138\ 78TL5386Ł[ A subsequent paper showed
that direct oxidation of enolates with dioxiranes was also successful ð80TL604Ł[ A series of reagents
which have been used very successfully for the introduction of an a!hydroxy group are the sulfonyl
oxaziridines "e[g[\ "13##\ which react with ketone enolates\ silyl enol ethers\ or with enamines[ An
asymmetric version of this oxidation\ using oxaziridines derived from the homochiral imine "14#
"RH\ Cl#\ has also been developed ð81CRV808Ł[ Other methods reported for the oxidation of
enol silanes include those using oxygen and a nickel"II# catalyst ð80CL170\ 82CL0468Ł\ OsO3:
N!methylmorpholine oxide ð70TL596Ł and the Sharpless asymmetric dihydroxylation conditions[ In
the last case\ either enantiomer of the product can be obtained in high chemical and stereochemical
yield ð81JOC4956Ł[ Many methods are available for the direct oxidation of ketones to a!sulphonyloxy
ketones "see Section 2[93[3[2#\ and subsequent hydrolysis gives a!hydroxy ketones ð75JOC029Ł[ A
very useful double hydroxylation of enol silanes derived from methyl s!alkyl ketones gives a\a?!
dihydroxy ketones "Equation "43## ð78TL2212Ł[ SAMP and RAMP hydrazones\ which have proved
extremely useful in the enantioselective a!functionalization of ketones\ have been used in an asym!
metric synthesis of a!hydroxy ketones ð77TL1326\ 78HCA879Ł[

R
O O
R33SiO R1 Ph R
N
R4 R2 PhSO2
S N
O
O
(23) (24) (25)
Bearin` An Oxy`en 046
OSiR3 O
HO
mcpba OSiR3
(54)
72%

Hydroxymethyl anion equivalents "e[g[\ "15## will attack acids or their derivatives to give
a!hydroxy ketones ð68JOC3506\ 76TL0736Ł[ A complementary approach involves attack by
organometallic reagents at O!TMS cyanohydrins ð72TL3964\ 75TL0822Ł\ and many examples of this
transformation have appeared in the literature[
Li O

TMS O OLi
(26)

The development and use of acyl anion equivalents ðB!76MI 293!90\ 80COS"0#494Ł\ including
0\2!dithiane ð78T6532Ł\ has been one of the more important advances in organic chemistry in the last
two decades[ Ogura|s research group has reported extensively on the use of acyl anions in which
the anion is stabilized by sulfur in a higher oxidation state "e[g[\ "16##[ These acyl anions have been
used for the preparation of a!hydroxy carbonyls ð75TL2554\ 80COS"0#494Ł[ The anion "17# has been
shown to react with aldehydes or ketones to give a!hydroxy methyl or a!hydroxy methyl!a?!hydroxy
ketones depending on the reaction conditions ð78H"17#410Ł[ Heteroatom substituted alkenyl anions like
"17# are\ in fact\ well recognized acyl anion equivalents and readily attack aldehydes and ketones[
SMe O OCONEt2
Li
SO2Ar O Li Li
(27) (28) (29)

Other variations "e[g[\ "18## also give oxygenated ketones ð63JA6014\ 89JOC4579\ 80T2642Ł[ Knochel
and co!workers have recently disclosed the use of alkenyl boronate esters as acyl anion equivalents
"Scheme 22#[ The organozinc reagents add to a number of electrophiles\ including aldehydes\ to
give multifunctional ketones ð81TL2606Ł[ Cyanohydrins are also well!known acyl anion equivalents\
and their use has been reviewed ð80COS"0#430Ł[ The use of thiazoles and also thiazolium salts for the
preparation of hydroxy aldehydes "Chapter 2[90[3[0# has also been applied to
a!hydroxy ketones[ The anion of 2!methylbenzothiazolium bromide reacts chemoselectively\ _rst with
aldehydes and then paraformaldehyde to give the expected product "Scheme 23# ð74JOC592Ł[ The
adduct between an aldehyde or ketone and 1!lithiobenzothiazole can be further elaborated via
alkylation\ attack by organometallics and hydrolysis "cf[\ Scheme 18 in Chapter 2[90[3[0[0#
ð77BCJ2526Ł[

i, RCHO, BF3•Et2O O
O i, Zn, THF O ii, H2O2
Prn R
B B
Prn O ii, CuCN•2LiCl Prn O 75–87%
OH
I Cu(CN)ZnI

Scheme 33

S S R
base, RCHO, CH2O O– O
N+ N+ OH OH
R
Me Me

Scheme 34

A series of papers from Katritzky|s group has demonstrated the use of benzotriazoles for the
preparation of a variety of functional groups[ In one of these publications\ the authors disclose the
use of the anion derived from "29# as an acyl anion\ and describe its capture by aldehydes[ Subsequent
047 Dialkyl Ketones
hydrolysis gives hydroxy ketones ð80JOC5806Ł[ This paper also gives an extensive list of references
to other acyl anions[ A method for the hydroxyalkylation of acyl anions under mild\ nonbasic
conditions has been reported[ Alkyl halides add to aryl isocyanides in the presence of samarium"II#
to give a metalloimine which can add to ketones "Scheme 24#[ A number of acid! and base!sensitive
groups are compatible with the reaction conditions^ thus\ the method can be used to prepare highly
functionalized a!hydroxy ketones ð82JOC0347Ł[ The direct metallation of aldehydes to acyllithium
reagents can be achieved in only a few speci_c cases\ in particular where there are no a protons[ When
generated in situ\ however\ by the attack of BunLi on carbon monoxide at very low temperatures\
acyllithium reagents containing a protons can be formed and will attack ketones and a\b!unsaturated
ketones "0\1!addition# to give the expected products in high yield ð81JOC4519Ł[

Ar i, cyclohexanone
SmI2, –15 °C N ii, H3O+
Br +
SmI2 60%
NC

O
OH

Scheme 35

N
N
N
N
Ph

(30)

Many procedures have been published for the selective oxidation of secondary over primary
alcohols\ but not all of these have examples where the two functional groups are within the same
molecule "for a recent review see ðB!78MI 293!90Ł[ Methods that selectively oxidize the secondary
alcohol of 0\1!diols include chromium on a solid support ð89TL4674Ł and catalytic cerium"IV# in the
presence of NaBrO2 ð75BCJ094Ł[
The oxidation of alkenes or the hydrolysis of alkynes where the multiple bond is similarly
substituted or unactivated may give mixtures of products owing to regiochemical problems or over!
oxidation[ However\ terminal alkenes can be selectively oxidized to a!hydroxymethyl ketones in
good yield ð80CL0388\ 82CL0656Ł[ Regiochemical problems can be overcome when a neighbouring
group is used to control the addition to the alkene "Scheme 25# ð73JOC690Ł\ by the presence of
silicon "Equation "44## ð75TL54Ł or phosphorus ð73S0914Ł on the alkene\ or using allylic ethers or
acetates to give a!hydroxy a?!oxygenated ketones ð80CL0388\ 82CL0656\ 82JOC1818Ł[ Tertiary pro!
pargylic alcohols with a terminal alkyne undergo smooth hydration to a\a?!dihydroxy ketones using
iodine"III#\ whereas terminal alkynes give hydroxymethyl ketones ð74TL2726Ł[ A ~exible approach
to dioxygenated ketones has recently been disclosed which can be used to make a variety of systems
"Scheme 26# ð80BCJ0471\ 80JOC3018Ł[

n-C5H11 I
O
n-C5H11 i, BunLi, CO2 Amberlyst A26 F– form
n-C5H11
O O
OH ii, I2
OH
O

Scheme 36
Bearin` An Oxy`en 048

i, mcpba O
SiMe2(OR) ii, KHF2, KHCO3 n-C6H13 (55)
n-C6H13 80% Prn
Prn
OH

O i, LDA, –78 °C, 2-indanone HO


ii, xylene, reflux OsO4, N-methylmorpholine-N-oxide
S Cl
Ar 90% 80%
Cl

HO

HO
O

Scheme 37

2[93[3[0[1 b!OH!functionalized ketones


The most popular method for the preparation of compounds in this class\ and one of the most
widely studied of all chemical transformations is the aldol reaction[ Many reviews of this area have
already been published ð80COS"1#0\ B!81MI 293!90Ł\ and only a few recent developments will be
discussed here[ It appears highly likely that the enzyme!catalysed aldol reaction will become widely
adopted by synthetic chemists during the next decade ð80S388Ł[ The coupling of dihydroxyacetone
phosphate ð82JOC0776Ł and other enolate donors ð81JA630\ 81JOC315Ł with an increasingly wide range
of aldehydes has been demonstrated\ and some of these reactions can be done on a preparatively
useful scale[ The products are often highly oxygenated and the method has already been applied to
carbohydrate synthesis[ Similar products might also be prepared from the boron enolates "20#
"R0 H\ OR2#\ which demonstrate a high preference for the anti con_guration at the new car!
bon0carbon bond in their reactions with aldehydes ð82JOC3071Ł[ New catalysts that have been
reported recently for the aldol reaction include BiCl2 ð82JOC0724Ł and Me1Si"OTf#1 "OTftri~ate#\
which can be used for silyl enol ether formation and subsequent in situ aldol reaction ð82JOC1536Ł[
OBR22

OBn
R1
(31)

Developments have been made in the chemoselective coupling of silyl enol ethers with aldehydes
in the presence of acetals\ for example an InCl2!catalysed aldol reaction ð80CL838Ł and an organo!
aluminum!promoted ene reaction ð82TL5170Ł[ A remarkably chemoselective aldol:Mukaiyama aldol
reaction has been demonstrated by Otera and co!workers[ Thus\ in the presence of dibutyltin
ditri~ate\ aldehydes but not ketones react with silyl enol ethers to give b!hydroxy ketones[ Following
acetalization\ however\ acetals derived from ketones give b!alkoxy ketones whereas\ under the same
reaction conditions\ aldehyde acetals are recovered in high yield[ This communication would indicate
the prospect of unique selective functionalization ð89JA890Ł[ For all of these reactions\ careful
exclusion of water is important\ but Kobayashi and co!workers have developed a procedure which
allows aldol coupling reactions between silyl enol ethers and aldehydes in a mixture of water and
THF ð81TL0514Ł[ The key to the reaction appears to be the use of lanthanide tri~ates and an increase
in the scale of the reaction could make this particularly useful\ as the catalyst can be reused[
Treatment of 0\2\4!trioxane with methylaluminum bis"3!bromo!1\5!di!t!butyl phenoxide#
"MAPH# results in the cleavage of the trioxane and complexation of the resulting formaldehyde
with the metal[ The complex is stable at 9>C for several hours and is a valuable source of this
highly reactive electrophile[ It has been shown to undergo enolate hydroxymethylation and an
intermolecular ene reaction with silyl enol ethers "Scheme 27#\ both in good yields ð89JA6311Ł[
The importance of b!hydroxy ketones has meant that many non!aldol!based routes to these
systems have been developed[ The chiral ortho esters "21# react with silyl enol ethers in the presence
of a Lewis acid to give monoprotected 0\2!diketones[ Diastereoselective reduction of the ketone
gives mixtures of stereoisomers whose ratio depends on the substrate ð81T0188Ł[ In a similar method\
a combination of conjugate addition\ enolate trapping\ ketone reduction and hydrolysis of acyl
059 Dialkyl Ketones
O-TMS

O-TMS
O
MAPH
H2CO MAPH OH
O O 71%

MAPH = methylaluminum bis(4-bromo-2,6-di-t-butylphenoxide)

Scheme 38

ketene acetals "e[g[\ "22## gives stereochemically enriched products ð80T864Ł[ A reduction step is also
involved in a preparation of terminal b!hydroxy ketones which relies on readily available starting
materials and a mild deprotection step "Scheme 28# ð89S0948Ł[ The presence of a silyl group can
often be considered as equivalent to a hydroxy group as the carbonÐsilicon bond can be cleaved by
oxidizing agents[ When combined with the conjugate addition of a silyl group to an enone\ this can be
used to prepare b!hydroxy ketones ð73CC18Ł[ Recently\ this has been combined with an asymmetric
hydrosilylation of enones to give optically active b!hydroxy ketones ð83T224Ł[ An elegant and widely
exploited method for the synthesis of b!hydroxy ketones is the nitrile oxideÐalkene cycloaddition
ð80COS"3#0958\ 80COS"3#0000Ł[ This produces an intermediate isoxazoline\ in which the stereochemistry
of the substituents is controlled using an appropriately substituted alkene and\ if required\ chirality
transfer can occur to other positions[ Ultimately\ the isoxazoline is converted into the desired
product "Scheme 39#[ Cyclization of allylsilanes with nitrosium tetra~uoroborate can also be used
to give isoxazolines and\ hence\ hydroxy ketones ð82JA6787Ł[

MeO2C CO2Me Ph
O O
O O Ph
O
R OMe
(32) (33)

O O O O
O O i, LiAlH4, 0 °C
(CH2OH)2, C6H6, reflux ii, SiO2, H2O, (CO2H)2
EtO EtO HO
93% 82%

Ph Ph Ph

Scheme 39

R3 R1 O OH
+
R3 N O– + R2
R1 R3 R2
N
O R2 R1

Scheme 40

A series of papers has dealt with a study of the rearrangement of epoxy silyl ethers to b!oxygenated
aldehydes "see Chapter 2[90[3[2# or ketones[ The epoxides are available in enantiomerically pure
form by use of the Sharpless asymmetric epoxidation and\ as the rearrangement is concerted\ this
leads to stereochemically pure b!silyloxy ketones[ The silyl group can be removed in situ if required[
As little as 4 mol) catalyst is su.cient to promote the rearrangement ð76TL2404Ł\ which can also
be used to construct quaternary centres "Equation 45# ð76TL4780Ł[ a\b!Epoxy ketones undergo
reductive ring opening at the a position with a number of reagents\ including NaI ð65CB2896Ł\ SmI1
ð75JOC1485Ł and PhSeNa ð76TL3182Ł to give b!hydroxy ketones[ Ring opening reactions of epoxides
with acyl anions also gives b!hydroxy ketones ðB!76MI 293!90\ 78T6532Ł[
Bearin` An Oxy`en 050

Ar
BF3•Et2O HO
(56)
O Ar 97%, 87% ee
OH O
The selective oxidation of 0\2!diols in which one of the hydroxyls is attached to a primary carbon
can be achieved using many reagents\ including trichloroisocyanuric acid ð81SC0478Ł\ H1O1 and a
tungsten complex ð80JOC4813Ł\ chromium on a solid support ð89TL4674Ł and cerium"IV# ð75BCJ094Ł[
Asymmetric reduction with baker|s yeast has been applied to cyclic and acyclic 0\2!diketones with
mixed results[ 1!Methyl!1!alkylcyclopentane!0\2!diones give preferentially the syn adducts "23#\
whereas similarly substituted cyclohexanediones favour the anti isomer\ although with more varied
stereochemical yields[ Larger ring 0\2!diones appear to be poor substrates[ For 1!monosubstituted
acyclic 0\2!diones\ stereoselectivities can also be very high\ although this is sometimes at the expense
of chemical yield ð89S0\ 80CRV38Ł[
R
O OH

(34)

2[93[3[0[2 g!Functionalized and more remotely OH!functionalized ketones


Selective oxidations of a secondary alcohol separated from a primary one by at least two methylene
groups can be achieved using molybdenumÐButO1H ð73TL3306Ł or cerium"IV# ð73TL2206Ł "see also
Section 2[93[3[0[1#[ The preferential reduction of aldehydes over ketones is relatively facile\ with
many methods available ðB!78MI 293!91Ł[ Among the more recently reported reagents which will
e}ect this transformation are Zn"BH3#1 ð89TL6552Ł and NaBH3 at low temperature ð77SC0816Ł[
Carbonyl! or protected carbonyl!containing anions which react with aldehydes and:or ketones
include "24# ð77JOC0232Ł^ the acetal "25# and homologues\ which also react with a!silyloxy ketones
ð81JOC649\ 82T3812Ł^ "26#\ prepared from reductive lithiation of the corresponding phenyl sul_des
ð81JOC5Ł^ "27#\ which acts as a source of the g!hydroxymethylacyl anion ð80T2642Ł^ and "28#
ð83T2326Ł[ Anions containing a protected hydroxyl group which undergo acylation include the
oxathiane "39# ð81S741Ł and nitro compounds "e[g[\ "30## which are deprotonated under much less
basic conditions ð89T6360Ł[ Other hydroxyalkyl anion equivalents have been demonstrated to add
to enones to give remote hydroxy ketones "Scheme 30\ Equation 46# ð71CJC83\ 89TL6438Ł[ Alkyl!
idenations of lactones give enol ethers which can be considered as protected hydroxy ketones
ð76JOC3309Ł[ An earlier review has dealt with the subject of nucleophilic three!carbon homologating
agents\ including those containing protected alcohols and carbonyl groups ð73CRV398Ł[

R2
O O O
O O
IZn Li Li Li
Ph O
R1
(35) (36) (37) (38)

OR
O
O-TBDMS
O S O
NO2
Li
Li
(39) (40) (41)

O
O O
dabco, CH2(COSEt)2 Raney Ni

93% COSEt 80%


OH
COSEt
dabco = 1,4-diazabicyclo[2.2.2]octane

Scheme 41
051 Dialkyl Ketones
O
O
O
O hν, Ph2CO, MeOH
(57)
71% O
O
HO

2[93[3[1 OR!functionalized Ketones


Alkoxymethyl anion equivalents add to acid derivatives to give a!alkoxy ketones\ and there are
many approaches to this problem\ including the use of the lithium salt derived from MeOBut
ð72TL2054Ł and the stannane "31# ð74JOC3544Ł[ Cuprates related to "31# will add to enones "0\3!
addition# to give g!alkoxy ketones ð77TL2800Ł[ Knochel and co!workers have capitalized on the
chemoselectivity of organozinc reagents to prepare compounds having oxygenation adjacent to\ or
remote from\ the metal[ These reagents undergo a number of useful reactions\ including addition
to acid chlorides or 0\3!addition to enones to give a!oxygenated or more remotely oxygenated
ketones ð82CRV1006\ 82JOC477Ł[

BnO O

R SnBu3
(42)

Several methods are available for the direct oxidation of ketones\ including the use of iodine"III# to
prepare a!methoxy ketones ð76JOC049Ł and a mild method involving treatment with a manganese"III#
carboxylate to give a!acyloxy ketones[ A range of carboxylate groups can be introduced at the a
position using this approach ð89SC1168Ł[ This reaction has been shown to occur in high yield at the
a sp2 carbon of aryl alkyl and alkyl alkenyl ketones and to be highly chemoselective ð81S124Ł[ A
review has recently appeared on the oxidation of a\b!unsaturated ketones at the a? position ð81S124Ł[
The addition of oxygen anions to nitroalkenes is a facile process which occurs under mild
conditions[ Silylation of the resulting nitronate permits an especially mild Nef reaction\ giving a!
alkoxy ketones in high yield ð76TL4250Ł[ Nucleophilic attack at sul_nyl epoxides occurs regio!
speci_cally b to the sul_nyl group to give an intermediate alkoxide anion which collapses with
elimination of PhSOH "Scheme 31#[ Intermolecular nucleophilic attack by alkoxides is not an
e.cient process\ but intramolecular cyclization gives the corresponding cyclic ethers[ Intermolecular
acetoxylation can be achieved using Pb"OAc#3:CsOAc to give a!acetoxy ketones[ These authors
have written a recent review which covers this area ð81SL344Ł[ The treatment of a!halo ketones with
oxygen nucleophiles is one possible method for the formation of a!oxygenated ketones\ but the
outcome is very dependent on the structure of the substrate and the conditions used "for a recent
review see ðB!77MI 293!91Ł#[ Oxidative cleavage of allylic acetates with alkenes is an obvious method
for the synthesis of a!acetoxy ketones\ and many examples are known[ Terminal alkynes can be
converted into a!acyloxymethyl ketones using NaBO2:Hg"OAc#1 ð78SC1484Ł\ whilst addition to
alkynylphenyl iodonium salts under acidic or basic conditions gives similar products ð78JOC3927Ł[
As an alternative\ the addition of water to propargylic alcohols or acetates using catalytic ruthenium
ð76JOC1129Ł or NaAuCl3 ð80JOC2618Ł also gives acetoxy ketones[

O R2 R2
SOPh O– O
R2 R3O R3O
R1 SOPh
R1 R1

Scheme 42

Among the recent developments in the Mukaiyama aldol reaction enol acetates have been
shown to act as enolate donors to give b!alkoxy ketones ð81CL1928Ł[ Lanthanide tri~uoromethane
sulfonates\ reusable catalysts\ can be used for a similar transformation ð82S260Ł and TMS bis"~uoro!
sulfonyl#imide has been reported to be a more active catalyst than TMS!OTf ð82TL6224Ł[ Oxidative
Bearin` An Oxy`en 052
cleavage of 2!substituted 3\4!dihydropyrans gives g!formyloxy ketones in high yields and\ using one
equivalent of ozone\ remote\ isolated alkenes survive ð82JOC2058Ł[
A novel intramolecular reduction is part of a recent synthesis of d!acyloxy ketones[ Thus\
treatment of an iodo ester with SmI1 and an acylating agent results in rearrangement to an
equilibrium mixture of d!hydroxy ketones in which steric crowding is believed to control the direction
of the reduction "Equation 47# ð82JA4710Ł[
i, SmI2
O ii, AcCl OAc O
Ph I (58)
79%, 90% ee
Ph
O

2[93[3[2 OX!functionalized Ketones


The high reactivity of the a carbon in a!sulfonyloxy ketones has meant an increased interest in
their synthesis ð89SL254\ 80T0098Ł[ Enol acetates\ silyl enol ethers and enamines have been shown to
react regiospeci_cally with arylsulfonyl peroxides to give the desired products in high yields
ð75TL4700Ł[ a!Sulfonyloxy ketones can also be prepared directly from aromatic and symmetrical
ketones using iodine"III# reagents ð77JOC109\ 81TL6536Ł and the even more reactive a!tri~uoro!
methanesulfonyloxy ketones can be prepared by the oxidation of enol silanes under similar con!
ditions ð78TL556Ł[ A number of methods are available for the synthesis of a!phosphoryloxy ketones[
These include the direct phosphoryloxylation of ketones ð77JA1876Ł\ the oxidation of enol phosphates
with dioxiranes ð80CB1250Ł and the hydration of alkynes using iodine"III# ð82TL668Ł[ Of these\ the
last two are perhaps the most attractive\ as they avoid the formation of isomeric mixtures or the
use of sensitive reagents[
Silyloxy ketones are isolable intermediates in several of the procedures for the direct oxidation of
ketones\ see Section 2[93[3[0\ and could also be prepared from many other intermediates in that
section[ A direct preparation of silyloxy ketones uses morpholine enamines derived from aldehydes
which react with CO and a silane "Scheme 32# ð81JOC1Ł[ Depending on the speci_c protecting group
and the structure of the substrate\ many oxidants are capable of demonstrating selectivity for one
silyl ether in the presence of another[ This has been the subject of a very useful review ð82S00Ł[
MeEt2SiO
MeEt2SiH, [RhCl(CO)2]2
N 50 atm CO, 140 °C p-TsOH, H2O, 70 °C
O N
72% 100%
O

OSiEt2Me

Scheme 43

The aldol reaction of an enol derivative with a C!0 electrophile often requires the use of formal!
dehyde\ which can be di.cult to generate from its commercially available form\ and so a number of
formaldehyde equivalents have been developed including chloromethyl benzyl ether ð78CC0523Ł
and b!trimethylsilylethoxymethyl chloride ð89SL006Ł used to introduce an alkoxymethyl and a
siloxymethyl group respectively "Equation 48#[ In a surprising reaction\ THF act as an electrophile
in the TMS!OTf!catalysed reaction with SAMP or RAMP hydrazones[ A 3!silyloxy butyl group is
introduced at the a position of the hydrazone and the ketone can be unmasked without removal of
the silyl group[ Chemical and stereochemical yields are very good ð82S0981Ł[

O O
base, ROCH2Cl
OR (59)

R = CH2CH2–TMS, Bn
053 Dialkyl Ketones
2[93[4 KETONES BEARING A SULFUR FUNCTION

2[93[4[0 SH! and SR!functionalized Ketones

2[93[4[0[0 a!SH! and SR!functionalized ketones


The synthesis of a!thiol ketones is complicated by their chemical instability[ Their usual prep!
aration\ involving the treatment of a!bromo ketones with sodium hydrogen sul_de\ requires a large
excess of the sul_de to prevent formation of "32# ð74TL0870Ł and results in the isolation of the cyclic
dimer "33# ð64JOC0183Ł[ The formation of "32# can be eliminated by the use of monoprotected sulfur
nucleophiles such as thioacetate or thiocarbamates[ The thiol ketone is then released by hydrolysis
ð74JA3064Ł[ The synthesis of thiol ketones has been part of a previous review ð66HOU"6:1C#1206Ł[

O O R2
S R1
S HO
R2 R2 OH
R1 R1 R1 S
R2
(43) (44)

The two best!established methods for the synthesis of a!sulfenyl ketones are the direct sul!
fenylation of ketones or their derivatives or via substitution at a!halo ketones by a thiolate anion[
For the former\ the success of the method depends on the ability to control a number of side
reactions[ Many sulfenylating agents are known\ including thiocyanates\ sulfenyl acetates\ thios!
ulfonates\ sulfenyl chlorides\ disul_des\ thioamines and N!thioamides\ with the choice of the most
appropriate reagent being dependent on the reactivity of the enolate donor[ For example\ silyl enol
ethers frequently require the use of the highly reactive sulfenyl chlorides\ whose use may be
incompatible with other functional groups[ Conversely\ enolate anions will react readily with
disul_des[ Other problems associated with the sulfenylation of ketones include the formation of
regioisomeric mixtures\ the possibility for a\a or a\a? bissulfenylation\ a facile elimination of PhSH
from the product to give a\b!unsaturated carbonyl compounds and the greater acidity of the product
with respect to the starting material\ which means that an extra equivalent of base may be required
to compensate for proton transfer[ Additionally\ regiospeci_c sulfenylation is\ as expected\ crucially
dependent on regiospeci_c enolate generation[ The acidity of a!sulfenyl ketones means that the
introduction of further substituents at the a position is relatively easy to achieve "for a review of
much of the early work in this area see ð67CRV252Ł^ see also ð80COS"6#008Ł[ Recent developments
have lead to a number of improvements in the procedures or reagents used for the sulfenylation of
ketones[ Usually a!phenyl sulfenyl or a!methyl sulfenyl ketones are prepared as intermediates for
further elaboration^ however\ alkylation of the potassium salt of thiosulfonic acids with appropriate
alkyl halides allows access to a greater range of sulfenylating agents[ Using these thiosulfonate
esters\ one equivalent of base may be enough for e}ective reaction with ketones ð73LA148Ł[ Thio!
sulfonate esters have also been used for the sulfenylation of silyl enol ethers[ Under the reaction
conditions\ the silyl enol ether is cleaved by tetra!n!butylammonium ~uoride\ and the resulting
ammonium enolate reacts within a few minutes even at low temperatures ð78S353Ł[ For chiral
ketones\ where diastereofacially selective addition is observed\ the use of lithium amide bases or
thioamines as sulfenylating agents may be problematic because the presence of a basic amine as the
by!product can cause epimerization at the a position[ Under these circumstances\ the use of silyl
enol ethers and N!phenylthio lactams may be bene_cial ð81JOC0837Ł[ Sulfenylation of enol borinates
occurs in very high yields with phenyl sulfenyl chloride or the ester "34#[ Reaction occurs at the less
highly substituted side of the ketone and bissulfenylation occurs as a minor pathway in only one
case ð80SL034Ł[ Diastereofacial addition to an enantiomerically pure enol borinate ð80SL034Ł or tin
enolate ð75CL0798Ł gives only low selectivities\ but this may be improved using bulkier sulfenylating
agents ð75CL0798\ 81JOC0837Ł[ A recently reported reagent for the sulfenylation of silyl enol ethers
"35# appears to have a number of advantages over other reagents[ No activating agent or Lewis acid
is required to facilitate the reaction\ which proceeds without the use of very low temperatures to
give monosulfenyl ketones ð81TL5000Ł[
In many of the examples discussed above\ modern methods for regiospeci_c ketone enolization
ensure regioisomerically pure products^ however\ this is not always the case and in addition attempts
to prepare a\a bissulfenyl ketones using this approach often gives mixtures of isomers[ An alternative
procedure for a\a bissulfenylation has been developed for cyclic ketones which involves a one!
Bearin` a Sulfur 054
NTs
CO2Me Ph S
ClS N SPh
Ts
(45) (46)

carbon ring expansion[ In cases where the two a positions are substituted to di}erent degrees\ bond
migration is selective with only a small amount of the alternative isomer being formed "Scheme 33#
ð79TL3290Ł[ For acyclic ketones\ bissulfenylation can follow a two!carbon homologation\ although
the _nal hydrolysis requires the use of a strong acid "Scheme 34# ð76S492Ł[
O O
HO C(SMe)3 SMe
(MeS)3CLi (MeCN)4CuClO4
SMe
73% 60%

Scheme 44

OH O
O R1 i, BF3•Et2O, HS(CH2)3SH
i, ButLi, –78 °C O ii, 40% H2SO4, THF S R1
R2
ii, R1R2CO 60–90%
O S R2
O

Scheme 45

An experimentally simple procedure has been reported for the synthesis of a!methoxy!
carbonylsulfenyl ketones which involves neither base nor low temperatures[ Under the standard
conditions\ the thermodynamically favoured isomer predominates "Equation "59##^ however\ kin!
etically generated silyl enol ethers react regiospeci_cally to give the kinetic product ð81JOC0942Ł[
a!Thiocyanato acetophenones\ which are useful reagents for the preparation of heterocycles\ can be
prepared from acetophenones and potassium thiocyanate using iodine"III# in a one!pot procedure
ð82SC0344Ł[
O O
MeOCOSCl, 0 °C, CH2Cl2
(60)
68%
SCO2Me

Treatment of a!halo ketones with sulfur nucleophiles is a standard method for the preparation
of a!sulfenyl ketones and many examples exist in the literature ð79JA2437\ 71TL4920Ł[ Bromides\
chlorides or iodides act as substrates and organic or inorganic bases can be used to form the thiolate
anion[ A previous review has covered in detail much of the work in this area ðB!77MI 293!91Ł[ Thiols
themselves are pungent\ readily oxidizable materials which may not store for prolonged periods\
and therefore methods have been developed for their generation and use in situ from thioimidates
ð76IJC"B#0000Ł or disul_des ð78BCJ0247Ł[ Despite the presence of an easily oxidizable sul_de\
b!hydroxy sul_des\ prepared from the ring opening of epoxides by sul_des or the reduction of
a!sulfenyl esters with LiBH3\ can be oxidized to a!sulfenyl ketones using the DessÐMartin reagent
or SO2 = pyridine ð77JMC1088Ł or chloral on Al1O2 ð66TL2116Ł[
Alkenes or epoxides act as intermediates in a number of syntheses of a!sulphenyl ketones[ Thus\
regiospeci_c sulfenylation is achieved using alkenyl sul_des or alkenyl silanes as substrates\ where
the carbonyl group arises from the heterofunctionalized carbon atom "Equation "50##[ The majority
of the published examples lead to terminal phenyl sulfenyl methyl ketones\ and hydroxy and keto
groups survive the reaction conditions ð77CC0357\ 82T1900Ł[ Thiolate anions add to a!substituted
b!aryl nitroalkenes in the presence of a reducing agent to give isolable a!sulfenyl oximes which can
be hydrolysed to the corresponding ketones ð74SC332Ł[ The bisfunctionalization of alkenes to
sulfenyl ketones is not a trivial process but one that has been achieved via initial electrophilic attack
with dimethyl"methylsulfenyl#sulfonium tetra~uoroborate[ The resulting sulfonium ion can be trap!
ped with DMSO\ and\ after elimination of dimethyl sul_de\ a!methyl sulfenyl ketones are obtained
in good yield[ Terminal alkenes give a!methyl sulfenyl methyl ketones and 0!phenyl propene gives
055 Dialkyl Ketones
0!phenyl!1!methyl sulfenyl propanone "Scheme 35# ð71JA2117Ł[ It might be anticipated that addition
to nonsymmetric\ dialkyl alkenes or alkynes would give mixtures of regioisomers[ This has been
observed with a related method "Equation "51##\ although again in this case terminal alkynes give
good yields of a!sulfenyl methyl ketones ð77TL1270Ł[

O
R1 X
R4S (61)
R3
R2 R3 R1
R2
X = SR5, SiR63

Me
S+ O
Me2S+SMe•BF4– Me O Pri2NEt
Ph Ph
then DMSO 80%
Ph SMe
SMe

Scheme 46

+
O SPh
i, ArNH(SPh)BF3–
Prn + (62)
ii, H3O+
SPh O
30% 40%
Ar = C6H4NO2-p

Several procedures for the regioselective synthesis of a!sulfenyl ketones have been reported which
rely on a homologation reaction[ Phenylthiotrimethylsilylmethyl lithium adds e.ciently to esters\
but not to acid chlorides or to anhydrides[ On exposure to silica gel\ the adducts lose the TMS
group via a protiodesilylation to give a!phenyl sulfenyl methyl ketones ð70TL1792Ł[ A methyl sulfenyl
methyl group can also be introduced using the reaction between the ketene silyl acetal of ethyl
a!methyl thioacetate and an acid chloride followed by a decarboxylation "Scheme 36# ð68JOC3506Ł[
Decarboxylation forms part of another one!pot synthesis of sulfenyl ketones "Equation "52##[ In
this case\ the method works best for a!substituted ketones ð67BCJ2997Ł[ A bissulfur!stabilized anion
adds to aldehydes in high yield\ and the adducts undergo an acid!catalysed rearrangement "Scheme
37# ð68JCS"P0#0963Ł[ Conjugate addition of an alkyl thiol to the vinyl phosphonate "36# generates an
ylide which reacts with aryl aldehydes as shown in Scheme 38 ð72S221Ł[

TMS-O O
MeS OEt H 3O + O
C7H15COCl
C7H15 OEt SMe
O-TMS 57% C7H15
SMe

Scheme 47

O O
Ph2S2, HMPA, NaI, 160 °C
(63)
CO2Me 49% SPh

Another method which does not require regiospeci_c enolate generation is the Rh1"OAc#3!cat!
alysed addition of thiophenol to a!diazo ketones[ As the diazo ketones are readily available from
the corresponding acid chloride and diazo alkanes\ and the sulfenylation occurs in high yield\ the
transformation could be widely applicable\ limited only\ perhaps\ by the need to generate potentially
hazardous diazo alkanes on a large scale[ The reaction can be used to make nonterminal sulfenyl
ketones by use of the appropriate diazo ketone "e[g[\ "37## ð71TL1498Ł or heterocyclic ketones
following an intramolecular reaction "Scheme 49# ð89T5490Ł[ In the presence of phenyl sulfenyl
chloride\ diazo ketones are converted into the adducts "38#[ These undergo inter! "Scheme 40# or
Bearin` a Sulfur 056
O
R1 R1 OH p-TsOH, C6H6
R2CHO R1
PhS Li PhS R2
PhS PhS R2
SPh
R1 = H, alkyl

Scheme 48

SMe MeSNa, PhCHO SMe TiCl4, H2O, MeCN O


Ph SMe Ph SMe
(EtO)2PO 70% 73%
(47)
Scheme 49

intramolecular FriedelÐCrafts reactions to replace the chloride with an aryl group at the a position
ð72TL006Ł[ Aryl sulfenyl alkyl boronate esters "e[g[\ "49## can be deprotonated adjacent to the sulfur\
and the resulting anion reacts with esters[ Under the reaction conditions\ the boron group migrates
from carbon to oxygen and the enol borinate is hydrolysed to the ketone using acid ð71OM179Ł[ A
review has some examples of sulfur!stabilized anions ðB!76MI 293!90Ł[

O
O
Ph N2
B
Ph O
SPh
(48) (50)

O
O Li CO2Me O
CO2Me
N2 Rh2(OAc)4 CO2Me
S N2
58% 34% S

SH
Scheme 50

O O
O PhSCl C6H6, SnCl4
Cl Ph
N2 Ph Ph
Ph 96% 70%
SPh SPh
(49)

Scheme 51

Anions stabilized by an adjacent sul_nyl group have been used in a number of syntheses of
a!heterofunctionalized ketones[ For example\ the treatment of "40# with lithium diisopropylamide
"LDA#\ followed by an aldehyde or ketone\ gives a b!chloro alcohol which could be elaborated in
a number of di}erent ways[ In one example\ thermal elimination of phenyl sulfenic acid followed
by epoxidation gives an epoxide\ which can be readily attacked by thiolate anions to give a!sulfenyl!
a?!oxygenated ketones "Scheme 41#[ An alternative procedure\ but one which can give structurally
complementary products\ involves a Darzens condensation of chlorosulfoxides with aldehydes or
ketones to give a\b!epoxy sulfoxides[ Nucleophilic attack at such systems is directed towards the b
position to give an alkoxide anion which can react further by spontaneous elimination of the geminal
sul_nyl group[ Dioxolanes remain una}ected by the reaction conditions\ and thiols containing
esters\ heterocycles or alcohols can be used in addition to simple alkyl or aryl thiols "Scheme 42#[
Further examples of the use of haloalkyl aryl sulfoxides for the synthesis of a!heterofunctionalized
aldehydes and ketones can be found in the review ð81SL344Ł[
057 Dialkyl Ketones
O O OH
i, LDA, –60 °C
Cl R2
S Cl S PhMe, 110 °C
Tol Tol R3
ii, R2R3CO
R1 R1
(51)
OH OH
R2 R2 O
Cl VO(acac)2, ButO2H, C6H6 Cl R4SNa, EtOH
R3 R3 R1 R3
O
R2
R1 SR4 OH
R1

Scheme 52

i, LDA, –60 °C
O
O
Cl ii, MeCHO PhSO NaSCH2CO2Me, EtOH Ph
Ph
SOPh iii, KOH, MeOH
Ph S CO2Me

Scheme 53

2[93[4[0[1 b!Functionalized and more remotely substituted SH! and SR!functionalized ketones
There appear to be fewer published methods for the synthesis of b and more remote sulfenyl
ketones\ although the thio analogue of the Mukaiyama reaction using chloroalkyl sul_des and silyl
enol ethers "Scheme 43# has been used with some success in this regard ð68TL1068Ł[ A number of
Lewis acids have been shown to promote the reaction\ which is characterized by high regioselectivity
at the silyl enol ether and a tolerance for a number of functional groups\ including alkyl halides\
esters\ ketones\ alkenes and silyl ethers ð77T3196Ł[ The chloro sul_des are easily prepared from the
corresponding sul_des[ Since these initial reports\ other sources including dithioacetals ð74CL0760\
89JOC4855Ł\ vinyl sul_des ð75TL2918Ł and a!nitro sul_des ð76CC836Ł of the presumed thionium
intermediate have been disclosed[ Thionium ions a to a carbonyl "e[g[\ "41## also act as substrates
for silyl enol ethers to give products in which the sulfenyl group is both a and b to carbonyl groups
within the same molecule ð73CL0420Ł[ b\b!Disulfenyl ketones can be prepared by an analogous
Mukaiyama reaction between cyclic or acyclic silyl enol ethers and trimethylthio orthoformate
ð74TL5402Ł and from the conjugate addition of propane!0\2!dithiol to a\b!ynones ð81JOC6238Ł[
OSiR43
SR2 + SR2
SR2 R3 O

R1 Cl R1 R1 R3

Scheme 54

O
+
SAr

(52)

The number of synthetically useful homoenolate anion equivalents has been increasing steadily
since the 0879s\ and some of these have been shown to react with sulfenylating agents to give b or
more remote sulfenyl ketones[ Much of the work in this area has been the subject of the review
ðB!76MI 293!91Ł[ Among the preparations of stable sulfur ylides "i[e[\ "42## one of the more recent is
perhaps the most direct\ involving coupling of a 0\2!dicarbonyl compound with the CoreyÐKim
reagent ð89CPB2203Ł[
The sul_nyl epoxide "43#\ prepared analogously to that shown in Scheme 42\ can be used to
prepare b!sulfenyl or a\b?!disulfenyl ketones\ depending on the reaction conditions "Scheme 44#
ð81SL344Ł[ b\g!Epoxy nitro compounds\ which are readily available from allylic nitro compounds\
Bearin` a Sulfur 058
undergo a base!catalysed ring opening and double!bond rearrangement accompanied by dis!
placement of the nitro group\ to give b!sulfenyl ketones "Scheme 45# ð89JOC484Ł[
O O

R1 R2
+ SMe

(53)

PhS O PhOS PhS O


SPh O
PhS
PhS– PhSe–
97% 96%

O O O O O O

(54)

Scheme 55

O PhS
O 2N
O
O
i, MeNO2, H2NC2H4NMe2, C6H6, reflux PhSH, Et3N, DMF, 70 °C

ii, mcpba, CH2Cl2 65%


O O O O O O

Scheme 56

The lithium enolates of cyclic ketones have recently been shown to undergo a 0\3 addition to
a\b!unsaturated sulfoxides in good yield[ Reduction of the sul_nyl group then givesg!sulfenyl ketones
ð82JOC5365Ł[ Earlier\ this same conjugate addition had been achieved for acyclic ketones using the
lithium enolate of acetone or via the dianion of ethyl acetoacetate and a subsequent decarboxylation
ð72TL394Ł[ As an alternative to this\ episulfonium ions\ generated from alkenes ð72TL850Ł or
1!phenyl sulfenyl alcohols ð81CL128Ł react with silyl enol ethers to give similar products[ In the latter
case\ reaction takes place at the most!substituted terminus of the episulfonium ion^ homochiral
alcohols have been used to give optically active products "Equation "53##\ and the reaction could be
used to generate compounds with adjacent quaternary centres[ The conjugate additions of 1!lithio!
0\2!dithiane ð76S0015\ 78T6532Ł and a!lithiosul_des "Equation "54## ð66TL0850Ł to a\b!unsaturated
ketones has also been reported[ The synthesis of sulfenyl ketones has been part of a previous review
ð66HOU"6:1C#1206Ł[
O-TMS
O
OH Pri
H SPh Pri (64)
TiCl4 H SPh
Ph
Ph
100% ee 92%, 100% ee

O
O
SPh ButLi, HMPA
+ (65)
57%
SPh
069 Dialkyl Ketones
2[93[4[1 Higher!coordinated Sulfur!functionalized Ketones
Oxidations of a!sulfenyl ketones "see Section 2[93[4[0[0# can be an excellent method for the
synthesis of a!sul_nyl ketones\ and one for which a number of reagents are known[ This is perhaps
the most frequently used method\ particularly where the products are to be thermolysed to the
corresponding a\b!unsaturated carbonyls[ However\ direct sul_nylation of ketones or their deriva!
tives is a viable alternative\ and a number of sul_nylating reagents have been developed\ including O!
alkyl aryl sul_nates ð64TL810\ 82JOC0468Ł\ aryl sul_nyl aryl sulfones ð82SC0404Ł and sul_nyl chlorides
ð71S172Ł[ Interest in the synthesis of a!sul_nyl ketones "b!keto sulfoxides# has greatly increased as
the importance of a homochiral sul_nyl group in chirality transfer reactions has become widely
recognized ðB!72MI 293!91\ 80COS"5#022Ł\ and optically active sul_nates capable of reacting with ketone
enolates are becoming available ð75CL54\ 81JOC6124\ 82JOC3444Ł[ The other widely recognized method
involves the reaction of a sulfoxide stabilized anion with an acid derivative\ and many similar
procedures have been developed to achieve this ðB!77MI 293!92\ B!77MI 293!93\ 80COS"5#022\ 80JOC217Ł[
Anions stabilized by an adjacent sul_nyl group have been used in a number of other syntheses of
a!heterofunctionalized ketones[ For example\ treatment of chloromethyl phenyl sulfoxide with LDA
and an aldehyde gives a highly functionalized adduct which can\ on further exposure to LDA\
undergo elimination of HCl to give an a!sul_nyl ketone "Scheme 46# ð89BCJ0155Ł[ On treatment
with a ketone\ however\ a di}erent mechanistic pathway results[ Under these conditions "Scheme
47#\ a 0\1 elimination of HCl is not possible and so\ on the basis of the products formed\ a 0\0
elimination is postulated to give a sul_nyl carbene which rearranges to give the observed products
ð81TL6070Ł[ The di}erence in the relative migratory aptitude of the two groups adjacent to the
carbene will determine the selectivity and\ hence\ the usefulness of the procedure[

LDA, –65 °C O OH
O n-C9H19CHO LDA (3 equiv.) O O
S
S Cl Ph n-C9H19 S
Ph 98% 95% Ph n-C9H19
Cl
Scheme 57

O Ph Ph
O Ph
S Cl S O S O
Li OH LDA : OLi H2O
Cl
100% 70%

O
Ph S
O

Scheme 58

a!Sulfonyl ketones are generally prepared by the addition of sulfonyl!stabilized carbanions to


acid derivatives\ and many examples of this reaction can be found in the literature "for reviews on
all aspects of sulfone chemistry see ðB!77MI 293!92\ 80COS"5#022\ B!82MI 293!90Ł[ Acid chlorides and
esters have been used as the acylating agent\ and the reaction requires either an extra equivalent of
base or the use of an a\a!sulfonyl dianion ð77JOC895Ł for complete conversion\ owing to the enhanced
acidity of the keto sulfone with respect to the lithio sulfone[ A one!pot preparation of a!sul_nyl or
a!sulphonyl ketones was reported recently\ involving in situ generation of an acyl imidazole "Scheme
48# ð78JOC4519Ł[ The sulfonylation of enamines with sulfonyl halides has been reported to give
a!sulfonyl ketones ðB!82MI 293!91Ł\ but the reaction of sulfonyl halides with ketone enolates has been
shown to be strongly dependent on the counterion[ Lithium enolates react predominantly from the
a position\ whereas larger cations promote increasing amounts of O!sulfonylation ð71CB2576Ł[
a!Sulfonyl ketones can undergo further reaction at the a or a? positions via alkylation of their mono
Bearin` a Sulfur 060
or dianions ð89SL171\ B!82MI 293!92Ł[ Sulfonate esters can also stabilize adjacent anions which undergo
subsequent acylations ð80JOU0120Ł[

N
CO2H O
O N SO2Me
Im2CO LiCH2SO2Me
N N
N 67%

Scheme 59

One method for the preparation of b!keto sulfones which may be particularly attractive for large!
scale work involves the oxidation of a!sulfenyl ketones "see Section 2[93[4[0[0# with Oxone ð76SC712Ł[
Other methods for the synthesis of a!sulfonyl ketones include one of unsaturated sulfonyl ketones
using a carbanion!accelerated Claisen rearrangement "Scheme 59# ð71JA3861Ł and a recently reported
procedure which occurs in the absence of base "Equation "55##[ In the latter case\ branching at the
a position of the aldehyde leads to a reduction in yield ð81TL0020Ł[ Two procedures involving
conjugate addition reactions have been used as routes to a!sul_nyl or a!sulfonyl ketones[ The
Michael addition of diethyl amine to allenic sulfoxides generates an unstable enamine "Scheme 50#
ð71LA0985Ł\ and alkenyl selenoxides undergo hydrolysis via conjugate addition of water or alcohols
"Scheme 51# ð72JOC2966Ł[
PhSO2 O
ONa KH, HMPA, 50 °C O
PhSO2
• 65% PhSO2
80%

Scheme 60

O O
S O SnCl2 O O O
Ar + S (66)
Ph 80% Ph Ar
N2

SOAr NEt2 H3O+ O


Et2NH
• SOAr
SOAr 82%

Scheme 61

KOH, HOCH2CH2OH SeOPh HClO4, H2O O


O O
SO2Ph SO2Ph SO2Ph
76% C8H19 60% C8H19
C8H19

Scheme 62

A number of more unusual\ higher!coordinated a!S!functionalized ketones\ which may attract


increasing attention owing to their potential for further elaboration or structural similarity to
biologically active structures\ have been reported sporadically in the literature[ Keto sulfoxonium
ylides "e[g[\ "44##\ prepared from the reaction between an acid derivative and dimethyl sulfoxonium
methylide\ have been shown under photolytic conditions or following treatment with transition
metal salts to give products characteristic of a!keto carbenes "Equation "56## ð82CC0323Ł[ The
sulfonamide group can also stabilize adjacent anions and this has been used to prepare sulfonamide!
containing renin inhibitors "Equation "57## ð81TL6180Ł[ a!Sulfonamido ketones "e[g[\ "45##\ have also
been prepared by the reaction of enamines ð74S55Ł or silyl enol ethers ð81TL2566Ł with sulfamoyl
chlorides\ and when the keto sulphonic acid is available they can be made from the corresponding
ketosulfonic acid chloride "Equation "58## ð89OS"58#047Ł[ a!Oxo sul_nes\ "e[g[\ "46##\ can be prepared
from silyl enol ethers and SOCl1 ð70S550\ 73TL4836Ł\ although under apparently similar conditions a
061 Dialkyl Ketones
di}erent product\ "e[g[\ "47## may predominate ð83T716Ł[ These chloro sulfenyl chlorides can be
converted into the sulfenamide\ "i[e[\ "48##\ in good yield[

O
O O– CO2Bn Rh2(OAc)4
S (67)
62% N CO2Bn
Me NH-BOC
Me
(55) BOC

O LiCH2SO2NHR O
SO2NHR (68)
BOC-N NMeOMe 98% BOC-N
O O

O O O O
SCl SNEt2

S Cl Cl
SO2NHMe O S S
(56) (57) (58) (59)

i, PCl5 or SOCl2
(69)
ii, NH4OH
O O
SO3H SO2NH2

A multistep but high!yielding synthesis of b!sul_nyl ketones has been reported which appears
~exible enough to be used for a number of di}erent systems "Scheme 52# ð68TL2056Ł[ Potentially
also this could be used to prepare b!sulfonyl ketones[ Propargylic sulfones can be used to prepare
a! or b!sulfonyl ketones depending on the reaction conditions[ On simple treatment with NaOMe\
followed by dilute HCl\ a!sulfonyl ketones were isolated in excellent overall yield[ In the presence
of a mercury"II#\ salt however\ the regioselectivity of the hydration is reversed to give b!sulfonyl
ketones ð78TL6278Ł[

i, BunLi, –40 °C
i, R1SH, Et3N ii, R2I
O ii, HS(CH2)3SH, BF3•Et2O S iii, Tl(ONO2)3

86–92% R1S S 70–90%

O
O NaIO4 R1
S R2
R1S R2 76–93%
O

Scheme 63

The conjugate addition of enolate anions to alkenyl sulfoxides has been used sparingly despite its
being potentially the most direct route to g!sul_nyl ketones[ Ten years ago it was shown that the
acetone enolate or the dianion derived from ethyl acetoacetate could be used in this manner
ð72TL394Ł\ and since then enolates derived from acyclic ð72JOC803Ł or cyclic ð82JOC5365Ł ketones
have been shown to behave in the same way[ a\b!Unsaturated sulfones also serve as Michael
acceptors in their reaction with SAMP and RAMP hydrazones to give g!sulfonyl ketones[ Good
diastereoselectivity is observed in the addition of a homochiral hydrazone to b!substituted sulphones
ð82T0710Ł[
Bearin` a Selenium or Tellurium 062
2[93[5 KETONES BEARING A Se OR Te FUNCTION

2[93[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Ketones


The conversion of ketones to a\b!enones is often a di.cult process\ but one that is facilitated by
the facile syn elimination of selenic acids from a!selinyl ketones[ This has lead to considerable
interest in the synthesis of the immediate precursor\ a!selenyl ketones "Scheme 53# "for excellent
reviews on selenium chemistry see ð67T0938\ 74T3616\ B!75MI 293!90\ B!76MI 293!92Ł#[

O O
O O
R2 R1 R2
R1
R1 R2 Se R1 R2
SeR3 R3
O

Scheme 64

The a!selenylation of carbonyl groups was _rst studied independently by three research groups
ð62CC584\ 62JA4702\ 62JA5026Ł\ although the substrates varied from enol acetates\ to enolates\ and to
ketones\ respectively[ In situ enolization and selenylation of ketones is obviously the most direct
ð62JA5026\ 64JA4323Ł and can be surprisingly chemoselective with esters\ silyl ethers\ isolated alkenes\
epoxides and ketals being some of the groups that remain una}ected ð67JOC3441\ B!76MI 293!93Ł[ The
reaction proceeds via the enol form of the ketone\ and\ in di.cult cases\ enolization may be
enhanced by the presence of hydrogen chloride or an acidic ion exchange resin ð67JOC3441Ł[
N!"Phenylselenyl#phthalimide also requires the presence of acid "one equivalent of p!TsOH# in order
to react directly with ketones[ Selenylation occurs preferentially at the more!substituted side of a
cycloalkanone\ and 1!cyclohexenone gives 5!phenyl selenyl 1!cyclohexenone in 49) yield
ð82TL6644Ł[
The requirement in most of these methods for acidic conditions to promote enol formation is
incompatible with the presence of some functional groups\ and it may be more practical to use a
preformed enol derivative[ This can lead to a complementary or more regioisomerically predictable
outcome because of the myriad of methods that are available for regioisomeric ketone enolization[
Enol acetates ð62CC584Ł\ enol borinates ð80SL034Ł and silyl enol ethers ð66S763Ł\ the last even in the
presence of ketones ð70JACS2359Ł\ undergo direct reaction with PhSeCl or PhSeBr\ to give the
corresponding a!phenyl selenyl ketones[ With silyl enol ethers two new selenium species\ "59# and
"50#\ have been shown to give high yields ð81TL5000\ 82CC0520Ł[ The latter introduces an acyl seleno
group at the a position[
NTs
Ph Se O

N SePh R SeCl
Ts
(60) (61)

Metal enolates have also been used for the formation of a!phenyl selenyl ketones\ and the greater
reactivity of such systems may allow for the use of the less reactive\ but more stable\ diselenides as
the selenylating agents[ In some examples\ however\ this procedure is complicated by the estab!
lishment of an equilibrium reaction owing to the selenophilic nature of the selenate anion "Equation
"69##[ Lithium enolates generated by direct deprotonation ð62JA4702\ 64JA4323Ł or conjugate addition
ð64JA4323Ł and aluminum or zirconium enolates generated by conjugate addition ð79TL0386Ł are
among those that have proved e}ective in their reaction with selenylating reagents[

O
OM
+ PhSeSePh R2 + PhSeM (70)
R2 R1
R1
SePh
M = metal

The most common selenylating agents\ Ph1Se1\ PhSeCl and PhSeBr have already been mentioned\
although the last occasionally acts as a brominating agent[ There are\ however\ a number of other
reagents or methods that can be used[ Perhaps the most cost e}ective\ involves the reaction of an
063 Dialkyl Ketones
enolate with selenium metal to give a selenate anion[ This can then be alkylated on selenium with a
variety of alkyl halides to give less common a!selenyl ketones ð79TL2532Ł[
Several published procedures do not require the use of a strong base[ Thus\ PhSeBr\ generated in
situ from the electrolysis of Ph1Se1 reacts directly with ketones ð79TL0752Ł\ and the oxidation of
diselenides with SeO1 gives a more electrophilic selenylating species which can also react directly
with simple ketones ð71TL3702Ł[ A selenylation which is promoted by acid!catalysed enol formation
employs 1!pyridyl selenyl bromide[ Prior work had indicated that the pyridyl group would enhance
selenoxide elimination when compared to phenyl and\ as expected\ yields of a\b!unsaturated car!
bonyl compounds were increased by approximately 19) for otherwise identical reactions
ð71TL1094Ł[ A later paper from the same group demonstrated that ketone enolates and silyl enol
ethers react with the same reagent ð73JOC2685Ł[ 0\2!Diketones or 0\2!keto aldehydes are selenylated
at the central position with PhSeCl in pyridine ð70JOC1819Ł or selenium metal ð70TL2932Ł[ Remark!
ably\ ketones protected as cyclic acetals react directly to introduce a phenyl selenyl group at the a
position without loss of the protecting group ð68S871Ł[
Diazo groups have been involved in two conceptually di}erent syntheses of a!selenyl ketones[
Seleno esters\ which are readily available from the corresponding carboxylic acids\ undergo insertion
into diazomethane to give terminal a!methyl selenyl or a!phenyl selenyl ketones "Equation "60##
ð74T3648Ł[ Alternatively\ cyclic and acyclic a!diazo ketones undergo spontaneous a\a addition of
PhSeCl\ PhSeBr or PhSeOAc to give bis heterofunctionalized adducts "e[g[\ "51#\ XCl\ Br\ OAc#[
Elimination of either of the a substituents is possible under di}erent conditions "Scheme 54#
ð74JCS"P0#1082Ł[ a!Phenyl selenyl a\b!unsaturated ketones are available using a more convenient
procedure via the addition of PhSeCl to enones in the presence of base ð74T3770Ł[

O CH2N2, CuI O
SePh (71)
SePh 55%

O O O
SePh
Cl H2O2 Li2CO3 SePh
X
82% 77%

(62)

Scheme 65

Nucleophilic displacement of halides by selenate anions is a well!established method for the


synthesis of selenides\ but for a!selenyl ketones this reaction is complicated by nucleophilic attack
at the initial product to give the reduced ketone "see Equation "69##[ However\ some successful
examples have appeared in the literature ð79JOC79\ 70JOC1485Ł[ For mechanistic reasons\ reduction
may be less of a problem in the nucleophilic addition of selenate anions to a!chloro tosyl hydrazones[
The conversion of hydrazone into ketone can be achieved without elimination of the selenide
ð71JCS"P0#1608Ł[
Phenyl selenyl acetaldehyde has been shown to be a useful reagent for the preparation of a!selenyl
ketones "Scheme 55#[ Nucleophilic attack by Grignard reagents gives a secondary alcohol which
can be oxidized to the ketone\ without oxidation at selenium\ using 1\2!dichloro!4\5!dicyano!0\3!
benzoquinone or the CoreyÐKim procedure ð68HCA0395Ł[ 1!Hydroxy alkyl or 2!hydroxy alkyl
selenides can be prepared from the hydroxyselenylation of alkenes\ the ring opening of epoxides by
selenium anions and the attack of selenium!stabilized carbanions at aldehydes\ ketones or epoxides
ðB!75MI 293!91\ B!76MI 293!92Ł[ Thus\ these methods also constitute indirect approaches to a! or
b!selenyl ketones[
O MgBr OH ddq O
SePh 74% SePh SePh
63%

ddq = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

Scheme 66

Terminal alkenes undergo Markovnikov addition of PhSeBr to give bromo selenides "Scheme
56#[ Subsequent treatment with silver"I# in DMSO results in displacement of the bromide by the
Bearin` a Selenium or Tellurium 064
solvent to give a sulfonium salt which\ on exposure to Et2N\ gives a terminal a!selenyl ketone[ The
reaction may go through the episelenonium ion "52# as the isomeric bromo selenide "53# gives the
same a!phenyl selenyl ketone rather than a selenyl aldehyde ð67TL1150Ł[ An identical transformation
has been achieved using PhSeOSnBu2 or "PhSe#1O generated in situ ð70BCJ2099Ł[ With these last two
reagents\ the proportion of a!selenyl aldehyde formed can be higher\ indicating poor regiochemical
control during the addition[ In the oxyselenylation of allylic alcohols\ ethers or acetates\ addition
to the alkene was predictable and consistent\ with the selenyl group becoming bonded to the
terminus of the double bond adjacent to the pre!existing oxygenation "Equations "61# and "62##[
The regioselectivity of the addition is lower in homoallylic ethers ð67TL0166\ 70BCJ2409Ł[ Addition of
PhSeBr to alkenes in a protic solvent has been shown to result in isolable alkoxy alkyl selenides
"e[g[\ "54##[ Oxidation at selenium to the selenoxide was followed by a thermally catalysed rearrange!
ment to the a!phenyl selenyl ketone ð67TL688Ł[ Vinyl selenides can also be oxidized to a!selenyl
ketones ð79CC840Ł[ a!Chloro sul_des are valuable sources of the thionium ion and the corresponding
selenides can be prepared as shown in Equation "63# ð78TL1554Ł[

PhSeBr AgI SePh Et3N


SePh O + Me SePh
DMSO DMSO 70%
Br S O
Me

Scheme 67

Ph
SePh OEt
Se+
Br n-C5H11 SePh
Pri
Pri
(63) (64) (65)

O
PhSeOSnBu3
AcO Ph AcO Ph (72)
73%
SePh

TBDMS-O O
TBDMS-O PhSeOSePh
Ph (73)
Ph 89%
SePh

O
O Cl pyridine
Cl Se
Se Ar R (74)
Ar R
Cl

Selenium\ like sulfur\ has the ability to stabilize adjacent carbanions[ In fact\ the di}erence in the
acidity between the a protons of otherwise identical sul_des and selenides may be as little as 0Ð1
pKa units[ The two most common methods for the synthesis of a!selenyl carbanions are the direct
deprotonation of selenides ð68JACS5527Ł and metalÐselenium exchange in diseleno acetals
ð58AG"E#349Ł\ and using di}erent electrophiles a number of remote selenyl ketone substitution
patterns can be constructed[ Reactions with acid derivatives ð65TL342Ł or aldehydes lead directly\
or following oxidation\ to a!selenyl ketones[ A number of recent reviews have dealt with the synthesis
and reactivity of selenium!stabilized anions ð79T1420\ B!75MI 293!93\ B!76MI 293!94\ B!76MI 293!95Ł[
The conjugate addition of selenol anions to a\b!unsaturated ketones can be facilitated by a
number of di}erent reaction conditions[ Using base catalysis\ benzeneselenol adds as its potassium
ð67TL4976Ł or sodium salt ð62TL0868Ł[ The former is generated from PhSe!TMS and KF\ but this silyl
selenide can react directly with enones using PPh2 ð67TL4980Ł or TMS!I ð68TL3078Ł[ Neutralization of
PhSeNa with a slight excess of acetic acid allows conjugate addition to occur under mildly acidic
conditions ð79S553Ł[ Aluminum and titanium complexes have also been shown to promote the
addition of selenate ions to enones ð74TL5320Ł[ In a related transformation\ ketals derived from
065 Dialkyl Ketones
b!amino ketones undergo direct substitution of the amino group to give a selenide "Equation "64##
ð79JA1345Ł[ In the presence of a Lewis acid\ seleno acetals ð73TL3330Ł or selenyl orthoformates
ð74TL5402Ł lose a selenate group to generate monoselenyl! or bisselenyl!stabilized carbocations\
respectively[ These react in situ with silyl enol ethers to give b!monoselenyl or bisselenyl ketones\
respectively "Equation "65##[

O O PhSeNa, RuCl3 O O
NMe2 SePh (75)
98%

O-TMS O SePh
(PhSe)3CH, SnCl4
SePh (76)
97%

Two procedures for the synthesis of g!selenyl ketones have been published which use readily
available starting materials[ The _rst involves ring opening of cyclopropyl ketones or
bicycloðn[0[9Łalkanones by phenyl selenide ð67TL0538Ł[ For the second\ the well!known ability of
selenate anions to cleave esters or lactones is exploited to transform 1!acetyl!3!butyrolactone into
4!phenylselenyl!1!pentanone by nucleophilic attack at the 3 position of the lactone "Equation "66##
ð66TL3250Ł[ Both of these methods would seem suitable for application to more complex systems[

O O
PhSeNa, DMF, 110 °C O
O SePh (77)
92%

Until recently\ there appeared to be little interest in the use of organotellurium compounds in
organic synthesis[ This situation is slowly changing\ but there are still very few reports describing
the synthesis of isolable tellurium!substituted ketones[ a!Phenyl telluro ketones have been prepared
by the reaction of ketone enolates with PhTeI[ The products decompose rapidly in light and air\
but can be handled in an inert atmosphere[ The application of other procedures for the synthesis of
a!selenyl ketones\ for example the reaction between silyl enol ethers and selenyl halides and the
displacement of halo ketones by selenate anions\ did not work for telluro ketones ð76S0985Ł[ Ketals
derived from a!bromo ketones\ however\ will undergo displacement of the halide with PhTeNa
ð75JCS"P0#0872Ł[ Diphenacyl tellurides or phenacyl tellurides have been prepared from reduction of
the dichloro derivatives "55# "R0 Ar\ ArCOCH1# "see Section 2[93[5[1# ð75OM316Ł and the diphen!
acyl tellurides can also be prepared from the reaction of bis"triphenylstannyl#telluride with phenacyl
bromide ð89TL5180Ł[ Tellurium salts can be prepared from dialkyl tellurides and phenacyl halides[
Their ylides give alkenes on reaction with carbonyl compounds ð77JOC3751Ł[
Conjugate addition of a phenyl telluro group to cyclic and acyclic a\b!unsaturated ketones can
be achieved using PhTeAlBui1[ The products are slightly air sensitive but can be isolated[ The
intermediate aluminum enolate can be used in aldol reactions to generate more heavily functionalized
b!telluro ketones "Scheme 57# ð78CL596Ł[ A recent review has dealt with the use of tellurium reagents
in organic synthesis ð80S682\ 80S786Ł[
Cl O
Cl
Te
R Ar
(66)

Bui2Al O OH
O O
PhTeAlBui2 n-C3H7CHO

76%
TePh
TePh

Scheme 68
Bearin` a Selenium or Tellurium 066
2[93[5[1 Higher!coordinated Se! or Te!functionalized Ketones
Although higher!coordinated selenium species are not uncommon\ very few of these have a
proximal aldehyde or ketone group[ The main exception to this are the b!keto selenoxides "a!selinyl
ketones#\ formed as intermediates during the oxidative elimination of selenyl aldehydes or ketones
"see Chapter 2[90[5[0 and Section 2[93[5[0# to a\b!unsaturated carbonyl compounds[ This trans!
formation has proved particularly successful because the syn elimination of benzene selenic acid
occurs at room temperature\ a process which has been studied by NMR ð74T3660Ł[ Therefore\
b!keto selenoxides can be isolated in only a few speci_c cases] where there is steric crowding at the
carbon b to the selenoxide\ where there are no b!hydrogen atoms\ or where the selenoxide and its
b!hydrogen cannot adopt the correct syn conformation[ The more highly oxidized selenones are
even less well known ðB!75MI 293!92Ł[ Direct introduction of a selenoxide is possible with phenyl
selinyl chloride\ although again elimination occurs without isolation of the a!phenyl selinyl ketone
ð64JA4323Ł[ Selenium oxychloride reacts with phenacyl chlorides to give the adducts "56# ð77TL0288Ł[
O Cl Cl O
Se
Ph Ph
(67)

On simple treatment with ketones\ PhSeCl2 acts in a manner analogous to PhSeCl except that the
product contains a tetravalent selenium group "e[g[\ "57##[ Further transformation of the product
can result in the enone\ via the selenoxide\ or the selenide "Scheme 58# ð74TL5274Ł[ Stabilized
selenonium and tellurium ylides\ "e[g[ "58## can be prepared by the reaction between selenium
dichlorides ð61JOM"31#288Ł or selenoxides or telluroxides ð79BCJ706Ł and 0\2!diketones[
O
O
Ar2Se
PhCl2Se

O
(68) (69)

O O O
NaHCO3 thiourea
R1 PhCl2Se R1 PhSe R1
50–97% 71–99%

R2 R2 R2
Scheme 69

a!"Aryldichlorotelluro#ketones "i[e[\ "69## have been prepared by the reaction between an aryl
tellurium trichloride and either a ketone or silyl enol ether[ The yields are typically quite high
"79Ð099)# ð75OM316\ 76SC332\ 82CL450Ł[ Alkyltellurium trichlorides react only poorly with aromatic
ketones but give much higher yields with their silyl enol ethers ð80OM0067Ł[ Cycloalkanones give
either the dichlorides "60# or the trichlorides "61# with TeCl3 depending on the ketone used
ð75OM316Ł[ Silyloxy cyclopropanes undergo a regioselective ring opening with TeCl3 to give either
b!trichlorotelluro ketones or the corresponding dimers depending on the amount of metal chloride
used "Scheme 69# ð80TL118Ł[

O Cl Cl O O
O
Te TeCl3

TeCl2Ar

(70) (71) (72)


067 Dialkyl Ketones
O O
O TeCl3 TMS-O
TeCl4 (1 equiv.) TeCl4 (0.5 equiv.)
But Te But
But 96% But 95%
Cl Cl
Scheme 70

2[93[6 KETONES BEARING A NITROGEN FUNCTION

2[93[6[0 NH1\ NHR and NR1!functionalized Ketones


The combination of adjacent nucleophilic and electrophilic centres within the same molecule
makes the isolation of free primary or secondary amino ketones less than straightforward because
of a competing dimerization reaction[ For this reason\ the majority of methods for the preparation
of compounds within these two classes involve the isolation of a species in which either the amino
group "as the amide\ carbamate or salt# or the carbonyl group "as the acetal or hydrazone# is in a
protected form[ Sometimes interconversion of these stabilizing groups is necessary prior to further
derivatization[ Under appropriate conditions\ amine salts can be converted into the corresponding
amides without base "Equation "67## ð81SL380Ł\ or into the t!butoxycarbonyl "BOC# carbamates
using an ultrasonically accelerated reaction "Equation "68## ð80SL26Ł[ An excellent review has
recently been published dealing with the synthesis of amino ketones ð89OPP288Ł[

O O
O NH3Cl (RCO)2O, DMF (cat.), 55 °C O NHCOR
N N (78)
50–99%

R = Me, Et, Ph

O (BOC)2O, NaHCO3, ultrasound O


(79)
XH3N 98% BOC-HN

2[93[6[0[0 a!NH1\ NHR and NR1!functionalized ketones


The displacement of a halide from an a!halo ketone with a nitrogen nucleophile is a well!
established reaction which has been widely employed in organic synthesis[ The reaction is most
useful when using secondary amines and primary halo ketones since primary amines often give bis
adducts "Equation "79## and secondary or tertiary a!haloketones can undergo elimination under the
reaction conditions "for a review see ðB!77MI 293!94Ł#[ In cases where this is a problem\ the use of a
less!basic aminating agent may be bene_cial^ imidates are ideal in this respect\ retaining a signi_cant
degree of nucleophilicity and able to provide a range of alkyl!substituted amine nucleophiles
"Equation "70##[ The reaction works even with secondary halo ketones\ and the formyl group can
be removed using acid hydrolysis ð70JOC0113Ł[ The direct oxidation of ketones to their a!amino
derivatives using a nucleophilic aminating agent\ in this case a secondary amine\ can be achieved
using iodine"III#[ Regiospeci_c amination is observed only when enolization is directed to one a
position by thermodynamic factors ð89SL254Ł[

O R2NH2 O R2 O
Br N (80)
R1 R1 R1

O O CHO
BzO Br MeCN, reflux BzO N
+ Ph Ph
N OMe (81)
91%
BzO BzO

The transformations outlined above demonstrate that useful direct aminations of a!halo ketones
exist\ but\ particularly for the introduction of an NH1 group\ a number of alternatives exist[ For
Bearin` a Nitro`en 068
example\ reduction of a!azido ketones "see Section 2[93[6[2# gives primary a!amino ketones ð74LA674\
75JOC2263Ł[ The same products can be obtained from the reaction between a!bromo ketones and
hexamethylene tetramine "Equation "71##\ although the strongly acidic conditions required to hydro!
lyse the intermediate adduct might limit the opportunities for its use ð53RTC0936\ 71JHC58Ł[ The
allylic chlorides "62# "R0 H\ Cl# react in an SN1 manner with LiN!TMS1 to give protected amino
ketones ð82JOC6339Ł[

O O O O
i, hexamethylene tetramine
(82)
Br Br ii, HCl, EtOH Br NH3Cl

O-TMS
R Cl

(73)

Potassium phthalimide ð57AG"E#808\ 57JPR01\ 80COS"5#54Ł and sodium diformylamide ð89S504Ł are
powerful nitrogen nucleophiles which readily displace halides[ The latter has the advantage that one
or both of the formyl groups can be removed selectively "Scheme 60#[ Although no experimental
details were given\ the monoformyl derivatives "63# were alkylated at the a position to give products
that could not be made by direct substitution[ The a!alkylation of a!amino ketones has\ however\
been studied by other groups and full details are available[ As might be expected\ the presence of
an electron!de_cient nitrogen "amide or carbamate# favours deprotonation between carbonyl and
amino groups "Equation "72## and the resulting enolate can be trapped and isolated as the silyl enol
ether ð79JOC1296Ł[ Later papers by Muchowski and co!workers explored the reactivity of these
enolates with a number of alkylating agents ð75JOC2263\ 80CJC1948Ł[ These researchers demonstrated
that the monoanions of N!formyl and N!BOC amino ketones react with primary and secondary
alkyl\ benzyl and allyl halides to give the a!substituted adducts in\ usually\ good yield "Equation
"73##[ The activating groups are easily removed\ and\ therefore\ the method can be used to prepare
a series of a!alkyl a!amino ketones[ As already discussed\ however "see Chapter 2[90[6[0[0#\ an
N!8!phenyl ~uorenyl "PhFl# protecting group prevents racemization at the a position during treatment
with a variety of reagents[ In fact\ it does so to such an extent that deprotonation occurs regio!
speci_cally at the a? position "Equation "74## to give the isomeric a?!alkyl a!amino ketones
ð77JA6336Ł[

O H
NaOH, EtOH N
Ar CHO
O CHO MeCN, RT, 2 h O CHO 91–98% (74)
Br + NaN N
Ar 87–98% Ar CHO HCl, EtOH
CHO O
91–99%
NH3Cl
Ar

Scheme 71

MeO2C O LiHMDS, –78 °C to 0 °C


MeO2C OSiR3
N N (83)
Ph Ph
LiHMDS = lithium hexamethyldisilazide

O H
O H i, NaH
N
N Ph R (84)
Ph R ii, BunI
Bun
R = CHO, 45%
R = BOC, 60%
079 Dialkyl Ketones
O O
i, KN(TMS)2
ii, allyl bromide
(85)
85%
N N
PhFl H PhFl H

In a rather speci_c example of amino ketone monoalkylation\ and one which goes via a fun!
damentally di}erent mechanism\ allyl!substituted imines are subjected to a thermally catalysed
rearrangement[ Two competing pathways\ a ð2\2Ł sigmatropic rearrangement to give the N!allyl
ketone "64# or a 0\1!allylic transposition to give "65# are theoretically possible "Scheme 61#[ In the
end\ only the latter was observed\ to give a!amino!a!allyl ketones in reasonable yield[ A number of
N!functionalized imines\ such as "66# and "67#\ rearrange in the same way to give compounds
suitable for further synthetic elaboration[ Propargylic imines rearrange as shown in Equation "75#
ð89TL1166Ł[

R1 O HO R1 O

R2 R1
R2 N
BnHN R2 NBn
Bn
(76) (75)
Scheme 72

OH O
TMS
(86)
58%
TMS
NBn NHBn

OH
OH

N
N
OMe
CO2Me
OMe
(77) (78)

Just as the reduction of amino acid derivatives is an excellent method for the preparation of
amino aldehydes "see Chapter 2[90[6[0[0#\ their reaction with organometallic reagents to give amino
ketones has been equally widely exploited[ Most conveniently\ Rapoport and co!workers have shown
that amino acids in which the amino group is protected as an amide\ carbamate or sulfonamide can
be used directly in such transformations[ The acidity of the carboxyl and amino groups must be
compensated for by the use of an excess of the organometallic reagent\ but this\ at least in part\ can
be done with relatively cheap organolithium reagents "Scheme 62#[ Very little tertiary alcohol was
formed\ and\ despite the use of at least three equivalents of a strong base\ no racemization at the a
position was observed ð72JOC1159\ 73JA0984Ł[ The same group had earlier shown that N!acyl a!amino
acid chlorides were also susceptible to attack by Grignard reagents to give the corresponding
ketones[ Using this approach\ the addition of a second equivalent of Grignard reagent to give a
tertiary alcohol may be a competing process[ In those cases where this is a problem\ stabilization of
the tetrahedral intermediate by intramolecular chelation can result in an improved yield of the
ketone[ This has been achieved using 1!pyridyl thioesters ð71TL1422Ł\ although in one direct com!
parison these were shown to be less e}ective than N\O!dimethyl hydroxamates or acyl oxazolidines
ð74JOC2861\ 75JCS"P0#0784Ł[
The reaction of an acylating agent with an amino acid to introduce an alkyl group and form an
alkyl ketone\ the DakinÐWest reaction\ was _rst reported in 0817 and has been the subject of
considerable synthetic and mechanistic interest[ Early indications were that the reaction was limited
to amino acids with at least one a proton and the use of acetic anhydride to form methyl ketones
"Equation "76## but\ although yields may be highest under these circumstances\ this has now been
Bearin` a Nitro`en 070

CO2H CO2Li MgBr (2 equiv.)


BunLi (1 equiv.)
N N
BnO H CO2Et BnO H CO2Et

LiO OLi O
H3 O+

N 71% N
BnO Li CO2Et BnO H CO2Et

Scheme 73

shown not to be the case[ Thus\ a broader range of alkyl ketones can be made using this method\
particularly as the most common acylating agents\ acid anhydrides\ are readily available[ The
conditions developed originally\ acetic anhydride at 099>C\ or 019>C for less reactive substrates\
were quite harsh\ but it has been demonstrated that the use of the acyl transfer catalyst 3!dimethyl!
aminopyridine dramatically reduces the reaction temperature ð77CSR80Ł[
O

CO2H (MeCO)2O, heat


N O (87)
NH2 70% H

The amination of ketone enolates is limited by the relative paucity of electrophilic aminating
agents\ although such species are known ð78CRV0836\ 80TL1248Ł[ Silyl enol ethers have been used in
conjunction with ethyl azidoformate "Equation "77## ð72TL482Ł or p!NO1PhSO1ONHCO1Et
ð83T2718Ł to introduce an N!ethoxycarbonyl amino group in reasonable yield and with azo!
dicarboxylates to give a!hydrazino ketones ð74SC538\ 83TL1316Ł[ The recent\ elegant work by Magnus
and co!workers on electrophilic addition to silyl enol ethers with double!bond transposition has
been extended to the synthesis of a!amino ketones "Equation "78##[ The p!toluenesulfonyl residue
can be removed without loss of the silyl group\ and the stereochemistry at the a position can be
inverted using an oxidationÐreduction sequence "Scheme 63#[ Perhaps the most unusual aspect of
the overall sequence is that the sulfonamide group is introduced initially into an axial position
ð89JA351Ł[

O-TMS O
EtOCON3, 110 °C, 15 h
NHCO2Et (88)
40%

Pri3SiO Pri3SiO

(p-TsN)2Se
NHTs
(89)
51%

Pri3SiO Pri3SiO Pri3SiO


NH2 Na, NH2 NHTs i, SeO2
NHTs

70% ii, NaBH4

Scheme 74

The addition of 1!lithio!0\2!dithiane to aromatic nitriles results in the formation of an enamine


whose anion reacts further from the a position "Scheme 64#[ The imine "68# is surprisingly stable
and undergoes further alkylation at nitrogen[ A _nal reduction gives a product resulting from
071 Dialkyl Ketones
addition of an acetyl anion to an imine ð76CC664Ł\ a transformation which can also be achieved
using the vinyl anion "79# ð89JOC4579Ł[ Acyl anion equivalents are also components of the benzoin
reaction\ of which there are many variants[ The thiazolium salt "70# has recently proved quite
e}ective in its addition to aldehydes and in the stabilization of the resulting anion[ In the presence
of an iminium salt\ an a!amino ketone results "Equation "89## ð77S203Ł[ The chemistry of acyl anions
has been covered in a recent review ðB!76MI 293!96Ł[

i, BunLi, MeI HN i, BunLi, MeI


S S NH2 ii, NH4Cl ii, B2H6
PhCN S
Li Ph
S S Ph 100% 63%
S
(79)
MeHN
S
Ph

Scheme 75

O
+ ArCHO, (81) Ar
O N (90)
25–50% O N

S
OCONEt2
N + Cl–
Li
Bn
(80) (81)

This same connectivity can be achieved in the opposite sense by the addition of an a!nitrogen
anion to an acylating agent[ One obvious example involves the acylation of a nitronate anion "see
Section 2[93[6[1#\ although this requires an additional step involving reduction of the nitro group
to an amine[ There are\ however\ many ways in which nitrogen in a lower oxidation state can
stabilize adjacent anions\ although not all of these have been shown to react with acylating agents
ðB!76MI 293!97Ł[ Perhaps the most common approach involves the use of an amine substituted with
a cleavable\ electron!withdrawing group capable of coordination to\ and hence stabilization of\ an
adjacent anion "Scheme 65#[ This frequently means employing amides "e[g[\ "71##\ thioamides\ "e[g[\
"72## or formamidines "e[g[\ "73## ð65AG"E#202\ 79JA6014\ 70JOC3205\ 78JOC4540\ 78TL0086Ł[ The use
of formamidine!stabilized carbanions has been extensively exploited by Meyers and co!workers\
particularly for the synthesis of anions derived from cyclic amines ð74JOC0908\ 80JOC1640Ł[ Amino
methyl stannanes can act as amino alkyl anion equivalents without the need for strong base\
providing the electrophile is a highly reactive one such as an acid chloride[ Simple mixing of both
reagents\ in the absence of solvent for liquid acid halides\ gives tertiary a!amino ketones "Equation
"80##[ Aliphatic or aromatic acid chlorides behave as expected\ and formyl and nitrile groups remain
intact ð75TL1250Ł[ Additional anion stabilization can be provided by an adjacent conjugated
p!system[ Thus\ the dianion derived from ethyl N!benzoyl glycinate reacts from the a position with
acid anhydrides to give a!amido b!keto esters\ and decarboxylation proceeds smoothly to give
a!amino or amido ketones ð67CC642Ł[ Two complementary modes of reactivity are demonstrated by
the adduct "74#\ which is readily prepared by condensation of an aldehyde with an amino!substituted
phosphine oxide[ In the presence of base\ a conventional Wittig reaction gives the corresponding
enamine\ but\ in the presence of a proton source\ a thermal elimination of Ph1POH gives the amino
ketone ð70TL1688Ł[ A similar reaction occurs using a nitrile!stabilized carbanion[ Following addition
to an aldehyde\ elimination of HCN occurs regioselectively to give the desired product "Scheme 66#[
This route has excellent synthetic ~exibility\ relying\ as it does\ on readily available aldehyde and
Bearin` a Nitro`en 072
amine starting materials ð71TL528Ł[ The synthesis and reactions of nitrogen!stabilized carbanions
has been covered in a previous reviews ð73CRV360\ B!76MI 293!92Ł[

O S NR O OH

Et Me Me P
N N But N Ph R3
Et Ph
Et Me Me N
R1 R2
(82) (83) (84) (85)

X X Li
BunLi i, E+ E
R1 N R3 R1 N R3
ii, H3O+ R2HN R3
R2 R2
X = O, N, S

Scheme 76

O O
NEt2
Cl THF, 60 °C
+ Et2N SnBu3 (91)
84%
O O
O O

i, LDA, –78 °C, cinnamaldehyde O


KCN, H2O NEt2 ii, distil
MeCHO + Et2NH Ph
CN 79%
NEt2

Scheme 77

Epoxides bearing a geminal leaving group have been used extensively for the preparation of
a!heterosubstituted ketones\ as the electron!de_cient substituent serves to activate nucleophilic attack
at the b position of the epoxide as well as providing the means for carbonyl group formation via a
0\0!elimination[ A number of substituents have acted in this way "Equation "81## ð89OPP288Ł\ of
which the most successful are the sul_nyl epoxides[ The substrates "e[g[\ "75## are easily prepared
using a Darzens type condensation of sul_nyl!stabilized carbanions with an aldehyde or ketone\
and the addition of a secondary amine gives good yields of the expected products "Equation "82##
ð75BCJ346\ 81SL344Ł[ 0\1!Disubstituted enamines react with sulfonyl oxaziridines to give a!amino
ketones via the possible intermediacy of a!amino epoxides[ For example\ the morpholine enamine
of cyclohexanone is converted into 1!morpholinocyclohexanone in 55) yield under mild reaction
conditions ð77TL3254Ł[
O
O
R2 R4XH R1 (92)
R1 R2
Z
XR4
Z = Hal, OR3, NO2, PhSO

O
O Ph
PhSO pyrrolidine
(93)
100% N
Ph
(86)

Despite their high reactivity as acylating agents\ acyl cyanides\ readily available from a carboxylic
acid derivative\ can be reduced to a!amino ketone hydrochlorides using SnCl1 ð61JOC207Ł or to
acetamido ketones "Equation "83## ð73TL1866Ł[ In the latter case\ isolated alkene\ ester or ketone
073 Dialkyl Ketones
groups survive\ although a\b!unsaturated acyl cyanides give mixtures of products[ Chemoselective
reduction of an a!nitro ketone to an a!amino ketone hydrochloride is possible using a poisoned
platinum catalyst ð75TL4648Ł[ Azides can also be reduced in the presence of ketones using catalytic
hydrogenation ð58CJC2378\ 74LA674Ł[ The Neber\ and mechanistically related\ rearrangements are
valuable routes to a!amino ketones which still _nd wide applicability owing to the ready availability
of the principal substrate\ O!tosyl oximes ð89OPP288\ 80COS"5#652Ł[ In fact\ any imine with an attached
leaving group will participate in the reaction\ and hence N!chloroimines and quaternary salts of
hydrazones behave in an analogous manner[ A common intermediate is an azirine "Scheme 67#
whose hydrolysis gives the desired products in which the carbonyl group is attached at the original
imine carbon[ For unsymmetrical imines\ the product arises from thermodynamic deprotonation
during the azirine!forming step[ Using anhydrous alcohols as solvents\ the amino ketals can be
formed instead of the ketones ð79S218Ł[ a!Halo imines can be used in an analogous manner "Scheme
67# ð71S654Ł[
O Ac2O, AcOH, Zn O
NHAc (94)
MeO2C CN 83% MeO2C

NOTs base N
R1 R2 R2
R1
R 4O –
H(R3) O
N H2O, HCl R1 R2
OR4
R1
R2 NH2(HR3)•HCl
R4O–

NR3
R1 R2

Hal
Scheme 78

The oxidation of 0\1!amino alcohols is an obvious method for the preparation of a!amino ketones\
although it can only be used for the formation of N!protected compounds^ otherwise\ side reactions
may cause a reduction in yield[ The other problem is the con_gurational instability of the products\
although this can be reduced by using N!phenyl~uorenyl ð76JA125Ł or N!TBDMS protecting groups
ð75TL3280Ł[ The alcohol oxidation can be done under Swern conditions ð75TL3280Ł\ with the CoreyÐ
Kim reagent ð77JA6336Ł or using chromium"VI# species ð89OPP288Ł[

2[93[6[0[1 b!Functionalized and more remotely NH1\ NHR and NR1!functionalized ketones
The importance of the Mannich reaction as a method for the formation of b!amino ketones is
enhanced by the biological activity of the products and also because of their value as intermediates
to a\b!unsaturated ketones and\ hence\ other multifunctional systems[ The immense amount of
literature in this area ð68T502\ 89T0680\ 80COS"1#782\ 80COS"1#842\ 80COS"1#0996Ł cannot be covered com!
prehensively in the space available here^ as a consequence\ only a brief summary of this reaction
and recent developments will be discussed[
The archetypal Mannich reaction consists of a three!component coupling between ammonia\ or
an amine\ a nonenolizable aldehyde and a carbon acid "pKa ³19#[ The optimum yields are obtained
using formaldehyde\ a ketone and a secondary amine "Equation "84## because primary amines
possess the ability to undergo dialkylation "Equation "85## and aldehydes as enolate donors tend to
undergo competing aldol reactions[ The former drawback can be overcome using additional\
temporary protection on the amine\ but the latter has been less successfully addressed[ Typical
conditions involve the use of an acid or\ occasionally\ base catalyst in a protic solvent where the
commonly accepted mechanism is as shown in Scheme 68[ Control of the regiochemistry of the
amino alkylation may be di.cult\ although the thermodynamic conditions mean that enolization
tends to occur towards the more!substituted a position "Equation 86#[ The main focus of recent
research has been directed towards the discovery of new methods that permit the use of the Mannich
Bearin` a Nitro`en 074
or related reactions in aprotic solvents\ without the use of acid or base catalysis or with increased
regioselectivity[

O
O CH2O, R2R3NH R1 R1
(95)
R1 R1
NR2R3

O O
O CH2O, R2NH2
R1 R1 (96)
R1 R1 N
R1 R2 R1

OH
R2 R2 + R1 R1
R2R3NH + CH2O N X N
R3 R3
O
R1 R1

NR2R3
X = OH, R2R3N

Scheme 79

O O O
Me2NH, CH2O
+ (97)
Me2N NMe2

1 : 3.5

One important component of this search has been the development of new procedures for the
formation of the intermediate aminal\ imine or iminium salt\ particularly those which allow for
the preformation or isolation of these reactive intermediates[ The simplest and most frequently
encountered Mannich reaction\ the introduction of a dimethylaminomethyl group as a means to
generate an a\b!unsaturated carbonyl compound\ is often done using the preformed iminium salts
"76# "XI\ Cl\ CF2CO1 or tri~ate "OTf## of which the _rst is the most familiar\ being Eschenmoser|s
salt[ The solubilities of these salts are very dependent on the counterion\ with the TFA and OTf
salts being most soluble\ particularly in less polar solvents where the use of these two reagents is
bene_cial ð68T502Ł[ The iminium salts can be prepared in a number of ways\ perhaps the most
common being one of the variations of the Bohme procedure in which N\N\N?\N?!tetra!
methylmethylenediamine undergoes elimination of dimethylamine promoted by TMS!I\ TMS!Cl or
AcCl[ However "77#\ "78# and many other compounds have been used to prepare similar iminium
species[
R1 R1
Me N N
+
N X– BunO NMe2
Me N
R1
(87) (88) (89)

As indicated above\ many Mannich reactions use a mixture of ketone\ formaldehyde and sec!
ondary amine\ although the frequent need for an acid or base catalyst and the regioselectivity
problems make this procedure far from general[ The use of preformed iminium salts "see above#\
which often work in the absence of a catalyst\ and the methodological advances that have been
made in the preparation of regioisomerically pure ketone enolates have enhanced the use of this
transformation[ The regioselective introduction of a dialkylaminomethyl group can be achieved
075 Dialkyl Ketones
using cyclic TMS enol ethers and Eschenmoser|s salt ð79TL794Ł or dialkylaminomethyl ethers
ð71TL436Ł[ Since these initial reports\ many other applications of the aminoalkylation of silyl enol
ethers have appeared\ demonstrating high levels of chemoselectivity ð80COS"1#782Ł[ Silyl dienyl ethers
may react preferentially from the g position "Equation "87## ð79TL794Ł\ while acyclic TBDMS enol
ethers undergo a synthetically useful amino methylation with double!bond inversion "Equation
"88## ð73TL4394Ł[ The low reactivity of these enol ethers and the related enol borinates is such that
useful yields can only generally be obtained with iminium salts[ Other than iminium salts\ a few
other species have been shown to act as e}ective partners in Mannich type reactions[ Imines or acyl
imines will react under some conditions\ but the reaction is often restricted to imines derived from
aryl or other nonenolizable aldehydes because of a competing isomerization of the imine to the
enamine ð83SC788Ł[ The more reactive N!acyl iminium salts will react with silyl enol ethers under
mild conditions to give the expected adducts in moderate diastereomeric excess "Equation "099##
ð89SL508Ł[

Me2NCH2•I
(98)
65%
O
TMS-O
NMe2

O-TBDMS O-TBDMS
Me2NCH2•I
(99)
NMe2
58%

O-TMS

OMe O Ph O O
TMS-OTf, –40 °C
N OBn (100)
61% Ph N OBn
Me Me
syn:anti 86:14

Two procedures have extended the Mannich reaction to the preparation of nonterminal b!amino
ketones by the use of aldehydes other than formaldehyde[ As indicated above\ this transformation
is very di.cult under classical Mannich conditions because of the self!condensation of enolisable
aldehydes[ Seebach and co!workers showed that aminoalkyl titanium alkoxides\ "89#\ prepared from
the corresponding aldehydes\ react directly with ketone enolates at low temperature "Scheme 79#
ð73HCA0482Ł[ In the second\ lithium enolates react with aminomethyl benzotriazoles to give amino
ketones[ This reaction is particularly useful for the preparation of highly hindered a\a!disubstituted
amino ketones "Equation "090## ð89T876Ł[

OLi
i, BunLi, –78 °C TiCl4, –70 °C
N
N ii, PrnCHO
H

OLi
OTiCl3 Prn O

N N

(90)

Scheme 80
Bearin` a Nitro`en 076
N
N OLi
O
N O
N + (101)
66% N
O

The development of the Mannich reaction as a method for the introduction of an NH1 or an RNH
group has not been particularly successful until comparatively recently[ Using the benzotriazole
methodology developed by Katritzky and co!workers\ however\ this can be achieved directly for
aromatic amines "Equation "091## or\ potentially\ from further derivatization of a secondary amide
"Equation "092## ð89T876Ł[ The imine "80#\ derived from formaldehyde and ammonia has been
generated\ in situ\ from TMS azidomethane and reacts with TMS enol ethers to give the expected
amines\ which could only be isolated following benzoylation "Scheme 70#[ Under otherwise identical
conditions\ 0\0\2\2!triisopropylsilyl "tips# enol ethers react with inversion of the double bond to give
compounds containing a primary amine "Equation "093## ð81JOC6998Ł[

N OLi O
N
N + PhHN (102)
85%
NHPh

N OLi O
N
N + BzHN (103)
85%
NHBz

O-TMS O
AlCl2R1 R3
i, R2 R3
TMS N3 + R1AlCl2 N R2
ii, BzCl
TMS
NHBz
(91)

Scheme 81

tips-O tips-O
(91)
NH2 (104)
94%

cis:trans 6:94

Although the transformation is not primarily aimed at the preparation of simple b!amino ketones\
brief mention must be made of the intramolecular Mannich reaction for the preparation of saturated
nitrogen heterocycles ð80COS"1#0996Ł[ A number of elegant syntheses have involved this reaction as
one of the key steps "Scheme 71# ð82JOC3551Ł[
The conjugate addition of nitrogen nucleophiles to electron!de_cient alkenes is a facile process
for which many procedures are available ð80COS"3#0Ł[ Benzophenone imine has been used as an
ammonia equivalent in the Michael addition to a\b!unsaturated carbonyl compounds[ Not sur!
prisingly\ perhaps\ with such a bulky nucleophile\ the addition is prevented by the presence of some
substituents at the b position of the enone ð78S248Ł[ For the addition of a dialkyl amine to exocyclic
a!methylene ketones\ a dramatic improvement was observed using aluminum oxide as a catalyst
ð79TL798Ł[ Using titanium"IV# amides in aprotic solvents\ one of the dialkyl amino groups is
delivered from the metal to the b position of an enone to give a titanium enolate which can undergo
further in situ aldol or Mukaiyama aldol reactions resulting in a b!amino b?!oxygenated ketones
ð80TL1260Ł[ b!Chloro ketones\ when accessible\ can act as surrogates for enones ð60JA1381Ł[
One problem with the Gabriel synthesis of amines is that the removal of the phthalimide group
requires relatively harsh conditions which may be incompatible with the presence of some other
077 Dialkyl Ketones
Ar
O–
Ar
BF3•Et2O, –20 °C aza-Cope
O
+
N
N H
Bn
H Bn

O– O Ar
H
Mannich
+
Ar
N 97% N
Bn H Bn

Scheme 82

functional groups\ and a number of modi_cations have been developed to address this "for a review
on the Gabriel reaction see ð80COS"5#54Ł#[ Among the ammonia equivalents which have been used
to prepare protected a! or b!amino ketones are the iminocarboxylates ð67JCS"P0#0977Ł\ dibenzylamine
ð80JOC346Ł and the sodium salts of tri~uoromethyl acetamide ð73S830Ł and the phosphoramidate
"81# ð71S811Ł[
O O
P
EtO N OBut
EtO Na
(92)

The reductive amination of aldehydes or ketones is often done using conditions where acid!
sensitive groups do not survive[ Using Ti"OPri#3 as a Lewis acid catalyst and NaBH2CN as the
reducing agent\ cyclic and acyclic acetals remain intact\ demonstrating the usefulness of this pro!
cedure for the synthesis of a wide range of carbonyl!protected amino ketones "Equation "094##
ð89JOC1441Ł[ 0\2!Diimines can be reduced to b!amino ketones ð72JOC1144Ł[

i, Ti(OPri)4
O ii, NaBH3CN O
O + N (105)
O N 50% O
H

The conjugate addition to enones of carbanions stabilized by an adjacent nitrogen atom has
recently been shown to be feasible\ although not without some problems[ Higher!order cyano!
cuprates derived from lithio formamidines undergo e}ective 0\3!addition "Equation 095#\ but
attempts to hydrolyse the formamidine lead to a mixture of products ð81TL4582Ł[ More successful
was the use of carbamate!stabilized anions\ generated by transmetallation "Equation 096#\ which
give good yields even with b\b!disubstituted ketones[ In some examples\ direct deprotonation of the
carbamate is e}ective\ and this obviously eliminates the requirement for formation of the stannyl
amine "Equation "097## ð82SL396Ł[ Unlike the formamidine protecting group\ the BOC group can
easily be removed[ Dianions derived from ethyl acetoacetate react with N!tosyl aziridines ð82SL653Ł[

O Me But ButLi, CuCN, TMS-Cl Me O


+ N N (106)
N N
Me 98% But

O
O
Me CuCN, –78 °C
+ N SnBu3 (107)
BOC 64% Me
N
BOC
Bearin` a Nitro`en 078

O O
Me Me BusLi, TMEDA, CuCN, –78 °C
+ N Me (108)
BOC 63%
N
BOC

The reductive cleavage of the isoxazole ring was demonstrated many years ago to be a viable
method for the synthesis of b!amino ketones "Scheme 72# ð61JA8017Ł\ the isoxazole being prepared
from oxidation of the corresponding a\b!unsaturated oxime using iodine[ Now such ring systems
can be prepared from the 0\2!dipolar cycloaddition of nitrile oxides to acetylenes[ The regioselectivity
of the cycloaddition and the isolated yields of the adducts are often very high\ making the inter!
mediacy of isoxazoles one possible route to the preparation of b!amino ketones "for reviews on
0\2!dipolar cycloadditions see ðB!78MI 293!92\ 80COS"3#0958\ 80COS"3#0000Ł#[

NOH I2, KI O N Na, NH3, ButOH O NH2

R1 R2 R1 R2 R1 R2

Scheme 83

2[93[6[1 NHX and NX1!functionalized Ketones


In a procedure developed by Oppolzer and co!workers\ nitroso compounds have been used for
the introduction of a hydroxylamine group[ Enantiomerically pure "82# reacts with zinc enolates to
give the nitrone adduct in at least 89) enantiomeric excess and good chemical yield "Scheme 73#[
This nitrone can be hydrolysed to the keto hydroxylamine and the chiral auxiliary recovered and
recycled if required ð81JA4899Ł[ A nitro group can be reduced to the corresponding hydroxylamine
using SmI1[ Under the obviously mild conditions\ cyclic and acyclic acetals remain intact\ thus
allowing this method to be used for the synthesis of protected keto hydroxylamines "e[g[\ "83##
ð80TL0588Ł[ On the basis that the oxidation of amino alcohols is an attractive preparation of amino
ketones "see Section 2[93[6[0#\ a similar transformation of hydroxylamino alcohols "Equation "098##
should give hydroxylamino ketones ð80TL2444Ł[ The reaction between an a!bromo ketone and the
oxime of benzaldehyde gives a keto nitrone arising from nucleophilic displacement of the bromide
by the oxime nitrogen[ Hydrolysis then releases the hydroxylamino ketone\ which is isolated at the
hydrochloride salt ð60ZOR0576Ł[

O
O OZnCl
LiHMDS, THF (93) 1 mol l–1 HCl

ZnCl2 90%, 90% ee + 65%


N
–O
Xc
O

NHOH•HCl

Scheme 84

CHO HO
NHOBn
CH2NOBn, SmI2, ROH, HMPA
(109)
59%
089 Dialkyl Ketones

O O
NHOH
Cl
R2NO2S N
O
(93) (94)

2[93[6[2 NY!functionalized Ketones


a!Nitro ketones are valuable intermediates in a number of synthetic transformations\ despite the
fact that the direct nitration of ketones is not a facile or high!yielding process ð68LA501\ 79S150Ł[
Prior conversion of the ketone into a more reactive enol derivative results in increased yields[ Of
the enolate anions\ the potassium enolates appear most useful\ and they undergo nitration with
alkyl nitrates ð70JOC4040\ 71S286Ł\ although with poor regioselectivity for dialkyl ketones ð55JOC2041Ł[
Enol acetates\ both regioisomers of which can be prepared from unsymmetrical\ 1!substituted
ketones\ generally give much higher yields of the desired nitro ketone using a variety of nitrating
agents\ the nitration being regiospeci_c in each case[ The more substituted enol acetate may undergo
a competing carbonÐcarbon bond cleavage reaction\ although the use of a mixture of tri~uoroacetic
anhydride and ammonium nitrate as the nitrating agent may minimize this ð71JOC0065\ 72S434\
80TL4242Ł[ Potentially the most useful procedure would involve nitration of silyl enol ethers and this
has been achieved under particularly mild conditions using tetranitromethane as the nitrating agent[
Unfortunately\ dialkyl ketones give the lowest yields and the reaction is not regiospeci_c "Equation
"009## indicating that the mechanism probably involves charge transfer activation rather than
straightforward electrophilic addition ð82TL0748Ł[ Most simple a!nitro ketones can be prepared
using one of these approaches\ and additional substituents can then be introduced at the a or a?
positions by alkylation[ Thus\ allyl carbonates and vinyl epoxides react at the a position of a!nitro
ketones using palladium"9# "Scheme 74# ð75HCA0503\ 75JOC1721Ł\ and 1!nitro cyclohexanone gives
1!methyl!1!nitro cyclohexanone under basic conditions ð71JOC0065Ł[ In the presence of excess base\
1!nitro ketones give the a\a? dianions\ which undergo alkylation at the less stablized a? position
ð71JOC0065\ 81SL53Ł[ The alkylation of the a\a?!dianions derived from a!nitro hydrazones has also
been shown to occur at the a? position ð77JOC0140Ł[
TMS-O TMS-O O
C(NO2)4
or (110)
NO2

O
OCO2Et
O O O
Pd(PPh3)4 Pd(PPh3)4
R2 R2 R1 R2 OH
70–80% 73–94%
O2N R1 NO2 O2N R1

Scheme 85

The conjugate addition of ButO1Li to b!nitro styrenes results in one of two products\ depending
on the substituents on the aromatic ring[ In the presence of electron!withdrawing groups the nitro
ketone is formed in good yield^ on the other hand\ for adjacent electron!donating groups the reaction
gives the nitro epoxide "Scheme 75#[ The latter pathway can be avoided by the addition of excess
base to accelerate deprotonation at the benzylic position ð77S118Ł[
The very strong anion!stabilizing properties of an NO1 group have a signi_cant impact on the
acidity of the adjacent protons "pKa ½09# and\ as a result\ there is an enormous body of literature
on the synthesis and reactions of anions adjacent to a nitro group[ Although alkylation of such
systems is di.cult\ they react with a\b!unsaturated ketones "0\3 addition#\ acid derivatives and
aldehydes[ C!Acylation adjacent to the nitro group is complicated by competing O!acylation\ but a
few acid derivatives have been used successfully\ including phenyl esters ð68S184Ł or\ more
commonly\ acyl imidazoles[ The latter can be used either with isolated lithium nitronate salts
ð71JOC3939Ł or with potassium or sodium salts generated in situ ð67S367\ 76S421Ł[ In a series of papers
Bearin` a Nitro`en 080
O
NO2
Ar
ButO 2 R
R BuLi, ButO2H NO2
Ar Ar 30–80%
NO2
R O
Ar
NO2
R

Scheme 86

Seebach and co!workers have demonstrated that the a\a!dianions of primary nitro compounds
demonstrate enhanced nucleophilic character with respect to the monoanions to the extent that
even simple esters act as e}ective C!acylating agents "Scheme 76# ð68HCA1147Ł[ The e.ciency of the
nitro group in charge delocalization is demonstrated by the fact that b!alkoxy groups\ as in "84#\ do
not undergo elimination during the deprotonation or subsequent acylation ð74JA2590Ł[
NO2
NO2 BuLi (2 equiv.)
NO2Li Me2CHCH2CO2Me

Li 70%
O
Scheme 87

O
O
NO2
O-THP
(95)

The coupling of nitronate anions to aldehydes to give 0\1!nitro alcohols\ the Henry nitroaldol
reaction\ is a facile process for which many experimental variations are known[ The products can
be oxidized to a!nitro ketones\ although elimination and retro aldol reactions may act as competing
pathways[ The optimum conditions appear to involve the use of chromium!based oxidants\ either
in the presence of a phase transfer catalyst ð73S596Ł or adsorbed onto a solid support ð75TL382Ł[
The synthesis and reactions of a!nitro ketones has been part of a recent review ð89OPP696Ł[
The formation of dianions from primary nitro compounds is complicated by the possibility of
generating two structural isomers[ Under Seebach|s conditions "Scheme 76# the a\a!dianion is
favoured and reacts with carbonyl!containing electrophiles to give 0\1!nitro alcohols[ However\ by
changing the concentration of HMPA and reversing the order of addition of the nitro alkane to the
base\ the a\b!dianion is preferred\ giving rise to 0\2!nitro alcohols "Equation "000## ð78CC009Ł[ Such
compounds could represent useful intermediates to b!nitro ketones\ but these can be prepared
directly from the addition of nitrite anions to a\b!unsaturated ketones or b!halo ketones ð70CL0566\
71CL72Ł[

OH
i, BunLi, THF, HMPA
OH
NO2 NO2 + (111)
Ph
ii, PhCHO Ph NO2

Addition of BunLi to EtNO2 85 : 15


Addition of EtNO2 to BunLi 5 : 95

The other class of electrophile most frequently employed with nitronate anions are a\b!unsaturated
carbonyl compounds to give g!nitro ketones[ A wide variety of bases\ organic\ inorganic\ homo!
geneous and heterogeneous ð77S722Ł\ has been demonstrated to promote the addition\ although
competing side reactions\ such as polymerization of the intermediate enolate and the addition of
two molecules of enone to one of nitro alkane\ can reduce the yield in some cases[ One experimentally
simple procedure has been developed which requires no solvent and gives good yields of 0 ] 0 adducts
081 Dialkyl Ketones
"Equation "001##\ although it is susceptible to steric hindrance at the b position of the enone ð75S126Ł[
In a related reaction\ simple mixing of methyl vinyl ketone with nitromethane\ in water\ without
additional catalyst gives\ in quantitative yield\ a 3 ] 0 mixture of the adducts "85# and "86#[ There is
a strong rate enhancement of this reaction in the presence of sugars which has been attributed to
the hydrophobic e}ect ð81TL7962Ł[ The allylic anion derived from nitro alkenes adds from the
a!carbon to the b position of enones to give adducts like "87# ð76S147Ł[

O
NO2 O Al2O3, 5–8 h
O O + (112)
88% O O
NO2

O O O
O
O2N
NO2 NO2
(96) (97) (98)

g!Nitro ketones can also be obtained from the addition of enolate equivalents to nitro alkenes
ð75CRV640\ 76T702\ 81TL4530Ł[ The products are frequently required only as intermediates to
0\3!dicarbonyl compounds ð78CC730Ł\ obtained following a Nef reaction\ but can be isolated in
good yield[ For the reaction between substituted enolates and substituted nitro alkenes\ the diastereo!
selectivity of the addition has been extensively investigated ð74HCA051\ 89JOC0238Ł[ Variants of this
Michael addition which retain a nitro alkene in the product have been reported[ One proceeds via
exclusive SN1? addition to an allylic ester "Equation "002## ð74T3750Ł and the other via an additionÐ
elimination to a b!nitro enamine "Equation "003## ð76S618Ł[ This retention of the double bond allows
greater ~exibility in synthetic planning\ and in these two examples the position of the alkene is
complementary[ Chemoselective reduction of the nitro alkene in the presence of the ketone is
possible "Equation "004## ð77BCJ3918Ł[

OLi NO2 O Bun


–78 °C
+ ButCO 2 (113)
75%
Bun NO2

OLi O
NO2 –78 °C to 0 °C
N NO2
+ (114)
O 55%

O O
NO2 Hantzsch ester NO2
(115)
90%

The preparation of a!keto oximes "a!hydroxyimino ketones# from ketones or from 0\1!diketones
is limited by the paucity of good electrophilic oxaminating agents or by regiochemical problems\
respectively[ Twenty years ago\ Hassner and co!workers demonstrated that silyl enol ethers react
with NOCl to give a!hydroxyimino ketones or a!nitroso ketones\ depending on the substitution
pattern at the a position "Scheme 77# ð63JOC1447Ł[ That a!nitroso ketones could not be isolated but
rapidly dimerized at room temperature was con_rmed later following the reaction between an enol
ether and methyl nitrite[ The dimers\ however\ are stable and could be isolated\ in some cases in
crystalline form[ Isomerization of the nitroso ketone dimers to the a!oximino ketones can be
achieved using acid\ base or heat ð68JOC164Ł[ Regiochemical control of the oxamination can also
be achieved using an in situ 0\3!reduction and enolate trapping procedure "Scheme 78# ð80BCJ1837Ł[
The reaction between a diazoalkane and an acid chloride to produce an a!diazo ketone is\ perhaps\
the best method for the preparation of such systems and one which has been widely used for many
Bearin` a Nitro`en 082
O O-TMS O
NOCl NOCl
R2 R2 R2
R1 R1 R1
R3 R2, R3 = alkyl, aryl R3 =H
NO R3 NOH

Scheme 88

NOH
O CoII, PhSiH3, BunONO OCoL2
O
67%

Scheme 89

years[ The reaction is most useful when using diazomethane to give terminal diazo ketones although
higher diazoalkanes have been used in some circumstances[ The diazotization of amino ketones is
rarely useful for the synthesis of a!diazo ketones\ except for a few speci_c examples\ but a more
general approach employs the Forster reaction "Equation "005##[ Some of the diazo ketones prepared
using these approaches can be found in the reviews ðB!75MI 293!94\ B!76MI 293!98\ 80COS"2#776Ł[ See
Chapter 2[01 for further discussion of diazo ketones[
O O
R1 chloramine R1 (116)
R2 R2
NOH N2

The diazotization of 0\2!dicarbonyl compounds with azides is a reaction which has been known
for many years and for which there are many experimental variations incorporating changes in the
azide used\ the solvent and the presence or absence of catalysts[ The relative safety of some of the
more common organic azides has been evaluated ð70SC836Ł\ but it is important to recognize that
any use of these reagents is potentially hazardous[ More recently\ 1!diazo!0\2!dicarbonyl compounds
have been prepared in the absence of solvent ð80SC080Ł\ using KF or K1CO2 as the base ð78SC1456\
89CC541\ 80S084Ł or with p!acetamidobenzenesulphonyl azide as the diazo source ð76SC0698Ł[ Two
diazotizing reagents which may be useful in speci_c cases are the phosphonium azide "88# ð89TL3876Ł\
which requires only a catalytic amount of base\ and the pyridinium salt "099#\ which works under
neutral conditions ð76SC872Ł[
N2+
N
+
P N N3
Et2N NEt2
NEt2 Et BF4–
(99) (100)

The diazotization of simple ketones is a less facile process owing to the reduced acidity of the
substrates\ but it can be achieved using mesyl azide ð75JOC3966Ł or arylsulphonyl azides in the
presence of phase transfer catalysts ð79S257Ł[ The former is attractive because of the lower cost\
although regioisomeric mixtures may result[ A more indirect route to the same products requires
temporary activation of the ketone with an electron!withdrawing group to direct diazotization
"Scheme 89# followed by in situ removal of the activating group ð57JOC2509\ 80SC080Ł[ A recently
reported version of this reaction involves regiospeci_c ketone tri~uoromethyl acylation prior to
diazo transfer "Scheme 80# ð89JOC0848Ł[ Possibly\ one of the many methods for regiospeci_c ketone
enolisation could be used to introduce the diazo group at either of the a!positions[

O O O
O
R1 R1 N2
R1 R2 R3
R2 R2

R3 = H, Ph

Scheme 90
083 Dialkyl Ketones
O i, LiTMP, –78 °C O O MeSO2N3
C5H11 C5H11
ii, CF3CO2Et CF3
O
O
C5H11
C5H11 N2 +
N2
9:1
LiTMP = lithium tetramethylpiperidide

Scheme 91

In the presence of an oxidizing agent\ azides react with dicarbonyl compounds to give di}erent
products[ For example\ using iodosobenzene\ 0\2!diketones undergo incorporation of azide at the
central position ð77T0592Ł[ In a more recent procedure\ Magnus and co!workers have disclosed a
useful a!azidonation of triisopropyl silyl enol ethers using NaN2 and cerium ammonium nitrate[
The isolated yields are good\ the reaction is regiospeci_c\ even for the thermodynamic enol silane
derived from 1!methylcyclohexanone\ and acetals and ethers survive the reaction conditions
ð81TL1666Ł[ In a highly unusual reaction from the same group\ triisopropyl silyl enol ethers react
with TMS azide and iodosobenzene to introduce azide regiospeci_cally at the b!position in high
yield "Equation "006##[ In this case\ the silyl group is retained during the oxidation ð81JA656Ł[
a!Azido ketones can be prepared from a!diazo ketones via the intermediate bromo ketones "Equation
"007## ð82CC83Ł\ and halo ketones in general react with NaN2 to give products arising from halide
displacement ð79TL820\ 75JOC2263\ B!77MI 293!94Ł[
O-tips O-tips

TMS-N3, PhIO
(117)
76% N3
O O O O

O i, HBr (1 equiv.) O
N2 ii, NaN3
N3
(118)
70%
NHZ NHZ

2[93[6[3 NZ!functionalized Ketones


The synthesis of 1!keto isocyanates and isothiocyanates is complicated by their spontaneous
cyclization to oxazolidines "Scheme 81#[ Compounds without hydrogens at the a position can be
isolated easily using the method shown "Scheme 81# ð65CB043Ł but for enolizable ketones\ an
alternative method involving condensation of amino ketones with thiophosgene may be more useful
ð72CCC2310Ł[ The treatment of a!halo ketones with cyanate or thiocyanate salts gives identical
products[ The anion derived from methyl isocyanide has been shown to react with electrophiles
ð60AG"E#380Ł and b!keto isocyanides are isolable intermediates during the reaction of acid chlorides
with tosylmethyl isocyanide ð66TL3122Ł[
The decomposition of a!azido ketones using triphenylphosphine has been used in a number of
important synthetic transformations and the intermediate imino phosphoranes "090# react with aryl
isocyanates or isothiocyanates to give the corresponding b!keto carbodiimides "091# ð80PS"59#70Ł[
The ability of a nitrosamine to stabilize an adjacent anion has been demonstrated in the synthesis
of b!keto nitrosamines "Equation "008## ð67CB1529Ł[

HO R2 S
R1 R3 O O
H
N SH carbodiimide NCS R2 = H
O NH
S NH R1 R1
R2 R3 R3
S R2
S R1 R3
Scheme 92
Bearin` a P\ As\ Sb or Bi 084
O O
N ArNCN
Ph3P R R
(101) (102)

NO i, BuLi, KOBut NO O
N N (119)
R1 Me ii, R2COCN R1 R2

2[93[7 KETONES BEARING A P\ As\ Sb OR Bi FUNCTION


Much of the interest in the synthesis of ketones substituted by a phosphorus atom in one of its
oxidation states stems from the use of such species in the Wittig\ Horner and WadsworthÐEmmons
reactions to construct alkenes "for reviews see ð66OR"14#62\ 77CSR0\ 78CRV752Ł#[ More recently\ the
ylides derived from organoarsenic\ antimony and bismuth compounds have also attracted increased
attention[

2[93[7[0 XR1 and X¦R2!functionalized Ketones


The reaction of ketone enolates with phosphorus"III# halides usually results in O!phosphinylation
to give a compound which can be readily isomerized "Scheme 82#\ ð72JGU545Ł and the phos!
phoramide "092# can be made via phosphinylation of the corresponding ketone with "Et1N#1PCl
ð67MI 293!90Ł[ An identical transformation involves the reaction between the same halides and a
b!keto stannane to give "093# "Equation "019## ð61CA"67#025269Ł or the coupling of a dialkylphosphine
to an a!bromo ketone ð79JCS"D#188Ł[ These keto phosphines can be converted into the corresponding
phosphonium salts "094# by treatment with the appropriate alkyl halide ð72JGU509Ł[

Na+ –O Et2PCl Et2PO


heat
O
PEt2
Ph Ph Ph

Scheme 93

O
O
+
PMePri2
Ph
P(NEt2)2
(103) (105)

O R2PCl O
Bu3Sn R2P (120)

(104)

The use of phosphonium salts for the Wittig reaction explains the vast amount of literature
dealing with the synthesis of these species and their derived ylides[ Such a body of literature cannot
be covered comprehensively here\ but other recent reviews are available ð80COS"5#060\ B!83MI 293!90Ł[
The usual method for the preparation of b!keto phosphonium salts involves treatment of an a!halo
ketone with a phosphine "see the above reviews and ð76S0944\ 80T2236Ł#\ although the acylation of
ylides has also been reported ð77JOC4447Ł[ More remote keto phosphonium salts "e[g[\ "095# and
"096## can be prepared by the 0\3!addition of phosphines to enones ð80COS"5#060Ł or the addition of
085 Dialkyl Ketones
phosphines to cyclopropyl ketones ð76S537Ł[ Phosphonium salts "097# can be prepared from the
electrochemical oxidation of 0\2!diketones with PPh2 ð77CPB502Ł[
O O
O O
+
+ Ph3P R1 R2
Ph3P Ph +
PPh3
(106) (107) (108)

The chemistry of arsonium ylides has attracted recent attention owing to their ease of preparation
and the fact that their reaction with aldehydes or ketones can give alkenes with stabilized ylides or
epoxides with nonstabilized ylides[ For semistabilized ylides the outcome of the reaction depends
on other factors such as solvent\ base and the substituents on the arsine "for recent reviews see
ð76CSR34\ B!89MI 293!91Ł#[ Normally\ arsonium ylides are prepared by treatment of an alkyl halide
with an arsine ð69JOC1567\ 76TL1044\ 77S864Ł\ although for less reactive substrates a combination of
an alkyl tri~ate and a lithio diarylarsine may be more useful ð70JA0172Ł[ The arsonium salts and
their ylides are relatively easy to handle but the more volatile arsines should be treated with extreme
caution[ Arsenium ylides stabilized by two electron!withdrawing groups can be prepared from
1!diazo!0\2!dicarbonyl compounds and arsines ð71T2244Ł or 0\2!dicarbonyl compounds and arsine
oxides ð62T0586Ł\ and similar routes can be used for the preparation of stibonium ylides ð75T2776\
89TL4786Ł[
Ylides derived from bismuth and antimony are less well known than those derived from phos!
phorus and arsenic and are largely restricted to those derived from 0\2!dicarbonyl compounds[ The
_rst examples of bismuth and stibonium ylides were reported by Lloyd et al[ in the 0869|s and were
made by a thermal decomposition of a 0\2!diazo carbonyl compound in the presence of triaryl
bismuth or triaryl antimony species[ These two\ and arsenium ylides\ can be made using the same
procedure\ but at lower temperature\ by employing a copper catalyst ð77S208Ł[ An alternative
procedure for bismuth ylides has been developed using a b!diketone and a bismuth dichloride or a
bismuth oxide ð89BCJ849Ł[ This procedure has since been used to prepare one of the _rst examples
of a monocarbonylbismuth salt in very high yield "Equation "010## ð82TL7346Ł[ The chemistry of
arsenic\ antimony and bismuth compounds has been reviewed ðB!83MI 293!91Ł

TMS-O O
Ar3BiF2, BF3•Et2O
+
BiAr3 BF4– (121)
R 87–100% R

2[93[7[1 Higher!coordinated P\ As\ Sb or Bi!functionalized Ketones

2[93[7[1[0 a!Higher!coordinated P\ As\ Sb or Bi!functionalized ketones


Perhaps the two best!known methods for the synthesis of b!keto phosphonates are the reaction
of phosphonate!stabilized carbanions with acid derivatives and the Arbuzov reaction of a!halo
ketones with trialkyl or triaryl phosphites[ The latter\ discovered in the late 0799|s\ has been widely
used for the synthesis of b!keto phosphonates\ although there is a competing rearrangement "Perkow
rearrangement# which may predominate for a!chloro or a!bromo ketones[ a!Iodo ketones do appear
to give useful yields of the desired Arbuzov products "Scheme 83#[ Under appropriate conditions\
that is with a readily available\ nucleophilic phosphorus"III# ester and a primary halo ketone\ the
Arbuzov method can be useful for the synthesis of simple b!keto phosphonates or more complex
derivatives "Equation "011## ð81CC174Ł^ for a review see ð70CRV304Ł[
O Arbuzov O Perkow OPO(OEt)2
PO(OEt)2 X
R X=I R X = Cl, Br R

Scheme 94

O O O
(EtO)2PN(Bn)Pri
Br P (122)
Ph 50% Ph N(Bn)Pri
OEt
Bearin` a P\ As\ Sb or Bi 086
A number of methods which rely on a nucleophilic phosphorus species have been developed other
than the Arbuzov reaction[ Sodium diethyl phosphite reacts with a!halo ketones or 3!halo 0\2!
dicarbonyl compounds ð79TL1176\ 76TL234Ł to introduce a phosphonate group\ as in "098#\ and
trialkyl phosphite esters or dialkyl phosphite anions react with chloro or sulfonyl epoxides "Equation
"012## ð71CB590\ 82TL1036Ł[

O O
O SO2Ar NaPO(OEt)2
P (123)
82% EtO
EtO

O O O
P
EtO OEt
EtO
(109)

Many applications of organophosphorus chemistry are dependent on the ability of phosphorus


to stabilize an adjacent carbanion[ Anions derived from phosphine oxides react with esters\ lactones
or acid chlorides to give b!keto phosphine oxides ð76JCS"P0#1458\ 77JCS"P0#0688Ł[ In the acylation of
phosphonate!stabilized carbanions\ many acid derivatives have been used\ including acid chlorides
ð67S25\ 75SC0634Ł\ esters ð72JOC4990\ 73S580\ 76TL500Ł\ nitriles ð80SC168Ł and lactones ð89TL1480Ł[ The
presence of halogens adjacent to the phosphonate group is well tolerated "Equation "013## ð77JOC0412\
81JOC1652Ł[ The doubly activated methylene group in b!keto phosphonates means that introduction
of additional alkyl groups at the central position is a facile process "Scheme 84# ð81CC089Ł[ A
heteroatom substituent can be introduced at the a position using enamine anions\ which undergo
exclusive C!functionalization "Scheme 85# ð80SC168Ł or via direct dichlorination of b!keto phos!
phonates to give "009# ð76JGU194Ł[

O i, Zn, CuBr O O
ii, RCOCl
P Br P (124)
EtO EtO R
EtO F 40–60% EtO F
F F

O O O O O O
P Bun4NBr, NaOH P piperidine, (CH2O)n P
OEt OEt OEt
OEt MeI OEt OEt

Scheme 95

O i, BunLi, RCN O NH2 O O


ii, EX H 3O +
P P P
EtO Me EtO R EtO R
66–90% EtO 50–83% EtO
EtO E E
E = PhS, PhSe, Cl

Scheme 96

O O
P
EtO
EtO Cl
Cl
(110)

An alternative procedure has been developed by Oh and co!workers for the synthesis of b!keto
phosphonates having substitution at the a position[ Conjugate addition of organolithium reagents
to the silyl!substituted vinyl phosphonate "000# generates an intermediate anion which can be
acylated and desilylated in a one!pot procedure "Scheme 86# ð78TL2296Ł[ Another procedure starts
087 Dialkyl Ketones
with formyl phosphonates\ which can be converted into the corresponding enamines "Scheme 87#[
These enamines undergo kinetic deprotonation adjacent to the heterocycle to give an anion which
reacts with a range of electrophiles including alkyl\ allyl and benzyl halides and chloroformates
ð78TL3676Ł[ More conventionally\ perhaps\ the acid chlorides "001# react with a range of organo!
metallics to give the corresponding ketones ð75S550Ł[ Hydrolysis of b!keto phosphonates to b!keto
phosphonic acids can be done with TMS!Br ð78JMC0775Ł[

O
PO(OEt)2 i, PhCOCl
PO(OEt)2 ButLi, –78 °C ii, H3O+ (EtO)2OP
But Ph
TMS TMS 73%
Li
(111) But

Scheme 97

O i, BunLi, –78 °C, THF then DMF O i, BunLi, –78 °C, THF then MeI
ii, pyrrolidine, C6H6, reflux ii, H3O+
P R P
EtO EtO N
EtO
60–70% EtO 70–80%
R

O O
P
EtO
EtO
R

Scheme 98

O O
P
EtO Cl
EtO
R
(112)

Wiemer and co!workers have developed several procedures for the synthesis of b!keto phos!
phonates using electrophilic phosphorus species[ In one of their early publications\ a!bromo ketones
were converted into dilithium reagents which react with chloro phosphates as shown in Scheme 88[
The phosphonates "002# and "003#\ which cannot be made by conventional Arbuzov chemistry
owing to competing elimination in the bromo ketone or the low nucleophilicity of an electron!
de_cient ~uorinated phosphine\ respectively\ can be made in 51) and 39) yields using this
approach ð75JOC3231Ł[ A modi_cation of this procedure was reported subsequently in which
O!phosphorylation of anenolate anion was followed by a base!promoted 0\2!shift of the phosphonate
group[ This migration occurs without the need for potentially hazardous ButLi and in higher yield
"Scheme 099^ cf[ Scheme 88#[ Unfortunately\ this procedure does not work for acyclic ketones or
for cyclic ones larger than cyclohexanone[ For ketones with more than one set of a protons\ a
mixture of products may be obtained "Equation "014##\ suggesting\ in these cases\ the intermediacy
of an allylic anion[ However\ in cases where the steric environment at the two a positions is
signi_cantly di}erent\ the reaction may still be synthetically useful "Equation "015## ð75TL3154\
76JOC3074Ł[ Cyclohexadienyl phosphates\ prepared as shown in Scheme 090\ also undergo a regio!
speci_c migration arising from removal of the proton at the terminal position of the diene ð89JOC1731\
81JOC206Ł[ Tertiary b!keto phosphonates\ which may not be generally available using the methods
outlined above\ can be prepared from a!hydroxy ketones and diethyl chlorophosphite "Equation
"016##[ The reaction may proceed via the intermediate mixed phosphite ester ð78JOC516Ł[ Perhaps
the most intriguing method developed by this group involves the C!phosphitidation of ketone
enolates followed by air oxidation to the phosphonate "Scheme 091#[ Unlike some of the methods
described earlier\ this route is applicable to the synthesis of medium! and large!ring keto
phosphonates and acyclic ones\ and it has been used on a scale up to 9[0 mol ð80JOC4445Ł[ This
method was independently investigated by another group who used H1O1 as the oxidant
ð80TL1470Ł[
Bearin` a P\ As\ Sb or Bi 088

i, LiHMDS, –78 °C ClPO(OEt)2


Br Li PO(OEt)2
ii, ButLi, –100 °C 20%
O OLi O

Scheme 99

LDA, ClPO(OEt)2 LDA


PO(OEt)2
70%
O OPO(OEt)2 O

Scheme 100

OPO(OEt)2 O O
LDA (EtO)2OP PO(OEt)2
+ (125)

D D D
1:1

OPO(OEt)2 O
LDA (EtO)2OP
(126)
80%

O OPO(OEt)2 O
i, LDA LDA (EtO)2OP
ii, ClPO(OEt)2 58%

Scheme 101

O O
(EtO)2PCl, FeCl3
(127)

OR PO(OEt)2
R = H, 96%
R = Et3Si, 67%

O OLi i, ClP(OEt)2 O
LDA, Et2O, HMPA ii, air or O2
R1 R1 R1 PO(OEt)2
44–80%
R2 R2 R2

Scheme 102

O O O O
P P
Ph OEt Ph OCH2CF3
OEt OCH2CF3

(113) (114)
199 Dialkyl Ketones
Two complementary procedures have been developed for the synthesis of b!keto phosphonates
or phosphine oxides using diazo compounds[ In the _rst\ 1!diazo ketones or 1!diazo 0\2!diketones
react directly with dialkyl hydrogenphosphite in the presence of a copper catalyst ð89S404Ł^ in the
second\ aldehydes insert into diazo phosphonates or phosphine oxides to give identical products
using SnCl1 as the catalyst "Equation "017## ð81TL0020Ł[ Nucleophilic addition of ethoxide to the
allenic phosphonate "004# occurs at the central carbon atom of the allene to give an enol ether which
can be hydrolysed to a b!keto phosphonate ð71AG"E#260Ł[ Allene oxides "005#\ which can be prepared
in enantiomerically pure form\ react with water as shown in Equation "018# ð82TL7432Ł\ and
hydroxy!substituted keto phosphonates can also be prepared using a 0\2!dipolar cycloaddition
"Equation "029## ð76BCJ1352Ł[ The hydration of alkynes is a well!known method for the synthesis
of ketones\ and the presence of a phosphonate group on the alkyne does not appear to prevent the
reaction from occurring as expected "Equation "020## ð76JOC3709Ł[

O O
SnCl2
P N2 + Ph (128)
Ph CHO POPh2
53% Ph
Ph

O PO(OEt)2
O •
C5H11
(115)

O O
H2O
Bun PO(OR)2 (129)
Bun
74%
PO(OR)2 OH
(116)

i, CO2Me
ii, Raney Ni O OH
(EtO)2OP
+
(EtO)2OP (130)
N O– 52% CO2Me

O O
HgSO4, H2SO4
PO(OEt)2 (131)
98%
PO(OEt)2 O

2[93[7[1[1 g!Coordinated and more remotely higher coordinated P\ As\ Sb or Bi!functionalized


ketones
A number of procedures have been developed to promote the conjugate addition of phosphorus
nucleophiles to enones[ Simple mixing of diethyl methyl phosphonite with a\b!unsaturated ketones\
even methyl vinyl ketone "MVK#\ in EtOH gives the corresponding acetals\ from which the ketones
can be regenerated by hydrolysis "Scheme 092# ð77JOC3958Ł[ In the presence of a silylating agent\ the
phosphinate "006# and ammonium phosphinate are converted into the nucleophilic phosphorus"III#
species "007# and bis"trimethylsilyl#phosphonite "BTSP#\ respectively[ Both of these will add to the
b!position of enones to give the expected adducts "i[e[\ "008# and "019## ð73TL3630\ 81TL702Ł[ The use
of BTSP "010# may be particularly attractive in some applications because it can participate in
successive Michael addition reactions "Scheme 093# ð81TL702Ł[ One procedure which involves mild
conditions uses Me2Al as the catalyst and appears relatively resistant to steric hindrance\ as evidenced
by the formation of "011# in 73) yield ð78TL3796Ł[ Treatment of MVK with triethyl phosphite has
been demonstrated to give the heterocycle "012#[ This undergoes a synthetically useful reaction with
Bearin` a P\ As\ Sb or Bi 190
bromine\ nitrogen and oxygen electrophiles to introduce a heteroatom adjacent to the ketone "e[g[\
"013## ð80TL4202Ł[

O MeP(OEt)2, EtOH EtO OEt O


HCl
PO(Me)OEt PO(Me)OEt
Scheme 103

O
Ph O-TMS O
Ph P O
PO(OEt)H Ph
OEt P H(HO)OP
OEt
(117) (118) (119) (120)

O i, 2-hexen-4-one
O-TMS i, 1-hexen-3-one ii, H3O+
O-TMS
P Prn P
H O-TMS ii, HMDS 83%
O-TMS
(121)
O O
O
Prn P Et
OH
HMDS = hexamethyldisilazide

Scheme 104

O
O
O OEt
P OEt PO(OEt)2
PO(OMe)2 OEt
OH

(122) (123) (124)

Although the preparation of a!phosphonate carbanions can be accomplished by simple depro!


tonation\ the b anions are not so accessible[ Knochel and co!workers have demonstrated that the
zinc and copper salts "014# can be made by metalÐhalogen exchange\ and that they will add to
enones and nitro alkenes to give 0\3! or 0\4!keto phosphonates "Scheme 094# ð89TL0722Ł[

R
PhCHCHCOMe
(EtO)2OP
R = H, 88%
Ph O
M
(EtO)2OP
R
(125) i, PrnCHC(Et)NO2 R O
ii, O3 (EtO)2OP
R = H, 70%
Prn

Scheme 105
191 Dialkyl Ketones
2[93[8 KETONES BEARING A METALLOID FUNCTION

2[93[8[0 Silicon!functionalized Ketones

2[93[8[0[0 a!Silyl ketones

"i# From alcohols


b!Hydroxy silanes have been oxidized to a!silyl ketones with chromium trioxide in pyridine
ð80JCS"P0#0782Ł\ and with tetrakis"triphenylphosphine#rhodium hydride in the presence of an enone
as hydrogen acceptor ð74TL3118Ł[ The rhodium catalyst can also be used to prepare a!silyl ketones
by the double!bond migration of a b!silyl alcohol "Equation "021## ð77JOM"233#60Ł[ The TFA!
mediated silapinacol rearrangement of a\b!dihydroxy silanes has been found to provide a general
route to a!t!butyldimethylsilyl ketones which\ because of the stabilization of cations b to silicon and
the good migrating propensity of silyl groups\ is both regiospeci_c and high yielding "Equation
"022## ð75TL3158Ł[

TMS TMS
RhH(PPh3)4
(132)
Ph 56% Ph
HO O

HO OH TFA
O TBDMS
TBDMS (133)
Prn Prn 90% Prn Prn

"ii# From aldehydes or ketones


Reaction of a ketone enolate with a silyl electrophile occurs speci_cally on oxygen to give enol
silane products[ a!Silylation can\ however\ be achieved via ketone dianions which are prepared by
metalÐhalogen exchange of lithium enolates of a!bromo ketones with t!butyllithium "Scheme 095#
ð79JA4300Ł[ Homochiral trialkylsilyl ketones can be prepared by the reaction of metallated SAMP
or RAMP derived ketone hydrazones with t!butyldimethylsilyl tri~ate\ followed by hydrolysis[
Although the overall yields of the sequence are quite modest\ the enantiomeric excesses of the
products are excellent ð76AG"E#240Ł[ In the presence of magnesium bromide\ trimethyl!
silyldiazomethane reacts with aldehydes to give reasonable yields of trimethylsilylmethyl ketones
"Equation "023## ð77S117Ł[

i, TMS-Cl
i, MeLi ii, TFA
OAc OLi O
ii, ButLi 64%
Br Li TMS

Scheme 106

MgBr2 O
n-C9H19CHO + TMS-CHN2 TMS (134)
57% n-C9H19

"iii# From acids and their derivatives


The reaction of a!silyl esters with Grignard reagents\ which has been developed for the synthesis
of unsubstituted ketones\ may also be used with a modi_ed workup that avoids protodesilylation
to prepare a!silyl ketones "Equation "024## ð74JOC4159Ł[ An alternative approach to a!dimethyl!
phenylsilyl ketones from acid chlorides introduces the silyl group in the form of an
Bearin` A Metalloid 192
a!silylalkylmagnesium halide "Equation "025## ð81JOC275Ł[ In both methods the bulky a!silyl substi!
tuent is responsible for preventing over!reaction to form a tertiary carbinol[
O i, PrnMgBr O
n-C8H17 ii, H3O+ n-C8H17
OEt Prn (135)
78%
SiPh2Me SiPh2Me

i, activated Mg O
n-C5H11 SiMe2Ph ii, CuBr•Me2S
n-C5H11 (136)
n-C7H15
Cl iii, n-C7H15COCl
SiMe2Ph

"iv# Miscellaneous preparations


The hydroboration of silylacetylenes with 8!borabicycloð2[2[0Łnonane followed by oxidation with
alkaline hydrogen peroxide provides a convenient preparation of a!triisopropylsilylmethyl ketones
ð78JA3762Ł[ Rather more generally\ a!diazoketones\ which are well established as precursors of a
wide variety of a!hetero!substituted ketones\ can also be used to prepare a!triethylsilyl ketones by
a rhodium"II#!catalysed reaction with triethylsilane "Equation "026## ð77JOC5047Ł[
O O
N2 SiEt3
Rh2(OAc)4, Et3SiH
(137)
88%

But But

2[93[8[0[1 b!Silyl ketones


b!Trialkylsilyl ketones are most conveniently prepared by the conjugate addition of tri!
alkylsilylithium ð67TL1548Ł or of trialkylsilylcopper reagents ð73JCS"P0#0794\ 78SC164Ł to enones[
Conjugate additionÐenolate trapping is possible with the silyl cuprate reagents and has been shown
to proceed with high diastereoselectivity "Equation "027## ð73CC17Ł[
i, (PhMe2Si)2CuLi PhMe2Si O PhMe2Si O
O ii, MeI
+ (138)
n-C6H13 78%
n-C6H13 n-C6H13

>95 : <5

2[93[8[1 Germanium!functionalized Ketones


b!Triphenylgermyl ketones can be prepared by the photoinduced radical cyclization of unsat!
urated acyl germanes[ The reaction may be used for the preparation of both cyclopentanone and
cyclohexanone derivatives\ and has the advantage over tin hydride!based radical cyclization chem!
istry of giving a highly functionalized product suitable for further elaboration "Equation "028##
ð89JOC4451Ł[
O
O hν
(139)
GePh3 92% GePh3

2[93[8[2 Boron!functionalized Ketones


Despite their importance as synthetic intermediates\ most compounds containing a boron0
carbon bond are too reactive to be readily isolated[ An important exception to this generalization
193 Dialkyl Ketones
are boronates\ and methods for the preparation of b! and g!boronate ketones are known[ Both
preparations depend on the ready availability of a!halo boronic esters\ which react with enolates to
give the b!boronate derivatives "Equation "039## ð82T066Ł or can be used as precursors of organo!
copper reagents which add 0\3 to enones to give g!boronate compounds ð89JA6320Ł[

O O
O B , LDA
Cl O
B O (140)
83%
O

2[93[09 KETONES BEARING A METAL FUNCTION

2[93[09[0 Tin!functionalized Ketones


b!Trialkylstannyl ketones can be prepared by the addition of a trialkylstannyllithium ð67TL1548Ł
or a trialkylstannyl cuprate ð78TL3506Ł to an enone[ In the former case the addition occurs initially
0\1 but the adduct rapidly isomerises to give the 0\3 system[ Homochiral b!stannyl ketones have
been prepared by the addition of trialkylstannyllithiums to the hydrazone derivatives of enones
with SAMP or RAMP "Scheme 096# ð82AG"E#487Ł[

OMe OMe OMe


O N
i, Me3SnLi N
N
NH2 N ii, MeI N O3

90% 77% 77%

SnMe3
O

SnMe3
de > 98%, ee, > 96%

Scheme 107

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.05
Ketones: a,b-Unsaturated Ketones
WARREN J. EBENEZER and PAUL WIGHT
ZENECA Specialties, Manchester, UK
2[94[0 KETONES BEARING AN a\b!ALKENIC BOND 195
2[94[0[0 a\b!Unsaturated Ketones without Further Unsaturation 195
2[94[0[0[0 From diazo ketones 195
2[94[0[0[1 By elimination reactions 195
2[94[0[0[2 From vinyl compounds and carboxylic acid halides or their equivalents 109
2[94[0[0[3 From a\b!unsaturated acid chlorides or their equivalents and carbon nucleophiles 101
2[94[0[0[4 From alkylations of a!b!unsaturated aldehydes and their equivalents 102
2[94[0[0[5 By oxidation reactions 104
2[94[0[0[6 Rearran`ement reactions 105
2[94[0[0[7 By displacements of a b!leavin` `roup on an a\b!unsaturated ketone 106
2[94[0[0[8 OxyÐCope and Claisen rearran`ements 106
2[94[0[0[09 Carbonylation and related reactions 107
2[94[0[0[00 By isomerisations 107
2[94[0[0[01 By aldol condensation reactions 108
2[94[0[0[02 By Witti` reactions 119
2[94[0[0[03 By DielsÐAlder reactions 110
2[94[0[0[04 By oxidations of furans 110
2[94[0[0[05 From alkynes 111
2[94[0[0[06 From cyclopropanes 113
2[94[0[0[07 By ð2¦1Ł cycloaddition reactions 114
2[94[0[0[08 Miscellaneous reactions 114
2[94[0[1 a\b!Unsaturated Ketones with Further Unsaturation 114
2[94[0[1[0 By elimination reactions 114
2[94[0[1[1 By displacement reactions of a b!leavin` `roup with a vinyl nucleophile 117
2[94[0[1[2 By isomerisations of double and triple bonds 118
2[94[0[1[3 From oxidations of further unsaturated allylic alcohols 118
2[94[0[1[4 From reactions of further unsaturated a\b!unsaturated acids and their equivalents with
carbon nucleophiles 118
2[94[0[1[5 By FriedelÐCrafts acylations of dienes 129
2[94[0[1[6 a!Allenic ketones 129
2[94[0[1[7 By aldol condensation reactions 129
2[94[0[1[8 By Witti` reactions 120
2[94[0[1[09 From pyrilium salts 121
2[94[0[1[00 From cyclopropanes 121
2[94[0[1[01 By Claisen rearran`ements 122
2[94[0[1[02 Carbonylation reactions 122
2[94[0[1[03 Miscellaneous methods 122
2[94[0[2 Halo`enated a\b!Unsaturated Ketones 123
2[94[0[2[0 1!Halo`enated a\b!unsaturated ketones 123
2[94[0[2[1 2!Halo`enated a\b!unsaturated ketones 127
2[94[0[3 Oxy`en!substituted a\b!Unsaturated Ketones 139
2[94[0[3[0 1!Oxy`en!substituted a\b!unsaturated ketones 139
2[94[0[3[1 2!Oxy`en!substituted a\b!unsaturated ketones 132
2[94[0[4 a\b!Alkenic Ketones with Sulfur!based Substituents 136
2[94[0[4[0 1!Thio a\b!unsaturated ketones 136
2[94[0[4[1 2!Thio a\b!unsaturated ketones 140
2[94[0[5 Selenium! and Tellurium!substituted a\b!Unsaturated Ketones 145
2[94[0[6 a\b!Alkenic Ketones with Nitro`en!based Substituents 146
2[94[0[6[0 1!Nitro`en!substituted a\b!unsaturated ketones 146
2[94[0[6[1 2!Nitro`en!substituted a\b!unsaturated ketones 150

194
195 a\b!Unsaturated Ketones
2[94[0[7 Phosphorus! and Arsenic!substituted a\b!Unsaturated Ketones 158
2[94[0[8 a\b!Alkenic Ketones with Silicon!based Substituents 169
2[94[0[8[0 1!Silyl a\b!unsaturated ketones 169
2[94[0[8[1 2!Silyl a\b!unsaturated ketones 160
2[94[0[09 a\b!Alkenic Ketones with Metal Substituents 161

2[94[1 KETONES BEARING AN a\b!TRIPLE BOND 162


2[94[1[0 By Acylations of Alkynes 162
2[94[1[1 Elimination Reactions 163
2[94[1[2 By Oxidation of Alkynic Alcohols and Propar`ylic Methylene Groups 164
2[94[1[3 By Reaction of a Carbon Nucleophile with Alkynic Acid Halides and Derivatives 164
2[94[1[4 Miscellaneous Methods 165

2[94[0 KETONES BEARING AN a\b!ALKENIC BOND

2[94[0[0 a\b!Unsaturated Ketones without Further Unsaturation

2[94[0[0[0 From diazo ketones


Diazo ketones have been reacted intermolecularly leading to a\b!unsaturated ketones on heating
with Cu"acac#1[ The reactions work best for larger rings "×6#\ and produce mainly the "E# isomers
for ×ten!membered rings "Equation "0## ð69CC610\ 67CC0958Ł[ Smith and co!workers have developed
a cycloalkenone synthesis using the diazoalkene cyclisation shown in Equation "1# ð64CC163\ 64TL3114\
70JA0885\ 73S418Ł[ Rhodium acetate ð80JCS"P0#843Ł\ cupric tri~ate ð73JOC0085Ł and HClO3 ð71JOC4242Ł
have also been used to catalyse the latter reaction[

O
O
Cu(acac)2, 60 °C
N2 (1)
N2 O
70%
O

(E):(Z) 10:1

O BF3•OEt2, 0 °C
(2)
65%
O
N2

2[94[0[0[1 By elimination reactions

"i# By oxidative elimination of H1 from a ketone


Oxidative reaction of an enol derivative with a Pd catalyst\ usually Pd"OAc#1\ is a very well!
known method for preparing a\b!unsaturated ketones[ The reaction has been studied extensively by
Tsuji and co!workers ð71JA4733\ 73CL0022\ 75TL1680Ł\ who have used enol acetates ð72TL4528Ł\ enol
carbonates ð72TL0686Ł and silyl enol ethers "Equation "2## ð72JA464\ 72TL4524Ł in conjunction with
diphosphine ligands[ If the enol can be made regiospeci_cally\ then only one regioisomer for the
double bond is seen\ and the reaction generally gives the "E# stereoisomer where possible "Equation
"3## ð67JOC0900Ł[ The thermodynamically favoured silyl enol ether\ as formed in Equation "4#\ gives
a single regioisomer ð70T1974Ł[ p!Quinone has been used as the oxidant\ and PdCl1 can also catalyse
the reaction ð66S662Ł[ The oxidation of silyl enol ethers by hydride abstraction with Ph2C¦BF3−
has been investigated\ and proceeds regioselectively if the enol ether is formed selectively "Equation
"5## ð66JOC2850\ 70JOC4237Ł[ 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq# and CrO2 = pyridine1
have been used to oxidise enol ethers to enones ð76TL20\ 89SC020Ł[
a\b!Alkenic Bond 196
O-TMS O
Pd(OAc)2
(3)
87%

O-TMS O
Pd(OAc)2, 25 °C
(4)
94%

(E)

O H CO2Me O H CO2Me
i, TMS-Cl, Et3N, DMF, 130 °C
ii, Pd(OAc)2, 20 °C
(5)
55%
H H

O-TMS O
Ph3C+ BF4–, 25 °C
(6)
70%

"ii# By elimination of selenoxides


Treatment of enolates or enol ethers with a selenyl halide "typically PhSeCl# gives the cor!
responding a!seleno compound\ which can be oxidised and then undergoes a subsequent thermal
elimination to give the corresponding enone ð64JA4323\ 67T0938Ł\ for example Equation "6# ð62JA4702Ł
and Equation "7# ð79TL2668Ł[ Oxidants commonly used include mcpba ð78JOC3543Ł\ H1O1 ð79JA1986\
70CPB1622\ 70JOC1819Ł and NaIO3 ð62CC584\ 79JA2853Ł[ The elimination of PhSeOH proceeds in a syn
fashion and usually produces "E# stereochemistry where possible[ Boron enolates have also been
used ð79SC556Ł\ and phenylselenyl chloride has been reported to react with ketones directly\ even in
the absence of base "Equation "8## ð62JA5026Ł[ Selenium can be used as the selenating reagent\
followed by an alkylation and oxidative elimination "Equation "09## ð70TL2932\ 71JOC0487Ł[
b!Selenoketones can also be oxidised and eliminated using CrO2 ð67TL076Ł[

O O
i, LDA, PhSeBr
ii, H2O2
(7)
72%

LDA = lithium diisopropylamide

O-TMS O
i, PhSeCl
ii, mcpba
(8)
CO2Me 51% CO2Me

i, PhSeCl, EtOAc
O ii, H2O2 O
(9)
64%
197 a\b!Unsaturated Ketones
O O O O
i–iv
(10)
62%

i, NaH, HMPA, THF; ii, Se; iii, MeI; iv, mcpba

HMPA = hexamethylphosphoramide

"iii# By elimination of HBr or HCl from an a!halo ketone


This method usually starts with monobromination of a ketone\ followed by base!induced elim!
ination to the alkenone "e[g[ Equation "00## ð61JOC157\ 61TL0742Ł[ Bromination is sometimes con!
trolled by _rst forming a ketal\ as in Equation "01#\ ð60JOC3013\ 75S769Ł[ The regiochemistry of the
bromination has been controlled by various means\ for example\ by making one site more enolisable
"Equation "02## ð89TL2746Ł[ Thionyl chloride selectively chlorinates a!alkylated ketones\ which can
then eliminate to give the enones "Equation "03## ð52OSC"3#051\ 70SC6Ł[ However\ it has been reported
that use of NBS:CCl3 in this reaction gives the same product as that produced when using thionyl
chloride\ but the reaction proceeds through the C!4!brominated material via a rearrangement
ð89S566Ł[ Similarly PhNMe2¦Br2− can be used in a regioselective enone formation "Equation "04##
ð51BSF89Ł[ In some cases\ a conjugative dehydrobromination occurs\ via an enol "e[g[ Equation
"05## ð54JOC1831\ 69JOC642Ł[ Phosphorus oxychloride has been used with a!hydroxy enol ethers to
a}ord enones "Equation "06## ð54JCS029\ 68JOC2955Ł^ see also ð50JCS1421\ 71TL0640Ł[

O i, Br2, CH2Cl2
O
ii, MgO, DMF, 140 °C
(11)
96%

O i–iv O
(12)
67%
OH
i, HO , p-TSA; ii, Br2; iii, KOH, DMSO; iv, p-TSA, H2O

i, NaH, THF
ii, Br2
iii, LiCl, DMF
(13)
O 70%
H O
MeO2C

O i, SO2Cl2, CCl4 O
ii, LiBr, Li2CO3, DMF, 153 °C
(14)
76%

O O
i, PhNMe3+ Br3–
ii, pyridine
(15)
77%

Ph O
H Ph O
Br HBr, 118 °C
(16)
55%

H
a\b!Alkenic Bond 198
OMe O
HO i, POCl3, pyridine
ii, H+
(17)
64%

"iv# By elimination of sulfoxides and sulfones


The reaction of an enolate with a sulfur electrophile such as "MeS#1 gives the corresponding
a!thio derivative\ which is easily oxidised and then undergoes elimination to give the enone\ for
example Equation "07# ð62JA5739Ł[ The method has been reviewed ð67CB252Ł[ The sul_de can be
oxidised to the sulfoxide using mcpba ð72JOC2141Ł[ Sulfones have also been used in the elimination\
and can be made from sulfonic acid esters "RSO2Me#\ for example Equation "08# ð71TL1512\ 72JA1929Ł[
Both Taber and Yamakawa have developed the transformation of ketones to homologated enones
using epoxy sulfoxides^ the reaction proceeds as shown in Scheme 0 ð68JOC349\ 75TL1360\ 76BCJ0728Ł[

i, LDA
O O
ii, MeSSMe
iii, NaIO4, 120 °C
(18)
79%

O O
MeO MeO
NaH, PhSO3Me, DME, ∆
(19)

Ph Ph
O O i, LDA S –O S
ii, CaCO3, 150 °C O O
+ Ph S O
+
62%
Cl

Ph
S
O
O

Scheme 1

"v# By elimination of a hydroxy or alkoxy `roup


Enones can be prepared from a!hydroxy ketones by dehydration under acid conditions "Equation
"19## ð68JOC2955Ł[ The a!hydroxy compounds themselves can sometimes be prepared by oxidation
of the ketone with persulfuric acid ð72JOU148Ł[ Silyloxy enol ethers can be dehydrated with phos!
phoric acid "Equation "10## ð79BCJ058Ł^ see also ð71SC684\ 72CB2691\ 77JOC0009Ł[
109 a\b!Unsaturated Ketones
OMe O
HO
p-TsOH
(20)
74%

O-TMS
H3PO4 O
O-TMS (21)
73%

"vi# By elimination of a leavin` `roup b to a ketone


A hydroxy group b to a ketone can be eliminated under mildly acidic conditions\ as in Equation
"11# ð76JOC0592Ł\ which is the synthetic equivalent of an Aldol reaction\ for a sterically hindered
ketone[ The b!hydroxy amide in Equation "12# could be alkylated intramolecularly and then
eliminated ð73TL3030Ł^ see also ð62JOC2526Ł[ b!Hydroxy and b!alkoxy groups have been used as
leaving groups from vinyl thioethers in the preparation of a\b!unsaturated ketones ð71CL704\ 72TL3714\
77T3352Ł[ Oxidative elimination of formic acid from b!keto acids can be achieved either chemically
"with\ e[g[ Pb"OAc#3## "Equation "13## ð44JA0488\ 63JOC1106Ł\ or electrochemically ð70CJC834Ł[ Other
examples of the elimination of b!leaving groups include with CN ð76HCA0282Ł\ PhSO1 ð68JOC2337Ł\
NO1 ð78TL2574Ł\ SO1 extrusion ð74JOC1009Ł[ The elimination of a b!amino group can be performed
by a Ho}mann reaction[ The ammonium compound is made by a Mannich reaction followed by
quaternisation of the nitrogen "Equation "14## ð62TL4926Ł[
i, Grignard reagent
O
ii, O3, Me2S
O iii, (CO2H)2
+ (22)
But But 30%
MgCl
But But

O Me O
O
S N LDA, THF S
Ph Ph Ph (23)
77%
OH O

H H
O O
Pb(OAc)4, Cu(OAc)2, pyridine
(24)
89%
H H
CO2H

i, Me2NH•HCl
O ii, MeI O
iii, DMF, 75 °C
CO2Me + HCHO (25)
n-C6H13 n-C6H13
52%

2[94[0[0[2 From vinyl compounds and carboxylic acid halides or their equivalents

"i# By reaction of a carboxylic acid derivative and a vinyl metallic rea`ent


a\b!Unsaturated ketones have been prepared from vinyllithium species and carboxylic acids in
good yields "Equation "15## ð63TL1766\ 76TL1976Ł[ Allylic lithium compounds have also been used\
and the double bond in the initial product isomerises into conjugation with the carbonyl group on
workup ð72JOC1159Ł[ Esters can also be used as the acylating agent "Equation "16## ð79TL0058\
77S453Ł[ For the more reactive acid chlorides\ various vinyl metallics can be used\ including
a\b!Alkenic Bond 100
palladium!catalysed vinyl Grignard reagents "Equation "17##\ vinylstannanes ð72JOC3523Ł\ vinyl!
manganese compounds ð74S49Ł and vinylmercury compounds ð67JOC609Ł[ The reactions occur with
retention of con_guration of the metalloalkene\ but isomerisation of the product to the most
thermodynamically stable product is sometimes seen[ Vinylzirconium compounds have been used
in this reaction and can be prepared in situ from the corresponding alkyne "Equation "18## ð70JA0166Ł[
Amides ð74JA7955\ 74S655Ł and even selenoesters ð72TL3248Ł have been used as the acylating agents[
In an interesting variant\ Meyers et al[ have used an oxazine and a vinyllithium to prepare
a!branched\ a\b!unsaturated ketones "Equation "29## ð62JOC1018Ł[
O Li DME O
+ (26)
OH 92%

O O
MgBr THF, Et2O
+ OEt OEt (27)
EtO
87%
O O

MgBr
O Pd(PPh3)4, Et2O O
+ (28)
But Cl 82%
But

O
O
Me AlMe2 Cl, AlCl3
CpZr + (29)
Cl 61%

N Li O
2
(30)
O 45%

"ii# From vinyl silanes and acid chlorides


Vinyl silanes react cleanly with acid chlorides under Lewis acid catalysed conditions\ for example
Equation "20# ð68TL0884\ 79JCS"P0#1374\ 70TL1874\ 74JOC0510Ł[ Intramolecular cyclisations of this type
are also well known\ using either AlCl2 or TiCl3 "Equation "21## ð70JOC1399\ 72CC388\ 72TL684Ł[ The
reaction has been used to prepare cyclopentenyl vinyl ketones "which subsequently undergo Naz!
arov!type cyclisations# ð79JOC2906\ 71OM0139\ 73S880Ł[

TMS O

O AlCl3, CH2Cl2, 0 °C
+ (31)
Cl 77%

COCl O
AlCl3, CH2Cl2
(32)
95%
TMS

"iii# From alkenes and an acid chloride\ anhydride or acid derivative


Alkenes are well known to react with acid chlorides in FriedelÐCrafts type reactions to a}ord
vinyl ketones "Equation "22## ð60OS"40#004\ 66CB0996Ł[ Use of an activated zinc species as the catalyst
101 a\b!Unsaturated Ketones
has also been described "Equation "23## ð72JOC1492Ł[ Corey has published an intramolecular variant\
which proceeds via formation of a mono acid chloride "Equation "24## ð89TL2746Ł\ and spiro
cyclisations are also known "Equation "25## ð61JA7526Ł[ Acid bromides have been used to acylate
alkenes leading to a\b!unsaturated ketones ð68TL3442Ł[ Similar cyclisations have been reported using
carboxylic acids with alkenes\ using P1O4 or phosphoric acid as the catalyst[ Frequently the pro!
cedure starts from a lactone\ and the alkene "or carbocation# is produced in situ "Equation "26##
ð62JOC3960\ 79TL0194\ 71CL576\ 78JOC2877Ł[ Alternatively\ a free acid is used\ and the reaction involves
a double bond shift "Equation "27## ð62JOC2718\ 63S667\ 64AJC1558\ 67TL1350Ł[ Acid anhydrides have
been reported to work under special conditions ð42JCS2517\ 70TL2240\ 71JMC149Ł[
O AlCl3, CCl4, 100 °C
O
+ (33)
n-C7H15 Cl 62% n-C7H15

i, Zn, CuCl, CH2Cl2 O


O ii, LiOH
+ (34)
Cl 76%

i, LiOH H
ii, (COCl)2, DMF
iii, EtAlCl2
(35)
MeO2C
72% O
H
MeO2C MeO2C

O
ClOC COCl
AlCl3, MeNO2
(36)
51%
O

O
i, P2O5
O ii, K2CO3
O (37)
94%

O
H3PO4, 110 °C
CO2H (38)
87%

2[94[0[0[3 From a\b!unsaturated acid chlorides or their equivalents and carbon nucleophiles

"i# From acid derivatives and or`anometallic rea`ents


Acrylic acid chlorides\ esters and amides are all known to react with organolithium compounds
to give vinyl ketones "Equation "28# ð75S833Ł and Equation "39# ð62S426\ 80CC457Ł#[ Grignard reagents
react well\ and the reaction can be palladium!catalysed "Equation "30## ð65TL2986\ 67S031\ 70CL0024\
72TL4970\ 75T0258\ 89JHC0698Ł[

O
O
CO2Et LDA
Me + (39)
N CO2Et
58%
OMe MeO OMe
MeO OMe
a\b!Alkenic Bond 102

O BF3•OEt2, BusLi N
+ (40)
OMe N 69%
Me
O

O O
OMe MeMgCl
N (41)
Me 79%
N N
Me Me

"ii# From a\b!unsaturated acid chlorides and an activated alkene


As a complement to the basic condition of the organometallics\ acid:neutral conditions have been
investigated[ If the alkene is su.ciently activated\ as in silyl ketene acetals "Equation "31##\ the acid
chlorides react directly ð62TL0186\ 74TL3084Ł[ Allyl silanes can also be acylated with a\b!unsaturated
acid chlorides "Equation "32## ð65TL0760\ 68TL318Ł[ Unactivated double bonds can be acylated by
FriedelÐCrafts catalysis "e[g[ SnCl3#\ similar to those reactions described in Section 2[94[0[0[2
ð64TL2188Ł[

O
O 20 °C
+ (42)
O O-TMS 80%
Cl
O O

O O
AlCl3
+ (43)
Cl TMS 90%

2[94[0[0[4 From alkylations of a!b!unsaturated aldehydes and their equivalents


The alkylation of {umpoled| a\b!unsaturated aldehydes and their equivalents is well established[
Hunig and co!workers have used the adducts of trimethylsilyl cyanide and a\b!unsaturated alde!
hydes\ which can subsequently be deprotonated and alkylated electrophilically "Equation "33##
ð79CB2672\ 78CB1020\ 89CB096Ł^ see also ð79TL0194Ł[ Sulfonyl allylcarbamates such as "0# can be
alkylated and undergo carbamyl transfer and elimination of sul_nate "a single diastereomer is
formed in this case# "Equation "34## ð78TL1808Ł^ see also ð73CL0148Ł for elimination of sul_de[
Takahashi has developed an intramolecular macrocyclisation leading to large ring enones using an
a\b!unsaturated aldehyde umpolung reaction "Equation "35## ð72TL2378\ 72TL3584\ 78JOC3162Ł[

i, LDA
ii, BunBr
O-TMS iii, Et3N, HF, NaOH O
(44)
CN 54%

i, BuLi O O-TMS
O O ii, Ti(OPri)4
iii, aldehyde
O NPri2 + (45)
62% O NPri2
SO2Tol O-TMS
O
(1)
103 a\b!Unsaturated Ketones

Cl
O
O CN NaN(TMS)2
(46)
50%

Corey has used the dithiane "1# which can be alkylated predominantly at the sulfur!substituted
carbon "Equation "36## ð64TL814Ł[ Similarly the anion of "2# is alkylated adjacent to the cyano group
"Equation "37## ð75CB611Ł^ see also ð62AG"E#58\ 73TL1474Ł[ Seebach has shown that the dithiane "3#
can act as a formyl dianion equivalent\ and can be alkylated with two di}erent electrophiles
"Equation "38## ð63TL2060Ł[ a\b!Unsaturated aldehydes can also be umpoled with a metal catalyst
such as CoCl1\ which is believed to proceed via a radical mechanism "Equation "49## ð77CC581Ł^ see
also ð77JOM"237#012\ 89JOC1443Ł for use of Ni"cod#1 in the addition a\b!unsaturated aldehydes to
alkynes[ A further aldehyde umpolung strategy is to use an allenyl ether\ which can be a!metallated
and alkylated[ Hydrolysis then gives the a\b!unsaturated ketone "Equation "40## ð62TL1474Ł[
Hegedus and co!workers have developed a palladium!catalysed version of this transformation\
which can be used to give divinyl ketones[ The reaction proceeds with retention of con_guration
"Equation "41## ð72JA832Ł[ Parsons has described a similar reaction using an allenyl thioether
ð67CC711Ł[

i, LDA O
S S ii, MeI
iii, HgCl2
(47)
74%

(2)

i, LDA
ii, MeI O
CN iii, Et3N•HF
(48)
O-TMS 59%

(3)

Li TMS I
O
O i, BuLi, HMPA
S S + + (49)
ii, NH2OH

(4)

O
O O O CoCl2, MeCN
+ (50)
O 89%
O

OMe O
i, BunLi, MeI
ii, H+
• (51)
100%
n-C5H11 n-C5H11

OMe I i, BuLi, ZnCl2 O



+ (52)
ii, Pd(dba)2PPh3, vinyl halide
iii, H+
a\b!Alkenic Bond 104
2[94[0[0[5 By oxidation reactions

"i# By oxidations of allylic alcohols


The oxidation of secondary allylic alcohols to a\b!unsaturated ketones is a very well!established
reaction[ A huge number of reagents have been described\ with varying selectivities[ One of the
mildest and most used is manganese dioxide\ for example Equation "42#[ The use of this reagent has
been reviewed ð48QR50\ 65S022Ł[ Other reagents include potassium dichromate ð60JOC276Ł\ ddq
ð74JOC4786Ł\ ddq:HIO3 ð67S737Ł\ CrO2 ð71JOC0676Ł and NiO1 ð71JA1531Ł[ Several authors have
reported the use of transition metal catalysed oxidations of secondary allylic alcohols\ for example
H1Ru"PPh2#3\ as in Equation "43# ð75TL0794Ł\ Cp1ZrH1:PhCHO ð75JOC139Ł\ and K1FeO3 "Equation
"44## ð74TL1764Ł^ see ðB!78MI 294!90Ł for a comprehensive list of reagents and references[
O O
O n-C5H11 MnO2, CH2Cl2
O n-C5H11
O O (53)
OH O

OH H2Ru(PPh3)4 O
(54)
95%

OH OH K2FeO4 O OH
(55)
Ph 95% Ph

"ii# By oxidations of allylic methylene `roups


Both hydrogens of an allylic methylene group can be oxidised to give a\b!unsaturated ketones
"Equation "45##[ This transformation has been reviewed ð75BSF54Ł[ Reagents include CrO2 "Equation
"46## ð76JOC2235Ł\ tBuO1H "Equation "47## ð74JCS"P0#156Ł and SeO1 ð65OR"13#150Ł[ Mercuric acetate
has also been used ð62CC45Ł^ for other reagents see ðB!78MI 294!90Ł[

[O]
R
R (56)
O

CrO3•pyridine
OMe (57)
O 58% OMe
O
O
O

O
CO2Me ButO2H, Cr(CO)6 (cat.) CO2Me (58)
83%

"iii# Miscellaneous oxidation reactions


Ozonolyses of dienes can lead to a\b!unsaturated ketones\ for example Equation "48# ð77CB0684Ł^
see also ð52JCS1319\ 52JCS2564\ 58JA2565\ 67JA5183Ł for related oxidations[
O
O3
But But (59)
But But
37%
105 a\b!Unsaturated Ketones
2[94[0[0[6 Rearrangement reactions

"i# By Rupe rearran`ements


The rearrangement of an a!alkynic alcohol to an a\b!unsaturated ketone is known as the Rupe
rearrangement\ and the reaction has been reviewed previously ð60CRV318Ł[ The mechanism is not
completely clear\ but it is a useful way of preparing a\b!unsaturated ketones\ although side products
have been reported in some cases[ The reaction is performed under acid conditions\ for example
with formic acid "Equation "59## ð70CL44Ł\ ion exchange resins ð70S362Ł or P1O4 ð44OSC"2#11Ł[
O
HO
HCO2H
(60)
63%

"ii# By rearran`ement of propar`ylic alcohols


Related to the Rupe rearrangement\ is the rearrangement of 1!butyn!3!diols\ for example\ Scheme
1\ which proceeds through a Nazarov reaction[ The reaction has been reviewed\ along with other
cyclopentenone syntheses ð73S418Ł[ The reagents are usually sulfuric acid ð68JA0488Ł\ phosphorus
pentoxide ð65HCA0115Ł or methanesulfonic acid ð77CB0350Ł[

OH O
O
R3 HO
R3
R3
R2
R2 R2
R1
R1 R1

Scheme 2

"iii# By ð1¦1Ł cycloaddition reactions


Ketenes react smoothly with allenes to give cyclobutenones "Equation "50## ð64T738Ł\ in which
the central carbon of the allene becomes attached to the carbonyl carbon of the ketene[ Under
harsher conditions\ alkenes add to ketenes "4#\ which can subsequently be oxidised and eliminated
to give the cyclobutenone "Equation "51## ð67CC01Ł[ Alkynes are not normally ketenophilic enough
to undergo reaction\ unless the ketene is activated\ for example dichloroketene "Equation "52##
ð76TL2188Ł[ The chlorines in the product can be removed by reduction[ Similarly\ keteniminium
salts\ formed in situ by dehydration of an amide\ cycloadd to alkynes[ The imine can then be
hydrolysed to release the cyclobutenone "Equation "53## ð73TL4932Ł[

O
50 °C
+ • (61)
90%

O

O O
mcpba, 150 °C
+ • (62)
45%
PhS
(5)
a\b!Alkenic Bond 106
O
O
+ OAc (63)
80% Cl
Cl3C Cl
AcO Cl

i, TFAA, collidine O
NMe2 ii, NaOH, 41 °C
+ But (64)
O 69%
But
TFAA = trifluoroacetic anhydride

2[94[0[0[7 By displacements of a b!leaving group on an a\b!unsaturated ketone


The reaction of an organometallic with an a!haloenone is well known[ Good yields can be
obtained\ even with sterically hindered groups present\ and the reaction usually proceeds with
retention of con_guration "Equation "54## ð67TL0252\ 71CJC0145Ł[ 0\2!Diones can be transformed
into disubstituted enones by displacement of a phosphonate leaving group "Equation "55##
ð68CJC0320Ł[ Alkyl and aryl thio moieties can also be used as leaving groups[ Deiter et al[ report
good stereoselectivity\ with con_guration "retention or inversion# depending on the solvent\ the
cuprate and other factors "Equation "56## ð75JOC3576Ł[ Thioketene acetals have been used and the
thio groups can be displaced sequentially with di}erent nucleophiles ð74JA3568Ł[

O O
ButCuLiSPh
(65)
70%
Br But

i, ClPO(OEt)2
O O ii, Me2CuLi O
(66)
83%

O SPh Bun2CuLi O Bun


(67)
99%

2[94[0[0[8 OxyÐCope and Claisen rearrangements


The oxyÐCope rearrangement is an important synthetic procedure for the preparation of func!
tionally complex a\b!unsaturated ketones[ The use of a propargylic alcohol leads directly to both
cyclic "Equation "57## ð73JA2758\ 75TL108\ 77TL5786Ł and acyclic\ unsaturated ketones ð79TL0236\
75T0222Ł\ and similarly the use of a doubly allylic alcohol leads directly to unsaturated ketones
"Equation "58## ð66JA3075\ 72JA2237\ 77BCJ0196\ 77JA789Ł[ The Claisen rearrangement can be used in
an analogous fashion to furnish acyclic ð58TL2132Ł and cyclic!a\b!unsaturated ketones "Equation
"69## ð80JA1509Ł[

MeO
O
170 °C
(68)
62% O OMe
O
HO
107 a\b!Unsaturated Ketones

KH, 18-crown-6, 25 °C
OH (69)
75%
O

O
O toluene, 180 °C
(70)
60%

2[94[0[0[09 Carbonylation and related reactions


The PausonÐKhand reaction is a versatile\ stereoselective synthetic route to cyclopentenones\
commonly as fused bicyclic systems ð74T4744Ł[ The reaction usually involves the treatment of an
enyne with Co1"CO#7 under an atmosphere of carbon monoxide\ and enables functionally complex
molecules to be assembled in a single step "Equation "60## ð77T1546\ 78JOC4037\ 78TL4754\ 89JA330Ł[ A
closely related transformation has been observed using Ni"CO#3 as the catalyst ð76TL3634Ł^ see
also ð57LA"601#68\ 74TL5286Ł[ The sequential insertion of carbon monoxide and alkynes into alkyl
manganese pentacarbonyl complexes\ followed by acidolysis\ leads to enone systems ð76TL1122Ł\
and if the alkyl manganese pentacarbonyl complex is derived from the ring opening of an epoxide\
cyclopentenones are isolated\ presumably via a Nazarov cyclisation ð77JOC3781Ł[ Palladium catalysis
facilitates the cross!coupling accompanied by carbon monoxide insertion of alkyl halides and
vinyltin reagents to produce unsymmetrical unsaturated ketones in good yield[ The reaction is mild\
tolerant of a wide spectrum of functionality\ and retention of double bond geometry in the vinyltin
reagent is observed "Equation "61## ð73JA3722Ł[ Palladium!catalysed carbonylation and cyclisation
of an iododiene system derived by zirconium!promoted allylmetallation of an alkyne has been used
to form doubly unsaturated cyclic ketone systems ð72JA5650Ł[ A bulky isonitrile behaves as a carbon
monoxide equivalent in a reaction involving sequential attack by a nucleophile followed by electrophilic
quench[ Unsymmetrical unsaturated ketones have been prepared by this route ð71JOC41Ł[

O-TBDMS O-TBDMS
i, Co2(CO)8
ii, sealed tube, CO, 85 °C
O (71)
64%
MOM-O MOM-O H

O OMe
CO2Et
Br CO2Et Bun3Sn CO, 50 °C, Pd(dba)2
+ (72)
OMe O-THP 74%

O-THP

2[94[0[0[00 By isomerisations
A common method of forming a\b!unsaturated ketones is to isomerise a b\g! or g\d!unsaturated
ketone to the more thermodynamically stable conjugated isomer[ These isomerisations occur most
readily with base catalysis often in very high yield ð59JOC0855\ 75JA1989\ 78TL6186Ł[ Acid catalysis has
also been reported ð42JA2157Ł as has thermal isomerisation ð75HCA117Ł and the use of rhodium
compounds which can be tuned to give either the more or less substituted enone where a choice is
available ð68TL0388Ł[ Oxidations of homoallylic alcohols can result in concomitant isomerisation to
the unsaturated ketone ð45JA765\ 76TL2004Ł[ Birch reductions of phenol derivatives are commonly
followed by isomerisation to the more stable cyclohexenone in situ or on acidic workup ð67CC741\
68BSF270Ł[
a\b!Alkenic Bond 108
2[94[0[0[01 By aldol condensation reactions
Probably the most important and versatile route to a\b!unsaturated ketones is the aldol conden!
sation[ This involves the reaction of an enolate or enol with an activated carbonyl\ followed by
dehydration or similar elimination of the resulting adduct[ Thus\ reaction of the 0\2!diketone "5#
with dichloroaldehyde "6# followed by elimination of acetic acid gives the ketone "7# in 66) yield
"Equation "62## ð70JOC2115Ł[ Aldol reactions are often carried out in situ after the removal of a
carbonyl protecting group and occur with both acid and base catalysis "Equations "63# and "64##
ð70JA2359\ 73JOC299Ł^ see also ð64JA5800\ 67TL1844\ 79JOC3491\ 70JOC1317\ 74CL0034\ 76JHC386Ł[ Similarly\
functionality can be manipulated to give a dicarbonyl compound which undergoes an intramolecular
aldol condensation leading to a cyclic unsaturated ketone[ Thus\ opening the lactone "8# with a
Grignard reagent gives a 0\4!diketone which cyclises under basic conditions to give the cyclo!
hexenone "09# in the FujimotoÐBelleau reaction "Equation "65## ð78JOC3691Ł^ see also ð54JCS0245\
71CJC1417Ł[ Another method of unmasking dicarbonyl functionality is to ozonise an alkene\
especially a cyclic alkene "Equation "66## ð60JA3221\ 71SC884\ 80TL4586Ł[ Other oxidations leading to
precursor dicarbonyl systems are known ð72JA4577\ 75NJC456Ł[ Reductions leading to dicarbonyl
systems have been reviewed ð78JOC3562Ł as have reductions of heteroaromatic ring systems "e[g
Equation "67## ð64JA279\ 71TL4998\ 89JOC1126Ł[

Cl O
O O K2CO3, THF, 67 °C
+ OHC Cl Cl (73)
77% Cl
(6) (7) (8)

MeO2C
p-TsOH, toluene, 130 °C O
(74)
MeO O 51%
O
MeO O

O
i, 1N HCl O
O
ii, 1N NaOH, 100 °C
N (75)
50%
N
O O

i, MeMgI, Et2O, –25 °C


BnN BnN (76)
ii, KOH, MeOH (aq.), 20 °C
O O O
(9) (10)

O
i, O3
ii, Me2S or Zn
iii, PhCH2NMe3Cl, 50% NaOH, CH2Cl2
(77)
38%

i, Na, NH3
ii, NaOH, EtOH (aq.)
O O iii, H3O+
O (78)
52%
N

O
119 a\b!Unsaturated Ketones
The aldol reaction can be made regioselective by preparing an enol derivative of the ketone\ in
order to ensure that coupling occurs on the desired side of an unsymmetrical ketone[ A number of
preformed enolates have been used\ the most common being the silyl enol ether which is reacted
with the aldehyde or ketone in the presence of a Lewis acid catalyst\ for example TiCl3 ð66AG"E#706Ł[
Silyl enol ethers also react with acetals in the presence of a stoichiometric amount of TiCl3 to
provide Aldol products in high yield ð76S0932Ł[ This reaction\ known as the MukaiyamaÐaldol
condensation\ has become an important synthetic tool facilitating aldol condensations which do
not proceed under conventional conditions "Equation "68## ð67TL3194\ 78JA7166Ł^ see also ð71TL0936\
73JOC2593Ł[ Enamines are also commonly used as preformed enolates ð51CB0384\ 70S088Ł[ Another
important aldol reaction leading to unsaturated cyclic ketones is the Robinson annulation reaction
in which a cyclic ketone is treated with methyl vinyl ketone "or a derivative# under basic conditions
ð65S666Ł[ Another annulation procedure for cyclic ketones has been reviewed ð76JOC0339Ł "Equation
"79## and other variants are known ð64JOC2510\ 66S597\ 67JA5183\ 67JOC3549\ 89S882\ 89TL5034Ł[

O
TMS-O
TiCl4, 0 °C
O (79)
60%
O

i, LDA, THF
O ii, (Ph3P)4Pd
iii, NaOH, EtOH (aq.)
+ Cl O (80)
OP(O)(OEt)2 79%

2[94[0[0[02 By Wittig reactions


The Wittig reaction is an important and well!used preparative tool in the synthesis of
a\b!unsaturated ketones[ The major route to these systems involves the reaction of an a!ketophos!
phorane with an aldehyde and leads to the "E# isomer stereoselectively "Equation "70## ð73TL3848Ł^
see also ð71TL1244\ 74JOC1087\ 76S0944\ 89JOC3386Ł[ The corresponding stabilised arsonium ylides have
also been investigated ð78CC501Ł[ The use of a!ketophosphonates "00#\ the WadsworthÐEmmons
reaction\ has several advantages over the use of phosphoranes\ for example the ylides are more
reactive than the corresponding phosphoranes enabling reactions with ketones\ and the phosphorus
containing side product is water!soluble\ unlike triphenylphosphine oxide\ simplifying the workup
ð76S0901\ 76TL0782Ł[ Intramolecular Wittig condensations enable the synthesis of cyclic unsaturated
ketones even when the product is highly strained ð67JOC3562\ 68AG0994\ 71TL2432Ł[ Condensation of
an a!ketophosphorane with an a\b!unsaturated aldehyde can result in an intramolecular Michael
addition to give cyclohexenone derivatives "Equation "71## ð77JOC1726Ł[ Intramolecular WadsworthÐ
Emmons cyclisations are also well known[ The reacting ylide is often derived by the treatment of
an ester with an a!lithioalkylphosphonate "Equation "72## ð67TL3486\ 74JA6856\ 74JOC0654\ 76JOC0264Ł[
Other routes to a\b!unsaturated ketones using Wittig methodology include] reaction of an unstabil!
ised ylide with a monoprotected 0\1!diketone ð66TL2494Ł\ use of a diphosphonium salt in a four
carbon annulation procedure with a b!ketoester ð74JOC3141Ł\ addition of a lithiated dithiane to a
vinylphosphonium salt generating an ylide which undergoes an intramolecular Wittig condensation
"Equation "73## ð63TL3112Ł and reaction of Grignard reagents with the ketenylidenetriphenyl!
phosphorane "01# and subsequent hydrolysis yielding a!ketophosphoranes which can then be con!
densed with aldehydes ð75TL0888\ 77S38Ł^ see also ð75S30Ł[
OAc OAc
PhH, 60 °C
MeCHO + (81)
Ph3P
90%
O O

O O
P(OR2)2
R1
(11)
a\b!Alkenic Bond 110
O
O NaH, THF CO2Et
Ph3P CO2Et
+ OHC (82)
38%

O THF, –78 °C
+ (MeO)2P Li (83)
37%
O
O O

O S
LDA, –5 °C S S
+
+ Ph3P O (84)
S 55%
O


+
• O
Ph3P
(12)

2[94[0[0[03 By DielsÐAlder reactions


The DielsÐAlder reaction enables the synthesis of several cyclohexenones especially via the use of
Danishefsky|s diene "Equation "74## ð64JOC427\ 72JOC030\ 78TL3298\ 80TA067Ł or via the use of an
alkynic ketone as dienophile ð80TL4610Ł^ see also ð76TL1570Ł[ DielsÐAlder reactions are sometimes
used to protect enone systems and thus a retro!DielsÐAlder unmasks the a\b!unsaturated ketone
"Equation "75## ð73CC068\ 76S196\ 78CC160\ 78JOC5997Ł[

O
O i, xylene, 140 °C
MeO H SO2Ph
ii, H+
+ (85)
O-TMS 69%
SO2Ph
O

MeAlCl2
O
H O O
H O , DCE, 70 °C

O
(86)
89%
H ( )7 ( )7
H
HO2C HO2C

DCE = 1,2-dichloroethane

2[94[0[0[04 By oxidations of furans


The oxidative ring opening of 1\4!disubstituted furans provides a useful route to enedicarbonyl
compounds in high yield "Equation "76## ð80CC669Ł[ A wide variety of oxidising agents have been
employed in this transformation including peracids\ bromine and singlet oxygen ð72S014\ 78IJC"B#2\
89TL6558Ł[ In some cases the oxidised furan has been isolated\ and it is then hydrolysed or reductively
cleaved to the dicarbonyl compound ð73JA4474\ 74TL1758\ 89TL6190Ł[ There are a number of reports
of the oxidative conversion of furanmethanols to 5!hydroxypyran!1!ones "e[g[ Equation "77##
111 a\b!Unsaturated Ketones
ð89JCS"P0#528Ł^ see also ð72SC196\ 76JOC4417\ 78JA6523\ 80JHC586\ 82TL6978Ł[ The application of Sharpless
epoxidation conditions to racemic secondary 1!furanmethanols results in a kinetic resolution fur!
nishing unchanged 1!furanmethanol and 5!hydroxy!1!pyranone both of high enantiomeric purity
ð89JCS"P0#0622\ 80TL0356Ł[

pcc, DCM, 20 °C
SMe (87)
O SMe 70% O O
pcc = pyridinium chlorochromate
DCM = dichloromethane

OH

OH NBS, THF, H2O O


O (88)
93%
C10H21 C10H21
O

2[94[0[0[05 From alkynes


a!Alkynic carbonyl compounds are useful precursors to a\b!unsaturated ketones[ Organocopper
reagents "RCu and R1CuLi# add exclusively in a 0\3 sense to a!alkynic ketones furnishing a\b!
unsaturated ketones usually as a mixture of "E# and "Z# isomers "Equation "78## ð76TL4970\ 89JOC116Ł[
Some intramolecular cyclisations of enolates onto alkynic ketones have also been observed\ leading
to both _ve! and six!ring unsaturated ketones ð75TL4344\ 76TL2346Ł[ Similarly 0\3!additions of
nucleophiles to a!alkynic esters\ followed by Dieckmann cyclisations lead to cyclic unsaturated
ketones ð73JOC2922\ 76TL4130Ł[ Additions of carbon nucleophiles 0\3 to an a!alkynic ketone can also
be achieved by an ene reaction "Equation "89## ð78HCA0404Ł[ The addition of lithium divinyl cuprate
across certain functionalised alkynes "02# has also been reported\ and leads to an intermediate
cuprate "03# which on hydrolysis furnishes an a\b!unsaturated ketone "Scheme 2# ð79T0850Ł[

O O-MOM O O-MOM

i, Me2CuLi
(89)
ii, PriSLi

O ZnI2
CH2Cl2, 20 °C
+ O + O (90)
64%

3:1

CuLi
Et2O, THF, –40 °C 20% HCl
Bun CuLi + 2 X Bun 2
2
75% overall
X
(13) X = SR, OR (14)

Bun

Scheme 3
a\b!Alkenic Bond 112
The reduction of a!alkynic ketones similarly leads to a\b!unsaturated ketones "Equation "80##
ð68CL0910\ 75S073Ł[ In general catalytic partial hydrogenation leads exclusively or predominantly to
"Z#!alkenes\ whereas reduction with metals and metal salts gives predominantly "E#!alkenes ðB!73MI
294!90Ł^ for a comprehensive list of reagents and references see ðB!78MI 294!90Ł[

O
CrSO4, DMF, H2O, 25 °C O
(91)
80%

The synthetically useful reaction of trialkylboranes with a!alkynic ketones occurs only in the
presence of catalytic amounts of oxygen and yields the a\b!unsaturated ketone\ as a mixture of
stereoisomers\ after hydrolysis of the intermediate allene "Equation "81## ð69JA2492Ł[ A multistage
synthetic procedure to 2\2!dimethyl unsaturated ketones has been reported which involves the
anionotropic rearrangement of 0!halodienylboranes with sodium methoxide followed by oxidation
and isomerisation "Scheme 3# ð77S029Ł^ see also ð62CC595Ł[

air O
O
THF, H2O, 20 °C
B + (92)
3
65%

I R
NaOMe, MeOH i, H2O2, NaOH (aq.), THF O
B B ii, ButOK, ButOH R
R OMe

Scheme 4

Dreiding has reported that the pyrolysis of a!alkynic ketones leads to fused and spiro!cyclo!
pentenone systems\ via an alkylidene carbene intermediate\ in high yield enabling a total synthesis
of the triquinane modhephene "Equation "82## ð70HCA0012\ 74HCA227Ł[ Radical chemistry also
enables the synthesis of a\b!unsaturated ketones from a!alkynic ketones[ Thus a radical cyclisation
followed by protiodestannylation provides a neat synthesis of a!methylenecyclohexenones "Equation
"83## ð89TL4928Ł^ also see ð89JA891Ł[ Electrophilic alkylation of an allenic anion\ derived by metal!
lation of the silyl alcohol "04# also leads to a\b!unsaturated ketones in high yield "Equation "84##
ð79TL512Ł[

620 °C
(93)
95%
O O

O i, Bun3SnH, AIBN, PhH


O
ii, HCl (conc.), Et2O
(94)
58%
CO2Me CO2Me

AIBN = 2,2'-azobisisobutyronitrile

HO TMS O
i, BunLi
Ph (95)
ii, MeI Ph

(15)
113 a\b!Unsaturated Ketones
2[94[0[0[06 From cyclopropanes
Cyclopropanes have proved useful intermediates in the synthesis of a\b!unsaturated ketones via
ring cleavage reactions[ Thus\ Conia et al[ have reported that the cycloadditions of chloro!
methylcarbene to the trimethylsilyl enol ethers of cyclic and acyclic ketones\ followed by elimination
of TMS!Cl with ring opening of the cyclopropane\ leads to a!methylalkenones "ring expanded by
one carbon atom in the case of cyclic ketones# "Equation "85## ð70S178\ 70S180Ł^ see also ð63TL898\
63TL2186Ł[ A similar overall result is achieved by the reaction of a!haloketones with dilithio!
alkylsulfones via a cyclopropane intermediate "Equation "86## ð74JOC2563Ł[ The acidic hydrolysis of
dichlorocyclopropylcarbinols such as "05# leads to cyclic enone systems in good yield[ This reaction
has been postulated to occur via conjugate dehydration\ Nazarov!type cyclisation and hydrolysis
of the resulting chlorodiene "Equation "87## ð63JA2602Ł\ and it is also applicable to forming bicyclic
systems ð67TL660\ 79BCJ0909Ł[

Cl
O
toluene, 111 °C, 6 d
(96)
TMS-O
91%

O O
Li THF, 0 °C
Cl
+ PhSO2 (97)
Li 45%

Cl Cl O
HBr (aq.), 100 °C
OH (98)
83%

(16)

Ring opening reactions of oxycyclopropane systems derived from the reaction of a!diazocarbonyl
intermediates with enol ethers or enol acetates lead to 0\3!dicarbonyl functionality which can then
undergo Aldol cyclisations leading to cyclic enones "Equation "88## ð60TL1464\ 67JA0156\ 89CB252Ł[
The ring opening of other oxycyclopropane systems has been widely used in synthesis[ Base!
catalysed cleavage of 0!siloxy!1!vinylcyclopropane leads to an a!methylenone function ð62TL1656Ł^
see also ð62JOC293Ł[ Treatment of bicyclic cyclopropanes such as "06# with FeCl2 followed by sodium
acetate results in cleavage of the bridging bond to give the cyclic enone "07#\ possibly via a radical
mechanism "Equation "099## ð65JOC1962\ 79OS"48#002\ 77CL810\ 82TL6180Ł[ By contrast treatment with
TeCl3 followed by dimethylsulfoxide provides the corresponding a!methylene in good yields via an
intermediate b!trichlorotelluro ketone ð80TL118Ł[

O
O
NaOH, MeOH, 100 °C, 1 h
OAc (99)
85%

i, FeCl3, py, DMF O


ii, NaOAc, MeOH
O-TMS (100)
98%

(17) (18)

The ring opening of cyclopropylphenyl sul_des has also been used synthetically to make
a\b!unsaturated ketones[ Thus the alcohol "08#\ prepared from the addition of 0!lithiocyclo!
propylphenyl sul_de to 3!methyl!0\1!epoxypentane\ has been cleaved\ hydrolysed and dehydrated
in a single pot using mercuric chloride\ to a}ord the enone "19# "Equation "090## ð71TL1268Ł[
a\b!Alkenic Bond 114
SPh
O

HgCl2, MeCN, H2O, reflux


HO (101)
42% SPh

(19) (20)

2[94[0[0[07 By ð2¦1Ł cycloaddition reactions


The ð2¦1Ł cycloaddition reaction has proved useful in the synthesis of cyclopentenone systems[
Thus the addition of a\a?!dibromoketones to enamines has been reported with a variety of reagents
including Fe1"CO#8 and a mixture of CeCl2 and SnCl1 "Equation "091## ð61JA0661\ 78BCJ1237Ł[ This
reaction does not occur intramolecularly onto an unactivated double bond\ but undergoes a ð2\3Ł
sigmatropic shift instead ð70BCJ1122Ł^ however such a cycloaddition\ with an alternative 0\2!dipole\
has been utilised to furnish an enone system ð89JCS"P0#242Ł[ A formal ð2¦1Ł cyclisation has also
been observed by the Michael addition of a zinc homoenolate to an alkynic ester\ followed by
intramolecular acylation of the intermediate allenolate\ leading to cyclopentenone systems "Equation
"092## ð89JOC3124Ł[
O
O
N Fe2(CO)9, PhH, 25 °C
+ O (102)
77%
Br Br

O
Zn
Et2O 2
MOM-O CuI, HMPA, 25 °C
CO2Et
CO2Et (103)
C5H11 71%
C5H11
MOM-O

2[94[0[0[08 Miscellaneous reactions


The palladium"II#!catalysed intramolecular cyclisation of a silyl enol ether onto an unactivated
alkene is another useful route to cyclopentenones "Equation "093## ð68JA383\ 75JA1989Ł^ see also the
related reactions ð70TL0004\ 73JOC849\ 75TL1112Ł[

Pd(OAc)2, 25 °C
(104)
99%

O-TMS O

2[94[0[1 a\b!Unsaturated Ketones with Further Unsaturation

2[94[0[1[0 By elimination reactions


"i# By oxidative elimination of H1
The elimination of hydrogen can be performed on a\b! and g\d!unsaturated ketones to give
a\b!unsaturated ketones with further unsaturation "Scheme 4#[ The commonest reagents used are
115 a\b!Unsaturated Ketones
chloranil\ ddq and chromium oxidising species[ Chloranil was used to oxidise the g\d!unsaturated
ketone in Equation "094# to the a\b\g\d!unsaturated ketone\ with the enamine functionality being
una}ected ð65JA2534Ł[ g\d!Dehydrogenation has been performed more frequently\ often on steroids\
using ddq "Equation "095## ð56JCS0619\ 60JCS748Ł\ chloranil ð59JA3182\ 78JOC2873Ł and CrCl1
ð56HCA158Ł[ A palladium!catalysed reaction has also been reported ð80TL0322Ł[

O [O] O

–H2

O [O] O

–H2

Scheme 5

N N N N
chloranil, C6H6, 20 °C
H H H H H H (105)
47%

O O

O O

H ddq, p-TsA, 25 °C H
(106)
90%
H H H H
O O

"ii# By elimination of halide


Elimination of hydrogen halide is known for both a\b and g\d!unsaturated ketones\ for example
from a!haloketones "Equation "096## ð59JA1391\ 62CC050Ł[ Similar conditions have been used for
g!halo!a\b!unsaturated ketones "Equation "097## ð42JA4378\ 89JCS"P0#0634Ł^ see also ð46BSF0178\
46JA0029Ł for related examples[

LiF, Li2CO3, 120 °C


(107)
85%
Br
O O

OAc OAc

Li2CO3, DMF, 120 °C


O O (108)
90%
Br

"iii# By elimination of hydroxy and alkoxy `roups


The elimination of b!hydroxy groups from g\d!unsaturated ketones to form dienones has been
reported\ as shown in Equation "098# ð71SC410Ł[ Formation of the mesylate prior to elimination
can also be used "Equation "009## ð65TL00\ 73TL2510Ł[ g!Hydroxy and alkoxy groups can be eliminated
a\b!Alkenic Bond 116
from a\b!unsaturated ketones "Equation "000## ð71S23\ 75JCS"P0#850Ł\ as can d!hydroxy and alkoxy
groups ð43JA4561\ 46JA5297\ 72JA4568Ł[ Hydrolysis of 1!alkoxy!2\3!bisalkoxymethylfurans gives rise
to further unsaturated a\b!unsaturated ketones ð73JA4474Ł[

EtO OEt
EtO silica, 20 °C O
(109)
OH 94%

O OH MeSO2Cl, Et3N O
(110)
85%

O O
Ph Ph
p-TsA, toluene, 110 °C
Ph Ph (111)
60%
OH

"iv# By elimination of sulfur and selenium `roups


The elimination of sulfoxides can be performed to produce dienones "Equation "001##\ similar to
the case where there is no further unsaturation ð75S736Ł[ The bis elimination of sulfoxides\ as in
Equation "002##\ gives the corresponding "E# dienones in good yields ð77CPB0058Ł^ see also ð67CC710Ł
for an example of a 0\2!pyrolytic elimination of a sulfoxide[ Julia and co!workers have used the
isoprenoid sulfoxide in Equation "003# ð67TL0044Ł as an isoprene cation equivalent[ After Michael
addition and liberation of the protected carbonyl\ the double bond is isomerised and the sulfoxide
eliminates to give the dienone[ Fleming et al[ have shown that the trimethylsilyl enol ethers of
b\g!unsaturated ketones are sulfenylated almost exclusively in the g!position\ and can then be
oxidised:pyrolysed to the corresponding dienone ð68TL2194Ł[ A versatile synthesis of enones utilising
the elimination of b!sulfoxides has been described by Albrecht et al[ "Scheme 5#[ A range of
electrophiles instead of the enone was used in the anion capture step ð77S109Ł^ see also ð77HCA0608Ł
for an example of a 0\5!elimination of a sulfoxide to form an a\b\g\d!dienone[ Chou has used the
extrusion of SO1 to produce novel dienes "Equation "004## ð70CL0230\ 77JOC4\ 78SC0482Ł[

O O

SMe NaIO4, NaHCO3, 110 °C


(112)
93%

O
mcpba O
n-C6H13 SPh (113)
75% n-C6H13
SPh

O– NC – O OEt i, HCl
+
ii, NaOH O
S + (114)
Ph 50%

O
Ph O
∆ Ph
(115)
80%
S
O O
117 a\b!Unsaturated Ketones

O SPh
SPh
CN
i, ButLi, THF i, HCl
SPh – CN N(Me)Ph
CN ii, mcpba
ii, N(Me)Ph
N(Me)Ph
O

Scheme 6

b!Selenoaldehydes undergo a stereoselective Wittig reaction followed by an oxidative elimination


to give the "E\E#!diene "Equation "005## ð75TL1838Ł^ see also ð79TL2198Ł[ Eliminations from
d!ammonium compounds "Equation "006## also give dienones ð65JCS"P0#1178\ 79TL794Ł[

O i, NaH, THF
ii, H2O2, HCO3– O
+ But (116)
PhSe O 87% But
PO(OMe)2

i, MeI
ii, dbu
(117)
O
73% O
NMe2

dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene

2[94[0[1[1 By displacement reactions of a b!leaving group with a vinyl nucleophile


Reactions of a substituted a\b!unsaturated ketone with a vinyl nucleophile can lead to dienones[
The nucleophile is often a Grignard reagent "Equation "007## ð75T0258Ł\ and the leaving group\ as
well as halo\ can be dialkylamino ð47CB0756\ 59BSF404Ł[ Normant has prepared "E#!alkynenones
from alkynic Grignard reagents and dialkylaminoenones ð59BSCF404Ł[ Brown has made use of vinyl
boranes as the nucleophilic component\ with an alkoxy enone "Equation "008## ð73JOC4913Ł\ and
alkynenones are also available from this route ð47CB0756\ 66JOC2095Ł[ Vinyl boranes have been used
with haloenones in a palladium!catalysed coupling ð76BCJ2360Ł[ Lithium acetylides also react with
alkoxyenones to give alkynenones ð42HCA371Ł[ a!Alkenylation of an a\b!unsaturated ketone has
been achieved by a lithiumÐhalogen exchange reaction "Equation "019## ð76CL0996Ł[

i, 3% Pd(PPh3)4
O ii, NH4Cl O
MgCl
+ (118)
n-C5H11 Cl 89% n-C5H11

O
O i, Et2O OH
ii, HO
+ (119)
B
n-C7H15 95%
OMe
n-C7H15
a\b!Alkenic Bond 118
i, BunLi
ii, ZnCl2
iii, alkenyl iodide, Pd(PPh3)4 O
O O iv, HCl
+ n-C6H13 n-C6H13 (120)
Br I
92%

2[94[0[1[2 By isomerisations of double and triple bonds


Alkynic ketones can be isomerised to conjugated dienones using Ru ð77TL0934Ł\ Ir ð78JOC0094Ł
"Equation "010##\ or Pd ð77JA1290Ł catalysts[ The reaction appears to give "E\E#!dienes exclusively[
The isomerisation of two double bonds into conjugation with a ketone is also known ð43JCS0291\
62JA2178Ł\ as is the isomerisation of b!allenes to a\b\g\d!unsaturated ketones ð56HCA0047Ł[

O
O
IrH5(PPri3)2, 60 °C
(121)
92%
n-C8H17
n-C6H13

2[94[0[1[3 From oxidations of further unsaturated allylic alcohols


The oxidation of further unsaturated allylic alcohols to further unsaturated a\b!unsaturated
ketones proceeds in much the same way as it does for a\b!unsaturated ketones without further
unsaturation "see Section 2[94[0[0[5 for reagents and references#[ Examples include the use of
BaMnO3 ð77HCA057Ł\ MnO1 ð41JCS0983Ł and Al"OiPr#2:acetone ð69HCA863Ł[ Oxidations of tertiary
dienols\ prepared by 0\1!reactions of a vinyl metallic with an enone\ can proceed via a 0\2!rearrange!
ment "Equation "011## to give dienones ð78TL0922Ł[ This reaction can also be performed on the
corresponding alkynols to give alkynenones ð64CC781\ 76TL0958Ł[

MeO2C
MeO2C OH
pdc, 25 °C
(122)
62%
O
pdc = pyridinium dichromate

2[94[0[1[4 From reactions of further unsaturated a\b!unsaturated acids and their equivalents with
carbon nucleophiles
These reactions are very similar to those used for simple a\b!unsaturated ketones "see Section
2[94[0[0[4#[ For example\ the lithio methylphosphonate in Equation "012# reacts with the dienoate
at the ester group to give the corresponding ketone ð73JA2764Ł[ The acid chloride can also be
used as the electrophile "Equation "013## ð35HCA693\ 41JCS2834Ł[ Nitriles "with Grignard reagents#
ð36HCA894Ł and amides "with organolithiums# ð79JCS"P0#1740Ł have also been reported[

O –78 °C O O
CO2Me + (123)
Li P(OMe)2 52%
P(OMe)2

i, Na, C6H6
O O ii, acid chloride
O iii, HOAc O
+ THP-O O-THP (124)
Cl 90% n-C6H13
n-C6H13
129 a\b!Unsaturated Ketones
2[94[0[1[5 By FriedelÐCrafts acylations of dienes
Acid chlorides and their equivalents have been reported to react with dienes to give further
unsaturated a\b!unsaturated ketones[ For example\ Naso et al[ have used the disilyl diene in
Equation "014#\ and were able to mono! and diacylate e}ectively ð80CC126Ł[ In other cases\ activation
of the double bond has been achieved by substitution with sulfur or nitrogen "Equation "015##
ð75TL242Ł[
i, AlCl3, 0 °C
O O ii, MeCOCl, AlCl3, 20 °C
TMS
TMS +
Cl OMe 39%

CO2Me (125)

S O O pyridine, CHCl3, 25 °C O S
+ (126)
S F3C O CF3 100% F3C S

2[94[0[1[6 a!Allenic ketones


a!Allenic ketones have been prepared by a variety of methods\ for example additions of Grignard
reagents to protected b!alkynones "Equation "016## ð74TL3812\ 76T1610Ł[ The reaction of propargylic
silanes with acid chlorides has been used to prepare allenic ketones "Equation "017## ð70TL2390Ł[
Reactions of ketones with the sodium acetylide in Equation "018# lead to a tertiary alcohol which
eliminates to the cumulene on treatment with acid ð79T0220Ł^ see also ð68JA1197Ł for the preparation
of allenic ketones from the ring opening of furans\ and ð67CC0995Ł for a reaction of dibromoketones
with alkynic compounds[

O
OEt
EtMgBr, CuBr, –60 °C
Et
OEt
• (127)
77%
THP-O OH
THP-O

O
MeCOCl, AlCl3, –60 °C
(128)
TMS 60% •

i, NH3(l)
O O
ii, NH4Cl (aq.)
EtO
iii, HCl, H2O •
Ph + (129)
Na 50%
Ph
OMe
OMe

2[94[0[1[7 By aldol condensation reactions


The aldol condensation provides a simple route to a\b!unsaturated ketones possessing further
unsaturation[ This is most often seen with an unsaturated aldehyde condensing with a ketone such
a\b!Alkenic Bond 120
as acetone\ under basic conditions to give the "E# product "Equation "029## ð32CB565\ 32OS"12#67\ 38JCS626\
40JA608Ł[ Anhydrous lithium iodide in diethyl ether has been reported as an exceedingly mild
reagent for such condensations ð79CC375Ł[ The reaction is also known using unsymmetrical ketones
ð49RTC296\ 67CPB2766\ 73JA2273\ 74TL1762Ł\ and the addition of one equivalent of trimethylsilyl chloride
results in improved yields when using lithium diisopropylamide as the base "Equation "020##
ð80TL0680Ł[ The intramolecular aldol condensation of a ketone with a second unsaturated ketone is
a useful annelation procedure\ and occurs under both acid ð69CC41\ 69TL3958\ 60TL2792\ 78CB0542Ł and
base catalysis ð43BSF679\ 68JA4969Ł "Equation "021## ð89JOC2Ł[ Vinylogous aldolisation reactions
lead to similar products "Equation "022## ð58JA1795\ 64JA279\ 64LA763Ł[

O 0.5% NaOH, 20 °C
+ O (130)
CHO O
O 71%

i, LDA, THF, hexane, –78 °C


O ii, aldehyde, TMS-Cl (1 equiv.), 20 °C But
+ CHO (131)
But 98% O

ButOK, ButOH, 20 °C
H (132)
H H
O 90% H
O
H OH
OH

p-TsOH
O (133)
84%

O O

2[94[0[1[8 By Wittig reactions


The Wittig and similar reactions are exceptionally useful in the synthesis of dienones[ The
WadsworthÐEmmons reaction is most commonly employed\ yielding the "E# product selectively
ð56BSF1366\ 57JGU290\ 79TL1176\ 74JA4108\ 74JCS"P0#1396\ 76TL448\ 80S102Ł\ and has been used intra!
molecularly to e}ect macrocyclisation "Equation "023## ð73JA0037Ł[ The use of the phosphonium
salt "10# "Equation "024## ð70T1280Ł and its arsenic equivalent ð76TL1044Ł have also been reported[

O O O
(EtO)2P

CHO K2CO3, 18-crown-6, 75 °C


(134)
S 76% S
O O
S S
Et O Et O

O ButOK, ButOH, 20 °C O
+
PPh3Br– + Ph CHO (135)
19% Ph
(21)
121 a\b!Unsaturated Ketones
2[94[0[1[09 From pyrilium salts
The reduction of 1\3\5!trisubstituted pyrilium salts with sodium borohydride leads to 1\3!dienones
in moderate yield "Equation "025## ð51T146\ 61BSF1409Ł[ These pyrilium salts can also be cleaved by
a range of other nucleophiles including Grignard reagents\ amines and cyanide\ to give 3!substituted
1\3!dienones ð47BSF0347\ 50JCS2455\ 51LA"543#020Ł[ A related reaction involves the preparation of an
intermediate pyran which undergoes an electrocyclic ring opening to a substituted 1\3!dienone
"Equation "026## ð89CL002Ł[

NaBH4, Et2O, H2O, 0 °C


(136)
+ 40%
O O

OEt
i, p-TsOH, 50 °C
ii, TFA, CHCl3, 40 °C
O
+ EtSH (137)
74% F3C SEt
F 3C O OEt

2[94[0[1[00 From cyclopropanes


The opening of cyclopropane ring systems has been used to synthesise doubly unsaturated ketones[
Treatment\ usually with base\ furnishes cyclic ring expanded ketones in moderate yields "Equation
"027## ð70TL534Ł^ see also ð45JA3394\ 54CI"L#073\ 72JA4568Ł[ Thermolysis of the cyclopropane "11# leads
to the ketone "12# via a homo ð0\4Ł sigmatropic H!migration\ in 53) yield "Equation "028##
ð70JCS"P0#2036Ł[ The reaction of a!ketocarbenes with furans\ followed by in situ electrocyclic ring
opening of the intermediate cyclopropane\ yields doubly unsaturated ketone systems mainly as the
"Z\E# isomer "Equation "039## ð66AG"E#535\ 72TL4074\ 73TL24\ 78JOC4015Ł[ This reaction has also been
reported to occur intramolecularly yielding cyclopentenones "Equation "030## ð63TL1144\ 76HCA0318Ł[
Similar reactions involving intramolecular cyclisations onto aromatic rings are also known ð62CC771\
89JCS"P0#0936Ł^ see also ð67JA6816Ł[

i, Cl2CHMe, BuLi, Et2O, –30 °C


TMS-O ii, MeOH, 25 °C
iii, Et3N, reflux
O (138)
42%

O O
300 °C, PhH
(139)
64%

(22) (23)

MeO2C
MeO2C
O [Rh(OAc)2]2, 20 °C O
O
+ (140)
+ 80%
CHO
N N–

N– O
N+
[Rh(OAc)2]2, CH2Cl2, 20 °C
O (141)
95%

O CHO
a\b!Alkenic Bond 122
2[94[0[1[01 By Claisen rearrangements
The Claisen reaction can also be used to synthesise doubly unsaturated ketones in high yield from
propargylic alcohols via an intermediate isolable allene which is isomerised under basic conditions
"Equation "031## ð56HCA0047Ł[ Pyrolysis of propargyl acetoacetates results in a similar Claisen
rearrangement followed by decarboxylation to give doubly unsaturated ketones ð46JOC0500Ł[ The
sulfoxide "13# undergoes a zinc carbonate induced Claisen rearrangement and subsequent elim!
ination of benzene sul_nic acid to yield the ketone "14# in 74) yield "Equation "032## ð67CC597Ł[ An
exceptionally facile Claisen rearrangement has also been reported which yields a cyclohexadienone
ð65JOC567Ł[

i, TsOH, ligroin, 10 atm, 92%


ii, NaOH, MeOH, 0–10 °C O
OH + (142)
MeO 95%

SOPh

ZnCO3
(143)
O O
85%

(24) (25)

2[94[0[1[02 Carbonylation reactions


Doubly unsaturated ketones can be prepared via acylation reactions of dienes using carbon
monoxide and methyl iodide with cobalt catalysis "Equation "033## ð67CC200\ 68TL1554Ł[ Related
reactions involving iron! and nickel!catalysed carbonylations include ð74AG"E#385\ 76CB12Ł[

CO, MeI, Co2(CO)8, 20 °C O


Ph (144)
86% Ph

2[94[0[1[03 Miscellaneous methods


Metal catalysis enables the coupling of an enone with a vinyl halide to give a dienone "Equation
"034## ð70T3924Ł^ related reactions reviewed include ð74JOC426\ 76S69\ 77S593\ 78CL0848Ł[ The thermal
ring opening of cyclobutene has been used to furnish dienone systems in high yield "Equation "035##
ð59JA3222\ 58TL3876Ł\ as has the retro DielsÐAlder reaction ð74S010Ł[ The novel selenium!substituted
halobutadiene "15# leads to seleno!substituted dienone systems via the DielsÐAlder reaction with
methyl vinyl ketone followed by subsequent elimination of HCl "Equation "036## ð72TL336Ł[ The
addition of enamines to propargylic ketones gives a!alkenyl a\b!unsaturated ketones "Equation
"037## ð46CB1154Ł[ This is in contrast to the reaction of the enamine in Equation "038# ð52JOC2021Ł
with dimethyl alkynedicarboxylate\ which Huebner et al[ report to occur via a cyclobutene to give
a dienone which is isomeric with the product that would have been obtained if the reaction had
gone according to Equation "037#[

O
O

PdCl2, MeCN, Et3N, 25 °C


I (145)
55%
O
O
O
O
123 a\b!Unsaturated Ketones

O O
320–330 °C
(146)
91%

Cl O
O
Cl BF3, 25 °C Cl
+ (147)
86%
PhSe PhSe
(26)

O O O
O
MeOH, 20 °C
+ (148)
90%
NH2 NH2

O MeO2C
THF, 20 °C
MeO2C CO2Me + NH2 (149)
63%
CO2Me
NH2 O

2[94[0[2 Halogenated a\b!Unsaturated Ketones

2[94[0[2[0 1!Halogenated a\b!unsaturated ketones


"i# By elimination reactions
Elimination of an acid function from a substituted ketone such as "16# or "17# "Scheme 6# leads
to halo!substituted conjugated ketones[ For cyclic and:or symmetric ketones\ the "E#:"Z# geometry
is unambiguous\ and thus the elimination reaction is most often applied to these substrates[ The
elimination of HBr from "18# thus leads to "29# in excellent yield "Equations "049# and "040##
ð36OS"16#8\ 47CCC1044Ł[ Alternatively\ the hydrogen b to the carbonyl group can also be eliminated
under more forcing conditions "Equation "041## ð50JCS0472Ł\ "Equation "042## ð79JOC1925\ 72JA6247\
74JCS"P0#1082Ł[ AdditionÐelimination sequences on unsaturated ketones leading to halo!substituted
unsaturated ketones are also well known "Equation "043## ð50CB0114\ 50JCS1421\ 69JOC3030\ 79JOC0098\
77SC0212Ł[ Some noncyclic\ asymmetric cases where "E#:"Z# isomers are possible have been reported\
and single isomers have resulted in some examples ð70TL2920\ 71CJC1157Ł[ Other less common
reagents used in additionÐelimination type reactions have been IN2 ð60CJC2934Ł\ IF ð74JOC2231Ł\
ICl ð56AJC528Ł\ FClO2 ð50BSF448\ 72JOC0996Ł\ FSO1Cl ð65S22Ł\ and SO1Cl1 ð51CPB318Ł[ In a related
reaction\ epoxyketones "Equation "044## ð45JOC0321\ 63TL3266\ 65CL384\ 77JCR"S#199Ł\ can be treated
with halide ion to give a!halo substituted a\b!unsaturated ketones[
O O
LG base X
R R
X
(27)

O
O
X base
R X
R
LG
(28)
X = halogen
Scheme 7
a\b!Alkenic Bond 124
Br O O
NaOAc, EtOH
Ph Ph Ph Ph (150)
94%
Br Br
(29) (30)

O O
pyridine, RT
Br Br (151)
80%
H Br H

O O
Br
collidine, 210 °C Br
Br (152)
90%
H H

O O
Cl
H2O2, pyridine, CH2Cl2 Cl
SePh (153)
82%

O O
py•HBr•Br2, pyridine Br
(154)
57%

H Cl
O
O LiCl, THF, 65 °C O
H (155)
80%
O OMe O OMe

"ii# From cyclopropanes


Silyl enol ethers react with dihalocarbenes to a}ord 0\0!dihalo!1!siloxycyclopropanes in good
yields[ The cyclopropane can undergo rapid and e.cient ring opening to give the a!halo!a\b!
unsaturated ketone "Scheme 7# ð65S085Ł[ This is a simpler and more general procedure than that
previously established for enol acetates ð62JA5544Ł[ A related reaction has been applied to several
cyclic enol ethers[ In Equation "045# the ketone "20# is postulated to be derived via a dichloro!
cyclopropene intermediate ð58JOC23Ł[ However\ treatment of the cyclopropane "21# with silver
nitrate leads to the ketone "22# "Equation "046## ð61JCS"P0#778Ł[ The chloroketone "23# was isolated
in good yield by the reaction of the enamine "24# with sodium trichloroacetate in DME "Equation
"047##^ there is supporting evidence for the involvement of a dichlorocyclopropane intermediate in
this reaction ð69CC270Ł[

O O-TMS O-TMS O
TMS-Cl, TEA CHBr3, KOBut PhH, reflux
Br
DMF 85–95% 86%
Br Br

Scheme 8
125 a\b!Unsaturated Ketones
Cl Cl
EtO Cl
NaOMe, DMSO
O (156)
2-9%
S
S
(31)

Br O Br
Br
EtO
AgNO3, EtOH
(157)
48%
N N
Ts Ts
(32) (33)

O O

NaO2CCCl3, DME, reflux


O (158)
N
Cl

(35) (34)

"iii# Miscellaneous methods


A one carbon ring expansion has been used in the preparation of the enantiomerically pure
a!chloroenone "25# "Scheme 8# ð76JA3641Ł[ The key ð1¦1Ł cycloaddition proceeded with very high
"84 ] 4# diastereofacial selection[ A one pot HornerÐWittig procedure has been developed for the
synthesis of "E#!a!chloro!a\b!unsaturated ketones in which the keto enolate reagent "26# is prepared
in situ and reacted with the requisite aldehyde "Scheme 09# ð67S18Ł[ This bears a strong resemblance
to the Wittig reaction between the halophosphorane "27# and benzaldehyde leading to the a!chloro!
a\b!unsaturated ketone "28# "Scheme 00# ð51JOC887Ł[ An alternative approach to the formation of
a!halo!unsaturated ketones involves the attack of a carbon nucleophile onto an a!halo!a\b!unsatu!
rated ester "Equation "048## ð76BSF750Ł[ Simple Grignard reagents can also be used as the nucleophile
ð69BSF880Ł[

Cl O O
O Cl
Cl3CCOCl Cl CH2N2 Cr(ClO4)2 Cl
Cl 0 °C
Zn-Cu
RO Ar
O RO Ar Ar
(36)
Ph

Scheme 9

O O O
O i, BunLi, –90 °C PhCHO, 40 °C
P(OEt)3
Cl3C P(OEt)3 But Ph But
ii, ButCOCl, –125 °C 76% overall
Cl Li Cl
(37)

Scheme 10
a\b!Alkenic Bond 126
O O
O i, Cl2 PhCHO, 90–95 °C
PPh3
PPh3Br Ph
ii, NaOH 98%
Cl Cl
(38) (39)

Scheme 11

O O–
F CO2Et
O– F S+
CH2Cl2, Et2O Me
+ S+ Me (159)
Me 93%
Me

A general route to tri~uorovinyl ketones involves a copper"I#!mediated acylation of tri~uorovinyl


zinc at room temperature "Equation "059## ð75BSF765Ł[ The same reaction has also been observed
using palladium as the catalyst ð74TL2888Ł[ A similar reaction involving benzoylsilanes as the
electrophile has been reported ð80TL72Ł[ A general procedure for the preparation of both a!~uoro
ð67S017Ł and a!chloro a\b!unsaturated ketones ð67S347Ł has been reported by Normant et al[ It
involves a three stage procedure via an intermediate carbinol "39# and subsequent isomerisation in
sulfuric acid at low temperature "Scheme 01#[ The same rearrangement has also been used in a
synthesis of the a!~uoroketone "30# "Scheme 02# ð78JOC4539Ł[
F F
CuBr, TRIGLYME
F + F But
ZnX But COCl (160)
81%
F F O

F X
OLi F OH F X
O F Li R1 i, R3Li R1 96% H2SO4
R1 O
R2 F R2 R3
R1 R2 X = F, Cl ii, H3O+ –30 °C
X X R2 R3
(40)

Scheme 12

F F F F
F OH MeLi, RT H2SO4, 100 °C, TCE
OH O
56%
F F
(41)

Scheme 13

A mild transformation for the conversion of a!hydroxy!a\b!unsaturated ketones into a!halo!a\b!


unsaturated ketones has been developed as a result of the failure of traditional reagents "e[g[ SOCl1#[
Thus the ketone "31# is halogenated as shown in Scheme 03 to give the ketone "32# in 79) overall
yield[ The reaction is general for both _ve! and six!membered rings\ and will tolerate signi_cant
substitution\ for example synthesis of the ketone "33#[ The mechanism is postulated as involving the
bicyclic intermediate "34# ð75JOC3640Ł[ Reaction of dichloroketene with alkynes gives an equilibrium
mixture of dichlorocyclobutenones following rearrangement of the primary products in situ with
zinc chloride "Equation "050## ð59JA2091\ 76HCA210Ł[
S
Me2NC(S)Cl, LiOH LiX, MeCN, AcOH
HO Me2N X
O
MeCl, H2O 80 °C
O O
O
(42) (43)

Scheme 14
127 a\b!Unsaturated Ketones

+
S
Me2N
Cl O
O O

(44) (45)

R1 O O
O
35 °C Cl R1
+ • R1 + Cl (161)
Cl Cl
Cl Cl
R2 R2 R2

2[94[0[2[1 2!Halogenated a\b!unsaturated ketones


The syntheses of b!halo substituted a\b!unsaturated ketones have been reviewed previously
ð55CRV050Ł[

"i# From alkynes


Reactions of acid halides with alkynes under FriedelÐCrafts conditions is a well!established
method for preparing b!halo substituted a\b!unsaturated ketones ð25JOC052\ 53JOC274\ B!53MI 294!90Ł[
Where the alkyne is acetylene\ solely trans b!addition is observed\ for example Equation "051#
ð52OSC"3#074Ł[ Apparently mixtures of "E# and "Z# isomers can be produced if other alkynes are
used ð69TL0710\ 62T3130\ 64T066Ł\ although the "E# and "Z# isomers of these compounds can be
interconverted under some reaction conditions[ A number of intramolecular cyclisations using this
reaction have also been reported "e[g[ Equation "052## ð67TL1290\ 79JHC178Ł[ In addition\ {alkyne
equivalents| have been used ð38JCS0329\ 74TL3800Ł\ for example vinylidene chloride "Equation "053##[

O O
AlCl3, acetylene
(162)
Cl 60%
Cl

Cl O Cl O
AlCl3, (CHCl2)2
(163)
64%
S S

Cl
O AlCl3
+ Cl (164)
Cl Cl Cl 80%
O

A highly ~exible general route to b!halo!substituted a\b!unsaturated ketones that can give good
yields of either "E# or "Z# isomers is the addition of HX to an alkyne ketone "Scheme 04#
ð58JCS"C#0193Ł[ Kishi et al[ have shown that TFA solutions of sodium iodide give good yields of the
"E#!iodo vinyl ketones "35# "Scheme 05#\ but in acetic acid the major product is the "Z# compound
"36# ð75TL652Ł[ The reaction will work even on disubstituted alkynes with TMS!I etc[ to give the
"E#!b!iodo vinyl ketones "37# "Equation "054## ð75TL3648Ł[ Alternatively\ the intermediate iodo!
metallated species can be trapped by other electrophiles "Scheme 06# ð75TL3656Ł[ The hydro!
chlorination of allenic ketones has been investigated and is useful for the preparation of the b!"E#
isomers "Equation "055## ð72BSF"1#78Ł[
a\b!Alkenic Bond 128
O
HX (or DX)
20 °C R X
O

R
O X
HX (or DX)
–40 °C
R

Scheme 15

O
NaI, TFA
95% n-C5H11 I
O
(46)
n-C5H11
O I
NaI, AcOH
70%
n-C5H11
(47)
Scheme 16

O O

TMS-I I
O O (165)
O O

(48)

O OH
O OM
MI, M = TMS, Et2Al or Bun4N RCHO
n-C5H11 R
n-C5H11 n-C5H11 • I
I

Scheme 17

Cl
• SnCl4
(166)
82%
O
O

"ii# By halo`enations of 0\2!dicarbonyl compounds


The halogenation of 0\2!dicarbonyl compounds or their equivalents is one of the most widely
reported reactions for the preparation of b!halo!a\b!unsaturated ketones[ The reaction proceeds in
a similar fashion to the VilsmeierÐHaackÐArnold reaction discussed in Section 2[91[0[2[1[ Unless
cyclic and symmetric diketones are used\ a mixture of stereo! and regioisomers can result[ Reagents
used for the reaction include "COCl#1 ð63S36Ł\ POCl2:DMF ð74S673Ł\ Br1:PPh2\ SOCl1\ PCl2 etc[
ð36G438\ 47JGU2913\ 63CJC509\ 67CL354\ 77JCR"S#197Ł[ Good yields can be obtained for cyclic symmetrical
ketones ð64S697\ 64SC082\ 71CJC109\ 78TL2642Ł\ for example Equation "056#[ For asymmetric cyclic
systems\ mixtures often result "Equation "057## ð75CJC419Ł\ but single regioisomers have been
isolated in certain cases\ "Equation "058## ð46JA3376Ł[ The regiochemistry has also been controlled
in cases where one carbonyl group is more readily enolisable "Equation "069## ð65JOC525Ł[ The
stereochemistry seems more complex\ with the "E#!isomer predominating in most cases "Equation
"060## ð70S761Ł\ although pure "Z#!isomers have also been reported ð65JOC525\ 71CJC109Ł[ Enol
sulfonates also react with halogen nucleophiles to produce b!halo!a\b!unsaturated ketones "Equa!
tion "061## ð58LA"612#000\ 70JOC086Ł[
139 a\b!Unsaturated Ketones
O O O Cl
Et3N, Ph3PCl2, 25 °C
(167)
91%

H O H O H Cl

LiH
+ (168)
PhOPOCl2
H O H Cl H O
EtO2C EtO2C EtO2C
2:3

O O
PCl3, CHCl3
(169)

O Cl

O O Cl
CHO (COCl)2
(170)

O O
Ph3PBr2
(171)

O Br
(E):(Z) 93:7

O O
BF3•Et2O, PhCH2NEt3X
(172)
72–93%
Ms X
X = Cl, Br, I

2[94[0[3 Oxygen!substituted a\b!Unsaturated Ketones

2[94[0[3[0 1!Oxygen!substituted a\b!unsaturated ketones


"i# From a!metallated enol ethers and acylatin` a`ents
The easiest method to achieve a!acylation of an enol ether is via a Pd!catalysed reaction of the
vinyltin derivative with an acid chloride "Equation "062## ð72TL1250\ 78JOC3610\ 89TL2322Ł\ as used
extensively by Kocienski et al[ The reaction has also been applied to stannyl dioxin compounds "38#
"Equation "063## ð89S644Ł[ The vinyllithium compounds have also been used\ but yields seem
generally lower "Equation "064## ð77H"16#540\ 78JOC2802Ł[ 1!Acyl benzodioxins have been prepared
by a FreidelÐCrafts acylation reaction of the 1!silyl substituted derivative "Equation "065## ð75S226Ł[
O
Me3Sn OMe Pd
+ n-C7H15COCl OMe (173)
85% n-C7H15

O
O
Cl PdCl(PPh3)2CH2Ph, C6H6
+ O (174)
95% O O
O SnBu3 O
O
(49)
a\b!Alkenic Bond 130

ButLi, THF
+ (175)
59%
O OH
O O O
O

O
O
AlCl3
+ n-C5H11COCl n-C5H11 (176)
66% O
O TMS
O

"ii# From a!alkoxyketones and a carbonyl compound


Condensation reactions of a!alkoxyketones with aldehydes or ketones\ as in Equation "066#\ lead
to the formation of an a!alkoxy a\b!unsaturated ketone[ This procedure has been used several times
with a!alkoxy vinylketones in a Robinson annelation type reaction "Equation "067## ð71JA2656\
74TL692Ł[ Synthetic equivalents to vinyl ketones have also been used in this procedure "Equation
"068## ð72JA1929Ł\ and enamines can be used instead of carbonyl compounds under acidic conditions
"Equation "079## ð68JOC2955Ł[ The condensation reactions of aldehydes with 2!furanones leading to
aurones "Equation "070## gives only the "Z# isomers ð61JCS"P0#1017\ 68JHC710Ł^ see also ð31JA271\
63BSF0932\ 66CB380Ł[ In a similar manner\ bromoketones have been used to prepare the aurones when
a b!hydroxy group is present in the ketone "Equation "071## ð44JCS751\ 53JOC1914\ 80JHC700Ł[
O
O O R2O
R2 O + R1 (177)
R1 R4 R3
R4 R3

O O O

O Zr(OPrn)4
i, O
ii, NaOMe
(178)
63% H

MeO MeO

O O
trans : cis 25 : 1

O
O
O MeO
OMe KOEt
+ (179)
57%
MeO

N O OMe
AcOH
+ OMe (180)
69%

O
O
O
i, EtOH
ii, HCl
+ O (181)
O 83%

OMe
OMe
131 a\b!Unsaturated Ketones
O O
OH Ph
MeOH O
Br + PhCHO (182)
89%

O O

"iii# From oxidative cyclisations of hydroxy!substituted vinyl ketones


A related scheme to that shown under "ii# above for the preparation of aurones is from
b!hydroxy chalcones "Equation "072## ð64CC661Ł[ Use of Hg"OAc#1 gives only the "Z#!aurones by a
stereoselective oxymercuration and deoxymercuration process[ Hydrogen peroxide has also been
used ð59CI"L#237\ 63IJC0941Ł\ and silver nitrate is reported to give only the "Z#!aurones on reaction
with "1!hydroxyaryl#alkynones ð89JCS"P0#312Ł[

O O
i, Hg(OAc)2
ii, CaO
Ph (183)
54%
MeO O Ph
MeO OH

"iv# By elimination reactions from a!alkoxy!substituted ketones


Additions of alcohols to a!epoxyketones under basic conditions lead to a!alkoxyenones "Equa!
tion "073## ð43JA3007\ 60JCS0181\ 73JOC0940Ł[ Alternatively\ Trost et al[ have shown that a!thioketones
can be a!acetoxylated\ then oxidised and pyrolysed to give a!acetoxyenones "Equation "074##
ð65JA4906Ł[
O
OMe
NaOH, MeOH, H2O
(184)
95%
O O

O O
SPh i, Pb(OAc)4 OAc
ii, mcpba
(185)
86%

OCOPh OCOPh

"v# From a\b!unsaturated ketones


The hydrazones of a\b!unsaturated ketones can be brominated and alkoxylated to give the
compounds "49# "Equation "075##[ These can subsequently be transformed into the corresponding
a!alkoxy!a\b!unsaturated ketones by a hydrazone exchange and elimination procedure ð89CB288Ł[

S N Me i, HCHO, HCl O
ii, dbu OMe
(186)
N
N 78%

OMe

Br
(50)
a\b!Alkenic Bond 132
"vi# Miscellaneous methods
Additions of Grignard reagents to a!alkoxyacrylonitrile give good yields of the a!alkoxy!
vinylketones "Equation "076## ð60CR"161#0934\ 72JCS"P0#50Ł[ Transition metal catalysed carbonyl inser!
tion reactions have been investigated\ including the Pd!catalysed coupling reactions of a!
alkoxyvinylstannanes and vinyl tri~ates "Equation "077## ð89JOC2003Ł\ and intramolecular PausonÐ
Khand reactions ð89TL6494Ł[ A Wittig!type reaction has also been described ð64TL3242Ł[

i, MgBr O
NC OEt
OEt (187)
ii, H+

O
O2SCF3 EtO SnMe3 CO, Pd(PPh3)4, LiCl, THF OEt
+ (188)
82%

2[94[0[3[1 2!Oxygen!substituted a\b!unsaturated ketones


Note] 2!hydroxy!a\b!unsaturated ketones are not covered here as these are tautomeric isomers of
0\2!diketones[

"i# By DielsÐAlder reactions


An important and well!used synthetic procedure furnishing cyclic 2!oxygen!substituted
a\b!unsaturated ketones "dihydro!g!pyrones# involves a hetero DielsÐAlder reaction between the
dioxygenated diene "40#\ commonly known as Danishefsky|s diene\ and an aldehyde carbonyl group\
as the dienophile\ in the presence of a Lewis acid catalyst "Equation "078## ð71JA247\ 71JOC2072Ł[
High Cram rule selectivity was observed in similar reactions with chiral aldehydes enabling the
synthesis of homochiral dihydropyrones "Equation "089## ð71JA259\ 71JOC0870\ 77JA6323Ł[ Numerous
modi_cations have been made to Danishefsky|s diene enabling greater functionality to be introduced
into the adduct[ The use of alkyl substituents on the diene leads to the possibility of cis:trans
isomerisation[ Thus the cyclocondensation of the diene "41# with aldehyde "42# gave the cis!1\2!
dihydropyran almost exclusively in the presence of zinc chloride\ whereas if BF2 = Et1O was used as
the Lewis acid catalyst\ the reaction is assumed to proceed via a di}erent pathway and the major
product is the trans!1\2!dihydropyran "Equation "080## ð74JA0135Ł[ Other noteworthy examples
which have been reviewed include ð74JOC3459\ 77JA3257Ł[

OMe O
PhH, ZnCl2, 20 °C O
+ (189)
87%
OBn
O
TMS-O OBn
(51)

OMe H O
H O O
O PhH, ZnCl2, 20 °C
+ (190)
O 72% O H
TMS-O O

OMe
O
ZnCl2, THF, 25 °C
+ Ph Ph (191)
O O
83%
TMS-O

(52) (53)
133 a\b!Unsaturated Ketones
The introduction of further oxygen functionality into the diene has also proved successful[ Thus
the diene "43# gave the oxygen!substituted pyrone "44# "Equation "081## ð73JOC281Ł "reaction of this
diene with an ordinary dienophile also leads to an oxygen!substituted enone system ð67JOC268Ł#\
whereas the diene "45# gave the cis!pyrone "46# which has been used in the total synthesis of
lincosamine "Equation "082## ð74JA0163Ł[ The diene "45# has also been substituted with further
unsaturation in the form of an aromatic system ð77JA2818Ł[ Asymmetric induction has been observed
via the use of chiral Lewis acid catalysts ð77JA209\ 78TL0078Ł\ and some ketones have been reported
to act as dienophiles for this cyclocondensation ð76CC645Ł[
OMe MeO O Ph
O Eu(fod)3, CDCl3
OMe + (192)
Ph 85%
TMS-O O
(54) (55)

fod = 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedionate

OMe
i, BF3•Et2O
O
ii, TFA
+ O (193)
67%
TMS-O BzO
OBz O
(56) (57)

"ii# From alkynes


Barrett et al[ have reported a reaction in which the dianion of a 0\2!diketone condenses with an
ester carbonyl to furnish a dihydropyrone in high yield ð70CC445Ł[ A very similar transformation
involves the addition of a lithium acetylide "47# to a lactone or other carbonyl group followed by
acid!catalysed cyclisation to give a 1\2!dihydro!3!pyrone "Equation "083## ð72TL4292\ 89JOC4783Ł[

MeO i, BunLi
ii, K2CO3, MeOH O
+ (194)
iii, HClO4 O
O O O
(58)

A commonly used route to 2!oxy!a\b!unsaturated ketones involves the addition of an alcohol to


an alkynyl ketone\ which can be carried out both intermolecularly ð36JA62\ 80JCS"P0#0228Ł and
intramolecularly ð66JOC2735\ 76TL2352Ł^ see also ð77TL4830\ 89SC2952Ł[ The hydration of substituted
acetylenic alcohols has been reported to lead to cyclic furanones in good yield[ Thus\ treatment of
the alkynic alcohol "48# with BF2 in ethanol\ catalytic mercuric oxide and trichloroacetic acid\
followed by aqueous work up gave the furanone "59# "Equation "084## ð70TL2454Ł[ Other examples
include ð52JOC576\ 72BCJ2977Ł\ and hydroxybutadiynes behave similarly ð64JOC0319Ł[
EtO
OEt
BF3•Et2O, CCl3CO2H O
HgO, EtOH
(195)
68%
OH O

(59) (60)

"iii# By Witti` reactions


The Wittig reaction has provided a useful route to 2!oxyenone systems[ 2"1H#!Furanones have
been synthesised by the intramolecular WadsworthÐEmmons condensation of g!"acyloxy#!b!
a\b!Alkenic Bond 134
ketophosphonates in high yield "Equation "085## ð73TL3356\ 75JOC1414\ 77JOC1900Ł[ This reaction was
used in a formal total synthesis of the triquinane modhephene ð80JOC3036Ł[ Other Wittig reactions
of interest include the reactions of a!ketophosphonates with formate esters ð89JCS"P0#0228Ł\ and the
addition of ketones to 1\1!diethoxyvinylidenetriphenylphosphorane "50# to give a new phosphorane
which then undergoes Wittig reactions with aldehydes "Scheme 07# ð65CB392\ 66AG"E#238Ł[

O O O
K2CO3, DMF, 115 °C
(EtO)2P O But (196)
70% But
O O

EtO acetone O OEt Ph CHO O OEt


• PPh3
PPh3 53%
EtO 55% Ph
(61)

Scheme 18

"iv# Preparation of 2"1H#!furanones


There have been many methods reported for the preparation of 2"1H#!furanones\ and these
include] oxidations of furans ð76TL1186Ł\ hydrolysis of substituted furans ð46HCA1351\ 52HCA0148Ł\
intramolecular alkylations and subsequent acid eliminations "Equation "086## ð75JHC0088Ł\ hydro!
lytic cyclisations of allene systems such as "51# "Equation "087## ð64TL0630Ł\ and cyclisation of
1\1?!dibromoketones with DMF under Fe1"CO#8 catalysis "Equation "088## ð62JA3092Ł[ An inter!
esting transannular aldol condensation has also been reported\ yielding the bicyclic 2"1H#!furanone
"52# "Equation "199## ð77TL5786Ł as the only product[

O i, Br2, CCl4 O
ii, NaOH, EtOH
Ph (197)
90% Ph
OH O

OMe O
• p-TsOH, H2O, MeCN, 100 °C
Ph (198)
MeS Ph 93%
Ph OH O Ph
(62)

Br Br O
Me2NCHO, Fe2(CO)9
(199)
64%
O O

O i, NaH, DMSO, 95 °C O
ii, H2SO4
O (200)
62%
O O

(63)

"v# By acylations of vinyl ethers


The Pd!catalysed Heck aroylation of vinyl ethers gives "E#!b!alkoxyenones "53# in good yields
"Equation "190## ð76TL3104\ 77JOC3146Ł[ b!Alkoxyvinylstannanes also couple with acid chlorides
under palladium catalysis ð89S644Ł[ More reactive acid halides and anhydrides "e[g[ trichloro or
tri~uoroacetyl# do not appear to need palladium catalysis\ and they react directly with vinyl ethers
135 a\b!Unsaturated Ketones
via an additionÐelimination mechanism\ to give the "E#!b!alkoxyenones "54# "Equation "191##
ð65CL388\ 71CB1655\ 77S163\ 78CB0068\ 80S372Ł[ Acetals can also be acetylated under similar conditions
"Equation "192## ð75S0902Ł and a similar procedure using silylenol ethers and oxalyl chloride
gives furandiones "Equation "193## ð64AG"E#525Ł[ Enol lactones have also been acylated by acetic
anhydride in perchloric acid ð58JOC1656Ł[ In a related reaction\ ketene acetals have been shown to
react with ketenes to give b\b!dialkoxyenones ð70JOC3936Ł[

O Cl O OBut

OBut Pd(OAc)2, Et3N


+ (201)
77%

OMe OMe
(64)

OEt O
O pyridine
+ (202)
79%
Cl3C OEt
Cl3C Cl

(65)

O
OMe pyridine, CHCl3
+ (CF3CO)2O CF3 (203)
OMe 94%
MeO

O O
Et2O
+ Cl (204)
Cl
Ph O-TMS 85%
Ph O
O O

"vi# From 0\2!dicarbonyl compounds\ and a 0\1! or 0\2!dielectrophile


Furan!2!ones\ e[g[ "55# can readily be prepared by the reaction of a 0\2!dione with an a!halo acid
chloride or other 0\1!dielectrophile "Equation "194## ð61CR"164#786\ 62CL314\ 62RTC620\ 64JOC0816\
67S180Ł[ There are also many examples of 0\2!diones reacting with 0\2!dielectrophiles to give dihydro!
pyranones "Equations "195# and "196## ð70T698\ 72TL1948\ 73JHC02\ 74TL3616\ 76BSF762\ 89CB0064Ł[
O
CO2Et EtO2C O
O
Mg(OEt)2
+ Cl
(205)
70% O
Cl MeO
OMe
(66)

O
O O O
MeLi CO2Et
CO2Et + (206)
Ph Cl Cl 52%
O O Ph

O
O O Mg(OEt)2 CO2Et
+ (207)
CO2Et 50%
Cl
O
a\b!Alkenic Bond 136
"vii# From ð1¦1Ł cycloaddition reactions between alkoxyalkynes and ketenes
Alkoxy and siloxy alkynes add smoothly to ketenes leading to 2!alkoxy!1!cyclobutenones "Equa!
tion "197## ð47RTC650\ 62JOC0340\ 74S0007\ 77JA2582Ł[

O
CH2Cl2
ButO + H2C • O (208)
70%
ButO

"viii# Miscellaneous methods


The displacement of a leaving group from a 2!substituted enone by an oxygen nucleophile has
been utilised to provide 2!oxy enone systems[ The leaving groups used have included chloride\
quaternary nitrogen and alkylthio ð60CB109\ 79S0902\ 89TL1102Ł[ Other miscellaneous reactions
include] alkoxy methylenations of 0\2!dicarbonyl compounds by treatment with an orthoester in
acetic anhydride ð40JA4057\ 50JCS2143Ł\ hydrogenations of 4!hydroxymethylisoxazoles under acidic
conditions furnishing dihydrofuranone systems in very good yield ð64JGU1461\ 80H"21#838Ł and
oxidations of 2!oxy!allylic alcohols using manganese dioxide and silver carbonate on celite
ð69HCA0378\ 72TL3640Ł[ The oxygenated furan "56# is an e}ective diene in DielsÐAlder reactions and
the resulting adducts rapidly ring open to give highly substituted cyclic 2!oxy enones in very good
yields "Equation "198## ð71TL242Ł[

O O O
MeO
+ O O (209)
80%
O O-TMS MeO
O OH O
(67)

2[94[0[4 a\b!Alkenic Ketones with Sulfur!based Substituents

2[94[0[4[0 1!Thio a\b!unsaturated ketones


"i# By aldol condensation reactions
Probably the most common procedure for the preparation of a 1!thio!a\b!unsaturated ketone is
via an aldol condensation from a 1!thioketone[ Thus condensation of the ketone "57# with the
aldehyde "58# gave a low yield of the natural product conjugated thietanone "69# "Equation "109##
ð63CB1004Ł[ Woodward et al[ found that 2!ketotetrahydrothiophene "60# condensed smoothly twice
with furfuraldehyde or benzaldehyde to give the doubly unsaturated ketone "61# in good yield
"Equation "100## ð35JA1118Ł[ A similar aldol condensation involving the thienothiophene "62# under
acidic catalysis gave the dinitro condensate "63# in high yield "Equation "101## ð51LA"548#89Ł[ This
type of methodology has been most commonly applied to make aromatic ketones from thioindoxyl
type systems "Scheme 08# ð36JIC362\ 42JIC268\ 47CB219\ 51JOC2777Ł\ and isothiachromanone systems
ð68ACS"B#558\ 79CB0697Ł[ A similar condensation involving the dialdehyde "64# led to the bicycle "65#
"Equation "102## ð65AG"E#271Ł[ Activation of the methylene a to the carbonyl group by a sulfone
moiety accelerates the reaction "Equation "103## ð41JGU167\ 58JOC1228Ł[ A related condensation gave
the ketone "66# by acylation of the precursor "67# "Equation "104## ð65CB1817Ł[

O O
KOH, MeOH
+ (210)
S CHO S S
S
(69) (68) (70)
137 a\b!Unsaturated Ketones
O R
O
NaOH (aq.), EtOH
+ R O (211)
S
S
R
(71) (72)

R = Ph,
O

NO2

CHO O O
O OH
Ac2O, AcOH, 120 °C
+ (212)
82% S S
S S
NO2
(73)
O2N
(74)

O Cl Cl
Cl Cl
Cl
Cl CHO
S
O BF3•Et2O
86%

S O
O
O S
HCl, AcOH, 110 °C
87%

S O

Scheme 19

O O OHC CHO
S morpholine
+
84%
N
Cl Cl H
(75)

O O
S

(213)
Cl Cl

N
H
(76)

O
CO2Et
NaH, DMSO, THF
SO2Me (214)
70%
CO2Et
SO2Me
a\b!Alkenic Bond 138
O
S i, ButLi
ii, AcCl, 70 °C S
O (215)
33% OH
S
S
(78) (77)

"ii# By Pummerer reactions


The Pummerer reaction has proved to be an e}ective tool in the synthesis of a number of sulfur!
substituted cyclopentenones "Equation "105## ð74S532Ł[ A related Pummerer rearrangement has
given rise to a number of 1!phenylthio!a\b!unsaturated ketones\ both cyclic and acyclic\ in high
yield under mild conditions\ from the precursor sulfoxides "Equation "106## ð64S326Ł[ A Pummerer
reaction was used by Trost et al[ to give the ketone "68# in order to characterise the sulfoxide "79#\
an intermediate in the synthesis of a gibberellin model compound "Equation "107## ð67JOC0920Ł[ A
related procedure involves the treatment of cyclopentanone with an excess of phenylsulfenyl chloride
and gives the ketone "70# in 59) yield via 1!phenylthio!1!cyclopentanone "Equation "108##
ð66JOC1213Ł[

O SMe
S
Me p-TsOH, PhH, 80 °C H
O (216)
O 75%

O O O

S Ac2O, MeSO3H SPh


Ph (217)
75%

O
S O S O
I2, MeOH
(218)

Ph3CO Ph3CO

(80) (79)

O O
PhSCl, MeCN, 20 °C
SPh (219)
60%

(81)

"iii# Miscellaneous methods


A general method leading to 1!alkylthio!1!cyclohexenones involves the nucleophilic cleavage of
a 1\2!epoxycyclohexanone by a sulfur nucleophile followed by in situ dehydration\ for example
with an alkylthiol as nucleophile "Equation "119## ð69JOC0698Ł or with thiocyanate as nucleophile
ð68TL0018Ł[ Treatment of a series of butanones with thionyl chloride produces 2!thiatanones via
exclusive oxidation of the methylene position and subsequent cyclisation "Scheme 19# "Equation
"110## ð69JA4147\ 64JOC2068Ł[ 1!Sulfonyl!1\2!enones have been prepared via formation of the sul!
fonylvinyl anion from phenylvinyl sulfone and quenching with an aldehyde to give an intermediate
carbinol "71#[ The alcohol is then oxidised by a modi_ed Jones oxidation to give the requisite ketone
149 a\b!Unsaturated Ketones
"72# in moderate yield "Scheme 10# ð80JOC3987Ł[ Similarly acylation of the lithiated propenoate "73#
with the acid chloride "74# gave the ketone "75# in good yield "Equation "111## ð68CL674Ł[

O O
NaOH, EtOH, 20 °C S
+ SH (220)
O 81%

Cl
Cl SCl Cl S
Ar
Ar Ar
O
O O
H

Cl S Ar S
Ar

H O O

Scheme 20

NO2
S
SOCl2, pyridine, 70 °C
O (221)
43% O2N

OH O
dabco, RCHO Jones oxidation
PhSO2 PhSO2 PhSO2
R R

(82) (83)
dabco = 1,4-diazabicyclo[2.2.2]octane

Scheme 21

Li But O
ButCOCl (85), THF, –80 °C
CO2Me CO2Me (222)
PhS 72% PhS

(84) (86)

Thermal rearrangement of the diazoketone "76# gives a quantitative yield of the ketone "77#\ and
the reaction is postulated to proceed via a Wol} rearrangement involving a selective shift of the
sulfur bridge "Equation "112## ð79JOC3793Ł[ A similar rearrangement occurs with the ketone "78# in
the presence of triphenylphosphine dibromide^ this reaction is thought to involve an unstable
sulfonium salt formed by transannular reaction "Equation "113## ð58RTC883Ł[ 1!Sulfonyl!a\b!unsatu!
rated ketones can be prepared by the oxidative ring cleavage of 3!isoxazolines with mcpba in
excellent yield[ The starting isoxazolines are easily prepared by the cycloaddition of nitrones and
alkynes "Equation "114## ð76TL802\ 77JOC1127Ł[ Additions of 0!lithio!0!phenylpropa!0\1!diene to
ketones\ followed by tri~uoroacetylation\ 2\2!rearrangement and methanolysis of the resulting
dienol tri~uoroacetate\ lead to the C!2 homologated a!phenylthioenones in moderate yield "Equation
"115## ð72CC374Ł[ An exactly analogous reaction has been achieved by the photolysis of a diketone
with a sulfur substituted alkyne^ this reaction is thought to proceed via ring cleavage of an inter!
mediate oxete "Equation "116## ð63TL3068Ł[ An excellent yield of the 1!alkylidene!3\4!dihydro!
thiophen!2!one "89# can be obtained by the cyclo!condensation of a!thiolcinnamic acid "80# with
the nitrostyrene "81# under DeanÐStark conditions "Equation "117## ð62IJC017Ł[
a\b!Alkenic Bond 140
N–
O
O N +
99 °C
(223)
100%
S
S
(87) (88)

O OH
O
Ph3P•Br2, DMF, 153 °C
(224)
55%
S
S
(89)

Me
Ph Ph
N
mcpba, 25 °C PhSO2
O (225)
PhSO2 98%
O

i, TFAA, 0 °C O
O PhS Li ii, 65 °C SPh
iii, MeOH, K2CO3
+ •
(226)
47%

O SBut O
O
hν, PhH
Ph + (227)
Ph Ph SBut
45%
O Ph

S Ph
SH PhH, 80 °C
Ph + Ph Ph
O2N (228)
CO2H 90%
O NO2
(91) (92) (90)

2[94[0[4[1 2!Thio a\b!unsaturated ketones

"i# By condensation reactions


The condensation of an enolate with carbon disul_de and subsequent alkylation is a facile
procedure to 2\2!dithio a\b!unsaturated ketones[ The usual method is to use a hindered base to
form the enolate "Equation "118## ð70JOC4920Ł^ however\ potassium ~uoride on alumina has been
found to be e}ective ð80S290Ł as has the use of a silyl enol ether ð72CC0267Ł[ This reaction has also
been used in the preparation of the dihydrothiapyrone "82# involving intramolecular cyclisation of
the intermediate dithiocarboxylic acid "Equation "129## ð66S361Ł[ A very similar preparation of a
thiapyrone has also been reported ð76TL3156Ł[ A related reaction involves treatment of a ketone
with two equivalents of 0\2!benzodithiolylium "83# to a}ord the unsaturated ketone "84# as product[
It is postulated that the second equivalent of "83# is involved in oxidising the intermediate adduct
formed by alkylation of the ketone enolate "Equation "120## ð76CL828Ł[ The 2!hydroxythiophene
"85# can be dimerized oxidatively using ferric chloride to give the purple pigment "86# "Equation
"121## ð43CB730Ł[ This methodology has been widely used in the synthesis of thioindigo and related
species ð95CB0959\ 61JHC060\ 79CB0697Ł[
O i, LDA, CS2, 0 °C O SMe
ii, LDA, MeI
SMe (229)
84%
141 a\b!Unsaturated Ketones

O i, NaH O
ii, CS2
CN iii, MeI CN
(230)
75%
Ph Ph S SMe
(93)

O S
S DCM, 20 °C
BF4 –
+ +
S
(231)
S 74%
O
(94) (95)

OH O O
FeCl3, 20 °C
(232)
HO2C S S S
HO2C CO2H
(96) (97)

"ii# By b!leavin` `roup displacement reactions


The displacement of a halogen leaving group from an activated 2!halo!1!alkenone by a sulfur
nucleophile has been used to prepare b!thioalkenones in very high yields[ Thus\ reaction of the
b!chloroenone "87# with thiophenol "88# gave the ketone "099# in quantitative yield "Equation "122##
ð65JCS"P0#0035Ł[ Similarly\ the hindered thiol "090# reacts with b!chloroenone "091# under basic
conditions to yield the ketone "092# "Equation "123## ð68TL1798Ł[ Sodium thiocyanate has also been
used as the nucleophile ð52JOC1422Ł as has sodium sul_de ð65IZV1939Ł[ An analogous procedure
utilising a nitrogen leaving group has also been reported[ Thus the thiophene precursor "093# was
isolated from the condensation reaction between the ketone "094# and the thiol ester "095# "Equation
"124## ð89SC1426Ł[

Cl S
SH
NaOEt, EtOH, 20 °C
+ (233)
100% NH2
NH2
O O
(99) (98) (100)

Cl NaOH (aq.), 25 °C O
ButSH + (234)
O 85% SBut
(101) (102) (103)

O EtOH, reflux O
+ + HS CO2Et (235)
NEt3 82% S CO2Et
(105) (106) (104)

"iii# From alkynes


Additions of H0S across the triple bond of an acetylenic ketone provide a general route to
2!thio a\b!unsaturated ketones[ Exposure of the alkynic ketone "096# to hydrogen sul_de gave
predominantly the trans!dihydrothiapyrone "097# in very good yield "Equation "125## ð70JA3486Ł[
Similarly the thiophenol "88# added twice to the ketone "098# to give the adduct "009# in 49) yield
"Equation "126## ð63JOC732Ł[ Other similar additions reviewed include ð35JCS834\ 40JA1433Ł[ Tandem
a\b!Alkenic Bond 142
additions to two alkynes have also been observed\ "Equation "127## ð56CB096Ł\ and similarly other
reviews include ð57T3174\ 66JOU368Ł[
CO2Me CO2Me
O O
H
H2S, NaOAc, EtOH, 80 °C
(236)
OMe 78% OMe
S
H
OMe OMe
(107) (108)

SH O O
NaOMe, MeOH, 20 °C
+ (237)
50%
S S
NH2
NH2 NH2
(99) (109) (110)

O
Na2S2, MeOH, 20 °C
O
S S
(238)
94%

"iv# From 0\2!dicarbonyl compounds


2!Thio a\b!unsaturated ketones can be prepared from the corresponding 2!hydroxy compound
by condensation reactions with a thiol under acidic DeanÐStark conditions[ Then!butylthiomethylene
group has been used as a blocking group for the directed alkylation of ketones "Equation "128##
ð51JOC0504Ł[ Other examples reviewed include ð62JA149\ 71TL3720\ 76RTC438Ł[ The conversion of 2!
hydroxy to 2!thiol can also be achieved under nonacidic conditions via the tosyl ester ð51JOC0504Ł[
O O
Ph BunSH, TsOH, 80 °C Ph
OH SBun (239)
80%

"v# By acylation reactions


C!Acylations of ketene thiols provide a useful route to 2\2!dithio!a\b!unsaturated ketones[ Thus
treatment of the ketene dithioacetal "000# with tri~uoroacetic anhydride under basic conditions has
been shown to give the tri~uoromethyl ketone "001# in high yield "Equation "139## ð64TL0998Ł^
oxalyl chloride and its half ester can also be used as the acylating agent ð75S026Ł[ Related reactions
include an intramolecular acylation of a thioenol ether "Equation "130## ð72JOC012Ł\ and a useful
annulation involving the reaction of thiovinylsilane with a cyclic a\b!unsaturated acid chloride to
give a sulfur!substituted cyclopentenone "Equation "131##[ The annulation is postulated to proceed
via initial C!acylation and subsequent Nazarov cyclisation ð74JOC0510Ł[

S S TFAA, pyridine, CHCl3, 20 °C


(240)
93% S S

CF3

O
(111) (112)
143 a\b!Unsaturated Ketones

R CO2Et O
NaH, DMSO, 0 °C R
(241)
EtO2C 82%
SEt EtS CO2Et

NO2 H O
O
AgBF4, CH2Cl2, –25 °C
Cl + (242)
TMS S 58%
NO2 H SAr

"vi# By Witti` reactions


The Wittig reaction is an e}ective procedure for the synthesis of sulfur!substituted unsaturated
ketones[ Thus\ the phosphonium salt "002# reacts smoothly with the dicarbonyl compound "003#
giving a quantitative yield of the ketone "004# "Equation "132## ð68JOC829Ł[ Condensation of the
phosphonium salt "005# with the dithio lactone "006# gave the ketone "007# in 79) yield "Equation
"133## ð67SC204Ł[ Reaction of the dithiane anion derived from the dithioacetal "008# with the vinyl
phosphonium salt "019# leads to an intermediate ylide which then condenses with the neighbouring
diketone functionality to form a cyclopentenone "010# used in the synthesis of prostaglandin D0
"Equation "134## ð71TL450Ł[

MeO2C CO2Me
MeO2C CO2Me O O
S S
Et3N, 5 °C
S S + (243)
100%
+ O
PBu3

(113) (114) (115)

OMe
O O
O NaNH2, PhH, 20 °C Ph OMe
+ (244)
S 80%
+ Ph S S S
PPh3
(116) (117) (118)

S
MeS NaH S S
O
S + O (245)
Ph3P + 79%
R O
R SMe
(119) (120) (121)

"vii# From 0\1 and 0\2!dithioles


A large number of 2!thio!a\b!unsaturated ketones have been synthesised via the reactions of 0\1!
and 0\2!dithiole ring systems[ Treatment of 2!methylthio "or 2!chloro#!4!phenyl!0\1!dithiolylium
salts with ketone enolates gives dithiolidene ketones in very good to moderate yields[ Thus reaction
of the 0\1!dithiolylium salt "011# with sodium benzoyl acetate "012# in ethanol occurred rapidly to
give the 2!phenacylidene!0\1!dithiole "013# in 35) yield "Equation "135## ð69JCS"C#0191Ł^ closely
related reactions include ð55JOC2378\ 69BSF1907\ 69TL0148\ 66CC740Ł[ Hydrolysis of dithiolylium salts
a\b!Alkenic Bond 144
leads to 2!thiol!1\2!enone anions which can subsequently be alkylated "Equation "136## ð54JCS21Ł[
Similarly\ hydrolysis of trithiapentalenes "a cyclised form of dithiolylidene thioketones# yields
dithiolidene ketones "Equation "137## ð47G0115\ 59AG304\ 62BSF2228Ł[ The reaction of a!diazoketones
with 0\1!dithiole!2!thione also forms dithiolidene ketones "Equation "138## ð53CI"L#350\ 62ACS2770Ł[
0\2!Dithiolylium salts react very similarly to the corresponding 0\1!dithiolylium salts\ condensing
with an enolate to give dithiolidene ketones[ Thus 4!methyl!1!morpholino!0\2!dithiolylium!3!thio!
late "014# condenses with pentane!1\3!dione "015# under basic conditions to provide the product
diketone "016# in excellent yield "Equation "149## ð74TL0516Ł[ A methylthio group can be used in
place of the morpholine leaving group and an enamine can be utilised instead of an enolate ð64JPR026\
66CL176\ 70CL794Ł[ A very similar reaction has also been reported using a 0\2!oxathiolylium salt
"Equation "140## ð60CPB1083\ 60TL0026Ł[

Ph
SMe
O NaOEt, EtOH
+ HO2C O (246)
Ph S+ Ph 46%
S Ph S
S
(122) (123) (124)

Ph Ph O
i, 2N KOH
(247)
S+ ii, PhCH2Cl, 20 °C Ph S Ph
Ph S

S S S H2SO4, H2O
S S O
(248)

Ph Ph
Ph
+ O (249)
S N2 S
S S O
S Ph

S+ O O dbn, pyridine, 110 °C S O


N O + (250)
S 94% S O
HS HS

(125) (126) (127)

dbn = 1,5-diazabicyclo[4.3.0]non-5-ene

+
N Et3N, CH2Cl2 O O
+ (251)
S O 56%
O O S O

Ph
Ph

Thiapyrylium iodide reacts in a similar fashion to 0\1!dithiolylium salts with activated methylene
compounds "Equation "141## ð63BSF0085Ł[ Treatment of pyran!3!thiones with sodium hydrogen
sul_de and subsequent oxidation yields dithiolidene ketones in good yield "Equation "142##
ð53BSF2143\ 69JCS"C#1301Ł[

Ph
Ph O
pyridine O
+ Ph (252)
97%
+
CN Ph S Ph
Ph S S–
CN
145 a\b!Unsaturated Ketones
S Ph
i, NaSH
ii, K3Fe(CN)6
O (253)
67% S
Ph O S

"viii# Miscellaneous methods


The annulation of the lithiated propenoate "017# with an a\b!unsaturated ester yields a highly
substituted cyclopentenone in good yield "Equation "143## ð68CL674\ 70CC603\ 71CL704Ł[ Vinyl sulfones
can be alkylated similarly ð77JOC3697Ł[ Treatment of the cyclic sulfoxide "018# with TMS!Cl produces
the enone "029# via a Pummerer rearrangement "Equation "144## ð73TL0928Ł[ Elimination of HI
from the sulfone "020# gave a high yield of the vinyl sulfone "021# "Equation "145## ð77JCS"P0#0918Ł[
Oxidation of dithiocarboxylic acids produces 0\1\3!trithiolanes "Equation "146## ð60CJC0366\
61JOC2115\ 65JCS"P0#0695Ł[

TBDMS-O SPh
PhS Li
–50 °C
+ MeO2C O-TBDMS (254)
70% MeO2C
CO2Me
O
(128)

O
O
CO2Me
TMS-Cl, DCM, 42 °C CO2Me
(255)
74%
S
S
O
(129) (130)

TEA, CH2Cl2
O SO2Ar (256)
95% O SO2Ar
I
(131) (132)
TEA = triethylamine

i, NaNH2 S S
O ii, (NH4)2S2O8
+ CS2 S (257)
But But
But 34%
O O

2[94[0[5 Selenium! and Tellurium!substituted a\b!Unsaturated Ketones


a!Selenium! and a!tellurium!substituted a\b!unsaturated ketones can be made by chemoselective
elimination of HCl from a!phenylselenoketones "Equation "147## and a!phenyltelluroketones respec!
tively ð74JCS"P0#1082Ł[ Phenylselenyl chloride undergoes addition to enones and eliminates in situ
with pyridine to give the a!selenoenones ð68SC586Ł\ and propargyl selenoxides can undergo a
1\2!sigmatropic rearrangement as shown in Equation "148# ð68TL3322\ 70JA2001Ł[ a!Seleno and telluro
ketones are converted into a!seleno!a\b!unsaturated ketones by condensation reactions "Equation
"159## ð01CB0724\ 51CB0126\ 65BSF183Ł\ or by oxidative dimerisation ð01CB0724\ 61CB808\ 70JOM"197#24Ł[
b!Selenoenones have been made from isoselenoazoles and a Grignard reagent as illustrated in
Equation "150# ð78H"18#238Ł[ They have also been prepared from phenacyl benzselenazoles
ð68JPR219Ł[
O O
Cl
Li2CO3, DMF SePh
(258)
SePh
77%
a\b!Alkenic Bond 146

O
OH O O
i, mcpba
ii, pyridine OH
O O (259)
78%
O
SePh SePh O

O O O
piperidine
+ O (260)
71% NH
Se N Se
H
O

i,. PhMgBr O SePh


(261)
N ii, H+
Se
(E):(Z) 12:41

2[94[0[6 a\b!Alkenic Ketones with Nitrogen!based Substituents

2[94[0[6[0 1!Nitrogen!substituted a\b!unsaturated ketones


"i# From nitro`en substituted ketones and carbonyl compounds
The reaction of an a!nitrogen!substituted ketone with a carbonyl compound\ as illustrated in
Equation "151#\ leads to an unsaturated a!nitrogen!substituted ketone[ So\ for example\ N!acetyl
indole!2!one "022# reacts with benzaldehydes "Equation "152## ð77JHC0176Ł to give the dyes "023#
""Z# isomers# in good yields[ Thiophene aldehydes also react with the indole!2!one to give the
thienylideneindoxyls "024# "Equation "153## ð64CCC0649Ł[ Similarly the a!sulfonamidoketone "025#
reacts moderately well with benzaldehydes to give the a!nitrogen!substituted ketone "026# "Equation
"154## ð57JCS"C#1370Ł\ although the "E#:"Z# geometry was not determined in this case[

O O
O Nsubst.
R3 R2
Nsubst. R1 (262)
R1
R3 R2

O
O O

Et3N, DMF
+ N (263)
N 88% H

O NMe2
NMe2
(133) (134)

O O

C6H6
+ (264)
N S CHO 74% N
H
S
O
(135)
147 a\b!Unsaturated Ketones

O O
Ph
+ PhCHO (265)
60%
N N
Ts Ts

(136) (137)

Bender et al[ showed that the "Z# geometry was exclusively obtained on condensation of the
quinoline aldehyde "027# with the quinuclidone "028# "Equation "155## ð57JOC1493Ł[ A mixture of
"E#:"Z# isomers can be prepared by treating "039# with acid\ but the "E# isomer is unstable and
slowly rearranges to the "Z# compound[ a!Pyridinium salts "e[g[ "030## also react well with aldehydes\
giving the highly coloured betainecyanine "031# in excellent yield "Equation "156## ð59CB0957Ł[

O
CHO
O
MeO NaOEt N
+ (266)
91% MeO
N
N
N
(138) (139) (140)

O Me
O +
N Ph
N
O
Ac2O Br
+ (267)
96%
Me N +
N
Br
Ph
(141) (142)

a!Nitro substituted a\b!unsaturated ketones have been reported[ For example\ nitroacetone "032#
reacts with the imine "033# to give a mixture of "E# and "Z# isomers of the nitro!substituted ketone
"034# "Equation "157## ð46LA"591#03Ł[ Apparently\ if the aldehyde derivative of "033# is used\ reaction
occurs at the methyl group of the nitroacetone[ Nitromethyl 0\3!diketones\ for example "035# have
been cyclised to give the novel nitro!1!cycloalkene!0!ones "036# in good yield "Equation "158##
ð80S518Ł[

Bu O

N
NO2
O Ac2O
+ NO2
(268)
69%

Cl Cl
(144) (143) (145)

O
K2CO3, MeOH
O (269)
87%
O NO2 NO2
(146) (147)

Azidoacetophenones "037# have been reported to react with substituted benzaldehydes to give
a!azidovinylketones "038# "Equation "169## ð69M046Ł[
a\b!Alkenic Bond 148
O
CHO
N3
O Ph
N3 + (270)
Ph
X
X

(148) (149)

"ii# From a!halo ketones and an azide


a!Azidovinylketones have been prepared by several methods[ Reactions of the dibromides of
a\b!unsaturated ketones "049# with two equivalents of sodium azide in DMF a}ord the "Z#!a!
azidovinyl ketone "040# "Equation "160## ð60JA870\ 60JOC147\ 68LA063Ł[ Alternatively\ IN2 can be
added and eliminated from a\b!unsaturated ketones[ Addition of IN2 to "041# gave a 59 ] 39 mixture
of the a! and b!iodo compounds "042# and "043#\ which were subsequently reacted with sodium
azide in DMF to give the azido vinyl ketone "044# "via a rearrangement# "Scheme 11# ð60JOC147Ł[
A third method involves treatment of a!bromovinylketones "e[g[ "045## with equimolar amounts of
NaN2 and HN2 in DMF "Equation "161## ð60JA870Ł[
Br N3
O Ph O Ph
NaN3, DMF
TsO TsO (271)
Br
81%

(150) (151)

I N3 N3
Ph IN3 Ph + Ph Ph
83%
O
O N3 O I O
(152) (153) 40 : 60 (154) (155)

Scheme 22

O O
NaN3, HN3, DMF
Ph Ph (272)
72%
Br N3
(156)

"iii# From enamines and an acylatin` a`ent


a!Haloenamines "e[g[ "046## can be metallated and substituted with electrophiles\ including acy!
lating agents "e[g[ "047##\ to give a!amino!substituted a\b!unsaturated ketones "048# "Equation "162##
ð65AG"E#260Ł[ The a!metalloenamines can also be formed under harsher conditions by use of ButLi
on the enamine "e[g[ "059##\ as in Equation "163# ð65AG"E#060Ł[ This gives excellent yields of the
aminovinylketone "050#[

Cl O

Me i, Mg, THF Me
N ii, Ac2O (158) N
(273)
56%

(157) (159)
159 a\b!Unsaturated Ketones

O O Ph
i, ButLi, –110 °C O
ii, PhCO2Me
Et2N N (274)
87% Et2N N

(160) (161)

"iv# Miscellaneous methods


a!Diketones react with amines to give aminovinylketones[ For example\ cyclohexane!0\1!dione
"051# reacts with the chiral amine "052# under DeanÐStark conditions to a}ord the product "053#
"Equation "164## ð73CL1944Ł[ 0\2!Diketones can be attacked by nitrogen electrophiles such as the
nitrosyl cation\ and the resulting nitroso compound reduced to the aminovinylketone\ for example
"054# "Equation "165## ð51LA"548#53Ł[ a!Diazovinyl ketones have been synthesised by the use of a
diazonium ion coupling onto an activated vinylketone[ Thus the ketene aminal "055# is electron!
rich enough to undergo coupling with the aryl diazonium ion "056# "Equation "166## ð80SC0296Ł\ to
give "057#[ Oxidation of the 0\1!aminoalcohol "058# a}ords the a!amino!a\b!unsaturated ketone
"069# directly "Equation "167## ð60JOC598Ł[

OMe
O H
N C6H6
O O
+ OMe OMe (275)
85% N
MeO

(162) (163) (164)

i, NaNO2
ii, H2, PtO2
O O (276)
90%
NH2
O OH
(165)

O HN

N2+ Ph N
H
O HN N
DMF, EtOH N
+ (277)
Ph N 67%
H
Br

Br
(166) (167) (168)

Ag2CO3
(278)
N 57% N
H H
OH O
(169) (170)
a\b!Alkenic Bond 150
2[94[0[6[1 2!Nitrogen!substituted a\b!unsaturated ketones
The chemistry and reactions of enaminones have been reviewed ð35CRV72\ 66CSR166Ł[

"i# From enamines and an acid chloride


A commonly used method for preparing enaminones is reaction of an enamine with an acid
chloride\ as illustrated in Equation "168#[ "E#:"Z# Isomers are possible for open chain enamines\ and
mixtures of isomers often result\ but there is evidence that enaminones with a free NH exist mainly
in the cis form\ held by intramolecular hydrogen bonding[ The trans isomer is normally produced
predominantly when no N0H [ [ [ O1C hydrogen bonding is possible ð46CB1722Ł[ The reaction is
most useful for cyclic enamines\ for example the enecarbamate "060# reacts with acetyl chloride:SnCl3
to give the enaminone "061# "Equation "179## ð71JA5586\ 71TL0190Ł[ More reactive enamines can be
acylated without the need for a catalyst[ For example\ "062#\ "063# and "064# all react directly with
acid chlorides "Equations "170#Ð"172## ð69S476\ 63JHC108\ 65TL410\ 71TL0190Ł[ More reactive acylating
agents\ such as tri~uoroacetic anhydride have also been examined and give tri~uoromethyl enam!
inones "e[g[ "065## in excellent yields "Equation "173## ð65CL388Ł[

R22N
R1COCl
R22N R1 (279)

O SnCl4, CH2Cl2
+ (280)
N 58%
Cl N
CO2Me
CO2Me
(171) (172)

COCl
O
Et3N, CHCl3
NEt2 + (281)
Ph Ph NO2
32%
NEt2
(173) NO2

COCl
O
MeHN Et3N, toluene MeHN
+ (282)
62%
CO2Me CO2Me
(174)

F
NO2 COCl
O
NMe2 F Et3N, C6H6 NO2
+ (283)
NMe2

(175)

NHSO2Ph (CF3CO)2O, pyridine


O Ph
(284)
Ph 92% F3C NHSO2Ph

(176)
151 a\b!Unsaturated Ketones
Intramolecular cyclisations of an enamine and acylating agent are well known\ generally with an
ester as the acylating group[ In Equation "174# the N!b!carbomethoxyethyl enaminone "066# is
cyclised to the dihydro!3!pyridone "067# in good yield ð50JPR183Ł[ Similarly\ the N!b!carbo!
ethoxyethyl pyrrolidone "068# a}ords the hexahydro indolizine "079#\ via a mixed anhydride
"Equation "175## ð79TL0262Ł[ In addition\ the enamine can be prepared in situ and cyclised directly[
For example\ substituted cyclohexanones react with pyrrolidones and cyclise under the action of
catalytic p!TsOH "Equation "176## ð65JCS"P0#893Ł[ The b!aminoester "070# in Equation "177# con!
denses and cyclises\ in the same manner\ with cyclopentanone "or cyclohexanone# ð68JHC416Ł[
O
MeO2C CO2Me
MeO2C
NaOMe, MeOH
(285)
N 84%
H N
Ph H
Ph
(177) (178)

EtO2C
i, NaOH
N ii, Ac2O, MeCN EtO2C
N (286)
71%
O
CO2Et
(179) (180)

O
O
p-TsOH N
+ CO2Me (287)
N 60%
H

N
N
TFA, toluene N
NH + (288)
81%
O
CO2Me
O
(181)

Alternative tactics for performing the acylation of an enamine or derivative have been investigated[
Formation of an organometallic reagent such as a lithium derivative directly from the imine followed
by the addition of an ester gives excellent yields of the enaminone "Equation "178## ð89S784Ł[ The
"Z#!enaminone can be formed stereospeci_cally and in good yield under more mild conditions if the
intermediate vinyl bromide is formed _rst\ as in Equation "189# ð72JCR"S#111Ł[ This reaction would
appear to be very useful\ since other methods of preparing N\N!dialkylenaminones would give the
"E# isomer[ A related reaction that has been observed to proceed quite well is the oxidation of
tertiary amines to give "E#!enaminones "071# "Equation "180## ð70TL712Ł[

Ph
i, LDA
ii, PhCO2Me
O (289)
N NH
86%

i, Br2
ii, Et3N
O iii, BunLi Et2N
Et2N + (290)
But Cl 80% O But
a\b!Alkenic Bond 152
O

Cl3C CCl3
N N CCl3 (291)
65%
O
(182)

"ii# From b!dicarbonyl compounds or derivatives\ and an amine


A second common strategy for the formation of enaminones is the condensation of amino
compounds with 0\2!dicarbonyl compounds "Equation "181## ð69AJC730\ 70S779\ 72S891Ł[ The regio!
chemistry is usually controlled by using symmetrical 0\2!dicarbonyl compounds\ or having one of
the carbonyl groups more electrophilic "e[g[ b!ketoaldehydes#[ Although some cases of single "E#:"Z#
stereoisomer production have been reported\ in many examples mixtures of isomers are isolated[
The simplest cases are for cyclic diketones[ For example\ with primary amines\ cyclohexane!0\2!
diones "072# give excellent yields of the corresponding enaminone "073# "Equation "182## ð72S891Ł[
Secondary amines react well\ for example Equation "183#\ and ammonia itself can also undergo the
reaction "Equation "184## ð54JA763\ 58JCS"B#188Ł[ The reaction is also sensitive to steric factors\ since
1!methylcyclopentane!0\2!dione "074# reacts well with primary amines and some secondary amines
"e[g[ pyrrolidine#\ but not with Et1NH\ PhNHMe or Pri1NH "Equation "185## ð80S004Ł[ Intra!
molecular cyclisations of amines and 0\2!diones have been reported "Equation "186## ð35CRV72Ł[

O O R32NH O NR32
(292)
R1 R2 R1 R2

O O O NHEt
EtNH2
(293)
96%

(183) (184)

O O O NEt2
Et2NH
(294)
65%

O NH2
NH4OAc
Ph Ph (295)
97%

O O

MeNH2, AcOH
O O O NHMe (296)
90%

(185)

NHPh Ph
O N Ph
Ph
AcOH, NaOAc
O (297)
O 35%
Ph Ph
O O

For open chain 0\2!dicarbonyl compounds the simplest cases of amination are for symmetrical
0\2!diones[ Thus aqueous ammonia and acetoacetone a}ord the enaminone "075# very conveniently
"Equation "187## ð89S784Ł[ In non!symmetrical cases\ the most electrophilic carbonyl group seems
to be aminated[ For example\ in "076# "Equation "188## ð73S552Ł\ the carbonyl group next to the methyl
group is aminated\ and similarly in Equation "299# ð56JOC2706Ł[ The stereochemistry can depend on
the solvent\ with internal hydrogen bonding providing cis isomers in many cases ð63JPR358Ł[
153 a\b!Unsaturated Ketones
O O NH3 (aq.) O NH2
(298)
90%

(186)

O O NH2 O Ph
xylene
+ (299)
Ph Ph CO2Et 81% Ph N CO2Et
H
(187)

O O O PhNH2, EtOH O O NHPh


(300)
Ph 75% Ph

Other nitrogen nucleophiles that have been used include hydrazones and hydroxylamines[ Thus
cyclohexane!0\2!dione reacts with N!methylhydrazones "077#\ but only in moderate yields "Equation
"290## ð62CB349Ł[ Similarly\ phenylhydroxylamine "078# gives the N!hydroxyenaminone "089# in
excellent yield "Equation "291## ð62TL3422Ł[ The purpose of the ascorbic acid in this reaction is to
prevent decomposition of the phenylhydroxylamine[

Me
O O TsOH, C6H6
NHMe O N
+ Ph N N Ph (301)
30%
(188)

OH
O O ascorbic acid, C6H6 O N
+ PhNHOH Ph (302)
93%

(189) (190)

A reaction related to the amination of 0\2!diones is the intramolecular cyclisation of nitriles with
0\2!diones\ for example "080# in Equation "292# gives the dihydropyridone "081# ð54TL1150\ 65JOC525Ł[

CN
O
MeCOCl
O N (303)
O O H
39%

(191) (192)

In addition to using the 0\2!diones directly\ b!alkoxy!a\b!unsaturated ketones have been used[
Stereoselectivity is observed in some cases\ but not in others[ In this respect\ cyclic alkoxyenones
are the simplest and can give excellent yields of enaminones with amines[ For example\ the
alkoxycyclopentenone "082# gives the aminocyclopentenone "083# when reacted with ammonia
under pressure "Equation "293## ð80S065Ł[ Alternatively\ the alkoxyenone can be formed in situ and
reacted directly with a nitrogen nucleophile "Equation "294## ð70S114Ł[ The same method may be
used for open chain compounds\ for example "084#\ and gives the "E# compound under these
conditions\ as expected for dialkylated enaminones "Equation "295## ð77S027Ł[ DMF acetals have
also been used ð68T0564\ 79JOC3411\ 71SC24Ł[

O O
NH3
(304)
95%

OEt NH2
(193) (194)
a\b!Alkenic Bond 154
O NH2

O O O AcOH, DMF
N
H
+ (EtO)3CH + (305)
H2N NH2 85% O O

O O
(EtO)3CH, Et2NH
Et2N (306)
44%

(195)

Reaction of the alkoxyenone "085# with a primary amine "086# leads to the formation of the "Z#
enaminone "087# in quantitative yield "Equation "296## ð78TL5062Ł[ The "Z#!enaminone is also
reported by Tietze et al[\ from the reaction of benzylamine with the alkoxyenone "088# "Equation
"297## ð78CB72Ł[ Dialkoxyenones "ketene acetals# also undergo the reaction and are reported to give
the "E# isomer "as shown# in most cases "Equation "298## ð89S084Ł\ even though this is an N\N!
dialkylenaminone[
CF3
EtO CF3
+ NH2 N O (307)
O H

(196) (197) (198)

O
O
PhCH2NH2 MeO2C
MeO2C H (308)
87% N
EtO
Ph
(199)

EtO CF3 Me2NH, MeCN EtO CF3


(309)
EtO O 100% Me2N O

Gerus et al[ have reported that the reaction of the "E#!enol ether "199# gives rise to the
"Z#!enaminone "190# when a primary amine is used\ due to internal hydrogen bonding\ but secondary
amines "such as pyrrolidine# give the "Z# product "Equation "209## ð80S196Ł[ Silyl enol ethers can
also be used "Equation "200## ð78CB72Ł[ In addition to alkoxy derivatives of 0\2!dicarbonyls\ other
heteroatom based leaving groups have been investigated "e[g[ S or N#[ Equation "201# illustrates the
transformation of a ketene S\S acetal "191# into a ketene S\N acetal "192# ð66JPR434\ 89S051Ł[ Sulfonic
acid and sulfones have also been used as the leaving group "Equation "202## ð67TL632\ 89JCS"P0#0780Ł[
CO2H
CO2H
O 1N NaOH H
+ O N (310)
NH2
F3 C OEt 89%
F3C
(200) (201)

NH2

H OMe
O O-TMS CH2Cl2 O N
+ (311)
88%
OMe OMe

OMe
155 a\b!Unsaturated Ketones

MeS O EtOH S O
+ NH2 (312)
HS
MeS O 92% N O
H

(202) (203)

O O
O O
PhNHMe, Ni(OAc)2, AcOH
(313)
42%

SO3– N(Me)Ph

b!Halo substituted a\b!unsaturated ketones have been used to prepare b!nitrogen!substituted


a\b!unsaturated ketones[ For cyclic haloenones the reaction works extremely well "Equation "203##
ð53JOC683\ 58JCS"B#188Ł[ For open chain cases\ the stereochemistry is usually "Z# if an internal
hydrogen bond is possible\ but this can be converted to "E# by acetylation of the free N0H
"Equation "204## ð60JA2188Ł[ Use of stereochemically pure b!haloeneones provides products with
retention of con_guration when reacted with tertiary amines "Equation "205## ð53JOC274Ł[

O
O
EtOH
+ But NH2 (314)
79% But
N
Br
H

O
NH2 H
O Et3N N
+ (315)
N Cl 92%
H N
H

O Me3N
O
+ (316)
Cl 88% NMe3

"iii# From ketones and a formamide acetal


Equation "206# outlines the production of a b!dialkylamino enone from a ketone and a dialkyl!
formamide acetal[ The "E# isomer is often observed\ but can depend on the other substituents of the
ketone[ For unsymmetrical ketones with two enolisable sites\ a mixture results unless one site is
more readily enolisable[ For example\ the ketone "193# is aminomethylated at the benzylic carbon
"Equation "207## ð79S125\ 72LA189Ł[ Generally\ this problem is overcome by having only one enolis!
able site\ and the "E# stereoisomer is usually produced "Equation "208## ð62JA6751\ 68S890Ł[
OMe O
R32N
O R1
OMe
R2 (317)
R1
R2
R32N

OMe NMe2
OMe OMe
Me2N
OMe
(318)
O O
(204)
a\b!Alkenic Bond 156
Me2N
Me2N
O OBut
Me2N
O (319)
95%

Thio!substituted ketones also work well "Equation "219## ð76S785Ł[ Variations on this reaction
include the use of other aminomethylenating agents for which conditions have been reported that
can select one carbon of an unsymmetrical ketone\ and the use of the novel N!acyl imido!
thiocarbamate "194# under basic conditions to give the cis compound "195# "Equation "210##
ð72JOC512Ł[

OMe O
O Me2N
OMe PhS OEt
PhS OEt (320)
100%
O
O Me2N

Ph O Ph
N SEt ButOK, THF H
O N (321)
78% O
O SEt
O SEt
(205) (206)

"iv# From amines and a ketoalkyne


Primary and secondary amines\ including aromatic amines\ react smoothly with alkynyl ketones
to give enaminones "Equation "211## ð35JCS34\ 54JCS2509\ 55JCS"B#0106Ł[ Some investigators report
equilibrium mixtures of cis and trans isomers\ with the ratio depending on the solvent[ Single isomers
have been reported however\ that is cis when intramolecular hydrogen bonding is possible "Equation
"212## ð68JCS"P0#25Ł and trans products in other examples[ Tertiary amines\ for example "196# in
Equation "213# ð77JA2854Ł\ and nitroamines in Equation "214# also undergo the reaction ð43BSF623\
62JOC3213\ 73JGU17\ 78JOC5901Ł[

OMe O OMe O
Et2NH, MeOH
NEt2 (322)

O H Ph
O N
PhNH2
(323)
75%
MeO MeO

O O
Me3NH+ BF4– (207), MeOH
+ (324)
58% NMe3

O
O Et3N
+ MeNHNO2 NO2 (325)
Ph N
Ph
Me
157 a\b!Unsaturated Ketones
"v# Reactions of ketones with a cyano compound
Nucleophilic addition of an enolate to a nitrile leads to an enaminone\ "Equation "215##
ð66H"5#0874Ł[ Interestingly\ b!diketones such as "197# can add to benzoyl cyanide at the cyano
carbon\ when Ni"acac#1 is used as a catalyst "Equation "216## ð73CC0482\ 73JOC3585Ł[ Tin"IV# chloride
also catalyses the reaction\ and in these cases the nitrile seems to need further activation by an
electron withdrawing group\ for example CO1Et\ etc[ "Equation "217## ð77JCR"S#135Ł[

O MeNH2
+ O (326)
O CN 80%
NH2 O

O O

O O O Ni(acac)2 Ph
+ (327)
Ph CN Ph 87% Ph
H2N
(208) O

O CCl3
O O SnCl4
Cl3C CN + NH2 (328)

"vi# From carbonyl or thiocarbonyl compounds and Witti`!type rea`ents


Reaction of the reagent "198# in a Wittig!type reaction with an imide "e[g[ succinimide "109##
gives only poor yields of the enaminone "100# as the "Z# isomer "Equation "218## ð73LA0767Ł[
Intramolecular examples of the reaction are also known and proceed rather better "Equation "229##
ð76TL3284\ 77LA276\ 89LA286Ł[ In a variant of this reaction\ thioamides can be S!alkylated and
desulfurised by PPh2 or P"OEt#2 to give enaminones "Equation "220## ð60HCA609\ 74HCA0124\
78TL3768Ł[

O
Ph3P
Ph
(209)
O N (329)
O N O 17% H
H Ph
O
(210) (211)

O
O PPh3

N (330)
56% N
O
O
O

O OMe
OMe O i, RT
N S
Br ii, PPh3, Et3N N
+ (331)
88%

CN CN
a\b!Alkenic Bond 158
"vii# From ketenes and an enamine
Ketenes react with enamines at 9>C to give cyclobutanones which spontaneously ring open to
give the b!enaminones in excellent yield "Equation "221## ð50JOC3664\ 51AG21\ 52LA"551#067Ł[ This
reaction is similar to the acylation of an enamine which has already been discussed in "i# above[
NMe2

Me2N + H2C • O (332)


93%
O

"viii# From oxime sulfonates and a silyl enol ether


Oxime sulfonates react with silyl enol ethers under Lewis acid catalysis conditions to provide
b!enaminones[ The reaction is reported to proceed as illustrated in Scheme 12 ð72JA5201Ł[

OMs
N
N O-TMS
+
Et2AlCl

O
H
N N
90%
O

Scheme 23

"ix# Miscellaneous methods


Other methods reported to lead to b!enaminones are the reductions of isoxazoles or isoxazilines
ð74JCS"P0#0390\ 77JOC1315Ł\ Fries!type rearrangements of N!acyl enamines ð63JOC2965\ 75CC728Ł\ and
reactions of isothiocyanates with haloketones ð66S596\ 68JCR"S#139Ł[ Nitro!substituted a\b!unsatu!
rated ketones have been made by the nitration of a\b!unsaturated ketones ð68HCA386\ 68JHC0546Ł[

2[94[0[7 Phosphorus! and Arsenic!substituted a\b!Unsaturated Ketones


a!Phosphorus!substituted ketones can be condensed with aldehydes as illustrated in Equation
"222# to give a!phosphorus!substituted enones ð57JGU290Ł[ A variation of this reaction has been
reported\ using a DielsÐAlder reaction to make a pyran\ followed by a ring opening and condensation
reaction "Equation "223## ð78BCJ759Ł[ Wittig!type reactions have also been reported ð73S24Ł[ DielsÐ
Alder reactions of arsabenzenes with propargylic ketones lead to mixtures of both a! and b!arsenic!
substituted a\b!unsaturated ketones ð67TL1426Ł[
O O
P(OEt)2
O O O piperidine
+ (333)
P(OEt)2 72%
Ph

Ph
169 a\b!Unsaturated Ketones

i, Pri2NEt O O
BuO O O ii, HCl (aq.), THF P(OEt)2
+ (334)
P(OEt)2 78%

b!Phosphorus substituted enones can be made by the oxidation of an alcohol^ the reaction
incorporates an allylic transposition "Equation "224## ð80S246Ł[ Arbuzov reactions starting from
b!halovinyl ketones and Wittig!type alkenation are also known ð68LA381\ 74M66Ł[

O
O
(MeO)2P OH CrO3
(335)
76% P(OMe)2
O

2[94[0[8 a\b!Alkenic Ketones with Silicon!based Substituents

2[94[0[8[0 1!Silyl a\b!unsaturated ketones


The PausonÐKhand reaction is a very useful method for the stereoselective synthesis of
1!silylcyclopentenones\ usually as 5\4! or 4\4!fused bicycles[ Magnus et al[ have reported that the
silylenyne "101# can be cyclised most e.ciently if the Co"CO#5!acetylene complex "102# is puri_ed
prior to thermolysis[ The metal complex is then heated under carbon monoxide in a sealed tube to
give the fused tricycle "103# in 40) yield as a single stereoisomer "Scheme 13# ð76JA6384Ł[ Similar
syntheses of 4\4! and 5\4!bicyclic 1!silylcyclopentenones reviewed include ð79AG"E#0912\ 72JA1366\
74TL3740\ 77LA780Ł[ A closely related zirconium!mediated intramolecular enyne carbocyclisation
proceeds via an intermediate isolable zirconabicycle "104# which is converted easily to the silylenone
"105# by treatment with carbon monoxide at 9>C "Scheme 14# ð74JA1457Ł[ Similar examples include
ð75JOC3979\ 78JA2225Ł[ This reaction has been used to great e}ect by Wender et al[ in the synthesis
of fused 4\6!bicycle systems present in several natural products ð89TL2580Ł[ An intermolecular
cyclisation involving a chromium alkylidene complex also yields a 1!silyl!a\b!unsaturated cyclic
ketone ð74JA492Ł[

TMS TMS O

TMS Co
Co2(CO)6, 22 °C Co CO(g), Bu3PO, 85 °C H
O H H
94% 51%
O O
O
O O

(212) (213) (214)

Scheme 24

TMS TMS TMS


Cl2ZrCp2, Mg, HgCl2 CO(g), 0 °C

90–95% ZnCp2 55–60% O

(215) (216)

Scheme 25

1!Silyl!2!chloro!a\b!unsaturated ketones can be prepared by the addition of an acid chloride


across a silyl alkyne\ both intermolecularly ð70JGU0094Ł and intramolecularly "Equation "225##
ð67TL1290Ł[ Closely related reactions include ð61JOM"26#34\ 71TL3812Ł[
a\b!Alkenic Bond 160
O
Cl AlCl3, 40 °C
(336)
O TMS 74% TMS
Cl

1!Silyl!a\b!unsaturated ketones are available by a DielsÐAlder reaction of the silylketone "106#


with many dienophiles "Equation "226## ð79JOC3709Ł\ and also by ð1¦1Ł cycloadditions of dichloro!
ketene with alkynylsilanes ð72TL12Ł[ Metallations and subsequent acylations of halovinylsilanes
yield unsaturated silylketones in good yields\ both inter! and intramolecularly ð62CJC1913\ 75TL664Ł[

O O O
O H
TMS • CHCl3, 25 °C
TMS
+ O O (337)
89%

O H O
(217)

Metallation of the readily available dibromocyclopropane "107#\ followed by a TMS!Cl quench


and hydrolytic ring opening has given rise to the silylketone "108# cleanly "Equation "227##
ð67TL2936Ł[ Protected 1!bromo!a\b!unsaturated ketones can be treated similarly to give the cor!
responding silylketones in reasonable yield ð67TL3550Ł[ Oxidations of trimethylsilylcylclopropenes
have been reported to produce 1!silyl!a\b!unsaturated ketones under mild conditions ð75TL4032Ł[

i, BunLi, –95 °C
OMe ii, TMS-Cl
Br iii, MeOH, K2CO3 O
(338)
Br 57%
H TMS
(218) (219)

2[94[0[8[1 2!Silyl a\b!unsaturated ketones


Fleming et al[ have worked extensively in the area of b!silylenones and presented a brief summary
of the synthetic methods reported prior to 0870 along with three new methods ð70T3916Ł[ The _rst
method involves the addition of an alkyl cuprate to a silylynone\ whereas in the second method
phenyldimethylsilyl cuprate is reacted with a b!chloroenone to yield the corresponding b!silylenone
in high yield[ The third method uses phenylthiotrimethylsilylmethylation followed by oxidation and
base!catalysed elimination "Scheme 15#[ The oxidation must be taken to the sulfone level in order
to avoid the sila!Pummerer rearrangement which occurs with the corresponding sulfoxide[ The use
of a!halo!a!"trimethylsilyl#methyl ether in an analogous trimethylsilylmethylenation has also been
reported ð76ACS"B#425Ł[ A related approach involves the allylic sul_de "119# as a homoenolate
dianion equivalent enabling the synthesis of functionally substituted b!trimethylsilyl!a\b!unsatu!
rated ketones via two alkylations "Scheme 16# ð74TL1566Ł[

O-TMS O SPh i, mcpba O


SPh ZnBr2 ii, dbu
+ TMS TMS
Cl TMS 84% 67%

Scheme 26

Silyltin alkenes are readily available by the addition of silylstannanes to terminal alkynes under
palladium catalysis\ and they undergo e.cient Stille coupling reactions with acid chlorides to
give 2!silyldivinyl ketones "Equation "228## ð75TL1790Ł^ see also ð73JA6499\ 75JOC2450\ 89SC0554Ł[ A
conceptually similar approach involves the coupling of a b!silylvinyl cuprate\ derived from the
addition of a silyl anion to a terminal alkyne\ with an acid chloride ð79CC165\ 77HCA057Ł[ Vinyl
silanes can also be acylated with acid chlorides in the presence of Lewis acid catalysts ð71TL0834\
77TL774Ł[
161 a\b!Unsaturated Ketones
PhS OMe BunLi, R1X PhS OMe SiO2, hexane
R1
TMS TMS
(220)

R1 SPh BunLi, R2X R1 SPh NaIO4 R1 R2


R2
TMS OMe TMS OMe TMS O

Scheme 27

SnMe3
COCl PdCl2(MeCN)2, 60 °C
+ (339)
87% O
TBDMS
TBDMS

Rhodium!catalysed allylic oxidation of 2!"trimethylsilyl# cycloalkenes with molecular oxygen


a}ords b!silylcycloalkenones regiospeci_cally and in high yields "Equation "239## ð67JOC1327Ł[
Oxidations of b!silylallylic alcohols to the corresponding ketones have been reported using a variety
of oxidising agents ð72HCA1266\ 77HCA057\ 89SC0984Ł[ The reaction of a\b!unsaturated acylsilanes
"110# with allenylsilanes "111# in the presence of a Lewis acid catalyst provides a novel ð2¦2Ł!
annulation procedure to b!silylcyclohexenones which proceeds in moderate yield "Equation "230##
ð74TL1402Ł[

O
Rh(1), O2, 97 °C
(340)
83%
TMS
TMS

O
O
• TMS TiCl4, –50 °C
+ (341)
TMS 56%
TMS
(221) (222)

2[94[0[09 a\b!Alkenic Ketones with Metal Substituents


ortho!Diketodiynes react with transition metals "Rh\ Ir\ Pt and Pd# to form metallocyclo!
pentadienes\ some in high yield[ Thus the diketone "112# reacts with rhodium"I# to give the complex
"113# in high yield "Equation "231##[ The metal complexes are synthetically useful due to the ease of
replacement of the metal with alkynes\ chalcogens and nitrogen ð60LA"643#53\ 64CB126Ł[

O Ph
O
Ph
RhCl(PPh3)4, 140 °C RhCl(PPh3)2
(342)
89%
S Ph Ph
S
O O
(223) (224)

b!Trimethylstannyl!a\b!unsaturated ketones can be prepared from the corresponding


b!iodo!enones via reaction with the cuprate\ PhS"Me2Sn#CuLi\ at low temperature\ in yields up
a\b!Triple Bond 162
to 75) ð67CC0922Ł[ An analogous reaction with the b!chloroenone "114# has also been observed
using a tributylstannyl cuprate to give the stannyl ketone "115# in high yield "Equation "232##
ð70TL0326Ł[

TBDMS-O Cl TBDMS-O SnBu3


Me2 S(Bun3Sn)2CuLi, –25 °C
(343)
84%
O O
(225) (226)

2[94[1 KETONES BEARING AN a\b!TRIPLE BOND

2[94[1[0 By Acylations of Alkynes


Probably the most important method for preparing an alkynone is via the acylation of an acetylide
anion or equivalent[ The lithio acetylide is easily prepared by deprotonation of an alkyne using a
lithium base or by metalÐhalogen exchange and elimination from a trichloroethylene system
ð70C225Ł[ The lithio acetylide can then be acylated using an anhydride "Equation "233## ð53CB0538\
63S246\ 73TL1300\ 74JOC2861\ 89S132Ł\ an ester ð65SC492\ 67TL826\ 78TL874Ł\ an amide "Equation "234##
ð70TL2704\ 73TL700\ 76TL0746\ 77JA1290Ł\ an acid chloride ð62JOC2477Ł or an acyl cyanide ð64BSF668Ł[
Magnesium acetylides behave similarly and have been acylated using anhydrides and imides
ð38JCS0716\ 60CPB280\ 89JCS"P0#0496Ł\ whereas alkynyl cuprates have only been reported to undergo
acylations with acid chlorides ð58JA5353\ 69TL1548\ 62BSF1026\ 64JOC020Ł[ The formation of copper"I#
acetylides\ via an intermediate metal acetylide\ can sometimes be di.cult and a convenient alter!
native is to treat the alkyne with copper"I# iodide:triphenylphosphine palladium chloride in tri!
ethylamine and acylate with an acid chloride "Equation "235## ð66S666\ 73JCS"P0#424\ 78SC0634Ł[

i, ClCO2Et, Et3N, petrol, –20 °C O


ii, Bun Li, THF, ether, –50 °C
HO2C Bun (344)
80%
Bun Bun

Ph
N(Me)OMe THF, 20 °C
+ Ph Li (345)
Ph O 97%

Ph O

O
O (Ph3P)2PdCl2, CuI, Et3N, 20 °C
Ph + Ph (346)
Ph Cl 96%
Ph

The acylation of tin alkyne compounds requires palladium catalysis if the alkyne is carbon!
substituted ð71JOC1438\ 74HCA227Ł[ However this is not necessary if the alkyne is activated with a
heteroatom "Equation "236## ð79JOM"073#206\ 70LA0896\ 70TL1526\ 77CB1052Ł[ Other less widely used
acetylides for which acylations have been reported include] manganese ð74S49\ 78TL2434Ł\ zinc
ð77JOM"227#178Ł\ silver ð45JA0564Ł\ boron ð56AG"E#73Ł and vanadium\ which undergoes oxidative
addition to aldehydes in good yields "Equation "237## ð75TL822Ł[ The acylation of silyl acetylides is
carried out with Lewis acid catalysis and usually involves the use of aluminum trichloride with an
acid chloride "Equation "238## ð52CB2179\ 68S327\ 70S18\ 74S851\ 75HCA459Ł\ intramolecular examples
have been reported ð67TL1290Ł[ Silver tetra~uoroborate as Lewis acid with a thioester acylating
agent is also e}ective with silyl alkynes ð72TL4020Ł\ and the use of titanium tetrachloride with
diketene is also known ð76S0981Ł[
163 a\b!Unsaturated Ketones
Me
O Cl Me N
Et2O, 0 °C Ph
+ Bu3Sn N O (347)
57%
Ph Cl Ph
Ph Cl

i, VCl3, CH2Cl2
ii, PrnCHO, –78 °C to 40 °C
BrMg Bun (348)
63% O
Bun

O
TMS O
AlCl3, CH2Cl2, 0 °C
+ (349)
Cl 89%
TMS
TMS

2[94[1[1 Elimination Reactions


Elimination of hydrogen halide from an a! or b!haloenone or dihaloalkanone is a useful way of
preparing alkynic ketones[ Common reagents include triethylamine "Equation "249## ð40JOC40\
70JGU0942Ł\ potassium carbonate ð56JA4611Ł and Triton B ð63CR"167#0042Ł[ The parentenones can be
used as the starting material by _rst brominating and then performing a double elimination "Equa!
tion "240## ð57AG332Ł[ Elimination of iodide is facile\ and the intermediate iodoenones can be made
from an iodophosphorane and an aldehyde "Equation "241## ð89S520Ł[ The enol form of 0\2
b!diketones can eliminate water to give good yields of ynones "Equation "242## ð79CL0216Ł[ The
per~uorinated acid halide in Equation "243# reacts with the phosphorane to give a per~uoroacylated
ylide[ The ylide then eliminates Ph2PO in both possible directions to give a roughly 0 ] 0 mixture of
ketone and aldehyde which can be separated by distillation ð73S24\ 74S048Ł[ See ð54JOC0904\ 71JCS"P0#0452Ł
for other reactions involving elimination\ and ð61SC220Ł for a reaction starting from an a!diazoalcohol[

O Br i, ButOK, DMF O Ph
ii, Et3N, 20 °C
Ph
(350)
100%
O Br O

i, Br2
ii, Et3N
O iii, ButOK O
Me2N (351)
Me2N 70%

O
OMe O
O OMe
+ Ph
K2CO3, MeOH, 60 °C
+ Ph3P (352)
Ph
66%
I
OMe
OMe

O
O OH KF, MeCN, Et2NCF2CFHCF3, 20 °C
(353)
Ph 72%
Ph

i, C6H6, 80 °C O
O O
+ ii, 200 °C
+ Ph3P CHO + (354)
n-C3F7 Cl – 85% n-C3F7
n-C3F7
1:1
a\b!Triple Bond 164
2[94[1[2 By Oxidation of Alkynic Alcohols and Propargylic Methylene Groups
Oxidations of alkynic alcohols proceed in much the same way as oxidations of allylic alcohols
"see Section 2[94[0[0[5#[ Manganese dioxide is a common reagent "Equation "244## ð53JA360\ 62CB28\
68CL0910\ 78HCA006Ł^ see also ð76JOC1426Ł for a ring opening reaction of cyclohexadienols using
MnO1 and ð49JGU0151Ł for use of a Mn"OAc#2 reagent[ Chromium trioxide:pyridine has been
used in several cases ð35JCS28\ 70JA3486\ 75S073Ł\ and other reagents used include ortho!chloranil
ð45JCS2969Ł\ oxalyl chloride:DMSO ð73JA4474Ł\ Na1WO3 ð75TL494Ł and electrochemical oxidation
ð89JOC2547Ł[

i, BuLi, THF O
EtO OEt ii, aldehyde
O iii, MnO2
+ Ph
OEt (355)
Ph 89%
OEt

The methylene group adjacent to a triple bond has been oxidised with chromium trioxide:pyridine
to a}ord an alkynone "Equation "245## ð60TL3268Ł^ t!butyl hydroperoxide can be used similarly
"also for terminal alkynes# ð77TL1210\ 78SC1950Ł[ In a related oxidative procedure\ Brown et al[ have
used the hydroboration of a haloalkyne to give a bromoalkenylborinate intermediate\ which was
then reacted with a lithioacetylide[ Oxidation of the resulting alkynenylborinate with H1O1:NaOH
gave the ynone "Equation "246## ð72S774Ł[

CrO3•pyr•2, 25 °C
(356)
42%
O

O
i–iv
+ (357)
Br Li

i, PriCMe2BHCl•SMe2, BBr3; ii, PriOH; iii, RLi, THF; iv, NaOH, H2O2

2[94[1[3 By Reaction of a Carbon Nucleophile with Alkynic Acid Halides and Derivatives
The reactions of alkynic acid halides "e[g[ Equation "247## with carbon nucleophiles have been
reported ð41JCS2834Ł[ Other similar examples using an alkynic ester and an enolate as the nucleophile
are known ð63JHC0090Ł[ Dimethyl alkynedicarboxylate reacts with certain enamines at the ester
group to give alkynic ketones ð71CPB52Ł[ The propargylic dithiane in Equation "248# can be
deprotonated and alkylated in an umpoled carbonyl synthesis ð70JOC0401Ł[

O i, Na, C6H6
O ii, RCOCl O
O-THP
iii, C6H6, AcOH, 80 °C n-C6H13
Cl + n-C6H13 (358)
O-THP 85%
Ph Ph
O

S S O
i–iv
+ Cl (359)
72%

TMS TMS

i, BunLi; ii, enyne; iii, Tl(NO3)2; iv, HCl


165 a\b!Unsaturated Ketones
2[94[1[4 Miscellaneous Methods
The palladium!catalysed carbonylation reactions of phenyl alkynes have been investigated "Equa!
tion "259## ð70CC222Ł[ Brown has used dichloromethyl ether as a carbonylating reagent for alkynyl!
borinates "Equation "250## ð77JOC0280Ł[ Jacobi has reported an oxy!Cope rearrangement of a vinyl
alkynyl carbinol leading to an alkynic ketone ð89JOC191Ł\ and vinyl alkynyl carbinols also undergo
a Lewis acid catalysed 0\1!rearrangement "Equation "251## ð75TL262Ł\ using the low migratory
aptitude of the alkyne group to confer selectivity[ See ð71JOC41Ł for a reaction of an isocyanate with
an alkyllithium to form an a!lithioaldimine\ which can be trapped with a 0!bromoalkyne leading to
an alkynic ketone[
I PdCl2, CO, Et3N, 80 °C O
Ph + Ph (360)
93% Ph

Cl Cl
i, LiOCEt3
O OH Cl O
B ii, H2O2, NaOH
+ MeO (361)
Cl 70%
O O

Ph
TMS O
AlMe3, –45 °C
HO
(362)
TMS 88%
Ph
OMs

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.06
Ketones Bearing an a,b-Aryl or
-Hetaryl Substituent
DARYL S. WALTER
University of Nottingham, UK
2[95[0 GENERAL METHODS 167
2[95[0[0 FriedelÐCrafts Acylations 167
2[95[0[0[0 Reactions with acyl halides 167
2[95[0[0[1 Reactions with carboxylic acids and anhydrides 179
2[95[0[0[2 Reactions with miscellaneous acylatin` a`ents 170
2[95[0[0[3 The Houben!Hoesch synthesis 171
2[95[0[0[4 Reactions with other acyl cation equivalents 172
2[95[0[1 Electrophilic Acylations of Or`anometallic Species 173
2[95[0[1[0 Acylations of or`anolithium rea`ents 173
2[95[0[1[1 Acylations of Gri`nard rea`ents 174
2[95[0[1[2 Acylations of or`anocopper rea`ents 175
2[95[0[1[3 Acylations of or`anotin rea`ents 176
2[95[0[1[4 Acylations of or`anozinc rea`ents 177
2[95[0[1[5 Acylations of miscellaneous or`anometallic rea`ents 178
2[95[0[2 Aryl Ketones by Carbonylative Cross!couplin` Reactions 178
2[95[0[3 Acyl Anion Equivalents in Aromatic Ketone Synthesis 180
2[95[0[3[0 1!Alkyl!0\2!dithianes 180
2[95[0[3[1 Protected cyanohydrins 181
2[95[0[3[2 Acyl radicals 181
2[95[0[3[3 Miscellaneous acyl anion equivalents 182
2[95[0[4 Oxidation 182
2[95[0[4[0 Oxidations of benzylic methylene `roups 182
2[95[0[4[1 Oxidations of secondary benzylic alcohols 183
2[95[0[4[2 Oxidative cleava`es of double bonds 183
2[95[1 PHENYL KETONES AND SUBSTITUTED ANALOGUES 184
2[95[1[0 Phenyl Ketones 184
2[95[1[1 Monoalkyl Phenyl Ketones 184
2[95[1[2 Dialkyl! and Polyalkylphenyl Ketones 185
2[95[1[3 Halophenyl Ketones 185
2[95[1[4 Phenolic Ketones 185
2[95[1[5 Alkoxyaryl Ketones 187
2[95[1[6 Thiophenyl Ketones 188
2[95[1[7 N!Substituted Phenyl Ketones 188
2[95[1[8 Other Substituents 299
2[95[2 POLYCYCLIC ARYL KETONES 299
2[95[2[0 Naphthyl Ketones 299
2[95[2[1 Anthryl Ketones 290
2[95[2[2 Phenanthryl Ketones 290
2[95[2[3 Other Polycyclic Aryl Ketones 291
2[95[3 HETARYL KETONES 291
2[95[3[0 Furanyl Ketones 291
2[95[3[1 Benzofuranyl Ketones 293
2[95[3[2 Ketothiophenes 294

166
167 Ketones With an a\b!Aryl or !Hetaryl
2[95[3[3 Benzothiophenyl Ketones 295
2[95[3[4 Pyrrolic Ketones 295
2[95[3[5 Ketoindoles 298
2[95[3[6 Pyridyl Ketones 209
2[95[3[7 Ketones Derived from Imidazoles\ Thiazoles and Oxazoles 200

2[95[0 GENERAL METHODS


Aromatic ketones serve as useful intermediates for the synthesis of a range of other functionalised
systems[ However\ a comparison of the number of synthetic routes to aliphatic ketones and aromatic
ketones respectively\ reveals that the latter group of compounds are accessible by relatively fewer
methods[ Advances in the application of organometallic species have served to remedy these
shortcomings to a considerable degree but in many cases more classical approaches are still
employed[ This section summarises the most widely used direct methods currently available for the
synthesis of aromatic ketones[ To avoid duplication the emphasis is placed _rmly on those methods
which speci_cally apply to aromatic systems although many of the methods described for the
synthesis of saturated ketones "Section 2[92[0# will often be suitable[

2[95[0[0 FriedelÐCrafts Acylations


The FriedelÐCrafts reaction is one of the oldest and best!known approaches to the synthesis
of aromatic ketones\ and the method has been extensively reviewed ðB!53MI 295!90\ B!62MI 295!90\
80COS"1#622Ł[ The ketone is generally prepared by treatment of an aromatic substrate with an
acylating agent and a suitable electrophilic catalyst[ Aluminum chloride and boron tri~uoride are
two of the most commonly employed catalysts but many other Lewis acids and protic acids have
found similar utility[ Molar quantities of catalyst are generally required\ as metal complexes are
formed with both the acyl halide and the carbonyl product[ Exceptions include the reactions of
electron!rich aromatic systems which can often be acylated in the presence of small amounts of
milder Lewis acids or in the complete absence of catalysts[ Similarly\ acylations using highly reactive
species such as certain mixed anhydrides again often require no or little catalyst[ The choice of
acylating species has become increasingly varied\ but acyl halides and carboxylic acids and their
anhydrides comprise the majority of literature examples[ The electron!de_cient nature of the aro!
matic moiety in the product ketone usually ensures that the reaction stops cleanly after the initial
acylation[

2[95[0[0[0 Reactions with acyl halides


The reactions of aromatic substrates with acyl halides is very general and all four types of halo!
substituent "i[e[\ ~uorides\ chlorides\ bromides and iodides# can be used[ However\ the reaction of
acyl chlorides in the presence of aluminum trichloride is the most frequently used combination for
the preparation of alkyl aryl ketones[ Electron!rich arenes and electron!de_cient acyl halides result
in the best yields[ Unfunctionalised acyl and aroyl halides generally give high yields of the desired
ketones under such classical FriedelÐCrafts conditions[ In certain cases however\ side reactions and
decomposition can be problematic[ For example\ acylation with pivaloyl chloride can be severely
hampered by decarbonylation and subsequent competing t!butylation of the aromatic substrate[
This problem has been studied extensively ð38JCS0835Ł\ and is usually avoided by employing more
reactive aromatic systems[ More highly functionalised substrates are also tolerated but the often
strongly acidic reaction medium can present problems[ In such cases\ and when substrate reactivity
permits\ resorting to milder acylation conditions can lead to high ketone yields in the presence of
acid!labile groups[ In a synthesis of the iso~avone jamaicin ð76JOC0861Ł\ a key acylation failed under
standard Lewis and protic acid catalysis but gave the desired ketone on treatment with titanium
tetrachloride in dichloromethane at −67>C "Equation "0##[ Other methods which have been
employed to reduce unwanted reactions promoted by acids\ include the removal of hydrogen
chloride from the solvent by passing air through the reaction mixture ð41BSB583Ł\ and the use of
acid scavengers such as potassium carbonate and 1\5!lutidine ð61JOC2507Ł[
General Methods 168

Cl O O OH
TiCl4
O OH + (1)
O O CH2Cl2, –78 °C
MeO O

O O
MeO

Reactions requiring molar quantities of catalyst require workup procedures to decompose prod!
uct complexes and the catalyst is consequently not usually recovered[ Reactive aromatics "e[g[\
thiophenes# can be acylated over sulfonated polystyrene resins ð44USP1600303Ł\ and benzoyl chlorides
will yield benzophenones on exposure to arenes and the solid Na_on!H catalyst ð67S561Ł[
Ammonium salts of Keggin!type heteropolyacids ð81CL0876Ł have also shown promise as solid!
phase FriedelÐCrafts catalysts[ These heterogeneous procedures allow for easy recovery of both the
products and the catalyst[
Acylations of active aromatic nuclei such as aryl ethers\ polynuclear arenes\ and thiophene with
acyl halides do not always require a catalyst but trace amounts of a variety of metallic and non!
metallic catalysts greatly increase the reactions rates and the yields ð61S422Ł[ The most frequently
employed catalysts of this ilk are ferric chloride "Equation "1## ð74BSB786Ł\ iodine "Equation "2##
ð37JA0536\ 42JA634Ł\ zinc chloride "Equation "3## ð43JA4358Ł and iron "Equation "4## ð69MI 295!90Ł[
Attractive aspects of these methods are the ease of product puri_cation and low costs[ Relatively
high reaction temperatures are required and aromatic acid chlorides generally give better yields
than aliphatic ones[

O FeCl3 (0.08 equiv.) O


4 h, 200 °C
+ Cl (2)
71%

5 equiv. 1 equiv.

O O
MeO
I2, reflux, 8 h
+ Cl (3)
89%
MeO

OMe
O O
ZnCl2 (0.02 equiv.), reflux But
+ Cl (4)
66%
OMe
But

OMe O O
Fe (0.01 equiv.), 85 °C
+ Cl (5)
90%
MeO

Catalytic quantities "ca[ 0)# of tri~uoromethanesulfonic acid e}ectively increase rates and yields
in FriedelÐCrafts acylations with acyl halides ð61AG"E#299Ł and presumably proceed via the inter!
mediacy of labile tri~uoromethanesulfonic!carboxylic anhydrides[ This method allows for acylations
with pivaloyl chloride without the decarbonylation and t!butylation complications mentioned earlier
"Equation "5##[ In contrast to all of the above catalytic methods\ acylations of aryl ethers are
promoted e}ectively by small quantities of diphenylboryl hexachloroantimonate ð75CL054Ł at room
temperature in dichloromethane solutions "Equation "6##[

OMe O
O CF3SO3H (cat.), 154 °C, 12 h
+ But (6)
But Cl 54%
MeO
179 Ketones With an a\b!Aryl or !Hetaryl

OMe O
O Ph2BSbCl6 (cat.), CH2Cl2, RT, 24 h
+ Bun (7)
Bun Cl 88%
MeO

2[95[0[0[1 Reactions with carboxylic acids and anhydrides


FriedelÐCrafts acylations with carboxylic acids are possible and although not as popular as
acylating agents as the corresponding acyl halides or acid anhydrides\ they have shown considerable
utility particularly when preparation of such acid derivatives is di.cult[ In general the catalysts
used are milder than those popular with acyl halide reactions\ and the aromatic substrate usually
needs to be substantially activated "e[g[\ aryl ethers#[ Zinc chloride ð30OS"10#092Ł is a reasonably
useful catalyst but reactions are somewhat prone to the formation of side!products[ More frequently
used catalysts are boron tri~uoride "the Meerwein reaction ð22CB300Ł# and polyphosphoric acid[
Boron tri~uoride is particularly suited to acetylations when used in conjunction with acetic acid
"Equation "7## ð50JOC2549Ł and to the formation of aryl alkyl ketones with long side!chains "Equation
"8## ð50JOC1390\ 64CB0469Ł[ Other protic acids which have been used successfully include phosphoric
acid ð78JHC0436Ł\ sulfuric acid ð80TL5698Ł and hydro~uoric acid ð60CI"L#571Ł[

O
OH O BF3, 0–25 °C, 48 h OH
+ (8)
OH 90%
OMe
OMe

OH OH O
O BF3, HF, p-xylene, 70 °C HO
HO OH
+ ( )18 (9)
HO ( )18 90%
HO

Toluene and xylene can be acylated with fatty acids in the presence of a Y!faujasite!type zeolite
after exchange with Ce2¦ cations ð75JOC1017Ł[ The shape!selectivity imposed by the dimensions of
the zeolite channels results in no acylation with acetic acid and increasing ketone yields with higher
homologs\ and maximum yields using dodecanoic and palmitic acids with toluene and p!xylene
respectively[ Carboxylic acids and phosphorus pentachloride ð60AP"293#432\ 77CB006Ł\ phosphorus
oxychloride ð72CI"L#368Ł\ and sulfonyl chloride ð73JOC3115Ł provide alternative acylation conditions\
but a Lewis acid is usually required and the reactions probably proceed via the corresponding acyl
chlorides[
Along with acyl chlorides\ acid anhydrides are the most popular acylating species in the FriedelÐ
Crafts ketone synthesis\ particularly when using reactive aromatic substrates[ Used in conjunction
with stoichiometric quantities of catalysts such as aluminum chloride\ ferric chloride\ zinc chloride\
boron tri~uoride and tri~uoroacetic acid they provide a convenient route to ketones[ However\
practical considerations such as the thermal instability and moisture sensitivity of many anhydrides
has largely limited the reactions to acetylation "for which this method is particularly good#\ pro!
panoylation and butanoylation[ The in situ preparation of highly reactive mixed anhydrides avoids
these problems and provides a useful route to ketones based on the corresponding carboxylic
acids[ Carboxylic dihalophosphoric anhydrides ð70CB815Ł and acyl tri~uoroacetates ð68S292\ 79S028\
77BCJ344Ł have both found some use "Equations "09# and "00##[

OMe MeO
O TFAA, MeCN, 85% H3PO4
+ (10)
OH 66%
O
TFAA = trifluoroacetic anhydride
General Methods 170
O
O
2-PyOTf, TFA
+ OH (11)
99%

As with the reactions of acyl halides\ carboxylic acid anhydrides can serve as useful acylating
agents for active aromatic nuclei in the presence of little or no catalyst ð61S422Ł\ but usually under
rather drastic conditions[ However\ later work\ mostly by Mukaiyama and his co!workers\ has seen
the development of substoichiometric catalysts which provide aromatic ketones using anhydrides
under very mild experimental conditions[ Diphenylboryl hexachloroantimonate ð75CL054Ł\ gallium
chloride:silver perchlorate "Equation "01## ð80CL0948\ 80S0105Ł\ antimony chloride:lithium per!
chlorate ð81CL324Ł and lanthanide tri~uoromethanesulfonates ð82CC0046Ł all provide high yields of
ketones with electron!rich aromatic substrates\ and with one exception\ at room temperature in
dichloromethane[ Carboxylic acids "or their trimethylsilyl esters# and p!tri~uoromethylbenzoic
anhydride in the presence of a silicon tetrachloride:silver perchlorate catalyst system constitute an
e.cient and mild route to the corresponding ketones "Equation "02## ð81CL0640\ 82BCJ2618Ł[

OMe
GaCl3 (10 mol%)/AgClO4
O
CH2Cl2, RT
+ (C5H11CO)2O C5H11 (12)
91%
MeO

OMe O O
SiCl4 (20 mol%)/AgClO4
CH2Cl2, RT
+ O-TMS (13)
100%
MeO

2[95[0[0[2 Reactions with miscellaneous acylating agents


Esters and amides are sometimes used as electrophilic substrates in the FriedelÐCrafts reaction[
Esters usually result in alkylation products but intramolecular reactions with protic acid catalysts are
known ð62CI"L#078Ł[ Treating aromatic substrates with acyl enolates and stoichiometric quantities of
aluminum trichloride "Equation "03## ð69JOC1240Ł or catalytic amounts of diphenylboryl hexa!
chloroantimonate "Equation "04## ð75CL054Ł result in moderate to good yields of ketones[ These
reactions have only acetone as a by!product and\ particularly in the latter case\ provide a mild and
essentially neutral procedure for electrophilic acylation[ Amides have been used to acylate electron!
rich aromatic substrates using either acid catalysts ð48JCS0452Ł or phosphorus oxychloride
ð48HCA0548\ 55LA"690#110Ł and N!acyl!2\4!dimethylpyrazoles and N!acylimidazoles with aluminum
chloride provide access to weaker acylating agents than the corresponding acid chlorides
ð51LA"542#070Ł[

O AlCl3, reflux
+ ( )15 (14)
83% ( )15
O
O

O
OMe SbCl5/Ph2BCl, NaHCO3 (aq.)
O CH2Cl2, RT
MeO
+ (15)
O 71%
MeO
OMe
171 Ketones With an a\b!Aryl or !Hetaryl
Seleno esters provide a useful alternative to classical FriedelÐCrafts acylating agents and give
good to high yields of ketones using active aromatic substrates "e[g[\ anisole\ furan#\ and the
crystalline complex of copper"I# tri~ate and benzene ð"CuOTf#1PhHŁ as catalyst ð79JA759Ł[ The tri~ic
acid generated can be scavenged by inclusion of calcium carbonate in the reaction mixture[
Some useful reactive reagents for acetylation and tri~uoroacetylation of aromatic systems include
acetylmethanesulfonate ð78SL43Ł\ tri~uoroacetyl tri~ate ð68JOC202Ł and 1!"tri~uoroacetoxy#pyridine
ð89CL672Ł[ The _rst two reagents require no catalysts for e.cient reaction\ and the latter compound
produces\ in the presence of aluminum trichloride\ the tri~uoroacetyl derivative of benzene in
moderate yield at 9>C in dichloromethane "Equation "05##[ In a similar vein\ oxocarbonium hexa!
~uoroantimonates are equally reactive and provide benzene derived ketones in good yields with no
need for catalysts "Equation "06## ð52JA0217\ 53JA1192Ł[

O
O AlCl3
+ CF3 (16)
N O CF3 53%

O
O benzene, warm
SbF6–
+ (17)
+
93%

Finally\ ketones behave as internal anhydrides and will acylate aromatic compounds in the
presence of aluminum trichloride and some other catalysts ðB!53MI 295!90\ B!62MI 295!91Ł[ The varied
outcomes of such reactions have led to little practical application[

2[95[0[0[3 The HoubenÐHoesch synthesis


FriedelÐCrafts acylations with nitriles and HCl "H1SO3 is sometimes used instead#\ and subsequent
hydrolysis of the so!formed ketiminium salts to give the desired ketones is generally referred to as
the HoubenÐHoesch reaction ð51RCR504\ B!53MI 295!90Ł[ In most cases a Lewis acid catalyst is also
required[ Zinc chloride has been used most frequently\ but boron trichloride has often replaced this
in later work[ The reaction usually requires relatively electron!rich aromatic substrates and is most
useful with polyhydric phenols "Equation "07## ð77MI 295!90\ 78BCJ2260Ł "monohydric phenols give
imino esters#\ phenolic ethers\ aromatic amines ð67JA3731\ 79TL062Ł and combinations thereof "Equa!
tion "08## ð64HCA63Ł[ Some reactive heterocyclic compounds can also be acylated[ Aromatic sub!
strates lacking electron!releasing substituents can be acylated in some cases if the nitrile moiety
contains electron!withdrawing groups that increase the electrophilicity of the reactive species[
Equation "19# shows an example where toluene participates in such a reaction ð73LA0289Ł[
N!Methylnitrilium salts which are prepared by treating nitriles with methyl tri~ate ð72JCS"P0#0964Ł
or trimethyloxonium ~uoroborate ð74TL3538Ł are good acyl cation equivalents and give particularly
good yields with heteroaromatic substrates such as pyrroles and indoles[

OH OH
HO OH CN HO OH
ZnCl2, HCl, Et2O
+ (18)
63%

OH OH O

NC
H
N N Me O Me
N
H2SO4 (conc.) MeO
(19)
CHCl3
N
MeO MeO H
OMe
General Methods 172

NC CN NH2 O
AlCl3, toluene
N (20)
N 34%
H N
N

2[95[0[0[4 Reactions with other acyl cation equivalents


The formylation of aromatic systems with chloroform and hydroxide ion is a well documented
process known as the ReimerÐTiemann reaction[ The reaction proceeds via an electrophilic dichloro!
carbene species to give a dichloromethyl benzene product which is then converted into the desired
aldehyde on hydrolytic workup[ The analogous reactions with alkyl trichloromethyl substrates
have only received limited attention but some examples include the formation of purinyl ketones
ð52JOC0268Ł and a very e.cient benzoylation\ under FriedelÐCrafts conditions\ using "trichloro!
methyl# benzene "Equation "10## ð80S211Ł[ The latter method allows for benzoylation under relatively
mild reaction conditions and makes use of a cheap\ nonhygroscopic\ and nonlachrymatory reagent[

O
H CCl3 i, AlCl3
N ii, H2O
+ O (21)
O 98%
N
H

Some sulfur!based functional groups which serve as alternative masked acylating agents include
1!substituted 0\2!benzoxathiolium tetra~uoroborates ð76S200Ł\ bisphenylthionium ions ð76T0736Ł
and acyl sulfones ð73JA1358Ł[ The former reagents add e}ectively to active aromatic substrates to
provide intermediate benzoxathioles which are easily hydrolysed to the corresponding ketones[ The
reactions proceed under mild conditions and o}er the possibility of introducing tertiary acyl groups
"Equation "11##[ Bisphenylthionium ions are generated by the action of dimethyl"methylthio#
sulfonium ~uoroborate "dmtsf# or silver tri~ate on tris"phenylthio#alkanes and\ through sub!
sequent hydrolysis of the thioacetals obtained\ provide a useful method for intramolecular acylation
"Scheme 0#[ Intramolecular acylations are also possible with reactive acyl sulfones\ generated in situ
by the action of Lewis acids "BCl2 and TiCl3# on protected alkoxy!bis"sulfonyl# derivatives\ and lead
directly to the required ketone "Equation "12##[ These three methods are signi_cant in that the
starting materials are easily prepared and are inert to various other functional group manipulations\
thus allowing for selective unmasking of the active acylation species as required[

OMe OMe O
S i, pyridine, MeCN, 50 °C
ii, HgO, THF, HBF4 (aq.), RT
+ + But But (22)
O BF4– 60%
MeO MeO

SPh PhS SPh O


SPh AgOTf
CH2Cl2, RT hydrolysis
SPh
91%
MeO MeO MeO

Scheme 1

O2S
O O
TMS
S TiCl4, CH2Cl2, –10 °C to 0 °C
O2 (23)
68%
173 Ketones With an a\b!Aryl or !Hetaryl
2[95[0[1 Electrophilic Acylations of Organometallic Species
For a long time the synthesis of ketones by acylation of nonstabilised organometallic species
with carboxylic acid derivatives was a problematic process[ The fact that the required ketone was
often considerably more reactive than the usually weakly electrophilic substrate resulted in over!
addition and the formation of alcohols[ Relatively recent developments have largely solved such
problems\ and various single step methodologies are now available ð80COS"0#286Ł[ The aromatic
component of the ketone target can be introduced as a nucleophilic or electrophilic moiety
"Scheme 1#\ and consequently allows for considerable ~exibility in synthetic design\ often providing
more practical or complementary alternatives to methods such as the FriedelÐCrafts acylation[ The
ease of preparation of aromatic anions is central to the importance of these methods[
O O O
ArM + + RM
X R Ar R Ar X

Scheme 2

2[95[0[1[0 Acylations of organolithium reagents


Carboxylic acids can be converted directly into ketones on exposure to many easily accessible
organolithium species ð69OR0Ł[ Benzoic acid derivatives and phenyllithium species are both com!
patible with this method\ and they can provide the corresponding aromatic ketones in good yields[
The main side!reaction is over!addition to give tertiary alcohols as products[ The extent to which
this occurs is highly dependent on the stability of the relevant dilithium intermediates[ Stabilisation
of these intermediates can greatly improve yields\ and this can be achieved by addition of TMS!
Cl to the reaction mixture ð72JOC0449\ 75JOC840Ł[ Complications can also arise from competitive
deprotonation of substrates although careful choice of conditions or of protecting groups usually
allows for the circumvention of such problems[ The reaction is e.cient for the annulation of
bromoaromatic acids "Equation "13## ð71ACR299Ł\ but phenyllithium and o!benzylbenzoic acid\ for
example\ give 8!phenylanthracene as the only product ð46JA282Ł[ The formation of the latter is
postulated to occur via competitive deprotonation to give the benzhydryl carbanion[ a!Amino acids
have been used as substrates with successful preservation of their stereochemical integrity "Equation
"14## ð70JA5046\ 73JA0984Ł[ Ketones can be prepared by sequential addition of organolithium reagents
to carbon dioxide and the intermediate carboxylates ð81AG"E#0924Ł[
O
2BuLi, –100 °C
(24)
Br CO2H 77%

O O
MeO Li
–78 °C MeO
+ HO OH OH (25)
83%
MeO NHSO2Ph NHSO2Ph
MeO

Acylations of organolithium species by simple carboxylic acid derivatives are generally not widely
applicable\ due largely to the poor stability of the so!formed tetrahedral intermediates\ but examples
have been reported for a number of such substrates[ Thus\ acid chlorides "Equation "15##
ð71JOC0474Ł\ esters ð75JOC840Ł\ lactones "Equation "16## ð72JA6533\ 73CC429Ł\ and amides "Equation
"17## ð73TL700Ł have all been utilised in this manner[

O
N N O
BuLi O
+ Cl (26)
O
MeO
OMe
General Methods 174
OMe O OMe O
MeO2C OH
O
hydrolysis
+ O OMe (27)
O 60%
Li
OMe OMe O OMe OMe O

O
Li O
+ (28)
N

The best acylating agents to date are the N!methoxy!N!methylamides developed by Weinreb
ð70TL2704Ł[ These species are readily available from the corresponding carboxylic acids\ are tolerant
of many reaction conditions\ and selectively yield the desired ketone products even in the presence
of excess organolithium reagent[ The product speci_city of these compounds is due to the exceptional
stability of the tetrahedral intermediate which e}ectively masks the ketone product from further
reaction[ The aromatic moiety may be incorporated into either the nucleophilic ð76JOC1504Ł or
electrophilic ð70TL2704Ł substrate\ and can also be applied in an intramolecular fashion as dem!
onstrated in a recent approach to benzocyclobutenones starting from iodo!substituted aromatic
Weinreb amides "Equation "18## ð81TL4320Ł[
Me
MeO
MeO N ButLi, THF, –78 °C
OMe (29)
67% MeO
O O
MeO I

2[95[0[1[1 Acylations of Grignard reagents


Organomagnesium or Grignard reagents bear some similarities to the lithium species discussed
in the previous section[ Once again\ addition of these organometallics to carboxylic acid derivatives
can result in isolation of the requisite ketones ð43OR"7#17Ł[ Additions to carboxylic acids themselves
are hampered by the unstable nature of the intermediates and tertiary alcohols are the usual
products[ In contrast to alkyllithium species\ Grignard reagents are acylated by acid chlorides
although the mechanism is not fully understood[ Thus acetophenones are readily formed from the
stoichiometric combination of aryl magnesium species and benzoyl chlorides ð68TL3292Ł[ Additives
such as vanadium trichloride "Equation "29## ð75TL818Ł and iron"III# salts "Equation "20## ð73TL3794\
74TL0174\ 76TL1942Ł promote monoacylations of Grignard reagents\ the latter in substoichiometric
quantities[ Alkyl aryl ketones have been prepared by nickel"II# and then iron"III# salt catalysed
additions of Grignard reagents to S!phenyl carbonochloridothioate ð74TL2484\ 77TL2476Ł[ These
methods tolerate functionality such as esters\ nitriles and alkyl halides[

O O
MgBr
VCl3, CH2Cl2 OEt
+ Cl
OEt (30)
76%
O O

O
MgBr O Fe(acac)3 (3 mol%), THF
+ (31)
Cl 55%
MeO
OMe

Some Grignard reagents will react with aryl esters in the presence of triethylamine to give the
desired ketones ð79S766Ł[ This method relies on masking of the intermediate ketone by basic
enolisation\ and is consequently highly substrate dependent[ As in the previous section\ Weinreb
amides ð70TL2704Ł are good acylating agents for organomagnesium compounds but a number of
175 Ketones With an a\b!Aryl or !Hetaryl
other acid derivatives rival their success in such transformations[ Some of the best such substrates
are the S!"1!pyridyl# thioates developed by Mukaiyama ð62JA3652\ 63BCJ0666Ł[ Derived from the
corresponding acids or acid chlorides\ these compounds do not stabilise tetrahedral intermediates
but\ rather\ provide highly reactive species by coordination to the divalent magnesium ion\ which
are selectively attacked in preference to other ketone functionality "Equation "21## or ketone
intermediates[ In a similar vein\ esters derived from 7!hydroxyquinoline ð51JA3788Ł\ 1!hydroxy!2!
methylpyrazine "Equation "22## ð66CL534Ł\ 1!pyridyl ketone oximes "Equation "23## ð75CL338Ł and
N\N!diphenyl!p!methoxyphenylchloromethyleneiminium chloride "Equation "24## ð71TL4948Ł have
all shown some utility in aromatic ketone synthesis\ as have anhydrides ð37JOC481Ł\ mixed an!
hydrides of phosphorus ð67SC48Ł and acylimidazoles ð51LA"544#89Ł[
O O
S PhMgBr, THF, 0 °C Ph
(32)
O N O

O
N
O PhMgBr
(33)
O N 79%

O N
PhMgBr O
C15H31 O N (34)
85% C15H31 Ph

Ph
O N+
Ph
PhMgBr Ph
O Cl– (35)
66% O

OMe

Finally\ aryl Grignard reagents can add to nitriles to give iminyl intermediates which are easily
hydrolysed to the corresponding ketones on workup ð58JA4775\ 61JOC2258Ł[ Mild Lewis acids such
as LiClO3 ð64JOM"88#30Ł and TMS!Cl "Equation "25## ð80TL5620Ł often improve the e.ciency of
this transformation[

i, TMS-Cl O
MgBr O
O ii, H3O+ O-TBDMS
+ NC O-TBDMS (36)
96%

TBDMS = t-butyldimethylsilyl

2[95[0[1[2 Acylations of organocopper reagents


Dialkylcuprates derived from the corresponding organolithium or magnesium reagents and cop!
per"I# iodide are relatively unreactive towards ketone functionality at low temperature[ Conse!
quently\ additions of these reagents to acid chlorides constitute a useful ketone synthesis ð69TL3536Ł[
Some limitations of functional group compatibility in the preparation of these reagents can be
avoided by the direct preparation of simple cuprates from functionalised bromides using highly
reactive copper derived from lithium naphthalide reduction of copper"I# iodide triphenylphosphine
complex ð77JOC3371\ 77TL3402Ł\ copper"I# cyanide lithium bromide complex ð80JA3561Ł\ or lithium
"1!thienylcyano#cuprate ð78SC0722\ 82JOC1381Ł[ This method is compatible with ester\ nitrile\ chloride\
General Methods 176
and some epoxide and ketone functionalities "Equation "26##[ However\ both methods have draw!
backs[ In the former case three equivalents of the dialkylcuprate are required\ and in the latter case
a similar quantity of the acid chloride must be used[

CN CN O
O DME, 0 °C
Cu
+ Ph (37)
Ph Cl 71%

Alternatives to acid chlorides include thiol esters "Equation "27## ð79TL1902Ł\ and 1!pyridyl esters
"Equation "28## ð72JOC1597Ł[ The latter are particularly useful as their high reactivity promotes
reaction with the intermediate lithium alkyl "1!pyridyloxy# cuprate complex\ and hence allows for
e}ective reaction using a single equivalent of dialkyl cuprate[ The conditions also tolerate functional
groups such as bromide\ ketone and ester in the pyridyl ester moiety[

SPh Ph
Ph2MgCuX, Et2O, THF
N O N O (38)
O PPh3 O PPh3
CO2NB CO2NB

O N THF, –78 °C O
+ But2CuLi (1 equiv.) (39)
Ph O 74% Ph But

The uneconomical nature of nonstoichiometric dialkyl cuprates and the thermal instability of
s! and t!alkylcuprates ð58JA3760Ł has led to the development of mixed cuprates with only a single
transferable ligand[ The most successful nontransferable ligands for acylation of cuprates have been
various heteroalkyls[ Phenylthio and t!butoxide "Equation "39## ligands give good to excellent
results ð62TL0704\ 62JA6677Ł at −67>C\ and diphenyl "Equation "30## and dicyclohexyl phosphido
ligands show similar utility at room temperature ð71JA4713\ 73JOC0008Ł[ More recently\ Knochel and
his co!workers have developed a new class of organocopper reagents "RCu"CN#ZnI# which are
easily prepared from alkyl iodides[ These reagents are stable up to 9>C\ they have one transferable
group and furthermore they tolerate a wide range of functionality "Equation "31## ð77JOC1289Ł[

O O
THF, –78 °C
Cl + But(ButO)CuLi But (40)
82%

O O
Et2O, 0 °C
Cl + ButCu(PPh2)Li But (41)
80%

O
O O O
O i, ii, iii
O (42)
I 80%
O
O

i, Zn, THF; ii, CuCN•2LiCl; iii, Cl , 0 °C

2[95[0[1[3 Acylations of organotin reagents


Aryl stannanes themselves react readily with acyl halides in the presence of excess Lewis acid to
give the corresponding aromatic ketones ð60MI 295!90Ł[ However\ the reactions of the analogous
177 Ketones With an a\b!Aryl or !Hetaryl
organosilanes are usually the reagents of choice in such reactions[ Transition!metal catalysed
couplings of acid halides with organotin compounds have also developed into a mild and selective
approach to aryl ketones[ Pioneering work by Migita ð66CL0312Ł and by Stille ð67JA2525\ 68JOC0502\
75AG"E#497Ł has shown that palladium"9# e.ciently catalyses the reaction and that aromatic and
heteroaromatic acid chlorides give high yields of ketones[ The reaction is general with respect to the
organotin compound ð72JOC3523Ł and the acid chloride "Equations "32# and "33##\ it works well in
sterically demanding cases "Equation "34## and su}ers from virtually no side!reactions while remain!
ing experimentally simple[ In the catalytic cycle\ aryl groups are transferred from tin in preference
to alkyl groups and the use of aromatic trimethyl! or tributyltin derivatives provides an economical
route to ketones incorporating expensive or synthetically demanding fragments[ The catalyst of
choice is usually benzoylchloro!bis"triphenylphosphine# palladium"II# "from which the palladium"9#
species required is formed in situ#\ and as both this reagent and most organostannanes are air!stable\
the reaction can be carried out under an oxygen atmosphere which in turn has been found to
accelerate the transformation[ Finally\ the mild conditions tolerate a variety of functionality\
including nitro\ nitrile\ aryl halide "Br#\ alkenyl\ methoxy\ ester\ and even aldehyde functions
"Equation "35##[

O PhCH2Pd(PPh3)2Cl O
+ Ph4Sn (43)
Cl 76% Ph

O O
PhCH2Pd(PPh3)2Cl
Cl + Me4Sn (44)
100%
NC NC

O PhCH2Pd(PPh3)2Cl O
+ Me4Sn (45)
But Cl 82% But

O Cl O

PhCH2Pd(PPh3)2Cl
+ Me4Sn (46)
86%

CHO CHO

2[95[0[1[4 Acylations of organozinc reagents


The reactions of arylzinc reagents with alkyl acid chlorides and of alkylzincs with aroyl chlorides
have found considerable use in the synthesis of aryl ketones\ and they are often used in preference
to the corresponding reactions of Grignard reagents ð43OR"7#17Ł[ The lower reactivity of zinc reagents
towards ketones is often su.cient to prevent over!addition and formation of tertiary alcohols[
However\ in many cases only low yields are obtained and the development of other organometallics
has led to a decline in the use of these reagents[ Developments in transition!metal catalysis and
particularly the use of palladium catalysts has led to a reexamination of the role of organozincs in
synthesis[ Thus\ as with organostannanes\ organozinc compounds are readily acylated by acid
chlorides in the presence of catalysts such as benzylchloro!bis"triphenylphosphine#palladium\
"dppf#PdCl1 "Equation "36## ð73JOC1177Ł\ tetrakis"triphenylphosphine#palladium "Equation "37##
ð72TL4070Ł\ and Pd"PPh2#1Cl1 ð70CL0024Ł[ Equation "38# ð78CC533Ł illustrates an application of this
methodology to the synthesis of amino acid derivatives[

O O
(dppf)PdCl2, THF, Et2O
Cl + Bun2Zn (47)
82%
General Methods 178
O
ZnCl O Pd(PPh3)4, THF
+ Ph (48)
Ph Cl 95%
Cl
Cl

O NHBOC (Ph3P)2PdCl2 Ph NHBOC


+ IZn
(49)
Ph Cl CO2Bn 70% O CO2Bn

2[95[0[1[5 Acylations of miscellaneous organometallic reagents


A number of organometallic species not mentioned above have been used in the synthesis of
aromatic ketones[ Historically\ organocadmium reagents are of considerable importance and pro!
vide ketones on addition to acyl halides ð43OR"7#17Ł[ However\ the instability of many of these
reagents ð59JOC366Ł and high toxicity have led to their relatively low contemporary popularity[
Organoaluminum reagents in the presence of a palladium catalyst have been applied to the synthesis
of simple alkyl aryl ketones ð74BCJ1314Ł and boronate complexes have been used to prepare ketones
in conjunction with acid chlorides with "Equation "49## ð82JOM"332#142Ł or without ð64JOC0564\
64TL3128Ł palladium catalysts[ Nickel"9# catalyses the addition of benzylic halides to aroyl chlorides
ð72TL1340\ 74JOC0262Ł\ and work by Mukaiyama and co!workers ð70CL420Ł has shown that alkyl
iodides can be acylated in good yields with aromatic 1!"5!"1!methoxy!ethyl#pyridyl# carboxylates in
the presence of nickel"II# chloride "09 mol)# and zinc dust "Equation "40##[ The latter method is
tolerant of functional groups such as ketones\ esters\ chlorides and a\b!unsaturated carboxylic acid
derivatives[ Lastly\ although the role of rhodium in acylation has been largely overshadowed by the
use of palladium catalysts\ alkyl rhodium complexes provide a mild method for the acylation of
simple alkyl! and aryllithiums or Grignard reagents ð62JA2939\ 64JA4337Ł[

O O
Pd(PPh3)4 (1 mol%), THF
Cl + Na+ –BPh4 Ph (50)
76%
O2N O2N

O
Cl O
NiCl2 (10 mol%), Zn, DMF Cl
+ I (51)
N
81%

OMe

2[95[0[2 Aryl Ketones by Carbonylative Cross!coupling Reactions


As described in the previous section\ the transition!metal catalysed coupling of organometallics
"e[g[\ organostannanes# with acid chlorides provides a very useful entry to aromatic ketones[ In a
related manner\ metal!catalysed coupling reactions of various organometallic species with certain
electrophiles produce ketones when executed under a carbon monoxide atmosphere "Equation "41##[
This carbonylative cross!coupling methodology consequently expands the utility of organometallic
reagents in aromatic ketone synthesis\ and in many cases allows for a greater tolerance of func!
tionality within the relevant substrates[

transition-metal catalyst O
ArX + RM (52)
CO atmosphere Ar R

Palladium catalysts give access to the most general methods for the above!mentioned trans!
formations[ Tanaka ð68TL1590\ 70BCJ526Ł _rst showed that aryl halides and organotin compounds
give ketones in the presence of C5H4PdI"PPh2#1 and carbon monoxide[ However\ this method
requires high CO pressures and HMPA as cosolvent\ two factors which detract from this reagent
189 Ketones With an a\b!Aryl or !Hetaryl
combination[ Aryl diazonium salts react with tetramethyltin and carbon monoxide\ using palladium
diacetate as catalyst\ to give good yields of acyl arenes ð71CL24Ł[ This method is compatible with
various aryl substituents "i[e[\ Me\ Cl\ Br\ I\ NO1^ Equation "42## but does not work as well with
other tetralkyltin compounds and again requires high CO pressures[

O
N2+ BF4–
Pd(OAc)2 (2 mol%), CO
+ Me4Sn (53)
85%
O2N
O2N

Coupling reactions of aryl iodides with alkyl! or benzylzinc compounds and using tetra!
kis"triphenylphosphine#palladium gives the desired ketones in moderate to good yield under an
atmospheric pressure of carbon monoxide "Equation "43## ð72TL2758Ł[ Aryl tri~ates\ which are
readily available from phenols\ react with organostannanes in the presence of carbon monoxide
"0 atm#\ dichloroð0\0!bis"diphenylphosphino#ferroceneŁpalladium"II#\ and lithium chloride to a}ord
a variety of aryl ketones\ again in variable yields ð77JA0446Ł[ Many functional groups are tolerated
by this method "e[g[\ Equation "44##\ but strong electron!withdrawing groups on the organo!
stannanes should be avoided[ Unsymmetrical diaryl and aryl!hetaryl ketones are conveniently
accessed by cross!coupling reactions of organo~uorosilanes with aryl halides in the presence of
carbon monoxide "0 atm#\ potassium ~uoride and "h2!C2H4PdCl#1 ð78CL1938\ 81T1002Ł[ The reaction
conditions tolerate reactive functional groups such as esters\ ketones\ aldehydes "Equation "45## and
nitriles[

O
Pd(PPh3)4 (1 mol%), CO (1 atm)
I
Zn–Cu, THF
+ I (54)
91%

O
OTf
PdCl2(dppf) (4 mol%), CO (1 atm)
LiCl, DMF
+ PhSnMe3 (55)
78%
OAc
OAc

(η3-C3H5PdCl)2, CO (1 atm)
KF, DMI
+ S
(56)
S Si(Et)F2 72% CHO
I CHO
O

Unsymmetrical biaryl ketones and alkyl aryl ketones are available by palladium!catalysed
"PdCl1"PPh2#1# carbonylative cross!coupling of 8!alkyl!8!BBN derivatives or arylboronic acids with
iodoarenes as described by Suzuki and his co!workers ð80BCJ0888\ 80TL5812\ 82TL6484Ł[ These reactions
"e[g[\ Equation "46## generally give good yields of ketones and the conditions used are intrinsically
non!intrusive to a range of functionality[ Sodium tetraphenylborate ð77JOM"234#286Ł and aryl!
aluminum compounds ð74TL3708Ł undergo carbonylative cross!coupling with alkyl! and aryliodides
respectively[ The former requires a platinum catalyst and high CO pressure\ whereas the latter
proceeds at atmospheric pressure with PdCl1"MeCN#1[ The nature of the organometallic species
somewhat limits the synthetic value of these methods[ Rhodium"I# catalysts have found some use
in the carbonylation of arylmercury ð79JOC2739\ 71IZV110Ł and arylbismuth reagents ð81CC342Ł[
Isocyanides\ which are isoelectronic with carbon monoxide\ can be utilised in palladium!catalysed
iminocarbonylative cross!coupling reactions to yield imines which are readily hydrolysed to the
corresponding aryl ketones[ Both organotin ð74TL2352\ 75BCJ566\ 75CL0086Ł and 8!alkyl!8!BBN "8!
BBN8!borabicycloð2[2[0Łnonyl# derivatives ð81TL3354Ł can be utilised in this manner[ The former
react with imidoyl chlorides and Pd"PPh2#3\ whereas the latter combine with t!butylisocyanide and
aryl halides in the presence of Pd"PPh2#3 and K2PO3 to give good yields of functionalised aryl alkyl
ketones after hydrolytic workup "Equation "47##[
General Methods 180
F CO2Me
B(OH)2 CO2Me PdCl2(PPh3)2 (3 mol%)
CO (1 atm), K2CO3, anisole
+ (57)
76%
F I
O

O
I O O
i, ii
+ B (58)
O 89%
O
MOM-O
MOM-O
i, Pd(PPh3)4 (5 mol%), ButNC, K3PO4, dioxane, THF; ii, 2M HCl
MOM = methoxymethyl

2[95[0[3 Acyl Anion Equivalents in Aromatic Ketone Synthesis


Acyl anion equivalents ð80COS"0#430Ł are umpoled synthons ð68AG"E#128Ł\ which on alkylation ðAŁ
or arylation ðBŁ "Scheme 2#\ can provide aryl alkyl ketones either spontaneously or after a simple
hydrolytic step[ This section brie~y summarises some of the more commonly used members of this
class of reagent and examples of their application to the synthesis of aromatic ketones[
O R+ O Ar+ O
– –
Ar [A] Ar R [B] R

Scheme 3

2[95[0[3[0 1!Alkyl!0\2!dithianes
1!Alkyl!0\2!dithianes\ which are derived from the corresponding aldehydes or by alkylation of
1!lithio!0\2!dithiane\ are readily lithiated\ and the resulting anions can then be alkylated with a
variety of electrophiles to give masked ketones which are henceforth unveiled on hydrolysis ð66S246Ł[
Similarly\ 1!aryl!0\2!dithianes are readily prepared from benzaldehyde and its derivatives or from
other aryl aldehydes ð66OS"45#7Ł[ Examples of metallation and electrophilic alkylation of such com!
pounds are found in an approach to lignan lactones "Equation "48## ð67JOC874Ł\ the synthesis of
2!acetylindole ð61HCA64Ł\ and in studies of conjugate additions to a!alkylidene!g!butyrolactones
ð74TL2916Ł and to a\b!unsaturated esters ð74TL2920Ł[ Alkylations with alkyl halides\ epoxides "Equa!
tion "59## and carbonyl compounds are all relatively high yielding ð66S246Ł[ Conversely\ 1!aryl!
1!lithio!0\2!dithianes have been successfully arylated using "h5!alkylbenzene# Cr"CO#2 complexes
"Equation "50## ð72OM356Ł[
O
H
O
O
i, 2-butenolide
S S ii, 3,4,5-trimethoxybenzyl chloride O
O H O (59)
Li iii, HgO–BF3, THF, H2O

O
MeO OMe
OMe

O-MOM O-MOM

i, BunLi
(60)
S O MOM-O
MOM-O ii, S S
S OH
181 Ketones With an a\b!Aryl or !Hetaryl

But
But But
Ar Li
S S + Ar
Ar + (61)
80% S S
S S
(OC)3Cr

63 : 37
Ar = NMe2

2[95[0[3[1 Protected cyanohydrins


By in situ formation of a cyanohydrin carbanion\ cyanide ions catalyse the conjugate addition of
aromatic and heteroaromatic aldehydes to a\b!unsaturated ketones\ esters and nitriles ð65AG"E#528Ł[
More commonly\ the cyanohydrin silyl ethers ðB!70MI 295!90\ 72T2196Ł derived from aryl and hetaryl
aldehydes ð68CB1934Ł are used[ These are deprotonated with LDA\ and the resulting anions then
react smoothly with a range of alkylating agents "e[g[\ Equation "51## ð79CB291Ł[ Fluoride!ion
induced hydrolysis subsequently unmasks the ketone functionality "Equation "52## ð73OR36Ł[ Other
types of protected cyanohydrin\ although perhaps not as popular as the silyl ethers\ can be metallated
and show similar reactivities[ Acetals ð73OR36Ł\ esters ð72CPB2840Ł and carbonates ð73SC632\ 73SC638Ł
are all useful and the corresponding reagents have all been applied to the synthesis of aryl ketones[
As in the case of metallated dithianes\ cyanohydrins derived from alkyl aldehydes can undergo
arylation with p!chromium tricarbonyl complexes ð69MI 295!90Ł[ Subsequent workup again provides
the aryl alkyl ketones[

O-TMS TMS-O CN
i, LDA
CN (62)
O
ii, O

86%

i, LDA
O-TMS O O O
ii, Br
O
CN O (63)
iii, [(C2H5)3NH]F
60%

2[95[0[3[2 Acyl radicals


Free!radical reaction conditions are compatible with most functional groups and have led to the
emergence of such methods as important modern synthetic tools ðB!75MI 295!90\ 77S306\ 77S378Ł\
particularly in the construction of carbocyclic systems[ Acyl radicals\ and particularly those derived
from phenylselenoesters by thermally induced trialkyltin hydride:1\1?!azobisisobutyronitrile "AIBN#
homolytic cleavage\ constitute an e}ective method of ketone preparation on addition to double
bonds ð77JOC2266\ 89T1024Ł[ Aryl acyl radicals give the corresponding aryl ketones in useful yields
on intermolecular addition to activated alkenes "Equation "53## ð78JOC0666Ł or on analogous
intramolecular cyclisation "Equation "54## ð81JOC0318Ł[ Aryl acyl radicals are less prone to decar!
bonylation than some of the alkyl acyl species and are usually immune to intramolecular 0\4!
hydrogen abstraction[ Alkyl acyl radicals add to some heteroaromatic systems to give ketones
ð77HCA420Ł[
General Methods 182
O O
Bun3SnH, AIBN
OMe benzene, ∆ OMe
SePh + (64)
O 74%
O
MeO (5 equiv.) MeO

O
O OMe
Bun3SnH, AIBN O
SePh benzene, ∆
(65)
OMe 84%

2[95[0[3[3 Miscellaneous acyl anion equivalents


Aromatic halides are readily acetylated by enol ethers ð70JOC4303Ł\ or by the zinc ð72JA832Ł and
tin ð76BCJ656Ł derivatives of lithiated enol ethers\ in the presence of palladium catalysts[ Similarly\
aryl tri~ates undergo a Heck reaction with butyl vinyl ether ð89JOC2543Ł[ These reactions are
particularly useful for acetylations of electron!de_cient aromatics such as nitrobenzene "Equation
"55##[ Lithiated diethyl a!trimethylsilyloxy!benzylphosphonate ð67TL252Ł and t!butylhydrazones
ð72CC0939Ł have been used as acyl anion equivalents in the preparations of simple phenyl ketones\
as have a number of acyl metal complexes[ Acyl tetracarbonylferrates couple with alkyl and acyl
halides ð58TL4078Ł\ and with aryl halides and a palladium catalyst "Equation "56## ð77CL0030Ł[
Unsymmetrical and symmetrical diaryl ketones have been prepared from arylmercury"II# halides in
the presence of nickel tetracarbonyl ð66S665Ł or dicobalt octacarbonyl ð57JA439Ł[
i, PdCl2(PPh3)2
Bun3Sn OEt ii, H3O+ O
O2N Br + O2N (66)
91%

O
O
Pd(PPh3)4, ZnCl2 MeO
Na[BuiCOFe(CO)3L] + MeO (67)
69% Bui
I
O

2[95[0[4 Oxidation
Ketones are readily prepared by oxidative methods\ and the extra facility imparted to such
procedures by the proximity of aromatic groups often makes oxidation a viable route to the desired
aryl and hetaryl ketones[ Benzylic methylene carbon atoms\ secondary alcohols and alkenes can all
be e.ciently transformed into ketones in this manner[

2[95[0[4[0 Oxidations of benzylic methylene groups


Benzylic methylene groups are activated towards oxidation and can be converted into ketones by
a variety of reagents[ Diarylmethanes are similarly converted into benzophenones with the extra
activation further facilitating oxidation[ The product ketones are relatively inert to over!oxidation\
a feature which often allows for the application of more vigorous conditions when required[ Some
of the most commonly employed reagents are chromium based reagents such as sodium and
potassium dichromate ð44JCS1575\ 78CC0244Ł\ pyridinium chlorochromate ð75SC0382Ł\ chromic acid in
acetic acid "Equation "57## ð40JA2352Ł and chromate:t!butylhydroperoxide combinations ð75TL2028\
76TL1020Ł^ potassium permanganate "Equation "58## ð50JOC3040\ 61CJC0814\ 78S182Ł^ selenium dioxide
ð30JCS424\ 58BSF804\ 63HCA1190Ł^ 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq# ð66CL476\
77JOC3476Ł^ ceric ammonium nitrate ð89SC2148Ł^ manganese dioxide ð72IJC"B#0135Ł^ lead tetraacetate
183 Ketones With an a\b!Aryl or !Hetaryl
ð64H"2#338Ł and ruthenium oxide:sodium periodate ð62MI 295!90Ł[ Autooxidations in air "Equation
"69## ð60JA3210Ł are sometimes useful\ although a catalyst may be necessary ð56TL2554Ł[ Other
procedures include photochemical oxidations with iron trichloride in wet acetone ð73HCA755Ł and
oxidations of carbanions ð79JOC1674Ł[

Ph Ph
H H
AcO CrO3, NaOH (0.5N) AcO O
HOAc (80%)
(68)
70%

MeO MeO
MeO MeO

OMe KMnO4 (excess), AcOH, acetone OMe


(69)
82%
N N O
Me O
OMe OMe
H H

O O
NMe NMe
O air, EtOH O
OMe OMe (70)
OMe O 63% MeO O O
OMe OMe
O O

2[95[0[4[1 Oxidations of secondary benzylic alcohols


Secondary benzylic alcohols are readily accessible by nucleophilic additions to aldehydes\ and
their subsequent oxidations provide an alternative to ketone syntheses by direct acylations of
nucleophiles[ The activated nature of the benzylic C0H bond makes for facile reactions\ and a
large variety of reagents successfully accomplish this transformation[ Chromium! and per!
manganate!based reagents are a popular choice "e[g[\ ð64JCS"P0#511Ł and ð53JOC463Ł# "compare
the previous section#\ but many others\ including nickel bromide:benzoyl peroxide ð68JOC1844Ł\
ruthenium chloride with acetone ð81CC226Ł or t!butyl hydroperoxide ð82S322Ł\ sodium chlorate
ð62TL2524Ł\ diethyl azodicarboxylate "dead# ð55JA1217Ł\ bromine ð55JOC1697Ł\ Swern conditions
ð77TL4450Ł\ DessÐMartin periodinane ð89JOC5050Ł and mcpba ð89SC526Ł have been used in high
yielding ketone preparations[ Manganese dioxide "e[g[\ ð64TL1446\ 77CL0276Ł is particularly useful\
since the oxidations of benzylic alcohols occur selectively in the presence of other unprotected
alcohol functionality "excluding allyl alcohols\ which are also oxidised#[ Benzyl ð81JOC4730Ł and
silyl ethers ð79S786\ 72S461\ 89SL234\ 80TL2882\ 81SC0882Ł of secondary benzylic alcohols can be converted
into ketones directly without a primary group deprotection step[

2[95[0[4[2 Oxidative cleavages of double bonds


Although not a particularly common method for the synthesis of aromatic ketones\ oxidative
cleavages of double bonds have found some use[ Permanganate is e.cient under phase!transfer
conditions and will selectively cleave aryl!substituted double bonds in the presence of alkyl!sub!
stituted double bonds ð75JCR"S#347Ł[ The actions of osmium tetroxide:sodium periodate "Equation
"60## ð76CC0259Ł and osmium tetroxide:Jones reagent ð82JOC3634Ł on aryl substituted double bonds
Phenyl Ketones and Analo`ues 184
give the desired ketones\ as do hexavalent chromium compounds[ Chromium trioxide has found
the most utility in aromatic ketone synthesis ð37JA2241\ 50JOC569Ł[

O
O OEt OsO4, NaIO4, Et2O, H2O
(71)
O 65%
MeO MeO CO2H

2[95[1 PHENYL KETONES AND SUBSTITUTED ANALOGUES


The FriedelÐCrafts acylation was\ and to a large extent often still is\ the method of choice for the
synthesis of aromatic ketones[ However\ the development of various organometallic methodologies
now allows for varied and often complementary approaches to this class of organic functionality[
This section concentrates on aspects of synthetic methods which are particularly important when
preparing speci_cally substituted aromatic substrates[

2[95[1[0 Phenyl Ketones


The thermodynamic stability of benzene tends to make FriedelÐCrafts acylations relatively di.!
cult[ However\ quite a considerable number of simple phenyl ketones have been prepared from
benzene in good yield by\ in most cases\ the combination of aluminum trichloride and the requisite
acid chloride or anhydride ðB!53MI 295!90Ł[ Benzene has been successfully acylated under somewhat
milder conditions using reactive carboxylic tri~uoromethanesulfonic anhydrides ð61AG"E#299\
72CB0084Ł\ and 1!"tri~uoroacetoxy#pyridine is a useful reagent for the analogous tri~uoroacetylations
ð89CL672Ł[
The ready availability and:or ease of preparation of phenyl metal species "e[g[\ PhLi# makes the
preparation of phenyl ketones by acylations of such species particularly attractive\ and in many
cases the desired products are isolated in excellent yield ð75TL818\ 76JOC1504Ł[ In some cases the
inherent basicity of some reagents may be problematic\ and other electrophilic centres may require
protection[ Palladium catalysed ketone forming reactions of iodobenzene\ phenylboronic acid\ and
the tri~ate of phenol are extremely mild and tolerant to a range of functionality ð72TL2758\ 77JA0446\
80TL5812Ł[ Derivatives of benzaldehyde such as dithioacetals and cyanohydrins are easily prepared
ð66S246\ 68CB1934Ł and provide umpoled synthons for the synthesis of phenyl ketones[ Benzoic acid
derivatives such as phenylseleno esters give access to nucleophilic acyl radicals\ and other derivatives
"e[g[\ benzoyl chloride# are also often used as the electrophilic component in acylations of organo!
metallic species or in FriedelÐCrafts acylation and alkylation reactions[ Alkylations of enolates\
although not discussed in this section\ are however particularly relevant to the synthesis of phenyl
ketones due to the ready availability of acetophenone[

2[95[1[1 Monoalkyl Phenyl Ketones


Toluene and other monoalkylbenzenes often give high yields of mostly para!substituted ketones
on FriedelÐCrafts acylation with acid chlorides and aluminum trichloride[ Some alkyl groups "e[g[\
propyl\ i!propyl\ t!butyl# are prone to migration under such conditions ð42JOC133\ 45JCS3832Ł\ and
dehydrogenation of side chain can sometimes be problematic[ However\ more reactive acylating
agents and lower reaction temperatures can prevent such occurrences[ For example\ tri~uoro!
acetylations of various alkylbenzenes using 1!"tri~uoroacetoxy#pyridine and aluminum trichloride
at 9>C gives only the desired para!isomers in good yield ð89CL672Ł[ A number of other reactive
acylating agents have shown promise with monoalkylbenzenes ð61AG"E#299\ 79JA759\ 72CB0084\ 74T3710\
80S211Ł\ and toluene itself reacts with aroyl chlorides in the presence of catalytic quantities of ferric
trichloride\ zinc chloride or iron ð61S422Ł and the heterogeneous catalyst\ Na_on!H\ is similarly
e}ective ð67S561Ł[ Lithiations at the benzylic positions of alkyl side chains usually prevent direct
metallations of the aromatic rings with alkyllithium reagents\ but halogenÐmetal exchange reactions
allow for the ready preparation of many monoalkyl phenyl organometallic species and for the
subsequent ketone forming acylations of such reagents[ Similarly\ the relevant halides\ tri~ates
185 Ketones With an a\b!Aryl or !Hetaryl
and boronic acids facilitate palladium!catalysed ketone synthesis by carbonylative cross!coupling
ð72TL2758\ 77JA0446Ł\ or by Stille ð67JA2525Ł and Suzuki ð82TL6484Ł methodologies[ Many
monoalkylphenyl aldehydes and carboxylic acids are commercially available and provide obvious
building blocks for a variety of the general methods of ketone synthesis already discussed[

2[95[1[2 Dialkyl! and Polyalkylphenyl Ketones


Aluminum trichloride and acid chlorides usually acylate symmetrically "R0 R1# substituted
dialkylbenzenes to give ketones largely as isomers "0#\ "1# and "2# respectively and\ as expected\ the
reactivity of xylenes increases in the order m!xylene×o!xylene×p!xylene[ When R0 R1 the prod!
uct ratios are determined largely by relative steric interactions[ Dealkylative processes or alkyl!
substituent rearrangements can occur but\ due to the greater general reactivity of these systems\ to
a far lesser extent than with monoalkylbenzenes[ This increased nucleophilic character allows for
successful FriedelÐCrafts acylations under a variety of more modern conditions ð61S422\ 67S561\
70CB815\ 72CB0084\ 89CL672\ 80S211Ł[ Polyalkylbenzenes\ being even more activated towards elec!
trophiles\ are readily acylated under most FriedelÐCrafts conditions as well as with milder methods
utilising mixed anhydrides ð68S292\ 79S028\ 72CB0084Ł or those employing substoichiometric quantities
of catalysts ð61S422\ 81CL324Ł[ The trimethylbenzenes\ pseudocumene and mesitylene are acylated to
give the expected ketones "3# and "4# and hemimellitene\ presumably for steric reasons\ tends to give
product mixtures rich in the ketone "5#[ Symmetrical tetra! and pentamethyl benzenes give the
expected products in good yield[

R2 R2 R2
R1

R3 R
R1

R1 O O O R O R
O R3 O R3
(1) (2) (3) (4) (5) (6)

2[95[1[3 Halophenyl Ketones


Halobenzenes are acylated predominantly in the p!position in the FriedelÐCrafts reaction[ The
halogen substituents are considerably deactivating and necessitate the use of strong Lewis acids
"e[g[\ AlCl2#[ Benzoylations of halobenzenes relative to benzene have been shown to occur with
relative rates decreasing in the order benzene×~uorobenzene×iodobenzene×bromo!
benzene×chlorobenzene[ "Trichloromethyl# benzene and aluminum trichloride constitute a par!
ticularly active reagent combination which reacts at room temperature to give\ on hydrolysis\
benzoylated halobenzenes in high yield ð80S211Ł[ With few exceptions haloalkylbenzenes can be
acylated with predictable regioselectivity and\ although very unreactive\ dihalobenzenes can undergo
successful FriedelÐCrafts acylation ðB!53MI 295!90Ł[ Suzuki ð82TL6484Ł and Stille ð67JA2525Ł coupling
reactions tolerate most aryl halide functionality with the exception of aryl bromides ð75AG"E#497Ł
in the latter methodology\ and haloarylzinc compounds\ prepared by selective metallation of one
of two carbonÐhalogen bonds\ give ketones an exposure to acid chlorides in the presence of
palladium"9# catalysts ð70CL0024Ł[ Halogens can function as directing groups in ortho!metallations
ð89CRV768Ł thus providing a regioselective entry to ketones upon acylation of the corresponding
organometallic species[

2[95[1[4 Phenolic Ketones


Phenol is acylated under FriedelÐCrafts conditions to give ortho!para substituted!ketone mixtures[
The para to ortho ratio is maximised by the use of boron tri~uoride as the Lewis acid[ Boron
tri~uoride and zinc chloride are the best Lewis acids for electrophilic acylations of di! and trihydric
phenols\ and generally lead to the ketones expected on the grounds of other known aromatic
substitutions[ Equation "61# illustrates a reaction in which only 0 mol) of zinc chloride provided
Phenyl Ketones and Analo`ues 186
the required acetyl derivative in good yield ð61S422Ł[ In problematic cases the temporary protection
of phenols as the corresponding trimethylsilyl ethers has been recommended ð45AG507Ł[ For obvious
reasons the free 0OH group is not usually tolerated in acylation reactions of organometallic species[

OH
OH
O O ZnCl2, 140 °C
+ (72)
O 70% OH
OH
O

Of considerable importance in the preparation of phenolic ketones is the Fries rearrangement[


This thermal rearrangement of phenolic esters occurs in the presence of FriedelÐCrafts catalysts to
provide the ketones in synthetically useful yields ðB!53MI 295!90\ B!56MI 295!90\ 80COS"1#622Ł[ The
reaction can often be tuned by careful selection of temperature\ solvent and catalyst to provide
either the o! or p!acylphenol with good selectivity[ Various substituents on the aromatic ring are
tolerated but electron!withdrawing groups are generally detrimental to the success of the reaction[
Equations "62# to "66# ð52CR"145#4483\ 62JOC0813\ 73JCS"P0#0228\ 74JMC0721\ 81T6470Ł detail some litera!
ture examples of this transformation[

OH
O
TiCl4
(73)
O 96%
O

O O

OMe AlCl3 O OMe


(74)
O 73%

MeO O MeO OH

O
OMe OH O
OMe O
BF3
(75)
86%

OMe
OMe

O
O O
O
N O AlCl3
N OH (76)
49%

OH O
O Ph
HF Ph
(77)
O 76%

The Fries rearrangement can also be accomplished in the absence of a catalyst by irradiation with
UV light[ Known as the photo!Fries rearrangement ð56CRV488Ł\ both o! and p!adducts can be
prepared and some success has been achieved with deactivated aromatic substrates[ Two examples
are shown in Equations "67# and "68# ð51JOC1182\ 75H"13#1400Ł[
187 Ketones With an a\b!Aryl or !Hetaryl
O
OH O
O
hν, benzene
Cl (78)
72%
Cl
But
But

O OH O
Ph O O
O hν, benzene
Ph
O (79)
65%
O
MeO OMe

2[95[1[5 Alkoxyaryl Ketones


Anisole is a reactive aromatic substrate and undergoes FriedelÐCrafts acylations under a diverse
range of conditions to give p!ketone "6# "the o!isomer is sometimes observed\ e[g[\ ð72CB0084Ł#[
Besides the standard reactions with carboxylic acids\ acid chlorides\ or anhydrides and a strong
Lewis acid\ many less active catalysts "e[g[\ AgClO3\ TiCl3\ AlBr2# are e}ective[ A host of mixed
anhydrides and related species readily acylate aryl ethers under mild conditions ð61AG"E#299\ 68S292\
79S028\ 70CB815Ł[ Furthermore\ catalytic quantities of iron trichloride\ iodine\ zinc chloride and
iron all promote acylations with acid chlorides and anhydrides\ although usually at quite high
temperatures ð61S422Ł[ A number of novel catalytic systems allow for high yielding ketone synthesis
using acid chlorides and anhydrides ð75CL054\ 80CL0948\ 80S0105\ 81CL324\ 82CC0046Ł or carboxylic acids
and their TMS derivatives ð81CL0640\ 82BCJ2618Ł under very mild conditions[ Aryl ethers with a
further alkyl substituent are generally acylated para to the alkoxy group or ortho if that position is
blocked ""7# and "8##[ m!Alkyl anisole tends to give mixtures of isomeric products with ratios being
determined largely by steric demands[ Ketones "09#\ "00# and "01# are all formed\ usually as the sole
products\ from the corresponding diethers[ Similarly\ higher ethers give the expected products[ In
cases where o!acyl substituents are introduced "e[g[\ "8#\ "00#\ "01## dealkylation of the ether function
may occur[ Hydrogen bonding in the derived adduct presumably favours this process "Equation
"79## ð65LA0403Ł[

OMe OMe OMe O OMe OMe O


R1 OMe MeO OMe
R2 R
R

R1 O OMe
O R O R2 O R
(7) (8) (9) (10) (11) (12)

OMe H
O O O
BF3
+ (80)
HO 73%
MeO OMe MeO OMe

Substitution of groups such as i!propyl and t!butyl by the acyl species occurs in some cases\
particularly as the substitution of the aromatic substrate is increased[
Organolithium derivatives of aryl ethers can be prepared by metalÐhalide exchange reactions or
by ortho!metallations using the O!alkyl substituents as directing groups ð89CRV768Ł[ Acylations of
such species or of compounds derived therefrom provide routes to ketones which would not be
accessible by FriedelÐCrafts methodology[ For instance\ Equation "70# illustrates an example where
o!lithiated anisole is acylated regioselectively to give the ketone product which is usually only
Phenyl Ketones and Analo`ues 188
produced in relatively small amounts in the FriedelÐCrafts reaction[ Alkoxy aromatic substituents
are generally quite inert and compatible with most general methods[

O
+ BnO OMe (81)
Li N 90% OBn
OMe Me OMe O

2[95[1[6 Thiophenyl Ketones


Aromatic thioethers behave similarly to the analogous oxygen compounds under FriedelÐCrafts
conditions and exhibit similar selectivities ðB!53MI 295!90Ł[ However\ the o\p!directing capability of
sulfur is considerably weaker than oxygen\ and substituents such as alkoxy groups and halogens
exert considerably greater electronic e}ects in the course of such reactions[ The sulfur groups are
compatible with most other aryl ketone syntheses\ although sulfur residues often poison catalysts
in palladium!mediated reactions\ and oxidation of sulfur is a potential complication in certain
oxidative procedures[

2[95[1[7 N!Substituted Phenyl Ketones


Aryl amides tend to form complexes with FriedelÐCrafts catalysts resulting in deactivation and
poor yields of the desired ketones[ In some cases bulky substituents on the aromatic ring or on
nitrogen can prevent such interactions and ketones can be produced in moderate yields[ Recently\
dimethylaniline has been acetylated in good yield using acetic anhydride and a catalytic quantity
of ytterbium"III# tri~ate "Yb"OTf#2# "Equation "71## ð82CC0046Ł[ Acetanilides are less prone to
complexation with Lewis acids and can be acylated successfully with acid chlorides and aluminum
trichloride[ The acetylation of 0\1\2\3!tetrahydroquinoline "Equation "72## illustrates how di}erent
0NH protecting groups can dramatically alter both reaction yields and regioselectivities
ð81JCS"P0#2390Ł[ Equation "73# illustrates another such example used in the synthesis of lysergic acids
ð73JA0702Ł[
O
O O Yb(OTf)3
+ (82)
Me2N O 76%
Me2N

O
O AlCl3
+ + (83)
N N
Cl N
R R O
R
R = CONHMe >98 : <2 96%
R = COCF3 10 : 87 13%

Ph
O
O H
O N
O
Ph
H N AlCl3
H (84)
60%
N
N
Ph
O Ph
O

Nitro!arenes form very tight deactivated complexes with Lewis acids and generally do not undergo
FriedelÐCrafts acylations[ However\ electron!donating substituents can sometimes override this
299 Ketones With an a\b!Aryl or !Hetaryl
e}ect\ and the use of an AlCl2:DMF complex provides an isolated example of the FriedelÐCrafts
acylation of nitrobenzene itself ð89JOC2850Ł[ In an analogous fashion to the Fries!rearrangement\
aryl amides can undergo both Lewis acid catalysed and photochemical rearrangement to the
corresponding acyl anilines in good yields "Equations "74# to "76## ð65TL2106\ 73IJC"B#052\ 75SC374Ł[
O Cl
H NH2 O Cl
N
BiCl3
(85)
80%

OMe
OMe

O OH O
Cl
B(OH)3, H2SO4, SO3
(86)
63%
N
O
H NH2 O

H NH2
N Ph hν, H2O
Ph (87)
O O2N
O2N O

Amines\ amides and urethanes can serve as directing groups in o!lithiation reactions ð89CRV768Ł\
and nitro substitution is tolerated by Stille reaction conditions ð75AG"E#497Ł[ Both methods conse!
quently provide alternative direct routes to N!substituted phenyl ketones\ although examples in the
literature are comparatively rare at present[

2[95[1[8 Other Substituents


Aromatic carboxylic acids\ esters\ amides\ and aldehydes and ketones are considerably deactivated
and cannot be acylated under FriedelÐCrafts conditions[ However\ if the deactivating e}ects of
these groups are o}set by electron!rich substituents\ or if steric interactions with o!alkyl groups
prevent the necessary coplanar orientation required for e}ective deactivating conjugation\ acylation
can occur at positions ortho and para to the activating group ðB!53MI 295!90Ł[ Some of these
functional groups\ or derivatives thereof "e[g[\ acetals\ nitriles#\ can be used to direct metallations
and hence control regioselectivity in subsequent ketone forming acylations ð89CRV768Ł[ Further!
more\ esters\ nitriles and aldehydes have been shown to be tolerant to various palladium!catalysed
reaction conditions\ and the desired ketones can consequently be prepared from\ for example\ the
relevant halogenated substrates by carbonylative cross!coupling ð81T1002Ł[

2[95[2 POLYCYCLIC ARYL KETONES

2[95[2[0 Naphthyl Ketones


Naphthalene is readily acylated under FriedelÐCrafts conditions but generally gives isomeric
mixtures of ketone products[ The relative ratios of these products are highly dependent on factors
such as the solvent and catalyst used ðB!53MI 295!90Ł[ 0!Alkylnaphthalenes and 1!alkylnaphthalenes
are acylated in the 1! and 0!positions respectively\ and dialkylnaphthalenes are usually acylated at
an unsubstituted a!carbon[ Heterosubstituted naphthalenes "e[g[\ halonaphthalenes\ naphthols\
naphthol ethers\ naphthylamines# can all be acylated in high yields under FriedelÐCrafts conditions\
Polycyclic Aryl Ketones 290
although the regioselectivity of ketone formation is once again highly dependent on factors such as
solvent and the relative positions of other substituents ðB!53MI 295!90\ 89SC272Ł[ Acylations using
stoichiometric quantities of aluminum trichloride and acid chlorides comprise the majority of
literature examples\ but catalytic amounts of iron\ ferric trichloride\ zinc chloride and iodine can
also provide the requisite ketones in good to excellent yield "Equation "77## ð61S422Ł[ Many of the
general methods "Section 2[95[0# discussed earlier have obvious applicability to the synthesis of
naphthyl ketones[ For example\ Equation "78# illustrates the palladium!catalysed carbonylative
cross!coupling reaction of a naphthyl boronic acid with an iodoarene to give the corresponding
ketone in high yield ð82TL6484Ł[

O R
OMe O FeCl3 (cat.)
+ OMe (88)
R Cl 66–90%

B(OH)2 CO (1 atm), K2CO3 O


I O PdCl2(PPh3)2 (3 mol%)
+ O (89)
O 86%
O

2[95[2[1 Anthryl Ketones


FriedelÐCrafts acylations of anthracene often lead to the formation of mixtures of the 0!\ 1! and
8! isomers ðB!53MI 295!90Ł[ The 0! and 1!isomeric ketones have been shown to form by rearrangement
of the 8!isomer\ and consequently the 8!isomer can be cleanly isolated by using solvents in which the
product!Lewis acid complex is insoluble or by applying generally milder methodologies[ Examples
of the latter procedures include tri~uoroacetylation with tri~uoroacetyl tri~ate "Equation "89##
ð68JOC202Ł and benzoylation with benzoyl chloride and a catalytic amount of iodine "Equation
"80## ð61S422Ł[ Many general methods are potentially applicable to the construction of anthryl
ketones but literature examples are scarce[

O CF3
CF3CO2Tf, base
(90)
81%

O Ph
O I2 (cat.)
+ (91)
Ph Cl 68%

2[95[2[2 Phenanthryl Ketones


The vast majority of phenanthryl ketones have been prepared by FriedelÐCrafts acylation
methods[ The 1! and 2!isomers ""02# and "03# respectively# are usually isolated preferentially\
although the 0! and 8!phenanthryl ketones are formed to varying extent in some cases ðB!53MI 295!90Ł[
Similarly\ most substituted phenanthrenes give more than one ketone isomer on acylation[
291 Ketones With an a\b!Aryl or !Hetaryl

O O R

(13) (14)

2[95[2[3 Other Polycyclic Aryl Ketones


Higher polycyclic aryl ketones are relatively reactive and usually undergo FriedelÐCrafts acylations
quite readily ðB!53MI 295!90Ł[ In some cases the introduction of a second acyl group occurs and\
under su.ciently vigorous conditions\ even tri! and tetra!substitution has been known to occur[
Pyrene is acylated selectively at the 0!position to give the ketone "04#[ Chrysene and benzoðcŁ
phenanthrene give the ketones "05# and "06# respectively[ Once again\ other methods "e[g[\ lithiation
of halides# are potentially useful but have little or no literature precedent[
O
O
R
R

O R

(15) (16) (17)

2[95[3 HETARYL KETONES


This section again\ in order to avoid duplication\ makes little reference to methods of saturated
ketone synthesis that are equally applicable to hetaryl ketone synthesis "e[g[\ alkylation of hetaryl
methyl ketone enolates#\ and instead highlights methods which exploit the chemical properties of
the relevant heteroaromatic ring systems[ A further point to note with the synthesis of hetaryl
ketones\ particularly in highly substituted cases\ is that synthesis of the required heteroaromatic
ring\ from an open!chain or cyclic precursor with the ketone function already intact\ can be a viable
route to a chosen target[ However\ the generality of such reactions is not always entirely clear and
the emphasis on synthesis of the heteroaromatic ring rather than on the ketone function itself have
led to the exclusion of examples using such methodology[

2[95[3[0 Furanyl Ketones


Furan can be acetylated in good yield under a range of FriedelÐCrafts like conditions using a
plethora of catalysts ðB!53MI 295!90Ł[ Being less aromatic than pyrrole\ for instance\ furan and simple
alkyl furans are cleaved or polymerise when exposed to strong mineral acids or Lewis acids such as
aluminum trichloride\ and such conditions should therefore be avoided[ Higher furanyl ketones are
accessible via the FriedelÐCrafts methodology using anhydrides and mixed anhydrides with catalysts
such as tin tetrachloride ð55JOC3141Ł\ boron tri~uoride ð68JOC2319Ł and ion!exchange resins
ð71SC0010Ł\ or with acid chlorides under similar conditions ð60JOC2080\ 80LA0254Ł[ However\ the
yields in these reactions are often low\ and milder methods such as copper!catalysed acylation with
selenoesters "Equation "81## ð79JA759\ 74T3710Ł or similar reactions of thioesters in the presence of
mercury salts "Equation "82## ð89TL0866Ł give better yields of ketones[ The acylation of furan itself
occurs exclusively at the 1!position but the electronic e}ects of substituents on more complex furans
markedly in~uence selectivity[ 1\4!Dialkylfurans are acylated at the 2!position\ and 1!monoalkyl
furans usually give the 4!substituted product[ If the 1!substituent is electron withdrawing\ reaction
at the 3!position becomes more prevalent and product mixtures may result "Equation "83##
Hetaryl Ketones 292
ð55JOC3141Ł[ 2!Alkylfurans are also often not acylated with particularly high selectivity under
FriedelÐCrafts conditions ð60T2212Ł[

O
O (CuOTf)2Ph
+ O (92)
( )5
O ( )5 SeMe 100%

O O
TBDMS-O TBDMS-O

Hg(OCOCF3)2, MeCN
(93)
O H 65%
O H
SBut
O O

( )4
O
SnCl4, benzene
MeO
+ (n-C5H11CO)2O MeO ( )4 + (94)
O O
21% MeO
O O O O
O
62 : 38

Acylations of lithiated furans are of considerable contemporary importance and allow for regio!
selective and often high yielding ketone syntheses[ Furans can be lithiated selectively at the 1!
position using alkyllithium reagents\ and at the 1! or 2!position by lithiumÐhalogen exchange[
Furthermore\ lithiation of the 2!position is possible using various functional groups at the 1!
position to direct the metallations ð71JCS"P0#0232Ł[ A range of electrophiles including Weinreb amides
"Equation "84## ð82TL1354Ł\ dimethylamides ð78SC676Ł\ anhydrides and acids ð58JHC030\ 81AG"E#0924Ł
have proved useful\ and transmetallations of the lithium species to the corresponding organocuprates
ð68TL3466Ł or organomanganates ð81TL4134Ł allow for e}ective acylations with acid chlorides[
Stannylated furans and acid chlorides in the presence of palladium"9# catalysts undergo extremely
e}ective coupling reactions and constitute a very mild ketone synthesis ð80ACS803\ 80OM255\ 80S132Ł[
2\3!Distannyl furans can similarly be mono!acylated and subsequently arylated or vinylated to
provide furanyl ketones which could otherwise prove somewhat di.cult to access "Equation "85##
ð81CC545Ł[ Carbonylative cross!coupling reactions of stannyl furans with allyl chlorides\ again in
the presence of a palladium catalyst\ also provide the corresponding ketones in high yields ð73JA3722Ł
and have been applied to the synthesis of relatively complex ketones "Equation "86## ð77TL0062Ł[
An obvious aspect of such reactions is the use of furanyl acid chlorides as the electrophilic partners
in such palladium!catalysed reactions[ A number of such examples are found in the various catalysed
and uncatalysed reactions of other organometallic species "e[g[\ Equation "87## ð56T786\ 71CL0448\
72TL1340\ 78JOC4191\ 81TL4134Ł[ Anions of cyanohydrins derived from furanyl aldehydes have found
some use as umpoled synthons for ketone synthesis ð68CB1934\ 73SC632Ł\ and the additions of organo!
metallic reagents to furanyl aldehydes with subsequent oxidations of the resulting alcohols is a fairly
popular route to the corresponding ketones[ Oxidations of furan methanols using chromium reagents
ð73JA1004\ 75JA0945Ł\ t!butyl hydroperoxide ð82TL6978Ł\ Swern conditions ð89JCS"P0#1566Ł\ barium
manganate "Equation "88## ð74JA4108Ł and manganese dioxide ð76JA2870Ł have all been reported[

Me
O O
Li + N (95)
O OMe 79% O
O O O
O

O O2N
i, Cl , PdCl2(PPh3)2
Bu3Sn SnBu3 O
(96)
Br
O ii, , Pd(PPh3)4
O2N
O
293 Ketones With an a\b!Aryl or !Hetaryl
MeO OMe

SnBu3
Pd(acac)2, PPh3, CO (1 atm)
+
Cl TMS O

MeO OMe

O
(97)

O
TMS

O
O Zn, CuCN(LiCl)2, THF
Cl
O + But O O (98)
But O I 81%
O O

BaMnO4, CH2Cl2
OBn OBn (99)
O 80% O
OH O-TBDMS O O-TBDMS

2[95[3[1 Benzofuranyl Ketones


Benzofurans are only weakly aromatic in nature and they are cleaved by many oxidative and
reductive conditions[ They are also prone to polymerisation in the presence of concentrated mineral
acids and Lewis acids[ Consequently\ ring synthesis is often preferred ð40JA643Ł to electrophilic
substitution[ FriedelÐCrafts acylations are possible using acid chlorides in the presence of stannous
chloride "Equation "099## ð44JCS2582Ł and stannic chloride ð66JHC750Ł\ although regioselectivities
are not always high[ The reactions are usually only applicable to 1!substituted derivatives\ which
are more stable to the Lewis acidic conditions required\ thus providing the 2!acyl compounds[
1!Acyl derivatives which\ in contrast to indoles\ are the favoured products in electrophilic sub!
stitutions of benzofurans\ are e.ciently prepared by ipso!substitution of 1!trimethylsilyl benzofurans
using acid chlorides and tin tetrachloride as the catalyst "Equation "090## ð73T510Ł[ 1\2!Disubstituted
benzofurans can be acylated on their benzene ring portions\ in moderate yields\ using acid chlorides
and aluminum trichloride[ The regiochemical outcome in these reactions is highly dependent on the
relative positioning of other substituents ð69BCJ1773\ 69BCJ2385Ł[ Similarly\ benzofurans with elec!
tron!withdrawing groups in the 1!position are acylated in high yield on the benzene ring if carboxylic
acids or anhydrides\ and boron tri~uoride are used "Equation "091## ð52JOC287Ł[ Benzofuran is
lithiated selectively at the 1!position using alkyllithium reagents\ and 2!lithio derivatives "although
thermally unstable# can be prepared by halogenÐmetal exchange[ However\ the application of such
methodology to the direct synthesis of ketone derivatives is conspicuously lacking[

Ph
O
O SnCl2
+ (100)
O Cl 60%

O TiCl4 But
TMS + (101)
O But Cl 75% O O
Hetaryl Ketones 294
OMe
OMe OEt
O BF3•OEt2
OEt + (102)
HO 88% O O
O O
O

2[95[3[2 Ketothiophenes
Thiophenes have considerable aromatic character but they are also considerably more reactive
toward electrophiles than is benzene[ Consequently FriedelÐCrafts acylations can be e}ected under
various conditions ðB!53MI 295!90Ł[ Acid chlorides\ anhydrides and carboxylic acids are the most
commonly used electrophiles\ and the most popular catalysts are aluminum trichloride "e[g[\
ð82ACS176Ł# and tin tetrachloride "Equation "092## "e[g[\ ð73JOC1211\ 73TL4328Ł# in the case of acid
chlorides^ pyridyltri~ate:TFA ð68S292\ 79S028\ 77BCJ344Ł and protic acids such as ppa for carboxylic
acids ð79JHC76Ł^ and iodine ð61S422Ł boron tri~uoride ð37JA756Ł\ perchloric acid ð60HCA242Ł and
phosphoric acid ð44OSC"2#03Ł with the corresponding anhydrides[ Thiophene has been similarly
acylated in high yield using selenoesters and a copper catalyst ð79JA759\ 74T3710Ł\ and benzoylated
with equal facility using trichloromethylbenzene and aluminum trichloride ð80S211Ł[ Fries!
rearrangements involving substituted thiophenes are also possible but not particularly general
"Equation "093## ð75JCS"P0#496Ł[ Acylations under FriedelÐCrafts conditions are highly selective and
give the 1!substituted products exclusively[ 1!Substituted thiophenes react with similar dis!
criminations to give the 1\4!products\ and 1\4!disubstituted thiophenes are acylated at the 2! or
3!position as dictated by relative steric and electronic e}ects[ An exception to the latter occurs in
the case of 1\4!dihalothiophenes where the acylating species can substitute for either halogen
ð70JHC0234Ł[ Finally\ 2!substituted thiophenes react to give 1\2! and 2\4!disubstituted products in
distributions which are determined by the nature of the substituent[

O O SnCl4 Ph OMe
Ph + ( )6 S (103)
( )6 S Cl OMe CH2Cl2
O O

O
O HO
O AlCl3, HCl, CH2Cl2 OMe
OMe (104)
79%
O S
S
O

Thiophenes are readily metallated to produce reagents which can be acylated in high yield with
complete regioselectivity[ Thienyllithium compounds are by far the most popular of such species
and are readily prepared by halogenÐmetal exchange reactions using butyllithium "e[g[ ð81JHC136Ł#[
1!Lithiothiophenes can be prepared by the direct action of strong lithium bases "e[g[ ð80JOC3159Ł#\
and directed lithiations are a viable route to 2!lithio species ð89CRV768Ł[ The best general method
for the direct conversion of thienyllithiums into the corresponding ketones is by reaction with
Weinreb amides "Equation "094## ð80JOC1800\ 80JOC3159\ 80TL610\ 81JHC136Ł[
O Ph

+ OMe (105)
Li N 91% S
S
Ph Me O

1!Iodothiophenes and organoaluminum compounds have been converted into the corresponding
1!keto products by palladium!catalysed carbonylations ð74TL3708Ł\ and the related imino!
carbonylative cross!coupling with 8!alkyl!8!BBN derivatives "Equation "095## ð81TL3354Ł has also
been reported[ Furthermore\ 1!ethyldi~uorosilyl thiophene and aryl halides undergo similar pal!
ladium!catalysed carbonylative cross!coupling reactions to give diaryl ketones "Equation "096##
ð78CL1938\ 81T1002Ł[ All of these palladium!catalysed reactions are high yielding and provide an
extremely mild methodology for ketone synthesis[ Acid chlorides and other derivatives of thiophenyl
295 Ketones With an a\b!Aryl or !Hetaryl
carboxylic acids have been used as electrophiles in the acylations of various organometallic species
"Equation "097## ð65JCS"P0#638\ 76TL1942\ 81TL4134\ 82JOC4751Ł to produce the corresponding ketones[
i, Pd(PPh3)4 (5 mol%), K3PO4
9-BBN ii, H3O+
+ + ButNC (106)
S I 83% S
O

CO (1 atm), (η3-C3H5PdCl2) (2.5 mol%)


KI, DMI
+ (107)
S Si(Et)F2 72% S CHO
I CHO
O

Me
MgBr
N +
S N + (108)
90% S
O N
O
Me

2[95[3[3 Benzothiophenyl Ketones


FriedelÐCrafts acylations of benzothiophene give the 2!acyl products predominantly\ but sel!
ectivity varies quite markedly with di}erent catalysts ðB!53MI 295!90Ł[ 1!Substituted benzothiophenes
yield the expected 2!acyl products\ and 2!substituted benzothiophenes the corresponding 0!acyl
derivatives[ Electron!withdrawing groups on the heteroaromatic ring generally activate the carbo!
cyclic ring to electrophilic substitution\ as do electron!donating groups on the carbocyclic ring
"Equation "098## ð82JCR"S#081Ł[ Rearrangements of the Fries!type have also been reported
ð62JCS"P0#0085Ł[

O
O O
ppa
OH (109)
72% O
S S
ppa = polyphosphoric acid

As is the case with thiophenes\ 1!lithio derivatives of benzothiophenes are readily prepared by
the action of butyllithium\ and they can be acylated successfully "e[g[ ð79TL1018\ 80TL1992Ł[
2!Lithiobenzothiophenes are not thermally stable and have only found limited use in ketone
synthesis[ However\ 2!aroylbenzothiophenes have been prepared in high yields by palladium!
catalysed carbonylative cross!coupling reactions of arylboronic acids with 2!iodo benzothiophene
"Equation "009## ð82TL6484Ł[

O
I CO (1 atm) Ph
PdCl2(PPh3)2 (3 mol%)
+ PhB(OH)2 (110)
K2CO3
S
S

2[95[3[4 Pyrrolic Ketones


The preparation of pyrrolic ketones using FriedelÐCrafts conditions is not always a useful method\
as the conditions required for such reactions often result in polymerisation\ particularly in the case
of pyrrole itself[ However\ pyrroles can sometimes be acylated using a Lewis acid "usually aluminum
trichloride# and an acid chloride "Equation "000## ð69LA"622#16\ 82JCS"P0#162Ł[
Hetaryl Ketones 296

O O
O
AlCl3
+ Cl (111)
55%
N N
H H
O

Selenoesters in the presence of copper catalysts are also an e}ective acylating combination
ð79JA759\ 74T3710Ł\ as are dimethylamino! ð74JMC0926Ł and morpholido amides "Equation "001##
ð66JOC3137\ 73JOC3192Ł in the presence of phosphorus oxychloride in what amounts to an extension
of VilsmeierÐHaack type formylations[ Although requiring subsequent hydrolysis to the ketone\ the
HoubenÐHoesch synthesis has found some utility "Equation "002## ð72JHC0454Ł as have reactions
using 0\2!benzoxathioyl ð82JCS"P0#162Ł and dialkoxycarbenium tetra~uoroborates ð78JHC0452Ł[
N!Alkyl and other N!protected pyrroles can often be acylated "and acetylated in particular# by simply
heating with acid chlorides ð74JMC0926Ł or active anhydrides ð47JOC0271Ł\ and N!phthaloylamino
pyrroles can be acylated with acid chlorides using zinc chloride as catalyst ð77JHC406Ł[

OBn OBn
O
POCl3
+ N Ph (112)
N 71% N
H H
O O

O
N HCl, H2O Cl
+ Cl CN (113)
N
NO2 53%
NO2

Electrophilic acylations of the FriedelÐCrafts type occurs preferentially at the 1!position "Equa!
tions "000# to "002##\ but the substitution pattern of the particular pyrrole substrate can markedly
e}ect this aspect of the reaction[ If the 1! and the 4!position are blocked\ acylations occur at the
2!position "Equation "003## ð79SC662Ł\ and a similar e}ect is noted if only the 1!position bears an
electron!releasing group or if the pyrrole nitrogen is protected with a bulky group ð74S242Ł[ Examples
of the latter include t!butyldimethylsilyl ð74TL4924Ł\ triisopropylsilyl "Equation "004## ð72TL2344Ł\
trityl ð72JCS"P0#82Ł\ t!butyl and adamantyl ð79JCR"S#31Ł[ Furthermore\ deactivating N!sulfonyl pro!
tection also promotes acylation at the 2!position "Equation "005## ð70TL3788\ 70TL3890\ 72JOC2103Ł^
electron!withdrawing groups at the 1!position direct acylation to the 3!position ð68TL1494\ 79CJC1416\
77H"16#0744Ł^ and in a somewhat surprisingly general manner 1!keto pyrroles can be isomerised to
the corresponding 2!keto derivatives on exposure to acidic conditions ð70JOC728\ 71JOC2557Ł[ Delivery
of acylating species by tethering to the nitrogen atom can provide 1!keto pyrroles selectively\
although mechanistic details are uncertain ð89TL884Ł[

But
N HI
+ (ButCO)2O N (114)
71%

OMe
OMe

O
O OEt
pyridine, CH2Cl2
+ OEt (115)
N Cl
70% O
tips O N
tips
tips = 1,1,3,3-tetraisopropyldisiloxane
297 Ketones With an a\b!Aryl or !Hetaryl
O

O
AlCl3
N + (116)
O S O Cl 99% N
Ph O S O
Ph
Pyrroles can be acylated in their C!1 positions using acid chlorides and bases such as sodium
hydroxide ð53AJC0945Ł\ triethylamine ð69LA"622#16Ł and 1\5!lutidine ð61JOC2507Ł[ However\ yields
are not usually good under such conditions\ and acylation reactions of lithio! and magnesiopyrroles
is far more e}ective[ N!Substituted pyrroles are readily lithiated at the 1!position on exposure to
alkyllithiums\ and the lithium species can then be successfully acylated with nitriles ð71SC120Ł\
benzamides ð80S0968Ł and lactones "Equation "006## ð70JOC2659\ 72CC529\ 73JOC2492Ł to provide the
corresponding ketones with complete regiocontrol[ Treatment of pyrroles with simple Grignard
reagents "e[g[\ MeMgBr# or transmetallation reactions of lithiated derivatives ð70JOC2659Ł provide
the corresponding magnesiopyrroles that will then react with acid chlorides ð54JHC362Ł to give
ketones in low yields\ or with low regiocontrol\ but are best acylated with pyridyl thioesters to
give high product yields "Equation "007## ð70TL3536Ł[ This latter approach is e}ective under mild
conditions and has been used in the preparation of a number of functionally complex compounds
"Equation "008## ð70JA5858\ 75T5354\ 76JA6442Ł[ Additions of metallated pyrroles to aldehydes and
subsequent oxidation\ usually with manganese dioxide ð72OS"51#000Ł\ of the resulting alcohols have
been used to prepare some ketones\ and the use of pyrrolic carboxylic acid derivatives as acylating
species for organometallic or aromatic substrates has also found utility in the preparation of pyrrolic
ketones "Equation "019# ð55T"S#130\ 70H"05#288\ 76AP"219#0919Ł[

O
O O
N
DME, 0 °C SEM
N Li + (117)
62% HO
SEM

SEM = β-trimethylsilylethoxymethyl

O toluene, –78 °C R
N + N (118)
R S N 90–95% H
MgCl O

O SPy
H
toluene, THF, –20 °C
+ O
N H H
MeO2C 90%
MgCl
H

O
N
H H
(119)
O
H H
MeO2C
H

O
O O
O O
EtO OEt
NaH EtO
OEt (120)
N 66%
N N
N
Me O
O OEt Me OEt
O
Hetaryl Ketones 298
2[95[3[5 Ketoindoles
Indoles are considerably nucleophilic and sometimes undergo uncatalysed FriedelÐCrafts acyl!
ation reactions with acid chlorides and anhydrides\ particularly on heating with the more reactive
of such compounds ðB!53MI 295!90Ł[ However\ most examples require a Lewis acid catalyst of which
zinc chloride ð61S422Ł\ and especially aluminum trichloride ðB!53MI 295!90Ł\ are the most popular
and e}ective[ Acylations with carboxylic acids and protic acid catalysts "Equation "010## ð58JA1231\
79H"03#0828Ł or with selenoesters and copper catalysts "Equation "011## ð79JA759\ 74T3710Ł have also
proved relatively useful\ as has the two!step method utilising 1!substituted!0\2!benzoxathiolium
ions ð76S200Ł[ In contrast to the analogous reactions of pyrroles\ electrophilic acylations of this type
generally occur at the 2!position[ However\ when blocked\ acylation at the 1!position occurs with
equal facility[ FriedelÐCrafts acylations can occur selectively at the 1!position when the 2!position
is unsubstituted by ipso!substitution of a trimethylsilyl group "Equation "012## ð78JOC3249Ł[ This
type of reaction has also been used in acylations of the 3!position ð73JOC3398Ł[ Competitive acylation
at the 2!position is avoided by acetylation of nitrogen and concomitant deactivation of the hetero!
cyclic ring "Equation "013##[ The 3!position can also be acylated electrophilically in indoles bearing
an activating group "e[g[\ OMe# at the 4! or 6!position\ and usually also with an electron!withdrawing
group on either the nitrogen atom or the 1!position ð30LA"438#127\ 66CPB2912\ 73JOC2084Ł[ FriedelÐ
Crafts acylations of simple indoles are not common at the 4! and 6!positions\ but they can occur
with varying selectivity when electron!withdrawing groups are present at the 1!position ð77CPB1912\
89CPB2150Ł[ 5!Acylations can occur in useful yields in the case of N!acetyl indoles ð30LA"438#127\
73JOC3398Ł[

O O
N
O H3PO4
N
(121)
OH 85%
N N
H H O

O CuOTf, benzene
N
+ (122)
MeSe 85%
Me N
Me

TMS
AlCl3, CH2Cl2
N + (MeCO)2O N O (123)
O 86% O
O S O S
Ph Ph

TMS O Cl

Cl O AlCl3
+ (124)
N Cl 75% N

O O

0!Indolylmagnesium halides are acylated preferentially at the 2!position "e[g[\ ð38RTC4\ 76TL2630Ł#
but often only in moderate yields[ 0!Methylindoles ð79JA0346Ł and 0!phenylsulfonylindoles
ð62JOC2213\ 70JOC1868\ 78JOC2153Ł are selectively lithiated in the 1!position using strong bases\ and
can subsequently be acylated e.ciently using acid chlorides or anhydrides[ In a related manner
0!"N!aroylcarbamoyl# indoles\ prepared from 0!"1!oxazolinyl#indole\ give 1!aroyl!0H!indoles\ on
treatment with lithium diisopropylamide "LDA#\ by an intramolecular acyl transfer "Equation "014##
ð82H"24#462Ł[ Additions of aldehydes to metallated indoles\ and oxidation of the resulting alcohols\
usually with manganese dioxide ð64JOC1502\ 73T2228\ 75T1200\ 89SC2958\ 82T1774Ł\ provide the desired
ketones\ and direct oxidation of an a!methylene in substituted indoles can lead directly to ketones
209 Ketones With an a\b!Aryl or !Hetaryl
using oxidants such as selenium dioxide "Equation "015## ð80CC0576Ł\ hydroiodic acid ð55JA0938Ł\
ddq ð65H"3#0748\ 78JOC1069\ 89T5512Ł and iodine pentoxide "Equation "016## ð70JA5889\ 76CPB3699Ł[

Ph
N i, PhCOCl, 95%
(125)
N ii, LDA, 73% N O
O H

O O
H OBn SeO2, dioxane H OBn
N (126)
N 43%
N H N H
H H O

Cl Cl
O O
I2O5, THF (aq.)
N (127)
N 65%

N N
H H
O

2[95[3[6 Pyridyl Ketones


Pyridine is essentially an electron!de_cient aromatic heterocycle and is about a million times less
reactive than benzene towards electrophilic substitution[ Furthermore\ N!acylation and the resulting
further deactivation generally results in FriedelÐCrafts acylations being of little use in the preparation
of pyridyl ketones[ Alkoxy and amino groups can o}set such e}ects to some extent and acylations
of such systems\ particularly of the intramolecular variety\ are known ð65RTC119\ 66JCS"P0#678\
89JHC0416Ł[ Readily available pyridyl carboxylic acids and their derivatives can serve as electrophiles
in FriedelÐCrafts acylations of electron!rich aromatic substrates providing aryl pyridyl ketones
"Equation "017## ð74SC0160\ 75JOC1910Ł[

O
O
OH ppa
F (128)
N 85%
N
F

Direct lithiations of pyridines can be problematic due to the ready addition of alkyllithiums to
the pyridine ring system[ However\ transmetallations of pyridyl bromides are readily achieved at
low temperature\ and the resulting organometallic species can be acylated successfully[ Lithiated
pyridines prepared in this way are acylated in moderate yields with tertiary amides "Equation "018##
ð80JOC0711\ 81JOC650Ł\ nitriles ð48JA0827Ł and carboxylic acids ð82SC874Ł[ Grignard reagents show
similar utility "e[g[ ð82TL2572Ł#\ and they can also be prepared by the reaction of phenyl magnesium
bromide with pyridyl sulfoxides ð75TL2788Ł[ Pyridine N!oxides and some of their derivatives can be
deprotonated at the 1!position and subsequently acylated ð61JOC2473\ 75CB168\ 89H"20#316Ł[ Direct
lithiation of pyridines is possible with ortho!directing groups such as acylamino ð76CJC0047Ł\ chloro
ð70JOM"105#028\ 75S775Ł and amido groups "Equation "029## ð79JA0346\ 76T4170Ł[ Directing groups in
the 2!position usually stabilise 3!lithio derivatives\ but in some cases the 1!position can be lithiated
selectively ð70JOM"105#028Ł[
Hetaryl Ketones 200
O O
Cl Br ButLi Cl
NMe2 (129)
57%
N N

OMe O O NPri2
Li O OMe O
MeO
NMe2 MeO
+ NPri2 (130)
58%
N
N
OMe
OMe

1! and 3!Trimethylstannyl pyridines are acylated in variable yields on direct reaction with acid
chlorides ð71CPB1992\ 71H"08#30\ 74JOC4325Ł[ The 2!stannyl compounds require a palladium catalyst
for reaction to occur "Equation "020## ð81TL2992Ł\ as do similar reactions between pyridyl zinc
compounds and anhydrides ð81TL4262Ł[ Palladium catalysts are also e}ective in promoting imino
carbonylative cross!coupling reactions between bromopyridine and 8!alkyl!8!BBN derivatives
ð81TL3354Ł\ and between iodopyridine and boronic acids ð82TL6484Ł[ Under somewhat harsher
conditions\ a ruthenium catalyst has been shown to promote carbonylative coupling between
pyridine and alkenes ð81JA4777Ł[ Nucleophilic acyl radicals can add at the 1!position of pyridine to
give ketones in good to excellent yield "Equation "021## ð63JCS"P1#0588\ 78H"17#378\ 80JOC1755Ł\ and
cyanohydrins derived from pyridyl aldehydes are readily lithiated\ alkylated and _nally hydrolysed
to provide the desired ketones ð68CB1934\ 73SC632Ł[ Oxidations of alcohols to pyridyl ketones are
best achieved with relatively mild oxidants such as manganese dioxide ð71JA425Ł and DessÐMartin
periodinane ð82TL220Ł[

OBn OBn

SnMe3 O O
O N PdCl2(PPh3)2 O N
+ O (131)
O 48%
N Cl
O O
N

O
O

FeSO4, H2SO4 (aq.)


+ MeCHO (132)
N
N
O

2[95[3[7 Ketones Derived from Imidazoles\ Thiazoles and Oxazoles


These aromatic heterocycles fail to undergo C!acylation under FriedelÐCrafts conditions due to
heteroatom complexation and consequent deactivation[ Two notable exceptions\ 1!hydroxy thia!
zoles and N!methyl!1!phenyl!3!benzamino imidazole\ are su.ciently activated to give the desired
ketones ð28CB0369\ 60JOC2257Ł[ However\ the 1!keto products are formed on treatment with acid
chlorides in the presence of triethylamine[ These reactions are thought to occur via initial heteroatom
acylation followed by ylide formation and rearrangement to the product "Equation 022# ð66LA034\
67S564\ 73JOC489Ł[ A similar reaction has been observed with dichloroketene ð73JOC2367Ł[ Oxazoles\
thiazoles and N!alkyl imidazoles are readily lithiated at the 1!position and react with electrophiles
such as tertiary amides ð73S0937\ 75CPB3805Ł and esters ð80CC0202Ł to give the 1!keto adducts directly
in moderate to excellent yield[ The example shown in Equation "023# proceeded without loss of
stereochemical integrity at the a!chiral centre[ 3!Acyl imidazoles have been prepared by C!1 and
N!protection\ followed by selective lithiation at C!3 prior to reaction with acid chlorides "Equation
024# ð80S0910Ł "the protecting groups are removed in quantitative yield using dilute HCI#[ Thermal
rearrangement of 4!keto imidazoles can give the 3!C adduct ð73JOC4992Ł and acylation of lithiated
4!"0\2!dithianyl#oxazole leads to mixtures of two 3!keto!oxazoles after a subsequent Cornforth
201 Ketones With an a\b!Aryl or !Hetaryl
rearrangement ð82TL6694Ł[ 1!Trimethylsilyl or 1!stannyl derivatives of oxazoles\ thiazoles\ imi!
dazoles and their benzoderivatives can be acylated with acid chlorides ð72JHC0900Ł and in the case
of the silylated compounds\ with ketenes ð70CC544Ł and anhydrides "Equation "025## ð75G022Ł[
O
S O Et3N, benzene
+ S (133)
CCl3
N Cl CCl3 45%
N

O O
S
S OMe
O O
Li + (134)
N 80% N N
N O O
ButO ButO

i, BuLi

N Cl
ii, N
N TBDMS O
TBDMS (135)
O S O N
91%
OO S O
NMe2
NMe2

Cl
N Cl O N
tbaf, THF, benzene
TMS + (136)
O O O 60%
S HO S
O
tbaf = tetra-n-butylammonium fluoride

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.07
Aldehyde and Ketone Functions
Further Substituted on Oxygen
DONALD A. WHITING
University of Nottingham, UK
2[96[0 CARBONYL YLIDES 202
2[96[0[0 Introduction 202
2[96[0[1 Carbonyl Ylides From Oxiranes 204
2[96[0[1[0 Intramolecular cycloadditions^ oxirane to oxy`en heterocycle 204
2[96[0[1[1 Intermolecular cycloadditions^ oxirane to oxy`en heterocycle 206
2[96[0[1[2 Electrocyclizations leadin` to furans and oxepines 207
2[96[0[1[3 Trappin` by hydroxyl functions leadin` to acetals 208
2[96[0[1[4 Trappin` by oxy`en leadin` to ozonides 208
2[96[0[2 Carbonyl Ylides From Carbenes 208
2[96[0[2[0 Intramolecular cycloadditions^ diazocarbonyl to oxy`en heterocycle 208
2[96[0[2[1 Intermolecular cycloadditions^ carbene to oxy`en heterocycle 219
2[96[0[2[2 Electrocyclizations leadin` to furans 210
2[96[0[2[3 Hydro`en mi`ration leadin` to enol ethers 212
2[96[0[2[4 Halo`en mi`ration and decarbonylation reactions 212
2[96[0[3 Carbonyl Ylides From Cycloreversions 212
2[96[0[4 Carbonyl Ylides From Elimination Reactions 213

2[96[1 CARBONYL OXIDES 215


2[96[1[0 Other Carbonyl Derivatives 216

2[96[0 CARBONYL YLIDES

2[96[0[0 Introduction
Carbonyl ylides are 0\2!dipolar species\ represented by the parent 1!oxatrimethylene structure
"0#[ This ylide is conveniently shown in the zwitterionic form\ although calculations show signi_cant
diradical character ð68JA0984\ 68JA0090\ 79JA0493Ł and indicate a preferred nonlinear\ planar geometry
"the 9>\ 9> conformation#[ Theoretical studies also suggest that the stability of such ylides would be
increased by substitution by electron!donating groups at one carbon centre and electron!with!
drawing groups at the other\ when dipolar zwitterionic character is enhanced and the energy barriers
to rotation are lowered[ In an extreme case "1#\ the "9>\ 89># conformation should be favoured[

+
+ H2N O – CN
H O H

CN
H2N
H H
(1) (2)

202
203 Further Substituted on Oxy`en
Carbonyl ylides are generally encountered as reactive intermediates rather than stable species^
they have been observed spectroscopically "at low temperatures and trapped in matrices# in several
cases[ Thus irradiation of tetraphenyloxetanone "2# at wavelengths ×166 nm leads to expulsion of
carbon monoxide and production of the blue ylide "3#\ identical to that obtained by irradiation of
tetraphenyloxirane "4# "Scheme 0# ð69JA0391Ł[ Both thermolysis and photolysis of the 4!oxabicyclo!
ð1[0[9Łpentane "5# have yielded the colored\ _ve!membered ring ylide "6# "Equation "0##[ In the case
of the ylide "6#\ when RPh\ the species displayed a t0:1 of 7 min[ This relatively long lifetime is
ascribed to the unfeasibility of thermal ring closure to the highly strained trans!fused bicycle\
through the allowed conrotatory process ð69JA0393\ 69PAC412\ 60JHC0986Ł[ A study of the reaction
with acetone of the carbene "7#\ generated by laser photolysis of diazo~uorene\ showed the formation
of the ylide "8# "Scheme 1#[ The decay of the intermediate "8# was interpreted as requiring rotation
from the initial 9>\ 9> conformation to the 9>\ 89> geometry before collapse to the oxirane "09#
"Scheme 1# ð74JA6193Ł[ One example is known of a stable carbonyl ylide\ this is "00#\ which exists
as a crystalline solid in the 9>\ 89> shape[ The stability of "00# arises from the extreme {push!pull|
electronic e}ects ð72JA4818Ł[ One metal complex "01# of a carbonyl ylide has also been reported
ð61JOM"35#C18Ł[

Ph O Ph + O
hν, > 277 nm Ph O Ph 254 nm Ph Ph
Ph Ph –
77 K 77 K Ph Ph
O Ph Ph
(3) (4) (5)

Scheme 1

O +
Ph R Ph O – R
∆ or hν
(1)

(6) (7)
:

+O O
Me2CO –

(8) (9) (10)

Scheme 2

+
CF3
Me2N O – O
NC CN
CF3
Me2N NC Pt CN
F3C
CF3 Ph3P PPh3
(11) (12)

This review concentrates on synthetic aspects of the carbonyl ylide area[ Historical\ theoretical\
and mechanistic aspects are outside the scope of this chapter\ and the reader is referred to major
general reviews of the _eld\ inter alia ðB!73MI 296!90\ 80COS"3#0978\ 80COS"3#0048Ł[ Carbonyl ylides are
formed by four general processes] "i# thermal or photochemical carbon0carbon bond cleavage in
epoxides^ "ii# carbene additions to carbonyl groups^ "iii# cycloreversion reactions^ and "iv# elimination
processes[ The _rst three of these processes are exempli_ed in the formation of the ylides "3#\ "6#\
and "8#[ The various subsections of this review will treat each mode of ylide formation in turn\
illustrating the transformations observed with examples chosen to highlight the range of reactions
of these reactive novel intermediates[
Carbonyl Ylides 204
2[96[0[1 Carbonyl Ylides From Oxiranes
Carbon0carbon bond cleavage of oxiranes\ induced thermally\ photochemically\ or by electron
transfer catalysis\ is a common method of generating carbonyl ylides[ Either conrotatory or dis!
rotatory ring openings are possible^ these are formally allowed either thermally "conrotatory# or
photochemically "disrotatory#^ exo!exo or exo!endo ylide conformations result "Scheme 2#[ In prac!
tice\ situations are complicated by the thermal interconversion of the two conformations\ and by
violation of orbital symmetry control in the face of acute steric constraints ð60CC0089\ 60CC0081\
65TL3532\ 66CC328\ 66CC339Ł[ The overall outcome is dependent on the relative kinetics of ring opening\
conformational equilibration\ and the rate of trapping by a dipolarophile[ As a consequence\ varying
degrees of stereospeci_city have been observed[ The cycloaddition reactions of carbonyl ylides are
usually regioselective\ and the regiochemistry can be rationalized by Frontier Molecular Orbital
"FMO# theory\ with the HOMO of the dipole dominant for reactions with electron!de_cient species\
while the LUMO becomes important for addition to electron!rich alkenes[

O ∆, conrotatory +
R H R O R

H R exo-exo

hν, disrotatory

+
O ∆, conrotatory R O
R R –

H H R
exo-endo

Scheme 3

2[96[0[1[0 Intramolecular cycloadditions^ oxirane to oxygen heterocycle


Eberbach and co!workers have accessed an interesting range of heterocycles in which a tetra!
hydrofuran moiety is incorporated into di! and trifused!ring systems\ etc[\ including macrocyclic
systems[ Thus irradiation of the "Z#!stilbene oxide "02# yielded the oxabicycle "03# with disrotatory
epoxide opening\ and the same isomer was produced by ~ash thermolysis of the "E#!oxide "04#
"Scheme 3# ð73TL0026Ł[ Heating the epoxide "05^ RH# gave rise to the trans!fused furan "06#\
together with its cis!isomer "Equation "1## ð79AG"E#36\ 73CB1046Ł^ intramolecular cycloaddition to
the unactivated alkene was slower than intermolecular trapping with\ for example N!phenyl!
maleimide[ A series of similar reactions with the corresponding ylide separated from its reacting
partner by tethers of di}erent length ð79TL3898Ł a}orded a set of macrocyclic ethers\ for instance
"05^ RCO1Me\ n09# at 129>C\ 09[4 h\ gave mainly the bridged furan "07# with opposite
regiochemistry from that shown by lower homologues[ Trapping of the ylides by cyclic alkenes has
also proved viable\ as in the transformation of the cyclohex!1!enol derivative "08# to the tetracycle
"19# "Equation "2## ð72CB1272Ł[ In another example the 07!membered dioxacycle "11# "2a\ 2\3 trans
and 2b\ 2\3 cis# was produced by intramolecular trapping by the cinnamate unit in the precursor
"10# "Equation "3## ð71TL3554Ł[ Terminal alkynes also act as e}ective ylide interceptors as shown by
the conversion of the propargyl ether "12# into the chromanodihydrofuran "13# "Equation "4##
ð80T6602Ł[ The indanone oxides "14# and "16# yielded the bridged tetracyclic products "15# and "17#
respectively\ on irradiation "Equations "5# and "6## ð72TL4474Ł[

Ph O Ph Ph Ph O Ph
O 450 °C, 10 s
hν, disrotatory conrotatory
Ph
35% 25%
CO2Me H CO2Me CO2Me
(13) (14) (15)

Scheme 4
205 Further Substituted on Oxy`en
O
Ph Ph
H
R = H, 175 °C, 9 h CN
CN (2)
n = 1, 75% (40% conversion)
n = 1, 66% (30% conversion) ( )n H
n( )
R
(16) (17)

O Ph

CN
O
MeO2C

(18)

O
Ph

CN 180 °C, 6 h O
O H CN (3)
90% O
Ph
H H

(19) (20)

Ph MeO2C
O NC
245 °C, 22 h NC 3 O
10( ) 4
(4)
O 42% Ph O O

MeO2C
(21) (22)

MeO2C
O
CO2Me CO2Me
O
160 °C, 13 h
CO2Me (5)
76%
O
O
(23) (24)

O O
300 nm, PhH
(6)
65% O
O

(25) (26)

O O

O 300 nm, PhH


O (7)
34%

(27) (28)
Carbonyl Ylides 206
2[96[0[1[1 Intermolecular cycloadditions^ oxirane to oxygen heterocycle
An early example of these cycloadditions is a}orded by the thermal C0C bond scission of
tetracyanoethylene oxide "18#^ the resulting ylide was particularly reactive\ not only yielding an
adduct "29# "49)# with styrene\ but also a product "20# "32)# with p!xylene ð54JA2546Ł[ A cyclic
ylide is formed on photolysis or pyrolysis of the indenone oxide "21#\ which can be trapped with\
for example dimethyl acetylenedicarboxylate "DMAD#\ bicycloð1[1[0Łheptadiene\ or cyclohexanone
to provide the varied products "22#\ "23#\ and "24# respectively "Scheme 4# ð51JA0204\ 53JA2703\
53TL0736\ 60CJC2332Ł[

CN
NC CN H CN
O O
NC CN
NC CN O
NC CN
Ph H CN
CN
(29) (30) (31)

CO2Me
O Ph
R hν, PhH
O CO2Me
O 40%

Ph R
O
(32) (33)
145 °C, 16 h
hν, 63% 83%

O Ph
O
O

Ph Ph
O
O
(34) (35)

Scheme 5

Electron transfer photosensitization o}ers an alternative mode of generating carbonyl ylides from
epoxides[ A sensitizer\ for example dicyanonaphthalene or dicyanoanthracene\ in a photochemically
excited state extracts an electron from the oxide\ which then ring opens to the corresponding cation
radical equivalent of the ylide before reclaiming an electron ð67CJC1874Ł[ The isomerization of cis!
to trans!stilbene oxide\ "25#:"26# "Equation "7##\ can be observed under these conditions\ and
the intermediate can be trapped with fumaronitrile and maleonitrile to yield the corresponding
tetrahydrofurans "27# "76)# and "28# "42)# with other minor stereoisomers in each case ð67CJC1874Ł[
Interception with maleic anhydride\ and the less reactive 1!butenolide\ has a}orded the bicyclic
ethers "39# "52)# and "30# "32)# respectively ð89JCS"P0#042Ł[ Attempts to generate a carbonyl ylide
from bis"3!methoxyphenyl#oxirane "31^ Ar3!methoxyphenyl# thermally or by direct or triplet
sensitized irradiation were frustrated by preferential C0O bond cleavage\ leading to deoxyanisoin
and bis"3!methoxyphenyl#ethanal[ However electron transfer sensitization "ET sens# using dicyano!
naphthalene\ and through phenanthrene!toluene _lters\ allowed formation of the desired ylide\
trapped by DMAD to a}ord "32# "43)# ð89JCS"P0#042Ł[

O hν, ET sens O
(8)
Ph Ph Ph Ph
(36) (37)

The oxirane "33^ Ar2\3!methylenedioxyphenyl# has been ring!opened on thermolysis to a highly


polarized ylide\ which nevertheless reacted with ethyl acrylate in a nonregioselective manner\ giving
207 Further Substituted on Oxy`en
NC CN NC CN

Ph O Ph Ph O Ph
(38) (39)

Ph O Ph Ph O Ph
Ar O Ar
O
H H H H
Ar Ar
O O O MeO2C CO2Me
O O
(40) (41) (42) (43)
Ar = 4-methoxyphenyl

rise to products "34# and "35# in nearly equal proportions "Equation "8## ð76TL2044\ 89JCS"P0#0082Ł[
Related cases were observed\ and the ylide intermediates may have high radical character[

Ar1 Ar1
O NO2 O Ar2 O Ar2
110 °C
NC + NC (9)
Ar 75%
CN MeO2C CO2Me
(44) (45) (46)
Ar1 = 4-nitrophenyl; Ar2 = 3,4-methylenedioxyphenyl

2[96[0[1[2 Electrocyclizations leading to furans and oxepines


Carbonyl ylides generated from butadiene or hexatriene monooxides readily undergo electro!
cyclization to a}ord O!heterocycles\ for instance the spirooxirane "36# undergoes ring expansion on
heating leading to the bicyclic ether "37# "Equation "09## ð67TL3764Ł[ The cyclic epoxide "38# cleaved
to a seven!membered ylide intermediate which was then observed to cyclize to the strained bicycle
"49#^ ethene was excised from the latter under the reaction conditions to a}ord 1\2!bis"carbo!
methoxy#furan "40# "Scheme 5# ð69PAC412\ 65TL2188\ 65TL2292Ł[ A synthetic route to a variety of
furan and g!lactone compounds has been devised which rests on synthesis of the vinyl epoxide "41#
and its rearrangement in high yield to dihydrofurans "42# "Equation "00##\ which have proved to be
extremely versatile intermediates ð71CC0944Ł[ The oxepine "44# is obtained as a minor product from
the thermolysis of the hexatriene oxide "43#\ with 0\6!electrocyclization less favoured than the
0\4!electrocyclization\ which leads to the major bicyclic furans "45# "Equation "01## ð68TL3938\
70CB1868\ 70TL3842\ 74CB3924Ł[

NC NC Ph

O 325 °C
O (10)
Ph 65%

(47) (48) cis : trans = 9 : 1

O CO2Me O
MeO2C CO2Me
CO2Me 390 °C
O
50%
MeO2C CO2Me
(49) (50) (51)

Scheme 6
Carbonyl Ylides 208
R2 R1 R2
R1 SMe SMe (11)
O SMe O SMe
(52) (53)

O
Ph Ph
200 °C, 1 h O
+ (12)
O Ph
CO2Me CO2Me
MeO2C
(54) (55) 22% (56) 53%
cis : trans = 4 : 3

2[96[0[1[3 Trapping by hydroxyl functions leading to acetals


Carbonyl ylides react with water or alcohols to yield hemiacetal or acetals[ This reaction has been
rarely used but a nice example is provided by the synthesis of the bridged bicyclic acetal "47# by
photolysis "p:p# of the epoxy hydroxy ionone "46# "Equation "02## ð71HCA1252Ł[ In a related
reaction an ylide intermediate was formed photochemically from the epoxide "48#^ reaction with
methanol then gave the primary product "59# which subsequently underwent 2\2!sigmatropic
rearrangement leading to the cycloheptanone "50# "Scheme 6# ð68HCA0534Ł[

HO 254 nm, MeCN O


O O (13)
O O
55%

(57) (58)

O
O
O hν, MeOH O [3,3]
O
O 43%
OMe
OMe
(59) (60) (61)

Scheme 7

2[96[0[1[4 Trapping by oxygen leading to ozonides


Carbonyl ylide cation radicals\ generated from oxiranes by electron transfer photosensitization\
react e.ciently with oxygen\ to form ozonides\ a rare alternative to ozonolysis ð71CC0112\ 72JA552Ł[
Thus tetraphenyloxirane "51# gave the ozonide "52# in 53) yield using dicyanoanthracene as
sensitizer^ this yield was raised to 82) on addition of biphenyl "Equation "03##[
O Ph Ph
hν, ET sens, O2 O
Ph Ph
(14)
64% Ph Ph
Ph Ph O O
(62) (63)

2[96[0[2 Carbonyl Ylides From Carbenes

2[96[0[2[0 Intramolecular cycloadditions^ diazocarbonyl to oxygen heterocycle


As has been pointed out by Padwa and Hornbuckle ð80CRV102Ł\ reactions of carbalkoxycarbene
precursors with carbonyl compounds were described as early as 0774 ð0774CB1260Ł\ and the structures
219 Further Substituted on Oxy`en
of the dioxolane products were assigned early in the twentieth century ð09CB0913Ł[ The carbeneÐ
carbonyl reaction leads to a carbonyl ylide intermediate\ as shown in Equation "04#\ and ylide
interception reactions follow[ From a synthetic standpoint this route allows the formation of a
carbonyl ylide from quite di}erent functional assemblies from the oxirane units described above[
+
R1 R3
R1 O – R3
O + : (15)
R2 R4 R2 R4

In the 0879s the formation of carbenes from diazocarbonyl compounds catalyzed by rhodium"II#
salts\ especially rhodium acetate\ has attracted much attention[ This method allows mild conditions\
reactions often taking place at ambient temperature in a few hours[ Thus the diazoketone "53# with
rhodium acetate loses nitrogen to form the corresponding ketocarbene^ the carbene then is trapped
by the adjacent ester carbonyl functionality to give an ylide which _nally undergoes intramolecular
cycloaddition to form the tricyclic furanone "54# "Scheme 7# ð71T0366Ł[ The phthalate derivative
"55# under similar circumstances yields the bridged furofuran "56# "Equation "05##^ the intermediate
in this reaction can also be intercepted with DMAD ð77JA1783Ł[ The acyclic functional assemblies
"57# and "69# undergo related reaction cascades to provide the tricyclic heterocycles "58# and "60#
respectively "Equations "06# and "07##^ in the _rst case an isomunchone!like ylide intermediate
participates ð77TL0566\ 78JOC706Ł^ cf[ ð82TL6742Ł[

O O
COCHN2 Rh2(OAc)4, 3 h, RT

CO2Et 43% EtO2C
EtO O+ O

(64) (65)
Scheme 8

N2 O

Rh2(OAc)4, 25 °C
O O (16)
O 87%

O O

(66) (67)

O
O O O
Rh2(OAc)4, 110 °C O
( )3 N (17)
91% N O
N2
Ph
Ph
(68) (69)

O
Rh2(OAc)4
( )3 N2 O (18)
O
O
(70) (71)

2[96[0[2[1 Intermolecular cycloadditions^ carbene to oxygen heterocycle


Modern interest in the carbeneÐcarbonyl reaction was awakened by a study of the example shown
in Equation "08# by de March and Huisgen ð71JA3841\ 71JA3842Ł[ The involvement of a carbonyl
ylide was indicated by the production of the epoxide "61# with equimolar reactants "61)\ copper
powder\ re~uxing chlorobenzene#\ and by the isolation of the dioxolane "62# with excess
Carbonyl Ylides 210
benzaldehyde "01 equivalents\ 014>C\ 45)\ cis ] trans47 ] 31#[ Trapping by other dipolarophiles
was achieved and catalysis by copper metal\ copper acetylacetonate\ copper tri~ate\ and rhodium
acetate was also observed[ Arylmercuric compounds are an alternative source of carbenes[ Thus\
heating together bromodichloromethyl phenylmercury\ an aldehyde\ and a suitable ylide co!reactant
"Equation "19## a}ords the dihydrofurans "63#\ which eliminate hydrogen chloride under the reaction
conditions to form furans "64# in reasonable yield "RPh\ 35)# ð71TL4988\ 72JOC0940Ł[

O CO2Me
CO2Me Ph O Ph
∆, cat. CO2Me
PhCHO + N2 + CO2Me (19)
CO2Me O
CO2Me
Ph
(72) (73)

Cl O
Ar O Ar Cl
DMAD
ArCHO + PhHgCBrCl2 Cl + (20)
PhH, 80 °C
MeO2C CO2Me MeO2C CO2Me
(74) (75)

Two examples of intermolecular reactions of ylides from diazocarbonyl reactants are provided
by the work of Padwa and co!workers ð78CC810\ 78TL0380\ 89JA2099\ 82JOC3535Ł[ Thus\ the diazoester
"65# with N!phenylmaleimide gave the bridged furolactone "66# "Equation "10##\ while the diazo!
ketone "67# reacted with propanal to yield bridged cyclic acetals "68^ XO# and "79^ XO#
"59)\ 1 ] 0#\ which were deoxygenated to exo! and endo!brevicomin "68^ XH1# and "79^ XH1#
respectively "Equation "11##[ The last case in this subsection illustrates the scope for intramolecular
reactions of carbenes with amide carbonyl groups "70# to form ylides "71#\ which can equilibrate
with their isomers "72# through hydrogen transfer^ both of the ylides can be trapped by DMAD
"Scheme 8# ð81JA482Ł[
Ph

O N2 O N O
Rh2+, 80 °C, N-Phenylmaleimide
O
R Z (21)
75–85% R Z
O
O
(76) O O
Z = CO2Et, CN; R = Me, Ph
(77)

O
N2 Rh2+, EtCHO O O
O + O H (22)
O Et
X X Et
(78) (79) (80)

O – O
O Rh2+
N N N

R O N2 R O+ R O+

(81) (82) (83)

Scheme 9

2[96[0[2[2 Electrocyclizations leading to furans


Vinyl carbonyl ylides formed from carbenes and a!unsaturated ketones cyclize to furan sub!
structures\ as exempli_ed in methodology developed for the elaboration of fused furans by Spencer
211 Further Substituted on Oxy`en
and co!workers ð56JA4386\ 56TL0754Ł and used in the synthesis of the diterpene methyl vinhaticoate[
The key step\ "73# to "74#\ is illustrated "Equation "12##[ If aryl esters or amides are employed then
isobenzofurans result\ as in the conversion of "75# into "76#^ these new reactive intermediates can in
turn be trapped by suitable dienophiles\ as in the formation of dihydronaphthalene "77# "Scheme
09# ð72TL1834Ł[ This sequence has been exploited to form 00!oxasteroids\ centred around the
transformation of diazo ester "78# into an isobenzofuran\ which undergoes intramolecular DielsÐ
Alder reaction leading to the adduct "89# "Equation "13## ð77TL1934Ł[
CO2Et
O
O
N2 CO2Et
OMe
H CuSO4, 160 °C
H (23)
H 30%
H

CO2Me
CO2Me
(84) (85)

NPri2 NPri2
NPri2 CO2Me
O Cu(acac)2 dimethyl maleate

O 75%
CO2Me
N2 OH
(86) (87) (88)

Scheme 10

O O
O O
O O
Cu (F6 - acac)2
(24)
O
O H
N2
MeO MeO
CO2Me CO2Me
(89) (90)

Further variants are o}ered by the cyclization of vinyl carbenes to fused furans[ The diazoketone
"80# with an alkyne side chain is converted by rhodium acetate into the corresponding ketocarbene\
which cyclizes _rst to the vinyl carbene "81#\ then to the furan "82# through a formal 0\2!dipole
"Scheme 00# ð89JOC303Ł[ Parallel chemistry is displayed in the formation of the furolactone "84#
from the acyclic diazoester "83# "Equation "14## ð89TL5724\ 82JOC10Ł[

O O
:

O
Rh2(OAc)4
N2
85%

(91) (92) (93)

Scheme 11

R
R O

O O Rh2(OAc)4, 80 °C
(25)
O O
O
N2
(94) (95)
Carbonyl Ylides 212
2[96[0[2[3 Hydrogen migration leading to enol ethers
Carbonyl ylides with suitably disposed hydrogen atoms can rearrange by hydrogen migration to
the anionic site\ as illustrated in Scheme 01[ The enol ether "83# is the major product although a
little ylide is trapped by cyclohexanone to form the dioxolane "84# ð42JOC0929\ 78TL3978Ł[ With
1!methylcyclohexanone\ regioselective enolization results ð67JOC0133Ł[ Another example arises in
the decomposition of the diazoketone "85# where 0\2!hydrogen shift in the ylide leads to the furan!
2!one "86# "Equation "15## ð80JOC2160Ł[

CO2Et CO2Et
N2 EtO2C
O CO2Et
+ –
Cu, 90 °C O O
+ O O

(94) 43% (95)

Scheme 12

O O
N2 Rh2+, 25 °C
(26)
90%
EtO O
EtO O
(96) (97)

2[96[0[2[4 Halogen migration and decarbonylation reactions


Ylides derived from halocarbenes can react by way of 0\2!halide shift\ formally generating a
carbene which then fragments with a second halide shift to form a 0\0!dihalide and carbon monoxide
"Scheme 02# ð63S613\ 67JOC0960\ 72JOC0787\ 72TL1718Ł[ The ylide intermediate in this sequence can\ in
favourable cases\ collapse to the corresponding oxirane in good yield ð63JOM"56#230Ł[

+
80 °C Ar O – Cl
ArCHO + PhHgCBrCl2 CO + ArCHCl2
Cl

Scheme 13

2[96[0[3 Carbonyl Ylides From Cycloreversions


Cycloreversion of carbonyl ylide adducts has been observed in a number of cases[ Examples are
limited to those cases in which a heterocycle fragments to an ylide essentially irreversibly[ The best!
known examples are those in which nitrogen is extruded\ such as in the thermolysis of the oxadiazole
"87#\ which at 59Ð54>C a}ords the corresponding ylide\ trapped by N!phenylmaleimide with sub!
sequent loss of acetic acid to yield the dihydrofuran "88# "Equation "16## ð56TL1578Ł[ Low regio!
selectivity in the interception of the ylide oxadiazole "099# by D3!methanol was demonstrated\ with
isolation of both the bisacetal "090# and the orthoester "091# "2 ] 6# "Equation "17## ð72CJC508Ł\ and
competitive 0\3!hydrogen shifts were observed on heating the related oxadiazole "092#\ when the
isomeric enol ethers "093# and "094# were formed "Equation "18##] di}erences in product distribution
between cis and trans "092# indicated that the conformationally di}erent ylides did not equilibrate
in their lifetime ð78CJC0642Ł[ Thermolysis of the diazaheterocycle "095# is a convenient method of
213 Further Substituted on Oxy`en
generating dialkoxy carbenes "096# "Equation "29## ð81JA7640Ł[ Diazirenes pursue a similar reaction
path on heating^ thus the arylchlorodiazirene "097# generates the corresponding carbene at 79>C in
acetone\ and subsequent reaction with the solvent a}ords the ylide "098# "Equation "20## ð75TL3272Ł^
cf[ ð75TL3272\ 76CL1024\ 76TL0900\ 89JA633Ł[ The bicyclic compound "009# reversibly eliminates dimethyl
fumarate on heating\ to form the mesoionic isomunchone dipole "000#\ which in the presence of
dimethyl acetylenedicarboxylate undergoes addition followed by elimination of methylisocyanate
to form the _nal furan product "001# "Scheme 03# ð64CL388Ł[

O
N-phenylmaleimide, 60–65 °C Ph
O OAc (27)
51% O
N N Ph N O
Ph
(98) (99)

MeO MeO O OCD3 MeO O D


O CD3OD, 80 °C
+ (28)
D3CO
N N D
(100) (101) (102)

AcO AcO O AcO O


O PhH, 80 °C
+ (29)
N N
(103) (104) (105)

RO
O PhH, 100 °C MeO OR (30)
MeO
:

N N
(106) (107)

+
Ar N Me2CO, 80 °C Ar O
– (31)
Cl N
Cl
(108) (109)

Me O
Me O– MeO2C CO2Me
N
N DMAD
Ph Ar
O
Ph O Ar –MeNCO Ph Ar
+
O
MeO2C CO2Me
(110) (111) (112)

Scheme 14

2[96[0[4 Carbonyl Ylides From Elimination Reactions


Heating the thionoacid "002# with acetic anhydride induces cyclodehydration to give the mesoionic
heterocycle "003#^ addition to methyl propargylate and elimination of carbonyl sul_de then yields
the furan "004# "Scheme 04# ð64AG"E#311Ł[ Sammes and co!workers have exploited the mild elim!
ination of acetic acid from 1!acetoxydihydropyran!2!ones to form 2!oxidopyrilium ylides to
synthesize a variety of bridged furans and other O!heterocycles ð71CC0945\ 72CC555\ 72JCS"P0#0150\
75JCS"P0#0614\ 76JCS"P0#084Ł[ An example of intramolecular cycloaddition is provided by 0\4!
diazabicycloð3[2[9Łnon!4!ene "dbn#!catalyzed elimination from the 2!pyranone "005# at ambient
temperature to a}ord the tricyclic product "007# via the ylide "006# "Scheme 05#[ Substituted relatives
Carbonyl Ylides 214
of "007# have been used to synthesize various sesquiterpenoids of the hydrazulene series\ for example
"2#!b!bulnesol\ "2#!b!bulnesene\ "2#!cryptofauronol\ "2#!fauronol acetate\ and "2#!valeranone[
Intermolecular trapping of these 2!oxidopyrilium ylides by both electron!rich and electron!de_cient
alkenes has also been observed[ Thus\ the precursor "008# with triethylamine and ethyl vinyl ether
gave the bicyclic ether "019#\ and with 1\2!dimethylbutadiene ð3¦3Ł cycloaddition occurred to yield
"010#[ The isochroman derivative "011# reacted with cyclohexenone\ for example\ to provide the
stereoisomers "012# and "013# "Equation "21##\ with minor quantities of a regioisomer[ Wender and
co!workers have employed the generation of the 2!oxidopyrilium ylide from the pyranone "014#\
yielding "015# through intramolecular cycloaddition\ as a key step in the synthesis of a general
precursor to the tiglianes\ daphnanes\ and ingenanes "Equation "22## ð78JA7843Ł[ This chemistry
was then developed into an elegant total synthesis of phorbol ð78JA7846Ł[ An approach to the
tigliane system using a carbonyl ylide strategy has also been reported ð82JOC6524Ł[

Ph O Ph
+O Ph
O Ac2O, 80 °C CO2Me N
N
N CO2H –COS
S O–
S MeO2C
(113) (114) (115)

Scheme 15

O O O
dbn, RT O

AcO O O 75%
–AcOH +

H
(116) (117) (118)

Scheme 16

O
O
O O

AcO O
EtO O
(119) (120) (121)

O O
O
H H
Et3N, RT
O + O (32)
O cyclohexenone
H H
OAc
O O
(122) (123) (124)

OAc
OAc
O
dbu, RT
O (33)
O
O-TBDMS
O-TBDMS O
OAc
(125) (126)
dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene; TBDMS = t-butyldimethylsilyl
215 Further Substituted on Oxy`en
0\2!Elimination from chloromethyl!a!trimethylsilyl!a!arylmethyl ethers "016# has been shown to
lead to the formation of simple aryl carbonyl ylides "017# under mild neutral conditions following
chemistry parallel to that of the nitrogen analogues "Equation "23## ð82TL4832Ł[

Ar
Ar CsF, RT
– (34)
O
TMS O Cl
+

(127) (128)

Finally an isolatable 2!oxidopyrilium ylide has been obtained from the thiopyrilium perchlorate
"018#[ S!Phenylation of "018# followed by treatment with oxygen _rst gave the cyclic peroxide "029#
which next rearranged on reaction with hydrogen chloride with loss of thiophenol to form the ylide
"020# as a dark red solid "Scheme 06#^ the ylide "020# then gave an adduct with maleic anhydride
ð51JA1983Ł[
Ph Ph Ph
i, PhLi HCl, Et2O O–
O O
Ph S Ph ii, O2
+
Ph S Ph Ph O Ph
ClO4 – Ph +

(129) (130) (131)

Scheme 17

2[96[1 CARBONYL OXIDES


Carbonyl oxides are generated as reactive species in ozonolysis reactions of alkenes ðB!67MI 296!90\
B!71MI 296!90\ B!73MI 296!91Ł[Scheme 07 indicates the accepted general course of events where the
initial molozonide fragments "reverse 0\2!dipolar cycloaddition# into carbonyl oxide and aldehyde
or ketone[ This pair may then add together with reverse regiochemistry to form the normal ozonide\
but other courses are open to the carbonyl oxide\ including interception by a more reactive carbonyl
compound to give a new ozonide\ reaction with alcohols to form an a!methoxy hydroperoxide\
dimerization to a cyclic bisperoxide\ or polymerization[ This scheme implies that a speci_c ozonide
may not be formed exclusively from a simple alkene\ and this has been borne out by several
experimental studies\ for example ozonolysis of neat pent!1!ene at −69>C gave a mixture of all
three possible ozonides\ each as a cisÐtrans pair "Equation 24# ð54JA626Ł[ The intramolecular
trapping of a carbonyl oxide has been demonstrated in the ozonolysis of the unsaturated diketone
"021#^ intermediate "022# reacts to yield the bicyclic peroxide "023# "Scheme 08# ð43CB0697\ 57CB352Ł[
Criegee et al[ ð64CB0531Ł have shown that a carbonyl oxide has a long enough lifetime to choose
between two available carbonyl groups in the ozonolysis of the deuteriated compound "024#[ Equal
quantities of the two ozonides "025# and "026# were obtained "Equation "25##[ An intramolecular
rearrangement of the initial molozonide was ruled out[ Carbonyl oxides have been shown to react
with suitable dicarbonyl compounds to give either monoozonides or novel 0\1\3\5!trioxepanes
ð83JCS"P0#532Ł[

O3, –70 °C O O O O O O
+ + (35)
O O O

O D D3C D
O D D
D
D O3 O O
O D D + O (36)
D D O O
D
D
O
(135) (136) (137)
216
R1 OOH O O
R1
R2 O
R1 OMe R1

MeOH
R2CHO

O O–
O O + O O O
O R1 R1
+
R1 R1
R1 R1 R1 R1 R1 O R1
R1 R1

R1 O O R1

R1 O O R1

Scheme 18

O O O O
O3 +
O O
O–
O
(132) (133) (134)

Scheme 19

Sensitized photooxygenation of furans\ for example "027# has been shown to lead to a reaction
sequence involving a!unsaturated carbonyl oxides "028# as intermediates "Equation "26##[ The latter
display a range of reactions\ including cycloadditions ð83JCS"P0#036Ł[

CO2Me CO2Me
hν, O2
(37)
Ar CO2Me
Ar O OMe O O–
+
(138) (139)

2[96[1[0 Other Carbonyl Derivatives


Various analogues of carbonyl oxides can be envisaged\ for instance carbonyl imines "039#\ and
{{carbonyl sul_des|| "030#[ The former have attracted theoretical attention\ and calculations have
indicated that such species should be stable enough to be detected ð62JA6176\ 72JCR"S#151Ł[ However
no signi_cant experimental work on these and other analogous intermediates has yet been reported[
+ +
R O – R O –
NR S(R2)
R R
(140) (141)

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.08
Thioaldehydes and Thioketones
WILLIAM G. WHITTINGHAM
ZENECA Agrochemicals, Bracknell, UK
2[97[0 INTRODUCTION 229
2[97[1 THIOALDEHYDES 220
2[97[1[0 Alkyl Thioaldehydes 220
2[97[1[0[0 Photolysis of phenacyl sul_des 220
2[97[1[0[1 Formation of the a C0C bond 221
2[97[1[0[2 0\1!Elimination reactions 222
2[97[1[0[3 Cycloreversion and related reactions 223
2[97[1[0[4 Sulfuration of aldehydes and derivatives 225
2[97[1[0[5 Other methods 225
2[97[1[1 a\b!Unsaturated Thioaldehydes 226
2[97[1[1[0 Thioaldehydes bearin` an a\b!alkenic bond 226
2[97[1[1[1 Thioaldehydes bearin` an a\b!aryl or hetaryl substituent 239
2[97[1[1[2 Thioaldehydes bearin` an a\b!alkynic bond 231
2[97[2 THIOKETONES 231
2[97[2[0 Dialkyl Thioketones 231
2[97[2[0[0 Dialkyl thioketones by sulfuration of ketones 232
2[97[2[0[1 Dialkyl thioketones by direct sulfuration of other compounds 236
2[97[2[0[2 Dialkyl thioketones by other methods 238
2[97[2[1 a\b!Unsaturated Thioketones 241
2[97[2[1[0 Thioketones bearin` an a\b!alkenic bond 241
2[97[2[1[1 Thioketones bearin` an a\b!aryl or hetaryl substituent 259
2[97[2[1[2 Thioketones Bearin` an a\b!Alkynic Bond 255
2[97[3 THIOALDEHYDE AND THIOKETONE FUNCTIONS FURTHER SUBSTITUTED
ON SULFUR 255
2[97[3[0 Two!coordinate Sulfur Functions 256
2[97[3[0[0 Thiocarbonyl ylides 256
2[97[3[0[1 Sul_nes 257
2[97[3[0[2 Thiosul_nes 269
2[97[3[0[3 Thiocarbonyl S!imides 269
2[97[3[0[4 Metal complexes of thioaldehydes and thioketones 269
2[97[3[0[5 Thiopyrylium salts 269
2[97[3[0[6 0\1!Dithiolium salts 260
2[97[3[0[7 Nonclassical thiophenes 260
2[97[3[0[8 Other heterocycles 261
2[97[3[1 Three!coordinate Sulfur Functions 261
2[97[3[1[0 Sulfonium ylides 261
2[97[3[1[1 Sulfenes 264
2[97[3[1[2 Other simple systems 264
2[97[3[1[3 Thiabenzenes 264
2[97[3[1[4 0\5\5al3!Trithiapentalenes and related systems 265
2[97[3[2 Four!coordinate Sulfur Functions 267
2[97[3[2[0 Sulfoxonium ylides 267
2[97[3[2[1 Other simple compounds 268
2[97[3[2[2 Thiabenzene S!oxides 268
2[97[3[3 Five!coordinate Sulfur Functions 279
2[97[3[3[0 Alkylidene sulfur tetra~uorides 279

218
229 Thioaldehydes and Thioketones
2[97[0 INTRODUCTION
Although the chemistry of the C1S double bond bears many similarities to that of the C1O
bond\ there are some signi_cant di}erences[ The C1S bond is much less polarized than the C1O
bond\ because of the much smaller di}erence between the electronegativities of carbon "1[49# and
sulfur "1[47# than between those of carbon and oxygen "2[33#[ Thus\ whereas the carbonyl bond has
a clear polarization\ with a partial negative charge on oxygen and a partial positive charge on
carbon\ the situation for the thiocarbonyl bond is much less clear cut[ The greater length of the
C1S bond also leads to a bond that is more easily polarized by neighboring groups[ This results in
large variations in the reactivity of di}erent thiocarbonyl groups^ an e}ect that is not seen for
carbonyl compounds[ For example\ electron!withdrawing groups on the thiocarbonyl carbon atom\
as in hexa~uorothioacetone\ signi_cantly reduce the electron density on sulfur\ and can reverse the
expected polarity of the C1S bond\ resulting in nucleophilic attack occuring at sulfur rather than
carbon ð54JOC0273Ł[ On the other hand\ conjugative electron!donating groups "as in\ for example\
thioesters and thioamides# result in the opposite sense of polarization and hence in compounds with
a strongly nucleophilic sulfur atom[
Thiocarbonyl compounds bearing electroneutral groups\ such as carbon and hydrogen\ tend to
have nonpolarized C1S bonds and can thus react in di}erent ways\ depending on the conditions[
This results in the very ready oligomerization or polymerization of thioaldehydes and thioketones\
and many of these compounds are highly unstable and can only be isolated under special conditions\
if at all[ For this reason many simple thioaldehydes and thioketones\ and their derivatives\ have
been generated and characterized only at very low temperatures\ or in the gas phase[ Although these
compounds are not strictly within the scope of this review\ their preparation will be detailed where
it demonstrates a useful principle\ or if the method could potentially be applied to the synthesis of
stable compounds[ The same criteria have been applied to those cases where the thiocarbonyl
compounds have been generated and then trapped in situ without isolation or characterization[ This
approach has been widely used\ not only for the characterization of the thiocarbonyl compounds\
but also in a number of synthetic applications[
The C1S double bond is also signi_cantly weaker than the C1O bond "004 kcal mol−0 "370 kJ
mol−0# against 051 kcal mol−0 "567 kJ mol−0##[ This not only increases the reactivity of the
thiocarbonyl group\ it also radically changes the balance of the tautomerism between the thione
and enethiol forms of these compounds[ Thus the enethiol form is often the more stable and\ under
some circumstances\ can be formed exclusively in a reaction or by subsequent equilibration[ A
slightly di}erent manifestation of this e}ect occurs in the case of a!dithiones\ which can tautomerize
to 0\1!dithietes "Equation "0##[ In this case the position of the equilibrium is very dependent on the
further substitution of the system ð72HCA790Ł[ A similar acyclicÐcyclic tautomerism is possible for
a!ketothiones and a\b!unsaturated thiocarbonyls[ In these cases the equilibrium lies completely
toward the acyclic thione tautomer\ unless there is a very strong driving force for formation of the
C1C double bond as in\ for example\ monothio o!quinones "Equation "1## and o!thioquinone!
methides[ A more detailed analysis of the tautomerism of thiocarbonyl compounds is given by
Schaumann in his recent excellent review of the thiocarbonyl group ðB!78MI 297!90Ł and by Duus in
an earlier review ð68COC"2#262Ł[ For the purpose of this work\ brief mention will be made of synthetic
methods which result in the exclusive formation of enethiols or cyclic tautomers*further details
can be found in Chapter 1[03[0[

R S R
S
(1)
S
R S R

S
S
(2)
O
O

A further notable di}erence between thiocarbonyl and carbonyl compounds is a result of the
ability of the sulfur 2d orbitals to participate in bonding[ This\ combined with the lower elec!
tronegativity of sulfur than oxygen\ results in a rich chemistry of thiocarbonyl compounds that are
further substituted on sulfur which has no real equivalent in the chemistry of the carbonyl group[
A wide range of compounds of this type have been prepared\ and are discussed in Section 2[97[3[
Thioaldehydes 220
2[97[1 THIOALDEHYDES
As has been mentioned above\ the low polarization of the thioaldehyde bond means that many
of these compounds are unstable\ often forming cyclic dimers or trimers\ or polymers[ Indeed\ the
only thioaldehydes that can be isolated under normal conditions are those which have stabilizing
steric or electronic interactions[ This has resulted in the chemistry of thioaldehydes being much less
well developed than that of thioketones\ in which there are two potentially stabilizing groups[ The
_rst stable thioaldehyde was only prepared in 0859\ by Woodward et al[ as an intermediate in their
synthesis of chlorophyll a ð59JA2799Ł[
Signi_cant advances have followed\ notably in the use of reactive thioaldehydes in total synthesis
by the in situ trapping of these compounds as they are generated[ In particular\ thioaldehydes react
readily as dienophiles in the DielsÐAlder reaction\ a technique that has been developed extensively
by the groups of Baldwin\ Kirby\ and Vedejs[ The use of this method\ and of thiocarbonyl chemistry
in general\ for the formation of carbonÐcarbon bonds has recently been reviewed ð81S0074Ł[ A
number of stable thioaldehydes have been prepared and isolated\ generally in those cases where
electronic factors allow conjugation and delocalization of the thiocarbonyl bond\ or where extreme
steric crowding disfavors polymerization[

2[97[1[0 Alkyl Thioaldehydes


A number of methods for the preparation of simple alkyl thioaldehydes have been developed\
some of which have recently been reviewed ð77YGK0038Ł[

2[97[1[0[0 Photolysis of phenacyl sul_des


Vedejs and co!workers have developed the Norrish type II photolytic cleavage of phenacyl sul_des
into a versatile method for the synthesis of thioaldehydes "Scheme 0# ð71JA0334Ł[ A wide variety of
alkyl thioaldehydes\ including several bearing nitrogen substituents ð77JOC1115Ł\ have been prepared
and trapped in situ as DielsÐAlder adducts ð75JOC0445\ 77JA4341Ł[ Several dienes have been used as
the trapping reagent\ and the yields for this process are generally good[ This methodology has been
applied to more complex systems as a key step in the total synthesis of cytochalasans ð73JA3506Ł
and zygosporin E ð77JA3711Ł[ The intramolecular DielsÐAlder reaction of thioaldehydes generated
in this manner has also been examined "Scheme 1# ð77JOC1119Ł[

S R1 S R1 S R1
hν R2O

Ph O Ph OH R2O

Scheme 1

H

71%
S S S
H
Ph

O
Scheme 2

Vedejs and co!workers have used this technique to prepare thiopivaldehyde "0#\ the _rst example
of a stable simple alkyl thioaldehyde ð72JA0572\ 75JA1874Ł[ Photolytic cleavage of phenacyl neopentyl
sul_de "1# provided the white insoluble thiopivaldehyde polymer[ The yield of this fragmentation
could be improved to 49Ð59) under optimum conditions "photolysis in benzene solution containing
an excess of 1\2!dimethylbutadiene\ using light _ltered through aqueous copper sulfate to remove
short!wavelength radiation that decomposes the polymer#[ Cracking the polymer at 149>C\ and
collection of the volatiles in a liquid nitrogen trap\ provided monomeric thiopivaldehyde "0# as a
magenta solid "Scheme 2#[ Addition of an inert solvent and warming to room temperature resulted
in a pink solution that was stable for up to 05 h\ depending on the cleanliness of the glassware and
221 Thioaldehydes and Thioketones
the purity of the solvents used[ Impurities\ especially protic or Lewis acids\ resulted in a more rapid
decomposition to the polymer and trimer[ The thiopivaldehyde was not particularly air!sensitive\
and underwent many reactions typical of thioaldehydes[ Other tertiary thioaldehydes can also be
prepared as monomers by this method ð75JA1874Ł[
S But
hν ∆
(ButCHS)n S But
59%
Ph O
(2) (1)
Scheme 3

2[97[1[0[1 Formation of the a C0C bond


A uniquely stable group of alkyl thioaldehydes are those in which the C1S bond is conjugated
to an adjacent phosphonium ylide[ Yoshida et al[ have prepared compounds of this type by the
condensation of a triphenyl phosphonium ylide with methyl thionoformate "Scheme 3# ð64BCJ1896Ł[
The stability of these compounds is presumably a result of the contribution of the canonical form
"2#\ the importance of which is suggested by the occurrence of slowly interconverting geometric
isomers of the thioaldehyde "3#[
S S–
HCSOMe +
Ph3P CH2 Ph3P Ph3P

(4) (3)

Scheme 4

Vedejs et al[ have prepared thiopivaldehyde by an alternative route to the photolytic method
described above\ which is conceptually similar to that used for the synthesis of the phosphonium
ylide!stabilized thioaldehydes "Scheme 4# ð75JA1874Ł[ Addition of t!butyllithium to ethyl thiono!
formate provided the hemithioacetal "4#\ which underwent acid!catalyzed decomposition to thio!
pivaldehyde\ which was distilled and trapped as before[ A similar technique has been applied to
the preparation of the highly sterically hindered thioaldehyde "5# by Okazaki et al[ "Equation "2##
ð76JA168Ł[ In this case\ reaction of the alkyllithium with ethyl thionoformate gave a 05) yield of
the thioaldehyde "5#\ a stable crystalline compound which could be puri_ed by chromatography
and recrystallization[ A further product "6# was isolated in 14) yield and is believed to derive from
the hemithioacetal "7#\ suggesting that an improvement in the yield of the thioaldehyde is possible
if "7# could be decomposed following Vedejs| method[
S ButLi SH H+, ∆ S

OEt 70% But OEt 31% But


(5)

Scheme 5

TMS
S TMS Li
S
TMS TMS
OEt (3)
16% TMS
TMS
(6)

SH
TMS TMS
OEt OEt
TMS
TMS TMS
(7) (8)
Thioaldehydes 222
A related method has been used by Hartke and Gunther to prepare thioformyl acetonitrile
ð62LA0526Ł[ This compound could not be isolated\ but was moderately stable in solution\ existing
exclusively as the enethiol tautomer[

2[97[1[0[2 0\1!Elimination reactions


A widely used approach to the synthesis of thioaldehydes has been 0\1!elimination\ from a suitable
precursor containing a C0S single bond\ to generate the C1S double bond "Equation "3##[ This
area has been developed by Kirby and co!workers\ who have demonstrated that base!catalyzed
elimination from sulfenyl halides ð72CC312\ 74JCS"P0#0430Ł\ phthalimides "Equation "4## ð72CC0214Ł\
Bunte salts "Equation "5## ð73CC811Ł\ and a!sulfonyl disul_des ð73CC0358Ł generated the thioal!
dehyde "8#\ which was readily trapped as DielsÐAlder adducts[ Kirby and Sclare have extended this
method to the preparation of the a!keto thioaldehyde "09# "Equation "6##\ which was reacted in situ
with thebaine ð80JCS"P0#1218Ł[ Although these methods have only been applied to the preparation
of a very limited range of alkyl and aryl "see Section 2[97[1[1[1# thioaldehydes\ there appears to be
no reason why they could not be used to prepare any thioaldehyde bearing a suitable electron!
withdrawing group[

H
X R S
+ HX (4)
R S

O
Et3N
S N EtO2C S (5)
EtO2C 78%
O (9)

SO3– Na+ Et3N


EtO2C S EtO2C S (6)
67%
(9)

SO2Tol Et3N, CaCl2


S S (7)
74%
O O
(10)

A further development of this general method has been reported by Kra}t and Meinke\ who have
used the ~uoride!induced cleavage of a!silyl disul_des "00# to generate a range of alkyl thioaldehydes\
which have been trapped by reaction with cyclopentadiene\ in good yields "Equation "7## ð74TL0836Ł[
A related approach has been described by Vedejs et al[ "Equation "8## ð77JA4341Ł\ although this
method has not been applied widely[ These two modi_cations of the 0\1!elimination technique have
the advantage that a wider range of thioaldehydes can be prepared\ as no adjacent activating group
is required[

CsF or tbaf
R2Me2Si S R1 S (8)
S 58–94%
X
R1
(11)

SO2Ph Et2NH
R S (9)
R SAc 29–77%

A related elimination strategy has been devised which relies on elimination from "or cycloreversion
of# a suitably activated dithiolane or derivative[ Thus\ deprotonation of the sulfonium salt "01#
forms an ylide which fragments to generate a thioaldehyde "Scheme 5# ð74TL4154Ł[ This method has
been used to prepare thioformaldehyde and thioacetaldehyde\ both of which were trapped in situ[
223 Thioaldehydes and Thioketones
Thiopivaldehyde was also prepared as a polymer\ which could be thermally cracked to the monomer
as described above[ A recent modi_cation of this method has also been used to synthesize thio!
pivaldehyde "Equation "09## ð89JOC3199Ł[ A variation of the procedure\ the thermolysis of a 0\0!
dioxodithiolane\ has been used to generate tri~uorothioacetaldehyde\ which was characterized in
an argon matrix and trapped as DielsÐAlder adducts ð78TL3000\ 89CB066Ł[ This thioaldehyde proved
to be rather unstable\ forming a polymer in a few minutes at −085>C[

S CO2Me CO2Me
EtNPri2 S
R R R S
+ + – 24–65%
S CO2Me S CO2Me

(12)
Scheme 6

O
TBDMS-OTf, EtNPri2
S But S (10)
But 39%
S
TBDMS = t-butyldimethylsilyl

Vedejs et al[ have demonstrated that cyanothioformaldehyde can be prepared by the reaction of
dibromoacetonitrile with EtOCS1−K¦\ a reaction that is mechanistically similar to other 0\1!
elimination approaches ð79JOC1590Ł[ The thioaldehyde could be trapped by dienes in low yield
"Scheme 6#[ This method could potentially be extended to the synthesis of other thioaldehydes\ but
appears to have been superseded by the Norrish type II photofragmentation technique[

S S CN
Br2HCCN EtO
S CN
K+ –S OEt 15%
EtO

Scheme 7

A technique closely related to the 0\1!elimination approach is the thermal rearrangement of


S!alkyl thiosul_nates[ The earliest example of this reaction is the work of Block and O|Connor\
who thermally decomposed alkylthiosul_nate esters to generate a sulfenic acid and a thioaldehyde
ð61JA531\ 63JA2818Ł[ The main aim of these studies appears to have been the preparation and
characterization of the sulfenic acids\ as little mention of the thioaldehydes was made\ although the
reaction of methyl alkylthiosul_nates was shown to generate thioformaldehyde polymer[ Baldwin
and Lopez have developed this reaction into a general method for the preparation of thioaldehydes\
which were trapped as DielsÐAlder adducts with anthracene "Scheme 7# ð71CC0918Ł[ The method
has also been used to synthesize a thioaldehyde which underwent intramolecular DielsÐAlder
cyclization ð72T0376Ł[

O
∆ S
S S
S 74%

Scheme 8

2[97[1[0[3 Cycloreversion and related reactions


One of the most widely used methods for the generation of simple thioaldehydes is the cyclo!
reversion of various precursors[ The ð1¦1Ł cycloreversion reaction of sulfur!containing four!mem!
bered rings\ under thermolytic or photolytic conditions\ has been employed to prepare thioaldehydes\
and the reaction has been reviewed by Schaumann and Ketcham ð71AG"E#114Ł[ This technique has
been used to generate and characterize thioformaldehyde and dideuterothioformaldehyde isolated
Thioaldehydes 224
in an argon matrix ð80BCJ0278Ł[ A range of variations of this method have been used ð63CJC2407\
71JA2008Ł\ typi_ed by that shown in Equation "00# ð56JPC3000Ł[ The ð3¦0Ł cycloreversion of "02#
has been used to prepare monothioglyoxal "03#\ which was isolated and characterized in an argon
matrix "Equation "01## ð72NJC158Ł[ The same technique has been used to prepare dithioglyoxal and
t!butyl dithioglyoxal ð67NJC220Ł[


HCHS + H2C CH2 (11)
S

S S

O (12)
O O
(13) (14)

The most widely used method of this type involves the retro DielsÐAlder reaction[ As has been
discussed above\ the trapping of reactive thioaldehydes with dienes\ most commonly cyclo!
pentadiene\ is the method of choice for the isolation and characterization of these unstable
compounds[ Heating the DielsÐAlder adducts regenerates the free thioaldehydes\ which can be
trapped ð72CC0214Ł or\ in the case of thiopivaldehyde\ isolated in a liquid nitrogen trap "Equation
"02## ð77JA4341Ł[ A wide range of thioaldehydes can be generated in this way\ and conventional
chemistry can be used to elaborate the starting DielsÐAlder adducts and hence the _nal thioaldehydes
"Scheme 8# ð77JOC1119Ł[ A variety of di}erent adducts can be used to prepare thioaldehydes in good
yield ð72CC312\ 72T0376\ 74JCS"P0#0430\ 89JOC1485Ł[ A particularly useful variant of this reaction has
been reported by Lee et al[ "Scheme 09# ð74JOC2105Ł[ In this case the precursor "04# is prepared by
a di}erent route\ potentially allowing the synthesis of thioaldehydes not available by other methods[

S ∆
But S (13)
75%
But

O
O O
i, NaH, MeI S
ii, NaH, ClCH2C(Me)CH2, NaI ∆ EtO2C
CO2Et
S 35% S
CO2Et

Scheme 9

EtO2C
Cl3C SCl2 S CCl3 ∆
CO2Et EtO2C S
HN N
NH2 33% 85%
O
CCl3
(15)

Scheme 10

The retro ene reaction of allyl sul_des "Equation "03## ð65CJC426\ 82JA213Ł and a retro ð2¦1Ł
cycloaddition "Equation "04## ð74TL4154Ł have also been used to generate thioaldehydes[


S S (14)
S S

S Ph

But But S (15)
N 39%
O Ph
225 Thioaldehydes and Thioketones
2[97[1[0[4 Sulfuration of aldehydes and derivatives
Although the direct conversion of a carbonyl group into a thiocarbonyl group is the most widely
used procedure for the preparation of stable thioketones "see Section 2[97[2#\ it has received little
attention for the synthesis of thioaldehydes[ This may be because the reagents and conditions that
are routinely used are incompatible with these comparatively unstable compounds[ However\
hexamethyl disilathiane "TMS!S!TMS# has been used either on its own ð68ZOB0973Ł\ or in com!
bination with boron trichloride ð71JA2093Ł\ n!butyllithium ð77JA0865Ł\ or cobalt chloride
ð80JOC6212Ł\ to prepare a range of thioaldehydes which could readily be trapped as DielsÐAlder
adducts in good yield[ The n!butyllithium!promoted reaction has also been applied to the dienal
"05#^ the thioaldehyde thus formed undergoes intramolecular DielsÐAlder cyclization "Scheme 00#
ð78SC1320Ł[
H
TMS-S-TMS, BunLi
54%
O S S
H
(16)

Scheme 11

Aldehyde dimethyl acetals can be converted into the corresponding thioaldehydes by reaction
with "Me1Al#1S^ the products were trapped with phosphonium ylides\ to give alkenes in reasonable
yields ð82CE42Ł[

2[97[1[0[5 Other methods


An interesting approach to the synthesis of thioaldehydes\ which may _nd wide application\ is
the reaction of phosphonium ylides with elemental sulfur "Scheme 01# ð77CL0034\ 80BCJ1391\
81RHA006Ł[ The thioaldehydes prepared by this method were trapped by reaction with secondary
amines to produce thioamides or enamines[ A modi_cation of this technique\ which allows milder
conditions to be employed\ utilizes the cyclic polysul_des "06# or "07# as the sulfur source ð80S674Ł[
S8 Me2NH
MeO2C PPh3 MeO2C S MeO2C S

NMe2

Scheme 12

S S
S
S
S
S S S S
(17) (18)

Another potentially versatile method for the formation of thioaldehydes has recently been
described by Dzhemilev et al[ ð81IZV059Ł[ Reaction of the sulfoxide "08# with catalytic Ni"acac#1\
triphenylphosphine\ and triethylaluminum\ in the presence of butadiene gave an 71) yield of the
DielsÐAlder adduct "19# "Equation "05##[ This technique has been applied to a range of dialkyl
sulfoxides\ and a number of alternative catalysts have been described ð80URP0579588\ 81URP0609459Ł[
Given the ready access to a wide variety of sulfoxides\ this method should prove to be applicable to
the preparation of a range of thioaldehydes[
C6H13

Ni(acac)2, PPh3, Et3Al S


C6H13 S C6H13 (16)
O
(19) 82% (20)
Thioaldehydes 226
The zirconation of thioketenes has been used for the preparation of stable\ highly sterically
hindered\ enethiolizable thioaldehydes\ as mixtures with the enethiol tautomers "Equation "06##
ð80JA6671Ł[

i, Cp2ZrCl2. BunLi
S But But
But • ii, 2 equiv. HCl
S + SH
(17)
62%
But But But
40% 60%

A number of photolytic and thermal techniques have been used to generate simple thioaldehydes
for characterization in the gas phase or by matrix isolation[ The 0\1!elimination of hydrogen
chloride from alkylsulfenyl chlorides discussed above has been carried out thermally to prepare
thioformaldehyde ð65JA5943Ł and thioformyl cyanide ð80T3816Ł\ and photolytically to produce
thioacetaldehyde ð80CB1598Ł[ The thermolysis of thiocyanohydrins has also been used to prepare
thioaldehydes ð77TL4788\ 80T3816Ł[ The thermal elimination of sulfur from 0\1\3!trithiolane has been
employed in the preparation of thioformaldehyde ð66CC176Ł[ A range of thermal methods for the
formation of thioaldehydes has been summarized in a paper by Bock et al[ ð71CB381Ł[
A number of synthetic approaches have been described which selectively produce vinyl thiols "the
enethiol tautomers of thioaldehydes#[ These include the addition of hydrogen sul_de to alkynes
ð52JA852\ 54CJC606Ł and the cleavage of vinyl sul_des ð69RTC482\ 60IJS"B#74Ł and vinyl thiocyanates
ð89JCR"S#219Ł[ The vinyl thiols formed\ with the exception of ethenethiol which has a half!life of
between an hour and several days ð66CC372Ł\ were stable enough to be isolated\ although a slow
tautomerization to the corresponding thioaldehyde\ followed by polymerization\ was observed[ For
more details of these methods\ see Chapter 1[03[0[

2[97[1[1 a\b!Unsaturated Thioaldehydes


Simple a\b!unsaturated thioaldehydes are similar in many respects to the alkyl thioaldehydes
discussed in the previous section[ Thus\ they are highly reactive species which often oligomerize
unless trapped in situ\ and they have generally been characterized in the gas phase\ at low tempera!
tures\ or as stable derivatives such as DielsÐAlder adducts[ In a single case\ that of 1\3\5!tri!
"t!butyl#thiobenzaldehyde\ steric protection has resulted in a stable compound ð73TL738Ł[ However\
there is the possibility of electronic stabilization of unsaturated thioaldehydes in those cases where
a suitable electron!donating group is conjugated to the C1S double bond[ A number of compounds
of this type have been prepared\ and the resulting vinylogous thioamides or thioesters and het!
erocyclic thioaldehydes have proved to be stable isolable compounds[

2[97[1[1[0 Thioaldehydes bearing an a\b!alkenic bond


This section covers the preparation of thioaldehydes containing an a\b C1C double bond[
Thioaldehydes that are conjugated to other types of double bond\ such as C1O\ C1S\ or C1P\
have been described in Section 2[97[1[0 on alkyl thioaldehydes[

"i# Simple alkenyl thioaldehydes


A number of the techniques used for the preparation of alkyl thioaldehydes have been applied to
the synthesis of thioacrolein and related reactive unsaturated thioaldehydes[ Thus the ~ash ther!
molysis of diallyl sul_de ð63CC398\ 65CJC426\ 71JA201Ł or diallyl sulfoxide ð89TL4992Ł yielded thioac!
rolein\ which was characterized at low temperature\ as DielsÐAlder adducts with dienophiles\ or as
a mixture of its isomeric DielsÐAlder dimers "10# and "11# "Scheme 02#[ Thermolysis of the dimer
mixture\ which can be readily isolated and puri_ed\ provides a convenient source of pure thioacrolein
ð71JA201Ł[ Thioacrolein was also produced by the thermolysis of various cyclopropyl sul_des
ð67JA6325Ł[ The authors postulated a ring opening\ followed by a retro ene or 0\1!elimination
reaction to explain this unexpected result "Scheme 03#[ 0\1!Elimination from a dithiolane ð74TL4154Ł
or from the reaction product of 1!propen!0!thiol and Ebselen oxide "12# "Scheme 04# ð78JOC0981Ł
has been used to generate thioacrolein\ as has the photochemical method of Vedejs ð77JA4341Ł[
Direct sulfuration of acrolein has been used to prepare the thioacrolein dimers "10# and "11#
227 Thioaldehydes and Thioketones
ð72JHC0642Ł\ and the analogous dimers of thiomethacrolein may be the actual products from the
treatment of methacrolein with phosphorus pentasul_de\ rather than the thioaldehydes postulated
ð68JOC375Ł[
S S S
∆ S S
+
S

(21) (22)

Scheme 13

S
Cl

S –HX
SX SX S
• •

Scheme 14

O O
HS
NHPh S
N Ph
S 69%
Se Se
O O
(23)
Scheme 15

"ii# Electronically stabilized alkenyl thioaldehydes


Simple enamino thioaldehydes can be regarded as vinylogous thioamides\ and are stable for
months at room temperature ð70PS"09#0Ł[ The _rst example of this type of compound\ 2!dimethyl!
aminopropenethial\ was prepared by treatment of the corresponding aldehyde with P1S4 "Equation
"07## ð61OMR"3#310Ł[ Perhaps surprisingly\ this simple method has not been further applied to the
preparation of this type of compound[
P2S5
Me2N O Me2N S (18)

Muraoka et al[ have prepared a series of a!cyano!b!imino thioaldehydes by the condensation of


the anion of b!imino nitriles with potassium dithioformate "Scheme 05# ð71CL090Ł[
NH NH NH2
HCSS– K+, t-C5H11O– Na+
R R S R S
23–96%
CN CN CN
Scheme 16

A more versatile method for the synthesis of this class of compounds\ in moderate yields\ is a
modi_cation of the VilsmeierÐHaack reaction ð74CC0188\ 78JCS"P0#0130Ł[ Thus\ reaction of enamines
with phosphoryl chloride and DMF or N!methylformanilide\ followed by hydrolysis of the resulting
Vilsmeier salts with methanolic sodium hydrogensul_de\ provided a wide range of stable thio!
aldehydes "Scheme 06#[ Proton NMR data showed that these compounds existed exclusively as the
Thioaldehydes 228
enamino thioaldehyde tautomer\ rather than the alternative imino thioaldehyde or iminovinyl thiol
form ð78JCS"P0#0130Ł[ A related approach has been applied to the synthesis of a diselenovinyl
thioaldehyde ð77JOC2418Ł[

R2 R2 R2
+
POCl3, DMF NaSH
R1 R1 NMe2 R1 S
37–87%
R3R4N R3 R4 N R3 R4 N

Scheme 17

An interesting approach to the preparation of enamino thioaldehydes has been developed by


Holm and co!workers in connection with the synthesis of tetraaza macrocycles ð62IC1478\ 62JA502Ł[
Treatment of the 3!phenyldithiolium cation with one equivalent of a diamine produced the enam!
inothial "13# in good yield[ This compound was then cyclized with further diamine to provide the
desired macrocycle "14# "Scheme 07#[ This method has been further developed and applied to simple
monoamines by Quiniou and co!workers ð76BSF406Ł[ These workers have studied the reaction in
detail\ in particular the structures of the products and by!products of the reaction[ Isothiazolium
salts also react with amines to produce enamino thioaldehydes\ although in this case the products
formed depend upon the substitution pattern of the isothiazole and the exact conditions employed
ð74T0774Ł[ Reaction of the 3!arylthiazolium perchlorate "15# with benzylamine gave only the
N!methyl product "16# "Equation "08##[ In contrast\ the 2!phenyl compound "17# gave a mixture of
N!methyl and N!benzyl products when reacted with one equivalent of benzylamine\ and exclusively
the N!benzyl compound when three equivalents were used "Equation "19##[

H2N NH2 S S H2N NH2 N HN


S+
Ph Ph Ph Ph Ph
S 60–80% 40%
NH HN NH N

(24) (25)

Scheme 18

+
Ph NH2 Ph
N S
Ph (19)
S 51%
NHMe
(26) (27)

Ph
+
N 3 equiv. Ph NH2
S
(20)
S 39%
Ph NHBn
(28)

Activated alkynes undergo a ð2¦1Ł cycloaddition with 0\1!dithiole!2!thiones "18# to produce


thioformylmethylene dithioles "29#\ which were stable enough to be isolated but could not be puri_ed
"Equation "10## ð60CJC2188\ 61CR"C#512\ 64BSF"1#0324Ł[ This method can also be applied to benzyne\
resulting in the formation of the benzo!fused 0\2!dithiole ð63CR"C#148Ł[ A by!product of these
processes is the 0\5\5al3!trithiapentalene\ which can be formed by isomerization of the thioaldehydes
"see Section 2[97[3[1[4#[ The use of 0\1!dithiole!2!ones in this reaction results in the formation of
the 0\2!oxathiole!substituted thioaldehydes ð79BSF"1#429Ł[
MeO2C
S S dimethyl S
acetylenedicarboxylate
S MeO2C S (21)
85% S
Ph Ph
(29) (30)
239 Thioaldehydes and Thioketones
2[97[1[1[1 Thioaldehydes bearing an a\b!aryl or hetaryl substituent

"i# Simple aryl thioaldehydes


Many of the general methods described in the previous sections have been applied to the prep!
aration of thiobenzaldehyde "Scheme 08#[ Several substituted thiobenzaldehydes and simple het!
erocyclic thioaldehydes have also been prepared\ notably by the 0\1!elimination of Bunte salts
ð73CC811Ł or a!sulfonyl disul_des ð73CC0358Ł\ and by the direct sulfuration of aldehydes ð71JA2093\
77JA0865\ 80JOC6212Ł or acetals ð82CE42Ł[ In all these cases the products were unstable and were
characterized at low temperature or in the gas phase\ or trapped as DielsÐAlder or other adducts[
The Lewis acid!catalyzed cycloreversion of heterocycles "20# has also been used to generate aromatic
thioaldehydes for further reaction ð77MI 297!90Ł[
Ph S
Ts
S
Ph S
〈74CC409〉 S Ph

Ph 〈84CC1469〉
〈83T1487〉
Ph O S+ CO2Me
∆ 75%
∆ Et3N Ph
S Ph 92% S CO2Me
〈86JOC1556〉 hν LDA 〈85TL5265〉
84% 48% O
O
S
Ph SH
N
Ph TMS-S-TMS, additive
Se
〈8 2JA3104, 88JA1976, 85–96% O
91JOC7323〉 〈87JA5549〉
Ni(acac)2, Ph3P TBDMS-OTf (see also 〈89JOC1092〉)
Ph Et3Al EtNPri2
O
39%
Ph S S8
S
O Et2NH Ph
56% S
〈92IZV160〉 15%
〈90JOC4200〉
∆ 97% CsF 90%
Ph PPh3 Ph SAc

〈88CL1145〉 SAc
Cl
Ph S 〈88JA5452〉
S Ph
Ph S
O S
〈82CC1029〉 TMS
〈85TL1947〉
LDA = lithium diisopropylamide
Scheme 19

Ar S Ar

S NH

Ar
(31)

The only stable thiobenzaldehyde to have been prepared\ isolated\ and fully characterized is the
highly sterically crowded 1\3\5!tri!"t!butyl#thiobenzaldehyde "21#\ synthesized by Okazaki et al[ by
the addition of an aryllithium to ethyl thionoformate "Equation "11## or the sulfuration of hydrazone
"22# "Equation "12## ð71CC0076Ł[ This thiobenzaldehyde is quite stable\ and has been used to study
the reactions of the thioformyl group ð73TL738\ 73TL762Ł[ More recently\ Okazaki and co!workers
Thioaldehydes 230
have prepared deuterated 1\3\5!tri!"t!butyl#thiobenzaldehyde in 26) yield by reaction of the aryl!
lithium with O!cholesteryl deuterothionoformate ð76BCJ0926Ł[ Crossley and Curran reported the
preparation of thioveratraldehyde from the corresponding aldehyde by reaction with H1S and HCl\
but the data presented suggest that this compound was probably not monomeric ð63JCS"P0#1216Ł[

But But
S
Li
OEt S
(22)
56%
But But But But
(32)

But But

NNH2 S2Cl2, Et3N S


(23)
40%
But But But But
(33) (32)

"ii# Electronically stabilized aryl thioaldehydes


In contrast to the low stability of simple aryl and hetaryl thioaldehydes\ those compounds in
which the C1S double bond can be stabilized by interaction with a nitrogen lone pair are often
perfectly stable compounds[ This exactly parallels the stability of the vinylogous thioamides
described in the previous section[ Thus\ the _rst thioaldehyde to be prepared and isolated was the
dipyrrylmethane "23# prepared by Woodward et al[ as an intermediate in the synthesis of chlorophyll
a ð59JA2799\ 89T6488Ł[ This compound was prepared from the corresponding aldehyde "24# via the
iminium salt "25#\ which was hydrolyzed by treatment with hydrogen sul_de and sodium methoxide
"Scheme 19#[ The thioaldehyde "23# was remarkably stable\ crystallizing from benzene:cyclohexane
and surviving storage for 29 years with only slight decomposition ð89T6488Ł[
O EtHN+ S

HN HN HN
EtNH2, AcOH H2S, NaOMe
HN HN HN
94% 86%
O O O

CO2Me CO2Me CO2Me


MeO2C MeO2C MeO2C
(35) (36) (34)

Scheme 20

Following this precedent\ a number of stable hetaryl thioaldehydes have been prepared using
related methods[ Reid and co!workers have developed a modi_cation of the Vilsmeier reaction
which has proved to be applicable to a number of heterocyclic systems ð55CC390\ 69JCS"C#034\
62JCS"P0#546\ 76KGS0583\ 89KGS0174Ł[ As an example\ reaction of the indolizidine "26# with phosphoryl
chloride and DMF produced the Vilsmeier salt "27#[ This was then treated directly with aqueous
sodium hydrogensul_de to produce the thioformyl indolizidine "28# in 75) yield "Scheme 10#
ð55CC390\ 69JCS"C#034Ł[ A modi_cation of this procedure\ utilizing dimethyl thioformamide in place
of DMF\ has proved to give better results in some cases ð58JCS"C#802Ł[ McKenzie and Reid also
demonstrated that the thioaldehydes could be prepared via an enol ether\ although the thiolysis
only proceeded in 22) yield ð55CC390\ 69JCS"C#034Ł[
Direct sulfuration of heteroaromatic aldehydes has been employed for the preparation of stable
thioaldehydes[ McKenzie and Reid _rst described the reaction of formyl indolizidines with P1S4 as
an alternative to the Vilsmeier synthesis\ the thioaldehydes being formed in good yield "Equation
"13## ð69JCS"C#034Ł[ Becher et al[ have demonstrated that treatment of o!amino heteroaromatic
231 Thioaldehydes and Thioketones

POCl3, DMF NaSH

N N 86% N
+
NMe2 S
(37) (38) (39)

Scheme 21

aldehydes with either hydrogen sul_de:hydrogen chloride or Lawesson|s reagent generated the
corresponding stable thioaldehydes "Equation "14## ð80S598Ł[ They also showed that these com!
pounds could be prepared in good yield by the one!pot reaction of o!azido aldehydes with hydrogen
sul_de\ _rst in the presence of piperidine to catalyze reduction of the azide\ then with an excess of
hydrogen chloride to catalyze the thionation of the aldehyde[

P2S5, C5H5N
(24)
N 59% N

O S

Ph O Ph S
H2S, HCl
(25)
N N
N NH2 55%
N NH2

2[97[1[1[2 Thioaldehydes bearing an a\b!alkynic bond


The only example of an a\b!alkynic thioaldehyde reported is propynethial\ which was prepared
by the gas phase pyrolysis of dipropynyl sul_de\ a reaction optimized by Korolev and co!workers
ð76IZV1210\ 76IZV1287\ 81MC56Ł[ The compound has been characterized in the gas phase\ and as its
DielsÐAlder dimer ð72PS"06#36Ł[ The 23S compound has also been prepared ð71AJC0636Ł[

2[97[2 THIOKETONES
Thioketones are generally more stable than the corresponding thioaldehydes[ This is particularly
so for diaryl thioketones in which the C1S electron density is delocalized through both aromatic
rings[ Even the simplest of this class of compound\ thiobenzophenone\ is a relatively stable molecule\
and diaryl thioketones have been known for many years[ However\ simple thioketones which are
not stabilized by electronic or steric factors are still highly reactive compounds which have frequently
been generated and trapped in situ\ or characterized at low temperature or in the gas phase[
One consequence of the greater stability of thioketones than thioaldehydes is that rather more
vigorous methods can be used for their formation without signi_cant decomposition of the products[
This\ combined with the very ready availability of ketones\ means that the predominant method for
the preparation of thioketones is the direct conversion of a carbonyl group\ or a simple carbonyl
derivative\ into a thiocarbonyl[ Various other methods have been used to synthesize thioketones\
but they tend to have been applied to only a few speci_c cases rather than being of general utility[
Early work in this area has been reviewed by Campaigne ðB!55MI 297!90Ł[

2[97[2[0 Dialkyl Thioketones


Mayer et al[ ð53AG"E#166Ł and Paquer ð61IJS"B#158Ł have reviewed the early progress in this area
and have discussed the preparation and physical and chemical properties of aliphatic thioketones[
Thioketones 232
2[97[2[0[0 Dialkyl thioketones by sulfuration of ketones

"i# Usin` hydro`en sul_de


The most widely used method for the conversion of aliphatic ketones into thioketones is reaction
with hydrogen sul_de in the presence of HCl[ However\ if this reaction is carried out at ambient
temperature the major product is often a `eminal dithiol[ These compounds can be isolated and
thermolyzed to give the thioketone "see Section 2[97[2[0[2[i#\ but more conveniently their formation
can be suppressed by conducting the reaction at low temperature\ generally −69>C to −79>C
"Scheme 11# ð56CB82Ł[ Working at low temperature has the added advantage that the thioketones
are usually formed as monomers rather than trimers\ the formation of which is catalyzed by acid at
higher temperatures ð62BCJ1142Ł[ The amount of trimer formed is also dependent on the substrate
used\ with greater steric hindrance favoring formation of the monomer[ Thus\ reaction of cyclo!
butanone with H1S and HCl gave exclusively a trimer\ whereas a series of relatively stable\ mono!
meric 1\1!dimethylcyclobutanethiones were prepared under identical conditions "Equation "15##
ð67RTC010Ł[ Increased steric hindrance also favors the formation of the thioketone rather than the
dithiol[ Dimers can sometimes be formed\ especially in those cases where steric hindrance results in
a slow reaction and disfavors trimer formation ð67T1178Ł[ A systematic study of the di}erent
products formed in the reaction of a series of aralkyl ketones has been conducted ð51JOC2659Ł[

HS SH O S
H2S, HCl, –25 °C H2S, HCl, –80 °C

32% 55%

Scheme 22

O S
H2S, HCl, 0 °C
(26)
40%

The reaction is commonly performed in methanol or ethanol\ but co!solvents such as ether can
be used[ Additives such as trialkyl orthoformates have also been employed\ and appear to allow the
reaction to be conducted at higher temperature without the formation of dithiols ð63JCS"P0#0683\
68TL1566Ł[ In the reaction of adamantanone with H1S and HCl in ethanol at −44>C an alternative
product\ the `eminal ethoxythiol "39#\ was formed in reasonable yield ð58CJC2604\ 69CJC2429Ł[ This
was converted into adamantanethione in excellent yield by heating under vacuum "Scheme 12#[

OEt
O S
H2S, HCl, EtOH, –55 °C SH 100 °C, 15 torr

57% 93%

(40)

Scheme 23

When applied to ketones bearing one or more a!hydrogen atoms there is the possibility of the
formation of the enethiol tautomer of the product thioketones[ With simple thioketones the enethiols
are not generally seen ð67RTC010Ł\ although the reaction of naltrexone is reported to give the
corresponding enethiol ð80JMC0181Ł[ The situation with b!oxothioketones is considerably more
complex "see below#[
A somewhat less acidic variant of this technique\ which uses anhydrous zinc chloride instead of
HCl\ has been applied to a series of bicyclic ketones by Vialle and co!workers ð79JOC1406Ł[ The
product formed was dependent on which isomer of the starting material was used\ with some of the
initially formed thioketone products undergoing rearrangement under the reaction conditions[
When applied to diketones this method can yield either monothio or dithio products\ depending
upon the precise conditions used[ Thus\ the monothiodiketone "30# was prepared from the diketone
by reaction with H1S and HCl at −69>C for 1[4 h "Equation "16## ð65TL3186\ 66T2978Ł[ Reaction of
various cyclobutanediones with H1S in the presence of HCl and zinc chloride produced either the
233 Thioaldehydes and Thioketones
dithiones selectively ð60JOC2774Ł\ or a mixture of the mono! and dithiones ð76JOC1043Ł\ depending
upon the exact conditions used[
O O O S
H2S, HCl, –70 °C
(27)
35–65%

(41)

Enolizable b!oxo thioketones can also be prepared by this technique\ thioacetylacetone being
formed from acetylacetone in excellent yield under carefully controlled conditions ð66ACS"B#39Ł[
Interesting selectivity was observed when the same conditions were applied to nonsymmetrical
diketones ð66JOC2012Ł[ 1!Acetylcyclohexanone reacted selectively at the endocyclic carbonyl "Equa!
tion "17##\ whereas the analogous cyclopentanone gave the exocyclic thione as the only product in
low yield "Equation "18##[ The selectivity for the endocyclic carbonyl in cyclohexanones appears to
be general for several substituted compounds ð75JA529Ł[ b!Keto esters ð61T4812\ 63T2642\ 65RTC061Ł\
b!keto thioesters ð57T4212Ł\ b!keto dithioesters ð62BSF"1#0862Ł\ and b!keto lactones and thiolactones
ð58T4692Ł react selectively at the ketone carbonyl to give good yields of the b!thioxo compounds[
These b!oxo thioketones can exist in a number of tautomeric forms\ the relative amounts of which
depend upon a number of factors\ including solvent\ temperature\ and molecular structure[ The
di}erent tautomers can be interconverted by photolysis at suitable wavelengths "Equation "29##
ð68JCS"P1#0421Ł[ This area has been extensively investigated by Duus and co!workers\ who have
studied the tautomerism in detail and proposed a model to explain the observations ð71JA4811\
72JCS"P1#0210\ 75JA529Ł[ A more detailed discussion of this complex area is given in the review of the
thiocarbonyl group by Duus ð68COC"2#262Ł[

O O S O

H2S, HCl, –40 °C


(28)
30–39%

O O S
O
H2S, HCl, –40 °C
(29)
4.5%

H H
S O hν (353 nm) S O
(30)
hν (288 nm)

Hydrogen sul_de will also react with ketones under basic conditions[ The usual product formed
in this case is the dithiol\ but some ketones give low yields of thioketones "Equation "20##
ð52AG"E#269Ł[ 0\2!Diketones react to give the corresponding monothiodiketones\ predominantly in
the enethiol form\ but 0\1!diketones are reduced to either the a!hydroxy ketone or the monoketone[

O S

H2S, BunNH2, DMF


(31)
22%

"ii# Usin` phosphorus!based rea`ents


Another widely used reagent for the conversion of ketones into thioketones is phosphorus
pentasul_de[ The most commonly used conditions for this reaction involve heating the ketone and
P1S4 in pyridine[ Good yields of the thioketone are generally obtained\ although the quantity of
P1S4 used must be calculated carefully\ as an excess can cause decomposition of the products
ð69CJC2429Ł[ Other solvents have also been employed e}ectively\ including toluene ð54MI 297!90Ł\
xylene ð81CJC863Ł\ and ethers such as DIGLYME ð62S038Ł[ The use of a polar solvent such as
DIGLYME generally results in a more rapid reaction\ suggesting the participation of a polar
Thioketones 234
intermediate[ The addition of bases such as sodium hydrogencarbonate ð62S038Ł further accelerates
the reaction\ providing support for an anionic species being the active reagent[ A wide range of
aliphatic thioketones have been prepared using variations of this method^ a selection is shown in
Table 0[

Table 0 Aliphatic thioketones prepared using phosphorus pentasul_de[

Thioketone Conditions Yield Ref.


(%)

S
Pyridine 90 70CJC3530
90 °C, 11 h

S
Pyridine 93 91JOC5932
F 90 °C, 11 h

DIGLYME, NaHCO3 70 73S149


S 120 °C, 5h

Pyridine 69 75JCS(P1)2513
S 110 °C, 30 min
O2

S DME, NaHCO3 85 80CB2255


RT, 65 h

S Pyridine 15 83JOC214
110 °C, 3 h

S
DIGLYME, NaHCO3 20 83JOC214
110 °C, 2 h

S
Pyridine 60 (Diels–Alder adduct) 90JCS(P1)3175
EtO2C CO2Et 110 °C, 1 h

As is the case with other reagents\ the reaction of P1S4 with diketones can result in the formation
of either monothio or dithio compounds\ depending upon the conditions used[ Thus the sulfuration
of cyclobutanedione "31# gave either the monothiodione "32# or the dithione "33# as the major
product\ depending on the amount of P1S4 used and the reaction time ð56JOC0451Ł[ A by!product\
the thione "34#\ was formed in one of the reactions "Scheme 13#[ Similar mixtures of mono! and
dithiodiketones have been observed in other systems ð81CJC863Ł[ An interesting example is the
reaction of P1S4 with a 1!keto!0\2!diamide[ The major product from this reaction was the ketodithio!
amide\ but a small amount of thioketone was also produced ð72LA0583Ł[
The preparation of the thioketone "35# has been reported by Lipkowitz and Mundy ð66TL2306Ł[
This compound could be prepared by reaction of the corresponding ketone with P1S4 ð68JOC375Ł\
but was also one of the products formed in the reaction of methyl vinyl ketone with P1S4 in pyridine\
together with a smaller amount of the regioisomer "36# "Equation "21##[ Presumably the reaction
235 Thioaldehydes and Thioketones
initially produces methyl vinyl thioketone\ which then undergoes a DielsÐAlder reaction with
unreacted ketone[

P2S5 (0.45 equiv.) P2S5 (1 equiv.) S S


40 min 90 min
S O O O S S + S
40% 50% S S

(43) (42) (44) (45)


Scheme 24

P2S5, pyridine
+ (32)
O O O
S
(46) 13% (47) 1%

Although P1S4 is a versatile reagent for the synthesis of thioketones\ in some circumstances the
conditions required for the reaction to proceed are such that the initially formed thioketone
decomposes or undergoes further reaction[ In this way\ treatment of the diketone "37# with P1S4 in
re~uxing pyridine did not give the desired dithioketone\ but the dithiolactone "38# "Equation "22##
ð72JOC3371Ł[ In contrast\ the dithioketone could be prepared\ in 69) yield\ by using H1S\ HCl\ and
zinc chloride[ A similar rearrangement product was isolated from the reaction of P1S4 with the
cyclobutanedione "31# ð56JOC0451Ł[ Interestingly\ this product could be converted into the desired
cyclobutanedithione "33# by photolysis in nonprotic solvents ð79CC132Ł[

P2S5, pyridine
O O (33)
S
S

(48) (49)

Lawesson|s reagent "49# has also been used for the conversion of ketones into the corresponding
thioketones ð67BSB112\ 79CB1144\ 80TL0676Ł\ and its use has been reviewed ð74T4950Ł[ In some cases\
enethiols can be formed ð71T882Ł\ and di!t!butyl dithiet "40# was formed in the reaction of "49# with
the monothiodiketone "41# "Equation "23## ð71JCR"S#203Ł[ Interestingly\ neither the dithiet "40# nor
the thioketone "41# could be prepared directly from the diketone ð67NJC220Ł[

S S
MeO P P OMe
S S

(50)

But But (50), ∆ But But


(34)
45%
O S S S
(52) (51)

"iii# Usin` other rea`ents


A number of other sulfuration reagents have been employed in the synthesis of simple thioketones\
although they have not been widely utilized[ Bis"trimethylsilyl# sul_de\ in combination with either
boron trichloride ð71JA2093Ł or trimethylsilyl tri~ate ð80JOC6212\ 82TL762Ł\ has been used to prepare
Thioketones 236
a range of thioketones in good yield[ Several tin sul_des have also been used in conjunction with
boron trichloride ð71JA2093Ł[
A slightly di}erent approach has been applied to the synthesis of thiodimedone from dimedone
ð63ACS"B#0966Ł[ Reaction with PCl2 gave the vinyl chloride "42#\ which\ upon reaction with sodium
sul_de and acidi_cation\ gave thiodimedone "43#\ which exists exclusively as the conjugated enethiol
tautomer in solution "Scheme 14#[ The same method has also been used for the formation of acyclic
b!thioketo aldehydes ð62ZOR0606Ł[ A related technique has been applied to the preparation of
thioketones conjugated to a phosphonium ylide "Scheme 15# ð81TL4844Ł[

OH Cl i, Na2S SH
PCl3 ii, HCl

95%

O O O
(53) (54)

Scheme 25

O OTf S
(TfO)2O Na2S
But But But
70% 82%
PPh3 +PPh PPh3
3
Tf = trifyl

Scheme 26

2[97[2[0[1 Dialkyl thioketones by direct sulfuration of other compounds

"i# Acetals and enol ethers


A range of simple thioketones has been prepared by the reaction of dimethyl or diethyl ketals
with H1S in the presence of HCl\ tosic acid\ or zinc chloride ð52CB2985\ 61CJC2812\ 81TL5040Ł[ This
method is particularly mild\ and gives the pure thioketones not containing any of the enethiol form
ð81TL5040Ł[ Similar reaction conditions can also be applied to enol ethers ð52CB2985Ł[

"ii# Hydrazones
Hydrazones have proved to be useful intermediates in the conversion of ketones into thioketones\
and have found particular application to the preparation of highly sterically hindered thioketones[
The thermal decomposition of triphenylphosphorylidene hydrazones "easily prepared from the
hydrazone itself# in the presence of elemental sulfur was used by de Mayo et al[ to prepare several
thioketones\ in varying yields "Scheme 16# ð67TL3510Ł[ However\ in a number of cases this method
failed\ particularly with enethiolizable compounds[

PPh3
NH2 N
O H2NNH2, ∆ N Ph3PBr2, Et3N N S8, ∆ S

But But But But But But 83% But But


Scheme 27

An alternative method which has found wider application to the formation of sterically hindered
thioketones has been developed by Okazaki et al[ ð68TL2562\ 70BCJ2430Ł[ Reaction of hydrazones
with S1Cl1 provides thioketones directly\ probably via an unstable thiosul_ne "44# which eliminates
237 Thioaldehydes and Thioketones
sulfur in situ "Scheme 17#[ The yields of this process are generally good\ and it has been used
to prepare various thioketones as intermediates in the synthesis of hindered alkenes ð72TL4750\
73CB166Ł[

NH2 S
N S2Cl2, Et3N S S

But But 66% But But But But


(55)

Scheme 28

"iii# Imines
The reaction of N!phenylimines with H1S in the presence of benzoic anhydride provides pure
thioketones in good yield ð64ZN"B#659Ł[ b!Keto thioketones can be prepared from the corresponding
b!keto imines by this method[ The lithium or sodium salts of imines react with carbon disul_de to
form thioketones in good yield[ This method has been applied to the preparation of di!t!butyl
thioketone "Equation "24## ð63JCS"P0#0683\ 64BCJ1392Ł and other hindered thioketones ð66JCR"S#035\
73CB166Ł[

NH i, MeLi S
ii, CS2
(35)
But But 100% But But

"iv# Enamines
Enamines can be converted into thioketones in good yield by reaction with H1S ð59BCJ0632Ł[ This
method can be used to prepare\ in monomeric form\ thioketones "e[g[\ cyclohexanethione# which
tend to form trimers under other conditions[ The reaction has been extended to the synthesis of b!
thioxo esters*in this case tri~uoroacetic acid is used as an additive ð68JOC2160Ł[

"v# Miscellaneous compounds


An interesting approach to the preparation of isotopically labeled thioketones from labeled
elemental sulfur has been developed by Klages and Voss ð66AG"E#614Ł[ Heating a selenoketone with
elemental sulfur in an ampoule results in formation of the thioketone by sulfurÐselenium exchange[
Direct sulfur exchange of thioketones with labeled sulfur is also possible under similar conditions*
an equilibrium mixture is obtained\ so the use of an excess of labeled sulfur should allow a good
conversion to the labeled thioketone[
Middleton et al[ have developed several novel methods for the preparation of per~uorothioketones
ð50JA1478\ 54JOC0264Ł[ Reaction of bis"per~uoroisopropyl#mercury with re~uxing sulfur vapour gave
a 59) yield of hexa~uorothioacetone\ a reasonably stable but highly reactive compound which
dimerizes in the presence of a base "Scheme 18#[ This type of compound can also be prepared in
very good yield by the reaction of per~uoroalkyl iodides with phosphorus pentasul_de at re~ux
"Equation "25##[

CF3
F F3C CF3
S8, ∆ S
Hg CF3 base
S S
60% F3C CF3
F3C CF3 F3C CF3
F

Scheme 29
Thioketones 238
I S
F
F3C P 2S 5 , ∆ F3C
CF3 CF3 (36)
F 92% F
F F

A number of a\a!dioxo thioketones have been generated by the reaction of b!diketones with
dithiobissuccinimide and pyridine[ The resulting thioketones were not stable\ but could be trapped
as DielsÐAlder adducts ð76JOC058Ł[

2[97[2[0[2 Dialkyl thioketones by other methods


Although the techniques described above are by far the most widely used for the synthesis of
thioketones\ a number of other methods have also been employed\ including several that have been
developed primarily for the formation of thioaldehydes "see Section 2[97[1[0#[

"i# 0\1!Elimination reactions


An early example of this approach to the synthesis of thioketones was the dehydro~uorination
of a per~uorothiol to produce\ in quantitative yield\ the per~uorothioketone "45# "Equation "26##
ð54JOC0264Ł[ Geminal dithiols eliminate H1S on heating\ and a range of aliphatic thioketones
have been prepared by this method ð55CB0660Ł[ Similarly\ elimination of ethanol from a `eminal
ethoxythiol has been used to synthesize adamantanethione "see Scheme 12# ð58CJC2604\ 69CJC2429Ł[
The reaction of a suitably activated Bunte salt with base has been used by Voss and co!workers to
prepare stable a!oxothioketones ð70LA09\ 72LA0583Ł\ and by Kirby and McGregor to synthesize
diethyl thioxomalonate ð89JCS"P0#2064Ł[ Diethyl thioxomalonate has also been prepared "as its dimer#
by the triphenylphosphine!promoted elimination from an a!chlorosulfenyl chloride ð68JOC0625Ł[

F S
SH
F3C NaF F3C
CF3 CF3 (37)
F 100% F
F F
(56)

The most widely used variant of the 0\1!elimination technique has been the cycloreversion of 1\1!
disubstituted 0\2!dithiolanes or derivatives\ under basic or pyrolytic conditions[ In general\ the
product from the reaction of a thioketal with butyllithium is the corresponding thiol\ formed by the
reduction of the _rst!formed thioketone by butyllithium ð71JOC2208Ł[ However\ in the case of
camphor thioketal the major product is thiocamphor\ apparently because this thioketone undergoes
deprotonation to form an enethiolate rather than being reduced[ Base!induced elimination from 0\0!
dioxo!0\2!dithiolane "46# has been employed by Schaumann and co!workers to prepare thiocamphor
"Equation "27## ð71AG52\ 72AG"E#44Ł[ Several of the methods used to generate thioaldehydes described
in Section 2[97[1[0[2 have also been applied to the preparation of thioketones "see Scheme 5 and
Equation "09## ð77CB0048\ 89CB066\ 89JOC3199Ł[ A related method\ the reaction of a\a!dibromo!
carbonyl compounds with EtOCS1−K¦\ has been used to prepare reactive a!oxo thioketones which
can be trapped as DielsÐAlder adducts ð64CB562\ 67ZN"B#306\ 70TL1860\ 89JCS"P0#2064Ł[

S LDA
S (38)
S 47%
O O

(57)

"ii# Formation of the a C0C bond


The Claisen condensation between a ketone and a thionoester has been widely employed for the
synthesis of b!oxo thioketones "Equation "28##[ Sodamide is commonly used as the base\ and the
249 Thioaldehydes and Thioketones
reaction has proved to be applicable to aryl methyl ketones and some aliphatic ketones ð66JCS"P0#0016\
66JOC2012\ 66S145Ł[ However\ for some aliphatic ketones the reaction is unsuccessful\ and t!butyl!
lithium is used as the base in order to achieve satisfactory results ð74S561\ 75JA529Ł[ The self!
condensation of ethyl thionoacetate produces a b!thioketo thionoester\ which exists largely in the
enethiol form ð61AJC146Ł[ The anion of acetonitrile can also be employed in this type of reaction\
the product being a rather unstable enethiol ð62LA0526Ł[

i, NaNH2
ii, S
O O S
EtO R2
(39)
R1 R1 R2

An interesting alternative approach has been reported by Hayashi and Midorikawa ð62TL1350\
64JAP"K#6438140Ł[ In this case\ condensation of the anion of ethyl trimethylsilylthioacetate with an
aromatic aldehyde produced the a!thioketo ester "47#\ which existed exclusively as the enethiol form
"48# "Scheme 29#[

TMS i, NaH, PhCHO S SH


S ii, HCl
Ph Ph
63% CO2Et CO2Et
CO2Et
(58) (59)

Scheme 30

"iii# Rin` openin` of heterocycles


Rhodanine "59# can be condensed with aldehydes to produce heterocycles "50#[ These compounds
undergo ring opening upon treatment with base to give thiopyruvic acids "51# in excellent yields
"Scheme 20#[ This approach has been applied to the synthesis of aromatic ð24JA0015Ł and hetero!
aromatic ð49JOC70\ 89EUP9268868Ł substituted thiopyruvic acids[ A similar fragmentation occurs with
thiazolidinediones ð37BSF0019Ł[ The cleavage of oxathiolanone "52# with sodium methoxide produces
the enethiol tautomer of methyl thiopyruvate "53# "Equation "39##[ This reaction is applicable to
aliphatic systems which cannot be accessed via rhodanine derivatives\ and has been applied to the
partial synthesis of the antibiotic griseoviridin ð74JOC2565Ł[

S S
S S S
RCHO NaOH
R R
NH NH
CO2H
O O
(60) (61) (62)

Scheme 31

S SH
Ph NaOMe
O Ph (40)
CO2Me
O
(63) (64)

1!Alkyl 0\2!thiazines undergo hydrolysis under very mild conditions to produce the enethiol
tautomers of b!thioketoamides in reasonable yields ð72CPB0818Ł[
Thioketones 240
"iv# Reduction of sul_nes
In the reaction of di!t!butyl sul_ne with Grignard reagents\ di!t!butyl thioketone was formed\ in
varying yield depending on the Grignard reagent used[ The best result was obtained with
t!butylmagnesium chloride\ which gave 36) of the thioketone ð68JOC1133Ł[ Phosphorus pentasul_de
can also be used as the reducing agent in these reactions ð72CB55Ł[

"v# Cycloreversion and related reactions


Although not as widely employed as in thioaldehyde chemistry\ DielsÐAlder adducts provide a
valuable source of thioketones for further reaction ð65JPR016\ 68TL1566\ 89JCS"P0#2064\ 89TL5072Ł[
The photolytic retro ð3¦0Ł reaction of a dithiolane has been used to prepare t!butyl thioglyoxal
ð67NJC220Ł[
Retro ð1¦1Ł reactions\ often of thioketone dimers\ have also been used to prepare monomeric
thioketones ð54JOC0264\ 62BCJ2174\ 75JA2700Ł^ this area has been reviewed ð71AG"E#114Ł[ Cyclic trimers
of thioketones can be pyrolyzed to give the monomeric compounds in good yield\ sometimes as
mixtures with the enethiol tautomer ð63JOC1498Ł[ The retro ene reaction of allyl sul_des is also a
convenient source of reactive thioketones ð63CC398\ 65CJC426\ 89TL5072Ł[ The hetero!Cope rearrange!
ment of the disul_de "54#\ readily formed by the oxidation of thiocamphor with chloramine T\ gave
the dithione "55# as a single isomer in excellent yield "Scheme 21# ð62JCS"P0#1755Ł[ This reaction
provides a novel method for the a\a?!coupling of thioketones[ The thio!Claisen rearrangement has
also been employed in the formation of a C0C bond a to a thioketone[ Thus the reaction of
thioketones with allyl bromide and sodium hydride gives allyl vinyl sul_des\ which upon heating
rearrange to a!allyl thioketones ð66BSF577Ł[ An allenic thioketone was produced by a similar
sequence of reactions using propargyl bromide[

chloramine T ∆ S
S
50% S S 88%
S
H
H
(65) (66)
Scheme 32

"vi# Miscellaneous methods


The reaction of sulfur vapour with hexa~uoropropene at elevated temperature provides an
e.cient synthesis of hexa~uorothioacetone\ largely as a monomer ð53JCS1833Ł[ Vedejs has applied
the photofragmentation reaction of phenacyl sul_des to the preparation of a macrocyclic thioketone
ð73ACR247Ł[ 0\1!Dithiones have been prepared by the photolysis of cyclic polysul_des\ the product
being trapped with dienophiles "Scheme 22# ð76TL3722\ 78TL1844Ł[ Photolysis of the corresponding
cyclic selenopolysul_de produced a mixture of the 0\1!dithione and 0\1!selenoxothione[ A number
of thermolytic methods have been applied to the synthesis of aliphatic thioketones ð71CB381\ 89TL2460\
80T3816Ł[

S S S S CN
hν CN
O S O O
85%
S S S S

Scheme 33

An unusual spirocyclic thioketone was obtained as one product from the reaction of a polycyclic
dithietane with triphenylphosphine ð89JA2918Ł\ and an interesting trithiocarbonyl compound was
formed from the reaction of a dithiomalonamide with an azodicarboxamide ð81LA816Ł[ A number
of other rearrangement reactions have given thioketones as products ð66AG"E#611\ 72JA5040\ 80CB0636\
241 Thioaldehydes and Thioketones
82CB62Ł\ occasionally in good yield\ but none appear to be generally applicable[ The electrolysis of
alkenes using a sulfurÐcarbon cathode produces a range of products\ including thioketones\ but
again this technique appears to be of limited synthetic use ð89BSF316Ł[ The photolysis of thiocarbonyl
compounds has been extensively studied\ and in several reactions new thioketones form at least
some of the products[ However\ these reactions appear to be more of theoretical interest than useful
synthetic methods\ and the reader is referred to a review of this work by Coyle for further details
ð74T4282Ł[
The enethiol tautomers of thioketones have been prepared by the cleavage of vinyl sul_des with
alkali metals in ammonia ð69RTC482Ł\ and by the addition of H1S to alkynes ð52JA852Ł[ The reaction
of alkynes with elemental sulfur has been used to prepare a number of 0\1!dithietes\ which appear
to exist in the cyclic form rather than as 0\1!dithiones ð59JA0404\ 50JA2323\ 68H"01#0042\ 82TL004Ł[

2[97[2[1 a\b!Unsaturated Thioketones


As is the case for alkyl thioketones\ the most widely applied method for the synthesis of a\b!
unsaturated thioketones is the direct conversion of a carbonyl group or a derivative into a thio!
carbonyl group[ However\ given the generally greater stability of the unsaturated\ and particularly
diaryl\ compounds\ the phosphorus!based reagents P1S4 and Lawesson|s reagent are more commonly
used than the milder\ but less convenient\ combination of H1S and HCl[

2[97[2[1[0 Thioketones bearing an a\b!alkenic bond


As in Section 2[97[1[1[0\ this section covers only those thioketones conjugated to a C1C double
bond^ molecules in which the thioketone is conjugated to other types of double bond are covered
in Section 2[97[2[0 above[
Simple acyclic unsaturated thioketones are very reactive compounds which readily undergo DielsÐ
Alder dimerization[ Cyclic enethiones which cannot self!condense in this manner tend to be rather
more stable\ and can usually be isolated\ especially if the thiocarbonyl group is sterically hindered[
As is the case for the corresponding thioaldehydes\ the presence of one or two vinylic atoms which
can donate a lone pair into the C1S bond results in relatively stable compounds "vinylogous
thioamides\ thioesters\ and dithioesters#[ A special class of this kind of molecule is typi_ed by
pyridin!3!thione^ in this compound the thiocarbonyl group is cross!conjugated to a heteroatom\
resulting in a highly stable system\ many examples of which have been reported[ In this section the
synthesis of these three classes of compound will be discussed separately\ although many of the
methods utilized are common to all three[

"i# Simple alkenyl thioketones


Early work in this area has been described in a review by Paquer ð61IJS"B#158Ł[ Hydrogen
sul_de:hydrogen chloride has been used for the synthesis of a number of unsaturated cyclic thio!
ketones containing three! to six!membered rings ð61BSF2027\ 74RTC8Ł[ As described above "see
Section 2[97[2[0[0[ii\ Equation "21##\ the reaction of methyl vinyl ketone with P1S4 in pyridine
resulted in the formation of a mixture of DielsÐAlder adducts\ each containing one molecule of the
starting material and one molecule of the thioketone ð66TL2306Ł^ a similar result has been observed
in the reaction of a dialkenyl ketone ð77CL606Ł[ However\ P1S4 in a variety of solvents has been
successfully applied to the preparation of a number of cross!conjugated thioketones derived from
steroids "Equation "30## ð64CC446\ 68JCS"P0#0055Ł\ as well as to simple acyclic enethiones ð77JOC221Ł
and diphenyl cyclopropenethione ð53BCJ0786Ł[ Tropothione\ and several more stable analogues
bearing a lone pair!donating substituent at C!1\ have been synthesized using P1S4\ alone or in
combination with triethylamine ð65HCA636\ 76TL192\ 89CL452Ł[ P1S4 in toluene at room temperature
has been used to prepare unsaturated thioketones in good yield from propargylic alcohols
ð76CL0188Ł[ This process is selective for reaction and rearrangement of the propargylic alcohol
rather than reaction of a ketone also present in the molecule "Equation "31##^ the mechanism of the
process is not clear[
Thioketones 242
O O

H P2S5, RT H
(41)
70%
H H H H
O S

OH
Ph Ph S
P2S5, RT
Ph Ph (42)
Ph 85%
Ph
O
O

Lawesson|s reagent "49# has been employed extensively for the formation of a\b!alkenyl thio!
ketones[ The reaction is generally conducted in toluene at or above room temperature\ and proceeds
in good yield ð71T882\ 89JMC456\ 89SC602Ł[ THF has also been used as the solvent ð81S640Ł[ When
applied to acyclic systems the products are often isolated as dimers ð81MI 297!90Ł[ Davy|s reagent
"56# has been used with some success "Equation "32##^ the dithione can also be prepared by using a
longer reaction time ð80CB0286Ł[ The combination of "TMS#1S and TMS!OTf can be used to
synthesize acyclic and cyclic enethiones in moderate yield ð82TL762Ł[ Thioacetic acid has also been
used as a sulfuration reagent in combination with a strong acid catalyst ð70S25Ł[ The mechanism of
this process is not certain\ although performing the reaction in an alcoholic solvent resulted in the
isolation of a bis"thioester#\ which could then be converted into the thioketone in good yield using
a strong acid in dichloromethane[

O S
Ph Ph (67), PhMe, ∆, 1 h
Ph Ph
(43)
Ph Ph 58% Ph Ph
O O

S S
MeS P P SMe
S S

(67)

A number of other methods have been used for the formation of a\b!alkenyl thioketones\ although
none has found wide application[ As mentioned above\ acyclic thioketones of this type readily
dimerize\ and these dimers have been employed as sources of the monomers by the retro DielsÐ
Alder reaction*the monomers can then undergo further reaction "Scheme 23# ð81MI 297!90Ł[ The
reaction of the ketone "57# with an excess of P1S4 resulted in the formation of the phosphorus!
containing bicycle "58#[ Thermolysis of this compound generated an alkenyl thioketone\ which could
be trapped with dienophiles "Scheme 24# ð71TL0152\ 77CL606Ł[

Ar
O
(50)
Ar [dimers]
35–44% 37–50%
S

Scheme 34

Ando and co!workers have developed a novel Lewis acid!promoted rearrangement of alkenic
episul_des which forms cyclopentenethiones in moderate yield "Equation "33## ð78JOC3559Ł[ They
have also applied a similar rearrangement to the preparation of an allenic cyclobutanethione in low
yield ð78TL3160Ł\ and to other systems ð78TL3714Ł[ A number of other rearrangement processes have
given rise to alkenic thioketones ð79JA5523\ 79NJC692\ 70AG"E#469Ł[
243 Thioaldehydes and Thioketones
Ph Ph
Ph
O CN CN
P2S5, Et3N, CS2 ,∆
But
Ph But 20% P 96%
But S S But S
S
(68) (69)

Scheme 35

S
Ph
S TMS
Ph BF3•Et2O
Ph (44)
Ph 35%
TMS

a\b!Alkenyl thioketones have also been prepared from thioketones by aldol reaction with an
aldehyde followed by dehydration ð54MI 297!90Ł\ but as this reaction does not involve formation of
the thioketone function\ these reactions will not be discussed in detail in this chapter[

"ii# Electronically stabilized a\b!alkenyl thioketones


A wide range of compounds in which the thioketone is stabilized by conjugation to a heteroatom
have been reported^ the synthesis and properties of enamino thioketones ð77ZC234Ł and routes to
stabilized cyclohexenethiones ð75MI 297!90Ł have recently been reviewed[ An area that has received
considerable attention is that of derivatives of squaric acid\ for example the dithione "69#\ prepared
by sulfuration of the corresponding diketone "Equation "34## ð63S467Ł[ This is a complex area\ a
full description of which is beyond the scope of the current work^ for a detailed overview of the
area\ the review by Schmidt should be consulted ð79S850Ł[

NMe2 NMe2
P2S5
O NMe2 S NMe2 (45)

O S
(70)

Another complex area is that of linear multisulfur systems and related compounds[ The simplest
of this class of molecules\ 0\5\5al3!trithiapentalenes\ can be regarded either as bicyclic systems
containing tetravalent sulfur "60# or as a mixture of the isomers "61# and "62# in equilibrium
"Equation "35##[ For the purpose of this review the structure "60# will be taken as the best description
of these molecules\ the synthesis of which is discussed in Section 2[97[3[1[4[ The situation is more
complex with four! and _ve!sulfur systems\ for example "63#\ prepared by the action of P1S4 on the
corresponding ketone "Equation "36## ð60BSF3318\ 66CC740Ł\ the structures of which show signi_cant
SÐS interaction ð69ACS0353\ 60ACS2466\ 62ACS1406Ł[ For a detailed discussion of the structures\ reac!
tivity\ and synthesis of this type of compound\ the review by Lozac|h should be consulted
ð73CHEC"5#0938Ł[
S S S

(71)

S S S S
S S
(46)

(72) (73)
Thioketones 244
S S O S S P2S5 S S S S S
Ph Ph Ph Ph (47)
63%

(74)

Phosphorus pentasul_de has been used to prepare a variety of electronically stabilized thioketones\
including vinylogous thioamides "Equation "37## ð60BAP438\ 78MI 297!91Ł\ doubly vinylogous thio!
amides ð80KGS0321Ł\ and triply vinylogous thioamides "Equation "38## ð70HCA1258Ł[ Compounds
stabilized by the presence of two vinylic heteroatoms have also been prepared by this method
ð71BRP1970694\ 80AG"E#760Ł\ as have various squaramide derivatives ð65S334\ 66CB1495\ 68S250Ł and
cyclopropenethiones ð73AG"E#618Ł[
Me2N O P 2S 5 Me2N S
(48)
22%

O S
P2S5, Et3N
(49)
10%
NPri2 NPri 2

Lawesson|s reagent "49# has been applied to the synthesis of enamino thioketones ð68S830\
76TL5350Ł\ and its use has been reviewed ð74T4950Ł[ The optimum conditions for the formation of
this type of compound appear to be reaction at room temperature with dimethoxyethane as the
solvent\ although heating in toluene has also proved to be e}ective ð81MI 297!91Ł[ A number of
stabilized dithioketones have been prepared by Sandstrom and co!workers by reaction of the
dioxygen analogues with Lawesson|s reagent "Scheme 25# ð80JOC0891\ 80JOC3808Ł[ These compounds
are highly polarized\ with signi_cant electron transfer from nitrogen to sulfur taking place\ and may
be better described by formula "64#\ especially as "65# is reported to have a large twist angle about
the nominal C1C bond ð80JOC0891Ł[ These workers have also developed a sulfur analog "66# of
Lawesson|s reagent which they claim to be more stable and easier to handle ð80JOC0891Ł[

(50)
O O S S S S–
Bn Pri 82% Bn Pri Bn Pri
N N N N N +
N

(76) (75)

Scheme 36

S S
MeS P P SMe
S S

(77)

Ethoxycarbonyl isothiocyanate has been used to prepare monothio derivatives of squaric acid
diamides "Equation "49## ð67S720Ł[ This reaction is unsuccessful for compounds containing free NH
groups\ as in this case heterocycles are formed\ but the reagent may be of wider utility than has
been demonstrated to date[

O O
EtOCONCS, MeNO2
Me2N O Me2N S (50)
54%
NMe2 NMe2
245 Thioaldehydes and Thioketones
Iminium salts can be hydrolyzed e.ciently by reaction with H1S and catalytic amine base to
produce the corresponding thioketone ð67ZOR555\ 68ZOR71Ł[ This reaction has been used in the
preparation of amine!stabilized cyclopropenethiones "Equation "40## ð65S581\ 80CB554Ł and of dithio!
vinyl thioketones ð64JPR026Ł[ The additionÐelimination reaction of vinylic chlorides with sodium
sul_de has also been applied to the formation of cyclopropenethiones ð62JA2932Ł and acyclic
enaminothione "67# "Equation "41## ð80LA000Ł[
+
NMe2 S
H2S, pyridine
(51)
83%
Ph NMe2 Ph NMe2

Cl S
Na2S
+ (52)
Me2N NMe2 60% Me2N NMe2
(78)

A number of the methods described in detail in Section 2[97[1[1[0[ii have been employed to
prepare stabilized thioketones[ Isothiazolium salts can be opened by hydride reagents to give
enamino thioketones in good yield "Equation "42## ð77SC0736Ł^ a similar compound has been
observed as a by!product in the preparation of pentalenes ð68JCS"P0#1239Ł[ The thiazolidine derivative
"68# can be opened with an enaminonitrile to produce the cyclic thione "79# "Equation "43##
ð89JCS"P0#2992Ł[ A closely related reaction has been applied to the synthesis of pyridin!3!thiones
ð73JHC0334Ł[ The cycloaddition reaction of 0\1!dithiole!2!thiones with alkynes has also been suc!
cessfully used for the synthesis of thiocarbonylmethylene dithioles "Equation "44## ð61JCS"P0#30\
79BSF"1#429\ 81MI 297!92Ł[

Et
N+ S NaBH4, –20 °C EtHN S
(53)
90%

S S
Ph NH2 Ph
NC NC
S KOBut,
(54)
N 68% N
S H H
(79) (80)

CO2Me
S S
S DMAD S S
CO2Me (55)
65% S
Et Et

DMAD = dimethyl acetylenedicarboxylate

Carbon monosul_de undergoes cycloaddition with ynamines to produce amino cyclo!


propenethiones in reasonable yield ð73AG"E#618Ł[ Several other methods give rise to electronically
stabilized thioketones\ but none have been widely applied ð63ACS"B#256\ 63CL0090\ 80SUL102\ 80TL4908Ł[
Enamino thioketones can also be formed from the reaction of amines with b!thioxo aldehydes
"Equation "45## ð62ZOR0606\ 89ZC136Ł[ The compounds can be isomerized by heating "Equation "46##\
the reaction proceeding through an intermolecular mechanism ð78ZOR0754Ł[
SH S
CHO ButNH2
F 3C F3C NHBut (56)
Ph Ph

NH2 S S NH2
100 °C
(57)
F3C F3C
Thioketones 246
"iii# Cross!conju`ated electronically stabilized thioketones
Pyridin!3!thiones\ pyran!3!thiones\ and thiopyran!3!thiones are stable thioketones in which the
C1S bond is stabilized by cross!conjugation with the heteroatom lone pair[ These compounds bear
many similarities to the simple electronically stabilized thioketones considered above\ but have been
very widely studied and are thus worthy of separate consideration[
The compounds are most commonly prepared from the corresponding oxo species by reaction
with P1S4[ N!Alkylpyridones have been popular starting materials\ the reaction being performed by
heating in the absence of solvent ð47JCS2509\ 53JCS1659\ 89JAN0049Ł\ in pyridine ð80EUP9351420Ł\ or
xylene ð64JCS"P0#521Ł[ The free NH compounds have also been employed successfully ð80DP038Ł[ A
number of 3!thiopyrones have been prepared^ in this case benzene has been the favoured solvent
"Equation "47## ð40JA299\ 48JCS1477\ 51JCS0746\ 67BCJ068Ł[ 3!Thiothiopyrones have also been syn!
thesized by this method ð56JOC2039Ł[ Silicon disul_de ð64JCS"P0#0224Ł and dimethyl thio!
formamide:acetic anhydride ð81JHC730Ł have been utilized for the conversion of 3!pyrones into
3!thiopyrones[ This transformation has also been achieved via the dichloride "70# "Scheme 26#\ a
method which has been demonstrated to give better results than the direct reaction with P1S4 in
some cases ð47JA5201Ł[ Pyridin!3!thiones have been formed from 3!halopyridines by treatment with
sodium or potassium hydrogensul_de "Equation "48## ð58ACS0864\ 65JOC2673\ 89EUP9265613\ 80CPB561\
80EUP9398053Ł[

O S

P2S5, PhH
(58)
85%
O O

O Cl Cl S

SOCl2 MeCOSH

47%
Ph O Ph Ph O Ph Ph O Ph
(81)

Scheme 37

Cl S
NO2 NH2
NaSH
(59)
66%
H2N N NH2 H2N N NH2
H

3!Thiothiopyrones have been synthesized by the reaction of alkynes with 4!unsubstituted 0\1!
dithiole!2!thiones ð79BSF"1#429Ł or 0\1!dithiole!2!iminium iodides and NaSH "Equation "59##
ð79BSF"1#428Ł[ This latter process may occur by rearrangement of a _rst!formed trithiapentalene\ as
it has been shown that these compounds rearrange to the thiopyran!3!thiones upon treatment with
NaSH or Na1S ð57CC752Ł[ Reductive ring opening of a suitably substituted dithiolium salt with
potassium borohydride gave a 3!thiothiopyrone as the _nal product\ formed by cyclization of the
intermediate enamino thioketone ð70TL3496Ł[

S
S S MeCCNEt2, NaSH
+ (60)
Ph NEt2 55%
Ph S NEt2

The cycloaddition of diphenyl cyclopropenethione with heterocycles has been utilized as a con!
venient synthesis of pyridin!3!thiones ð62CC722\ 63T3914\ 64JCS"P0#521\ 65JOC707Ł[ This reaction pre!
sumably involves initial 0\2!dipolar cycloaddition to give the intermediate "71#\ which then fragments
with loss of carbon oxysul_de to give the observed product "Scheme 27#[ Other heterocycles have
also been shown to undergo fragmentation and rearrangement to produce pyridin!3!thionesð73H"11#652\
73JHC0334Ł[ Alternative condensation reactions have produced 3!thiopyrones ð80EGP183830Ł and
247 Thioaldehydes and Thioketones
3!thiothiopyrones ð65TL3172Ł\ but these appear to be limited in their applicability[ Pyridin!3!thiones
can be formed in reasonable yield from the corresponding 3!thiopyrones by reaction with ammonia
ð67BCJ068Ł[
Me S
Ph S N Ph Ph
O S
S +
20%
N+ O– S N Ph
Me Ph Ph Ph Ph
Ph Me
(82)
Scheme 38

"iv# Thioquinones and thioquinone methides


A number of attempts to synthesize dithio!o!benzoquinone have been made using various cyclo!
reversion reactions^ in each case only the benzodithiet tautomer "72# was observed "Scheme 28#
ð71JOC0868Ł[ A steroid!derived benzothiet has been prepared by a retro DielsÐAlder reaction and
fully characterized ð64CC645\ 66JCS"P0#404Ł[ Similar results have been reported by de Mayo et al[\
although they describe the DielsÐAlder trapping of both mono! and dithio!o!benzoquinones with
dienes ð68JOC0866Ł[ The photolytic retro ð3¦0Ł reaction of the dithiolanone "73# produces the
dithioquinone "74#\ which interconverts with the trisdithiet "75# "Scheme 39#[ None of the cyclo!
hexanehexathione tautomer was observed ð81CB154Ł[ Dithio!p!benzoquinone and monothio!p!
benzoquinone have been prepared by pyrolysis of bis"allylthio# and allyloxy allylthio benzene
precursors and characterized in an argon matrix\ but decomposed on warming ð72CB162Ł[ An early
report of a diamine!stabilized dithio!p!benzoquinone ð92JCS0190Ł proved to be mistaken\ the product
being in fact a dithio!o!benzoquinone dimer ð76JOC0763Ł[
S

720 °C
S

S 690 °C S
O
S
S
540 °C
(83)
S
S O
S
Scheme 39

O
S S S
S S
S
hν S S hν S
O
S S S hν S
S S
S S S
O
(84) (85) (86)

Scheme 40

In contrast to the reactivity of monothio!p!benzoquinone\ monothioanthraquinone "76# has been


prepared by reaction of the diazo compound "77# with elemental sulfur "Equation "50##\ and is a
stable solid ð68JOC521Ł[ Compound "76# has also been synthesized by the reaction of anthrone with
a bis!succinimido disul_de ð76JOC058Ł[ Dithioanthraquinone\ however\ appears to be a much less
stable compound\ prone to polymerization\ and attempts to prepare it by the reaction of anthra!
quinone with Lawesson|s reagent have met with limited success ð75BSF172\ 75JOC300Ł[
Thioketones 248
O O

S, 150 °C
(61)
57%

N2 S
(88) (87)

o!Thiobenzoquinone methide "78# has been generated by photolysis of a dithiole dioxide "89#
ð67JOC2263Ł or a retro DielsÐAlder reaction ð80TL1902Ł\ but is more commonly produced by ther!
molysis of benzothiet "80# ð75TL4692Ł[ The compound has been characterized from photolysis of
"80# in an argon matrix ð78JST"087#296Ł\ but cannot be isolated\ and has been trapped as DielsÐAlder
adducts ð76AG"E#0935\ 89CB0032\ 80JHC462Ł or a ð3¦3Ł dimer "81# "Scheme 30#[ o!Thiobenzoquinone
methides stabilized by a dithiole ring have been prepared by the photolytic reaction of benzodithiole!
thione "82# with alkenes ð63CC766\ 63CL0328Ł^ these compounds cannot be obtained pure\ but exist
in equilibrium with their head!to!head dimers "83# "Scheme 31#[ The monomers can be trapped by
the DielsÐAlder reaction with dienophiles ð66CJC2652\ 68BCJ385Ł[ The related thionaphthoquinone
methide "84# has been prepared\ and is a stable monomer "Equation "51## ð65TL2704\ 71BCJ132Ł[
Thiobenzoquinone methides bearing nitrogen and oxygen\ as well as sulfur\ stabilizing groups have
also been prepared ð68BCJ2539\ 71LA03Ł[ A nitrile!substituted thiobenzoquinone methide has been
postulated as a decomposition product of an azidobenzothiophene\ and has been trapped with
alkenes ð74CC0330Ł[

O H O
O N Ph
S N Ph
S O hν
O S
(90) H O
43%

S

(89) S

S
S
(91) (92)

Scheme 41

S S S
S
S S
, hν S
S
90%
S S S S
(93) (94)

Scheme 42

S S

S
S cyclohexene, hν
(62)
S 100% S

(95)
259 Thioaldehydes and Thioketones
2[97[2[1[1 Thioketones bearing an a\b!aryl or hetaryl substituent
The chemistry of diaryl thioketones has been thoroughly explored\ and the early work in this
area has been reviewed ðB!55MI 297!90\ 62IJS062Ł[ Alkyl aryl thioketones are in many cases similar\
although less stable\ and the same methods of preparation can be applied as to diaryl compounds[
The synthesis of these compounds is discussed in Section 2[97[2[1[1[iv[ Aryl thioketones bearing an
a\b!alkenyl bond are generally more closely related to the alkenic compounds covered in Section
2[97[2[1[0 than to other aryl thioketones\ and will be covered separately in Sections 2[97[2[1[1[iÐiii[
Thioanthraquinones and naphthoquinone methides\ although strictly aryl thioketones\ have been
discussed with their benzo analogs in Section 2[97[2[1[0[iv[

"i# Simple alkenyl aryl thioketones


The reaction of simple alkenyl aryl ketones with P1S4 or Lawesson|s reagent ð67JOC3036\ 71CL682Ł
produces the DielsÐAlder dimer of the initially formed thioketone[ In the presence of an excess of
P1S4 a phosphorus!containing product "analogous to "58# in Scheme 24# is formed ð71TL0152\
74BCJ556Ł[ Heating either the dimer or phosphorus!containing adduct regenerates the unsaturated
thioketone monomer\ which can be trapped as a DielsÐAlder adduct with dienophiles[ This technique
for the retro DielsÐAlder generation of reactive alkenyl aryl thioketones\ and their trapping with a
wide range of dienophiles\ has been pioneered by Motoki and co!workers ð68JOC3040\ 79JOC816\
75BCJ2168\ 80JCS"P0#1170\ 81BCJ812\ 81JCS"P0#1832Ł[ Thioketones of this type can be trapped intra!
molecularly by a double bond\ although in circumstances where the intramolecular DielsÐAlder
reaction is slow\ dimers can still be formed ð89CC0554Ł[ Interestingly the thioketone "85# has been
prepared in monomeric form by sulfuration with rearrangement of a propargyl alcohol "Equation
"52## ð76CL0188Ł[ Presumably the product is su.ciently sterically hindered to disfavor dimerization[
Ph
P2S5 Ph S
Ph (63)
Ph 23% Ph Ph
OH
(96)

"ii# Electronically stabilized alkenyl aryl thioketones


A number of compounds of this type have been prepared by treatment of the corresponding
ketones with P1S4 ð54JCS21\ 70JCS"P0#1841Ł or Lawesson|s reagent ð70T086\ 78CZ189Ł[ Perhaps surpris!
ingly\ reaction of the phenylthio ketone "86# with either of these reagents produced a dimer "87#\
which on further heating rearranged to the more stable isomer "88#\ presumably by a retro DielsÐ
Alder ] DielsÐAlder route ð75BCJ224Ł[ Clearly the phenylthio substituent has only a weak stabilizing
e}ect upon the thioketone in this case[ The dimer "87# can function as a source of the monomeric
thioketone for further reaction "Scheme 32# ð78MI 297!92Ł[
SPh S

Ph

Ph S SPh
SPh SPh 78%
Ph (99)
(50) SPh
CO2Me
46% S
Ph O Ph S ,∆ SPh
(97) (98) 56% CO2Me

Ph S

Scheme 43

The additionÐelimination reaction of sodium sul_de or sodium hydrogensul_de with iminovinyl


chlorides or ethers has been used to prepare enamino aryl thioketones ð64ZOR0834\ 79JOC3746\
Thioketones 250
77JPR554Ł[ In a novel variant of this type of reaction\ the enone "099# was oxidatively sulfurated by
reaction with sodium sul_de and elemental sulfur to produce the b!oxo thioketone "090# "Equation
"53##\ which exists as a rapidly equilibrating mixture of tautomers ð78CC494Ł[ Iminium salts can be
hydrolyzed with H1S to produce stabilized thioketones ð79ZOR0731Ł[

S
O O
Na2S, S8, NaOH
O O (64)
O 65% O

(100) (101)

As described in Section 2[97[2[1[0[ii\ the reaction between a 0\1!dithiole!2!thione and an alkyne


gives rise to a dithiole!stabilized thioketone "Equation "54## ð58CJC1928\ 61JCS"P0#30\ 80JHC0134Ł[ In
some cases the product is mixed with a small amount of the isomeric trithiapentalene ð65BSF"1#019\
67ZOR1348\ 79ZOR772Ł[ The analogous reaction with alkenes also gives stabilized thioketones in good
yield ð61CL8\ 64JCS"P0#169\ 66ZOR1901\ 79ZOR332Ł[ Nucleophilic attack on 0\1!dithiolium salts ð54JCS21\
57CJC0744Ł or isothiazolium salts ð61JCS"P0#1294\ 62CJC2970\ 74T0774Ł produces enamino aryl thio!
ketones[ An interesting intramolecular variant of this reaction has been observed "Equation "55##
ð64TL1572Ł[ 0\1!Dithioles can be opened with amines to produce thioacyl ketene aminals "Equation
"56## ð68BCJ2539\ 75CB051Ł[ The same class of compounds has been prepared by the reaction of an
amidine with an aryl aldehyde and sulfur in a variant of the WillgerodtÐKindler reaction "Equation
"57## ð71T0562Ł[ Enamino aryl thioketones can also be formed by the reaction of amines with aryl
thioketones bearing a b!aldehyde group ð66ZC82Ł[

O O
S CO2Me
S DMAD, ∆
(65)
64%
S CO2Me
S
S S

S S 290 °C S S
(66)
+
Ph N 90% N
Ph
Ph Ph

Me
S S NHMe
,∆ S N
MeHN
(67)
Ph S 62%
Ph N
Me

N ArCHO, S8, ∆ S HN
(68)
5–38%
N Ar N
Me Me

"iii# Cross!conju`ated electronically stabilized aryl thioketones


Aryl fused ring analogs of pyridin!3!thiones\ pyran!3!thiones\ and thiopyran!3!thiones are well!
known compounds\ many examples of which have been reported in the literature[ They are com!
monly prepared by reaction of the oxo compounds with P1S4 ð70JHC752\ 89SC2974Ł or Lawesson|s
reagent ð80BSF865\ 81JCR"S#052\ 81JCS"P0#240Ł[ The yields for the reaction are generally good^ illustrative
examples are shown in Equations "58# ð89SC2974Ł and "69# ð81JCR"S#052Ł[ Boron sul_de and silicon
disul_de have also been applied to the preparation of a variety of systems of this type\ and are
claimed to be superior to P1S4 ð58JCS"C#1081Ł[ P1S4 has also been used to prepare the chromene
251 Thioaldehydes and Thioketones
thione "091# by concomitant sulfuration and cyclization "Equation "60## ð72PS"03#028Ł[ 3!Thio~avone
has been synthesized by the reaction of a ~avone imine with H1S ð52JA2878Ł[ Oxidation of acridines
with elemental sulfur gives excellent yields of acridine!8!thiones ð90JPR071\ 51JOC3235Ł[ Lithiation of
a bisthiophene ketal\ followed by reaction with sulfur\ unexpectedly gave a cyclized thione as one
product ð63T2510Ł[

O S

P2S5, Na2CO3
(69)
N 96% N
H H

O S
Ph (50), ∆ Ph
(70)
68%
AcO O Ph AcO O Ph

O S

P2S5, pyridine
(71)
75%
OH O O
(102)

This type of compound can also be formed by the reaction of chloro compounds with NaSH
"Equation "61## ð49JOC599\ 65JOC2673\ 67JOC3809Ł or thiourea ð49JOC599\ 55TL5288\ 78MI 297!93Ł[ The
reaction of H1S with 8!amino derivatives of acridine has been employed for the preparation of
acridine!8!thione ð37JCS0070Ł[ Xanthane dichloride has been converted into xanthane thione in
excellent yield by reaction with EtOCS1−K¦\ followed by basic hydrolysis ð57CB605Ł[ Other reported
methods include the cyclization of the enamine "092# to produce the thione "093# in good yield
"Equation "62## ð80JHC0134Ł\ and the cleavage of dialkyl thioquinanthrenes with H1S to form
quinoline thiones ð81H"23#136Ł[

Cl S
N N
N N
N NaSH, DMF N
EtO2CNH N EtO2CNH N (72)
H
HO 65% HO
O O

OH OH OH OH

S O S
O
SMe
Ph2O, ∆
(73)
N 76% N
H H
(103) (104)

"iv# Alkyl aryl and diaryl thioketones


"a# Sulfuration of aryl ketones[ The direct conversion of a carbonyl into a thiocarbonyl group
has been widely used for the preparation of aryl thioketones[ Similar conditions to those used to
form dialkyl thioketones have generally been used "see Section 2[97[2[0[0#[ Thus the combination
of H1S and HCl gives good yields of the desired products\ especially if precautions are taken to
avoid the formation of dithiols ð63JCS"P0#1448Ł[ Trimer formation is not a signi_cant problem for
Thioketones 252
these compounds\ presumably due to a combination of steric and electronic factors[ The use of H1S
with anhydrous HF as the solvent has been advocated as a more e.cient method in some cases\
although a careful choice of co!solvent is required ð53JOC0244Ł[ The use of H1S under basic conditions
is not a good method for the synthesis of aryl thioketones*benzophenone does not react\ and
thioacetophenone is only formed in poor yield ð52AG"E#269Ł[
P1S4 has also been widely used to e}ect this transformation\ using a variety of solvents and basic
additives ð58BSF716\ 62S038\ 65IJC"B#888\ 65JA5107Ł[ In general the yields tend to be rather lower for the
formation of enolizable alkyl aryl thioketones than for the diaryl compounds ð62S038Ł[ Acyl and
0\0?!diacyl ferrocenes can be converted into the thioacyl derivatives using P1S4 in nonpolar solvents
"Equation "63## ð89JCS"D#2586\ 89JOM"274#258\ 80JCR"S#33Ł[ Lawesson|s reagent has also been exten!
sively employed for the synthesis of aryl and hetaryl thioketones ð56TL1852\ 67BSB112\ 89H"29#894\
80CPB378Ł^ the mechanism of the reaction has been investigated ð75TL2334Ł[ A range of aryl thio!
ketones has been prepared\ including unstable a!hydrazones "Equation "64## ð80S432Ł and diferrocenyl
thioketone ð81JOM"329#094Ł[ Again\ diaryl thioketones seem to be formed in higher yield than alkyl
aryl analogs ð80JCS"P0#072Ł\ and a range of products were formed in the reaction with some diketones
"Equation "65## ð89JOC1310Ł[ A number of other reagents have been used to prepare aryl thioketones
with good results] "TMS#1S:BCl2 ð71JA2093\ 89JOC1310Ł\ "c!Hex2Sn#1S:BCl2 ð71JA2093Ł\
"TMS#1S:TMS!OTf ð80JOC6212Ł\ and "Et1Al#1S ð60MI 297!90Ł[

But But But But


P2S5, Et2O
Fe O Fe S (74)
39%
But But
But But

O (50) S
N N (75)
Ph NMe2 50% Ph NMe2

Ph OO Ph Ph XY Ph Ph S Ph S S
Ph Ph
(50), PhMe, ∆ S
S + (76)
+
62%

68% (X = Y = S) 3% 8%
21% (X = S, Y = O)

As described in Section 2[97[2[1[1[i above\ the sulfuration of simple alkenyl aryl ketones results
in the formation of DielsÐAlder dimers "88#\ which are themselves alkyl aryl thioketones[
"b# Sulfuration of aryl ketone derivatives[ A number of carbonyl derivatives have been converted
into aryl thioketones[ The Vilsmeier approach developed by McKenzie and Reid for the preparation
of heteroaryl thioaldehydes can also be applied to thioketones "Scheme 33# ð55CC390Ł[ The reaction
of imines with carbon disul_de has also been shown to produce diaryl thioketones in good yield
ð58TL2500\ 69T706Ł^ dimethylthioformamide can be used in place of carbon disul_de\ although the
yields are lower ð58TL2500Ł[ The hydrolysis of enamines with H1S has been used for the preparation
of b!oxo ð68JOC2160Ł and b!thioketo ð61IJS"A#105Ł thioketones[ The reaction of hydrazones with
S1Cl1 has also been demonstrated to produce thiobenzophenone ð68TL2562\ 70BCJ2430Ł\ but it gives
rise to cyclic adducts when applied to the monohydrazone of a diketone "Equation "66##\ presumably
by intramolecular trapping of the intermediate thiosul_ne ð81CC6Ł[ An interesting reaction is the
cycloaddition of diphenyldiazomethane with the thioketone "094#\ which gave thiobenzophenone
and the episul_de "095# as products ð80MI 297!90Ł[ These products presumably arise from the two
di}erent orientations possible for the cycloaddition "Scheme 34#\ or\ in the case of "095#\ by the
cyclization of a thiocarbonyl ylide[ Diaryl thioketones can also be prepared from the corresponding
`em!dichlorides by reaction with "TMS#1S ð61ZOR0711Ł or with t!butyl thiol and TFA ð67BSB112Ł[
The reaction of a phosphonium ylide with cyclic polysul_des "see Section 2[97[1[0[5# has been used
to form ~uorene thione\ although this compound was trapped as a DielsÐAlder adduct rather than
being isolated ð80S674Ł[ Diaryl thioketones can also be prepared by the oxidative sulfuration of
the corresponding diarylmethanes ð18CB2937\ 34JCS747Ł or aminodiarylmethanes ð91CB264Ł with
elemental sulfur[ The reaction of a polycyclic ethoxy compound with NaSH produced the cor!
responding thioketone ð74S528Ł[ A related additionÐelimination approach has been applied to the
preparation of phosphonium ylide!stabilized aryl thioketones "see Scheme 15\ But Ph# ð81TL4844Ł[
253 Thioaldehydes and Thioketones

dimethylacetamide
POCl3 NaSH
N N+ 66% N

Me2N S

Scheme 44

NH2
O N S S
Ph Ph S2Cl2, Et3N Ph Ph
O (77)
56%

Ph
Ph S N2
S
But +
N Ph Ph But TMS
Ph2CN2 N
TMS
S

But TMS
Ph2CN2
(105)
S N S
But
N But Ph + N2
TMS
Ph Ph TMS Ph
(106)

Scheme 45

"c# Formation of the a C0C bond[ Phosphonium ylide!stabilized aryl thioketones have been
synthesized by the condensation of methylene triphenylphosphorane with methyl dithiobenzoate
ð64BCJ1896Ł[ A sulfoxonium ylide!stabilized aryl thioketone has been prepared by a similar route
involving the reaction of dimethylsulfoxonium methylide with thiobenzoyl chloride "see Equation
"019## ð65BCJ2017Ł[ The reaction of Grignard reagents with chloro dithioformates did not produce
the expected dithioesters\ and instead thioketones were formed[ A possible mechanism for this
reaction\ involving initial thiophilic attack by the Grignard reagent\ has been proposed "Scheme 35#
ð64RTC0Ł[ Symmetric thioketones can be prepared by the FriedelÐCrafts reaction of electron!
rich aromatics ð0784CB1758Ł or heteroaromatics ð58AJC128Ł with thiophosgene "Equation "67##[
Thiobenzoyl chlorides can also be used in this reaction to give mixed thiobenzophenones in reason!
able yields ð57CB2406Ł[ By direct analogy with the preparation of other b!oxo thioketones\ the
condensation of enolizable ketones with O!alkyl thiobenzoates has been used to synthesize a wide
range of b!oxo aryl thioketones ð54AG"E#043\ 66JCS"P0#0016\ 66S145\ 74S561Ł[
S

PhMgBr EtS Ph
S S
S EtS–
PhS PhS
Ph Ph
EtS Cl PhMgBr EtS 31%
Cl SEt
SPh

EtS Cl

Scheme 46

CSCl2
(78)
N N N
H H S H
Thioketones 254
"d# 0\1!Elimination reactions[ The 0\1!elimination reaction "see Section 2[97[1[0[2# has been used
extensively for the formation of aryl thioketones[ Bunte salts have been widely employed as the
starting materials\ base!catalyzed elimination giving rise to a variety of a!oxo aryl thioketones\
including monothiobenzils ð68CB1633\ 79JHC0544\ 70LA09Ł[ In some of these reactions the initially
produced thioketones were unstable and rapidly formed dimers ð64TL426\ 66JCR"S#133\ 66JOC1710\
73JOC3641Ł[ 0\1!Elimination reactions from thiocyanates ð55CC475Ł\ phenyl disul_des ð57CC613\
69JCS"B#214Ł\ a!chlorosulfenyl chlorides "Equation "68## ð68JOC0625Ł\ and thiosulfonates ð74JOC21Ł
have been used to prepare diaryl thioketones[ The product of the reaction between `em!dichlorides
and EtOCS1−K¦ undergoes 0\1!elimination upon treatment with aqueous alkali to give diaryl
thioketones in excellent yield ð57CB605Ł[ The reaction of thioacids with imines ð48MI 297!90Ł\ oximes\
and nitrones ð66BCJ1640Ł gives rise to addition products which spontaneously undergo 0\1!elim!
ination to produce diaryl thioketones in good yield[

Cl S
SCl Ph3P
Ph Ph (79)
Ph Ph
72%
O O

A number of 0\2!dithiolane derivatives have also been used to generate alkyl aryl and diaryl
thioketones by 0\1!elimination "or cycloreversion# ð71AG52\ 72AG"E#44\ 77CB0048\ 89CB066\ 89JOC3199Ł*
these methods have been discussed in detail in Section 2[97[2[0[2[i[ An interesting reaction of this
general type is the reaction of dithioketals with tungsten hexacarbonyl[ This process usually gives
alkenes by coupling of two molecules of the dithioketal\ but in highly hindered systems thioketones\
postulated to be intermediates in the coupling reaction\ can be isolated in modest yield ð89JOC0763Ł[
"e# Reduction of sul_nes[ Thermolysis of thiobenzophenone S!oxide produces small quantities
of thiobenzophenone ð66ACS"B#568Ł[ A much more e}ective technique for this reduction has been
developed by Zwanenburg and co!workers\ who demonstrated that P1S4 or PSBr2 reduces a variety
of diaryl sul_nes to diaryl thioketones in excellent yield ð70S184Ł[ This technique\ combined with a
number of methods for the preparation of sul_nes that do not involve thioketone oxidation\ make
this a practical synthetic method for the preparation of thioketones[
"f# Other methods[ A number of cycloreversions and related reactions have been used to syn!
thesize aryl thioketones[ Kusters and de Mayo have prepared the substituted dithiobenzil "096# by
photolysis of "097# "Equation "79##[ Compound "096# was found to exist mostly as the dithione\ not
the tautomeric dithiet ð62JA1272Ł[ It was not possible\ however\ to prepare the unsubstituted parent
compound by this method ð63JA2491Ł[ An attempt to prepare acenaphthenedithione by the same
method did not lead to the desired product\ although it could be trapped by the DielsÐAlder reaction
with dienophiles ð74JOC0449Ł[ The thio!Claisen rearrangement of allyl "0!arylvinyl# sul_des has been
successful in forming alkyl aryl thioketones ð61CC51\ 78CPB0888Ł[ As the starting material can be
made by S!allylation of thioketones\ this technique provides a method for the C!allylation of
aryl thioketones[ The dimers of aryl thioketones\ such as monothiobenzil\ can undergo ð1¦1Ł
cycloreversion to generate the monomeric compound on heating or irradiation ð79ZN"B#261Ł[

Me2N Me2N

S S

O (80)
50%
S S

Me2N Me2N
(108) (107)

An interesting formation of an aryl thioketone is the reaction of the sulfoxide "098# with tosyl
isocyanate to produce "009#\ an imino analog of monothiobenzil "Equation "70## ð74JOC0096Ł[

O S
TsNCO
S Ph (81)
Ph
28%
Ph Ph NTs
(109) (110)
255 Thioaldehydes and Thioketones
Aryl hetaryl thioketones can be prepared by forming the heteroaromatic ring\ as in the synthesis
of thiobenzoyl thiophenes developed by Mollier and co!workers involving cyclization of a diene
nitrile with elemental sulfur "Equation "71## ð60CR"C#167\ 63BSF"1#360Ł[ The diene nitrile can be formed
in situ by the reaction of cinnamaldehyde with ethyl cyanoacetate[

CO2Et
CO2Et
CN Et3N, S8, 100 °C
S (82)
63% S NH2
Ph
Ph

Several photolytic syntheses of aryl thioketones have been reported "Equations "72# ð56JA1682\
69JOC3113Ł\ "73# ð61CC521\ 62JCS"P0#0479Ł\ and "74# ð63ZC06\ 73JOC0726Ł#\ although these have not been
generalized[ Photolytic ð61TL4102Ł or cathodic ð63AG"E#238Ł reduction of a 2\4!diphenyldithiolium
salt gives rise to dithiobenzoyl methane[

O S
O O hν
S Ph (83)
Ph
56%
Ph Ph
Ph Ph O

Ph S OH
S hν
(84)
Ph But
37%
Ph O But Ph

S O
hν S
Ph N Ph NH (85)
95% Ph
O Ph

The enethiol tautomer of b!oxo aryl thioketones has been prepared by the Michael addition of
thioacetic acid to aroylphenylalkynes ð54LA"571#077Ł[ Elemental sulfur can be added to phenylalkynes
to provide the dithiet isomers of alkyl phenyl a!dithiones ð82TL004Ł[
A number of other reactions have produced aryl thioketones ð65TL1850\ 73AG"E#799\ 77JPR24\
89TL6530\ 82CB62Ł\ but none appear to be of general synthetic utility[

2[97[2[1[2 Thioketones Bearing an a\b!Alkynic Bond


No reports of the preparation and isolation of alkynyl thioketones have appeared in the literature[
However\ methyl phenylethynyl thione has been observed in the attempted methylation of a thio!
amide ð67CPB1981Ł[ A bisalkynyl dithioketone\ existing as a cyclic tautomer\ has been isolated from
various plant species ð54CB2970Ł[

2[97[3 THIOALDEHYDE AND THIOKETONE FUNCTIONS FURTHER


SUBSTITUTED ON SULFUR
The availability of sulfur d orbitals to participate in bonding results in there being a wide
variety of relatively stable compounds in which the sulfur atom of a thiocarbonyl group is further
substituted[ As well as many simple compounds of this type\ there exist a wide range of heterocyclic
species which can be regarded as containing a C1S bond[ The extent to which these compounds
can be considered as derivatives of thioaldehydes and thioketones is a matter of judgement^ for the
purpose of this review only those compounds for which the usual representation contains a C1S
bond will be discussed "thus\ for example\ thiophenes are not included but 0\1!dithiolium salts are#[
Another area of uncertainty is that of sulfur ylides and related compounds\ which can be regarded
as charge!separated species "000# or as containing a C1S double bond "001#[ Although the dipolar
Further Substituted on Sulfur 256
representation in some cases describes the properties of these compounds more satisfactorily\ for
the purposes of this work they will be considered as containing a C1S bond\ and will be discussed
in the relevant section below[

– +
S S

(111) (112)

Given the wide range of compound types which fall within the scope of this section\ it is impossible\
in the available space\ to give a fully comprehensive account of all the preparative methods that
have been used[ This survey will attempt to give a brief summary of the key synthetic methods for
each compound type\ and also refer to important reviews and other leading references from which
more detailed information can be obtained[ For the many heterocycles which will be mentioned\ it
is recommended that Comprehensive Heterocyclic Chemistry be consulted for a more detailed
consideration of the synthesis and properties of these compounds[
In the sections below\ the compounds will be divided according to the coordination state of the
sulfur atom[ Within each section\ simple compounds will be discussed _rst\ followed by heterocycles
containing a C1S bond[

2[97[3[0 Two!coordinate Sulfur Functions

2[97[3[0[0 Thiocarbonyl ylides


Simple thiocarbonyl ylides bearing no stabilizing groups are highly reactive compounds which
cannot be isolated\ but are generated and trapped in situ\ generally by 0\2!dipolar cycloaddition[
The most widely used technique for the generation of these species is by elimination of nitrogen
from a D2!0\2\3!thiadiazoline "002#\ which is prepared by the reaction of a diazo compound with a
thioketone "Scheme 36# ð72TL3070\ 74JCS"P0#0050Ł[ The addition of the diazo compound to the
thioketone can occur in two orientations\ depending upon the structures of the reacting species
ð78TL6934Ł[ The mechanism of this reaction\ and of the reactions of the thiocarbonyl ylide products\
have been investigated ð70JA6921\ 78TL6930Ł[
Thiocarbonyl ylides which have substituents which stabilize the charge!separated form of the
compounds\ for example "003#\ are often stable species[ However\ thiocarbonyl ylides in which the
electron!donating groups are vinylic to the C1S bond "a similar e}ect to that seen with the
vinylogous thioamides described in Section 2[97[2[1[0[ii# have been prepared and isolated "Equation
"75## ð66AG"E#755Ł[ This equation provides an example of another widely applied method for the
formation of thiocarbonyl ylides\ the reaction between an iodonium ylide and a thioketone[ A
further approach which has found some application is the generation of thiocarbonyl S!methylides
from the corresponding thioketone and trimethylsilylmethyl tri~ate ð76CL0740Ł[

Ph S Ph
H2CN2, –78 °C S –45 °C Ph S
Ph >95%
Ph N N Ph
(113)

Scheme 47

Me2N S CN Me2N S CN
+ –
Me2N CN Me2N CN
(114)
257 Thioaldehydes and Thioketones
CN CN
Pri2N S Pri2N S
I CHCl3, ∆
Ph
+ CN (86)
CN 86%
NPri2 NC Pri2N NC

The preparation\ properties\ and reactions of thiocarbonyl ylides have been reviewed ð61JOC3934\
65T1054\ 68COC"2#262Ł[

2[97[3[0[1 Sul_nes
Sul_nes\ or thiocarbonyl S!oxides\ are well!studied compounds\ and many stable examples have
been prepared[ By far the most widely used method for the synthesis of sul_nes is oxidation of the
corresponding thioketone[ The oxidation of thioketones by molecular oxygen is a reaction of
considerable mechanistic interest\ and has been the subject of detailed investigation\ notably by
Ramamurthy and co!workers ð71JOC016\ 72JOC103Ł[ Of more importance as a preparative method is
the use of peroxy acids or hydrogen peroxide as the oxidant[ m!Chloroperoxybenzoic acid is the
most commonly employed\ and in general good yields are obtained "Equation "76## ð62JCS"P0#62Ł[
A report has extended the scope of this reaction to enethiolizable thioketones ð80TL636Ł[ Mono!
peroxyphthalic acid has also proved to be an e}ective oxidant ð66LA0418Ł[ In these reactions the
conditions must be carefully controlled to avoid over!oxidation and formation of the ketone
ð69JOC0605\ 60JCS"B#0436Ł[ A similar problem is encountered when ozone is used as the oxidant\
although this method is e}ective for the preparation of sterically hindered sul_nes ð62S506Ł[ Dimethyl
dioxirane has also been used with some success ð80JCS"P0#2932Ł[

S S
mcpba O
(87)
75%

A conceptually di}erent approach is the alkylidenation of sulfur dioxide[ This can be achieved
by the reaction of SO1 with phosphonium ylides "Equation "77## ð67TL796Ł\ or by a Peterson reaction
using an a!silyl carbanion[ The latter approach may be more versatile\ as the silyl component can
be readily prepared by silylation of an active methylene compound\ the overall reaction proceeding
in good yield "Scheme 37# ð67TL700Ł[ An alternative approach to the generation of the anion is by
addition of a nucleophile to a vinyl silane\ although the yields for this method are generally rather
lower ð67TL2272Ł[ In situ generated sulfur monoxide will also react with ylides to produce sul_nes\
although the yields are very substrate!dependent ð68JCS"P0#0619Ł[ The reaction between sulfur mon!
oxide and diazoalkanes also generates sul_nes in modest yield ð58TL3350\ 65CC320Ł[

O
PPh3 S
SO2, PhH, 60 °C
(88)
80%

O
TMS S
i, BunLi i, BunLi
ii, TMS-Cl ii, SO2
80%
O O O

Scheme 48

The base!promoted elimination of HCl from sul_nyl chlorides was one of the earliest methods
used for the synthesis of sul_nes "Equation "78## ð53JA0780Ł[ More recently\ a convenient one!pot
approach for the preparation and elimination of the sul_nyl chloride has been described "Scheme
38# ð73CC491\ 73TL4836\ 78T2630\ 81CJC853Ł[ This 0\1!elimination approach\ analogous to that widely
employed for the formation of thioaldehydes\ has been extended to other types of substrate and has
been the subject of extensive study by Kice and co!workers ð80JOC0313\ 80JOC0320Ł[ A novel variant
Further Substituted on Sulfur 258
of this method is the elimination of chloroform from allyl or benzyl trichloromethyl sulfoxides to
produce vinyl or aryl thioaldehyde S!oxides "Equation "89## ð83TL842Ł[

Cl O O
S S
Et3N
(89)
75%

O-TMS O O
SOCl2 Cl
S S
48%
O O

Scheme 49

O DABCO O
Ph S Ph S (90)
CCl3 95%

DABCO = 1,4-diazabicyclo[2.2.2]octane

The retro DielsÐAlder reaction of a variety of precursors has been employed to prepare a!oxo!
and a!iminosul_nes "Scheme 49# ð77CB722\ 89JCS"P0#2064\ 89TL4614\ 80NJC422\ 80PS"48#308Ł[ The thio!
Claisen reaction of allyl vinyl sulfoxides is a rapid reaction leading to the formation of sul_nes in
excellent yield "Equation "80## ð74JA5620\ 80JCS"P0#2088\ 81JOC2019\ 81SL898Ł[ Retro cyclization of a
dithiolane trioxide has also been used to prepare sul_nes ð89CB066Ł[

Ph
Ph
PhMeN O Ph
O S RT
PhMeN + S PhMeN O
O N S
O N 96%
O
Tol Tol

Scheme 50

O O
S 0 °C S
(91)
98%
Ph Ph

Many simple sul_nes are unstable and have either been generated and trapped in situ or char!
acterized in the gas phase[ This is particularly true of sul_ne itself\ which has been the subject of
detailed study[ The usual way of generating sul_ne and simple analogs is the retro ð1¦1Ł cyclization
of a suitable precursor "Equation "81## ð65JA0153\ 71JA2008\ 89JST"127#60Ł^ this type of reaction has
been reviewed ð71AG"E#114\ 73CHEC"6#338Ł[

500 °C S
S S O O (92)

A number of other approaches have given rise to sul_nes\ although none has been widely used[
These include the oxidation of certain thiophenes with singlet oxygen ð69TL680Ł or peroxy acids
ð89CB1954Ł\ and the desilylation of alkyltrimethylsilylsul_nes to produce thioaldehyde S!oxides\
which are di.cult to prepare by other routes ð75CC853\ 89JOC2633Ł[ For further details of these and
other methods for the formation of sul_nes\ the many reviews of the area should be consulted
ð56AG"E#096\ 69QRS68\ 68COC"2#262\ 71RTC0\ 78PS"32#0Ł[
269 Thioaldehydes and Thioketones
2[97[3[0[2 Thiosul_nes
In contrast to their oxygen analogs\ thiosul_nes are highly reactive species which have so far
eluded isolation[ However\ there is considerable evidence for their existence\ from both mechanistic
arguments and trapping experiments ð76JA891\ 81CC300\ 81CC599Ł[ For a discussion of the chemistry
of these transient species\ other reviews should be consulted ð78PS"32#52\ 89SUL72Ł[

2[97[3[0[3 Thiocarbonyl S!imides


A number of thiocarbonyl S!imides have been prepared and characterized[ However\ many of
these compounds are unstable\ readily undergoing cyclization and loss of sulfur to produce the
corresponding imines ð66TL1828Ł[ This process is retarded by steric hindrance\ and many of the
more stable compounds of this type are those bearing bulky substituents[ Four major methods have
been employed for the preparation of these compounds] the 0\2!elimination of HCl from a!chloro
sulfenamides "Equation "82## ð62JA168\ 63JOC1774\ 66ACS"B#789\ 89CB0364Ł\ the reaction of a thioketone
with chloramine T ð66TL148\ 68RTC016Ł\ the alkylidenation of sul_nyl amines using either a phos!
phonium ylide ð66JOC2811Ł or an a!silyl carbanion "Equation "83## ð72JOC3471Ł\ and the reaction of
a sul_ne with an amine anion ð72JOC3471Ł[ The chemistry of thione S!imides has been reviewed
ð73SR22Ł[

O O
S Cl
S
ButNH2 NBut
Cl (93)
73%

N
TMS i, BunLi S Ar
ii, ArNSO
(94)
76%

2[97[3[0[4 Metal complexes of thioaldehydes and thioketones


The coordination chemistry of thiocarbonyl compounds\ and of thioaldehydes in particular\ has
been extensively studied\ and many stable complexes have been prepared\ often of thioaldehydes
that cannot otherwise be isolated[ In the case of stable thiocarbonyl compounds\ the complexes are
generally formed by direct reaction of the compound with a suitable metal salt^ for unstable species
a wide variety of approaches have been used[ A detailed discussion of the preparation of these
complexes is inappropriate in this review*other works ð77JA2060\ 81IC612Ł and the references therein
should be consulted for further information[

2[97[3[0[5 Thiopyrylium salts


Thiopyrylium salts\ which nominally contain a C1S double bond\ have been prepared and
isolated as stable compounds[ They can be prepared by hydride abstraction from thiopyrans
ð64JCS"P0#1988Ł[ An alternative route to these molecules is by ring formation "Scheme 40#*the
initially formed thiopyran disproportionates to the thiopyrylium salt and a dihydrothiopyran ð55T6\
63TL2800Ł[ Reynolds has reported two e.cient syntheses of aryl!substituted thiopyrylium salts\
starting from the corresponding pyrylium salt or from a 3!ketotetrahydrothiopyran ð64S527Ł[ A
di}erent approach to these compounds is by the S!methylation of thiopyran!3!thiones
Further Substituted on Sulfur 260
ð69JCS"C#0191Ł[ Further details of these and other routes to thiopyrylium salts may be found in the
review by Ingall ð73CHEC"2#774Ł[

HClO4
+
71% +
S S S S
50% 50%

Scheme 51

The related thiophenium ions can be formed by the direct protonation of thiophenes with
~uorosulfonic acid ð62TL2818Ł[

2[97[3[0[6 0\1!Dithiolium salts


0\1!Dithiolium salts are well!known compounds which have been very widely employed as
synthetic intermediates[ Many di}erent synthetic methods have been used for their formation^ for
a comprehensive coverage of these\ and a discussion of the reactivity of these compounds\ see the
review by McKinnon ð73CHEC"5#672Ł[
A versatile reaction is the sulfurationÐcyclization of b!diketones\ commonly carried out using
P1S4 ð54LA"571#077Ł\ or hydrogen polysul_des\ H1Sx "x1Ð4#\ in the presence of acid ð51JCS4093\
57CB166Ł[ A more recent modi_cation of this method is the use of hydrogen sul_de in combination
with FeBr2 and bromine "Equation "84## ð68BCJ0124Ł[

O O H2S, Br2, FeBr3 S+ S


(95)
Ph Ph 62% Ph Ph

The peracetic acid oxidation of 0\1!dithiole!2!thiones is also a widely used technique "Equation
"85## ð50JA1823\ 57CJC0744Ł[ Acid!promoted cyclization of thioketones bearing a suitably positioned
thiocyanate group has proved to be a useful method for the formation of a range of fused ring
dithiolium salts "Equation "86## ð89JCS"P0#1770Ł[ Dithiolium salts can also be formed by the ring
opening of trithiapentalenes and related compounds\ brought about by protonation ð64JCS"P0#1986Ł
or alkylation ð57JOC1804Ł[

S S S+ S
MeCO3H
Ph Ph (96)
S
61%

S SCN S+ S
HClO4
(97)
93%
MeO OMe MeO OMe

2[97[3[0[7 Nonclassical thiophenes


This fascinating class of compounds\ of general structure "004#\ has been the subject of extensive
studies\ notably by the groups of Potts and Cava[ They can be regarded as cyclic thiocarbonyl
ylides\ and much of their chemistry is similar\ the compounds readily undergoing 0\2!dipolar
cycloaddition[ However\ a large number of nonclassical thiophenes are stable compounds that can
be easily isolated and characterized[ The structure of this class of compound is of theoretical interest
and has been discussed in detail ð67JOC2782\ 73CHEC"3#602\ 73CHEC"3#0926\ 73CHEC"5#0916Ł[ Molecules
with a wide variety of rings fused to the thiophene have been prepared\ including "005# ð58JA2841Ł\
261 Thioaldehydes and Thioketones
"006# ð63JA0706Ł\ "007# ð58JA5780Ł\ "008# ð61JA5104Ł\ "019# ð68CB159Ł\ and "010# ð66H"5#0062Ł\ as well
as several polycyclic systems[

X
Y S
Z
(115)

Ph Ph Ph Ph Ph Ph Ph Ph Ph
N N
S S MeN S S S PhN S S S O S
N N N N
Ph Ph Ph Ph Ph Ph Ph Ph
(116) (117) (118) (119) (120) (121)

The most widely utilized method for the preparation of this class of compound is the reaction of
a diketone with P1S4 "Equation "87## ð63JA3157Ł[ This reaction is versatile and has been employed
in the synthesis of many nonclassical thiophenes[ An alternative\ somewhat milder\ technique is the
dehydration of sulfoxides\ usually with acetic anhydride "Equation "88## ð58JA2841Ł[ The early work
in this area has been reviewed ð64ACR028Ł^ more recent reviews are provided in Comprehensive
Heterocyclic Chemistry ð73CHEC"3#0926\ 73CHEC"5#0916Ł[

Ph
Ph Ph Ph
O P2S5, pyridine
S S S (98)
O 83%
Ph Ph Ph
Ph

Ph Ph Ph Ph
Ac2O
S S O S S (99)
87%

Ph Ph Ph Ph

The analogous six!membered ring system has been prepared in 72) yield by the reaction of a
diketone with P1S4 in pyridine ð58JA2842Ł[

2[97[3[0[8 Other heterocycles


A number of unusual heterocycles containing a C1S1N unit have been prepared ð45JCS2078\
76JCS"P0#196\ 78JCS"P0#1378Ł[

2[97[3[1 Three!coordinate Sulfur Functions

2[97[3[1[0 Sulfonium ylides


Sulfonium ylides bearing two carbon!based groups on sulfur are versatile reagents that have
been widely utilized in organic synthesis[ The simplest compound of this type\ dimethylsulfonium
methylide\ has found extensive use for epoxide formation from ketones since its introduction by
Corey and Chaykovsky in 0854 ð54JA0242Ł[ Simple sulfonium ylides of this type\ which have
hydrogen or alkyl groups on carbon\ are usually generated and used directly\ as they are reactive
intermediates which decompose rapidly at room temperature[ In contrast to this reactivity\ sul!
fonium ylides bearing anion!stabilizing groups on carbon are stable compounds that can be
prepared\ isolated\ and stored without special precautions ð55JOC0074Ł[ An interesting stabilized
Further Substituted on Sulfur 262
ylide is dimethylsulfonium cyclopentadienylide "011#\ where the stabilization comes from the canoni!
cal form "012# in which the ring attains aromaticity ð54TL0646Ł[

+
S S

(122) (123)

A number of methods have been employed for the formation of sulfonium ylides\ the most widely
used\ especially for unstabilized ylides\ being deprotonation of the corresponding sulfonium salt[
The base used depends upon the type of ylide being formed[ For stabilized ylides\ weak bases such
as triethylamine are generally used[ For simple sulfonium ylides\ stronger bases are required\ and
the precise choice of base and reaction conditions can be critical for the successful formation of the
ylide ð56TL1214Ł[ A number of modi_cations to the conditions for deprotonation have been
suggested\ including the use of heterogeneous reaction conditions ð76T2834Ł and a polymerically
supported reagent ð68TL192Ł[
Another versatile method for the formation of sulfonium ylides is the reaction of a diazo com!
pound with a sul_de under photolytic\ thermal\ or metal!catalyzed conditions "Equation "099##
ð61JOC0610Ł[ A wide range of structural types have been prepared by this method\ including
cyclopentadienylides ð56CI"L#007Ł\ thiophenium ylide "013# "Equation "090## ð67CC72\ 68JCS"P0#1513Ł\
dicyanomethylidene ylides ð65LA530Ł\ and cyclic ylides "Equation "091## ð76TL260Ł[ Some early
examples of this technique have been reviewed by Ando ð61IJS"B#078\ 66ACR068Ł[

Me Me Me Me
N2 S , hν S
(100)
88%
MeO2C CO2Me MeO2C CO2Me

N2 thiophene, Rh2(OAc)4
S (101)
MeO2C CO2Me 93%
MeO2C CO2Me
(124)

O O
CO2Et CO2Et
Rh2(OAc)4
(102)
N2 67% S
Ph
SPh

Stabilized sulfonium ylides can also be prepared from the corresponding active methylene com!
pounds by reaction with sulfoxides\ or ethoxysulfonium salts\ under a variety of conditions "Equa!
tion "092## ð56T3168Ł[ The yields for this process are generally modest\ although in some cases\
which appear to be substrate!dependent\ better results have been obtained ð57JA639Ł[ Various
modi_cations to the method have been reported to give improved yields ð67S567Ł[ b!Hydroxy
ketones can be directly converted into diketosulfonium ylides by oxidation in the presence of DMSO
"Equation "093## ð72JOC0888Ł[ A similar result has been obtained using the CoreyÐKim reagent
"014# ð77S067Ł\ and this reagent has also been used to convert active methylene compounds into
dimethylsulfonium ylides in good yields "Equation "094## ð78CL862Ł[ Active methylene compounds
can be transformed into vinylic sulfonium ylides by reaction with a base and an enaminosulfonium
salt "Equation "095## ð68CB2996Ł[

O Ph
S
S
Ph Me , Ac2O, 100 °C
(103)
44%
O O O O
263 Thioaldehydes and Thioketones

H DMSO, Et3N, SO3•C5H5N S H


(104)
R1 N 90–97% R1 N
N R2 N R2
H OH O H O O

S+ N

O
(125)

S
Ph (125), Et3N
Ph (105)
O O 96%
O O

+
S EtO2C CN, NaH NC S
(106)
Me2N 70%
CO2Et EtO2C CO2Et

The addition of a nucleophile to a vinyl! or polyvinylsulfonium salt has been used to prepare
several sulfonium ylides "Equation "096## ð62TL3922\ 64TL1974Ł[ A number of other techniques have
given rise to sulfonium ylides\ but none has received wide application ð69CPB389\ 63TL0960\ 64JOC2746\
66CL614Ł[ Sulfonium ylides can also be functionalized to form more complex sulfonium ylides by
alkylation\ acylation\ or other processes "Equation "097## ð57JOC2406\ 69TL4186\ 63BCJ898\ 64CC178\
65JCS"P0#0577Ł[

O O
S+ N S
piperidine
(107)

S MeO2C S
O MeO2C
DMAD
(108)
100% O

A number of reviews have discussed the synthesis and properties of sulfonium ylides ðB!55MI 297!91\
B!64MI 297!90\ 68COC"2#136Ł[
Several S!aminosulfonium ylides have also been prepared\ either from an active methylene
compound ð65S209\ 67ZOR0548Ł or from a thioketone S!imide ð63JOC1774Ł[ An interesting reaction
is shown in Equation "098#\ although it is not clear whether this could be developed into a general
method ð80ZOR106Ł[

O
SAr
– NBS Ar N
S (109)
CO2Et
O
O CO2Et
O
Further Substituted on Sulfur 264
There are a number of species that are structurally related to sulfonium ylides\ notably the anions
of sul_limines and sulfoxides[ These species are almost exclusively formed by deprotonation and
reacted in situ\ although it is possible to isolate the anions if required ð79JA1359Ł[ They will not be
considered further here[

2[97[3[1[1 Sulfenes
Sulfenes\ or thiocarbonyl S\S!dioxides\ have been the subject of intense study[ However\ despite
this interest\ no stable sulfene has yet been isolated[ They have been prepared and trapped in situ\
and are implicated as intermediates in several common reactions^ for example\ the reaction of a
base and methanesulfonyl chloride is believed to generate sulfene\ which then reacts with alcohols
to form mesylates[ A number of experiments have been reported in which sulfene has been generated
and studied in the gas phase or at low temperature ð58CJC3498\ 60JA5293\ 63JA1853Ł[
Tertiary amines interact with sulfenes generated by base!induced elimination of HCl from sulfonyl
chlorides ð65CJC1541Ł\ but it is not clear whether the adduct is a zwitterion "015# or the sulfene
interacting noncovalently with the amine "016# "Scheme 41#[ However\ Sundermeyer and co!workers
have reported the isolation of an adduct between bis"tri~uoromethyl#sulfene and quinuclidine
"Equation "009## ð78AG"E#110\ 89CB484Ł[ The x!ray crystal structure of this adduct suggests that the
SÐN interaction is relatively weak and the C0S bond has considerable double bond character[

R3N O R3N – O O
Ph SO2Cl Ph S Ph S + Ph S
NR3
O O O NR3
(126) (127)
Scheme 52

O O F3C O
S quinuclidine
F3C CF3 S N (110)
F3C CF3 74% F3C
S O

For a detailed examination of sulfene generation and chemistry the review by King and Rathore
should be consulted ðB!80MI 297!91Ł[

2[97[3[1[2 Other simple systems


Iminosulfenes have been postulated as reactive intermediates\ and trapped ð69JA2704Ł[
A single example of a simple S\S!dimethoxy thioketone has been reported ð66ACS"B#789Ł[ This
compound\ formed unexpectedly in the reaction of sodium methoxide with an a!chlorosulfenyl
chloride "Equation "000##\ could be isolated\ but gradually decomposed\ even at −08>C[

O O OMe
SCl
S
NaOMe OMe
Cl (111)
71%

A number of metal complexes of thioaldehydes and thioketones have been reported in which two
metal atoms are coordinated to the thiocarbonyl sulfur[ A discussion of the structure and formation
of these complexes is beyond the scope of this review^ for an example and further references a paper
by Werner and Paul should be consulted ð73AG"E#47Ł[

2[97[3[1[3 Thiabenzenes
Thiabenzenes\ and their polycyclic analogs\ are an interesting class of compounds which bear
many resemblances to simple sulfonium ylides[ Much of the early work in this area\ which involved
the preparation of thiabenzenes by the addition of phenyllithium to thiopyrylium salts\ has been
265 Thioaldehydes and Thioketones
called into question by the detailed studies of Mislow and co!workers ð63JA4537\ 63JA4549\ 63JA4540\
64JA1607Ł and by Hortmann et al[ ð63JA5008Ł[ However\ this technique can\ in some circumstances\
be successfully applied to the synthesis of thiabenzenes and 1!thianaphthalenes ð64JA1607Ł[ A much
more widely applicable method is the deprotonation of thiinium salts "Equation "001## ð64JA1607Ł[
Thiabenzenes are somewhat unstable\ and tend to undergo decomposition or rearrangement readily[
However\ they can be stabilized by the presence of electron!donating groups on sulfur ð65JA2504Ł\
or electron!withdrawing groups on carbon ð67TL140\ 79JOC1357Ł[ The chemistry of thiabenzenes has
been reviewed ð73CHEC"2#774\ 76YGK121Ł[

NaOMe
(112)
S+ 37% S
Me Me
Ar Ar
An example of a four!membered analog\ a thiacyclobutadiene\ has been reported ð63TL2800Ł[

2[97[3[1[4 0\5\5al3!Trithiapentalenes and related systems


A wide range of compounds of the general structure "017# has been prepared[ As mentioned in
Section 2[97[2[1[0[ii\ these compounds can be regarded either as the bicyclic species "017# or as
monocyclic[ The choice of which representation is most accurate is complex\ and depends upon the
identity of X\ Y\ Z\ and A[ For the purposes of this review\ all of these compounds will be considered
in this section[ In the space available it is not possible to give a comprehensive account of the
preparation of each of these compounds\ and only a brief summary of the key methods will be
given[ More detailed information is available in the review by Lozac|h ð73CHEC"5#0938Ł[
Y S Z
X A

(128)

The starting materials for many syntheses of these heterocycles are 0\1!dithioles or derivatives[
The reaction of a 0\1!dithiole!2!thione with an alkyne\ described in Section 2[97[1[1[0[ii as a method
for the synthesis of electronically stabilized alkenyl thioaldehydes\ also produces variable amounts
of trithiapentalenes[ In general the yields of pentalenes are low\ but this depends on the substrate
structure ð65BSF"1#019Ł\ and alteration of the reaction conditions can also result in a higher yield of
the bicyclic system ð67ZOR1348Ł[ 4!Alkyl!0\1!dithiolium salts react with dimethyl thioformamide in
acetic anhydride or phosphoryl chloride to produce Vilsmeier salts[ When treated with NaSH these
are hydrolyzed and cyclize to form trithiapentalenes "Scheme 42# ð57JCS"C#1432\ 58JCS"C#802Ł[
A related approach is the preparation of enaminodithioles\ followed by hydrolysis "Scheme
43# ð69JCS"C#0191Ł[ Acylmethylenedithioles\ available by a similar route\ can be converted into
trithiapentalenes by reaction with P1S4 in pyridine ð52JA2133\ 53CI"L#350Ł[ Related approaches
can be employed to give trithiapentalenes directly from dithiolium salts ð63CR"C#682\ 63JCS"P0#611Ł[
Diazadithiapentalenes are also prepared from 4!alkyl!0\1!dithiolium salts\ by coupling with arene
diazonium salts "Equation "002## ð65JCS"P0#117Ł[

+ +
S S S S S S S
Me2N NaSH
Me2NCHS, POCl3

59%

Scheme 53

+ S S S
S S N + N KSH Ph
+ S S
Ph Cl
Ph

Scheme 54
Further Substituted on Sulfur 266
Ar
+ S S N
S S ArN2+
N (113)
90–99%

Various structural types can be formed by the cyclization of appropriate precursors "Equations
"003# ð63JCS"P0#131Ł and "004# ð68JCS"P0#1239Ł#[ This method for the formation of these compounds
has been exploited in the conversion of one ring system into another[ Thus\ in several cases\
substitution reactions on the heterocycles are accompanied by rearrangement to produce an alter!
native heterocyclic system "Equation "005## ð63JCS"P0#611\ 65JCS"P0#779Ł[

Me Me
Me
+ SMe N S N
N S MeNH2
(114)
50%

Me
Me
+ OH N S O
N S Na2CO3
N N (115)
87%

O S S O S S
NaNO2
Ph N Ph (116)
60%
OHC

Pyran!3!thiones can be rearranged oxidatively to dioxathiapentalenes by reaction with thal!


lium"III# tri~uoroacetate^ a mechanism has been proposed for this transformation "Scheme 44#
ð64JCS"P0#664Ł[ Dilute sodium sul_de in combination with potassium ferricyanide brought about the
same conversion\ whereas a more concentrated solution of Na1S introduced an extra sulfur atom\
to produce "018# ð61JCS"P0#0336\ 64JCS"P0#0224Ł[ These authors also report the conversion of the
dioxathiapentalene "029# into the trithiapentalene "020# "Scheme 45#\ a process that presumably
takes place via ring!opened intermediates[
TlL2 TlL2
S S S
TlL2
OH S O O S O
Tl(O2CCF3)3 H2O ≡
61%
O O OH O
+

Scheme 55

O S O S S
S
P 2S 5
Na2S (dil.), K3Fe(CN)6
O O
O O
O
(130) (131)

S O
S O S
O Na2S (conc.), K3Fe(CN)6
O
O
(129)

Scheme 56
267 Thioaldehydes and Thioketones
Trithiapentalenes and derivatives have also been prepared from acyclic precursors[ Thus\ 0\2\4!
triketones\ upon reaction with P1S4\ undergo sulfuration and cyclization to trithiapentalenes
ð52JA2133Ł[ The bisoximes of b!diketones react with SCl1 or S1Cl1 to produce a mixture of diaza!
pentalenes "Equation "006## ð61TL0724\ 68BSF"1#088Ł[ The use of S1Cl1 favors formation of the dithia
compound "021#\ whereas the dioxa compound "022# is the major product from the reaction with
SCl1[ Bishydrazones react under the same conditions to produce tetraazathiapentalenes in reasonable
yield ð68BSF"1#194Ł[ Trithiapentalenes have also been prepared from acylalkynes by reaction with
thioacetic acid ð54LA"571#077Ł[

OH OH O S S O S O
N N N N N N
SCl2 or S2Cl2
+ (117)

(132) (133)

Related systems containing four or _ve sulfur atoms in a linear array have also been prepared[
They are commonly made by sulfuration of a ketone\ either directly "see Equation "36## or with
rearrangement "Equation "007## ð60BSF3318\ 66CC740Ł[

O
S S S S S S S S S
But But P2S5
But But (118)

2[97[3[2 Four!coordinate Sulfur Functions

2[97[3[2[0 Sulfoxonium ylides


Sulfoxonium ylides\ like their sulfonium counterparts\ have been very widely used as reagents for
organic synthesis[ Dimethylsulfoxonium methylide was introduced by Corey and Chaykovsky at
the same time as dimethylsulfonium methylide ð54JA0242Ł\ and has been extensively employed for
the preparation of epoxides from ketones[ The sulfoxonium ylide is signi_cantly more stable^
solutions only decompose slowly at room temperature and are stable inde_nitely at low temperature
under an inert atmosphere[ For this reason\ dimethylsulfoxonium methylide has\ despite its lower
reactivity\ been more frequently used than the equivalent sulfonium ylide\ and its use has been
reviewed ð76T1598Ł[ There are some interesting di}erences in reactivity between these two ylides\
which are discussed by Corey and Chaykovsky ð54JA0242Ł\ and have been the subject of further
study ð60JA4292\ 62JA6313Ł[
The main methods for the formation of sulfoxonium ylides are analogous to those employed for
sulfonium ylides[ Thus\ dimethylsulfoxonium methylide is prepared by the deprotonation of a
trimethylsulfoxonium salt by treatment with a strong base\ typically sodium hydride[ More complex\
and in particular carbonyl!stabilized\ sulfoxonium ylides have been prepared by the reaction of
diazo compounds with dimethyl sulfoxide "Equation "008## ð61IJS"B#078\ 61JOC0610\ 66ACR068Ł[ Sul!
foximines can replace DMSO in this reaction ð66TL2522\ 68T206Ł[

Me
Me O
N2 DMSO, CuSO4 S
(119)
CO2Et 50–65% CO2Et

A widely employed method for the preparation of sulfoxonium ylides is the elaboration of
dimethylsulfoxonium methylide[ This simple ylide can be acylated by reaction with ketenes or
anhydrides\ or carbamoylated with isocyanates[ These reactions can also be combined to give doubly
functionalized ylides "Scheme 46# ð54CB2622Ł[ Thiocarbonyl!stabilized ylides can also be prepared
"Equation "019## ð65BCJ2017Ł[ Dimethylsulfoxonium methylide will also undergo Michael addition
to activated alkynes ð55TL0676Ł\ and additionÐelimination reactions "Equation "010## ð63JCS"P0#0014\
63JOC2064Ł to produce vinylic ylides in moderate yields[ The reaction with imidoyl and related
Further Substituted on Sulfur 268
chlorides has been successfully applied to the synthesis of a number of sulfoxonium ylides "Equation
"011## ð66JCS"P0#0085\ 77CB0994Ł[
Me Me Me
Me O Ac2O
Me O PhNCO Me O
S S S
80% NHPh

O O O

Scheme 57

Me Me
Me O PhCSCl Me O
S S (120)
30% Ph

O O
O
O
+ S Me (121)
Me 28% S
Cl Me Me

O
N N O
+ S Me (122)
Me 52% S
N Cl Me N Me

A number of other species bear close structural and chemical similarities to sulfoxonium ylides[
Anions derived from sulfones can be regarded as containing a C1S double bond\ and have been
widely used in synthesis[ They are generated by deprotonation of the sulfone\ and are almost
invariably reacted in situ without isolation[ The anions produced by deprotonation of sulfoximines
have also proved to be useful reagents\ their reactivity being similar to that of sulfoxonium ylides
ð80TL0164Ł[ They are reasonably stable in solution ð62JA3176Ł\ and have been used in a number of
synthetic applications[ These reagents are again formed by deprotonation of the precursor with a
strong base and reacted immediately[ Their use has been pioneered by Johnson\ who has reviewed
the area ð62ACR230\ 74MI 297!90Ł[

2[97[3[2[1 Other simple compounds


A structurally novel compound is the alkylidenesulfur di~uoride oxide "023#\ prepared by con!
trolled hydrolysis of alkylidenesulfur tetra~uoride "024# "Equation "012## ð77CB0866Ł[ This reaction
is interesting in that hydrolysis of the SF3 group occurs before that of the acyl ~uoride[ Compound
"023# exists as a mixture of isomers at low temperature[
F F H2O F F
F F
S S (123)
O F 39% O O
F
(135) (134)

Many metal complexes of sulfur ylides have been prepared\ and although the precise nature of
the bonding in many of these species is unclear\ in some cases a C1S bond may\ at least nominally\
be present[ This area of chemistry has been reviewed by Weber ð72AG"E#405Ł[

2[97[3[2[2 Thiabenzene S!oxides


Thiabenzene oxides are generally stable compounds which can be isolated and characterized[ An
x!ray crystal structure of one of these compounds\ which showed both C0S bonds to be of similar
279 Thioaldehydes and Thioketones
length and intermediate in character between single and double bonds\ has been reported ð67CC086Ł[
The compounds are readily prepared by the addition of dimethylsulfoxonium methylide to an
acylalkyne and cyclization "in situ or as a separate step# of the intermediate ylide "Scheme 47#
ð60JA1360Ł[ More highly functionalized compounds can be prepared by a related approach "Equation
"013## ð63JOC2408\ 77CB0994Ł[

Ph Ph
Me
Ph Me NaOMe
+ S O
69% 84% S
O Me S
O Me O
Me O

Scheme 58

O
O
Me
Me
+ S (124)
33%
O
EtO O S
Me O

2[97[3[3 Five!coordinate Sulfur Functions

2[97[3[3[0 Alkylidene sulfur tetra~uorides


A number of compounds containing the C1SF3 group have been prepared and characterized by
Seppelt and co!workers[ The simplest of these\ methylenesulfur tetra~uoride\ was prepared from
bromomethylsulfur penta~uoride by halogenÐmetal exchange\ followed by elimination of lithium
~uoride "Scheme 48# ð67AG"E#405\ 72CB534Ł[ This compound is a stable gas\ and structural studies
have shown that it contains a C1S double bond with less charge separation than in sulfur ylides
ð68AG"E#833Ł[ The compound has also been prepared by the decomposition of metal sulfur pen!
ta~uoride complexes ð78ZAAC"467#009Ł[ Several other compounds of this class have been prepared
using the same metal!promoted elimination route ð71IC2036\ 73CB2144Ł\ and a crystal structure of
one has been obtained ð80JA122Ł[ An interesting molecule of this class\ "024#\ has been synthesized
by the thermal isomerization of the ketene "025# in the presence of glass "Scheme 59# ð76AG"E#688\
77CB0866Ł[

BunLi, –110 °C –70 °C


Br SF5 Li SF5 H2C SF4

Scheme 59

F
P2O5 O glass, 270 °C
HO2C SF5 • SF5 SF4
70% 50% O
(136) (135)

Scheme 60

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.09
Seleno- and Telluroaldehydes
and -ketones
FRANK S. GUZIEC, Jr and LYNN J. GUZIEC
New Mexico State University, Las Cruces, NM, USA
2[98[0 OVERVIEW 270
2[98[1 SELENOALDEHYDES "SELENALS#\ RHC1Se 271
2[98[1[0 Simple Selenoaldehydes 271
2[98[1[1 Metal!stabilized Selenals 275
2[98[1[2 Conju`atively Stabilized Selenals 277
2[98[2 TELLUROALDEHYDES "TELLURALS#\ RHC1Te 278
2[98[3 SELENOKETONES "SELONES#\ R1C1Se 280
2[98[3[0 Simple Selones 280
2[98[3[1 Metal!stabilized Selones 285
2[98[3[2 Resonance!stabilized Selones 287
2[98[4 TELLUROKETONES "TELLONES# 399

2[98[0 OVERVIEW
Despite a number of early reports describing the synthesis of selenium and tellurium analogues
of simple aldehydes and ketones\ the preparation of well!characterized derivatives of these classes
of compounds only dates from the mid!0869s[ Careful examination of the earlier reports suggests
that researchers were initially often led astray by signi_cant limitations in analytical techniques[ The
desired seleno! and tellurocarbonyl compounds were often unstable under the preparative conditions
used and decomposed during the attempted synthesis[ In many cases dimeric and trimeric derivatives
of the desired compounds were obtained\ adding to the confusion[ The early di.culties associated
with the attempted preparation of seleno! and telluroaldehydes and !ketones have been reviewed
ðB!62MI 298!90Ł[
Despite these early problems\ advances in methodology in the late 0879s\ and the introduction of
a variety of novel reagents\ have made these seleno! and tellurocarbonyl derivatives much more
common[ It should be noted that\ in general\ these classes of compounds are not stable enough to
be isolated at room temperature unless the seleno! or tellurocarbonyl functional group is shielded
sterically\ is stabilized by complexation to a metal center\ or is conjugated in a vinylogous manner
to other stabilizing functions[ A number of reviews concentrating on aspects of the preparation and
reactions of seleno! and telluroaldehydes and !ketones have been published ðB!75MI 298!90\ B!76MI
298!90\ B!76MI 298!91Ł[
Finally\ the di.culties associated with the nomenclature of seleno! and tellurocarbonyl analogues
of aldehydes and ketones should be noted[ The terms selenoaldehyde\ selenoketone\ telluroaldehyde\
and telluroketone in the literature often refer to carbonyl compounds with selenium or tellurium
substituents[ Better terms for these compounds are selenal\ selone\ tellural\ and tellone\ respectively[

270
271 Seleno! and Telluroaldehydes and !ketones
It should also be noted that the terms selenone and tellurone are occasionally used incorrectly in
the literature to describe selenium and tellurium analogues of ketones[ These names\ in fact\ refer
to the selenium and tellurium analogues of sulfones[ The detailed nomenclature of seleno! and
tellurocarbonyl compounds has been discussed ðB!76MI 298!91Ł[

2[98[1 SELENOALDEHYDES "SELENALS#\ RHC1Se

2[98[1[0 Simple Selenoaldehydes


Despite descriptions of the preparation of selenoaldehydes "selenals# dating back to the nineteenth
century\ well!characterized preparative routes to these compounds have only been reported since
the mid twentieth century[ Many of these early routes to selenals involved reaction of an aldehyde
with hydrogen selenide in the presence of acid ðB!62MI 298!90Ł[ These reactions generally lead to
cyclic trimers of the desired selenal "Scheme 0# ð49JCS0260Ł[ The trimeric nature of {{seleno!
formaldehyde|| "0# ð54JCS796Ł and {{selenoacetaldehyde|| "1# ð56JCS"B#006Ł were con_rmed by
x!ray analysis[ Trimeric {{selenobenzaldehyde|| "2# ð21RZC169Ł and linear polymeric {{seleno!
formaldehyde|| ð54JPS"B#470\ 55JPS"A#137Ł have also been reported[ It should be noted that the presence
of true monomeric selenal intermediates has not been established in these preparations[ Vacuum
pyrolysis of these cyclic trimers at very high temperatures did a}ord the monomeric selenals as
transient species "Equation "0##\ where FVP represents ~ash vacuum pyrolysis ð73CB076Ł[

O R –H2O Se Se
H+
+ H2Se SeH
R HO R Se R
R = H, alkyl, aryl, (1) R = H
(2) R = Me
(3) R = Ph
Scheme 1

R Se R
FVP Se
(1)
Se Se
1000–1100 K
R
R
R = H, Me

Selenoformaldehyde "0# has also been generated as a transient species by reaction of methylene
with a selenium mirror "Scheme 1# ð57CC348Ł or by FVP of dimethyl selenide "Equation "1##
ð73JA4395Ł[ Irradiation of selone "3#\ isolated in an argon matrix by pyrolysis of a selenadiazole\
a}orded propyneselenal "4# which was characterized spectroscopically "Scheme 2# ð74JOC432Ł[

H Se
CH2N2 [CH2] + Se Se
Se Se
H
(1)

Scheme 2

FVP H
Me2Se Se + CH4 (2)
700 °C H
Selenoaldehydes 272
N FVP hν
Se
N • • Se
Se 700 °C [1,3]-shift

matrix isolation matrix isolation


12 K 12 K
(4) (5)

Scheme 3

Despite the extreme reactivity of unstabilized selenals\ they can be readily prepared as transient
species\ and these intermediates trapped as DielsÐAlder adducts "6# by ~uoride!induced elimination
of cyanide from a!silylselenocyanates "5# "Scheme 3# ð75JA0203Ł[ This was the _rst general\ con!
venient preparative method for selenals[ In this procedure an aldehyde is treated with phenyl!
dimethylsilyllithium and the intermediate alkoxide is trapped with p!toluenesulfonyl chloride[
Treatment of the resulting a!silyl tosylate with potassium selenocyanate a}ords the required
a!silylselenocyanate[ DielsÐAlder adducts of the intermediate selenals are isolated in 28Ð78) yield
"Table 0#[
O i, PhMe2Si– Li+ SiPhMe2 KSeCN SiPhMe2

R ii, TsCl R OTs 18-C-6 R SeCN


(6)

SiPhMe2 Bun4N+ F – Se Se
R SeCN R
R
(6) (7)

Scheme 4

Table 0 Generation of selenals "RCHSe# via


a!silylselenocyanates "5# to "6#[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry R Yield a
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 H 55
1 Me 72
2 Et 67
3 Pr 65
4 Ph 70
5 PhCH1 78
6 But 28
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
Isolated yield of selenal DielsÐAlder adducts "6#[

The _rst stable isolable selenal\ 1\3\5!tri!t!butylselenobenzaldehyde "7#\ was prepared using the
above mentioned a!silylselenocyanate method ð78JA4838Ł[ This selenal is a reasonably stable blue
crystalline compound\ which in solution is very sensitive to oxygen even at low temperatures
"−49>C#\ rapidly a}ording the corresponding aldehyde under these conditions[ The selenocarbonyl
compound is also quite reactive\ undergoing thermal cyclization to the benzoselenane "8# at 69>C
"Equation "2##[ This cyclization con_rmed the intermediacy of the selenal "7# in the reaction of tri!
t!butylphenyllithium with hindered selenoformates "Scheme 4# ð75CC60Ł[

But
But
Se
70 °C
But (3)
Se

But But

(8) (9)
273 Seleno! and Telluroaldehydes and !ketones

But But
Se Se But
But Li + But
But Se
O
But But
But
(8) (9)

Scheme 5

Another route to an uncomplexed selenal involves 0\1!elimination of various selenenyl derivatives


"Scheme 5# ð75CC0041Ł[ In this approach\ ethyl bromoacetate was converted to a {{seleno Bunte
salt|| "09# which could be oxidized to the corresponding diselenide "00#[ Cleavage with sulfuryl
chloride and displacement with potassium phthalimide a}orded the key intermediate phthalimido
derivative "01# as a crystalline solid "Scheme 5#[ Treatment of "01# with triethylamine in benzene
under re~ux in the presence of an appropriate diene a}orded the DielsÐAlder adduct "03# of the
intermediate selenal "02# "Scheme 6#[ Other selenyl derivatives behaved similarly\ although they
a}orded more complex mixtures containing the selenal adducts[

K2SeSO3 I2 SO2Cl2
RO2C Br RO2C SeSO3K RO2C Se Se CO2R
H2O–ROH H2O, EtOH benzene
(10) (11)
R = Me, Et
O
O
N K

RO2C SeCl O Se N
RO2C
O
(12)
Scheme 6

O
Et3N Se Se
Se N
RO2C RO2C CO2R
O
(12) (13) (14)

R = Me, Et Scheme 7

Another route to the generation of monomeric selenal intermediates involves the thermal reaction
of a Wittig reagent with selenium in an inert solvent "Scheme 7# ð76TL5538Ł[ Stabilized Wittig species
such as "04# react with elemental selenium at elevated temperatures a}ording intermediate unstable
selenals "05#\ which further react with "04# ultimately leading to the corresponding symmetrical
alkenes[ The intermediate selenals can also be trapped by dienes\ a}ording the corresponding DielsÐ
Alder adducts[

MeO2C
Ph3P toluene Se (15)
+ Se + Ph3P Se
CO2Me 105 °C
CO2Me
74% CO2Me
(15) (16)

Scheme 8
Selenoaldehydes 274
These reactions also proceed with unstabilized alkyl!substituted ylides "Scheme 8# ð77JA513Ł[ The
selenal anthracene DielsÐAlder adducts "06# are particularly interesting compounds since\ upon
mild thermolysis\ the selenals can be regenerated by retrocyclization and trapped by other reagents
"Scheme 09#[
R

Se
PPh3 90 °C
Se
+ Se
21%
R R
R = Ph, Et, Bun (17)

Scheme 9

Se

Se Se
75 °C
R R
(17)
R = Ph, Et, Bun, Ph
Scheme 10

A number of reagents have been developed in the 0879s which can be used to introduce selenium
into molecules directly\ converting a carbonyl group into a selenocarbonyl moiety[ Bis"trimethylsilyl#
selenide "07# reacts with aldehydes in the presence of a catalytic amount of n!butyl lithium to
generate a selenal which can be trapped in a variety of ways "Scheme 00# "Table 1# ð77JA0865Ł[ The
driving force for the reaction is the large energy di}erence between the selenide "07# and its oxygen
analogue disiloxane[

O BunLi (cat.) Se
Se O Se
+ TMS TMS + TMS TMS
THF 45–85%
R R
(18) R
Scheme 11

Table 1 Direct generation of selenals "RCHSe#


from aldehydes using bis"trimethylsilyl#
selenide "07#[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry R Yield a
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 Ph 62
1 3!ClPh 61
2 1!furyl 74
3 Prn 60
4 Pri 70
t
5 Bu 34
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
Isolated yield of selenal DielsÐAlder Adducts[

Appropriately substituted selenals can be generated using this method and trapped intra!
molecularly in a DielsÐAlder process "Scheme 01# ð77TL5854Ł[
Bis"dimethylaluminum# selenide "08# is reported to react with acetals to a}ord selenals which can
be trapped with Wittig reagents to a}ord the corresponding alkenes "Scheme 02# ð82CE42Ł[
Trimethylselenophosphate "19# reacts with v!H!per~uoroalkanals to a}ord the corresponding
selenals which can be trapped under normal conditions "Scheme 03# ð80ZOR397Ł[
275 Seleno! and Telluroaldehydes and !ketones

( )n ( )n ( )n
BunLi (cat.)
+ Se
TMS TMS
O THF Se Se

R R R

Scheme 12

(Me2Al)2Se R2
OMe PPh3 R1
(19) R1
R1
Se
OMe R2

R1 = PhCH2, Ph, C7H15 Scheme 13

O Se Se O
H + P H + P
(CF2)n MeO OMe (CF2)n MeO OMe 49–52%
OMe OMe
n = 4, 6 (20)

Se
H
(CF2)n

Scheme 14

2[98[1[1 Metal!stabilized Selenals


As previously mentioned\ selenals can be stabilized by complexation to metal centers[ Metal
complexes of selenobenzaldehydes "11# can be prepared from the reactions of the corresponding
benzylidene metal complexes "10# and selenocyanate ion "Equation "3## ð73AG"E#615\ 78JOM"266#094Ł[
These complexes have a variety of isomeric forms which are in equilibrium in solution "Scheme 04#[
The complexes can undergo a variety of transformations without a}ecting the selenal ligand
"Equation "4## ð76CB0894Ł[

(CO)5M –Et4NCN (CO)5MSe


+ [Et4N]+ [N C Se]– (4)
R R
(21) (22)
M = W, Cr
R = H, OMe, CF3

Ph Ph
(CO)5W Se + 2 But (CO) [ But ]2 W Se (5)

The metal complexes can react spontaneously in solution with elimination of the selenal to a}ord
related bimolecular metal complexes "12# "Equation "5## ð74JOM"178#C10Ł[ Fischer et al[ have utilized
the ability of these metal complexes to act as a stable source of selenals in order to carry out a
variety of synthetic transformations of transient selenal species under very mild conditions ð76CC448\
77JOM"247#118\ 78CC556\ 78JOM"253#044\ 89JOM"273#294\ 81CC452Ł[
Selenoaldehydes 276
CO CO
CO CO
– + – +
OC M Se OC M Se

:
OC C6H4R OC
CO CO
C6H4R
(E)-η1 (Z)-η1

CO
CO Se
OC M
OC H C6H4R
CO
η2

Scheme 15

W(CO)5

2 (CO)5W Se (CO)5W Se H Se

+ (6)

R R R

R = H, OMe, CF3 (23)

Some formal metal complexes of selenoformaldehyde "13# and "14# can be prepared by dis!
placement reactions on diiodide complexes "Equations "6# and "7## ð72AG"E#205\ 73AG"E#47Ł[ The latter
complex can also be prepared by extrusion of carbonyl selenide from an osmiumÐdiselenocarbonate
complex "Equation "8## ð72JOM"133#C42Ł[

I
NaHSe Se
CpLRh CpLRh (7)
I
L = Me3P (24)

I
NaHSe
L2(CO)2Os L2(CO)2Os (8)
Se
I
(25)

O –COSe
L2(CO)2Os L2(CO)2Os (9)
∆ Se
Se Se
(25)

The electron!rich osmium methylene complex "15# reacts with elemental selenium to form the
selenoformaldehyde complex "16# "Equation "09## ð72JA4828Ł[ Selenoformaldehyde can also act as
a bridging ligand in organometallic complexes[ Reactions of the selenium complexes "17# or "18#
with diazomethane a}ord the bridged complex "29# "Scheme 05# ð72AG"E#203Ł[

L L
NO Se NO
Os Os (10)
Cl Cl Se
L L
(26) L = PPh3 (27)
277 Seleno! and Telluroaldehydes and !ketones
M
Se CH2N2 Se CH2N2 M
Se
M Se
M M –N2 –N2
M
(28) (30) (29)

M = (η−C5Me5)Mn(CO)2, (η-C5H5)Mn(CO)2

Scheme 16

2[98[1[2 Conjugatively Stabilized Selenals


A number of selenal derivatives which exhibit particular stability because of resonance interactions
have also been prepared[ The fact that these compounds can be readily isolated suggests that special
vinylogous or resonance interactions lower the carbonÐselenium double bond character of the
selenocarbonyl moieties[
It has been reported that the selenal "20# could be prepared directly from the formyl derivative
by treatment with phosphorus pentaselenide "Equation "00## ð43GEP809088Ł[ It should be noted\
however\ that phosphorus pentaselenide is not a particularly useful selenating agent in most cases
ðB!76MI 298!92Ł[

R R
P2Se5
(11)
N O N Se
Me Me
(31)

Other related stabilized selenals "21#Ð"23# can be prepared from heterocyclic amines by a VilsmeierÐ
Haack transformation followed by sodium hydrogen selenide treatment "Equation "01##
ð68JCS"P0#1223Ł[ These selenal compounds can also be prepared from the corresponding formyl
derivatives by treatment with phenylselenophosphonic dichloride "24# "Equation "02## ð77CC0383Ł[
R R R R
Cl +
R i, NMe2 PO2Cl2– R
R R (12)
N ii, NaHSe N
R R
28–46%
R R
Se
R = H, alkyl (32)

Se

R S R S

N N

Se
(33) (34)

Se
R2 R3 Ph
P
Cl
R2 R3
Cl
R1 R1
(35)
R4 R4 (13)
N 62–81% N

CHO Se
Telluroaldehydes 278
The _nal class of stabilized selenals includes compounds which formally contain a selenocarbonyl
moiety in a contributing resonance form such as "25#\ but which are probably better described as
hypervalent sulfur "26# or selenium "27# species ð60JCS"C#2076Ł[ Compounds of this type can be
prepared by selenation of the corresponding aldehyde using phosphorus pentaselenide ð55JA4934Ł\
or more e.ciently by using phenylselenophosphonic dichloride "24# "Scheme 06# ð77CC0383Ł[ The
unsubstituted derivative "27# can be prepared via a displacement and oxidation sequence "Scheme 07#
ð60JCS"C#2076Ł[
Se
P
Ph Ph Cl Ph
Cl Ph Ph
(35)
Ph

Ph Ph Ph
S O S Se S S S
S S Se S Se
(36) (37)

Scheme 17

Se
i, Na2S
ii, Se2–
Se S
Se Se S
iii, K3Fe(CN)6 Se S Se
S Se
(38)

Scheme 18

2[98[2 TELLUROALDEHYDES "TELLURALS#\ RHC1Te


The preparation of telluroaldehydes "tellurals# very much parallels the previously described
chemistry of selenals\ although signi_cantly less has been published on this topic[ In general\
tellurals*like selenals*cannot be isolated in their free state unless they are stabilized[ In the case
of tellurals\ only metal complexation has led to successful stabilization of these compounds[
The preparation of gaseous monomeric telluroformaldehyde "28# via the reaction of a tellurium
mirror with methylene generated by thermal decomposition of diazomethane or photolysis of ketene
has been reported ð23JA1270\ 27JCS398Ł[ This material trimerizes to tritelluroformaldehyde "39#
"Equation "03## ð57CC348Ł[

H Te
Te + CH2 Te (14)
H Te Te

(39) (40)

Tellurobenzaldehyde "31# can be prepared as a transient intermediate by the thermal reaction


of the Wittig reagent "30# with tellurium[ The tellural can be trapped by a diene "Scheme 08#
ð78AG"E#068Ł[ If only a catalytic amount of tellurium is used\ the corresponding {{dimerized|| alkene
is isolated[ This is due to the fact that the by!product triphenylphosphine telluride is thermally
unstable\ regenerating the elemental tellurium "Scheme 19#[

Ph Te Ph Te
PPh3 Te 11%
toluene
105 ° Ph
(41) (42)

Scheme 19

Bis"dimethylaluminum# telluride "32# acts as an e}ective direct tellurating agent for the prep!
aration of tellurals from the corresponding aldehydes[ The transient intermediate tellurals can be
289 Seleno! and Telluroaldehydes and !ketones
Ph
Te PPh3
Ph
Ph Ph
+ Ph3P Te
PPh3 cat. Te
Ph
100 °C
61%

100 °C
Ph3P Te Ph3P + Te

Scheme 20

trapped as their DielsÐAlder adducts "Scheme 10# ð78JA7638Ł[ The key tellurating agent bis"dimethyl!
aluminum# telluride "32# can be readily prepared via transmetallation of bis"trimethyltin# telluride
"Equation "04## ð78JA7638Ł[ It should also be noted that bis"trimethylsilyl# telluride "33# was not an
e}ective tellurating reagent\ in contrast to its selenium analogue "07# which acts as a convenient
selenating agent "cf[ Scheme 00#[

O OAlMe2 Te
dioxane –(Me2Al)2O Te
(Me2Al)2Te + R
44–62%
R TeAlMe2 R R

(43) R = Ph, Prn, But

Scheme 21

toluene
Bu3SnTeSnBu3 + 2Me3Al (Me2Al)2Te + 2Bu3SnMe (15)
90 °C
(43)

(Bu3Si)2Te
(44)

A number of metal complexes of tellurals have also been reported[ The tungsten pentacarbonyl
complex of tellurobenzaldehyde "34# can be prepared by tellurium insertion into the metal carbene
complex "Equation "05## ð80JOM"304#100Ł[ These complexes have structures analogous to the selenal
complexes previously mentioned "cf[ Scheme 04#[ Thermolysis of "34# a}ords the free tellural as a
transient species which can be trapped by dienes "Scheme 11#[

(CO)5W –Et4NCN (CO)5WTe


+ [Et4]+ [N=C=Te]– (16)
18%
(45)

(CO)5WTe ∆ Te Te

(45) Ph

Scheme 22

A number of formal complexes of telluroformaldehyde have been reported[ Treatment of the m2!
tellurium complex "35# with diazomethane a}ords the bridged complex of telluroformaldehyde "36#
"Equation "06## ð72AG"E#203Ł[
Selenoketones 280
M H
M CH2N2 Te (17)
Te
M M –N2 H
M
(46) (47)

M = (η−C5Me5)Mn(CO)2, (η-C5H5)Mn(CO)2

The electron!rich osmium complex "37# also reacts with elemental tellurium to a}ord the osmium
complex of telluroformaldehyde "38# "Equation "07##[ Finally\ the diiodorhodium complex reacts
with sodium hydrogen telluride to a}ord the telluroformaldehyde complex "49# "Equation "08##
ð72AG"E#205Ł[

L L
NO Te NO
Os Os (18)
Cl Cl Te
L L
(48) L = Ph3P (49)

I
NaHTe Te
CpLRh CpLRh (19)
I
L = PMe3 (50)

2[98[3 SELENOKETONES "SELONES#\ R1C1Se

2[98[3[0 Simple Selones


As previously described for selenals\ early reports of the preparation of selenoketones "selones#
by acid!promoted reaction of a ketone with hydrogen selenide are in fact incorrect[ Under these
conditions the presumed intermediate selone "40# was reduced further to the selenol\ which was
oxidized in air to the diselenide "41# upon work up "Scheme 12# ð46JCS688Ł[ These unsuccessful
attempts at the preparation of simple selones have been reviewed ðB!62MI 298!90Ł[

O H+ HO SeH –H2O Se H2Se


+ H2Se
R R R R R R
(51)

SeH [O]
R R
Se + Se Se
R R R R
(52)

Scheme 23

The _rst preparation of a monomeric selone\ not stabilized by metal complexation or resonance
interactions\ involved thermolysis of a phosphoranylidene hydrazone "42# in the presence of selenium
powder "Scheme 13# ð64CC428Ł[ The required phosphoranylidene hydrazones are readily available
by treatment of a hydrazone with triphenylphosphine dibromide in the presence of a tertiary amine
base ð50CB1366Ł[ As well as the selone\ molecular nitrogen and triphenylphosphine selenide are also
formed[ The method remains a general one for the preparation of sterically hindered stable selones
ð65CC194\ 65JCS"P0#1968\ 65JPC0890\ 79JOC1789\ 70TL3452\ 71JOC2452Ł[ Less hindered ketones such as
benzophenone and camphor do not a}ord selones under these conditions[ Instead\ only the
corresponding diazo compound decomposition products and dimeric alkenes are obtained
ð65JCS"P0#1968Ł[ These products can also predominate in more hindered cases if the reaction con!
ditions are not carefully controlled[
The phosphoranylidene hydrazone reaction probably occurs via the reaction of an intermediate
diazo compound "43# with a reactive form of selenium[ If the reaction temperature is too high\ diazo
compound decomposition occurs[ If the selone cannot be readily removed from the reaction mixture\
281 Seleno! and Telluroaldehydes and !ketones
But But N PPh3 But
Et3N Se (excess)
NNH2 + Ph3PBr2 N Se + N2 + Ph3P Se
But But But
(53) 29–75%

Scheme 24

a cycloaddition reaction of the diazo compound with the selone can occur as the latter is formed\
a}ording the alkene via a twofold extrusion reaction[ Attempts at preparation of selones via direct
reaction of diazo compounds with selenium were generally limited by this process "Scheme 14#
ð74T3732Ł[

N2
N PPh3
∆ Se
N N2 Se

(54)

+ Se + N2

Scheme 25

Generally\ a more convenient method for the preparation of sterically hindered selones involves
the reaction of the hydrazone with selenium"I# bromide in the presence of triethylamine "Scheme 15#
ð73JOC078Ł[ A related alternative route uses the hydrazone dimagnesium salt with selenium"I#
chloride ð72CC0318\ 77BCJ750Ł[ Both reactions presumably involve nitrogen extrusion from an inter!
mediate N!selenonitrosimine "44#[ Again\ no selones could be obtained from unhindered ketones[

N Se N
2Et3N –N2
NNH2 + Se2Br2 N N Se
68%
Se

(55)

Scheme 26

Aryl selones such as "45# and "46# are less stable than hindered aliphatic selones[ They can be
prepared using a modi_ed selenium"I# chloride route "Equation "19## ð81CL1178Ł[ The attempted
preparation of selones from the hydrazone "47# failed\ a}ording the cyclic di! and triselenides "59#
and "50#[ These are presumably formed via reactions of the intermediate selone "48# "Scheme 16#[
H2NN Ph Ph NNH2 Ph Se Se Ph Ph Se O Ph
Bun3N, PhH
+ Se2Cl2 + (20)

(56) 33:14 (57)

The reaction of fenchone with bistricyclohexyltin selenide "51# and boron trichloride is reported
to a}ord selenofenchone "53# in 89) yield[ It is believed that this reaction proceeds via a non!
aggregated form of boron selenide "52# "Scheme 17# ð71JA2093Ł[ A comparison of the above methods
for the preparation of stable sterically hindered selone has been compiled ð74T3732Ł and is sum!
marized in Table 2 ð74T3732\ 77BCJ750Ł[
A useful method for the in situ generation of selones involves base!promoted elimination of HCN
from selenocyanates[ This route proved convenient for preparation of an intermediate seleno!
Selenoketones 282

H2NN Ph Ph NNH2 Ph Se Se Ph
Se2Cl2 Se2Cl2

(58) (59)

Ph Se Ph Ph Ph
Se Se
Se + Se

(60) (61)

Scheme 27

Table 2 Comparison of methods of preparation of sterically hindered selones[


Entry Selone Method Yield e
(%)

But a 29–(75)
1 Se b 65
But c 58

a 75
2 Se b 80
c 82

a 53
3 Se b 70

a 54
4 Se b 68
c 18

a 40
5 Se b 73

a 25
Se b 76
6 c 24
d 90

Se

7 c 53

Se

8 But c 43

a Via phosphoranylidene hydrazone–selenium pyrolysis.b Via selenium(I) bromide–hydrazone.c Via selenium(I) chloride–hydrazone
dimagnesium salt.d Via bis(tricyclohexyltin) selenide.e Isolated yields of purified products.
283 Seleno! and Telluroaldehydes and !ketones

Se
(C6H11)3Sn Sn(C6H11)3 + BCl3 [B2Se3]
Se 90%

(62) (63) (64)

Scheme 28

~uorenone "54# which could be trapped as its DielsÐAlder adduct "Scheme 18# ð76TL2776Ł[ The
method has been extended to the preparation of a variety of selones containing electron!withdrawing
substituents "56# "Table 3#[ The key selenocyanate intermediates "55# can be readily prepared via
displacements on the corresponding halides "Scheme 29# ð77JA7568Ł[

Et3N
98%
Se
SeCN Se
(65)

Scheme 29

Table 3 Generation of selones "R1C1Se# via selenocyanates "55#[


Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry R0 R1 Yield a
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 CO1Et PO"OEt#1 52
1 CO1Et Ph 43
2 CO1Et Me 51
3 PhCO Me 34
4 Ph CN 84
5 PhSO1 Me 74
6 CO1Et CO1Et 54
7 Ph Ph 69
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
Yields of isolated DielsÐAlder adducts[

X SeCN Se
KSeCN Et3N Se
R2
R1 R2 R1 R2 R1 R2
(66) (67) R1

Scheme 30

A number of other methods previously described for the generation of transient selenals can also
be used for the preparation of selones[ Wittig reagents react with elemental selenium to a}ord
transient diarylselones "57# which readily dimerize to the 0\2!diselenacyclobutane "58# "Scheme 20#
ð89AG"E#0956\ 80CL0942Ł[ The dimer is in equilibrium with the monomeric selone in solution[ The
intermediate selone can be trapped by dienes or reduced to the corresponding diselenide "Scheme 21#
ð76TL5538Ł[ The selone also reacts with dimethyl acetylenedicarboxylate to a}ord the heterocyclic
derivatives "69# and "60#[ The alkene generated by reaction of the selone with the Wittig reagent is
also observed "Scheme 22# ð81TL0222Ł[
Selenoketones can also be prepared by reactions of ketones with selenating agents[ Although
bis"trimethylsilyl# selenide "07# was a useful reagent for selenating aldehydes "cf[ Scheme 00#\
selenation failed in the case of ketones[ Bis"dimethylaluminum#selenide "61#\ however\ proved to be
an e.cient reagent for the preparation of selones "Scheme 23# ð78TL1984Ł[ A variety of aryl and
alkyl derivatives could be prepared using this method "Table 4#[
Hexa~uoroselenoacetone "64# can be prepared as an unstable deep purple oil via pyrolysis of the
Selenoketones 284

Ph Ph Ph Se Ph
PPh3 + 2Se Ph3P Se + Se
Ph Ph Ph Se Ph

(68) (69)

Scheme 31

Se

Ph
Ph

Ph i, NaBH4
Ph Ph
Se Se Se
Ph ii, O2 Ph Ph

Se
Ph

Ph

Scheme 32

Ph
Ph PPh3 Ph Ph
Sen
Ph
Ph
PPh3 Se + Ph3P Se
Ph Ph Ph Ph

MeO2C CO2Me

Ph Ph Ph
Ph
Se
+ Se
CO2Me
CO2Me
CO2Me MeO2C
(70) (71)

Scheme 33

O Se
Se
toluene
+ (Me2Al)2Se
reflux 53%
(72)

Scheme 34

0\2!diselenetane "62# as well as by reaction of bis"per~uoroisopropyl# mercury "63# with diethyl!


aluminum iodide "Scheme 24# ð80CB312Ł[ This selone can also be generated by reaction of hexa!
~uoropropene "65# with selenium and caesium ~uoride\ and trapped by anthracene or other dienes
"Scheme 25#[ The seloneÐanthracene adduct "66# is thermally unstable\ regenerating the selone in a
mild retrocyclization[ The resulting free selone can be trapped by other dienes "Scheme 26#[
285 Seleno! and Telluroaldehydes and !ketones
Table 4 Generation of selones via selanation of ketones using bis"dimethylaluminum# selenide[

Entry Selone Yield a


(%)
Se

1 77

Se
2 63

Se

3 53

Se
4 55

Se
5 44
Ph

Se
6 72
Ph TMS
a Isolated yields of selone Diels–Alder adducts with cyclopentadiene.

F3C Se CF3 KF
+ HgF2 Hg[SeCF(CF3)]2
F3C Se CF3 DMF
100 °C
(73) (74)

Et2AlI

F3C
Se
F3C
(75)

Scheme 35

F3C
CF3
F3C F F3C
CsF
+ Sen Se Se
F F DMF F3C

(76) (77)
Scheme 36

2[98[3[1 Metal!stabilized Selones


Metal!stabilized selones can be prepared by many of the same methods used for the preparation
of selenals[ Reaction of the chromium or tungsten carbene complexes "67# with phenylisocyanate
or potassium selenocyanate a}ords the corresponding selone pentacarbonyl metal complexes "68#
Selenoketones 286
F3C
CF3
– Se Se
Se
CF3
benzene reflux F3C CF3
CF3
(77)
Scheme 37

"Equation "10## ð72ZN"B#0254Ł[ Similar to the selenal metal complexes\ these complexes behave as if
the selone moiety retains true selenocarbonyl character ð76CC448Ł[

Ph Ph

(CO)5M –KCN (CO)5MSe


+ KSeCN (21)
R R
(78) (79)
M = W, Cr
R = H, OMe, CF3, Me, Br, NMe2

A number of stable metal complexes of selenium analogues of b!diketones have been prepared[
Complexes such as "79# can be prepared in situ by reactions of b!diketones such as acetylacetone
with hydrogen selenide in the presence of metal ions "Equation "11## ð58AJC780Ł[ Related complexes
can be prepared via displacement reactions on activated vinyl halides "Equation "12## ð63ZC177Ł or
via a selenation sequence using selenourea "Scheme 27# ð64ZC55Ł[ An uncomplexed b!diselone "71#
has been prepared by ring opening of the selenopyrone "70#\ but exists primarily in its dienediselenol
form "72# "Scheme 28# ð51G748Ł[

O O HCl Se Se
+ NiCO3 Ni (22)
H2Se
Se Se

(80)

Ph Ph
Ph Ph Se Se
+ NaHSe + Ni(OAc)2 Ph Ni Ph (23)
Cl CHO O O

Se Ph
O
O Se H2O
Ph + H2N NH2 NH2
Ph
Ph HN

Ph Ph
H
Se Se
O Se M2+
M
O O
Ph Ph
Ph Ph
Scheme 38

Metal!promoted cleavage of the 0\1!diselenatene derivative "73# also a}ords the metal seleno!
carbonyl complex "74# "Equation "13## ð56CC569\ 69IC0719Ł[ Spectroscopic studies indicate that this
complex may have signi_cant diselone character[
287 Seleno! and Telluroaldehydes and !ketones
Se
Se Se O SeH SeH O
H2O
+ Na2Se
O
(81) (82) (83)

Scheme 39

F3C F3C CF3


Se Se Se
+ M(CO)x M (24)
Se
F3C Se Se CF3
F3C
(84) (85)

M = Mo, Ni, W

2[98[3[2 Resonance!stabilized Selones


A number of resonance!stabilized selone derivatives\ which are in actuality amide and carbonate
derivatives stabilized in a vinylogous manner\ have also been reported[ Selenoacridone "75# can be
prepared by treating 8!chloroacridine with sodium hydrogen selenide "Equation "14## ð92JPR61Ł[

Cl Se

+ NaHSe + NaCl (25)


N N
H
(86)

Substituted selenoacridones "76# can be prepared from the corresponding acridones by a similar
sequence "Scheme 39# ð28CB0135Ł[ N!Substituted selenopyridones such as "77# can be prepared in a
similar manner "Scheme 30# ð93LA134Ł[

+
O Cl

K2SeSO3, H+
+ POCl3 + [PO2Cl2]–
N N
R R

+
SeSO3H Se

hydrolysis

N N
R R
(87)

Scheme 40

Selena!g!pyrone derivatives such as "78# can be prepared from the corresponding thiones by an
alkylationÐdisplacement sequence "Equation "15## ð46AC"R#0133\ 66CC066Ł[ Related compounds such
as "89# can also be prepared via halogenationÐselenation\ similar to the method used to prepare
selenoacridines "Equation "16## ð60JCS"C#2076Ł[
Selenoketones 288
O Cl Cl Se

RI
+ PCl5
N N N+ N
H
R I– R
(88)
Scheme 41

S SMe Se

MeI NaHSe
+ I– (26)
R X R R X R R X R
X = O, S (89)

O Cl Se
R R R R R R
POCl3 K2SeO3
(27)
Me2NCHO
R S R R S R R S R
+
(90)

The resonance!stabilized selone "80# can also be prepared via a similar displacement "Scheme 31#
ð64CC248Ł[ The spectroscopic properties of this molecule\ described as a {{quasi!selenourea\|| indicate
a strong p!conjugation interaction between the amino groups and the selenocarbonyl group through
the cyclopropene ring[

R2N

+ Cl
NaHSe, EtOH, H2O
+
R2N ClO4– R2N R2N R2N

Se + Se– Se–

R2N R2N R2N R2N


(91)
+ NR2
NaHSe, EtOH, H2O
R2N ClO4 –
R = Pri
Scheme 42

An anionic resonance!stabilized selone "81# can also be prepared via a displacement sequence
"Equation "17## ð65AG"E#693Ł[

O O Ph Se Ph Se– Ph Se–
H2Se
2+ (28)
pyridine
Ph Br –O O O O –O O–
(92)

Finally\ the preparation of compounds "82# and "83#*formally containing a selone moiety*involves
the thionation of a diselenacyclopentene "Equation "18##\ readily available via ring opening of the
selenopyrone followed by oxidation "cf[ Scheme 28# ð51G748\ 53G37Ł[ These compounds are probably
better envisioned as containing hypervalent selenium and sulfur\ stabilized by {{no!bond resonance||[
399 Seleno! and Telluroaldehydes and !ketones

Se Se O P2S5 Se Se S Se S S
(29)

Se Se S Se S S

(93) (94)

2[98[4 TELLUROKETONES "TELLONES#


A single report of telluroketone "tellone# preparation via acid!promoted addition of hydrogen
telluride to a ketone has been published ð20CB429Ł[ This report is almost certainly incorrect in that
the authors had also previously claimed that they had prepared selones via the analogous method
using hydrogen selenide ð16CB713Ł[ As previously discussed "Section 2[98[3[0#\ this reaction does
not give selones[ Unfortunately\ the actual products of the hydrogen telluride reaction have not yet
been characterized[
Tellones can\ however\ be prepared via a telluration sequence using bis"dimethylaluminum# telluride
"84#[ As expected\ the tellone "85# is generally unstable and spontaneously dimerizes "Scheme 32#
ð78JA7638Ł[ Alternatively\ the intermediate tellone can be trapped by dienes in a DielsÐAlder
sequence[

Te
Te

O Te 28%
dioxane
+ (Me2Al)2Te
100 °C
Te
(95) (96)

Scheme 43

The _rst stable tellone\ 0\0\2\2!tetramethylindanetellone "87#\ has been reported in the early 0889s[
This compound can be prepared by thermolysis of the corresponding 0\2\3!telluradiazoline "86#
"Scheme 33# ð82JA6908Ł[ The telluradiazoline "86# was prepared by a telluration sequence involving
the N!telluronitrosoimine "88# as an intermediate "Scheme 34# ð82CL0936Ł[ This sequence is similar
to that described for the preparation of selones "cf[ Scheme 15#[ The intermediate "88# can lose
tellurium to a}ord the diazo compound or extrude nitrogen to a}ord the tellone[ The tellone and
the diazo compound undergo a cycloaddition to a}ord the telluradiazoline[

N N
TeCl2, Et3N 80 °C
NNH2 Te
5 °C, benzene Te

(97) (98)

Scheme 44

A stable metal complex of tellurobenzophenone "099# has been prepared by reaction of the
corresponding metal carbene complex with tellurocyanate "Equation "29## ð72JOM"141#C52Ł[ Similar
Telluroketones 390
R
N2
–Te R
R NH2 R N Te
TeCl2
N N
R R
R Te R
(99) N –N2
Te
R N
R

R R N N
Te + N2 R R
R R R Te R

Scheme 45

to the related selenocarbonyl metal complexes\ these compounds retain tellurocarbonyl character
and react as would be expected for a free tellone ð75JOM"188#C6\ 77JOM"237#C0Ł[

(CO)5W + [Te=C=N]– (CO)5WTe (30)


18%

(100)

Finally\ a bridged metal complex of telluroacetone "091# has been prepared by insertion of
dimethyldiazomethane into the tellurium complex "090# "Scheme 35# ð73CC575Ł[


Al2Te3, HCl • • –N2

Mn Te N2
OC O Mn Mn
CO OC CO OC CO
(101)


OC CO
Mn Te
Mn
OC CO

(102)

Scheme 46

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.10
Imines and Their N-Substituted
Derivatives: NH, NR and
N-Haloimines
GRAEME M. ROBERTSON
Glaxo Research and Development, Stevenage, UK
2[09[0 IMINES 393
2[09[0[0 General Methods for Imine Synthesis 393
2[09[1 N!H IMINES 393
2[09[1[0 N!H Aldimines 393
2[09[1[1 N!H Ketimines 394
2[09[2 N!CARBON!SUBSTITUTED IMINES 394
2[09[2[0 N!Carbon!substituted Aldimines 395
2[09[2[1 N!Carbon!substituted Ketimines 396
2[09[2[1[0 Formation of N!carbon!substituted ketimines via condensation reactions 396
2[09[2[1[1 Formation of N!carbon!substituted ketimines via rearran`ement reactions 396
2[09[2[1[2 Formation of N!carbon!substituted ketimines via oxidation or reduction reactions 396
2[09[2[1[3 Formation of N!carbon!substituted ketimines via miscellaneous methods 397
2[09[2[2 Cyclic Imines 398
2[09[2[3 a\b!Unsaturated Imines 300
2[09[2[3[0 Aryl aldimines 300
2[09[2[3[1 Aryl ketimines 301
2[09[2[3[2 a\b!Unsaturated ketimines 302
2[09[2[3[3 Aza!0\2!dienes 302
2[09[2[4 Chiral Imines 303
2[09[2[5 a! and b!Haloimines 304
2[09[2[6 Acylimines 306
2[09[2[6[0 N!Acylimines 306
2[09[2[6[1 a!Acylimines 306
2[09[2[7 Diimines 306
2[09[2[8 C!Metal Derivatives of Imines 307
2[09[2[09 a!Sulfenylimines 307
2[09[3 N!HALOIMINES 308
2[09[4 IMINIUM ION SALTS 308
2[09[4[0 Iminium Ions 308
2[09[4[0[0 Iminium ion cyclizations 319
2[09[4[1 N!Acyliminium Ions 311

392
393 Imines and NH\ NR and N!Haloimines
2[09[0 IMINES

2[09[0[0 General Methods for Imine Synthesis


Imines and their derivatives are important synthetic intermediates[ They perform a signi_cant
role in functional group transformations\ carbonÐcarbon bond formation\ and ring construction[
Their early importance as precursors to amines\ including highly substituted examples\ and to
azaallyl anions ð62AG473\ 77TL650Ł has latterly been augmented by the developments in chiral
induction and iminium ion chemistry "Scheme 0#[

NHR R R
N [E+] N

E

[H] base

R
N

acid
R = chiral auxiliary R = (CH2)nCH=CH2

H R
N HN
( )n

Scheme 1

The literature on the synthesis\ properties\ and chemical reactions of imines "and azaallyl anions#
up to 0868 has been reviewed previously ð68COC"1#274Ł[ Several other reviews are available "in
addition to those that cover enamine or imine anion chemistry# ð52CRV378\ B!69MI 209!90\ 71T0864\
71T2252\ 72S406\ B!72MI 209!90\ 75T4046Ł[ The traditional method for the formation of ketimines by
condensation of a primary amine with a ketone is generally quite straightforward[ In contrast\ the
corresponding preparation of aldimines can be di.cult\ especially with relatively unhindered and
thereby reactive aldehydes\ where further reaction including the formation of aminals can be a
problem[ However\ these aminals often undergo loss of one amine unit thermally "typically during
distillation# to generate the imine ð47JCS1198Ł[
Iminations of aldehydes\ ketones\ and acid chlorides have been achieved using bis"dichloro!
aluminum# phenylimide\ which in turn is prepared from ethylaluminum chloride and aniline
ð75JOC0737Ł[ This oxophilic iminating reagent is especially useful for the selective conversion of a\b!
unsaturated ketones into anils\ with no detectable addition to the C1C linkage[

2[09[1 N!H IMINES

2[09[1[0 N!H Aldimines


The addition of ammonia to aldehydes is not a general procedure for the preparation of N!H
aldimines since\ with the exception of diaryl aldimines\ they tend to be unstable and readily
polymerize[ N!H Aldimines may\ however\ be produced via acid! or base!catalyzed decomposition
of oxaziridines bearing an a!hydrogen atom on the N!alkyl group ð74JCS"P0#1012Ł[ Unfortunately
the reaction conditions employed generally prevent isolation of the free aldimine[ This can be
overcome by the addition of 0\3!diazabicycloð1[1[1Łoctane "dabco# or 0\4!diazabicycloð3[2[9Łnon!4!
ene "dbn# to solutions of the oxaziridine "0# allowing isolation\ or at least detection\ of the N!H
aldimine\ depending on the nature of R2 "Equation "0## ð68TL2190Ł[
O
R1 N R3
dabco
HN R3 (1)
R2
(1)
N!Carbon!Substituted Imines 394
Aldehydes react under mild conditions with lithium aluminum amides "LiAl"NHR#3# to give
aldimines in high yields with no polymerization ð82SC0572Ł[ Likewise\ reactions of ketones with
lithium aluminum amides give the corresponding ketimines[ The lithium aluminum reagents can be
readily prepared from the desired amine and LiAlH3[

2[09[1[1 N!H Ketimines


N!H Ketimines are also not very common compounds\ and only the bis aryl variants are stable[
However\ in contrast to N!H aldimines\ the direct synthesis of N!H ketimines from ketones and
ammonia can be e}ected\ but requires the use of an ammonium chloride!catalyzed reaction at 49
bar pressure at 019>C ð77SC0490Ł[
An important route to N!unsubstituted imines is their preparation from carbonyl compounds
and their derivatives[ Thus\ in situ reduction of oximes to N!H imines is possible\ but the unstable
products generally need to be trapped out with reagents such as Bu2P0SPh1 ð73CC226Ł or Ru2"CO#01
ð89CL524Ł or intramolecularly\ for example\ to give pyrroles ð73TL2696Ł[ The same reagents also
reduce nitroalkanes to imines[
Nitriles can also serve as the starting point for the synthesis of N!H ketimines[ Thus\ the addition
of Grignard reagents to nitriles can be stopped at the imine stage to give N!unsubstituted\ especially
diaryl N!H\ ketimines ð50JOC3775Ł[ Yields can be improved by the use of copper"I# salts or by using
benzene containing one equivalent of ether as the solvent ð79TL044Ł[ Sterically hindered N!H
ketimines can also be prepared by copper"I#!catalyzed addition of the appropriate Grignard reagents
to either alkyl or aryl nitriles "Scheme 1# ð76JOC2890Ł[

MgCl NH
R2MgCl, THF, CuBr N NH3 (dry)
R1 CN
∆ R1 R2
R1 R2

Scheme 2

N!H Ketimines have also been prepared by routes not involving carbonyl derivatives[ For
example\ in a related manner to N!H aldimines\ N!H ketimines "R0 or R1 aryl# can be prepared
by the base!catalyzed decomposition of N!alkyloxaziridines "Equation "1## ð75JCS"P0#756Ł[ Alter!
natively\ direct lithiation in the presence of phenanthrene as a hydrogen acceptor\ allows the
preparation of lithiated imines[ Alkylation of the resulting anions then leads to the synthesis of
homologated products ð73S836Ł[

O NH
dabco or ButOK
(2)
N R1 R2
R2
R1

2[09[2 N!CARBON!SUBSTITUTED IMINES


The formation of N!substituted imines from primary amines and aldehydes or ketones is a
fundamental feature in the synthesis of a wide range of natural products ranging from nitrogen
heterocycles to amino acids[
Simple condensation of primary amines to carbonyl compounds is an e}ective route to
N!carbon!substituted imines ðB!69MI 209!90\ B!69MI 209!91Ł\ since in contrast to N!H!imines\ N!
carbon!substituted imines are generally stable enough for isolation[ With simple R groups\ however\
decomposition or polymerization can still be a problem\ especially for imines derived from benzyl!
amine\ which decompose with evolution of the amine on standing ð36BSF605Ł[ Stability can be
conferred by the presence by the delocalization e}ect provided by at least one aryl group on the
nitrogen\ or the carbon[
395 Imines and NH\ NR and N!Haloimines
The preparation of N!substituted imines becomes progressively more di.cult from aldehydes to
ketones "as the steric demands increase# and with aromatic\ rather than aliphatic amines "as the
nucleophilicity of the amine decreases# ð52CRV378Ł[ Ketones react slower than aldehydes\ with
higher temperatures and longer reaction times often required[ Moreover\ the equilibrium must be
shifted\ usually by the removal of water\ either azeotropically\ or with molecular sieves ð54JOC3497\
60JOC0469Ł\ or with a catalyst prepared from molecular sieves\ silica gel\ and alumina ð61RTC594Ł[
Lewis acids\ such as TiCl3 ð56JOC2135\ 69S030Ł\ ZnCl1 ð47JOC424Ł\ or AlCl2 ð74S568Ł\ are also suitable
catalysts for imine formation\ by increasing the polarization of the carbonyl moiety via complexation
of the oxygen atom with the Lewis acid[
The conversion of ketones to imines is often used to e}ect ring closure ð76T4060Ł[ The Friedlander
quinoline synthesis ð71OR"17#26Ł is an example[ The use of unreactive carbonyl compounds and:or
volatile imines can also cause problems\ but these can be overcome by utilizing alumina as a basic
catalyst[ Supporting both reagents on alumina\ and reacting them together in the absence of solvent\
allows the synthesis of a range of sensitive imines ð74S568Ł[
Alternatively\ a transiminating reagent\ such as benzophenone imine\ can be used to overcome
problems associated with the instability of the amine component to the reaction conditions or for
amines that readily self!condense ð71JOC1552Ł[ This approach allows the synthesis of Schi}|s base
derivatives of a variety of amino acid esters in high yield "Equation "2##[ An alternative method for
the synthesis of Schi} bases is the reaction of N\N!bis"silyl#amines with carbonyl compounds
catalyzed by a zincÐcopper couple ð63S701Ł\ or TMS!tri~ate ð74CL0260Ł[ The TMS!tri~ate method
is particularly useful as it is e}ected at modest temperatures and so allows the use of volatile amines[

R1
NH R1 R2
+ R2 CO2R3 N CO2R3 (3)
Ph Ph H2N
HCl
Ph Ph

2[09[2[0 N!Carbon!substituted Aldimines


A general route to aldimines is provided by the addition of Grignard reagents\ homo! or hetero!
cuprates to N!aryl\ N!alkyl\ and especially N!silylated formamidines "Equation "3## ð77S073Ł[

O
R1MgBr, THF, –80 °C to –20 °C
R2 (4)
N R1 N
R2 TMS

N!Substituted aldimines can be prepared via the hydrogenation of imidoyl chlorides using
dichlorobis"triphenylphosphine#palladium in the presence of triethylamine as acid scavenger
"Scheme 2# ð74S856Ł[ This procedure permits the indirect synthesis of N!substituted aldimines
from secondary amides[
O
R2 R2
N H2, PdCl2(PPh3)2 N
H
R1 N
Et3N, C6H6, 120 °C
R2 R1 Cl R1

Scheme 3

Remotely functionalized aldimines can be obtained from the Michael addition of enamino!
stannanes to a\b!unsaturated esters and nitriles "Equation "4## ð79JOM"075#C8Ł[ Iminocyclopropanes
can be prepared by the base!induced cyclization of a!bromoketimines via a 0\2!elimination of HBr
ð79LA0703Ł[

SnBu3 N
R1
N R2
R1 + CO2Me (5)

R2 CO2Me
N!Carbon!Substituted Imines 396
2[09[2[1 N!Carbon!substituted Ketimines

2[09[2[1[0 Formation of N!carbon!substituted ketimines via condensation reactions


A wide range of methods are available for the formation of ketimines by condensation of an
amine with a carbonyl derivative "see section 2[09[1#[ The e.ciency of the process is dependent not
only on the stability of the amine but also on steric crowding in the carbonyl derivative[ Thus
condensation of less hindered ketones can be catalyzed by both acids ð65JA2921Ł and bases
ð44USP1699570Ł or by the azeotropic removal of water ð66JOC266Ł[ With hindered ketones\ titanium
tetrachloride provides better results ð56JOC2135Ł[ Hindered ketones are also e.ciently converted
into their imine counterparts under neutral conditions by using dibutyltin dichloride as the catalyst
"Equation "5## ð71SC384Ł[

R1
O
R1 Bu2SnCl2, toluene, ∆ R2 N
X
+ (6)
X
R2 NH2

Further\ with dibutyltin dichloride as the catalyst\ the extent of racemization in chiral ketones
occurs is not as marked as with other reagents[
The reaction of ""trimethylsilyl#methyl#iminotrophenylphosphorane\ prepared in situ from "tri!
methylsilyl#methyl azide and triphenylphosphine\ with carbonyl compounds or heterocumulenes\
provides a one!pot synthesis of the corresponding N!""trimethylsilyl#methyl#imines or ""trimethyl!
silyl#methyl#!substituted heterocumulenes respectively\ which are versatile reagents for heterocyclic
synthesis ð73JOC1577Ł[

2[09[2[1[1 Formation of N!carbon!substituted ketimines via rearrangement reactions


Alkyl azides can be pyrolyzed to imines ðB!62MI 209!90Ł in a reaction analogous to the Curtius
rearrangement of acyl azides to isocyanates\ although the rearrangement of tertiary alkyl azides
may involve free alkyl nitrene intermediates ðB!69MI 209!92Ł[ Cycloalkyl ðB!52MI 209!90Ł and aryl
ð47CB01Ł azides likewise undergo ring expansion to give cyclic imines[ The Stiegliz rearrangement
of trityl N!haloamines and hydroxylamines gives the corresponding N!aryl imines\ and similarly
lead tetraacetate!induced rearrangement of tritylamines gives N!arylimines ð63JOC2812Ł[
Beckmann!type rearrangements of oxime sulfonates induced by organoaluminum reagents lead to
the formation of imines\ via nucleophilic attack of one of the alkyl groups from the organoaluminum
reagent on an intermediate carbonium ion ð74AG"E#557Ł[ Alternatively\ treatment of oxime sulfonates
with Grignard reagents in nonpolar solvents such as benzene or toluene also produces imines
ð71TL2284Ł which\ in turn\ can be further converted to a!alkyl! and a\a!dialkylamines[

2[09[2[1[2 Formation of N!carbon!substituted ketimines via oxidation or reduction reactions

"i# Oxidation reactions


Several methods have been reported for the oxidation of amines to imines ðB!69MI 209!90Ł[
Direct methods include the treatment of amines with an Na1WO30H1O1 system\ or with t!butyl
hydroperoxide in the presence of catalytic amounts of dichlorotris"triphenylphosphine#ruthenium
and 3A molecular sieves ð74CC502Ł\ or NiSO30K1S1O7 ð81CL712Ł[ The latter two methods have also
been applied to the synthesis of dihydroquinolines from tetrahydroquinolines[ Di!t!butyliminoxyl
in pentane likewise promotes the direct conversion of secondary\ and primary\ amines into the
corresponding imines ð74JOC4271Ł[
Alternatively\ amines can be oxidized indirectly to the corresponding imine via reaction of
potassium superoxide with primary or secondary N!chloramines ð67JOC0356Ł[
397 Imines and NH\ NR and N!Haloimines
"ii# Reduction reactions
In contrast to the synthesis of imines by oxidative procedures\ the reduction of higher oxidized
species to imines has not been as widely studied\ and only a limited number of methods are available[
Thus nitrones are reduced to imines by treatment with sodium hydrogen telluride at pH 09Ð00
ð74TL3592Ł[ Variation of the reaction pH changes the reducing power of this tellurium reagent^ thus at
pH 5 complete reduction to the corresponding secondary amine occurs[ Tributylphosphinediphenyl
disul_de reduces ketoximes and secondary aliphatic nitro compounds to the corresponding imines\
under anhydrous conditions ð75JCS"P0#1132Ł[ The imine may subsequently be alkynated to give an
enamide\ reduced to give an amine\ or captured by hydrogen cyanide to give an a!aminonitrile[

2[09[2[1[3 Formation of N!carbon!substituted ketimines via miscellaneous methods


The addition of N!diphenylmethylenebenzylamine to Schi} bases can be catalyzed by ammonium
salts and leads to the formation of 0\1!diarylethane!0\1!diamine derivatives "Equation "6## ð73S0927Ł[
These compounds can serve as percursors to azaallyl carbanions[

Ph Ph Ph H
+
PhCH2NEt3 Cl–
N + Ar2 N (7)
Ar1 N Ph N Ar2

Ph Ph Ar1

Primary amines add to triple bonds to give enamines that have a hydrogen on the nitrogen and
tautomerize to the more stable imines ð54RCR558Ł[
Treatment of enamines with a nitrilium salt\ also gives imines ðB!77MI 209!90Ł[
Imines can be prepared from active hydrogen compounds by the treatment with a nitroso
compound ðB!81MI 209!90Ł[
Bis"dichloroaluminum# phenylimide\ prepared from ethylaluminum dichloride and aniline\ is
a highly selective reagent for the formation of N!substituted imines from carbonyl compounds
ð75JOC0737Ł[ It is of particular use for ketimines bearing two or more aromatic groups and for the
transformation of a\b!unsaturated ketones into anils[ Palladium"9#!catalyzed additions of disilanes
to isocyanides provide a convenient method for the preparation of N!substituted bis"silyl#imines
"Equation "7## ð76TL0182Ł via a palladium"9#!mediated insertion of isocyanide into the siliconÐtin
bond[

SiR3
Pd(PPh3)4, toluene, ∆
R3Si SiR3 + R1 NC R3Si N (8)
R1

Tertiary alkyl ketimines can be prepared by the reaction between a tertiary alkyl isocyanide and
t!butyllithium to give a tertiary lithium aldimine "1#[ This lithium imine acts as an acyl anion
equivalent and undergoes alkylation with aryl\ vinyl\ and alkynic halides\ to give the corresponding
imines\ which upon hydrolysis yield the parent ketones "Scheme 3# ð71JOC41Ł[

ButLi, –40 °C
Li
NC RI
But But
N But
(2)

R H3O+ O
But
N But R But

Scheme 4

Imines can be obtained by the palladium!catalyzed reaction of ternary systems comprising bromo!
benzene\ t!butyl isocyanide\ and an organotin compound "Equation "8## ð75CL0086Ł[
N!Carbon!Substituted Imines 398

Pd(PPh3)4 Ph N
PhBr + ButNC + Bu3SnR But (9)
R

Ketimines can be prepared by the reaction of imidoyl chlorides with a variety of organotin
compounds in the presence of a catalytic amount of a palladium complex\ such as dichloro!
bis"triphenylphosphine#palladium at 019>C in xylene ð75BCJ566Ł[
An improved synthesis of trialkylketimines by the reaction of a!cyanoenamines with MeLi has
been published ð71OPP102Ł[
Cyanimides have been obtained by treatment of cyanamides with lead tetraacetate ð75S0944Ł[
Since cyanimides can be hydrolyzed to carbonyl compounds\ the method can also be used to prepare
aldehydes and ketones from primary amines "Scheme 4#[

O NH

i or ii
iv
CN
N
CN Pb(OAc)2 CN
iii
N H N
O O H

Reagents: i, BrCN, Et2O, –30 °C to 25 °C; ii, EtOH, AcOH, NaOCN, ∆; MsCl, pyridine, 0 °C to 25 °C;
iii, c-C6H12, Pb(OAc)4; iv, benzene, Al2O3

Scheme 5

A wide range of N!"cyanomethyl#! and N!"a!cyanobenzyl#imines have been prepared ð75BCJ0798Ł^


they undergo tautomerism to the N!protonated azomethine ylides which\ in turn\ undergo cyclo!
addition reactions with alkenic dipolarophiles[
Van Braun!type dechloroalkylations of heterocyclic phosgeniminium salts\ by thermolysis at
039>C\ provide a direct method for the formation of v!chloroalkylisocyanide dichlorides and N!
trichloromethyl chloroformamidines from cyclic amines "Equation "09## ð78SC1714Ł[

Cl Cl

+ 140 °C, Kugelrohr apparatus Cl


N (10)
Cl
N Cl

a\a!Dichloro!b!iminocarbonyl compounds a}ord a\a!dichloroketimines upon treatment with


various reagents "e[g[ NaOMe\ KOBut\ KCN\ K1CO2# via regiospeci_c fragmentation ð74TL1698Ł[
Regiospeci_c alkylations and dialkylations of a!haloketimines have also been demonstrated
ð74AG"E#770Ł[

2[09[2[2 Cyclic Imines


The methods available for the synthesis of cyclic imines\ which feature as intermediates of nitrogen
containing natural products\ are not as developed as those for their acyclic counterparts\ but have
seen strong development the 0879s and 0889s[
Imines\ and in particular cyclic imines and azadienes\ may be prepared from N\N!disubstituted
hydroxylamines upon treatment with titanium trichloride under anhydrous conditions ð74TL3522Ł[
In contrast\ upon treatment with aqueous titanium trichloride further reduction occurs to give the
corresponding amine[
Stereoselective thermally induced cyclizations of N!ðbis"trimethylsilyl#methylŁ!0!aza!0\2!dienes
309 Imines and NH\ NR and N!Haloimines
give 4!trimethylsilyl!D1!pyrrolidines[ Subsequent removal of the TMS!group and concomitant enam!
ineÐimine isomerization leads to the corresponding D0!pyrrolidine "Scheme 5# ð80CC413Ł[
Ph
Ph Ph
Ph Ph Ph
240 °C TMS-Cl, MeOH
N TMS N TMS
N TMS
TMS
TMS

Scheme 6

Acyl nitronates are readily obtained from ketones and nitroalkenes\ and they serve as useful
intermediates for the synthesis of cyclic imines and amines "Scheme 6# ð89CL128Ł[

R2
H2, 5% Rh on Al2O3, MeOH
R1 + OAc R1 R2
N N
H
O O–

H2, PtO2, AcOH

R1 pyridinium p-toluenesulfonate
R2 R2
HO N CHCl3, 60 °C R1 N
H

Scheme 7

Copper"I#!catalyzed formation of nitrogen!centered radicals from oxaziradines bearing an alkenyl


side chain\ results in stereoselective formation of 4!substituted!D0!pyrrolines "Scheme 7# ð81JA4355Ł[

Ar
Ar
[Cu(PPh3)Cl]4, THF, ∆
Ar N O N•
N
Ph
Ph
Cu–O Ph

Scheme 8

The intramolecular ð1¦1Ł!cycloaddition of monocyclopentadienyltitanium"IV# metal imido


complexes with alkynes provides a novel synthesis of D0!pyrrolines and tetrahydropyridine deriva!
tives "Scheme 8# ð81JA4348Ł[ Subsequent transformations then allow access to indolizidine alkaloids\
in appropriate cases[

Cp
Cp
NH2 Ti Cl N
CpTiCl3, MeLi, THF N Ti Cl
N
R
R
R
R

Scheme 9

Similarly\ intramolecular aminopalladations of alkynylamines lead to intermediate alky!


enylpalladium complexes\ which upon hydrolysis isomerize to the thermodynamically stable cyclic
imines[ Thus\ treatment of 2!alkynylamines with catalytic PdCl1"MeCN#1 gives exclusively D0!
pyrrolines\ while 4!alkynylamines a}ord 1\2\3\4!tetrahydropyridines ð80JOC4701Ł[
1!Cyclopropyl substituted piperidine imines can be obtained by 0\2!dipolar cycloaddition reac!
N!Carbon!Substituted Imines 300
tions involving cyclopropylidine azides "Scheme 09# ð89TL4430Ł[ Acid!catalyzed rearrangement and
subsequent reduction then provides indolizidines[

H
PPh3, THF
Cbz Cbz N
N N3 N N
H 2N
Ph Ph

Scheme 10

Cyclic imines ranging from D0!pyrrolines to 0!aza!0!cycloheptenes can also be prepared via the
boric acid mediated decarboxylation of the corresponding exocyclic b!enaminoester "Equation "00##
ð76TL1242Ł[

R H3BO3, 180 °C
( )n R (11)
N ( )n
EtO2C H N

Cyclic imines\ like their acyclic counterparts ð67JOC0356Ł\ can be generated from the parent amine
via conversion into an N!chloramine precursor with t!butyl hypochlorite\ followed by treatment
with potassium superoxide in ether ð79JOC0404Ł[ The imine can then be used in a subsequent reaction
with organolithium reagents to give alkylated amines regioselectively "Scheme 00#[
( )n ( )n
KO2-crown ether ( )n
ButOCl
N N
H N
Cl

Scheme 11

Speci_c baseÐsolvent combinations that promote kinetic deprotonation can control the orien!
tation of 0\1!eliminations from cyclic imines to give the thermodynamically disfavored isomer
ð68TL1098Ł[ Thus N!chloro!1!ethylpyrrolidine gives substantial proportions of 4!ethyl!0!pyrroline
"2# "Equation "01##[

( )n
( )n ( )n
base
N Et + (12)
N Et Et N
Cl
(3)
NaOMe, MeOH 96:4
ButOK, ButOH 73:27
ButOK, hexane 58:42

Primary aminoalkenes of the type H1C1CH"CH1#nNH1 "n2 or 3# can be cyclized to pyrrolines


and piperidines under the conditions of the Wacker oxidation ð72JOC5766Ł[ Aminoalkanes with
secondary or tertiary amino groups yield cyclic enamines and aminoalkenes\ respectively\ under the
same conditions[

2[09[2[3 a\b!Unsaturated Imines

2[09[2[3[0 Aryl aldimines


Aryl imines can be prepared by a range of methods\ such as thermal elimination of HNO from
N!nitrosoamines ð79BSB136Ł\ from aldehydes by reaction with iminophosphoranes ð79JPC225Ł\ from
oxaziridines by ring!opening with lithium azide ð79JOC0378Ł\ and from nitrosobenzenes by reaction
with active methyl groups ð79BCJ2585Ł[
Isocyanides can be converted into aromatic aldimines by treatment with an iron complex followed
by photolysis in benzene ð76JA4936Ł[ The iodotrichlorosilane!induced reactions of aromatic alde!
301 Imines and NH\ NR and N!Haloimines
hydes with acrylonitrile provide a direct method for the synthesis of unsaturated iminoaldehydes
"Equation "02## ð80TL4310Ł[

ISiCl3, ClCH2CH2Cl
ArCHO + CHO (13)
CN Ar N

Two reports of the N!alkylation of Schi} bases by a\b!unsaturated esters and nitriles have
been published ð68CB0186\ 68TL2342Ł[ a\b!Unsaturated imines are also formed from thiazolidine!3!
carboxylic acid esters upon treatment with Ag1CO2 in aprotic solvents "Equation "03## ð68CB096Ł[

RO2C CO2R
NH Ag2CO3
(14)
N
S Ar
Ar

a!Aryl!N!phenylnitrones can be reduced to N!benzylideneanilines by treatment with


diiodotriphenylphosphorane\ which is formed in situ from triphenyl phosphine and iodine
ð78NKK0637Ł[
Primary benzylamines are e.ciently oxidized by excess Fremy|s salt in 4) sodium carbonate at
room temperature to give the imines "3#\ which undergo self!condensation with unreacted amine to
give the corresponding N!carbon substituted imines "4# "Scheme 01# ð71T0458Ł[

H
Fremy's salt + Ar NH2 H2N N Ar Ar N Ar
Ar NH2 Ar NH2
5% Na2CO3
Ar (5)
(4)

Scheme 12

2[09[2[3[1 Aryl ketimines


0\1!Additions of aryl Grignards to aryl thiobenzamides lead to bisarylimines in good yield\ which
can be isolated as their hydrochloride salts "Equation "04## ð68BCJ2358Ł[

S NH•HCl
+ Ar1MgBr (15)
Ar NH2 Ar Ar1

A methoxy!group at the ortho!position of both benzophenones and anilines is unfavorable for


catalytic condensations leading to imines[ This problem can now be partially overcome by the
use of the aryliminomagnesium reagents "5#\ which react with benzophenones to produce the
corresponding imines in high yields "Scheme 02# ð79BCJ170Ł[

EtMgBr Ph2CO N Ph
Ar
ArNH2 ArN(MgBr)2
Ph
(6)

Scheme 13

Cobalt Schi} base complexes catalyze the selective oxidations of secondary anilines with t!butyl
hydroperoxide to give the corresponding imines ð80CL0982Ł via a single electron transfer "SET#
dehydrogenation mechanism[
Arylimines can be obtained by the addition of N!silylated amides to the corresponding arylÐ
N!Carbon!Substituted Imines 302
lithium compound "Scheme 03# ð75TL496Ł[ Imine formation is strongly dependent on the basicity
of the lithium reagent\ and fails for alkylÐlithium analogues[

O R1 R2
ArLi Ar N
TMS TMS
R1 N LiO N
R2 Ar R1
R2

Scheme 14

In the absence of a base\ N!alkyl!O!"arylsulfonyl#hydroxylamines undergo cationic carbon!to!


nitrogen rearrangements to give imines ð74JOC0748Ł[ In the presence of base\ N!alkyl!O!"aryl!
sulfonyl#hydroxylamines give imines via a bimolecular elimination process[

2[09[2[3[2 a\b!Unsaturated ketimines


Palladium"9#!catalysts\ in particular\ tetrakis"triphenylphosphine#palladium have been found to
catalyze the 2!aza!Cope rearrangements of N!allylenamines to d\o!unsaturated imines in the presence
of TFA as a cocatalyst ð74TL4452Ł[
Secondary enaminones "6# react with benzoyl or pivaloyl chloride to give iminovinyl carboxylates
"7# ð75CB0984Ł[ In contrast they react with acetyl chloride to give the corresponding O\N!diacetyl
compounds "8# "Scheme 04#[

O R2 O OAc
R2COCl, C5H5N, THF AcCl, C5H5N, THF
O
R2 = Ph, But
N N N
R1 H R1 Ac R1
(8) (7) (9)

Scheme 15

1!Methyl!0!aza!0!cycloalkenes react with aldehydes and ketones to yield 1!hydroxyamines\ which


are readily dehydrated by dicyclohexylcarbodiimide "dcc#\ in the presence of catalytic CuCl\ to
provide the corresponding alkenylimine ð80SL805Ł[
The synthesis of ynimines\ the imines of a\b!alkynic ketones\ can be achieved by condensation
reactions between the aliphatic imines and the desired a\b!alkynic ketone at 14>C and 099 torr for
19 h ð72JOC0814Ł[ The syntheses and photochemical reactivities of a\b!unsaturated imines have been
reported ð75JCR"S#35Ł[

2[09[2[3[3 Aza!0\2!dienes
The extensive use of azadienes in DielsÐAlder reactions has been reviewed with particular emphasis
on mono! and bisaza systems ð72T1758Ł[

"i# 0!Aza!0\2!butadienes
Advances in the 0879s in the chemistry of imines with an emphasis on 0!aza!0\2!butadienes and
their cycloaddition reactions have been reviewed ð76H"15#666Ł[
The increasing use of azabutadiene systems in synthesis has led to renewed e}orts directed towards
their preparation[ 0!Aza!0\2!dienes can be prepared by the mercury"II# chloride!mediated addition
of amines to 0\2!enynes in basic wet THF "THF ] H1O\ 3 ] 0# ð74CC0264Ł[
303 Imines and NH\ NR and N!Haloimines
"ii# 1!Aza!0\2!butadienes
1!Aza!0\2!butadienes have been widely studied as a result of their importance in DielsÐAlder
reactions ð72T1758\ 74TL36Ł[ Several routes are available for their synthesis including caesium ~uoride!
induced protiodesilylation of N!"0!trimethylsilylallyl#imines ð74TL36Ł[ Unactivated 1!aza!0\2!buta!
dienes\ which can be prepared by an imine dimerization reaction e}ected with TFA in THF
ð74CB2541Ł\ undergo cycloaddition reactions with dialkyl azodicarboxylates and heterocumulenes
ð75CC0068Ł[
1!Aza!0\2!butadienes can be prepared by base!catalyzed isomerization of the corresponding
unconjugated analogues "09# "Scheme 05#\ and have been used in a three!step N!heterocyclic
annulation procedure for the synthesis of 2\3!dihydro!1!quinolines ð72JOC4237Ł based in the thermal
electrocyclization of 0!aryl!1!azabuta!0\2!dienes[
R
R R R
600 °C N
Ar
Ar O Ar N Ar N
(10)

Scheme 16

0!Aryl!1!aza!0\2!dienes can be prepared by rhodium"0#!catalyzed isomerization of N!allylimines


ð72S0998Ł\ and 0!amino!1!azabutadienes are formed by the acid decomposition of 4!amino!0!vinyl!
3\4!dihydro!0H!0\1\2!triazoles ð72BCJ530Ł[
b!Hydroxy!g!imino esters are of interest as azadiene precursors and they can be prepared by
reaction of a!iminoketones with lithium ester enolates ð74TL3392Ł[
Functionalized 1!aza!0\2!dienes have been prepared ð75JCS"P0#1910Ł via the alkynation of carb!
anions derived from N!"diphenylmethyl#arylmethanimines using aroyl chlorides to a}ord a wide
range of the 1!azadienes\ in which the imino group is conjugated with an enol ester "Equation "05##[
The site selectivity for electrophilic attack on the intermediate azaallyl anion is a function of the
substituents on the carbanion and on the hardness of the electrophile[

Ar2
Ar1 N Ph i, NaH–HMPA, THF
N Ph (16)
Ar2CO2
Ph ii, Ar2COCl, THF, 0 °C
Ar1 Ph

Several substituted 0!thia!2!azabutadienes have been prepared and their reactions with ketenes
a}ord 5H!0\2!thiazine!5!ones ð75PS"16#216Ł[
Wittig reactions of N!acrylic phospha!l4!azenes with aldehydes provide a useful entry to 2!ethoxy!
carbonyl 1!aza!0\2!dienes "Equation "06## ð77TL3752Ł[
CO2Et
CO2Et R1
R1 R2CHO, CHCl3, 60 °C
N (17)
N
PPh3
R2

2[09[2[4 Chiral Imines


The use of chiral imines in asymmetric Michael reactions is an important area\ and has been
reviewed ð81TA348Ł[ The reaction involves an imineÐsecondary enamine tautomerization to generate
the nucleophilic reactant "Scheme 06#[

R* R* R*
N N N
H

EWG EWG

Scheme 17
N!Carbon!Substituted Imines 304
The reaction can be highly regio! and stereoselective\ and is a powerful alternative to the Stork
enamine reaction[ For example\ Michael!type alkylations of chiral imines have facilitated the
enantioselective synthesis of molecules containing quarternary centers ð74JA162Ł[ Although generally
used for the synthesis of functionalized ketones\ the process can be arrested at the imine stage to
give similarly functionalized chiral imines[
The other major areas for chiral imines\ is as intermediates for the preparation of chiral amines
and ketones[ For example\ alkylation of the "R#!camphor imine of t!butylglycinate "00# a}ords the
imines "01# for which de|s of 64Ð099) were observed when Rallyl "Equation "07## ð75CJC615Ł[
The greater diasteroselectivities in the cases of allylic imines "with de of about 49)# probably results
from an interaction between the p!systems of the allylating agent and the imine\ so that alkylation
occurs from the pro!R!face\ for steric reasons[

i, lithium diisopropylamide, THF


(18)
ii, HMPA, RX R
N N
COBut COBut
(11) (12)

Chiral camphor derived imines have also been used for the enantioselective synthesis of "R#!a!
substituted primary benzyl amines\ via alkylation of the 09!substituted "¦#!camphor derivative "02#
ð89SC04Ł[

H
N Ph
N
O
OH

(13)

Asymmetric syntheses of both "R#! and "S#!a!substituted benzylamines\ are possible via the
alkylation of chiral pinanone ketimines "Scheme 07# ð78SC0312Ł[ An important feature of this
procedure is that the diastereoselectivity of the alkylation is independent of the alkylating agent
used[

OH N BuLi, hexane, –78 °C OH N H2NOH, AcOH, EtOH

RX, –78 °C *
R

H2N
*
R

Scheme 18

Some examples of work in the preparation of chiral ketones include] "i# the use of chiral imines
prepared from cyclohexane and methoxyamines derived from D!camphor derivatives which readily
undergo metallation and alkylation to give 1!alkylcyclohexanones of high enantiomeric purities
ð75CPB0949Ł\ and "ii# ~uoroacetone imines of cyclohexylamines which undergo regioselective depro!
tonation with BunLi\ followed by stereoselective alkylation "Scheme 08# ð77JOC1880Ł and subsequent
hydrolysis to give 1!~uoro!1!alkylcyclohexanones[

2[09[2[5 a! and b!Haloimines


The reactivity of a!halogenated imino compounds has been reviewed ð79OPP38Ł[ The synthesis\
reactivity\ and properties of a!haloimines and the applications of a!halogenated imino compounds\
305 Imines and NH\ NR and N!Haloimines
Ph Ph
O
OMe OMe
F PhCH2CH(NH2)CH2OMe N BuLi, THF, –90 °C N
F
CCl4, molecular sieves, 0 °C F RI, THF, –90 °C
R

Scheme 19

in particular in the synthesis of cyclopropanimines\ have also been surveyed ðB!77MI 209!91Ł[ Other\
more speci_c\ reviews covering their synthesis ð68OPP004Ł and reactivity ð79OPP38Ł are also available[
There are two main strategies for the synthesis of a!haloimines[ The _rst strategy was the
condensation of an a!halogenated carbonyl compound with a primary amine under suitable reaction
conditions\ similar to the usual synthesis of imines from carbonyl compounds and primary amines[
The second approach involves the halogenation of imines[ The _rst method gives rise to a!haloimines
only in special cases[ A range of side reactions is commonly encountered\ including] nucleophilic
a!substitution\ elimination of hydrogen halide\ haloform!type reactions\ Favorskii rearrangements
ð75JOC2728Ł\ and rearrangements via intermediate epoxides[ In many cases the initially formed
a!haloimino compounds undergo further transformations under the given reaction conditions[ Thus
cyclopropylidene amines can be isolated from the treatment of a!haloimines with base under
Favorskii!type conditions ð79LA0703\ 75JOC2728Ł[
The second approach to a!haloimines\ via halogenation of imines\ can also be problematical\
owing to formation of unstable immonium!type compounds during these reactions prior to aqueous
workup[ Aldimimes are selectively a!monochlorinated by a sequence of reactions involving
a!trimethylsilylation of preformed 0!azaenolates\ a!chlorination using NCS\ and desilylation in
MeOH ð80CC637Ł[ a!Chloroketimines can be prepared from ketones via simple chlorination ð71S32Ł\
and they undergo facile conversions into cyclopropylimines upon treatment with base "Scheme 19#
ð77CC714Ł[

R2 R2
O i, chlorination
N LDA, THF, 0 °C
N
NaOMe, MeOH
R1 R1 R1
ii, R2NH2, TiCl4 R3X
R3
Cl Cl

R2 H R2
N R2HN OMe N
LiAlH4, Et2O
R1
R1 R1
R3
R3 R3

Scheme 20

a!Bromoaldimines\ a!chloroaldimines\ and aromatic a!bromoketimines have also been used as


precursors to 0\1!diamines and 1!imidazolidinone derivatives via conversion into the corresponding
a!azido imines ð82S0902Ł[ The a!haloaldimines were prepared by reaction of the required aldimine
with the appropriate N!halosuccinimide\ whilst the a!bromoketimines were synthesized via the
condensation of an aromatic a!bromo ketone with the desired amine in the presence of stoichiometric
amounts of TiCl3[
b!Chloroimines\ the parent compounds of a comparatively rare class of halogenated imino
compounds\ can be prepared by condensation of b!chloroaldehydes with primary amines in the
presence of MgSO3 or TiCl3 ð75S081Ł\ as for the synthesis of a!haloimines ð71S32Ł[ They are also
available by a sequence involving the condensation of the appropriate b!chloroketone with a primary
amine ð82S78Ł[ b!Chloroimines serve as useful precursors for functionalized azetidines ð82S78Ł
via organometallic reagent addition across the imino bond of the b!chloroimine\ followed by
intramolecular substitution[
N!Carbon!Substituted Imines 306
2[09[2[6 Acylimines

2[09[2[6[0 N!Acylimines
N!Acylations of alkylimidate hydrochlorides to a}ord alkyl N!acylimidates\ have been
accomplished with triethylamine ð74CB2978Ł[ N!Acylimines can be prepared from methyl trichloro!
pyruvate\ by reaction with amides\ followed by chlorination and treatment of the resulting
a!chloroacylamine with triethylamine ð74S066Ł[ The utilization of N!acylimines and especially
N!acyl and N!thioacylimines\ as the heterodiene in ð3¦1Łcycloaddition reactions has been reviewed
ð78CR0414Ł[

2[09[2[6[1 a!Acylimines
a!Bromo esters and ketones can both be converted into their respective a!acylimines[ Thus
conversion of a!bromo esters to the corresponding azide\ and treatment with lithium ethoxide in
ethanol gives a quantitative yield of the target a!imino ester o}ering an improved method for the
preparation of such compounds "Scheme 10# ð79JOC3841Ł[
Br N3 NH
OEt NaN3, DMF OEt LiOEt OEt
R R R
O O O

Scheme 21

The preparation of a! or b!ketimines is often problematical[ The conversion of a!bromoketones


into sulfonamidoketones\ followed by base!induced elimination of tri~uoromethanesul_nic acid
results in the formation of N!phenyl!a!ketimines ð79JOC050Ł[
a!Ketimines were the unexpected products of the reaction between a\a?!dibromoketones and
primary amines ð71TL678Ł[ Enaminosilanes\ the nitrogen analogues of silyl enol ethers\ undergo
selective a!alkylation with simple acid chlorides in the presence of potassium ~uoride and a crown
ether as catalyst to give b!ketimines "Equation "08## ð71TL2962Ł[

Ph TMS Ph
N O N O
KF, crown ether
R3 + (19)
R1 R4 Cl R1 R4
R2 R2 R3

a!Iminonitriles\ which are useful as intermediates for heterocyclic synthesis\ have classically been
prepared from nitrones and sodium or potassium cyanide ð67S781Ł[ Improved yields of b!ketimines
can be obtained by the alternative reaction of aldonitrones with cyanotrimethylsilane in the presence
of Et2N ð74SC224Ł[
Reactions of phenyl glyoxal with primary amines have allowed the synthesis of some monoimines
ð73JCR"S#033Ł[
a!Ketodicarboxylic acid chloride imine chlorides\ which readily undergo cyclization to N!hetero!
cycles\ can be prepared by a!addition of dicarboxylic acid chlorides to isocyanides "Equation "19##
ð75LA021Ł[

O
(COCl)2 O NR
R NC (20)

Cl Cl

2[09[2[7 Diimines
0\1!Diimines "together with a!iminoketones and a!aminopropionamidines# can be prepared by
oxidative alkyl and arylaminomercurations of prop!1!ynyl alcohols ð72JCS"P0#0982Ł[
0\1! and 0\2!Diimines can be prepared directly from the corresponding dicarbonyl compounds
307 Imines and NH\ NR and N!Haloimines
via titanium tetrachloride!catalyzed condensation reactions with the appropriate amine "Scheme
11# ð76OPP070Ł[

R3
O N
R2 R3NH2, C6H6, TiCl4, 25 °C
R2
R1 R1
O N
R3

O O R3 R3
R3NH2, C6H6, TiCl4, 25 °C N N
R1 R2
R1 R2

Scheme 22

The preparations and reactions of mono! and diimines of quinones have been reviewed ðB!69MI
209!93Ł[
In principle\ the condensation reaction of 0\1!diones with amines should be a straightforward
reaction\ but condensations with branched amines can be problematical[ However\ branched amines
with secondary or tertiary a!carbons can be condensed with glyoxal to give chiral 0\1!diimines
"diazadienes# by using formic acid as a catalyst and an excess of a drying agent in a nonpolar solvent
ð73CB583Ł[
Symmetrical 0\3!diimines can be prepared by dehydrodimerization of a!bromoimines using LDA
ð75TL0696Ł via a single electron transfer reaction[

2[09[2[8 C!Metal Derivatives of Imines


C!Metallated derivatives of imines are the nitrogen analogues of acylmetals and correspondingly
they serve as acyl anion equivalents[ These metallated aldimines are versatile nucleophiles and they
react with various substrates to give aldehydes\ ketones\ a!keto acids\ or a! or b!hydroxy ketones[
Their use has been limited by the sparsity of available methods for their preparation ð58JA6667Ł[
Lithium aldimines were the _rst reported variants ð58JA6667Ł[ Isocyanides that lack any a!hydrogens
react with alkyllithium compounds ð89SL134Ł\ as well as with Grignard reagents to give lithium or
magnesium aldimines ð63JOC599\ 67JOC620\ 70JOC4394Ł[
Copper"I# aldimines generated from the corresponding lithio species "prepared by addition of an
alkyllithium to an isocyanide# undergo conjugative addition to a\b!unsaturated carbonyl compounds
to give 3!iminoketones ð73TL2980Ł[ N!Substituted organo"silyliminomethyl#stannanes "stannyl ald!
imines# ð75CC879\ 76JA6777\ 77TL244Ł serve as synthetic equivalents to organosilylcarbonyl anions and
carbonyl dianions[ They can be prepared by the palladium"9#!catalyzed insertion of nitriles into the
siliconÐtin bond of organosilylstannanes ð75CC879Ł[ Zinc aldimines can be prepared similarly via
the a!addition of organozinc reagents to isocyanides ð77JOC3047Ł[

2[09[2[09 a!Sulfenylimines
a!Sulfenylations of simple imines can be achieved via nucleophilic substitution of their a!halo
counterparts with the desired sodium thiolate in re~uxing methanol\ or by the condensation of
a!"alkylthio#aldehydes with a primary amine "Scheme 12# ð72S521Ł[

Cl NaSR4, MeOH, ∆ SR4 R1NH2, Et2O, TiCl4 SR4


R3 R3 R3
N R1 N R1 O
R2 R2 R2

Scheme 23

a!Sulfenylations of more specialized imines\ such as N!activated a\a!dichloroimines ð67ZOR497Ł\


0!chloromethyl!2\3!dihydroisoquinoloine ð65JAP6521458Ł\ and 2!halo!0!pyrrolines ð70LA0962Ł\ have
also been reported[
Iminium Ion Salts 308
2[09[3 N!HALOIMINES
N!Haloimines are a relatively rare class of compounds\ being both light sensitive and potentially
unstable ð51JA1226Ł[ They can be prepared via the addition of per~uoroalkyl nitriles and bromine
to activated caesium ~uoride "Equation "10## ð73JOC0356Ł[

R
Br2, CsF
R CN F N (21)

Br

2[09[4 IMINIUM ION SALTS

2[09[4[0 Iminium Ions


Iminium ions have long been important functional groups for the synthesis of heterocyclic ring
systems[ Milder methods of iminium preparation\ e.cient modern strategies such as their use in
tandem reaction procedures "e[g[\ aza!Cope Mannich cyclizations#\ and counter!nucleophile reac!
tions demonstrate their increasing value as synthetic tools ð78MI 209!90Ł[
Iminium salts can commonly be prepared from the reaction of amines with aldehydes and ketones[
In addition\ iminium ions can be generated from enamines and imines by reaction with electrophiles
such as H¦ ð44CI"L#0928Ł[ Other sp2!nitrogen!containing derivatives\ such as a!amino alcohols
ð78JA260Ł\ a!amino ethers ð76S713Ł\ e[g[ oxazolidines ð74HCA634Ł\ a!amino sul_des\ e[g[ thiazolidines
ð77IJC"B#021Ł\ and a!amino nitriles ð77TL5430Ł\ are e.cient sources of iminium ions[
Iminium ions can be prepared from noncarbonyl sources via oxidative functionalization of tertiary
amines and subsequent b!elimination ð60JCS"C#2959Ł\ such as in the Polonovski reaction ð65BSF0111Ł\
and via decarbonylation of a!amino acids ð70JOC3803\ 75S624Ł[
The chemical\ spectroscopic\ and structural properties of iminium salts have been comprehensively
reviewed ðB!65MI 209!90Ł[
The syntheses of iminium salts\ including halomethyleneiminium salts\ alkoxymethyleneinium
salts alkylmercaptomethyleneiminium salts\ amidinium salts\ and related compounds have been
reviewed ð80COS"2#374Ł[ Alkyldiphenylsulfonium salts are useful reagents for the O!alkylation of
amides and ureas\ and in particular for the formation of alkoxymethyleneiminium salts ð72T322Ł[
Arylsilanes are e}ective as an activating group for ipso!attack in the PictetÐSpengler synthesis of
7!methoxytetrahydroisoquinolines ð77TL5604Ł^ in the absence of the silyl group only the 5!methoxy
isomer is formed[
t!Butoxycarbonyl deprotection of amines using TFA can be coupled with in situ trapping of
carbonyl groups to provide cyclic iminium ions\ such as "03# "Equation "11## ð78TL3428Ł[

O O
H H
Ph N Ph N
TFA, CH2Cl2 +
BocHN H N (22)

O N CF3CO2– N
Z Z
(14)

Intramolecular 0\2!dipolar cycloaddition of azides with v!chloroalkenes gives the thermally labile
triazolines "04#[ In situ rearrangement and intramolecular N!alkylation then gives the bicyclic 0!
pyrroline iminium ion "05# "Scheme 13# ð89TL6460Ł[
Imination of N!alkyl pyridinium and quinolinium salts can be achieved via oxidation of the
appropriate substrates with potassium permanganate in liquid ammonia ð73TL2652Ł[ Quinone imin!
ium dyes are of particular use in copying and other printing processes and can be prepared
straightforwardly from aromatic amines using DMSO as the methylating agent\ with a Lewis acid
such as TiCl3 as a catalyst ð75T3406Ł[
2!"a!Dialkylaminoarylidene#!0!alkylthiotriazenes\ which are readily obtained from thioamide
salts\ a}ord diamidinium iodides when treated with methyl iodide "Equation "12## ð75JCS"P0#508Ł[
319 Imines and NH\ NR and N!Haloimines

Cl
O O Cl
O C6H6, ∆
O N
N N
N3
(15)

O OH
O H
ii, ButNH2, KHMDS
O O
iii, BH3•THF, NaOAc, MeOH, H2O2
N N
Cl– +

(16)

Scheme 24

+
NR22 MeI, Me2CO R22N N NR22
(23)
N SMe
R1 N N R1 R1

The photochemistry of iminium salts and related heteroaromatic systems has been reviewed
ð72T2734Ł[ The SET!induced photospirocyclizations of allylsilane!terminated iminium ions\ such as
"06#\ have been utilized by Mariano and his co!workers as a versatile route to spirocyclic amines
including the harringtonine alkaloids "Scheme 14# ð78TL3074Ł[
Ar
ButCO2 Ph O
+
Ph Ar N
N hν, MeCN, NaHCO3 ButCO2 N O

ButCO2
TMS
(17)
Scheme 25

The possibility of forming C!vinylazomethine ylides via a photoinitiated\ sequential electron


transfer desilylation pathway has been examined ð72JA5059Ł[
Pyrylium ions react with ammonia or primary amines to give pyridinium ions ð71RCR358Ł[

2[09[4[0[0 Iminium ion cyclizations


An excellent review of the use of iminium ions in heterocyclic synthesis has been presented by
Overman and Ricca ð80COS"1#0996Ł[
Iminium ion cyclizations have been of importance in two major areas] "i# the iminium ionÐ
vinylsilane cyclizations\ and "ii# the tandem cationic aza!Cope rearrangementÐMannich cyclization
protocol[
Iminium ionÐvinylsilane cyclizations are particularly useful for the construction of cyclic amine
natural products\ such as the pumiliotoxins[ For example\ liberation of the incipient iminium ion
in the a!aminonitrile "07# followed by reaction with the in situ vinyl silane provides the allo!
pumiliotoxin A ring system ð77TL5430\ 80COS"1#0996Ł[

NC

N H OH
TMS
OBn

(18)
Iminium Ion Salts 310
An elegant and focused method for iminium ion cyclizations of this type is the antarafacial
addition of an internal iminium ion and an external nucleophile to an alkyne\ via an intermediate
delocalized cation "08# "Scheme 15# ð77TL890Ł[ This method of nucleophile promoted iminium ion
cyclization allows the facile conversion of amines into cyclic amines with a b!exocyclic double bond
of de_ned geometry ð77JA501Ł[ Iminium ion vinyl silane cyclizations can also be induced with Lewis
acid catalysts such as TiCl3 as in the synthesis of the piperidine "19# "Scheme 16# ð89JOC0975Ł[
Reverse addition of the a!aminonitrile to TiCl3 in CH1Cl1 is critical to achieve a successful cyclization[

+
CSA, (HCHO)n, NaI, H2O, 100 °C
NH N
H

H
OH OH
(19)

i, BuLi, Et2O, –78 °C; MeOH


N I N
ii, Li, NH3, THF, –78 °C
H H
OH OH

Scheme 26

R
TMS CN R
TiCl4, CH2Cl2 Pd/C, H2, MeOH
N N
R NH
Ph Ph
(20)

Scheme 27

Iminium ions can be conveniently generated from a!methoxy amines in a Lewis acid catalyzed
procedure[ The required a!methoxy amines are readily generated electrochemically via the oxidation
of the parent amine to provide a chemoselective entry to functionalized substrates for iminium ion
cyclization ð82JA0323Ł[ This method has been utilized in a synthesis of the angiotensin!converting
enzyme inhibitors "−#!A47254A and "2#!A47254B "Scheme 17#[

OH OMe
O O O O O
O
i, Anodic oxidation
N OH N OMe ii, TiCl4

( )n ( )n

OH Cl

OMe
O O O

N OMe

( )n

Scheme 28
311 Imines and NH\ NR and N!Haloimines
The in situ generation of iminium ions for use in tandem reaction sequences\ such as the cationic
aza!Cope "1!azonia!ð2\2Ł!sigmatropic# rearrangement of iminium salts "Scheme 18# was _rst reported
in a ring expansionÐpyrrolidine annulation reaction of cyclopentane!derived amino alcohols
ð72JOC2282Ł[ This tandem cationic aza!Cope rearrangementÐMannich cyclization procedure has
since been applied to the synthesis of a range of alkaloids\ including Aspidosperma ð72JOC1574Ł\
Melodinus ð78JOC0125Ł\ and Amaryllidaceae ð78TL536Ł alkaloids[

Ar Ar Ar O
HO HO HO Ar
R2CHO, H+
+ +
R2
H
N N R2 N R2 N
R1 R1 R1 R1

Scheme 29

An improved version of Grieco|s method for the formation of 3!hydroxypiperidenes by the


iminium ion cyclization of homoallylic amines\ has been used to prepare the N!methyl!D!aspartic
acid "NMDA# antagonist cis!3!"phosphonoxy#!1!piperidine carboxylic acid ð80JOC3973Ł[
Iminium ion cyclizations have also been used in the _eld of chiral induction through the formation
of intermediate chiral oxazolidines[ The required heterocycles can either be formed via in situ
iminium ion formation from a carbonyl amine condensation ð77T1346Ł\ or via photoinduced oxi!
dation of a preprepared amine ð77TL3042Ł[ Chiral oxazolidines have been applied to a number of
targets\ for example\ tetrahydroisoquinoline "10# "Scheme 29# ð77TL5838Ł[

MeO
MeO Br
H2NCH(Ph)CH2OH + Et3N, CH2Cl2, –78 °C
N Ph
MeO
AcOH, EtOH
MeO CHO Br–
HO

MeO MeO
i, MeMgI, THF, Et2O, –78 °C
N NH
MeO Ph ii, H2, Pd/C, acidic EtOH MeO
O
(21)

Scheme 30

2[09[4[1 N!Acyliminium Ions


The syntheses\ properties\ and utilization of N!acyliminium ions in heterocyclic synthesis have
been reviewed ð80COS"2#633Ł[ Like their iminium ion counterparts\ N!acyliminium ion cyclizations
have been utilized in a number of areas\ for example\ in the synthesis of alkaloids such as the
pentacycle\ gelsemine ð77JOC2771\ 77TL2670Ł\ and the Aspidosperma alkaloids "Scheme 20# ð89T3938Ł[
Silicon!assisted N!acyliminium ion cyclizations have also been investigated ð78JA1477Ł[
0!Alkoxy!1!azaallenium salts "11# are prepared by the reaction of N!methyleneamides with tri!
alkyloxonium salts "Scheme 21# ð75CB746Ł^ protonation of the amides "12# occurs exclusively at
nitrogen to give N!acyliminium salts[
Secondary amine perchlorates react with aldehydes and ketones to give iminium salts ð52JOC2910Ł[
Iminium Ion Salts 312
O
O
NH
NH LiOBut, ButOH, THF, 5 °C
O
O
N H OR
N OR
Ac

TMS
O
O
+
N
N H
BF3•OEt2, CH2Cl2

N OR
N H OR
Ac
Ac

N
H
CO2Me

Scheme 31

R1 Ph H
R1 OR4 +
+ R43O+ SbCl6– N TFA N
N
O O
R2 CF3SO3–
R2 R3
R3 R
(22) (23)

Scheme 32

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.11
Imines and their N-Substituted
Derivatives: Oximes and their
O-R Substituted Analogues
GRAEME M. ROBERTSON
Glaxo Research and Development, Stevenage, UK
2[00[0 OXIMES AND THEIR DERIVATIVES 314
2[00[0[0 Oximes of Aldehydes and Ketones 314
2[00[0[0[0 Preparations of oximes from carbonyl compounds 314
2[00[0[0[1 Preparations of oximes from noncarbonyl compounds 315
2[00[0[0[2 Miscellaneous methods for the preparation of oximes 316
2[00[0[0[3 a\b!Unsaturated oximes 318
2[00[0[0[4 Cyclic oximes 329
2[00[0[1 O!Carbon!substituted Oximes 329
2[00[0[2 Nitrones and Related Derivatives 320
2[00[0[2[0 Acyclic nitrones 320
2[00[0[2[1 Cyclic nitrones 323
2[00[0[2[2 Miscellaneous nitrone derivatives 324
2[00[0[3 O!Chalco`en!substituted Oximes 324
2[00[0[4 O!Arsenic!substituted Oximes 324
2[00[0[5 O!Silicon!substituted Oximes 325
2[00[1 N!HETEROATOM ANALOGUES OF OXIMES 325
2[00[1[0 Sulfur Analo`ues 325
2[00[1[0[0 Sulfenimines 325
2[00[1[0[1 Sul_nimines 326
2[00[1[0[2 Sulfonimines 326
2[00[1[1 Phosphorus Analo`ues 328
2[00[1[2 Nitro`en Analo`ues 328
2[00[1[3 N!Silicon!substituted Imines 328

2[00[0 OXIMES AND THEIR DERIVATIVES

2[00[0[0 Oximes of Aldehydes and Ketones


Oximes are important functional groups in organic chemistry\ but in particular they feature as
protecting groups for carbonyl groups and as intermediates in the Beckmann rearrangement
ð77OR"24#0\ B!78MI 200!90Ł[ Unlike imines the geometric isomers of oximes are isolable and the
measurement of syn! and anti!oximes by chemical and especially NMR methods has been reviewed
ð63MI 200!90Ł[

2[00[0[0[0 Preparations of oximes from carbonyl compounds


Oximes are customarily prepared from the corresponding carbonyl compound\ and the prep!
aration of oximes by the addition of hydroxylamine to aldehydes or ketones has been reviewed

314
315 Oximes and their O!R Substituted Analo`ues
ðB!61MI 200!90Ł[ Derivatives of hydroxylamine\ e[g[\ NH1OSO2H and HON"SO2Na#1\ have also been
used[
For hindered ketones\ such as hexamethylacetone\ high pressures ð48JA1040Ł or prolonged reaction
times may be necessary[ It has also been shown ð48JA362\ 53MI 200!90Ł that the rates of formation of
oximes are at a maximum when the acidity of the mixture is about pH3[
Ketones can also be converted into their oximes by a trans!oximation reaction[ Other oximes
such as ethyl a!"isopropylidene#aminooxylpropionate ð54JOC0296\ 62OSC"4#0920Ł\ and aldehydes or
ketones can be converted into oximes using acetone oxime in acetic acid ð78JPR769Ł[

2[00[0[0[1 Preparations of oximes from noncarbonyl compounds


Oximes may be prepared from noncarbonyl compounds via redox reactions of other N0O
species[ Thus the reduction of nitroalkenes is a useful method for the preparation of oximes\ and a
wide range of reagents "typically transition metal!based catalysts#\ and conditions have been
developed[ Some of the methods are quite general\ whereas others such as reductions with zinc in
acetic acid ð33JA241Ł\ or Na1SnO1 ð74TL5902Ł are restricted to the synthesis of ketoximes[
a\b!Unsaturated nitroalkenes are readily reduced to aldoximes in high yield by tin"II# chloride at
room temperature ð77SC582Ł[ Ketoximes can be formed similarly by the reduction of a\b!unsaturated
nitroalkenes with Na1SnO1 "produced in situ from aqueous SnCl1 and aqueous NaOH# ð74TL5902Ł[
However\ these conditions are not suitable for the preparation of aldoximes[ Corresponding reac!
tions carried out under acidic ð59CB21Ł or neutral ð74CL132Ł conditions result in the formation of
a!substituted oxime derivatives[ Thus SnCl1 in the presence of an alcohol or thiol gives high yields
of the corresponding a!alkoxy! and a!alkylthiooximes\ respectively ð74CL132Ł[ The latter compounds
can also be prepared by metallation of saturated oximes with lithium diisopropylamide\ followed
by reactions of the resulting O\C!dianions with diphenyl disul_de ð74OPP072Ł[
a\b!Unsaturated nitroalkenes are also readily converted into ketoximes\ by reduction with chro!
mium"II# chloride ð74SC0214Ł[ Unfortunately the corresponding reductions of a!unsubstituted
nitroalkenes to aldoximes are accompanied by signi_cant polymerization[ a\b!Unsaturated nitro!
alkenes are reduced to the corresponding oximes by sodium hypophosphite in the presence of
palladium ð75SC80Ł whereas a\b!unsaturated nitroalkanes are readily reduced to the corresponding
oximes via palladium!assisted transfer hydrogenation with ammonium formate ð89SC1342Ł[ a\b!
Unsaturated nitroalkanes can also be reduced to oximes with leadÐacetic acid in DMF ð89SL366Ł[
Reductions of nitroalkenes with hydride reagents can be capricious\ leading to over!reduction and
to mixtures of products ð74JOC022Ł[ However\ zinc borohydride reduces a!substituted conjugated
nitroalkenes to the corresponding a\b!unsaturated oximes ð80TL2468Ł\ although nona!substituted
analogues undergo 0\3!reduction to the corresponding nitroalkanes[
Electroreductions of nitroalkenes are also possible using an aqueous perchloric acidÐdichloro!
methaneÐdioxaneÐlead electrode system followed by a hydroxylamine hydrochlorideÐsodium acet!
ate workup to yield mixtures of ketoximes and ketones ð72CL596Ł\ or ketoximes and ketals
ð72JOC1092Ł depending on the conditions used[
Examples of conjugate additions to a\b!unsaturated nitro compounds are rare[ However\ the
conjugate addition of lithium organocuprates has been observed in the reactions of both 0!"3!
chlorophenyl#!1!nitropropene ð64TL2480Ł and 2b!acetoxy!5!nitrocholest!4!ene ð72CC49Ł[
Aliphatic nitro compounds that contain an a!hydrogen can be reduced to oximes with a range of
reagents\ such as zinc dust in AcOH ð28JA2083Ł\ Co0CuII salts in alkanediamines ð62JOC2185Ł\
CrCl1 ð69JCS"C#0071\ 63S0Ł\ and "for a!nitro sulfones# NaNO1 ð63S38Ł[ Tin"II# complexes prepared
by treatment of SnCl1 or Sn"SR#1 with appropriate amounts of RSH and Et2N reduce primary and
secondary aliphatic nitro compounds to oximes ð89CL524Ł[ Secondary nitro compounds are also
converted into oximes by reaction with KH and TMS!TMS or MeS!TMS in THF or 0\3!dioxane
"Equation "0## ð89T6302Ł[ Primary nitro compounds are converted into the corresponding thio!
hydroximates under these conditions[ Secondary nitroalkanes are deoxygenated to the cor!
responding ketoximes\ under mild and neutral conditions\ by treatment with iodotrimethylsilane
and hexamethyldisilazane ð72JOC1655Ł[ In contrast\ primary nitroalkanes are converted into nitriles\
and tertiary nitroalkanes give the corresponding iodoalkanes via cleavage of the carbonÐnitrogen
bond[

NO2 OH
KH, (TMS)2S, THF, ∆ N
R1 (1)
R2 R1
R2
Oximes 316
Methods available for the direct conversion of aliphatic nitro compounds into oximes in the
presence of acid!sensitive groups\ or other reducible functionalities\ are relatively rare[ The best
conditions for such systems is reduction in carbon disul_de\ in the presence of triethylamine
ð76T440\ 89S222Ł[ Alternatively\ nitro compounds can be converted into oximes photochemically by
irradiation in acetone in the presence of Et2N "Equation "1## ð78S195Ł[ a!Nitroketones can also be
converted into the corresponding oxime\ by irradiation in 1!propanol ð62BCJ2087Ł[ Primary aliphatic
amines that lack an a!hydrogen can be oxidized to oximes under acidic conditions\ via an inter!
mediate nitroso compound ð59CB021Ł[

NO2 OH
hν, Et3N, acetone N
(2)
R1 R2 R1 R2

Homologated oximes can be obtained in good yields from nitro compounds after activation
with N\N!dimethylchloromethyleniminium chloride followed by treatment with a Grignard reagent
"Scheme 0# ð72CL0426Ł[ Alternatively\ homologated ketoximes can be prepared via carbonÐcarbon
bond formation by regioselective attack of Grignard reagents at the a!position of aci!nitro com!
pounds activated by Vilsmeier|s salt in the presence of copper"I# iodide as a catalyst ð72CL0426Ł[
Since aci!nitro compounds are available by the treatment of nitro compounds with n!butyllithium\
this method provides an indirect route for the conversion of nitro compounds into homologated
ketoximes[

BuLi, THF
+ O– DMF, (COCl)2, CH2Cl2
R1 N
R1 NO2
O– Li+

R2
Me CuI, R2MgX, THF
+
O N Cl– R1 N
R1 N Me
OH

Scheme 1

2[00[0[0[2 Miscellaneous methods for the preparation of oximes


Metallations of oximes\ and in particular aldoximes\ have been the subject of several studies\ and
the resulting anions can be alkylated in high yield ð73TL152Ł[ Anions generated from trimethylsilyl
ethers of methyl ketoximes undergo rearrangement with 0\3!migration of the silyl moiety^ this
sequence is reversed in a thermal 0\3!migration of silicon from carbon to oxygen ð73TL2382Ł[
Nontertiary carbon atoms that are activated by an electron!withdrawing group can be nitrosated
to provide oximes ðB!77MI 200!90Ł[ The initially formed C!nitroso compound is not stable and
isomerizes rapidly to give the more stable imine[
The formation of an oxime is a classical means of derivatizing a carbonyl compound[ This
transformation can also be applied to a!ketocarboxylate systems\ and an example is found in
the synthesis of a!alkoximinocarboxylic acids from a!keto!thiolic acid esters and alkoxyamines
ð73JAN421Ł[ Alkylnitriles can be converted into the corresponding a!"tosyloxyimino#alkylnitriles by
nitrosation with freshly distilled nitrosyl chloride in chloroform\ and subsequent O!tosylation
ð72OPP30Ł[
Quinone monooximes can be prepared from phenols by photolysis of equimolar amounts of the
phenol and N!nitrosodimethylamine in dioxane ð74JA2227Ł[ This procedure involves a dual proton
and energy transfer process utilizing the enhanced acidity of single!state phenols to cause photo!
dissociation of the N!nitrosodimethylamine[
The di}erent methods for the synthesis of a!hydroxylaminooximes\ their properties and their use
in heterocyclic synthesis\ have been reviewed ð75S693Ł[ a!Hydroxylaminooximes have a number of
distinctive properties associated with the vicinal reactive groups[ They have been utilized in the
synthesis of four!\ _ve!\ and six!membered heterocyclic compounds\ with a special emphasis on
N!oxide analogues and are also important as metal chelators[ Chiral a!hydroxyoximes are available
in high optical purity via resolution using "0R\ 1R#!"−#!0\1!cyclohexanediamine as the resolving
317 Oximes and their O!R Substituted Analo`ues
agent ð80CL652Ł[ a\b!Unsaturated carbonyl compounds are converted directly into the cor!
responding a!hydroimino carbonyl compounds upon treatment with butyl nitrite and phenylsilane
in the presence of a catalytic amount of N\N?!bis"1!ethoxycarbonyl!2!oxobutylidene#
ethylenediaminatocobalt"II# complex "eobe# "Equation "2## ð80BCJ1837Ł[

O OH
Co(eobe)2, PhSiH3, BuONO, THF O N
(3)
R R

The synthesis of aldohydroximino lactones via oxidations of sugar oximes have been reported
ð74HCA1143Ł[ The oxidations were e}ected by manganese dioxide\ or by mercury"II# acetate and
oxygen in the presence of cuprous chlorideÐpyridine[
Oximes have been generated by electrocyclic ring!opening reactions involving four!membered
cyclic nitrones "N!hydroxy!0\1!dihydroazetes# following treatment with potassium t!butoxide
"Scheme 1# ð75RTC092Ł[

R1 + O– R1 O–
N KOBut N NH4Cl (aq.)
+
CONEt2 CONEt2 K
R2 R2
R3 R3

R1 NOH R1 NOH

CONEt2 + R3
R2 R2
R3 CONEt2

Scheme 2

In the steroid series\ 5!nitro!alkene derivatives have been shown to undergo facile reactions with
ammonia\ methanol\ and zinc to a}ord exclusively the oximes of the corresponding 5!keto!steroids
ð73IJC"B#790Ł[
Cyclic ketones can be cleaved by treatment with NOCl and an alcohol in liquid SO1 to give
v!oximinocarboxylic acids "Equation "3## ð48JA4140Ł[

O CO2Et
NOCl, EtOH, SO2
(4)
N HCl
OH

C!Alkylations or arylations of aldoximes have not been widely reported[ The only examples of
both alkylation ð75S352Ł and arylation ð43JCS0186Ł involve homolytic reaction of free C!radicals[
Thus aldoximes are C!arylated e.ciently by decomposition of arenediazonium salts ð75S352Ł\ and
aldoximes are converted into ketoximes using a mixture of a peroxy ester and a cycloalkane or ether
as the C!alkylating agent ð75S352Ł[ Monosubstituted ketene O!alkyl!O?!silylacetals\ unlike their
disubstituted analogues\ react with nitric oxide or isoamyl nitrite in the presence of TiCl3\ to give
a!ketoxime esters "Equation "4## ð77S794Ł[ This method permits the introduction of a nitrogen
substituent at the a!carbon of the parent carboxylic ester[ a!Ketoxime esters can also be prepared
from electron!de_cient nitroalkenes via formation of cyclic nitronic esters intermediates followed
by their fragmentation by a catalytic amount of base "Equation "5## ð77BCJ350Ł[

O OH
R1 R2 C5H11ONO, TiCl4, CH2Cl2 N
(5)
O-TMS R1 CO2R2

Ar Ar
R1 CO2Me NaOMe, THF R1 CO2Me
(6)
+
N N
R2O O O– OH
Oximes 318
Nitronate salts "RCHNO1Na# act as precursors of hydroxynitrilium ion equivalents\ and react
with aromatic compounds under acidic conditions to give the corresponding oximes via protonated
nitronic acids ð78TL4652Ł[
The a!methyl groups of oximes can be functionalized regiospeci_cally via a cyclopalladation
reaction with sodium tetrachloropalladate to form the dimeric organopalladium species "0# ð74CC015\
74T588Ł[ A variety of b!functionalized products can then be prepared via subsequent func!
tionalization of the C0H bond "Scheme 2#[ For 1!disubstituted cyclohexanone oximes\ A"0\1# strain
dominates and subsequent reactions lead to the selective functionalization of the smaller 1!substituent[

HO Cl Cl
N HO HO
Na2PdCl4, NaOAc, EtOH N Pd PPh3 N Pd PPh3
R1
R3 R1 R1
R2 R2 R3 R2 R3
2
(1)
i, Ac2O, pyridine
ii, Pb(OAc)4
iii, NaBH4
pyridine

HO Cl HO
N Cl HO N OAc
i, Cl2, CCl4 N Pd py i, Pb(OAc)4, AcOH
R1 ii, NaCNBH3 R1 ii, NaBH4, 1M NaOH R1
R2 R3 R3 R2 R3
R2

Scheme 3

The initial product of the addition of NOCl to alkenes is a b!chloro nitroso compound\ and\ if
the carbon bearing the nitroso group also has a hydrogen atom\ isomerization occurs to give a!halo
oximes ð57RCR432Ł[
Procedures for the synthesis of 0\2!dioximes have been reviewed ð80OPP482Ł[

2[00[0[0[3 a\b!Unsaturated oximes


Substituted styrenes are converted regiospeci_cally into ketoximes through reaction with ethyl
nitrite in the presence of a cobalt complex and BH3− ion "Equation "6## ð77JOC3786Ł[ The reaction
proceeds via the formation of an alkylcobalt intermediate and subsequent reaction with ethyl nitrite[
Catalytic nitrosations of styrene derivatives could become a useful method for the synthesis of
oximes following the report that the catalyst ðCo"DMGH#1"py#ClŁ promotes the regioselective
hydronitrosation of styrene to give acetophenone oxime ð73CC178Ł[ Nitronate salts\ from nitro!
methane or nitroethane\ react with aromatic compounds in acidic media to yield aromatic oximes
ð80BSF629Ł[ Reductive condensations of trichloromethylarenes with hydroxylamines in pyridine also
provide a route to aryl oximes "Equation "7## ð80T336Ł[

OH
N
EtONO, ClCo(DH2)py, Et4NBH4, C6H6
R (7)
R

CCl3 OH
NH2OH, py, ∆ N
(8)

1\2!Dioximinopiperazines are formed from the additions of 0\1!diamines to dichloroglyoxime in


methanol ð74H"49#4012Ł[
329 Oximes and their O!R Substituted Analo`ues
Allylic nitro compounds are converted into allylic oximes using CS1 under solidÐliquid phase!
transfer conditions with K1CO2 as the base "Equation "8## ð89S222Ł[ This method complements the
related procedure of Barton et al[ for the reduction of aliphatic nitro compounds to oximes in CS1
with Et2N as the base ð76T440Ł[
CS2, K2CO3, PhCH2NEt3Cl
R NO2 R N (9)
OH
H2O, CH2Cl2

"E#!1!Hydroxyimino!1!arylacetonitriles\ which are useful as synthetic blocks in peptide protecting


group chemistry\ can be synthesized from styrenes via cycloaddition reactions to 3!azido!2!aryl!
furazan!1!oxides\ followed by stereoselective photolysis in EtOH:CH1Cl1 "Scheme 3# ð89BCJ0732Ł[
Ar N3 Ar
Ar NaNO2, NaN3 hν, EtOH, CH2Cl2
+ NC N
18-crown-6, AcOH –O N N
O OH

Scheme 4

2[00[0[0[4 Cyclic oximes


Relatively hindered a!chloronitroso compounds\ such as "1#\ can undergo fragmentation followed
by ring closure in an overall sequence which leads to a ring expansion and the formation of cyclic
oximes "Scheme 4# ð75RTC11Ł[

O Cl
N Cl HO
Me3Al, n-C6H14, –80 °C N Me3Al, n-C6H14, –80 °C

H2O H2O N
OH
(2)
Scheme 5

2[00[0[1 O!Carbon!substituted Oximes


Oximes can be smoothly alkylated using alkyl halides or sulfates[ N!Alkylation is a possible side
reaction\ leading to a nitrone ðB!77MI 200!90Ł[ The relative yields of oxime ether versus nitrone
depend on the nature of the reagent used\ the con_guration of the oxime\ and on the reaction
conditions ðB!72MI 200!90Ł[ For example\ anti!benzaldoximes give nitrones\ while the syn!isomers
lead to oxime ethers ð56JOC150Ł[ The syntheses of the four isomers of benzylideneacetone oxime O!
methyl ether is possible via direct or sensitized irradiation of the "E\E#!isomer or the "Z\E#!isomer
and subsequent equilibration ð75JCS"P0#0580Ł[
Alkylations of pyridine aldoximes with alkyl and benzyl halides\ under phase!transfer conditions
in a benzeneÐ09) aqueous NaOH system\ proceed regiospeci_cally to give O!alkylated oxime ethers
ð78SC2018Ł[ Alternatively\ alkali metal alkoxides in the corresponding alcohols ð65MI 200!90Ł\ or
sodium hydride in DMF ð77LA0980Ł\ can be used to generate the necessary anion[
Oximes can be converted into their O!"0!butoxyethyl#oximes analogues by O!alkylation with
butyl vinyl ether catalyzed by either Lewis acids\ such as ZnCl1\ or with mild protic acids such as
p!TSA "para!toluene sulfonic acid# ð74ZOR655Ł[ a!Chloro nitroso compounds react with ether
complexes of trialkylaluminum compounds to give oxime ethers via a radical reaction ð75RTC050Ł[
O!Aryloximes can be prepared from arenetricarbonyl chromium"9# complexes followed by reac!
tion under phase!transfer conditions "KOH\ tetraoctylammonium bromide# with oximes and sub!
sequent decomplexation with iodine ð74CC306Ł[
O!Methyl aldoximes can be prepared from the corresponding carboxylic acid via hydrogenation
of N!methoxyimidoyl halides ð80S649\ 81JOC2134Ł\ or by the one!pot reaction of the carboxylic acid
with methoxyamine and Ph2P0CBr3[ As O!methyl aldoximes can be converted into aldehydes or
Oximes 320
ketones by deoximation with paraformaldehyde and Amberlyst!04 in aqueous acetone ð82S452Ł\
this procedure not only protects the carbonyl functionality\ but also provides a mild route for the
conversion of carboxylic acids into aldehydes[
O!Allyl ethers have been developed as an acid! and base!stable protecting group for oximes
ð76TL3446Ł[ O!Oxime alkylation is selective in the presence of hydroxyl and amino groups\ whilst
palladium!catalyzed deprotection using triethylammonium formate as the reducing agent is straight!
forward even in the presence of acid! or base!sensitive functional groups "Scheme 5#[
OH allyl bromide, KOH, DMF, 0 °C to 40 °C O
N N
Pd(OAc)2, PPh3, HCO2HNEt3, EtOH (aq.), ∆
R1 R2 R1 R2

Scheme 6

Oximes can be prepared directly from carbonyl compounds via a Peterson!type reaction with the
bissilyl derivative "2# ð76S720Ł\ proceeding via an intermediate adduct which can be quenched
directly to the parent oxime\ or trapped with a range of electrophiles to give O!substituted oxime
derivatives "Scheme 6#[

O O– K+ OE
TMS-(TMS-O)N– K+ (3), THF, –78 °C to 25 °C N ECl, –78 °C N

R1 R2 R2 R1 R2
R1

Scheme 7

O!Alkyloximes are deprotonated regiospeci_cally by n!butyllithium to give the corresponding


syn!a!lithium species\ which then undergo regiospeci_c carbonÐcarbon and carbonÐhalogen bond!
forming reactions leading to syn!functionalized oximes ð78IJ076Ł[
Oxime esters are important as chemoselective acylating reagents\ particularly for bifunctional
substrates such as amino alcohols ð80S602Ł[ They can be prepared from the parent oxime either
chemically ð80S602Ł\ or using lipases biocatalysts ð82S61Ł\ via reaction with vinyl esters or di!t!butyl
carbonate to give O!acyloximes and O!"t!butoxycarbonyl#oximes\ respectively[

2[00[0[2 Nitrones and Related Derivatives

2[00[0[2[0 Acyclic nitrones


Nitrones are extremely versatile synthetic intermediates ð74OPP12Ł\ and they are of particular
importance as 0\2!dipoles in cycloaddition reactions with multiple bond systems leading to the
production of a wide variety of _ve!membered heterocyclic ring systems[ A range of reviews is
available covering this area ð64S491\ B73!MI 200!90\ 75MI 200!90\ 77OR"24#0\ 78G142\ 80G174Ł[
The traditional method for the preparation of nitrones is by the condensation of carbonyl
compounds with hydroxylamines ð68COC"1#499Ł\ or by direct oxidation of hydroxylamines[
For example\ nitrones of the type "3# were prepared by the reaction of the corresponding
hydroxymethylene compounds with hydroxylamines "Equation "09## ð75CB1645Ł[ With the exception
of the N!phenyl nitrone derived from indanone\ the nitrones formed were found to exist in the
enolic form[
O +
O– OH
HO RNHOH R N
(10)
( )n ( )n
(4)
R = Ph, Me or Bu; n = 1 or 2

The treatment of N\N!disubstituted hydroxylamines with palladium black results in formation of


nitrones ð72TL0938Ł[ Furthermore\ if this reaction is carried out in the presence of an alkene\ a regio!
321 Oximes and their O!R Substituted Analo`ues
and stereoselective heterocycle formation is possible "Scheme 7#[ Hydroxylamines are also oxidized
to nitrones by a suspension of Ag1O in ether ð68OPP138Ł[ The oxidations of hydroxylamines with
PbO1 in dichloromethane a}ord 0\3!dinitronesdehydrodimers of vinylaminyl oxides ð74CB0094Ł
presumably via isomerization of initially formed mononitrones to vinyl!substituted hydroxylamines\
followed by abstraction of a hydrogen radical[
R3
R1 R1 X R1
Pd black, 80–110 °C X
+
N N N
HO R2 –O R2 R3 O R2

Scheme 8

Both these methods are controlled by the availability of the appropriate hydroxylamine[ An
alternative general synthesis of nitrones from aldimines and ketimines is their reaction with the
hydroxylamine derivative\ MeNHOSO2H[ This method has been employed in a convenient prep!
aration of ~uorenone methylnitrone\ a previously di.cult compound to prepare "Equation "00##
ð68OPP84Ł[

NPh Me + O–
N
MeNHOSO3H, MeOH, 0 °C
(11)

Nitrones have been obtained from secondary amines in one step by sodium tungstate catalyzed
oxidation with hydrogen peroxide ð73CC763\ 73H"10#372Ł\ or by oxidation with hydrogen peroxide in
the presence of selenium dioxide as catalyst ð76TL1272Ł[ The latter method is also suitable for the
preparation of nitrones in the presence of alkenes[ Imines can be converted into nitrones by treatment
with potassium permanganate under phase!transfer conditions\ via a ð2¦1Ł cycloaddition type
reaction "Equation "01## ð78JOC015Ł[

R3
R3 KMnO4, CH2Cl2, H2O, pH 4.1
+ R2 (12)
R2 R1 N
R1 N Bu4NCl, NaHSO3, H2O
O–

Nitrones are also available via the electrochemical oxidation of N!hydroxy secondary amines
using a supporting electrolyte such as sodium iodide ð75JOC438Ł[
Ene!type reactions of alkenes ð68T036Ł or allenes ð68RTC07Ł with a!chloronitroso compounds
lead to the formation of N!a!chloroalkyl!N!alkenylhydroxylamine intermediates[ Rearrangement
then provides access to aliphatic ketonitrones\ in excellent yields[
An investigation of the reaction of a!chloronitrosoadamantane with Grignard reagents has shown
that adamantylidene nitrones "4# are formed in yields that vary widely with the nature of the
Grignard reagent "Equation "02## ð79RTC135Ł[ With MeMgX and PhMgX\ the N!methyl! and
N!phenylnitrones can be obtained in 48) and 76) yield\ respectively\ but with all other Grignard
reagents nitrone yields are much lower[ Similarly\ methyl and phenyl Grignard reagents react with
simple a!chloronitroso compounds to give the expected nitrones "5# "Equation "03## ð79RTC167Ł[

NO O–
RMgX N+
Cl R (13)

(5)

R1
Cl NO R3MgX
+ O– (14)
R1 R2 R2 N
R3
(6)
Oximes 322
The reaction between N!chlorosuccinimide and benzil "E#!monooxime\ in the presence of dimethyl
sul_de and Et2N\ a}ords a 3 ] 0 mixture of "E#! and "Z#!isomers of C!benzoyl!C!phenyl!N!methyl!
thiomethylnitrone ð79JCR"S#255Ł[ These methylthiomethylnitrones undergo cyclization under ther!
mal or photochemical stimulation\ leading to oxazoles[
C!t!Butyl!N!phenylnitrone has been prepared\ and its chemistry has been investigated in some
detail ð79JCR"S#011Ł[
Functionally modi_ed cyclic nitrones appear to o}er synthetic potential[ However\ the fact that
such nitrones have not been so utilized re~ects the problems associated with their preparation[
Nitrones of type "6# have now been prepared in high yield\ and their 0\2!dipolar cycloaddition
reactions investigated "Scheme 8# ð79JA262Ł[

O OMe OMe OMe


OMe OMe OMe
HC(OMe)3, HCl, MeOH HgO

N N N N+
Et Et OH O–
(7)
Scheme 9

Treatment of methyl 2\4!dimethoxybenzoate with thallium"III# nitrate in TFA at low temperature


has been shown to lead to the formation of 3!"1!methoxycarbonyl!3\5!dimethoxyphenyl#imino!2!
methoxycarbonyl!4!methoxycyclohexa!1\4!dien!0!one N!oxide "7# ð72SC538Ł[
MeO OMe
MeO O
+
N
CO2Me O– CO2Me

(8)

N!Alkylations of oximes by alkyl halides or sulfonates yield nitrones ðB!77MI 200!90Ł[ Nitrones
have also been obtained by alkylation of O!trimethylsilyloximes with either trialkyloxonium tetra!
~uoroborates or alkyl tri~ates in dichloromethane solution ð74TL3220Ł[ The same research group
also prepared medium!ring cyclic nitrones by heterolytic fragmentation reactions of bicyclic
g!N!hydroxylaminosulfonates[ This procedure enabled the conversions of decahydroquinolines to
perhydroazulenes to be performed ð74JOC2827Ł[
N!Methylnitrones have been generated in excellent yields by reacting carbonyl compounds with
N!methyl!N\O!bis"trimethylsilyl#hydroxylamine ð74JOC4802Ł\ and a!aroyl!N!phenylnitrones have
been obtained upon oxidation of the adducts derived from silyl enol ethers and nitrosobenzene with
silver oxide ð74S168Ł[
The addition of 1!methyl!1!nitropropane and activated zinc dust to a cold ethanolic solution of
a p!substituted benzaldehyde a}ords derivatives of phenyl!t!butylnitrone in high yields ð74JOC0420Ł[
A nitrone derived from an N!hydroxytryptophan ester and methyl ortho!formate provides a route
to b!carbolines via nitrone cycloadditions ð75JOC298Ł[
Sterically unhindered and certain moderately hindered a!chloronitroso compounds "8# react with
trimethylaluminum to give methyl nitrones "09# "Scheme 09# ð75RTC11Ł[

O Me O Me + O–
N Me3Al, n-C6H14, –80 °C N AlMe2 H2O N
R Cl R Cl R R
R R
(9) (10)

Scheme 10

As part of a mild\ multistep procedure for the oxidative deamination of benzylamines\ 3\5!
diphenylpyridinium!1!carboxylates have been converted into nitrones by reaction with p!nitroso!
N\N!dimethylaniline in re~uxing dichloromethane "Equation "04## ð72MI 200!90Ł[
323 Oximes and their O!R Substituted Analo`ues
Ph
NMe2

p-Me2NC6H4NO –O +
N (15)
Ph N CO2 –
+
Ar
Ar

A selection of methods for the stereocontrolled preparation of "Z#!nitrones is available[ Thus\


"Z#!nitrones have been synthesized under mild conditions by addition of alkoxyamines to aldehydes
in the presence of sodium bicarbonate and calcium chloride ð73JOC2310Ł\ and the adamantone!
derived nitrone "00# reacts with aromatic and aliphatic aldehydes to give the corresponding "Z#!
aldonitrone selectively\ via the fragmentation of an initially formed 0\3\1!dioxazolidine to an oxazi!
ridine intermediate\ which then rearranges to the "Z#!nitrone "Equation "05## ð89HCA058Ł[

Me
N+ + Me
RCHO, THF, ∆ R N
O– (16)
O–

(11)

C!Aryl!N!"0!carboxyalkyl#!nitrones are prepared by alkylation of aromatic "Z#!aldoximes or by


condensation of a!hydroxyiminocarboxylic acids with aromatic aldehydes ð73LA0434Ł[
N!Carbamoylnitrones were prepared by low!temperature addition of isocyanates to aldoximes
ð73ZOR877Ł[
The rearrangements of 1!chloro!1!nitrosofenchane and 1!chloro!1!nitrosocamphane to chloro!
nitrones have been recorded ð73RTC217Ł[
Acyclic a!heteroatom!substituted nitrones are available via the regioselective alkylation of hy!
droxamic acids\ under neutral conditions\ with alkyl tri~ates to give nitrone hydrotri~ates[ Subsequent
displacement of the a!O!alkyl group from these highly reactive nitrones by heteronucleophiles then
produces new nitrones with amino\ thio\ and cyano groups in the a!position "Scheme 00# ð78JOC0625Ł[

O R3
O
R3OTf, CH2Cl2 Et3N, MeCN
OH
R1 N + R2
R1 N –OTf
R2
OH

R3 Nuc
O
NucH, Et3N, MeCN + R2
+ R2 R1 N
R1 N
O–
O–
Scheme 11

1!Butenylmagnesium chloride undergoes 0\1!addition to both aryl and alkyl nitro compounds to
give\ after workup\ the corresponding "E#!nitrone "Equation "06## ð89JOC3345Ł[

MgCl, THF, –70 °C +


R NO2 R N (17)
O–

2[00[0[2[1 Cyclic nitrones


The syntheses and reactivity of four!membered cyclic nitrones have been reviewed ð89BSF693Ł[
An e.cient synthesis of _ve!ring cyclic nitrones has been achieved by the reduction of g!nitro
ketones with ammonium formate:Pd!on!carbon "Equation "07## ð77TL0574Ł[
Oximes 324
OH –O
N
HCO2NH4, Pd/C, MeOH, 60 °C +
CO2Me
R N (18)
CO2Me R
NO2

The treatment of N!"benzyloxy#amines with concentrated hydrogen peroxide solution in AcOH


enables the one!pot preparation of seven!membered cyclic nitrones in respectable yields ð71CB1568Ł\
and o}ers some advantages compared with conventional routes[
Four!membered cyclic nitrones are the major products of the reaction between nitroalkenes and
0!aminoalkynes[ In all cases only one of the two possible diastereomers is formed "Equation "08##
ð72JOC0705Ł[

R4 R4
N –O CONR42
R1 NO2 +
+ N R3
(19)
R2 R2
R1
R3

2[00[0[2[2 Miscellaneous nitrone derivatives


Acetic nitronic anhydrides are readily prepared via reaction between aliphatic nitroalkenes and
lithium enolates in the presence of acetic anhydride "Equation "19## ð89T6458Ł[ Thioimidate N!oxides
"nitrones of thio esters# have been prepared by S!alkylations of N!alkylthiohydroxamic acids with
alkyl iodides\ followed by treatment of the resulting hydroiodide salts with base "Scheme 01#
ð75JOC4087Ł[

OAc O
NO2 O LDA, Ac2O, THF, –78 °C +
+ N
R1 –O R2 (20)
R2
R1

S R2
O S
R1NHOH (aq.) R2I, Me2CO NaHCO3
OH +
Ph N OH
Ph S CO2H Ph N
R1 I–
R1
R2
S
+ O–
Ph N
R1

Scheme 12

2[00[0[3 O!Chalcogen!substituted Oximes


The Neber rearrangement involves the base!catalyzed conversion of oxime tosylates "or quat!
ernary salts of hydrazones or N!chloroimines# into a!amino ketones via isolable azirine intermediates
ð53CRV70\ B!69MI 200!90\ 60MI 200!90\ B!62MI 200!90Ł[ For a review of the conversion of ketoxime
sulphonates into a!amino ketones via the Neber rearrangement the reader is referred to Maruoka
and Yamaoto\ {{Functional Group Transformations via Carbonyl Derivatives|| ð80COS"5#675Ł[

2[00[0[4 O!Arsenic!substituted Oximes


The chemistry and physical properties of arsinooximes have been reviewed ð66C125\ 66CZ022Ł[
325 Oximes and their O!R Substituted Analo`ues
2[00[0[5 O!Silicon!substituted Oximes
Silylations of a!ketoximes leading to O!silylated ketoximes "i[e[\ no silylation of the ketone
function# have been achieved using mixtures of zinc chloride and triethylsilane in dioxane at 099>C
ð74ZOB1966Ł[ 1!"Trialkylsilyloxy#oxime O!trialkylsilyl ethers can be formed from nitroalkanes by
reaction with trialkylsilyl tri~ates\ via a 0\2!trialkylsiloxy migration "Scheme 02# ð75LA317Ł[

R2 R2 R2
TMS-OTf, Et3N
R3 R3 N
R1 R1 R1 O-TMS
NO2 N(O-TMS)2 R3

Scheme 13

2[00[1 N!HETEROATOM ANALOGUES OF OXIMES


N!Heteroatom substituted aldimines "e[g[\ sulfenimes RCH1NSAr\ silylimines R0CH1N
SiR12\ sulfonylimines R0CH1NSO1R1\ and the corresponding oximes# are useful synthons for
the unstable N0H aldimine anions\ especially in the synthesis of a!branched primary amines
ð80COS"1#883Ł[ Oximes\ oxime ethers\ and sulfenimines have been the most widely studied
compounds[ Silylimines and sulfonimines have similarly been used to prepare a!aryl!substituted
homoallylamines[ The corresponding ketimine analogues are also known\ but are much less
common[

2[00[1[0 Sulfur Analogues

2[00[1[0[0 Sulfenimines
The preparations of sulfenimines "also known as sulfenylimines and N!alkylidenesulfenamides#\
together with their structural characteristics\ their reactions\ and the methods for their conversion
into sul_nimines have been reviewed previously\ and the interested reader is directed to these
comprehensive articles ð75JOC4913\ 78CR578\ B!89MI 200!90Ł[
Unlike imines and oximes\ sulfenimines undergo relatively facile stereomutation\ but examples of
stereoisomers of sulfenimines are limited to constrained analogues ð78CR578Ł[ Sulfenimines are
available from sulfenamides by three main routes\ namely] "i# via condensation reactions with
carbonyl compounds^ "ii# from disul_des via reactions with metal salts and carbonyl compounds\
and "iii# via the condensation reactions between sulfenyl halides and imines ð78CR578\ B!89MI 200!90Ł[
They can also be prepared directly from the corresponding sulfenamide\ by treatment with
N!chlorosuccinimide and Et2N ð83SL056Ł[ Application to glycine provides an electrophilic glycine
equivalent for amino acid synthesis[
Sulfenimines are versatile synthetic intermediates\ and undergo nucleophilic additions at the
iminyl carbon\ electrophilic additions at the nitrogen centre\ and alkylation reactions at sulfur
ð78CR578\ B!89MI 200!90Ł[ They have also been reduced to N!sulfur!substituted amines by treatment
with NaBH2CN in TFA ð72JOC2420Ł[ Sulfenimines undergo oxidation to both sul_nimines "sul_nyl
imines# and sulfonimines "sulfonyl imines# "see Sections 2[00[0[1 and 2[00[1[0[2#[
The focus in the 0889s has been on the preparation of chiral sulfenimines ð83MI 200!90Ł and their
utilization as electrophilic glycine equivalents in the synthesis of amino acids "Scheme 03# ð83SL056Ł[

R CO2But

R i, LiN(TMS)2, THF, –20 °C O N TFA-H2O R CO2H


H S
O ii, ButO2CCH=NS(o-NO2C6H4), THF, 0 °C NO2 O NH2

Scheme 14
N!Heteroatom Analo`ues 326
2[00[1[0[1 Sul_nimines
Sul_nimines are more reactive than their sulfenyl analogues\ and they act as ammonia imine
synthons[ Thus\ reduction of the C1N bond with either LAH or NaBH3 a}ords the corresponding
sul_namides\ which readily undergo cleavage at the S0N bond with TFA to give the parent amino
compound ð78CR578\ B!89MI 200!90Ł[ Alternatively\ the intermediate sul_namide can be oxidized to
the corresponding sulfonamide ð71JCS"P0#228Ł[ Chiral sul_nimines are therefore valuable as chiral
ammonia imine synthons in the synthesis of nonracemic amines ð71JCS"P0#228Ł[ They are also
valuable in the synthesis of a!\ b!\ or g!amino acid derivatives\ via either reaction with diethyl!
aluminum cyanide to form a!amino nitriles\ which are readily hydrolyzed to the corresponding
amino acids ð80JOC3\ 83TL8240Ł\ or reaction of nitriles with an alkyllithium followed by reaction
with "−#!L!menthyl "S#!p!tolylsul_nate ð80JOC3Ł[ They also undergo Darzen|s!type reactions with
lithium enolates to form cis!aziridine!1!carboxylic acids ð83JOC2132Ł[
Sul_nimines are generally accessed by asymmetric oxidations of the corresponding sulfenimines
with reagents such as chiral N!sulfonyloxaziridines ð81JOC5276\ 82PAC522Ł\ or by Andersen!type
procedures from metalloimines and menthyl p!tolyl sul_nate "Scheme 04# ð82TL5118Ł\ although this
procedure is limited to the formation of alkyl aryl sul_nimines[

: O
S
p-Tolyl O
dibal MeLi –
R CN AlBui2 AlBui2 Li+
R N R N
:

O
S
p-Tolyl N R

Scheme 15

2[00[1[0[2 Sulfonimines
As with most N!heteroatom!substituted oxime derivatives\ sulfonimines are known by a range of
titles such as sulfonyl imines or oxime sulfonates[ They are highly versatile and reactive reagents
and are readily available from oximes by reaction with sulfonyl halides in the presence of base
ð64S491Ł[ An alternative and general procedure for the preparation of sulfonimines\ even in systems
prone to tautomerization\ is the treatment of carbonyl compounds with sulfonyl chlorides in the
presence of tertiary amines\ such as Et2N ð81JOC3666Ł[ Sulfonimine formation results from a reaction
cascade of amine!catalyzed rearrangement of the initial sulfonyl chloride to a sul_nyl cyanate\
followed by oxime O!sul_nylate formation and subsequent homolytic rearrangement to the sul!
fonimine[
Sulfonimines have proved to be highly useful precursors ð81BSB270Ł[ In particular\ they readily
undergo Beckmann!type rearrangements under a variety of conditions to give a number of
compounds\ e[g[\ in the presence of dialkylaluminum thiolates or selenoates to give iminothioethers
"valuable as activated amide surrogates# and iminoselenoethers\ respectively ð72JA1720Ł[ A similar
reaction with cyanotrimethylsilane and diethylaluminum chloride has a}orded iminonitriles and a!
alkylated amines are available via organoaluminum!promoted Beckmann rearrangement of sul!
fonimines ð72JA1720Ł[ Rearrangement in the presence of TMS!I or Et1AlI gives imidoyl iodides
ð72TL2144Ł[ Regio! and chemospeci_c carbonÐcarbon bond formation results from the Lewis acid
promoted reaction of sulfonimines with silyl enol ethers and provides an e.cient method for the
synthesis of enaminones\ which are useful building blocks for the synthesis of fused carbocycles and
polyheterocycles\ in addition to their reduction to functionalized amino alcohols ð72JA5201Ł[
Alkenic cyclizations promoted by Beckmann rearrangement of sulfonimines provide access to a
range of ring systems\ via four distinct cyclization modes "Scheme 05#\ controlled by the Lewis acid
employed as the initiator and the migratory aptitude of the rearranged group ð72JA561\ 72TL832Ł[
Natural product applications of these reactions have included syntheses of solenopsin B and
327 Oximes and their O!R Substituted Analo`ues
muscopyridine ð72JA561Ł[ Beckmann rearrangement of sulfonimines by reaction with Grignard
reagents gives functionalized imines\ which upon reduction give a!alkylamines ð71TL2284Ł[

endo(B)–endo mode
R
R N
N H
OMs

R2
R2
endo(B)–exo mode

R1 R1 R1
R1 N
N
OMs

( )n
exo(B)–endo mode ( )n
Ph

N NHPh
MsO

exo–exo mode
R
N R
N
MsO

Scheme 16

The C1N bond of sulfonimines is readily reduced under mild conditions with NaBH3
ð70JCS"P0#1332Ł or LAH ð76S608Ł to give the corresponding sulfonamide[ N!Aryl sulfonimines were
used as dienophiles in some of the earliest examples of heterocycle formation via imino DielsÐAlder
reactions ðB!56MI 200!90Ł[ Sulfonimines can also be generated in situ for use in both inter! and
intramolecular DielsÐAlder reactions by treatment of an aldehyde and 0\2!diene with N!sul_nyl!p!
tolylsulfonamide and BF2 = Et1O ð89JOC2926Ł[
Sulfonimines are e.cient acceptors and they readily undergo nucleophilic reactions with organo!
metallic reagents ð72S443\ 73TL4840\ 76TL4004Ł to give a!functionalized N!arylsulfonamides[ Hitherto
the reaction has been of little use for amine synthesis however\ due to the problems of removal of
the sulfonyl group[ This problem has now been overcome by the use of diarylsulfamylimines as the
masked amine functionality\ as these groups are readily hydrolyzed in re~uxing aqueous pyridine
"Scheme 06# ð75TL2846Ł[

R O O R R
O O RM i, pyridine, H2O
S S
Ar N N Ar Ar N N Ar ii, NaOH Ar NH2
H H

Scheme 17

In situ generation of the sulfonimine has also been used for the generation of aldehyde derived
sulfonimine examples\ thus treatment with N!sul_nylsulfonamides a}ords sulfonimines which react
with Grignard reagents to give N!sulfonylamines ð89JOC282Ł[
N!Tosylimines have been synthesized in variable yields by a diisobutyl telluride:copper powder!
induced reaction of aldehydes with tosylazide ð74CL568Ł which does not react even under forcing
conditions[ An organotellurilimine has been proposed as an intermediate "Scheme 07#[
N!Heteroatom Analo`ues 328

Ts
R1CHO R2Te+ N –R2TeO R1
TsN3 + R2Te R2Te NTs
–O NTs
R1

Scheme 18

2[00[1[1 Phosphorus Analogues


N!Phosphinoyl imines are highly electrophilic imines[ They are usually prepared by the reactions
of oximes with chlorophosphorus"III# reagents in the presence of Et2N "Scheme 08# ð71S169\ 74CC471Ł[
N!Phosphinoyl imines can be reduced by a variety of hydride reagents under mild conditions
ð67S410Ł to N!phosphinylamines\ which are then cleaved under mild acidic conditions to the parent
amines[ Diastereoselective reductions have also been performed using LiBHBus2 ð76TL4508Ł\ and
enantioselective reductions of N!diphenylphosphinylimines are also possible ð71S169\ 76JOC691Ł[

Ar Ar Ar
R2PCl [O]
O
ArCHO N N N
OH P(O)R2 P(O)R2

Scheme 19

N!Phosphinoyl imines serve as precursors to N!phosphinoyloxaziridines\ the phosphorus equiv!


alents of the Davis reagents N!sulfonoyloxaziridines "Scheme 08# ð74CC471Ł\ and can also be
converted into primary amines in a stereoselective manner ð76JOC691Ł[
Reactions of phosphinamides or sulfonamides with aryl aldehydes in the presence of TiCl3 and
Et2N provide a simple one!step synthesis of N!phosphinoyl! and N!sulfonoyl imines\ respectively
ð77TL2614\ 80T4450Ł[ Extension of this reaction to ketone examples failed owing to competing aldol
condensation reactions\ although nonenolizable ketones or bulky ketones\ such as camphor\ can
form both N!phosphinoyl! and N!sulfonoyl imines under more forcing conditions of re~ux in
toluene[

2[00[1[2 Nitrogen Analogues


The chemistry of N!nitrosoimines and N!nitrosamines has been reviewed in depth ðB!71MI 200!90Ł[
The chemistry of N!nitrosoimines\ and especially their use in the preparation of heterocycles\ has
also been reviewed ð66H"6#0020Ł[
The formation of sterically hindered nitroimines is possible via the direct treatment of the parent
oxime with NOCl\ although concomitant formation of the parent ketone via intramolecular reaction
of the intermediate N!nitrosonitrone can be a problem ð73S368Ł[
The chemistry of N!nitrosoimines as synthetic intermediates\ for example\ in the preparation of
azamonomethinecyanines ð67BCJ424Ł\ or their reduction with LAH ð65BCJ0802Ł\ has been studied
in a series of papers by Akiba et al[ ð65BCJ449Ł[
As for the other N!heteroatom!substituted oximes derivatives\ N!nitroimines "also known as
nitrimines# are also reduced by NaBH3 in this case to N!nitroamines "nitramines# ð66JOC2335Ł[
However\ in this series\ the reduction must be carried out in AcOH in order to be successful[

2[00[1[3 N!Silicon!substituted Imines


Like their sulfur counterparts\ N!silylimines have been employed as masked N!H imines\ since
the labile silyl group is readily removed even in situ[ Thus nonenolizable carbonyl compounds
can be converted into primary amines by reaction with lithium hexamethyldisilazide to give
N!trimethylsilylaldimines\ which spontaneously lose trimethyl silyl oxide\ in analogy to the
Peterson alkenation\ to give the target amine "Scheme 19# ð72JOC178Ł[ Trimethylsilylimines also
339 Oximes and their O!R Substituted Analo`ues
react with organolithium and Grignard reagents to give primary amines\ after hydrolysis ð71S350Ł[
Attempts to prepare N!silylimines from enolizable carbonyl compounds have largely been thwarted
by the problems of competing enolization and tautomerization to the corresponding enamines
ð71S350Ł[ N!Silylimines from enolizable aldehydes have nevertheless been prepared and reacted in
situ with ester enolates to provide b!lactams ð76TL4258Ł[ The temperature at which the N!silylimine
is generated\ −29>C\ may be the key to success\ since nonenolizable N!silylimines are normally
generated at −69>C[ Enolizable N!trimethylaldimines can also be prepared by the reaction of
bis"trimethylsilyl#formamide with organolithium reagents ð78TL3164Ł[ Again this method was
developed as a route to b!lactams "Scheme 10#[

O–
LHMDS TMS TMS
RCHO R N R N
TMS

Scheme 20

O OH
TMS BuLi, THF, –78 °C TMS
R1 N R1 N
TMS TMS

R2 R1
R2CH2CO2Et, LDA
TMS
R1 N
THF, < –70 °C NH
O

Scheme 21

A detailed coverage of the methods available for the preparation of N!silylimines\ their mechanism
of formation\ and their structure\ is presented in an article by Colvin et al[ on the condensations of
silyl ketene acetals with N!silylimines ð77T3046Ł[ N!Silylimines are also available via the condensation
reactions between N!"trimethylsilyl#phosphimines and carbonyl compounds ð65CB0380Ł and the
reaction of nitriles with organometallic reagents when quenched with TMS!Cl ð56JOM"8#120Ł[
As mentioned earlier\ N!silylimines provide a valuable alternative to oxime ethers for the synthesis
of N!unsubstituted b!lactams\ as the silyl group is readily removed by protodesilylation during
workup[ N!Silylimines are similar in reactivity and stereoselectivity to N!arylimines in their reactions
with enolates and silyl ketene acetals[
Like acyclic imines\ they exist in one geometrical form\ presumably the "E#!isomer[
Pioneering investigations by Hart et al[ have provided much insight into the scope and stereo!
selectivity of enolate!N!silylimine condensations[ In their original paper\ the viability of these
reactions was demonstrated using mainly a\a!disubstituted esters\ which add via their lithium
enolates to nonenolizable N!silylimines to a}ord mixtures of diastereomeric N!unsubstituted
b!lactams\ following aqueous workup "Equation "10## ð72JOC178Ł[ For a review of this aspect of
N!silylimine chemistry\ see Kleinman and Volkman ð80COS"1#823Ł[

R2 R3
R2 LDA, THF, –78 °C; R3CHN-TMS R1 (21)
R1 CO2Et NH
O

A simple route to N!"trimethylsilylmethyl#imines\ which are useful as precursors to {{non!


stabilized|| azomethane ylides\ involves the reduction of trimethylsilylmethylazide using LiAlH3\
followed by standard imine formation with carbonyl compounds "Scheme 11# ð77SC0864Ł[
330
O
LiAlH4, Et2O, < 10 °C R1 R2 R1
TMS N3 TMS NH2
Na2SO4
40nm molecular sieves TMS N R2

Scheme 22

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.12
Imines and Their N-Substituted
Derivatives: Hydrazones and
Other 1NN Derivatives
Including Diazo Compounds
J. STEPHEN CLARK
University of Nottingham, UK
2[01[0 HYDRAZONES AND THEIR DERIVATIVES 333
2[01[0[0 Hydrazones and Azines Derived from Hydrazine 333
2[01[0[1 N!Substituted and N\N!Disubstituted Hydrazones 335
2[01[0[2 Hydrazones from Azo Compounds 337
2[01[0[3 Semicarbazones 338
2[01[0[4 Osazones 349
2[01[0[5 Cyclic Hydrazone and Azine Derivatives 340
2[01[0[5[0 1!Pyrazolines and 1!pyrazolin!4!ones 340
2[01[0[5[1 Tetrahydropyridazines 342
2[01[0[5[2 Cyclic azines 342
2[01[1 R1C1NX FUNCTIONS "XP\ As\ Sb\ Bi\ Si\ Ge\ B or METAL# 344
2[01[1[0 Imines Substituted with Phosphorus or Arsenic 344
2[01[1[1 Imines Substituted with Silicon\ Germanium\ Tin or Lead 345
2[01[1[2 Imines Substituted with Boron or Aluminium 346
2[01[1[3 Imines Substituted with Lithium 348
2[01[1[4 Imines Substituted with Beryllium or Ma`nesium 348
2[01[1[5 Imines Substituted with Titanium\ Zirconium or Hafnium 359
2[01[1[6 Imines Substituted with Molybdenum or Tun`sten 359
2[01[1[7 Imines Substituted with Man`anese 359
2[01[1[8 Imines Substituted with Iron 359
2[01[1[09 Imines Substituted with Platinum or Rhodium 350
2[01[1[00 Imines Substituted with Zinc 350
2[01[2 DIAZO COMPOUNDS 350
2[01[2[0 General Methods for the Preparation of Diazo Compounds 350
2[01[2[1 Alkyl and Aryl Diazo Compounds 351
2[01[2[1[0 Diazotization of amines 351
2[01[2[1[1 Forster reaction of oximes 352
2[01[2[1[2 Dehydro`enation of hydrazones 352
2[01[2[1[3 BamfordÐStevens reaction of tosyl hydrazones 353
2[01[2[1[4 Cleava`e of N!nitrosoamines 354
2[01[2[1[5 Diazo `roup transfer 356
2[01[2[2 a!Diazo Carbonyl and b!Dicarbonyl Compounds 357
2[01[2[2[0 Diazotization of a!amino carbonyl compounds 357
2[01[2[2[1 Forster reaction of a!keto oximes 358
2[01[2[2[2 Direct nitrozation of carbonyl compounds 358
2[01[2[2[3 Dehydro`enation of a!keto hydrazones 358
2[01[2[2[4 BamfordÐStevens reaction of a!keto tosyl hydrazones 369

332
333 Hydrazones and Other 1NN Derivatives
2[01[2[2[5 Cleava`e of N!nitrosoamides 360
2[01[2[2[6 Diazo `roup transfer to carbonyl compounds 360
2[01[2[2[7 Substitution at the diazo carbon of a!diazo carbonyl compounds 363
2[01[2[3 a!Diazo Imines\ Amidines\ Imidates and Nitriles 365
2[01[2[3[0 a!Diazo imines 365
2[01[2[3[1 a!Diazo amidines and imidates 366
2[01[2[3[2 a!Diazo nitriles 366
2[01[2[4 Diazo Alkanes Containin` Heteroatoms at the Diazo Carbon 367
2[01[2[4[0 Diazo alkanes substituted with halo`ens 367
2[01[2[4[1 Diazo alkanes substituted with sulfur 367
2[01[2[4[2 Diazo alkanes substituted with nitro`en 368
2[01[2[4[3 Diazo alkanes substituted with phosphorus 379
2[01[2[4[4 Diazo alkanes substituted with arsenic\ antimony or bismuth 371
2[01[2[4[5 Diazo alkanes substituted with silicon\ `ermanium\ tin or lead 371
2[01[2[4[6 Diazo alkanes substituted with boron or thallium 374
2[01[2[4[7 Diazo alkanes substituted with lithium or sodium 374
2[01[2[4[8 Diazo alkanes substituted with ma`nesium 375
2[01[2[4[09 Diazo alkanes substituted with transition metals 375
2[01[2[4[00 Diazo alkanes substituted with silver 376
2[01[2[4[01 Diazo alkanes substituted with zinc\ cadmium or mercury 377
2[01[2[5 Unsaturated Diazo Alkanes 377
2[01[2[5[0 Diazo alkylidenes 377
2[01[2[5[1 a\b!Unsaturated diazo alkanes 378
2[01[2[5[2 Diazo alkynes 389

2[01[0 HYDRAZONES AND THEIR DERIVATIVES

2[01[0[0 Hydrazones and Azines Derived from Hydrazine


The most common method for the preparation of N!unsubstituted hydrazones is reaction of an
aldehyde or ketone with a hydrazine[ During the reaction\ one of the available amino groups of the
hydrazine reacts to form a hydrazone\ or both amino groups react to form an azine\ depending on
the stoichiometry and the experimental conditions "Scheme 0#[ Aldehydes and dialkyl ketones react
readily with hydrazine in aqueous or alcoholic solvents to give the corresponding azines ð32OSC"1#284\
47JOC528Ł[ To obtain hydrazones rather than azines\ a large excess of hydrazine is required and
traces of acid must be excluded ð59JOC0664Ł[ In some cases\ hydrazones may be prepared by
treatment of azines with an excess of hydrazine "Scheme 0# ð91CB2123\ 59JOC0664\ 69OS"49#2Ł[ Hydrazones
prepared by reaction of hydrazine with aromatic aldehydes bearing electron!donating substituents
are unstable and form azines in alcoholic solvents[ In contrast\ hydrazones of electron!de_cient
aromatic aldehydes are stable even when heated in alcoholic solvents ð0899CB1359\ 59JOC0664Ł[

R1 R2
O H2NNH2 (<1 equiv.), EtOH, reflux
N
N
R1 R2
R1 R2
H+, EtOH
(R1R2CO)
H2NNH2 (excess) NH2
N H2NNH2 (excess)
EtOH, reflux
EtOH, reflux
R1 R2
R1, R2 = H, alkyl, aryl

Scheme 1

Arylalkyl ketones can be converted into hydrazones by treatment with hydrazine in an alcoholic
solvent\ but the azine product predominates in the presence of acids ð35JA0872\ 47CB491\ 50JCS4459Ł[
The formation of hydrazones of diaryl ketones usually requires prolonged reaction times and high
temperatures ð18CB1022\ 35JA803\ 44OSC"2#240Ł\ and in some cases it is necessary to add a water!
absorbing agent to the reaction ð49JA1789Ł[ Azines can be prepared by the addition of a mineral
acid to alcoholic solutions of hydrazones at room temperature ð49JA1789Ł\ or by heating hydrazones
Hydrazones 334
with ketones in the presence of acids "Scheme 0# ð0899CB1359\ 47JA2937Ł[ The latter method is useful
for the preparation of unsymmetrical azines[
N!Unsubstituted hydrazones can also be prepared by exchange reactions of N\N!dialkyl hydra!
zones with hydrazine ð55JOC566Ł[ This procedure avoids the problem of azine formation frequently
encountered when aldehydes or ketones are treated directly with hydrazine[ The carbonyl compound
is usually _rst converted into the corresponding N\N!dimethyl hydrazone\ and this compound is
then treated with hydrazine to give the required hydrazone "Scheme 1# ð55JOC566Ł[

O NMe2 NH2
Me2NNH2 (anh.) N H2NNH2 (excess) N

R1 R2 EtOH, reflux
R1 R2
EtOH, reflux
R1 R2

Scheme 2

An unusual example of hydrazone formation is the reaction of the cyclic nitrone "1# with hydrazine
to a}ord the ring!contracted hydrazone "0# "Scheme 2# ð56AJC228Ł[ In this case\ hydrazine attacks
the carbon centre adjacent to nitrogen rather than the carbonyl group\ and subsequent ring closure
then gives "0#[ In contrast\ the nitrone "1# reacts with 1\3!dinitrophenylhydrazone to give "2#\ the
expected hydrazone product[

O 2N NO2

NH2 O H
N
N H2NNH2 (anh.) Brady's reagent
+ + N
N C6H6 N EtOH, H2SO4
O– O– +
N
O–
(1) (2) (3)

Scheme 3

There are several routes to azines from compounds other than aldehydes and ketones[ For
example\ symmetrical azines can be formed by hydrogenation of nitriles with Raney nickel in
hydrazine "Scheme 3# ð44G0694\ 51JOC2605Ł[ This sequence proceeds by addition of hydrazine to the
nitrile to a}ord an imino hydrazide "3#\ followed by reduction and elimination to give a hydrazone\
which reacts with more of the nitrile to give "4#\ and _nally conversion to the symmetrical azine[

H NH2 NH2
H2NNH2 N Raney Ni, H2 N RCN
R CN
–NH3
R NH R
(4)

R NH R
Raney Ni, H2
N N
N H N
–NH3

R R
(5)

Scheme 4

Unsymmetrical azines can be prepared by reaction of phosphoranes with diazo compounds


ð50TL700\ 51T0912Ł[ Treatment of phenyldiazomethane or an a!diazo carbonyl compound with a
phosphonium ylide a}ords the azine product "5# in reasonable yield\ but signi_cant amounts of the
phosphazine "6# may be produced by reaction of the diazo compound with the triphenylphosphine
generated during the reaction "Scheme 4#[
335 Hydrazones and Other 1NN Derivatives
R1
+
R2 Ph3P R1
R1 N
+ N
Ph3P N –
N2
N R2
R2
(6)
Ph3P
+
R2 Ph3P N
+ PPh3 –
N
N2 N
N R2
R2
(7)

Scheme 5

2[01[0[1 N!Substituted and N\N!Disubstituted Hydrazones


Reactions of N!alkyl and N\N!dialkyl hydrazines with aldehydes and ketones usually a}ord the
expected substituted hydrazones ð11JCS0537\ 46JOC193\ 48JOC0814\ 59JOC0664Ł[ Although these reactions
are reversible\ the equilibrium usually favours the condensation product "Scheme 5#[ Two isomers
of the hydrazone are possible\ and with aryl hydrazones of aliphatic aldehydes and ketones\ the
isomer in which the amino group "NHR2 or NR2R3# is trans to the bulkiest group of the carbonyl
compound predominates ð51JA642\ 52JA1673\ 52JA2513Ł[
R3 R3
H2NNHR3 O H2NNR3R4
N N
N H N R4
solvent, heat R1 R2 solvent, heat
R1 R2 R1 R2

Scheme 6

Monoalkyl hydrazones derived from aromatic aldehydes have a labile N!hydrogen\ and addition
of the hydrazone to unreacted aldehyde is possible\ especially when the latter is in excess ð11JCS0537Ł[
The degree to which this side reaction occurs depends on the experimental conditions employed[
Aryl hydrazines such as phenyl\ p!nitrophenyl\ and o\p!dinitrophenyl hydrazine react with most
aldehydes or ketones to a}ord hydrazones\ and a large number of these compounds have been
prepared ð58QR26Ł[ N!Aryl hydrazones are usually solids\ and their melting points can be used to
identify the parent carbonyl compounds ð38JA2725\ 58QR26Ł[ N!Aryl hydrazones\ and especially
those substituted with nitro groups\ are stable to acids and are usually prepared under strongly
acidic conditions[
Reactions of aryl hydrazines with formaldehyde do not usually a}ord simple methylene hydra!
zones\ but it has been reported that the reaction of p!methylphenylhydrazine with formaldehyde
in acetic acid a}ords N!methylene!p!methylphenyl hydrazone as well as polymeric by!products
ð51CA"45#3534Ł[
Hydrazones can be prepared by exchange reactions of hydrazines with the imines derived from
aniline ð47M607Ł\ or with oximes ð45JOC533Ł "Scheme 6#[ Exchange reactions can also be performed
by treatment of the hydrazone of a low boiling ketone\ such as acetone\ with a less volatile aldehyde
or ketone "Scheme 6# ð47CA"41#8879Ł[ The reaction is forced to completion by the removal of the low
boiling ketone by distillation[
Tosyl hydrazones are useful precursors for the BamfordÐStevens and Shapiro reactions ð41JCS3624\
52JOC769Ł[ These compounds can be prepared by treatment of an aldehyde or ketone with tosyl
hydrazine under acidic or neutral conditions\ usually with ethanol or acetic acid as solvent[ Mono!
tosylhydrazones of a!diketones are important precursors to a!diazoketones "see Section 2[01[2[2[4#\
and they can be prepared directly by treatment of a!diketones with tosyl hydrazine ð47JA1146Ł[
Substituted tosyl hydrazines can be converted directly into hydrazones by treatment with base
ð50JCS0632\ 53JA1284Ł[ When N!aryl!N!benzyl!N?!tosyl hydrazines are heated with aqueous or
alcoholic alkali\ they rearrange to hydrazones with intramolecular migration of the benzyl group
"Scheme 7# ð50JCS0632Ł[ The same reaction can be accomplished by heating sodium salts of ben!
zenesulfonyl hydrazones in diethylene glycol ð53JA1284Ł[
Oxidation reactions of hydrazines can be useful for the preparation of hydrazones[ Treatment
Hydrazones 336
R3
OH N Ph
N H2NNR3R4 H2NNR3R4 N
N R4
solvent, heat solvent, heat
R1 R2 R1 R2 R1 R2

R1R2CO
–Me2CO

R3
N
N R4

Scheme 7

Ph

N N+
Ph
–Ts–

Ts Ph Ts Ph Ph Ph
base
N N N N N N Ph N H

H Ph Ph Ph N

–Ts–
Ts Ph
N N

Ph

Scheme 8

of hydrazines with oxidising agents\ such as mercury"I# oxide ð00JPR011\ 53CRV038Ł\ or bromine
ð51JOC2835Ł\ under carefully controlled conditions\ a}ords either hydrazone or azine products[
Oxidation of trimethylhydrazine with bromine a}ords the hydrobromide salt of formaldehyde
dimethylhydrazone "Equation "0## ð51JOC2835Ł[ In certain cases\ rearranged hydrazones may be
obtained from oxidation reactions[ For example\ the hydrazone "8# is obtained via the azo compound
"7# produced by oxidative rearrangement of N!benzyl!N!phenylhydrazine with mercury"I# oxide
"Scheme 8# ð53CRV038Ł[
Me Me Me
HBr, Br2, heat
N N N N HBr (1)
Me H Me

Ph Ph H Ph
HgO
N NH2 N N N N
Ph Ph Ph
(8) (9)

Scheme 9

Hydrazones can also be prepared by reaction of alkynes or phenyl!substituted alkenes with


sodium hydrazide in hydrazine ð53AG195\ 53AG"E#231\ 54CB801Ł[ For example\ diphenylethyne can be
converted into the hydrazone "09# by reaction with sodium hydrazide in ether at 9>C "Scheme 09#
ð53AG195\ 53AG"E#231Ł[ This reaction is of limited synthetic use because a mixture of two products is
337 Hydrazones and Other 1NN Derivatives
usually formed with unsymmetrical alkynes\ and the reaction is not applicable to terminal alkynes[
Monoalkyl! and N\N?!dialkylhydrazines can be used as substrates for the reaction\ but the reaction
is not successful with N\N!dialkylhydrazines and more highly substituted hydrazines[

NH2 NH2
– N N
H2NNH2 H3O+
H2N NH– + Ph Ph
Ph Ph
Ph Ph
(10)

Scheme 10

2[01[0[2 Hydrazones from Azo Compounds


Aliphatic azo compounds which contain a hydrogen adjacent to the azo group are unstable
and will readily tautomerize to the more stable isomeric hydrazones ð52JA2513\ 54JCS2417Ł[ The
tautomerization between the hydrazone\ azo and ene!hydrazone forms of phenylhydrazones has
been the subject of extensive studies ð36BSF327\ 54JCS2417Ł[ In nonpolar solvents or in the pure state\
phenylhydrazones exist in the hydrazone form ð52JA2513\ 54JCS1677Ł[ However\ all three tautomers
are present in an aqueous methanol solution ð52BAU397Ł[
The conversion of azo compounds into hydrazones can be exploited to prepare hydrazones from
diazonium salts[ Aliphatic compounds which contain an activated methylene group can be coupled
to aryl diazonium salts in the presence of a mild base\ to produce aryl hydrazones "Scheme 00#
ð48OR"09#0Ł[ The reaction proceeds by nucleophilic attack of the stabilised carbanion of the methyl!
ene compound on to the diazonium ion to form an azo compound which then tautomerizes to
a}ord a hydrazone[ The reaction is usually performed in bu}ered aqueous solution\ although it can
be accomplished at lower pH when the activated methylene compound possesses strongly electron!
withdrawing substituents[ Coupling is followed by decarboxylation when one of the activating
groups is a carboxyl group[

Ar
Y Ar N Y
+ –CO2 N
Ar N N – N N H
Z Z = CO2H
Z
Y

Ar N Y
N
H Z
Y, Z = electron-withdrawing groups

Scheme 11

When a compound containing an activated methine group is coupled to an aryl diazonium ion\
the intermediate azo compound cannot tautomerize[ If one of the activating groups is an acyl or
carboxyl group\ this is cleaved by hydrolysis on workup "Scheme 01#[ This reaction is known as the
JappÐKlingemann reaction\ and there are many examples of its utility ð48OR032Ł[ For those sub!
strates in which there is more than one cleavable activating group\ the acyl group corresponding to
the weaker acid is usually lost ð91CB804Ł[ The tendency of various activating groups to undergo
cleavage is illustrated by the behaviour of various a!substituted cyclohexanones "Scheme 02#[ The
side chain is cleaved when it is either a carboxyl or formyl group\ but when the side chain is an ester
or acetyl group\ ring scission is observed ð48OR"09#032Ł[ It is possible to isolate the azo intermediates
formed during the JappÐKlingemann reaction\ by performing addition at low temperature in
weakly acidic media ð42LA"468#17\ 46CB0959\ 48OR032\ 51JA2403\ 51JA3776\ 51JA3781\ 54JCS6074Ł[ Hydrolytic
Hydrazones 338
cleavage of these azo intermediates is catalysed by acid or base\ and nucleophilic reagents such as
ethanol\ phenol or aniline also promote this reaction ð51JA2403Ł[

HO H Ar
Y
+ R1
Ar N N R1 – Ar N Y N
N N H
R2
O –OH
O R2 Y R1

Y = electron-withdrawing group

Scheme 12

O
N Ar
N
Y = H, OH H
O O
O O
ArN2+X–, base Y
Y N
N
Ar Y = R, OR H Ar
O N O
N
HO R

Scheme 13

Compounds activated by nitro rather than acyl groups react with aryl diazonium salts to a}ord
hydrazones ð42LA"468#17Ł[ Primary nitroalkanes react to give the corresponding aryl hydrazones of
a!nitro aldehydes ð48OR"09#0Ł[ For example\ nitromethane reacts with benzenediazonium salts in dilute
hydrochloric acid "pH 3[4# to give the phenyl hydrazone of nitroformaldehyde ð37JA0270Ł[ When
aryl dinitromethanes and diaryl nitromethanes react with benzenediazonium ion\ the nitro group
migrates to the aromatic ring and p!nitrophenylhydrazones are produced "Scheme 03# ð48OR"09#0Ł[
In cases where the para position is blocked\ the nitro group migrates to the ortho position[
H Ar
Ar Ph Ar
Y
ArN2+ X–, base N N N
N Y
NO2 Y NO2 H
O 2N
Y = Ar, NO2

Scheme 14

Aryl diazonium salts will also couple with a variety of unsaturated compounds to a}ord aryl
hydrazones ð48OR0Ł[ For example\ enamines couple e.ciently with aryl diazonium salts[ Substrates
with a hydrogen atom on the b!carbon a}ord glyoxal b!arylhydrazones\ and those without a
hydrogen atom on the b!carbon are cleaved to furnish ketone hydrazones "Scheme 04# ð45JA4473Ł[

2[01[0[3 Semicarbazones
Semicarbazones and thiosemicarbazones can be prepared by treatment of a ketone or aldehyde
with semicarbazide or thiosemicarbazide "Scheme 05#[ The reaction is general acid catalysed\ and
the yield of semicarbazone and the rate of reaction are dependent on the pH of the reaction medium
ð21JA1770\ 48JA364\ 55BSB590Ł[ The formation of semicarbazones from ketones can be catalysed by
the addition of anilines ð51JA715Ł[ In this case\ a Schi} base is formed as an intermediate which
then undergoes exchange with semicarbazide in a subsequent step "Scheme 05#[ The rate of reaction
349 Hydrazones and Other 1NN Derivatives
Ar
R3
H N
N H + N CHO
R1 and R2 = alkyl
R3 R3
R1 R2
+ R1 N R3
Ar N N X– +
N Ar
R3
R2 C H N
R 2= H H N + N H
O R3
R1

Scheme 15

of semicarbazide with the intermediate imine is much greater than on the parent carbonyl compound
ð47M607\ 51JA715Ł[
X NH2
O H2NNHC(X)NH2
N
N H
R1 R2
R1 R2

ArNH2
H2NNHC(X)NH2

Ar
N

R1 R2

X = O, S; R1, R2 = H, alkyl, aryl

Scheme 16

Aliphatic and aromatic nitriles can be converted into semicarbazones of the corresponding
aldehydes by reduction with Raney nickel in the presence of semicarbazide ð44CB0845\ 48JA1404Ł[
This reaction is analogous to that used to prepare azines from nitriles and hydrazine "see Section
2[01[0[0#[

2[01[0[4 Osazones
Osazones are formed by the addition of hydrazines to a!diketones or a!hydroxy ketones[ These
compounds have been known since the early days of carbohydrate chemistry\ when Fischer _rst
isolated sugar phenylosazones ð0773CB468\ 0776CB710Ł[ Sugar osazones have a {quasi!aromatic| struc!
ture "00#\ _rst proposed by Fieser and Fieser "Equation "1## ð52ACS448\ 54AG479\ 54AG"E#463\ 54JA485Ł[
This structure accounts for the di}erences in spectral and chemical properties in comparison to
nonsugar osazones ð54AG479\ 54AG"E#463Ł[ In aqueous or alcoholic solutions\ reactions of aryl
hydrazines bearing electron!withdrawing substituents\ with aldoses or ketoses a}ord the cor!
responding hydrazones ð47CB1534Ł[

Ph
CHO N H Ph
H N N
CHOH
N
CHOH PhNHNH2
(2)
CHOH CHOH
CHOH CHOH
CH2OH CHOH
CH2OH
(11)
Hydrazones 340
During osazonization of sugars by phenylhydrazine\ hydrazone formation occurs with oxidation
of the hydroxyl group adjacent to the carbonyl group\ but the other hydroxyl groups are una}ected[
However\ reactions of sugars with N!methyl!N!phenylhydrazine give osazones in which the quasi!
aromatic structure cannot be formed\ and all primary and secondary hydroxyl groups are converted
into hydrazones ð53JA621Ł[
Osazones may be prepared from a!diketones by treatment with an excess of a substituted hydra!
zine\ or from a!hydroxy\ a!halo\ a!methoxy\ a!acetoxy and a!dialkylamino ketones "Scheme 06#[
The reaction of aryl hydrazines with a!hydroxy ketones or aldehydes leads to formation of aryl
hydrazones\ osazones\ or both[ The ratio of products is dependent on the stoichiometry of reactants\
the experimental conditions employed\ and the structure of the reactants[ Several alternative mech!
anisms have been proposed to account for the formation of osazones from a!hydroxy ketones
ð25CB230\ 41JA3220\ 55JA2754Ł[ Hydrazones are produced in the presence of strong acids ð46CB241\
47CB1534\ 52CB540\ 52CB547Ł\ but in mildly acidic media both the hydrazone and osazone products
may be obtained[ In aqueous acetic acid\ the proportion of osazone to hydrazone rises with
increasing acid concentration ð52CB547Ł[ Hydrazones rather than osazones are favoured in neutral
aqueous or alcoholic solutions ð46CB241\ 52CB540Ł[
R4
R4 N
O R3 N O
N
R3R4NHNH2 R3 N R3R4NHNH2 R2
R2 + R2
R1 R1 R1
R2
O R1 N R3 X
O N
R4
X = OH, Cl, Br, OMe, OAc, NR2

Scheme 17

a!Halo carbonyl compounds react with hydrazines to give hydrazones or osazones depending on
the structure of the reactants\ stoichiometry and the experimental conditions used ð41JA3220Ł[ For
example\ Brady|s reagent reacts with a variety of a!halocycloalkanones at room temperature to
furnish the corresponding a!halo hydrazones\ and osazones can be prepared from these a!halo
hydrazones by heating them with an excess of the reagent ð41JA3220\ 44JA0992Ł[ In contrast\ treatment
of dichloroacetaldehyde with either phenyl hydrazine or o\p!dinitrophenyl hydrazine a}ords only
the corresponding glyoxal osazones ð29JCS85\ 50JOC468Ł[ In general\ if the hydrazone of an a!halo
aldehyde is required\ the reaction should be performed in a concentrated mineral acid ð50JOC468Ł[
The a!halo hydrazones are very reactive and will react with methanol to a}ord a!methoxy
hydrazones ð41JA3220\ 44JA0992Ł\ and with acetic acid to give a!acetoxy hydrazones ð42JA5915Ł[ a\b!
Unsaturated hydrazones can be formed by elimination reactions of these compounds ð41JA3220Ł[
Aryl hydrazines oxidise benzylic or allylic primary and secondary alcohols to give ketones which
then react further to a}ord hydrazones ð40JCS0651\ 47JOC1903Ł[ The reaction is acid catalysed and
osazone formation is favoured when aryl hydrazines with electron!withdrawing substituents are
used ð25CB230\ 49JCS0217Ł[ The mechanism of this reaction is similar to that proposed for the
formation of sugar osazones ð41JCS550Ł[

2[01[0[5 Cyclic Hydrazone and Azine Derivatives


There are many synthetic methods for the preparation of cyclic hydrazones and azines ð73CHEC"2#0\
73CHEC"4#056\ 73CHEC"4#294Ł[ The following brief survey focuses on those methods of general pre!
parative use or of special interest\ in which ring construction occurs concurrently with hydrazone
or azine formation[

2[01[0[5[0 1!Pyrazolines and 1!pyrazolin!4!ones


One of the simplest methods of preparing 1!pyrazolines is by reaction of a\b!unsaturated ketones
with hydrazines[ Aryl hydrazines react with a\b!unsaturated ketones under acidic or basic conditions
ðB!73MI 201!92Ł[ Terminal enones are the best substrates for the reaction\ and catalysts are not
341 Hydrazones and Other 1NN Derivatives
usually required with these substrates[ For example\ reaction of phenylhydrazine with the ketone
"01# occurs at re~ux in ethanol\ in the absence of catalysts\ to give the 1!pyrazoline "02# "Equation
"2## ð44JA873Ł[ In contrast\ a\b!unsaturated aldehydes tend to be reluctant to undergo cyclization\
and usually a}ord hydrazones when treated with aryl hydrazines ð14CB0863Ł[

Ph
Ph
PhNHNH2 Ph
Ph (3)
EtOH, reflux N N
O
Ph
(12) (13)

Many b!substituted ketones will react with hydrazine or aryl hydrazines to give 1!pyrazolines[
The reaction can be performed using b!chloro ð25JA1949\ 42JCS1723\ 50CA"44#06415Ł\ b!bromo
ð42JCS1723Ł\ b!seleno ð40JA0963Ł\ b!hydroxy ð12CB0025Ł and b!amino ketones ð13CB0097\ 34JCS015\
41JCS0210Ł "Equation "3##[

O X R5
R5NHNH2 N N
(4)
R1 R4 EtOH, reflux R1 R4
R2 R3
R2 R3

1!Pyrazolines can also be prepared by 0\2!dipolar cycloaddition reactions with alkenes[ For
example\ nitrilimine "05# can be generated from either the tetrazole "03# or the a!chloro imine "04#\
and reacts readily with the alkene "06# to a}ord the 1!pyrazoline "07# in good yield "Scheme 07#
ð51T2Ł[ Many other alkenes can participate in this reaction ð51T2Ł[

N Ph
Ph N
N N heat, 15 0–160 °C
Ph
–N2 H
(14)
+ – (17)
Ph N N Ph N
N
(16) H
Ph Et3N, C6H6, 20 °C Ph
(18)
N
N H

Ph Cl
(15)

Scheme 18

N!Formyl!1!pyrazolines can be prepared by the acid!catalysed cyclization of azines "Equation


"4## ð69BSF3008Ł[ The reaction occurs readily with aldazines and with ketazines which have small alkyl
groups\ but hydrazone or ketone products are obtained with more hindered ketazines ð69BSF3008Ł[

R1 R2 R2 R1
R2 R1
N HCO2H
N N R2 + N R2 (5)
N N
R1 R2 R1 R1
CHO CHO

Acetone azine can be converted to a 1!pyrazoline hydrochloride salt by reaction with methyl!
magnesium bromide followed by treatment with dilute hydrochloric acid "Equation "5## ð51JOC1654Ł[
The reaction is presumed to occur by a!deprotonation by the Grignard reagent followed by cycli!
zation\ but the same reaction has been reported to yield t!butylhydrazine as the major product
ð30LA"436#0Ł[
Hydrazones 342

i, MeMgBr
N N (6)
N HCl
ii, HCl (aq.) N
H

There are many methods for the preparation of 1!pyrazolin!4!ones\ the most general being the
reaction of hydrazines with b!aldehydo or b!keto esters "Equation "6##[ A variety of substituents
can be present in the dicarbonyl compound\ and b!thiono esters\ b!oximino esters and b!keto amides
can be used[ In general\ substrates with small substituents give the highest yields\ and reactions fail
when R0 and R1 are both very large[ The reaction is usually performed by heating the dicarbonyl
compound with the hydrazine at 099Ð199>C\ without the addition of a catalyst[ Formation of the
hydrazone occurs at lower temperatures than those required to accomplish cyclization\ and hydra!
zone formation and cyclization can be performed in separate reactions if required ð42CJC0914Ł[
Acids and bases can be used to promote the cyclization reaction ð37JA0879Ł[

R5
O O
N N
+ H2N NHR5 (7)
R1 OR4 R1 O
R2 R3
R2 R3
R1–R3 = H, alkyl, aryl; R4, R5 = alkyl, aryl

1!Pyrazol!4!ones can be prepared by treatment of alkynyl acids\ esters or amides with phenyl
hydrazine "Equation "7## ð30JA0040Ł[ b!Alkoxy!\ b!alkylthio! and b!acylthio!a\b!unsaturated esters
react with hydrazine in a similar manner[ 1!Pyrazol!4!ones can also be prepared by reaction of
many other heterocyclic compounds with hydrazine\ as summarized in Scheme 08[

Ph
O N N
R1 + H2N NHPh (8)
X R1 O

R1 = alkyl, aryl; X = OR2, NR22

2[01[0[5[1 Tetrahydropyridazines
0\3\4\5!Tetrahydropyridazin!5!one "10# can be prepared from the hydrazone "19# formed by
treatment of the g!keto nitrile "08# with a diazo compound[ Treatment of hydrazone "19# with HBr
in acetic acid leads to the formation of "10# in good yield "Scheme 19# ð58LA"615#70Ł[
0\3\4\5!Tetrahydropyridazin!3!ones "12# can be prepared by JappÐKlingemann reaction of g\d!
unsaturated b!keto esters and b!diketones "Scheme 10# ð79S512Ł[ The reaction proceeds via the
intermediate hydrazone "11#[
0\3\4\5!Tetrahydropyridazines can be prepared by ð3¦1Ł!cycloaddition reactions[ For example\
the diazadiene "13# generated from an a!chloro hydrazone\ undergoes an inverse!electron!demand
DielsÐAlder reaction with cyclopentene to give the cycloaddition product "14# in good yield "Scheme
11# ð66TL006Ł[
An unusual example of the preparation of 0\3\4\5!tetrahydropyridazine involving ring expansion
of pyrrolidine has been reported ð54JA282Ł[ Treatment of pyrrolidine with Angeli|s salt a}ords
0\3\4\5!tetrahydropyridazine\ presumably by formation and rearrangement of the diazene "15#
"Scheme 12#[ This reaction is of limited synthetic value\ and is not successful when piperidine or
morpholine are used as substrates ð54JA282Ł[

2[01[0[5[2 Cyclic azines


Cyclic azines such as 3\4!dihydropyridazines can be prepared by reaction of 0\3!diketones with
hydrazine "Equation "8## ð59JOC845Ł[ This is usually the simplest way of making these compounds[
Other 0\3!dicarbonyl compounds can be used as substrates for this reaction[ For example\ reactions
of g!keto esters with hydrazine a}ord dihydropyridazinones[ The reaction can also be applied to
343 Hydrazones and Other 1NN Derivatives
N O

NH2

〈54CA3342〉

HO N OH H2NNH2
N O
N Ph O
H2NNH2 H2NNH2
〈24CR(178)811〉 〈1893CB2053〉
H
N N

R1 O

H2NNH2 R2 H2NNH2

O O O O

EtO2C H2NNH2

O O
〈54JA4931〉 HO2C O O 〈1894CB970, 05CB2023〉

〈1894CB970〉

Scheme 19

Cl
Cl CN
O HO CN
O i, HBr, HOAc
+
N ii, H2O
Cl N
Cl N2 CO2Et
H CO2Et
(19) (20)

Cl
HO

N CO2Et
Cl N

O
(21)

Scheme 20

R2 O O O O
R2 O O
ArN2+ X– R1 Y Y
R1 Y R1 N
H N
R3 N N
R2 Ar
Ar
(22) (23)

R1, R2 = H, alkyl, aryl; Y = R3, OR3

Scheme 21
R1C1NX Functions 344
Cl CO2Me CO2Me
H
CO2Me NaHCO3 (aq.), Et2O (17)
N H N N
N N N
H
CONH2 CONH2 CONH2
(24) (25)

Scheme 22

Na2ONNO2 +
N N N
H N
N– H
(26)

Scheme 23

the preparation of larger cyclic azines[ For example\ the diazepine "17# can be synthesized in good
yield by reaction of 0\4!diketones such as "16# with hydrazine "Equation "09## ð45JA3369Ł[

R2 R2
H2NNH2
(9)
O N
R1 O R1 N

R2 R2

H2NNH2
O N (10)
O N
R1 R1
(27) (28)

An interesting reaction occurs when cyclopropane!0\1!dicarboxaldehyde is treated with hydrazine


ð57CB0243Ł[ The unusual polycyclic compound "29# is obtained as a mixture of three isomers\ instead
of dihydropyridazine "18# "Scheme 13#[

CHO
H2NNH2 N N N
N N
N
CHO N
N
(29) (30)

Scheme 24

2[01[1 R1C1NX FUNCTIONS "XP\ As\ Sb\ Bi\ Si\ Ge\ B or METAL#

2[01[1[0 Imines Substituted with Phosphorus or Arsenic


Phosphorus!substituted ketimines can be prepared straightforwardly from N!unsubstituted keti!
mines or from N!metallo imines[ The reaction of phosphines of the type PX1Cl with imines in the
presence of triethylamine a}ords the corresponding N!phosphinyl ketimines X1PNCR1 in good yield[
The N!phosphinyl ketimines from this reaction can be converted to N!thiophosphinyl ketimines
345 Hydrazones and Other 1NN Derivatives
PPh1"S#NCR1 "RPh\ OMe\ OEt# by treatment with sulfur\ or converted to phosphonium salts
"MeX1PNCR1#¦ I− "XCl\ Me\ Ph and RPh\ OMe\ OEt# by treatment with iodomethane
ð60CB0088Ł[
Reactions of phosphorus chlorides such as PCl2\ Ph1PCl and P"O#Cl2 with one\ two or
three equivalents of LiNCR1 at low temperature a}ord compounds of the type Cl1P"NCR1#\
P"NCR1#2\ Ph1P"NCR1#\ Cl1P"O#"NCR1#\ ClP"O#"NCR1#1\ P"O#"NCR1#2 "RBut\ Ph\ p!MeC5H3#
ð67JCS"D#875Ł[ Similarly\ treatment of PCl2\ PF2 or PF1Cl with three equivalents of LiNC"CF2#1 at
room temperature results in formation of PðNC"CF2#1Ł2 ð60MI 201!91\ 61IC131Ł[ Compounds of the
type ClP"NCR1#1 cannot be prepared by this procedure because of disproportionation of these
compounds to mixtures of Cl1P"NCR1# and P"NCR1#2[
Arsenic!substituted imines can be prepared by reactions that are analogous to those used to
prepare the phosphorus compounds above[ Thus\ treatment of AsCl2 with three equivalents of
LiNC"CF2#1 at low temperature a}ords As"NCR1#2 in modest yield ð60MI 201!91\ 61IC131Ł[

2[01[1[1 Imines Substituted with Silicon\ Germanium\ Tin or Lead


There are many ways of preparing N!silyl aldimines and ketimines\ and these compounds have
been used extensively as intermediates for the synthesis of b!lactams[ The simplest route to N!
silyl imines involves treatment of an appropriate carbonyl compound with a sodium or lithium
bis"trialkylsilyl#amide "Scheme 14# ð52CB1021Ł[ This method has the disadvantage that it is only
generally suitable for the preparation of N!silyl imines from nonenolizable aldehydes and ketones
ð72JOC178\ 74CC428\ 78JCS"P0#168Ł\ although some enolizable aldehydes can be converted into N!silyl
aldimines when the reaction is performed at low temperature ð76TL4258\ 80TL1856Ł[

O SiR33 R1 SiR33 SiR33


–78 °C to RT –MOSiR33 N
+ M N R2 N
R1 R2 SiR33 MO SiR33 R1 R2
M = Li, Na

Scheme 25

Because of the problems associated with the preparation of N!silyl imines from enolizable carbonyl
compounds\ several alternative methods of preparing these compounds have been developed[ Enol!
izable N!trimethylsilyl aldimines can be prepared in good yield by treatment of "TMS#1NCHO with
organolithium reagents at low temperature "Scheme 15# ð78TL3164Ł[ N!Silyl imines can also be
prepared by the reaction of silyl chlorides with N!lithio imines ð56JOM"8#120\ 61IC131\ 62JCS"D#046\
65JCS"D#0Ł\ iminoborates ð65JOM"007#C0Ł\ iminoaluminates ð75TL0584Ł\ or N!trialkylstannyl imines
"Scheme 16# ð89PAC594Ł[

TMS TMS OLi TMS


–78 °C, THF –LiO-TMS N
N CHO + RLi N
TMS TMS R R

Scheme 26

Li SiR3 SnR3
N R3SiCl, –LiCl N R3SiCl, (R3Sn)2O N
–[(R3Sn)3O]+ Cl–
R1 R2 R1 R2 R1 R2

R3SiCl
–LiCl, –Al(OR)3 (R2 = H)

Al(OR)3Li
N

R1

Scheme 27
R1C1NX Functions 346
Enolizable N!trimethylsilyl aldimines can be synthesized in good yield by vacuum gasÐsolid
reactions "VGSR# in which a!"N!silylamino#nitriles are dehydrocyanated on solid potassium hydr!
oxide "Scheme 17# ð77TL0176Ł[

NH2 R2Me2Si H SiMe2R2


R2Me2SiCl, Et3N, CH2Cl2, –60 °C N KOH, 60 °C (VGSR) N
R1 CN MeCN, 50 °C –HCN
R1 CN R1

R1 = H, Me, Et, Pr; R2 = Me, But

Scheme 28

The reaction of N!trialkylsilyl iminophosphoranes with ketones provides an interesting route to


N!trimethylsilyl imines[ For example\ reaction of the iminophosphorane "20# with the ketone "21#
in dichloromethane or diethyl ether a}ords the N!trimethylsilyl imine "22# in good yield "Equation
"00## ð65CB0380Ł[

TMS TMS
N O CH2Cl2, Et2O N
P + (11)
Ph Ph F3C CN –Ph3PO F3C CN
Ph
(31) (32) (33)

N!Germyl imines can be prepared by reaction of alkyl germanium chlorides or GeX3 "XCl\
Br# with N!lithio imines ð56JOM"8#120\ 60JA5692\ 62JCS"D#046\ 65JCS"D#0Ł\ and mixed imino germyleneÐ
chromium complexes such as "CO#4CrGe"Cl#NCPh1 and "CO#4CrGe"NCPh1#1 can be synthesized by
reaction of one or two equivalents of Et2GeNCPh1 with Cl1GeCr"CO#4 = THF at room temperature
ð76JOM"220#00Ł[
N!Stannyl imines are easily synthesized by reaction of alkyl tin halides or SnX3 "XCl\ Br# with
N!lithio imines ð56JOM"8#120\ 62JCS"D#040\ 62JCS"D#046\ 65JCS"D#0Ł[ These compounds can also be
prepared directly from the corresponding aldehyde or ketone by treatment with N"SnMe2#2 "Scheme
18# ð89PAC594\ 80SL132Ł[ Because of the low basicity of N"SnMe2#2\ enolizable carbonyl compounds
are not deprotonated\ and N!stannyl imines are obtained in good yield ð89PAC594Ł[

Me3Sn SnMe3
O Me3Sn
N OSnMe3 –(Me3Sn)2O N
+ N SnMe3 Me3Sn
R1 R2 Me3Sn R2 R2
R1 R1

Scheme 29

Rearrangement reactions of a!azidostannanes provide a rather unusual but mild method of


preparing N!trimethylstannyl imines "Equation "01## ð81JA0218Ł[ Although there are very few exam!
ples of this reaction\ it may prove to be useful for the preparation of N!stannyl aldimines that are
di.cult to prepare by conventional methods[
N3 21 °C, –N2 N
SnMe3 (12)
SnMe3

It has been reported that the N!plumbyl imine Ph2PbNCPh1 can be prepared by reaction of
LiNCPh1 with Me2PbCl ð56JOM"8#120Ł[ However\ only impure material was obtained\ and the
compound was not fully characterized[

2[01[1[2 Imines Substituted with Boron or Aluminium


Alkyl and aryl nitriles can be converted into N!boryl imines by partial reduction with dialkyl!
boranes "Equation "02## ð53JCS0538\ 81TL516Ł[ Monoalkylboranes can also be used\ and reaction
347 Hydrazones and Other 1NN Derivatives
times are usually shorter than with dialkylboranes ð81TL516Ł[ The N!boryl imines produced by
reaction of nitriles with monoalkylboranes contain a hydrogen which exhibits low reactivity with
imines\ and so overreduction does not occur ð81TL516Ł[ N!Boryl imines can also be prepared
by partial reduction of nitriles using diborane or boraneÐtetrahydrofuran complex ð59JCS1503\
80JCS"P0#0656Ł\ and these compounds have been used as intermediates in the synthesis of secondary
amines from nitriles ð80JCS"P0#0656Ł[ A related reaction has been used to prepare iminoborate
compounds[ For example\ treatment of RCN "RBut\ c!C5H00\ Ph# with one equivalent of
M¦"HBEt2#− "MNa\ Li# a}ords the corresponding iminoborate M¦"Et2BNCHR#− in good
yield ð65JOM"007#C2Ł[ Trialkyl boranes can also be used to prepare N!boryl imines from nitriles
ð58JCS"A#322Ł[ For example\ reaction of Bun2B with ButCN at 049Ð059>C gives Bun1BNCHBut
ð57CC149A\ 58JCS"A#322Ł[

R2
R2
THF, RT B
R1 CN + H B N R3 (13)
R3
R1
R1 = alkyl, aryl; R2, R3 = H, alkyl

Many N!boryl imines have been prepared by the reaction of haloboranes with N!trialkylsilyl or
N!lithio imines\ or from free imines "Scheme 29# ð57CC149B\ 69JCS"A#1909\ 61JCS"D#269Ł[ Good yields
of N!boryl imines can be obtained using this method ð61IC131Ł[

Li BRnX2–n H
N BRnX3–n, –196 °C to RT N BRnX3–n, toluene, reflux, –HX N

R1 R2 R1 R2 R1 R2

X = F, Cl, Br, I; R1, R2 = alkyl, aryl

Scheme 30

N!Alumino imines are useful precursors for the synthesis of other substituted imines and can be
prepared by a variety of routes ð89PAC594Ł[ The simplest method of preparing aluminum aldimines
is by treatment of nitriles with diisobutylaluminum hydride "Equation "03## ð89JOC3088Ł[ A large
number of aluminum imines have been prepared from nitriles ð56AG"E#792\ 56AG707\ 82JOM"345#050Ł\
or cyanohydrins in this manner ð89TL2370\ 82T2798Ł[

Bui
Bui
C5H12, –78 °C Al
R CN + Al H Bui N (14)
Bui
R
R = alkyl, aryl

Aldimino aluminates can be prepared in good yield by partial reduction of aromatic and aliphatic
nitriles with lithium triethoxyaluminum hydride ð53JA0974\ 75TL0584Ł[ Lithium aluminum hydride
can be used to perform the same reaction\ but overreduction can be a problem with certain substrates
ð53JA0974Ł[ Sodium or lithium trialkylaluminum hydrides of the type M¦"R02AlH#− "MLi\ Na\
R0 Et\ Bui# react with nitriles of the type R1CN "R1 Et\ Pr\ Ph\ p!MeC5H3\ p!MeOC5H3\ c!C5H00\
PhCHCH\ 1!furyl\ 1!thienyl# to give the imino aluminates M¦"R02AlNCHR1#− ð65JOM"007#C2\
¦ t −
77JCS"P0#834Ł[ The aluminate Li ðAl"NCBu 1#3Ł can be prepared by reaction of aluminium chloride
t
with four equivalents of LiNCBu 1 ð60CC0164Ł[
N!Alumino ketimines can be prepared by the addition of trialkylaluminum reagents to nitriles[
Addition of a trialkylaluminum to an alkyl or aryl nitrile furnishes complex "23# which rearranges
to the corresponding dimeric N!alumino ketimine "24# in good yield when heated to 099Ð199>C
"Scheme 20# ð53CB1550\ 54JCS1551\ 54JCS4972Ł[
The gallium!substituted imines "Et1GaNCHPh#1 and "Et1GaNCHBut#1 can be synthesized by
thermal rearrangement of the complexes produced by reaction of GaEt2 with PhCN or ButCN
ð56JCS"A#0111Ł[ These reactions are analogous to those of trialkylaluminum reagents with nitriles[
R1C1NX Functions 348
R2 R 2
R1 Al R2
100–200 °C
2R1 C N + AlR23 2R1 C N AlR2 3 N N
R2 Al R1
R2 R2
(34) (35)

Scheme 31

2[01[1[3 Imines Substituted with Lithium


N!Lithio ketimines are usually prepared by reaction of alkyl lithiums with nitriles or by depro!
tonation of N!unsubstituted ketimines[ Both methods are of limited synthetic use because competing
deprotonation can occur with substrates containing labile hydrogen atoms adjacent to the nitrile or
imine ð63BSF0609Ł[ N!Lithio ketimines such as LiNCBut1\ LiNCPh1\ and LiNCPhBut have been
prepared by addition of ButLi or PhLi to t!butylnitrile or benzonitrile ð61JCS"D#0490\ 76JCS"D#0960\
76JCS"D#1030Ł\ and LiNCBut1\ LiNCPhBut and LiNC"CF2#1 have been prepared by deprotonation
of the corresponding N!unsubstituted ketimines ð61IC131\ 82CB846Ł[ The ketimine precursors are
easily obtained by Grignard additions to the corresponding nitriles and subsequent hydrolysis[ The
imine HNC"CF2#1 can be prepared from hex~uoroacetone ð54JOC0287Ł\ and then deprotonated with
an alkyl lithium reagent to give the potentially explosive compound LiN1C"CF2#1 ð54JOC0287\
61IC131Ł[

2[01[1[4 Imines Substituted with Beryllium or Magnesium


Beryllium!substituted imines can be prepared by reaction of N!lithio ketimines with beryllium
chloride ð69JCS"A#1905Ł[ Reactions of beryllium chloride with LiNC"p!MeC5H3#1 or LiNC"p!MeC5
H3#"But# a}ord "BeClðNC"p!MeC5H3#1Ł#1 and "BeðNC"p!MeC5H3#1Ł1#2\ or "BeClðNC"p!MeC5H3#
"But#Ł#1 and "BeðNC"p!MeC5H3#"But#Ł1#1\ depending on the reaction stoichiometry ð69JCS"A#1905Ł[
The oligomeric complex ðBe"NCPh1#1Łn can be obtained by treatment of beryllium chloride with
LiNCPh1\ and the dimeric complex ðBeCl"NCPh1#Ł1 can be prepared by reaction of beryllium
chloride with TMS!NCPh1 in diethyl ether ð69JCS"A#1905Ł[ The compound ðBe"NCBut1#1Ł1 can be
prepared by reaction of two equivalents of HNCBut1 with BePri1 in diethyl ether ð65CC059Ł[
Addition of Grignard reagents to nitriles is the most direct method of preparing N!magnesio
ketimines[ Many examples of the reaction are known ð37JA1901\ 49JA765\ 40JA31\ 44OSC"2#15\
44OSC"2#451Ł\ and the reaction mechanism has been studied in detail ð36JA1295Ł[ Rates of addition
are markedly altered by the amount of magnesium bromide added to the reaction ð55JOC2264Ł\ and
product yields can be improved by using benzene containing one equivalent of diethyl ether as
solvent\ rather than diethyl ether alone ð79TL044Ł[ Competing deprotonation can be a problem
when acetonitrile is reacted with Grignard reagents\ but nitriles without a!hydrogens\ or those with
longer alkyl chains\ react to form N!magnesio ketimines in good yield ð61JOC2258Ł[ Even sensitive
a\b!epoxy nitriles can be converted into the corresponding N!magnesio imines by reactions with
Grignard reagents ð81JOC4945Ł[
N!Magnesio imines can be prepared by treatment of d! or o!iodonitriles with magnesium in ether
"Scheme 21# ð64JOM"76#14Ł[ Intramolecular reactions between the nitrile group and the Grignard
reagent formed from the iodide a}ord the corresponding metallated cyclopentyl or cyclohexyl
imine[

MgI
N
R2 Mg, Et2O, reflux R2
R1 R1 R1
I IMg ( )n
( )n CN ( )n CN R2

n = 1, 2; R1 = H, alkyl; R2 = alkyl

Scheme 32
359 Hydrazones and Other 1NN Derivatives
2[01[1[5 Imines Substituted with Titanium\ Zirconium or Hafnium
Several titanium and zirconium N!metallo ketimines are known[ The complexes Cp1MCl"NCR1#
and Cp1M"NCR1#1 "MTi\ Zr and RPh\ p!MeC5H3\ But# can be prepared by treatment of
titanocene or zironocene dichloride with either one or two equivalents of an appropriate N!lithio
ketimine in diethyl ether ð60MI 201!90Ł[ Forcing conditions are usually necessary for successful
addition of a second equivalent of the N!lithio ketimine\ and with bulky substrates\ such as LiNCPh1
and LiNCBut1\ the second chlorine on titanium is not replaced[ The complexes Cp1TiClðNC"CF2#1Ł
and Cp1TiðNC"CF2#1Ł1 have been prepared in an analogous fashion by treatment of titanocene
dichloride with one or two equivalents of LiNC"CF2#1 ð60CC104\ 60MI 201!90Ł[
The compound Cp1TiCl"NCPh1# can be prepared by reaction of titanocene dichloride with
Me2SiNCPh1 in xylene at re~ux\ with removal of the trimethylsilyl chloride produced during the
reaction ð60MI 201!90Ł\ and Cp1TiClðNC"CF2#1Ł can be obtained by treatment of titanocene dichloride
with Me2SnNC"CF2#1 in benzene at re~ux ð62JCS"D#040Ł[
The complexes Cp1Zr"NCPh1#1\ Cp1Hf"NCPh1#1 and Ti"NCPh1#3 can be synthesized by treatment
of Cp1Zr"NMe1#1\ Cp1Hf"NEt1#1 and Ti"NMe1#3 with either two or four equivalents of HNCPh1 in
diethyl ether at re~ux ð60MI 201!90Ł[

2[01[1[6 Imines Substituted with Molybdenum or Tungsten


Molybdenum and tungsten N!metallo ketimines can be prepared in good yield from N!trialkylsilyl
imines[ For example\ heating TMS!NCPh1 with CpM"CO#2X "MMo\ W and XCl\ Br\ I#
a}ords the complexes ðCpM"CO#"NCPh1#Ł1 and CpM"CO#1"NCPh1# in good yield ð69JCS"A#1168Ł[
When CpMo"CO#2X is used\ the reaction proceeds via a dinuclear complex\ and careful control of
the reaction conditions is required if the mononuclear complex is to be isolated[
The corresponding reactions of LiNCPh1 with CpM"CO#2X "MMo\ W and XCl\ Br\ I# are
not successful\ and a}ord complexes of the type CpM"CO#1"Ph1CNCPh1# "MMo\ W# rather than
N!metallo ketimine complexes ð69JCS"A#1168Ł[ Other N!lithio imines such as LiNCPhBut and LiNC
But1 do react to give the desired N!metallo imines ð69CC441\ 60JCS"A#181Ł[ When LiNC"p!MeC5H3#1
is used\ mixtures of the N!metallo imine complex and CpM"CO#1"Ar1CNCAr1# "MMo\ W# are
produced[ The relative amount of each product depends on the reaction conditions employed and
the metal ð61JCS"D#042Ł[

2[01[1[7 Imines Substituted with Manganese


N!Metallo imines of manganese can be prepared from either N!lithio or N!stannyl imines ð79MI
201!90Ł[ Reaction of either LiNC"CF2#1 or Me2SnNC"CF2#1 with Mn"CO#4Br at room temperature in
an appropriate solvent a}ords the dimeric complex Mn1ðNC"CF2#1Ł1"CO#6 in good yield ð64IC0564Ł[
Addition of a phosphine "Ph2P\ Ph1MeP\ or PhMe1P# to this dimeric complex gives the monomeric
complex Mn"CO#1"PR2#1ðNC"CF2#1Ł in good yield[

2[01[1[8 Imines Substituted with Iron


The dimeric complex di!m!"3\3?!dimethylbenzophenoniminato#bis"tricarbonyliron# "25# has been
prepared by the reaction of Fe"CO#4 with the azine "Ph1CN#1 "Equation "04## ð56CC134Ł[
CO
OC CO
Ph
Ph Fe Ph
Ph N –4CO
2Fe(CO)5 + N Ph N N (15)
Ph Fe Ph
Ph
OC CO
CO
(36)

A more general approach to the synthesis of iron!substituted imines involves reaction of iron
complexes of the type CpFe"CO#1X "XCl\ Br\ I#\ or Fe"CO#3X1 "XBr\ I#\ with N!lithio ketimines
at low temperature ð63JCS"D#0519Ł[ The complexes CpFe"CO#"NCBut1#\ ðFe"CO#2"NCPh1#Ł1\
Diazo Compounds 350
"Fe"CO#2ðNC"3!MeC5H3#1Ł#1\ ðFe"CO#2"NCPhBut#Ł1\ Fe1"CO#5I"NCPh1#\ Fe"CO#5I"NCPh1#\ Fe"CO#5
IðNC"3!MeC5H3#1Ł\ and Fe"CO#5I"NCPhBut# have been prepared in low yield by this route
ð63JCS"D#0519Ł[

2[01[1[09 Imines Substituted with Platinum or Rhodium


Several platinum!substituted ketimines are known\ and they can be prepared from N!lithio
ketimines ð60CC104Ł[ For example\ reaction of LiNC"CF2#1 with cis!"Ph2P#1PtCl1 a}ords cis!
"Ph2P#1PtClðNC"CF2#1Ł in good yield\ even when an excess of LiNC"CF2#1 is used[ In contrast cis!
"Me1PhP#1PtCl1 reacts with LiNC"CF2#1 to give cis!"Me1PhP#1PtðNC"CF2#1Ł1 as the major product\
even when the reactants are present in equimolar amounts[ Platinum complexes such as trans!
"Ph2P#1PtHðNC"CF2#1Ł and trans!"Me1PhP#1PtHðNC"CF2#1Ł can be prepared by similar reactions\
and the rhodium complex "Ph2P#2RhðNC"CF2#1Ł has been prepared by reaction of "Ph2P#2RhCl
with LiNC"CF2#1 ð60CC104Ł[ Treatment of cis!"Ph2P#1PtCl1 with HNC"CF2#1 in the presence of
triethylamine provides a low yielding alternative route to "Ph2P#1PtClðNC"CF2#1Ł ð60CC104Ł[
The preparation of platinum!substituted ketimines can also be accomplished from the cor!
responding N!stannyl ketimines[ For example\ treatment of cis!"Ph2P#1PtCl1 with either
Me2SnNC"CF2#1 or Me2SnNCPh1 in benzene at re~ux a}ords cis!"Ph2P#1PtClðNC"CF2#1Ł or cis!
"Ph2P#1PtClðNCPh1Ł in excellent yield ð62JCS"D#040Ł[ The more bulkly imine Me2SnNCBut1 fails to
react with cis!"Ph2P#1PtCl1 under these conditions[ Reaction of trans!"Ph2P#1Pt"Cl#H with
Me2SnNC"CF2#1 in xylene at re~ux gives a low yield of trans!"Ph2P#1Pt"SnMe2#ðNC"CF2#1Ł\ the
major product being "Ph2P#1PtðHN1C"CF2#1Ł ð62JCS"D#040Ł[

2[01[1[00 Imines Substituted with Zinc


The formation of zinc ketimines by addition of zinc ester enolates to nitriles has been known for
many years ð90CR"021#367Ł\ and provides a useful route to b!keto esters "Scheme 22# ð72JOC2722Ł[
The Blaise reaction is analogous to the Reformatsky reaction and works best with bromoesters
which contain at least one alkyl group in the a!position ð42JOC0483\ 55BSF0708Ł[ Acetonitrile is a
poor substrate for the reaction when the original procedure is used "reaction in benzene at re~ux#
ð42JOC0483Ł\ but later reports suggest that acetonitrile and nitriles with labile a!hydrogen atoms
react in a satisfactory manner under modi_ed conditions ð55BSF0708\ 63JOM"70#028Ł[ High yields of
addition products are obtained when the Reformatsky reagent is prepared using activated zinc dust\
and the reaction is performed by slow addition of the a!bromo ester to the metal in tetrahydrofuran
at re~ux in order to minimize self!condensation ð72JOC2722Ł[ Even a!unsubstituted bromoacetates
react e.ciently with nitriles when these conditions are used[

O O ZnBr
O N
Br Zn, THF, reflux ZnBr R3CN, THF, reflux
R1O R1O R1O R3
R2 R2 R2

Scheme 33

Dialkyl zinc reagents add to benzonitrile to give zinc!substituted imines ð57JCS"A#46Ł[ Addition
of R1Zn "RMe\ Et\ Ph# to benzonitrile at low temperature\ followed by warming to room
temperature\ a}ords zinc complexes of the type "RZnNCPh1#1 "RMe\ Et\ Ph# ð57JCS"A#46Ł[ When
these complexes are heated to 79>C they disproportionate to give Zn"NCPh1#1 and R1Zn[

2[01[2 DIAZO COMPOUNDS

2[01[2[0 General Methods for the Preparation of Diazo Compounds


There is a wide array of methods available for the preparation of diazo compounds\ and choice
of method is largely dictated by the nature of the functional groups required in the diazo compound[
The most commonly used and widely applicable methods for the synthesis of diazo compounds fall
351 Hydrazones and Other 1NN Derivatives
into three general categories] "i# reaction of two nitrogen!containing compounds to form a diazo
compound\ "ii# conversion of a group which contains two nitrogen atoms into a diazo group\ and
"iii# diazo group transfer to a substrate from a suitable donor compound[
Diazo compounds can be modi_ed\ usually by electrophilic substitution at the diazo carbon or
by functionalization at remote sites\ but the reactive nature of the diazo group limits the choice
of reagent in subsequent functionalization reactions and precludes the use of many standard
transformations[
A comprehensive account of the synthesis and properties of diazo compounds\ in which the
preparation of diazo compounds is listed according to reaction type\ is given in an excellent book
by Regitz and Maas ðB!75MI 201!90Ł[

2[01[2[1 Alkyl and Aryl Diazo Compounds

2[01[2[1[0 Diazotization of amines


Diazotization of amines with nitrous acid is one of the oldest methods of preparing aliphatic
diazo compounds "Scheme 23# ð0772CB1129Ł[ The success of this reaction is dependent on the nature
of the substituents that are adjacent to the amino group in the precursor[ It is usually necessary to
have one or more electron!withdrawing substituents "R0 or R1# at the a!position in order to facilitate
deprotonation of the intermediate diazonium species "26#\ otherwise loss of nitrogen a}ords a
carbocation which then reacts further[

R1
N2
–H+ R2
R1 H+, HNO2 R1
NH2 N2+
R2 –2H2O R2
–N2 R1
(37)
+
R2
R1 or R2 = electron-withdrawing group

Scheme 34

Methylamine can be converted into diazomethane using nitrosyl chloride under basic conditions
"Scheme 24# ð59CB0430Ł[ In this case\ an intermediate nitrosoamine "27# is formed and activating
groups are not required[ Other diazo alkanes can be prepared by this reaction\ but careful control
of the stoichiometry is necessary in order to obtain good yields ð57ACS0722Ł[ The same trans!
formation can be accomplished by reacting an amine with nitrosyl chloride and then treatment of
the resulting diazohydroxide "28# with acetic acid and ammonia "Scheme 25#[ Partial decomposition
of the diazo compound by acetic acid may occur during the reaction\ and in many cases poor yields
of the diazo compound are obtained ð70ACS"B#068\ 71ACS"B#016Ł[

O– K+
N N
EtOK, –EtOH Me
NOCl, Et2O, –80 °C
H
KOH (aq.)
Me NH2 N NO
Me
(38) KOH (aq.) H2C N2+

Scheme 35
Diazo Compounds 352
OH
R1 MeCO2H R1 R1
NOCl, Et2O, –78 °C N N
NH2 N2+ N2 + MeCO2H
R1 –H2O
R2 R2 R2
R2
MeCO2–
(39)

Scheme 36

2[01[2[1[1 Forster reaction of oximes


The Forster reaction is useful for the synthesis of diazomethane and aryldiazoalkanes "Scheme
26# ð48JA3640Ł[ In this reaction\ an oxime is treated with chloramine to give the intermediate "39#
which decomposes to a}ord the diazo compound ð04JCS159Ł[ Diazomethane can be prepared from
the sodium salt of formaldehyde oxime using this reaction\ but application of the method to the
synthesis of diazo compounds possessing alkyl substituents has not been successful ð51AG358\
51AG"E#392Ł[ Aryl!substituted diazo compounds can be synthesized in modest yield using this reaction
ð48JA3640Ł[
R1 OH R1 OH R1
–Cl– –H+, –H2O
N + H2N Cl N + N2
R2 R2 NH2 R2
(40)

Scheme 37

2[01[2[1[2 Dehydrogenation of hydrazones


A variety of oxidizing agents can be used to dehydrogenate hydrazones\ and this reaction is
especially useful in cases where the hydrazone precursor can be prepared directly from the cor!
responding carbonyl compound "Equation "05##[

R1 NH2
–'H2'
R1
N N2 (16)
oxidant
R2 R2
oxidant = HgO, AgO, MnO2, Pb(OAc)4, I2, NBS, Ph3Bi(CO)3

Mercury"II# oxide is often used to dehydrogenate hydrazones "Scheme 27#[ The reaction can be
performed in a variety of solvents\ and sodium sulfate can be used to trap the water liberated during
the reaction[ Addition of trace amounts of alcoholic KOH promotes the deprotonation step and
accelerates the reaction ð48JOC459Ł[ Mercury"II# acetamide and mercury"II# tri~uoroaetamide can
be used as dehydrogenating agents in some cases ð09JCS1045\ 48JOC274Ł[
H –
R1 NH2 R1 N Hg–OH R1
HgO R1 N Hg–OH KOH, –H+ –Hg, –HO–
N N N2
N
R2 R2 R2
R2
(41) (42)
Scheme 38

In certain circumstances\ the dehydrogenation of a hydrazone with mercury"II# oxide results in


the formation of products other than the desired diazo compounds[ When the reaction is performed
with secondary hydrazones\ azine formation is sometimes observed "see Section 2[01[0[0# ð00CB1086\
05CB0786\ 05CB0812\ 46LA"593#022\ 55JCS"C#356Ł[ If the initial product is a reactive diazo methyl com!
pound then further reaction to give the metallated diazo compound is also possible "see Section
2[01[2[4[5#[
Another reagent that is frequently used to dehydrogenate hydrazones is silver"II# oxide
ð46LA"593#022Ł[ The reaction is promoted by the use of water absorbing agents and catalytic amounts
353 Hydrazones and Other 1NN Derivatives
of base[ Reactions of hydrazones with silver"II# oxide are generally faster than those with mercury"II#
oxide\ and they can be performed at lower temperatures[ Consequently\ it is usually better to use
silver"II# oxide rather than mercury"II# oxide when preparing sensitive diazo compounds from
hydrazones[
Activated manganese"IV# oxide has also been used to prepare alkyl and aryl diazoketones from
hydrazones ð50JOC1506\ 58JPR"200#593Ł[ It is essential to use freshly prepared manganese"IV# oxide
otherwise a large excess of the reagent is required and yields may be reduced ð43JOC607Ł[
There are many cases in which hydrazones have been dehydrogenated using lead"IV# acetate[
However\ signi_cant amounts of acetic acid are produced during the reaction\ so the method is only
suitable for the preparation of moderately acid stable diazo compounds such as those which possess
one or more electron!withdrawing groups at the diazo carbon[ The stoichiometry of the reaction is
also important and use of excess lead"IV# acetate can lead to secondary reactions[ For example\
benzophenone hydrazone is converted into diphenyldiazomethane in quantitative yield when one
equivalent of lead"IV# acetate is used under optimum conditions ð63JCS"P0#0683Ł[ When two equi!
valents of lead"IV# acetate are used\ side reactions occur and the yield is signi_cantly reduced
ð44CB416\ 69T0090Ł[
Hydrazones can be dehydrogenated to the corresponding diazo compounds using iodine in the
presence of a tertiary amine base "Scheme 28# ð51JCS369Ł[ However\ further reactions can occur in
some cases leading to the formation of vinyl iodides\ and azine formation is observed in the absence
of base ð00LA"270#118\ 51JCS369Ł[

R1 R1 H R1
I2, R3N –R3NH+ I–
N NH2 N N N2
R2 R2 I R2

Scheme 39

Several other reagents can be used for the dehydrogenation of hydrazones to diazo compounds[
Reactions of metallated hydrazones with molecular oxygen have been used to prepare some simple
diazo compounds ð56JA4201Ł[ Nickel peroxide has found occasional use\ and good yields of the
diazo products have been obtained ð55CC629\ 70TL3826Ł[ N!Bromosuccinimide has been used to
accomplish dehydrogenation\ but signi_cant amounts of azines are formed which detract from the
synthetic utility of this reagent ð44JA0569Ł[ Triphenylbismuth carbonate has been used to prepare
diphenyldiazomethane from benzophenone hydrazone in excellent yield\ but the generality of this
reaction has not been explored ð68CC694Ł[

2[01[2[1[3 BamfordÐStevens reaction of tosyl hydrazones


The BamfordÐStevens reaction provides a versatile method for converting carbonyl compounds
into diazo compounds ð41JCS3624Ł[ During the reaction\ an aryl sulfonyl hydrazone of an aldehyde
or ketone is cleaved to give a diazo compound and an aryl sul_nate "Scheme 39#[ The success of the
reaction is dependent on the nature of the substrate and the reaction conditions employed[ For!
mation of carbenes\ cationic intermediates or vinyl anions can be problematic\ and azine formation
is sometimes observed ðB!75MI 201!90Ł[
H –
R1 N SO2Ar R1
R1 N SO2Ar base, –H+
N2 + –SO
N 2Ar
N
R2 R2
R2
Scheme 40

The BamfordÐStevens reaction of tosyl hydrazones derived from alkyl or aryl ketones is usually
achieved by heating the substrate with a base[ A variety of solvent and base combinations have
been used to e}ect the reaction ðB!75MI 201!90Ł[ Unfortunately\ the rather harsh conditions required
to promote the reaction often lead to low yields of sensitive diazo compounds[
The BamfordÐStevens reaction can also be accomplished by alkaline cleavage of methylsul_nyl
or 1!nitrophenylsulfenyl hydrazones ð64CC003\ 64TL0454Ł[ In the _rst case\ the diazo compound is
usually isolated after treatment of the unsubstituted hydrazone with methanesul_nyl chloride in the
Diazo Compounds 354
presence of two equivalents of triethylamine\ without isolation of the intermediate methylsul_nyl
hydrazone[
It is possible to transform aldehyde and ketone tosyl hydrazones to diazo compounds under
biphasic conditions ð66BSB628\ 67SC458Ł[ Triisopropyl benzenesulfonyl hydrazones may be used as
substrates in this reaction\ and they are cleaved more rapidly than the corresponding tosyl hydra!
zones ð71S308Ł[
Dialkyl diazo compounds are often unstable under the conditions of the BamfordÐStevens
reaction\ even when the reaction is performed in an aprotic solvent[ Vacuum pyrolysis of salts of
tosyl hydrazones is an alternative method for the preparation of these compounds ð54JA824Ł[ The
pyrolysis reaction is useful for the synthesis of aryl diazoalkanes\ but gives only low yields when
heat!sensitive diazoalkanes are produced[ Phenyldiazomethane can be prepared in good yield from
the sodium salt of benzaldehyde tosylhydrazone using this method ð75OS"53#196Ł[ The reaction can
also be performed by photochemical methods ð70JOC3574Ł[

2[01[2[1[4 Cleavage of N!nitrosoamines


Cleavage of b!"N!alkyl!N!nitrosoamino#ketones or !sulfones under alkali conditions results in
formation of diazo alkanes[ For example\ cleavage of b!"N!alkyl!N!nitrosoamino#methylpentan!3!
ones has been used to prepare many diazo alkanes "Scheme 30# ð24JCS175Ł[ The reaction precursors
are readily prepared by addition of the appropriate primary amine to mesityl oxide and subsequent
nitrosation ð22JCS252\ 44OSC"2#133Ł\ and sodium alkoxides are usually the bases of choice for the
cleavage reaction ð26JCS0440\ 38JA0518Ł[ The yield of diazoalkane may be reduced as a result of
ð2¦1Ł!cycloaddition of the product with the enone liberated during the reaction[ The main use of
this procedure is for the synthesis of diazomethane and homologous diazo alkanes ð24JCS175\
55JA3624Ł[


O
–H2O
R
RO– N O
N O N +
N N2
O R N
O R HO N R
RO H

Scheme 41

Diazo alkanes can be prepared by cleavage of "N!alkyl!N!nitrosoaminomethyl#carboxamides\ by


analogy to the reaction discussed above "Scheme 31#[ The reaction precursors are prepared by the
condensation of carboxamides with formaldehyde and an appropriate alkylamine hydrochloride\
followed by nitrozation of the resulting amine hydrochlorides[ Both amides and urethanes have
been used as precursors in this reaction ð65CPB258\ 68CPB571Ł[

HCHO O R2
O O R2
R2CH2NH4Cl NaNO2 KOH (aq.)
+ R1 N N
R1 NH2 –H2O R1 N N Cl– H
H H H N
O

O OH R2
+
R1 N N2
H

Scheme 42

Diazomethane and other diazo alkanes can be prepared by the cleavage of N!acyl!N!nitroso!
amines "Scheme 32#[ Urethanes\ ureas\ carboxamides\ arylsulfonamides and guanidines can be used
as precursors[ With urethanes and carboxamides\ nucleophilic attack of the base at the carbonyl
group leads to the formation of a diazotate ð51OS"30#05Ł[ The diazotate intermediates have been isolated
ð91CB786\ 59ZN"B#640\ 50AG110\ 52CB0601\ 54JOC3146\ 55JOC0971\ 57T1770Ł\ but are usually protonated in
situ to form diazohydroxides which are then converted diazonium ions[ The diazonium ion is either
deprotonated to a}ord the diazo compound or loses nitrogen and forms a carbonium ion[ The
355 Hydrazones and Other 1NN Derivatives
course of the reaction is in~uenced by the nature of the substituents present in the precursor
ð63ACR310Ł\ with branched alkyl groups favouring the formation of carbonium ions ð55JOC0971Ł[
When both substituents are primary alkyl groups\ the diazo alkane is produced along with products
arising from cationic species ð40LA"462#052\ 55JOC0971Ł\ but with methyl\ benzyl and allyl substituents\
diazo alkane formation is favoured ð91CB786\ 61TL4036\ 62JOC0710Ł[

R1
ROH, RO– R1 –HO–
R1 R2 –H+
R1 R2
X
N R2 N
HO N R2 N2+ N2
N
O
X = RO2C, R2NCO, RCO, ArSO2, (O2NNH)C=NH

Scheme 43

Decomposition of N!methyl!N!nitrosourethanes is accomplished by treatment with catalytic


amounts of a base\ such as potassium carbonate\ in an alcoholic solvent ð41LA"464#063Ł[ Base!
promoted cleavage of N!alkyl!N!nitrosoureas can also be used to prepare diazo alkanes[ In this
reaction\ deprotonation is followed by fragmentation to isocyanic acid and an alkyl diazotate[
Proton transfer then a}ords the diazohydroxide which loses water to form the diazo alkane
"Scheme 33# ð56LA"696#33\ 61TL4036\ 62JOC0710Ł[ N!Methyl!N!nitrosourea has been widely used for
the generation of diazomethane by this process\ in spite of the fact that it is thermally unstable[ The
reaction is usually performed in a two!phase system of aqueous potassium hydroxide and either
benzene or diethyl ether ð08JCS0982\ 32OSC"1#350Ł[ Removal of diazomethane by distillation allows
organic solvents to be omitted from the reaction ð52BSF30\ 53JA0704Ł[ Other diazoalkanes have been
synthesised in good yield from their respective N!nitrosoureas under these conditions\ although
diazocycloalkanes are usually generated at lower temperatures because of their instability[


H2N NO K+ HN N O
N KOH, –H+ N
O R2 O R2
R1 R1

R1 N OH R1 R2
–H2O
N + KOCN
R2 N2

Scheme 44

Diazo alkanes can be prepared by treatment of N!alkyl!N?!nitro!N!nitrosoguanidines with a base


"Scheme 34# ð36JA2917\ 37JA0863Ł[ The reaction proceeds by deprotonation of the amino group and
subsequent decomposition to a diazotate and nitrocyanamide\ followed by proton transfer to give
a nitrocyanamide salt and the diazo hydroxide which then decomposes to the diazo compound[ The
synthesis of diazo alkanes by this method can be hampered by di.culties associated with the
preparation of the nitrosoguanidine precursors[

H H
O2N N NO O2N N N O
KOH, –H+ –O2NNCN–K+
N N
HN R2 K+ – N R2
R1 R1

R1 N OH R1 R2
–H2O
N
R2 N2

Scheme 45
Diazo Compounds 356
Diazo alkanes have been prepared by base!promoted fragmentation reactions of N!alkyl!N!
nitrosocarboxamides[ For example\ treatment of N!methyl!N!nitrosoacetamide with potassium
hydroxide in methanol a}ords a solution of diazomethane ð42CB65\ 42CB167Ł[ The same trans!
formation can be e}ected using alkyllithium reagents ð50AG110Ł[ Diazomethane can also be prepared
by cleavage of N\N!dimethyl!N\N!dinitrosooxalamide with methylamine "Equation "06##[ Diazo!
methane may be distilled from the reaction mixture when a high boiling alcohol solvent is used\ or
can be generated and reacted in situ using methanolic potassium carbonate in the presence of an
appropriate substrate ð50CB1436Ł[

NO
O N O NHMe
Me MeNH2 or K2CO3, MeOH
+ 2H2C=N2 (17)
Me
O N O NHMe
NO

a\v!Bis"diazo# alkanes can be synthesized from the corresponding dinitroso compounds "Equation
"07##[ Although 0\1!bis"diazo#ethane has not been observed directly\ the existence of this compound
has been shown by trapping experiments ð43JA330Ł[ 0\2!Bis"diazo#propane has marginal stability in
solution and can be prepared by treatment of N\N?!dibenzoyl!N\N?!dinitroso!0\2!propanediamine
with sodium hydroxide in methanol ð58JA695Ł[

RO2C CO2R
N ( )n N base
N2 ( )n N2 (18)
NO NO

Longer chain a\v!bis"diazo# alkanes have been prepared and fully characterized ð49CB026\
43JA330Ł[A useful and high yielding route to 0\5!bis"diazo#hexane has been developed in which the
nitrosamide polymer formed by nitrozation of Nylon 55\ is treated with potassium hydroxide in
aqueous methanol "Equation "08## ðB!75MI 201!90Ł[

O ON N2
N KOH, MeOH, H2O, Et2O
N (19)
O NO N2
n

Diazo alkanes can be prepared in good yield by reaction of N!alkyl!N!nitroso!p!toluene!


sulfonamides with base[ The stable commercially available compound N!methyl!N!nitroso!p!tolu!
enesulfonamide "Diazald# has a good shelf!life and has become the reagent of choice for the
generation of diazomethane "Equation "19##[ Reaction temperatures of 49Ð69>C are required to
accomplish cleavage of this compound with base\ and gaseous diazomethane or alcohol free solutions
of diazomethane can be obtained when a high boiling solvent is used ð43RTC118\ 52OSC"3#149\
79JOC4266Ł[

O N O O
KOH, ROH
S N H 2C N2 + S OR (20)
O Me O

2[01[2[1[5 Diazo group transfer


Enamines readily undergo regioselective cycloaddition with azides\ and during the reaction the
electrophilic azide nitrogen becomes bonded to the electron!rich carbon atom "Scheme 35# ð52CB791\
54CB0027Ł[ The triazoline intermediates are isolable\ but usually decompose to the diazo alkane and
an amidine during the reaction ð54CB0027\ 54CB1604\ 69LA"623#69Ł[ The reaction pathway is determined
by the nature of the substituents present in the precursor\ and the method has been used mainly for
the synthesis of diazomethane ð52CB791\ 54CB1604\ 66T754Ł[
357 Hydrazones and Other 1NN Derivatives

R2 R2
R1 R2 N N2+ R1 R2 N R5
R5N3 R1 R1
N + R3
R3 R3
NR42 N N– N2 NR42
R3
R42N R5 R42N R5

Scheme 46

2[01[2[2 a!Diazo Carbonyl and b!Dicarbonyl Compounds

2[01[2[2[0 Diazotization of a!amino carbonyl compounds


Diazotization of a!amino carbonyl compounds is an important reaction for the synthesis of a!
diazo carbonyl compounds "Equation "10##[ This reaction was _rst used to synthesize ethyl diazo!
acetate from glycine ethyl ester hydrochloride ð0772CB1129Ł\ and has been studied extensively since
then ð0773CB842\ 91JCS487\ 13JA620\ 52OSC"3#313Ł[ The reaction is especially useful for the preparation
of a!diazo esters\ a!diazo acetamides ð64JHC0080Ł\ and peptidic diazoesters ð93CB0173\ 95CB0262\
95CB0268Ł[ 5!Diazopenicillinic acid derivatives have also been prepared using this reaction
ð56HCA0216\ 63JOC0333\ 67JOC1192Ł[

O O
NaNO2, H+
R1 R1 (21)
Y Y
NH2 N2
Y = R2, OR2, NR22

It is possible to accomplish selective monodiazotization of substrates which contain more than


one amino group by controlling the pH of the reaction[ The reaction has been used to good e}ect
in order to synthesize a!diazo esters of serine ð43JA1773\ 43JA1776\ 67JOC3555Ł[ A variety of diazo
acetates ð93CB0150Ł\ diazo succinates ð29CB691\ 21CB154Ł and diesters of diazo glutaric acid ð21CB154Ł
have also been synthesized in this manner\ although yields are generally low[ a!Diazo esters can be
prepared by treatment of a!amino acid esters with isoamyl nitrite and acetic acid rather than sodium
nitrite ð60TL3384\ 64T116\ 71TL0764Ł[
Diazotization of a!amino ketones is not usually a good method for the preparation of a!diazo
ketones[ Rearrangement with loss of the amino group usually occurs during the reaction ð48JOC1960\
50JA288Ł[ There are some exceptions however\ and compounds such as 2!diazocamphor ð0770CB0264Ł
can be prepared using this reaction[
Diazotization of reactions of certain aromatic amines a}ord the corresponding a!diazo
compounds[ For example\ 8!amino!09!nitrophenanthrene reacts with nitrous acid under acidic
conditions to form 8!diazo!09!phenanthrenone "Scheme 36# ð60JCS"C#0273Ł[ In a similar fashion\
diazotization of 0!aminophenazine a}ords the corresponding a!diazo ketone "Scheme 37#
ð66JHC0144Ł[

NaNO2, H2SO4, AcOH H2O

NO2 NO2 O
NH2 N2+ N2

Scheme 47

a!Diazo b!dicarbonyl compounds are readily accessible by diazotization of amines\ and there are
many examples which testify to the success of the reaction ðB!75MI 201!90Ł[ The side reactions
encountered during diazotization of a!amino ketones do not usually occur with a!amino!b!dicar!
bonyl compounds because proton loss from the diazonium intermediate is facilitated by the presence
of two electron!withdrawing groups[
Diazo Compounds 358
NH2 Cl– N2+ N2
N NaNO2, HCl N H2O N O

N N N

Scheme 48

2[01[2[2[1 Forster reaction of a!keto oximes


The Forster reaction "see Section 2[01[2[1[1[# can be used to convert a!keto oximes into a!diazo
ketones "Scheme 38#[ The reaction has been used extensively for the preparation of cyclic a!diazo
ketones and can also be applied to the synthesis of a\a?!bis"diazo#ketones[ In special cases\ the
transformation may be accomplished by condensation of an oxime with phenylhydrazine[ This
reaction has been used to prepare 2!diazo!1\3!chromanedione "32# "Scheme 49# ð54G872Ł[
O O
O R2 H2NCl
oxime formation R2
R2 R1 R1
R1 N
HO N2

Scheme 49

O O H O
N H2NNHPh N N –PhNH2 N2
OH N Ph
–H2O H
O O O O O O
(43)
Scheme 50

2[01[2[2[2 Direct nitrozation of carbonyl compounds


The synthesis of a!diazo carbonyl compounds can be accomplished by direct nitrozation of certain
substrates[ For example\ nitrozation of the lactone "33# leads to a complex mixture which contains
"34a# and "34b# "Scheme 40# ð57BCJ1696Ł[ This method has also been used to convert 0\5!
diarylhexane!0\2\3\5!tetraones into bis"diazo#compounds ð79JCS"P0#1569Ł[

CO2Et CO2Et OR
CO2Et
NaNO2, AcOH (aq.)
H
O O O
CO2H 5 to 10 °C
N N2
O O OH
O
(44) (45) a; R = H
b; R = OAc

Scheme 51

2[01[2[2[3 Dehydrogenation of a!keto hydrazones


Many a!diazo carbonyl and b!dicarbonyl compounds have been prepared by dehydrogenation of
hydrazones "see Section 2[01[2[1[2#[ Mercury"II# oxide\ silver"II# oxide and manganese"IV# oxide
are the oxidizing agents most commonly used[
When mercury"II# oxide is employed in this reaction\ a metallated a!diazo ketone may be produced
if the _rst formed product is a diazomethyl ketone "see Section 2[01[2[4[01#[ The success of the
369 Hydrazones and Other 1NN Derivatives
dehydrogenation reaction with mercury"II# oxide depends on the quality of the reagent[ For example\
reaction of the hydrazone "35# with active mercury"II# oxide a}ords the a!diazo ketone "36#\ whereas
treatment of "35# with a reagent of lower activity results in Wol}ÐKishner reduction and subsequent
oxidation to the a!diketone "37# "Scheme 41# ð57HCA532Ł[

O
O
Ar deactivated HgO O
oxidation Ar
Ar Ar Ar
N Ar
NH2 O
(46) Ar = p-MeC6H4 (48)

HgO, THF, –20 °C


Na2SO4, KOH

O
Ar
Ar
N2
(47)

Scheme 52

Some less widely used dehydrogenation reagents can be used to dehydrogenate monohydrazones
of a!diketones[ For example\ 1!diazo!0\1!diphenyl!0!ethanone has been prepared in very high
yield by treatment of benzil monohydrazone with copper"II# chloride and pyridine ð62TL3462Ł[
Dehydrogenation of monohydrazones of a!diketones has also been accomplished using calcium
hypochlorite in methanol ð50JOC1506Ł[
Oxidation of monosemicarbazones of a!dicarbonyl compounds with lead"IV# acetate is also a
useful method of preparing a!diazo carbonyl compounds\ and proceeds in a similar fashion to the
oxidation reactions discussed above ð67S424Ł[

2[01[2[2[4 BamfordÐStevens reaction of a!keto tosyl hydrazones


BamfordÐStevens reactions of monotosylhydrazones of a!diketones are performed by reaction
with base at room temperature\ and are especially useful for the preparation of cyclic a!diazo
ketones[ The harsh conditions necessary for the formation of alkyl or aryl diazo alkanes are not
usually required[ Treatment with basic alumina in a suitable solvent is often su.cient to promote
reaction ð47JA1146Ł\ and reactive substrates such as phenanthraquinone\ can be transformed into
the a!diazo carbonyl compound directly without base ð47JA1146\ 47LA"506#19\ 69JA1480Ł[
In some cases iminocarbonyl compounds can be used as substrates in the BamfordÐStevens
reaction ð55LA"580#49\ 58TL2392Ł[ For example\ the a!diazo ketone "49# is produced by reaction of
"38# with tosyl hydrazine\ and subsequent hydrolysis of this compound then a}ords the diazo dione
"40# "Scheme 42# ð58TL2392Ł[

Ph Ph Ph Ph Ph Ph
Ar TsNHNH2, C6H6 Ar H3O+
O N O N O O
N N2 N2
Ar
(49) (50) (51)

Scheme 53

The BamfordÐStevens reaction is also useful for the preparation of a!diazoacetates of unsaturated
alcohols[ For example\ acylation of "E#!but!1!en!0!ol with tosyl hydrazonoacetyl chloride gives the
ester "41#\ which upon treatment with triethylamine in dichloromethane a}ords the a!diazoacetate
Diazo Compounds 360
"42# "Scheme 43# ð57JOC42Ł[ The transformation may also be achieved in a one!pot fashion by
performing the acylation reaction in the presence of two equivalents of base[

Ts
Ts
N N O NaHCO3 Et3N
OH + O N N O N2
H CH2Cl2 CH2Cl2
H
Cl
O O
(52) (53)

Scheme 54

The a!diazo succinate diester "44# can be prepared in good yield from methyl alkynedicarboxylate
"Scheme 44# ð64BSF136Ł[ Nucleophilic addition of tosylhydrazine to the alkyne and subsequent
isomerization a}ords the tosyl hydrazone "43#\ and the a!diazo ester "44# is then obtained by
treatment of "43# with potassium carbonate[
CO2Me
MeO2C CO2Me
TsNHNH2 K2CO3 (aq.), 80 °C MeO2C
MeO2C CO2Me H N
MONOGLYME N N2
Ts
(54) (55)

Scheme 55

2[01[2[2[5 Cleavage of N!nitrosoamides


There are a few examples of the preparation of a!diazo carbonyl compounds from N!alkyl!N!
nitrosocarboxamides[ For example\ the a!diazo penicillin derivatives "46a# and "46b# have been
prepared from the acetamides "45a# and "45b# "Equation "11## ð56HCA0216\ 63JOC033Ł[ Ethyl diazo!
acetate can be prepared in high yield by treatment of the nitrosoacetamide "47# with a mixture of
barium oxide and barium hydroxide in methanol "Equation "12## ð59AG22\ 59CB1051\ 53JOC1969Ł\ and
t!butyl diazo acetate can be obtained in a similar manner ð59CB1051Ł[

O
N N2 H
H H S
R1 N S C5H5N, CHCl3, silica gel
(22)
N
O N O CO2 R2
O CO2R2 H
H
(56) a; R1 = Ph, R2 = CH2CCl3 (57) a; R2 = CH2CCl3
b; R1 = PhO, R2 = CH2Ph b; R2 = CH2Ph

O
O
EtO BaO, Ba(OH)2, MeOH
EtO (23)
N
ON N2
O
(58)

2[01[2[2[6 Diazo group transfer to carbonyl compounds


Diazo group transfer reactions are transformations in which an intact diazo unit is transferred
from a donor to an acceptor molecule ð56AG675\ 56AG"E#622\ 61S240Ł[ This is undoubtedly the most
versatile class of reactions for the synthesis of a!diazo carbonyl and a!diazo b!dicarbonyl
compounds[
361 Hydrazones and Other 1NN Derivatives
The most useful substrates for diazo group transfer are those possessing active methylene groups[
For example\ diazo transfer to b!dicarbonyl compounds from sulfonyl azides is performed in the
presence of tertiary amine bases "Scheme 45#[ Because of the mildness\ simplicity and reliability of
this reaction\ it has replaced amine diazotization as the method of choice for the preparation of a!
diazo b!dicarbonyl compounds[ In most cases\ diazo group transfer to an active methylene com!
pound proceeds via an intermediate triazine which is formed by attack on the azide by the anion of
the active methylene compound[ Spontaneous decomposition of this intermediate\ accompanied by
a proton shift\ then leads to the product diazo compound[ A wide variety of azides\ including tosyl
azide ð56AG675\ 56AG"E#622\ 89CC541Ł\ methanesulfonyl azide ð75JOC3966Ł\ p!carboxybenzenesulfonyl
azide ð57JOC2509Ł and azidotris"diethylamino#phosphonium bromide ð89TL3876Ł\ have been used as
diazo transfer reagents in this reaction[
R1

base, –H+ H+, –TsNH2 R1 R2


R1 R2 TsN3 N R2
R1 R2
– N N2
N–
Ts

Scheme 56

A limitation of diazo transfer reactions of this type is the requirement of two electron!withdrawing
substituents to activate the methylene group[ This problem can be circumvented by temporary
activation with a formyl group\ which can be introduced by Claisen condensation and is lost during
diazo group transfer[ The reaction can be performed in a one!pot sequence by using the alkali
salt formed during Claisen condensation directly in the diazo group transfer reaction ð56TL628\
57CB1511Ł[
Deformylative diazo group transfer is very useful for the synthesis of a!diazo ketones\ a!diazo
aldehydes\ a!diazo esters and a\b!unsaturated diazo ketones ð57CB1511\ 69LA"628#063Ł\ and can pro!
ceed by two possible pathways "Scheme 46#[ In the _rst pathway "a#\ a triazoline intermediate is
formed which decomposes to give the sulfonylformamide and the a!diazo ketone product[ In the
alternative mechanism "b#\ an intermediate triazine is formed\ and loss of the formyl group occurs
by alcoholysis[ When the diazo transfer reaction of a formyl ketone is performed in dichloromethane
in the presence of triethylamine\ there is evidence that the reaction proceeds by way of a triazoline
intermediate ð56TL628\ 57CB1511Ł[ The formation of a triazoline intermediate can be a problem
during diazo group transfer to some types of a!formyl cycloalkanones\ and may lead to formation
of a b!keto amide rather than the a!diazo cycloalkanone ð56TL628\ 57CB0152Ł[
O
O
O–
–Ts(CHO)N–
R
TsN3, ROH N N N2
N Ts
O O O O (a)
base, –H+
ROH, –HCO2R
R R
– (b)

TsN3, ROH
COR
O O
N CHO –TsNH–
R
N
N– N2
Ts

Scheme 57

Other proton!activating groups can be employed to achieve temporary activation of the methylene
group during the formation of a!diazo ketones[ For example\ the benzoyl group has been used as
an activator in the synthesis of steroidal a!diazo ketones ð79TL04Ł\ and the alkoxyoxalyl group has
been used as an activator during the synthesis of a\b!unsaturated diazo ketones ð57CB1511\ 63S466Ł[
A useful new diazo group transfer method for the synthesis of a!diazo ketones has been developed[
In this procedure\ tri~uoroacetylation of a ketone enolate\ followed by treatment of the resulting
Diazo Compounds 362
b!diketone with methanesulfonyl azide in the presence of triethylamine a}ords the a!diazo ketone
"Scheme 47# ð89JOC0848Ł[ This protocol is especially useful for diazo group transfer to a\b!unsatu!
rated ketones which are poor substrates for deformylative diazo group transfer[ Yields are superior
to those obtained by deformylative diazo group transfer in many other cases[

O O O O
LiN(TMS)2, CF3CO2CH2CF3 MsN3, Et3N, MeCN (aq.), RT R2
R1 R1 CF3 R1
THF, –78 °C
R2 R2 N2

R1 = aryl, α,β-unsaturated, heteroaromatic; R2 = H, Me, cycloalkane

Scheme 58

Phase transfer conditions can be employed in cases where deformylative diazo group transfer
cannot be used[ Tosyl azide is usually utilized as the diazo group transfer reagent\ but azidinium
salts have also been used[ When p!carboxybenzenesulfonyl azide is used as the diazo transfer reagent\
excess azide and the product sulfonamide can be removed from the product by treatment with
aqueous base[ This can be advantageous in cases where incomplete reaction complicates puri_cation
of the a!diazo carbonyl product ð57JOC2509Ł[
In some cases it is possible to accomplish diazo group transfer from diazo compounds rather
than sulfonyl azides[ For example\ reaction of 0\0!dimethylcyclohexane!2\4!dione with ethyl diazo!
nitroacetate a}ords the product of diazo group exchange "Scheme 48# ð54LA"576#103\ 58LA"611#34Ł[

O O
CO2Et O2N
Et3N, EtOH, –H+ – H+
+ N2 CO2Et
NO2 N N
O O
O

N2 + O2N CO2Et

Scheme 59

a!Diazo ketones can be prepared by diazo group transfer from azidinium compounds to activated
substrates under acidic or neutral conditions rather than basic conditions ð50LA"536#00Ł[ This reaction
can also be accomplished under acidic or neutral conditions using azidochloromethylene!
dimethylammonium chloride ð79AG643\ 79AG"E#605Ł[
Although diazo group transfer to enamines is usually employed to prepare diazo alkanes which
do not possess adjacent carbonyl groups\ the reaction can also be used to synthesize a!diazo carbonyl
compounds\ and is especially useful for the preparation of a!diazo aldehydes[ Treatment of a formyl
enamine with tosyl azide gives the corresponding a!diazo aldehyde in good yield "Scheme 59#
ð55TL0098\ 56CC188\ 69CCC2507Ł[ Ethyl diazoacetate and various diacyldiazomethanes have been
prepared from their respective enamines in this fashion ð69LA"623#69Ł[

R2
R2
R2 R3 TsN3 R1 N R3 R3 CHO
CHO + N
N R1
R1 CHO N2
N N NTs
Ts N

Scheme 60

a\b!Unsaturated diazo ketones can be prepared by cycloaddition of diazo alkanes to strained


cycloalkenones followed by ring opening of the resulting bicyclic pyrazoline[ For example\ addition
of a diazo alkane to the cyclopropenone "48# results in formation of an a\b!unsaturated diazo ketone
"59# "Scheme 50# ð58TL1548\ 61JA3676Ł[
363 Hydrazones and Other 1NN Derivatives

O
O O R2
R2 R2 R1
R1 R1
+ R2
N2 R2
R1 R1 N
N N2 R1
R2
(59) (60)

Scheme 61

2[01[2[2[7 Substitution at the diazo carbon of a!diazo carbonyl compounds


Many carbon electrophiles can be used for the alkylation or acylation of diazomethyl compounds[
Metallated diazo compounds "see Section 2[01[2[4# can be alkylated with reactive electrophiles[ For
example\ lithium "ethyl diazoacetate# reacts smoothly with allyl iodide or methyl iodide ð69AG180\
69AG"E#290Ł\ and silver "ethyl diazoacetate# reacts with allyl bromide\ crotyl bromide and benzyl
bromide ð56AG127\ 56AG"E#150\ 58CB377Ł[ Many similar alkylation reactions of metallated diazo
carbonyl compounds are known[
Diazomethyl compounds possessing electron!withdrawing groups will undergo nucleophilic
addition to reactive aldehydes[ The method is a general one\ and there are many examples of
additions of ethyl diazoacetate to aldehydes promoted by potassium hydroxide[ Additions of a!
diazomethyl ketones and ethyl diazoacetate to aldehydes can be performed at low temperature using
strong bases such as lithium diisopropylamide "LDA# or n!butyl lithium "Equation "13## ð63LA0656Ł[
Aldehydes react with ethyl diazotrimethylsilylacetate in the presence of 07!crown!5 and potassium
cyanide to a}ord the silylated product "50# "Equation "14## ð65JOC2224Ł[

O O OH
O i, base
X + X R (24)
R ii, H3O+
N2 N2
X = R, OR

O-TMS
EtO2C TMS O 18-crown-6-KCN EtO2C
+ R (25)
N2 R
N2
(61)

The acylation of diazo alkanes is probably the most important and widely used method for the
synthesis of a!diazo ketones and there are many examples "Scheme 51# ð05CB0867Ł[ This method of
preparing a!diazo ketones has become popular with the advent of protocols which minimize a!halo
ketone formation during the reaction ð04JCS0380\ 05CB0867\ 13JA1440\ 13JA1445\ 14JA0617Ł[ The reaction
is a general one\ and has been applied to the synthesis of many a!diazo carbonyl compounds
ð31OR"0#27\ B!75MI 201!90Ł[ Acyl halides and anhydrides are particularly good substrates for the
reaction\ and cyclic imide chlorides also react readily ð46JA833\ 47JCS0023Ł[ Diazomethane can also
be acylated with various vinylogous acid chlorides ð70TL330Ł[
O
O excess R2CHN2 or R2CHN2 (2 equiv.) O O
R2
R1
R1 X R2CHN2, R3N –R1CO2CH2R2 R1 O R1
N2
X = Cl, Br

Scheme 62

During the formation of a!diazo ketones by reaction of diazomethane with acid chlorides\ a large
excess of diazomethane is used to scavenge the acid evolved during the reaction and prevent
decomposition of the diazo ketone ð17JCS0209Ł[ Bases such as triethylamine can be used as acid
scavengers\ and only one equivalent of the diazomethane is required in these cases ð38JA0495\
38JA0518\ 46LA"591#088\ 66JOC2646Ł[ a!Diazo ketones can be prepared by reaction of acid chlorides
Diazo Compounds 364
with diazomethane generated in situ from an N!nitrosourethane or N!nitrosourea\ however\ this
procedure can a}ord unwanted by!products ð31OR"0#27Ł[ In certain circumstances it may be advan!
tageous to acylate trimethylsilyl diazomethane rather than diazomethane because of the relative
thermal stability and reduced toxicity of this compound ð79TL3350Ł[
Carboxylic acid anhydrides are good acylating agents for diazomethane\ and two moles of
diazomethane are consumed during the reaction "Scheme 51# ð46JOC134Ł[ Attack occurs at the more
electrophilic carbonyl group of mixed anhydrides ð69HCA0946Ł[ Symmetical anhydrides formed by
treatment of carboxylic acids with dicyclohexylcarbodiimide can be used directly in the reaction
without further puri_cation ð69HCA0946\ 60LA"636#10Ł[ The disadvantage of this technique is that half
of the original acid is converted to the methyl ester rather than the diazo ketone[
a!Diazo b!dicarbonyl compounds can be prepared by acylation of a!diazo carbonyl compounds\
usually a!diazo esters\ with acid chlorides "Scheme 52#[ Another method of acylation which has a
broad scope is the reaction of diazomethyl carbonyl compounds with acyl isocyanates to give the
corresponding a!diazo b!dicarbonyl compounds "Scheme 52# ð62CB0385\ 62T0872Ł[ Some acyl ketenes
will react with diazo ketones in an analogous fashion ð67ZOR1123Ł[

O O O O O O
R2COCl R2CONCO
R1 R2 R1 R1 N R2
H
N2 N2 N2

ArCOCHCO

O O O

R1 Ar
N2

Scheme 63

Diazo acetates are less prone to undergo cycloaddition to electron!de_cient alkenes than diazo!
methane\ and react with a\b!unsaturated acyl chlorides to give the corresponding unsaturated a!
diazo b!dicarbonyl compounds ð05CB0867Ł[ However cycloaddition is problematic when additional
electron!withdrawing groups are present in the a\b!unsaturated acyl chloride ð53LA"564#36Ł[ The
ratio of reactants may in~uence the outcome of this reaction\ and an excess of diazo substrate can
lead to acylation and cycloaddition ð56CJC0616Ł[
a!Diazo b!dicarbonyl compounds can be converted into a!diazo carbonyl compounds by alkaline
cleavage "Scheme 53# ð01LA"283#12\ 05CB0867Ł[ For example\ t!butyl diazoacetate can be prepared in
good yield by treatment of t!butyl diazoacetoacetate with sodium methoxide in methanol
ð57OS"37#25Ł[ The same compound is formed when t!butyl acetoacetate is reacted with tosylazide in
aqueous acetonitrile in the presence of potassium hydroxide ð58OPP88Ł[ In this case\ isolation of t!
butyl diazoacetoacetate is not required\ and high yields are obtained if this reaction is performed in
a two!phase system in the presence of a phase transfer catalyst ð63S236Ł[ Diazophenylmethane can
be prepared from azibenzil by a reaction which is analogous to those described above ð47JOC648Ł[

O O i, NaOH (aq.) O O O
ii, H3O+ NaOMe, MeOH
R R –RCO2H X X R
–RCO2Me
N2 X=R N2 X = OR N2

Scheme 64

a!Diazo carbonyl compounds can sometimes be prepared from other a!diazo carbonyl compounds
by substitution reactions[ For example\ diazoacetic acid can be converted to diazoacetyl chloride
by treatment with the a!chloroenamine "51# "Scheme 54# ð68CC0079Ł[ Diazoacetyl chloride can then
be converted to a variety of a!diazo esters and amides with preservation of the diazo group ð68AG0901\
68AG"E#836Ł[
a!Diazo esters can be converted into the corresponding a!diazo amides by substitution with
ammonia or amines\ and this reaction can be used to prepare a!diazo acetamide from methyl
365 Hydrazones and Other 1NN Derivatives
+ O
CO2H Cl NMe2 O NMe2
+ N2 + Me2CHCONMe2
Cl
N2 Cl– O N2
(62)
Scheme 65

diazoacetate ð93CB0173\ 95CB0272\ 97CB233Ł[ p!Nitrophenyl diazoacetate is an especially good substrate


for this reaction "Equation "15## ð57JA3977\ 69JA5695\ 61JA0518Ł[
NO2 O
O R1 NO2
ROH or H2O R1
+ H N N + (26)
O
R2 HO
N2 N2 R2

2[01[2[3 a!Diazo Imines\ Amidines\ Imidates and Nitriles

2[01[2[3[0 a!Diazo imines


a!Diazo N!cyano imines can be prepared directly from the reaction of alkynes with cyanogen
azide[ Cycloaddition a}ords the 0\1\2!triazole "52# which then undergoes ring opening to the a!
diazo imine "53# "Scheme 55# ð56JA3659Ł[ Unsymmetrical alkynes give mixtures of isomeric products\
which obviously limits the utility of this method ð70BSB504Ł[
R R R R
MeCN, 45 °C
R R + N3 CN
N N N2 N CN
N CN
(63) (64)

Scheme 66

Alkynes possessing electron!withdrawing groups do not react with cyanogen azide\ but react with
trimethylsilyl azide to a}ord triazoles which can be converted into a!diazo N!cyano imines by
deprotonation and subsequent reaction with cyanogen bromide "Scheme 56# ð70BSB504Ł[
i, TMS-N3 Y R Y R Y R
ii, H2O BrCN
Y R
iii, NaH, THF N – N –NaBr N N
CN N2 N CN
N N
Na +

Y = electron-withdrawing group

Scheme 67

a!Diazo imines can be synthesized by the reaction of acyl phosphoranes with azides "Scheme 57#[
Treatment of cyanogen azide with an acyl phosphorane results in formation of the triazoline which
eliminates a phosphine oxide to form the triazole "54# ð55JOC0476\ 69TL4114Ł\ which then undergoes
ring opening to a}ord the a!diazo imine ð79TL898\ 70AG007\ 70AG"E#002\ 70BSB504Ł[

+
O R1 R2
Ph3P O– R1 R
R2 NCN3 –Ph3PO
R1 R2
R1
N N N2 N CN
PPh3 N N N CN
N CN
(65)

Scheme 68
Diazo Compounds 366
2[01[2[3[1 a!Diazo amidines and imidates
The most general method of preparing a!diazo amidines is by diazo group transfer to ynamines[
Ynamines function as acceptors in diazo group transfer reactions and undergo sequential ð1¦2Ł!
addition and ring opening with various azides "Scheme 58# ð70ZN"B#107Ł[ In principle\ diazo amidines
can be in equilibrium with the corresponding triazoles[ However\ in cases where the imine substituent
is a good electron!acceptor group\ the open chain compound predominates ð61CB1852\ 68LA0717Ł[ In
cases where the azide substituent is a weak electron!acceptor or an electron!donor\ the triazole is
favoured ð55JOC0476\ 62LA0494Ł[ The presence of bulky N!substituents or electron!acceptor groups
on the ynamine tends to favour formation of the open chain products ð61S460\ 63CB1402Ł[

R1 NR22 R1 NR22
R1 NR22 + N3 Y
N N N2 N Y
N Y
(65)
Y = electron-withdrawing group

Scheme 69

a!Diazo imidates\ such as "55#\ can be prepared by reaction of alkynyl ethers with azides "Scheme
69# ð52TL0728\ 54CB512\ 61CB1864\ 70BSB504\ 71S038Ł[ In contrast to the alkynyl amines\ the reaction
between alkynyl ethers and 3!dimethylaminobenzene sulfonyl azide occurs without isolation of the
presumed intermediate triazoles[ However\ addition of sulfonyl azides to substituted alkynyl ethers
results in an equilibrium between the triazoles and their corresponding a!diazo imidates ð61CB1864\
62LA0494Ł[

R1 OR2 R1 OR2
R1 OR2 + N3 R3
N N N2 N R3
N R3
(66)

Scheme 70

2[01[2[3[2 a!Diazo nitriles


a!Amino nitriles readily undergo diazotization to a!diazo nitriles due to the large activating
e}ect of the electron!withdrawing cyano group[ The explosive compounds diazoacetonitrile and
diazophenylacetonitrile have been prepared using this method ð0783CB48\ 0787CB1378\ 45JA4341\
47JA4880Ł[
a!Diazo nitriles bearing aryl\ carbonyl\ sulfonyl\ phosphoryl and aryl substituents can be prepared
by diazo group transfer from 1!azido!2!ethylbenzthiazolium tetra~uoroborate "Equation "16##
ð67HCA86Ł[ Tosyl azide is not a suitable diazo transfer reagent in these reactions because the
products undergo further reactions with the base required to facilitate deprotonation ð57CB1240Ł[

S S
Y CN
N3 ROH (aq.) NH2
Y CN + + (27)
N + BF4– N + BF4–
N2
Et Et
Y = COR, CO2R, CONH2, SO2R, Ar

There are several methods for the preparation of a!diazo nitriles which do not rely on diazo group
transfer reactions[ For example\ the explosive compound dicyano diazomethane can be obtained
by oxidation of the corresponding hydrazone with lead tetraacetate ð54JOC3087Ł\ and ethyl cyano!
diazoacetate has been prepared in quantitative yield by thermal fragmentation of the a!diazo
thiatriazole "56# "Equation "17## ð71TL0092Ł[
367 Hydrazones and Other 1NN Derivatives

N N
N CHCl3, 60 °C EtO2C CN
EtO2C (28)
S
N2
N2
(67)

The cycloaddition reaction of acrylonitrile with phenylazide produces the triazoline "57#\ which
can be converted into the a!diazo nitrile "58# by treatment with triethylamine in benzene "Scheme
60# ð55CB364Ł[ However\ only an equilibrium mixture of "57# and "58# is obtained by this method[
NC NC
PhN3
NC
N N N2 NHPh
N Ph
(68) (69)

Scheme 71

a!Diazo nitriles such as diazophenylacetonitrile can be prepared by decomposition of hydrazones


bearing an aziridine ð64T0706Ł[ For example\ reaction of the iminophosphorane "69# with the
acylnitrile "60# a}ords the hydrazone "61#\ which undergoes decomposition to diazophenyl!
acetonitrile upon heating at re~ux in benzene "Scheme 61#[
R R
O Ph C6H6 Ph CN
N N PPh3 + N N + R
Ph
Ph CN CN reflux N2
Ph Ph
(70) (71) (72)

Scheme 72

2[01[2[4 Diazo Alkanes Containing Heteroatoms at the Diazo Carbon

2[01[2[4[0 Diazo alkanes substituted with halogens


Direct halogenation reactions of diazo compounds are of little general preparative use\ although
diazomethane can be chlorinated with t!butyl hypochlorite to a}ord chlorodiazomethane\ and
bromodiazomethane has been prepared in an analogous fashion ð54JA3169Ł[
Diazohalogenmethyl carbonyl and phosphoryl compounds can be prepared by metalÐhalogen
exchange[ Thus\ treatment of the corresponding silver or mercury derivatives with the free halogen
or halogenating reagents such as sulfuryl chloride or cyanogen bromide a}ords the corresponding
halogenated compound in good yield[ For example\ ethyl chlorodiazoacetate can be prepared by
treatment of mercury bis"ethyl diazoacetate# with sulfuryl chloride at −29>C ð57LA"605#193Ł\ and
ethyl bromodiazoacetate and ethyl iododiazoacetate can be prepared from reaction of mercury or
silver ethyl diazoacetate with bromine or iodine ð56AG49\ 56AG"E#63\ 57LA"605#193\ 58CB377Ł[
Halodiazomethyl phosphoryl compounds have been prepared by treatment of silver diazomethyl
phosphoryl compounds with either cyanogen bromide or iodine ð68LA0991Ł[

2[01[2[4[1 Diazo alkanes substituted with sulfur


Many a!diazo sulfoxides and sulfones are known\ and there are many possible synthetic
approaches to these compounds[
Dehydrogenation of hydrazones is a useful method for the preparation of a!diazo sulfones[ For
example\ bis"arylsulfonyl#formaldehyde hydrazones can be dehydrogenated to the corresponding
bis"arylsulfonyl#diazomethanes using manganese dioxide ð52JOC1822\ 54JOC1161Ł[
a!Methylenesulphones are not su.ciently acidic to participate in diazo group transfer reactions[
In contrast\ b!oxosulfonyl and bis"sulfonylmethanes# are good substrates for diazo group transfer\
Diazo Compounds 368
and many a!diazo b!oxosulphonyl and bis"alkylsulfonyl# diazomethanes or bis"arylsulfonyl# diazo!
methanes have been prepared using this reaction[ Sulfonyl diazomethanes can be prepared by
reaction of arylsulfonylmethylenetriphenylphosphorane with p!carboxybenzenesulfonyl azide
"Scheme 62# ð64T486\ 70JOC0780Ł[
CO2H CO2H
RSO2
RSO2 RSO2
PPh3
+ +
PPh3 N N N2
N SO2Ar
SO2N3 SO2NPPh3

Scheme 73

Diazo group transfer reactions can also be used to prepare a!diazo sul_nyl compounds[ An
additional electron!withdrawing group is required in the sulfoxide precursor to facilitate the reaction[
For example\ the diazo cephem "62# can be prepared directly by diazo group transfer because
a vinylogous carbonyl group is present in the precursor "Equation "18## ð65CC427\ 66JCS"P0#1187\
68JOC3586Ł[

O O
H H H H
S S N2
R1 R43N, MeCN or CH2Cl2 R1
(29)
N N
O R3 O R3
CO2R2 CO2R2
(73)

Deformylative diazo group transfer provides an indirect route to a!diazo sulfonyl compounds
which do not possess additional electron!withdrawing groups\ and compounds such as a!phenyl"p!
toluenesulfonyl#diazomethane and t!butylsulfonyldiazomethane have been prepared using this
approach ð62TL4196\ 64T486Ł[
Diazo vinyl sulfones can be synthesized by reaction of diazo alkanes with thiiriene!0\0!dioxides
"Scheme 63#[ However\ formation of the diazo compound "63# is always accompanied by a signi_cant
amount of pyrazole formation ð60JA365\ 79CB0521Ł\ and when the reaction is performed with diazo!
methane\ the product reacts further to give a pyrazoline ð79CB0521Ł[
N R2 O O R1 R1
R1 R1 N
R1 S R1
+ R2 CHN2 +
S R1 R1 N
S N2 N R2
O O R2
O O H
(74)
Scheme 74

Diazo substitution provides an alternative to diazo group transfer for the preparation of sulfur!
substituted diazo compounds[ Although sulfonyl chlorides are generally not electrophilic enough
to react with diazo alkanes ð22CB0901Ł\ there are some exceptions[ For example\ diazophenylmethane
will react with tosyl chloride to give diazophenyltosylmethane ð62C219Ł\ and phenylsul_nyl diazo!
methane can be prepared by treatment of diazomethane with phenylsul_nyl chloride[

2[01[2[4[2 Diazo alkanes substituted with nitrogen


Diazo group transfer to alkyl nitro compounds using sulfonyl azides is not usually possible
ð76JOC2355Ł[ Although azidinium salts have been used to accomplish diazo group transfer to methyl
nitroacetate and nitroacetophenone\ this method is not successful for nitromethane and other alkyl
nitro compounds ð55TL4710\ 67HCA86Ł[
Direct nitration of diazo compounds bearing electron!withdrawing groups at the a!position is
possible using dinitrogen pentoxide in an inert solvent[ For example\ ethyl diazoacetate can be
nitrated with dinitrogen pentoxide "Scheme 64# ð54AG268\ 54AG"E#247\ 58LA"611#34\ 78TL3086Ł[ The
379 Hydrazones and Other 1NN Derivatives
maximum possible yield is only 49) because half of the diazoacetate is converted into the cor!
responding nitrate ester "65# by proton transfer from the diazonium intermediate "64# to ethyl
diazoacetate and reaction of nitrate with the resulting diazonium compound[ Attempts to prevent
this side reaction by deprotonation of "64# with tertiary amine bases have not been successful
ð58LA"611#34Ł[
CO2Et CCl4, –30 °C O2N CO2Et N2CHCO2Et O2N CO2Et CO2Et
+ N2O5 +
N2 +
N2 NO3– N2 ONO2
(75) (76)

Scheme 75

t!Butyl diazonitroacetate can be prepared by reaction of mercury bis"t!butyl diazoacetate# with


dinitrogen pentoxide "Equation "29## ð55TL5088\ 58LA"611#34Ł[ Nitrodiazomethane is an extremely
explosive compound\ but can be prepared in high yield by deacylation of t!butyl diazonitroacetate
with tri~uoroacetic acid "Equation "29## ð55TL5088\ 60LA"637#196\ 77TL5920\ 89T6230Ł[ Dinitro!
diazomethane can be prepared directly by treatment of nitrodiazomethane with dinitrogen
pentoxide\ but the maximum yield for this reaction is only 49) ð58AG466\ 58AG"E#501Ł[

ButO2C Hg CO2But O2N CO2But CF3CO2H, Et2O O2N


+ N2O5 (30)
N2 N2 N2 –CH2CMe2, –CO2 N2

2[01[2[4[3 Diazo alkanes substituted with phosphorus


Many a!diazo phosphine oxides\ phosphinates and phosphonates are known and can be prepared
by many of the methods used for preparation of other diazo compounds[
Diazomethyl phosphonates\ methyl "diazobenzyl#phosphinate\ and diazomethyldiphenyl!
phosphine oxide are available from the corresponding amines by diazotization "Equation "20##
ð54AG0027\ 54AG"E#0967\ 69TL1382\ 60JOC0268\ 60LA"637#196\ 64CB1939Ł[ Phosphoryl diazomethanes are
more acid sensitive than the corresponding carbonyl compounds\ and consequently diazotization
reactions are often performed in acetic acid rather than in mineral acids ð50TL8\ 79CB2292Ł[

O O
NaNO2, AcOH
P NH2 P N2 (31)
R1 R1
R2 R2
R1, R2 = OMe, Ph

The BamfordÐStevens reaction provides an important route to a!diazo phosphoryl compounds


such as a!diazo phosphonates\ and is usually the reaction of choice for the synthesis of a!diazophos!
phinates[ The starting a!ketophosphoryl compounds are readily available\ and the reaction is
generally performed using sodium or potassium hydroxide or carbonate to deprotonate the inter!
mediate hydrazone "Scheme 65#[ Sodium borohydride in methanol can also be used to cleave
dimethyl a!tosylhydrazono phosphonates ð64S33Ł[
O
O O
P R3
P R3 TosNHNH2, EtOH, heat R1 O KOH P R3
R1O R2 R1O
N Tos R2
R2 N
O N2
H
Scheme 76

Diazo transfer is an important method for the synthesis of a!diazo phosphoryl compounds
which possess electron!withdrawing groups "Equation "21##[ Several a!diazo phosphine oxides\
phosphonates and phosphinates have been prepared by this method ð64AG148\ 64AG"E#111Ł[
Thiophosphoryl diazo alkanes have also been synthesized by diazo group transfer ð68T070\ 68TL1304Ł[
Diazo Compounds 370
In some cases\ azide transfer competes with diazo group transfer and thiophosphoryl azides may
be isolated instead of the required diazo compounds ð68T070Ł[

O O
base, TosN3, solvent P X
P X R1 (32)
R1
R2 R2
N2

R1, R2 = Ar, RO; X = COR, CO2R, CONR2, Ar, P(O)Ar2, P(O)(OR)2

Deformylative diazo group transfer is of limited use for the synthesis of diazo phosphoryl
compounds[ For example\ deprotonation of diethyl "1!oxoethyl# phosphonate followed by reaction
with tosyl azide a}ords only a low yield of diethyl "diazomethyl#phosphonate ð48CB0234\
58LA"629#083Ł[ The major products of these reactions are triazoles such as "66# "Scheme 66#[

O
P R2 –
R1 + OHC NTs
O O O– R1
R2 N2
P CHO P
R1 R1
R1 N Tos
R1 N N
R2 O R2
P +
R1 O– N NH
R1 N
(77)
R1 = OEt, Ph; R2 = H, OEt, Ph

Scheme 77

g\d!Unsaturated a!diazophosphoryl compounds are readily prepared by photochemical or thermal


isomerization of bicycloð2[0[9Łdiazahexenes produced by addition of diazoalkanes to 0!cyclo!
propenylphosphonates or 0!cyclopropenylphosphine oxides "Scheme 67# ð63TL0714\ 68CB1498\
79LA489Ł[

R2 R3
R5 R2 R3
R1 POR42 R5 R6 Et2O, 0 °C R1 POR4 2 heat or hν POR42
+ R6
R5
N2 N
R2 R3 R1 N2
N
R6

Scheme 78

b!Imino!phosphoryldiazoalkanes can be prepared by diazo group transfer from methyl or phenyl


azide to 0!cyclopropenylphosphonates ð68CB1498Ł[ The b!imino!phosphoryldiazoalkane products
are moisture sensitive and are hydrolysed to the corresponding b!oxo!phosphoryldiazoalkanes
during chromatography on silica gel "Scheme 68#[

R1 R2 R1 R2
PO(OR3)2
R4N3 PO(OR3)2 silica gel, H2O PO(OR3)2

R1 R2 N N2 O N2
R4

Scheme 79

A diazomethyl phosphonium salt is produced by diazo group transfer to a phosphacumulenylide\


presumably via formation and subsequent ring opening of the triazole intermediate "67# "Scheme
79# ð66AG250\ 66AG"E#238Ł[ Other a!diazo phosphonium salts are produced in high yield by reaction
of "acylmethyl#triphenylphosphonium salts with azidinium salts in ethanol or benzene ð68S794\
371 Hydrazones and Other 1NN Derivatives
70LA0754Ł[This method can also be used to prepare diazo bis"phosphonium# salts and bis"diazo#
bis"phosphonium# disalts ð70LA0754Ł[

+ O
Ph3P O– +
TsN3 Ph3P –
Ph3P • • O NTs
N N
N Ts N2
(78)

Scheme 80

A variety of phosphoryl diazo alkanes can be prepared by alkylation of metallated a!diazomethyl


phosphonates\ phosphinates or phosphine oxides[ The silver!substituted compounds react with alkyl
halides by SN0 addition to give alkylated products ð69TL1382\ 60JOC0268Ł[ Mercury derivatives have
also been used for this reaction ð68LA0991Ł[
a!Diazomethyl phosphoryl compounds can be acylated directly with acid chlorides in the presence
of tertiary amine bases ð65CB1928\ 68LA0991Ł\ and many acyl diazo phosphine oxides and phos!
phonates have been prepared in this way[ Bis"a!diazo b!oxophosphonates# can be prepared by
acylation with bis!acid chlorides such as oxalyl chloride ð68LA0991Ł[ The carbamoylation of phos!
phorylated a!diazomethyl compounds can be performed with acyl isocyanates and isothiocyanates
ð79LA294Ł[
a!Diazo phosphonates and phosphinates can be cleaved to give their respective a!diazomethyl
phosphonic and phosphinic acids[ Cleavage is usually accomplished by reaction with trimethylsilyl
bromide\ but sodium iodide in acetone or aqueous sodium hydroxide can be used ð65JA6216\ 66JA0156\
71JOC0173Ł[ Many dimethyl a!diazo phosphonates\ a!diazophosphonic acid methyl ester amides and
methyl a!diazo phosphinates react with trimethylsilyl bromide to give trimethylsilyl esters in high
yield[ The trimethylsilyl groups can be cleaved with t!butylamine under mild conditions to give t!
butylammonium a!diazo phosphonates or phosphinates ð74T708Ł[

2[01[2[4[4 Diazo alkanes substituted with arsenic\ antimony or bismuth


Ethyl diazodimethylarsylacetate can be prepared by treatment of ethyl diazoacetate with dimethyl!
aminodimethylarsane\ and an analogous reaction occurs with tris"dimethylamino#arsane
ð64JOM"86#48Ł[ Diazomethane does not react under these conditions\ but bis"dimethyl!
arsano#diazomethane is formed if trimethylstannyl chloride is added to the reaction "Scheme 70#
ð64JOM"82#228Ł[ Trimethylstannyl chloride increases the electrophilicity of the arsenic centre and
thus promotes nucleophilic attack of diazomethane[ Although the arsyl!substituted diazomethane
is more nucleophilic than diazomethane and the diarsylated product is usually obtained\
diazomethyldimethylarsane can be isolated when diazomethane is used in large excess
ð65JOM"009#084Ł[ Mixed substituted diazomethylarsanes containing silyl and germyl groups have
been prepared using this method ð66JOM"021#248\ 79JOM"080#260Ł[

Me3SnCl, Et2O Me2As Me2AsNMe2 Me2As AsMe2


Me2As NMe2 + H 2C N2
–HNMe2 N2 –HNMe2 N2

Scheme 81

Bis"dimethylantimony#diazomethane and ethyl "dimethylantimony#diazoacetate have been pre!


pared by the reaction above\ but without trimethylstannyl chloride as an activator[ Bis"dimethyl!
bismuth#diazomethane and ethyl "dimethylbismuth#diazoacetate have been synthesized by
analogous reactions ð64JOM"82#228Ł[

2[01[2[4[5 Diazo alkanes substituted with silicon\ germanium\ tin or lead


Trimethylsilyldiazomethane can be prepared by silylation of diazomethyllithium with tri!
methylsilyl chloride ð56CC725Ł\ and this compound can then be converted to bis"trimethylsilyl#
Diazo Compounds 372
diazomethane by deprotonation at low temperature and subsequent reaction with trimethylsilyl
chloride "Scheme 71# ð79JOM"080#260Ł[

TMS BunLi, pet. ether TMS Li TMS TMS


TMS-Cl TMS-Cl
LiHC N2
N2 –110 °C to 80 °C N2 N2

Scheme 82

a!Diazo!a!"trialkylsilyl#alkanones can be prepared by acylation of trimethylsilyldiazomethane


with acid chlorides ð79TL3350Ł\ or by treatment of diazomethyl ketones with trialkylsilyl tri~ates in
the presence of Hunig|s base ð76CB524Ł[ Reaction of mercury bis"diazocarbonyl# compounds with
disilylmercury compounds provides an alternative route to trialkylsilyl substituted a!diazo carbonyl
compounds "Scheme 72# ð66JOM"031#044Ł[ Silyl!substituted ethyl diazoacetates can be obtained in
excellent yield by reaction of mercury bis"ethyl diazoacetate# with appropriate iodo trialkylsilanes
ð57ZC151Ł\ and the unusual compound ethyl diazopentamethyldisilanylacetate "79# has been pre!
pared by reaction of mercury!bis"ethyl diazoacetate# with the disul_de "68# "Equation "22##
ð70JA4462Ł[

O O O O
Hg THF, 20 °C Et3SiHg –Hg Et3Si
(Et3Si)2Hg + R R R R
N2 N2 N2 N2
R = Me, OMe

Scheme 83

Me Me
EtO2C Hg CO2Et Me Me
Si S TMS Si CO2Et
+ TMS S Si TMS (33)
N2 N2 Me
Me N2
(79) (80)

There are many methods other than substitution of diazo alkanes which can be used to prepare
silicon!substituted diazo alkanes[ For example\ triphenylsilylphenyldiazomethane has been prepared
by the oxidation of the corresponding hydrazone with manganese"IV# oxide ð57TL3862Ł[ The Bam!
fordÐStevens reaction of trialkylsilyl!substituted hydrazones has also been used to prepare silicon!
substituted diazo alkanes ð58CJC3242\ 67JA883Ł[
Trimethylsilyldiazomethane can be synthesized in reasonable yield by treatment of N!"trimethyl!
silyl#methyl!N!nitrosourea with potassium hydroxide "Scheme 73# ð57JA0979\ 61JOM"33#168\
62JCS"D#372Ł[ Treatment of lithiated trimethylsilylmethane with tosyl azide at 9>C a}ords the same
compound in modest yield\ and this method can be employed to prepare bis"trimethyl!
silyl#diazomethane ð79JA0473Ł[ Bis"trimethylsilyl#diazomethane can be prepared by diazo group
transfer of trimethylsilyl azide to the silaethene "70# via the triazasilacyclopentene "71# "Scheme 74#
ð70CB2407Ł[

H2N NO 20% KOH, C5H12, pentane


TMS
0 °C
N TsN3 + Li TMS
O TMS N2

Scheme 84

There are many examples of the synthesis of germyl!substituted diazo compounds[ Diazomethane
and diazoacetates can be metallated directly using dimethylaminotrimethylgermane "Scheme 75#
ð69JCS"A#1843\ 60JOM"16#292\ 66JOM"016#08Ł\ and bis"trimethylgermyl#diazomethane can be prepared
analogously[ Trimethylgermyltrimethylsilyl diazomethane has been prepared from trimethyl!
silyldiazomethyl lithium ð79JOM"080#260Ł\ and this compound and bis"trimethylgermyl# diazo!
methane have been synthesized by diazo group transfer "Equation "23## ð79JA0473Ł[
373 Hydrazones and Other 1NN Derivatives

Me TMS
TMS Et2O, –10 °C TMS TMS
Me Si TMS
Me2Si + TMS N3
TMS N N N2
TMS N

(81) (82)

Scheme 85

Me3Ge CO2Et N2CHCO2Et, 80 °C CH2N2, Et2O Me3Ge


Me3GeNMe2
N2 N2

Scheme 86

Me3N i, ButLi, C5H12, THF, HMPA, –78 °C


Me3N
N2 (34)
Me3N ii, TsN3, –78 °C to 20 °C Me3N
M = Si, Ge

Diazomethyl compounds can be stannylated directly with either dimethylaminotrimethylstannane


or dimethylaminotriphenylstannane "Scheme 76# ð69JCS"A#1843Ł[ Diazomethane can be di!
stannylated using these reagents\ and both diazoacetates and a!diazomethyl ketones can be metallated
directly ð57JOM"04#140Ł[ Diazoacetates can also be stannylated by reaction with triethyl!
methoxystannane ð64ZOB708Ł[ Bifunctional stannylating agents\ such as bis"dimethylamino#
dimethylstannane\ react with ethyl diazoacetate to form dimethyltin bis"ethyl diazoacetate#
ð57JOM"04#140Ł[
O
N2CHCOR2, Et2O CH2N2, Et2O R13Sn SnR33
R13Sn R13SnNMe2
R2
N2
N2
R1 = Me, Ph; R2 = Me, Ph, OEt

Scheme 87

Treatment of lithium diazoacetate with an appropriate trialkylsilyl trialkylstannyl or tri!


alkylplumbyl halide can be used as a general method for the preparation of diazoacetates substituted
with silicon\ tin or lead at the diazo carbon ð61LA"650#026\ 63LA0656Ł[ Silyl\ stannyl and germyl groups
can also be introduced by reaction of mercury bis"ethyl diazoacetate# with the respective metal
sul_des ð56AG895\ 58AG"E#773\ 58LA"629#0\ 61LA"650#026Ł[
Lead!substituted diazomethyl compounds can be prepared by reactions that are analogous to
those described for tin!substituted diazo compounds[ For example\ bis"trimethylplumbyl#
diazomethane is produced upon treatment of diazomethane with dimethylaminotrimethylplumbane
"Equation "24## ð69JCS"A#1843\ 63JOM"67#110Ł\ and trimethylplumbyltrimethylsilyldiazomethane can
be prepared by reaction of trimethylðbis"trimethylsilyl#aminoŁplumbane with trimethylsilyl diazo!
methane ð60JOM"16#292\ 79JOM"080#260Ł[ Direct metallation of ethyl diazoacetate can be accomplished
by treatment with dimethylaminotrimethylplumbane ð60JOM"16#292\ 61LA"650#026\ 63JOM"67#110Ł\ and
a variety of other trimethylplumbyl a!diazo ketones have been prepared using this method "Equation
"25## ð63JOM"67#110Ł[
Me3Pb PbMe3
Me3PbNR2 + H2C N2 (35)
N2
R = Me, SiMe3

O O
Et2O, –30 °C to 20 °C Me3Pb
Me3PbN(TMS)2 + R R (36)
N2 N2
R = Me, Ph, OEt
Diazo Compounds 374
2[01[2[4[6 Diazo alkanes substituted with boron or thallium
The _rst boron!substituted diazo alkane to be prepared was ethyl "0\1\2!benzodioxaborol!
1!yl#diazoacetate "72#\ which was prepared by reaction of 1!chloro!0\1\2!benzodioxaborole and
lithium or mercury "ethyl diazoacetate# "Scheme 77# ð63LA0656Ł[ Two other examples of diazoalkyl
boranes are known ð78CB484\ 80JA4745Ł[ For example\ ðbis"diisopropylamino#boranylŁdiazomethane
was isolated after treatment of an ethereal solution of lithiated diazomethane with bis"diiso!
propylamino#chloroborane at low temperature "Equation "26##[

O O
EtO2C Hg CO2Et B Cl O CO 2Et B Cl Li CO2Et
O O
B
N2 N2 CH2Cl2, –10 °C to 0 °C C5H12, THF, Et2O, –100 °C N2
O N2
(83)

Scheme 88

Pri2N Pri2N
N2 Et2O, –78 °C
B Cl + B (37)
Li
Pri2N Pri2N N2

a!Diazoalkyl borates can be synthesized by treatment of bis"diisopropylamino#!chloro!


diazomethylene phosphorane with either boron tri~uorideÐetherate or boraneÐtetrahydrofuran
complex "Equation "27## ð80AG0063\ 80AG"E#0043Ł[

Pri2N Pri2N +
N2
PhMe, RT
Cl P • N2 + BY3 Cl P (38)
Pri2N Pri2N BY3–
BY3 = BF3•OEt2, BH3•THF

There are few examples of thallium!substituted diazo compounds\ but diazo bis"dimethyl!
thallium#methane can be prepared by treatment of diazomethane with either the metallated amine
"73# or trimethylthallium "Scheme 78# ð65JOM"019#020Ł[

Et2O Me2Tl TlMe2 Et2O


H 2C N2 + Me2TlNMe2 H2C N2 + Me3Tl
(84) –190 °C to 0 °C N2 –190 °C to 0 °C

Scheme 89

2[01[2[4[7 Diazo alkanes substituted with lithium or sodium


Diazomethyl lithium can be prepared directly by treatment of diazomethane with an alkyl lithium
or lithium N!methyl!N!trimethylsilylamide in ether ð43CB0776\ 54ZN"B#0998Ł\ or by reaction of methyl
lithium with dinitrogen monoxide "Scheme 89# ð46CB0291Ł[ The related sodium derivative can be
prepared by treatment of diazomethane with tritylsodium ð23LA"401#149Ł[ Both compounds are
highly explosive[

RLi or N2 MeLi
H2C N2 N2O
TMS(Me)NLi Li

Scheme 90
375 Hydrazones and Other 1NN Derivatives
Metallation of ethyl diazoacetate can be accomplished by reaction with butyl lithium at low
temperature in an ethereal solvent "Scheme 80# ð69AG180\ 69AG"E#290Ł[ The reagent can be prepared
by transmetallation from mercury bis"ethyl diazoacetate# "see Section 2[01[2[4[01# using phenyl or
butyl lithium\ or lithium thiolates[
O O O O
BuLi, –100 °C RLi or RSLi Hg
Li
OEt OEt EtO OEt
–70 °C
N2 N2 N2 N2

Scheme 91

2[01[2[4[8 Diazo alkanes substituted with magnesium


Ethyl diazoacetate reacts with Grignard reagents at low temperature to form the corresponding
magnesiated species "Scheme 81#[ For example\ iodomagnesium ethyl diazoacetate can be prepared
by treatment of ethyl diazoacetate with methyl magnesium bromide\ but the diazo magnesium
species is stable only in solution ð63LA0656Ł[ It is likely that Schlenk equilibrium gives rise to the
magnesium bis"diazoester# "74# in this case[
O O O O
MeMgI, Et2O, –65 °C MgI Mg
2 EtO 2 EtO EtO OEt + MgI2
N2 N2 N2 N2
(85)

Scheme 92

2[01[2[4[09 Diazo alkanes substituted with transition metals


Although diazo compounds can react with many late transition metal complexes to form highly
reactive carbenoid species\ it is possible to synthesize diazo compounds that are substituted with a
transition metal at the diazo carbon\ usually by transmetallation from the corresponding lithium or
mercury diazo compound[
The synthesis of the a!diazomethyl osmium complex "75# by reaction of OsCl"NO#"PPh2#2 with
HgðC"N1#CO1EtŁ1 has been reported "Scheme 82# ð73CC0991Ł[ Treatment of the complex "75# with
excess iodine results in loss of mercury and a}ords the new complex "76#[
PPh3
Cl NO
Os CO2Et I2
OsCl(NO)(PPh3)3 + Hg(CN2CO2Et)2 N2 Hg
Ph3P N2
CO2Et
(86)

PPh3 PPh3
Cl NO Cl NO
I2
Os CO2Et Os CO2Et
Hg I
I Ph P Ph3P
3 N2 N2
(87)

Scheme 93

The unstable diazomethyl rhodium complex RhðC"N1#TMSŁIMe"PMe2#2 has been prepared by


reaction of LiC"N1#TMS with Rh"PMe2#3Cl at low temperature ð76OM0711Ł[ The complex was not
isolated in pure form and decomposed after several days in the solid state or in solution[ Treatment
Diazo Compounds 376
of this complex with iodomethane a}orded a new air!stable complex "77# which was isolated and
characterized by x!ray crystallography[

TMS N2
I PMe3
Rh
Me3P Me
PMe3
(88)

The diazomethyl nickel complex NiðC"N1#TMSŁCl"PMe2#1 has been prepared by reaction of


LiC"N1#TMS with "PMe2#1NiCl1 in tetrahydrofuran at −14>C[ The air!sensitive complex was
characterized spectroscopically but decomposed at temperatures above −14>C ð89JA4240Ł[
Several a!diazo palladium complexes have been synthesized[ Palladium complexes such as "78#
can be prepared in moderate yield by reaction of diazo mercury compounds with bis"trialkyl!
phosphine#! or bis"triarylphosphine#palladium"II# halides "Equation "28## ð68CC349\ 75OM245Ł[
Complexes such as "89# have been synthesized by treatment of the appropriate palladium"II#
complex with two equivalents of an a!lithiodiazo compound at low temperature\ or by addition of
a bis"a!diazomethyl# mercury compound to Pd"Ph2P#3 at room temperature "Scheme 83#[ Both
types of complex are relatively stable and several have been characterized by x!ray crystallography
ð68CC349\ 75MI 201!90Ł[

R2 PR13
C6H6
(PR13)PdX2 + Hg[C(N2)R2]2 Pd X (39)
N2 PR1 3
(89)

R2 PR13 N2
THF C6H6
(PR13)PdX2 + LiC(N2 )R2 Pd (PR13)4Pd + Hg[C(N2)R2]2
N2 2
PR13 R
(90)
R1 = Et, Bu, Ph; R2 = CO2Et, C(O)Me, Ph, p-MeC6H4, Pri, But; X = Cl, Br, I

Scheme 94

Lanthanide!substituted diazo alkanes can be prepared by transmetallation[ Reaction of lithium


trimethylsilyldiazomethane with the lanthanide complexes YClCp1\ LuClCp1\ or YbClCp1
"Cppentamethylcyclopentadienyl# in tetrahydrofuran at low temperature a}ords the air! and
heat!sensitive complexes MðC"N1#TMSŁCp1 = THF "MY\ Lu\ Yb#\ in which the diazo carbon is
s!bonded to the metal ð81JOM"327#72Ł[

2[01[2[4[00 Diazo alkanes substituted with silver


The hydrogen of a diazomethyl compound is rather acidic when there is an adjacent electron!
withdrawing group\ and direct metallation of the diazo carbon with silver"I# oxide is possible[ Silver
"ethyl diazoacetate# and a variety of other silver "a!diazocarbonyl# compounds have been prepared
directly by this reaction "Equation "39## ð56AG127\ 56AG"E#150\ 58CB377Ł[ These compounds are of
synthetic importance because the silver is easily replaced with other metals and with carbon elec!
trophiles[ Silver "a!diazocarbonyl# compounds are rather unstable and must be prepared and used
at temperatures below 9>C[ Diazomethane can be metallated directly using silver acetate in a mixture
of diethyl ether and pyridine to give disilver!diazomethane\ which crystallizes with an equivalent of
pyridine "Equation "30## ð63CC355Ł[
377 Hydrazones and Other 1NN Derivatives
R Ag2O, –H2O
R Ag
(40)
N2 N2
R = CO2Et, COMe, COPh, PO(OEt)2, PO(OMe)(Ph), PO(Ph)2

Et2O Ag Ag
2MeCO2Ag + 3 H2C N2 • + 2MeCO2Me + 2N2 (41)
pyridine N2 N

2[01[2[4[01 Diazo alkanes substituted with zinc\ cadmium or mercury


Zinc and cadmium bis"ethyl diazoacetate# can be prepared by treatment of ethyl diazoacetate with
zinc or cadmium bisðbis"trimethylsilyl#amideŁ\ and are unstable but isolable compounds "Scheme 84#
ð60JOM"16#292Ł[ The polymeric compounds diazomethyl zinc and diazomethyl cadmium can be
prepared from diazomethane in an analogous fashion "Scheme 84# ð60JOM"16#292Ł\ and
bis"diazomethyl# cadmium has been prepared from diazomethyl lithium by transmetallation with
cadmium"II# chloride at low temperature ð57TL4126Ł[
N2CH2, Et2O, –40 °C N2CHCO2Et, Et2O, –35 °C
EtO2C M CO2Et
(MC=N2)n M[N(TMS)2]2
N2 N2
M = Zn, Cd

Scheme 95

Mercury may be introduced directly into diazomethyl compounds which possess an electron!
withdrawing group on the diazo carbon ð0784CB104Ł[ This transformation is usually accomplished
by treatment of the diazo compound with mercury"I# oxide in the presence of a water!absorbing
agent[
Mercury bis"ethyl diazoacetate# can be prepared in high yield by treatment of ethyl diazoacetate
with mercury bisðbis"trimethylsilyl#amideŁ at −19>C in diethyl ether ð60JOM"16#292Ł[
Bis"diazomethyl# mercury is a highly explosive compound\ and has been prepared by reaction of
mercury"II# acetate with diazomethane "Scheme 85# ð52NAT892Ł[ This compound has also been
prepared by lithiumÐmercury exchange from diazomethyl lithium with mercury"II# chloride
ð57TL4126Ł[ Alkyl! and arylmercury diazo alkanes can be prepared in good yield by metallation
of diazo alkanes with alkylmercury bis"trimethylsilyl#amides or by reaction of diazo alkanes with
alkyl! or arylmercury ethoxides "Scheme 86# ð60JOM"16#292\ 62JOM"43#12Ł[
H2C N2 + Hg[N(TMS)2]2 Hg(H2C N2)2 H2C N2 + Hg(OAc)2

Scheme 96

TMS R1 HgR2
R1HC N2 + R2Hg N R1HC N2 + R2HgOEt
TMS N2

R1 = CO2Me, CO2Et, COMe, COPh, CN; R2 = Me, Et, Ph

Scheme 97

2[01[2[5 Unsaturated Diazo Alkanes

2[01[2[5[0 Diazo alkylidenes


Diazo alkylidenes have not been isolated\ but they have been identi_ed as transient intermediates
in a number of reactions[ For example\ cleavage of the N!nitroso!oxazolidone "80# with lithium
ethoxide results in formation of 0!diazo!1!methylpropene which decomposes "Scheme 87#
Diazo Compounds 378
ð58JA5350Ł[ The resulting vinylcarbene can be trapped with alkenes in situ to give cyclopropanes[ A
similar sequence of reactions occurs when the spiro!fused system "81# is treated with base in the
presence of an alkene "Scheme 88# ð57JA3078\ 58JOC0119Ł[
CO2Et
R R
O
O
EtOLi R R
O • R R
N N N2+ N2
NO N R R
O– Li+
(91)
Scheme 98

R R

O base R R

N O • R R
NO N2
R R
(92)

Scheme 99

The diazoallene "83# has been implicated as an intermediate during the base!catalysed decompo!
sition of the bis"N!nitrosourethane#cyclopropane "82# "Scheme 099# ð60TL206\ 61JOC582Ł[ The prod!
uct isolated from this reaction was that produced by trapping of the carbene derived from "83# with
1\2!dimethylbut!1!ene[
NO
N ON
Ph Ph
CO2Et MeONa Ph N CO2Et MeONa
• • N2
Ph CO2Et •
N Ph
Ph
NO
(93) (94)

Scheme 100

Diazoketene "84# has been prepared by treatment of diazoacetyl chloride with 0\3!diazabicyclo!
ð1[1[1Łoctane "dabco# "Equation "31## ð68AG0901\ 68AG"E#836Ł[
O
dabco, Et2O, heat
O • • N2 (42)
Cl N2 (95)

2[01[2[5[1 a\b!Unsaturated diazo alkanes


The preparation of a\b!unsaturated diazo alkanes via the BamfordÐStevens reaction is of limited
use because of secondary reactions ð52JA2685\ 64CC348Ł[ Vinyl diazo alkanes produced by this reaction
can form cyclopropenes by way of a carbene intermediate\ or may cyclize to form a 2H!pyrazole
which can then undergo a ð0\4Ł!sigmatropic shift[ Although BamfordÐStevens reactions of tos!
ylhydrazones derived from a\b!unsaturated cycloalkanones usually result in formation of pyrazoles
and allyl ethers ð66JOC0241Ł\ a\b!unsaturated diazo cycloalkanes have been prepared by vacuum
pyrolysis of tosylhydrazone salts ðB!75MI 201!90Ł[
"0!Diazo!1!alken!0!yl# phosphonates can be prepared by the BamfordÐStevens reaction of the
tosylhydrazones ð60JOC017\ 63TL0714\ 67CB2957Ł[ The nature of the substituents determines whether
these compounds are isolable or isomerize to the corresponding pyrazoles ð60JOC017\ 67CB2957Ł[
Many a\b!unsaturated diazo alkanes have been prepared from N!nitrosourethanes and N!nitroso!
ureas[ Cleavage of N!allyl!N!nitrosourethane "85# by potassium hydroxide or sodium methoxide
389 Hydrazones and Other 1NN Derivatives
a}ords 2!diazopropene\ which slowly cyclizes to give pyrazole "Scheme 090# ð24JA1545\ 24JCS175\
64JOC645Ł[ The same compound can be prepared from an N!nitrosourea in an analogous fashion
ð43CB0388\ 60OPP36Ł[
NO
base
N
N N
CO2Et N2
H
(96)
Scheme 101

A variety of diazo cycloalkenes can be prepared by diazo transfer[ For example\ 4!diazo!0\1\2\3!
tetraphenylcyclopentadiene can be synthesized in high yield by treatment of the 0\1\2\3!tetra!
phenylcyclopentadiene with p!toluenesulfonyl azide and triethylamine in dichloromethane
ð79TL898Ł[
o! and p!Quinone diazides are synthesized in good yield by diazotization of amino phenols[
Although the intermediate diazonium salts may be isolated in some cases\ they are readily depro!
tonated in acidic media[ Deprotonation can also be accomplished with a mild base ð34JA844\
54LA"570#34\ 60S370Ł[
The conjugated diazo allene "87# has been implicated as an intermediate during the ~ash vacuum
pyrolysis of the heterocyclic compound "86# "Scheme 091# ð79JOC3954Ł[ The compound actually
isolated from the reaction was the enyne "099#\ produced by ring opening of the carbene!derived
methylenecyclopropene "88#[

N2
N N
Ph Ph
Ph O O • Ph
(97) (98) (99) (100)

Scheme 102

2[01[2[5[2 Diazo alkynes


Diazopropyne can be prepared from an N!methyl!N!nitrosurea or the N!nitrosoacetamide "090#
ð59JA136\ 51AG141\ 51AG"E#105\ 57LA"602#002Ł[ This compound can also be prepared from "091# via
tris"diazo#propane "Scheme 092# ð57LA"602#002Ł[
NO ON
N2 N2 MeOC COMe
O NO N N
NaOMe, MeOH –2N2
N
Et2O, –15 °C N2
N2 N
ON COMe
(101) (102)
Scheme 103

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.13
Synthesis of P, As, Sb and Bi
Ylides (R3P1CR2, etc.)
ÉAMONN J. COYNE and DECLAN G. GILHEANY
University College Dublin, Republic of Ireland
2[02[0 PHOSPHONIUM YLIDES FROM PHOSPHONIUM SALTS 381
2[02[0[0 Preparations of Phosphonium Salts 381
2[02[0[1 Deprotonations of Phosphonium Salts 382
2[02[0[2 Dehalo`enations of Phosphonium Salts 384
2[02[0[3 Desilylations of Phosphonium Salts 385
2[02[0[4 Ylides from Vinylphosphonium Salts 385
2[02[0[5 Ylides from Cyclopropylphosphonium Salts 385
2[02[0[6 Ylides by the Electrolysis of Phosphonium Salts 386
2[02[1 PHOSPHONIUM YLIDES FROM PHOSPHINES 386
2[02[1[0 Reactions with Carbenes 386
2[02[1[1 Via Azines 386
2[02[1[2 Reactions with Activated Multiple Bonds 387
2[02[1[3 Reactions with Aziridines 387
2[02[1[4 Reactions with Arynes 387
2[02[2 PHOSPHONIUM YLIDES FROM PHOSPHORANES 388
2[02[3 PHOSPHONIUM YLIDES FROM OTHER PHOSPHONIUM YLIDES 388
2[02[3[0 By Halo`enations 388
2[02[3[1 By Alkylations and Acylations 388
2[02[4 PREPARATION OF As\ Sb AND Bi YLIDES 499
2[02[4[0 From the Precursor Onium Salts 499
2[02[4[1 From Arsines\ Stibines and Bismuthines 499
2[02[4[2 From the Dihalo Pentacoordinate Derivatives 499
2[02[4[3 From the Tertiary Oxides 499

There are a great many more preparations of the phosphonium ylides than of their group 04
analogues and this is re~ected in this review[ Thus 2[02[0Ð2[02[3 are concerned with the preparation
of phosphorus ylides and 2[02[4 deals with the other ylides\ classi_ed in a similar manner[
There is a good variety of methods available for the construction of the P1C bond[ However\
by far the most commonly used method for the synthesis of phosphonium ylides is by deprotonation
of an appropriate precursor phosphonium salt*the {salt method|[ Therefore this method is discussed
_rst\ including reference to methods for obtaining the requisite phosphonium salts\ followed by the
related dehalogenation and desilylation of phosphonium salts[ Thereafter\ all the other preparatively
useful methods are discussed\ grouped according to the source of the phosphorus atom viz[ phos!
phonium salts\ phosphines and phosphoranes[ Finally\ although they are not strictly methods for
construction of the P1C bond\ the most common interconversions of ylides are brie~y described[
Phosphorus ylides have been comprehensively reviewed by Johnson ðB!82MI 202!90Ł\ and the older
compilation of methods for the Wittig reaction by Gosney and Rowley is still very useful ðB!68MI

380
381 P\ As\ Sb and Bi Ylides
202!90Ł[Sections on ylides can also be found in other series ðB!68MI 202!91\ 80COSŁ although mention
of arsenic\ antimony and bismuth ylides is brief at most[ However\ these ylides have been reviewed
"with particular attention to arsenic# by Lloyd\ Gosney and Ormiston ð76CSR34Ł[

2[02[0 PHOSPHONIUM YLIDES FROM PHOSPHONIUM SALTS


Scheme 0 shows the {salt method| for the formation of ylides which involves two distinct steps]
"i# the formation of the phosphonium salt^ and "ii# the deprotonation of that salt to produce the
ylide[ These separate steps are discussed in the following two subsections[ Further subsections deal
with the related dehalogenation and desilylation of appropriate precursor phosphonium salts and
with nucleophilic attack on vinyl phosphonium salts[ Finally\ the electrolysis of phosphonium salts
is brie~y mentioned[

R2 R2 R2
+ –H+
PR13 + X R13P X– R13P
R3 R3 R3

Scheme 1

2[02[0[0 Preparations of Phosphonium Salts


Tertiary phosphines are good nucleophiles\ so simple SN1 quaternisation of trialkyl or triaryl
phosphines with alkyl halides forms the phosphonium halides[ As with many other substitution
reactions\ halide reactivity is typically I×Br×Cl with other leaving groups being employed more
rarely\ for example\ the trimethylammonium group ð50LA"539#68\ 52JCS1889Ł[ Usually only mild
reaction conditions are required for salt synthesis "heat is sometimes required for some higher
halides# and a wide range of solvents have been used to that end "e[g[\ benzene\ ether\ chloroform\
acetone\ acetonitrile\ dimethylformamide\ nitromethane#[ Choice of solvent is often determined by
the ease of isolation of the produced salt\ most commonly by its direct precipitation from solution[
Solvent electrophilicity\ polarity and polarisability\ in that order were also found to be important
ð71G14Ł[
Since most ylide chemistry is designed to produce a phosphorus!free _nal product\ the choice of
phosphine to be employed is virtually unlimited[ Despite this\ however\ the phosphine of choice for
most ylides has been triphenylphosphine for a number of reasons] it is crystalline\ safe\ easy to
handle and air stable^ it is relatively cheap and readily available^ it is of the correct nucleophilicity
for quaternisation and it has no hydrogen adjacent to the phosphorus that would compete in
the ylide!forming deprotonation step[ Trialkylphosphines are also e}ective and may have certain
advantages over their aryl analogues[ In particular they are more nucleophilic than the tri!
arylphosphines producing ylides of increased nucleophilicity ð55JA0842Ł and further manipulation
of the produced ylide "e[g[\ hydrolysis# may require alkyl substituents rather than aryl ones[ However\
these trialkylphosphines have also associated problems] they are easily oxidised and are therefore
di.cult and hazardous to handle and may pose the risk of competitive deprotonation at the
a!position[ The use of phosphines other than the commercially available triphenylphosphine and tri!
n!butylphosphine has been limited to specialised studies[ For example\ substituted triarylphosphines
such as "XC5H3#2P ð55JA0842Ł\ and mixed alkyl!arylphosphines such as MenPh2−nP ð59CI822Ł\ have
readily produced useful phosphonium salts[ Similarly optically active phosphines have been used to
produce optically active phosphonium salts and consequently ylides ð51JA565\ 54LA"574#0Ł[
A wide variety of alkyl halides have been used to quaternise triphenylphosphine[ Thus in the
phosphonium salts R0CH10PPh2¦X−\ R may be alkyl\ aryl\ alkoxy\ thioalkyl\ carboalkoxy\
carbamido\ keto\ formyl\ cyano\ halo\ alkenyl\ alkynyl or silyl[ Dihalides may form mono! or bis!
phosphonium salts\ and allylic halides can give rearranged products[ Table 0 gives some speci_c
halides with appropriate references for quaternisation to the phosphonium salt[
This process is very reliable and would rarely be the step which causes di.culty in synthesis
of ylides[ However some problems can occur\ including the possibility of HX elimination from
the alkyl halide\ as has happened in the reaction shown in Equation "0# ð78S574Ł[ More seriously\
the reaction with a!bromoketones is less reliable with the competing Perkov:Arbusov process
From Phosphonium Salts 382
Table 0 Halides used for the preparation of phosphonium salts[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Halide Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Methyl iodide 42LA"479#33
n!Butyl bromide 47JA3275
Chloromethyl ether 47JA5049
Chloromethylthioethers 56AG"E#138
Phenacyl bromide 0788CB0455\ 46JOC30
Chloroacetimides 89JA6990
Imidoyl chlorides 66S515
Cyclopropyl bromide 55CC555
Cyclohexyl bromide 50AG16
Benzylic bromides 48CB1645
8!Bromo~uorene 36JA612
0\1!Dibromoethane 47LA"508#09\ 48CB1645\ 55JA3989
Dibromides "0\2! and 0\3!# 46LA"592#004\ 48CB1645\ 52NAT0025\ 54JCS6039
0\1!Dibromobenzocyclobutene 56JA3885
Di"bromomethyl#benzenes 48CB1645
Allyl chloride 60HCA0656
0\3!Dibromo!1!butene 50MI 202!90
Farnesyl bromide 69JA1028
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

ðB!89MI 202!90Ł[ The preparation of phosphonium salts has been comprehensively reviewed by
Cristau and Plenat ðB!83MI 202!90Ł[
Br Ph3P +
PPh3 Br– (1)
F3C
F3C

2[02[0[1 Deprotonations of Phosphonium Salts


This process is commonly done by addition of base to a slurry of the phosphonium salt in an
appropriate solvent at\ or below\ room temperature[ The ylide obtained will be coloured and soluble\
enabling visual monitoring and leaving the product ready for further reaction[ A range of solvents
is possible with the restriction that it must be inert to reaction with base and ylide[ Common solvents
are hexane\ benzene\ ether\ THF\ DMF and DMSO[ If the salt is of high enough acidity then water\
alcohols and chlorinated solvents may be present[ For example\ benzylides are commonly generated
for Wittig reaction using a two!phase CH1Cl1*H1O system with the salt and acceptor dissolved in
the organic layer and NaOH as a base[
The base used in ylide!forming reactions has been the subject of much research\ with attention
being paid particularly to the acidity of the phosphonium salt and the nature of the by!products[
Salt acidity depends on the phosphonium moiety and especially on the substituents "R# of carbon[
Ylides are often loosely classi_ed as being nonstabilised "Ralkyl\ halo#\ semistabilised "Raryl\
alkenyl# or stabilised "Rcarbonyl\ cyano etc[# and this is the order of increasing acidity of the
parent phosphonium salt[ Thus the base required varies from organolithium for preparation of
alkylides\ to methoxide for carbomethoxymethylides\ and ammonia for ~uorenylides[ This is
re~ected in the ordering in Table 1 which lists typical baseÐsolvent combinations for ylide generation
from phosphonium salts[ Interestingly\ the base used can be another "more basic# ylide\ in which
case the process is called transylidation ðB!82MI 202!91Ł[ Other bases which have been used include
sodium metal\ acetylide\ trityl and tetraalkylammonium ~uoride ðB!68MI 202!90\ B!82MI 202!91Ł[
Obviously the choice of base is limited by the other functional groups present "especially carbonyl#
in the phosphonium salt[ However\ more important is the counterion which will be present in the
ylidic solution\ especially if that ylide is to be used in situ[ Because of the popularity of organolithium
reagents as bases\ many ylides are produced with lithium salts as by!products[ However\ these salts
are not innocuous because the lithium may complex to the ylide[ In particular they cause variation
of the E:Z ratios of alkene products in Wittig reactions ðB!68MI 202!90Ł and seriously complicate the
interpretation of the mechanistic studies of that reaction ð78CRV752Ł[ For this reason\ much work
has gone into producing {salt!free| ylides\ which in this context means free of lithium cations and
most of the inorganic salts[ The di}erence that this makes is highlighted by the striking di}erences
in 20P NMR between these {salt!free| ylides "20P ¼ 1[9 ppm^ JP!C ¼ 89Ð099 Hz# and lithium!
383 P\ As\ Sb and Bi Ylides
Table 1 Base and solvent combinations used for the deprotonation of phosphonium salts[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Base Solvent Ylide type Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Na1CO2 Water Ester\ phenyl 49CB180\ 51JCS1226\ 53CB2108
Aqueous methanol Acyl 52JOC1335
NH3OH EtOH Fluorenylide 58JA612
NEt2 CH1Cl1\ EtOH Acyl\ ester 50JCS0155\ 51CB2992\ 51JOC887\ 79HCA327
Pyridine CH1Cl1 Acyl\ ester 50JCS0155\ 51JOC887
NaOH Water Ester 51JOC887\ 78JCS"P1#0394
Aqueous CH1Cl1 Phenyl 62S184\ 63TL1476
NaOCH2 Methanol Phenyl 55JCS56\ 60CR"161#617
NaOEt Ethanol Phenyl\ benzoyl 44CB0543\ 59JA2808\ 71S486
t t
KO!Bu Bu OH Phenyl 54JOC0362
THF Alkyl\ vinyl 64JA3216
DMF Phenyl\ vinyl 62AG"E#126
DMSO Alkyl 54CB593
− ¦
MeSOCH1 Na DMSO Alkyl\ phenyl\ vinyl 58CC622\ 69JA286\ 69JA2318\ 69T0180\
"Dimsyl# 64JOC2345\ 65JCS"P0#0355\ 66JOC1672\
66HCA0050
NaH THF Alkyl 57JCS"C#1337\ 57JOC2971
NaNH1 Liquid NH2\ C5H5 Alkyl\ phenyl 59JA2808\ 54JCS6039\ 56LA"697#0
LiNEt1 Toluene Phenyl 51CB1452
LiN!Pri1 THF Alkyl\ phenyl\ vinyl 64TL0248
NaHMDS THF Alkyl\ phenyl 67CB137\ 75CB0249\ 89JGU502
Li piperidide Ether Alkyl 51AG22\ 54JCS6039
n
Bu Li Et1O Alkyl\ vinyl 59JOC82\ 52JOC261\ 62OSC"4#640\ 64HCA0905\
66T0734
THF Alkyl 58CC292\ 60CJC1032\ 60T4868\ 62JA4667\
71SC358
Toluene Alkyl 66JOC1251
DMSO Alkyl 69SCI76
DMF Alkyl\ phenyl 56T1698\ 69BRP0191242
PhLi Et1O Alkyl\ vinyl 43CB0207\ 62TL3314
THF Alkyl\ vinyl 58S27\ 60JA4200
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

complexed ylides "20P ¼ 11 ppm^ JP!C ¼ 49Ð54 Hz# ð65JOC0057Ł[ The earliest procedure for salt!free
ylide solutions\ due to Bestmann and Arnason ð51CB0402Ł used sodium amide in liquid ammonia to
deprotonate the salt\ followed by addition of benzene\ ammonia evaporation and airless _ltration
of the insoluble Na¦ salts[ Later THF replaced benzene but more recently the need for liquid ammonia
has been circumvented by use of NaH in THF ð69LA"628#100Ł or sodium hexamethyldisilazide "Na!
HMDS# in a variety of solvents ð65CB0583\ 75CB0249Ł\ again with _ltration of the insoluble sodium salts[
Other complications which attend the deprotonation of phosphonium salts include ligand ex!
change and elimination[ It is known ð53JOM"1#090\ 54JA2356\ 55AG"E#857Ł that treatment of phos!
phonium salts with carbanionic reagents can result in a ligand exchange process via a pentavalent
intermediate "Scheme 1#[ This process is favoured where RPh and has in fact been used as a route
to ylides\ for example the cyclopropylide in Scheme 2 ð56CC299Ł[ b!Elimination must be taken into
account when there is a potential leaving group at the b!position or another acidic hydrogen[ Thus
b!bromoethyltriphenylphosphonium bromide and b!triphenylphosphonioethyltriphenylphos!
phonium bromide undergo initial elimination of hydrogen bromide and triphenylphosphine\ respec!
tively\ when treated with phenyllithium ð55JOM"5#194Ł[

R1
+ R2Li R1 +
R14 PX– R2 P R13PR2 Br– + R1Li
R1
R1

Scheme 2

+
Ph4PBr– + –C6H6
Li PPh3 Br– PPh3
–LiBr
+
PhLi

Scheme 3
From Phosphonium Salts 384
2[02[0[2 Dehalogenations of Phosphonium Salts
Ylides may be derived from phosphonium salts by abstraction of an a!halogen rather than an
a!H[ This can be a problem when both are present\ but it can be controlled by variation of the
halide and the base[ This is shown in Table 2 where it can be seen that a!halogen attack increases
Cl×Br×I and BunLi×PhLi×Li piperidide×HMDS[ Abstraction of halogen is also a useful
route to otherwise inaccessible ylides and thence to alkenes[ Thus Smithers ð67JOC1722Ł was able to
prepare terminal vinyl bromides by the route shown in Scheme 3[

Table 2 a!Halogen vs[ a!H abstraction in halogenomethylphosphonium salts[


Base
Ph2¦PCH1X− 004 Ph2P1CH1 ¦Ph2P1CHX
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Methylide Halomethylide
X Base ")# ")# Ref[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Cl PhLi ³0 ×88 55JOM"4#156
Br PhLi 49 49 55JOM"4#156
I PhLi 64 14 55JOM"4#156
Br BuLi ×88 ³0 51AG22\ 55CB578
Br Lipip ³0 ×88 51AG22\ 55CB578
I NaHMDS minor product major product 78TL1062
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

Br R1 R1
R1Br + BuLi
Ph3P Ph3P Br Br–
Br Br R2CHO R2 Br

Scheme 4

The system resulting from the addition of triphenylphosphine to tetrahalomethanes is also quite
useful for the production of haloylides[ This complex reaction system is summarised in Scheme 4[
With careful control of conditions it is possible to select each of the di}erent possible pathways[
Thus the addition of controlled amounts of water gives the dichloro and monochloro salts
ð64AG"E#790\ 66S568\ B!68MI 202!92Ł\ and the system is a well!known reagent for the conversion of
alcohols to halides ðB!68MI 202!92Ł[ Also the dichloro ylide "0# has been used for the preparation of
a wide variety of dichlorovinyl systems ð60JOC2275\ 65BSF1957\ 77TL2992\ 80SL472Ł[ Vorbruggen et al[
ð89T2378Ł cleverly combined these aspects of the system\ _rst converting a carboxylic acid into the
chloride which subsequently acylated the ylide "0#[ The dibromo derivative is easier to generate
and use ð51JA0634\ 61TL2658\ 67JOC1722\ 89S774Ł\ but the di~uoro case ð62JA7356\ 89T4102Ł is more
complicated[ This is because\ on generation\ in the absence of other reactants\ it dissociates giving
di~uorocarbene which in turn can be trapped by more nucleophilic phosphines ð72JOC2505Ł "see
2[02[1#[ The monochloro! and mono~uoromethylides can also be prepared using this sort of system
with iodochloromethane ð68BCJ0086Ł and iodo~uoromethane ð64JOC1685Ł respectively\ as the elec!
trophiles[ Fluorine!containing ylides have also been reviewed ð70RCR179\ 71RCR0Ł[

Cl– Cl–
+
Cl
PPh3 (1) + +
Ph3P + CCl4 Ph3PCCl3 Cl– Ph3P + Ph3PCl2 Ph3P PPh3
Cl
Cl Cl
(1)

Ph3P H2O

Cl
+ +
Ph3P + Ph3P Cl
Cl

Scheme 5
385 P\ As\ Sb and Bi Ylides
2[02[0[3 Desilylations of Phosphonium Salts
This is another alternative to deprotonation and is the best way of making truly salt!free non!
stabilised ylides[ Usually it is the trimethylsilyl group which is removed\ for example\ meth!
ylenetrimethyphosphorane was _rst made by the route shown in Scheme 5 ð57CB484Ł[ A shorter
modern version of this route uses the nonnucleophilic tri~ate anion as shown in Scheme 6\ but is
only applicable to methylides ð68JA5341\ 75CRV830Ł[

Me3P + –HCl ROH


TMS Cl TMS PMe3 Cl– TMS PMe3

+ –RO-TMS
TMS PMe3 –OR Me3P CH2

Scheme 6

Ph3P +
CsF
TMS OTf TMS PPh3 Ph3P CH2
–TMS-F

Scheme 7

2[02[0[4 Ylides from Vinylphosphonium Salts


In principle\ nucleophilic attack at the b!position of a vinylphosphonium salt can lead to an ylide
"Equation "1##[ Obviously there are a number of possible complicating side reactions\ such as attack
at phosphorus[ However\ it has been found that dialkyllithium cuprates are especially e}ective
ð74TL0688\ 80CB0760Ł\ and the process is often used where the resulting ylide is already set up for
further reaction*especially intramolecular[ For example\ Schweizer et al[ ð53JA1633\ 55JOC356Ł
have used the salicylaldehyde anion as a nucleophile on vinyltriphenylphosphonium bromide in a
synthesis of chromene "Scheme 7#[ The necessary precursor salts can be made in a number of ways]
from vinyltri~ates ð78JOC1672\ 89JOC4922Ł^ from alkenes by electrolysis ð74TL1088\ 76CPB3859Ł and by
rearrangement of allylic salts ð78IZV0071\ 89S290\ B!83MI 202!90Ł[ There is a fairly wide variety of other
nucleophiles which can also be used in this process\ including amines ð67JA0437\ 70JOC2008\ 72TL2932Ł\
enolates ð63TL3944\ 63TL3112\ 64JOC099\ 72JCS"P0#1868\ 81TL466Ł and alkoxides ð72JOC1458\ 78JOC863Ł[
The formation of heterocycles in this way has been reviewed ðB!68MI 202!93Ł\ as has the participation
of 0!cycloalkenylphosphonium salts ð80RHA169Ł[

+ NUC (2)
NUC – PPh3 PPh3

CHO +
CHO
–Ph3PO
+ PPh3
PPh3 62%
O– O O

Scheme 8

2[02[0[5 Ylides from Cyclopropylphosphonium Salts


In a manner analogous to that in the previous section\ nucleophilic ring opening of a cyclo!
propylphosphonium salt can also lead to an ylide "Equation "2##[ Ring opening can be in both
directions which was observed in the case of salicylate ring opening of the unsubstituted cyclo!
propylphosphonium bromide ð57JOC225Ł[ However\ if the phosphonium salt bears an ylide sta!
bilising group at the a!position only one product is obtained ð63JA0596\ 64TL3242\ 74TL4340Ł as shown\
for example ð64TL3242Ł\ in Equation "3#[ Other nucleophiles used have included enolates ð63JA0596Ł
and thiolates ð74TL4340Ł[
From Phosphines 386
+
PPh3 NUC PPh3 (3)
NUC –

CO2Et RCO2–
RCO2 CO2Et (4)
+
PPh3 Ph3P

2[02[0[6 Ylides by the Electrolysis of Phosphonium Salts


Phosphonium salts usually undergo electrolytic reductive cleavage to a hydrocarbon and a
phosphine ðB!82MI 202!92Ł[ However\ under certain conditions a two!electron transfer process can
result in the formation of ylides as shown in Scheme 8 ð57JA1617\ 61BSF2438\ 66JOC0131\ 70JCS"P0#0419Ł[
+
+e • +e R PPh3
+ •
R PPh3 R PPh3 RCH2 + Ph3P RCH2– R PPh3 + RMe

Scheme 9

2[02[1 PHOSPHONIUM YLIDES FROM PHOSPHINES

2[02[1[0 Reactions with Carbenes


In principle\ the direct interaction of a phosphine and a carbene could lead to an ylide[ Such a
reaction is known and has been studied theoretically in some detail ð68JA6058\ 75CB0220Ł[ However\
at least for phosphonium ylides\ it is not very useful preparatively[ The early experiments involved
treating polyhalomethanes with a base such as t!butoxide or an organolithium reagent\ trapping
the resulting carbenes with triphenylphosphine and detecting the resulting ylide by Wittig reaction
ð50JA0506\ 50CB0262\ 51JA743Ł[ Yields were at most modest[ With the advent of smoother routes to
the carbenes\ yields have been improved somewhat[ Thus\ decarboxylation of sodium di~uoroacetate
in the presence of triphenylphosphine and a carbonyl compound gives the phosphine oxide and the
di~uorovinyl compound ð54JOC0916\ 54JOC1432\ 57TL60Ł[ The smoothest reaction of this type is
from the phenyldihalomethylmercuric bromides shown in Scheme 09 "XH\ Cl\ Br^ YCl\ Br#
ð55JOM"4#156Ł[ This route to halomethylides is better than that described in 2[02[0[2 because there
are no by!products such as Ph2PCl1[ Dithio! and diselenomethylides can be made by carbene
routes\ either by tosylhydrazone reduction ð53TL134Ł "Equation "4##\ or from tri"phenylseleno#! or
tri"phenylthio#methanes ð56AG"E#332\ 61CB376\ 61CB400Ł "Equation "5#^ ES\ Se#[

X X O X
C6H6
PhHg Y + Ph3P Ph3P
∆ –Ph3PO
Br Y Y
Scheme 10

SEt NaH
SEt
TsNHN Ph3P (5)
SEt Ph3P SEt

EPh PhLi
EPh
PhE Ph3P (6)
EPh Ph3P EPh

2[02[1[1 Via Azines


In a method related to that in the previous section\ ylides can result from the thermal decompo!
sition of phosphine azines[ In fact the _rst phosphonium ylide was produced in this way "Scheme
387 P\ As\ Sb and Bi Ylides
00# ð08HCA508Ł[ However\ the method is not generally applicable to the synthesis of phosphonium
ylides\ the only useful cases being cyclopentadienylides ð47JOC1925\ 56CI213\ 56T1690\ 61T242Ł which
also require the presence of a copper"I# catalyst[
Ph N PPh3 Ph

Ph2CN2 + Ph3P N PPh3
–N2, 195 °C
Ph Ph

Scheme 11

2[02[1[2 Reactions with Activated Multiple Bonds


Activated alkenes undergo nucleophilic attack by tertiary phosphines to yield ylides after pro!
totropy in the initially formed carbanionic intermediate ð39JCS0263\ 50ACS581\ 50CB0220\ 52HCA1067\
53JOC2610\ 54TL190\ 55T456\ 57T1130Ł[ The process is straightforward if the alkene is doubly activated
as this provides an adjacent ylide stabilising group\ e[g[\ Equation "6# ð39JCS0263\ 50ACS581\ 52HCA1067\
57T1130Ł[ However\ even if there is no second ylide stabilising group\ the intermediate adduct can
be trapped as the silylenol ether ð75JOC2391\ 77TL4302Ł and the ylide can then be generated by
deprotonation of the resulting phosphonium salt "Scheme 01#[
O O
Ph3P
PPh3 + O O (7)

O O

O OSiMe2But O

Ph3P/THF i, BuLi
(CH2)n TfOSiMe2But (CH2)n + ii, RCHO (CH2)n R
PPh3 iii, HF

Scheme 12

These reactions have the drawback that they may turn out to be rather complex when examined
in detail[ An example of this would be the addition of phosphines to acrylonitrile where very careful
control of conditions and addition of an agent to promote proton transfer are necessary ð51JA378\
53TL0542\ 54JOC0246\ 56TL1390\ 57BCJ1704\ 69JOC2934\ 73SC0156\ 77T3542\ 78TL1620Ł[
The reactions of phosphines with activated alkynes are not as useful because the reactions tend
to be very complicated[ A case in point is the reaction with dimethyl acetylenedicarboxylate "DMAD#
which with careful control yields a bis!ylide "Equation "7## ð56JCS"C#1331Ł but which can also yield
several other products ð50JCS1015\ 54CB252\ 56JCS"C#1331\ 58JCS"C#0099\ 78JCS"P0#1314Ł[ Dibenzoyl!
acetylene reacts similarly ð69JCS"C#4Ł[
Ph3P PPh3
PPh3
MeO2C CO2Me (8)
MeO2C CO2Me

2[02[1[3 Reactions with Aziridines


Again in a manner analogous to that in the previous section\ ring opening of aziridines with
phosphines leads to b!amino ylides\ e[g[\ Equation "8# ð89TL1550Ł[

Ph3P + N BOCt Ph3P BOCt (9)


N
H

2[02[1[4 Reactions with Arynes


Tertiary phosphines bearing an a!H add to arynes to produce ylides ð52JOC1352Ł[ It is assumed
that the initial adduct undergoes proton transfer as shown in Scheme 02[
From Other Phosphonium Ylides 388
Me CH2
+
PPh2 PPh2
Ph2PMe

Scheme 13

2[02[2 PHOSPHONIUM YLIDES FROM PHOSPHORANES


Highly stabilised ylides can be made by the reaction of dichlorotriphenylphosphorane with active
methylenes in the presence of triethylamine "Equation "09##^ X\ YCO1R\ CN\ SO1Ph\ COR#
ð47CB326\ 56JPS"B#0928Ł[

X
Et3N
Ph3PCl2 + X Y Ph3P (10)
Y

2[02[3 PHOSPHONIUM YLIDES FROM OTHER PHOSPHONIUM YLIDES


Although not strictly involving construction of the P1C bond\ the following reactions are
powerful methods for changing the substituents at the ylidic carbon atom[

2[02[3[0 By Halogenations
A variety of halogenating agents will convert an ylide bearing an a!H to the halo!substituted
derivative ðB!82MI 202!93Ł[ This is the preferred route to a!halo ylides because the alternative salt
method is complicated by the possibility of base attack at the halogen "see 2[02[0[2#[ In the absence
of any other reagent the maximum yield of ylide is 49) with the other 49) being the conjugate
acid of the original ylide\ because the initial product is the a!halophosphonium salt which undergoes
transylidation ð50CB1885Ł "Scheme 03#[ However\ there are several ways to raise the theoretical yield
to 099)] use of excess halogen ð51JOC887\ 52JOC354Ł^ use of added base\ e[g[\ pyridine or triethylamine
ð51JOC887Ł^ use of t!butylhypohalite as halogenating agent*the t!butoxide generated acts as the
base ð51JOC887Ł[
X Ph3P X
X2 + R +
Ph3P R Ph3P X– Ph3P + Ph3P R
R R

Scheme 14

2[02[3[1 By Alkylations and Acylations


Most alkylating agents will react with the nucleophilic ylidic carbon to give the corresponding
phosphonium salts "Equation "00##[ This is a powerful way to elaborate the carbon skeleton of the
original ylide and there has been a great deal of work done to explore all the possibilities of the
reaction\ including transylidation e}ects ðB!82MI 202!93Ł[
+
Ph3P CH2 + RX Ph3P R X– (11)

Acylation of ylides is similar and has been studied in as great detail ðB!82MI202!93Ł[ The acylating
agent of choice is the acyl halide or acyclic acid anhydride[ Acylation is particularly useful for the
preparation of b!keto ylides which are not reliably available by quaternisation of a!bromoketones
"see 2[02[0[0#[ Once again the reaction is invariably complicated by transylidation e}ects because of
the extra carbanion stabilising e}ect of the added acyl group\ and again various strategies have been
devised to overcome the resulting loss of yield ðB!82MI 202!93Ł[
499 P\ As\ Sb and Bi Ylides
2[02[4 PREPARATION OF As\ Sb AND Bi YLIDES
Methods used for the preparation of As\ Sb and Bi ylides are in general similar to those used for
phosphorus ylide generation[ Perhaps a di}erence could be noted in the shift of emphasis away
from the salt method towards the carbene method[

2[02[4[0 From the Precursor Onium Salts


This is a comparable method to that described in 2[02[0 and subsequent subsections[ Salts are
made and converted into ylides as usual\ the only real di}erence being that the pKa of these tend
to be higher than that of their phosphorus analogues and therefore a stronger base may be necessary[
Ylides which have been prepared using the salt method include] various types of methylides ð54IC0347\
57JOM152\ 69ACS2661\ 60JCS"C#0003\ 67CB1691\ 68IJC"B#526Ł^ propynylides ð77S210Ł^ cyclopenta!
dienylides ð60JCS"C#1830Ł and ~uorenylides ð42LA"479#46\ 59JOC072\ 67IJC"B#512Ł[

2[02[4[1 From Arsines\ Stibines and Bismuthines


This method is directly related to 2[02[1 in that the ylide is prepared by the direct interaction of
an arsine\ stibine or bismuthine and a carbene[ This method has been used extensively in the
synthesis of As\ Sb and Bi ylides where thermal decomposition of diazo compounds or iodonium
ylides\ usually in the presence of copper\ provides the source of the carbene[ This carbene method
has again a}orded various types of ylides including\ from diazo compounds] methylides ð75T2776\
77S208\ 77JCS"P1#0718Ł^ cyclohexylides ð77CL736\ 77JCS"P1#0718\ 77S208Ł and cyclopentadienylides
ð61CC805\ 61T232\ 71T2244\ 72T186\ 75T2776\ 77JCS"P1#0718\ 77S208Ł^ and from iodonium ylides] methylides
ð71T2244\ 76JCR"S#263\ 77S802Ł^ cyclohexylides ð71T2244\ 78TL5562Ł and cyclopentadienylides ð71T2244Ł[

2[02[4[2 From the Dihalo Pentacoordinate Derivatives


As in 2[02[3\ numerous methylides have been prepared by the reaction of triphenylarsine dichloride
with various substituted active methylene compounds in the presence of triethylamine ð47CB326\
48LA031Ł[ Schmidbaur and Hasslberger described the preparation of pentakisð"trimethylsilyl#methylŁ
antimony by the trimethylsilylmethylation of trisð"trimethylsilyl#methylŁantimony dibromide
ð67CB1691Ł[ More recently\ bismuthonium ylides have been prepared by the reaction of the sodium
salts of some active methylene compounds with triphenylbismuth in THF ð89BCJ849Ł[

2[02[4[3 From the Tertiary Oxides


This is the only preparative method for As\ Sb and Bi ylides which has no counterpart in the
phosphorus analogues[ It is analogous to that described above "2[02[4[2#\ the only di}erence being
that H1O is produced as the by!product rather than a hydrogen halide[ Thus an active methylene
compound reacts with Ph2MO "MAs\ Sb and Bi# in acetic anhydride or in triethylamine "with
phosphorus pentoxide also present# to give an ylide and H1O[ This method has been used to prepare\
among others\ methylides ð72T186\ 89BCJ849Ł and cyclopentadienylides ð60JCS"C#1830\ 62T0586\ 63T1146\
72T186Ł[

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.14
Doubly Bonded Metalloid
Functions (Si, Ge, B)
TAO YE and M. ANTHONY McKERVEY
The Queen’s University of Belfast, UK
2[03[0 GENERAL METHODS FOR THE PREPARATION OF C1METALLOID
FUNCTIONS "Si\ Ge\ B# 490
2[03[0[0 Doubly!bonded Silicon Functions 490
2[03[0[1 Doubly!bonded Germanium Functions 492
2[03[0[2 Doubly!bonded Boron Functions 493

2[03[0 GENERAL METHODS FOR THE PREPARATION OF C1METALLOID


FUNCTIONS "Si\ Ge\ B#
Those compounds with general structures "0#Ð"2# are named\ in general\ as silenes\ germenes
and methyleneboranes\ respectively[ Reviews containing information on the synthesis of these
compounds have appeared "silenes] ð68CRV418\ 73JOM"162#030\ 74CRV308\ 75AOC"14#0\ B!78MI 203!90Ł^
germenes] ð71AOC"10#130\ 73JOM"162#030\ 89CRV172\ 83CCR316Ł^ methyleneboranes] ð82AG"E#874Ł[ Only
the formation of these silenes\ germenes and methyleneboranes in which the two sigma bonds of
the carbenic atom are not directly attached to a heteroatom will be surveyed in this Chapter[ Many
silenes and germenes have been recognised or identi_ed as transient intermediates\ very few of which
are stable enough to be isolated[ In addition\ nonheteroatom!containing methyleneboranes are rare[

R1 R3 R1 R3 R2
Si Ge R1 B
R4 R4 R3
R2 R2
(1) (2) (3)

Several routes leading to the formation of C1metalloid functions "Si\ Ge\ B# have been exploited[
The principal methods may be assigned to one of three general categories] "i# photochemical
generation\ "ii# generation by pyrolysis and "iii# processes involving 0\1!elimination reactions[

2[03[0[0 Doubly!bonded Silicon Functions


A large number of silenes can be generated from the photoinduced or thermal decomposition of
suitable precursors[ Silenes of the general type "4# can be synthesised via ð1¦1Ł cycloreversion
processes from the thermolysis of silacyclobutanes "3# at high temperature "Equation "0## ð63JA6094\
68CRV418\ 79JOM"077#040\ 79JOM"086#02Ł[ The larger the substitutent at the silicon atom in "3# the
poorer the yield of "4#[ More substituted silacyclobutane precursors are also suitable for the

490
491 Doubly Bonded Metalloids "Si\ Ge\ B#
generation of silenes ð76OM0395Ł[ In addition\ photochemical methods for the generation of silenes
"4# from the silacyclobutanes "3# are also possible ð68JA1380\ 70T1764Ł[ The silene ""4#\ R0 R1 Me#
has been detected by IR spectroscopy of products trapped by the matrix!isolation technique
ð74CRV308Ł[ Silenes "6# and "8# can be prepared via ð1¦3Ł cycloreversion processes from pyrolysis
of silabicycloð1[1[1Łoctadiene derivatives "5# and "7# "Scheme 0# ð71OM109\ 71JA5039\ 79JA3869\
72JA5614Ł[ Two indirect routes to silenes\ one derived from silylenes and the other from silylcarbenes\
are of some generality and importance ð75AOC"14#0Ł[ Photolytic decomposition of trimethyl!
silydiazomethane "09# yields a!silylcarbenes which then smoothly rearrange to give 0\0\1!trimethyl!
silaethylene "00# "Equation "1## ð65JA6733\ 65JA6735Ł[ 0!Methylsilene "03# can be produced from
photoconversion of dimethylsilylene "02# and is stable for many hours in argon at 24 K[ Dimethyl!
silylene "02# can be obtained\ in turn\ by irradiation of dodecamethylcyclohexasilane "01# "Scheme
1# ð70JA0734\ 72JA5065\ 73JA414Ł[ Similarly\ irradiation of the cyclic divinyldisilane "04# yields the
cyclic silene "05# "Equation "2## ð80JA2875Ł[ Alternative routes to the formation of silenes involve
0\1!elimination reactions[ Thus addition of t!butyllithium to vinyl chlorosilanes "06# produces silenes
"07# by 0\1!elimination of lithium chloride "Equation "3## ð79JA3869\ 80AG"E#333\ 80OM1418Ł[ In 0881
Apeloig and co!workers reported a new route for silene formation which involves a Peterson!type
elimination process[ One example is shown in Equation "4# ð81OM1215Ł[

R2 R1
400–700 °C
R1 Si (1)
Si
5–100%
R2
(4) (5)

R1 = R2 = Me, vinyl, Ph; R1 = Me, R2 = Ph; R1 = Ph, R2 = vinyl

Me
R
Si
Me

CF3 Si
R
CF3
(6) (7)
R = H or TMS

Me
R
Si Me But

But Si
R

(8) (9)
R = Me or Ph

Scheme 1

Me
TMS hν
Si (2)
N2
Me
(10) (11)

hν hν H
(Me2Si)6 (Me2Si)5 + Me2Si Si
254 nm 450 nm
Me
(12) (13) (14)
Scheme 2
C1Metalloids "Si\ Ge\ B# 492
TMS

TMS hν
Si Si Me (3)
Me

(15) (16)

R1 R1
LiBut
R2 Si Si (4)
Cl R2 But
(17) (18)

R1 = R2 = Me, Cl; R1 = Ph, R2 = vinyl

TMS
O
(TMS)3SiLi•3THF Si
TMS (5)

2[03[0[1 Doubly!bonded Germanium Functions


Transient germene "19# can be prepared via ð1¦3Ł cycloreversion processes involving pyrolysis
of the bicyclic compound "08# "Equation "5## ð62JA2967Ł[ Transient germenes can also be generated
from a!germylcarbenes[ Pyrolysis of phenyltrimethylgermyldiazomethane "10# has yielded transient
germene "11# "Equation "6## ð79JA0473Ł[ Alternative routes to the formation of germenes involve
interaction between germylenes and carbenes[ Examples are shown in Equation "7# ð79JA4302Ł[
Other important routes to the formation of germene involve 0\1!elimination reactions[ A few
thermally stable but highly air! and moisture!sensitive germenes "13# have been obtained as orange
crystals by dehydrohalogenation reactions involving the corresponding chloro! or ~uorogermanes
at low temperature[ Thus\ addition of t!butyllithium to the halogermanes "12# at −67>C a}orded
the corresponding germenes "13# in good yields "Equation "8## ð76JA3300\ 80JOM"392#82\ 80POL0042Ł[
Similarly\ addition of t!butyllithium to ~uorovinylgermane "14# followed by elimination of LiF has
a}orded the stable dimesitylneopentylgermene "15# in 89) yield "Scheme 2# ð81OM2065Ł[

Et
Et
Ge Et
450 °C
CF3 Ge (6)
Et
Cl CF3
(19) (20)

Me3Ge
450 °C
N2 GeMe2 (7)
Ph Ph
(21) (22)

Ph
N2 Cu, 60 °C
Ph2Ge + Ge (8)
R
Ph R
R = Ph, CO2Et
493 Doubly Bonded Metalloids "Si\ Ge\ B#

R2 R2
ButLi, –78 °C
R1 Ge Ge (9)
–ButH, –LiX
X R1

(23) (24)

R1 = R2 = ;X=F R1 = R2 = ;X=F R1 =But, R2 = ; X = Cl

R1 = R2 = (TMS)2CH; X = F R1 = (TMS)2CH, R2 = ;X=F

Li
F MgBr ButLi –50 °C
Ge Ge Ge But Ge
F F –78 °C F –LiF But

(25) (26)

Scheme 3

2[03[0[2 Doubly!bonded Boron Functions


Simple substituted boraethenes "17# can be prepared via ð1¦3Ł cycloreversion processes from
pyrolysis of corresponding bicyclic compounds such as "16# "Equation "09## ð74AG"E#0954Ł[ Alter!
native routes to the formation of methyleneborane involve a dehalogenation process[ Thus\ treat!
ment of 8!~uorenyltetramethylpiperidinoboron halides "18# with lithium or sodium amide at room
temperature has been shown to lead to the amino"methylene#borane "29# in 59Ð69) yield "Equation
"00## ð74AG"E#305Ł[

X
B

CF3 X B (10)

CF3
(27) (28)
X = OMe or NMe2
C1Metalloids "Si\ Ge\ B# 494

X
N B
MNR2
N B (11)
–MX, –HNR2

(29) (30)
X = F, Cl; M = Li, Na; NR2 = N(TMS)2, N(TMS)But

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.15
Doubly Bonded Metal Functions
TAO YE and M. ANTHONY McKERVEY
The Queen’s University of Belfast, UK
2[04[0 INTRODUCTION 496
2[04[1 GENERAL METHODS FOR THE PREPARATION OF THE C1METAL FUNCTION 497
2[04[2 THE C1Ti FUNCTION 497
2[04[3 THE C1Zr FUNCTION 498
2[04[4 THE C1V FUNCTION 409
2[04[5 THE C1Nb FUNCTION 409
2[04[6 THE C1Ta FUNCTION 400
2[04[7 THE C1Cr FUNCTION 402
2[04[8 THE C1Mo FUNCTION 402
2[04[09 THE C1W FUNCTION 403
2[04[00 THE C1Mn FUNCTION 407
2[04[01 THE C1Fe FUNCTION 408
2[04[02 THE C1Ru FUNCTION 419
2[04[03 THE C1Rh FUNCTION 419
2[04[04 THE C1Re FUNCTION 410
2[04[05 THE C1Os FUNCTION 411

2[04[0 INTRODUCTION
These compounds\ LnM1CR0R1\ are generally named as metal carbene "alkylidene# complexes
and are often subdivided into two broad groups[ In the _rst group the ligated carbene carbon
typically possesses heteroatom substituents or aryl groups[ These carbene complexes act as carbon
electrophiles toward other chemical species and are referred to as Fischer!type carbenes[ The second
group of metal complexes are called Schrock!type carbenes or alkylidene complexes[ The ligated
carbon of this type of carbene species is attached directly to a metal by a double bond while the
other two bonds are not attached directly to any heteroatom[ In contrast to the Fischer!type
carbenes\ the Schrock!type carbene "alkylidene# complexes behave chemically as carbon nucleo!
philes[
This chapter will concentrate on the methods for the synthesis of the nonheteroatom!stabilised
carbene "alkylidene# complexes[ Methods for the preparation of heteroatom!stabilised carbene
complexes are summarised in Chapter 4[13[1[ Although some workers have preferred to use the
terms {carbene| and {alkylidene| to distinguish complexes having di}erent types of reactivity\ in this
chapter no distinction will be made between the two terms and all the nonheteroatom!stabilised
metal complexes which will be discussed are simply referred to as carbenes[

496
497 Doubly Bonded Metal Functions
2[04[1 GENERAL METHODS FOR THE PREPARATION OF THE C1METAL FUNCTION
Reviews containing information on the synthesis of nonheteroatom!stabilised carbenes have
appeared ð79MI 204!90\ B!72MI 204!90\ B!75MI 204!90\ B!77MI 204!90\ 80MI 204!90Ł[ Several routes leading
to the formation of carbene complexes have been exploited[ The principal methods may be divided
into three broad categories] "i# carbonÐmetal double bond formation via an intermolecular reaction
of a metal complex with a carbene or carbene precursor "Equation "0##^ "ii# transformation of a
molecule containing a carbonÐmetal single bond or triple bond into a metal carbene "Scheme 0#^
and "iii# modi_cation of a preformed metal carbene molecule\ that is exchange or modi_cation of
the carbene ligand\ exchange or modi_cation of the ligand"s# on the metal\ or by changing the
oxidation state of the metal "Scheme 1#[

R1 R1
MLn1 + Ln2M (1)
R2 R2

R1 R1
Ln1M Ln2M Ln1M R1
R2 R2

Scheme 1

Changing the oxidation state

R1
LnM Exchange or modification
R2

Exchange or modification

Scheme 2

A wide range of synthetic procedures can be used for the preparation of nonheteroatom!stabilised
carbenes and some of these have proved very successful[ However\ no general methods exist which
are suitable for preparing all types of nonheteroatom!stabilised carbenes[ In this chapter\ the general
survey of the synthetic routes leading to metal carbenes has been organized according to the nature
of the metal involved[ Representative examples have been chosen to demonstrate the synthetic
strategies[ Metal carbenes which are incapable of isolation\ but can be generated mainly by metal!
catalysed decomposition of diazo compounds\ are not included in this chapter ð83CR0980Ł[

2[04[2 THE C1Ti FUNCTION


The titanium methylene complex\ Cp1TiCH1\ can be generated from a number of precursors
ð73PAC48Ł[ These include titanacyclobutane complexes ð72PAC0622Ł as well as titanium adducts with
Lewis acids ð67JA2500\ 72TL1932\ 72TL2824Ł[ A variety of titanacyclobutanes can be prepared in turn
from the Tebbe reagent ð67JA2500Ł\ and these titanacyclobutanes can be handled in air for reasonable
periods of time ð70JA6247\ 72PAC0622Ł[ Titanium methylene complexes derived from the thermolysis
of the titanacyclobutanes\ or from base removal of the Lewis acid of the {Lewis acid adducts|
such as the Tebbe reagent Cp1Ti"m!CH1#"m!Cl#AlMe1 ð67JA2500Ł\ are usually observed as reactive
intermediates "Scheme 2#[ However\ reaction of the bicyclic titanacyclobutane "0# at room tem!
perature with an appropriate alkylphosphine a}ords the monophosphine!containing carbene com!
plex "1# which can be cleanly isolated ð75OM610Ł[ The titanacyclobutane "0# was obtained from a
reaction of the Tebbe reagent with 2\2!dimethylcyclopropene in the presence of "dimethyl!
amino#pyridine "Scheme 3#[ Similarly\ treatment of a solution of b\b!dialkyltitanacyclobutane "2#
with excess trialkylphosphine at room temperature yields the corresponding titanocene methylidene
phosphine complex "3# "Equation "1##[ The carbene complex "3# can be isolated as an extremely air!
and moisture!sensitive\ thermally unstable\ yellow!brown powder ð78OM472Ł[ In the late 0879s\
Binger et al[ reported that the titanocene"vinylcarbene# complex "6# can be prepared via a new
C1Zr Function 498
route as shown in Equation "2#[ Thus\ treatment of the readily accessible cyclopropene "5# with
titanocenebis"trimethylphosphine# "4# a}ords "6# in good isolated yield ð78AG"E#509Ł[ The vinyl
carbene complexes "6# seem to be more stable than the methylene or substituted carbene complexes
shown in Schemes 2 and 3 and Equation "1#[

R1 5–60 °C base, –40 °C Me


Cp2Ti Cp2Ti Cp2Ti Al
R2 Cl Me
R1 = R2 = Me; R1 = Me, R2 = Prn; R1 = H, R2 = But

Scheme 3

Me dmap Cp2Ti PMeR2


Cp2Ti Al +
Cl Me 50–55% Cp2(PMeR2)Ti
R = Me, Ph (1) (2)

Scheme 4

vacuum
Cp2Ti + phosphine Cp2Ti (2)
49–77% Phosphine
(3) (4)
phosphine = PMe3, PMe2Ph, PEt3

PMe3
R R Cp2Ti
0–20 °C
Cp2Ti(PMe3)2 + (3)
R
R
(5) (6) (7) a; R = Me, 81%
b; R = Ph, 72%

2[04[3 THE C1Zr FUNCTION


The thermally labile zirconium carbene complex "8#\ formed via reaction of H1C1PPh2 with the
zirconocene phosphine complex "7#\ has only been detected in situ and not isolated "Equation "3##
ð79JOM"073#C0Ł[ However\ Cp1Zr1CHCH1R"L# complexes of type "00# can be isolated as thermally
labile oils by hexamethylphosphoramide "HMPA#!induced bridge cleavage of the zirconoceneÐ
aluminum precursors "09# ð72JA539Ł[ Yields for the formation of the carbene complex "00# vary as
a function of the trapping phosphine ligand used "see Equation "4##[ The zirconocene"vinylcarbene#
complex "02# can be prepared in an analogous manner[ Thus\ reaction of the cyclopropene "5^
RPh# with the zirconoceneÐalkene complex "01# a}orded equal amounts of the zircono!
cene"vinylcarbene# complex "02# and the "h1!diphenylcyclopropene# complex "03# "Equation "5##
ð78AG"E#509Ł[ The stable zirconium carbene complex "05# has been prepared via the a!hydrogen
abstraction process shown in Equation "6#[ Thus\ reaction of the zirconium complex "04# with one
equivalent of MgBn1 =THF generated a mixture of the corresponding monobenzyl derivative which
was then photolysed or thermolysed to provide the stable zirconium carbene complex "05# in 74)
yield ð82JA4225Ł[

Cp2Zr(PPh2Me)2 + Ph3P Cp2(PPh2Me)Zr (4)


(8) (9)
409 Doubly Bonded Metal Functions
R
i, L R
Bui Cp2LZr
(5)
Cp2Zr Al ii, HMPA
Cl Bui
(10) (11)
R= But,
L = PPh3, 54%; R = But,
L = PMe2Ph, 70%
R = c-C6H11, L = PPh3, 69%; R = c-C6H11, L = PMe2Ph, 59%
R = CMeEt, L = PPh3, 33%; R = CMeEt, L = PMe2Ph, 52%

PMe3 PMe3
PMe3 Cp2Zr Cp2Zr
Ph Ph 20 °C
Cp2Zr + + (6)
Ph Ph
Ph Ph
(12) (6b) (13) (14)

Me Me Me Me

Me Si Si Me i, MgBn2•2THF Me Si Si Me
Cl (7)
Zr ii, hν or ∆ (–Bn) P Zr P
P P
Pri Cl3 Pri Pri Pri
Pri Pri Pri
Pri Ph
(15) (16)

2[04[4 THE C1V FUNCTION


Nonheteroatom!stabilised vanadium carbene complexes are rare[ Teuben and co!workers have
reported the preparation of the _rst vanadium carbene complex "19#\ which probably involved the
a!hydrogen abstraction process shown in Scheme 4[ Thus\ the vanadium complex "06# was treated
with two equivalents of the Grignard reagent "07# to give the extremely air!sensitive carbene
precursor "08#[ When "08# was decomposed thermally in the presence of the chelating phosphine
dmpe "dmpe0\1!bis"dimethylphosphino#ethane#\ the greenish!brown vanadium carbene complex
"19# was isolated ð78JA4866Ł[

Me But
+ (Me2PCH2)2
+ Me P V
CpVCl2(PMe3)2 2ButCH2MgCl CpV(CH2But)2PMe3 Me
–C(Me3)4, –PMe3 P
Me
(17) (18) (19) (20)

Scheme 5

2[04[5 THE C1Nb FUNCTION


Niobium carbene complexes can be prepared from the corresponding complexes containing a
carbonÐniobium single bond[ Reaction of the niobium complex "10# with two equivalents of LiCH1!
But in pentane at −67>C provided the thermolabile niobium carbene "11# in 72) yield ð67JA2248Ł[
When the niobium carbene "11# was treated subsequently with two equivalents of the chelating
phosphine PMe2 or PMe1Ph\ a new niobium carbene "12# was isolated in 64) yield "Scheme 5#
ð67JA4853Ł[ The thermally stable niobium carbene "14# can be obtained as golden orange crystals in
31) yield via reaction of the niobium complex "13# with two equivalents of TiCp as shown in
Equation "7# ð67JA2682Ł[ The simplest type of niobium carbene complex is the THF ligated niobium
carbene complex "16#\ which can be prepared in good yield simply by adding THF to the niobium
complex "15# "Equation "8## ð79JA5125Ł[ The THF ligands of the niobium carbene complex "16# are
C1Ta Function 400
labile and can be readily displaced thereby allowing other types of niobium carbene complexes to
be prepared[

But But
2 LiCH2But, –78 °C 2L But
Cl2Nb(CH2But)3 (ButCH2)3Nb
83% 75% Nb
L L But
(21) (22) L = PMe3, PMe2Ph (23)

Scheme 6

toluene, 6 h But
Nb(CH2But)2Cl3 + TiCp Cp2ClNb (8)
(24) 42% (25)

But
–30 °C to 25 °C
Nb(CH2But)2Cl3 + THF Cl3(THF)2Nb (9)
(26) (27)

2[04[6 THE C1Ta FUNCTION


The _rst example of an isolable tantalum carbene was accidentally obtained by Schrock via an
intramolecular a!hydrogen abstraction process "Equation "09## ð63JA5685Ł[ More thermally stable
tantalum carbenes\ such as "17#\ can be obtained by introducing a cyclopentadienyl ligand "Equation
"00## ð67JA2248\ 68JA2109Ł[ The a!hydrogen abstraction process has proved to be a very e}ective
strategy for the preparation of tantalum carbene complexes[ Structural and steric crowding about
the tantalum are both believed to be important factors in determining where a!hydrogen atom
abstraction occurs to give carbene complexes ð67JA2248Ł[ A number of tantalum carbene complexes
have been prepared through the use of an a!hydrogen abstraction protocol\ and some representative
examples are shown in Equations "01#Ð"03# and Schemes 6 and 7 ð64JA5466\ 67JA1278\ 79JA5125\
79JA5633\ 75JA4236Ł[ As shown in Equation "01# ð79JA5125Ł the donor ligands\ such as tertiary
phosphine\ readily promote the a!hydrogen abstraction process[ Furthermore\ the terminal tantalum
carbene "29# can be obtained by using a similar technique "Scheme 7# ð64JA5466\ 67JA1278Ł[ In
addition\ the tantalum carbene "18# can also be prepared by a dehydrohalogenation protocol\ as
shown in Equation "04# ð79JA5633Ł[

2LiCH2But But
Cl2Ta(CH2But)3 MeCMe3 + (ButCH2)3Ta (10)

TiCp
But
Ta(CH2But)2+nCl3–n Cp(ButCH2)nCl2–nTa (11)
(28)
n = 2 or n = 0

2L But
Ta(CH2But)2X3 X3L2Ta (12)
X = Cl, Br; L = PMe3, PPhMe2, PPh2Me, THF

2PMe3 Ph
TaBn2X3 (13)
70–79%
X3(PMe3)2Ta

X = Cl, Br

12 h Ph
TaBn3Cl2 + LiCp* (14)
70%
Cp*(Bn)(Cl)Ta
(29)
401 Doubly Bonded Metal Functions
2MeLi, Et2O CH2PMe3
Cp*2TaCl2 Cp*2(H)Ta Cp*2MeTa
80% ~100%

Scheme 7

Ph3C+ BF4– base


TaCp2Me3 (TaCp2Me2)+BF4– Cp2MeTa
–Ph3CMe 82%
(30)
base = Me3P(CH2), LiN(TMS)2 or NaOMe

Scheme 8

toluene, –Ph3P+Me Cl– Ph


TaCp*Bn2Cl2 + Ph3P (15)
~100%
Cp*(Bn)(Cl)Ta
(29)

Formation of a carbene hydride complex from a tantalum alkyl complex is also possible[ The
carbene hydride complex "21# can be obtained in moderate yield as beige crystals by reducing
Ta"CH1But#Cl3 "20# with two equivalents of sodium amalgam "Equation "05## ð79JA5597Ł[ An
alternative route to the tantalum carbene complex "21# is via transformation of a carbene moiety
from a main group ylide to tantalum"III# under the appropriate conditions[ Two examples are shown
in Equation "06#\ and both the tantalum carbene complexes are thermally stable ð68JOM"060#32Ł[ On
photolysis in hydrocarbon solution with an ultraviolet light source\ the methyl complexes "22#
containing very bulky aryloxide ligands lose one equivalent of methane to form tantalum carbene
complexes "23# in essentially quantitative yields "Equation "07## ð75JA0491Ł[

Et2O/THF But
Ta(CH2But)Cl4 + 2Na/Hg + 5PMe3 (H)(PMe3)3Cl2Ta (16)

(31) (32)

Et3P PhH, 60 °C Cp2MeTa


Cp2Ta(PMe2R)Me + (17)
R 40–50% R
R = Me, Ph

OAr OAr
Me Ta Me hν
Me Ta (18)
Me ~100%
OAr OAr
(33) (34)
ArO = 2,6-di-t-butylphenoxide
2,6-di-t-butyl-4-methoxyphenoxide

A number of new tantalum carbene complexes can be prepared from preexisting tantalum carbene
complexes via modi_cation of the carbene ligand or the tantalum ligand[ The tantalum carbene
complex "24# reacts with two equivalents of LiOCMe2 to give "25# as light yellow crystals in 54)
yield "Equation "08## ð70JA0339Ł[ Similarly\ bulky tantalum carbene complexes containing phenoxide
or benzenethiolate ligands of type "27# can be prepared from the readily accessible tantalum carbene
"26# ð79JA5125Ł in good yield by analogous methods ð75OM1051\ 77JA3853\ 89IC0093Ł[ The related
pyridine and diethyl sul_de adducts "28# can be easily obtained from "27# in high yields "Equation
"19##[ Another interesting tantalum carbene complex "39# with the terdentate monoanionic 1\5!
bis"dimethylamino#methyl#phenyl ligand has been prepared in 89) yield starting from "26# "Equa!
tion "10##\ and it is thermally stable at room temperature ð89RTC335Ł[

But –PMe3 But


Cl3(PMe3)2Ta + 2LiOBut (ButO)2Cl(PMe3)Ta (19)

(35) (36)
C1Mo Function 402

But –3LiCl But Y But


Cl3(THF)2Ta + 3LiX X3(THF)Ta X3YTa
(20)
61–85% 61–75%
(37) (38) (39)

2,6-diisopropylphenoxide;
pyridine;
X= 2,6-dimethylphenoxide; Y=
SEt2
2,4,6-triisopropylbenzenethiolate

But
Me2N Li NMe2 Cl Cl
Ta
But –78 °C, Et2O Me2N NMe2
Cl3(THF)2Ta
+ (21)
90%
(37)

(40)

2[04[7 THE C1Cr FUNCTION


Syntheses of nonheteroatom!stabilised chromium carbene complexes are rare\ although the syn!
thesis of their heteroatom!stabilised counterparts has been thoroughly investigated[ The geminal
dichlorocyclopropene "30# reacts with the pentacarbonylchromium complex "31# to give a novel
cyclopropenylcarbene complex "32# "Equation "11## ð57AG"E#849Ł[ However\ this technique is of
limited applicability[ Nonheteroatom!stabilised chromium carbene complexes can be obtained from
the corresponding heteroatom!stabilised chromium carbenes by reaction with an aryl lithium reagent
"Scheme 8#[ The methoxy group of the anionic aryl chromium complex of type "33# can be eliminated
by silica as shown in Scheme 8 ð66CB545Ł[

Ph Ph
Cl –20 °C
+ (CO)5CrNa2 (CO)5Cr (22)
Cl –NaCl
Ph Ph
(41) (42) (43)

OMe ArLi OMe SiO2 Ar



(CO)5Cr (CO)5Cr Ar (CO)5Cr
–78 °C –30 °C
Ph Ph Ph
~80%
(44)
Ar = Ph, p-MeC6H4, p-CF3C6H4

Scheme 9

2[04[8 THE C1Mo FUNCTION


Nonheteroatom!stabilised molybdenum carbene complexes can be prepared from corresponding
complexes containing the carbonÐmolybdenum triple bond[ Thus\ reaction of the molybdenum
carbyne complex "34# with excess t!butylalkyne yields the molybdenum carbene complex "35# in
high yield "Scheme 09# ð74JA4888Ł[ Analogous molybdenum carbene complexes of type "36# can be
obtained by treatment of "35# with two equivalents of a carboxylic acid "Scheme 09#[ Molybdenum
carbene complexes of the type Mo"CHR0#"NAr#"OR1#1 "49# can be obtained from MoO1Cl1"THF#1
by the routes shown in Scheme 00 ð76OM0262\ 89JA2764Ł[ Key intermediates "37# are readily prepared
quantitatively in dimethoxyethane at 14>C[ Reaction of "37# with Grignard reagents and tri~ic acid
resulted in the formation of the carbene complexes "38#[ More thermally stable carbene complexes
"49# have been prepared straightforwardly from "38# in good yield "Scheme 00# ð89JA2764Ł[
403 Doubly Bonded Metal Functions
Furthermore\ reaction of "49# with 6!isopropylidene!1\2!dicarbomethoxynornadiene has provided
the molybdenum carbene complex "40# in high isolated yield "Equation "12## ð89JA7267Ł[
But But
Me
But RCO2H
O OCH(CF3)2 (excess), Et2O But CH2Cl2 But
O Mo But (F3C)2HCO RCO2
Me 91% 78–83%
(F3C)2HCO OCH(CF3)2 Mo But Mo But
(F3C)2HCO But RCO2 But
(45) (46) (47)

R = Me, Pri, CF3

Scheme 10

i, DME
ii, 2.6-lutidine NAr i, R1CH2MgCl
Cl NAr
iii, TMS-Cl Me ii, 3TfOH
MoO2Cl2(THF) + 2ArNH(TMS) O Mo
95% Cl R1 = But, 65%
O
Me R1 = PhMe2C, 76%
(48)
NAr
TfO NAr
Me 2LiOR2
O Mo R1 R2O Mo
OTf 50–95%
O 1
Me OR2 R
(49) (50)
Ar = 2,6-diisopropylphenyl
R 2 = But, 2,6-diisopropylphenyl, 2-t-butylphenyl

Scheme 11

NAr
NAr ButO Mo
45–55 °C
ButO Mo + (23)
CO2Me ButO
But 90–95%
ButO MeO2C But
CO2Me
CO2Me
(50) Ar = 2,6-diisopropylphenyl (51)

Four!coordinate molybdenum carbene complexes that contain the t!butylimido ligand have been
prepared by the routes shown in Schemes 01 and 02[ Reaction of the molybdenum complex "41#
with ButNCO\ followed by alkylation with "ButCH1#1Mg resulted in the formation of the imido!
alkyl compound "42#[ Treatment of "42# with ButCH1Li then yielded the molybdenum carbene
complex "43# in 64) yield[ The new carbene complex "44# can be obtained by reaction of "43# with
Ph2SiOH "Scheme 01# ð76CC018Ł[ The molybdenum carbene complex "48#\ which is analogous to
"49#\ has been prepared by treatment of "45# with hexa~uoroisopropanol "Scheme 02#[ When "48# was
treated with a terminal alkene such as styrene\ its carbene ligand was exchanged stoichiometrically to
form the phenyl carbene complex "59#[ Five!coordinate molybdenum carbene complexes such as
"47# can be prepared from the key complex "46# by replacement of the t!butylamine ligand with
stronger Lewis bases "Scheme 02# ð78CC0951Ł[

2[04[09 THE C1W FUNCTION


Nonheteroatom!stabilised tungsten carbene complexes can be prepared via an a!hydrogen
abstraction process[ Thus\ reaction of the tungsten complex "50# with trimethylphosphine in a sealed
tube at 099>C provided the carbene complex "51# as yellow crystals "Equation "13## ð67JA5663Ł[
Similarly\ both of the phenylimino tungsten carbene complexes "53# and "54# can be obtained from
the tungsten complex "52# in good yield "Scheme 03# ð71JA6372Ł[ Osborn and co!workers have
C1W Function 404
i, ButNCO
ii, (ButCH2)2Mg•dioxane ButCH2Li
MoO2Cl2(MeCN)2 Mo(NBut)(CH2But)3Cl
35% 75%
(52) (53)

NBut NBut
ButCH2 ButCH2
Ph3SiOH
Mo Mo
Ph3SiO
ButCH 2
But But
(54) (55)
Scheme 12

i, ButNCO NBut
ii, 2LiCH2But 2HOCH(CF3)2 (CF3)2HCO
MoO2Cl2 Mo(NBut)2(CH2But)2 Mo
81% 80% (CF3)2HCO But
(56) ButNH2
(57)

MeCN, vacuum L

(CF3)2HCO NBut (CF3)2HCO NBut NBut


Ph (CF3)2HCO
Mo Mo Mo
90% (CF3)2HCO
(CF3)2HCO (CF3)2HCO But
Ph But L
(60) (59) (58)
L = PMe3, pyridine

Scheme 13

reported a general protocol for the synthesis of tungsten carbene complexes of the type "56#\ which
simply involves reaction of the oxo ligand!containing tungsten complexes "55# with aluminum
halides "Equation "14## ð71CC403\ 74CC682Ł[ In addition\ other types of tungsten carbene complexes
are readily prepared from "56# by a metathesis reaction ð76JA2842Ł[ The phenylimino tungsten
carbene complex "58# can also be synthesised from the readily available precursor "57# by using a
similar technique\ as shown in Scheme 04 ð89OM1151Ł[ In 0882\ oxygen! and moisture!stable tungsten
carbene complexes "69# containing a bulky hydridotris"pyrazolyl#borate ligand were prepared in
modest yields by an a!hydrogen abstraction reaction "Scheme 05# ð82OM1703Ł[

But But
100 °C, –CMe4
+ 2PMe3 ButCH2 (24)
ButCH2 W CH2But W
~100%
Me3P t
CH2But PMe3 Bu
(61) (62)

But Cl NaCp, THF, 36 h


But Cp But
But –NaCl, –CMe4
W W
NPh 80%
But NPh
(63) PMe3 (64)

But But
But Cl Me3P•HCl Cl
Me3P
W W
60% Cl
NPh NPh
Me3P Me3P
(65)

Scheme 14
405 Doubly Bonded Metal Functions

O CH But But
2 + AlX3 X
ButCH2O W
ButCH2O W (25)
t
ButCH2O CH2Bu –CMe4
X
ButCH2O
(66) (67)
X = Cl, Br, I

i, ArNCO Me Cl NAr
ButO OBut
ii, 2 LiOBut PCl5, DME O W
ButCH2 W
WOCl4 O Cl
iii, 2 (ButCH2)MgCl
ButCH2 NAr 90% But
62% Me
(68) (69)
Ar = N-2,6-C6H3-Pri2

Scheme 15

NAr KHB N N N
NAr N NAr
Cl Cl 3ClMgR
RCH2 CH2R 3
W W HB N N W CHR
Cl Cl Cl CH2R
22–38%
OEt2 N N CH 2R

(70)
R = Me, Ar = Ph; R = Ar = Ph; R = Me, Ar = 2,6-Pri2C6H3

Scheme 16

Tungsten carbene complexes can be prepared from the corresponding complexes containing the
carbonÐtungsten triple bond[ Thus\ reaction of the carbyne complexes "60# with two equivalents of
HX "XCl\ Br\ MeCO1\ OPh\ OC5F4\ O!p!C5H3Cl# gave the carbene complexes "61# "Equation
"15## ð74OM0826Ł[ The halide complexes are the least thermally stable members of this class\ while
the carboxylate derivatives appear to be quite stable[ Protonation of the carbonyl!containing carbyne
complexes "62# in dichloromethane with excess concentrated HCl at room temperature gave the
tungsten carbene complexes "63# "Equation "16## ð76OM322Ł[ Lewis acid!free\ four!coordinate tung!
sten carbene complexes "67# have been prepared from the tungsten carbyne complex "64#\ as shown
in Scheme 06 ð75JA1660Ł[ Catalytic proton transfer in the carbyne complex "65# to give the tungsten
carbene complex "66# is the key step in the synthesis[ All these reactions proceed in high yield[ The
asymmetric tungsten carbene complexes "70# and "71# have been prepared via reactions analogous
to those shown in Equation "15#[ The carbyne complex "68# reacts with one or two equivalents of
the ligand "79# to give "70# and "71#\ respectively "Scheme 07# ð82OM1454Ł[

ButO X
+ 2HX ButO
ButO W But W (26)
–ButOH ButO
ButO X But
(71) (72)
X = Cl, Br, MeCO2, OPh, OC6F5, O-p-C6H4Cl

Me3P Cl HCl Me3P Cl


Me3P W R Me3P W (27)
Me3P CO CH2Cl2 Cl CO R
(73) (74)
R = Ph, p-Me-C6H4
C1W Function 406

Me Cl Cl Me Cl NHAr NEt3 Me Cl NAr


NAr
O W +ArNH(TMS) O W (0.2 equiv.) O W +2 LiOR
But But RO W
O Cl O Cl O Cl
–TMS-Cl –40 °C But –DME, But
–2 LiCl RO
Me Me Me
(75) (76) (77) (78)
R= OBut, OCMe2(CF3), OCMe(CF3)2, OAr; Ar = 2,6-diisopropylphenyl

Scheme 17

ButO
ButO W Ph
ButO
(79)

OH OH
2
OH OH

–ButOH –3ButOH
(80) (80)

Ph Ph

O W OBut O W O
O OBut O O

(81) (82)

Scheme 18

A number of nonheteroatom!stabilised tungsten carbene complexes can be prepared via inter!


molecular reactions of a tungsten complex with a carbene or carbene precursor[ Casey et al[ have
successfully synthesised the diphenylcarbene adduct "73# from the heteroatom!stabilised tungsten
carbene "72#\ as shown in Scheme 08 ð66JA1016Ł[ Tungsten oxocarbene complexes "76# can be
prepared in high yield by carbene transfer from the tantalum carbene complex "74# to the tungsten
complex "75# "Equation "17## ð79JMOC62Ł[ Bryan and Mayer have reported the remarkable reaction
between the tungsten complex "77# with the C1O double bond of a cyclic ketone\ forming a six!
coordinate tungsten oxocarbene complex[ Thus\ treatment of the tungsten"II# complex "77# with
two equivalents of cyclopentanone in benzene at room temperature a}orded the tungsten carbene
complexes "78# "Equation "18## ð76JA6102Ł[ In addition\ six!coordinate tungsten carbene complexes
"81# can also be prepared by transformation of a carbene moiety from variously substituted aryl
ylides "80# to the tungsten complex "89#[ A few examples are shown in Equation "29# ð82JA7056Ł[
Furthermore\ the vinyl tungsten carbene complex "83# can be prepared in good isolated yield from
reaction of the tungsten complex "82# with diphenylcyclopropene\ as shown in Scheme 19 ð82JA7029Ł[
Reaction of "83# with two equivalents of LiOR "RCMe"CF2#1\ or 1\5!C5H2Pri1# yielded the
corresponding tungsten alkoxide complexes "84#[
OMe PhLi OMe HCl/–78 °C Ph

(CO)5W (CO)5W Ph (CO)5W
Ph –78 °C Ph 50% Ph
(83) (84)
Scheme 19

pentane
Ta(CHBut)X3L2 + W(O)(OBut)4 Ta(OBut)X + W(O)(CHBut)X2L2 (28)
(85) (86) (87)
L = PMe3 or PEt3; X = Cl or Br
407 Doubly Bonded Metal Functions
O PMePh2
–2PMePh2 Cl W
WCl2(PMePh2)4 + 2 O (29)
–cyclopentanone Ph2MeP
(88) Cl
(89)

NPh NPh
Cl PMePh2 Ph3P –PPh3 Cl PMePh2
W + W (30)
Ph2MeP PMePh2 R –PMePh2 Ph2MeP CHR
Cl Cl
(90) (91) (92)

R = Ph, C6H4-p-Me, C6H4-m-Me, C6H4-o-Me, C6H4-p-OEt, C6H4-o-OMe, C6H4-p-CF3, C6F5, CH=CMe2

NAr NAr
80 °C, 2 h Cl P(OMe)3 2LiOR RO P(OMe)3
NAr W W
Cl P(OMe)3 Ph –P(OMe)3 (MeO)3P –78 °C (MeO)3P
W + Cl RO
(MeO)3P P(OMe)3 Ph 72% Ph 64% Ph
Cl
Ph Ph
(93) (94) (95)
Ar = 2,6-C6H3Pri2; OR = OCMe(CF3)2 or O-2,6-C6H3Pri2

Scheme 20

Finally\ a variety of new tungsten carbene complexes can be prepared from preexisting tungsten
carbene complexes[ Thus\ the carbene complexes "85# were readily obtained from "56# by metathesis
reactions involving a terminal alkene\ as shown in Scheme 10 ð76JA2842Ł[ Further reaction of "85#
with one equivalent of Li"OCH1But# then yielded trineopentoxo complexes "86#[ In addition\ the
_ve!coordinate tungsten carbene complex "88# can be prepared from the corresponding six!coor!
dinate carbene complex "87# by scavenging one phosphine ligand with PdCl1"PhCN#1 "Equation
"20## ð71OM037Ł[

Br Br ButCH2O
+ H2C=CR1R2
R1 Li(OCH2But) (1 equiv.) R1
ButCH2O ButCH2O ButCH2O
W W W
ButCH2O – H2C=CHBut ButCH2O pentane ButCH2O
Br But Br R2 Br R2
69–98%
(67) (96) (97)

R1 = H, R2 = Bun; R1 = H, R2 = Bus; R 1= H, R2 = Ph; H2C=CR1R2 = H2C

Scheme 21

Pd(PhCN)2Cl2
W(O)(CHBut)Cl2(PEt3)2 W(O)(CHBut)Cl2(PEt3) (31)
80%
(98) (99)

2[04[00 THE C1Mn FUNCTION


The dimethylcarbene complex "090# has been prepared by treating the corresponding cationic
carbyne complex "099# with MeLi at low temperature\ as shown in Equation "21# ð65AG"E#432Ł[
Alternatively\ nonheteroatom!stabilised manganese carbene complexes can be obtained via an
C1Fe Function 408
intermolecular reaction of a manganese complex with a diazo compound[ Some examples are
shown in Equation "22# ð63AG"E#488Ł and Equation "23# ð73JOM"153#216Ł[ These manganese carbene
complexes\ in general\ can be isolated in high yield[

MeLi, –50 °C
[Cp(CO)2Mn≡CMe]+BCl4– Cp(CO)2Mn (32)
15%
(100) (101)

O
–N2, –THF
Ph Mn Ph
Mn + Ph OC (33)
OC THF 37% CO
CO N2
O Ph

R1 –N2, –THF
R1
MnCp(CO)2(THF) + N2 Cp(CO)2Mn (34)
R2 72–82% R2

=
R2 R1 Ph Ph

2[04[01 THE C1Fe FUNCTION


Almost all the types of nonheteroatom!stabilised iron carbene complexes are obtained from
the corresponding carbonÐiron single bonded complexes[ Brookhart and Studabaker\ in 0876\
summarised some general techniques for generating iron carbene complexes ð76CR300Ł[ The most
widely used approach to the preparation of these compounds is by ionisation of a leaving group
attached directly to the potential carbene carbon of a carbonÐiron single bond containing complex[
Removal of the leaving group\ in general\ can then be accomplished by using Bronsted or Lewis
acids[ Some representative examples concerning the preparation of ironÐcarbene complexes by this
ionisation protocol are shown in Scheme 11 ð55JA4933\ 72JA147\ 72JOM"143#222\ 74JA1813\ B!78MI 204!91Ł[
The a!ether precursors "092# are readily accessible from the corresponding heteroatom!stabilised
iron carbene complexes "091#[ In general\ the a!ether precursors "092# exhibit varying degrees of
sensitivity to air and temperature[ Additionally\ the carbene complexes "091# can be obtained from
the readily available ferrate Cp"CO#1Fe−Na¦[ Iron carbene complexes "093# can also be easily
generated from the a!thioether complexes "094#[ Thus\ methylation of "094# with FSO2Me or
Me2O¦BF3− gives the corresponding sulfonium salts "095# which can be decomposed to give "093#
"Scheme 12# ð68JA5362\ 70JA0751\ 74JOC4787Ł[ In contrast with the a!ether carbene precursors "092#\
the sulfonium salts "095# are quite stable^ in selected cases\ these sulfonium salts can be stored in air
at room temperature for long periods[

+ +
R1 [R2]–
R1 H+ or CF3SO2-TMS R1
Cp(CO)LFe Cp(CO)LFe R2 Cp(CO)LFe
OMe OMe R2
(102) (103) (104)
L = CO, PMe3, PPh3; R1 = Me, Et, Pri, Bun, Ph, C6H4-p-Me, c-C3H5; R2 = H, Me

Scheme 22
419 Doubly Bonded Metal Functions
+
R1 FSO3Me R1 R1
25–100 °C
Cp(CO)2Fe R2 Cp(CO)2Fe R2 Cp(CO)2Fe
or Me3O+BF4– + SMeR3
SR3 R2
(105) (106) (104)
R1 = H, Me, Et; R2 = H, Me; R3 = Me, Ph

Scheme 23

An alternative approach to the preparation of iron carbene complexes "009# is through pro!
tonation of h0!vinyl iron complexes "098#[ The h0!vinyl iron complexes "098# can be prepared from
either the sodium ferrate "096# or the iron iodide "097#\ as shown in Scheme 13 ð71JA2650\ 71JA5008Ł[

R2
O R2
R1
Cp(CO)2Fe–Na+ +
Cp(CO)2Fe
Cl R1
(107) O

–CO
hν 60–90%

+
R2 R2 HBF4
R2
Cp(CO)2FeI + M Cp(CO)2Fe Cp(CO)2Fe
25–40%
R1 R1 R1
(108) M = Li or MgBr (109) (110)

R1 = H, Me, Ph; R2 = H, Me, C(CH2)Me

Scheme 24

2[04[02 THE C1Ru FUNCTION


The stable ruthenium carbene complex "001# can be prepared from the reaction of the ruthenium
complex "000# with diazomethane "Equation "24## ð75JOM"299#056\ B!78MI 204!90Ł[ In the early 0889s\
Grubbs and co!workers reported the reaction of an Ru"II# complex with 2\2!diphenylcyclopropene
to produce the stable ruthenium carbene complex "002# in essentially quantitative yield "Equation
"25## ð81JA2863Ł[

CH2N2
RuCl(NO)(PPh3)2 Cl(NO)(PPh3)Ru (35)
(111) (112)

Ph Ph
CH2Cl2/PhH, 53 °C, 11 h
RuCl2(PPh3)n + (36)
Ph ~100% Cl2(PPh3)2Ru Ph
(113)
n = 3 or 4

2[04[03 THE C1Rh FUNCTION


In general\ rhodium carbene complexes generated from reactions between rhodium"II# complexes
and diazo compounds are incapable of isolation[ However\ reaction of the rhodium complex "003#
C1Re Function 410
ð81CB1530Ł with diphenyl diazomethane has led to the stable rhodium carbene complex "004# in
85) isolated yield[ Stable rhodium carbene complexes "005#\ "006# and "007# can be obtained by
modi_cation of the rhodium ligands of "004#\ as shown in Scheme 14 ð82AG"E#0379Ł[

Ph
Pri3Sb N2 Pri3Sb Ph Ph
Ph NaCp
Cl Rh Cl Rh Rh
96% 78%
Pri3Sb Pri3Sb Ph Pri3Sb Ph
(114) (115) (116)

PPri3 L
4SbPri3 87–89%
98%
82%

[RhCl(C2H4)2]2 Pri3P Ph
Ph
Cl Rh Rh
Pri3P Ph L Ph
(117) (118)
L = CO or CNBut

Scheme 25

2[04[04 THE C1Re FUNCTION


The stable rhenium carbene complex "019# can be isolated from the reaction of the rhenium
complex "008# with three equiv[ of a Grignard reagent\ as shown in Scheme 15 ð72OM0494Ł[ Casey
and Nagashima have reported that reaction of h1!acylzirconium compounds "010# with the rhenium
complex "011# leads to the formation of rhenium carbene complexes "012# as orange solids "Equation
"26## ð78JA1241Ł[ A few rhenium carbene complexes can also be obtained from the corresponding
carbonÐrhenium single bond containing complexes[ Dehydrohalogenation of the rhenium complex
"013# using 0[94 equivalents of 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# in ether at −29>C proceeded
smoothly to give rhenium carbene complexes "014# in 69) isolated yield[ The chloride ligand in
"014# can be replaced by alkoxide ligands to give the new carbene complexes "015# "Scheme 16#
ð76OM782\ 77POL0730Ł[

But
4HCl 3ButCH2MgCl
Re(NBut)3(O-TMS) Re(NBut)2Cl3 ButN Re
–TMS-OH –CMe4 But
ButN
(119) (120)

Scheme 26

THF, RT Cp(CO)2Re
Cp2Zr(η2-COR)Cl + K+Cp(CO)2ReH– (37)
52–58% R
(121) (122) (123)
R = Me, CH2CH2But

dbu Cl(ArN)2Re LiOR (RO)(ArN)2Re


Re(NAr)2(CH2But)Cl2
70%
But 45–65%
But
(124) (125) (126)
Ar = 2,6-C6H3Pri2; R = CH(CF3)2, 2,6-OC6H3Pri2

Scheme 27

Oxocarbene complexes "017# have been prepared in 65) isolated yield by photolysis of
the rhenium cis!dioxo complex "016# in pyridine\ as shown in Equation "27# ð77CC0378Ł[
411 Doubly Bonded Metal Functions
Nonheteroatom!stabilised rhenium carbene complexes have been synthesised from the reaction of
cationic rheniumÐcarbyne complexes[ Thus\ addition of diethylaluminum hydride or methyllithium
to the phenylcarbyne complex "029# has a}orded the rhenium carbene complexes "018# and "020#\
in 63) and 35) yields\ respectively "Scheme 17# ð65JOM"019#C5\ 67CB2639Ł[ Furthermore\ a series of
new rhenium carbene complexes can be prepared from preexisting rhenium carbene complexes[
Addition of excess gaseous hydrogen chloride to rhenium carbene complexes "021# in di!
methoxyethane yielded the rhenium complexes "022# in 74) yield[ Addition of excess t!butylamine
to "022# then a}orded the new carbene complex "023# in 84) yield\ as bright yellow _bres "Scheme
18# ð81JA2256Ł[ Similarly\ four!coordinate rhenium carbene complexes "026# can be prepared in a
manner analogous to that described for "023#[ Thus\ addition of two equivalents of gaseous hydrogen
chloride to the carbene complex "024# a}orded the rhenium complex "025# in high yield[ The complex
"025# reacts with two equivalents of lithium or potassium alkoxide to give "026# quantitatively
"Scheme 29# ð81JA2256Ł[

hν, pyridine
But
ReO2(CH2But)3 O Re (38)
76%
O But
(127) (128)

Et2AlH LiMe
Cp(CO)2Re –78 °C, 15 min –40 °C, 8 h
[Cp(CO)2Re≡CPh][BCl4] Cp(CO)2Re
Ph 74% 46% Ph
(129) (130) (131)

Scheme 28

t
ButH2N Bu
6HCl, DME ButNH 2 (excess) Cl
2Re(NAr)2(CHBut)(CH2But) [Re(CBut)(CHBut)(ArNH2)Cl2]2 2 Re
–ArNH3Cl 95% Cl
But
ButH2N
(132) (133) (134)

Ar = 2,6-C6H3Pri2, But

Scheme 29

+2HCl But
–2H2O +2MOR
Re(O)2(CHBut)(CH2But) 1/ [Re(CBut)(CHBut)Cl ]
x 2 x
RO
~100%
Re
85% RO
But
(135) (136) (137)
M = K, Li; R = But, CMe2(CF3), CMe(CF3)2, 2,6-C6H3Pri2, SiBut3

Scheme 30

2[04[05 THE C1Os FUNCTION


The osmium carbene complex "028# can be prepared in 71) isolated yield from the reaction of
the osmium complex "027# with diazomethane "Equation "28## ð72JA4828Ł[ Osmium carbene com!
plexes "039Ð031# can be obtained in a similar manner\ as shown in Equation "28# ð75JOM"299#056Ł[
Grubbs and co!workers have demonstrated that the osmium carbene complex "033# can be prepared
from "032# via a reaction analogous to that described for the preparation of "002#\ as shown in
Equation "39# ð81JA2863Ł[
C1Os Function 412
PhH R
OsCl(NO)(PPh3)2 + CHRN2 (39)
Cl(NO)(PPh3)Os
R = H, 82%
(138) (139) R = H
(140) R = Me
(141) R = Ph
(142) R = CO2Et

Ph Ph
CH2Cl2/PhH
OsCl2(PPh3)4 + (40)
Ph ∆ Cl2(PPh3)2Os Ph
(143) (144)

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3-16
Ketenes, their Cumulene
Analogues and their S, Se
and Te Analogues
DAVID C. HARROWVEN and SHELAGH T. DENNISON
University of Southampton, UK
3.16.1 KETENES 525
3.16.1.1 From Acid Halides 526
3.16.1.2 From 2-Haloacyl Halides 530
3.16.1.3 From a-Diazocarbonyl Compounds 530
3.16.1.4 From Carboxylic Acid Anhydrides 534
3.16.1.5 From Other Acyclic Ketones, Carboxylic Acids and their Derivatives 535
3.16.1.6 From Carbocyclic Ketones and Related Compounds 537
3.16.1.7 From Alkoxyalkynes 540
3.16.1.8 From Heterocyclic Materials 541
3.16.1.9 From Transition Metal Complexes 544
3.16.1.10 Miscellaneous Methods 545
3.16.2 THIOKETENES 546
3.16.2.1 From Ketenes and Thioketenes 546
3.16.2.2 From Acid Chlorides and Thioacyl Chlorides 547
3.16.2.3 From the Sulfur Analogues of Carboxylic Acids and Esters 547
3.16.2.4 Via Alkynyl Sulfides and Alkynyl Thiolates 548
3.16.2.5 From Sulfides of Carbon 549
3.16.2.6 From Ketene-S,X-Acetals 550
3.16.2.7 From Heterocyclic Materials 550
3.16.2.8 From Vinylidene Transition Metal Complexes 552
3.16.3 SELENOKETENES 553

3.16.1 KETENES
Ketenes are inherently reactive species that show a strong tendency to dimerise, suffer nucleophilic
attack or undergo aerial oxidation. As a result, they are often difficult to isolate and relatively few
have been properly characterised. The stability of a ketene is, however, greatly influenced by
its substituents. Dialkylketenes are considerably more stable than the corresponding monoalkyl
derivatives; for example, dimethylketene dimerises at room temperature in about an hour whilst
methylketene suffers this fate in just a few minutes. Electronic factors also play an important role,
with phenyl, silicon, germanium and tin substituents imparting a stabilising effect on the system.
Halogen and chalcogen substituents, by contrast, tend to accelerate the polymerisation process.
For synthetic purposes the instability of a ketene is often of little consequence, especially when
an in situ preparation is available. In this chapter, therefore, those processes that have resulted
unambiguously in the formation of ketenes are presented alongside those for which it is reasonable

525
526 Ketenes, Cumulenes and S, Se and Te Analogues

to assume their intermediacy. Limitations on space prohibit a truly comprehensive overview. The
interested reader is therefore directed to the excellent monologues by Ward <B-8OMI 316-01 >, Buehler
and Pearson <B-70MI 316-01), Luknitskii and Vovsi <69RCR487>, Borrmann <68HOU(7/4)65>, Lacey
<B-64MI 316-01 >, Wagner and Zook <B-53MI 316-01 >, Hanford and Sauer <46OR(3)l08>, and the remark-
able pioneer of ketene research Staudinger <B-12MI 316-01 >, for additional examples of ketene
syntheses.

3.16.1.1 From Acid Halides


The most widely encountered method for the preparation of ketenes involves the dehydro-
halogenation of acid halides by treatment with tertiary amines (Equation (1)). There are several
reasons for this popularity. First, the reaction is easy to perform and is readily adapted to enable
access to unstable ketenes through in situ generation. Moreover, it is extremely broad in scope with
almost all acyl halides that possess an a-hydrogen undergoing the reaction.

(i)

The mechanism through which this conversion occurs has been subject to much speculation. It is
now generally accepted that ketene formation arises through the collapse of an intermediate acyl
ammonium salt (49JA2242, 52JA4962, 62CJC2362). Some confusion arose when a series of experiments
revealed that the dehydrohalogenation of a-haloacyl halides by tertiary amines first led to the
formation of enolate salts <68HCA1466, 68TL1977, 70HCA120, 70JOC1515>. These studies appeared to
suggest that a second mechanistic route to ketenes might be operative <73JA7447>. This idea was
dispelled by Brady and Scherubel when they showed that the two salts could be interconverted, by
the series of equilibrations outlined in Scheme 1, and that the reactions each exhibited were distinct
<74JOC3790>. The observation that sodamide may be used in the analogous preparation of di-r-
butylketene from the corresponding acid chloride would appear to be exceptional (60JA2498,81T4189).

Scheme 1

Nevertheless, the propensity for the deprotonation of acid halides by amine bases introduces
some additional complications to this protocol as exemplified by the formation of the vinyl ester (2)
when the dichloride (1) was treated with triethylamine (Equation (2)) <68TL6003>. This difficulty can
be circumvented by the slow addition of the acyl halide to a solution of the amine <74JOC3790>.

(2)

The fact that this protocol has found most favour for the in situ generation of ketenes may also
be due to the presence of residual trialkylammonium hydrohalides. These have been shown to
catalyse the addition of nucleophiles to ketenes and many of the cycloaddition reactions they
undergo. Unfortunately, the rate of polymerisation of ketenes is also dramatically increased and so
their isolation is rendered more difficult.
As a preparative route for the in situ generation of ketenes, this is of little consequence and
Ketenes 527

countless references to its use could be cited. There would appear to be few limitations and the list
of ketenes that have been accessed in this fashion is impressive. These include simple di- and
monoalkylated ketenes, aryl-, vinyl-, acyl- and allylketene together with an array of ketenes bearing
heteroatom substituents. The examples in Table 1 serve to illustrate the diversity in application of
this synthetic entry.

Table 1 Ketenes prepared by dehydrohalogenation of acid halides.

1 Bu' L^~~~J CF3 Ph


67JCS(B)360 60JA2498 70RTC23 67FCR107 72OS36
76JCS(P1)2O79
/O ^0 o
ci Br
v* ^-* -^-* Y T Y
F Br 1
70TL2963 69JA5679 74JOC763 67DOK1117 66JOC2676 77JOC4157
O O EtS
^0 ^O
^O ^O PhCV ^ - * PhS^^»* \^*" ™S-^^'"
MeO^.* EtO^-* Y Y Y Y
1 1 SEt Br
79JOC1208 70JA1766 71JOC1486 79JOC2067 77JHC249 76TL1553
70HCA417 70JA1768

o * °
67T4769 68CB1120 70TL3657 77JOC2111 57JA6261
76JOC3303

Interestingly, when a,j9-unsaturated acid halides are exposed to tertiary amines, the products
usually appear to implicate the intermediacy of the corresponding methyleneketenes <66JOC718>. In
all the examples investigated to date, this assumption has been shown to be erroneous <B-80MI 316-03)
and the reaction actually proceeds via 1,4-dehydrohalogenation. Trapping of the resulting vinyl-
ketene then leads to a /?,y-unsaturated ketone, which suffers alkene migration under the conditions
employed, as, for example, in Scheme 2 <7OHCA2159>.

Scheme 2

The use of pyrolysis or photolysis to initiate elimination of HCl from acid chlorides has, by
comparison, received scant attention. The thermal decomposition of acetyl chloride to ketene has
been established for many years <77AG(E)1O5>, but extensions are few and have tended to be confined
to 0^/z0-substituted aroyl halides. The pyrolysis of salicyloyl chloride, for example, provides ready
access to the highly reactive ketoketene (3; X = O) <68M1958>, whereas ortho-toloy\ chloride and
528 Ketenes, Cumulenes and S, Se and Te Analogues
related homologues yield products derived from the corresponding vinylketenes (Scheme 3)
<77AG(E)469>.

Scheme 3

In the 1980s and 1990s, considerable attention has focused on the synthesis of ketenes that bare
chiral substituents as they offer a convenient and enantioselective entry towards /Mactams by
means of a ketene-imine cycloaddition <81CC344>. Several encouraging developments of this general
stratagem have been reported, of which two examples are highlighted (Schemes 4 and 5) <91TL1O39,
92TL4823).

Scheme 4

Scheme 5

Synthetic entries towards several other naturally occurring ring systems have incorporated this
methodology as a key feature. Oppolzer and Nakao, for example, explored an ingenious entry
towards 6-protoilludene (6) in which the conversion of the acid chloride (4) to the ketene (5) with
Pr' 2 EtN played a pivotal role (Scheme 6) <86TL547l>. A strategically similar approach to isocomene
(11) by Snider and Beal proved equally rewarding. Thus, when the mixture of acid chlorides (7)
was treated with triethylamine, the tricyclo[5.3.0.0]decane (9) was provided via an intramolecular
[2 + 2] cycloaddition of the transient ketene (8). Isomerisation of the exo-cyclic alkene in (9) to (10)
using HI then completed a formal total synthesis (Scheme 7) <88JOC4508>.

Scheme 6

Syntheses of a diverse array of terpenes have utilised this strategy <82JA747, 87CC1728, 88CC1421,
91JOC321). Few have been as efficient as that described by Corey et al. in their total synthesis of
retigeranic acid (12) (Scheme 8) <85JA4339>. An interesting extension was described by Brady et al.
who found that treatment of the acid chloride (13) with triethylamine initiated sequential ketene
Ketenes 529

Scheme 7

formation, cycloaddition and decarboxylation giving the benzofuran (14) in high yield (Scheme 9)
<86JOC2145>. The in situ generation and intermolecular trapping of ketenes by alkenes has found more
general application. For example, in the early stages of Ghosez's approach to the prostaglandins,
dehydrohalogenation of the acid chloride (15) first produced the ketene (16) which was then trapped
with cyclopentadiene to give the bicycle (17). A short sequence of standard transformations was then
established to convert this material (17) into the Corey intermediate (18) (Scheme 10) <8UA4616>.

Scheme 8

Scheme 9

Scheme 10
530 Ketenes, Cumulenes and S, Se and Te Analogues
3.16.1.2 From 2-Haloacyl Halides
The preparation of ketenes by dehalogenation of 2-haloacyl halides was first described by Stau-
dinger in 1905 and remains to this day a popular and convenient route to these materials (Equation
(3)) <05CB1735>. The most common method used to accomplish this conversion involves the treat-
ment of an ethereal solution of the dihalide with zinc <82JOC387l, 93S606). In later years this has
often been used in the form of a zinc-copper couple <9UOC7048> where the presence of phosphoryl
chloride may be beneficial (78JOC2879, 87JOC4885). Other reagents such as magnesium <O9CB4213>,
silver <08LA(356)51>, mercury <46OR132>, triphenylphosphine <68JOC3974> and pentacarbonyl-
manganate salts <86JOC3558> have also been successfully employed, and would appear to be advan-
tageous in some cases.

(3)

Various methods have been described for the isolation of ketenes prepared in this manner. When
sufficiently inert, residual salts may be removed by aqueous workup, though this is more commonly
achieved by distillation under reduced pressure <63OSC(4)348, 86S43>. In the cases of methyl- and
dimethylketene, higher yields have been observed when the reaction is conducted under reduced
pressure with the ketene removed, in solvent, as it is formed <63OSC(4)348,75JCS(P1)16OO>.
The reaction has also been widely used as a convenient method for the in situ generation of ketenes
<62AG32>. Their intermediacy is usually inferred but may often be established more rigorously by
spectroscopic means (e.g., by a strong infrared active band at ca. 2130 cm" 1 ) <B-80MI 316-02). This
has greatly increased the scope of this methodology, and numerous examples have now been
documented (Table 2).
The fact that this method has not found as much favour as the dehydrohalogenation of acid
halides may reflect the greater synthetic challenge involved in the preparation of the requisite starting
materials, though the presence of residual zinc bromide may also be deleterious.

3.16.1.3 From a-Diazocarbonyl Compounds


The turn of the century was undoubtedly the most important era in the history of ketene chemistry.
Most of the common entries to ketenes that are in use today were first formulated during this
period. Indeed, in 1902 Wolff inadvertently stumbled upon a route to ketenes that, although not
recognised at the time, remains important to the present day <02LA(325)129>.
Wolff showed that treatment of diazoacetophenone with water and silver oxide gave phenyl acetic
acid rather than the anticipated hydroxyketone. Furthermore, when aqueous ammonia was present
in the reaction medium, the corresponding amide was formed in good yield (Equation (4))
<04LA(333)l, 12LA(394)23>. The intermediacy of ketenes in this type of rearrangement was first recog-
nised by Schroeter who found that thermolysis of PhCOC(N2)Ph led smoothly to the production of
diphenylketene <09CB2336,09CB3356,16CB2697).

The precise manner in which the ketene is formed has been the subject of considerable debate,
and there would appear to be no single mechanistic description for the reaction. In fact, there is
compelling evidence for both concerted <85JA7597> and nonconcerted rearrangement, the latter
involving the intermediacy of a-ketocarbenes <88JA1O25> and oxirenes (Scheme 11) <72JCS(P2)2623,
80PAC1623, 83CRV519, 85JOC135>. An overview containing numerous pertinent references has been
presented by Gill, and the interested reader is referred to this text for further details <91COS(3)887>.
While the production of a ketene intermediate is a pivotal feature of the Wolff rearrangement,
these species are seldom isolated. The reaction is most widely used for the preparation of carboxylic
Ketenes 531
Table 2 Various routes to ketenes involving dehalogenation of a-halo acylhalides.

z
Br X « \^**0 II Zn

Br
>^*< —- Y -^Br ^
63OSC(4)348 PPh3,68JOC3974
ZnorMg,09CB4213

0 O °

87JOC4885 05CB1735
78JOC2879 93CB297

F 3 C ^ a - F3C .-° But H^ zn Bu. .^°


F3C Cp BU BuI
lr 3 " Cl
68T1341 86S43

,— ph ci /—\ Ph fl ^ n ^%

73AG(E)25 ^^^ ^^^


06CB3062

II Mn(CO)5- ^O ||

86JOC3558 Ph
88JOC4877

Scheme 11

acids, esters and amides and is therefore well represented in other chapters. The limited discussion
presented here reflects this fact.
Several methods to initiate the Wolff rearrangement have been described. Typically, the decompo-
sition of a-diazoketones is achieved by exposure to light <59CB528>, heat <82CPB526> or transition
metals <4UOC669>. Each of these methods has limitations. Thermolysis of these materials often
requires temperatures in the region of 200 °C, where other electrocyclic processes may also be facile
<91COS(3)887>. The addition of transition metal catalysts lowers the decomposition temperature
appreciably but these may alter the reactivity profile of the carbene intermediate. Rhodium, pal-
ladium and copper catalysts, for example, readily form complexes with these carbenes and are
normally avoided when ketene formation is desirable <B-71MI 316-01, B-78MI 316-0l>. Most commonly,
WolfFs original catalyst, freshly prepared silver oxide, is employed together with either sodium
carbonate or a tertiary amine <35CB85O, 71T1317). Silver salts such as the benzoate <70OS(50)77> or
532 Ketenes, Cumulenes and S, Se and Te Analogues
nitrate <58JOC1166> have also found common usage. A selection of illustrative examples are collected
in Table 3.

Table 3 Ketene intermediates derived by Wolff rearrangement.

0 r -,
JL hv ^0 HSEt II
59CB528
|1
N2
' ^' ' \ASEt
o r 1 i 1 o
. 11 , A 1 -*° PhCH2OH 1 U
YY ^^^f~ " ^ Y ^ O Ph 82CPB526
' N2 SO2Bn S0 2 Bn

/ V n [ 0
41JOC669
i^Xx L
r y : J
fX ^
N2

O r -i
N
\ — \ /=' =O \ /~C02H

° [ *°1 if
rn
^ ^ ^ ^ Y ^ ^ T Ph y NH2 48JCS1674
N2 L / J ^/
O^^^. °*. CO2Et

r^Yi "^S0B^ I ^ V ^ J
^^ f \ * \ 70OS?7

The greatest drawback of this method is the number of competing side reactions that may occur.
Diazoketones are themselves very reactive species which can participate in 1,3-dipolar cycloadditions
<(38CB1179>, suffer attack by soft nucleophiles <63CB1948), undergo other rearrangements
<85JOC280l), and react in aldol-type condensations <72S35l>. The ketocarbene intermediate adds to
these difficulties; being prone to collapse by 1,2-hydrogen shift <72JCS(Pl)2623>, inter- and intra-
molecular hydrogen abstraction <B-71MI 316-01, B-78MI316-01), insertion into vicinal carbon to carbon
and other sigma bonds <70JA6706> or through cycloaddition to an appropriately situated Tt-system
<68BSF4913>. Perseverance often holds the key to success. For example, when the diazoketone (19)
was exposed to copper salts, the product of carbene insertion (21) predominates. By contrast,
photolytic rearrangement of (19) leads to the bicycle (23) via the intermediate ketene (22) (Scheme
12) <65CI(L)424, 65CI(L)425>.
Increasingly, the photolytically induced Wolff rearrangement has found favour <84SC163,
85JOC4404). On many occasions, a greater selectivity towards ketene formation is observed when
this method, rather than the thermolytic and transition metal-catalysed variants, are employed
<51LA(573)17,52CB225,55CB934). This has been attributed to a lesser tendency to exhibit carbenoid
insertion reactions. Most commonly, irradiation is conducted at 0°C using a medium pressure
mercury arc. The use of higher energy photons and elevated temperatures has, on occasions, been
profitable though complications associated with the photolabile nature of the products may arise
(66T209, 69T2121).
While carbene insertion usually prevents ketene formation, in the vinylogous Wolff rearrangement
it is a prerequisite for their formation <74JOC3355>. Thus, when /?,y-unsaturated diazoketones are
exposed to copper(II) salts, the intermediate carbene is intercepted by the vicinal alkene with the
generation of a bicyclo[2.1.0]pentanone. Rupture of this highly strained intermediate then provides
the ketene which is usually trapped in situ by a suitable nucleophile (Scheme 13).
Ketenes 533

Scheme 12

Scheme 13

The yields and degree of selectivity observed in this process are moderate to high, and it has
found many applications <84JA3995, 84JA4001, 86TL3913). A few illustrative examples are given in
Schemes 14^16. Interestingly, /?,>>-unsaturated diazoketones can also be encouraged to undergo
normal Wolff rearrangement through exposure to silver ions or by conducting the reaction under
thermolytic or photolytic conditions. These processes are however, prone to give complex mixtures
arising from the competitive vinylogous rearrangement <74CC695, 76JA7456, 77JOC3165,84JOC2052).
Finally, it has been shown that a-silyl- and a-germyl-a-diazocarbonyls may be converted into
bismetalloketenes by treatment with bis(triethylsilyl)mercury (75IZV199, 76ZOB930).

Scheme 14

Scheme 15

Scheme 16
534 Ketenes, Cumulenes and S, Se and Te Analogues
3.16.1.4 From Carboxylic Acid Anhydrides
In 1907 Wilsmore and Stewart disclosed their finding that the immersion of a hot platinum wire
into acetic anhydride could be used to generate ketene, H ; C==G=O <O7JCS1938). While this process
was of little preparative use, subsequent modifications to the procedure have established this source
of the parent compound invaluable for the preparation of ketene in the laboratory <53JOCI055>.
The method has also found application in the synthesis of other ketenes in moderate to high yield
<61CP6!8722.68MI 316-03). For example, pyrolysis of isobutyric anhydride to dimethyl ketene (68M1316-
01), and the preparation of silyl- and germylketenes from the requisite met a Elated acetic anhydrides
produced these materials in good yield and a high state of purity (Equation (5)) <69ZOB467,70ZOB707).

(5)

Another convenient route to ketenes involves the pyrolysis of malonic acid anhydrides <08CB2208.
13CB3539). These materials, on gentle warming (100"C) under reduced pressure, readily extrude
carbon dioxide with the liberation of a ketene (Equation (6)). The synthetic value of this entry lies
in the preparation of dialkylketenes where yields in excess of 50% are usually achievable <23HCA29i,
63AG(E)608>. The reaction is capricious, especially when the anhydride is prepared HI situ by dehy-
dration of the malonic acid derivative with acetic anhydride. Extreme care has to be exercised to
remove all traces of residua! acetic anhydride from the vessel prior to thermolysis if side reactions
are to be avoided. An alternative, more forgiving protocol has been developed in which isobutyric
anhydride is used to accomplish dehydration of the malonic acids <63AG{E)608).

(6)

A variety of mixed anhydrides of malonic acids have also been employed in the synthesis of
ketenes. Commonly, these are either the diphenylacetic anhydride (Scheme 17), interestingly pre-
pared by the action of diphenylketene on the malonic acid derivative <I3CB3539>, or the bis(tri-
fluoroacetic) anhydride, formed by reaction with trifluoroacetic anhydride (TFAA) <62JOC3146>.
Again, decomposition of these materials is usually effected by the action of heat, but in the latter
instance may also be accomplished using triethylamine (Scheme 18) <90CPB]60!>.

Scheme 17

Scheme 18
Ketenes 535

The synthesis of vinylketenes can be achieved by flash vacuum pyrolysis of crotonic anhydrides.
This method has been exploited in a synthesis of sibirinone (23), a metabolite of Hypomyces
semitranslucens G. Arnold (Scheme 19) <82JA6779>.

Scheme 19

3.16.1.5 From Other Acyclic Ketones, Carboxylic Acids and their Derivatives
The preparation of ketene by pyrolysis of either acetone or ethyl acetate was among the first routes
towards this compound (07JCS1938,07NAT510,07PCS229). In the following years it was established that
almost any molecule containing a methyl group directly bound to a carbonyl will liberate ketene on
thermolysis. Thus, syntheses of ketene through the action of heat on acetic acid <29JA3614>, biacetyl
<25JA1779>, acetaldehyde <25BRP273622>, together with numerous methylalkyl ketones <23JA3095>,
acetic esters <23JA2167> and amides <32JA2432> have been established (Scheme 20).

Scheme 20

The preferred method to accomplish these conversions consists of passing a vaporised sample
over a heated metallic surface. A detailed overview of the experimental procedures that have been
established was presented by Hanford and Sauer <46OR132>, and the interested reader is directed to
this account for further information. For most laboratory-scale uses, the generation of ketene by
pyrolysis of acetone has found most favour <40JOC122,46OR132).
One drawback of the protocol is that it fails to provide a general synthetic entry towards
homologous ketenes owing to the difficulties associated with the control of cracking processes. The
elevated temperatures necessary to induce fragmentation of ketones, for example (typically > 600 °C)
also induce rupture in pendant side chains; as exemplified by the thermolytic conversion of diethyl-
ketone to ketene rather than the anticipated methylketene <23JA3095>. In spite of these difficulties,
these reactions are not without synthetic value. For example, Streith and Tschamber found that,
although pyrolysis of butanone provided a 7:3 mixture of ketene and methylketene, the rate of
reaction of the latter with imines was several powers often greater than that observed with ketene.
536 Ketenes, Cumulenes and S, Se and Te Analogues
Consequently, good yields of 8-methyl-5-azanonamdienes could be obtained by exposure of the
corresponding diazepines to the pyrolysis gas of butanone (Scheme 21) <83LA1393>.

Scheme 21

There are, however, a growing number of exceptions to this rule. The pyrolysis of higher homo-
logues of aliphatic carboxylic acids have been used successfully in the generation of a variety of
mono- and dialkylketenes <63CI(M)1216>, and high yields of these materials have been reported
when the reaction is conducted in the presence of catalytic quantities of triethylthiophosphate
<60GEP1081455>. In exceptional cases, dehydration has even been achieved using phosphorus pent-
oxide <72ZOR654>. More recently, other dehydrating agents have been developed that achieve this
conversion under considerably milder conditions<87JOC3457,91S1027,92CB571 > as exemplified by Funk
et al. in their total synthesis of clovene (24) (Scheme 22) <88TL1493>.

Scheme 22

The thermally induced degradation of alkylphthalimides (Equation (7)) and also dehydration of
malonic acid monoesters, have found general application, since both of these processes may be
accomplished at greatly reduced temperatures <35JA774>. In addition, there exist a plethora of
synthetic entries to specific classes of ketenes. For example, phenylketene may be prepared by
irradiation of benzoyldimethylsulfonium methylide (64JA4866, 66JA1587) while the generation of the
acylketene (26) may be accomplished by dehydrohalogenation of 2-bromocyclohexane-l,3-dione
(25) (Scheme 23).

(7)

Scheme 23

Similarly noteworthy is the preparation of cyclopentadienylketenes by flash vacuum pyrolysis


(FVP) of ortho-hy&roxy aromatic esters (Scheme 24) which is strikingly contrasted by the analogous
pyrolysis of or?/!o-mercaptobenzoic acid (Scheme 25). The thermolysis of isopropenyl esters also
Ketenes 537

provides a smooth entry towards ketenes (Equation (8)) <68MI 316-02), a process that has found
considerable use in the synthesis of vinyl acetates <60JA320l, 65JOC2502).

Scheme 24

Scheme 25

(8)

Finally, it should be mentioned that some useful entries to metalloketenes have been reported.
Rathke et al. have uncovered two unusual routes to bis(trimethylsilyl)ketene. First, they showed
that this material could be prepared from /-butyl bis(trimethylsilyl) acetate simply by generation of
its lithium enolate (Scheme 26) <77JOC2038>, and second through sequential treatment of tri-
methylsilylketene with butyllithium (— 100°C) and trimethylsilyl chloride (Scheme 27) <78JOC376>.
The former has now been extended towards a variety of dialkylketenes <85JA5396>.

Scheme 26

Scheme 27

Bryce-Smith and co-workers have also prepared copper(I), silver(I) and gold(I) ketenides
<70JCS(D)699, 73CC921, 74CC513). In a typical procedure, silver ketenide is formed by the action of
acetic anhydride on silver acetate in the presence of pyridine (Equation (9)) <7lGP2047373>.

(9)

3.16.1.6 From Carbocyclic Ketones and Related Compounds


The photochemically induced cleavage of cyclic ketones has often been shown to produce ketenes
as either transient species or isolable products. Thus, when the bicyclo[5,2,l]decanone (27) was
irradiated using a medium pressure arc, the initial Norrish type 1 cleavage was accompanied by a
radical abstraction to afford cycloundecanylketene (28) (Scheme 28). A similar rearrangement has
538 Ketenes, Cumulenes and S, Se and Te Analogues

been implicated in many other cases including the photochemical interconversion of the bicycles
(29), (30) and (31) (Scheme 29) (62JA4148, 62TL221, 62TL1297, 64CB1799, 68JA2449).

Scheme 28

Scheme 29

The diradical intermediate produced by a Norrish cleavage of this type may also yield ketenes by
other means. Thus, when 5,5-dimethylcyclopentenone was subjected to photolysis, the cyclo-
propylketene (32) was generated by recombination of the radical species through the allylic carbon
centre (Scheme 30) <69TL4517>. A similar rearrangement occurs when ethano-bridged anthracenes
are subject to irradiation, as exemplified by the conversion of (33) into ketene (34). These systems
are also prone to undergo cycloreversion, with the release of anthracene and the generation of
highly reactive cumulated ketene (Scheme 31) (68TL4995,73JA6294,77JA4554). Indeed, it is this process
that prevails when the related saturated analogues are photolysed <77T389>.

Scheme 30

Scheme 31

The cycloreversion of cyclobutane-l,3-diones is also best achieved by pyrolysis. The process is


well documented as a method for regeneration of ketene monomers from ketene dimers, and is
rarely used as a truly independent method of synthesis. The reaction is none the less valuable as it
provides a convenient source of these materials in a high state of purity (Scheme 32) <46OR(3)l08>.

Scheme 32

In fact, ketenes may be accessed from almost all cyclobutanone derivatives. The photochemically
induced fragmentation of the parent system has been established for many years (67TL545, 72JA663,
Ketenes 539

73CC795, 83T1567), and has featured in a rearrangement of hydroxybicyclo[3.2.0]heptanones to lac-


tones (Scheme 33) <89CC303>.

Scheme 33

The thermally induced, electrocyclic ring opening of cyclobutenones (68JA2449,85JA3392) had, for
many years, received scant attention. However, the use of this protocol in a highly imaginative
synthesis of A-6-tetrahydrocannabinol by Kowalski and Lai (Scheme 34) <88JA3693> and related
entries towards benzoquinones <85JA3392, 86JOC3067> and bicyclo[3.2.0]heptenones <9UOC6094>
described by Moore et al. will undoubtedly inspire further exploration of this chemistry.

Scheme 34

The cycloreversion of benzocyclobutenediones <73JA6134> provides a valuable entry to bisketene


dienophiles. The utility of these intermediates has been highlighted in a short synthetic entry to the
anthracyclinones (Scheme 35) <88LA943>. Methylenecyclobutenones <76BSJ2645> and cyclobutene-
1,2-diones <69TL1179> may also undergo scission to transient ketene intermediates. The latter
provides a particularly valuable route to cyanoketenes, as exemplified by the high yields of chloro-
cyanoketene that were obtained from 3,4-dichlorocyclobutenedione by treatment with sodium azide
(Scheme 36) <84JOC2190>. In this example the reaction was spontaneous at ambient temperature. A
variety of cyanoketenes have also been prepared by the thermolysis of 2,5-diazidoquinones (Equa-
tion (10)) <76OS(55)32, 81CSR289, 88RRC83), while vinylogous cyanoketenes are available by similar
treatment of azidotropones <68CC764> or 3-azido-l,2-benzoquinones <86JOC2814>.

Scheme 35

(10)
540 Ketenes, Cumulenes and S, Se and Te Analogues

Scheme 36

Finally, mention should be made of the conversion of cyclohexa-2,4-dienones to vinylketenes by


pyrolytic or photolytic cleavage (Equation (11)) <60JCSl, 65AG(E)2ll, 67JCS(C)ll97,68JA5296,77CB3582),
and of the surprising observation that diphenylcyclopropenone may be converted into ketene
phosphorenes with triphenylphosphine (Equation (12)) <72TL1849,75CPB2933).

(11)

(12)

3.16.1.7 From Alkoxyalkynes


Another important route to ketenes involves the thermolysis of alkoxyalkynes. Provided there is
a hydrogen atom situated on the j3-carbon of the ether, these materials readily suffer elimination of
an alkene to provide the corresponding 'aldoketene', often in almost quantitative yield (Equation
(13)) (61RTC810, 73ZOB2088, 77TL4437, 89SL36>.

(13)

The resulting ketenes usually react with the parent alkyne to afford a cyclobutanone (Scheme 37)
<85S1118>, or they suffer attack by a suitable nucleophile (Scheme 38) <93TL207l>. However, when
silyl- <65DOK(164)357,68DOK(164)892> and germyl alkoxyalkynes are thermolysed, the increased stab-
ility of the resulting ketene allows these materials to be isolated by simple distillation <65DOK(179)357,
90JOC395). By contrast, when ethoxy(trimethylstannyl) acetylene was thermolysed, only bis(tri-
methylstannyl) ketene was obtained <73AG(E)675>. More conveniently, dimetalloketenes (Si, Ge, Sn,
B and combinations thereof) may be prepared from the requisite metallated alkoxyacetylene in
moderate to high yield by the action of R3MBr (M = Si, Ge or Sn) in the presence of magnesium
bromide <71ZOB240, 73AG(E)675> or exposure to boron trihalide (Scheme 39) <84ZOB1817>.

Scheme 37

Alkyl (trimethylsilyl)ketenes may also be accessed from alkyl alkoxyacetylenes by treatment with
trimethylsilyl iodide (Equation (14)) <79S740>. A substantial improvement to this procedure has
Ketenes 541

Scheme 38

Scheme 39

(14)

been developed by Kocienski and Pons during their syntheses of tetrahydrolipstatin <89TL1833> and
(-)-lipstatin (Scheme 40) <93JCS(P1)1549>.

Scheme 40

3.16.1.8 From Heterocyclic Materials


Numerous heterocyclic materials have been converted into ketenes, the advent of flash vacuum
pyrolysis and low temperature photolytic techniques undoubtedly being responsible for the renewed
interest in this field of chemistry. Dialkyl ketenes, for example, have been accessed from an array
of sources, and some representative examples are highlighted in Scheme 41 (08CB2208, 13CB3539,
32JA2432, 35JA774, 48JA3426, 63AG(E)608, 64JA4871, 64JOC2200, 64JOC2242, 66JA1242, 70CC206, 70JCS(B)830,
74AJC2373, 75CB844).
Of these methods, the pyrolytic fragmentation of disubstituted malonic anhydride and Meldrum's
acid derivatives are most commonly exploited <54JA5563, 77AJC179, 85TL833, 86CC369,88TL5919). The
latter of these is particularly valued since numerous derivatives can be easily prepared, allowing
access to a broad spectrum of ketenes. These include dialkyl- and heterosubstituted ketenes, together
with the highly reactive methyleneketenes that are difficult to access by other means (Scheme 42)
(74AJC2385, 76JA7421, 77AJC459, B-80MI 316-03, 87TL885>.
Other heterocyclic materials have been used to access these cumulated systems, but none has
assumed such universal application. Dimethylmethyleneketene, for example, has been postulated
as an intermediate in the photolytic cleavage of the a-methylene-/Mactam (35), though this is subject
to some speculation (Scheme 43) (77JCC53, B-80MI316-03). By contrast, spectroscopic evidence has
been obtained to verify that the parent methyleneketene (38) is produced when an argon matrix
542 Ketenes, Cumulenes and S, Se and Te Analogues

Scheme 41

Scheme 42

containing the a-diazo-y-lactone (36) is subject to photolysis (Scheme 44) <J5JA6586>. Interestingly,
this reaction proceeds via the ketene (37) and has been extended towards o-quinonoid methyl-
eneketenes, for example, (39) (Scheme 45) (75JA6586,80TL343).

Scheme 43

Scheme 44

A number of routes to o-quinonoid ketenes from condensed heteroaromatics have also been
disclosed, a selection of which are highlighted in Scheme 46 (62JOC3365,64M1053,66TL3465,68JCS(C)2730,
70JA7001, 7UCS(C)3328, 72CC451, 72TL3443, 73JA406l>. In each case acyl-, thioacyl- or iminoketenes are
Ketenes 543

Scheme 45

provided, and some parallels can be drawn between these entries and the more generally applicable
routes to such materials outlined in Scheme 47 <72TL1849, 73JA244, 73CC247, 73JA247, 73JA248,73JA5412,
73TL2875, 74HCA2583, 75AG(E)636, 75CPB2933, 76TL2961, 79TL59, 84H(22)2563, 85S224, 90CPB94, 90TL3677,
91T5689, 92S977).

Scheme 46

Phosphorylketenes have also been reported. Indeed, treatment of diphenylcyclopropenone with


triphenylphosphine provides a stable example of such a compound (72TL1849). In the reaction of
diphenylcyclopropenone with triethylphosphite, however, a ketene could only be implicated as a
transient intermediate (Scheme 47) <75CPB2933>. Vinylketenes have also been accessed by cyclo-
reversion of condensed heteroaromatic materials. Of those entries highlighted in Scheme 47 the
photo-induced Wolff rearrangement of 5-acyl-3/f-pyrazoles has found most widespread application.
Several other examples of ketene syntheses from heterocyclic materials are worthy of note. For
example, pyrolysis of the o-phenylene carbonate (40) has been shown to produce the Wolff-type
intermediate (41) on route to cyclopentadienylketene (42) (Scheme 48) <70JOC4204,71CC77O>. Similar
treatment of 4-azido-3-halo-5-methoxy-5(//)furan-2-ones, on the other hand, facilitates rearrange-
ment with extrusion of nitrogen to provide halocyanoketenes (Equation (15)) <76JA3728, 78TL929,
84JOC2190). Nitrogen extrusion from the cycloadducts of 6-oxo-l,3,4-oxadiazines also leads to the
production of ketenes (Scheme 49) <90CB2031 > as does the photolysis of dihydrocoumarin <69JA4309>.
Finally, mention should be given to the BuLi-initiated fragmentation of 3,4-diphenylisoxazole which
gives rise to phenyltrimethylsilylketene upon quenching with chlorotrimethylsilane (Scheme 50)
<75AG(E)765>.
544 Ketenes, Cumulenes and S, Se and Te Analogues

Scheme 47

Scheme 48

(15)

Scheme 49

Scheme 50

3.16.1.9 From Transition Metal Complexes


Reports concerning the formation of transition metal 71-complexes of ketenes and vinylogous
ketenes abound in the contemporary literature. These include a variety of cobalt <85JA6715>, chro-
mium <92JA299l,93JOC538>, manganese <79JA3133>, niobium <89JA8738>, osmium <88JA7868>, rhenium
Ketenes 545
<85JA3172>, titanium <86JA3318>, tungsten <86AG(E)643> and zirconium (84JA5178, 84CC220) species.
Since these are beyond the scope of this chapter, only a few leading references are presented here.
One reason for their inclusion is that, on occasions, the presence of additional 7t-donors may cause
these materials to rearrange to the corresponding metalloketene (Equation (16)) <86AG(E)643>. This
chemistry has yet to be studied in detail. Similarly, there are reported examples of ketenes bound to
transition metals through donor substituents, for example, (43), that are worthy of note
<88JOM(355)267>.

(16)

Several routes to c-bound metalloketenes have been described. Thus, exposure of a THF solution
of Cp 2 Sm(THF) 2 to an atmosphere of carbon monoxide resulted in the smooth formation of the
ketene carboxylate (44) <85JA3728>. Treatment of ((Bu'3Si)3TaCO)n in a similar manner facilitated
the formation of the moderately stable ketene (45) <89JA9057>, while the reaction between
Cl2W(PPh2Me)4 and carbon suboxide leads to the ketene (46) baring both tungsten and phosphorus
substituents <88JA4855>.

Perhaps more useful is the observation that, when the tungsten, molybdenum or chromium
complexes (47) were exposed to an atmosphere of carbon monoxide, the stable silyl ketene (48) was
furnished in reasonable yield (Equation (17)) <89JOM(373)203>. Similarly, treatment of chromium
carbene complexes, for example, (49) with bistrimethylsilylacetylene, provided the vinylogous silyl-
ketenes (50) and (51), in useful quantity (Equation (18)) <79AG(E)954>.

(17)

(18)

3.16.1.10 Miscellaneous Methods


Some very unusual, highly fluorinated ketenes have been described by England, using chemistry
that would appear to be unique. For example, the polyfluorinated ether (52) could be transformed
into the acyl ketene (53) by treatment with sulfur trioxide (Equation (19)) <8UOC147,8UOC153).

(19)
546 Ketenes, Cumulenes and S, Se and Te Analogues

3.16.2 THIOKETENES
Thioketenes are considerably less stable than ketenes, due in part to less efficient Tt-orbital overlap
between the carbon and the sulfur atom. This is compounded further by a tendency for these
materials to form dimers and higher oligomers (Equations (20) and (21)). An unfortunate conse-
quence of this is that many early reports detailing the preparation of thioketenes, including the first
claimed synthesis <1877CB70l, 88T1827), were in error <189OCB1571,88T1827>.

(20)

(21)

As with ketenes, the stability of this functional group is greatly influenced by the nature of any
substituents. Highly congested thioketenes such as di-/-butylthioketene are stable indefinitely at
ambient temperature, whereas the parent compound H 2 C = C = S dimerises when warmed above
— 200°C! <(88T1827>. Electronic factors also play an important role with silicon, phosphorus and
trifiuoromethyl substituents imparting a clear stabilising influence on the system. In general,
however, the synthesis of thioketene monomers is difficult, and requires the use of techniques
such as flash vacuum pyrolysis, matrix isolation or careful generation and characterisation at low
temperature. It is therefore wise to treat thioketenes as transient species, to be prepared in situ for
most synthetic purposes. For that reason the authors again highlight those processes which have
resulted in the isolation and characterisation of thioketenes, alongside those for which it is reasonable
to assume their intermediacy.
The interested reader is directed to a series of invaluable overviews. Of particular note are two
early articles by Borrmann <68HOU(7/4)312> and Mayer and Krober <75ZC91>, respectively, which
critically evaluate many of the pioneering studies. Two later articles by Schaumann <85HOU(El 1)233,
88T1827) are especially noteworthy since they provide a detailed and learned account on all aspects
of thioketene chemistry, and give a most valuable insight into this curious functional group.

3.16.2.1 From Ketenes and Thioketenes


The observation by Newman et al. <60JA2498> that di-?-butylketene was extremely unreactive, led
workers in the Kodak laboratories to rationalise, correctly, that the corresponding thioketene
might be similarly inert <68JOC2738>. Indeed, they found that simply reacting dw-butylketene with
phosphorus pentasulfide in refluxing pyridine for 15 hours gave the corresponding thioketene in an
isolated yield of 4 1 % . It was, however, observed that under these conditions, most thioketenes
oligomerised (Equation (22)) <79CB2698, 82CB2755>.

(22)

Interestingly, when r-butylcyanoketene was treated with triphenylphosphine sulfide, the reaction
profile indicated the presence of a thioketene intermediate. This has yet to be rigorously established,
with spectroscopic analysis failing to detect the presence of a thioketene <7OJA4132, 71JA2812).
Triphenylphosphoranylidenethioketene, on the other hand, has been prepared from the cor-
Thioketenes 547
responding ketene through the action of carbon disulfide <(68JA3842>; and when this material is
added to electron-deficient alkynes a (2 + 2)-cycloaddition, electrocyclic ring opening sequence is
initiated that provides access to cumulated thioketenes (Scheme 51) <75AG(E)53>.

Scheme 51

3.16.2.2 From Acid Chlorides and Thioacyl Chlorides


Di-?-butylthioketene can also be prepared from di-?-butylacetyl chloride through the action of
P2S5 in refluxing pyridine (Scheme 52) (68JOC2738). This method has been used in the synthesis of
several thioketenes, and yields tend to be superior to corresponding reactions with ketenes
<82CB2755>. Conceptually, the elimination of HX from thioacyl chlorides should offer a concise and
versatile entry to thioketenes. Unfortunately, the use of this tactic is limited by the scant methods
available to access the highly reactive thioacyl chlorides. Consequently, the use of this protocol has
been limited (Scheme 52) <81BCJ2845,83AG(E)32i>.

Scheme 52

3.16.2.3 From the Sulfur Analogues of Carboxylic Acids and Esters


One of the earliest routes to thioketene involved the pyrolysis of thioacetic acid <77CPH(22)453,
77JA1663). This method of synthesis has been used widely, particularly as a means to study the
spectroscopic characteristics of this material, but has few useful extensions <33CB237>. An alternative
route to thioketenes from dithiocarboxylic acids first involves the generation of the corresponding
dianion. On occasions these intermediates may even collapse to the thioketene spontaneously,
although it is more usual to promote this degradation by the addition of electrophiles such as
acid chlorides (62CB2861, 74ZC92, 79LA1715), alkoxycarbonyl chlorides or tx-chloroenamines (75ZC19,
81 LAI361 >. In all cases the reaction conditions employed render the thioketene a transient species.
<62CB287i, 71CJC1456). One potentially useful modification of these methods, that has led to thio-
ketene monomers, first involves monoacylation of the dithiocarboxylic acid dianion. The resulting
dithioanhydrides may then be transformed into the corresponding thioketene through the action of
heat (Scheme 53) <88T1827>. This method, while showing much initial promise, has yet to be fully
evaluated and may prove to be less versatile than the analogous procedure using phosgene (details
in Section 3.16.2.4).
The sulfur analogues of carboxylic esters have also, on occasions, been used to access thioketenes.
For example, pyrolysis of phenyl diphenyldithiocarboxylate has been shown to yield the dimer
of diphenylthioketene <31CB237>, while treatment of methyl triphenylphosphoranylidene dithio-
acetate with sodium hexamethyldisilylamide provides a useful synthesis of triphenylphos-
phoranylidenethioketene <75AG(E)634>. The use of alkynyl thiocarboxylates represents a special case
which is considered in more detail in the following section.
548 Ketenes, Cumulenes and S, Se and Te Analogues

Scheme 53

3.16.2.4 Via Alkynyl Sulfides and Alkynyl Thiolates


Alkynyl thiolates are a convenient source of thioketenes since they are tautomerically equivalent
to the aldothioketene anion. Indeed, protonolysis of these species first provides the alkynyl thiol
which may then undergo a 1,3-hydrogen shift to the thioketene <68RTC38>. These species are most
conveniently generated and used in situ, and a variety of preparations have been disclosed. For
example, treatment of alkynyl thiocarboxylates with nucleophiles <67RTC907>; protonolysis of alky-
nyl thiocyanates <82RTC31O>; addition of sulfur to the alkynyl anion or pyrolysis of alkynylalkyl
sulfides (62USP3O35O3O, 62ZOR1759, 66RTC889) have variously been explored (Scheme 54), although
only the latter procedure has allowed the isolation of monomeric thioketene <60RTC866,71ZOR1120>.

Scheme 54

One important extension to these studies has shown that trimethylsilylalkynyl sulfides readily
rearrange to the corresponding trimethylsilylthioketenes under thermolysis or by the action of a
Lewis base (Scheme 55). Moreover, silylalkynyl sulfides display considerable 'thioketenoid' character
in their reactions. For example, the addition of methanol to trimethylsilylethynyltriethylsilyl sulfide
first provides trimethylsilylthioketene <77JOM(127)Cl>, which may then be quenched by a further
equivalent of methanol <76CC1008, 77RTC179, 78ZOB2137, 80CB3024, 83CB66, 83CB509, 84AG(E)439>.

Scheme 55

With alkynylallyl sulfides the thia-Cope rearrangement is also facile, providing a ready access to
allylthioketenes (Equation (23)) <68RTC1236, 74CB3562, 77TL4307, 79LA1746>. Similarly, thermolysis of
alkynylpropargyl sulfides <74RTC26,79RTC55) and alkynylallenyl sulfides <72RTC578> can be readily
accomplished thereby providing access to allenic and propargylic thioketenes respectively (Equa-
tions (24) and (25)).
Thioketenes 549

(23)

(24)

(25)

3.16.2.5 From Sulfides of Carbon


The use of carbon disulfide in Wittig, and related, alkeneation sequences has resulted in the
formation of products which can be considered to have arisen through the intermediacy of thio-
ketenes (Scheme 56) <20HCA853, 62CB3077, 76JCS(P1)692, 82CB3653, 84JCR(S)370>. This has only been
established formally in the case of triphenylphosphoranylidenethioketene <66TL5707>. An interesting
extension to this protocol has been described by Kolodyazhnyi who found that treatment of tertiary
phosphines with carbon disulfide in carbon tetrachloride smoothly led to the production of stable
phosphorylated thioketenes (Equation (26)) <87TL88l>.

Scheme 56

(26)

Several other alkeneation procedures have been extended towards reaction with carbon disulfide,
albeit in less detail. The use of the Peterson protocol (Scheme 57) <88TL1827> and of sulfur ylides
(Scheme 58) <71T1781> to effect construction of the carbon to carbon double bond have also been
reported, but the true effectiveness of these methods has yet to be fully determined. For completion,
the conversion of P h 3 P = C = C = O to P h 3 P = C = C = S by the action of carbon disulfide should also
be mentioned <68JA3842>.

Scheme 57

Scheme 58
550 Ketenes, Cumulenes and S, Se and Te Analogues
Another conceptionally simple approach to thioketenes is through the union of a carbenoid
species and carbon monosulfide. Unfortunately, this process has proven to be of limited use
<9UOC1317> owing to the readiness with which most thioketenes undergo [3 + 2] cycloaddition
reactions with diazo complexes (see Scheme 61) <70JOC3470>.

3.16.2.6 From Ketene-S,X-Acetals


Ketene-S,X-acetals provide an excellent route to thioketenes through ^-elimination (70CB949,
9UA5120). Ketene-N,S-acetals <79JOC4877> and ketene-O,S-acetals <76TL3093> have each been
employed in this way, but as yet these have only provided trapped and oligomeric products (Scheme
59). Ketene-5'-methyl-5'-(trimethylsilyl)acetals, by contrast, readily undergo flash vacuum pyrolysis
to the corresponding thioketene. In the case of the anthracene derivative (54) a [4 + 2]-cycloreversion
was used in conjunction with the /^-elimination sequence to access methylenethioketene (Equation
(27)) <86TL4313>. In fact, a plethora of cycloreversion strategies have been used to access thioketenes
from cyclic ketene-S,X-acetals, and these are presented in the following section.

Scheme 59

(27)

3.16.2.7 From Heterocyclic Materials


The deprotonations of 2-alkylidene-l,3-dithiolanes 1,1-dioxides, which are easily derived from the
corresponding ketenthioacetals by oxidation, offer a convenient in situ method for the preparation of
several thioketenes <83AG(E)55, 88TL1827). A similar fragmentation sequence can also be
accomplished through alkylation or arylation of 2-alkylidene-l,3-dithiolanes. The resulting dithio-
lonium salts readily extrude alkyl- or arylvinyl sulfide on treatment with base (Scheme 60) (85TL5269,
88TL1827).
[2 + 2] Cycloreversions offer many routes to thioketenes. For example, dithietanones, which are
readily formed by the addition of phosgene to the dianions of dithiocarboxylic acids, may be cleaved
to thioketenes by pyrolysis, photolysis or by the action of a Lewis base <82AG(E)225>. Flash vacuum
pyrolysis of 2,2,4,4-tetramethylcyclobuta-l,3-dithione may be used in the preparation of di-
methylthioketene <74TL555>. Cyclobutanethiones too, when exposed to similar conditions, readily
cleave to give an alkene and a thioketene <87CC573). More importantly, the [2 + 2] cycloreversion
of 2,4-bis(alkylidene)-l,3-dithietanones, that is cracking of the dimer, can often provide an effective
route to the monomeric species (66CC577, 70JOC3470, 91CB1485). For completion the addition of
carbon monosulfide to diazo compounds and the addition of carbon disulfide to phosphorus ylides
Thioketenes 551

Scheme 60

are also noted here, as the intermediacy of diazetinethiones and thiaphosphetanes, respectively,
have been implicated in these processes <91JOC1317> (Scheme 61).

Scheme 61

Interestingly, cracking of the thioacetone trimer, 2,2,4,4,6,6-hexamethyl-l,3,5-trithiane, at


900 °C produces thioketene. The reaction proceeds first to give thioacetone, which then suffers loss
of methane on extended thermolysis (Scheme 62) <74CC739>. The photochemical degradation of
2-alkylidene-l,3,4-thiadiazolines <90TL357l> and the chemically induced reteroreversion of 2-alkyl-
idene-l,3-oxathioles <89TL1249> have also provided access to thioketenes, albeit in low yield. The
synthetic utility of each is of limited interest as these materials are accessed from the thioketenes
each provides!

Scheme 62

One of the most important routes to thioketenes involves the extrusion of nitrogen from 1,2,3-
thiadiazoles <77AG(E)835> which leads to the generation of a Wolff-type intermediate that may
undergo rearrangement to a thioketene <58LA(614)4, 71T5953). Several methods have been described
552 Ketenes, Cumulenes and S, Se and Te Analogues
to accomplish this transformation, including the use of thermolysis (20HCA833, 77T449, 87CC573),
photolysis <85LA(614)4> and, needless to say, flash vacuum pyrolysis <75AG(E)248,77CB1225,79LA1734).
Of these techniques, the former and the latter have found most favour since they are less prone to
side reactions (Scheme 63).

Scheme 63

Nitrogen extrusion from 1,2,3-thiadiazoles can also be brought about by treatment with alkyl
lithium reagents (66RTC889, 68RTC38, 77S888, 79CL535). This procedure is believed to proceed via the
lithium alkynyl thiolate (Scheme 64), the chemistry of which has been discussed in Section 3.16.2.4.

Scheme 64

The intermediacy of carbenoid species has been implicated in several other thioketene syntheses.
For example, flash vacuum pyrolysis of 2-mercaptoaryloic acid derivatives is believed to give
rise to thioketenes via sequential dehydration to the jS-thiolactone, loss of carbon monoxide and
rearrangement of the carbenoid precursor (Scheme 65) <83AG(E)543>. l,3-Dithiolen-2-thiolones
<79NJC149> and isothiazoles <77JA4842> also suffer elimination, of carbon disulfide and hydrogen
cyanide, respectively, to give first carbenoid intermediates which rearrange to thioketenes. The
photochemically induced extrusion of carbon monoxide from l,3-dithiolen-2-ones, on the other
hand, leads to an unstable a-dithione which then equilibrates to the corresponding mer-
captothioketenes (Scheme 66) <82NJC40l>. 1,2-Dithiolene-3-thiones <74CB502> and isothiazol-5-
thiones <85CB85l> have also been transformed into thioketenes through phosphine-induced desul-
furisations, while l,2-dithiolen-3-ones <75LA1513> and 3-isothiazolthiones <70T1493>, each suffer
decomposition in the presence of base with the formation of thioketene dimers.

Scheme 65

Scheme 66

3.16.2.8 From Vinylidene Transition Metal Complexes


A plethora of accounts have recently appeared concerning the chemistry of transition metal
bound thioketenes. Indeed, r\ 1 (S), r]2 (CS) and even rjl> (CCS), complexes of thioketenes to all manner
of transition metal centres have been described (e.g., Ir and Pt <70JCS(A)944>, Cr <76JOM(118)C4l>, Co
Selenoketenes 553
and Rh <81AG(E)593>, M n and W <82CB1332>, V <84JOM(272)C40>, Co <84JOM(270)93, 85CB873), Ti
<85JOM(288)C47». The most commonly employed route for the synthesis of such materials involves
simple ligand displacement, and is not considered in detail here.
An alternative entry to the r\l (CS bound) complexes, through the addition of elemental sulfur to
vinylidene rhodium and osmium carbene complexes, is perhaps more noteworthy since it formally
constitutes a new synthetic entry to thioketenes (Equation (28)) <83AG(E)981, 85CC1145). Moreover,
these complexes have been shown to possess significantly improved thermal stability compared to
the free ligand <91OM3967>. However, this chemistry is still in its infancy, and as yet no method for
the liberation of these ligands from a metal centre has been disclosed.

(28)

3.16.3 SELENOKETENES
Very few selenoketenes have been reported, and access to this curious functional group has
generally followed analogous procedures towards thioketenes. Thus, a variety of 1,2,3-selenodiazoles
have been converted into the corresponding selenoketene by thermolysis <79CC99> or photolysis
(Equation (29)) <72TL445, 76JA7872, 77JA4842). Similarly, the thermally induced rearrangement of
benzo-l,2,3-selenodiazole (Equation (30)) <80AG(E)69> and the seleno-Cope rearrangement of vari-
ous allyl butynyl selenides have provided routes to selenoketenes, albeit transiently (Equation (31))
<79RTC55, 80TL4251). In addition, a [3 + 2]-cycloaddition reaction between a transient selenoketene
and its anion has been postulated in the base-catalysed conversion of 4-aryl-1,2,3-selenodiazoles
into diselenofulvenes (Scheme 67) <73JOC338, 74JOC3906). Phenylselenoketene has also been invoked
as an intermediate in the reaction between bis(dimethylaluminium)selenide and the ketene silyl
acetal (55), on the basis that the adduct (56) was obtained (28%) when the reaction was performed
in the presence of cyclopentadiene (Scheme 68) <92TL7865>.

(29)

(30)

(31)

Scheme 67
554 Ketenes, Cumulenes and S, Se and Te Analogues

Scheme 68

Transition metal complexes of selenoketenes are usually considerably more stable than the parent
compound. Indeed, by analogy with thioketenes these may be synthesised by the addition of selenium
to vinylidene transition metal complexes <91OM3967>. Again, a method of liberating the monomer
from the metal centre has yet to be described. Finally, it is necessary to note that a Chemical
Abstracts Service on-line search failed to reference any example of a telluroketene (R 2 C=C=Te).
Whether such compounds can be prepared is a matter for speculation; however, their use in synthesis
would surely be limited.

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.17
Ketenimines and Their P, As, Sb,
and Bi Analogues
JOSEPH P. MICHAEL and CHARLES B. DE KONING
University of the Witwatersrand, South Africa
2[06[0 KETENIMINES AND THEIR DERIVATIVES "R1C1C1NH"R#\ ETC[# 444
2[06[0[0 Introduction 444
2[06[0[1 Ketenimines from Precursors Containin` the CCN Triad 445
2[06[0[1[0 By elimination reactions 445
2[06[0[1[1 By elimination reactions accompanied by skeletal rearran`ement 452
2[06[0[1[2 From alkanenitriles\ their a!anions or their a!radicals 454
2[06[0[1[3 By cleava`e of heterocyclic compounds 463
2[06[0[1[4 From other ketenimines 479
2[06[0[1[5 By miscellaneous pericyclic processes 471
2[06[0[2 Ketenimines from "CC¦N# Precursors 473
2[06[0[2[0 From ketenes "or related precursors# and iminophosphoranes "or related precursors# 473
2[06[0[2[1 From haloalkenes or haloalkynes and amines or amine derivatives 477
2[06[0[3 Ketenimines from "C¦CN# Precursors 480
2[06[0[3[0 From phosphorus ylides and isocyanates or related compounds 480
2[06[0[3[1 By alkylation of isocyanides 482
2[06[0[3[2 Formal cycloaddition processes 599
2[06[0[4 Keteniminium Salts 590

2[06[1 P\ As\ Sb\ AND Bi ANALOGUES OF KETENES AND THEIR DERIVATIVES


"R1C1C1P0R\ ETC[# 591
2[06[1[0 0l4!Phosphaallenes and 0l4!Phosphacumulenes 592
2[06[1[0[0 From precursors containin` the CCP triad 592
2[06[1[0[1 From "C¦CP# precursors 593
2[06[1[1 0l2!Phosphaallenes and 0l2!Phosphacumulenes 594
2[06[1[1[0 By the Peterson reaction and related ole_nations 594
2[06[1[1[1 By other routes 596
2[06[1[1[2 Transition metal complexes of 0l2!phosphaallenes and 0l2!phosphacumulenes 598
2[06[1[2 0!Arsacumulenes 598

2[06[0 KETENIMINES AND THEIR DERIVATIVES "R1C1C1NH"R#\ ETC[#

2[06[0[0 Introduction
Ketenimines "IUPAC name] 0!alkenylideneamines# are comparative latecomers to organic chem!
istry\ the _rst stable member of the group having been reported by Staudinger in 0808 ð08HCA524Ł[
Their relatively recent discovery and continuing rarity re~ect the susceptibility of the C1C1N unit
to decomposition by hydrolysis\ dimerization\ and polymerization\ amongst other reactions[ In
general\ hydrogen!substituted ketenimines and those with small unbranched alkyl substituents are
elusive substances[ For example\ the simplest ketenimine\ H1C1C1NH\ was _rst isolated in an
argon matrix at 3 K ð52JA167Ł[ Although longevity\ and hence synthetic signi_cance\ is conferred
445 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
by substituents that stabilize the 0!azaallene core either electronically or sterically\ many ketenimines
that do not survive puri_cation are stable for limited periods at low temperature or in solution[
Ketenimines also play a role as discrete but transient intermediates in many interconversions\
especially in eliminationÐaddition processes and in the formation of heterocyclic systems[ The
selection of material for this chapter has thus been complicated by the hazy distinction that exists
between unstable but spectroscopically characterizable ketenimines\ and ephemeral species produced
by methods that nonetheless have synthetic value[
The inherent axial dissymmetry of the formal C1C1N unit means that appropriately substituted
ketenimines should\ in principle\ be obtained in two enantiomeric forms[ However\ such enantiomers
have never been isolated\ though ketenimine diastereomers have been detected in one highly spe!
cialized case ð70CL416Ł[ Inversion at nitrogen appears to constitute the principal mechanism for
racemization\ and spectroscopically determined barriers to racemization for a substantial number
of ketenimines are in the range 29Ð52 kcal mol−0 "015Ð153 kJ mol−0# ð70CB2640\ 73T782Ł[ In fact\ the
description of ketenimines as 0!azaallenes "0a# may well be an oversimpli_cation[ Other feasible
canonical forms include a zwitterionic form "0b# highlighting the nucleophilicity of the b!carbon
atom\ and an alternative zwitterion "0c# in which the electrophilicity of the central carbon atom is
emphasized "Scheme 0#[ Single!crystal x!ray di}raction studies have con_rmed the approximately
linear "069Ð065># nature of the CCN triad\ but several examples "e[g[\ with R0 R1 MeSO1# in
which a linear C1N
0R2 angle is apparent point to a large contribution from the canonical form
"0b# ðB!79MI 206!90\ 78AX"C#371Ł[ The pronounced shielding of the terminal allenic carbon "dC 26Ð67
ppm for various methyl! and phenyl!substituted ketenimines# also suggests the conjugative inter!
action between the C1C bond and the nitrogen lone pair implicit in the canonical form "0b#
ð64CL40Ł^ and a similar conclusion can be drawn from up_eld 04N chemical shifts ð70OMR"06#079Ł[

R1 R3 R1 R1 N R3
– +
• N N R3
+
:

R2 R2 R2
(1a) (1b) (1c)

Scheme 1

The _rst review dealing with the synthesis and reactions of ketenimines was published in 0857\
and contained experimental procedures for preparing representative compounds ð57HOU"6:3#212Ł[
Subsequent reviews by Krow ð60AG"E#324Ł and by Barker and McHenry ðB!79MI 206!91Ł also
included structural and spectroscopic properties of ketenimines[ Specialized reviews by Gambaryan
ð65RCR529Ł and Aumann ð77AG"E#0345Ł cover the topics of ~uorinated ketenimines and metal
complexes of ketenimines respectively[ A very thorough review of post!0857 ketenimine chemistry
has appeared in the Houben!Weyl series ð82HOU"E04:2#1420Ł[

2[06[0[1 Ketenimines from Precursors Containing the CCN Triad

2[06[0[1[0 By elimination reactions


Elimination reactions from substrates incorporating the intact CCN triad have proved to be
reasonably versatile and general reactions for preparing ketenimines bearing a variety of substitu!
ents[ In virtually all of the examples that _t this category\ the substrates undergoing elimination are
amides or compounds readily prepared from amides[

"i# Dehydration of secondary amides with phosphorus pentoxide


A much!cited method for accomplishing this reaction\ introduced in 0853 by Stevens and Singhal\
involves heating secondary amides with phosphorus pentoxide in re~uxing pyridine ð53JOC23Ł[
Florisil\ sand\ or alumina\ added to the reaction mixture to facilitate stirring\ were found to increase
the rate of reaction[ Some representative examples are shown in Table 0[ Most of the compounds
originally prepared weretriaryl ketenimines derived from anilides of diphenylacetic acid "entries 0Ð4#\
but strongly electron!withdrawing substituents on the N!aryl group inhibited the reaction "entry 1#[
The high boiling point of pyridine makes the reaction unsuitable for preparing thermally labile
Ketenimines 446
ketenimines such as those bearing N!alkyl and C!alkyl substituents "entries 4 and 5#[ However\ by
changing to the lower!boiling solvent triethylamine\ Singer and Davis succeeded in preparing mixed
alkylÐaryl ketenimines and even a trialkyl ketenimine "entries 6 and 7#\ although in general their
yields were low "½19)# ð56JA487Ł[ Other workers have been more successful with this variation
"entry 00# ð73T782Ł[

Table 0 Representative ketenimines\ R0R1C1C1NR2\ prepared by dehydration of secondary amides\


R0R1CHCONHR2\ with phosphorus pentoxide[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Ketenimine Method a Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 Ph1C1C1N"C5H3R# "Ro!Me\ o!OMe\ p!Me\ p!OMe\ i 56Ð76 53JOC23
p!Br\ p!SMe#
1 Ph1C1C1N"p!C5H3R# "RSO1Me\ NO1# i 29\ 9 53JOC23
2 ðPh1C1C1N"p!C5H3#Ł1X "XCH1\ S1# i 73\ 16 53JOC23
n
3 Ph1C1C1NBu ii 49 53JOC23
4 Ph1C1C1NBut i 9b 53JOC23
5 Et"Bun#C1C1NR "Rp!Tol\ Bun# i 08\ 9 53JOC23
6 Me1C1C1NR "Rc!C5H00\ Ph# ii ½19 56JA487
7 Et"Ph#C1C1NR "RPh\ Bu # s
ii ½19 56JA487
8 0\n!"Ph1C1C1N#1C5H3 "n2\ 3# i 55\ 60 66MI 206!90
09 Me"R#C1C1N"p!C5H3NMe1# "RPri\ BnMe1C# ii 21\ low 70CB2640
00 Me"Pri#C1C1N"1!Cl\5!R0C5H2# "RCl\ Me# ii 34\ 61 73T782
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a b
i\ P1O4:pyridine\ re~ux^ ii\ P1O4:NEt2\ re~ux[ Diphenylacetonitrile "58)# was formed[

"ii# Dehydration of secondary amides with dihalotriphenylphosphoranes


A milder procedure for dehydrating secondary amides to ketenimines uses reagents of the form
Ph2PX1 "Scheme 1#[ Bestmann and co!workers originally employed dibromotriphenylphosphorane
"prepared in situ from triphenylphosphine and bromine#\ which\ in conjunction with triethylamine
in re~uxing dichloromethane\ provided convenient access to trisubstituted ketenimines
ð57LA"607#13Ł[ The putative intermediate in this reaction is "1#\ though it is conceivable that an
imidoyl bromide is subsequently formed "see the following section#[ The reaction conditions are
compatible with a variety of substituents\ and some typical compounds prepared by the method are
listed in Table 1[ The method has also been used for making the exotic ketenimine "2# ð66TL2242Ł\
and for producing ketenimine intermediates such as "3# en route to heterocyclic systems ð74TL0536Ł[
+
O OPPh3
R1
R1 Ph3P, Br2 R1 NEt3
NHR3 NR3 • NR3
R2 R2 R2
Br–

(2)

Scheme 2

The Bestmann method lends itself to the synthesis of ketenimines bearing heteroatomic sub!
stituents on carbon[ For example\ But"Br#C1C1NBut has been obtained from the corresponding
a!bromo amide in 39) yield ð63JOC378Ł\ and C!phosphoryl ketenimines\ "EtO#1PO"R0#C1C1NR1
"R0 Me\ Ph^ R1 Et\ Ph#\ were made by the standard procedure in yields of 58Ð82) ð68CC899\
79JOC4274\ 80S0052Ł[ Bestmann and Lehnen have even succeeded in making a bis"phosphoryl# keten!
imine\ ð"EtO#1POŁ1C1C1NPh\ as a comparatively stable\ distillable liquid "76) yield# ð80TL3168Ł[
The C!sulfenyl ketenimines "R0S#R1C1C1NR2 "R0 Me\ Ph^ R1 Me\ Et\ Pri^ R2 Et\ Ph# have
been prepared in yields of 42Ð52) ð70JCS"P0#1616Ł\ and the sulfone PhSO1C"Me#1C1NEt was
also accessible in 28) yield if re~uxing 0\1!dichloroethane was used as the solvent ð80S0052Ł[
A potentially valuable modi_cation of the Bestmann procedure uses 1) cross!linked polystyrene
as a support for the phosphine ð79MI 206!92Ł[ The e}ective reagent is poly"styryldiphenylphosphine
dibromide#\ which\ when used with triethylamine in re~uxing benzene\ gave high yields "69Ð89)#
of trisubstituted ketenimines from secondary amides[ Polymeric phosphine oxide was easily
447 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Table 1 Representative ketenimines\ R0R1C1C1NR2\ prepared by dehydration of secondary amides\
R0R1CHCONHR2\ with dibromotriphenylphosphorane[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Ketenimine Method a Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 Ph1C1C1N"C5H3R# "RH\ o!Me\ p!Me# i 79Ð74 57LA"607#13
1 Ph1C1C1NBun i 53 57LA"607#13
2 R1C1C1NPh "RMe\ EtO1C# i 34\ 49 57LA"607#13
3 0\3!"Ph1C1C1N#1C5H3 i 24 63JHC522
4 H1C1CH"Me#C1C1N"p!C5H3Me# i 34 62JA4306
5 H1C1CHCH1C1N"p!C5H3Me# i Ð 71JOC2887
6 PhCH1C1NR "RMe\ c!C5H00\ Ph\ 1\3\5!C5H1Me2# ii 54Ð74 79JOC2655
7 MeCO"R#C1C1NPh "RMe\ Et\ Pri# iii 39Ð49 62TL4056
8 EtO1C"R#C1C1NPh "RMe\ Et# iii 79\ 65 62TL4056
09 NC"Me#C1C1NEt iv 10 80S0052
00 "C5Me4#1C1C1NBn i 51 81JOC251
01 Me1C1C1NSO10p!Tol i b 79TL2970\ 71TL1898
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
PPh2\ Br1\ NEt2^ solvents and temperatures are as follows] i\ CH1Cl1\ re~ux^ ii\ CCl3\ re~ux^ iii\ C5H5\ ³09>C^ iv\ ClCH1CH1Cl\ RT[
b
Characterized spectroscopically[

Ph
O Ph
CN
N N
N •
Me
• Ph
O
Ph

O O MeO2C
N
Me
(3) (4)

removed by _ltration\ after which the phosphine could be regenerated by reduction with tri!
chlorosilane[
A di}erent variation uses dichlorotriphenylphosphorane\ prepared in situ from triphenylphos!
phine and tetrachloromethane\ for generating trisubstituted "mostly triaryl# ketenimines from
amides in yields of 44Ð76) ð66ZC82Ł[ This combination of reagents has also been used for the
synthesis of imino ketenimines by formal 0\3 elimination from 2!aminoacrylamides "Equation "0##
ð61TL0408Ł[

EtO2C EtO2C
CONHBut Ph3P/CCl4, NEt3, CH2Cl2, RT • NBut
(1)
R1HN R1N
R2 R2
R1 R2 Yield (%)
Ph Me 54
Ph Ph 61
2,6-C6H3Me2 Me 69

"iii# Dehydrohalo`enation of imidoyl halides


Stevens and French introduced this frequently used method for preparing ketenimines in 0843
ð43JA3287Ł[ Imidoyl chlorides\ prepared as isolable intermediates from secondary amides and phos!
phorus pentachloride in re~uxing benzene\ undergo dehydrochlorination when treated with tri!
ethylamine "Scheme 2#[ An apparent limitation is dimerization of the products\ which is promoted
by triethylammonium hydrochloride formed as a by!product[ However\ the relatively mild con!
ditions are conducive to the formation of rather sensitive ketenimines "e[g[\ trialkyl ketenimines\ cf[
Table 2\ entry 1#[ Other workers have used this method\ occasionally varying the chlorinating agent
or the base\ for preparing both trisubstituted ketenimines and C\N!disubstituted ketenimines\ and
a representative selection of accessible compounds and reaction conditions is shown in Table 2[ The
Ketenimines 448
last entry records a unique attempt to prepare an N!alkoxy ketenimine\ Ph"Me#C1C1NOEt^ the
highly unstable 0!azaallene rearranged to 1!ethoxy!1!phenylpropanenitrile ð81BAU1928Ł[

O Cl
PCl5, C6H6 NEt3
R1 R3
R1 R1
NHR3 NR3 • N
R2 R2 R2

Scheme 3

The imidoyl chloride method is suitable for the preparation of ketenimines bearing chiral sub!
stituents on nitrogen^ for example\ compounds "4#Ð"8# were obtained from secondary amides via
imidoyl chlorides in yields of 61Ð099) ð74CPB1220\ 74CPB3580Ł[ More unusual ketenimines include
the penicillin derivatives "09a# and "09b#\ prepared in a 8 ] 0 ratio "69) yield# from an epimeric
mixture of the corresponding imidoyl chlorides ð63TL0404Ł[ The 5!deutero analogue of "09a# was
accessible from the imidoyl chloride on treatment with triethylamine and deuterium chloride
ð63TL0404Ł[ Similar reactions have been demonstrated for cephalosporins ð65CC405\ 66GEP"O#1617773Ł[
By contrast\ treatment of penicillin derivatives such as "00# with phosphorus pentachloride and
pyridine in benzene gave the ketenimine "01# directly^ no intermediate imidoyl chloride was detected
"Equation "1## ð66TL2720Ł[

Et
R2
• N R2
R1 • N
R1
(5) (6)
R1 R2 R1 R2
H Ph Me Ph
Me Ph Et Ph
Et Ph H2C=CHCH2 Ph
CH2=CHCH2 Ph Et o-C6H4OMe
Et o-C6H4OMe

OMe Ph
• N
Ph R Ph
Et H
• N • N
Et Et
(7) (8) (9)
R = Me, Pri, Bn

Ph Ph
• N H • N H
S S
6
N N
O O
CO2CH2O2 CBut CO2CH2O2CBut
(10a) (10b)

Ph Ph
H H H
N • N
S PCl5, pyridine, C6H6, 5 °C S
PhO2C PhO2C (2)
O N 85% N
O O
O O
O NO2 O NO2

(11) (12)
459 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Table 2 Representative ketenimines\ R0R1C1C1NR2\ prepared from secondary amides\ R0R1CHCONHR2\
via imidoyl chlorides\ R0R1CHC"Cl#1NR2[

Entry Ketenimine Methoda Yield Ref.


(%)
Ph
1 • NBun i, then ii 69 54JA4398
Ph
Et
2 • NBun i, then iii 57 54JA4398
Bun

3 • N(C6H4R) (R = o-Me, p-OMe, p-Me) i, then iv 58–70 54JA4398


66LA(700)32
Pri
4 i, then iii 39 72JOC2364
• NPh

5 • N(C6H3-2,6-Me2) i, then iii 61 74JHC241

Ph
6 • NPri (R = H, D, Me) i, then iii 34–50 80JCS(P2)579
R
BnMe2C
7 • NR (R = Bun, Bus) i, then v 85, 61 81CB3751

BnMe2C
81CB3751
8 • N(C6H4R) (R = H, p-Me, p-F, p-Cl, p-Br, i, then v 22–87
84T893

p-OMe, p-NO2, p-CN, o-F, o-OMe, o-NO2, o-CN)


p-C6H4R
9 • NPri (R = H, Me) i, then v 54–65 81CB3751
Pri
Ar
10 • NBun (Ar = p-C6H4OMe, i, then v 34–48 81CB3751
Pri C6H3-3-NO2-4-OMe)

11 • N(C6H3-2,6-Me2) i, then vi 47 84JOC2200

But
12 i, then iii 54–64 86CB3411
• N(p-C6H4R) (R = H, Me, OMe, Cl, NO2)
C6Me5
13 • NCHPh2 vii 30 92JOC362
C6Me5
O N(c-C6H11)

14 N i, then viii b 80TL3081

O
Ph
15 • NOEt i, then ix c 92BAU2039

a i, PCl /C H , reflux; ii, Et N/Et O, RT; iii, Et N/C H , reflux; iv, Et N/C H Me, 110 °C; v, Et N/Et O, reflux; vi, KOBut/THF, 0 °C;
5 6 6 3 2 3 6 6 3 6 5 3 2
vii, SOCl2/pyridine, RT; viii Et3N, CHCl3, reflux; ix, NaH, 18-crown-6, THF, reflux. b Not reported. c Ph(Me)C(OEt)CN was isolated (58%).

Ketenimine formation from imidoyl halides other than imidoyl chlorides is rare[ Elimination of
hydrogen ~uoride from imidoyl ~uorides with powdered potassium hydroxide in ether has been
used for preparing bis"tri~uoromethyl# ketenimines\ "F2C#1C1C1NR "Raryl\ alkyl\ cycloalkyl#\
in yields of 47Ð89) ð62BAU0639Ł[ The preparation of the ketene hydrazone "F2C#1C1C1NNMe1
Ketenimines 450
by this method "34) yield# has also been claimed ð62BAU0639Ł[ Imidoyl bromides are the presumed
intermediates in the rearrangementÐelimination reaction to be described in Section 2[06[0[1[1"i#
below[

"iv# Dechlorination of a!chloro imidoyl chlorides


As long ago as 0896\ Staudinger failed in his attempts to prepare ketenimines "referred to by him
as {imenes|# by dechlorinating a!chloro imidoyl chlorides with zinc metal ð96LA"245#44\ 19CB61Ł[ Over
34 years later\ the transformation was successfully accomplished by Stevens and French ð42JA546Ł[
The substrates\ prepared by treating secondary a!chloro amides with phosphorus pentachloride in
boiling benzene\ were dechlorinated with sodium iodide in re~uxing acetone "Scheme 3#[ The
limited range of ketenimines prepared in this way included N!"p!tolyl#diphenylketenimine "72[4)#
ð42JA546Ł\ N!methyldiphenylketenimine "35)# and its corresponding N!"n!butyl# homologue
ð43JA3287Ł\ and N!isopropyldiphenylketenimine "43)# ð54JOC2607Ł[ The comparatively mild\ neu!
tral conditions lend themselves to the preparation of ketenimines that are susceptible to dimerization[

O Cl
R1 R3
R1 PCl5, C6H6, heat R1 NaI, Me2CO, heat
NHR3 NR3 • N
R2 R2 R2
Cl Cl

Scheme 4

Few improvements to the original reaction conditions have been reported[ Lithium amalgam in
ether o}ers advantages over sodium iodide in acetone for preparing the bis"ketenimine# "02# from
the corresponding bis"dichloro# precursor "50) versus 12) yield# ð54JOC2607Ł[ Various triaryl
ketenimines\ including N!"p!nitrophenyl#diphenylketenimine\ have been obtained from a!chloro
imidoyl chlorides in yields of 46Ð80) by dechlorination with copper powder in re~uxing benzene
ð58JCED397Ł[ Ethylmagnesium bromide is the reagent in the unique dehalogenation shown in
Equation "2# ð68LA72Ł[

Me Me
N EtMgBr, Et2O N
–106 °C to –60 °C But
But + But (3)
Cl • NMe
Br Br
22% 66%

Cl Cl

• •
N N
Cl Cl
(13)

"v# Eliminations from thioamides and their derivatives


Ketenimines have been prepared from secondary thioamides by formal elimination of hydrogen
sul_de upon treatment with mercuric oxide ð51AG"E#401\ 69BCJ0763Ł[ Eliminations from sulfone!
substituted thioamides\ "EtSO1#1CHCSNHR\ have been more reliably accomplished with
diisopropylcarbodiimide and acetyl chloride^ the reaction a}orded stable bis"ethanesulfonyl#
ketenimines\ "EtSO1#1C1C1NR "RMe\ Pri\ Ph#\ in yields of 42Ð76) ð55CB2052Ł[ Mitsunobu
conditions "diethyl azodicarboxylate and triphenylphosphine# have been used for inducing elim!
ination from N!aryldiphenylthioacetamides\ Ph1CHCSNHAr\ but the ketenimines Ph1C1C1NAr
proved to be di.cult to separate from by!products ð60BCJ0251Ł[ For formal 0\3 elimination from
451 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
2!aminothioacrylamides "Equation "3##\ both diisopropylcarbodiimide:acetyl chloride andN!methyl!
benzimidoyl chloride have been explored as activating agents^ in most cases\ the unstable imino
ketenimines were immediately treated with aniline to give amidines\ the yields of which "38Ð70)#
indicated that the elimination step was\ in general\ e.cient ð79CB1498Ł[
Y

R S R
PriN • NPri/AcCl, NEt3, CH2Cl2,
Cl • N
H
X N N Y or NMe, CH2Cl2 X N
H Ph
(4)
X X

X = H, Me; Y = H, Cl, OMe; R = Ph, CO2Et

A useful large!scale synthesis of N!phenyl!C\C!bis"ethoxycarbonyl#ketenimine "69) yield# by


reaction of the thioamide "03# with DMF and phosgene followed by triethylamine "Scheme 4# has
been reported in the patent literature ð53GEP0055660\ 54MI 206!90Ł[ This reaction\ carried out on a
1 M scale and presumably proceeding via an imidoyl chloride\ was less e.ciently performed with
thionyl chloride "45) yield#[ Related compounds prepared by this route included the naphthalene!
based bis"ketenimine# "04# ð53GEP0055660\ 54MI 206!90Ł[
S Cl
COCl2, DMF, C6H6 NEt3
EtO2C
EtO2C EtO2C
NHPh NPh • NPh
CO2Et CO2Et EtO2C

(14) Scheme 5

CO2Et

• CO2Et
N

N
EtO2C •

CO2Et
(15)

The reaction of imino thioesters with organometallic reagents produced ketones by a pathway in
which ketenimines have been postulated as intermediates ð77BSF772Ł[ When the silylated imino
thioether "05# was treated with n!butyllithium and one equivalent of allyl bromide "present to
intercept the expelled methanethiolate anion#\ the disubstituted ketenimine "06# "RH# was isolated
in a remarkable 72) yield via an N!lithiated enamine "Scheme 5# ð80JCS"P0#2278\ 80PS"48#030Ł[ With
two equivalents of base and of haloalkane\ compound "06# "RH# apparently underwent C!
lithiation followed by alkylation^ the ketenimines "06# "RMe\ Et\ Bn\ allyl\ crotyl# were obtained
in 44Ð63) yields[ Alternative but related routes to less stable ketenimines "characterized only by
low!temperature IR and 02C NMR spectroscopy# involved "i# ~ash vacuum thermolysis of the N!
silyl enamine "07#\ which yielded N!phenyl!C!methylketenimine after expulsion of TMS!SMe\ and
"ii# direct ~ash vacuum thermolysis of the imino thioether "05#\ which gave N!phenylketenimine
itself ð80PS030Ł[

"vi# Miscellaneous 0\1 eliminations


Heating the imino ether "08# with excess methyllithium in ether\ or with t!butyllithium in hexane\
gave a high "but unspeci_ed# yield of the N\C!bis"t!butyl#ketenimine "19# "Scheme 6# ð68AG"E#677Ł[
Ketenimines 452
Ph i, BunLi, THF, –78 °C to 5 °C TMS
N
ii, RX • NPh
TMS
SMe R
(16) (17)
R = Me, Et, Bn, allyl, crotyl
Scheme 6

TMS Ph
N

SMe
(18)

The same product was formed in moderate yield by sequential treatment of N!"t!butyl#!2\2!di!
methylbutyramide "10# with n!butyllithium\ benzenesulfonyl chloride\ and again n!butyllithium
ð68AG"E#677Ł[ The synthesis of 0\2!diketones from N!phenylacrylimidates and Grignard reagents
probably also involves ketenimine intermediates that result from conjugate addition followed by an
elimination akin to that shown in Scheme 6 ð74CC0662Ł[
But i, BunLi
N MeLi, Et2O, or But O
ButLi, hexane ii, PhSO2Cl
But • NBut But
OMe iii, BunLi NHBut
(20)
(19) (21)
Scheme 7

a!Cyano enamines "11# underwent elimination of hydrogen cyanide when treated with methyl!
magnesium iodide in ether^ trialkyl ketenimines were isolated in yields of 16Ð50) ð67JOC1569Ł[
Yields were improved to 44Ð77) when methyllithium was used as the base ð71OPP102Ł[ Imidoyl
cyanides "12#\ which are structural isomers of "11#\ can be prepared by N!chlorination:
dehydrochlorination of a!aminonitriles^ they lose hydrogen cyanide when passed in the gaseous
phase over solid potassium t!butoxide heated to 009>C ð76JOC0036Ł[ The products\ C!unsubstituted!
and C!monomethyl!N!alkyl ketenimines\ were isolated "59Ð54) yields# by condensation on a cold
_nger\ and were stable for several days in solution[
R3
HN N R2
R1 R1
CN CN
R2
(22) (23)
R1, R2 = Me, Et; R3 = Pri, But R1, R2 = H, Me

Thiolesters of N!monoalkyl a!amino thiocarboxylic acids may be dehydrated to C!alkylthio


ketenimines with phosphonic acid dichlorides\ RP"O#Cl1\ and triethylamine ð66JOU0878Ł[ From
BunSC"1O#CH1NHBun\ for example\ BunSCH1C1NBun was prepared in 34) yield[

2[06[0[1[1 By elimination reactions accompanied by skeletal rearrangement


In these reactions\ a substituent on the central carbon atom migrates to nitrogen[ The elimination
process may follow the migration\ or the two processes may be synchronous[

"i# From oximes


When treated with dibromotriphenylphosphorane and triethylamine\ the oximes of acetophenone
and desoxybenzoin underwent sequential Beckmann rearrangement and elimination ð56JOC2453Ł[
The ketenimines Ph"R#C1C1NPh "RH\ Ph# were formed in 34) and 64) yields\ respectively\
perhaps via imidoyl bromides "cf[ Section 2[06[0[1[0"iii##[ Similar transformations have been
453 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
accomplished with methanesulfonyl chloride and triethylamine^ the initially formed oxime sulfonates
underwent base!induced elimination in toluene at 099>C to give ketenimines\ including the trialkyl
ketenimine Me1C1C1NPri\ in yields of 79Ð84) ð57AG"E#293Ł[
An interesting application of the Beckmann route\ shown in Scheme 7\ involves rearrangement
of the cycloheptanone oxime "13# with triphenylphosphine and tetrachloromethane ð70CL416Ł[
Elimination of hydrogen chloride from the intermediate imidoyl chloride "14# with triethylamine
produced the eight!membered cyclic ketenimine "15# in 43) yield[ There are two chirality elements
in this strained compound^ furthermore\ con_gurational inversion of the heterocumulene system
was slow enough on the NMR time!scale to permit the observation of two distinct diastereomers\
which at ambient temperature occur in the ratio 1[6 ] 0[ The barrier to interconversion is approxi!
mately 08 kcal mol−0 "79 kJ mol−0#[ This is the only example to date of observable axial dissymmetry
in a ketenimine system[

Bn N OH Bn Cl Bn
PPh3, CCl4, NEt3 •
Bn 80 °C N N
54%
Bn Bn
(24) (25) (26)

Scheme 8

"ii# From vinyl azides


The thermal or photochemical decomposition of vinyl azides is rarely an e.cient process for
forming ketenimines ð75JOC2065Ł[ Azirines or rearranged nitriles are usually the dominant products[
When the formation of ketenimines does occur\ it is by a Curtius!like rearrangement in which a
substituent on the central carbon migrates to the adjacent nitrogen with concomitant\ or perhaps
prior\ expulsion of nitrogen "Scheme 8#[ Furthermore\ most ketenimines prepared by this route are
highly unstable ones whose formation has been deduced only from spectroscopic data or after
trapping with nucleophiles[ Thus\ vapour phase pyrolysis of a!azidoalkenes\ H1C1C"R#N2\ gave
no more than about 4) of the ketenimines H1C1C1NR "RPh\ o!Tol\ Bun# together with other
products ð51JOC2446Ł\ while photolysis of b!azidoacrylates "16# yielded product mixtures containing
½14) of the ketenimine "17# "Equation "4## ð55JOC2896Ł[ Ketenimine formation is promoted by
stabilizing groups\ as in the case of thermolysis of "NC#1C1CHN2\ from which the tetra!
methylammonium salt of dicyanoketenimine\ "NC#1C1C1NH\ could even be isolated on heating
at 59Ð69>C in aqueous acetone ð56AG"E#848Ł[ The formation of other trappable or isolable ket!
enimines from vinyl azides is illustrated in Scheme 09 ð69CB0871\ 64BCJ1780\ 77JOC568Ł[ The arch!
etypical ketenimine H1C1C1NH has been detected spectroscopically at low temperatures amongst
the thermolysis or photolysis products of vinyl azide itself ð77T3336Ł or of a vinyl azide precursor
ð78T148Ł[

R R
• N
+
:N N N

R
R

N :N:

Scheme 9
EtO2C C6H6, hν EtO2C EtO2C Me
(253 nm)
+ • N (5)
R
R N3 93% N R
(27) 3:1 (28)
Ketenimines 454

EtO2C R E tO2C EtO2C NHR


EtOH, ∆
• NR
60–84%
NC N3 NC NC OEt
R = H, Me, Ph

Et Et Et
c-C6H12, hν • NH CN
(EtO)2P N3
+
(EtO)2P (EtO)2P
O O O
30% 7%

EtO2C C6H4-p-NO2 KN3, MeCN, RT EtO2C C6H4-p-NO2 EtO2C C6H4-p-NO2


+ • N
EtO2C Br EtO2C N3 EtO2C
15 : 85

Scheme 10

The related photochemical decomposition of aryl azides via singlet nitrenes and thence ring
expansion to unstable but trappable cyclic ketenimines such as "18# "Scheme 00# has been reviewed
ð81MI 206!90Ł[ The much slower ring expansion of 1\5!di~uorinated phenyl azides during laser ~ash
photolysis suggests that ready interception of the nitrenes may make the compounds useful as
photoa.nity labels ð82MI 206!90Ł[
: :

N3 N N

(29)
Scheme 11

2[06[0[1[2 From alkanenitriles\ their a!anions or their a!radicals

"i# Tautomerism of alkanenitriles


Alkanenitriles "29a# bearing at least one hydrogen atom a to the C2N functional group can in
principle exist in equilibrium with ketenimine tautomers "29b#\ the relative importance of the latter
depending on the nature of substituents R0 and R1 "Scheme 01# ðB!69MI 206!90Ł[ Strongly electron!
withdrawing groups favour the 0!azaallene\ formally at least because they stabilize the zwitterionic
canonical form "29c# by resonance[ For instance\ Arndt and Loewe speculated in 0827 on the
existence of the ketenimine tautomer of bis"p!toluenesulfonyl#acetonitrile "29b# "R0 R1 
p!MeC5H3SO1# in solution ð27CB0516Ł[ A similar stable tautomer of dinitroacetonitrile is also feas!
ible ð51T68Ł[ Concrete evidence for a discrete ketenimine tautomer was subsequently provided
for tricyanomethane "cyanoform\ "29b# "R0 R1 CN## ð52JOC106Ł[ Mobile substituents other
than hydrogen may also migrate to give a preferred ketenimine isomer\ as in the quantitative re!
arrangement at 049>C of trimethyl isocyanide\ TMS!NC\ via trimethylsilylacetonitrile\ to tris
"trimethylsilyl#ketenimine\ "TMS#1C1C1N!TMS ð69JOM"14#274Ł[ In less favorable cases\ nitrileÐ
ketenimine interconversion can be stimulated by using unusual conditions\ as in the formation of
H1C1C1NH by reaction of acetonitrile with excited argon atoms at 03 K ð68CPH046Ł^ or in the
production at 0 K of the carbene ]C1C1C1NH from cyanoacetylene in a microwave spectrometer
with a pulsed discharge nozzle ð82MI 206!91Ł[ Finally\ ynamines\ too\ can participate in tautomeric
455 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
equilibria\ especially when the alkanenitrile has the general formula RCH1CN ð65T0338Ł[ The
photochemically induced interconversion shown in Scheme 02 represents a rare instance of a proven
transformation of ynamine\ via ketenimine\ to an alkanenitrile ð69CC778Ł[

R1 R1 R1
– +
N • NH NH
R2 R2 R2
(30a) (30b) (30c)

Scheme 12

hν (254 nm)
c-C6H12, 96 h
Ph NMe2 • NMe N
Ph Ph

Scheme 13

"ii# Direct alkylation of alkanenitriles


Early work by Arndt and co!workers showed that reaction of the tosyl!substituted cyanoacetic
ester "20# with diazomethane at −49>C gave a mixture of the ketenimine "21# and the C!methylated
product "22# "Equation "5## ð25LA"410#84Ł[ Dijkstra and Backer broadened the scope of this
reaction to include the synthesis of other reasonably stable sulfone!substituted ketenimines\
MeSO1"R#C1C1NMe "RMeSO1\ 69)^ EtO1C\ 26)^ PhSO1\ 16)#\ from the corresponding
sulfonylacetonitriles ð43RTC464Ł[

CO2Me CO2Me CO2Me


CH2N2, Et2O, –50 °C
p-Tol-SO2 p-Tol-SO2 + p-Tol-SO2 (6)
CN • CN
NMe
(31) (32) (33)

In the reaction shown in Scheme 03\ direct alkylation of nitriles by the t!butyl cation yields
nitrilium ions "23# that are subsequently deprotonated with organic bases "triethylamine or N!"t!
butyl#!N?\N?!pentamethyleneisobutyramidine# to give N!"t!butyl# ketenimines in fair yields
ð77JOC07Ł[ This mild procedure provides access to the C\C!disubstituted ketenimines
R1C1C1NBut"RPh\ 62)^ RMe\ 4)#\ the C!monosubstituted ketenimines RCH1C1NBut
"RMe\ Et\ Prn\ Bun\ Ph\ CO1Et\ vinyl\ 29Ð79)#\ the very labile ClCH1C1NBut "19)#\ and the
C!unsubstituted compound H1C1C1NBut "14)#\ reputedly the smallest member of the ketenimine
family to be isolated on a preparative scale[

ButCl, FeCl3 i, base, –80 °C


R1 R1 R1
CH2Cl2, 0 °C + ii, NaOH
N NBut FeCl4– • NBut
R2 R2 R2
(34)

Scheme 14

"iii# Reaction of a!deprotonated alkanenitriles with electrophiles


The cyano group is capable of stabilizing a carbanion by mesomerism "Equation "6##[ There is
some spectroscopic evidence that ion pairs with lithium as the counterion exist as N!lithio rather
than C!lithio salts ð75AG"E#262\ 81JOC0839Ł^ and unequivocal crystallographic studies provide _rm
evidence for N!lithiated {ketenimines|\ for example in the lithiated dimer "24# ð75AG"E#262Ł and the
quasi!dianion complex "25# ð78AG"E#0281Ł[ Although the anions are ambident nucleophiles\ reaction
Ketenimines 456
with electrophiles usually occurs at carbon unless steric or electronic factors direct the reaction
towards nitrogen[

R1 R1
– N • N– (7)
R2 R2

Me2N NMe2 Me2N NMe2


Ph Li H Ph Li
Pri
• N N • • N N
Li Li Pri
H Ph H
Me2N NMe2 Me2N NMe2

(35) (36)

An early example of the sterically controlled N!alkylation of cyano!stabilized carbanions involved


treatment of t!butylacetonitrile with sodium amide followed by isopropyl iodide to give the ket!
enimine ButCH1C1NPri as the sole product "45)# ð59JA762Ł[ Mixtures of C! and N!alkylated
products were obtained in other investigations of this synthetically limited reaction ð59JA762\ 50JOC34\
79T664Ł\ for example in the competing N! and C!methylthiomethylation shown in Equation "7#
ð71T416Ł[ N!Acylation is even rarer^ for example\ reaction between the anion of di!t!butylaceto!
nitrile and benzoyl chloride or methyl chloroformate produced "But#1C1C1NCOPh and
"But#1C1C1NCO1Me in yields of 70) and 53)\ respectively ð89CB1228Ł[ A similar reaction with
0!chlorothioformimidates\ ðRN1C"SMe#ClŁ\ gave unstable but spectroscopically detectable
N!imidoyl ketenimines such as "26# ð74JOC660Ł[ There is but a single report of N!halogenation] the
action of bromine on the sodium salt of cyanoform yielded crystalline "NC#1C1C1NBr in 79)
yield ð60JOU302Ł[ A rare base!induced prototropic shift has been reported for the conversion of
aroylmalononitriles into ArCO"CN#C1C1NH ð52CR"145#1308Ł[ The putative ferrocenyl ketenimine
"27#\ supposedly obtained by protonation of the anion prepared from ferrocenylacetonitrile and
methylmagnesium chloride ð57TL3196Ł\ was subsequently shown to be the dimeric product "28# of a
Thorpe condensation ð60TL2256Ł[ Finally\ the curious reaction shown in Scheme 04 illustrates two
di}erent aspects of the nitrile group of "39# as a ketenimine precursor\ and contains a rare example
of the intermediacy of one ketenimine in the synthesis of another ð64CR"C#40Ł[

R1 CO2Me MeSCH2Cl, THF–CH2Cl2 R1 CO2Me R1 CO2Me


RT or reflux
NC – Na+ NC + NC (8)
R2 CN R2 • SMe R2 CN SMe
N

R1 R2 Yield
Ph Ph 60%(20:80)
Ph Me 65%(25:75)
Ph Et 55%(30:70)
Bn Bn 85%(32:68)

CO2Me CN
R1
• NR2 •
Fe NH Fe NH2 Fe
N
SMe
(37) (38) (39)
R1 = 2,4,6-C6H2Me3, R2 = But
R1 = Ph2C(Me), R2 = 2,6-C6H3Me2

Silylation on nitrogen represents the most generally useful way of exploiting a!anions of alkane!
nitriles as precursors for ketenimines[ For example\ trimethylsilylation of the acetonitrile anion has
been shown to yield the remarkably stable C\C\N!tris"trimethylsilyl#ketenimine "30# ð45JA1163Ł\ not
457 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
PPh3
+ N
N N PPh3
Ph Ph Ph N
• Ph Ph
Ph Ph •
PPh3, Br2, NEt3 Br– (40), NEt3
Ph

O O O O O N O
N N 76% O O
N
Me Me Me
Me
(40)

Scheme 15

via a trianion as was once thought ð52AG"E#506Ł\ but by sequential deprotonation and progressive
silylation ð60JA0603Ł[ The speci_c case shown in Scheme 05 also demonstrates the concurrent
formation of a trisilyl ynamine "31#\ which rearranged quantitatively to the ketenimine "30# on
heating at 059>C ð60JA0603Ł[ In silylation\ as in alkylation\ steric factors play a signi_cant role in
swinging the reaction towards N!silyl ketenimines rather than a!C!silyl alkanenitriles ð81JOC0839Ł[
Variations in the nature of the substituents on the acetonitrile framework\ in the base\ and in the
silylating agent have been explored\ and Table 3 gives an indication of some of these variations[
The silylation of cyanohydrin anions "entries 01 and 02# is particularly interesting because it provides
access to ketenimines with oxygen substituents on the carbon terminus ð81JOC0191Ł[

160 °C

i, 3ButLi, Et2O, –78 °C


TMS TMS TMS
ii, TMS-Cl, THF
MeCN TMS N + • N
TMS TMS
(42) 20:80 (41)

Scheme 16

Ketenimines bearing transition metal substituents on nitrogen may be prepared by treating salts
of cyanoform with suitable metal complexes\ followed by ligand exchange if necessary[ Spectro!
scopic studies "especially IR# have provided good evidence for C0N s bonding in the follow!
ing keteniminato complexes] "NC#1C1C1NM"PR2#"NO#1 "MCo\ Ni^ RPh\ c!C5H00#
ð55ZAAC"233#174Ł^ "NC#1C1C1NFe"CO#1Cp and "NC#1C1C1NM"CO#4−NEt3¦ "MCr\ Mo\
W# ð56JOM"7#436Ł^ trans!"NC#1C1C1NPt"H#"PPh2#1\ cis!"NC#1C1C1NPt"X#"PPh2#1 "XCl\ Et#\
and "NC#1C1C1NIr"CO#"L#"PPh2#1 "LSO1\ TCNE\ fumaronitrile#\ amongst othersð61JOM"28#106Ł^
trans!"NC#1C1C1NM"CO#"PPh2#1 "MIr\ Rh# ð61JOM"28#106\ 62CB1033Ł^ "NC#1C1C1NM
"CO#2"PPh2#1 "MMn\ Re# and polymeric "ðNCŁ1C1C1NMðCOŁ2#n ð62CB1033Ł[ A similar reaction
has been demonstrated with some main group metals\ and the complexes "NC#1C1C1NSnPh2\
"NC#1C1C1NPbPh2 and "NC#1C1C1NTlPh1 have been characterized by IR spectroscopy
ð56ZAAC"243#58Ł[ Reaction of methyl cyanoacetate with hydroxoplatinum complexes\ Pt"OH#PhL1
"Lphosphine#\ similarly gave keteniminato complexes of the form MeO1CCH1C1NPtPhL1
ð79JOM"088#008Ł[

"iv# Perkow reaction of a!haloalkanenitriles


Chlorodiphenylacetonitrile and triethyl phosphite react under aprotic conditions to give the N!
phosphoryl ketenimine "32# "80) yield# ð54JA4957Ł[ In this unusual variant of the Perkow reaction\
abstraction of chlorine by the phosphite apparently yields the ion pairs "33# and "34#\ the second of
which decomposes to the observed product "32# and chloroethane "Scheme 06#[
Competing Perkow reactions take place when a!halo!a!cyanoesters are treated with trimethyl or
triethyl phosphite[ Both N!phosphoryl ketenimines "35# and vinyl phosphates "36# have been
detected by NMR spectroscopy ð58TL498\ 61T3320Ł[ Only the former products were formed when
triisopropyl phosphite was used[ The three examples illustrated "Equation "8## represent the only
crystalline ketenimines in the 19 or so cases studied[ Replacing the phosphite with sodium arene!
Ketenimines 458

Table 3 Synthesis of silylated ketenimines by silylation of the anions of alkanenitriles[

Entry R1R2CHCN Conditions Product Yield Ref.


(%)

TMS TMS
1 MeCN NaN(TMS)2, TMS-Cl • N 63AG(E)617
TMS
Ph TMS
2 PhCH2CN NaN(TMS)2, TMS-Cl • N 63AG(E)617
TMS
Ph TMS
3 Ph2CHCN NaN(TMS) 2, TMS-Cl • N 63AG(E)617
Ph
RMe2Si SiMe2R
• N
4 MeCN ButLi, RMe2SiCl RMe2Si (R = H, Me, But) 71JA1714

+ RMe2Si N(SiMe2R)2
Ph SiR3
5 PhCH2CN NaH/DME, R3SiCl • N 83–94 73CR(C)1803
Ph (R = Me, Et, Prn)
ButMe2Si SiButMe2
• N
6 RCH2CN LDA, ButMe2SiCl 98–100 74SC127
R
(R = Me, Et, Prn, n-C6H13, H2C=CH)

Ph Ph SiButMe2
7 CN LDA, ButMe • N 74JOC2799
2SiCl 73–94
R R 83JOC4087
(R = Me, Et, Pri, n-C8H17, Ph)
TMS TMS TMS
8 MeCN TMS-OTf, Et3N • N + TMS CN 73 (56:43) 77S636
TMS TMS
(Pri)3Si Si(Pri)3
9 CN LDA, (Pri)3SiCl 77 87TL397
• N

But But TMS


10 CN LDA, TMS-Cl • N 68 90CB2339
But But

CN TMS
11 LDA, TMS-Cl • N 86 90CB2339

TMS-O TMS
12 TMS-OCH2CN LDA, TMS-Cl • N 75 92JOC1202
TMS
TMS-O TMS-O TMS
13 CN LDA, TMS-Cl • N 81 92JOC1202
Pri Pri
C6Me5 C6Me5 SiButMe2
14 CN BunLi/TMEDA, • N 92JOC1940
C6Me5 ButMe2SiCl C6Me5
469 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
O
Ph P(OEt)3 Ph Ph Ph P(OEt)2
C6H6, ∆ + +

Cl N N ClP(OEt)3 • NP(OEt)3 Cl– • N
91%
Ph Ph Ph Ph
(44) (45) (43)

Scheme 17

sul_nates gave yet another variation of the Perkow reaction\ a}ording the N!sulfonyl ketenimines
"37# in yields of ½39) ð61CR"C#0298Ł[
O
P(OMe)2
O
R1 CO2Et R1 CO2Et R1 OEt
P(OMe)3, C6H6, 0 °C
R2 CN R2 + R2 (9)
NC Br NC • O NC
N P(OMe)2 N
(46) (47)
R1 = R2 = Ph 85 15
R1 = R2 = Bn 80 20
R1 = Ph, R2 = Me 70 30

R1 CO2Et
R2 R1, R2 = Ph, Bn
NC • Ar = Ph, p-Tol
N SO2Ar

(48)

"v# Conju`ate addition to a\b!unsaturated nitriles


The addition of nucleophiles to the activated C1C bond of vinyl cyanides formally produces an
intermediate carbanion a to the nitrile group[ When the reaction is quenched by adding electrophiles\
the products isolated are usually those obtained from 0\1 addition^ 0\3 addition\ which results in
the formation of ketenimines\ is encountered only in exceptional cases involving highly activated
substrates such as 0\0!dicyanoalkenes[ The reaction partners that participate in conjugate addition
are so diverse that mechanisms more complex than the simple one postulated here must frequently
be implicated[ The route comes into its own for producing ketenimines bearing main group metallic
"Pb\ Sn# or metalloidal "Si\ Ge\ As\ B# substituents on nitrogen[ Table 4 shows the range of unusual
ketenimines accessible from alkylidenemalononitriles[ Related reactions leading to a bis"ketenimine#
and a tris"ketenimine# are illustrated in Scheme 07 ð58CC856\ 61JCS"D#676Ł[ Many of the N!metallated
ketenimines are nonvolatile solids^ the water!stable tin compounds\ in particular\ probably consist
of polymeric chains containing _ve!coordinate tin associated with the nitrile group of an adjacent
molecule as shown in "38# ð57LA"607#0\ 61JCS"D#676Ł[
Formal 0\3 addition of transition metal complexes of the form X0MLn to the very reactive
acceptor TCNE has been used for making keteniminato complexes of the general formula
ðX"NC#1CŁC"CN#1C1NMLn[ The following complexes were prepared in this way] ðBn"NC#1CŁ
C"CN#1C1NFe"CO#1Cp "31) yield# ð69JOM"10#P10Ł^ ðMe1C1CHCH1"CN#1CŁC"CN#1C1NMo
"CO#1ðP"OPh#2ŁCp "04) yield# ð63ICA44Ł^ and the polymeric uraniumÐketeniminato complexes
ðX"CN#1CŁC"CN#1C1NUCp2 "XCl\ Me\ Bun\ Ph# ð76ICA164Ł[ The organouranium precursors
RUCp2 "RMe\ Bun# even add to tetracyanoquinodimethane\ yielding keteniminato complexes
"49# ð76ICA164Ł[ Another unusual N!metalloketenimine "40#\ prepared in 69) yield by the addition
of IrH"CO#1"PPh2#1 to excess TCNE\ has been characterized by single!crystal x!ray crystallography
ð69JA2378\ 60JA1280\ 61JOM"24#392Ł[
A fascinating application of the conjugate addition route occurred during the thermolysis of the
Table 4 Synthesis of representative ketenimines by 0\3 addition of X0MLn to alkylidenemalonodinitriles\ R0R1C1C"CN#1[
*
Ð ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Substrate Rea`ents\ conditions Product Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 RCH1C"CN#1 HPb"Bun#2\ C5H5\ 9Ð19>C RCH1C"CN#1C1NPb"Bun#2 "RMe\ Ph\ 1!furyl# a 55TL2304
1 RCH1C"CN#1 HSnEt2\ C5H5\ 39Ð59>C RCH1C"CN#1C1NSnEt2 "RMe\ Ph\ 1!furyl\ EtO\ p!Tol\ PhCH1CH\ etc[# a 55AG"E#403\
57LA"607#0
2 R"Me#C1C"CN#1 HSnEt2\ C5H5\ 39Ð59>C RMeCHC"CN#1C1NSnEt2 "RMe\ Ph\ p!C5H3Cl# a 57LA"607#0
3 "CH1#4C1C"CN#1 HSnEt2\ Me1CHCN\ 39>C c!C5H00CHC"CN#1C1NSnEt2 a 57LA"607#0
4 "F2C#1C1C"CN#1 X0TMS\ RT ðX"F2C#1CŁC"CN#1C1N!TMS "XH\ MeS\ PhNH# ½099 61JCS"D#676
5 "F2C#1C1C"CN#1 "MeS#1SiMe1\ RT ðMeS"F2C#1CŁC"CN#1C1N"SiMe1SMe# ½099 61JCS"D#676
6 61JCS"D#676
Ketenimines

"F2C#1C1C"CN#1 X0SnMe2\ RT ðX"F2C#1CŁC"CN#1C1NSnMe2 "XMeS\ Me1As# ½099


7 "F2C#1C1C"CN#1 Me1N0Ge"Bun#2\ RT ðMe1N"F2C#1CŁC"CN#1C1NGe"Bun#2 ½099 61JCS"D#676
8 "F2C#1C1C"CN#1 Ph1BCl\ RT ðCl"F2C#1CŁC"CN#1C1NBPh1 ½099 61JCS"D#676
t t b
09 "p!C5H3X#CH1C"CN#1 Bu Hg0TMS\ C5H5:CH1Cl1\ RT ð"p!C5H3X#Bu CHŁC"CN#1C1N!TMS "XH\ Me\ OMe\ Cl\ NO1\ NMe1# ×84 63JOM"60#28
00 PhCH1C"CN#1 ButHg0SnR2\ RT ðPh"But#CHŁC"CN#1C1NSnR2 ½099 63JOM"60#28
01 PhCH1C"CN#1 ButHg0TMS:EtO0SnEt2\ RT ðPh"But#CHŁC"CN#1C1NSnEt2 85 63JOM"60#28
02 PhCH1C"CN#1 "But#1Hg\ then Et2SnH\ RT ðPh"But#CHŁC"CN#1C1NSnEt2 ×84b 63JOM"60#28
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a b
Spectroscopic characterization only[ Based on recovered mercury^ ketenimine was obtained as a viscous oil[
460
461 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
F3C SMe F3C NMe2
CF3 Me2N CF3 CF3
N • F3C CN F 3C N •
CN Et2Sn(SMe)2 B(NMe2)3 CN
Et2Sn • N B
CN CN
N • F3C CN NC N •
CF3 CF3
F3C SMe F3C NMe2
Scheme 18

F 3C SMe
CF3
F3C SMe
• R CF3
N Sn N
• R
R R
N Sn N
R R
(49)

N NC CN
NC • UCp3

NC • Ph3P PPh3
N Ir CO
NC CN
NC CN NC
R CN

(50) (51)

thiadiazoline "41# in the presence of 0\1!dicyano!0\1!bis"tri~uoromethyl#ethene ð78H"18#1958Ł[ The


intermediate thiocarbonyl ylide "42# acted as a nucleophile towards the acceptor\ and a mixture of
the seven!membered cyclic ketenimine "43# and the thiolane "44# "67 ] 11# was formed via the
zwitterion "45# "Scheme 08#[ The moisture!sensitive but crystalline ketenimine is noteworthy in
containing the smallest known isolable ring to incorporate a heterocumulene system[ The related
cyclic ketenimine "46#\ recently prepared in a similar manner in 75) yield\ has been characterized
by x!ray crystallography ð89JOC0301Ł[ The C1C1N bond is bent to about 053>\ and considerable
torsion about the 0!azaallene system is apparent[

F 3C CN
S
O CDCl3 O F3C CN O
N S+ S+ CN
N 40 °C CH2– CF3

CF3
NC
(52) (53) (56)
CF3
S S
O O
CN + CF3
N CF3 CN

F3 C CN
(54) 78:22 (55)
Scheme 19
Ketenimines 462

S CF3

CN
N
• CF3
(57)

"vi# Reactions mediated by cyanoalkyl radicals


Thermal decomposition of 1\1?!azoisobutyronitrile "AIBN# gave ambident radical fragments that
dimerized to form tetramethylsuccinodinitrile "47# and a small quantity "½04)# of the isolable
ketenimine "48#\ which itself rearranged to "47# "Equation "09## ð44JA2609\ 48JA3767Ł[ Cage e}ects
appear to govern the recombination of the radical fragments ð59JA4283Ł[ The ketenimine "48# has
been prepared somewhat more e.ciently from AIBN "24) yield# upon photolysis in benzene at
254 nm ð51JOC3942Ł[ Similarly\ 0\0?!azocyanocyclohexane "59# was thermally decomposed to the
ketenimine "50# ð59JA4275Ł[
CN
CN
∆ or hν
N N NC CN + (10)
–N2 • N
NC (58) (59)

NC
• N
N N
NC
CN
(60) (61)

Oxidation of hindered a!cyano acetic esters with iodobenzene diacetate in methanol gave good
yields of the dimeric ketenimines "51#\ apparently by way of the hypervalent N!iodo ketenimine
intermediates "52# "Scheme 19# ð66TL2238Ł[ These unusual intermediates are assumed to decompose
homolytically\ after which the radical fragments couple to give varying amounts of C\N! and C\C!
dimers depending on the solvent used[ IR spectroscopy provided good evidence for the intermediacy
of the N!iodo ketenimine "53# when the oxidation was performed on the cyanosuccinimide substrate
"54# "RH#^ spectroscopic evidence for the iodine!linked bis"ketenimine# "55# was adduced in the
case of the analogous N!methyl compound "54# "RMe# ð66TL2242Ł[

X MeO2C R
MeO2C PhI(OAc)2 MeO2C I Ph MeO2C CN
MeOH, 20 °C –PhI
CN • N • N
R R R
(63) (62)

R Yield (%)
Ph2C(CN) 85
Bn2C(CN) 70
Ph2CH 20
Scheme 20

Ph N OAc Ph CN Ph N N Ph
• I • I •
Ph Ph Ph Ph
Ph Ph
O O O O O O O O
N N N N
H R Me Me
(64) (65) (66)
463 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
"vii# Reactions of a!cyanoalkylsulfonium salts
Ketenimines have been prepared from a!cyanoalkylsulfonium salts by two distinct pathways
according to whether the reaction partner acts as a nucleophile or as a base[ For example\ the
reaction shown in Scheme 10 commences with nucleophilic attack of the stabilized enolate "56# on
the sulfonium salt "57#[ Homolysis of the unstable sulfurane intermediate "58# produced radicals\
the recombination of which gave various dimeric products that included the ketenimine "69#
ð67TL2608Ł[ By contrast\ the same sulfonium salt "57# was converted into the sulfonium ylide
"60# on treatment with triethylamine^ rapid ð1\2Ł!sigmatropic rearrangement yielded both the N!
"methylthiomethyl# ketenimine "61# and the nitrile "62#\ the latter the result of an e}ective SommeletÐ
Hauser rearrangement "Scheme 11# ð67TL2608Ł[ Although the action of n!butyllithium on "57#
resulted in products of the nucleophilic pathway only\ other sulfonium salts have given ketenimines
from the ð1\2Ł!sigmatropic pathway with both triethylamine and n!butyllithium ð67CC163Ł[ The
reaction of stabilized enolates "63# with S\S!dialkylsuccinimidosulfonium salts "64# was more
complex\ and depended on many variables\ including time\ temperature\ and the nature of the
counterion[ Scheme 12 shows examples in which products from both the homolytic and the sig!
matropic pathways were formed simultaneously ð71T416Ł[ Other succinimidosulfonium salts "e[g[\
"65# and "66## also gave rise to unusual ketenimines "e[g[\ "67#Ð"79## ð71T416Ł\ but in general the
reactions described here were too sensitive to conditions to be synthetically useful[

MeO2C Ph MeO2C
+ THF, 20 °C
Na+ – CN + p-Tol SMe2 PF6–
NC Ph NC
(67) (68)

Ph CO2Me
Ph CN
NC Ph CN
MeO2C Me Ph
Ph • Ph
p-Tol S CO2Me N CO2Me
NC Me CN
CN
(69) (70)
Scheme 21

CO2Me
MeO2C MeO2C Me MeO2C SMe
+ NEt3 + CN
p-Tol SMe2 PF6– p-Tol S • N +
SMe
NC CH2– p-Tol
N
(68)
(71) (72) (73)
Scheme 22

2[06[0[1[3 By cleavage of heterocyclic compounds

"i# Cleava`e of aziridines


0\2\2!Triaryl!1\1!dichloroaziridines\ formed by the addition of dichlorocarbene to aromatic
imines\ are easily cleaved on treatment with sodium iodide in acetone to give ketenimines in yields
of 72Ð86)\ probably via a!chloro imidoyl chlorides "Equation "00## ð55TL796\ 56BCJ0822Ł[ The use
of zinc metal with a trace of hydrochloric acid in THF has been recommended as an alternative to
sodium iodide for preparing the bis"ketenimine# "70# "71) yield# ð65RTC043Ł[ Treatment of related
0\2!diaryl!1\1!dibromoaziridines "71# with triethylamine in acetonitrile has yielded unusual C!bromo
ketenimines "72# "54Ð75) yield#\ probably by dehydrohalogenation of intermediate a!halo imidoyl
halides "Equation "01## ð70CL0086Ł[
Ketenimines 464
O

N SMe2+
Cl–
O
R1 CO2Me (75)
NC – Na+
THF, CH2Cl2, < 0 °C
R2 CN
(74)
R1 CO2Me
R1 CO2Me
NC
NC R1 CO2Me
R2 • CO2Me
R2 • + NC + CN
N
N R2 CN SMe
R2
SMe
R1 CN
R1 R2 Yield
Ph Ph 60%(74:13:13)
Bn Bn 30%(80:20:0)
Ph Me 70%(97:3:0)
Ph Et 65%(95:5:0)

Scheme 23

O O CO2Me CO2Me CO2Me


Me R R R
+ +
N S N S • SMe • SEt • S
Et N N N
O X– O X–
(76) (77) (78) (79) (80)

Ph X N
NaI, Me2CO, reflux
N • X (11)
Ph 83–97% Ph
Cl Cl Ph
X = H, m-Cl, m-Me, p-Cl, p-Me

N N
• •
Ph Ph
Ph Ph
(81)

R1 R2 R2
N NEt3, MeCN, RT
R1
• N (12)
65–86% Br
Br Br
(82) R1, R2 = Ph, p-C6H4Cl (83)

N!Methylketenimine has been detected as the major product of the pyrolysis of N!chloro!
propylenimine at 319>C "Equation "02## ð76JSP"012#365Ł[
Cl 420 °C Me
N (13)
• N

"ii# Cleava`e of cyclic imino ethers


Meyers and co!workers have shown that deprotonation of dihydro!0\2!oxazines such as "73# with
lithium diisopropylamide "LDA# resulted in rapid ring scission to give the lithium salt of the
465 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
ketenimine "74# ð58JA4776\ 62JOC1018Ł[ The salts could also be made by the nucleophilic addition of
organometallics to 1!vinyloxazines such as "75# ð69TL3244Ł[ The lithiated ketenimine alkoxides could
be trapped with various electrophiles\ including water\ chlorotrimethylsilane\ dimethyl sulfate and
benzoyl chloride "Scheme 13#[ The cleavage reaction also applies to oxazoline "76#\ from which the
ketenimine "77# was prepared in 54) yield "Equation "03## ð62JOC1018Ł[ Under controlled
conditions\ deprotonation and silylation of the oxazoline "78# gave the silylated ketenimine "89#
"Equation "04## ð77AG"E#0431Ł[

O LiO MeO
LDA, THF, 0 °C (MeO)2SO2
N N N
35%
• •
(84)

(85)
PhCOCl
TMS-Cl 80%
30%

TMS-O PhCO2

N N
• •

Scheme 24

N
Ph
(86)

TMS-O
O LDA, THF, 0 °C
then TMS-Cl
N (14)
N
65%

(87) (88)

TMS-O
3BunLi, 3TMS-Cl
O Et2O, –55 °C
N (15)
N •

TMS TMS
(89) (90)

"iii# Cleava`e of isoxazoles and isoxazolium salts


Irradiation of triphenylisoxazole at 143 nm or 299 nm gave a 39) yield of the isolable C!acyl
ketenimine "80# by a pathway in which 0\1 migration of a phenyl group on to nitrogen probably
Ketenimines 466
occurred through nitrene intermediates "Scheme 14# ð55CC578Ł[ A similar reaction on the bicyclic
isoxazole "81# yielded the interesting but unstable ketenimine "82# "Scheme 15#\ which could also be
generated by base!induced elimination from the isoxazolium salt "83# "cf[ below# ð65JOC02Ł[

Ph Ph
O
Ph hν (254 nm) Ph Ph
O O
40% • NPh
N N:
Ph

:
Ph Ph
(91)
Scheme 25

NEt3, CH2Cl2
hν (254 nm), –77 °C –77 °C
O
O
O • N + I–
N
NMe Me
(92) (93) (94)
Scheme 26

Woodward|s {{reagent K|| "84#\ a zwitterionic isoxazolium salt\ was introduced in 0850 ð50JA0909Ł
as the prototype of a group of useful reagents for peptide synthesis ð69T0668Ł[ The reactivity of
these isoxazolium salts was ascribed to initial deprotonation at the unsubstituted 2 position followed
by ring cleavage to form C!acyl ketenimines "85# ð50JA0996Ł\ after which interception by a car!
boxylate yielded enol esters ð57JA0260Ł suitably activated for further attack "Scheme 16#[ Subsequent
investigations by Woodward and co!workers provided _rm spectroscopic evidence for acyl ket!
enimine intermediates ð55T"S#304Ł[ For preparative purposes\ this route is limited to relatively
stable compounds such as N!"t!butyl#benzoylketenimine and the corresponding acetyl compound\
prepared in 59) and 69Ð79) yields\ respectively\ from isoxazolium perchlorates and triethylamine
ð55JA2058Ł[ Isolable C!acyl ketenimines "86#Ð"099# have also been obtained from 3\4!disubstituted
isoxazolium perchlorates or tetra~uoroborates ð58JOC2340\ 69T0668Ł[ The rather unstable C!acyl
ketenimine "85# from reagent K itself has recently been prepared in acetonitrile solution by reaction
of the salt with triethylamine ð75JA4432Ł^ other sensitive acyl ketenimines have been intercepted by
the addition of cuprates ð78SC0928Ł[ Several isoxazolium salts bearing heteroatomic substituents have
also been shown to yield ketenimines on treatment with base[ These include the 4!aminoisoxazolium
precursor "090# of the ketenimineÐamide "091# "Equation "05## ð63CB02Ł^ and 3!azido isoxazolium
salts "092#\ from which the unique C!azido ketenimines "093#\ stable only below −59>C\ were
obtained "Scheme 17# ð72CC637Ł[

SO3– SO3–

base

O O
N+ – N+
Et Et
(95)
R
SO3– SO3– SO3– O
O– O RCO2H O
NHEt
+ • NEt
N Et
(96) O

Scheme 27
467 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
O O O
R1
• NR3 • NR • NR
R2
(97) R1 = H, R2 = Ph, R3 = But, CH(Me)Ph (99) R = Me, Et (100) R = Me, Et
(98) R1 = Ph, R2 = Me, R3 = Bn, Ph, But

NH2
O
Ph NaOH, CCl4 H2N
O (16)
• NMe
N + Cl–
Ph
Me
(101) (102)

R
R ButOH, HClO4 O
NEt3, CH2Cl2
0 °C N3 –90 °C R
N3 O
O – • NBut
17–50% N + ClO4
N N3
But
(103) (104)
R = Me, Ph
Scheme 28

Isoxazolium salts may or may not be involved in the rapid transformation "Scheme 18# of N!"1!
benzoylstyryl#hydroxylamine "094a# and its hydroxyisoxazolidine tautomer "094b# to C!benzoyl!
C\N!diphenylketenimine "095#\ which was detected by IR spectroscopy ð67JCS"P0#0002Ł[ The trans!
formation can be preparatively useful\ as in the synthesis of the N!"t!butyl# analogue of "095# in
50) yield from t!butylhydroxylamine and 0\1!diphenylpropane!0\2!dione in chloroform at room
temperature ð77JOC3886Ł[
PhCO
EtOH, 5–10 °C
CHO + PhNHOH
Ph
Ph OH
Ph O PhCO
OH Ph
O • NPh
N N
Ph Ph Ph
Ph
(106)
(105a) (105b)
Scheme 29

"iv# Cleava`e of other _ve!membered rin`s containin` two heteroatoms


N!Acyl ketenimines have been detected by IR spectroscopy amongst the pyrolysis products of
azlactones ð79AG"E#453Ł[ They are formally formed by a cheletropic reaction in which carbon
monoxide is expelled "Equation "06##[

O O R i, 600 °C, 10–4 torr O


ii, collect at –196 °C
Ph R (17)
N
Ph • N

R = Me, Ph

Treatment of isoxazol!4!ones with base yielded spectroscopically detectable ketenimine!C!car!


boxylate salts that spontaneously cyclized to four!membered rings ð65JA5925Ł[ In the speci_c case
shown in Equation "07#\ the moisture!sensitive potassium salt "096# could actually be isolated
ð66H"6#136Ł[ Gas phase ~ow thermolysis at 699>C of a di}erent type of isoxazol!4!one\ for example
Ketenimines 468
"097#\ has been used for forming the simple unstable ketenimines H1C1C1NR "RH\ Me\ Ph#
for spectroscopic studies ð79AG"E#619\ 78JCS"P1#0730Ł[
O
i, KOBut, THF
ii, hexane
K+ –O
2C
Ph (18)
O • NBut
N Ph
But
(107)

O
RHN
N
H
(108)

4!Iminothiazolines "098#\ formed by oxidative cyclization of 2!aminocrotonic thioamides with


bromine\ underwent a formal cheletropic loss of sulfur on treatment with tributylphosphine
"Scheme 29#[ The products\ imino ketenimines "009#\ were occasionally isolable ð63CB491Ł\ but in
most cases cyclized to 0\1!dihydropyrimidines ð70CB425Ł[ The 0\1!dithiole!2!imine "000# underwent
a similar reaction\ but in this case the unstable thioacyl ketenimine intermediate "001# was trapped
by addition of secondary amines "Scheme 20# ð75CB051Ł[

R3 R2
R1
Bu3P, CH2Cl2 R1 N
R1 N R2
N
NR4 41–87% N
S • NR4
R2 R4 R3
R3
(109) (110)

Scheme 30

p-MeOC6H4
Bu3P, CH2Cl2, 0 °C • N-p-Tol HNEt2
p-MeOC6H4
S S 66%
S N-p-Tol
(111) (112)

NH-p-Tol

p-MeOC6H4 NEt2
S

Scheme 31

"v# Cleava`e of triazoles


0!Vinylbenzotriazoles undergo ~ash vacuum pyrolysis at 499Ð699>C with expulsion of nitrogen
gas^ N!phenyl ketenimines are the primary products\ but indoles are the major products at higher
temperatures ð77JCS"P1#0960Ł[ However\ in only one reported case "Equation "08## has a ketenimine
actually been isolated ð89JCS"P0#374Ł[ The photolysis of N!phenyl!0\1\2!triazoles yielded ketenimines
by a di}erent path involving migration of substituents from C!4 to C!3 "Equation "19##*perhaps a
Wol} rearrangement of a carbene intermediate ð57JA0812Ł[ Hydrogen migration was e.cient and
gave a high yield of ketenimine\ but the less mobile 4!phenyl group resulted in signi_cant amounts
of the indole "002# being formed as well[ In a related case\ transient N!cyanotriazoles "003# underwent
spontaneous ring!opening to N!cyano a!diazo imines "004#\ which could in turn be photolyzed to
spectroscopically detectable N!cyano ketenimines "005# "Scheme 21# ð68AG"E#219\ 79TL898Ł[
479 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
N
i, 600 °C, 10–2 torr
N
ii, trap at –78°C
N • NPh (19)

R1
R1 N hν (450 W mercury lamp)
R1
N C6H6
• NPh + R2 (20)
N
R2 N
R2 Ph
Ph
(113)
R1 R2 Yield(%)
Ph Ph 60 (1:1)
H Ph 70 (3:1)
Ph H 85 (40:1)

N N2
N MeO CN
CN hν, MeOH R CN
N
N N • N
R
R CN R
(114) (115) (116)
R = H, Me, Et, 2-furyl, 2-thienyl
Scheme 32

Loss of nitrogen on gentle warming of the lithiated triazole "006# resulted in the formation of the
lithiated ketenimine "007#\ which showed a strong IR absorption at 1039 cm−0 ð60CJC0681Ł[ This
salt was trapped with iodomethane to give the ketenimine "008# and ketenimine dimer in 34) and
08) yields\ respectively "Scheme 22#[ Other electrophiles reacted at nitrogen to give ynamine
products[ However\ with aldehydes\ reaction presumably occurred at carbon\ since acrylamides
were obtained in good yield on work!up ð63LA0544Ł[

Ph BunLi, THF Ph Li Ph MeI, THF


20 °C, –N2 –60 °C Ph
–20 °C
• NPh • NPh
N N N N Li 45%
N Ph N Ph
(117) (118) (119)

Scheme 33

2[06[0[1[4 From other ketenimines


The most useful application of this route involves replacing the silyl substituent in N!trimethylsilyl
ketenimines with other electrophiles[ For example\ N!stannylation\ N!germylation\ and N!plum!
bylation proceeded exothermically and quantitatively on treating the ketenimine "019# with tri!
alkylmetal alkoxides or acetates "Equation "10## ð63JOM"60#28Ł[ The silyl substituent has also been
replaced by an acyl group "Equation "11## ð89CB1228Ł[ In a related example "Equation "12##\ an
N!stannyl ketenimine has been converted into an N!nitroso ketenimine with nitrosyl chloride
ð69TL0046Ł[

But But
Ph TMS + R3MX Ph MR3
(21)
• N – TMS-X • N
NC NC
(120)
M = Ge, Sn, Pb
X = OMe, OAc
Ketenimines 470

But TMS PhCOCl, CH2Cl2, RT But COPh


• N • N (22)
52%
But But

NC Sn(But)3 NC NO
NOCl, THF, –20 °C
• N • N (23)
Ph Ph
Ph Ph

Keteniminylidene phosphoranes "010# "see Section 2[06[1[0# are able to react with various
electrophiles to yield both transient and stable ketenimines[ Examples are shown in Scheme 23
ð63AG"E#362\ 64AG"E#42Ł[ Photolysis of hexakis"t!butyl#cyclotrisilane "011# in the presence of two
equivalents of tris"trimethylsilyl#ketenimine initiated a surprising sequence of cycloadditionÐcyclo!
reversion processes\ at the end of which the novel ketenimine "012# was produced in 61) yield
"Equation "13## ð81JOM"312#218Ł[
R1
R1 R1 NPh
R2
O + Ph3P • • NPh • • NPh
R2 (121) R2
PhN PPh3
R1 R2 Yield (%)
p-C6H4NO2 H 64
Ph COPh 58
2,2'-C6H4–C6H4 75

MeO2C MeO2C PPh3


MeO2C CO2Me PPh3
+
70% MeO2C •
Ph3P • • NPh MeO2C • •
NPh NPh
(121)
Scheme 34

TMS TMS (But)2Si Si(But)2 hν, n-C6H14, RT


2 • N +
Si(But)2 72%
TMS
(122) TMS
TMS TMS N
(But)2Si • + TMS Si(But)2 (24)
TMS • N
TMS
(123)

Ketenimine!bearing penicillins\ for example "013#\ have been converted into a!methoxy ket!
enimines by addition of chlorine followed by treatment with lithium methoxide in methanol
ð66TL2720Ł[ The putative intermediate is the a!chloroimidoyl chloride "014#\ which undergoes 0\3
elimination of hydrogen chloride followed by SN? displacement of the chloride ion by methoxide
"Scheme 24#[ That similar products\ for example "015#\ can be prepared in the cephalosporin
series from preformed a!chloroimidoyl chlorides "Equation "14## lends credence to the proposed
mechanism ð65TL0296Ł[ Direct replacement of hydrogen by the methylthio group occurred on
treatment of "016# with methyl methanethiosulfonate "Equation "15## ð66TL2720Ł[

Ph H H MeO H
N S N S
LiOMe, MeOH, –78 °C •
Br N Ph N (25)
O 60% O
CO2CHPh2 CO2CHPh2
(126)
471 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
H H H H
Cl
N S p-TolO2C N S
• Cl2
S N N
O Cl O
CO2p-Tol CO2CH2-p-C6H4NO2 S CO2CH2-p-C6H4NO2
(124) (125)

LiOMe, MeOH, –70 °C

CO2p-Tol
MeO H
N S H
• N
S S S
N 39%
O Cl
N
CO2p-Tol CO2CH2-p-C6H4NO2 O
CO2CH2-p-C6H4NO2

Scheme 35

H H MeS H
N S N S
MeS-SO2Me, DMF, K2CO3, 0 °C
• • (26)
Ph N Ph N
28%
O O
PhO2C CO2Bn PhO2C CO2Bn
(127)

C\N!Diphenylketenimine has been deprotonated at carbon with potassium t!butoxide in THF at


−59>C\ and the resulting metallated ketenimine has been trapped with aldehydes ð63LA0544Ł[
Another unique transformation\ shown in Equation "16#\ involves an additionÐelimination process
between methyllithium and a C!bromo ketenimine ð68LA72Ł[

But MeLi, Et2O-hexane, –20 °C But


• NBut • NBut (27)
52%
Br

2[06[0[1[5 By miscellaneous pericyclic processes


The retro DielsÐAlder reaction of 3!iminocyclohexenes at high temperatures has a certain limited
utility when the smallest members of the ketenimine family are required[ The ~ash vacuum ther!
molyses illustrated in Scheme 25 have been used for making H1C1C1NH\ a ketenimine so
transient that it cannot even be trapped\ though it can be characterized by IR\ microwave\ and UV
photoelectron spectroscopy at very low temperature ð72CC127\ 73CPL336\ 78JCS"F1#630Ł[ The rather
more stable N!methyl analog has similarly been made by the cycloreversions shown in Scheme 26
ð67TL352\ 75JCR"S#077Ł[ The parent ketenimine H1C1C1NH has also been prepared "along with its
tautomer acetonitrile\ acrylonitrile\ and formaldehyde# by vacuum pyrolysis of 2!hydroxy!
propionitrile at 799Ð0099>C by the formal pericyclic process shown in Scheme 27 ð73CPL336\ 77JA0226\
89JA2668Ł[
C!Dienyl ketenimines "017# may be generated from cyclohexadienimines "018# by the photo!
chemically induced electrocyclic process shown in Equation "17# ð67AG"E#354Ł[ The products were
stable at room temperature in THF for several days\ but slowly reverted to imines[ N!Acyl C!dienyl
ketenimines "029#\ formed in the same way\ could be detected by IR spectroscopy at 66 K\ above
which they underwent an intramolecular DielsÐAlder reaction followed by elimination of acetic acid
to give bicyclic oxazines "020# "Scheme 28# ð68TL1014Ł[ A four!electron photochemical electrocyclic
process "Equation "18## underlies the synthesis of the unique ketene!ketenimine "021#\ which could
be kept for several days at −67>C in the dark ð60CC476Ł[
Ketenimines 472

850 °C, 10–3 torr • NH 850 °C, 10–3 torr

+ MeCN + Diene

NH NH
850 °C, 10–3 torr

NH
Scheme 36

650 °C, 10–5 torr 650 °C, 10–5 torr


• NMe
75% + EtCN (20%) 20% + HC≡CNMe2 (80%)

NMe NMe2
Scheme 37

O H 800 –1100 °C O
CN
H2O + N + • NH MeCN
0.1–1 Pa H H
Scheme 38

Ph Ph

Ph hν R1 (28)
Ph
R1 ∆ Ph
N Ph •
R2 NR2
(129) (128)
R1 = Me, OMe, OAc
R2 = Me, Pri

Ph Ph Ph
Ph Ph
hν (mercury lamp), OAc
Ph C6H6 RT, –HOAc O
Ph Ph •
OAc 17–55%
N N R
N R
Ph
O R
O
(130) (131)
R = Me, Ph, p-C6H4X
(X = Me, OMe, Cl, NO2)
Scheme 39

Ph O O
hν (500 W mercury lamp) Ph •
C6H6
(29)
Ph N ∆ Ph •
N

(132)
473 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Ketenimines are formed as end products of the sequence of pericyclic reactions shown in Scheme
39 ð62TL2616Ł[ Equilibrium at room temperature in THF favors the azetidinoð2\1!bŁpyridine inter!
mediates "022#\ but heating in benzene induces sequential valence tautomerism\ ð0\2Ł!sigmatropic
alkyl shift\ and _nally a cycloreversion to give pyrroles "023# and the spectroscopically characterized
ketenimines "024#[ These compounds were subsequently hydrolyzed to amides\ the high isolated
yields of which "71Ð82)# re~ect the e.ciency of the entire process[
R
CO2Me R MeO2C Ph MeO2C
Ph N
N cycloaddition R N R Ph R
+ R +
MeO2C • N
MeO2C N
CO2Me Ph N Ph Ph
(134) 87–92% (135) 82–93%
( as amide)
electrocyclic cycloeversion
reaction with 1,2-H shift
R R R
Ph electrocyclic
N reaction N Ph N
MeO2C [1,3]-sigmatropic MeO2C Ph
MeO2C R C6H6, ∆ shift of R
R
THF, RT
N MeO2C MeO2C
MeO2C 73–91% N N
Ph Ph Ph R

(133) R = c-C6H11, c-C12H23, But

Scheme 40

Flash vacuum pyrolysis of the substituted 1\2!dihydropyrrole!1\2!dione "025# produced the C!


acyl ketenimine "026# via an imidoylketene "027# "Scheme 30# ð81CC376Ł[ The ketenimine\ char!
acterized by 0H and 02C NMR spectroscopy at −59>C\ was stable up to about 9>C\ above which
irreversible changes took place[ The corresponding N!phenyl ketenimine was less long!lived because
its imidoyl ketenimine isomer was rapidly and quantitatively converted into the quinolinone "028#[
Related interconversions have been probed for the comparatively stable N!adamantyl ketenimine
"039# ð81CC377Ł[ Flash vacuum pyrolysis of the Meldrum|s acid derivative "030# below 599>C also
initiated a sequence of pericyclic reactions resulting in the formation of the C!acyl ketenimine "026#
"Scheme 30# ð81CC376Ł[ Above 599>C\ however\ elimination of methanethiol gave another transient
but detectable ketenimine\ "031#\ from which the unusual cumulene "032#\ e}ectively an imine of
carbon suboxide\ was produced ð81CC0460Ł[ The higher!order heterocumulenes "032# and "033# were
also formed by pyrolysis of other heterocyclic precursors\ as shown in Scheme 31 ð81CC0460Ł[
These spectroscopically characterizable compounds\ amongst a mere handful of known ketenimines
containing more than two cumulated double bonds\ were intercepted with dimethylamine to give
yet another group of labile but characterizable ketenimines "034#[

2[06[0[2 Ketenimines from "CC¦N# Precursors

2[06[0[2[0 From ketenes "or related precursors# and iminophosphoranes "or related precursors#
The synthesis of ketenimines by the reaction of iminotriphenylphosphoranes "Ph2P1NR# with
ketenes was pioneered by Staudinger and co!workers in the early 0819s ð19CB61\ 10HCA776Ł[ Com!
pounds prepared included R1C1C1NPh "RPh\ Me\ EtO1C#\ Ph1C1C1NMe\ and
H1C1C1NPh\ the last only being stable at low temperatures[ The analogous compound
H1C1C1NEt polymerized too rapidly to be isolated[ Unfortunately\ yields of the products were
not speci_ed[
The reaction remained undeveloped for almost half a century until it was used to prepare
"CF2#1C1C1NBut "Table 5\ entry 0# ð58TL4068Ł[ A more important revival by Singer and co!
workers demonstrated that thermally labile C\C!diphenyl ketenimines\ including the _rst known
ketenimine bearing a chiral auxiliary on nitrogen\ were accessible under mild conditions and in fair
to good yields "29Ð74)# "Table 5\ entries 1Ð5# ð63CC851\ 63JOC2679\ 66JA1511Ł[ In this work\ general
reaction conditions were also clari_ed] the iminophosphoranes "generated in situ from dibromo!
Ketenimines 474
SMe
400–600 °C, 10–4 mbar SMe [1,3]-sigmatropic SMe
–CO shift of SMe
N O
O Me • NMe
• NMe
O O
(136) (138) (137)
[1,3]-sigmatropic
shift of H
O
400–600 °C, 10–4 mbar
O SMe SMe
–CO2, –Me2CO
O • •
O NHMe NHMe
O
(141)

>600 °C, 10–4 mbar


–MeSH

O
O –CO2, –Me2CO
• NMe O • • • NMe
O (143)
O
(142)
Scheme 41

SMe

Ph N
O N H

O

(139) (140)

O O O O
R 500–700 °C RN 310 °C
O 10–4 mbar
O NMe2
10–4 mbar •
NH NH • NMe
N –Me2NH
O O NHR
O N O N O O

O
Me2NH
O • • • NR Me2N
• NR
(143) R = Me (145)
(144) R = Ph

Scheme 42

triphenylphosphorane\ a primary amine and base# reacted with ketene components "prepared in
advance or generated in situ from appropriate precursors# in inert solvents at temperatures no higher
than room temperature[ The diverse range of ketenimines subsequently made by this method
includes N!acyl ketenimines "entries 6 and 7# ð65M426\ 89CB1228Ł\ an N!cyanoalkyl ketenimine
"entry 8# ð65M426Ł\ C!phosphoryl ketenimines "entry 09# ð79JGU34Ł\ and a ~uorenylideneketenimine
"entry 01# ð70CB2640Ł[
No physical or spectroscopic data were furnished for the N!vinyl ketenimines "035#\ isolated as
viscous oils after short!column chromatography in a reaction sequence that ultimately yielded
~uorenoð1\2\3!i\ jŁisoquinolines "Scheme 32# ð89CC718\ 80JOC3997Ł[ It is of interest that an adduct
"compound "036## en route to N!vinyl ketenimines has recently been isolated from a related reaction
"Scheme 33# ð81LA04Ł[
475 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Table 5 Ketenimines\ R0R1C1C1NR2\ prepared by the reaction of ketenes\ R0R1C1C1O\ with imino!
phosphoranes\ Ph2P1NR2[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Ketenimine Conditions Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 "CF2#1C1C1NBut a 58TL4068
1 Ph1C1C1NR "RBn\ But# Et1O\ 9>C 54Ð79 63JOC2679
2 Ph1C1C1NCHPh1 Et1O\ 9>C b 63JOC2679
3 "S#!"−#!Ph1C1C1NCH"Ph#"Me# Et1O\ 9>C 79Ð74 63JOC2679\ 63CC851
4 Ph1C1C1NCH1"p!C5H3R# "RCl\ Me\ OMe\ Ph# Et1O\ 9>C 29Ð59 66JA1511
5 Ph1C1C1NCH1R "R0! and 1!naphthyl# Et1O\ 9>C 29Ð59 66JA1511
6 Ph1C1C1NCOR "RPh\ "E#!PhCH1CH# C5H5\ RT a\ c 65M426
7 Ph1C1C1NCOR "ROMe\ OEt# CH1Cl1\ 9>C 65\ 79 89CB1228
8 Ph1C1C1NC"CN#Me1 C5H5\ RT a\ c 65M426\ 73T782
09 "EtO#1POC"Ph#1C1NR "RMe\ Ph# THF\ 9>C 29\ 59 79JGU34
00 Ph1C1C1NCH1!TMS C5H5\ re~ux 82 73JOC1577
01 "1\1?!C5H30C5H3#C1C1N"p!C5H3Br# Et1O\ 11>C 59 70CB2640
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a b c
Yield not given[ Rearranges to Ph1CHPh1CCN[ Characterized spectroscopically[

OH
R2 OMe
OMe MeO CO2Et
• O O R2
O R1 R3
toluene, RT 150 °C N

R2 = Ph R3
R2
Ph3P • N CO2Et H
N CO2Et
R3
R1 = H, Me, Ph (146) R1
R2 = Ph, p-Tol
R3 = Et, Ph, p-Tol
Scheme 43

R
Ar Ar
• O +
R Ph3P Ph Ph
Ar –Ph3PO N
C6H6, 20 °C N
Ph3P Ph •
N R
–O
R R
R
(147)
Ar R Yield of (147) (%)
Ph Ph 77
p-C6H4Cl Ph 56

Ph 30

Scheme 44

N!Amino ketenimines "ketene hydrazones#\ notable for their rarity\ have been prepared by
Schweng and Zbiral from trimethylsilylketene and N!aziridinyl iminophosphoranes "Scheme 34#
ð65M426Ł[ The unstable products\ amongst them the unusual compound "037#\ were characterized
by IR spectroscopy[ Attempts to prepare other N!amino ketenimines from diphenylketene were
frustrated by the spontaneous decomposition of the desired products to a!amino nitriles "Scheme
35# ð65M426Ł[ A unique ketenimine azine\ Ph1C1C1N0N1CPh1\ has been prepared in 59)
yield from diphenylketene and the corresponding triphenylphosphazine ð50CB1366Ł[ Interestingly\
Staudinger had failed to isolate products from this reaction some 39 years earlier ð10HCA786Ł[
Capuano and co!workers have demonstrated that reactive ketenes\ generated in situ by a Wol}
rearrangement following the expulsion of nitrogen from 1!diazo!0\2!diketones\ may be intercepted
by iminophosphoranes "Scheme 36# ð72CB630\ 76LA072Ł[ Several of the resulting C!acyl ketenimines
"e[g[\ ArCO"Ar#C1C1N"p!Tol#\ ArPh\ p!C5H3Cl\ p!C5H3OMe# were isolated in good yield
Ketenimines 476
Ph3P N TMS
• N
N R1 • O TMS N R1

H R2 CH2Cl2 H R2
Ph Ph
R1 = R2 = H, Ph

Scheme 45

N
• N

TMS
(148)

Ph
• O Me
Ph
Me N N NC Me
CH2Cl2
N N • R Ph N
Ph3P R R = Me, 25%; Ph, 30% Ph Ph R
Ph

Scheme 46

"41Ð80)#\ while others were characterized by IR spectroscopy before conversion into various
heterocyclic products[ A similar reaction occurs with 1!diazo!2!sulfonylketones\ resulting in the
formation of C!sulfonyl ketenimines "Scheme 37# ð72CB630Ł[

N2 xylene R2 R2
100 °C, –N2 Ph3P=NR3
R1 R2 R1 R1
• •
O NR3
O O O O
Scheme 47

xylene Ph Ph
N2 100 °C, –N2 Ph3P=NAr
Ph • O • NAr
PhSO2 PhSO2 PhSO2
O
Ar Yield (%)
p-Tol 74
2,6-C6H3Me2 66

Scheme 48

Variations on the basic reaction described in this section encompass both reaction partners[ For
example\ the iminophosphorane can be replaced by the phosphoramidate anion "038#\ as reported
by Wadsworth and Emmons "Equation "29## ð51JA0205\ 53JOC1705Ł[ Ukrainian workers have similarly
prepared "EtO#1POC"Ph#1C1NR "RMe\ Ph# from sodium phosphoramidates and phos!
phorylketenes in yields of 49Ð59) ð79JGU34Ł[ Alternatively\ the ketene can be substituted by a
di}erent 0!heteroallene^ Bodeker et al[ have shown that both ketenes and ketenimines react with
N!pyridyl iminophosphorane "049# to a}ord the N!"1!pyridyl# ketenimine "040# "Equation "20##
ð79ZC100Ł[ Under the reaction conditions\ the ketenimine spontaneously dimerized to give hetero!
cyclic products[ Finally\ several ketenimines have been made by a unique method involving reaction
of bis"tri~uoromethyl#thioketene with iminosulfuranes "Equation "21## ð58USP2351378\ 61JOC0236Ł[
477 Ketenimines and P\ As\ Sb\ and Bi Analo`ues

Na+
Ph (MeOCH2)2, 20 °C Ph

• O + N • NR (30)
(EtO)2P R
Et Et
O
(149)
R Yield (%)
Ph 62
Bun 18
c-C6H11 58

N
C6H6 or
N Ph C6H3Me3, ∆ N
N + • X • (31)
Ph3P Ph Ph
Ph
(150) X = O or NPh (151)

F 3C CH2Cl2, RT F3C
• S + RN S NR • NR (32)
F 3C F3C
R Yield (%)
Me 17
Ph 38
Bun 20
But 48

2[06[0[2[1 From haloalkenes or haloalkynes and amines or amine derivatives


Most of the procedures in this section exploit the fact that tri~uoromethyl substituents on alkenes
impart pronounced electrophilic character to the double bond[ When the alkene also bears a leaving
group b to the activating substituent\ nucleophilic displacement can occur[ In particular\ amines
and amine derivatives displace the ~uoride ion from activated 0\0!di~uoroalkenes "041# to produce
imidoyl ~uorides "042# "see Section 2[06[0[1[0"iii##\ from which ketenimines "043# can be formed on
addition of base "Scheme 38#[

F3C RNH2
F3C NHR F3C
base
CF2 • NR
X X F X
(152) (153) (154)
Scheme 49

Gambaryan and co!workers were the _rst researchers to investigate the reaction between per!
~uoroisobutene "041# "XCF2# and nitrogen sources[ With the iminophosphorane Ph2P1NPh\
per~uoroisobutene gave "F2C#1C1C1NPh in 23) yield ð54BAU620Ł\ while primary amines in the
presence of triethylamine similarly yielded "F2C#1C1C1NR "RMe\ 18)^ Et\ 43)^ Ph\ 86)^
p!C5H3OMe\ 78)# ð62BAU0639Ł[ The outcome of the reaction between per~uoromethacrylic esters
"044# and aniline depended on the base used^ the intermediate imidoyl ~uoride "045# and its
enamine isomer "046# were isolated in the presence of pyridine\ but ketenimines "047# resulted when
triethylamine or powdered potassium hydroxide was present "Scheme 49# ð64BAU0163Ł[ Other
workers have shown that reaction of per~uoroisobutene with the potassium salt of ben!
zenesulfonamide gave the isolable salt "048#\ from which the imidoyl ~uoride "059# and\ ultimately\
the ketenimine "050# could be produced\ as shown in Scheme 40 ð64JFC"5#116\ 65BAU462Ł^ and that
methyl per~uoromethacrylate produced MeO1C"F2C#C1C1NMe "53) yield# on reaction with
N!methylhexamethyldisilazane ð75JOU0539Ł[
The basic process has been extended to per~uoro!1!methylpent!1!ene "051# "Scheme 41#
ð63CC023Ł[ After initial displacement of ~uoride by various amines\ the putative intermediate
~uoroalkenyl imines "052# reacted with a second equivalent of amine to give C!imino ketenimines
"053#[ However\ if aromatic amines without ortho substituents were used\ the ketenimines cyclized
to 3!arylaminoquinolines[ Reaction of "051# with t!butylamine a}orded a mixture of the two
Ketenimines 478
O H
RO2C RO2C NPh RO2C
PhNH2, Et2O RO NPh
CF2 + + • NPh
F3C base F 3C F F 3C
F 3C F
(155) R = Me, Et (156) (157) (158)
Pyridine (R = Et) 48% 41% 11%
KOH (R = Et) - - 73%
NEt3 (R = Me) - - 65%
Scheme 50

KNHSO2Ph, MeCN
F 3C –40 °C to 20 °C – HCl, CH2Cl2
CF2 (CF3)2C C NSO2Ph K+
95% F 90%
F3C
(159)

F Et3N•BF3
Et2O, 20 °C
F3C
F3C SO2Ph • NSO2Ph
N
35% F3C
CF3
(160) (161)
Scheme 51

ketenimines "053# "RBut# "34) yield# and "054# "19) yield#\ perhaps because "051# isomerizes to
per~uoro!1!methylpent!0!ene ð70JFC"06#154Ł[ An analogous reaction between the sul_de!bearing
per~uoroalkene "055# and t!butylamine yielded a mixture of the ketenimines "056# and "057# and
the imidoyl ~uoride "058# "Scheme 42#[ The tetra~uoroethene hexamer "069# reacted with primary
amines to form the expected ketenimines "060# "Scheme 43#\ but piperidine\ a secondary amine\
gave an imidoyl ~uoride "061# from which limited quantities of the ketenimines "062# and "063#
could be formed on thermolysis ð74JCS"P0#1074Ł[

F3C NR
F 3C F F3C NR
RNH2
R = But • C2F5
F3C C2F5 F2C C2F5
R = 2,6-C6H3Me2 RN
(162) (163) (164)

Scheme 52

F3C F
F
• CF2CF3
ButN
(165)

(F3C)2CFS F (F3C)2CFS F
F
F3C CF(CF3)2 F2C CF(CF3)2
(166)
ButNH2, Et2O
–50 °C to 40 °C

(F3C)2CFS NBut (F3C)2CFS F (F3C)2CFS NBut


F
+ +
• CF(CF3)2 • CF(CF3)2 ButN CF(CF3)2
ButN ButN F
(167) (168) (169)
19% 24% 19%

Scheme 53
489 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
F5C2 CF3 F5C2 CF3
F5C2 RNH2, Et2O F5C2
0 °C to reflux piperidine, Et2O, 18 °C
• NR CF2
F5C2 F5C2 52%
F3C F F3C F
(171) (170)

F5C2 CF3 F5C2 CF3


F5C2 CF3
F 5 C2 F5C2
F5C2 N
• N(CH2)3CH CH2 + • N(CH2)5F
120 °C
F5C2 F5C2
F5C2 F
F3C F F3C F
F3C F
(172) (173) (174)
11% 8%

R Yield of (171) (%)


Et 66
Ph 21
NH2 66
CH2CH2OH 57

Scheme 54

Isocyanates reacted with per~uoromethacryloyl ~uoride "064# to yield a range of cycloadducts\


amongst them the 0\2!oxazin!1!ones "065#[ Pyrolysis of these was accompanied by loss of carbon
dioxide and a ð0\2Ł!sigmatropic shift of ~uoride\ and led to ~uorinated ketenimines "066# in good
yields "Scheme 44# ð62JFC"2#80Ł[
F3C F
F3C F F F 3C
RN • O, ∆ 200 °C
F O • NR
F2C O R = Me (78%), Bun (67%) F3C
N
R O
(175) (176) + other products (177)
Scheme 55

There is but a single report of ketenimine production from activated chloroalkenes and amines
ð81PS"62#074Ł[ When the phosphorus!containing chloroalkene "067# was treated with primary amines\
ketenimines "068# were detected spectroscopically "Scheme 45#[ Only with t!butylamine\ however\
could the ketenimine be isolated "87) yield#[ In most cases\ the ketenimine added another equivalent
of amine\ thereby forming bisamino compounds "079#[
EtO O EtO O EtO O
RNH2, Et2O RNH2, Et2O
EtO P EtO P EtO P NHR
RT RT
CCl2 • NR
EtO P R = But, 98% EtO P EtO P NHR
EtO O EtO O EtO O
(178) (179) (180)

R Yield of (180) (%)


Et 93
Prn 88
–CH2CH2– 90
p-Tol 50
1,2-C6H4 84

Scheme 56

Ketenimines may also result from the reaction of amines with chloroalkynes[ For example\
perchlorobutenyne "070# reacted with branched aliphatic primary amines\ giving the unstable but
distillable ketenimines "071# or "072# in poor yield "8Ð07)# "Scheme 46# ð79CB700Ł[ Simple primary
amines RNH1 "RPrn\ Bun\ Me1CHCH1\ c!C5H00# also apparently gave ketenimines\ but their
Ketenimines 480
formation could be inferred only by hydrolysis to amides[ A more reliable reaction between chloro!
alkynes and amines used chloroethynyl phosphonates\ "RO#1POC2CCl\ as substrates ð72JGU194\
74JGU15Ł[ The reactions were performed with two equivalents of amine in dry ether at temperatures
below −4>C\ and it appears that ynamine intermediates may be involved[ The range of phos!
phorylated aldoketenimines prepared in this way is shown in Table 6[

Cl RNH2, Et2O Cl
Cl RT Cl

Cl Cl Cl NHR
(181)

Cl Cl
Cl
NR Cl Cl
Cl • Cl Cl

Cl • •
N N
(182) (183)

R Yield of (182) (%)


Pri 16
EtCH(Me) 11
But 9

Scheme 57

Table 6 Preparation of ketenimines\ R0R1POCH1C1NR2\ by


the reaction of R0R1POC2CCl with primary amines\ R2NH1
ð74JGU15Ł[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Ketenimine Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 "RO#1POCH1C1NBut "RMe\ Et\ Prn# 75Ð099
1 "R1N#1POCH1C1NBut "RMe\ Et# 82Ð099
2 "MeO#"Et1N#POCH1C1NBut 72
3 "MeO#1POCH1C1N"0!adamantyl# 84
4 "MeO#1POCH1C1N!TMS 18a
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
"Me2Si#1NNa was used as the base[

2[06[0[3 Ketenimines from "C¦CN# Precursors

2[06[0[3[0 From phosphorus ylides and isocyanates or related compounds


Staudinger and Meyer are credited with the _rst synthesis of a ketenimine\ Ph1C1C1NPh\
which they made from phenyl isocyanate and diphenylmethylenetriphenylphosphorane ð08HCA524\
19CB61Ł[ No yield was quoted\ and no e}orts were made to extend the synthesis to other ketenimines[
It was not until 0848 that Trippett and Walker showed that ketenimine formation is not the usual
outcome of reactions between phenyl isocyanate and ylides ð48JCS2763Ł[ For instance\ reaction with
the nonstabilized ylide Me1C1PPh2 stopped at the betaine stage "073# "Scheme 47#[ Furthermore\
betaines from nonstabilized ylides bearing at least one hydrogen on the methylene carbon then
rearranged to give new ylides "074#[ While reaction of nonstabilized ylides with isocyanates has
since proved to be possible "vide infra#\ it still appears that ylides containing an a hydrogen do not
give ketenimines on reaction with isocyanates[
Staudinger|s reaction remained\ with rare exceptions ð58JA5001\ 69JOC751Ł\ almost entirely un!
explored until Fro yen used it for preparing a range of ketenimines from various isocyanates
"Table 7# ð63ACS"B#475Ł[ Reaction conditions varied according to the nature of the ylide and the
method by which it was generated[ Stabilized ylides "e[g[\ entry 2# required milder conditions than
481 Ketenimines and P\ As\ Sb\ and Bi Analo`ues

R1 R2 R2 H
Ph3P=CR1R2 +
N • O PhP R1 = H
N
Ph NPh Ph3P Ph
R1R2 = H, Me
–O O
(184) (185)
Scheme 58

nonstabilized ylides "e[g[\ entry 7#\ a _nding attributed to the relative di.culty of inducing the
elimination of triphenylphosphine oxide from the betaine intermediates formed in the latter cases[
In general\ however\ yields of ketenimines were in the range 24Ð89)[ Other workers subsequently
extended the reaction to the synthesis of ~uorenylideneketenimines "entries 09 and 08# ð79BCJ1471\
78JCS"P0#1039Ł\ N!acyl ketenimines "entries 00 and 07# ð70CB0865\ 74LA1294Ł\ and vinyl ketenimines
"entries 01Ð04# ð71LA79Ł[ In many of these cases\ spectroscopic characterization alone con_rmed
the formation of the 0!azaallene system^ the ketenimines either underwent other reactions\ or were
deliberately converted into other products[ Fleeting ketenimines such as "075# and "076# could
not even be detected spectroscopically\ but underwent immediate cyclization to give a variety of
heterocyclic products ð78JCS"P0#1039Ł[ Finally\ because higher ketenimines "extended 0!aza!
cumulenes# are rare in the literature\ it is signi_cant that one of the earliest applications of the
isocyanate:ylide reaction involved the presumed intermediacy of Ph1C1C1C1C1NMe during
the reaction of Ph1C1C1C1PPh2 with methyl isocyanate ð58JA5001Ł[
Table 7 Ketenimines\ R0R1C1C1NR2\ prepared by the reaction of ylides\ R0R1C1PPh2\ with isocyanates\
O1C1NR2[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Ketenimine Conditions Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 MeO1C"Ph#C1C1NBut 092>C 81 69JOC751
1 Ph1C1C1NC"CF2#2 Et1O\ RT 61 62DOK"101#517
2 MeO1C"Me#C1C1NAr "ArPh\ p!Tol\ 0!naphthyl# C5H5\ RT 79Ð84 63ACS"B#475
3 MeO1C"Me#C1C1NR "REt\ But# C5H5\ re~ux 89 63ACS"B#475
4 PhCO"Me#C1C1NR "RPh\ Et# C5H5\ RT 89 63ACS"B#475
5 Ph1C1C1NEt C5H5\ 099>C 74 63ACS"B#475
"autoclave#
6 Ph1C1C1NR "RPh\ 0!naphthyl\ c!C5H00# C5H5\ re~ux 79Ð89 63ACS"B#475
7 Me1C1C1NAr "ArPh\ 0!naphthyl# Mesitylene\ 039>C 24Ð39 63ACS"B#475
8 EtO1C"CN#C1C1NPh C5H5\ re~ux 9 63ACS"B#475
09 "1\1?!C5H30C5H3#C1C1NR "RPh\ p!Tol\ C5H5\ re~ux 46Ð87 79BCJ1471
p!C5H3Cl\ 0!naphthyl\ c!C5H00#
00 EtO1C"Me#C1C1NCOR "RPh\ OEt# C5H5\ RT a 70CB0865
01 PhCH1CH"Me#C1C1NPrn C5H5\ RT 84 71LA79
02 PhCH1CH"Me#C1C1NAr "ArPh\ p!Tol# C5H5\ RT a 71LA79
03 PhCH1CH"Ph#C1C1NPh C5H5\ RT a 71LA79
04 PhCH1CHCH1C1NPrn C5H5\ RT a 71LA79
05 BunCO"R#C1C1NPh "RBun\ n!C4H00\ n!C5H02# C5H5\ RT a 72CB1697
06 EtO1C"Me#C1C1NR "RPh\ C"1N!xylyl#But# Toluene\ RT a 74LA1294
07 EtO1C"Me#C1C1NCSPh Toluene\ 09>C a 74LA1294
08 "1\1?!C5H30C5H3#C1C1NCH1CHPh C5H5\ re~ux 77 78JCS"P0#1039
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a
Yield not given[

N
Bn
• NPh
Ph • NPh
Ph
(186) (187)

Several variations on the basic procedure\ described above\ exist[ Phosphorus ylides other than
triphenylphosphoranes remain unexplored apart from the halophosphoranes "077#\ which reacted
Ketenimines 482
with phenyl isocyanate to a}ord C!phosphinoyl ketenimines "078# in 34) yield "Equation "22##
ð79TL2872Ł[ The HornerÐWittig reaction between anions derived from dialkyl alkylphosphonates
and phenyl isocyanate represents another successful route to ketenimines\ and some examples are
shown in Table 8 ð70JCS"P0#1616\ 75JHC486Ł[

PhN=C=O, petroleum O
But R
ether, –20 °C (But)2P
But P (33)
• NPh
X 45%
R
(188) (189)
X = Cl, Br; R = Me, Prn

Table 8 Preparation of ketenimines\ R0R1C1C1NPh\ from the reaction of phenyl isocyanate


with phosphonate anions\ "ðEtOŁ1POCR0R1#− Na¦[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Keteniminea Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 EtO1C"PhS#C1C1NPh 72 70JCS"P0#1616
1 Ph"PhS#C1C1NPh 32 70JCS"P0#1616
2 Me"PhS#C1C1NPh 9 70JCS"P0#1616
3 EtO1C"R#C1C1NPh "RPh\ Me\ Me1C1CHCH1# b 75JHC486
4 Me1C1CHCH1"MeO1C#C1C1NPh 43 75JHC486
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
a b
Formed by reacting phosphonates and isocyanate in benzene or THF in the presence of sodium hydride[ Yield not
reported\ but detected spectroscopically[

Phosphorus ylides undergo successful reaction with cumulenes other than isocyanates[ Capuano
and Djokar prepared a number of N!imidoyl ketenimines\ EtO1C"Me#C1C1NC"1NAr#Ar\ from
stabilized ylides and N!imidoyl isothiocyanates ð74LA1294Ł[ Unfortunately\ ylides were not speci_ed[
Diphenylcarbodiimide has also been reported to react with alkylidenetriphenylphosphoranes
ð69JOC1965Ł^ however\ only IR spectroscopic evidence was obtained for the otherwise well!known
product Ph1C1C1NPh[ It appears that ylides containing an a hydrogen also react with diphenyl!
carbodiimide to produce labile ketenimines\ RCH1C1NPh "RPh\ EtO1C#\ that undergo further
reaction with another equivalent of ylide ð69JOC1965Ł[

2[06[0[3[1 By alkylation of isocyanides

"i# Reaction with activated multiple bonds


Reaction of isocyanides with two equivalents of hexa~uoro!1!butyne in inert solvents a}orded
moderate "½ 29)# yields of the isolable cyclopropropenyl ketenimines "089#\ possibly by way of
the carbenes "080# "Scheme 48# ð58JA3650Ł[ The course of the reaction could be altered in alcoholic
solvents\ in which the carbene intermediates were intercepted to give imino ethers "081# in addition
to ketenimines "082# "e[g[\ reaction in methanol\ illustrated in Scheme 48# ð58JA3650\ 62JOC0208Ł[ A
reaction between aryl isocyanides and dimethyl acetylenedicarboxylate discovered by Takizawa and
co!workers probably also involves initial formation of a carbene\ which in this case was trapped by
a second equivalent of isocyanide to produce the bis"ketenimine# "083# in low yield before ultimately
yielding cyclopentene triimine hydrate "084# "Scheme 59# ð58TL2396Ł[ Aspects of both preceding
syntheses are probably involved in forming the unusual bicyclobutane!bis"ketenimine# "085# from
the reaction of t!butyl isocyanide with dimethyl acetylenedicarboxylate ð63T1442Ł[ The product
can be explained as arising from the coupling of two intermediates\ the cyclopropene!substituted
ketenimine "086# and the ketenimine!carbene "087# "Scheme 50#[
Cyclopropenes bearing electron!withdrawing substituents react with t!butyl isocyanide to a}ord
vinyl ketenimines "088#\ representative examples of which are shown in Equation "23# ð68AG"E#56\
68CB2055Ł[ Ketenimines have been postulated as intermediates in the reactions of cyclopropenones
or cyclobutanone with isocyanides ð58TL2392Ł[
483 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
F 3C
CN R , CHCl2, 2.4 bar • NR F3C CF3
F3C CF3
RT :
CF3
(191)

F 3C F3C
F3C H2, 3.4 bar, PtO2 F3C
• NR EtOH • NR

CF3 CF3
F3C F3C
(190) R Yield of (190)(%)
c-C6H11 29
Ph 33
But 35

CF3 F3C CF3


F3C CF3 MeOH, 1.7 bar OMe
RT
+ + MeO •
F3C N X N X
CN X
(192) (193)

X Yield (%)
NO2 80 (100:0)
Cl 73 (81:19)
H 94 (70:30)
Me 84 (72:28)
OMe 94 (71:29)

Scheme 59

C6H6, 0-5 °C
MeO2C CO2Me + CN Br
9%

MeO2C CO2Me
MeO2C CO2Me
• • CN-Ar
Br N N Br ArN NAr
HO NHAr

(194) (195)

Scheme 60

NBut

MeO2C CO2Me MeO2C
CO2Me

ButNC, C6H6, RT
(34)
X X
X Yield (%) (199)
– 62
CH2 82
CMe2 63
CH2CH2 53
Ketenimines 484

CO2Me
ButNC, Et2O CO2Me
–20 °C :
MeO2C
MeO2C CO2Me CO2Me +
12% • CO2Me
MeO2C ButN

NBut
(197) (198)

CO2Me
MeO2C
MeO2C CO2Me
MeO2C
CO2Me
• •
ButN NBut
(196)

Scheme 61

Reaction of two equivalents of 1\3\3!trimethylpent!1!ene with three equivalents of hydrogen


cyanide in the presence of hydro~uoric acid has been reported to a}ord the ketenimine "199# by a
complex pathway formally involving both isocyanide "190# and iminium ion "191# formation as
shown in Scheme 51 ð60JOC2331Ł[ More easily understood is an e.cient synthesis of ketenimines
from 1!acylaziridines "192# and t!butyl isocyanide in which initial ring cleavage to azomethine ylides
"193# precedes attack by the isocyanide "Scheme 52# ð64CC23Ł[

CN
But But +
i, HCN, HF, CH2Cl2 But N
CN
ii, MeSO3H, crystallize 60%
iii, KOH
(201) (202)

But
NC
But • N
N
H
(200)

Scheme 62

O Ph O
Ph ButNC, CCl4 Ph O Ph N
X + X
Ph N
N X •

Ph NBut
(203) (204)
X Yield (%)
OEt 92
NEt2 66
Scheme 63

The oddest ketenimine synthesis of all "Equation "24## involves combination of t!butyl isocyanide
and ~uorenylideneborane "194# in a 2 ] 0 ratio to give the 0\1!azaborolidine!ketenimine "195# in 40)
yield ð82CB0440Ł[ The structure of "195# has been con_rmed by x!ray crystallography[
485 Ketenimines and P\ As\ Sb\ and Bi Analo`ues

NBut
3ButNC
toluene, RT N
N B (35)
B 51% N
• But
ButN
(205) (206)

"ii# Reaction with carbenes


An early attempt to react dichlorocarbene "generated from chloroform and an alkoxide ion# with
cyclohexyl isocyanide produced no dichloroketenimine\ Cl1C1C1N"c!C5H00#\ but only dich!
loroacetimidates resulting from the capture of the reactive intermediate by the alkoxide ð53AG"E#641Ł[
Later workers also failed to isolate dihaloketenimines from the alkylation of isocyanides with
dihalocarbenes no matter how these intermediates were generated^ however\ various heterocyclic
products isolated suggest that the ketenimines were formed transiently ð64BCJ1176Ł[ It was only in
0889 that IR spectroscopic evidence was obtained for transitory dichloroketenimine intermediates\
Cl1C1C1NR\ formed from chloroform\ potassium t!butoxide\ and the isocyanides RNC "Riso!
butyl\ s!butyl\ t!butyl\ n!pentyl\ benzyl\ phenyl# ð89JOU0531Ł[
The _rst successful preparation of ketenimines from carbenes dates from 0858\ when two inde!
pendent research groups reported essentially identical procedures for preparing N!cyclohexyl!C\C!
diphenylketenimine "14Ð49) yield# by photolysis of diphenyldiazomethane in the presence of
cyclohexyl isocyanide ð58CC0266\ 58TL4982Ł[ The t!butyl analogue was similarly prepared in 39Ð49)
yield ð58TL4982Ł[ A poor thermolytic variation has since been used for making Ph1C1C1N"1\5!
xylyl#\ but other N!aryl analogues lacking ortho substituents underwent cyclizations with a second
equivalent of isocyanide ð64BCJ1176Ł[ The thermolytic route has been more successful for making
MeO1C"Ph#C1C1NBut from methyl phenyldiazoacetate and t!butyl isocyanide ð69JOC751Ł[
In 0878\ Bertrand and co!workers\ requiring evidence for the carbene character of the stable
trimethylsilylmethylenephosphine "196#\ showed that its reaction with t!butyl isocyanide followed
by sulfuration a}orded the unique ketenimine "197# in 89) yield "Scheme 53# ð78AG"E#510Ł[

S
[(Pri)2N]2P [(Pri)2N]2P
:

CNBut S8
[(Pri)2N]2P TMS • NBut • NBut
90%
(207) TMS TMS
(208)
Scheme 64

"iii# Reaction with transition metal or`anometallic compounds


The reaction of isocyanides with transition metal carbene complexes provides a useful method
for preparing metal complexes of ketenimines "198# according to the general Equation "25#[
However\ this equation fails to highlight the large range of structural types "109#Ð"103# encompassed
by the simple formula "198#[ While only those complexes in which the metal is s bonded to the
carbon or nitrogen of the ketenimine "i[e[\ in which the C1C1N unit remains intact# fall strictly
within the scope of the present review\ various other complexes are proven intermediates en route
to metal!free ketenimines[ The comprehensive review by Aumann should be consulted for further
details and references ð77AG"E#0345Ł[

R1XC MLn + C N R2 (R1XC • NR2)MLn (36)


(209)
Ketenimines 486
R
R R R R
R MLn R N
R R
• N • N • N R R N
R LnM R M M
MLn Ln Ln
(210) (211) (212) (213) (214)

In 0857 Aumann and Fischer reported that the chromium carbene complex "104# reacted with
cyclohexyl isocyanide to give an air!sensitive compound ð57CB843Ł\ the structure of which was later
shown to be the h0!ketenimine complex "105# by x!ray crystallography ð75CB2030Ł[ With a twofold
excess of isocyanide\ the ketenimine ligand "106# could be displaced from the intermediate complex
and isolated in 67) yield "Scheme 54# ð67CB0112Ł[ Other nucleophiles such as pyridine also liberated
the ketenimine ð74CB841Ł[ The voluminous subsequent publications by Aumann and co!workers
contained examples of the N!bonded ketenimine complexes "R0XC1C1NR1#MLn\ in which X is
OR\ SR\ SeR\ NR1\ or N1CR1\ and MLn is Cr"CO#4\ Mo"CO#4\ W"CO#4\ Mn"C4H3Me#"CO#1\ or
Fe"CO#3 ð77AG"E#0345\ 82CB0756Ł[ However\ only in a few instances was the ketenimine then liberated
from the metal template on which it was constructed "e[g[\ from a tungsten complex with acetonitrile
ð76CB0828Ł\ and from a manganese complex with excess isocyanide ð77CB0974Ł#[ Two especially
interesting examples*a C!amino ketenimine "107# generated from an "aminocarbene#chromium
complex ð78CB0028Ł\ and a C!phenylthio!C!vinyl ketenimine "108# generated from an alkenyl!
"thiocarbene#chromium complex ð89CB1942Ł*are shown in Scheme 55[

c-C6H11NC c-C6H11NC
MeO MeO c-C6H11 –(CO)5CrCN(c-C6H11) MeO
C6H14, 0°C
Cr(CO)5 • N • N(c-C6H11)
78%
Cr(CO)5
(215) (216) (217)
Scheme 65

i, PhCOCl, NEt3
PhCO2 PhCO2
H 2N CN-R
ii, CN-R N R N
Cr(CO)5
Ph • N R = But (92%), Ph • NR
Ph
Ph Cr(CO)5 c-C6H11 (95%) Ph
(218)

PhS PhS
Cr(CO)5 2 CN-R, Et2O • N(c-C6H11)
84%
Ph Ph
(219)
Scheme 66

Insertion of isocyanides into vinylidene and allenylidene complexes of transition metals should
in principle open up routes to higher 0!azacumulenes analogous to those described above[ In fact\
the only higher 0!azacumulene complexes described to date appear to be the unstable\ readily
hydrolyzed manganese complexes "119# and "110#\ prepared as shown in Equations "26# and "27#
ð78JOM"268#292Ł[ The free ligands have not been detached from the metal[ Transient vinylideneÐ
titanium complexes "111#\ trapped by alkynes as the titanacyclobutenes "112#\ are implicated in the
synthesis shown in Scheme 56 ð81CC24Ł[ In this case the metallacycles reacted with isocyanides to
give isolable "and previously undocumented# C!allenyl ketenimines "113# in yields of 79Ð86)[
Other h3!complexed vinyl ketenimines "e[g[\ "114#\ "115#\ and "116##\ made by treating a variety of
organometallic precursors with isocyanides\ have been characterized crystallographically but not
dissociated from the metal template ð79JOM"089#C28\ 89CC296\ 82JA8735Ł[
Ph Ph
CN-R, Et2O, 20 °C
• Mn(CO)2Cp • • NR Mn(CO)2Cp (37)
R= But, c-C6H11, Bn (220)
487 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Ph Ph
CN-But, Et2O, 20 °C
• • Mn(CO)2Cp • • • NButMn(CO)2Cp (38)
Ph Ph (221)

R2 R3
3 steps R1 HMPA, RT
R1 • TiCp2

(222)

CN-But R1 NBut
R1 n-C6H14, RT
TiCp2 • •
80–97%

R2 R3 R2 R3
(223) (224)
R1 = Prn, n-C5H11, Ph
R2 = H, Prn, n-C5H11, Ph
R3 = Prn, Ph, TMS
Scheme 67

N(c-C6H11) NBut Co NBut


• Ph • EtO2C •

CO2Me OMe TMS SO2Ph


Fe(CO)3 Fe(CO)3
(225) (226) (227)

The insertion of isocyanides into h1!acyl organometallic complexes\ which are also close relatives
of Fischer carbene complexes\ di}ers from the processes described above in that the metal remains
attached to oxygen in the product[ The acylthorium complex "117#\ for instance\ reacted quan!
titatively with one equivalent of isocyanide to yield gummy ketenimines "118#\ which reacted in turn
with a second equivalent of reagent to yield complexes "129# as tractable solids "Scheme 57# ð75JA45Ł[
An analogous zirconium!complexed ketenimine "120# has been detected by NMR spectroscopy\
though it rapidly decomposed when the synthesis "Equation "28## was tried on a preparative scale
ð76JA1938Ł[
Cp Cp
O Cp O
CN-R, RT Cp Th But CN-R, RT Th But
(Cp)2Th(Cl)(η2-COCH2But) Cl
~100 % Cl • ~100 % •
CN-R
NR NR
(228) (229) (230)
R = Ph, But, 2,6-C6H3Me2
Scheme 68

Cl
Cp2Zr
Cl O
Cp2Zr CD2Cl2, RT
+ TMS (39)
CN
O ~100% •
TMS N

(231)
Ketenimines 488
The synthesis of ketenimines from isocyanides and carbenes has been approached from a di}erent
perspective by Werner and co!workers\ who treated isocyanide complexes of cobalt with diaryl
diazoalkanes as an external carbene source "Scheme 58# ð89AG"E#164\ 80CB174Ł[ Intermediate ket!
enimine complexes were found to have either the h1!C\C or h1!N\C structures "121# or "122# depending
on the substituents on carbon[ These complexes could not be disrupted with additional isocyanide\
but on treatment with iodine\ ketenimines "123# and "124# were liberated in yields of 37Ð69)[

Me
Ar2CN2 Ar Ar
Me2CO, –78 °C to RT N I2, Et2O, RT
CpCo(CNMe)(PMe3) Ar • NMe
54–67% Co 50–70% Ar
Cp PMe3
Ar = Ph, p-Tol, p-C6H4Cl (232) (234)

Me3P
NR
CpCo(CNR)(PMe3) Co NR
Cp •
Me2CO, –78 °C to RT I2, Et2O, RT
+
52–68% R = Me (48%)
N2 R = Me, c-C6H11 CH(Me)Ph (68%)
CH(Me)Ph

(233) (235)

Scheme 69

Several alternative syntheses of ketenimines on palladium templates are known ð66TL0998\


79SC122Ł[ They involve insertion of isocyanides into Pd0C s bonds "e[g[\ Equation "39##\ p!allyl
palladium complexes "Equation "30##\ or diene complexes "Equations "31# and "32##[ s!Bonded
intermediates such as "125#\ previously isolated by other workers ð69JOM"12#164\ 60ICA366Ł\ are
implicated in the reaction pathway\ and a ready b elimination of H0PdLn with 0\4!
diazabicycloð4[3[9Łundec!4!ene "dbu# then a}ords the desired product[ The process has been made
catalytic in palladium as shown in Equation "33#\ and this variation a}ords aryl and vinyl ket!
enimines in moderate yields[ An insertion of isocyanides into s!bonded platinumÐallene complexes
"126# has been used for making the unusual but stable metallated vinyl ketenimines "127# in
48Ð78) yields "Equation "34##\ whereas the corresponding palladated vinyl ketenimines were too
unstable to be isolated ð82OM2753Ł[
1
i, R
Hal
R2 NBut
dbu, C6H6, RT R1
ii, ButNC
Pd(CNBut)2 R1 Hal
• NBut (40)
Pd
)2 R2
R2
CNBut
(236)

R1 R2 Yield (%)
Ph H 82
Prn H 62
Me Me 27

i, ButNC
Cl
PdCl2 ii, dbu
Pd • NBut (41)
)2 55%

OMe i, ButNC OMe


Cl MeOH, Na2CO3 ii, dbu
Pd (42)
Cl Cl 50%
Pd •
)2 NBut
599 Ketenimines and P\ As\ Sb\ and Bi Analo`ues

MeO i, ButNC
MeOH, Na2CO3 ii, dbu MeO
(43)
Pd Pd 38%

Cl Cl Cl )2 NBut

Pd(OAc)2 (cat.)
R1 Cl
– + dbu, THF R1
+ C N R (44)
• NR2

R1 R2 Yield (%)
Ph But 65
Ph X 57
p-Tol X 40 X=
H2C=CH But 20
PhCH=CH But 20

CN-R3
R1 THF, reflux; or R1 • NR3
• C6H5Me, RT
PPh3 (45)
R2 Pt R2 PPh3
Ph3P Pt
X Ph3P
X
(237) (238)
R1 R2 R3 X Yield (%)
Me Me But Br 89
Me Me But Cl 78
-(CH2)5- But Br 79
Me Et But Br 79
Me Me 2,6-Xylyl Br 59

2[06[0[3[2 Formal cycloaddition processes


0\2!Dipolar cycloaddition of aromatic nitrile oxides to phosphorus ylides gave rise to 3\4!dihydro!
0\1\4l4!oxazaphospholenes "128#\ which decomposed either spontaneously or on heating to give
ketenimines\ amongst other products ð58CB0705\ 58CB0722Ł[ For example\ use of the stabilized ylide
"139# gave only the ketenimine "130# "Scheme 69#\ whereas azirines "131# were the major products
from a nonstabilized ylide ð58CB0705Ł[

+
PhC≡N-O– Ph N
C6H6
PPh3 O • NPh
EtO2C P 68% EtO2C
EtO2C Ph3
(240) (239) (241)
Ph N
+ C6H6, 8 °C
X N O– + O
PPh3 X = H (74%) X = H (20% + 80%)
P
Cl (85%) Ph3 Cl (8% + 92%)

N
• N X + X

(242)
Scheme 70

Haszeldine and co!workers have shown that oxazetidines "132#\ isolated from the reaction of
tri~uoronitrosomethane with bis"tri~uoromethyl#aminoallenes "133#\ give excellent yields of N!
tri~uoromethyl ketenimines "134# upon ~ow pyrolysis ð69CC345\ 62JCS"P0#0450Ł[ The overall process\
shown in Scheme 60\ is e}ectively a metathesis reaction[
Formal ð1¦1Ł cycloaddition has been invoked to explain the reaction of alkyl isocyanates
Ketenimines 590

R1 F3C
F 3C CF3 N CF
R2 3 R1
R1 N CF3 N O, ∆ 200–300 °C, –HCON(CF3)2
• NCF3
• R1 = R2 = H, 47% N O R1 = R2 = H, 100%
R2
R2 R1 = H, R2 = N(CF3)2, 89% F3C R1 = H, R2 = N(CF3)2, 98%
R1 = R2 = N(CF3)2, 32% R1 = R2 = N(CF3)2, >90%
(244) (243) (245)

Scheme 71

with 0!diethylaminopropyne "Scheme 61# ð61TL0028\ 66JOC3150Ł[ Electrocyclic ring opening of the
iminooxete intermediate "135# leads to the formation of isolable C!carbamoyl ketenimines "136# in
moderate to good yields[

O=•=NR, RT NR NR
C6H6 or CCl4 O O •
Et2N
Et2N Et2N
(246) (247)
R Yield of (247) (%)
Me 78
Et 67
Bun 51
c-C6H11 45
2,6-C6H3Me2 35
Scheme 72

2[06[0[4 Keteniminium Salts


Although salts of ketenimines are of some consequence as reactive intermediates in ð1¦1Ł
cycloadditions ðB!65MI 206!90\ 77CRV682Ł\ very few have actually been isolated as stable intermediates\
or even characterized spectroscopically[ These salts are generally formed in situ under conditions
that favour their immediate conversion into cyclobutanone products[ They are e}ectively in equi!
librium with enamines bearing various heteroatomic substituents on the a position "Equation
"35##^ their interception by suitable reaction partners often constitutes the sole evidence for their
intermediacy[ a!Chloroenamines\ for instance\ have frequently been used as synthetic equivalents
for keteniminium salts ðB!65MI 206!90\ 82HOU"E04:1#0523Ł[ Secondary amides provide a more accessible
source\ since treatment with tri~uoromethanesulfonic "tri~ic# anhydride and collidine in an inert
solvent provides a simpler route to keteniminium intermediates via a!tri~yloxy enamines ð77CRV682Ł[
Some representative intramolecular and intermolecular cycloadditions involving transient ket!
eniminium salts prepared by these two methods are shown in Scheme 62[ In those rare cases in
which the keteniminium intermediates could actually be detected in solution\ the counterions
present were hexa~uorophosphate ð69JOC2869Ł\ tetra~uoroborate ð61JA1769Ł\ or trichlorozincate
ð63AG"E#156Ł\ as shown in Equation "36#\ for example[ The ethynylogous guanidinium salt "137#
represents a special case in which resonance e}ects play a part in stabilizing a keteniminium system
"Scheme 63# ð63JA3601Ł[

R1 X R1
+
• NR3R4 X– (46)
R2 NR3R4 R2
X = Cl, OSO2CF3

Cl Me
AgBF4, CH2Cl2, –60 °C +
• N BF4– (47)
NMe2 Me
591 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Cl
H O
i, cyclopentene, ZnCl2, CH2Cl2, 20 °C
ii, NaOH
N
70%, >97% ee
〈82JA2920〉 H
MeO

i, Tf2O, collidine, O
ClCH2CH2Cl, ∆
ii, H2O N

i, Tf2O, collidine, 65%


CHCl3, ∆
H O 〈85JA2192〉
O NMe2 ii, NaOH
+
50% O
i, Tf2O, 2,6-(But)2Py,
〈81AG(E)879〉 H ClCH2CH2Cl, 20 °C
ii, H2O N
88%, 98% ee
〈90TL4467〉

Scheme 73

+
Me2N Cl Et3N, MeCN +
ClO4– NMe2 ClO4– • • NMe2 ClO4–
+
Me2N Me2N
NMe2
(248)
Scheme 74

Transient keteniminium intermediates may also be involved in reaction of the nucleophilic b!


carbon site of ynamines with electrophiles "Equation "37##[ There is no conclusive evidence for the
intermediacy of the salts\ although in most cases the isolated product strongly suggests a ket!
eniminium precursor[ Relevant reviews should be consulted for examples of reactions assumed to
proceed through such keteniminium salts ð65T0338\ 82HOU"E04:2#2393Ł[

R2 R1 R2
El+ X– +
:

R1 N • N X– (48)
R3 El R3

The only truly isolable keteniminium salts bear bulky substituents that help to retard decompo!
sition[ Equation "38# shows an example in which N!methylation of a hindered ketenimine a}orded
a salt that survived recrystallization ð67JOC490Ł[ N!Methylation with trimethyloxonium tetra~uo!
roborate or hexachloroantimonate\ or with methyl ~uorosulfonate\ has subsequently been exploited
in the synthesis of a wider range of isolable keteniminium salts "138#Ð"140#\ one of which\ compound
"141#\ has even been examined by single!crystal x!ray di}raction ð71CB061Ł[

But MeOSO2F, Et2O, RT But Et


+ –OSO
• NEt • N 2F (49)
55%
But But Me

2[06[1 P\ As\ Sb\ AND Bi ANALOGUES OF KETENES AND THEIR DERIVATIVES


"R1C1C1P0R\ ETC[#
Antimony and bismuth analogues of ketenes have not been prepared to date[ The arsenic
analogues "0!arsaallenes# are also unknown\ though a few higher 0!arsacumulenes have been
prepared[ This section is thus dominated by the comparatively well!explored trivalent "l2# and
pentavalent "l4# phosphorus analogues of ketenes and higher cumulenes[ Reviews by Matthews
and Birum ð58ACR262Ł\ Bestmann ð66AG"E#238Ł\ Bestmann and Zimmermann ð71HOU"E0#648Ł\ and
Markovskii and Romanenko ð75JGU110Ł deal wholly or in part with the chemistry of these phos!
phorus compounds[
P\ As\ Sb\ and Bi Analo`ues 592

Bn Bn Bn
But But
+ + +
• N X– • N X– • N SbCl6–
R Me Me But Me
R = Pri, X– = FSO3–, SbCl6– X– = FSO3–, SbCl6–
R = But, X– = FSO3–, BF4–
(249) (250) (251)
But But
+
• N SbCl6–
But Me
(252)

2[06[1[0 0l4!Phosphaallenes and 0l4!Phosphacumulenes


0l4!Phosphaallenes "alkenylidene phosphoranes# "142a# are mesomers of ylides "142b#\ a rep!
resentation preferred by some authors[ Similar representations are possible for higher 0l4!phos!
phacumulenes\ X1C1C1PR2 "XC\ O\ S\ N\ P#[ With heteroatomic termini\ further resonance
forms\ for example "143#\ contribute to the stability of the structure "Scheme 64#[ Much experimental
and theoretical work has been devoted to assessing the relative importance of these canonical forms[
The present review side!steps this issue\ and includes all compounds for which a formal C1P bond
can be drawn[ However\ several x!ray crystallographic investigations have shown that the CC
P
angle is not linear\ but varies between 015> and 057> depending on substituents ð74CB0619Ł[ This
_nding is compatible with the C1C1P formalism if ppÐdp bonding is countenanced[
+
R1 R1 PX3
• PX3

R2 R2
(253a) (253b)
+
PX3
– +
Y • • PX3 Y • Y PX3

(254)
Scheme 75

2[06[1[0[0 From precursors containing the CCP triad


The simplest route to alkenylidene phosphoranes is by deprotonation of vinylphosphonium salts[
This process was _rst described by Gilman and Tomasi\ who prepared Ph1C1C1PPh2 "used in situ
in a Wittig reaction# from Ph1C1CHPPh2¦ Br− and phenyllithium ð51JOC2536Ł[ Bestmann and co!
workers later deprotonated the phosphonium salt "144#\ formed as shown in Scheme 65\ to the
crystalline ketene acetal "145# ð58AG"E#105\ 62CB1590Ł[ On prolonged heating in toluene\ "145#
was converted into the cyclic vinyl phosphorane "146#\ which underwent further elimination to
yield the cyclic phosphaallene "147# ð66AG"E#766Ł[ Deprotonation of vinylphosphonium salts has
also been used for preparing alkylthio analogs\ "RS#1C1C1PPh2 "RMe\ Et\ Prn\ Bun^ 38Ð60)#
ð70TL0570Ł\ and EtOCH1C1PPh2 "58)# ð71CB050Ł[ While isolable 0l4!phosphabutatrienes\
R1C1C1C1PPh2\ have yet to be prepared by this method\ both Ph1C1C1CHPPh2¦ Br− and
HC2CCH1PPh2¦ Br− reacted with base to form products whose structures imply the intermediacy
of Ph1C1C1C1PPh2 and H1C1C1C1PPh2\ respectively ð58JA5001\ 62TL0384Ł[
Acylmethylenetriphenylphosphoranes may also be deprotonated to give formal 0!phosphaallenes\
as in the conversion of PhCOCH1PPh2 into the reactive enolate Ph"LiO#C1C1PPh2 with lithiumÐ
HMPA ð64T0220Ł[ However\ when a leaving group is present on the b position\ 0!phosphacumulenes
may be formed instead[ For example\ sodium hexamethyldisilazide induced elimination of MeXH
from MeX1CCH1PPh2 "XO\ S# in benzene at 59Ð54>C\ yielding the ketenylidene phosphoranes
X1C1C1PPh2 "XO\ 79)^ XS\ 65)# ð64AG"E#523\ 79CB163Ł[ The former product has also
been isolated from the reaction of MeO1CCH1PPh2 with n!butyllithium and Me2MCl "MSi\
Sn#\ probably by rapid elimination of Me2M0OMe from a metallated intermediate ð63JOM"66#C11Ł[
593 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
Et3O+ BF4–
O CH2Cl2 EtO NaNH2, NH3 EtO
+
PPh3 PPh3 BF4 – • PPh3
EtO 68% EtO 48% EtO
(255) (256)

toluene, ∆
3d 81%

i, AcCl
ii, NaN(TMS)2
Ph Ph
P 82% P
EtO EtO Ph
Ph OEt
(258) (257)
Scheme 76

In a related reaction\ base!induced elimination of ethanol from b!ethoxyallylidenephosphoranes


"148#\ formed from the previously mentioned acetal "145# and active methylene compounds\ pro!
duced the stable 0!phosphabutatrienes "159# in moderate yields "Scheme 66# ð79CB163Ł[

EtO R1CH2R2, C6H6 R1 PPh3 NaN(TMS)2, C6H6 R1


• PPh3 • • PPh3
R1 = Ph, R2 = CN, 65%
EtO R2 OEt R1 = p-MeOC6H4, R2 = CN, 47% R2
(256) (259) R1 = Ph, R2 = CO2Me, 59% (260)
R1–R2 = –CH=CHCH=CH–, 51%

Scheme 77

2[06[1[0[1 From "C¦CP# precursors


Birum and Matthews\ pioneers in this _eld\ found that hexaphenylcarbodiphosphorane "150#
readily formed inner salts "151# "×82) yield# on treatment with carbon dioxide and related
heterocumulenes "Scheme 67# ð55CC625Ł[ These salts underwent elimination of Ph2P1X when
heated in DIGLYME\ thereby giving rise to a variety of 0!phosphacumulenes[ The stable
O1C1C1PPh2 was obtained from carbon dioxide "08) yield# ð55TL4696\ 57JA2731Ł\
S1C1C1PPh2 from carbon disul_de ð55TL4696Ł\ and the more labile ArN1C1C1PPh2
"ArPh\ p!Tol\ p!C5H3NO1# from aryl isothiocyanates ð57CI"L#542\ 57JA2731Ł[ More conventional
Wittig reactions of Ph2P1C1PPh2 with hexa~uoroacetone ð56CC026\ 56JOC2443Ł and benzophenone
ð71ACH24Ł gave the 0!phosphaallenes "F2C#1C1C1PPh2 and Ph1C1C1PPh2\ respectively[


X Y
X • Y –Ph3P=Y
Ph3P • PPh3 X • • PPh3
Ph3P + PPh3
(261) (262)
Scheme 78

A useful preparation of higher 0!phosphacumulenes by Bestmann and co!workers involves acyl!


ation of methylenetriphenylphosphorane with thio or imino analogues of phosgene "152#\ or with
0\0!dichloroalkenes "Scheme 68# ð63AG"E#162\ 64TL3914\ 79CB2258Ł[ The 2 ] 0 stoichiometry of the process
implies that two equivalents of ylide function as base\ _rst deprotonating the initially formed
phosphonium salts "153#\ and then\ after methylation\ inducing a b elimination of the sort described
in Section 2[06[1[0[0 above[ Compounds prepared by this procedure are presented in Table 09[
P\ As\ Sb\ and Bi Analo`ues 594
Methylenetriphenylphosphorane also reacted with isothiocyanates to produce "154# "Scheme 79#^
methylation followed by base!induced b elimination subsequently gave keteniminylidene phos!
phoranes "155# in good yield ð82CB1040Ł[
X X
3 H 2C +
PPh3 + PPh3 Hal–
Hal Hal Hal
(263) (264)

+
X • • PPh3 + 2 Ph3PMe Hal–

Scheme 79

Table 09 Preparation of 0l4!phosphacumulenes\ X1C1C1PPh2\ by the reaction of X1CY1 with


methylenetriphenylphosphorane\ H1C1PPh2[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Entry Reactant Product Yield Ref[
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 "MeO1C#1C1CCl1 "MeO1C#1C1C1C1PPh2 08 64TL3914
1 MeO1C"CN#C1CCl1 Me1OC"CN#C1C1C1PPh2 40 64TL3914
2 "1\1?!C5H30C5H3#C1CBr1 "1\1?!C5H3\C5H3#C1C1C1PPh2 79 64TL3914
3 S1CCl1 S1C1C1PPh2 59 79CB2258
4 RN1CCl1 RN1C1C1PPh2 "RMe\ c!C5H00# 57Ð69 79CB2258
5 "p!C5H3X#N1CCl1 "p!C5H3X#N1C1C1PPh2 "XH\ Cl\ Me# 58Ð74 79CB2258
6 "1\3!C5H2Cl1#N1CCl1 "1\3!C5H2Cl1#N1C1C1PPh2 62 79CB2258
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

i, MeI, CHCl3, 0 °C
C6H6, RT
S ii, NaOMe, MeOH, RT
H2C PPh3 + RN • S RHN
84–95% PPh3 67–75%
(265)

SMe NaN(TMS)2
C6H6, RT to 50 °C
RN RN • • PPh3
R = Me 71%
PPh3 (266)
Ph 86%
Prn 69%

Scheme 80

2[06[1[1 0l2!Phosphaallenes and 0l2!Phosphacumulenes


These unsaturated compounds tend to dimerize to 0\2!diphosphetanes ð75CB1355Ł unless the
phosphorus atom bears a sterically protecting substituent "invariably 1\3\5!tri!"t!butyl#phenyl\
denoted by Ar  in the following# to inhibit further reaction[

2[06[1[1[0 By the Peterson reaction and related ole_nations


Peterson ole_nation has been used by the research groups of both Markl and Yoshifuji in a
number of di}erent ways for preparing 0l2!phosphaallenes and 0l2!phosphacumulenes[ In the
simplest case\ the lithiated silylphosphine "156# reacted with ketenes to give 0!phosphaallenes "157#
in moderate yield "Equation "49## ð73TL0798\ 74PS"14#126\ 76PS"29#416\ 77AG"E#0259Ł[ Alternatively\ 0!
phosphaallenes could be formed by treating the lithiated l2!phosphaethenes "158# with aldehydes
or ketones "Equation "40## ð78TL728Ł[ The product formed from benzaldehyde is axially dissym!
metric\ and can exist as two enantiomers\ "R#!"169# and "S#!"169#[ These have recently been separated
by HPLC on a chiral column and their CD spectra recorded^ the compounds racemized when
exposed to light ð89TL1200Ł[ Tri!"t!butyl#cyclopropen!0!yl has also been used as a sterically encum!
595 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
bering group to inhibit dimerization of phosphaallene products "160# formed in a Peterson!like
elimination "Equation "41## ð82S0136Ł[
R
ButMe2Si • O , THF, –78 °C R Ar*
R
P Ar* • P (50)
Li R
(267) (268)
Ar* = 2,4,6-C6H2(But)3 R Yield (%)
Ph 58
TMS 40

R
Ar* O
Li R Ar*
Ph
P • P (51)
–78 °C to RT
TMS Ph
(269)
Ar* = 2,4,6-C6H2(But)3 R Yield (%)
Ph 45
H 16

H Ph
:

:
• P But • P But
Ph H
But But

But But
(R)-(270) (S)-(270)

But
But But
But
TMS-O NaOH, THF, 70 °C
R (52)
P
But • P
R TMS But
R
R
(271)
R Yield (%)
Ph 90
2,4,6-C6H2Me3 52

Lithiation of the alkynylphosphine "161# with n!butyllithium yielded a spectroscopically detectable


ion pair*apparently not a lithioallene*that underwent Peterson ole_nation with dialkyl and diaryl
ketones "Scheme 70# to produce fair yields of 0!phosphabutatrienes "162# ð78TL2828\ 89TL3318Ł[ The
labile phosphacumulenes from acetone and cyclohexanone immediately dimerized at the terminal
C1C bond\ giving 0\1!bis"phosphaallenyl# cyclobutanes "163# ð78TL2828Ł\ whereas products from
halogenated aromatic aldehydes or diaryl ketones dimerized at the P1C head to give 0\2!diphos!
phetanes "164# ð89TL3318Ł[

P Ar*
R1, R2 = Me, 15%
R2 •
R1–R2 = (CH2)5, 48% R1

R1
i, BunLi, THF •
R2 *
H
ii, R1R2C=O
R1 P Ar
–78 °C to RT (274)
TMS P
:

• • P
Ar* 48–70%
R2 Ar*
(272) (273) Ar*
R1, R2 = aromatic R1 P R1
• •
31–62% R2 P R2
Ar*
(275)
Scheme 81
P\ As\ Sb\ and Bi Analo`ues 596
Markl and co!workers have also investigated variants of the Peterson ole_nation in which
chlorotrimethylsilane is eliminated[ For example\ the reaction between the lithiated tri!
methylsilylallenes "165# and the sterically crowded ArPCl1 yielded 0!phosphabutatrienes "166# by
sequential displacement of the chloride ion and elimination of TMS!Cl "Equation "42##
ð75AG"E#0992Ł[ Propargylic rearrangements must have occurred during the synthesis of 3\3!bis"tri!
methylsilyl#!0!phosphabutatriene "167# from 0\2!dilithiated bis"trimethylsilyl# allene "168# and
ArPCl1 "Equation "43## ð81TL0870Ł[ The monolithiated allene "179# and ArPCl1 initially produced
alkynes "170# as a mixture of geometrical isomers^ subsequent lithiation of "170# followed by addition
of electrophiles then gave 0!phosphacumulenes "171# "Scheme 71#[ This variant of the Peterson
ole_nation also works with the lithiated phosphaallene "172#\ from which the 0\3!diphos!
phabutatriene "173# was obtained as an "E#:"Z# mixture "67 ] 11# via the isolable 0!phosphaallene
"174# "Scheme 72# ð77AG"E#0259Ł[

Ar*PCl2
R1 Li R1
THF, –78 °C to RT
• • • P (53)
R2 TMS R2 Ar*
(276) (277)
R1 R2 Yield (%)
TMS TMS 10
Ph Ph 45
Me TMS 10(E), 1(Z)

Ar*PCl2
Li Li THF, –78 °C to RT
TMS
• • • P (54)
TMS TMS 26% TMS Ar*
(279) (278)

Ar*PCl2 P BunLi
TMS Li TMS
THF, –78 °C to RT Ar* TMS-Cl, or MeI
• • • P
TMS R Ar*
TMS
(280) (281) (282) R = TMS, Me
Scheme 82

Ar*PCl2 Cl 18-crown-6
Li
THF, –78 °C to RT Ar*P toluene, ∆ P • • P
• P *Ar
• P Ar*
TMS Ar*
TMS Ar*
(283) (285) (284) (E):(Z) = 78:22
Scheme 83

2[06[1[1[1 By other routes


A conceptually simple route to l2!phosphaallenes and l2!phosphacumulenes involves exchange
of the phosphorus moiety in l4 precursors with a suitable l2!phosphine[ Markl and Bauer have
accomplished this transformation by the action of 1\3\5!tri"t!butyl#phenylchlorophosphine on l4!
phosphaallene "175# "n9# or l4!phosphacumulenes "175# "n0#\ prepared in situ by deprotonation
of phosphonium salts "see Section 2[06[1[0[0# "Scheme 73# ð82TL1804Ł[ The geometry of the unsym!
metrical product "176# "R0 Me\ R1 Et# is uncertain[
Just as ketenimines can be made by the reaction between alkylidenetriphenylphosphoranes and
isocyanates "see Section 2[06[0[3[0#\ 0!phosphaallenes are accessible in low yield from Ph2P1CR0R1
and O1C1PAr\ the phosphorus analogue of an isocyanate ð73AG"E#508\ 75CB1355Ł[ Products
prepared by this route include Ph1C1C1PAr "29) yield#\ PhCH1C1PAr "18)#\ and
EtO1CCH1C1PAr "13)#[
Yoshifuji et al[ have accomplished a one!carbon homologation of phosphaethenes and 0!phos!
phaallenes with dichlorocarbene "Equations "44# and "45## ð89CL716\ 80CC013Ł[ Organolithium
reagents cleaved the intermediate dichlorophosphiranes "177# and "178# to the desired products in
moderate yields[ The reaction of the symmetrical diphosphene "189# with the unsaturated carbene
597 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
+
R1 PPh3 Br– R1
BunLi, THF Ar*PHCl
• • • PPh3
n n n = 0. R1 = R2= Ph, 19%
R2 R2
n = 1, R1 = Me, R2 = Et, 26%
(286) n = 1, R = R = Et, Pri, Ph, 32–53%
1 2

R1
• • PAr*
n
R2
(287)
Scheme 84

Me1C1C] has been shown to produce a 6 ] 2 mixture of the diphosphirane "180# and the 0!
phosphaallene "181# "Equation "46## ð80TL2576Ł[

Ar* Ph Ar*
CHCl3, KOBut, pentane, RT P ButLi, Et2O, –78 °C Ph
P • PAr* (55)
35% from (E), 47% from (Z) 62%
Ph Cl Cl
(288)

Ph
CHCl3, NaOH, BnNEt3+ Cl–
Ph Ar* hexane, RT Ar* BunLi, Et2O, –78 °C
Ph
• P Ph P • • PAr* (56)
35% 68% Ph
Ph
Cl Cl
(289)

Cl

Ar* Ar*
Ar* BunLi, Et2O, 0 °C P P
P P + • PAr* (57)
Ar*

(290) (291) (292)


70% 30%

The reaction of alkynyllithium compounds with 1\3\5!tri"t!butyl#phenylchlorophosphine in THF


provides a short but ine.cient route to 0!phosphaallenes\ which are tautomers of the initially
formed alkynylphosphines "182# "Scheme 74# ð77TL352Ł[ The alkynes were isolated in yields of 30Ð
32) when alkynylmagnesium bromides were used in diethyl ether[ A similar reaction with TMS!
protected propargyl alcohols "183# led to the formation of 0!phosphaallene silyl ethers "184#\ two
of which were hydrolyzed to the free alcohols "185# "Scheme 75# ð77TL1824Ł[ When a stereogenic
centre complemented the chiral axis\ diastereomers of "184# "R0 R1# were detected by NMR
spectroscopy[ Chromatography of products bearing aryl substituents on the carbon terminus was
accompanied by spontaneous elimination of trimethylsilanol\ and 0!phosphabutatrienes "186# were
formed[

H R = Ph, 37%, R
Ar*PHCl
R Li R P • PAr*
THF, –78 °C to 0 °C But, 35%,
Ar*
Me, 17%
(293)
Scheme 85

Treatment of the quadricyclane "187# with copper"II# chloride in deuteriated benzene gives
rise to the phosphaallene "188#\ characterized by NMR spectroscopy ð82BSF074Ł[ The postulated
mechanism "Scheme 76# assumes that corner metallation of a cyclopropane ring is followed by
cleavage of the C!00C!1 bond to form the intermediate "299#[ After a Grob!type fragmention of
the C!30C!6 bond and elimination of copper\ the resulting cyclopentadien!4!yl phosphaallene "290#
rearranges to the more stable 0!substituted isomer "188#[
P\ As\ Sb\ and Bi Analo`ues 598

Ar*PHCl
TMS-O THF, –78 °C to 0 °C
TMS-O H
R1 Li R1 P
R2 R1, R2 = H, alkyl, aryl R2 Ar*
(294)

R1 chromatography R1 O-TMS 2 N HCl, MeOH R1 OH


• • P R2 R2
R1, R2 = Ph, 63% R1, R2 = H, Me
R2 Ar* • PAr* • PAr*
(297) (295) (296)
Scheme 86

Ar* Ar* Ar*


Ar* P P Ar*
P P P
CuCl2, C6D6 7

2 + •
1

+ 4
Cu Cu
(298) (300) (301) (299)
Scheme 87

2[06[1[1[2 Transition metal complexes of 0l2!phosphaallenes and 0l2!phosphacumulenes


The coordination chemistry of compounds containing phosphorusÐcarbon multiple bonds has
been reviewed ð77CRV0216Ł[ Complexes of 0l2!phosphaallenes are rare[ With the exception of a few
h1!P\C complexes\ the bonding mode is invariably h0!P\ that is\ with the metal coordinated to the
lone pair on phosphorus\ as shown in "291#[ Synthesis simply involves heating or irradiating the
ligand with a metal carbonyl[ Crystallographically characterized complexes include h0!
ð"Ph1C1C1PAr#Ni"CO#2Ł "52) yield# ð75JOM"296#82Ł and h0!ð"Ph1C1C1PAr#W"CO#3Ł "25)
yield# ð89HAC228Ł[ The chromium and molybdenum analogs of the latter were identi_ed by NMR
spectroscopy ð75JOM"200#C52Ł\ as was the tungsten complex "292# "19) yield# ð82S0136Ł[ The only
known h0 complex of a 0l2!phosphabutatriene\ "293#\ made in 82) yield\ was also characterized
crystallographically ð82JOM"350#70Ł[

But But
But
But
But Ph But
Ph • P Ph
But But
• P But Ph • • P
W(CO)5
Ph M Ph W(CO)5
M = Ni(CO)3, Cr(CO)5, (303) (304)
Mo(CO)5, W(CO)5
(302)

2[06[1[2 0!Arsacumulenes
By the end of 0882 there were only two documented syntheses of 0!arsacumulenes[ Bestmann and
Bansal prepared the ketenylidene l4!arsorane "294# by elimination of methanol from the stabilized
arsenic ylide "295# "Equation "47## ð70TL2728Ł according to the method previously described for the
corresponding phosphorus analogue ð64AG"E#523Ł "cf[ Section 2[06[1[0[0#[ Markl and Reithinger
have adapted one of the previously discussed Peterson ole_nation procedures "cf[ Section 2[06[1[1[0#
for preparing the unstable 0l2!arsabutatriene "296# as shown in Scheme 77 ð89TL5220Ł[ The product
dimerized spontaneously to the 0\2!diarsetane "297#[
509 Ketenimines and P\ As\ Sb\ and Bi Analo`ues
NaN(TMS)2
O toluene, RT
AsPh3 O • • AsPh3 (58)
MeO 60%
(306) (305)

(TMS)3C
i, THF, –78 °C
Ph Li (TMS)3C ii, NaOH, H2O–MeOH Ph As OMe
• + As OMe •
Ph TMS 52%
Cl Ph

But, Et2O, –78 °C

C(TMS)3
Ph As Ph Ph
• • • • AsC(TMS)3
As 47%
Ph Ph Ph
C(TMS)3
(308) (307)
Scheme 88

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.18
Nitriles: General Methods and
Aliphatic Nitriles
MICHAEL NORTH
University of Wales, Bangor, UK
2[07[0 GENERAL METHODS FOR NITRILE SYNTHESIS 500
2[07[0[0 Synthesis via Substitution Reactions 501
2[07[0[0[0 Nucleophilic substitutions 501
2[07[0[0[1 Electrophilic substitutions 503
2[07[0[1 Synthesis via Addition Reactions 503
2[07[0[1[0 Addition to CC multiple bonds 503
2[07[0[1[1 Addition to CX multiple bonds 504
2[07[0[2 Synthesis via Elimination Reactions 506
2[07[0[2[0 Elimination from carbonyl derivatives 506
2[07[0[2[1 Elimination from carboxylic acid derivatives 506
2[07[0[2[2 Elimination from nitro compounds 519
2[07[0[2[3 Elimination from amines and amino acids 519
2[07[0[3 Synthesis from other Nitriles 519
2[07[0[4 Miscellaneous Methods of Synthesis 510

2[07[1 ALIPHATIC NITRILE SYNTHESIS 511


2[07[1[0 Saturated Unsubstituted Nitriles 511
2[07[1[1 b! and More Remotely Unsaturated Nitriles 511
2[07[1[1[0 Aliphatic nitriles with one double bond 511
2[07[1[1[1 Aliphatic nitriles with more than one double bond 513
2[07[1[1[2 Aliphatic nitriles with aryl or heteroaryl substituents 514
2[07[1[1[3 Aliphatic nitriles with one or more C2C triple bonds 515
2[07[1[2 Halo!substituted Aliphatic Nitriles 516
2[07[1[3 Aliphatic Nitriles Bearin` an Oxy`en!based Functional Group 516
2[07[1[3[0 a!Oxy`enated nitriles 516
2[07[1[3[1 b!Oxy`enated nitriles 521
2[07[1[3[2 More remotely oxy`enated nitriles 522
2[07[1[4 Aliphatic Nitriles Bearin` a Sulfur!based Functional Group 523
2[07[1[5 Aliphatic Nitriles Bearin` a Se! or Te!based Functional Group 525
2[07[1[6 Aliphatic Nitriles Bearin` a Nitro`en!based Functional Group 526
2[07[1[7 Aliphatic Nitriles Bearin` a P!\ As!\ Sb! or Bi!based Functional Group 528
2[07[1[8 Aliphatic Nitriles Bearin` a Si! or B!based Functional Group 528
2[07[1[09 Aliphatic Nitriles Bearin` a Metal Functionality 539

2[07[0 GENERAL METHODS FOR NITRILE SYNTHESIS


A number of reviews dealing with the synthesis of nitriles have been published\ though many of
these deal with only one of the various approaches for the preparation of this functional group\ and
are referenced in the appropriate section of this chapter[ However\ two general reviews of nitrile
synthesis can be found in Rappoport|s 0869 book ðB!69MI 207!90Ł and Mowry|s 0837 review
ð37CRV078Ł[ The latter of these\ although somewhat dated\ provides a thoroughly comprehensive

500
501 Nitriles] General and Aliphatic Nitriles
review of the more classical methods of nitrile synthesis[ The general methods used in the synthesis
of nitriles can be classi_ed as] by substitutions\ by additions\ by eliminations\ synthesis from other
nitriles and miscellaneous methods[ Each of these is discussed in turn[

2[07[0[0 Synthesis via Substitution Reactions


Nitriles can be prepared by substitution reactions involving both nucleophilic and electrophilic
cyanide sources\ although the former are far more common[ For reactions involving nucleophilic
substitutions\ cyanide "CN−# can be used either as the sodium or potassium salt^ HCN is also an
excellent nucleophile[ Various electrophilic cyanide sources are known\ including cyanogen "C1N1#
and cyanogen bromide "BrCN#[

2[07[0[0[0 Nucleophilic substitutions


The synthetic utility of displacement reactions by cyanide is enhanced by the fact that in addition
to forming at least one functional group\ the reaction is also a carbonÐcarbon bond!forming
reaction[ Substitution can occur at sp2\ sp1\ or sp hybridised centres^ however\ the last two reactions
lead to a\b!unsaturated or aryl nitriles\ and are discussed in Chapter 2[08 so only displacement
reactions at sp2 hybridised carbon centres is discussed in this chapter[
Cyanide will displace a wide variety of leaving groups and the reaction is almost always an SN1
displacement\ hence primary carbon atoms react more easily than secondary and tertiary[ In the
case of secondary and tertiary centres\ the basicity of the cyanide anion means that elimination of
the leaving group to give an alkene is sometimes a serious side reaction[ A further side reaction can
arise from the ambident nature of the cyanide anion ð53AG"E#459Ł\ as substitution can occur on
either carbon or nitrogen\ giving nitriles and isonitriles respectively\ as shown in Scheme 0[ In
practice\ however\ use of NaCN or KCN results only in the formation of cyanides by SN1 displace!
ment[ Use of heavy metal cyanides such as silver cyanide\ however\ gives the isonitrile via a more
SN0 type reaction due to complexation of the halide with the heavy metal "cf[ Chapter 2[07[A21#[

NaCN AgCN
R CN R X R NC
Scheme 1

"i# Displacement of halide


The reaction of cyanide salts with alkyl halides was _rst reported in 0743 ð0743JPR"50#59Ł\ and is
now one of the most common ways of introducing a nitrile group into an organic compound[ The
reaction is often conducted in an alcoholic solvent ð30OSC"0#425\ 44OSC"2#261Ł\ and follows the
reactivities expected for an SN1 reaction[ Thus\ when comparing the halogens\ the order of reactivity
is iodide×bromide×chloride\ and ~uorides are inert[ It is possible to selectively displace one
halogen in the presence of a less reactive one\ as illustrated by the synthesis of 3!chlorobutyronitrile
from 2!chloropropyl bromide and KCN ð30OSC"0#045Ł[ The reactivity of alkyl chlorides may be
increased by adding a catalytic amount of sodium iodide to the reaction ð20IEC241Ł[ Neopentyl
halides are inert to reactions with the cyanide ion ð02M0782\ 22JA3050Ł\ whilst halides a! to oxygen
ð28JA0463\ 30JA1685Ł and nitrogen ð39JIC370Ł atoms\ as well as benzylic ð0770CB0534\ 30OSC"0#096\
34JA0138Ł\ and allylic ð25MI 207!90\ 30OSC"0#35\ 42JA2329Ł halides react easily[ The last named\ however\
may give products arising from allylic rearrangement ð21HCA143\ 33JA434Ł\ and from migration of
the double bond into conjugation with the nitrile ð0778JA78\ 96LA"240#243\ 12CB0061Ł[ Halides adjacent
to a carbonyl group are also often easily replaced "esters ð93JA0434Ł^ acids ð30OSC"0#070\ 30OSC"0#143Ł^
ketones ð23CB28\ 33JA107Ł#[ However\ in the last case\ elimination and reduction can be serious side
reactions "ð37CRV078Ł and references therein#[ Another problem with a!haloketones is competitive
attack of the cyanide ion at the carbonyl group "see Section 2[07[0[1[1#\ followed by displacement
of halide by the cyanohydrin\ leading to a!epoxynitriles "Equation "0## ð22JA3188\ 28G267\ 30G30\
33JA295Ł[
General Methods 502
O
O
R2 CN– NC
R1 (1)
R2
R1
Cl

Where necessary\ a variety of methods are available for increasing the nucleophilicity of the
cyanide anion[ Thus\ use of hexamethylphosphoramide "HMPA# as the solvent\ and NaCN rather
than KCN\ results in coordination of the HMPA to the sodium ions\ and the formation of highly
nucleophilic naked cyanide ð67JOC0906Ł[ A similar e}ect can be obtained for KCN by using a
mixture of HMPA and 07!crown!5 ð67JOC0906Ł\ or just 07!crown!5 ð63JOC2305Ł[ For primary and
secondary alkyl chlorides which normally react with cyanide only very slowly\ use of DMSO as the
solvent and temperatures of 89Ð059>C result in improved yields ð59JOC146Ł\ as do glycolic solvents
such as diethylene glycol and polyethylene glycol!299 ð45ACS0086Ł[ Adsorption of NaCN or KCN
onto alumina also gives a highly reactive cyanide source ð68JOC1918\ 79SC168Ł[ The use of lithium
cyanide has been reported to give superior results due to its greater solubility in organic solvents\
such as acetonitrile and DMF ð53JOC0869Ł[
Although the displacement of halides by cyanide is often a straightforward reaction\ one problem
that is sometimes encountered is _nding a suitable solvent for both the organic halide and NaCN[
Alcohols are not always suitable solvents since alcoholysis of the halide can be a side reaction
ð37CRV078Ł\ and solvents such as HMPA and DMSO can cause puri_cation di.culties particularly
for large!scale reactions[ One solution to this problem is to use a two!phase organic:aqueous solvent
system\ and a phase!transfer catalyst such as a quaternary ammonium salt ð62JA2502Ł\ polysorbate!
79 ð78JOC3365Ł\ or 07!crown!5 ð64TL60Ł[ The crown ether catalyses both solid:liquid reactions "e[g[\
BnBr:dry KCN#\ and liquidÐliquid reactions carried out in an acetonitrile:water solvent system[ A
further possibility is to use sonication to induce a reaction between an alkyl halide dissolved in
toluene\ and solid KCN and alumina as described by Ando et al[ ð73CL614Ł[ The yield of nitrile
obtained in this way is reported to be higher than that obtained using 07!crown!5 as a phase transfer
catalyst[ An alternative approach is to use acetone cyanohydrin as the cyanide source\ since in the
presence of 0\4!diazabicyclo ð4[3[9Łundec!4!ene "dbu# or tetramethylguanidine this reagent converts
alkyl halides into nitriles ð82SC1212Ł[
Tertiary alkyl halides are not susceptible to substitution under standard SN1 conditions\ and
under SN0 conditions give the isonitrile[ One solution to this problem has been developed by Reetz
et al[ ð70AG"E#0906\ 72T850Ł[ Thus\ reaction of a tertiary alkyl halide with TMS!CN in the presence
of a catalytic amount of SnCl3 results in formation of the corresponding nitrile with retention of
stereochemistry as shown in Equation "1#[ The reaction is thought to proceed via the corresponding
isonitrile\ with the SnCl3 isomerising this functionality to the nitrile product[ Other groups which
are susceptible to SN0 type reactions such as a!chloro ethers also undergo this reaction "cf[ Section
2[07[1[3#[

TMS-CN/SnCl4
Cl CN (2)

"ii# Displacement of oxy`en `roups


Alcohols can be displaced by cyanide in a one!pot procedure using TMS!Cl\ NaCN\ and catalytic
Nal in acetonitrile:DMF ð70JOC1874Ł[ The method gives good to excellent yields with primary\
secondary and tertiary alcohols^ an example is shown in Equation "2#[ An alternative process
involves a Mitsunobu!type reaction using PPh2\ diethyl azodicarboxylate "dead# and HCN
ð65HCA1099Ł^ acetone cyanohydrin can be used instead of HCN in this reaction ð82SC1370Ł[ For
primary alcohols\ the use of HCN can be avoided by utilising a reagent system composed of Bun2P:
CCl3:KCN:07!crown!5 ð79S0996Ł\ or Ph2P:CCl3:NaCN:DMSO ð56JOC744Ł[ A more common pro!
cedure for the displacement of an alcohol is to _rst form the corresponding tosylate or mesylate
and then displace the sulfonate with cyanide ð41LA"464#0\ 45JA349\ 47JOC686\ 51JCS843Ł[ Alcohols or
DMF are often chosen as the solvent for this reaction[
503 Nitriles] General and Aliphatic Nitriles

TMS-Cl/NaCN/NaI
(3)
OH CN
O O

2[07[0[0[1 Electrophilic substitutions


Cyanogen chloride reacts with the sodium salts of malonic acid and acetoacetate derivatives to
give the cyano derivatives ð0778AC"R#111\ 0785CB0060\ 0788CB532Ł[ However\ use of cyanogen bromide
often results in formation of the bromo derivatives instead[ Primary aliphatic Grignard reagents
also react with cyanogen chloride to give nitriles\ but secondary and tertiary Grignard reagents give
the corresponding chlorides instead ð00CMR"041#277\ 01CMR"044#33\ 03CMR"047#346\ 15BSF0478Ł[ This
problem can be overcome by using cyanogen instead of cyanogen chloride\ in which case all aliphatic
Grignard reagents give nitriles ð00MI 207!90\ 01MI 207!90\ 03MI 207!90\ 04AC"R#17\ 19AC"R#253Ł[ A wide
variety of highly functionalised organozinc compounds have been shown to react with Ts!CN
to give the corresponding nitriles with good yields ð82TL3512Ł[ Arylisocyanoates ð54CB2551Ł and
cyanamides ð41CB286Ł also react with Grignard reagents to give nitriles[

2[07[0[1 Synthesis via Addition Reactions

2[07[0[1[0 Addition to CC multiple bonds


HCN adds to unactivated alkenes only with di.culty\ requiring high temperatures and pressures\
and the reaction is generally not synthetically useful ð37CRV078Ł[ Nevertheless\ a number of organ!
ometallic catalysts for this reaction have been discovered\ and are the subject of a number of reviews
ð66OR"14#144\ B!71MI 207!90\ 74MI 207!90Ł[ Co1"CO#7 catalysed addition of HCN to unactivated alkenes
occurs in a sealed tube at 029>C ð43JA4253Ł[ Best results are obtained with terminal alkenes\ and
Markovnikov addition to the alkene is observed[ PdðP"OPh#2Ł3\ and NiðP"OPh#2Ł3 catalyse the
addition of HCN to both norbornene and ethene with yields of exo!1!cyano!norbornane up to 72)
from reactions carried out at 019>C in benzene ð58CC001Ł[ The mechanism of this reaction has been
investigated ð70CC0987Ł\ and it has been shown that the HCN adds in a cis fashion to the alkene[
Jackson and co!workers have modi_ed the above palladium and nickel catalysts by introducing
the chiral 1\2!O!isopropylidene!1\2!dihydroxy!0\3!bis"diphenylphosphino#butane "diop# ligand "0#\
giving catalysts "diop#1Pd\ and "diop#1Ni respectively ð68JA5017\ 71AJC1930Ł[ The addition of HCN
to norbornene catalysed by these chiral catalysts\ gave exo!1!cyanonorbornane in up to 84) yield
and 15) ee[ Linear alkenes gave mainly the product of anti!Markovnikov addition\ and the
reaction has been shown to be susceptible to steric hindrance\ as attempted hydrocyanation of
6\6!dimethylnorbornene was unsuccessful[ The mechanism of the reaction has been investigated
ð71AJC1942\ 71TL0510\ 77OM0650Ł\ and the corresponding platinum catalyst "diop#1Pt was found not
to be e}ective as a catalyst[

O
PPh2
PPh2
O
(1)

Anti!Markovnikov addition of HCN across an alkene can be achieved via a hydrozirconation


reaction as shown in Scheme 1 ð76TL184Ł[ Thus\ addition of zirconocene hydrochloride to an alkene
gives the alkyl zirconocene chloride "1# in which the zirconium adds to the least hindered end of the
alkene[ Treatment of compounds "1# with either t!butyl or TMS!isocyanide results in insertion into
the carbon zirconium bond giving the imine derivative "2#[ Treatment of compounds "2# with iodine
then gives the nitriles\ the best yield being obtained with t!butyl isocyanide derivatives[ The reaction
is normally highly regiospeci_c[ However\ internal alkenes are isomerised to terminal alkenes under
the reaction conditions\ and so give terminal nitriles[ Aromatic or heteroaromatic alkenes give
General Methods 504
signi_cant amounts of the more hindered nitrile\ as shown by 1!vinyl furan which gives 1!furyl!
propionitrile "3# as the sole product "see also Section 2[07[1[1[2#[

Cl N C NR2
H I2
Cp2Zr R2 NC
R1 + Cp2Zr R1 Cp2Zr R1 R1
Cl
Cl
R2 = But or TMS (2) (3)

O
CN
(4)

Scheme 2

Unlike unactivated alkenes\ cyanide adds with ease to both electron!de_cient conjugated alkenes
ðB!81MI 207!90Ł\ and electron!rich enol ethers and enamines[ However\ as these reactions inevitably
lead to nitriles containing heteroatoms\ they are dealt with in the appropriate sections later in this
chapter[

2[07[0[1[1 Addition to CX multiple bonds


The addition of cyanide to carbonyl compounds giving a!hydroxynitriles "cyanohydrins# was
discovered as early as 0721 when Winkler reacted HCN with benzaldehyde and obtained man!
delonitrile ð0721LA"3#135Ł[ Since then\ numerous variations to the reaction conditions have been
investigated\ so that conditions are available under which aromatic and aliphatic aldehydes\ and
aliphatic and monoaromatic ketones give good yields of the corresponding cyanohydrins
ð0761LA"053#144\ 95CB0745\ 05CB0272\ 33OSC"1#18\ 34JOC330\ 44OSC"2#325Ł[ However\ the addition of HCN
to a carbonyl group is reversible\ and for diaromatic ketones\ the position of equilibrium is towards
the carbonyl compound and HCN[ In many cases\ an advantageous procedure involves _rst forming
the bisul_te adduct of the carbonyl compound and then reacting this with cyanide ð0785CZ89\
05CB0272\ 21MI 207!90Ł[ For modi_cations leading to optically active cyanohydrins\ see Section
2[07[1[3[0[
The addition of TMS!CN to aldehydes and ketones was _rst reported simultaneously by Evans
et al[ ð62CC44\ 62TL3818Ł\ and by Lidy and Sundermeyer ð62CB476Ł[ With aldehydes\ the addition
occurs at RT\ but for ketones the reaction either needs to be conducted above 099>C\ or needs to
be catalysed[ The catalyst can be either a base "tertiary or hindered secondary amines\ phosphines\
triphenylarsine and triphenylantimony ð80CL426Ł\ calcium ~uoride ð78CL0282\ 82BCJ1905Ł\ solid cal!
cium or magnesium oxide ð82BCJ1905Ł\ KCN:07!crown!5 ð62TL3818\ 72TL3448Ł or Bu3NCN
ð62TL3818Ł# or a Lewis acid such as zinc iodide ð62CC44\ 73TL3472Ł\ TMS!OTs ð70T2788Ł\ a lanthanide
trichloride "SmCl2\ CeCl2\ and LaCl2#\ Eu"fod#2 ð76TL4402Ł\ ðHC"Py#2W"NO#1"CO#Ł"SbF5#1
ð82TL1164Ł\ or ferric or tin montmorillonite ð78CL0282\ 82BCJ1905Ł[ Yb"CN#2 also catalyses this
reaction\ despite not being a Lewis acid\ allowing the formation of cyanohydrins from acid sensitive
ketones ð80CL0336Ł[ Additionally\ zinc iodide and solid KCN can be used together in a combined
acid base catalyst ð67S108Ł[ Probably the most widely used catalyst is zinc iodide\ which has been
reported to catalyse the addition of TMS!CN ð67TL2662Ł\ t!butyldimethylsilyl cyanide "TBDMS!
CN#\ and t!butyldiphenylsilyl cyanide "TBDPS!CN# ð82JOC048Ł to even sterically hindered ketones\
and in the case of TMS!CN to give cyanohydrin silylethers from ketones which do not form stable
cyanohydrins ð63JOC803Ł[ However\ 07!crown!5:KCN has been reported to give even better results\
especially with ketones ð72TL3448Ł[ For the lanthanides\ depending upon the catalyst used the
product is the cyanohydrin\ the cyanohydrin silyl ether\ or a mixture of both in a combined yield
of 24Ð87)[ Best results are obtained with aromatic aldehydes\ and the worst results occur with
aliphatic ketones[ This method has been extended to chiral a!hydroxy\ and a!amino aldehydes
ð81CL0058Ł\ and Eu"fod#2 was found to catalyse the formation of the syn!diastereomer "Equation
"3##[ Good results have been obtained with benzyl!protected hydroxy aldehydes and with dibenzyl
and butoxycarbonyl!protected amino aldehydes\ and the degree of diastereoselection increases as
the steric bulk of the side chain R of the aldehyde increases[ The diastereoselective addition of TMS!
CN to a!dibenzylamino aldehydes has also been investigated by Reetz et al[\ who found that use of
505 Nitriles] General and Aliphatic Nitriles
TiCl3\ or MgBr1 as catalysts gave the chelation controlled product\ whilst BF2\ ZnBr1 and SnCl3
catalysts gave the diastereomeric products ð77TL2184Ł[

X X
TMS-CN/Eu(fod)3 CN
R R (4)

O OH

TMS!CN adds to a\b!unsaturated ketones in the presence of a variety of Lewis acid catalysts\ to
give either the cyanohydrin resulting from 0\1!addition\ or the 3!ketonitrile resulting from 0\3!
addition to the enone ð66OR"14#144\ 72T856Ł[ The product is determined by the structure of the
ketone\ although in some cases it is possible to isomerise the kinetically formed 0\1!adduct to the
thermodynamically more stable 0\3!adduct by prolonged reaction[ See also Section 2[07[1[3[2[
Acetone cyanohydrin can also be used as the cyanide source\ providing a catalyst is present[
Evans and Truesdale originally introduced the use of the cyanide ion as the catalyst at 019Ð039>C
ð62TL3818Ł\ though Lewis acid catalysts have since been found to be more e}ective[ Catalysts based
on lanthanide alkoxides ð82CL264Ł\ titanium and zirconium alkoxides\ and aluminum alkyls have
been used ð89CL0060Ł\ although with aluminum as the metal\ better results are obtained using
ligands which contain a phenol\ imine and an amide ð80CL034Ł[ Diethylaluminum cyanide is also
an e}ective cyanide source\ and has been reported to be advantageous in electronically di.cult
cases ð61JA3543Ł[
If cyanide is allowed to react with a carbonyl compound in the presence of a primary or secondary
amine\ then the product is the a!aminonitrile[ This procedure was discovered in 0749\ and is called
the Strecker reaction ð0749LA"64#16Ł[ Numerous reaction conditions have been developed for this
reaction\ allowing the preparation of a!aminonitriles derived from aromatic and aliphatic aldehydes\
aliphatic and monoaromatic ketones ð0779CB271\ 95CB0070\ 97CB1814\ 20JCS0280\ 20JCS0783\ 44OSC"2#164Ł[
A modi_ed procedure in which sodium hydrogensul_te is _rst added to the aldehyde to form the
bisul_te adduct has been reported to give higher yields in some cases ð62OSC"4#326\ 76TL436Ł[ The
mechanism of the Strecker reaction has been the topic of considerable debate[ However\ from a
synthetic point of view\ the most important point is that it is possible to treat a cyanohydrin with
an amine and obtain an a!aminonitrile[ This is often synthetically more convenient than the
traditional one!pot Strecker reaction ð23JA1086\ 23JPR164\ 33OSC"1#18Ł[ A chiral version of the Strecker
reaction has also been reported ð82BSF402Ł\ in which cyanide and ammonia are _rst reacted with a
chiral ketone to give a chiral aminonitrile[ This then functions as a chiral ammonia equivalent in a
second Strecker reaction with an aldehyde giving optically active aminonitriles after a hydrolytic
workup to cleave and regenerate the ketone!derived chiral auxiliary[ A number of other examples
of chiral Strecker reactions based on the use of chiral auxiliaries on the nitrogen atom have been
reported ð69CJC0770\ 60CB2483\ 79CB609\ 79LA101\ 74LA455Ł[
With hindered ketones\ the Strecker reaction sometimes gives the cyanohydrin rather than the
aminonitrile[ However\ it has been reported that sonication of the reaction mixture ensures for!
mation of the aminonitrile ð75TL2174Ł[ Alumina has been shown to be a good catalyst for the
Strecker synthesis of a!aminonitriles\ providing the reaction mixture is sonicated ð76CL576Ł[ The
method works well for aldehydes and acetophenone\ and has the advantage of a much simpler
workup procedure compared to more classical methods^ the solids are _ltered and the solvent
"acetonitrile# is evaporated to leave the aminonitrile[ Aminonitriles can also be prepared from the
TMS ethers of cyanohydrins by treatment with an amine ð73TL3472Ł[
Diethyl phosphorocyanidate can be used as a cyanide source for the Strecker reaction and this
has the advantage that the reaction can be carried out in an organic solvent under entirely anhydrous
conditions\ allowing the preparation of water!sensitive aminonitriles ð68TL3552Ł[ Mai and Patil
ð74SC046Ł have reported a general procedure for the preparation of a!aminonitriles from a wide
range of aldehydes\ methyl ketones and amines using TMS!CN as the cyanide source[ Thus\
treatment of the aldehyde or ketone with the amine for 0 minute at 099>C in the absence of a solvent
results in formation of the iminium salt which when treated with TMS!CN for a further minute at
099>C gives the a!aminonitrile[ The only limitation of this method appears to be that ammonia
cannot be used as the amine due to its volatility[
A reaction related to the Strecker synthesis is the addition of HCN to a preformed carbon
nitrogen double bond[ Suitable substrates for this reaction include imines ð23JA1984\ 35JA736Ł\ oximes
ð31JOC053\ 32JPR160\ 33JA0541Ł\ hydrazones ð0785CB51Ł and semicarbazones ð23JPR06\ 66JOC1990\
77OSC"5#223Ł[ The Lewis acid catalysed addition of TMS!CN to preformed imines and oximes has
also been reported ð64ABC460\ 64CL220Ł[ The most e}ective Lewis acid was found to be Znl1\ and by
General Methods 506
use of imines with a chiral auxiliary on the nitrogen atom\ chiral aminonitriles could be obtained
ð64CL626Ł[
With a\b!unsaturated aldehydes\ the Strecker reaction carried out under traditional conditions
often fails ð57JBC"132#5998\ 63ACS"B#206Ł[ However\ by using TMS!CN as the cyanide source\ and
reacting it with a preformed imine\ then good yields of b\g!unsaturated!a!aminonitriles can be
obtained ð73JOC1521Ł[

2[07[0[2 Synthesis via Elimination Reactions

2[07[0[2[0 Elimination from carbonyl derivatives


The dehydration of oximes is one of the most common ways of preparing nitriles\ and a large
number of reagents have been found to carry out this transformation\ some of which are set out in
Table 0[ As Table 0 shows\ many of the reagents which dehydrate oximes also dehydrate amides
"see Section 2[07[0[2[1#[ This reactivity can be explained by considering the similarity between the
structure of an oxime and the tautomeric form of an amide as indicated in "4# and "5#[ Botteghi et
al[ have examined the dehydration of chiral oximes to nitriles\ and report that many of the reagents
that carry out this transformation "Ac1O\ HCO1H\ SeO1\ dicyclohexylcarbodiimide "dcc#\ cause
partial racemisation[ However\ they found that carbonyl diimidazole dehydrated oximes without
causing any racemisation ð71SC14Ł[
OH H
N N

R R OH
(5) (6)

Dimethylhydrazones can be oxidised to nitriles in moderate to excellent yields using either


mcpba\ or H1O1 and SeO1 ð78S112Ł[ Alternatively\ reaction with methyl iodide gives the hydrazone!
ammonium salt which on treatment with NaOMe eliminates trimethylamine and Hl\ giving the
nitrile ð51JOC3261Ł[
Aldehydes can be converted directly into nitriles in one!pot procedures involving reaction with a
number of hydroxylamine!based reagents[ Examples include hydroxylamine hydrochloride and
selenium dioxide in pyridine ð68S611Ł\ hydroxylamine and formic acid in re~uxing water ð68S001Ł\
O!aminobenzoylhydroxylamine:BF2 ð77SC1068Ł\ O!"1\3!dinitrophenyl#hydroxylamine:KOH
ð64JOC015Ł\ O\N!ditri~uoroacetylhydroxylamine:pyridine ð48JA5239Ł and hydroxylamine sulfate
ð65HCA1675Ł[ Alternatively\ reaction of dimethylhydrazine with an epoxide gives the reagent "6#
which has been shown to react with various functionalised aldehydes leading to nitriles ð67S290Ł[
Reaction of an aldehyde with ammonia and an oxidising agent such as iodine ð55BCJ743Ł\
CuCl1:O1:NaOMe ð52RTC646Ł\ or lead tetraacetate ð54CI"L#877Ł also results in formation of the
nitrile[
Me Me

HN N + OH

(7)

2[07[0[2[1 Elimination from carboxylic acid derivatives


Heating an acid in the presence of anhydrous ammonia results in the formation of the nitrile via
dehydration of the ammonium salt ð35MI 207!90Ł[ Alternatively\ a dehydrating agent such as ethyl
polyphosphate ð72S031Ł or MsCl:pyridine ð71OPP285Ł can be used[ Acids can also be converted into
nitriles in a one!pot procedure involving treatment with phosphorus pentachloride and TsNH1
ð44OSC"2#535Ł[ Alternatively\ treatment of a carboxylic acid with O!methyl hydroxylamine and
PPh2:CBr3 followed by photolysis gives the corresponding nitrile ð82SC0950Ł[ When a carboxylic
acid is heated to 049Ð299>C in the presence of a nitrile\ an equilibrium is established in which the
original acid is converted into a nitrile[ The yield of this process can be improved if the original
507 Nitriles] General and Aliphatic Nitriles
Table 0 Reagents for the dehydration of amides or oximes to nitriles[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Rea`ent Amide dehydration Oxime dehydration Comments
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
TFA 68S45
Ac1O 96CB1698 44OSC"2#589
TFAA:pyridine 66TL0702 66TL0702 Pyridine is not always needed
89T7156[
CH2COCl 0773CB0460 Other acid chlorides can also be used[
CCl2COCl 74S073 72S637 Very mild conditions[
2\4!NO1C5H2COCl 34JA050 34JA0634
COCl1 91CB2536 Pyridine is usually the reaction solvent[
CCl2OCOCl 75TL1192 75S0926 Tolerates many other functional groups[
PhOCOCl 60CJC0210 Other chloroformates can also be used[
"Imidazole#1CO 73CPB1459 62CC514 With amides allyl bromide is a coreagent[
DCC 50JOC2245 59BCJ0271\ 63CB0110 Other dimides can also be used[
p!Cl!C5H3!SCOCl 69CC0903
Tf1O:Et2N 65TL592
Ph2P¦OTf Tf− 64TL166 PPh2 ¦Tf1O
SOCl1 0782LA"163#201 0783BSF0956
¦ −
Me1N 1CHCl Cl 79SC368 73TL2254 DMF¦ðSOCl1 or "ClCO#1Ł
Me1N¦1CCl1 Cl− 63S452
TsCl or PhSO1Cl 44JA0690 64S491 Pyridine or Et2N is added[
ClSO1NCO 68S116 68S116
ClSO1F 79S548
SCl1:Et2N 68ZN"B#400 Other similar sulfur compounds were
also used[
"1!Py#OSO1"!1!Py# 75TL0814 Also converts thioamides into nitriles[
Me1S:Cl1 64SC312
Me2N¦SO1− 67S691
MeSCH1NMe1¦I− 64SC188
Burgess reagent 77TL1044 Tolerates many other functional groups[
PCl4 33OSC"1#268
P1O4 44OSC"2#382 07M139
POCl2 34OS"14#52 67ZN"B#0922 For oximes\ similar reagents were also
used[
"EtO#2P:I1 68TL0614 68TL0614
Catechol!PCl2 52CB0276
PPh2:CCl3:Et2N 60CB0929 60CB1914 Also converts thioamides into nitriles[
PPh2!polymer 66S30 66S30
Pl2:Et2N or P1I3 67S894\ 79CC433
P"NEt1#2 62CL466 Also converts thioamides into nitriles[
Esters of PPA 71S480\ 78SC0320 50BCJ88
"Cl1PN#2 61CJC2746 62JOC0959
Cyanuric chloride 79S546 61CC0115 Reagent is cyclo"ClCN#2[
TiCl3:organic base 60TL0490
AlCl2:NaCl 39JA0321
BF2 26JA0191
Ag1O:Etl 82TL0470 Non!acidic conditions[
Cu"OAc#1 72S639 Acts catalytically[
Rh carbonyl clusters 77CL174 At 7 atm under a CO atmosphere[
MeCH1C"OEt#1:BF2 50JOC1191
CCl1 62TL1010 62TL1010
1\3!NO1C5H2F:KOtBu 64SC188
SeO1 67S692 Can be used catalytically[
Electrochemically 78JOC1138
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*

{donor| nitrile is a dinitrile ð60JOC2949Ł[ Treatment of a carboxylic acid with chloro!


sulfonylisocyanate\ followed by a tertiary amine\ also results in conversion of the acid into a nitrile
ð56CB1608\ 69OS"49#07Ł[ Dithioacids are converted into nitriles on treatment with hydroxylamine in
pyridine ð21BSB085Ł
Esters are converted into nitriles by treatment _rst with hydroxylamine to give the hydroxamic
acid\ then with phosphorus tribromide as shown in Scheme 2 ð76S057Ł[ An alternative one!pot
procedure involves treatment of an ester with two equivalents of aminodimethylaluminum\ giving
nitriles in 49Ð80) yield ð68TL3896Ł[ A variety of TMS esters are converted into nitriles by treatment
with P1O4\ "TMS#1NH\ and Nal at 89>C ð76IJC"B#396Ł[
Acid chlorides can be converted into nitriles in a one!pot procedure by treatment with
H1NSO1NH1\ and good!to!excellent yields are obtained for a variety of acid chlorides ð71TL0494Ł[
General Methods 508
O O
H2NOH•HCl 2PBr3
R CN
R OEt 70–98% R NHOH 83–94%

Scheme 3

Treatment of acid halides with the chlorophosphazine "7# "the reagent also contained 14) of the
eight!membered ring derivative#\ similarly gives nitriles in 4Ð84) yields ð62TL2714Ł[

Cl Cl
P
N N
Cl P P Cl
N
Cl Cl
(8)

A very large number of reagents have been reported to dehydrate unsubstituted amides to nitriles\
some of which are shown in Table 0[ For simple nitriles\ it is often su.cient to strongly heat the
amide and collect the nitrile by distillation as it forms ð44OSC"2#657Ł[ However\ many solids such as
silica\ pumice and alumina are known to catalyse the dehydration ð37CRV078Ł[ The Burgess reagent
"CH2O1CN−SO1N¦Et2# dehydrates even highly functionalised amides to nitriles in 71Ð81) yields
at RT in dichloromethane ð77TL1044Ł[ For small!scale reactions\ probably the reagent of choice is
tri~uoroacetic anhydride "TFAA# "either with pyridine ð66TL0702Ł or without ð89T7156Ł#\ which
dehydrates amides under very mild conditions at RT or below[ Furthermore\ the reagent causes no
racemisation of labile\ chiral centres ð89T7156Ł\ and gives only volatile by!products[ Chloro!
sulfonylisocyanate has also been reported to dehydrate chiral amides to nitriles without causing
racemisation ð71SC14Ł[ For large!scale dehydrations\ or for dehydrating unfunctionalised amides\
POCl2 ð96CB1698\ 23CB0651Ł or SOCl1 ð0782LA"163#201Ł is probably the reagent of choice[ In the case
of POCl2\ a number of di}erent reaction conditions involving addition of NaCl or P1O4 or use of
various solvents have been reported to result in increased yields ð37CRV078Ł[ Whilst both oxalyl
chloride and thionyl chloride act as dehydrating reagents in their own right\ addition of DMF to
the reaction mixture results in a much more reactive dehydrating agent[ It is thought that in both
cases the chloroiminium salt "8# is the actual dehydrating agent ð79SC368Ł[

Me + Cl
N Cl–
Me
(9)

N!Alkylated amides can also be converted into amides\ by a process called the Von Braun
reaction[ Thus\ N!t!butylamides are converted into nitriles upon treatment with POCl2 ð72OPP186Ł
or PCl4\ and N!TMS amides are converted into nitriles on treatment with an acid chloride ð61TL1946Ł[
Secondary amides are also converted into nitriles on treatment with Wilkinson|s reagent
"RhCl"PPh2#2# at 149>C ð69TL0852Ł[ Primary\ secondary and tertiary amides are all converted into
nitriles by treatment with bis"trimethylsilyl#amine at 079>C ð69JOC2142Ł[ Treatment of a primary
amide with two equivalents of TMS!Cl gives the N\O!bis!TMS adduct "09#\ which on treatment
with either a basic "Bu3NF# or acidic "FeCl2\ ZnCl1\ AlCl2\ or iron phthalocyanine# catalyst is
converted into the nitrile in 84Ð099) yield ð75TL236Ł[

N-TMS

R O-TMS
(10)

1\1?!Dipyridyl sul_te converts both amides and thioamides into nitriles ð75TL0814Ł\ as does CCl1
ð62TL1010Ł and PPh2:CCl3 ð60CB0929Ł\ whilst diethyl carbonate:N!methylmorpholine selectively
519 Nitriles] General and Aliphatic Nitriles
converts thioamides into nitriles ð74JOC1212Ł as does HgCl1:MeNH1 ð48JCS3939Ł[ Imino ethers are
converted into nitriles on treatment with sodium ethoxide ð57TL50Ł[

2[07[0[2[2 Elimination from nitro compounds


Aliphatic nitro compounds can be converted into nitriles by a number of reagents\ many of which
are phosphorus"III# compounds[ Thus\ the reaction with Pl2:Et2N occurs at RT in CH1Cl1 ð79CC433Ł\
and the same authors also report the use of P1I3 for this transformation ð68TL2884Ł[ Phosphorus
trichloride in pyridine has been reported to convert a variety of nitriles including unsaturated\
aryl\ and a!oxygenated derivatives into nitriles ð66JOC2845Ł[ Olah et al[ have reported that this
transformation can also be achieved either by treatment with hexamethylphosphorus triamide
"HMPT# in re~uxing dichloroethane\ or by reagents of the type R2N¦SO1− in re~uxing dichloro!
methane ð68S25Ł[ POCl2 is the only phosphorus"V# compound reported to dehydrate nitro groups
to nitriles ð69ACS2313Ł[ A rhodium cluster compound has been used to convert nitropropane
into propionitrile ð74CL0228Ł[ Treatment of sodium borohydride with sulfur gives a reagent of
composition NaBH1S2 which reduces aliphatic nitro compounds to nitriles ð60CJC1889Ł[ Treatment
of a nitro compound with KH followed by bis"TMS#!sul_de\ then photolysis also results in nitrile
formation ð80JCS"P0#0382Ł[

2[07[0[2[3 Elimination from amines and amino acids


Dehydrogenation of an amine to a nitrile can be e}ected in the gas phase by a variety of catalysts
including nickel\ copper\ zinc sul_de and cadmium sul_de ð37CRV078Ł[ Hydrocarbons are formed
as by!products[ However\ this can be suppressed by carrying out the dehydrogenation in the presence
of ammonia or oxygen[ A variety of similar processes have been developed in which the amine is
generated in situ by the dehydrogenation catalyst from a precursor such as an amide\ aldehyde\
alcohol\ alkene or alkyne ð37CRV078Ł[ A number of these processes are of considerable industrial
importance[
Oxidation of an amine with Pb"OAc#3 ð54TL350Ł\ IF4 ð50JOC1420Ł or NiO1 ð52CPB185Ł results in
formation of the nitrile[ Treatment of an amine with a brominating or chlorinating agent under
basic conditions results in the formation of the corresponding nitrile by an N!halogenation:
dehydrohalogenation mechanism ð0784AC"R#178\ 0784CB0571Ł[ The amine can also be generated in
situ by a Ho}mann degradation\ and this then provides a method for the conversion of an amide
into a nitrile with one less carbon atom ð0773CB0393\ 0773CB0819\ 0775CB0322\ 0775CB0711Ł[ In a related
reaction\ a!amino acids react with chloramine!T ð05BJ"09#208\ 05PRS121\ 06BJ"00#68Ł\ sodium hypo!
bromite ð51B42Ł or N!bromosuccinimide "NBS# ð50JBC"125#604Ł to give nitriles by an oxidative
decarboxylation process[

2[07[0[3 Synthesis from other Nitriles


The acidity of the protons adjacent to a nitrile group provides an easy way of converting a
relatively simple nitrile into a more complex one\ and a comprehensive review has been written on
this subject ð73OR0Ł[ A number of bases can be used to deprotonate nitriles\ including sodium
hydroxide ð44OSC"2#110\ 44OSC"2#112\ 63AG"E#554Ł\ sodamide ð44OSC"2#108\ 57JOC2391Ł\ BunLi
ð57JOC2391\ 70CCC0571\ 72TL2498Ł and LDA ð75JOC2996\ 82T7312Ł\ though with the weaker bases
polyalkylation of the resulting anions is sometimes a problem and the reagent of choice is probably
LDA or a similar lithium amide base[ The resulting carbanions have been reported to react with
various electrophiles including alkyl halides ð44OSC"2#108\ 63AG"E#554\ 79T664\ 82T7312Ł\ alkyl tosylates
ð72SC24Ł\ esters ð34JA1041\ 72TL1948Ł\ aldehydes ð57JOC2391Ł\ ketones ð57JOC2391\ 70CCC0571\ 75JA0200\
76TL0500Ł and cyanohydrins ð72TL2498Ł[ Nitrile carbanions will also react intramolecularly\ with
alkyl halides giving cyclic nitriles ð44OSC"2#112\ 63AG"E#554Ł\ with epoxides providing a route to
cyclic g!hydroxynitriles ð78TL3656Ł\ and with esters giving cyclic b!ketonitriles ð76TL353\ 76TL3534Ł[
Electrolysis of an aryl halide in acetonitrile results in formation of the acetonitrile enolate which
reacts with ketones and esters to give b!hydroxy and b!ketonitriles respectively ð82T4980Ł[
The protons of an alkyl cyanoacetate are very acidic\ and will undergo a variety of alkylation
reactions ð46OR"8#096\ 82T7312Ł\ including Michael additions with suitable a\b!unsaturated carbonyl
General Methods 510
derivatives ð75TL2242Ł\ and reductive alkylation by aldehydes in the presence of KHFe"CO#3
ð64JCS"P0#0162Ł[ Mitsunobu and co!workers have reported that the same compounds react with
diols in the presence of PPh2 and diethyl azodicarboxylate "dead# to give cyclic a!carboxynitriles
ð65TL1344Ł[ Alkyl dicyanoacetates are readily methylated under phase!transfer catalysis ð78S501Ł\
and react with other nucleophiles under basic conditions ð77S870Ł[
a\b!Unsaturated nitriles are readily prepared by a variety of methods "Chapter 2[08#\ and a variety
of reagents are available to reduce them to the corresponding saturated nitriles[ For nitriles that
contain no other reducible functional groups\ the reagents of choice are probably sodium borohy!
dride ð65BCJ1532\ 67CJC30Ł or Wilkinson|s catalyst ð58JOC2573Ł[ With some a\b!unsaturated nitriles\
sodium borohydride in conventional solvents is not an e}ective reducing agent[ However\ addition
of methanol and pyridine has been reported to give a more reactive reducing agent ð77SC570Ł\ as
has a combination of NaBH3 and PdCl1 ð63JOC2949Ł[ For more functionalised nitriles\ reducing
agents speci_c for a\b!unsaturated carbonyl derivatives including nitriles have been reported[ These
include] Mg in MeOH ð64JOC016Ł^ Mo"CO#5 and phenylsilylhydride ð76JOC1465Ł^ NaHFe1"CO#7
ð67JA0008Ł^ Fe"CO#4:NaOH ð61JOC0431Ł^ Rh5"CO#05:CO:H1O ð62CL268Ł^ diphenylsilane\ zinc chlo!
ride and Pd"PPh2#3 ð75JA6203Ł^ copper hydride complexes ð79JOC056Ł^ Pd:C:Et2NH¦HCO1−
ð67JOC2874Ł^ NaHCr1"CO#09 ð65S485Ł^ CrSO3:DMF:H1O ð55JA3853Ł^ and sodium hydrophosphite
ð74JOC2397Ł[
Acrylonitrile and other a\b!unsaturated nitriles are also very good Michael acceptors for both
radicals and carbanions\ and both have been widely used to prepare a!unsubstituted nitriles[ Suitable
radical sources include thioacyl imidazoles ð76TL3534Ł\ xanthates ð73AG"E#58Ł\ alkyl halides ð75JA139\
76CC0996\ 76JOC2548\ 89TL1864Ł\ organomercury compounds ð74T3914Ł and nitroalkanes ð74CL524\
74JA3221Ł[ Amongst the carbanion sources that have been used are enamines ð73JOC0202Ł\ cyanide
ð0767LA"080#22Ł\ hydrocarbons with acidic protons such as cyclopentadiene ð34JA590Ł and enolates
of esters\ aldehydes\ ketones\ nitriles\ cyanohydrins\ nitro compounds and sulfones ð37CRV078\
77OSC"5#755Ł[ In addition\ a\b!unsaturated nitriles are good alkene components for both DielsÐAlder
ð31CRV208\ 36JA462Ł and 0\2!dipolar cycloadditions ð72TL2336\ 73JOC165Ł\ thus providing access to a
wide variety of cyclic nitriles[

2[07[0[4 Miscellaneous Methods of Synthesis


Isonitriles can be thermally isomerised to the thermodynamically more stable nitriles[ By employ!
ing ~ash vacuum pyrolysis\ or short contact ~ow pyrolysis\ the rearrangement can be made to occur
without isomerising any double bonds in the isonitrile\ and with complete retention of con_guration
at the isonitrile centre as shown in Equation "4# ð76CB0Ł[

flash vacuum pyrolysis, 550 °C, 10–2 torr


Ph or short contact flow pyrolysis, 350 °C Ph
(5)
95%, 95% ee
NC CN

Aldehydes can be converted into the chain extended nitrile via the a\b!unsaturated nitro compound
as shown in Scheme 3[ Ketones are converted into the chain!extended nitriles on treatment with
tosylmethyl isocyanide "TsMIC# in the presence of potassium t!butoxide "Equation "5## ð62TL0246\
66JOC2003Ł\ or by treatment with carboethoxyhydrazine:HCN followed by Br1:NaOMe ð66JOC1990\
77OSC"5#223Ł[ The same chain!extending transformation can be carried out by treating either an
aldehyde or a ketone with 1\3\5!triisopropylphenylhydrazine followed by KCN in re~uxing methanol
ð66CC179Ł[ An alternative procedure involves treating a carbonyl compound with TMS!formamidine
"00# and sec!BuLi\ giving the enamine as shown in Scheme 4[ Exchange of the formamidine
for N\N!dimethylhydrazine followed by Ho}mann elimination with methyl iodide:base gives the
corresponding nitriles ð82TL4728Ł[ Electrochemical reduction of the nitro alkene in the presence of
TiCl3 gives the nitrile ð76S520Ł[

TiCl4/Et4N+TsO–
O +5– 6 e–
MeNO2
NO2
R 64–95% R CN
R
Scheme 4
511 Nitriles] General and Aliphatic Nitriles

R1 TosCH2N=C R1
O CN (6)
KOBut
R2 R2

R1
Me i, Me2NNH2
R1 TMS N ii, MeI R1
BusLi R2 N Me
O + CN
iii, NaOMe
R2 NBut R2
(11) NBut

Scheme 5

a!Amino ketones can be converted into imine derivatives\ as shown in Scheme 5\ which then
undergo a fragmentation reaction giving nitriles ð52HCA0089Ł[

O NX

R3 R3 R3 CN
N N
R1 R2 R1 R2
X = OH, O2CMe, O2CPh
Scheme 6

2[07[1 ALIPHATIC NITRILE SYNTHESIS

2[07[1[0 Saturated Unsubstituted Nitriles


A number of routes for the synthesis of unfunctionalised aliphatic nitriles have been developed
using organoboranes as the starting material[ Addition of a trialkylborane to methylcopper gives a
reagent which enables the boron alkyl groups to undergo a Michael addition to acrylonitrile\ as
shown in Equation "6# ð65TL144Ł[ Trialkylboranes also react with CuCN\ Cu"OAc#1\ and Cu"AcAc#1\
to give alkylnitriles in good!to!excellent yield ð78CC155Ł[ The same reaction can be achieved by
treating a trialkylborane with NaCN and lead tetraacetate ð73CC287Ł[ Electrolysis of a trialkylborane
"R2B# in acetonitrile results in transfer of the alkyl groups to the acetonitrile\ giving nitriles of the
form RCH1CN ð64CL412Ł[ Hydroboration of an alkene with 8!borabicycloð2[2[0Łnonyl "8!BBN#
gives a trialkylborane\ which in the presence of potassium 1\5!di!t!butyl!3!methylphenoxide reacts
with chloroacetonitrile to give the nitrile in which two carbon atoms have been added to the alkene
ð71TL1966Ł[ In the same way\ trialkylboranes react with dichloroacetonitrile to give a!branched
nitriles in which two groups have been transferred from boron to the acetonitrile[ The reaction can
also be carried out in two steps\ using two di}erent alkylboranes\ thus allowing two di}erent alkyl
groups to be introduced ð58JA5743\ 69JA4680Ł[ Trialkylboranes also react with diazoacetonitrile giving
alkylnitriles ð57JA5780Ł[
[R3BMe]Cu
R (7)
CN CN
84–93%

2[07[1[1 b! and More Remotely Unsaturated Nitriles

2[07[1[1[0 Aliphatic nitriles with one double bond


Treatment of an allyl alcohol with HCN in the presence of CuCl and NH3Cl results in formation
of the b\g!unsaturated nitrile ð40LA"461#38Ł[ Allylic acetates and carbonates are converted into b\g!
unsaturated nitriles by treatment with TMS!CN\ and Pd"PPh2#3 ð82JOC05Ł[ The reaction proceeds
via a p!allyl complex\ which is attacked by cyanide anion at the least hindered end[ Allyl phos!
phonates are converted into b\g!unsaturated nitriles on treatment with cyanide anions^ the reaction
proceeds without allylic transposition and has no e}ect on the double!bond geometry ð70BCJ518Ł[
Aliphatic Nitrile 512
Allyl methyl ethers are converted into b\g!unsaturated nitriles by treatment with TMS!CN in the
presence of p!methoxyphenyldiphenylmethyl perchlorate ð76CL0056Ł[ The reaction proceeds largely
without allylic displacement[ An alternative transformation of allyl ethers involves oxidation to the
allyl cation with 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#\ followed by cyanation with
TMS!CN in the presence of a catalytic amount of lithium perchlorate giving b\g!unsaturated
cyanohydrins as shown in Equation "7# ð76CL0700Ł[ Best results "×79)# are obtained with methyl
ethers\ t!butyldimethylsilyl "TBDMS# and phenyl ethers give much lower yields[

NC
R2 OR1 ddq/TMS-CN R2 OR1
(8)
LiClO4(cat.)
R3 R3

b\g!Unsaturated nitriles can be deprotonated with a suitable base such as LDA\ and the anions
then react with alkylating agents exclusively in the a!position\ providing a route to a!functionalised
b\g!unsaturated nitriles ð64TL3536Ł "see also Section 2[07[0[3#[ a\b!Unsaturated nitriles\ which are
readily prepared by a variety of routes "see Chapter 2[08#\ can also be deprotonated "LDA:HMPA#\
to give the same delocalised carbanion obtained from b\g!unsaturated nitriles\ and again alkylation
occurs a! to the nitrile ð64JOC0051\ 68JOC299Ł[ The readily prepared a!cyano allyl esters "01# undergo
a palladium!catalysed Carroll reaction\ leading to b\g!unsaturated nitriles as shown in Equation
"8# ð76JOC1877Ł[ Vinylboranes react with chloroacetonitrile in the presence of potassium 1\5!di!t!
butylphenoxide to give the corresponding b\g!unsaturated nitriles stereospeci_cally as shown in
Equation "09# ð70JOC118\ 75JOC287Ł[

O
Pd(PPh3)4, 100 °C
(9)
O
R CN R CN
(12)
R = H, or Bun

But

O–K+
R1 R1
But
+ ClCH2CN (10)
BR22 CN

g\d!Unsaturated nitriles can be prepared from allyl halides by reaction with cyanomethylcopper
as shown in Equation "00# ð61TL376Ł[ The reaction is highly speci_c for allyl halides\ as alkyl halides
and benzyl halides fail to react[ In a similar reaction\ allyl halides react with iodomethylzinc
iodide and either CuCN or an a!copper nitrile derivative to give g\d! and d\o!unsaturated nitriles\
respectively\ as indicated in Equation "01# ð78JA5363Ł[ The azo!Claisen rearrangement of allyl amides
is initiated by a variety of dehydrating agents such as TFAA\ triethylphosphite:iodine\ PCl4:Et2N
or COCl1:Et2N to give g\d!unsaturated nitriles as shown in Scheme 6 ð54JOC1453\ 82TL0342Ł[ In
addition to simple allyl amides\ a!aryl\ oxygen\ halide\ ester and nitrogen containing amides also
undergo this rearrangement\ giving a variety of functionalised g\d!unsaturated nitriles ð80TL068Ł[
The same rearrangement can be brought about starting from b\g!unsaturated azides by reaction
with PPh2 and a ketene "Scheme 7# ð80TL3930\ 82T4042Ł[

Br Br
+ CuCH2CN (11)
Br
CN

R3 R3
ICH2ZnI/CuX
X (12)
R2 Br R2
69–91%
R1 R1
X = CN, CH2CN, MeCHCN
513 Nitriles] General and Aliphatic Nitriles
O
R R • R CN
NH N

Scheme 7

R3
• O
R1 N3 PPh3 R1 N R4
PPh3
R2 R2

R1 N CN
• R3 R4
R2 R3
R4 R2 R1

Scheme 8

The ~uoride!initiated Michael addition of allyl silanes onto a\b!unsaturated nitriles provides a
route for the synthesis of d\o!unsaturated nitriles "Equation "02##[ The reaction is e}ective in both
inter! ð75JOC0634Ł\ and intramolecular senses ð75JOC0642Ł[ 0!Nitrocycloalkenes undergo a one!
pot reaction with trimethylsilylmethylmagnesium chloride followed by PCl2 to give terminally
unsaturated nitriles as shown in Equation "03# ð82CC558Ł[

CN CN
TMS F–
+ (13)
R R

NO2
( )n i, TMSCH2MgCl
( )n CN (14)
ii, PCl3

2[07[1[1[1 Aliphatic nitriles with more than one double bond


Very few {speci_c| methods have been reported for the preparation of nitriles with more than one
double bond\ as these compounds are prepared by general methods\ or by the methods described
in Section 2[07[1[1[0 for nitriles with one double bond[ One example\ however\ is the azo!Claisen
rearrangement of N!propargylamides leading to b!allenic nitriles "Scheme 8# ð54JOC1453Ł[

O Cl
COCl2 Et3N
N N
H

CN

N

Scheme 9
Aliphatic Nitrile 514
2[07[1[1[2 Aliphatic nitriles with aryl or heteroaryl substituents
The direct introduction of a cyanomethyl group onto an aromatic ring can be achieved by the
palladium!catalysed coupling of an aryl halide and cyanomethyltributyltin as illustrated in Equation
"04# ð73CL0400Ł[ The reaction works well with electron!rich aromatic systems\ but fails with electron!
de_cient species[ Alternatively\ in the presence of Cul and HMPA\ aryl halides react with the enolate
of alkyl cyanoacetates to give the a!arylmalonate derivatives\ which on heating with aqueous sodium
hydroxide decarboxylate give a!arylnitriles\ as shown in Scheme 09 ð72CL082Ł[ In the umpolun` of
this reaction\ arylzinc chlorides react with bromoacetonitrile in the presence of a Ni"AcAc#1 catalyst
and cyclohexyldiphenylphosphine to give a!arylnitriles in 26Ð81) yield ð76S39Ł[ Treatment of an
o! or p!hydroxy substituted benzyl alcohol with NaCN in DMF at 009>C results in substitution of
the alcohol by cyanide\ giving the benzylnitrile ð65JOC1491Ł[ The reaction is thought to proceed via
a methylenequinone intermediate as shown in Scheme 00[ Dimethyl!o! or p!"hydroxybenzyl#amines
can be displaced by KCN\ presumably by the same mechanism ð62T0820Ł[
CN
Br
Bu3SnCH2CN
PdCl2[P(o-tol)3]2
(15)

CO2Et CO2Et
CuI/HMPA NaOH
ArX + – Ar Ar
CN CN CN

Scheme 10

110 °C NaCN
HO O HO
OH CN

Scheme 11

As illustrated above\ there are a number of routes for the preparation of compounds of the type
ArCH1CN^ however\ more substituted a!arylnitriles are not so readily prepared by these methods[
Grigg et al[ have reported that treatment of an arylmethylenenitrile with an alcohol in the presence
of a ruthenium catalyst "RuH1"PPh2#3# results in coupling to give the arylmethinenitrile\ as shown
in Equation "05# ð70TL3096Ł[ Cainelli et al[ have shown that in the presence of KHFe"CO#3 and an
aldehyde\ phenyl acetonitrile undergoes a reductive alkylation giving a!alkyl!a!arylnitriles
ð64JCS"P0#0162Ł[ Arylmethylnitriles react with alcohols in the presence of sodium to give the a!aryl!
a!alkylnitriles ð55TL0498\ 56CPB0700\ 60JOC1837Ł[ Arylmethylenenitriles can be deprotonated with BuLi
"see also Section 2[07[0[3# to give a lithium anion that undergoes Michael addition to a\b!unsaturated
ketones\ providing access to a range of functionalised a!arylnitriles ð70T0816Ł[ Nitrile!stabilised
lithium anions add to arene chromiumtricarbonyl species giving a variety of a!arylnitriles after
oxidative elimination of the chromiun^ an example is shown in Equation "06# ð71JOM"139#C4\
82TL0288Ł[ The same anions also add to electron!de_cient nitrobenzene derivatives ð77LA192Ł[

R
RuH2(PPh3)4
ArCH2CN + ROH CN (16)
Ar

Ts Me i, Ts Me
N N
CN
Li
(17)
ii, I2
N N
(CO)3Cr Bn Bn

CN
515 Nitriles] General and Aliphatic Nitriles
Cyanide will add to aryl alkenes such as cyanostilbene\ giving 1\2!diphenylbutandinitrile
ð11JCS0588Ł[ Ni"PTol2#3 has been used to catalyse the Markovnikov addition of HCN to aryl alkenes
leading to a!arylacetonitrile derivatives ð74JOC4269Ł\ and a total synthesis of naproxen has been
achieved in this way as highlighted in Scheme 01[ The addition of HCN to styrene derivatives is not
so facile\ but use of ZnCl1 as a cocatalyst increases the yield in these cases "see also Section
2[07[0[1[0#[
CN CO2H

HCN/Ni(PTol3)4

MeO MeO MeO


naproxen
Scheme 12

Treatment of an aryl halide and a nitrile with sodium and liquid ammonia results in formation
of the a!arylnitrile via addition of the nitrile anion to a benzyne intermediate ð72JOC3286\ 74JOC0223\
76JOC0222\ 76JOC1508Ł[ The reaction is also e}ective in an intramolecular sense ð51JOC2725\ 62OSC"4#152\
70JOC3599Ł\ giving cyclic!a!arylnitriles with a 3Ð6 membered ring fused to the aromatic ring[ Nitrile
enolates also react with aryl and heteroaryl halides in a photochemical reaction\ giving a!arylnitriles
ð65JOC2260Ł[
Treatment of methylthioacetonitrile "see Section 2[07[1[4# with N!chlorosuccinimide "NCS# results
in formation of the a!chloro derivative[ FriedelÐCrafts reaction with an aromatic compound gives
the a!aryl!a!thiomethylacetonitrile which on reductive desulfurisation gives the arylacetonitrile\ as
shown in Scheme 02 ð71CPB2463Ł[ Deprotonation of a!cyanomethylphosphonate "see Section
2[07[1[7# with NaH:HMPA followed by addition of an aryl iodide and Cul results in formation of
the a!aryl!a!cyanophosphonate[ On thermolysis\ the phosphate group is eliminated and substituted
by an alkyl group from the phosphate ester\ as shown in Scheme 03 ð74CL0668Ł[
Cl ArH/SnCl4 Ar
NCS or TiCl4 Zn/AcOH
MeS CN MeS CN MeS CN Ar CN

Scheme 13

i, NaH/HMPA
RO CN RO CN CN
ii, ArI/CuI ∆
RO P RO P R
O O Ar Ar

Scheme 14

a\a!Diarylnitriles can be prepared by treating a diarylketone with tosylhydrazine followed by


sodium hydride and TMS!CN ð78OPP243Ł[ The reaction is a variation on the method of Orere and
Reese discussed in Section 2[07[0[4[ The lactone "02# reacts with KCN by opening of the lactone
ring to give o!carboxyphenylacetonitrile as shown in Equation "07# ð44OSC"2#063Ł[ Fer!
rocenylacetonitrile can be prepared by displacement of trimethylamine from N\N!dimethyl!
aminomethylferrocene methiodide with KCN ð62OSC"4#467Ł and b!arylnitriles can be prepared by
the Michael addition of aryl cuprates to alkyl a!cyanoacrylates ð75TL4208Ł[

KCN CN
O (18)
CO2H
O
(13)

2[07[1[1[3 Aliphatic nitriles with one or more C2C triple bonds


No speci_c methods for the synthesis of alkyne containing nitriles have been reported\ and these
compounds are prepared by the methods discussed in Section 2[07[0[
Aliphatic Nitrile 516
2[07[1[2 Halo!substituted Aliphatic Nitriles
Few speci_c methods for the preparation of halonitriles have been reported\ and many of the
general methods of nitrile synthesis described in Section 2[07[0 are applicable to these compounds[
Chloroacetonitrile is prepared by the dehydration of chloroacetamide by P1O4 ð52OSC"3#033Ł\ and
the same route can be used to prepare other halogenated acetonitrile derivatives including tri~uoro!
acetonitrile ð82T0430Ł[ Other a!chloronitriles can then be prepared from dichloroacetonitrile by
reaction with one equivalent of a trialkylborane and potassium 1\5!di!t!butylphenolate at 9>C
ð69JA4680Ł[ Barton et al[ have reported that radicals generated by the decarboxylation of carboxylic
acid derivatives will add to a!chloroacrylonitrile to give a!chloronitriles ð73TL0944Ł[ Treatment of a
cyanohydrin with thionyl chloride also gives a!chloronitriles ð60JCS"C#1040Ł[ a!Fluoronitriles can be
prepared from cyanohydrins by treatment with diethylaminosulfur tri~uoride "DAST# ð80JA5207Ł[
Reaction of tri~uoroacetonitrile with phenylmagnesium bromide\ followed by reaction of the imine
with HCN\ gives the a!amino!b!tri~uoronitrile "Scheme 04# ð82T0430Ł[ Epoxides of a\b!unsaturated
nitriles react with HF to give b!~uorocyanohydrins ð82SC1278Ł[

NH H2N CN
P2O5 PhMgBr HCN
CF3CONH2 CF3CN
Ph CF3 Ph CF3

Scheme 15

Active methylene compounds containing a nitrile group can be photolysed in the presence of
bromine to give a!bromonitriles ð89S657Ł and reaction of a cyanohydrin ether with NBS results in
formation of the corresponding a!bromocyanohydrin ether ð65JOC1735Ł[ The addition of cyanogen
chloride to an enol ether results in formation of b!chlorocyanohydrin ethers ð65JOC1735Ł\ and
a!iodomalononitriles undergo radical additions to alkenes\ leading to g!iododinitriles ð81JA3325Ł[

2[07[1[3 Aliphatic Nitriles Bearing an Oxygen!based Functional Group

2[07[1[3[0 a!Oxygenated nitriles


The principal method for the preparation of a!hydroxynitriles is the addition of cyanide anion to
carbonyl derivatives[ This is a very general reaction and is discussed in Section 2[07[0[1[1\ though
the preparation of optically active cyanohydrins is discussed later in this section[ The carbanions of
O!protected cyanohydrins can be formed\ and used to prepare functionalised cyanohydrin deriva!
tives ð72T2196Ł[ Reaction of a vinyl ether or vinyl acetate with HCN in pyridine gives the cor!
responding cyanohydrin derivatives ð37CRV078\ B!69MI 207!90Ł[ Reaction of a carbonyl compound
with LiCN and diethylphosphoroyl chloride results in direct formation of the cyanohydrin diethyl
phosphate ð82T3216Ł[ b\g!Unsaturated cyanohydrins can be prepared by the TaCl4:Zn!induced
addition of an alkyne to an acyl cyanide ð81BCJ0432Ł[ Ortho!esters react with HCN to give
a!cyanoacetals^ tertiary amide acetals\ and ester diaminals react similarly to give a!cyano!a!ami!
noethers ð60CB813Ł[ a!Chloro! and a!acetoxyethers react with TMS!CN in the presence of catalytic
SnCl3 to give the corresponding cyanoethers with retention of con_guration\ as shown in Equation
"08# ð72T850Ł[ Acetals\ ketals and ortho!esters similarly react with TMS!CN in the presence of
BF2OEt1\ SnCl1\ or ferric or tin montmorillonite giving a!cyanoethers and a!cyanoacetals respec!
tively^ however\ this reaction does not appear to be stereospeci_c ð70TL3168\ 72T856\ 82BCJ1905Ł[
AcO AcO
X CN
O TMS-CN/SnCl4 O (19)

OAc OAc OAc OAc


X = Cl or OAc

a\b!Unsaturated nitriles are epoxidised by treatment with mcpba\ giving a\b!epoxynitriles


ð68JOC56Ł[ These compounds can also be prepared by the Darzens condensation between chloro!
acetonitrile and an aldehyde in the presence of NaOH and a crown ether ð63AG"E#554Ł[ Treatment
of an acid chloride with TMS!CN and pyridine gives the a!cyano!cyanohydrin silylether "03#
517 Nitriles] General and Aliphatic Nitriles
ð62CB476\ 62TL0338Ł^ similarly\ phosgene gives tricyanomethyl!TMS!ether "04# and oxalyl chloride
gives adduct "05# ð62CB476Ł[
NC NC TMS-O O-TMS
R O-TMS NC O-TMS NC CN
NC NC NC CN
(14) (15) (16)

A number of methods are available for the preparation of optically active cyanohydrins\ based
on one of four basic methodologies] "i# use of a chiral catalyst "including enzymes# for the asymmetric
addition of HCN to aldehydes and ketones "this area has been reviewed ð82SL796Ł#^ "ii# resolution
of racemic cyanohydrins^ "iii# addition of HCN to optically active carbonyl derivatives^ and "iv#
addition of nucleophiles to chiral acyl cyanides[
The _rst catalyst to be discovered for the asymmetric addition of HCN to aldehydes was the
D!oxynitrilase enzyme isolated from almonds in 0897 by Rosenthaler ð97MI 207!90Ł[ This enzyme
"EC 3[0[1[09# which constitutes 9[3) by weight of almonds\ will catalyse the asymmetric addition
of HCN to a wide range of aromatic ð76AG"E#347\ 89S464\ 89T868\ 80JA5881\ 80SC0276\ 80TL1594\ 81TA0112\
82CB668Ł\ heteroaromatic ð76AG"E#347\ 89T868\ 80SC0276Ł and aliphatic aldehydes ð76AG"E#347\ 89S464\
89T868\ 80JA5881\ 80SC0276\ 80TL1594\ 81TA0112\ 82CB668Ł as well as methyl ketones ð89S464\ 80TL1594\
82CB668Ł[ The natural substrate for this enzyme is benzaldehyde ð54AG"E#0968Ł\ which is converted
into "R#!mandelonitrile in 87) yield with 88) ee[ In early synthetic work with this enzyme\ an
aqueous solvent was used\ and this is often the optimum condition[ However\ the enzyme can also
be immobilised onto cellulose ð76AG"E#347Ł\ used in organic solvents ð89S464\ 80TL1594\ 82CB668Ł\ or
crude almond meal can be used ð77TL3374\ 89T868\ 80SC0276Ł\ and in some cases these conditions give
superior enantiomeric excesses[ It is also possible to use acetone cyanohydrin as an in situ source of
HCN ð80JA5881\ 81TA0112Ł[
Oxynitrilase enzymes have been isolated from a variety of other sources\ but synthetic inves!
tigations have only been conducted on the enzyme derived from Sor`hum bicolour "EC 3[0[1[00#
ð89AG"E#275\ 89TL0138Ł\ and that derived from Hevea brasiliensis ð82TL3658Ł[ These enzymes have
complementary activity to the oxynitrilase derived from almonds\ as they always gives the
"S#!enantiomer of the cyanohydrin[ However\ the Sor`hum!derived enzyme has a much narrower
substrate speci_city than the almond!derived enzyme\ catalysing the addition of HCN only to
benzaldehyde derivatives ð89AG"E#275\ 89TL0138Ł[ Again\ the enzyme can be used in aqueous
ð89AG"E#275Ł or organic solvents ð89TL0138Ł\ and can be immobilised on Eupergit C ð89AG"E#275Ł[
The enzyme from Hevea brasiliensis has been reported to give "S#!cyanohydrins from both aromatic
and aliphatic aldehydes in transcyanation reactions with acetone cyanohydrin as the cyanide source
ð82TL3658Ł[
In 0868\ Inoue and co!workers reported that cyclic dipeptides "diketopiperazines# containing a
histidine residue catalysed the asymmetric addition of HCN to benzaldehyde giving optically active
mandelonitrile ð68MAC0978Ł[ The optimum catalysts were found to be cyclo!ð"S#!His!"S#!PheŁ "06#
ð70CC118\ 71MAC468Ł\ and cyclo!ð"S#!His!"S#!LeuŁ "07# ð78CL1008Ł\ which catalysed the formation of
"R#! and "S#! mandelonitrile respectively[ Catalyst "06# has been used to catalyse the asymmetric
addition of HCN to a large number of carbonyl compounds[ Aromatic ð75BCJ782\ 77AJC0586\
89JOC070Ł\ heteroaromatic ð77AJC0586\ 89JOC070Ł\ and aliphatic ð74MAC0644\ 77AJC0586\ 89JOC070Ł
aldehydes as well as ketones ð77AJC0586Ł were all found to be converted into optically active
cyanohydrins with ee|s of 4 to 86)[ Acetone cyanohydrin can be used as an in situ source of HCN
with catalyst "06#^ however\ this results in lower enantiomeric excesses in the cyanohydrins ð75CL820Ł[
The diketopiperazine "06# can also be incorporated into an insoluble polymer\ though this results
in a considerable decrease in asymmetric induction to a maximum of 07) ee ð83SC092Ł[ Although
the catalyst "07# has been studied less extensively than diketopiperazine "06#\ it has been observed
that not only does it give the opposite enantiomer of the cyanohydrin to the peptide "06#\ but that
it also gives the highest enantiomeric excesses with aliphatic aldehydes ð78CL1008Ł^ this is again in
contrast to "06# which reacts best with aromatic aldehydes[
A number of organometallic reagents based on chiral complexes of titanium\ aluminum\ tin and
magnesium have also been found to catalyse the asymmetric addition of HCN or TMS!CN to
aldehydes^ the various results are collected in Table 1[ Narasaka et al[ have described the use of the
titanium complex "08# in the asymmetric addition of TMS!CN to aldehydes ð76CL1962\ 77BCJ3268\
89CL0504Ł[ It was found to be necessary to use a full equivalent of the complex "08# in the presence
of 3Aý molecular sieves[ Oguni and co!workers have described a very similar catalytic system based
upon the modi_ed Sharpless catalyst ð89CC0253\ 81JCS"P0#2024Ł[ However\ in contrast to the complex
Aliphatic Nitrile 518
N N
O O
H H
N N Ph N N
H H

N N
H H
O O
(17) (18)

"08#\ only a catalytic amount of the Sharpless complex is required to catalyse the asymmetric
addition of TMS!CN to aldehydes[ The same research group ð80CC0641\ 82JOC0404Ł has reported
that the titanium complexes of chiral imino alcohols such as "19# also catalyse the asymmetric
addition of TMS!CN to aldehydes[ The tin"II# complex "10# of "¦#!cinchone was investigated by
Mukaiyama and co!workers ð80CL430Ł and found to catalyse the asymmetric addition of TMS!CN
to aldehydes[ Corey and Wang have reported that a mixed catalyst system based on the magnesium
complex of a chiral bisoxazoline catalyses the asymmetric addition of TMS!CN to aldehydes\ best
results being obtained with aliphatic aldehydes ð82TL3990Ł[

H
Ph
Ph
Ph O OH But N
CF3SO3SnO
/TiCl2(OPri)2
OH N OH
O
Ph
Ph
OH
N
(19) (20) (21)

The above methods all rely upon the use of TMS!CN as a cyanide source[ However\ Inoue and
co!workers ð80TL3222\ 81CL1332\ 81JA6858Ł have reported that the titanium complex of the peptide
derived ligand "11# "and related ligands derived from other amino acids# catalyses the asymmetric
addition of HCN to aldehydes giving the "R#!enantiomer of the cyanohydrin[ Based on molecular
modelling studies ð81JA6858Ł of the postulated catalytic intermediate\ the authors were able to design
a new ligand "12# derived from "S#!valine\ the titanium complex of which catalyses the formation
of "S#!cyanohydrins[ Interestingly\ although the titanium complexes of the ligands "11# do not
catalyse the asymmetric addition of TMS!CN to aldehydes\ the corresponding aluminum complexes
both of the peptides "11#\ and of the amino acid derivatives "13# do so\ but they do not catalyse the
asymmetric addition of HCN to aldehydes ð80SL452\ 81JOC5667Ł[ The aluminum complexes of a
variety of other N!protected amino acids and peptides were also found to catalyse the addition of
TMS!CN to aldehydes ð81JOC5667Ł[

Br
OH Ph
O OH
O
N
N CO2Me N
H Br N
H

(22) (23)

OH
O
N
N
H
R

(24) R = Pri
R = Bui
R = Ph
529 Nitriles] General and Aliphatic Nitriles
Table 1 Comparison of organometallic derivatives as catalysts for the asymmetric addition of cyanide to
aldehydes[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Aldehyde Catalyst Yield ee "con_`uration#
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Benzaldehyde "08# 68 85 "R#
Sharpless 73 80 "R#
"19# 56 74 "R#
"11# 77 77 "R#
Bisoxazoline:Mg 77 41 "S#
1!Methylbenzaldehyde "12# 85 81 "S#
2!Methoxybenzaldehyde "19# 65 45 "R#
"11# 60 74 "R#
"12# 68 86 "S#
2!Phenoxybenzaldehyde "19# 56 68 "R#
"11# 45 80 "S#
3!Methylbenzaldehyde Sharpless 68 54 "R#
"19# 57 60 "R#
3!Methoxybenzaldehyde Sharpless 77 66 "R#
"19# 51 80 "R#
3!Cyanobenzaldehyde "19# 59 19 "R#
1!Naphthaldehyde Sharpless 79 59 "R#
"19# 65 62 "R#
"11# 44 89 "R#
"12# 52 61 "R#
Furfural "11# 19 76 "S#
1!Thiophenecarboxaldehyde Sharpless 73 72 "R#
"19# 59 68 "R#
Butanal "19# 62 46 "R#
Heptanal "11# 60 55 "R#
Bisoxazoline:Mg 77 84 "S#
Nonanal "08# 74 82
"10# 78 61
Decanal "08# 72 74 "R#
"19# 37 55 "R#
Undec!09!enal "08# 81 82
Dodecanal "19# 37 55 "R#
1!Methylpropanal "19# 69 23 "R#
"10# 56 84
1\1!Dimethylpropanal "19# 47 69 "R#
"10# 38 72
Bisoxazoline:Mg 46 89 "S#
1!Ethylbutanal Bisoxazoline:Mg 75 80 "S#
1\1!Dimethylpent!3!enal "10# 16 82
Phenylethanal "08# 55 66
2!Phenylpropanal "08# 77 80
"19# 74 39 "R#
Cyclohexanecarbaldehyde "08# 66 57
"19# 61 54
"11# 74 43
"10# 68 85
Bisoxazoline:Mg 83 83 "S#
Sorbaldehyde Bisoxazoline:Mg 13 73 "S#
Propenal "19# 43 52 "R#
1!Methylpropenal "19# 51 74 "R#
"11# 89 61
E!But!1!enal "19# 69 78 "R#
E!1!Methylbut!1!enal "19# 57 85 "R#
"11# 11 26
2!Methylbut!1!enal "19# 52 78 "R#
"11# 63 69
Hex!1!enal "11# 82 74 "R#
Bisoxazoline:Mg 48 76 "S#
Hex!1\3!dienal "11# 67 59
E!1!Ethylhex!1!enal "11# 17 59
Hept!1!ynal "11# 67 59
Oct!1!enal "11# 72 78 "R#
Geranial Bisoxazoline:Mg 20 52 "S#
Cinnamaldehyde "19# 70 61 "R#
"11# 71 70 "R#
"12# 39 51 "S#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Aliphatic Nitrile 520
A number of enzymatic systems have been reported to resolve racemic cyanohydrins[ In particular\
lipases can be use to enantioselectively esterify\ transesterify\ or saponify cyanohydrins ð77TL5846\
78TL0806\ 80LA36Ł[ Usually\ the maximum yield from such a reaction would be 49)^ however\ it has
been reported that the lipase from Pseudomonas is compatible with the reaction conditions under
which quinidine\ anion!exchange resins\ or polymer!supported cinchona alkaloids reversibly catalyse
the transcyanation of aldehydes with acetone cyanohydrin ð81BCJ000\ 81JOC4532Ł[ Thus\ in the
presence of isoprenylacetate\ the enzyme catalyses the enantioselective esteri_cation of the
"S#!cyanohydrin\ which disturbs the equilibrium established in the transcyanation\ and eventually
results in high yields of "S#!cyanohydrin acetates "Scheme 05#[

OH lipase /AcO OAc

R CN R CN
O quinidine
+
R acetone
cyanohydrin OH

R CN

Scheme 16

Johnson and co!workers have reported that the TiCl3!catalysed addition of TMS!CN to chiral
acetals followed by hydrolysis of the chiral auxiliary gives optically active cyanohydrins\ as illustrated
in Scheme 06 ð72JOC1183\ 73TL480Ł[ Condensations of esters with optically active sulfoxides give
b!ketosulfoxides "14# as shown in Scheme 07 ð81JOC6124Ł[ Addition of cyanide "from diethyl!
aluminum cyanide# to the carbonyl group of compounds "14# is controlled by the chirality of the
sulfoxide\ giving cyanohydrins with ×85) de[ Reetz et al[ have investigated the TiCl3!catalysed
addition of allyl silanes and silyl enolethers to a! and b!benzyloxyacyl nitriles "15# and "16#\
respectively ð74AG"E#878Ł[ In all cases\ a greater than 85) de was observed\ with the major isomer
being the product of chelation!controlled addition of the silyl derivative to the acyl cyanide[

O OH
TMS-CN/TiCl4 O
R
R
O R CN
CN OH

Scheme 17

O O O O OH O
LDA Et2AlCN NC
+ R2 S S S
R1 OEt Tol R1 Tol R1 Tol
R2 R2
(25)

Scheme 18

O O

BnO CN OBn CN
(26) (27)

Optically active benzylic and allylic cyanohydrins can be converted into the opposite enantiomer
under Mitsunobu conditions "triphenylphosphine\ dead\ 3!nitrophenylacetic acid#\ followed by
acidic hydrolysis of the resulting ester ð82T0952Ł[ However\ alkyl cyanohydrins are esteri_ed with
retention of con_guration under these conditions[ By contrast\ aliphatic cyanohydrins can be
inverted by treatment of a sulfonyloxy derivative with acetate followed by hydrolysis of the cyano!
hydrin acetate ð82CB668Ł[ Under these conditions\ aromatic cyanohydrins are partially racemised[
521 Nitriles] General and Aliphatic Nitriles
2[07[1[3[1 b!Oxygenated nitriles
For racemic b!hydroxynitrile synthesis based on lithium enolates of nitriles see Section 2[07[0[3[
Reactions between bromoacetonitrile and zinc result in formation of the corresponding zinc enolate\
which then reacts with aldehydes and ketones in the presence of TMS!Cl to give b!silyloxynitriles
ð89TL1194Ł[ Treatment of a nitrile with a boron tri~ate such as 8!BBN tri~ate results in formation
of the boron enolate of the nitrile which reacts with aldehydes leading to b!hydroxynitriles
ð71CL0390Ł[ A chiral b!hydroxynitrile synthesis has been reported ð81TA566Ł in which cyano!
methylzinc bromide adds to aldehydes in the presence of N!methyl!diphenylprolinol "DPMPM#
"17# giving b!hydroxynitriles in 63Ð82) ee[

Ph
N OH
Me Ph

(28)

Treatment of TMS!acetonitrile with an aldehyde or ketone in the presence of a ~uoride or


methoxide catalyst also gives b!silyloxynitriles ð78JCS"P0#0581Ł[ Alcohols react with a\b!unsaturated
nitriles via a Michael addition to give b!oxynitriles ð34JA0494\ 34JCS424Ł\ and the reaction can also
be made to occur intramolecularly ð78T2620Ł[ Cyanide will react with both epoxides ð58BCJ0234\
62OSC"4#503\ 74JOC0446Ł\ and b!chloro alcohols ð30OSC"0#145Ł giving b!hydroxynitriles[ The use of
lithium cyanide ð81TL0320Ł\ or acetone cyanohydrin in the presence of triethylamine ð81TL2170Ł as
the cyanide source\ allows the use of nonaqueous conditions which are tolerated by many other
functional groups[ The transfer of cyanide from acetone cyanohydrin to epoxides is also catalysed
by lanthanoid"III# alkoxides ð82CL864Ł[ Diethylaluminum cyanide can also be used as the cyanide
source\ as can the complex of triethylaluminum and HCN ð69JCS"C#1254\ 78JOC0184Ł[ In each case\
cyanide reacts at the least hindered end of the epoxide\ with inversion of con_guration at the epoxide
centre[
Epoxides also react with TMS!CN\ though only in the presence of a catalyst\ which can be either
a base\ such as 07!crown!5:KCN ð89JOC1905Ł or solid calcium or magnesium oxide ð89CL370Ł^ or a
Lewis acid\ such as Ti"OPri#3 ð74JOC0446\ 77JMOCL12Ł\ Et1AlCN ð76JOC556Ł\ Et1AlCl ð71JOC1762Ł\
AlCl2 ð62TL0338Ł\ a lanthanide trichloride "LaCl2\ CeCl2 and SmCl2# ð76TL4402Ł\ an alkyl lanthanide
ð89TL5198Ł or Yb"CN#2 ð89TL5198Ł[ If a Lewis acid catalyst is used\ then the catalyst must be derived
from a hard metal\ as soft Lewis acids instead give the isonitrile ð76JOC0902Ł[ In each case\ the
cyanide ion is delivered to the less hindered end of the epoxide\ and reacts with inversion of
con_guration at that carbon\ whilst chirality elsewhere in the epoxide is preserved ð80TA326Ł[
Ti"OPri#3 is only a moderate catalyst for this reaction\ and often the reaction requires extended
heating to go to completion[ However\ Oguni and co!workers have reported that addition of 09
mol) of the ligand "18# to the reaction mixture results in a substantial rate enhancement\ with good
yields being obtained at room temperature ð81SL552Ł[

But
N OH

OH
(29)

Alkenes can be converted into b!hydroxynitriles via a 0\2!dipolar cycloaddition with carbo!
ethoxyformonitrile oxide as shown in Scheme 08[ Saponi_cation followed by thermal decar!
boxylation!induced fragmentation of the intermediate isoxazoline results in the formation of
b!hydroxynitriles[ The reaction is stereoselective\ the stereochemistry of the b!hydroxynitrile being
determined by the geometry of the alkene ð72JOC255Ł[
b!Hydroxynitriles can be resolved via the enantioselective hydrolysis of the thioacetylesters using
lipase!P ð78CL0494Ł[ The presence of a sulfur atom in the cyanohydrin ester has been found to be
essential in order to obtain a good enantiomeric excess[ Attempts to use bakers| yeast for the
asymmetric reduction of 2!ketobutyronitrile\ has resulted in concomitant introduction of an ethyl
group\ giving the a!ethyl!b!hydroxynitrile\ as shown in Equation "19# ð78TL2700Ł[ However\
Aliphatic Nitrile 522
R1 –O R1 i, NaOH R1 OH
N+ O
ii, ∆
+ N
R2 CO2Et R2 R2 CN
CO2Et

Scheme 19

1!substituted!2!ketobutyronitriles are reduced by bakers| yeast\ giving a mixture of syn and anti
optically active b!hydroxynitriles in which the substituent in the 1!position determines the syn:anti
ratio ð78BCJ2740Ł[

O OH OH
Baker's yeast
CN CN + CN (20)
88%
Et Et

b!Ketonitriles can be prepared from ketones by forming the corresponding kinetic enolate with
LDA\ and then allowing the enolate to react with tosylcyanide ð70TL4900Ł[ Yields are between 45)
and 79) for cyclic ketones\ but linear methyl ketones give only low yields[ Ketone enolates also
react with cyanogen chloride to give b!ketonitriles ð69JOC050Ł[ This transformation can also be
achieved under nonbasic conditions by reacting a ketone with chlorosulfonylisocyanate ð62S571Ł[
In a related reaction\ enamines react with arylisocyanates ð54CB2551Ł or cyanogen chloride
ð48JA4399Ł to give b!ketonitriles after an acidic workup[ The dianion of a b!ketonitrile cannot be
prepared directly from the b!ketonitrile[ However\ the dianion can be generated by treatment of an
isoxazole with sodium methoxide as shown in Scheme 19 ð34JA0634Ł[ The dianion can then be
alkylated regiospeci_cally at the g!position to give substituted b!ketonitriles ð67TL3110Ł[ The dianion
of cyanoacetic acid can be prepared with butyllithium\ and reacts with acid chlorides to give
b!ketonitriles after a decarboxylative acidic workup ð72S297Ł[ Similarly\ TMS a!cyanocarboxylates
are deprotonated by LDA and react with mixed anhydrides to give b!ketonitriles as illustrated
in Equation "10# ð68TL0474Ł[ b\g!Epoxynitriles can be prepared from b\g!unsaturated nitriles by
epoxidation with mcpba ð64JOC0051Ł[

R1 O O
2LDA R2 – CN E+ E CN
R2 N –
or NaOMe
O R1 R2 R1
Scheme 20

i, LDA
R1 ii, R2CO2CO2Et
R1
iii, H3O+ R2
NC CO2-TMS NC (21)
O

2[07[1[3[2 More remotely oxygenated nitriles


Oxetanes react with TMS!CN in the presence of diethylaluminum chloride\ giving g!hydroxy!
nitriles in which the cyanide ion adds to the least hindered end of the oxetane ð71JOC1762Ł[
g!Ketonitriles can be prepared by the cyanide!catalysed addition of aromatic aldehydes to a\b!
unsaturated nitriles ð77OSC"5#755Ł[
Additions of HCN or TMS!CN to a\b!unsaturated carbonyl compounds are catalysed by Lewis
acids and bases\ and can give either a g!ketonitrile\ by Michael addition of cyanide onto the enone
system ð33OSC"1#387\ 79TL278\ 72T856\ B!81MI 207!90Ł\ or the cyanohydrin by 0\1!addition to the carbonyl
"cf[ Section 2[07[1[3[0#[ The addition of HCN to conjugated carbonyl compounds has been com!
prehensively reviewed ð66OR"14#144\ B!81MI 207!90Ł[ The g!ketonitrile is the thermodynamic product
of this reaction\ whilst the cyanohydrin is formed under kinetic control\ so with some carbonyl
compounds it is possible to isolate either product by adjusting the reaction conditions ð72T856Ł[
With other carbonyl compounds however\ only the g!ketonitrile has been isolated ð79TL278Ł[ The
523 Nitriles] General and Aliphatic Nitriles
use of {naked| cyanide generated from acetone cyanohydrin in the presence of 07!crown!5 and a
catalytic amount of KCN is reported to always add 0\3! to a\b!unsaturated nitriles giving
g!ketonitriles ð66TL0006Ł[ Other reagents which favour formation of the g!ketonitrile include calcium
cyanide ð56JCS"C#1354Ł\ diethylaluminum cyanide and triethylaluminum:HCN ð61JA3524\ 61JA3533Ł[
In the presence of TMS!Cl\ diethylaluminum cyanide gives g!silyloxy enolethers of nitriles ð67SC120Ł[
Diethylaluminum cyanide also reacts with cyclopropylketones in a Michael!type reaction to give 4!
ketonitriles ð71CJC714Ł[ By using TMS!CN as the cyanide source for addition reactions to a\b!
unsaturated ketones\ it is possible to obtain either the cyanohydrin "by using a solid base as the
catalyst#\ or the g!ketonitrile by utilising a solid acid catalyst ð82BCJ1905Ł[
Additions of cyanide to other conjugated C1C double bonds also occur^ they are base catalysed\
and take place via a Michael!type addition giving the product where the nitrile is introduced b! to
the electron!withdrawing group ðB!81MI 207!90Ł[ Suitable Michael acceptors include esters\ alkylidene
malonates ð26JA633Ł and other nitriles ð11JCS0588Ł[
v!Cyanoaldehydes can be prepared from cycloalkenes as shown in Scheme 10 for 6!cyanoheptanal
ð62OSC"4#155Ł[ The key step is the Beckmann _ssion of an a!methoxyoxime[
i, NOCl NOH
ii, MeOH/Et3N PCl5 O CN
OMe

Scheme 21

2[07[1[4 Aliphatic Nitriles Bearing a Sulfur!based Functional Group


a!Thionitriles can be prepared by the reaction of a nitrile enolate "including a!heteroatom!
substituted nitrile enolates# with a disul_de ð62CL176\ 78LA192\ 89SL624Ł or with sulfenyl chloride
ð65JOC1735Ł^ reaction of the enolate of an a!thionitrile with an alkylating agent ð61TL1280\ 62SC154\
65TL2688\ 68H"01#570^ 76BSB"85#292\ 76S341Ł^ reaction of an a!chlorosul_de with TMS!CN in the presence
of SnCl3 ð89SC0832Ł^ or by treating bromo! or chloroacetonitrile with the sodium salt of a thiol
ð72BCJ146\ 73JA6789\ 73JOC2170Ł[ An electrolytic version of the latter reaction has also been reported
ð89S730Ł[ Other sulfur electrophiles such as thiocyanates ð89S657Ł\ sodium benzenesul_nate
ð73BCJ502\ 76CL776\ 76S45Ł\ sodium sul_te ð60JCS"C#1040Ł\ diphenyldithiophosphinic acid ð68CL612Ł\
N\N!dialkyl dithiocarbamates ð65TL1856Ł\ and thioamides ð74H"12#2958Ł also react with haloaceto!
nitriles providing access to a wide variety of S!substituted!a!thionitrile derivatives[ In the case of
thioamides\ the sulfur atom can be alkylated twice\ providing a route to di"cyanomethyl#sul_des
ð68SC458Ł[ Reaction of chloroacetonitrile with dithiocarbonates "29# in the presence of 0\1!diam!
inoethane also results in the formation of a!thionitriles ð76H"15#802Ł[ Sodium trithiocarbonate reacts
with chloroacetonitrile in the same way\ providing a route to cyanomethyl thiol although this is
reported to be unstable and explosive ð78SC0422Ł[ Thioacetals react with TMS!CN in the presence
of SnCl3 ð73TL2290Ł\ with Hg"CN#1 in the presence of iodine ð89H"29#728Ł\ or with cyanogen iodide
ð67OPP100Ł to give a!thionitriles by substitution of one of the sulfur groups[ Similarly\ reaction of a
vinyl sul_de with an alcohol in the presence of TiCl3\ gives an a!thiocarbocation which then reacts
with TMS!CN to give an a!thionitrile ð76CL0852Ł[
S

ArS OEt
(30)

Oxidation of a!thionitriles can give either the sulfoxide ð70S193\ 72BCJ146\ 73JA6789Ł or sulfone
ð76S341Ł\ depending upon the oxidising agent[ Optically active a!cyanosulfoxides can be prepared
either by the oxidation of the corresponding sul_de with a chiral oxaziridine ð81JA0317Ł or the
modi_ed Sharpless catalyst ð74NJC0Ł\ or by reaction of a nitrile enolate with a menthyl sul_nate
ð70JCS"P0#503Ł[ Nitrile enolates also react with sultines to give a!cyanosulfoxides\ and use of a chiral
sultine leads to the formation of optically active a!cyanosulfoxides ð70JOC4397Ł[ Optically active
a!cyanosulfoxides can also be prepared from suitable a!cyanovinylicsulfoxides by an intramolecular
ene reaction\ creating up to three new chiral centres with ×86) de as shown in Equation "11#
ð82T0720Ł[ a!Cyanosulfoxides undergo a stereospeci_c Pummerer rearrangement on treatment with
Aliphatic Nitrile 524
acetic anhydride\ giving a!thio!a!acetoxynitriles "Scheme 11# ð66TL0226\ 72BCJ146Ł[ Treatment of a
"b!arylethyl#cyanomethylsulfoxide with TFAA results in cyclisation of the Pummerer intermediate
as illustrated in Equation "12# ð77CPB0587Ł[ a!Cyanosulfoxides can be oxidised to the corresponding
a!cyanosulfones by treatment with mcpba^ the latter can then be deprotonated\ and react with 0\0!
dinitroalkanes to give b!nitro!a!cyanosulfones ð67TL652Ł\ and with alkyl halides to give a!alkylated!
a!cyanosulfones ð74BCJ654\ 74JOC1139Ł[ An alternative synthesis of ~uorinated a!cyanosulfones
involves deprotonating acetonitrile with LDA\ and reacting the resulting carbanion with a
per~uorosulfonyl ~uoride ð80S0194Ł[ The ~uorinated a!cyanosulfones can then be converted into
vinylcyanosulfones which undergo DielsÐAlder reactions to give cyclic a!cyanosulfones ð80S0194Ł[
Vinyl"aryl#sulfones can be converted into a!"arylsulfonyl#nitriles as shown in Scheme 12 ð67CPB673Ł[
Thus\ treatment with iodoazide followed by elimination of Hl gives the b!sulfonylvinylazide which
when heated eliminates nitrogen giving a!"arylsulfonyl#nitriles[ Cyanomethyl"aryl#sulfones can also
be prepared from arylsulfonyl chlorides and bromoacetonitrile by treatment with the compound
"20# ð89SC1180Ł[ Addition of methylsulfenyl chloride to acrylonitrile gives 2!chloro!1!methyl!
thiopropionitrile ð65JOC1735Ł[

O
S O
Tol
Et2AlCl S
CN Tol (22)
CN

mcpba O Ac2O S CN
RS– Na+ + Cl CN RS CN R
S CN
R OAc

Scheme 22

O
S CN
TFAA
(23)
S
R R
CN

I
IN3 N3 dabco N3 65 °C
ArSO2 ArSO2 ArSO2 ArSO2 CN

Scheme 23

O
EtO P Te–Na+
EtO
(31)

a!Cyanosulfoxides react with arenes in the presence of TiCl3 and TFAA to give a!aryl!a!cyano!
sulfoxides ð74TL366Ł[ Deprotonation of an a!cyanosulfone with NaH:Cul followed by addition of
an aryl iodide also gives a!aryl!a!cyanosulfones ð76CL776Ł[
The ylides of a!cyanosulfones act as sources of the corresponding carbenes which react with
alkenes to give cyclopropyl!a!cyanosulfones ð80CC369Ł[ The same reaction can be achieved starting
from a!chloro!a!thionitriles by treatment with SnCl3 followed by Et2N ð75JCS"P0#0652Ł[ Methyl
cyanodithioformate reacts as a dieneophile in the DielsÐAlder reaction\ giving cyclic\ a\a!dithio!
nitriles as shown in Equation "13# ð64JCS"P0#079\ 76JOC1331Ł[ Radicals generated from carboxylic
acids via a Barton decarboxylation undergo addition to acrylonitrile and its derivatives to give
a!pyridylthionitriles ð76T3186\ 81TL4906Ł[ The same chemistry can be used to prepare b!cyclic!a!
pyridylthionitriles by utilising v!tellurio!a\b!unsaturated nitriles as starting materials ð80TL3602Ł[
Chlorination of phenylthioacetonitrile with sulfuryl chloride gives a!chloro!a!phenylthioacetonitrile
525 Nitriles] General and Aliphatic Nitriles
which reacts with alcohols in the presence of silver ions to give a!oxygenated!a!phenyl!
thioacetonitriles ð80JA0933Ł[
R R
S S
+ SMe (24)
NC SMe
CN
R R

a\a!Diethylthionitriles can be prepared from diethylthioacetaldehyde "21# as shown in Scheme 13


ð72CJC1995Ł[ Thus formation of the oxime and dehydration with methane sulfonylchloride gives
diethylthioacetonitrile "22#\ which can then be deprotonated with potassium hydride to give a
carbanion which reacts with alkyl halides\ alkyl sulfonates\ and a\b!unsaturated aldehydes leading
to a variety of a\a!diethylthionitriles[ Dehydration of a\a!dimethylthioamides also gives a\a!
dimethylthionitriles\ as shown in Equation "14# for the synthesis of the naturally occurring insect
antifeedant dithyreanitrile ð82TL0974Ł[
i, NH2OH i, KH
EtS O EtS EtS
ii, MeSO2Cl ii, RX
CN NC R
EtS EtS EtS
(32) (33)

Scheme 24

MeS O MeS
MeS MeS CN
NH2
POCl3
(25)
pyridine
N N
H H
OMe OMe

b!Thionitriles can be prepared by the Michael addition of thiols onto b\g!unsaturated nitriles
ð36JA1217\ 44OSC"2#347\ 65JOC1735\ 67S591Ł[ Other sulfur!based nucleophiles such as benzenesul_nate
also add to b\g!unsaturated nitriles ð75TL4988Ł[ Cyanide undergoes Michael additions to vinyl!
sulfones\ also giving b!cyanosulfones ð37CRV078Ł[ Tosyl cyanide undergoes AIBN!initiated radical
additions to alkenes\ leading to b!cyanosulfones "Equation "15## ð76TL1742Ł[ With conjugated dienes\
0\3 addition occurs providing access to b\g!unsaturated d!cyanosulfones[ b\g!Unsaturated nitrile
g!silylenol ethers react with PhSCl to give b!phenylthio!g!ketonitriles as shown in Equation "16#
ð67SC120Ł[

Ts
TsCN/AIBN
(26)
CN
AIBN = 2,2-azobisisobutyronitrile

SPh
NC O-TMS PhSCl NC O
(27)
R R

2[07[1[5 Aliphatic Nitriles Bearing a Se! or Te!based Functional Group


The reaction of chloroacetonitrile with selenocyanate gives the corresponding a!selenonitrile
derivative as shown in Scheme 14\ reaction with 1!ethoxybutadiene then gives the selenodinitrile
ð77JA7560Ł[ A variety of other selenium!based nucleophiles also react with chloroacetonitrile to
give a!selenonitriles ð66CL724\ 75CC313\ 77JCS"P0#0802Ł[ a!Selenonitriles can also be prepared from
cyanohydrins by treatment with methanesulfonyl chloride followed by sodium phenylselenide
Aliphatic Nitrile 526
ð71JCS"P0#0292Ł[ a!Selenonitriles can be deprotonated by NaOH in the presence of tetra!
butylammonium iodide to give carbanions which then react with alkyl halides leading to more
substituted a!selenonitriles[ The process can be repeated\ giving a\a!disubstituted!a!selenonitriles
including cyclic derivatives ð66CL724Ł[

EtO O
NCSe– NC Se
Cl CN NCSe CN CN

Scheme 25

Selenoacetals "23#\ react with TMS!CN in the presence of SnCl3 as a Lewis acid\ to give
a!cyanoselenides "24# as shown in Equation "17# ð82SL010Ł[ Only selenoacetals with simple alkyl and
aryl substituents have been investigated[ However\ seleno!ortho!esters "25# react similarly to give
a!cyanoselenoacetals "26# as shown in Equation "18#[ Treatment of the anion of malononitrile
derivatives with phenylselenyl bromide results in formation of a!phenylselenodinitriles which can
then undergo a radical addition to alkenes giving g!phenylselenodinitriles ð81JA3325Ł[ Reaction of a
malononitrile derivative with dialkylselenium dichlorides results in formation of the a!cyano!
selenium ylides ð61JOM"31#288Ł[ Electrolysis of an a!arylselenonitrile in the presence of Et2N and HF
results in the formation of a!~uoro!a!arylselenonitriles ð81TL2050Ł[

R1Se SeR1 TMS-CN R1Se CN


(28)
R2 R3 SnCl4 R2 R3
(34) (35)

R1Se SeR1 TMS-CN R1Se CN


(29)
R2 SeR1 SnCl4 R2 SeR1
(36) (37)

Phenylselenyl cyanide adds to unactivated alkenes in the presence of SnCl3 to give b!phenylselenyl
nitriles "27# ð71CC760Ł[ The reaction is a trans addition across the double bond as shown in Equation
"29# for the case of cyclohexene[ Phenylselenyl cyanide also adds stereo! and regiospeci_cally to
enamines giving b!seleno!a!aminonitriles ð71TL0250Ł without the need for a Lewis acid catalyst[
Similarly\ in the presence of BF2 phenylselenotoluenesulfonate adds to acrylonitrile giving 1!phenyl!
seleno!2!tosyl!propionitrile ð70JOC2138Ł[

CN
PhSeCN
(30)
SnCl4
SePh
(38)

Reaction of dibutyltellurium with chloroacetonitrile gives dibutyl"cyanomethyl#telluronium


chloride\ which reacts with organolithium reagents to give alkyldibutylcyanomethyltellurium
ð80JCS"P0#0820Ł[ Other a!halonitriles also react with dibutyltellurium leading to tellurium salts ð80MI
207!90Ł[

2[07[1[6 Aliphatic Nitriles Bearing a Nitrogen!based Functional Group


For the synthesis of a!aminonitriles by the Strecker synthesis see Section 2[07[0[1[1[ Isoquinoline
systems will undergo a Strecker!type reaction with TMS!CN and benzoyl chloride\ giving the
a!aminonitriles as shown in Equation "20# ð79S273Ł[ Dihydropyridinium salts react similarly with
cyanide\ giving b\g!unsaturated!a!aminonitriles ð79JA0953Ł[ Addition of HCN to 0\0!diamino
alkenes occurs easily to give a\a!diaminonitriles ð54AG"E#840\ 60CB813Ł[
527 Nitriles] General and Aliphatic Nitriles
CN O

N TMS-CN/PhCOCl N Ph
(31)
N N
H H

Tertiary amines are oxidised to iminium salts by chlorine dioxide[ Addition of NaCN then gives
a one!pot procedure for the conversion of amines into a!aminonitriles\ as shown in Equation "21#
ð77JA3718Ł[ Alternatively\ the amine can be oxidised to the nitrile oxide with hydrogen peroxide\
which on treatment with TFAA gives the iminium salt\ and addition of KCN gives the a!aminonitrile
ð79SC384\ 71H"08#1004Ł[ This transformation can also be achieved electrochemically[ Thus\ electrolysis
of a tertiary amine in methanol:water in the presence of NaCN gives the a!aminonitrile ð58JA3070\
66JOC1862Ł[ A related process for secondary amines involves chlorination to give the N!chloroamine\
followed by elimination to the imine and addition of HCN\ as shown in Scheme 15 for piperidine
ð68TL660Ł[ Cyclic a!methoxyamides and carbamates react with TMS!CN in the presence of
BF2 = Et1O or SnCl3 to give a!aminonitriles "Equation "22## ð70TL030\ 82T66Ł[ Thioamides react with
alkyl halides to give the S!alkylated salt which then reacts with KCN to form a!thio!a!aminonitriles
ð66JCS"P0#0700\ 76BSB"85#292Ł[ a!Hydroxylaminonitriles can be prepared by the oxidation of secondary
amines with hydrogen peroxide and sodium tungstate\ followed by the addition of cyanide to the
resulting nitrone ð76TL5358Ł[ Aminomalononitrile "H1NCH"CN#1# can be prepared from malono!
nitrile by formation of the oxime with sodium nitrite followed by reduction of the oxime to the
amine with aluminum ð62OSC"4#21Ł[
i, ClO2
R2 R1 ii, NaCN R2 R1
N N (32)
67-83% CN
R3 R3

HCN

N N N N CN
H H
Cl
Scheme 26

TMS-CN/TiCl4
MeO N CO2Bn NC N CO2Bn (33)

CO2Me CO2Me

The a!protons of an a!aminonitrile can be deprotonated by a suitable base\ provided the amino
group is suitably protected[ Reactions with electrophiles then provide a versatile route to a variety
of functionalised a!aminonitriles ð68S016\ 89CJC0294\ 89JCS"P0#2254\ 82SL488Ł[ b\g!Unsaturated!a!
aminonitriles react similarly ð76TL5068Ł[
Amines react with a\b!unsaturated nitriles via a Michael addition\ to give b!aminonitriles ð31CB020\
31JA0298\ 33JA614\ 34JA0960\ 34JOC166\ 44OSC"2#82\ 54JOC2578\ 70S264Ł[ In appropriate cases\ the amine
can react with more than one molecule of the a\b!unsaturated nitrile\ giving di! and trialkylated
amines[ This reaction has been recently reviewed ðB!81MI 207!90Ł[ Cyanide undergoes Michael
additions to nitroalkenes giving b!nitronitriles ð32CB0164\ 36JCS0499Ł\ and to a\b!unsaturated nitriles
leading to butanodinitrile derivatives ð0767LA"080#22Ł[ N!Tosylaziridines react with TMS!CN in the
presence of catalytic Yb"CN#2\ Y"CN#2\ or Ce"CN#2 ð89TL5268Ł\ or with acetone cyanohydrin in the
presence of lanthanoid"III# alkoxides ð82CL864Ł to give b!N!tosylaminonitriles in which cyanide
attacks the least hindered end of the aziridine[ When the boron enolate of a nitrile is formed with
Et1NBCl1\ followed by the addition of an aromatic aldehyde\ the product is not the expected
b!hydroxynitrile\ but the b!diethylaminonitrile "Equation "23## ð68SC442Ł[ v!Aminonitriles can be
prepared from cyclic a!aminoketones by Beckmann fragmentation of the derived imine or oxime
derivatives "see Scheme 5 for an acyclic example# ð52HCA0089\ 82SL479Ł[

NC Et2NBCl2 NC NEt2
(34)
ArCHO
R R Ar
Aliphatic Nitrile 528
2[07[1[7 Aliphatic Nitriles Bearing a P!\ As!\ Sb! or Bi!based Functional Group
a!Cyanophosphonates are valuable synthetic intermediates for the formation of a\b!unsaturated
nitriles via the WadsworthÐEmmons reaction "see Chapter 2[08#[ They can be prepared by the
Arbuzov reaction from an a!bromonitrile ð50JA0622\ 65JOC1735Ł\ or by reaction of a nitrile enolate
with diethyl chlorophosphate ð76S300Ł[ Displacement of the tosylate of a hydroxymethyl!
phosphonate by cyanide anion provides an alternative route to a!cyanophosphonates^ this is a
particularly useful way of introducing 02C! or 03C!labelled cyanide into these compounds
ð80JCS"P0#254Ł[ The alkene "28# undergoes Michael additions to give a!cyanophosphonates as shown
in Equation "24# ð89TL1794Ł[ a!Aryl!a!cyanophosphonates can be prepared from nitroalkenes and
silylphosphites by treatment with TiCl3 and zinc "Equation "25## ð76SC842Ł[ The enolate of an
a!cyanophosphonate can be formed\ and reacts with alkyl dihalides\ giving cyclic a!cyano!
phosphonates ð89PS"43#060Ł^ with Tf1NF to give a!~uoro!a!cyanophosphonates ð81JCS"P0#202Ł^ and
with phenylsulfenyl chloride leading to a!phenylthio!a!cyanophosphonates ð65JOC1735Ł[

O
P(OEt)2
CN
NH N
BOCHN + BOCHN (35)
NH NH CN
P(OEt)2
O O O
(39)

i, TiCl4 Ar CN
NO2 + (EtO)2PO-TMS (36)
Ar ii, Zn PO(OEt)2

Cyanomethyl!containing phosphines can be prepared by a number of routes[ Thus\ reaction of


lithioacetonitrile with a diaryl "or dialkyl# chlorophosphine ð76S827Ł\ reaction of cyanomethylzinc
bromide with an alkylchlorophosphine ð72ACS"B#528Ł\ reaction of chloroacetonitrile with an
aryl"trimethylsilyl#phosphine ð65ACS"B#688\ 72ACS"B#528Ł and reaction of chloroacetonitrile with a
dialkyl"ethoxy#phosphine\ followed by deoxygenation of the resulting trialkylphosphine oxide with
Ph1SiH1 ð64ACS"B#752Ł\ all give cyanomethylphosphine derivatives[ Treatment of phosphorus
trichloride with tributyl"cyanomethyl#tin gives tri"cyanomethyl#phosphine ð68JCR"S#285Ł[
b!Cyanophosphines and phosphonium salts can be prepared by the Michael addition of suitable
phosphines onto a\b!unsaturated nitriles ð77OSC"5#821\ 77T5096Ł[
Reaction of the TMS ketene acetal of methyl cyanoacetate with trichloroarsine results in for!
mation of the corresponding a!dichloroarsine methyl malononitrile as shown in Equation "26#
ð80TL1644Ł[ Reaction with PCl2 similarly gives methyl a!dichlorophosphine!a!cyanoacetate
ð75TL4500Ł[ Treatment of malononitrile or methyl cyanoacetate with triphenylarsine oxide results
in elimination of water to give the a!cyanoarsonium ylides ð62T0586Ł[

NC OMe NC CO2Me
+ AsCl3 (37)
O-TMS AsCl2

Triphenyl"cyanomethyl#phosphonium chloride is prepared by the reaction of chloroacetonitrile


with triphenylphosphine ð71IJC"B#0935Ł[ Tributylantimony reacts with bromoacetonitrile to give
tributylcyanomethylantimonium bromide ð80JOC0270Ł[

2[07[1[8 Aliphatic Nitriles Bearing a Si! or B!based Functional Group


a!Silylnitriles can be obtained by reaction of a nitrile enolate with a silyl chloride ð73BCJ1657\
74TL4724Ł[ Thus\ TMS!acetonitrile is prepared by the reaction of chloro! or bromoacetonitrile with
TMS!Cl in the presence of zinc powder ð68JCS"P0#15Ł[ The enolate of a!silylacetonitrile can then be
formed\ and undergoes alkylation ð73JOC2593\ 81SC1118Ł and Michael additions ð73TL0488Ł\ giving
more functionalised a!silylnitriles[ Treatment of phenylthioacetonitrile with LDA\ followed by
"chloromethyl#trimethylsilane results in formation of 1!phenylthio!2!TMS!propionitrile
ð70JCS"P0#145Ł[ Treatment of an a!tertiary aminonitrile with TMS!Cl gives the ammonium salt which
539 Nitriles] General and Aliphatic Nitriles
on treatment with LDA rearranges to the corresponding a!amino!a!trimethylsilylnitrile\ as shown
in Scheme 16 ð76JOC1316Ł[ An alternative a!silylnitrile synthesis involves the use of Wilkinson|s
catalyst to catalyse the addition of a trialkylsilane to an a\b!unsaturated nitrile ð63TL3994Ł[ Reaction
of acetonitrile with TMS!OTf results in the formation of the tris!TMS!acetonitrile\ as shown in
Equation "27# ð66S525Ł[ Mono! and di!substituted nitriles react similarly to give the di! and monosilyl
derivatives\ respectively[ Reaction of MeSCH1CN with TMS!OTf and triethylamine\ however\
results in the formation of a!TMS!a!MeS!acetonitrile in which only one TMS group has been added
ð77SC1000Ł[ Reaction of a TMS!ketone with TMS!CN and TMS!OTf results in formation of the
O!TMS!a!TMS!cyanohydrin ð81JOC2220Ł[
Me TMS Me Me
TMS-Cl LDA
Ph N CN Ph N CN Ph N CN
+

TMS
Scheme 27

TMS
MeCN + TMS-OTf TMS CN (38)
TMS

Reaction of acrylonitrile with a TMS dialkylphosphite "or with a trialkylphosphite and TMS!Cl#
gives dialkyl 1!cyano!1!"TMS#ethanephosphonates ð71S804\ 72S806Ł[ Treatment of the lithium anion
of a nitrile with borane gives the lithium "a!cyanoalkyl#trihydroborate salt^ the lithium can then be
transmetallated to other alkali metals by treatment with the appropriate ~uoride salt ð78IC381Ł[

2[07[1[09 Aliphatic Nitriles Bearing a Metal Functionality


A number of bases will replace the acidic protons a! to a nitrile by a metal as described in Section
2[07[0[3[ However\ the resulting a!metal nitriles are usually reacted in situ\ and not isolated[ The
anions of a!heteroatom substituted nitriles can also be formed\ and these are discussed in the section
of this chapter appropriate to the particular heteroatom[ However\ sodium hexamethyldisilazide
deprotonates nitriles giving the a!sodium derivatives which can be isolated ð56JOM"8#014Ł[ Acetonitrile
can be deprotonated with butyllithium\ giving cyanomethyllithium "39# as shown in Scheme 17[
This can be transmetallated by treatment with Cul\ giving cyanomethylcopper ð61TL376Ł[
BuLi Li CN CuI Cu CN
Me CN
(40)

Scheme 28

Treatment of tributyltin methoxide with trimethylsilylacetonitrile under Lewis acid catalysis


results in the formation of cyanomethyltributyltin "Equation "28## ð56PNA"154#828Ł[ Tributyltin
hydride also undergoes a Michael addition to acrylonitrile\ giving b!tributylstannylproponyl nitrile
ð74JOM"174#062Ł[

Bu3Sn OMe + TMS CN Bu3Sn CN + TMS-OMe (39)

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.19
a,b-Unsaturated and Aryl Nitriles
MILTON J. KIEFEL
Monash University, Vic., Australia
2[08[0 GENERAL METHODS 530
2[08[1 NITRILES BEARING AN a\b!VINYLIC BOND 532
2[08[1[0 a\b!Alkenic Nitriles without Further Unsaturation 532
2[08[1[1 a\b!Alkenic Nitriles with Further Unsaturation 535
2[08[1[2 a\b!Alkenic Nitriles with Halo!substituents 538
2[08[1[3 a\b!Alkenic Nitriles with Oxy`en!based Substituents 549
2[08[1[4 a\b!Alkenic Nitriles with Sulphur!based Substituents 543
2[08[1[5 a\b!Alkenic Nitriles with Se! and Te!based Substituents 545
2[08[1[6 a\b!Alkenic Nitriles with Nitro`en!based Substituents 545
2[08[1[7 a\b!Alkenic Nitriles with P!\ As!\ Sb! and Bi!based Substituents 548
2[08[1[8 a\b!Alkenic Nitriles with Si! and B!based Substituents 559
2[08[1[09 a\b!Alkenic Nitriles with Metal Substituents 550
2[08[2 NITRILES BEARING AN a\b!ARYL OR !HETARYL SUBSTITUENT 550
2[08[2[0 General Methods 550
2[08[2[1 Benzonitrile and Substituted Benzonitriles 553
2[08[2[2 Polycyclic Aromatic Nitriles 556
2[08[2[3 Heterocyclic Aromatic Nitriles 558
2[08[3 NITRILES BEARING AN a\b!TRIPLE BOND 563

2[08[0 GENERAL METHODS


Nitriles represent one of the classical functional groups of organic chemistry[ The importance of
the carbonÐnitrogen triple bond lies in its ease of introduction into molecules\ as well as its
exceptional reactivity due to a unique combination of unsaturation\ polarizability and low steric
demand[ Many synthetic chemists have taken advantage of these characteristics of the nitrile
group in order to synthesize complex molecules\ in particular in the preparation of heterocyclic
compounds[
The synthesis of a\b!unsaturated and aryl nitriles is similarly of great interest to organic chemists\
the former especially so since they are versatile reagents which have been extensively used in the
synthesis of heterocycles[ Since this account is devoted solely to the synthesis of a\b!unsaturated
heterocycles and aryl nitriles\ and not to the use of such compounds as intermediates\ the interested
reader is directed to several excellent review articles to become more acquainted with this _eld
ð37CRV078\ B!69MI 208!90\ 72H"19#408\ B!72MI 208!90\ B!72MI 208!91\ 80COS"5#114Ł[ Given the comprehensive
nature of these outstanding articles\ as well as the space limitations of this chapter\ this account will
focus on general strategies towards a\b!unsaturated and aryl nitriles\ together with presenting
developments in this _eld since 0874[
There are several general methods for the preparation of a\b!unsaturated nitriles[ These include]
"i# the alkenation of either aldehydes or ketones "Wittig or WittigÐHorner condensations# and
modi_cations of this theme\ including cyanomethylation via acetonitrile^ "ii# from vinyl halides via
nucleophilic displacement with cyanide ion^ "iii# from a\b!alkynenitriles by direct reduction or via

530
531 a\b!Unsaturated and Aryl Nitriles
vinyl cuprates^ and "iv# by elimination\ such as in the dehydration of oximes[ Whilst speci_c examples
of these general approaches towards a\b!unsaturated nitriles will be presented throughout this
chapter\ it is appropriate at this stage to give an overview of these techniques[
The alkenations of aldehydes and ketones with cyanomethylenetriphenylphosphorane
ð50JCS0155Ł or diethyl cyanomethylenephosphonate ð62T1326Ł typically give the best results when
aromatic carbonyl compounds are employed ðB!72MI 208!90Ł\ although a few e.cient methods with
aliphatic carbonyl compounds have been reported ð60JOC1915\ 61TL558\ 63S758\ 66S518\ B!72MI 208!90Ł[
A modi_cation of this approach involves the use of cyanomethyldiphenylphosphine oxide in the
presence of base "Equation "0## ð66S015Ł[ In this way\ E!1!alkenenitriles are prepared with ×89)
selectivity for aromatic aldehydes and ½64) selectivity for aliphatic aldehydes and in excellent
chemical yield "generally ×89)#[ 0\1!Diketones can also react under Wittig conditions with cyano!
methylenetriphenylphosphorane to give the corresponding dialkene nitrile ð65T1868\ 66S455Ł[
O
ButOK
RCHO + P CN CN + (1)
Ph R R CN
THF or DMF
Ph trans cis
Vinyl halides generally have low reactivity towards nucleophilic displacement ð80COS"5#114Ł[ For
the preparation of vinyl nitriles\ the use of copper cyanide with base under high temperatures
"×199>C# is typically required ðB!69MI 208!90Ł[ However\ the use of potassium cyanide in the
presence of catalytic Pd"9# and 07!crown!5 "Equation "1## requires much milder conditions "59Ð
099>C# ð66TL3318Ł[ The reaction is highly stereospeci_c and high yielding "74Ð87)#[

R1 R3 R1 R3
Pd(PPh3)4, 18-crown-6
+ KCN (2)
Br benzene CN
R2 R2
a\b!Alkenic nitriles can also be prepared readily from a\b!alkynenitriles "see Section 2[08[3 for
the preparation of nitriles bearing an a\b!triple bond#[ Lithium aluminum hydride adds in a trans
manner to alkynenitriles to provide the alanate "0# "Scheme 0#\ which upon acidi_cation leads to
the E!a\b!unsaturated nitrile "1# ð68S329Ł[ Addition of an organocopper"I# reagent to an alkynenitrile
gives the a!cyanocuprate "2# "Scheme 1# which upon acidi_cation provides the 1!alkenenitrile "3#
ð67S343Ł[ It is worth noting that in this instance\ the R0 and CN groups "Scheme 1# are cis to each
other "cf[ Scheme 0#[ Furthermore\ addition of an organocuprate to an alkyne provides the vinyl
cuprate "4a# "Scheme 2# which\ upon exposure to cyanogen chloride in THF\ gives the corresponding
1!alkenic nitrile in ×89) yield ð66S673Ł[

CN CN
LiAlH4 H+
R CN CN
Al R
H2
R R
(1) (2)

Scheme 1

R1
R2[CuX]M H+
R1
R1 CN CN M
R2 CN
THF or Et2O R2
Cu X
(3) (4)

Scheme 2

R1 R1
[R2CuX]MgHal ClCN
R1 H MgHal
R2 R2
THF or Et2O THF
Cu X CN
(5a)

Scheme 3
Bearin` an a\b!Vinylic Bond 532
Elimination processes are also of interest as a general route into a\b!unsaturated nitriles[ The
dehydration of oximes\ an important method for the synthesis of saturated nitriles\ can also be
applied to the preparation of unsaturated nitriles[ In one reported example\ allylic nitro compounds
are deoxygenated with carbon disulphide under phase transfer conditions to provide the cor!
responding allylic oxime which is then dehydrated to an a\b!alkenic nitrile "Scheme 3# ð89SC854Ł[
Saturated nitriles can themselves be transformed into a\b!unsaturated nitriles via oxidative elim!
ination of an intermediate a!phenylselenonitrile with hydrogen peroxide "Scheme 4# ð63TL1168Ł[

NO2 K2CO3, CS2, H2O NOH


NaOH (aq.), CS2
CN
TBAB, CH2Cl2

Scheme 4

Li
N

i, SePh H2O2
CN CN
ii, PhSeSePh CN

Scheme 5

2[08[1 NITRILES BEARING AN a\b!VINYLIC BOND

2[08[1[0 a\b!Alkenic Nitriles without Further Unsaturation


As mentioned above\ the alkenation of aldehydes or ketones is an important route into
a\b!unsaturated nitriles[ The two!carbon homologation of 06!keto!androstane to 19!keto!pregnane
has been achieved via the intermediate a\b!unsaturated nitrile "5# "Scheme 5#[ Thus\ exposure of the
ketone "4# to the anion of 1!"diethylphosphono#!propionitrile a}orded the alkenic nitrile "5# in
excellent yield "66)# ð65JOC0762Ł\ which was then elaborated to the progesterone "6#[ In another
WittigÐHorner alkenation\ of either an aldehyde or ketone\ the use of a cyanophosphonate in
the presence of catalytic tetrabutylaminium iodide in an aqueous two!phase system provides the
corresponding unsaturated nitriles ð63S758Ł[ This simple procedure a}ords crotonitrile "40) yield#
and 2!methyl!1!butenenitrile "51) yield#\ the former as a mixture of geometrical isomers "50 ] 28#
in favour of the E!isomer[

O
O CN
(EtO)2P CN
steps
NaH

RO RO
(5) (6)

O
(7)

Scheme 6
533 a\b!Unsaturated and Aryl Nitriles
Moderate yields of several simple alkyl a\b!unsaturated nitriles from carbonyl compounds have
also been achieved using either O!ethyl S!cyanomethyl dithiocarbonate "7# or S!cyanomethyl
diethyl phosphorothioate "8#\ also in a two!phase system employing catalytic methyl!
trioctylammonium chloride "Scheme 6#[ It is believed that the reaction proceeds via the thiirane "09#
which\ upon extrusion of sulphur\ produces the nitriles in 25Ð68) yield ð68S789Ł[ Generally higher
yields result from the use of the dithiocarbonate "7#[
S R1 O
+
EtO S CN R2 R3 S R2 R1
(8)
NaOH, H2O, MeCN R2 R1 –S
(C8H17)3N+Me Cl– R3 CN CN
O R1 O R3
+ (10)
(EtO)2P
S CN R2 R3
(9)
R1 = H, Me; R2 = H, alkyl; R3 = alkyl

Scheme 7

The reaction of chloroacetonitriles and aldehydes mediated by tri!n!butylstibine at 019>C


furnishes a\b!alkenic nitriles in yields typically ×89) ð78SC72Ł\ but generally as 0 ] 0 mixtures of
trans ] cis isomers[ Similarly\ treatment of cyclic ketones under these conditions "Equation "2## yields
the corresponding unsaturated nitriles\ though in more moderate yield "22Ð49)#[ This
transformation is believed to proceed via the chloro!alkoxy!tri!n!butylstiborane "00# which
then decomposes to the a\b!unsaturated nitrile and chloro!hydroxy!tri!n!butylstiborane "01#
ð78SC72Ł[

Cl CN CN
O (3)
( )n Bun3Sb ( )n

n = 1, 2

Cl
Bun3Sb H Cl
O Bun3Sb
CN OH
2
R1 R
(11) (12)

Acetonitrile can itself be used in the direct conversion of aliphatic ketones into a\b!alkenic nitriles
ð66S518Ł[ The use of potassium hydroxide pellets as base in acetonitrile solution overcomes many
of the problems usually associated with this type of reaction\ most notably the aldol condensation
of the ketone under the polar\ protic conditions normally required for this transformation[ The
reaction gives moderate to excellent yields "29Ð79)# of a\b!unsaturated nitriles^ lower yields result
from ketones which are easily enolized "e[g[\ acetophonone# ð66S518Ł[ Interestingly\ the reaction
between acetonitrile and cyclohexanone "Equation "3## provides the a\b!unsaturated nitrile con!
taminated with the b\g!unsaturated nitrile ð66S518Ł[ The latter component constituted about 19)
of the product\ and could be easily separated from the desired conjugated nitrile[ This result is
contrary to the reaction between cyclohexanone and cyanoacetic acid which provides only the
b\g!unsaturated product after decarboxylation of the intermediate cyanoacrylic acid ð40OS"40#14Ł[

O
MeCN, KOH CN CN
+ (4)

4.5 : 1

As mentioned in Section 2[08[0 above\ the oxidative elimination of a!phenyl!selenonitriles is an


e.cient route into alkenic nitriles ð63TL1168Ł[ Similarly\ the direct cyanoselenylation of aldehydes
with aryl selenocyanates in the presence of tri!n!butylphosphine leads to cyanoselenides of the type
"02# "Scheme 7# ð66JA4109Ł[ Oxidative elimination of aryl selenoxide with hydrogen peroxide then
Bearin` an a\b!Vinylic Bond 534
leads to a\b!unsaturated nitriles in excellent chemical yield\ but as 0 ] 0 mixtures of geometrical
isomers[

ArSeCN, Bu3P, THF CN H2O2


R CHO R
R CN
SeAr
(13)
R = acyclic or cyclic alkyl

Scheme 8

Electrooxidative cleavage of the C0S bond in the ethylthiol "03# "Equation "4##\ using bromide
ion as the electrolyte\ results in the smooth formation "56Ð67) yield# of simple alkyl and branched
alkyl a\b!unsaturated nitriles ð75TL3066Ł[ As with the oxidative elimination of selenoxides\ this
oxidative elimination process results in essentially 0 ] 0 mixtures of cis]trans isomers[

SEt Br –, MeOH CN (5)


CN R
R
(14)

Reductive eliminations can also lead to alkenic nitriles "Equation "5##[ Thus\ exposure of the
a!cyano!b!nitrosulphone "04# to sodium sulphide in DMF at room temperature provides the cor!
responding a\b!unsaturated nitriles in good yield ð67TL652Ł[ In this way several acyclic and cyclic
alkyl substituted a\b!alkenic nitriles have been prepared\ again as 0 ] 0 mixtures of geometrical
isomers[ The direct dehydrocyanation of 0\1!cyclobutenedicarbonitrile "05# with sodium hydroxide
at ×199>C results in moderate yields of 0!cyclobutanecarbonitrile ð62JOC364Ł[ The same product
can be obtained by the dehydrochlorination of 1!chlorocyclobutanecarbonitrile during exposure to
base under much milder conditions "009>C# ð62JOC364Ł\ although problems with the formation of
the requisite chloronitrile substrate ð51JOC311Ł make this approach impractical on a preparative
scale[

R1 R3 R1 R3
Na2S, DMF
R2 CN (6)
O2N SO2Ar R2 CN
(15)

CN

CN
(16)

The use of alkynes in the preparation of a\b!unsaturated nitriles has already been mentioned in
the introductory remarks[ Further to this\ hydroboration of alkynes with bis"0\1!dimethyl!
propyl#borane in THF gives the corresponding alkenyldialkylborane "06# "Scheme 8# which\ upon
exposure to copper"I# cyanide and copper"II# acetate in HMPA\ produced the desired E!1!alkenic
nitriles "07# in excellent yield ð80CC637Ł[ The presence of a small amount of water in the _nal step
of this transformation is essential for cyanoalkene formation ð63BCJ1400\ 78CC155Ł[
R22BH, THF CuCN, Cu(OAc)2, HMPT, H2O
R1 R1 R1
BR22 CN
(17) (18)

Scheme 9

The palladium"9# catalysed decarboxylation*dehydrogenation of allyl a!cyanocarboxylates "08#


to a\b!unsaturated nitriles proceeds with generally high e.ciency for both cyclic and acyclic allyl
a!cyanocarboxylate substrates "Equation "6## ð75CC007Ł[ It has been found that when the allyl
a!cyanocarboxylate is substituted with two di}erent alkyl groups "e[g[\ "19##\ then the two isomers
"10# and "11# result from this reaction in almost equal amounts ð75CC007Ł[
535 a\b!Unsaturated and Aryl Nitriles
CN
R Pd0, PPh3, EtCN, ∆
CN (7)
R
O O
(19)

CN
CN CN

O O
(20) (21) (22)

In the early 0889s it was found that the reactions of organozinc halides with p!toluenesulphonyl
cyanide provide an excellent entry into a\b!unsaturated nitriles ð82TL3512Ł[ This method is illustrated
in Equation "7#[
TsCN, THF, 0 °C to 25 °C
Cl ZnI Cl CN (8)
72%

2[08[1[1 a\b!Alkenic Nitriles with Further Unsaturation


In an elegant one!step synthesis of 1!cyano!0\2!butadienes\ the WittigÐHorner alkenation has
been utilized to great advantage[ Thus\ diethyl 1!lithio!1!cyano!1!trimethylsilylethanephosphonate
"12# is condensed with an aldehyde "R0 Et\ Pri\ Ph\ Ar# or carbonyl compound "R0 R1 Ph# to
provide the intermediate 1!cyano!1!alkenephosphonate "13# "Scheme 09#[ Without isolation "13# is
lithiated "lithium diisopropylamide "LDA## a to the phosphorus and then reacted with a further
equivalent of carbonyl compound to give the desired 1!cyano!0\2!butadiene "14# "Scheme 09#[ In
practice only one addition of LDA "1 equivalents# and one addition of carbonyl compound "1[9
equivalents# to the starting phosphonate is required\ and yields of the 1!cyano!0\2!butadienes are
typically above 64) ð72S806Ł[ Dienenitriles have also been prepared by the treatment of aldehydes
with trimethylsilyl cyanide ð75CB1489\ 75CB2233Ł[

O R1 R2 O
O Li R1 R2 O
R1 R2 O LDA R1 R2
TMS
(EtO)2P (EtO)2P
–78 °C (EtO)2P CN –78 °C
CN
CN
Li
(23) (24)

R1
R1
R2
R2 CN
(25)
LDA = lithium diisopropylamide

Scheme 10

In a HornerÐEmmons reaction of a phosphononitrile with aldehydes "Equation "8##\ it has been


found that a bulky isopropyl group on the a!carbon of the phosphononitrile results in excellent
Z!selectivity of the resulting a\b!unsaturated nitrile ð83TL0470Ł[ The in~uence of solvent on the Z ] E
ratio was found to be signi_cant\ with the lower polarity solvents "Et1O\ toluene# giving the highest
Z!selectivity "up to 24 ] 0^ cf[ the use of THF as solvent which results in a Z ] E ratio of 1[1 ] 0#[ This
methodology has been applied successfully to the total synthesis of the natural product plaunotol
"15#[ The key step in the total synthesis of "15# involved the HornerÐEmmons reaction between the
phosphononitrile "16# and the aldehyde "17# to provide the alkenic nitrile "18# ð83TL0470Ł[
Bearin` an a\b!Vinylic Bond 536

O CHO

P(OEt)2 + CN (9)
CN

O
OH NC P(OEt)2 OR
CN
OH CHO OR

(26) (27) (28) (29)

Many examples of the synthesis of a\b!alkenic nitriles with further unsaturation involve
compounds containing an aromatic ring\ often deriving from aromatic carbonyl compounds
ðB!72MI 208!90Ł[ In one such example\ involving cyanophosphates "29#\ the cyanophosphorylation
of aromatic ketones with diethyl phosphorocyanide in the presence of lithium cyanide a}ords "29#
"Scheme 00#[ Treatment of the cyanophosphates "29# with boron tri~uoride etherate then leads to
the a\b!unsaturated nitriles in good to excellent overall yield "50Ð83)# from the ketone ð73TL316Ł[
Interestingly\ the cyanophosphate "20#\ derived from an aliphatic ketone\ remains intact under the
dephosphorylation conditions[
O
O
O (EtO)2P CN
CN P(OEt)2
R1 O BF3•Et2O
R1
Ar NC Ar
LiCN R1
R2 Ar R2
R2
(30)

Scheme 11

O
P(OEt)2
O
CN
Ar
(31)

The reactions of aromatic carbonyl compounds with an organotellurium ylide also results in the
formation of 1!alkenic nitriles ð77JOC3751Ł[ Thus\ condensation of various para!substituted aromatic
ketones with the cyanodibutyl telluronium ylide "21# gives the corresponding aryl a\b!unsaturated
nitrile "22# in good yield "50Ð72)# and high E!selectivity "up to 013 ] 0 E ] Z#[
Bun CN
Te+ –CHCN
Bun R
(32) (33)

Organometallic chemistry when applied to aryl halides also furnishes a\b!unsaturated nitriles[ In
this case\ the Heck reaction involving the palladium!catalysed coupling of an aryl iodide with
acrylonitrile provides the corresponding aryl a\b!unsaturated nitrile in 76Ð83) yield "Equation
"09## ð78JOM"260#286Ł[ This process gives mixtures of E! and Z!isomers\ although slightly in favour
of the Z!geometry[
Pd(OAc)2, H2O, K2CO3, 80–100 °C
Ar I + Ar (10)
CN CN
537 a\b!Unsaturated and Aryl Nitriles
The interest in organic molecules as synthetic metals ð73NAT008Ł has led to the synthesis of
four thiophene!fused tetracyanoquinodimethanes "e[g[\ "23##[ These compounds were prepared in
04Ð26) yield by the titanium tetrachloride mediated condensation of the corresponding quinone
with malononitrile "19 equivalents# in chloroform containing pyridine "39 equivalents# ð75CC0668Ł[
NC CN

S S

NC CN
(34)

Reaction of the anion of 3!cyano!2!oxo!tetrahydrothiophene "24#\ "which can be considered as a


synthetic equivalent to the a!acrylonitrile anion "25##\ with an alkyl halide leads to the C!alkylated
product "26^ RArCH1\ HC2C0CH1# "Equation "00##[ Exposure of "26# to 4) aqueous sodium
hydroxide results in a hydroxide promoted fragmentation via a series of inverse DieckmanÐMichael
reactions to give various substituted benzyl a\b!unsaturated nitriles together with the acetylenic
a\b!alkenic nitrile "27# "Equation "00## ð74S858Ł[ Only low to moderate yields "18Ð49)# of substituted
1!alkenic nitriles result from this transformation\ although the ease of availability of the substrates
and the mild reaction conditions make this a viable route into acrylonitrile syntheses[
O CN
– –
CN
S
(35) (36)

O CN
R NaOH (aq.) R
(11)
CN
S
(37)

CN
(38)

a\b!Unsaturated nitriles containing an additional triple bond can also be prepared from the
reaction of potassium cyanide with the quaternary salt of pyridazine 0!oxide "28#\ formed by the
reaction of pyridazine 0!oxide with either dimethyl sulphate or benzoyl chloride "Scheme 01#[ As
before\ only poor yields of the desired b!ethynylacrylonitriles "19Ð29)# were achieved ð62T1326Ł\
and as mixtures of geometrical isomers[ The reaction is believed to proceed via the dihydro derivative
"39# which undergoes electrocyclic opening to "30# which leads to the alkyne products upon elim!
ination of N1 and R20OH[ The intermediacy of the dihydro compound "39# is supported by its
slow conversion to the cyanopyridazine "31# "when R0 H# under the reaction conditions ð62T1326Ł[

R1 R2 Me2SO4 R1 R2 KCN R2
N N N N+
or PhCOCl R1 CN
O OR3
(39)
R1 = Ph, Me; R2 = H, Me

Scheme 12
Bearin` an a\b!Vinylic Bond 538

CN R1 CN
R1 N R2
R2 R CN
N N
N N N
OR3
OR3
(40) (41) (42)

The preparation of cyanoallenes "Equation "01## can be achieved by the treatment of substituted
1!propynols with potassium cyanide and HBr in the presence of copper cyanide and copper
ð57JCS"C#180\ 80COS"5#114Ł[ Alternatively\ the propynol can _rst be converted into the halide and then
treated with copper cyanide ð80COS"5#114Ł[

R R CN
CuCN, KCN, HBr, [Cu], 76 h
HO • (12)
R R
R = alkyl

2[08[1[2 a\b!Alkenic Nitriles with Halo!substituents


a!Halo!a\b!unsaturated nitriles are useful intermediates in organic synthesis[ They are generally
prepared by condensation reactions between a carbonyl compound and an a!halophosphorane
ð50CB1885Ł[ In one such example\ dichloromethylenetriphenylphosphorane has been successfully
used in the preparation of 1!aryl!2\2!dichloroacrylonitriles[ Thus\ exposure of 1!arylacrylonitriles
"Equation "02## "RH\ Me\ CI\ MeO# to triphenylphosphine in a large excess of carbon tetra!
chloride provides the desired aryl!2\2!dichloroacrylonitriles in 59Ð69) yield ð62JOC368Ł[ However\
the reaction fails when aliphatic acyl cyanides are used as substrates[

Cl
Ph3P CN
CN
Cl R
R (13)
∆, 2–4 h Cl
O
Cl

An alternative method for the preparation of a!halo!a\b!alkenic nitriles involves the use of the
readily available arsonium salt "32#[ Treatment of the arsonium bromide "32# with iodine in pot!
assium carbonate a}ords the iodoarsonium iodide "33# which\ without isolation\ was reacted with
a variety of aldehydes "RAr\ alkyl# to give the corresponding a!iodo!a\b!unsaturated nitriles in
good to excellent yield "47) when Ralkyl^ 79Ð86) when RAr# "Scheme 02# ð78SC1528Ł[

+ + R I
Ph3As CN I2, K2CO3 Ph3As CN RCHO, K2CO3

Br– I– CN
I
(43) (44)

Scheme 13

The use of a novel intramolecular Wittig reaction has been developed for the synthesis of
b!per~uoroalkyl!a\b!alkenic nitriles ð80JCS"P0#376Ł[ It was found that per~uoroacylmethylene!
triphenylphosphoranes were highly stable and did not react with aldehydes under Wittig conditions[
To overcome this problem\ treatment of the per~uoroacylcyanomethylenetriphenylphosphorane
"34^ Rf CF2 or C2F6# with an aryl or alkynyl lithium reagent leads to the ylide anion "35# "Scheme
03#[ Acidi_cation of "35# results in a spontaneous intramolecular Wittig reaction to give the desired
~uorinated a\b!unsaturated nitrile in excellent yield "89Ð85)# ð80JCS"P0#376Ł[ The products from
549 a\b!Unsaturated and Aryl Nitriles
this transformation are predominantly the E!isomers\ and in no examples did the authors observe
nucleophilic attack at the cyano group in "34#[
CN CN
R CN
Ph3P RLi Ph3P H+
Rf R
–O
Rf
O Rf
(45) (46)
Rf = CF3, C3F7; R = aryl, alkynyl

Scheme 14

The reaction of a!chlorocarbonyl compounds with lithium trimethylsilylacetonitrile in a Peterson!


type reaction is a convenient route into 2!chloro!0!cyano!prop!0!enes "Scheme 04# ð89SC1140Ł[ The
yields from this process are generally good "56Ð79)#\ although the products are mixtures of
geometrical isomers[ One advantage of this method over other routes into 2!chloro!0!cyano!prop!
0!enes\ for example the 0\1!elimination from 2!chloro!0!cyano!1!hydroxypropanes "see ð55BSF0204Ł\
and references therein#\ is the ready availability of the a!chlorocarbonyl substrates and the ease of
handling of lithium trimethylsilylacetonitrile ð89SC1140Ł[ 2!Chloro!0!cyano!prop!0!enes can also be
prepared by the free radical chlorination of a!ethylenic nitriles ð63JOC1596Ł[ For example\ treatment
of crotononitrile with t!butyl hypochlorite under radical generating conditions "hn and 1\1?!azo!
bisisobutyronitrile "AIBN## gave the corresponding allylic chlorinated product as a mixture of
cis ] trans isomers[ The ratio of the geometrical isomers obtained in this way was dependant upon
the concentration of the substrate\ and favoured the cis product at lower concentrations ð63JOC1596Ł[
O
R1
R2 Cl
LDA, THF, –78 °C
TMS CN Cl
TMS CN
–78 °C
R1 CN
Li
R2

R1 = H, alkyl; R2 = alkyl, aryl

Scheme 15

Treatment of the `em!dicyanoepoxide "36^ RAr\ alkyl# with Li1NiBr3 leads to the bromo!
enolate "37# which can then be trapped with acetic anhydride providing various 1!acetoxy!2!bromo!
1!propene nitriles "Scheme 05# ð75TL4380Ł[ The yields for this transformation are excellent "68Ð
87)#\ and the product is predominantly the Z!isomer when Raryl "typical Z ] E ratio around
2 ] 0#\ although 0 ] 0 mixtures of geometrical isomers result when Ralkyl[

CN Br OLi Br OAc
R Li2NiBr4, THF Ac2O, pyridine
CN
O R CN R CN

(47) (48)

R = Ar, alkyl

Scheme 16

2[08[1[3 a\b!Alkenic Nitriles with Oxygen!based Substituents


a\b!Unsaturated nitriles containing oxygen!based substituents are versatile synthetic inter!
mediates[ Their preparation from carbonyl compounds is the most widely reported method of access
into this class of compound\ typically employing HornerÐWittig type chemistry\ or the aldol!like
condensation with alkoxyacetonitriles[
a!t!Butoxy!a\b!unsaturated nitriles "38# have been prepared using diethyl t!butoxycyano!
methylphosphonate "49# with sodium hydride in a HornerÐEmmons reaction with several carbonyl
Bearin` an a\b!Vinylic Bond 540
compounds ð65JOC1735\ 66JA071Ł[ Of the many examples studied\ both with aldehydes "R0 H# and
ketones "RR0 "CH1#4!\ 1!methylcyclohexanone\ 1!cyclohexenone\ etc[# the chemical yields are
excellent "69Ð88)#[ It was found that the only limitation of this method is that\ due to the steric
bulk of the phosphonate "49#\ only ketones with three or more a!hydrogens will react ð66JA071Ł[
Indeed\ this {limitation| can be exploited\ as in the case of the regiospeci_c reaction of the phos!
phonate "49# with 4a!androstane!2\06!dione which gives a 81) yield of the a!t!butoxy!a\b!alkenic
nitrile "40#[
O

O
R1 CN
(EtO)2P CN

R2 OBut NC
OBut
H
ButO
(49) (50) (51)

The reaction of saturated aliphatic aldehydes with acrylonitrile in the presence of tri!butylphos!
phine "9[1 equivalent# and triethylaluminum "9[0 equivalent# at 79>C in dichloromethane under
pressure a}ords 1!"0!hydroxyalkyl#acrylonitriles "41# ð73SC0156Ł[ The reaction is e.cient "69Ð89)
isolated yield# for saturated aliphatic aldehydes\ but the same reaction with benzaldehyde yields
only 16) of the desired product[ It is believed that the reaction proceeds via the initially formed
betaine "42# which then reacts with the aldehyde to form "43# ð54JOC0246\ 69JOC2934Ł[ Elimination
of tri!butylphosphine from "43# gives the hydroxy substituted acrylonitrile "41#[
CN
+ + – CN
Bu3P – Bu3P
R CN
HO HO R
(52) (53) (54)

Rearrangement of O!silylated cyanohydrins can also be exploited to prepare b!substituted!a!


silyloxyacrylonitriles ð75SC506Ł[ Thus\ exposure of an a\b!unsaturated aldehyde to trimethylsilyl
cyanide in the presence of catalytic potassium cyanide and 07!crown!5 leads to the cyanohydrin
"44^ R0 PhCH1\ CH2\ C2H6\ H^ R1 H\ CH2# "Scheme 06#[ Without isolation\ the cyanohydrin is
treated with catalytic "4)# 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# and isomerizes to the
b!substituted!a!""trimethylsilyl#oxy#acrylonitrile[ The yields for this process are excellent "61Ð84)
from the a\b!unsaturated aldehyde#\ though the products are mixtures of geometrical isomers
ð75SC506Ł[

R2 R2
R2 TMS-CN, KCN, 18-crown-6 dbu
R1 O-TMS R1 O-TMS
R1
CHO
CN CN
(55)
dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene

R1 = PhCH2, Me, C3H7, H; R2 = H, Me

Scheme 17

Aldehydes can also be used in the preparation of g!hydroxy!a\b!alkenic nitriles[ Reaction of


a!"phenylsulphinyl#acetonitrile with aldehydes in the presence of piperidine in methanol a}ords the
g!hydroxy!a\b!unsaturated nitriles in excellent yield and exclusively as the E!isomers "Equation "03##
ð73JA6789Ł[ Ketones also undergo this reaction ð73JA6789Ł[ In a further application of this method
Nokami and co!workers have employed an optically active 1!"arylsulphinyl#acetonitrile "45# to
provide optically active 3!hydroxyalk!1!enenitriles "46^ Raliphatic# in good chemical yield "42Ð
66)# and high enantiomeric excess "49Ð79) ee# ð75TL4098Ł[
541 a\b!Unsaturated and Aryl Nitriles
O R CN
piperidine, methanol
R CHO + (14)
S CN
Ph OH

O
R * CN
S CN
Ar * OH
(56) (57)

3!Hydroxyalk!1!enenitriles can also be prepared by an aldol!like condensation between an


a!chlorocarbonyl compound and the dilithiated anion derived from treatment of acetonitrile with
LDA "Scheme 07# ð72S186Ł[ Under the basic reaction conditions the intermediate epoxide "47^
R0 H\ Me\ Et\ Ph^ R1 Me\ H# isomerizes spontaneously to the hydroxy!substituted a\b!unsatu!
rated nitrile "Scheme 07#\ formed in 40Ð76) yield from the a!chlorocarbonyl substrate[ Similarly\
the lithiated anion of acetonitrile when exposed to the a!methylene lactone "48# in THF at −67>C
produces the diene "59^ RH\ Et\ Ph# ð75CC0129Ł[ The anion derived from methoxyacetonitrile
reacts with arylaldehydes to provide the corresponding a!methoxy!a\b!unsaturated nitriles in good
yield "Equation "04## ð62CC670\ 72T0440Ł[

O R2
O
R1 LDA, THF HMPT
+ MeCN R1 CN
R2 R1 CN
R2
Cl OH
(58)

R1 = H, Me, Et, Ph; R2 = Me, H

Scheme 18

R R

CN
O O O
(59) (60)

Ar OMe
NaH, DMF, 110 °C
ArCHO + MeO CN (15)
CN

1!Alkoxy!1!alkene nitriles can also be prepared from vinyl ethers[ In a one!pot\ three!step
sequence\ bromination of vinyl ethers followed by cyanide displacement leads to bromonitriles of
the type "50#[ Piperidine induced dehydrobromination then leads to the desired 1!alkoxy!a\b!alkenic
nitriles in 59Ð84) yield ð75S437Ł[ Scheme 08 is illustrative\ and the sequence is applicable to both
cyclic and acyclic vinyl ethers[ The aluminum chloride catalysed DielsÐAlder reaction between
a\b!unsaturated acyl cyanides and simple alkenes also gives 1!alkoxy!1!alkenic nitriles "Equation
"05## ð71AG"E#748Ł[ Acyl cyanides can also undergo a self!condensation reaction under mild\ basic
conditions to provide lactones of the type "51# ð72TL1736Ł[

Br N
i, Br2, CCl4 H

O ii, CuCN, ∆ O CN
O CN
(61)

Scheme 19
Bearin` an a\b!Vinylic Bond 542

AlCl3
+ (16)

O CN O CN

O O CN

(62)

The Knoevenagel condensation of aromatic aldehydes or cyclohexanones with ethyl cyanoacetate\


catalysed by amino groups immobilised on silica gel\ results in excellent yields of the corresponding
a!carboxyethyl!a\b!unsaturated nitriles "e[g[\ "52## ð78JCS"P0#094Ł[ Angeletti et al[ found that the best
catalyst for this condensation was a 2!aminopropyl functionalized silica gel[
CN

Ph CO2Et
(63)

a!Carboxy!a\b!alkenic nitriles also result from exposure of methyl cyanoacetate to magnesium


methoxide in methanol ð83TL334Ł[ The resulting 2!hydroxy!1!methoxycarbonyl glutaconic dinitrile
"53# "67) yield# is di}erent from that product\ viz "54#\ arising from exposure of methyl cyanoactate
to sodium methoxide ð60ZN"B#0013\ 72S367Ł[ A further route into a!carboxy!b!hydroxy!a\b!unsatu!
rated nitriles stems from the pyrolysis of 1\4!diazo!2\5!dihexynyl!0\3!benzoquinones "Scheme 19#
ð73CC0955Ł[ The resulting\ highly reactive\ hexynylcyanoketene "55# upon exposure to alcohol
undergoes an addition and subsequent rearrangement to the allene "56#[ In the presence of further
alcohol "56# produces the a\b!unsaturated nitrile "57# ð73CC0955Ł[
CN
H2N CN
CN

MeO2C CO2Me
HO CO2Me
(64) (65)

O R1 R1
N3
C6H6, 80 °C R2OH

N3 • O
R1 O NC
(66)

CO2R2 R1 CN
R2OH

R1 CN R2O CO2R2
(67) (68)

Scheme 20

In a general and stereoselective synthesis of Z!b!silyloxyacrylonitriles ð75TL1916Ł\ exposure of


4!substituted isoxazoles "58^ R0 Me\ Ph# "Scheme 10# to LDA results in the formation of the
enolate "69#\ which can then be trapped in situ with either trimethyl! or t!butyldimethyl!chlorosilane
to give the Z!b!silyloxy!a\b!alkenic nitriles in 61Ð81) yield[
The b!cyanoenone "60# has been prepared in 76) yield from the dinitrile "61# "itself prepared by
radical cyclization of propargyliodomalononitrile# via ozonolysis and subsequent base treatment
ð89JA8390Ł[
The palladium!catalysed allylic etheri_cation of the b\g!unsaturated nitrile "62# with phenoxy!
543 a\b!Unsaturated and Aryl Nitriles
CN R1
LDA, –78 °C R23SiCl, –78 °C
N R1
R1 O O– R23SiO CN
(69) (70)

R1 = Ph, Me

Scheme 21

O H H

NC
NC H NC H
(71) (72)

tributyl tin in THF results in an 78) yield of the corresponding g!phenoxy!a\b!unsaturated nitrile
"63# ð74JOC2447Ł[ The product is predominantly the E!isomer[ Interestingly\ the same reaction with
methoxytributyl tin provides only a 44) yield of the g!methoxy!a\b!alkenic nitrile ð74JOC2447Ł[

OAc OPh

Ph CN Ph CN
(73) (74)

2[08[1[4 a\b!Alkenic Nitriles with Sulphur!based Substituents


In a general synthesis of a!thio!a\b!alkenic nitriles\ exposure of carbonyl compounds to the
Peterson reagent cyano"methylthio#methyltrimethylsilane "64# "Equation "06## in the presence of
LDA leads to the corresponding thiosubstituted a\b!unsaturated nitriles in good to excellent yield
"30Ð84)# ð77SC1000Ł[ Higher yields "67Ð84)# are obtained with arylaldehydes "R0 Ar^ R1 H#
whilst more moderate yields "30Ð67)# result from the use of ketones "both aliphatic and cyclic#
ð77SC1000Ł[

O CN R1 CN
LDA, –78 °C
+ TMS (17)
R1 R2 SMe R2 SMe
(75)

As in the preparations of a!alkoxy!a\b!alkenic nitriles from the reactions of carbonyl compounds


with the anion derived from alkoxyacetonitrile "Section 2[08[1[3\ ð62CC670\ 72T0440Ł#\ the anion
derived from methylthioacetonitrile reacts with carbonyl compounds to form a!methylthio!a\b!
unsaturated nitriles "Equation "07## ð61JOC0239\ 67CPB0763\ 67TL1572Ł[ Acetonitrile itself can be con!
densed with thioesters in the presence of butyllithium to form the lithiated intermediate "65#
ð62LA0526Ł[ Subsequent methylation of "65# gives 2!substituted!2!methylthio!1!alkenic nitriles in
30Ð79) yield but as mixtures of geometrical isomers "Scheme 11# ð62LA0526Ł[

O R1 CN
NC SMe Triton B or NaOEt
+ (18)
R1 R2 R2 SMe
R1 = alkyl, Ph, Ar; R2 = H, alkyl
Bearin` an a\b!Vinylic Bond 544

S CN CN
MeCN, BuLi MeI or CH2N2
Li+
R1 OR2 R1 S– R1 SMe
(76)

Scheme 22

Bromination of the a!thioether nitrile "66# leads to the bromothionitrile "67# "Scheme 12# which\
without isolation\ can be treated with triethylamine resulting in dehydrobromination to give the
corresponding a!ethylthio!a\b!unsaturated nitrile in 54Ð79) yield ð67TL1572Ł[ The eliminative
deoxygenation of a!cyanosulphoxides "68^ Ralkyl#\ by treatment with trimethylsilyl tri~ate in the
presence of hexamethyldisilazane\ leads to the a!thiophenyl!a\b!unsaturated nitriles "79# in excellent
yield "63Ð76)# ð74TL1284Ł[ a!Alkylthioacrylonitrile derivatives can also be prepared by the
rearrangement of a!chloro!b!alkylthionitriles induced by lithium bromide in N\N!dimethyl!
formamide ð45CB0152\ 63LA0550Ł[

R1 SEt Br2
R1 SEt Et3N
R1 SEt
Br
R2 CN R2 CN R2 CN
(77) (78)

R1 = alkyl, Ph; R2 = H, alkyl

Scheme 23

O
PhS R
Ph S R

NC
NC
(79) (80)

In an e.cient synthesis of b!alkylthio!a\b!alkenic nitriles "Equation "08##\ exposure of substituted


malononitriles to sodium alkylthiolate gives the desired b!amino!b!alkylthio!a\b!unsaturated nitrile
ð77S702Ł[ Yokoyama and Sato have also reported the reduction of 2\2!bis"alkylthio#methyl!
enemalononitriles "70# with sodium borohydride to give the bis"alkylthio#!a\b!unsaturated nitrile
"71# ð77S702Ł[ The reaction is believed to proceed via the alkylthiomalononitrile "72#\ which reacts
with alkylthiolate anion to furnish the desired unsaturated nitrile "71#[

R1 R1 SR2
R2SNa, H2O
CN (19)
NC NC NH2

CN
NC SR CN
H2N SR
SR
NC SR NC
SR
(81) (82) (83)

The addition of thiols to allenylnitriles can also be used to prepare b!thio!a\b!alkenic nitriles[
Thus\ treatment of allenylnitriles "73^ R0 R1 alkyl# "Scheme 13# with thiols in the presence of a
catalytic amount of base gives the b!thio!b\g!alkenic nitriles "74# as a mixture of geometrical isomers
in excellent yields "89Ð84)# ð73T1030Ł[ Heating "74# at 199>C a}ords an equilibrium mixture of the
b!thio!a\b!alkenic nitrile "75# and the starting b\g!alkenic nitrile "74#\ although the latter constitutes
545 a\b!Unsaturated and Aryl Nitriles
only a minor "¼09)# portion of the mixture[ A similar equilibrium can be obtained by heating the
unconjugated nitrile "74# in ethanol in the presence of sodium ethoxide ð73T1030Ł[ Once again it is
the desired b!thio!a\b!unsaturated nitrile "75# which constitutes ca[ 89) of the equilibrium mixture[
R1
R1 CN R1 CN
R3–SH, EtO– heat or NaOEt

R2 CN
R2 R2 SR3
SR3
(84) (85) (86)

R1 = R2 = alkyl; R3 = alkyl, aryl

Scheme 24

2[08[1[5 a\b!Alkenic Nitriles with Se! and Te!based Substituents


Whilst the oxidative elimination of selenoxides is a commonly used route into a\b!alkenic nitriles\
the preparation of a\b!unsaturated nitriles containing a selenium!based substituent is far less
common[ As already mentioned in Section 2[08[1[0\ cyanoselenations of aldehydes\ followed by
oxidative elimination of selenoxide produces a\b!unsaturated nitriles ð66JA4109Ł[ However\ reactions
of a\b!unsaturated ketones with phenylselenocyanide in the presence of tributylphosphines give rise
to g!phenylseleno!a\b!unsaturated nitriles in modest yield ð66JA4109Ł^ Equation "19# is illustrative[

O CN
PhSeCN, Bu3P
(20)

SePh

Reaction of the novel selenamidoacetonitrile "76#\ prepared by reaction of malononitrile with


hydrogen selenide in the presence of base\ with 0\2!diketones in triethylamine leads to the
3\5!disubstituted!2!cyanopyridine!1"0H#!selenone "77# in excellent yield "Scheme 14# ð74S87Ł[ The
same product also results from the reaction of "76# with 1!chloro!2!cyanopyridines in the presence
of either selenourea or sodium hydrogen selenide "Scheme 14#[
O O

R R
Et3N R
Se CN
R
NC
NH2 CN
R N Se
H
R N Cl
(87) (88)
H2N
Se or NaHSe
H2N

Scheme 25

To this author|s knowledge\ there have been no reports of a\b!alkenic nitriles containing tellurium
substituents[

2[08[1[6 a\b!Alkenic Nitriles with Nitrogen!based Substituents


Tetracyanoethylene "TCNE# "78# is perhaps the best known and certainly the most widely used
a\b!alkenic nitrile with nitrogen based substituents[ A comprehensive review of the synthesis and
chemistry of TCNE has appeared ð75S138Ł[ In the early 0889s\ an excellent review detailing the
synthesis of b!enaminonitriles "89# and their use in heterocyclic synthesis has been published
ð82CRV0880Ł[ An earlier report on the synthesis of cyano compounds "ðB!72MI 208!90Ł and references
Bearin` an a\b!Vinylic Bond 546
therein# has a section devoted to enaminonitriles[ The importance of the synthesis of enaminonitriles
and their subsequent use in the preparation of heterocycles is re~ected in all these accounts\ and the
interested reader is encouraged to consult these comprehensive articles[

NC CN H 2N CN

NC CN R
(89) (90)

For the preparation of simple b!enaminonitriles "89#\ the most commonly employed method is
the dimerization of substituted nitriles[ The dimerization of acetonitrile with sodium metal in organic
solvent leads to "89^ RMe# in quantitative yield "ð42CJC0100\ 58AG"E#347\ 82CRV0880Ł and references
therein#[ The 0858 production also reports the synthesis of simple b!enaminonitriles\ in moderate
yield\ from the lithium aluminum hydride reduction of substituted malononitriles "Equation "10##
ð58AG"E#347Ł[

R CN R CN
LiAlH4
(21)
CN 40% NH2

The synthesis of a!amino!a\b!alkenic nitriles has received considerable attention "ðB!72MI 208!90Ł
and references therein#[ One common method for access into this class of compound involves
deprotonation of saturated a!aminonitriles with strong base ð59JA0675\ 56CC107Ł[ Alternatively\
deprotonation of "80# with lithium diisopropylamide in THF at −67>C followed by silylation\ base
treatment and exposure to formaldehyde\ yields the desired a!amino!a\b!alkenic nitrile in 64) yield
"Equation "11## ð67S786\ 68S016Ł[ Another popular method for the synthesis of a!cyanoenamines
involves cyanation of enamines themselves ðB!72MI 208!90Ł[ In one example\ reaction of an enamine
with cyanogen bromide a}ords the b!cyanobromide "81#\ which upon exposure to triethylamine\
eliminates hydrogen bromide to give the desired a!amino!a\b!unsaturated nitrile "Scheme 15#
ð66S384Ł[

CN CN
i–iv
(22)
N Ph N Ph
Me Me
(91)
i, LDA; ii, TMS-Cl; iii, LDA; iv, H2CO

NR1R2 NR1R2 Et3N NR1R2


BrCN
Br
CN CN
(92)

Scheme 26

a!Amino!a\b!alkenic nitriles can also be prepared from carboxyamides[ Exposure of N!diethyl!


acrylamide to sodium benzenesul_nate leads to the amide "82a# which is treated with P3S09 to give
the thioamide "82b# "Scheme 16#[ Reaction of the thioamide "82b# with dimethyl sulfate and
then potassium cyanide gives the a!cyanoenamine "83# in 59) yield as the E!isomer ð73TL2364Ł[

O PhSO2Na
X i, Me2SO4 CN

NEt2 PhSO2 NEt2 ii, KCN PhSO2 NEt2


(93) a; X = O (94)
b; X = S

Scheme 27
547 a\b!Unsaturated and Aryl Nitriles
The g!phenylsulphonyl!a!cyanoenamine "83#\ in the presence of a strong base\ acts as a synthetic
equivalent of an a!carboxyl vinyl anion ð73TL2364Ł[ Exposure of an aldehyde to an amine\ followed
by chlorination and subsequent treatment with potassium cyanide also gives a!amino!a\b!alkenic
nitriles "Equation "12## ð68S630Ł[

i, R3NH2
R1 O
ii, NCS
R1 NHR3
(23)
iii, KCN CN
R2 R2

In a synthesis of a!amino!b!alkoxy!a\b!unsaturated nitriles\ exposure of acetals to two equivalents


of t!butylisocyanide in the presence of titanium tetrachloride leads to the imidoyl intermediate "84#
which then undergoes nucleophilic addition of isocyanide to ultimately give alkoxycyanoenamines
of the type "85# "Scheme 17# in moderate yield "25Ð58)# ð75TL2494Ł[ Interestingly\ Pellissier et
al[ have reported that treatment of the same acetal with t!butylisocyanide in the presence of
diethylaluminum chloride leads to the b!alkoxy!a!iminonitrile "86# "52Ð89) yield#[ If R2 H\ the
iminonitrile "86# can undergo an acid!catalysed isomerization to the a!cyanoenamine "85# ð78TL060Ł[

ButN NBut
OR2 NBut R2O NHBut
ButNC, TiCl4 ButNC
R1 R1
R1
OR2 OR2 R1 CN
OR2
(95) (96)

R1 = H, alkyl, Ph; R2 = Me

Scheme 28

R1 NBut
R3
R2O CN
(97)

b!Amino!a\b!alkenic nitriles are also valuable synthetic intermediates[ Commonly\ substitution


of a halogen with either cyanide ð62S098\ 65T2952Ł or with amines ð53JOC0799\ 55CRV050Ł leads to this
class of compound ðB!72MI 208!90Ł[ In a general synthesis of b!amino!a\b!unsaturated nitriles\
nucleophilic displacement of vinyl bromides by amines in carbon tetrachloride at room temperature
gives good to excellent yields "59Ð89)# of the desired products "Equation "13## ð77S025Ł[ The
reaction proceeds with retention of double bond geometry\ although the Z!isomer does slowly
isomerize to the more thermodynamically favoured E!isomer under the reaction conditions[

R1 CN R1 CN
HNR22, CCl4
(24)
Br R22N
(E)

The nucleophilic displacement of vinyl halides with cyanide ion also proceeds in high yield[
Thus\ exposure of the vinyl bromide "87# to potassium cyanide in dimethyl sulfoxide gives the
b!amino!a\b!alkenic nitrile "88# ð62S098Ł[ Compounds of the type "88# have also been prepared by
using phase!transfer catalysis ð67S781\ 67S783Ł[

Ar1 Ar2 Ar1 Ar2

Br NHAr3 NC NHAr3
(98) (99)

The reaction of carbonyl compounds under Wittig conditions has been successfully employed in
the synthesis of b!amino!a\b!alkenic nitriles[ Thus\ treatment of succinimides with cyano!
methylenetriphenylphosphorane gives the corresponding 1!cyanomethylene!4!pyrrolidones "099# in
Bearin` an a\b!Vinylic Bond 548
poor to moderate yields "12Ð59)# ð60CB1736Ł[ The best result "59) yield# occurs with succinimide
itself "RH#\ whilst the yields fall substantially with any substitution on the nitrogen[

CN
O N
R
(100)

b!Amino!a\b!unsaturated nitriles can also be prepared via the decarboxylation of enamino esters[
Whilst it has been reported that enamines like "090# can be formed by the treatment of enamino
esters "091# with aqueous base ð58AG"E#232\ 65CPB2900Ł\ the same reaction with cyanoesters of the
type "091^ ZCN# results in a retro!condensation to give a pyrrolidinone and ethyl cyanomalonate
ð70JOC2560Ł[ This problem has been overcome by heating cyanoesters of the type "091^ ZCN^
R0 Me\ H^ R1 H# at high temperature "199Ð149>C# with acidic alumina for 0 h "Equation "14##[
This transformation is highly temperature dependent ð74SC362Ł[

RO2C
N R2 N R2
Z R1 Z R1
(101) (102)

EtO2C Al2O3, 200–250 °C


N R2 N R2 (25)
NC R1 NC R1

2[08[1[7 a\b!Alkenic Nitriles with P!\ As!\ Sb! and Bi!based Substituents
There are very few publications detailing the synthesis of a\b!alkenic nitriles containing P!\ As!\
Sb! and Bi!based substituents[ Indeed\ apart from reports on the preparation of a\b!unsaturated
nitriles with phosphorus substituents\ it appears that a\b!alkenic nitriles with arsenic\ antimony or
bismuth!based substituents are unknown[
In one report\ detailing the preparation of 1!cyano!0\2!butadienes "Section 2[08[1[1\ ð72S806Ł#\
diethyl 1!lithio!1!cyano!1!trimethylsilylethanephosphonate "092# is condensed with an aldehyde to
give the 1!cyano!1!alkenephosphonate "093# "Equation "15##[ Whilst the cyanophosphonate "093# is
highly reactive and usually reacts in situ\ it has been isolated in moderate yield[
O
O Li R
TMS R O
(EtO)2P (26)
CN –78 °C (EtO)2P
CN
(103) (104)

Reactions of a\b!unsaturated carbonyl compounds with diethyl phosphorocyanidate in the


presence of lithium cyanide produces 1!diethylphosphonoxy!1!methyl!2!butenenitriles "094# "Sch!
eme 18#[ Subsequent allylic rearrangement of "094# with boron tri~uoride etherate provides the
g!phosphonoxy!a\b!alkenic nitrile "095# ð75CPB3519Ł[ Interestingly\ the Z!isomer of "095# results

O CN
O (EtO)2P CN O
CN, LiCN R
O O P(OEt)2
R P R O
EtO OEt

(105) (106)

Scheme 29
559 a\b!Unsaturated and Aryl Nitriles
from a\b!alkenic ketones whilst the E!isomer of "095# predominates when a!b!alkenic aldehydes are
used[ The high Z!stereospeci_city in the former case can be explained by considering the ð2\2Ł!
sigmatropic rearrangement of the low energy conformer of the initially formed "094# ð75CPB3519Ł[

2[08[1[8 a\b!Alkenic Nitriles with Si! and B!based Substituents


There are a few reports of the synthesis of a\b!alkenic nitriles containing silicon!based substituents
in the literature\ and in many of these reports such compounds are formed as intermediates in the
preparation of more elaborate molecules[ In one example\ silylation of trimethylsilylacetonitrile
gives the tris"trimethylsilyl#ketenimine "096# "Scheme 29# which reacts with aldehydes in the presence
of boron tri~uoride etherate to a}ord E!1!trimethylsilylalk!1!enenitriles "098# ð71CC45Ł[ Compounds
of the type "098# can be desilylated with ~uoride ion\ and the anion thus formed quenched with a
carbonyl compound to give E!1!"0!hydroxyalkyl#alk!1!enenitriles "097# ð72CC069Ł[

R1 CN
TMS R1 CN i, Bun4NF
TMS CN R1–CHO
• N-TMS
ii, R2COR3 R2
TMS TMS
HO R3
(107) (109) (108)

Scheme 30

The exposure of an arylalkyne "009# to trimethylsilyl cyanide in the presence of catalytic palladium
chloride and pyridine results in the addition of triethylsilyl cyanide across the carbonÐcarbon triple
bond to give b!cyano!b!arylalkenylsilanes of the type "000# "Equation "16## ð74CC727Ł[ The addition
of the trimethylsilyl cyanide stereoisomer proceeds with high regio! and stereoselectivity to give the
product "000# in generally high yield "up to 89)#[ As an aside\ the addition of trimethylsilyl cyanide
to allenes\ under either palladium or nickel catalysis\ gives E! and Z!isomeric mixtures of the
corresponding b!trimethylsilyl!b\g!unsaturated nitriles "001# ð75TL0730Ł[

Ar
PdCl2, pyridine
Ar + TMS-CN (27)
NC TMS
(110) (111)

R TMS

CN
(112)

In an alternative\ yet complementary approach\ exposure of silylated alkynes to hydrogen cyanide


in the presence of a nickel catalyst produces the corresponding E!silylalk!1!enenitriles "002# and
"003# in good to excellent yield "Equation "17## ð72AJC0864\ 74CC3Ł[ It has been found that when
t!butyldimethylsilyl alkynes are employed\ the steric bulk of the silicon substituent directs the nitrile
addition away from the silicon bearing carbon\ and thus favours the formation of "002# "up to 87 ] 1
in favour of "002##[ If a silicon group requiring less steric bulk is employed "viz trimethylsilyl# then\
in some cases "003# is the predominant product ð74CC3Ł[

HCN, Ni0
R13Si R2 R13Si R2
R13Si R2 + (28)
CN NC
(113) (114)
R2 = H, Me, Bu, Ph

Reports detailing the synthesis of a\b!alkenic nitriles containing boron!based substituents have
not appeared[
Bearin` an a\b!Aryl 550
2[08[1[09 a\b!Alkenic Nitriles with Metal Substituents
a\b!Alkenic nitriles with metal substituents are highly reactive species and as such have not been
isolated[ Such species are therefore considered as transient intermediates and will not be discussed
here[ However\ it is worth remembering that such species\ formed by deprotonations of
a\b!unsaturated nitriles with strong base\ are valuable intermediates in the preparations of sub!
stituted a\b!alkenic nitriles "ðB!72MI 208!90Ł and references therein#[

2[08[2 NITRILES BEARING AN a\b!ARYL OR !HETARYL SUBSTITUENT

2[08[2[0 General Methods


The reactions between an aryl halide and a metal cyanide remain one of the most popular
and convenient methods for the preparation of a\b!aryl nitriles "Equation "18##[ Typically the
transformation depicted in Equation "18#\ usually referred to as the RosenmundÐvon Braun reaction
ð08CB0638\ 20LA"377#000Ł\ is achieved by heating the aryl halide with copper"I# cyanide at 049Ð149>C
with or without solvent[ Several excellent articles provide a comprehensive introduction to the
cyanation of aromatic halides ðB!72MI 208!90\ B!72MI 208!91\ 76CRV668Ł^ the latter article contains more
than 199 examples\ as well as a detailed discussion of the mechanism ð74CJC000Ł[
150–250 °C
Ar X + CuCN Ar CN + CuX (29)

Furthermore\ several reviews ðB!69MI 208!90\ B!72MI 208!90\ B!72MI 208!91\ 80COS"5#114Ł provide an
excellent introduction to the synthesis of aromatic nitriles in general\ and readers interested in this
topic are urged to consult these comprehensive articles[ Once again\ space limitations dictate that
this section focuses on general strategies towards the synthesis of aryl and hetaryl nitriles\ and in
particular on developments since 0874 in the synthesis of such compounds[
The substitution of a halide by cyanide ion is the most common route into a\b!aryl nitriles
ð76CRV668Ł[ Indeed\ the preparation of aromatic nitriles by the substitution of a variety of functional
groups is the favoured method of many workers ðB!72MI 208!91Ł[ As detailed above\ the direct
cyanation of aromatic halides with copper"I# cyanide requires relatively forcing conditions "049Ð
149># ð76CRV668Ł[ In an attempt to carry out this transformation under far milder conditions\
several researchers have investigated the use of complexes of sodium or potassium cyanide with
transition metals or metal!triphenylphosphine ð76CRV668Ł[ It is considered that reactions with such
metal complexes proceed as illustrated in Scheme 20\ and may involve an oxidative one!electron
transfer ð60JOM"17#176Ł[
–CN
Ar X + M Ar M X Ar CN + M + X–

Scheme 31

Complexes of palladium and nickel are particularly useful for this reaction[ For example\
reactions of an aryl halide with sodium cyanide in the presence of tris"triphenylphosphine#nickel"9#
"Equation "29## in either methanol\ ethanol or acetone at 29Ð59>C give the corresponding a\b!aryl
nitriles in excellent yield "×89)# ð62JOM"43#C46Ł[ Other nickel catalysts\ including trans!chloro!
bis"triphenylphosphine#nickel "NiCl1"PPh2#1# have also been used and provide aryl nitriles in excel!
lent yields "×79)# ðB!63MI 208!90\ 68JOM"062#224\ B!72MI 208!90\ 76CRV668Ł[ Similarly\ conversions of
chloro! and iodoaryl compounds into aryl cyanides have been achieved in 71Ð80) yield using
tetrakis"triphenylphosphine# palladium"9# and potassium cyanide in re~uxing THF ð64CL166Ł[

Ni(PPh3)3
X + NaCN CN (30)
R R
X = Cl, Br, I

In an adaptation of these transition metal catalysed aromatic cyanations\ it has been found that
the reactions of aryl iodides with trimethylsilyl cyanide and catalytic tetrakis"triphenylphosphine#
palladium"9# in triethylamine at re~ux provide the corresponding a\b!aryl nitriles in high yield
"Equation "20## ð75JOC3603Ł[ Under these conditions both aryl bromides and aryl chlorides fail to
551 a\b!Unsaturated and Aryl Nitriles
react[ Catalysis of aryl iodide displacement by palladium"II# salts\ especially palladium"II# acetate\
also results in high yields of aryl nitriles ð64BCJ2187Ł[ Aryl halides also react with palladium"II# salts
in the presence of sodium cyanide on alumina giving aryl nitriles in excellent yield ð68JOC3332Ł[
Various cobalt complexes have also been used to catalyse the aromatic substitution of a halide with
a nitrile ð72JOM"132#84\ 76CRV668Ł[

Pd(PPh3)4, Et3N
I + TMS-CN CN (31)
R R
R = H, Me, Br, Cl, MeO, MeO2C

It must be remembered that in all these metal catalysed substitution processes\ the nature and
position of other substituents on the aromatic ring has an e}ect on the outcome of the reaction
ð76CRV668\ 80COS"5#114Ł[ In general terms\ the aromatic ring may carry various substituents "but not
nitro groups because of the interaction between the nitro group and the metal catalyst#\ although
ortho!substituents tend to give rise to lower yields of the corresponding a\b!aryl nitriles ð76CRV668Ł[
Functional groups other than halogens\ including oxygen\ hydrogen\ nitrogen and organometallic
groups\ may also be substituted by cyanide ion ðB!72MI 208!90\ B!72MI 208!91Ł[ Examples of these less
commonly used\ but nevertheless important\ transformations will be presented in the following
section "see 2[08[2[1#[
The preparation of aromatic nitriles via elimination reactions is perhaps the other general synthetic
approach towards these compounds[ The dehydration of oximes "Equation "21## is by far the most
common of these elimination reactions\ and several reagents have been used ðB!72MI 208!91Ł[ For
example\ the {phosphonium anhydride| species "004# resulting from the reaction of two equivalents
of triphenylphosphine oxide with one equivalent of tri~ic anhydride\ dehydrates aryl oximes to aryl
nitriles in 4 min at room temperature in ×89) yield ð76JOC3026Ł[

N OH –H2O
Ar CN (32)
Ar

OTf
Ph3P
O
Ph3P
OTf
(115)

The direct transformation of aryl aldehydes into nitriles via the oxime may be performed with a
variety of reagents ðB!72MI 208!91Ł[ In one report with several examples of the preparation of
substituted benzonitriles from the corresponding aldehydes ð63CB0110Ł\ the intermediate oxime is
not isolated but treated with dicyclohexylcarbodiimide in the presence of copper"II# ions and
triethylamine[ The yields are excellent for this transformation "×69)#[ Similarly\ the conversion
of aromatic aldehydes into aryl nitriles can be achieved using ortho!"1!aminobenzoyl#hydroxylamine
and BF2 = OEt1 "Scheme 21# ð77SC1068Ł[

+ BF3
COONH2 O
BF3•OEt2, EtOH
+ Ar CHO N Ar Ar CN
O
NH2
NH2

Scheme 32

The direct conversion of 1\3\5!trinitrotoluene into the corresponding benzonitrile derivative


"Scheme 22# can be achieved via the oxime nitrite intermediate "005# using nitrosyl chloride in
pyridine ð62JOC3252Ł[
Aromatic amides can be transformed e.ciently under very mild conditions to aryl nitriles "63Ð
76) yield# by the use of chlorosulphonyl isocyanate in the presence of triethylamine ð68S116Ł[ The
process is depicted in Scheme 23 and is believed to proceed via the intermediate "006#[
Another important elimination process which is used in the preparation of aryl nitriles is the
Bearin` an a\b!Aryl 552

NOCl, pyridine NOH NONO –HNO2


Ar Me Ar CN
Ar Ar
(116)

Scheme 33

Ar
N
O Et3N O– Cl–SO2–NCO Et3N
O H
Ar CN
Ar NH2 Ar NH N–
O S Cl
O2

(117)

Scheme 34

Beckmann fragmentation of ketoximes "Scheme 24# ðB!72MI 208!91Ł[ The requirement for this
fragmentation to succeed is that the substituent on the a!carbon "A# must be able to stabilize\ or
bear\ a positive charge[ This fragmentation is often performed using thionyl chloride\ as exempli_ed
by the transformation shown in Scheme 25 ð62JA1812Ł[ Despite some conjecture as to the role of
sulfur in this particular case ð57JA3813Ł\ it is believed ð62JA1812Ł that the sulfur is capable of
stabilizing the adjacent cation in the intermediate "007#[ Similarly\ the Beckmann fragmentation of
b!trimethylsilylketoximes\ e[g[\ "008# "Equation "22##\ catalysed by boron tri~uoride etherate\ pro!
vides the corresponding aryl nitrile in 84) yield ð77T1302Ł[
Ar Ar
N OH N X Ar CN
A A

Scheme 35

OH
N CN CN
SOCl2, C6H6, RT SOCl2

S +
S Cl
S
(118)

Scheme 36

OAc
N CN
BF3•Et2O
(33)
TMS

(119)

Rearrangement reactions can also be used to prepare aryl nitriles\ although less frequently than
the substitution or elimination processes detailed above[ The simplest of such rearrangements is
that involving the isothiocyanide to nitrile transformation ð68COC"1#417Ł\ which occurs irreversibly
at temperatures above 049>C "Scheme 26#[

(PhO)3P
Ar N C S Ar N : Ar CN

Scheme 37
553 a\b!Unsaturated and Aryl Nitriles
2[08[2[1 Benzonitrile and Substituted Benzonitriles
The substitution of various functional groups\ especially halides "Section 2[08[2[0#\ by cyanide
ion is the most widely used method for the preparation of benzonitriles[ The substitution of diazo
groups by cyanide ion\ _rst reported by Sandmeyer in 0773 ð0773CB0522Ł\ represents an important
route into aryl nitriles "Equation "23## ð80COS"5#114Ł[ The many reports of this transformation vary
mainly in the type of copper cyanide complex employed ð80COS"5#114Ł[ In a modi_cation of this
general approach\ treatment of aromatic diazo sul_des with tetrabutylammonium cyanide leads to
the corresponding benzonitriles ð76T3514\ 89T1194Ł[
[CuCN], ∆
Ar N2+ Ar CN (34)

The boron trichloride mediated cyanation of anilines with trichloroacetonitrile or with methyl!
thiocyanate "Scheme 27# gives ortho!cyanoanilines in moderate yield after basic workup ð89SC60Ł[
Similarly\ phenols undergo this same FriedelÐCrafts type reaction to give ortho!cyanophenols in
60Ð77) yield ð89SC60Ł[

H
NH2 N NH2
MeSCN, BCl3 BCl base
N CN
R R R
SMe

Scheme 38

Substitution of a hydrogen in nitroarenes containing an additional activating group by cyanide


ion can be accomplished under photolysis conditions in the presence of oxygen "Equation "24##
ð55JA1773Ł[ The photochemically assisted substitution of anisole with potassium cyanide in poly!
ethylene glycol and dichloromethane gives mixtures of ortho! and para!cyanoanisoles ð79CC0142Ł[

NO2 NO2

H2O, ButOH, O2, hν


+ KCN (35)
CN
OMe OMe

Cyanation of 3!nitrobenzophenone with potassium cyanide in dimethyl sulfoxide results in the


formation of 2!cyano!3!hydroxybenzophenone "Equation "25##[ It is assumed that the nitro group
is displaced by hydroxide after substitution of the cyanide ortho to the nitro group ðB!72MI 208!91Ł[

NO2 OH
CN
KCN, DMSO, 3 h, 100 °C
(36)

COPh COPh

The displacement of aromatic organometallic groups by cyanide ion has also been employed to
good e}ect in the synthesis of benzonitriles[ Thus\ electrophilic thallation of aromatic substrates
with thallium tris"tri~uoroacetate# "Scheme 28# followed by exposure to copper"I# cyanide in aceto!
nitrile leads to various aryl nitriles in good to excellent yield "42Ð73)# ð73TL4362Ł[ The reaction is
believed to proceed via an initial one!electron transfer from Cu"I#\ producing an unstable Tl"II#
species which then undergoes homolysis of the carbon to thallium bond leading to an aryl radical
"Scheme 28# ð73TL4362Ł[ Similar organometallic displacement reactions have been performed on
arylthallium acetate substrates with copper cyanide in pyridine ð61T2914Ł\ and an aryltin species
with cyanogen chloride ð61JOM"35#156Ł[
Another substitution process involving metallated aromatic compounds involves the reaction of
benzylic organozinc halides with tosyl cyanide "Equation "26##[ The transformation is completely
Bearin` an a\b!Aryl 554

TfO OTf TfO •


Tl • CN
Tl
CuCN, e– transfer CuIICN CuIICN

R R
R R

Scheme 39

regioselective\ can tolerate a variety of other functional groups\ and produces benzonitriles in 56Ð
64) yield ð82TL3512Ł[

ZnBr TsCN
R (37)
R 67–75%
CN

Alternatively\ metallated alkyl nitriles can be used in the preparation of benzonitriles[ Thus\
addition of a!lithioalkyl nitriles to the benzyne derived from aryloxazolines results in cyclization to
give the benzocyclobutanone imine "019# which then fragments to give 1!alkyl!2!cyanobenzoic acids
in high yield "Scheme 39# ð73TL1830Ł[

Oxz
Oxz Oxz R R
Li R
EtOH
+ CN
CN
N
Li
Li
(120)

Oxz CO2H
hydrolysis
R R

CN CN

Scheme 40

The substitution of alkoxy groups by cyanide can be achieved by the anodic oxidation of
cyanide!ion solutions containing alkoxy substituted aromatic substrates ð58JA3070\ B!72MI 208!91Ł[
Electrooxidation of 1\1\5\5!tetramethylpiperidinyl!0!oxy "TEMPO# forms the nitrosonium ion "010#
which reacts with benzylic amines to give the intermediate imine "011# "Scheme 30#[ The imine "011#
then reacts with a further nitrosonium ion "010# to give various benzonitriles "68Ð80) yield#
ð72JA5621Ł[ Benzylic amines can also be oxidized directly to benzonitriles in moderate yield "24Ð
30)# with copper"I# chloride and oxygen in the presence of pyridine ð66S134Ł[

+
N
O
+ + Ar NH2 Ar NH Ar CN
N
O
(121) (122)

Scheme 41

The preparations of benzonitriles from carbonyl compounds or their derivatives o}er many
alternative strategies ðB!72MI 208!91Ł[ The addition of trimethylsilyl azide to aromatic aldehydes in
the presence of zinc chloride gives the corresponding benzonitriles in 51Ð86) yield ð73CL662Ł[
Aromatic carboxylic acids can be converted directly into the corresponding nitriles with reagents
such as aminosulphonic acid and urea\ or with methanesulphonamide and phosphorus pentachloride
555 a\b!Unsaturated and Aryl Nitriles
ðB!72MI 208!91Ł[ Chlorosulphonyl isocyanate reacts with carboxylic acids to give N!chloro!
sulfonamides "Scheme 31# which decompose to nitriles in N\N!dimethylformamide ð56CB1608Ł[
MeO OMe
MeO OMe MeO OMe
ClSO2NCO H DMF
N
SO2Cl
CN
O

Scheme 42

Amides are also a common source of benzonitriles ðB!72MI 208!91Ł[ The thermal decomposition
of aryl amides in the presence of a catalyst above 149>C leads to benzonitriles ð69JOC2142\ 69TL0852Ł[
A series of substituted aryl nitriles have been prepared by the reaction of aromatic N!methoxy
amides with carbon tetrachloride or carbon tetrabromide and triphenylphosphine in acetonitrile to
give the intermediate N!alkoxyimidoyl halides "012^ XCl\ Br# "Scheme 32#\ which on exposure to
zinc in acetic acid a}ord the desired benzonitriles in generally excellent yield ð80S649Ł[ Similarly\
aryl N!hydroxyimidoyl chlorides lead to aryl nitriles upon exposure to the hydridoundeca!
carbonyltriferrate anion ðHFe2"CO#00Ł− in benzene at re~ux ð62JOC3254Ł[
O X
CX4, Ph3P, MeCN Zn, AcOH, DMF
OMe OMe Ar CN
Ar N Ar N
H
(123)
X = Cl, Br

Scheme 43

Exposure of O!alkyl!3!nitrobenzaldoximes to sodium hydride in N\N!dimethylformamide


"Scheme 33# a}ords the corresponding 3!alkoxybenzonitriles\ resulting from displacement of the
nitro group by the initially eliminated alkoxy group ð72JOC2094Ł "cf[ Equation "25##[ The yields for
several 3!alkoxy substituted benzonitriles prepared by this eliminationÐaromatic substitution pro!
cess are above 71)[ Similarly\ benzaldimines react with diisopropyl peroxidocarbonate to give
benzonitriles via a benzimidoyl radical intermediate ð69CC0590Ł[

N CN
OR CN

NaH, DMF
+ RONa

NO2 NO2 OR

Scheme 44

Other nitrogen containing functional groups which can be converted into nitriles include the
oxidation of aromatic hydrazones "Scheme 34# ð55JOC3099Ł and the preparation of benzonitriles by
the ring cleavage of heterocycles ðB!72MI 208!91Ł[ In the latter case\ mainly _ve! and six!membered
nitrogen heterocycles are used as substrates\ and oxidative\ thermal and photochemical processes
are usually involved ðB!72MI 208!91Ł[ For example\ lead tetraacetate oxidation of the triazole "013#
"Scheme 35# gives the corresponding nitrene "014# which then eliminates molecular nitrogen to
produce two moles of benzonitrile ð69TL2740Ł[

Ar
Ar 30% H2O2 N
+ Ar CN
NNMe2 NMe2
–O

Scheme 45
Bearin` an a\b!Aryl 556

N N N N
Pb(OAc)4 –N2
Ph N Ph Ph N Ph 2PhCN
NH2 :N:

(124) (125)

Scheme 46

Cycloaddition reactions can also be used to prepare benzonitriles[ In one example\ the ð3¦1Ł!
cycloadduct "015# eliminates hydrogen cyanide leading to various substituted biaryl!1!carbonitriles
in 54Ð79) yield "Scheme 36# ð89JOC1434Ł[

CN CN
CN
C6H6 –HCN
+ NR2 CN
Ar CN Ar
Ar
(126)

Scheme 47

2[08[2[2 Polycyclic Aromatic Nitriles


Syntheses of polycyclic aromatic nitriles are not widely reported in their own right\ since many
of the methodologies presented in the previous two sections "see 2[08[2[0 and 2[08[2[1# are as equally
applicable to polycyclic systems as they are to simpler aromatic systems[ As detailed earlier\ additions
of cyanide ion are a useful procedure for the synthesis of aromatic nitriles[ For example\ addition
of cyanide ion to ~uorene derivatives results in the formation of a stabilized carbanion system "016#
which is then oxidized to the polycyclic aromatic nitrile "Scheme 37# ð69JOC29Ł[

Ph NC NC
Ph Ph
–CN [O]

Ph Ph Ph
Ph Ph Ph
(127)

Scheme 48

The addition of cyanide ion to carbonyl compounds is also a convenient route into aromatic
nitriles[ Reaction of 8!benzoylanthracene with sodium cyanide at 79>C in N\N!dimethylformamide
followed by the addition of a mild oxidant leads to 8\09!dicyanoanthracene ð62JOC370Ł[ Alter!
natively\ the reaction between 5!methoxytetralone and trimethylsilyl cyanide in the presence of
catalytic boron tri~uoride a}ords the cyanohydrin derivative "017# "Scheme 38# ð72JOC4023Ł[
Exposure of "017# _rstly to phosphoryl chloride in pyridine and then to aromatization conditions
"09) palladium on carbon with sulphur# then gives the aryl nitrile "018#[ Similarly\ the bis"trimethyl!
silyl cyanohydrin# "029#\ obtained by the addition of trimethylsilyl cyanide to the corresponding
diketone\ upon exposure to phosphoryl chloride in pyridine leads to the biscyano aromatic com!
pound "020# ð68CL0316Ł[
The use of nitrogen based precursors is also a common avenue into polycyclic aromatic nitriles
"see Section 2[08[2[1#[ The reaction of aromatic diazosul_des with tetrabutylammonium cyanide
under photolytic conditions furnishes dicyanonaphthalenes in good yield ð89T1194Ł[ The photo!
induced cyanide ion displacement of aryl nitro groups "Equation "27## a}ords moderate yields of
the corresponding aryl nitrile compounds ð69TL3690Ł[
557 a\b!Unsaturated and Aryl Nitriles
O NC O-TMS CN
TMS-CN, BF3 i, POCl3, pyridine

ii, Pd on C, S
MeO MeO MeO
(128) (129)

Scheme 49

CN
NC O-TMS

NC O-TMS
CN
(130) (131)

NO2 CN
hν, –CN
(38)

The thermal\ potassium hydroxide!induced ring opening of the bis"tosylhydrazone# "021# gives
0\7!dicyanonaphthalene in moderate yield ð79CC680Ł[ Pyrolysis of the 0\1\4!thiadiazole!0\0!dioxide
"022# results in the extrusion of sulfur dioxide with concomitant ring cleavage to provide the bis
aryl nitrile "023# ð63S11Ł[

TsN N N NTs
N O CN
S
O CN
N

(132) (133) (134)

Treatment of aryl substituted acetamides with a hypochlorite liquid triphasic system results in
the loss of one carbon via a Hofmann rearrangement "Equation "28## producing aryl nitriles in
moderate yield ð83S0016Ł[
NH2 CN
NaOCl, NaBr, TBAHSO4
(39)
O benzene, H2O, Na3PO4

The reaction of bianthrone with malononitrile in pyridine a}ords the extensively conjugated
18\18\29\29!tetracyanobianthraquinodimethane "TBAQ# "024# in 61) yield ð75TL1300Ł[ TBAQ was
prepared as part of a study aimed at developing new electron acceptors with enhanced conductivity
"see for example ð73NAT008Ł#[
NC CN

NC CN
(135)
Bearin` an a\b!Aryl 558
Cycloaddition reactions also provide a route into polycyclic aromatic nitriles[ Condensation
between the benzylic nitrile "025# and the diene "026# in the presence of a base at elevated tem!
peratures gives rise to the polycyclic aromatic nitrile "027# "Equation "39## ðB!72MI 208!90Ł[ Acry!
lonitrile itself can act as the dienophile in cycloaddition reactions[ Thus\ reaction between "028# and
acrylonitrile in tetrahydrofuran at re~ux gives the aryl nitrile "039# after aromatization of the
intermediate adduct "Scheme 49# ð61JCS"P0#1943Ł[

Me
CN ClO4– CN
N+
Me base
+ (40)
i, 50–70 °C
R ii, 145–205 °C R
NMe2
(136) (137) (138)

Me
O
O– N Me2N
THF, reflux O i, MeI, EtOAc
+
+ CN ii, Ag2O, H2O
N CN
Me
NC
(139) (140)

Scheme 50

2[08[2[3 Heterocyclic Aromatic Nitriles


Methods for the preparation of heterocyclic aromatic nitriles are generally similar to those used
in the synthesis of other aromatic nitriles "Sections 2[08[2[0 and 2[08[2[1#[ The most widely used
method involves the cyanation of heterocyclic aromatic substrates[ An excellent review provides a
valuable insight into the displacement of a heterocyclic aromatic halide with cyanide ion "see also
Section 2[08[2[0# ð76CRV668Ł[ Such transformations are typically performed at elevated temperatures
"049Ð149>C#\ usually with copper"I# cyanide and either with or without solvent[ The variety of
heteroaryl nitriles which can be prepared in this way is enormous\ with over eighty examples in this
account alone ð76CRV668Ł[ Other comprehensive articles also give details concerning alternative
methods for the cyanation of heterocyclic aromatic substrates ð68H"01#708\ B!72MI 208!90Ł[ Three
further reviews also provide many examples of other avenues for the preparation of heteroaryl
nitriles[ One report concentrates on the use of cyanoacetamide "030^ XO# and cyanothioacetamide
"030^ XS# in heterocyclic synthesis in general ð75H"13#1912Ł\ whilst the other two focus on the use
of nitriles in heterocyclic synthesis ð72H"19#408\ 76H"15#386Ł[ These three articles contain several
examples of the synthesis of heterocyclic aromatic nitriles[
X
NC
NH2
(141)
X = O, S

Apart from the displacement of a heteroaryl halide with cyanide ion ð76CRV668Ł there are other
methods involving a variety of reagents for the direct cyanation of heterocyclic aromatic substrates
ð68H"01#708\ B!72MI 208!90Ł[ The cyanation of pyrrole with triphenylphosphineÐthiocyanogen complex
"Equation "30## a}ords 1!cyanopyrrole in 79) yield ð79JCS"P0#0021Ł[ Cyanation of indoles can also
be achieved with this reagent ð79JCS"P0#0021Ł\ although only if there are no electron!withdrawing
groups on the indole ring[ Indoles can also be cyanated with the powerful electrophile chlorosulfonyl
isocyanate ð67S263Ł[ This same reagent has also been used for the cyanation of pyrroles ð70CJC1562Ł\
thiophenes ð69OS"49#41Ł and furans ð72T2770Ł[ Moderate to excellent yields of the corresponding
heteroaryl nitriles are obtained in all of these examples[ The reaction proceeds through a chloro!
sulfonyl carboxamide intermediate\ such as "031# in the pyrrole series\ which liberates HCl and
SO2 upon the addition of N\N!dimethylformamide ð70CJC1562Ł[ Importantly\ the nature of other
569 a\b!Unsaturated and Aryl Nitriles
substituents on the heterocyclic ring can alter the position of cyanation[ Thus\ if a deactivating
group is in the 1!position of pyrrole "e[g[\ 1!carboxyaldehyde# the product is the corresponding
3!cyanopyrrole ð70CJC1562Ł[ Several examples of 1!substituted furans "032^ RH\ Me\ CH1OH\
CH1OAc\ CH1OMe# give 4!cyanofurans upon exposure to chlorosulfonyl isocyanate ð72T2770Ł[ If
1\4!disubstituted furans are employed then 2!cyanofurans result ð72T2770Ł[

CH2Cl2, –40 °C
+ Ph3P(SCN)2 CN (41)
N N
H H

H
N
N SO2Cl R
H O
O
(142) (143)
R = H, Me, CH2OH, CH2OAc, CH2OMe

Diethyl phosphorocyanidate in the presence of lithium cyanide reacts with 2!acylindoles "033# to
a}ord 1!cyano!2!indoleacetonitriles in excellent yield "Scheme 40# ð75CPB3434Ł[ In the several exam!
ples reported\ either R0 or R1 is hydrogen[ Indeed 0!methyl!2!acetylindole "033^ R0 R1 Me# is
recovered unchanged when exposed to these conditions[

O O NC
R2 O R2 CN R2
O P(OEt)2
(EtO)2P
CN
LiCN CN
–CN
N N N
R1 R1 R1
(144)

NC
R2

CN
N
R1
R1 = H, Me, Et, Ph, CH2Ph; R2 = H, Me, Ph

Scheme 51

The reaction of aryl organozinc halides with p!toluenesulphonyl cyanide leading to aromatic
nitriles has already been mentioned "Section 2[08[2[1#[ The same article ð82TL3512Ł also reports that
various heteroaryl organozinc iodides "indoles\ thiophenes\ benzothiazoles# a}ord the corresponding
nitriles in high yield under the same conditions[
1!Cyanoergolines "034# have been prepared by the electrochemical cyanation of ergolines in
moderate yield "30Ð37)# ð72TL1730Ł[ The reaction is performed in methanolic aqueous sodium
cyanide solution using a platinum electrode[

R2

N Me
H H

N CN

R1
(145)
Bearin` an a\b!Aryl 560
Trimethylsilyl cyanide is a valuable reagent in the preparation of heteroaryl nitriles[ For example\
treatment of pyridine N!oxide with trimethylsilyl cyanide in the presence of triethylamine in aceto!
nitrile a}ords 1!cyanopyridine in high yield "Scheme 41# ð72S205Ł[ Only traces of 3!cyanopyridine
are reported from this reaction[ This modi_cation of the ReissertÐHenze reaction can be performed
on a variety of substituted pyridine N!oxides\ including alkyl\ hydroxy\ carboxy and carboxamido
groups[ Quinoline N!oxides also react under these conditions to give 1!cyanoquinoline[ The same
transformation can also be carried out with trimethylsilyl cyanide in the presence of dimethyl!
carbamyl chloride\ resulting in excellent yields "83Ð099)# of substituted 1!cyanopyridines
ð72JOC0264Ł[ The reaction is believed to proceed as depicted in Scheme 42 ð72JOC0264\ 80COS"5#114Ł[

Et3N, MeCN H –TMS-OH


N + TMS-CN N
CN N CN
O O-TMS

Scheme 52

O + +
CN
N TMS-CN N –Me2NH, –CO2
N + H
Me2N Cl O NMe2 O NMe2
O
O O

N CN

Scheme 53

Trimethylsilyl cyanide also reacts with alkynes in the presence of a palladium or nickel catalyst
leading to 1!cyano!4!aminopyrroles "Equation "31## ð75TL3190Ł[ Diarylacetylenes "035^ RAr# give
the corresponding cyanopyrroles in 64Ð76) yield\ whilst arylalkynes "035^ RH# a}ord only
moderate yields of cyanopyrroles[

R Ar
PdCl2 or NiCl2
Ar R + TMS-CN (42)
(146) NC N N(TMS)2
H
R = Ar, H

Other metal catalysts can also be employed in heteroaryl nitrile synthesis[ Thus\ exposure of
a!hydrazononitriles "e[g[\ "036## to anhydrous aluminum chloride produces 3!amino!2!cyano!
cinnoline "037# ð76H386Ł[
NH2
CN
CN
PhNH N
CN N
N
(147) (148)

Carbonyl compounds have been widely used as substrates in the synthesis of heterocyclic aromatic
nitriles[ In one example\ reaction of o!phthalaldehyde with primary amines\ followed by the addition
of potassium cyanide gives 0!cyano!1!substituted!isoindoles in moderate to excellent yield "Scheme
43# ð74CL0376Ł[ o!Hydroxybenzaldehyde undergoes a Knoevenagel condensation with malononitrile
on an AlPO3ÐAl1O2 catalyst in the absence of solvent to produce the benzopyran "038# via the
initial intermediate "049# "Scheme 44# ð73JOC4084Ł[ Similarly\ a!hydroxyketones condense with
malononitrile to produce furan derivatives ð76H386Ł[
561 a\b!Unsaturated and Aryl Nitriles

H
CHO i, NaHSO3 (aq.) CN CN
ii, RNH2
N R
iii, KCN N R
CHO CN
H

Scheme 54

OH CN OH
AlPO4-Al2O3 CN
+
CHO CN CN

(150)

O NH O O
H3O+

CN CN
(149)

Scheme 55

Diketones or their derivatives are also valuable substrates in heteroaryl nitrile synthesis[
a!Chloroacetylacetone reacts with malononitrile to a}ord the cyanofuran "040# ð51CB170Ł\ whilst
1!acylcyclohexanones react with cyanoacetamide in diethylamine leading to a mixture of the cyano!
isoquinoline "041# and the cyanoquinoline "042# ð76H"15#386Ł[ The oximino ketone "043#\ prepared
from the enol ester "044# "Scheme 45#\ upon exposure to thionyl chloride leads to the 1!cyano!
imidazole "045# ð62JHC788Ł[ Similarly\ the 1!cyanobenzimidazole "046# results from thionyl chloride
induced fragmentation of the corresponding oximino ketone ð62JHC788Ł[ The imidazole derivative
"045# can also be prepared by the mild thermal decomposition of the oximino pyruvate "047#
ð62JHC788Ł[
CN
O R
CN OH
CN
N
O NH2 N OH
R
(151) (152) (153)

O
Ph O
N
O N Ph
HOSO2NO2 SOCl2 CN
N Ph
O2N N
O2N N NOH
Me
O2N N Me
Me
(155) (154) (156)

Scheme 56

O OEt
N
N
CN
O
N
O2N N N OH
R
Me
(157) (158)
Bearin` an a\b!Aryl 562
Glyoxal a!oximes have also been used as precursors to cyano substituted imidazoles[ In a three!
step procedure the nitroimidazole "048# is reacted with dimethylformamide dimethyl acetal leading
to the enamine "059# which on exposure to sodium nitrite in acetic acid gives the glyoxal a!oxime
"050# "Scheme 46#[ Tri~uoroacetic anhydride treatment of "050# then a}orded 3!cyano!0!alkyl!4!
nitroimidazole "051^ Ralkyl# ð74JOC4781Ł[ Similarly prepared was the isomeric 4!cyano!0!alkyl!
3!nitroimidazole "052#\ and in both instances the chemical yields were high for each step in the
sequence ð74JOC4781Ł[
N Me2N
N
Me2NCH(OMe)2, H+ NaNO2, AcOH, H2O

O 2N N N
O2N
R R
(159) (160)
OH
N NC N
OHC N
O 2N N
O2N N R
R
(161) (162)
R = alkyl

Scheme 57

R
NC N

O2N N

(163)

3!Cyanoimidazoles "053# have also been prepared by exposure of the corresponding 3!"tri~uoro!
methyl#imidazole to dilute ammonium hydroxide solution "Scheme 47# ð75JOC2117Ł[ The yields for
a variety of substituted cyanoimidazoles "053^ Rheteroaryl# prepared in this way are generally
excellent[

F
F3C N NC N
NH4OH
R F N R
N R N
N
H H
(164)
Scheme 58

1!Cyano!0!hydroxyimidazoles "054# can be prepared by the thermal decomposition of 1!azido!


pyrazine!0!oxides "055# ðB!72MI 208!91Ł[ Similarly\ 1!azidopyridine!0!oxides produce 1!cyano!0!
hydroxypyrroles "056# ðB!72MI 208!91Ł[ The thermal decomposition of azidoindoles has also been
used as a route into cyanoindole derivatives[ Thus\ exposure of either 1!chloro! or 1!phenylsulfonyl!
2!phenylsulfonyl indoles "057# to sodium azide in N\N!dimethylformamide at 89>C results in
moderate to high yields of 2!cyanoindoles "058# "Scheme 48# ð74TL0716Ł[ It is believed that the
reaction proceeds via the intermediate Schi} base "069#[

N
CN N CN
N N N3 N
OH OH
O
(165) (166) (167)
563 a\b!Unsaturated and Aryl Nitriles

SO2Ph SO2Ph
SO2Ph
CN

: :
NaN3, DMF N N N
X
N N
N
R H
R R
(170)
(168) CN

R
N
H
(169)
X = Cl, SO2Ph

Scheme 59

2[08[3 NITRILES BEARING AN a\b!TRIPLE BOND


A general review of the chemistry of a!cyanoalkynes has been published ð66RCR263Ł[ a!Cyanoal!
kynes "060# can be prepared by the dehydration of amides at elevated temperature in the presence
of phosphorus pentoxide although the yields are poor ðB!60MI 208!90\ 66RCR263Ł[ Similarly\ dicyano!
alkyne "061# results from the dehydration of the diamide "062# ð57T0418Ł\ although in a moderate
39) yield[ Cyanoalkyne can also be prepared by the dehydration of the oxime of propargyl aldehyde
with acetic anhydride ð50USP2995837Ł[

O O
R CN NC CN
H 2N NH2
(171) (172) (173)

Chlorination of acrylonitrile and pyrolysis of the resulting dichloro intermediate "063# "Scheme
59# leads to a!cyanoalkyne itself in 39) yield ð69JOC564Ł[ Similarly\ pyrolysis of the trichloro!
acrylonitrile derivative "064# at 899>C gives the b!chlorocyanoalkyne "065# in 64) yield ð69JOC564Ł[

Cl2 CN
Cl 1000 °C
CN CN
Cl
(174)

Scheme 60

CN
Cl Cl CN
Cl
Cl
(175) (176)

The pyrolysis of b!ketoalkylidenetriphenylphosphoranes of the type "066# under far milder con!
ditions "119>C# also provides a route to a\b!alkynic nitriles "067# ð51JCS1222Ł[ The phosphoranes
"066# can be prepared conveniently by the reaction of cyanomethylenetriphenylphosphorane with
acid chlorides[ This procedure was later extended to include the preparation of dialkynic nitriles
ð53JCS432Ł[ Thus\ pyrolysis of the b!ketoalkylidenephosphorane "068#\ this time prepared by the
reaction of the corresponding a\b!alkynic acid chloride with cyanomethylenetriphenylphosphorane\
at 179Ð299>C furnishes dialkynic nitriles of the type "079# "Equation "32##[
Bearin` an a\b!Triple Bond 564
R CN
+
R CN
–O PPh3
(177) (178)

CN
Ph3P 280–300 °C
NC R (43)
R
O
(179) (180)

In 0882 a novel synthesis of a\b!alkynic nitriles was published ð82TL4800Ł involving the iodine!
catalysed cyanation of terminal alkynes with cuprous cyanide "Equation "33##[ The yields for this
transformation are generally good to excellent "42Ð73)# with the best results when Raryl
"Equation "33##[ Importantly\ the authors found that the use of dimethyl sulfoxide with acetonitrile
in the ratio of 2 ] 0 was the ideal solvent system for this reaction\ with di}erent proportions of these
two solvents or other solvents "e[g[\ THF\ THF and HMPA\ benzene# resulting in signi_cantly
lower yields of the desired a\b!alkynic nitriles[

CuCN, TMS-Cl, NaI (cat.), H2O


R R CN (44)
DMSO/MeCN (3:1)

R = aryl, alkyl

Terminal alkynes can also be transformed into a\b!alkynic nitriles via reaction with copper
cyanide in the presence of bis"trimethylsilyl#peroxide "Equation "34## ð80TL1058Ł[ It is believed that
the reaction involves a formal transfer of CN¦ from CuCN to the terminal alkyne in an umpolung
fashion via the intermediate hypo species TMS0O0CN ð80TL1058Ł[

R
TMS-O O-TMS + CuCN R CN (45)
THF

The reaction of metallated alkynides with cyanogen chloride to furnish a\b!alkynic nitriles is a
classical method for the preparation of these compounds ð04BSF117\ 15AC"P#4\ 62RTC556Ł[ An obvious
problem with such an approach is the use of the highly toxic cyanogen chloride[ In an attempt to
overcome this problem it has been found that the reaction of cyanogen bromide "which is easier to
handle than cyanogen chloride# with the alkynyl cuprate "070# in diethyl ether:acetonitrile at 24>C
produces phenylpropynenitrile in 59) yield "Equation "35## ð65S337Ł[ Lower temperatures result in
poorer yields of the desired a\b!alkynic nitriles ð65S337Ł[ In a further modi_cation of this general
route into a\b!alkynyl nitriles\ phenyl cyanate "071# "prepared by the reaction of phenol with
cyanogen bromide in the presence of triethylamine# reacts with lithiated alkynides at −69>C in
diethyl ether to give a\b!alkynic nitriles "Equation "36## ð79S049Ł[ The reaction is quite general with
alkyl\ cycloakyl\ aryl and alkoxy substituted lithiated alkynides all providing the corresponding a\b!
alkynic nitriles in excellent yield "69Ð84)#[

BrCN
Cu CN (46)

(181)

R Li + Ph–O–CN R CN (47)
(182)

R = alkyl, cycloalkyl, aryl, alkoxy

Metallated alkynides can also react with p!toluenesulphonyl cyanide "TsCN# leading to
a\b!alkynic nitriles ð82TL3512Ł[ In this case alkynic organozinc iodides are found to react smoothly
with TsCN in THF under very mild conditions "9Ð14>C\ 1 h# to give the desired alkynic nitriles in
excellent yield "70Ð89)# "Equation "37## ð82TL3512Ł[
565 a\b!Unsaturated and Aryl Nitriles
THF, 0 °C to 25 °C
R ZnI + TsCN R CN (48)
R = alkyl

The utility of a\b!alkynic nitriles in organic synthesis has been aptly demonstrated by the synthesis
of bongkrekic acid "072# ð73JA351Ł via the alkynic nitrile "075#[ The nitrile "075# was itself prepared
in a novel two!step procedure starting with the a!cyanoketone "073# "Scheme 50#[ Thus\ exposure
of the cyanoketone "073# to sodium hydride and then tri~ic anhydride _rst led to the enol tri~ate
"074#[ Elimination of the elements of tri~ic acid from "074# with sodium hydride in diethyl ether
and dimethyl sulfoxide next gave the a\b!alkynic nitrile "075# in a 54) yield from the cyanoketone
"073# ð73JA351Ł[ Reaction of "075# with dimethylcopper lithium then gave the Z!a\b!alkenic nitrile
"075# which was _nally elaborated to the bromoalkyne "077#\ the immediate precursor to bongkrekic
acid "072#[
CO2H

CO2H
OMe

CO2H
(183)

OMe OMe
NaH, Tf2O NaH, Et2O, DMSO
CN CN
TIPS O TIPS OTf
(184) (185)

OMe OMe CN
Me2CuLi steps

TIPS CN TIPS
(186) (187)

CO2Me

OMe

Br
(188)

Scheme 61

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.20
N-Substituted Nitriles and Other
Heteroanalogues of Nitriles of the
Type RCZ
R. MICHAEL PATON
University of Edinburgh, UK
2[19[0 N!SUBSTITUTED NITRILES 566
2[19[0[0 General Methods for the Formation of Nitrilium Betaines 566
2[19[0[1 Nitrile Ylides 567
2[19[0[2 Nitrile Imides 579
2[19[0[2[0 Generation of transient nitrile imides 579
2[19[0[2[1 Preparation of stable nitrile imides 570
2[19[0[3 Nitrile Oxides 572
2[19[0[3[0 From aldoximes 572
2[19[0[3[1 From nitromethyl compounds 573
2[19[0[3[2 From a!nitroalkanoate esters 573
2[19[0[3[3 From furazan N!oxides 574
2[19[0[3[4 Generation of fulminic acid and heteroatom!substituted analo`ues 574
2[19[0[4 Nitrile Sul_des 575
2[19[0[5 Nitrilium Ions 576
2[19[1 N!SUBSTITUTED ANALOGUES OF NITRILES BEARING A HETEROATOM
OTHER THAN NITROGEN 576
2[19[1[0 Phosphaalkyne Synthesis 576
2[19[1[1 Methods for the Synthesis of AlkylidyneÐTransition Metal Compounds 589
2[19[1[1[0 Synthesis from nonalkylidyne precursors 589
2[19[1[1[1 Modi_cations of alkylidyneÐmetal complexes 580

2[19[0 N!SUBSTITUTED NITRILES

2[19[0[0 General Methods for the Formation of Nitrilium Betaines


The most important N!substituted nitriles from a synthetic point of view are the nitrilium betaines
ðB!73MI 219!90Ł[ These are propargyl!allenyl type 0\2!dipoles with nitrogen as the central atom and
can be represented as RC2N¦0Z− tRC−1N¦1Z where ZCR1\ NR\ O\ etc[ They undergo
concerted inter! and intramolecular 0\2!dipolar cycloaddition reactions with a variety of double!
and triple!bonded dipolarophiles "Scheme 0#\ and are thus uniquely well suited for the construction
of _ve!membered heterocycles incorporating the C1N0Z unit[ Their 0\4! and 0\6!electrocyclisation
reactions also have great synthetic potential ð79AG"E#836\ 80S070Ł[ Four classes of nitrilium betaine
will be discussed in this chapter] the nitrile ylides "RC2N¦0C−R1#\ nitrile imides
"RC2N¦0N−R#\ nitrile oxides "RC2N¦0O−# and nitrile sul_des "RC2N¦0S−#[ The cor!
responding nitrile selenides "RC2N¦0Se−# are also known and have been characterised spec!
troscopically with the aid of matrix isolation techniques ð66ACS"B#737Ł^ their chemistry\ however\

566
567 Nitriles and Other Heteroanalo`ues of Nitriles
has not yet been exploited synthetically and they are therefore omitted from the survey[ Methods
for the formation of nitrilium ions "RC2N¦R# are considered in the _nal section[ The generation
and reactions of the nitrilium betaines and mechanistic aspects of their chemistry have been described
in depth as part of wider reviews ð80COS"3#0958\ 80COS"3#0000Ł\ and also in a two!volume monograph
on 0\2!dipolar cycloaddition chemistry edited by Padwa ðB!73MI 219!90Ł[ Reference to reviews speci_c
for the individual classes of nitrilium betaine is made in the appropriate sections of this chapter[

R Y R Y
X Y + R X Y
X R N Z– + X
N –
N Z N
Z Z
Scheme 1

As most nitrilium betaines usually exist at ambient temperature only as short!lived intermediates\
it is common practice in synthetic applications for them to be generated in situ in the presence of
the dipolarophile[ In this way\ side reactions which compete with cycloaddition are minimised[ No
single method is applicable for the generation of all four classes of nitrilium betaine[ There are\
however\ two approaches which are common to more than one type and are widely used[ These are
outlined in the following paragraphs[
The most widely used route "Equation "0## involves the dehydrohalogenation of the appropriately
substituted imino compounds "RCX1NZH#[ Thus nitrile ylides\ nitrile imides and nitrile oxides
can be conveniently formed from imidoyl halides "RCX1N0CHR1#\ hydrazonoyl halides
"RCX1N0NHR# and hydroximoyl halides "RCX1N0OH#\ respectively[ The elimination of HX
is usually carried out by treatment with base but can sometimes be accomplished by thermolysis
alone[

X ZH base and/or heat


+
N R N Z– (1)
R –HX

X = Cl, Br; Z = CR2, NR, O

The second generally applicable approach involves thermally or photochemically induced frag!
mentation "with expulsion of a stable moiety such as carbon dioxide or nitrogen# of a _ve!membered
heterocyclic compound which already incorporates the C1N0Z moiety "Equation "1##
ð68AG"E#610Ł[ This is the method of choice for nitrile sul_des and is also widely used for nitrile ylides
and nitrile imides[

R Y heat or hν +
X R N Z– (2)
N Z –X = Y

XY = CO2, N2, etc.; Z = CR2 NR, S

2[19[0[1 Nitrile Ylides


Nitrile ylides are versatile intermediates which a}ord via their 0\2!dipolar cycloaddition reactions
a variety of C1N0C containing _ve!membered heterocycles[ They are Type I dipoles under
the Sustmann classi_cation for which cycloaddition is predominantly dipole!HOMO:dipolarophile!
LUMO controlled[ ð0¦1Ł!\ ð0¦2Ł! and ð2¦5Ł!Cycloadditions ðB!73MI 219!91Ł\ and ð0\4Ł! and ð0\6Ł!
electrocyclisation reactions ð79AG"E#836\ 80S070Ł have also been reported[ Their chemistry has been
reviewed ðB!65MI 219!90\ 66H"5#032\ B!73MI 219!91Ł and they have also been discussed as parts of wider
surveys ð89MI 219!90\ 80CRV152Ł[ Nitrile ylides undergo several side reactions which compete with
cycloaddition and thus in~uence the choice of synthetic method[ They readily dimerise in a head!
to!head manner to give 1\4!diaza!0\2\4!hexatrienes "0# "Scheme 1#[ Photocyclisation a}ords
1H!azirenes\ and for formonitrile ylides 0\2!hydrogen shifts yield the isomeric isonitriles[ 0\3!Shifts
and protonation at carbon have also been reported[
The original route described by Huisgen ð51AG"E#49Ł involving base!mediated de!
hydrochlorination of imidoyl chlorides "Scheme 2# remains one of the methods of choice for the in
Substituted Nitriles 568
R
R Y N
R R
X X Y +

R
N R N
R
R R R
R N
R
(1)
Scheme 2

situ generation of arenenitrile ylides[ The precursors are easily prepared from N!monoalkylated
carboxamides by treatment with SOCl1\ PCl4 or COCl1 and\ provided the proton at the alkyl group
attached to nitrogen is su.ciently acidic\ formation of the nitrile ylide is readily induced by addition
of a base such as triethylamine[ The process is faster in the presence of a dipolarophile and is
believed to involve an equilibrium between imidoyl halide and HCl:nitrile ylide\ the latter being
present only at low concentration[ It has been reported ð61CB0147Ł that triethylamine hydrochloride
also causes tautomerism between the regioisomeric imidoyl chlorides Ar0CCl1NCH1Ar1 and
Ar0CCH1N1CClAr1\ thus leading to the generation of both nitrile ylide isomers
Ar0C2N¦0C−HAr1 and Ar0CH−0N¦2CAr1[
R
R X
R R
Y
N N
X heat or hν R
base R
–HX –X Y (3) X = O, Y = CO
+
R (4) X = CO, Y = O
– (5) X = O, Y = PR3
R N R
: (6) X = S, Y = PR3
R
hν R
N
R
R N
R
R
Scheme 3

1H!Azirenes undergo photochemical\ but not thermal\ ring opening at C"1#0C"2# to a}ord nitrile
ylides "Scheme 2# and\ as there are e.cient methods available for the synthesis of such azirenes
bearing a wide range of substituents\ this is a valuable strategy for the generation of this class of
0\2!dipole ð73JOC2063Ł[ It is\ for instance\ suitable for low!temperature spectroscopic studies[ The
process can be reversible\ and with light of longer wavelength "249 nm#\ benzonitrile ylides are
transformed back into 2!phenyl!1H!azirenes[ Benzonitrile ylides are also formed on photolysis of
0!azido!0!phenylalkenes\ presumably via the 1H!azirene as intermediate ð63HCA0271Ł[ The photo!
chemistry of nitrile ylides has been reviewed ð65ACR260\ B!71MI 219!90Ł[
Additions of a singlet carbene or carbenoid to a nitrile represent an elegant alternative method
for nitrile ylide generation ð80CRV152Ł[ The reactions are particularly useful for alkyl! and acyl!
substituted nitrile ylides for which some of the traditional methods are unsuccessful[ For example\
singlet methylene\ generated by photolysis of either diazomethane or diazirene\ combines with
acetonitrile to a}ord acetonitrile methanide "CH2C2N¦0CH1−# ð75JA5628Ł[ Rhodium acetate!
mediated fragmentation of a!diazoketones and acetates in the presence of nitriles leads to C!acyl
and C!alkoxycarbonyl analogues ð81CL1086Ł[ The _rst stable nitrile ylide "1# was prepared by this
approach in 0873^ its unusual stability is attributed both to the steric bulk of the C!adamantyl
substituent inhibiting dimerisation and to charge delocalisation at the N!terminus into the cyclo!
pentadienyl ring ð73TL394Ł[

CF3
F3C
– +
N
F3C
CF3
(2)
579 Nitriles and Other Heteroanalo`ues of Nitriles
Nitrile ylides are formed on thermal or photochemically!induced fragmentation of several hetero!
cyclic systems "Scheme 2#[ Carbon dioxide is expelled on photolysis or thermolysis of 1! and
2!oxazolin!4!ones "2# and "3#\ which are readily prepared bearing a variety of substituents starting
from amino acids[ The temperature required "099Ð129>C# depends on the nature of the substituents
ð60CB2705\ 77HCA0066Ł\ 2!oxazolin!4!ones generally fragmenting more readily than their 1!oxazo!
linone isomers[ Similarly 1\2!dihydro!0\3\1l4!oxazaphospholes "4# and !thiazaphospholes "5# ther!
mally or photochemically extrude triakyl phosphate and thiophosphate respectively ð79CB1588\
75AG"E#74Ł[ 1\1!Bis"tri~uoromethyl#!2!oxazolin!4!one:P"OMe#2 acts as a synthon for formonitrile
hexa~uoro!1!propanide ð76S813Ł[ Benzonitrile bis"tri~uoromethyl#methanide is formed together
with phenyl isocyanide on ð2¦0Ł cycloreversion of azetidinimine "6# ð62AG"E#044Ł[

Ph NPh Ph N R TMS
NCO2Et N
N CF3 HN
PhS
CF3
(7) (8) (9)

Alternative approaches to nitrile ylides include oxidative photofragmentation of dihydrotriazole


derivative "7# ð63HCA0271Ł and silver ~uoride!induced desilylations of silylthioimidates "8#
ð75JA5628Ł[ The synthetic potential of addition of electrophiles to isonitriles is illustrated by the
formation of triphenylboron nitrile ylide anion Ph2B−0C2N¦0C−R1 ð57LA"602#0Ł[ Stable
iminocarbene complexes such as "CO#4W1CMe0N1CHPh have been shown to be useful nitrile
ylide synthons ð89OM1756Ł[ Organometallic analogues of the form ð"CO#4M0C2N¦0
CH−CO1EtŁ have also been described ð76CB1920Ł[

2[19[0[2 Nitrile Imides


The chemistry of the nitrile imides "nitrile imines# has been the subject of intensive investigation
since the original report in 0848 by Huisgen et al[ of their generation and formation of 0\2!dipolar
cycloadducts ð48JOC781Ł[ They are regarded as Sustmann Type II dipoles with contributions from
both dipole!HOMO:dipolarophile!LUMO and dipole!LUMO:dipolarophile!HOMO interactions[
The value of their cycloaddition reactions in heterocyclic synthesis\ particularly for the preparation
of pyrazoles and 1!pyrazolines\ is well documented ð79JHC722\ 73MI 219!92Ł and their chemistry has
been the subject of a recent review ð83AG"E#416Ł[ Various _ve! and seven!membered heterocycles
not readily accessible by other means have also been prepared via their electrocyclisation reactions
ð79AG"E#836\ 80S070Ł[ Until the early 0889s they were regarded solely as short!lived reactive inter!
mediates[ Evidence for their existence was based on trapping experiments and spectroscopic studies
at low temperatures using matrix isolation techniques[ However\ with a greater understanding of
the factors in~uencing their stability\ methods for the preparation of a variety of more stable
and isolable analogues have been developed\ thus allowing their structures and properties to be
investigated[
The nitrile imides\ like the other nitrilium betaines\ undergo several rearrangement and dim!
erisation processes[ Photolysis induces rearrangement to carbodiimides\ possibly via an intermediate
0H!diazirene "Scheme 3#[ Isomerisation to diazoalkanes and photofragmentation to the parent
nitrile have also been reported[ In the absence of a dipolarophile head!to!head dimerisation a}ords
thermally and photochemically labile 0\1!bisazoethenes "09#[ Symmetrical head!to!tail 0\1\3\4!tetra!
zine dimers "00# are sometimes also formed\ but these are thought to result from an alternative
pathway involving combination of the nitrile imide and its precursor[ For synthetic purposes it is
necessary for most nitrile imides to be prepared in situ in order to avoid these side reactions[ In the
following section the methods used for generating short!lived nitrile imides and the new approaches
developed for the synthesis and isolation of stable analogues are described[

2[19[0[2[0 Generation of transient nitrile imides


The _rst de_nitive report of nitrile imides ð48JOC781Ł described the generation of benzonitrile
N!phenylimide both by base!mediated dehydrochlorination of N!phenylbenzohydrazonoyl chloride
Substituted Nitriles 570

N R2
+ –

R1 N NR2 N N • N
R1 R2
R1

R2 R2
N N R1 N N
R1
N2 R1 R1
R2 R2 N N
R1 N N
R2
(10) (11)
Scheme 4

and by thermal decomposition of 1\4!diphenyltetrazole\ and these remain two of the most used
approaches to this class of nitrilium betaine[
Hydrazonoyl chlorides are readily prepared by a variety of methods including treatment of
hydrazides with PCl4 ðB!68MI 219!90Ł\ Ph2P:CCl3 ð76JHC466Ł or POCl2:pyridine ð65ZOR0565Ł and
by chlorination of aldehyde hydrazones ð61RCR384Ł^ use of Ph2P:CBr3 provides access to the
corresponding bromides ð64CJC0222Ł[ Coupling of diazonium salts with halogenated methylene
compounds and with diazo compounds can be used for the preparation of C!acyl and C!alkoxy!
carbonyl analogues ð48OR"09#032Ł[ Addition of a base such as triethylamine a}ords the nitrile imide
by a pathway which is believed to involve initial removal of the NH proton followed by loss of
halide ion ð61JCS"P1#33Ł[ Base!induced elimination of nitrous acid from a!nitro aldehyde hydrazones
has also been investigated "Scheme 4#\ and in some cases hydrazones can be oxidised to nitrile
imides directly\ for example with lead tetraacetate ð57CI"L#326\ 58JCS"C#1476Ł[
R1
NNHR2 R1 N
X N
X = Cl, Br, NO2 N N

base heat or hν R2
–HX –N2 (12)

+ –
R1 N NR2
heat or hν hν
–XO2 –CO2
hν –CO2 –O

R1 O O
R1 + N
X O N R1
N N O N
N R2
R2 R2
(14) X = C O (13)
(16) X = S (15)

Scheme 5

Tetrazoles "01# provide another valuable source of nitrile imides[ They are accessible by several
routes including oxidation of formazans\ treatment of aldehyde hydrazones with aryl azides and
diazotisation of amidrazones ð73CHEC"4#680Ł[ Photolysis\ or thermolysis in an inert solvent results
in extrusion of nitrogen^ the temperature required ranges from 059 to 119>C depending on the
electron donatingÐwithdrawing properties of the imide substituent[ The ~ash vacuum pyrolysis
technique coupled with low!temperature matrix isolation has also been used ð74AG"E#45Ł[ Thermal
or photochemically!induced fragmentation of various other diazoles a}ords nitrile imide derived
products ð68AG"E#610\ B!73MI 219!92Ł] for example\ the decarboxylation of the mesoionic compound
"02# and the oxadiazolinones "03# and "04#\ and extrusion of sulfur dioxide from the oxathiadiazole
"05#[

2[19[0[2[1 Preparation of stable nitrile imides


The _rst stable nitrile imide "06#\ which was reported by Bertrand and co!workers in 0877
ð77JA1552Ł\ was prepared by treatment of the lithium salt of a thiophosphinoyldiazomethane with
571 Nitriles and Other Heteroanalo`ues of Nitriles
a chlorophosphane "Equation "2##^ it is not air sensitive and is thermally quite stable[ Subsequently
a range of organometallic analogues has been synthesised bearing boryl\ germyl\ phosphino\
thiophosphinoyl\ silyl and stannyl substituents "R0C2N¦0N−R1 where R0 R1B\ R1P\ R1P"S#\
R2Si and R1 BR1\ GeR2\ PR1\ SiR2#[ The kinetic stablity of this class of compounds is attributed
primarily to steric factors\ although pushÐpull substituents can decrease the polarity of the nitrile
imide framework and further enhance their stability[ The various synthetic approaches to stable
nitrile imides have been surveyed by Bertrand and Wentrup ð83AG"E#416Ł[
+ –
(Pri2N)2P(S)C(Li) N2 + (Pri2N)2PCl LiCl + (Pri2N)2P(S)C N NP(NPri2)2 (3)
(17)

The original route employing diazolithium precursors has proved to be general and a wide range
of stable nitrile imides have been similarly prepared by combination of chlorosilanes\ chloroboranes
and chlorophosphanes with the lithium salts of phosphino!\ boryl! and silyl! as well as thiophos!
phinoyl!diazomethanes[ Electrophilic attack can occur at carbon yielding a substituted diazo com!
pound\ or at nitrogen to form the nitrile imide ð81JA5948Ł[ The balance between the two processes
has been shown to depend on steric factors\ bulky electrophiles reacting preferentially at nitrogen
and less sterically demanding analogues at carbon[ Diazo compounds can also result from iso!
merisation of the thermodynamically less stable nitrile imide "Scheme 5#[
+ –
N - attack R N NE

R
N2 + E+
Li R
C - attack
N2
E
Scheme 6

Trialkylstannyldiazo compounds also prove to be versatile precursors of stable nitrile imides\


with substitution possible at both carbon and nitrogen termini[ For example\ bis"stannyl!
diazo#methane "07# reacts with chloroboranes and chlorophosphanes to a}ord the bisboryl and
bisphosphinyl substituted nitrile imides "08# and "19# respectively "Equation "3## ð81JA5948Ł[ Of
particular interest is the preparation by this route of the stable organic C\N!ditrityl analogue "10#[

Me3Sn
+ –
N2 + RCl R N NR (4)
Me3Sn
(18) (19) R = B(NPri2)2
(20) R = P(NPri2)2
(21) R = CPh3

Some chemical modi_cations have also been performed on carbon and nitrogen substituents
without destroying the CNN skeleton^ for example\ a C!phosphino group can be converted into the
corresponding C!thiophosphinoyl by treatment with elemental sulfur ð80OM2194Ł[ An alternative
approach to stable nitrile imides involves replacement of boryl groups at both carbon and nitrogen
termini ð81S32Ł[ Reaction of the bis"diisopropylamino#boryl compound "11# with methyllithium
followed by a chlorophosphane a}ords the C!phosphino derivative "12# "Scheme 6#\ and the diboryl!
substituted analogue "13# is formed by a similar two!step sequence[
i, MeLi i, MeLi
+ ii, R12PCl +
ii, R22BCl +
– – –
R12P N NBR12 R12B N NBR12 R22B N NBR22
iii, MeLi
(23) (22) iv, R22BCl (24)

R1 = PriN, R2 = (c-C6H11)2N

Scheme 7

The stable organometallic nitrile imides described above are of interest in their own right and
have allowed the structure\ bonding and properties of the CNN framework to be examined in detail[
In some cases they also provide further scope\ as yet not fully realised\ for the synthesis of heterocyclic
Substituted Nitriles 572
compounds via the reactions of their substituents[ Whereas phosphorusÐcarbon bonds in the
cycloadducts are not readily cleaved\ the corresponding boronÐcarbon and siliconÐcarbon bonds
are more susceptible to substitution[ C!Silyl and C!boryl nitrile imides may therefore provide useful
building blocks for the preparation of _ve!membered heterocycles incorporating the C1N0N unit[

2[19[0[3 Nitrile Oxides


The nitrile oxides are the group of nitrilium betaines which have been studied in greatest detail[
Not only do they provide access via their 0\2!dipolar cycloaddition reactions to a wide variety of
C1N0O!containing heterocyclic systems but\ together with the manipulation of the isoxazoles
and 1!isoxazolines resulting from their reactions with alkynes and alkenes\ respectively\ nitrile oxide
cycloaddition chemistry has been developed into a versatile method for the stereocontrolled synthesis
of natural products and analogues ð73ACR309\ 74MI 219!90\ 77MI 219!90\ 89H"29#608\ 80CHE280Ł[ Function!
ality accessible by this approach includes b!hydroxyketones\ a!enones\ 0\2!diols\ g!aminoalcohols\
0\2!diones\ b!aminoketones and b!amino!a!enones[ They are mainly Type II dipoles and for appli!
cations in heterocyclic synthesis a very wide range of double! and triple!bonded unsaturation can
_ll the role of dipolarophile[ The chemistry of nitrile oxides has been the subject of several reviews
and monographs ðB!60MI 219!90\ B!73MI 219!92\ B!77MI 219!91Ł[ Like the other nitrilium betaines\ the
nitrile oxides undergo several reactions which compete with cycloaddition and therefore impose
constraints on the method of preparation\ including dimerisation to furazan N!oxides "furoxans\
14# at ambient temperature\ thermal or photochemically!induced rearrangement to the isomeric
isocyanates\ and 0\2!addition with nucleophiles "Scheme 7#[ Although it is possible to isolate some
nitrile oxides\ particularly those with bulky substituents "e[g[\ mesitonitrile and triphenylacetonitrile
oxides#\ it is usual in synthetic applications for the nitrile oxide to be generated at low concentration
in the presence of the dipolarophile in order to minimise the side reactions[ The two most used
methods involve the dehydrohalogenation of hydroximoyl halides derived from aldoximes and
dehydration of nitromethyl compounds[ In contrast to the chemistry of nitriles\ for which treatment
of an alkyl halide with a metal cyanide is an important synthetic route\ the analogous reaction with
metal fulminates does not provide a general approach to nitrile oxides\ the isomeric isocyanate
usually being isolated[
R X R X
X Y + X Y
Y R N O– Y
N O N O
heat or hν NuH

R
RN • O R R NOH
Nu
+
N N
O O–
(25)
Scheme 8

2[19[0[3[0 From aldoximes


The route to benzonitrile oxide described by Werner and Buss a century ago ð0783CB1082Ł
involving chlorination of benzaldoxime followed by base!mediated dehydrochlorination of the
resulting hydroximoyl chloride continues to be widely used "Scheme 8#[ Hydroximoyl chlorides can
be prepared by direct chlorination of aldoximes using chlorine in an inert solvent[ However\ this
procedure limits the functionality which the oxime and ultimately the nitrile oxide can carry[ Alkene
and acyl substituents\ and electron!rich aromatic rings are incompatible^ for example\ thiophene!1!
aldoxime on treatment with chlorine a}ords 4!chloro!1!thienohydroximoyl chloride[ Alternative
milder reagents now in widespread use include nitrosyl chloride ð57BCJ1843Ł\ N!bromosuccinimide
ð58JOC1905Ł and N!chlorosuccinimide ð73T1874Ł[ The dehydrochlorination step\ originally carried
out with aqueous sodium bicarbonate or sodium hydroxide\ is now usually accomplished by addition
of triethylamine\ the resulting triethylamine hydrochloride by!product being readily removed by
573 Nitriles and Other Heteroanalo`ues of Nitriles
_ltration[ Slow addition of the base ensures a low concentration of the nitrile oxide and minimal
formation of furazan N!oxide dimer[ The reaction is believed to involve removal of the oxime
proton by the base with concomitant loss of halide ion ð66JCS"P0#0346Ł^ a similar but cation!
like mechanism has been proposed for silver salt!induced eliminations[ Alternative hydrohalide
scavengers include molecular sieves ð89H"20#0582Ł\ potassium ~uoride ð80H"21#366Ł and its dihydrate
ð82JCS"P0#1040Ł[ O!Alkoxycarbonyl! and O!trimethylsilyl!hydroximoyl chlorides have also been
examined ð72JOC1679\ 80BCJ207Ł[ It is reported that the formation of ethoxycarbonylformonitrile
oxide from ethyl chloro"hydroxyimino#acetate:alumina is accelerated by microwave radiation
ð83JCR"S#005Ł[ The thermal dissociation of hydroximoyl chlorides in an inert solvent at 099Ð029>C
also generates the nitrile oxide at low concentration ð52BSB608\ 79JPS"A#524Ł[ The analogous elim!
ination of nitrous acid from nitrolic acids "O1NCR1NOH# takes place at or near room temperature
ð80JCS"P1#138Ł[
R –2H +
NOH R N O–

X+ –HX
base
R or heat
NOH
X
Scheme 9

As some hydroximoyl halides are di.cult to isolate in pure form and others are toxic\ for example\
as skin irritants\ it is common practice to generate them in situ using NCS or NBS\ and then to carry
out the dehydrochlorination:cycloaddition in one pot using triethylamine as the base[ Treatment of
aldoximes with t!butyl hypochlorite followed by bis"tributyltin# oxide also a}ords nitrile oxides\
presumably via the O!stannyl oxime "RCH1NOSnBu2# ð83JCS"P0#302Ł[ Other reagents which allow
one!pot halogenation:dehydrohalogenation include sodium hypochlorite ð71S4497Ł\ sodium hypo!
bromite ð56JOC1292Ł and Chloramine!T ð78S46Ł[ Oxidations of aldoximes to nitrile oxides have also
been accomplished using lead tetraacetate ð57T4140Ł\ mercuric acetate ð81OPP80Ł and dimethyl!
dioxirane ð81NKK319Ł[

2[19[0[3[1 From nitromethyl compounds


The dehydration of nitromethyl compounds\ which was _rst reported by Mukaiyama and Hoshino
in 0859 ð59JA4228Ł\ continues to provide a versatile approach to nitrile oxides which complements
the oxime oxidation method[ Mono! and difunctional diisocyanates are the most common dehy!
drating agents ðB!77MI 219!91\ 77CC0228Ł[ The reaction pathway "Scheme 09# is believed to involve
addition of the nitronate anion to the isocyanate and decarboxylation of the resulting adduct "15#
to the nitrile oxide and arylamine^ the latter then react with further isocyanate to a}ord an
insoluble and readily separable diarylurea as the coproduct[ Alternative dehydrating agents include
phosphorus oxychloride ð62OS"42#48Ł\ acid chlorides ð75BCJ1716Ł and anhydrides ð67CPB2143Ł\
methyl chloroformate ð73CC0402Ł\ p!toluenesulfonic acid with ð83JCR"S#005Ł or without microwave
radiation ð73BCJ1420Ł\ and tosyl chloride:potassium carbonate:07!crown!5 ð75M0980Ł[ Nitrile oxides
can also be formed from nitromethyl compounds via nitronate esters ð73JOC3484Ł[
O–
R N+
R ArNCO O –CO2
+
R NO2 NO2– R N O–
H – –ArNH2
N O
Ar
(26)
Scheme 10

2[19[0[3[2 From a!nitroalkanoate esters


Thermolysis in an inert solvent of alkyl esters of a!nitroalkanoic acids results in expulsion of
carbon dioxide and the alkanol\ and formation of a nitrile oxide which can be trapped in the
Substituted Nitriles 574
presence of a suitable dipolarophile ð76BCJ0837Ł[ The reaction pathway\ which is believed to proceed
via initial cyclisation to an intermediate oxazetidinone N!oxide "16# followed by decarboxylation\
is illustrated in Scheme 00 for the generation of ethoxycarbonylformonitrile oxide from diethyl
nitromalonate[ The method is suitable for aliphatic nitrile oxides as well as amide! and ester!
substituted analogues[ A similar mechanism involving decarboxylation of an intermediate
0\1!oxazetidine N!oxide has been invoked to explain the formation of arenenitrile oxides on photo!
lysis of a!nitrostilbenes ð73AJC0120Ł[

O
EtO2C EtO2C O
EtO2C –EtOH –CO2 +
NO2 OEt EtO2C N O–
+N O
EtO2C N+ –O
–O OH
(27)
Scheme 11

2[19[0[3[3 From furazan N!oxides


Dimerisation to furazan N!oxides "14#\ which is the normal decay pathway for nitrile oxides at
ambient temperature\ is a reversible process[ Thermolysis results in cleavage of the O"0#0N"1# and
C"2#0C"3# bonds to generate two nitrile oxide fragments\ the temperature required being critically
dependent on the steric and electronic properties of the substituents "Scheme 01#[ If the only access
to furazan N!oxides was by dimerisation of nitrile oxides then this approach would be of limited
synthetic value[ They can\ however\ be prepared by several other routes including oxidation of
glyoximes ð73CHEC680Ł and dehydration of a!nitroketoximes[ The latter can be prepared by a!
nitrosation and oximation of ketones and via the tautomeric vicinal nitronitroso compounds
"pseudonitrosites# by addition of dinitrogen trioxide to the corresponding alkene[ This approach is
generally of synthetic value for mononitrile oxides only when the furazan N!oxide is symmetrically
substituted[ Bicyclic furazan N!oxides\ formed\ for example\ from cycloalkenes and dinitrogen
trioxide\ are ideally suited for the generation of bis"nitrile oxides# "Equation "4## ð72JCS"P0#182Ł[
Nitrile oxides are also formed together with an equivalent amount of nitrile on thermal or photo!
chemical cleavage of furazans ð73CHEC"4#282Ł^ bicyclic furazans a}ord v!cyanonitrile oxides[
R R R R
50–250 °C heat
+
+ R N O–
N N < 50 °C –RCN N N
O O O
(25)
Scheme 12

(CH2)n
–O + + O–
heat
N N (5)
+ ( )n
N N
O O–

2[19[0[3[4 Generation of fulminic acid and heteroatom!substituted analogues


The parent nitrile oxide fulminic acid "formonitrile oxide\ HC2N¦0O−#\ which was the _rst
member of the series to be discovered ð0799MI 219!90Ł\ is somewhat of an exception in terms of its
reactivity and methods of formation ðB!60MI 219!90Ł[ For example\ although it can be generated by
the hydroximoyl halide route from formohydroximoyl iodide ð62CB2180Ł\ the MukaiyamaÐHoshino
procedure fails^ treatment of nitromethane with phenyl isocyanate:triethylamine instead a}ords
a!nitroacetanilide ð52BSF039Ł[ The original route of Howard via mercury fulminate is still utilised^
it involves reaction of nitric acid with ethanol\ acetaldehyde or glyoxylic acid oxime in the presence
of mercury or mercuric nitrate[ Alternative approaches include elimination of nitrous acid from
formonitrolic acid "O1NCH1NOH#\ hydrolysis of fulmidotrimethylsilane "TMSC2N¦0O−#
575 Nitriles and Other Heteroanalo`ues of Nitriles
formed by treatment of mercury fulminate with trimethylsilyl bromide ð71S608Ł\ hydrolysis of
bromo"hydroxyimino#acetic acid ð02CB3990Ł\ and ~ash vacuum pyrolysis of isoxazol!4!ones
ð68AG"E#356Ł[ Although it can be isolated\ formonitrile oxide is explosive and for synthetic applica!
tions it is best generated in situ[
The formation of various derivatives have been reportedðB!60MI 219!90Ł in which the acidic hydrogen
of formonitrile oxide is replaced by\ for example\ halide\ cyano or sulfonyl groups[ For example\
bromoformonitrile oxide ð82JCS"P0#1040Ł\ cyanogen oxide "N2CC2N¦0O−#\ cyanogen dioxide
"−O0¦N2CC2N¦0O−# ð76AG"E#044Ł and benzenesulfonylformonitrile oxide ð73JOC3484Ł have
all been generated by dehydrochlorination of the appropriate hydroximoyl halides[

2[19[0[4 Nitrile Sul_des


The nitrile sul_des "RC2N¦0S−# are ideally suited for the synthesis of _ve!membered het!
erocycles incorporating the C1N0S unit\ many of which are accessible only with di.culty by
other means[ Although nitrile sul_des are of very limited lifetime and\ unless matrix isolated
ð80TL0376Ł\ decompose rapidly at temperatures above 49K to sulfur and the corresponding nitrile\
they undergo preparatively useful cycloaddition reactions with various reactive dipolarophiles[
Electron!poor alkynes and nitriles add readily a}ording\ respectively\ isothiazoles and 0\1\3!thia!
diazoles^ unactivated alkynes and nitriles do not react[ Other applications include the formation of
1!isothiazolines from alkenes\ 0\2\3!oxathiazoles from aldehydes and ketones\ 0\3\1!dithiazoles
from thiones and thioesters ð80JCS"P0#072Ł\ 3\4!dihydro!0\1\3!thiadiazoles from imines and 0\1\3!
thiazaphospholes from phosphaalkynes[ The synthetic aspects of their chemistry have been reviewed
ð78CSR22Ł\ and they have also been discussed as part of a broader account of N!sul_des ð80CRV252Ł[
The principal method of generation of nitrile sul_des "Scheme 02# involves thermal decar!
boxylation at 099Ð039>C of 0\2\3!oxathiazol!1!ones "17#\ which are readily prepared by treatment
of the corresponding carboxamide with chlorocarbonylsulfenyl chloride ð67JOC2625Ł[ Photolysis of
"17# also a}ords nitrile sul_de!derived products\ but the yields are invariably lower[ Nitrile sul_des
can be trapped as their 0\2!dipolar cycloadducts on thermolysis of the closely related 0\3\1!dithiazol!
4!ones "18#\ which are accessible from the thiocarboxamide and trichloromethanesulfenyl chloride
followed by hydrolysis of the resulting 0\3\1!dithiazole!4!thiones ð71TL4342Ł[ 0\2\3!Oxathiazoles
"29#\ the adducts resulting from cycloaddition to the carbonyl group of aldehydes and ketones\
undergo thermal cycloreversion at 029Ð069>C regenerating the nitrile sul_de ð74JCS"P0#0406Ł[ The
3\4!dihydro!0\1\3!thiadiazoles formed by additions to imines also undergo cycloreversion and the
resulting nitrile sul_de can be trapped\ but the yields of adducts are low ð75JCR"S#045Ł[
R X heat
R O
heat
+
R
O R N S–
N S –COX –R2CO N S R
(28) X = O (30)
(29) X = S
Scheme 13

Two other preparatively useful approaches to nitrile sul_des have been reported[ Heating "ben!
zylimino#sulfur di~uoride\ prepared from benzylamine and SF3\ with sodium ~uoride and 07!crown!
5!polyether at 029>C generates benzonitrile sul_de which can be trapped by reactive dipolarophiles
such as dimethyl acetylenedicarboxylate ð68JOC409Ł[ The reaction is believed to involve 0\2!elim!
ination of two moles of HF\ as illustrated in Scheme 03^ acetonitrile sul_de and tri~uoroacetonitrile
sul_de have also been generated by this route ð79JOC2642Ł[

Ar F Ar Ar +
:

N S N S F N S
H F H
+
F– F– Ar N S–
S S– S
–Ph2S
N N N
+
Ar SPh2 Ar SPh2 Ar
(31)
Scheme 14
Nitriles Bearin` a Heteroatom Other Than Nitro`en 576
Thermolysis "49Ð69>C# of N!thioaroyl diphenylsul_mides\ which can be synthesised from diphenyl
sul_mide and methyl dithiobenzoates\ in the absence of a dipolarophile a}ords the corresponding
nitriles together with diphenyl sul_de and sulfur[ However\ when the reaction is repeated in the
presence of electron!poor alkynes isothiazoles are formed ð65BCJ2013Ł\ presumably via the unstable
antiaromatic thiazirine "20# and the arenenitrile sul_de as intermediates "Scheme 03#[
Benzonitrile sul_de has been invoked as a transient intermediate in the photofragmentation
reactions of various phenyl!substituted _ve!membered heterocycles incorporating C\ N and S[ In
each case the process is believed to involve extrusion of a stable fragment such as CO1\ COS\
CS1\ N1 or N1O forming the thiazirene "20#\ followed by rearrangement to benzonitrile sul_de[
Representative examples include dithiazolethiones "21# and "22#\ thiatriazole "23# and mesoionic
oxathiazolone "24# ð67JCS"P0#0334\ 70LA0914Ł[ Although the intermediates have been detected
spectroscopically\ the yields of cycloadducts in the presence of a dipolarophile are generally low
"4Ð18)#[
O–
Ph S Ph N Ph Ph
N
S S N + O
N S S S S N S N

(32) (33) (34) (35)

2[19[0[5 Nitrilium Ions


Nitrilium ions "25#\ which are isoelectronic and isostructural with acetylenes\ have been invoked
as intermediates in various well!known processes including the Beckmann and Curtius rearrange!
ments\ and the Ritter\ Gattermann and BischlerÐNapieralski reactions[ The _rst stable salts were
isolated in the 0849s by Klager and Grill ð44LA"483#10Ł and by Meerwein et al[ ð45CB198Ł[ They
are reactive electrophiles well suited for the synthesis of C!substituted imines\ imidates and
O!acylisoamides[ Reactions with a carboxylate followed by addition of a primary amine a}ord the
corresponding secondary amide and the procedure has been used as a mild method for peptide
synthesis ð79JA3426Ł[ Although they can be isolated\ for example\ as their ~uoroborate or hexa!
chloroantimonate salts\ for synthetic purposes further reactions with nucleophiles are often carried
out in situ[ The chemistry of nitrilium salts has been the subject of several reviews ð55AHC"5#84\
79ACR337\ 74HOU"E4#0461Ł[
A convenient source of nitrilium ions is provided by imidoyl halides "26# which are readily
accessible by direct halogenation of the imine ðB!68MI 219!90Ł or treatment of the corresponding
carboxamide with SOX1\ PX4 or Ph2P:CX3 ð64AG"E#790\ 64CJC0222Ł[ In aqueous organic solvent
mixtures\ ionisation takes place to the nitrilium salt "Scheme 04#\ the rate of the process being
dependent on the electronic nature of both carbon and nitrogen substituents and on the ionising
power of the solvent[ Beckmann rearrangement with SbCl4 of ketoxime O!chloroformates "27\
XCl# and O!chlorooxalates "27\ XCOCl# a}ords the hexachloroantimonate salts ð89S0017Ł[
An alternative and increasingly used approach involves N!alkylation of nitriles with\ for example\
trialkyloxonium tetra~uoroborate ð74TL3538Ł[ Tri~ate ð72JCS"P0#0956Ł\ hexachloroantimonate
ð73CB0899Ł and tetrachloroferrate salts ð79BCB322Ł have also been isolated[ Nitriles react with
alkyl chloroformates and SbCl4 to give nitrilium hexachloroantimonates in high yield ð82S315Ł[
N!Arylation occurs on heating a nitrile with a diazonium salt ð45CB198Ł[ Alternative precursors
include isonitriles which are su.ciently basic to undergo 0\0!addition at carbon\ and addition of
electrophiles to the C1C unit of ketenimines[

2[19[1 N!SUBSTITUTED ANALOGUES OF NITRILES BEARING A HETEROATOM


OTHER THAN NITROGEN

2[19[1[0 Phosphaalkyne Synthesis


In comparison with nitriles the corresponding trivalent monocoordinated l2s0!phosphorus com!
pounds\ the phosphaalkynes "RC2P#\ have a relatively brief history[ Although the parent member

 Some phosphaalkynes with heteroatom substituents attached to carbon are included here for convenience[ See also 2[19 and
4[22[
577 Nitriles and Other Heteroanalo`ues of Nitriles

R1 R2 +
–C N R2
N
X
(37)
–X– R1X

+
R1 N R2
(36) SbCl5
R2X
–CO2 R1 OCOX
R1 N N
R2
(38)
Scheme 15

of the series\ the unstable and highly reactive methylidynephosphane "phosphaacetylene\ HC2P#\
was characterised in 0850 ð50JA0658Ł it was not until 0870 that the preparation of a kinetically stable
analogue "tert!butylphosphaalkyne\ ButC2P# was _rst reported ð70ZN"B#05Ł[ Since this time a rich
and varied chemistry has emerged[ Despite in many cases substantial steric hindrance\ they undergo
a wide range of reactions including ð1¦0Ł!cycloadditions\ ð0\2Ł!dipolar cycloadditions and DielsÐ
Alder reactions^ ð1¦1Ł!cycloadditions\ HOMO!DielsÐAlder additions and ene reactions involving
C2P have also been described[ The synthesis and reactions of phosphaalkynes has been the
subject of several reviews by Regitz ð77AG"E#0373\ 89CRV080\ 81BSB248\ 83JHC552Ł\ and their impact on
organometallic chemistry has also been surveyed by Nixon ð77CRV0216\ 82CI"L#393Ł[
b!Elimination from suitably substituted phosphanes is the most generally applicable approach to
phosphaalkynes "Scheme 05#[ Flash pyrolysis of the dichlorophosphane "28# results in extrusion of
HCl which is removed by added base to avoid side and retro!reactions[ This method is suitable for
the generation of the short!lived parent phosphaacetylene and derivatives including RC2P\ where
RH\ Me\ F\ Cl[ Analogues with conjugating substituents such as HC2C0 and N2CC2
C0 are formed on co!pyrolysis of phosphorus trichloride with the propargyl halide[ The phosphino!
substituted compound "Me1N#2P¦0C2P[Ph3B− has been prepared by base!induced dehydro!
chlorination of the corresponding dichlorophosphane ð80CC291Ł[ Various transient phosphaalkynes
can be generated by dehydrochlorination of a\a!dichlorophosphanes "39# ð80AG"E#085Ł[ Flash vac!
uum pyrolysis "FVP#!induced b!elimination of trimethylsilyl chloride from chlorophosphaalkene
"30# proceeds similarly and has been used to form the phenyl and trimethylsilyl compounds[ Lithium
trimethylsilanoate is readily eliminated from the lithiated alkenes RC"OTMS#1PLi[
TMS
R PCl2 PCl
R
(39) heat heat (41)
–2 HCl –TMS-Cl

R P
K2CO3
heat heat
Cl TMS-O
–2 HCl –TMS-O-TMS
R PH2 P-TMS
Cl R
(40) (42)
Scheme 16

The most well!developed method for the synthesis of kinetically stable phosphaalkynes involves
NaOH!catalysed elimination of hexamethyldisiloxane from phosphaalkenes "31#[ The starting
materials can be prepared by acylation of tris"trimethylsilyl#phosphane\ a process which is believed
to involve initial formation of the acylphosphane RCOP"TMS#1 followed by a rapid 0\2!shift of a
trimethylsilyl group[
The 0 ] 0 adduct "32# between tris"trimethylsilyl#phosphane and isopropyl isocyanate provides a
source of the donor!substituted phosphaalkyne "33# ð78AG"E#42Ł which then undergoes NaOH!
catalysed elimination of hexamethyldisiloxane\ the _nal product being formed "Scheme 06# by a
0\2!silyl shift in the intermediate 0!aza!2!phosphaallene "34#[ The corresponding tert!butyl precursor
Nitriles Bearin` a Heteroatom Other Than Nitro`en 578
"35# reacts similarly and\ with replacement of the TMS group by hydrogen\ generates tert!
butylaminophosphaacetylene "ButNHC2P# ð80HAC466Ł[ The diisopropylamino compound
Pri1NC2P is prepared by the reaction of tri~uoromethylphosphane with excess diisopropylamine\
presumably via the phosphaalkene Pri1NCF1PH ð89CB1206Ł[
RN Pri
–TMS-O-TMS
P(TMS)2 PriN C P-TMS N P
TMS-O TMS
(43) R = Pri (45) (44)
(46) R = But
Scheme 17

Alternative sources include primary alkynylphosphines which undergo Lewis base!induced


rearrangement via an intermediate phosphallene ð81CC304Ł "Scheme 07#\ and di!tert!butyl!sub!
stituted phosphinodiazo compounds "36# derived from lithiated diazo compounds and di!tert!
butylchlorophosphane ð89CRV080Ł^ on FVP at 249>C:09−3 mbar "36# is converted into the phos!
phaalkyne with elimination of 1!methylpropene "Scheme 07#[ Under more forcing FVP conditions
"849>C:4×09−3 mbar# tert!butylphosphaacetylene itself also eliminates 1!methylpropene thus
providing an alternative\ albeit low yielding\ route to methylidynephosphane ð76JOM"227#218Ł[
Palladium! or platinum!promoted dechlorination of 1\1!dichlorophosphaalkenes has been reported
ð81TL1870\ 82OM3151Ł^ the process is believed to involve a highly reactive isocyaphide ligand[ Iso!
cyaphides have also been invoked as transient intermediates in the conversion of chloro!
lithiophosphaalkenes to phosphaalkynes ð80CB1566\ 81CL0942Ł "Scheme 08#[
R R
R PH2 • PH P

R
–N2 – CH2=CMe2
:
:

N2 RC PBut R PBut2 R P
PBut
(47)
Scheme 18

Li R
–LiCl R – +
P C P R R P
:C P
Cl
Scheme 19

The generation of stabilised quinquevalent "l4s2# phosphaalkynes has been the subject of inves!
tigation since the late 0879s[ These compounds show an interesting pattern of reactivity and can act
both as a phosphaalkyne "RC2PR1# in addition and cycloaddition reactions\ and as a nucleophilic
phosphanylcarbene "RC0PR1# capable of C0H insertion[ Two examples have been studied in
particular detail[ Bertrand and co!workers have shown that the trimethylsilyl derivative "37# bearing
diisopropylamino!stabilising substituents can be generated by photolysis of phosphiniodiazo com!
pound "38#\ which is readily prepared from the chlorophosphine and the lithiated diazo compound
"49# "Scheme 19# ð77JA5352\ 89PS"38#290Ł[ Under FVP conditions the product can be isolated[ A
similar procedure has been adopted by Regitz and co!workers to form phosphino analogue "40#
starting from the silver diazo compound "41# ð75TL0892Ł[ A few isolated examples of the related
l5s3!thiaalkynes have also been described ð74JA879\ 77AG"E#0423Ł^ the methylidynesulfur tri~uoride
derivatives RC2SF2 "RCF2\ SF2# were prepared by KOH!induced dehydro~uorination of
CF2CH1SF4 "or CF2CH1SF3# and SF2CH1SF4\ respectively[
Arsaalkynes have so far received much less attention[ Following the technique successfully

R R heat or hν
N2 + (Pri2N)2PCl N2 R P(NPri2)2
P(NPri2)2 –N2
X
(50) R = TMS, X = Li (49) R = TMS (48) R = TMS
(52) R = Ph2P(O), X = Ag (51) R = Ph2P(O)

Scheme 20
589 Nitriles and Other Heteroanalo`ues of Nitriles
developed for phosphaalkynes the kinetically stabilised l2s0!derivatives of the form RC2As\ where
RBut and 1\3\5!But2C5H1\ have been generated by ~uoride!ion induced elimination of hexa!
methyldisiloxane from the arsaalkene RC"OTMS#1AsTMS ð75AG"E#153\ 82AG"E#092Ł[

2[19[1[1 Methods for the Synthesis of AlkylidyneÐTransition Metal Compounds


Since the discovery of the _rst alkylidyne "carbyne# complexes of chromium\ molybdenum and
tungsten by Fischer et al[ in 0862 ð62AG"E#453Ł\ the chemistry of the carbonÐmetal triple bond has
developed rapidly\ and there is widespread current interest in their properties\ their potential in
organic synthesis\ their relationship to the better known alkylidene "carbene# complexes "see Chap!
ters 2[98 and 4[13#\ and particularly in their role as catalysts for metathesis and polymerisation of
alkenes and alkynes[ Although many of the known alkylidyne compounds are of Group 5 to 7
metals in low oxidation states "Fischer!type complexes#\ the corresponding complexes of {early|
transition metals and Group 5 metals in higher oxidation states "Schrock!type complexes# are also
well documented[ The chemistry of alkylidyne complexes "LnM2CR\ where MCr\ Mn\ Fe\ Nb\
Mo\ Ta\ W\ Re\ Os# has been the subject of several reviews and a multiauthor monograph published
in 0877 ðB!77MI 219!92Ł[ The literature up to 0875 ð76AOC"16#40Ł and from 0875 to 0889 ð80AOC"21#111Ł
has been surveyed in detail[ Carbyne complexes of ruthenium and osmium ð75AOC"14#010Ł\ high
oxidation!state molybdenum and tungsten complexes ð75ACR231Ł\ and the interplay between alkyl!
idyne and carborane ligands at metal centres ð82AOC"24#024Ł have also been reviewed[
The various synthetic strategies employed for the preparation of alkylidyneÐmetal complexes can
be divided into two broad categories] those that use non!alkylidyne precursors and those that
involve modi_cation of an existing alkylidyne compound[ These are summarised with representative
examples for illustration in the following sections\ in which the terms {alkylidyne| and {carbyne| are
used interchangeably for compounds containing a carbonÐmetal triple bond[ For detailed coverage
the reader is referred to the reviews cited above[

2[19[1[1[0 Synthesis from nonalkylidyne precursors


The conversion of existing groups into alkylidyne ligands is a common mode of entry to the series[
Alkylidene "carbene# complexes are useful starting materials as their chemistry is well established and
they undergo a variety of abstraction\ substitution and rearrangement reactions[ Lewis acid!
mediated abstraction of an alkoxy group has proved to be a versatile synthetic route[ When the
trans ligand is a strong p!acceptor\ e[g[ CO\ it is readily replaced by a halide from the Lewis acid to
a}ord a neutral trans!halocarbyne complex "Equation "5##^ a wide range of groups attached to the
carbyne carbon can be accommodated including alkyl\ aryl\ alkenyl\ alkynyl\ dialkylamino\ imino
and silyl[ The _rst ironÐcarbyne complex ð"CO#2"PPh2#Fe2CNPri1ŁBCl3 was prepared similarly[
The potential of dihalocarbene ligands to act as precursors of carbynes is demonstrated by the
conversion of the osmium complex Cl1"CO#"PPh2#1Os1CCl1 into Cl"CO#"PPh2#1Os2CCPh on
treatment with phenyllithium in a process which formally involves both elimination and substitution
of chlorine[ Rearrangement of carbene complexes can also lead to carbynes^ C : Cr migration of
the nucleophilic group "Nuhalogen\ SeR\ TePh\ SnPh2\ PbPh2# in "CO#4Cr1C"Nu#NR1 occurs
thermally with concomitant loss of CO a}ording trans!"Nu#"CO#3Cr2CNR1[
CO CO
CO R CO
OC M + 2 BX3 X M R + CO + MeOBX2 (6)
OC OMe OC
CO CO
M = Cr, Mo, W; X = Cl, Br, I

Abstraction with base of an a!hydrogen atom from a carbene ligand LnM1CHR has been
utilised for the preparation of various anionic carbyne complexes ðLnM2CRŁ−^ the conversion of
a neopentylidene into a neopentylidyne ligand involving abstraction of a proton by butyllithium is
illustrated by the formation of ð"CH1But#2Ta2CButŁLi"dmp#1 from "CH1But#2Ta1CHBut in the
presence of N\N?!dimethylpiperazine "dmp#[ Removal of two a!protons from "h4!C4Me4#
"CH1But#ReO using Ti"h4!C4H4#Cl2 a}ords the Re"VI# complex Cl1"h4!C4Me4#Re2CBut[ Depro!
tonation of h1!carbene complexes can also lead to carbynes[ Migration of an a!hydrogen promoted
by the addition of phosphines has also been observed^ trimethylphosphine with Cl"Cp#"CH1But#
Nitriles Bearin` a Heteroatom Other Than Nitro`en 580
Ta1CHBut a}ords Cl"Cp#"PMe2#1Ta2CBut and Cl"Cp#"CH1Ph#2Ta yields the corresponding
benzylidyne complex\ presumably via a carbene intermediate[ Alkenyl ligands in LnM0CR1CR1
are capable of rearrangement into carbynes LnM2CR2^ for example\ an H!shift in molybdenum\
the complex CpðP"OMe#2Ł2Mo0CH1CHBut leads to CpðP"OMe#2Ł2Mo2CCH1But[
The formal abstraction of oxide\ O1−\ from acyl or carbamoyl ligands is another direct route to
carbyne complexes[ The approach is illustrated by the formation of the alkylidyne"halo#tetra!
carbonyl complexes\ trans!X"CO#3M2CR where MCr\ Mo and W\ from the reaction of oxaloyl
halides with the anionic pentacarbonylmetal acyl complexes NMe3ð"CO#4MCORŁ[ The amino!
carbyne complex trans!Cl"CO#3W2CNEt1 is formed similarly by treatment of Lið"CO#4WCORŁ
with thionyl chloride[
b!Addition\ particularly of electrophiles\ to unsaturated ligands is another general approach
to carbynes "Scheme 10#[ Protonation of acetylide and alkylidene has proved useful for the
synthesis of high oxidation state molybdenumÐalkylidyne complexes^ for example\ Br"Cp#ðP
"OMe#2Ł1Mo1C1CHPh is converted into Br"Cp#ðP"OMe#2Ł1Mo2CCH1Ph in the presence of
HBF3\ and the manganese complex ðCp"CO#1Mn2CCPh1ŁBF3 is formed similarly from
Cp"CO#1Mn1C1CPh1[ b!Addition of hydride to alkylidene ligands is also possible[ Other ligands
which have been successfully converted into carbynes by b!addition of electrophiles include isocy!
anide\ carbonyl and thiocarbonyl "Scheme 10#[
E E
E+ E+
LnM R LnM • LnM R
R E
E
+ R E+
L nM N R LnM N
LnM • N
R

E+
LnM • X LnM X E
X = O, S
Scheme 21

By analogy with the generation of l4s2!phosphaalkynes from phosphiniodiazo compounds


"Scheme 19# the corresponding a!metallodiazoalkanes of the form LnM0CR1N1 are potential
precursors of metallocarbynes "LnM0C Ý RtLnM2CR# by thermal or photochemical extrusion of
nitrogen[
Metathesis of metalÐmetal triple bonds with alkynes achieves direct introduction of a new carbyne
ligand in a single step and has been used successfully for the preparation of complexes of tungsten
and molybdenum[ The process is promoted by the presence of bulky ligands such as tert!butoxide^
for example\ the reaction of hexakis"tert!butoxy#ditungsten "42# with symmetrically!substituted
alkynes is reported to a}ord the corresponding carbynes "43# quantitatively "Scheme 11#[ Nitriles
react similarly producing both carbyne and nitrido compounds[ Cycloalkenes yield bisalkylidyne
complexes of the form "ButO#2W2C"CH1#nC2W"OBut#2 ð78MM1458Ł[
2 (ButO)3W R
R R
(54)

(ButO)3W W(OBut)3
(53)
R N (ButO)3W R + (ButO)3W N
(54)
Scheme 22

2[19[1[1[1 Modi_cations of alkylidyneÐmetal complexes


Alkylidyne complexes can undergo a range of reactions while retaining intact the carbonÐmetal
triple bond\ and these have been widely exploited for the synthesis of new analogues[ This approach
can involve modi_cation of the metalÐligand framework\ modi_cation of the alkylidyne ligand or
oxidation:reduction of the metal centre[ Of these the former has been the most investigated[
581 Nitriles and Other Heteroanalo`ues of Nitriles
Ligand!substitution reactions have been used to prepare numerous derivatives[ Although the
donor molecule\ depending on its nucleophilicity\ can also attack the carbyne carbon\ displacement
of leaving groups such as CO can be accomplished[ The successful application of this approach is
illustrated in Equation "6# using trans!"halide#"CO#3M2R as the substrate and phosphines:
phosphites as the nucleophile\ a system which has been studied in particular detail from both a
mechanistic and synthetic viewpoint ð75JOM"206#076Ł^ disubstituted products are obtained when
nitrogen!donor ligands such as pyridine\ 1\1?!bipyridine and 0\09!phenanthroline are used[ Although
direct replacement of more than two carbonyl ligands by simple donor ligands does not occur
so readily the amino complexes are susceptible to substitution reactions^ the pyridine in
Cl"CO#1"py#1W2CPh can be replaced by PMe2 to a}ord Cl"CO#1"PMe2#1W2CPh which itself is
not readily accessible by direct substitution of CO by PMe2[ Treatment of the bromo analogue
Br"CO#1"py#1W2CPh with trimethylphosphite gives ClðP"OMe#2Ł3W2CPh and the tetra!
kisisocyanide analogue has also been made by the same approach ð89JOM"262#068Ł[ The weakly
coordinated BF3 ligand is labile and readily substituted by neutral or anionic nucleophiles including
PPh2\ AsPh2\ CN−\ SCN− and ButNC[ Carbyne complexes with a metalÐmetal\ e[`[\ "CO#4M!
n0W"2CPh#"CO#3\ have been prepared via substitution of the halide in the complex "44# by
carbonyl metallates[ Photochemically induced cis!to!trans isomerisation and photosubstitution reac!
tions of alkylidyne complexes have also been reported[
CO L
CO CO
X M R + L X M R + CO (7)
OC OC
CO CO
(55)
M = Cr, W; L = PPh3, P(OPh)3; X = Cl, Br, I; R = Ph, Me

Several novel alkylidyne complexes have been synthesised by modi_cation of the substituent
attached to the carbyne carbon[ This can involve manipulations within the group or its complete
replacement[ Examples in the former category include the addition of dimethylamine to ethynyl!
carbyne ditungsten compounds L"CO#3W2C0C2CPh yielding L"CO#3W2C0CH1C
"NMe1#Ph\ and desilylation of LðP"OMe#2Ł1Mo2CCH1TMS by NaF:aq[ MeCN to form LðP
"OMe#2Ł1Mo2CCH2[ Nucleophiles can displace leaving groups such as chloride from the carbyne^
for example\ treatment of trans!L"CO#1Mo2CCl with phenyllithium a}ords the benzylidyne deriva!
tive L"CO#1MoC2CPh[
Metal alkylidyne complexes undergo various oxidation and reduction reactions[ Thus\ bromine
oxidation of trans!Br"CO#3M2CR "MMo\ W^ RMe\ Ph\ CH1But# in the presence of 0\1!
dimethoxyethane "DME# a}ords the DME!stabilised complexes Br2"DME#M2CR and represents
conversion of a Fischer!type into a Schrock!type complex ð75JA437Ł[ Reductions of these products
"Zn:MeCN:PMe2# then provide access to carbonyl!free Fischer complexes of the form
Br"PMe2#3M2CR[

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
3.21
Isocyanides and their
Heteroanalogues (RZC)
IAN A. O’NEIL
University of Liverpool, UK
2[10[0 ISOCYANIDES 582
2[10[0[0 General Methods for Isocyanide Synthesis 582
2[10[0[0[0 The alkylation and alkynation of cyanides 583
2[10[0[0[1 The reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction# 584
2[10[0[0[2 a!Eliminations from formic acid derivatives of primary amines 584
2[10[0[0[3 Deprotonation and further elaboration of isocyanides 586
2[10[0[0[4 Use of or`anometallic isocyanides 587
2[10[0[0[5 Reduction of isocyanates\ isothiocyanates and isocyanide dihalides 587
2[10[0[0[6 Miscellanous methods 588
2[10[0[1 Aliphatic Isocyanide Synthesis 588
2[10[0[1[0 Saturated isocyanide synthesis 588
2[10[0[1[1 b and more remotely unsaturated isocyanides 699
2[10[0[1[2 Halo!substituted isocyanides 691
2[10[0[1[3 Aliphatic isocyanides bearin` an oxy`en!based functional `roup 692
2[10[0[1[4 Aliphatic isocyanides bearin` a sulfur!based functional `roup 697
2[10[0[1[5 Aliphatic isocyanides bearin` a Se! or Te!based functional `roup 698
2[10[0[1[6 Aliphatic isocyanides bearin` a nitro`en!based functional `roup 698
2[10[0[1[7 Aliphatic isocyanides bearin` other substituents 600
2[10[0[2 a\b!Unsaturated Isocyanides 601
2[10[0[2[0 General methods 601
2[10[0[2[1 Isocyanides bearin` an a\b!double bond 604
2[10[0[2[2 Isocyanides bearin` an a\b!aryl or hetaryl substituent 610
2[10[1 ISOCYANIDE ANALOGUES WITH A HETEROATOM OTHER THAN NITROGEN 615

2[10[0 ISOCYANIDES

2[10[0[0 General Methods for Isocyanide Synthesis


Caution] low molecular wei`ht isocyanides have a vile and penetratin` odor[ All preparative pro!
cedures should be performed in a well!ventilated fume hood[

The _rst isocyanide was prepared accidently by Lieke in 0748 when he treated allyl iodide with
silver cyanide in an attempt to prepare allyl cyanide ð0748LA"001#205Ł[ The product he obtained had
a {{penetrating and vile odor^|| indeed\ the odor was so unpleasant that many of his subsequent
experiments were performed outdoors[ Several years later\ Meyer reported the preparation of methyl
and ethyl isocyanide by the alkylation of silver cyanide ð0755JPR036Ł[ In 0756\ Hofmann described
the synthesis of isocyanides from primary amines by treating them with KOH and chloroform
ð0756LA"033#003Ł[ This synthesis subsequently became known as the Hofmann carbylamine reaction\
and was used for many years as a diagnostic test for primary amines[ The _rst truly general synthesis
of isocyanides\ the dehydration of N!monosubstituted formamides\ was developed in the 0859s[ The

582
583 Isocyanides and their Heteroanalo`ues
pioneering work of Ugi in this area led to the introduction of phosgene as the reagent of choice for
this transformation ð54AG"E#361Ł[ These developments allowed the general synthetic applications of
isocyanides to be explored[
In the nineteenth century\ the structure of isocyanides presented something of a dilemma[ Gautier
saw isocyanides as {{true homologs of hydrocyanic acid\|| since like the acid\ {{they have the greatest
deleterious e}ect on an organism[|| On the basis of his hydrolysis results\ Gautier proposed the _rst
structural formula for ethyl isocyanide "0# ð0758LA"035#008Ł[ He later went on to suggest structures
"1# and "2#[ Some years later\ Nef proposed structure "3# because of the large number of a!addition
reactions of the isocyanide carbon ð0781LA"169#156Ł[ In 0829\ a polar structure "4# was proposed by
Lindemann and Wiegrebe in analogy with the structure of carbon monoxide ð29CB0549Ł[

C
N + –
C2H5
Et N C Et N C Et N • R N C
(1) (2) (3) (4) (5)

Hammick found the partial dipole moment of the isocyano group to be opposite to that of the
cyano group ð29JCS0765Ł[ Shortly after\ Brockway ð25JA1405Ł and then Gordy and Pauling
ð31JA1841Ł\ presented electron di}raction data which supported a predominantly triple!bonded
structure[ The infrared data of isocyanides indicated an almost triple!bonded structure\ although
this did not rule out a double!bond structure entirely[ Finally\ two decades after the proposal of
Lindemann and Wiegrebe\ extensive microwave studies provided perhaps the most conclusive
evidence for structure "4# ð49MI 210!90Ł[ These results proved the linearity of the C0N0C bond
system beyond doubt[
The almost unique property of isocyanides in bearing a formally divalent carbon allows them to
engage in a range of unique reactions\ and they are endowed with a rich and versatile chemistry[
a!Addition reactions are particularly common\ and this has been exploited in the elegant work of
Passerini and Ugi ð80COS"3#0972Ł[ Ugi has shown that isocyanides participate in four!component
condensations "3CC# and this work has been extended to _ve! ð50CB1791\ 67M638Ł and even seven!
component condensations ð82AG"E#452Ł[ Schollkopf pioneered the use of a!metallated isocyanides
in synthesis ð66AG"E#228\ 68PAC0236Ł\ and the tosylmethyl isocyanide "TosMIC# reagent of van
Leusen has found widespread use in the synthetic community ð61SC170\ 63LA33\ 66TL3118\ 79S214\
74RTC49\ B!76MI 210!90\ 81S30\ 81TA176Ł[ Ito has contributed extensively to the synthetic chemistry of
isocyanides ð77JOC3047\ 77PAC472\ 89JA1326Ł[ Isocyanides have also found use in the synthesis of
novel polymers ð61CRV0909\ 81AG"E#0498\ 82JA8090Ł[ Finally\ the recent terrestrial synthesis of ethynyl
isocyanide ð80AG"E#0533Ł\ and its subsequent detection in interstellar space\ has implications for the
role of isocyanides in prebiotic chemistry ð60T2958Ł[
Until relatively recently\ very few naturally occurring isocyanides were known^ however\ there
are currently more than 199 isocyanide containing natural products[ This area has been reviewed
recently ð77MI 210!90\ 78PAC498\ 81ACR322Ł[ This review does not cover the extensive coordination
chemistry which isocyanides participate in ð79CCR082\ 72AOC"11#198\ 83AG"E#0204Ł\ but deals with the
synthetic organic methods for their preparation[ The chemistry of isocyanides was last reviewed
comprehensively by Ugi ðB!60MI 210!90Ł\ and several more general reviews of isocyanide chemistry
have been published ðB!72MI 210!90\ 74HOU"E4#500Ł[ Subsequent to this\ several updated and more
specialized reviews on isocyanides have been published[ These include the Ugi and Passerini
reactions ð71AG"E#709\ 80COS"3#0972Ł\ ~uorinated isocyanides ð83AG"E#0204Ł\ functionalized iso!
cyanide metal complexes ð82CRV0132Ł\ and multidentate isocyanides ð82AG"E#549Ł[
In this introductory section\ the various general methods for the synthesis of isocyanides are
discussed[ More speci_c examples are given in the appropriate section[
There are seven methods for isocyanide synthesis^ these are shown below]
"i# the alkylation and alkynation of cyanides\
"ii# the reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction#\
"iii# a!eliminations from formic acid derivatives of primary amines\
"iv# deprotonation and further elaboration of isocyanides\
"v# use of organometallic isocyanides\
"vi# reduction of isocyanates\ isothiocyanates and isocyanide dihalides\ and
"vii# miscellaneous methods[
2[10[0[0[0 The alkylation and alkynation of cyanides
The treatment of alkyl iodides with silver cyanide was the _rst preparative procedure for the
synthesis of isocyanides[ Treatment of ethyl iodide with silver cyanide yields the silver complex of
Isocyanides 584
ethyl isocyanide[ This is not routinely isolated\ but treated with potassium cyanide to liberate the
free isocyanide "Scheme 0# ð52OSC"3#327\ 68TL052Ł[ The mechanism of this reaction has been studied
in some detail ð74TL2270Ł[ In general\ the yields are modest and the use of expensive silver salts
limits the scale on which this reaction can be performed[

KCN
EtI + AgCN EtNC•AgI Et NC

Scheme 1

Songstad and co!workers have reported improved yields by the use of onium dicyanoargenates
in the preparation of di! and triphenyl isocyanides ð63ACS"A#144Ł[ Silver cyanide has also been used
in the synthesis of more highly functionalized isocyanides[ For example\ treatment of the glycosyl
bromide of 1!deoxy tri!O!benzyl!D!glucose gives the anomeric isocyanide in 79) as a single "a#
anomer "Equation "0## ð65TL2316Ł[

OBn OBn
O AgCN, 15 min O
BnO BnO (1)
BnO BnO
Br NC

Alkyl isocyanides can also be obtained by treating the alkylation products of silver hexa!
cyanoferrates or hexacyanocobaltates with the hydroxides ð16M60Ł\ or cyanides ð17JCS679Ł of the
group 0 metals\ or even simply by heating ð48AG275Ł[ When ethanolic solutions of hydrogen
hexacyanoferrate and HCN are heated to 019>C\ up to 39) of ethyl isocyanide is formed
ð50JOC2115Ł[

2[10[0[0[1 The reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction#
The carbylamine reaction\ _rst described by Hofmann\ was one of the earliest general methods
for isocyanide synthesis[ In its simplest form\ the reaction involves the treatment of a primary amine
and chloroform with an aqueous solution of KOH[ The reaction is thought to involve the generation
of dichlorocarbene\ its addition to the primary amine\ and a sequential b! and a!elimination
"Scheme 1#[

CHCl3, KOH – R
R + CCl2 proton transfer α-elimination
R NH2 N N R NC
[:CCl2] H2 β-elimination
Cl

Scheme 2

Several problems\ particularly with respect to yield were apparent in the earlier procedures[
Mainly due to the e}orts of Ugi ð61"AG"E#429Ł\ Weber ð61TL0526Ł and Gokel ð77OSC"5#121Ł who
introduced the use of phase transfer catalysts\ good yields of isocyanides can now be obtained using
this approach[ An interesting variation involves the use of aliphatic hydrazones as substrates[ On
treatment with chloroform:KOH under phase transfer conditions the isocyanoimines are isolated
ð65ACS"B#884Ł[ Mayer and co!workers have reported the conversion of N!sul_nylamines into iso!
cyanides by reaction with CHCl2 and solid KOH in the presence of a phase transfer catalyst ð66S164Ł[
Finally\ dichlorocarbene has been found to cleave carbodiimides to form isocyanides and isocyanide
dichlorides ð55TL078Ł[

2[10[0[0[2 a!Eliminations from formic acid derivatives of primary amines


Undoubtedly the most common preparative method for the synthesis of isocyanides involves the
dehydration of N!monosubstituted formamides "Equation "1##[
585 Isocyanides and their Heteroanalo`ues
O
–H2O
R R NC (2)
N
H

A large number of di}erent reagents are available to e}ect this transformation[ Currently\ the
most widely used dehydrating reagents used are based on phosgene[ Ugi was the _rst to describe
the use of phosgene in the presence of a tertiary amine ð50CB1703Ł[ A number of tertiary amines
have been used\ including trimethylamine\ triethylamine\ tri!n!butylamine\ N\N!dimethyl!
cyclohexylamine\ N\N!dimethylaniline\ pyridine\ quinoline\ and 0\3!diazabicycloð1[1[1Łoctane
"dabco# ð54AG"E#361Ł[ The base of choice does appear to be triethylamine\ owing to a combination
of cost and volatility[ The high toxicity and handling properties associated with phosgene have led
to the use of diphosgene and triphosgene in the preparation of isocyanides[ Diphosgene "trichloro!
methyl chloroformate# ð69OS"49#084Ł is a stable liquid which has been reported to give higher yields
than phosgene in the dehydration of formamides to isocyanides ð66AG"E#148Ł[ More recently\
triphosgene "bis"trichloromethyl#carbonate# in the presence of a tertiary amine base has been used
to e}ect the dehydration ð76AG"E#783Ł[ Triphosgene has the advantage that it is a crystalline material
of low volatility\ which can be readily weighed out under anhydrous conditions[
The use of POCl2 in the presence of a tertiary amine has also found widespread use in the
dehydration of formamides to isocyanides[ The bases that have been used include pyridine
ð62OSC"4#299\ 78TL0704\ 89T5240Ł\ triethylamine ð77OSC"5#876\ 77OSC"5#519Ł\ 1\5!lutidine ð73TL4964\
77OSC"5#121Ł\ diisopropylamine ð74S399\ 75SC754\ 77LA654\ 89CB524Ł\ and potassium t!butoxide
ð75ZN"B#021Ł[
Several other phosphorus!based dehydrating systems have been reported[ For example\ Appel et
al[ have shown that a combination of PPh2:CCl3:NEt2 will convert formamides into isocyanides
ð60AG"E#021\ 63JOC0128\ 65LA072\ 77TL0342Ł[ This system has also been used in the preparation of N!
isocyanoiminotriphenylphosphane ð79AG"E#379Ł[ Recently\ this dehydrating system has been modi!
_ed by Ichikawa who used CBr3:PPh2:Pri1NEt ð81JCS"P0#1024Ł[ Ugi and co!workers have reported
Mitsunobu!type conditions "PPh2:dead "diethyl azodicarboxylate## for the dehydration reaction
ð61AG"E#818Ł[ Triphenylphosphine dibromide has been utilized in the dehydration of formamides
to isocyanides ð57LA"607#13Ł\ as have phosphorus trichloride\ phosphorus tribromide\ phosphorus
pentachloride\ and phosphorus pentoxide ð59CB128Ł[
p!Toluenesulfonyl chloride or benzenesulfonyl chloride in conjunction with a base is still a widely
used method for the dehydration of formamides[ A variety of bases have been employed\ including
pyridine ð47JOC0110\ 75CJC1364\ 78S607\ 81JOC1907Ł and quinoline ð52JCS3179\ 62OSC"4#662Ł[ A par!
ticularly interesting use of the TsCl:pyridine dehydrating system was reported by Ugi and co!
workers who described the preparation of a variety of macromolecular isocyanides from polymer!
bound formamides ð71AG"E#263Ł[ The use of methanesulfonyl chloride:pyridine has also been dis!
closed ð68JA0597\ 68TL1634Ł[
The application of Vilsmeier!type dehydrating systems is also well documented in the synthesis
of isocyanides from formamides[ The classical SOCl1:DMF mixture\ generating chloro!
dimethylformiminium chloride at low temperature\ followed by addition of the formamide and then
Na1CO2 was used by Walborsky ð59CB128\ 61JOC076\ 66LA39\ 77OSC"5#640Ł[ A more recent variation
on this method utilizes 1!chloro!2!ethylbenzoxazolium tetra~uoroborate in the presence of tri!
ethylamine ð66CL586Ł[
A particularly mild dehydrating reagent oxomethylenebis!"2H¦!imidazolium# bis"methane!
sulfonate# was recently described by Ugi et al[ ð71JCR"S#68Ł[ This reagent\ which is prepared in situ by
the addition of methanesulfonic acid to oxomethylenebis"imidazole#\ is reported to be particularly ef!
fective in the preparation of homochiral isocyanoesters\ which are prone to racemization "Equation "2##[

O +
CO2Me CO2Me NH
+ +
+ N N + 2 Ms– + CO2
HN NH
Ph NHCHO Ph NC N
H (3)
2 Ms–

Very recently\ Baldwin et al[ have reported the use of tri~uoromethanesulfonic anhydride in
conjunction with diisopropylethylamine at −67>C as a highly e}ective method for the dehydration
of functionalized formamides to isocyanides ð89SL592Ł[ Several other examples of this dehydrating
system have subsequently been reported "Equation "3## ð89TL1936\ 80SL604\ 81JCS"P0#1024\ 82TL468\
83CC74Ł[
Isocyanides 586
H H
O (CF3SO2)2O, Pri2NH O
CH2Cl2, –78 °C
(4)
O 86% O
STol STol
NHCHO NC

In addition to the reagents cited above\ a number of less commonly encountered dehydrating
reagents have been employed[ For example\ cyanuric chloride in the presence of K1CO2 has been
used on several occasions ð50AG108\ 60OS"40#20\ 66AG"E#151Ł[ Other reagents in this category include
BF2:HgO ð50JOC1191Ł\ and di!1!pyridyl sul_te:NEt2 ð75TL0814Ł[

2[10[0[0[3 Deprotonation and further elaboration of isocyanides


Isocyanides that do not bear an a!hydrogen atom add Grignard reagents and organolithium
compounds\ generating metallated aldimines intermediates ð58JA6667\ 60TL3854\ 63JOC500Ł[ The lith!
ium derivatives have then been used as acyl anion equivalents ð69JA5564\ 63JOC599\ 63JOC593\ 67JOC623Ł[
In 0857\ Schollkopf was the _rst to report that isocyanides bearing an a!hydrogen atom can be
metallated at the a!position ð57AG"E#794Ł[ Metallation can be accomplished with a variety of bases\
including n!butyllithium\ potassium t!butoxide\ sodium methoxide\ 0\4!diazabicycloð4[3[9Łundec!4!
ene "dbu#\ NEt2\ and NaH ð63AG"E#678\ 66AG"E#228Ł[ The choice of base depends on the substituents
R0 and R1\ with acidifying substituents allowing the use of weaker bases in the metallation step
"Equation "4##[ The a!metallated isocyanides are not isolated but subjected to further reaction in
the same vessel[ A wide range of electrophiles has been used and these are discussed in more detail
in the appropriate section[

R1 R1
NC + base– M+ CN – M+ + base-H (5)
R2 R2

A particularly useful example involves the condensation of a!metallated isocyanides with com!
pounds containing polar multiple bonds[ The initial addition adduct to aldehydes and ketones
contains an electrophilic isocyanide carbon atom which can then be attacked intramolecularly by
the alkoxide[ The resulting heterocycle anion is in equilibrium with the precursor\ the equilibrium
lying on the side of noncyclized anion[ By careful choice of proton source\ either the heterocycle or
the substituted isocyanide can be obtained "Scheme 2#[ Thus\ certain heterocyclic ring systems can
be used as precursors to substituted isocyanides by a deprotonation:reprotonation protocol[
M
CN O CN O– M+
R1 – M+ + R1 R4 N O
R2 R3 R4 R2 R3 R1 R4
R2 R3
AcOH
MeOH

CN OH
R1 R4 N O
R2 R3
R1 R4
R2 R3

Scheme 3

a!Metallated isocyanides have also found extensive use as a!amino anion equivalents ð63AG"E#678\
66AG"E#228\ 68PAC0236Ł[
There are however\ limitations to this approach^ notably sec!alkyl isocyanides without activating
substituents cannot be metallated[ Cyclopropyl and cyclobutyl isocyanides are exceptions to this
rule[ The use of a!metallated isocyanides in synthesis has been reviewed several times ð63AG"E#678\
66AG"E#228\ B!68MI 210!90\ 68PAC0236Ł[
587 Isocyanides and their Heteroanalo`ues
2[10[0[0[4 Use of organometallic isocyanides
The use of TMS!CN in the presence of a catalytic Lewis acid promotes the ring opening of
oxiranes to give either the b!"trimethylsilyl#oxy cyanide or isocyanide[ In general\ harder Lewis
acids "those containing Al# favor the formation of cyanides\ while softer ones "containing zinc\ tin\
gallium and palladium# favour isocyanide formation ð76JOC0902\ 89JOC1905Ł[ This behaviour is a
consequence of the well!known equilibrium between TMS!CN and its isocyanide ð65IC490Ł[
Gassman and co!workers have carried out extensive studies on the ring opening of epoxides with
TMS!CN and ZnI1 to give b!hydroxy isocyanides ð71JA4738\ 72TL544\ 73TL2148Ł[ This methodology
has also been applied by Gassman to the ring opening of oxetanes to yield g!hydroxyisocyanides
ð74TL3860Ł[
Tertiary alkyl halides can also be utilized in transformations of this type[ For example\ Reetz et
al[ have shown that 0!chloroadamantane is converted into 0!isocyanoadamantane by treatment
with TMS!CN and TiCl3 "Equation "5## ð70JOC4334\ 72T850Ł[

TMS-CN, TiCl4
(6)
Cl CH2Cl2, 0 °C NC
78%

A particularly interesting preparation of isocyanides involves the treatment of alkenes "from


which tertiary carbocations can be generated# with HCN in the presence of cuprous halides at 099>C
ð55JOC3069Ł[ The initial product is the cuprous halideÐisocyanide product\ which on treatment with
NaCN\ yields the free isocyanide[

2[10[0[0[5 Reduction of isocyanates\ isothiocyanates and isocyanide dihalides


The reduction of isocyanates to isocyanides has been e}ected by a number of di}erent reagents[
The earliest reagents used were phosphines and phosphites[ However\ they su}er from the drawback
of requiring high temperature ð51JOC2540\ 55JOC2362Ł[ Mukaiyama|s reagent\ 1!phenyl!2!methyl!
0\2\1!oxazaphospholidine\ has proved an e}ective reducing agent for both isocyanates and iso!
thiocyanates at room temperature\ but it is di.cult to prepare and store ð54BCJ747Ł[
Baldwin and co!workers reported two silicon!based reagents\ namely\ diphenyl!t!butylsilyllithium
and trichlorosilane:triethylamine for the e.cient conversion of isocyanates into isocyanides "Scheme
3# ð71CC831Ł[ The latter reagent was preferred owing to its less basic nature and cost and ease
of product puri_cation[ A subsequent NMR study on the mechanistic pathway of diphenyl!t!
butylsilyllithium deoxygenation showed the presence of intermediates "5# and "6# "Scheme 3#
ð72T1878Ł[

Cl3SiH, NEt3
R NCO R NC

Ph2ButSiLi
R NCO R NC + Ph2ButSiO– Li+

O– Li+ OSiButPh2
R R
N SiButPh2 N Li
(6) (7)

Scheme 4

Collman|s reagent\ Na1Fe"CO#3\ has been shown to reduce both isocyanates and isothiocyanates
to the iron carbonyl complex of the isocyanide ð78OM0427Ł[
The reduction of isothiocyanates to isocyanides is more easily achieved than the corresponding
isocyanate reductions\ and can be carried out using a range of di}erent reagents[ These include
triethylphosphine ð0769CB655Ł\ copper ð0762CB109Ł\ triphenyltin hydride ð52JOC0696Ł\ tri!n!butyltin
Isocyanides 588
hydride ð75TL044Ł\ phenylacetyl chloroformamidine ð55CB2052Ł\ and photolysis ð53AG"E#530Ł[ The
use of SmI1 for the reduction of isothiocyanates to isocyanides has also been reported ð81CL0032Ł[
Isocyanide dihalides ð58AG"E#19Ł have proved to be valuable precursors to isocyanides[ They can
be prepared by the addition of the halogen "chlorine and bromine# to the parent isocyanide[ They
are frequently used as a {{protecting group\|| masking the reactivity of the isocyanide[ Isocyanide
dichlorides are the most commonly used dihalides[ Several methods exist for their conversion into
the parent isocyanide[ Aliphatic isocyanide dichlorides are reduced by iodide ion[ The intermediate
isocyanide diiodide is unstable and dissociates spontaneously into the isocyanide and iodine
ð53CA5684Ł[ Triethylphosphine also e}ects the reduction of isocyanide dichlorides ð0769CB655\
51AG737\ 53CA5684Ł as does LiAlH3 ð66JA6256Ł[
The electrochemical reduction of isocyanide dichlorides to give isocyanides has also been disclosed
ð81TL3668Ł[
The reaction of isocyanide dichlorides with certain transition metal complexes yields the cor!
responding isocyanide metal complex ð64AG"E#258\ 67JA3201\ 67TL2916\ 68AG"E#64Ł[ Magnesium metal
was used as the reducing agent by Lentz in the preparation of tri~uoromethyl isocyanide
ð73JFC"13#412Ł[

2[10[0[0[6 Miscellanous methods


Ho~e and Lange have reported a novel {{reagent!free|| isocyanide synthesis[ The starting materials
are 4!alkyl"aryl#aminotetrazoles\ which are prepared from 4!aminotetrazole or monosubstituted
thioureas[ Oxidation with sodium hypobromite or lead tetraacetate leads to liberation of the
isocyanide and nitrogen "Equation "6## ð65AG"E#002Ł[

N N
NaOBr, 0 °C
Ph N Ph NC + 2 N2 + NaBr + H2O (7)
N N
H H2O, CH2Cl2
H

Photochemical methods for the synthesis of isocyanides are rare but they are known[ Boyer
and co!workers have described the photodissociation of formimidoyl cyanides to produce the
corresponding N!alkylisocyanides ð64JCS"P0#0632Ł[ The irradiation of N!n!propyl!0\7!di!t!butyl!4\5!
di!oxo!1\2!benzobicycloocta!1\6!diene gives n!propyl isocyanide in good yields "Equation "7##
ð62CC588Ł[

N Pr
But
O But

PrNC + + CO (8)
But
But

The photolysis of dihydropyrazine derivatives in the presence of rose bengal and oxygen has been
reported to give isocyanides ð77TL0016\ 81JOC1138Ł[

2[10[0[1 Aliphatic Isocyanide Synthesis

2[10[0[1[0 Saturated isocyanide synthesis


The most common method for the synthesis of saturated isocyanide synthesis involves the
dehydration of the corresponding N!formamide[ The phosgene!based reagents are the most e}ective\
and this area has been covered in a number of review articles ð54AG"E#361\ B!60MI 210!90\ 66AG"E#148\
76AG"E#783Ł[ The combination of SOCl1:DMF in the presence of Na1CO2 or K1CO2 has also been
reported to be particularly e}ective in saturated aliphatic isocyanide synthesis ð61JOC076\ 77OS"5#519Ł[
Luning and co!workers have reported the use of POCl2:Pri1NH in the synthesis of the highly
hindered 1\1\4\4!tetramethyl cyclopentylisocyanide "Equation "8## ð74S399\ 80CB1444Ł[
699 Isocyanides and their Heteroanalo`ues
NHCHO NC
POCl3, HNPri2
(9)
80–85%

The phase transfer modi_cation of the carbylamine reaction has also been widely used in saturated
aliphatic isocyanide preparation ð77OSC"5#121Ł as have the methods of Ho~e and Lange ð65AG"E#002Ł
and Appel ð60AG"E#021Ł[
In their approach to the natural product 8!isocyanopupukeanane\ a fully saturated isocyanide\
Yamamoto and co!workers used TsCl:pyridine in the dehydration of the N!formamide to the
isocyanide "Equation "09## ð68JA0598Ł[

NHCHO NC

TsCl (1.5 equiv.)


(10)
pyridine, 1.5 h
89%

Schollkopf and co!workers have reported the synthesis of 0\1!ethylene diisocyanide\ 0\2!propylene
diisocyanide\ and 0\3!butylene diisocyanide ð79LA17\ 70LA092Ł[ All three diisocyanides were prepared
by the dehydration of the precursor diformamides with phosgene[ The simultaneous preparation of
three isocyano groups by dehydration of the precursor triformamide using diphosgene gives novel
tridentate isocyano ligands "Equation "00## ð80JOM"309#C8\ 80JOM"392#C04\ 81AG"E#0101\ 82AG"E#549Ł[

O
Cl3C
R O Cl R
NHCHO NC (11)
3 3

R = H, Me

The synthesis of both cis! and trans!1\1\3\3!tetramethylcyclobutane!0\2!diisocyanide has been


reported ð51CJC752Ł as has cis\ cis!0\2\4!cyclohexanetriisocyanide ð79IC2742\ 82AG"E#549Ł[
An unusual preparation of alkyl isocyanides\ reported by Bartoli et al[\ involves the sequential
reaction of iron"II# tetraphenylporphyrin "TPP# with dichlorocarbene and two equivalents of a
primary amine[ The initial product is the isocyanide iron"II# TPP complex[ Heating to 069>C under
reduced pressure then allows isolation of the free isocyanide ð67TL2916Ł[
Detailed experimental procedures for the preparation of the following aliphatic isocyanides
have been published] methyl isocyanide ð62OSC"4#662Ł\ ethyl isocyanide ð52OS"4#327Ł\ t!butyl iso!
cyanide ð77OS"5#121Ł\ 0\0\2\2!tetramethylbutyl isocyanide ð77OS"5#640Ł 0\3!diisocyanocyclohexane
ð54AG"E#361Ł\ and cyclohexyl isocyanide ð62OSC"4#299Ł[

2[10[0[1[1 b and more remotely unsaturated isocyanides


The most widely used approach to this class of isocyanide is very similar to the saturated
analogues\ namely the dehydration of the parent N!formamide[ A range of unsaturated isocyanides
have been prepared by Ruchardt and co!workers\ who used POCl2:Pri1NH to dehydrate the pre!
cursor formamides[ Examples include isocyanides with both allylic and propargylic substituents
"Table 0# ð81CB414Ł[
A number of naturally occurring compounds contain remote unsaturation[ For example\ the
natural product theonellin isocyanide was prepared by dehydration of the N!formamide with
tri~uoromethanesulfonic anhydride:Pri1NEt at −67>C in high yield "Equation "01## ð80SL604Ł[

OHCHN CN
Tf2O, EtNPri2
(12)
–78 °C
89%
Isocyanides 690

Table 0 Examples of allylic and propargylic isocyanates[

Isocyanide Yield
(%)

77
NC

NC 67
NC
48

NC
69

83
NC

NC
39

NC

67

O
POCl3, Pri2NH, CH2Cl2
R R NC
N
H

In the synthesis of the natural product hapalindole J\ Natsume et al[ chose to use the POCl2:
pyridine dehydrating protocol to convert the precursor formamide into the isocyanide ð78TL0704Ł[
In their synthesis of the natural product 7\04!diisocyano!00"19#!amphilectene ð78JOC0372Ł\ Piers et
al[ utilized the PPh2:CCl3:NEt2 methodology of Appel for the simultaneous dehydration of two N!
formamido groups "Equation "02##[

OHCHN CN
H PPh3, CCl4, NEt3 H
(13)
H H CH2Cl2, 55 °C, 6.5 h H H

OHCHN CN

Corey et al[ have reported the total synthesis of 6\19!diisocyanoadociane[ The introduction of
both isocyano groups was achieved by treatment of the bistri~uoroacetate "7# with TMS!CN in the
presence of TiCl3\ giving a mixture of four diastereoisomeric products "Equation "03## ð76JA176Ł[

CF3OCO CN
H H

H H TMS-CN (15 equiv.) H H


CF3OCO CN (14)
TiCl4 (20 equiv.)
CH2Cl2, 2.5 h
70%

(8)

Many naturally occurring isocyanides contain remote unsaturation[ Recent examples of these
can be found in the references ð81TL0482\ 81TL5712Ł[
691 Isocyanides and their Heteroanalo`ues
Schollkopf and co!workers have prepared E!3!phenyl!2!butenyl!isocyanide by treatment of cin!
namyl bromide with the lithio anion of methyl isocyanide ð66LA39Ł[ The preparation of b!ionyl
isocyanide and all trans!retinyl isocyanide using the dehydration of the parent formamides with
SOCl1:DMF:Na1CO2 has also been reported "Equation "04## ð62HCA0560Ł[

i, SOCl2/DMF
NHCHO –40 °C NC
(15)
ii, Na2CO3
88%

Makosza et al[ have shown that nitroarenes react with phenylthiomethyl isocyanide in the presence
of KOBut resulting in the introduction of an isocyanomethyl substituent into positions ortho or
para to the nitro group ð82S0104Ł[ Both chloro and cyano substituents were also present on the aryl
ring "Equation "05##[ Further examples of the synthesis of this class of compounds has been reported
ð89H"20#0744Ł[
NO2 NO2
i, ButOK/DMF
0 °C, 15–30 min
+ PhS NC (16)
NC
ii, CO2, AcOEt
47–72%
Z Z
Z = H, Cl, NO2, CN

The electrochemical reduction of a!mono and dialkyl derivatives of p!toluenesulfonyl methyl


isocyanides gives the parent primary and secondary alkyl and aralkyl isocyanides ð80TL4428Ł[
A detailed experimental procedure for the preparation of benzyl isocyanide has been reported
ð89OSC"6#16Ł[ Van Leusen has described the preparation of b\g!unsaturated isocyanides by the
condensation of TosMIC with hindered ketones\ followed by dehydration of the product formamide
with POCl2:NEt2 ð80RTC391Ł[
An unusual family of polyisocyanide compounds has been prepared by Mann and co!workers
ð89JOC3849Ł[ Treatment of diphenyl methyl isocyanide with BunLi followed by the addition of 9[4
equiv[ of 0\2!dibromopropane yielded 0\0\2\2!tetraphenyl!0\2!diisocyanopropane[ By varying the
amount of 0\2!dibromopropane\ a range of novel polyisocyanides was prepared "Scheme 4#[
CN
– Li+
Ph i, BunLi CN Ph CN Ph
Br
NC Ph Ph
Ph ii, Br Br Ph Ph NC

i, BunLi
i, BunLi
CN
Br CN
ii, Ph Br
Ph ii, Ph
Ph

Ph Ph CN Ph
Ph Ph Ph Ph
CN Ph Ph CN Ph CN Ph NC
NC NC

Scheme 5

2[10[0[1[2 Halo!substituted isocyanides


The synthesis of a!halogenated isocyanide chromium pentacarbonyl complexes has been reported
ð77CB350Ł^ examples of F\ Cl and Br substituents were described[
The preparation of a number of simple ~uorinated isocyanides has been disclosed[ Treatment of
di~uoromethanimines with PPh2 yielded the poly~uorinated isocyanides shown in Equation "06#
Isocyanides 692
ð83AG"E#0204Ł[ The dehydration protocol of Ugi has also been applied to the preparation of 1\1\1!
tri~uoroethyl isocyanide and 1!~uoroethyl isocyanide ð81ICA62Ł[
R F
PPh3
N R NC (17)
F
R = CF3, Et, C3F7

Lentz has reported the synthesis of tri~uoromethylisocyanide by the reduction of the tri~uoro!
methylisocyanide dibromide with magnesium metal ð73JFC"13#412\ 77CB0334\ 78AG"E#0145Ł[ The use of
zinc in DMF has also been reported to e}ect this transformation ð83AG"E#0204Ł[ The preparation
of trichloromethyl isocyanide as its chromium pentacarbonyl complex was described by Degel
ð68AG"E#64Ł[ The intriguing sulfur penta~uoride isocyanide has recently been prepared by a similar
reductive process "Equation "07## ð78AG"E#0145Ł[
Br Mg, THF
N F5S NC (18)
F5S Br

Hagedorn et al[ noted that N!1!hydroxy!1!phenylethyl formamide gave 1!chloro!1!phenylethyl


isocyanide on treatment with POCl2:pyridine in modest yield ð50AG15Ł[ The synthesis of 2\2!
diphenyl!2!isocyano!0!bromopropane has been described ð89JOC3849Ł[
Baldwin and Yamaguchi have reported the preparation of b!iodo isocyanides by the initial trans!
addition of iodine isocyanate across alkenes\ to give the intermediate b!iodo isocyanate[ Reduction
of the isocyanate with trichlorosilane:NEt2 then gives the b!iodo isocyanide in good yield ð78TL2224Ł^
examples of both cyclic and acyclic alkenes were given "Scheme 5#[
The synthesis of a number of remotely halogenated isocyanides has been reported ð50AG15\
74HOU"E4#500Ł[

I I
AgOCN Cl3SiH

I2 HNPri2, CH2Cl2
NCO NC

Scheme 6

2[10[0[1[3 Aliphatic isocyanides bearing an oxygen!based functional group


A number of di}erent approaches have been utilized in the synthesis of this class of compounds[
Examples of oxygen bound directly to the isocyano nitrogen are known[ Thus\ ~ash vacuum
pyrolysis of 2!methyl!4!oxo!3!phenyloximino!3\4!dihydro!4!oxazole gives phenoxy isocyanide
which was isolated at low temperature ð70JOC0935Ł[ More recently the matrix isolation of isofulminic
acid "CN0OH# has been described ð77AG"E#827Ł[ The preparation of a!oxygenated isocyanides has
recently been disclosed by Yoshida et al[ ð83CC438Ł[ Thus\ anodic oxidation of a!oxygenated
organotin compounds in the presence of Bu3NBF3 and TMS!CN gives good yields of the a!
oxygenated isocyanides "Equation "08##[

OMe Bu4NBF4, THF OMe


(19)
R SnBu3 TMS-CN, e– R NC

a!Acyloxy isocyanides were _rst reported by Ho~e\ who treated benzoyl bromide with silver
cyanide in acetone[ The free isocyanide is liberated by treatment with KCN[ In most cases the
products could be isolated\ although they became {{dark and resinous at room temperature and in
the presence of air|| "Equation "19## ð63AG"E#565\ 66AG"E#616Ł[

O O Br O i, AgCN NC O
+ (20)
Ph Br O Ph ii, KCN O Ph
693 Isocyanides and their Heteroanalo`ues
Acyl isocyanides were synthesized only relatively recently[ Ho~e and Lange have reported that
treatment of acyl iodides with silver cyanide yielded the corresponding acyl isocyanides ð66AG"E#151Ł[
These are highly unstable compounds that are best stored and used in solution "Equation "10##[

O AgCN O
(21)
R I R NC

The a!epoxy isocyano group is a highly unusual functional group[ There are only three natural
products\ isonitrin C "trichoviridin# ð65CPB721\ 79T404\ 71ABC0792Ł\ aerocyanidin ð77JAN343Ł and
cavernoisonitrile ð81TL5712Ł\ known to contain this moiety[ Schollkopf et al[ have reported that
ester!substituted a!epoxy isocyanides can be prepared by the conjugate addition of basic peroxide
to a!isocyano acrylates "Equation "11## ð73LA597Ł[

R1 NC O
30% H2O2
R1 NC (22)
NaOH, MeOH CO2Me
R2 CO2Me R2

Recently\ Baldwin and O|Neil have developed a more general route to this class of compounds
ð89TL1936Ł[ Epoxidation of a\b!unsaturated formamides with dimethyldioxirane at −67>C\ followed
by in situ dehydration of the intermediate epoxy formamide with tri~uoromethanesulfonic an!
hydride:Hunig|s base gave the epoxy isocyanides in modest yield "Scheme 6#[
H
NHCHO O O OHCN CN
O (CF3SO2)2O
O

CH2Cl2, –40 °C EtNPri2, –78 °C

Scheme 7

The pioneering work of Schollkopf et al[ has led to methodology for the preparation of a wide
range of isocyanides bearing oxygen functionality[ In 0857\ these authors reported that treatment
of simple alkyl isocyanides with BunLi at −67>C generated the corresponding a!lithio isocyanide[
Addition of an aldehyde or ketone then gave either the alkene "on warming# or with protonation
the oxazoline[ The source of proton was subsequently found to be important[ Addition of glacial
acetic acid immediately after addition of the carbonyl compound "kinetic protonation# leads to the
b!hydroxy isocyanide[ Protonation in alkaline medium is reversible and gives the oxazoline as the
thermodynamic product "Scheme 7# ð69AG"E#347\ 60AG"E#380Ł[ The crystal structure of an a!lithiated!
isocyanide has been reported ð81AG"E#68Ł[
The a!lithio isocyanide can be alkylated with alkyl bromides or iodides ð66LA39Ł[ The reaction
of a!lithio isocyanides with epoxides and oxetanes\ followed by protonation\ yields the b! and g!
hydroxy isocyanides\ respectively\ with attack occurring at the least hindered carbon "Scheme 8#
ð65LA1094Ł[
With an acidifying substituent on the a!position\ deprotonation can be achieved with weaker
bases ð63AG"E#678Ł[ a!Isocyanoalkanoic esters can be metallated with KOBut in THF[ With ethyl a!
isocyanopropionate\ alkylation leads to 1!isocyano!1!methylalkanoic esters[ From ethylisocyano!
acetate the major product is the dialkylated compound along with starting material ð60AG"E#220\
63AG"E#678\ 74SC156Ł[ When 0\2!dibromopropane is the alkylating agent\ ethyl isocyanoacetate gives
0!isocyanocyclopropanecarboxylate[ The use of other bis!electrophiles has also been described
ð60AG"E#220\ 64CB0479Ł[ The preparation of substituted 0!isocyanocyclopropane carboxylates has
also been achieved by the addition of dimethylsulfoxonium methylide to b!substituted ethyl a!
isocyanoacrylates "Scheme 09# ð62LA500Ł[ A detailed procedure for the preparation of ethyl
isocyanoacetate has been described ð77OSC"5#519Ł[ t!Butyl isocyanoacetate has also been prepared
and utilized in similar transformations ð75AG"E#643Ł[ The preparation of "¦#!7!phenylmenthyl
isocyanoacetate has been described ð81TA28Ł[
Ethyl 1!isocyano!1!lithiopropionate adds to epoxides to give\ after protonation with glacial acetic
acid\ g!isocyanoalcohols[ If no proton source is added and the solution allowed to warm to room
temperature\ cyclization of the alkoxide on to the ester occurs to give the unusual isocyano lactone
"Scheme 00# ð62AG"E#212Ł[
Isocyanides 694
O R3
Li+ R2 O– Li+
BunLi – R2 R3
R1 NC THF, –78 °C R1 NC –78 °C
R1 NC

R3 R3
R2 O– Li+ O R1 R2
–78 °C to RT
R2 + LiOCN
– Li+
N R3
R1 NC R1

AcOH MeOH
–70 °C

R3 R3
R2 OH O
R2

R1 NC R1 N

Scheme 8

O
R5
i, R3
R6 NC OH
–30 °C R1 R5
ii, AcOH R2 R4

R1 R1 R3
BunLi
NC R2 – Li+
THF, –78 °C O
R2 CN i, NC
OH
ii, AcOH R1

Scheme 9

O
+ O R1 R2
R1 NC Me2S –
CH2
Me2S + NC R1 NC

R2 CO2Et R1 CO2Et
CO2Et

Scheme 10

O NC NC
AcOH
CN – Li+
EtO2C
–70 °C to 0 °C EtO2C O– Li+ EtO2C OH

CN
O

Scheme 11
695 Isocyanides and their Heteroanalo`ues
The reaction of potassium ethyl isocyanoacetate with ethyl chloroformate gives potassium diethyl
isocyanomalonate\ which can be alkylated in situ by alkyl halides to give the diethyl a!alkyl!a!
isocyanomalonates ð64LA422Ł[
The conjugate addition of the sodium anion of both ethyl isocyanoacetate and ethyl isocyano!
propionate to both a\b!unsaturated esters and nitriles has been described by Schollkopf and co!
workers ð62LA0460\ 62CB2271Ł[ The reaction proceeds in both cases with a catalytic amount of sodium
ethoxide "Scheme 01#[
R2 R3
NaOEt i, NC R3
CN CN R1
NC
CO2Et EtO2C – Na+ EtO2C NC
R1 EtOH R1 ii, AcOH
R2
Scheme 12

The conjugate addition of carbanions to 1!isocyanoacrylic esters provides a useful route for the
preparation of a range of oxygenated isocyanides ð66LA0063Ł[ The carbanions used include Grignard
reagents and diethyl sodium malonate "Scheme 02#[
CO2Et
i,
i, R3MgHal CO2Et R1 R2
R1 NC Et2O, 0 °C R1 NC
NaOEt, EtOH EtO2C NC
R2
R3 CO2Et ii, AcOH R2 CO2Et ii, AcOH
EtO2C CO2Et

Scheme 13

It has been reported that naturally occurring isocyanide acids can be converted into the cor!
responding esters by reaction with alcohols:phenols in the presence of dicyclohexylcarbodiimide
"dcc# and a catalytic amount of 3!dimethylaminopyridine "dmap# ð89JCS"P0#1004Ł[
Van Leusen and co!workers have reported an unusual approach to the preparation of steroidal
isocyanides\ whereby the reduction of the parent a\b!unsaturated isocyanide with NaBH3 gives the
saturated isocyanide in excellent yield ð80S420Ł[
N!Alkylisocyanoacetamides can be readily prepared by the treatment of ethyl isocyanoacetate
with primary amines "Equation "12## ð78S530Ł[

R1NH2
NHR1 (23)
CN CO2Et CN
EtOH
O

The preparation of 1!aryl!1!isocyanoacetamides has also been reported\ by an initial Ugi con!
densation between aromatic aldehydes\ isocyanides and ammonium formate\ followed by dehy!
dration of the N!formamide with POCl2:NEt2 ð89LA824Ł[ This work has been extended to the
preparation of N!substituted 0!isocyano!0!cycloalkanecarboxamides ð80LA732Ł[ The condensation
of chiral amines with methyl isocyanoacetate has also been reported ð74ABC0650Ł[
The synthesis of dialkyl!0!isocyanomethylphosphonates has been reported by Schollkopf and co!
workers ð63LA33\ 70LA698\ 70LA0582\ 73LA599\ 73S0922\ 82LA316Ł[ Schollkopf and co!workers have shown
that the lithium anion of diethyl isocyanomethylphosphonate opens epoxides in the presence of
BF2OEt1 to give diethyl 2!hydroxy!0!isocyanoalkylphosphonates[ Mesylation of the hydroxy group
and base!promoted cyclization then leads to diethyl 0!isocyanocyclopropylphosphonates "Scheme
03# ð82CB316\ 75AG"E#643Ł[

R2 O R2 H
O i, BunLi i, MsCl, NEt3
HO P(OEt)2
CN P(OEt)2 O R1 NC
ii, C5H11tOK
ii, R1 R2
R1 NC H P(OEt)2
H H
BF3•OEt2 O
iii, H2O

Scheme 14
Isocyanides 696
A number of other routes to oxygenated isocyanides have been employed[ The ring opening of
both oxiranes and oxetanes in the presence of TMS!CN and a soft Lewis acid gives access to b! and
g!hydroxy isocyanides\ respectively ð71JA4738\ 72TL544\ 73TL2148\ 74TL3860\ 89OSC"6#183Ł[ A particularly
interesting variation of this reaction involves treatment of the ketone "8# with TMS!CN and TiCl3
to give the oxygenated adamantane "09# "Equation "13## ð89S535Ł[

O O-TMS
TMS-CN, ZnI2 (15 mol%)
(24)
CH2Cl2, ∆, 16 h NC

(9) (10)

The base!promoted ring opening of heterocycles has also found extensive use in the synthesis of
aliphatic isocyanides bearing oxygen functionality[ Meyers et al[ have shown that treatment of
dihydro!0\2!oxazines with BunLi at −67>C\ gives after hydrolytic workup\ g!hydroxy isocyanides
in good yield "Scheme 04# ð58TL4040Ł[

i, BunLi H2O
O O H 2O O– Li+ OH
ii, THF, –78 °C 80%
– Li+
N N NC NC

Scheme 15

1!Oxazolines also participate in this reaction ð66AG"E#228\ 76S582Ł[ A particularly elegant example
of this involves the in situ trapping of the anionic intermediate to generate the product isocyanide
"Scheme 05# ð68JOC1931Ł[
R1 R1 R1 NC R1
BunLi
N R2X R2 NC
N
–78 °C – Li+
EtO EtO EtO O– Li+
O O EtO O

Scheme 16

The direct base!promoted condensations of isocyanides have also been employed\ particularly
with a!isocyanoesters[ Ito has reported the ~uoride!catalyzed Michael addition of a!isocyanoesters
to enones ð78TL0146Ł and Pirrung has used the condensation of a!isocyanoesters with 0\1!dibromo!
propane\ in the synthesis of ethyl 1!methyl!0!isocyanocyclopropanecarboxylate ð75JOC1092Ł[ The
use of palladium!catalyzed allylation of a!isocyanoesters has also been disclosed "Equation "14##
ð76TL3738\ 77TL4040Ł[ Other examples of a!isocyanoester condensations have been reported
ð62LA0460\ 64CB0479\ 75AG"E#643\ 77TL5210Ł[

R1 Pd(PPh3)4
CO2Et + OAc (25)
CN
base, THF R1 CO2Et
NC

Seebach et al[ have reported the synthesis of a number of nonracemic oxygenated isocyanides
using the diphosgene dehydration protocol ð77CB496Ł[ Examples are given in Scheme 06[ Further
examples of homochiral isocyanides bearing oxygen functionality have been reported ð89CB524\
80JCS"P0#1384Ł[
The preparation of remotely hydroxylated isocyanides has been described[ Treatment of g! and
d!hydroxy formamides with phosgene:NEt2 yields the corresponding hydroxyisocyanides in good
yield ð63AG"E#488Ł[ The syntheses of 1!vinyloxyethyl isocyanide ð78ZOR0462Ł and methoxy!
isobutylisocyanide ð78OPP400Ł have also been reported[
Livinghouse et al[ have reported that the conjugate addition of the lithio anion of methyl
isocyanide to cyclohexenone proceeds smoothly\ and that the intermediate enolate anion can be O!
silylated to give the silyl enol ether isocyanide "Equation "15## ð76JA489\ 81JA3978\ 81T1198Ł[ In a
697 Isocyanides and their Heteroanalo`ues
OAc
NC OCHO
N NC
O NC

O
NC NC
N
H
CO2Me

O
O
O H
O
N
N H H
H NC
NC

Scheme 17

further study\ Livinghouse and co!workers examined the factors which a}ect the ratio of 0\1! to
0\3!addition in the reaction of a!metalomethyl isocyanides with a\b!unsaturated ketones ð76S280Ł[
The synthesis of g!isocyano silyl enol ethers has also been described ð78TL0146\ 80JOC6245Ł[

O O-TMS TMS-O NC
i, THF, –78 °C
Li NC + + (26)
ii, TMS-Cl

NC

The preparations of a number of sugars bearing isocyanides have been disclosed[ These include
2!isocyano!2!deoxythymidine ð78S607Ł\ 1\2\3\5!tetra!O!benzoyl!D!glucopyranosyl isocyanide "as a
mixture of anomers# ð65TL2316\ 67JOC0861\ 68TL052\ 74MI 210!90Ł\ 1\2 ] 4\5!di!O!isopropylidene!b!D!
mannofuranosyl isocyanide ð80JOC498Ł\ 1\2\3!tri!O!acetyl!b!D!xylopyranose isocyanide ð75TL044Ł\
and 4!O!tert!butyldimethylsilyl!1\2!O!isopropylidene!a!D!ribofuranosyl isocyanide ð77LA654Ł[ The
preparation of b!lactams bearing an isocyanide group has also been described ð63CC167\ 73TL4964Ł[

2[10[0[1[4 Aliphatic isocyanides bearing a sulfur!based functional group


Van Leusen and Schollkopf have described the preparation of thiomethyl isocyanides[ In both
cases the precursor formamides were dehydrated[ Van Leusen chose the use of POCl2:Et2N\ whereas
Schollkopf used PPh2:CCl3:NEt2 "Scheme 07# ð62TL516\ 62TL518Ł[ The synthesis of thionaphthyl!
methyl isocyanides has also been reported ð77TL0324Ł[
A potentially versatile route to a!thioisocyanides has been reported by Isoe and co!workers[ The

PPh3, CCl4
RS NHCHO RS NC
NEt3, CHCl3
60 °C

POCl3

(MeOCH2)2, Et3N

Scheme 18
Isocyanides 698
aniodic oxidation of a!substituted organotin compounds in THF:Bu3NBF3 in the presence of TMS!
CN yields the requisite a!thioisocyanides in good yield "Equation "16## ð83CC438Ł[

SPh Bu4NBF4 SPh


(27)
C8H17 SnBu3 TMS-CN, THF, e– C8H17 NC
53%

Katritzky et al[ have described a ~exible route to a!alkylthio isocyanides ð82S34Ł[ Reaction of
benzotriazole with formamide and an aldehyde gave the intermediate formamides in good yield[
These compounds next react with the sodium salts of both aromatic and aliphatic thiols to generate
the N!"a!alkylthioalkyl#formamides[ Dehydration with POCl2:Na1CO2 then gave the a!alkylthio
isocyanides "Scheme 08#[

R2SH, EtOH i, POCl3, CH2Cl2


N R1CHO N SR2 0 °C, 4 h SR2
Na, RT
N N
N H2NCHO N R1 NHCHO ii, Na2CO3 R1 NC
20 °C, 12 h
H NHCHO
R1

Scheme 19

In a study of the stereochemistry of the reactions of b!halothioethers with NaCN and AgCN\
Ruano et al[ have prepared a number of b!methylthioether isocyanides ð74TL2270Ł[
Arenesulfonylmethyl isocyanides have been used extensively in synthesis[ They can be prepared
either by the addition of a!lithiomethyl isocyanide to arenesulfonyl ~uorides ð61LA"655#029\ 61TL1258Ł\
or by the dehydration of the precursor formamide ð61LA"655#029\ 61TL1258\ 74RTC49Ł[ The most widely
used arenesulfonylisocyanide is tosylmethyl isocyanide "TosMIC# "for a detailed procedure for the
preparation of TosMIC\ see ð77OSC"5#876Ł#[ Treatment of TosMIC with a suitable base generates
the a!anion\ which can be quenched with electrophiles[ The most convenient procedure for the
alkylation of TosMIC involves the use of phase transfer catalysis ð64TL2376Ł[ Both mono! and
dialkylation of TosMIC is possible\ and many examples of these reactions exist in the literature
"Scheme 19# ð66TL3118\ 66TL3122\ 79S214\ 70JOC4048\ 71TL4224\ 72SC220\ 72SC268\ 77T6132\ 89TL5106\ 80SL76Ł[

NaH R1 NaH R1
Tos NC NC Tos NC
DMSO DMSO
Tos R2
R1X R2X

Scheme 20

Monoalkylated TosMIC derivatives can also be alkynated by treatment with base and an acid
chloride ð66TL3122Ł[ The use of silicon electrophiles has also been reported ð74RTC066Ł[ The chem!
istry of TosMIC has been reviewed ðB!76MI 210!90Ł[

2[10[0[1[5 Aliphatic isocyanides bearing a Se! or Te!based functional group


No examples of this functionality could be found in the primary literature[

2[10[0[1[6 Aliphatic isocyanides bearing a nitrogen!based functional group


A number of isocyanides bearing a nitrogen centre directly attached to the isocyanide nitrogen
atom have been reported[ Husigen et al[ have shown that thermolysis of arylhydrazono!2!methyl!
4!oxo!3\4!dihydro!0\1!oxazoles gives aryl amino isocyanides ð72CB2916Ł[ Simple dialkylamino iso!
cyanides have been prepared by the dehydration of formyl hydrazones using POCl2:NEt2 "Equation
"17## ð51AG"E#223\ 53AG"E#536\ 54LA"575#81Ł[ The chemistry of dialkylamino isocyanides has been
studied ð47JA3040\ 59JOC798Ł\ and the preparation of isodiazomethane metal complexes has been
reported ð66AG"E#696Ł[
609 Isocyanides and their Heteroanalo`ues
H COCl2
N R 2N NC (28)
R 2N CHO NEt3

Hegarty et al[ have shown that treatment of hydrazides with PCl4 gives N!"arylalkyl# amino
isocyanides\ and whose chemistry was then studied in solution ð75CC0085Ł[ The preparation of the
unstable secondary isocyanoamines has been reported "Equation "18## ð70JOC0934Ł[ The pyrolysis
of 3!hydrazonoisoxazol!4"3H#!ones yields the secondary isocyanoamines^ in all cases the substituent
on nitrogen was an aryl or heteroaryl group[

N NHR

RHN NC + CO2 + MeCN (29)
N
O O

The synthesis of imino isocyanides has been disclosed[ They are prepared by the dehydration of
the precursor formyl hydrazone ð51AG388\ 52AG294Ł[ This class of compounds has also been prepared
and isolated "as the dibromo addition adduct# via the bromination of arylidene hydrazinotetrazoles
ð69TL3968Ł[ The preparation of N!isocyanoiminotriphenylphosphane "CN0N1PPh2# has been
reported via the dehydration of formyl hydrazine with PPh2:NEt2:CCl3 ð79AG"E#379Ł[
Ignasiak and co!workers have studied the preparation and chemistry of aryl diazoisocyanides[
These compounds are prepared by the dehydration of formyl triazenes[ It was found that SOCl1:
pyridine was the only dehydrating system that yielded the desired isocyanide "Equation "29##
ð64JCS"P0#1011Ł[

NHCHO SOCl2 NC
(30)
N N N N
Ar Ar
N

The matrix isolation and characterization of the extremely reactive diisocyanogen "CN0NC# has
been described ð77AG"E#825Ł^ however\ subsequent studies showed that the authors had prepared
the isomeric isocyanogen "CN0CN# ð80JA5093Ł[ The _rst preparation of diisocyanogen was later
reported ð81AG"E#0107Ł\ by the thermolysis of norbornadienoneazine[
N!Imidoyl isocyanides have been prepared by the treatment of N!phenylimidoyl bromides with
silver cyanide in chloroform ð66AG"E#616Ł[ Compared to the N!acyl isocyanides\ they are con!
siderably more stable in solution[ However\ attempts to isolate them led to isomerization to the
corresponding imidoyl cyanides[
A number of a!amino isocyanides have been prepared\ including N!"isocyanomethyl#!N!nitro!
propylamine ð70AP"203#348Ł and 0!"isocyanomethyl#!azoles ð72CPB612Ł[ Katritzky et al[ have
reported the synthesis of a!"benzotriazolyl#alkyl isocyanides "Scheme 10# ð89JCS"P0#0736Ł\ and in an
extension of this chemistry\ developed a general route to a!amino isocyanides[ Thus\ treatment of
benzatriazole with formamide and the appropriate aldehyde gives the 0!substituted!N!for!
mylaminobenzatriazole[ On reaction with a secondary amine\ the corresponding 0!substituted N!
"a!amino#formamide is obtained[ These formamides are then dehydrated to the corresponding a!
amino isocyanides using POCl2:Na1CO2 ð82S34Ł[

N O O
N RCHO N H i, POCl3, CH2Cl2
N N
H2NCHO K2 CO3 ii, Na2CO3
N N MeOH N N
96%
H 62%
NHCHO
R R NHCHO R NC

R = Ph
Scheme 21

Katritzky has also described the preparation and use of 0H!benzotriazol!0!yl!methyl isocyanide
"BetMIC# "00# ð78TL5546\ 89JCS"P0#0736\ 80JOC3328\ 80S757Ł[
Schollkopf et al[ have prepared a!isocyanonitriles by the dehydration of a!formylamino nitriles
Isocyanides 600
N
N
N
NC
BetMIC
(11)

using POCl2:NEt2[ The deprotonation and subsequent chemistry of the a!anion has also been
investigated "Equation "20## ð64LA0420Ł[

NHCHO NC
POCl3, NEt3, CH2Cl2
R R (31)
CN CN

The unusual triisocyanide ligand shown in Equation "21# was prepared by dehydration of the
precursor triformamide with diphosgene ð80AG"E#192Ł[

N N
diphosgene
(32)
OHCHN NHCHO NC CN
NHCHO NC

The preparation of isocyanides bearing remote nitrogen functionality has been reported
ð47JOC0488Ł[ Thus treatment of primary amines bearing a remote tertiary amine group with
CHCl2:KOH gave the isocyanide in modest yield "Equation "22##[

R2N NH2 KOH, CHCl3 R2N NC


( )n ( )n (33)

R = Me, Et; n = 2,3

2[10[0[1[7 Aliphatic isocyanides bearing other substituents


The syntheses of aliphatic isocyanides bearing silicon\ germanium and tin substituents have been
reported[ Treatment of trimethyliodosilane with silver cyanide gave trimethylisocyanosilane in 79)
"Equation "23## ð41JA4136Ł^ the paper also reported the preparation of dimethyldiisocyanosilane[

AgCN
TMS-I TMS-NC + AgI (34)

Van Leusen and co!workers have published an improved procedure for the preparation of
trimethylsilylmethyl isocyanide ð75SC754Ł[ This useful compound was previously prepared by the
silylation of a!lithio methyl isocyanide ð73SC528Ł[ It was reported that treatment of chloro!
methyltrimethylsilane with formamide gave N!""trimethylsilyl#methyl# formamide in 62)[ De!
hydration using POCl2:Pri1NH then gave the desired product in 64)[ Bis! and tris"trimethyl!
silyl#methyl isocyanide have also been prepared ð69JOM"14#274Ł[
Trialkyl and triaryl isocyanosilanes have been prepared by a number of methods ð41JA4136\
47JA3040Ł^ the unusual disilanyl isocyanide has also been reported ð51JCS437Ł[
Trimethylisocyanogermane and trimethyltinisocyanide have been prepared ð59JOC798Ł by the
treatment of trimethyliodo metal derivative with silver cyanide[ They are both considered to be an
equilibrium mixture of the cyano and isocyano forms[ The synthesis of tetraisocyanogermane has
also been disclosed ð40JA4328\ 47AG545Ł[
601 Isocyanides and their Heteroanalo`ues
Van Leusen and co!workers have prepared a number of boron substituted methyl isocyanides
ð84TL1098Ł[ The synthesis of phosphine functionalized isocyanides as metal ligands has been reported
"Equation "24## ð74JOM"183#C10\ 89JOC3849Ł[

CN Li+ Ph2P– CN
Br PPh2 (35)
Ph Ph
Ph Ph

2[10[0[2 a\b!Unsaturated Isocyanides

2[10[0[2[0 General methods


The synthesis of a\b!unsaturated isocyanides has received somewhat less attention compared to
their saturated analogues[ The _rst synthesis of vinyl isocyanide appeared only in 0857 ð57JA2650Ł[
As a consequence\ they have been utilized far less in synthetic methodology[ A number of naturally
occurring a\b!unsaturated isocyanides have been isolated and synthesized including xanthocillin
ð51AG104Ł\ isonitrins A ð80SL440Ł and B ð78SL8Ł\ and dermadin ð70TL2648Ł "Scheme 11#[ Further
examples have also been reported ð74T0820\ 77MI 210!90\ 81ACR322Ł[

OH O
NC
CN

NC CO2H
HO
xanthocillin X dermadin

H H OH
O
OH

O O
NC NC
isonitrin A isonitrin B

Scheme 22

As with saturated isocyanides\ a number of general methods have been developed for their
synthesis^ these are given below]
"i# the dehydration of a\b!unsaturated formamides\
"ii# deprotonation and further elaboration of isocyanides and a\b!unsaturated isocyanides\
"iii# b!elimination from functionalized isocyanides\
"iv# base promoted ring opening of heterocycles\
"v# isomerization of allyl isocyanides[

"i# The dehydration of a\b!unsaturated formamides


The dehydration of a\b!unsaturated formamides has proved to be a popular method for the
synthesis of a\b!unsaturated isocyanides[ The synthesis of the acid labile precursor a\b!unsaturated
formamides has proved to be troublesome\ although several methods now exist for their preparation[
Their subsequent dehydration to a\b!unsaturated isocyanides has been e}ected using a number of
reagents\ all of which have been used in the synthesis of saturated isocyanides[
Barton et al[ have reported that the treatment of oximes with formicÐacetic anhydride and
imidazole followed by TiCl2 leads to a\b!unsaturated formamides in good yield[ Their dehydration
Isocyanides 602
to a\b!unsaturated isocyanides was then carried out using phosgene in the presence of 0\3!
diazabicycloð1[1[1Łoctane "dabco# "Scheme 12# ð77TL2232Ł[
OH CHO NC
N HN
i, AcOCHO, imidazole, DMF, 0 °C COCl2, dabco

ii, Ti(OAc)3 66% overall

Scheme 23

Baldwin and co!workers have reported that sulfenimines on treatment with formicÐacetic anhy!
dride in the presence of PPh2 and propylene oxide give a\b!unsaturated formamides in good yield
ð89TL1940Ł[ The precursor sulfenimines are accessible from either the parent ketone ð74CC0473Ł or
amine ð68JOC0107Ł[ The subsequent dehydration to give the a\b!unsaturated isocyanide was carried
out using tri~uoromethanesulfonic anhydride in the presence of Hunig|s base "Scheme 13#
ð89SL592Ł[
NH2

STol CHO NC
N HN
PPh3, AcOCHO (CF3SO2)2O, Pri2NEt
or
O , CH2Cl2 CH2Cl2, –78 °C
O

Scheme 24

Barrett and co!workers have recently reported a mild method for the preparation of a\b!unsatu!
rated formamides based upon the Bu2SnH reduction of selenocarbamates ð82CC0659Ł[ The dehy!
dration was e}ected using the methodology of Baldwin ð89SL592Ł or TsCl:pyridine "Scheme 14#[

O O H
NaN3 i, PhMe, ∆ N SePh Bu3SnH, AIBN
Ph
Ph Cl DMF Ph N3 ii, PhSeH, ButOK (cat.) PhH, ∆
O

H
N H (CF3SO2)2O, Pri2NEt
Ph NC
Ph
CH2Cl2, –78 °C
O

Scheme 25

Schollkopf et al[ have developed a general procedure for the synthesis of functionalized a\b!
unsaturated formamides^ these compounds can be readily dehydrated to give the a\b!unsaturated
isocyanides[ The process is known as formylaminomethylenation\ and involves the reaction of a!
metallated isocyanides bearing an acidifying substituent such as CO1R ð61LA"655#005\ 63MI 210!90\
65CB2853Ł\ SO1Ar ð61LA"655#029\ 80RTC391Ł\ P"O#"OR#1 ð81JOC1138Ł\ or 2! or 3!pyridyl ð65LA858Ł\
with aldehydes or ketones in aprotic media "Equation "25##[ Such compounds allow access to a wide
range of highly functionalized a\b!unsaturated isocyanides[ This area has been reviewed ð66AG"E#228\
63AG"E#678Ł[

R1 NC i, base R1 NHCHO
O + (36)
R2 X ii, H+ R2 X
X = CO2Et, SO2Ar, P(O)(OEt)2, 3,4-pyridyl
603 Isocyanides and their Heteroanalo`ues
"ii# Deprotonation and further elaboration of isocyanides and a\b!unsaturated isocyanides
A number of di}erent reagents which can be deprotonated and condensed with an appropriate
electrophile have been developed for the synthesis of a\b!unsaturated isocyanides[ Van Leusen and
co!workers were the _rst to report the use of lithio!a!"trimethylsilyl#tosylmethyl isocyanide
"TosMIC# in the synthesis of a\b!unsaturated isocyanides[ Reaction of lithio!a!"trimethyl!
silyl#tosylmethyl isocyanide with an appropriate aldehyde or ketone yields the a\b!unsaturated
isocyanide in good yield ð71RTC191Ł[ In a related approach based on WadsworthÐEmmons!type
chemistry\ Schollkopf et al[ have described the condensation of the lithio anion of diethyl"isocyano!
methyl#phosphonate with aldehydes to give the a\b!unsaturated isocyanide product ð63LA33\
66LA0056\ 73LA599Ł[
A Peterson!type alkeneation has been used in the synthesis of a\b!unsaturated isocyanides[ The
deprotonation of trimethylsilylmethyl isocyanide with BunLi at −67>C for 0 hour\ followed by
addition of 1\4!dimethoxybenzaldehyde has been reported to give the a\b!unsaturated isocyanide in
59) as a 0 ] 0 mixture of "E#:"Z# isomers ð89S457Ł[
The direct deprotonation of a\b!unsaturated isocyanides bearing an a!hydrogen has been
described by Schollkopf ð66LA0056Ł[ Thus\ treatment of the a\b!unsaturated isocyanide with BunLi
at low temperature\ followed by quenching with an electrophile gives the a!functionalized a\b!
unsaturated isocyanide "Scheme 15# ð66LA0056Ł[

R1 NC BunLi, THF/Et2O R1 NC R1 NC
E+

R2 –110 °C to –70 °C R2 Li R2 E
E+ = TMS-Cl, MeI, ClCO2R, CO2

Scheme 26

"iii# a and b!Elimination from functionalized isocyanides


"a# a!Eliminations[ Ugi and co!workers have reported the preparation of cyclohexenyl isocyanide
by the sequential dehydration:elimination "of HCN# from N!"0!cyanocyclohexyl# formamide on
reaction with POCl2:KOBut ð52LA"555#54Ł[
"b# b!Eliminations[ The b!elimination of a nucleofuge from a suitably functionalized isocyanide
is a particularly useful method for the synthesis of a\b!unsaturated isocyanides[ The _rst reported
synthesis of vinyl isocyanide involved the treatment of N!formylethanolamine with benzenesulfonyl
chloride followed by treatment with ethanolic KOH ð57JA2650Ł[ Other leaving groups that have
been reported include halogens ð50AG15\ 78TL2224Ł\ methanesulfonate ð70TL2648Ł\ p!toluenesulfonate
ð73CC022\ 66LA0056Ł\ and epoxide ð74CC705Ł[ For a general discussion of this reaction\ see ð75JA2042\
78CC0120Ł[

"iv# Base!promoted rin` openin` of heterocycles


Dondoni et al[ have used this approach in the synthesis of substituted a\b!unsaturated isocyanides
"Scheme 16# ð73CC147\ 76S582Ł[ Treatment of 3\4!substituted oxazoles with BunLi at low temperature
gives the 1!lithiated oxazole\ which is in equilibrium with the ring open isocyano tautomer[ Addition
of an electrophile\ such as acetyl chloride or trimethylsilyl chloride yields the substituted a\b!
unsaturated isocyanide in modest yield[ Further examples have been reported ð64LA422\ 68JOC1931Ł[

"v# Isomerization of allyl isocyanides


Several examples of this protocol have been reported[ Ito has reported that copper"I# oxide
catalyses the isomerization of allyl isocyanides to the corresponding a\b!isocyanides at room tem!
perature ð60T2684Ł[ In his synthesis of the isonitrile 169\ Baldwin et al[ utilized a 0\4!diazabicyclo!
ð4[3[9Łundec!4!ene "dbu# and iodine!catalyzed isomerization of the dienyl ester "00# to the dienyl
isocyanide "Scheme 17# ð73CC022Ł[
Isocyanides 604
R2 O R2 O
BunLi, Et2O, –78 °C
Li
R1 N R1 N

O
R2 OLi R2 O-TMS
R2 O MeCOCl TMS-Cl

R1 NC R1 NC
R1 NC

Scheme 27

CO2Et CO2Et CO2Et

dbu I2

NC NC NC

Scheme 28

2[10[0[2[1 Isocyanides bearing an a\b!double bond

"i# With no further substituents


The _rst synthesis of an a\b!unsaturated isocyanide was of simple vinyl isocyanide ð57JA2650Ł[
Sequential treatment of N!formylethanolamine with benzenesulfonyl chloride and KOH gives vinyl
isocyanide\ which was described as having an {{atrocious odor\ followed by a bitter aftertaste[||
King and Borodinsky ð74T2124Ł published the synthesis of a number of unfunctionalized a\b!
unsaturated isocyanides using the methodology of Schollkopf ð66LA0056Ł "addition of a!
lithiomethylisocyanide to the appropriate aldehyde:ketone\ followed by addition of TsCl and then
KOH:MeOH#\ and the allyl isocyanide:a\b!unsaturated isocyanide isomerization methodology of
Ito ð60T2684Ł "Scheme 18#[
O
O– Li+ OTs R1
R1 R2
R1 TsCl, THF, –70 °C R1 KOH
Li NC NC NC NC
THF, –78 °C
R2 R2 MeOH R2

Scheme 29

Scheme 29 shows examples of some of the a\b!unsaturated isocyanides that King and Borodinsky
prepared[
In the total synthesis of the antibiotic O?\O?!dimethylxanthocillin\ Hagedorn et al[ treated the

But NC
NC NC

Pri NC
NC

Scheme 30
605 Isocyanides and their Heteroanalo`ues
precursor dihydroxy formamide with POCl2:pyridine to give the bisb!chloro isocyanide[ Treatment
with KOH:pyridine resulted in elimination of HCl to give the a\b!unsaturated isocyanide "Scheme
20# ð51AG104\ 52AG294\ 54CB082Ł[
CHO OMe OMe
OH HN Cl NC
POCl3 KOH

pyridine pyridine
NH OH NC Cl
MeO OHC MeO

OMe
NC

NC
MeO

Scheme 31

The total synthesis of axisonitrile!3 by Hart et al[\ utilizes an unusual route to the precursor a\b!
unsaturated isocyanide[ Conversion of the a\b!unsaturated carboxylic acid to the corresponding
a\b!unsaturated acyl azide\ followed by Schmidt rearrangement and reduction of the a\b!unsaturated
isocyanate _rst gives the a\b!unsaturated formamide[ Dehydration with TsCl:pyridine then yielded
the natural product "Scheme 21#[

CO2H i, NaH NHCHO NC


H ii, (PhO)2PON3, ∆ H TsCl H

iii, LiEt3BH, THF, –78 °C pyridine

Scheme 32

In their synthesis of erbstatin\ van Leusen et al[ prepared the a\b!unsaturated isocyanide "01#
using the condensation of lithio diethyl "isocyanomethyl#phosphonate with 1\4!dimethoxy!
benzaldehyde[ The product was obtained in 64) yield as a 09 ] 0 mixture of "E#:"Z# isomers
"Equation "26## ð89S457Ł^ for related studies\ see ð76JAN0196Ł[

OMe OMe
CHO NC
O BunLi, THF, –78 °C
+ (37)
(EtO)2P NC

OMe OMe
(12)

The preparation of alkynyl and cyclobutenyl isocyanide complexes have recently been reported
ð83AG"E#229Ł\ and the matrix isolation of ethynyl isocyanide has also been disclosed ð80AG"E#0533Ł[

"ii# With halo!substituents


The synthesis of the highly ~uorinated a\b!unsaturated isocyanide "02# has been reported by
vacuum thermolysis of the precursor chromium pentacarbonyl complex at 139>C "Scheme 22#
ð81CC0412\ 82AG"E#0345Ł\ and the preparation of a number of chlorovinyl isocyanide chromium
pentacarbonyl complexes has been published ð78JOM"268#86Ł[
Matsumoto and co!workers have reported the preparation of b!bromo!a!isocyanoacrylic acid
esters[ Condensation of methyl isocyanoacetate with the appropriate aldehydes followed by brom!
ination with NBS _rst gave the b!bromo!a!formylaminoacrylic acid esters[ Dehydration with
POCl2:NEt2 then gave the a\b!unsaturated isocyanides in good yield "Scheme 23#[ These compounds
Isocyanides 606

F
CN F
F FVP, 240 °C
(CO)5CrCN
F F
F
(13)

F F F F F
F F F F
F 70 °C
+
(CO)5 CrCN
F (CO)5Cr C N N C
Cr(CO)5 (CO)5Cr C N N C
Cr(CO)5
F F F F

Scheme 33

are particularly useful\ because the b!bromine can be substituted with a variety of heteroatoms
using a conjugate addition:elimination procedure[ A variety of other substituents on the b!position
were also reported ð77T4356\ 89S670Ł[

R NHCHO R NHCHO R NC
NBS POCl3

CO2Me CCl4 Br CO2Me Et3N, CH2Cl2 Br CO2Me

Scheme 34

The synthesis of 0!chloro a\b!unsaturated isocyanides has been achieved by the condensation of
the lithio anion of a!chloro!a!isocyanomethylphosphonates with aldehydes and ketones
ð76JAN0088Ł\ and a synthesis of the natural product indsocin which contains an a\b!unsaturated
isocyanide bearing a chloro substituent\ has been reported ð76JAN0191Ł[

"iii# With oxy`en!based substituents


A large number of a\b!unsaturated isocyanides bearing oxygen!based substituents have been
reported[ The condensation of a!metallated ethyl isocyanoacetate with aldehydes or ketones leads
to the corresponding ethyl a!"formyl!amino#acrylates and a large range of aldehydes and ketones
have been shown to participate in this reaction ð58AG"E#561\ 61LA"655#005\ 63MI 210!90Ł[ Dehydration
to the isocyanide is then carried out using phosgene:NEt2 and yields the b!substituted ethyl a!
isocyanoacrylates "Scheme 24# ð62LA500Ł[ Schollkopf has examined the synthetic uses of these
compounds extensively ð66AG"E#228Ł[

i, base
O
ii, R1 NHCHO R1 NC
R1 R2 COCl2, NEt3
CN CO2Et
iii, H+ R2 CO2Et R2 CO2Et

Scheme 35

An unusual approach to the synthesis of a\b!unsaturated isocyanides bearing an ester substituent


involves the condensation between t!butyl isocyanoacetate and amide diethyl acetals ð75AP"208#362Ł[
The use of a!isocyanomethylphosphonates in the synthesis of a\b!unsaturated isocyanides has
also received much attention ð63LA33\ 70LA88\ 76JAN0196\ 80TL2796Ł[ Condensation of the a!lithio
anion of isocyanomethylphosphonatediethylester with aldehydes or ketones gives the a\b!unsatu!
rated isocyanide via elimination of lithium diethylphosphate[ Both aryl and alkyl ketones were used
and the condensation with glyoxal was also described ð63LA33Ł[ This methodology was applied to
the total synthesis of antibiotic B 260 "Scheme 25# ð73LA599Ł[ A wide range of aldehydes and ketones
participate in this condensation reaction[
607 Isocyanides and their Heteroanalo`ues
O
O THF, –70 °C
R2 NC
(EtO)2P Li +
NC R2 R3 R3 R1
R1

CHO
NC
O i, NaHMDS (2 equiv.), THF, –78 °C
+
(EtO)2P NC ii, AcOH
N N
H H
B 371

Scheme 36

Van Leusen and co!workers have prepared a number of steroid derivatives that contain an a\b!
unsaturated isocyanide by the condensation of isocyanomethylphosphonate!diethyl esters with the
parent steroidal ketone in the presence of KOBut\ followed by dehydration with POCl2:Pri1NH
ð80RTC282\ 81JOC1138Ł[ The reaction has been developed further by the use of t!butyl "diphenyl!
phosphinyl#isocyanoacetate[ Again\ deprotonation followed by union with an aldehyde or ketone
and subsequent elimination of lithium diphenylphosphinate gives a\b!unsaturated isocyanides
ð70LA88Ł[
Baldwin et al[ have published a number of total syntheses of highly oxygenated a\b!unsaturated
isocyanide containing natural products[ In their total synthesis of isonitrile 169\ the initial elim!
ination of a b!tosyl isocyanide gives an allyl isocyanide\ which is isomerized to the dienyl isocyanide
using dbu and iodine ð73CC022Ł[ The unusual isocyanide spirolactone "05# was prepared via an
initial ring opening of the b!epoxy isocyanide "03#\ followed by an oxidation with pyridinium
chlorochromate "pcc#[ The 0\1 addition of lithium "Z#!b!lithioacrylate to the ketoisocyanide "04#
furnished the spirolactone natural product in low yield "Scheme 26# ð74CC705Ł[
CO2Li
i,
NC NC NC O O
KOBut, THF PCC Li

CH2Cl2 ii, H3O+


O HO O NC
(14) (15) (16)

Scheme 37

The three related natural products] isonitrin A\ isonitrin B "deoxytrichoviridin#\ and isonitrin C
"trichoviridin#\ have all been synthesized by the Baldwin research group ð78SL8\ 80SL440Ł[ Isonitrins
A and B contain an a\b!unsaturated isocyanide in a _ve!membered ring along with a high degree
of oxygenation[ The a\b!unsaturated isocyanide in isonitrin B was prepared by treatment of the
sulfenimine "06# with aceticÐformic anhydride:PPh2:propylene oxide to give the a\b!unsaturated
formamide[ Dehydration to the a\b!unsaturated formamide was e}ected with tri~uoro!
methanesulfonic anhydride in the presence of Hunig|s base at −67>C "Scheme 27# ð78SL8\ 80SL440Ł[

H O-TBDMS H O-TBDMS H O-TBDMS

OH PPh3, HCO2Ac OH (CF3SO2)2O, Pri 2NEt OH


O CH2Cl2, –78 °C
O O O
N STol CH2Cl2 NHCHO NC
(17)

Scheme 38

Fukuyama et al[ have reported the total synthesis of the isocyanide ester "08# whereby the a\b!
unsaturated isocyanide moiety was introduced by treatment of the b!mesyl isocyanide "07# with
base "Equation "27## ð70TL2648Ł[
Isocyanides 608
OMs
O
O
KOBut, THF, PhMe, –78 °C NC
NC (38)

MeO2C
MeO2C
(18) (19)

The synthesis of the antibiotic A!21289A was reported by Schollkopf and co!workers using a
procedure where the a\b!unsaturated isocyanide was prepared by the dehydration of the precursor
a\b!unsaturated formamide utilizing POCl2:NEt2 "Equation "28## ð64CB0479\ 74LA0714Ł[

O O
NHCHO NC
O O

HCO2 H HO H
HCO2 H i, POCl3 (2.2 equiv.), NEt3 (2.2 equiv.) HO H
(39)
H O2CH ii, phosphate buffer (pH 7.3) H OH
H O2CH H OH

O O
OHCHN CN
O O

ANTIBIOTIC A 32390 A

More recently\ Baldwin and co!workers have applied their sulfenimine!based methodology in the
synthesis of analogues of antibiotic A!21289A[ The a\b!unsaturated formamide "10# was prepared
from the sulfenimine "19# as described earlier ð78SL8\ 80SL440Ł[ Dehydration to the a\b!unsaturated
isocyanide was then achieved using tri~uoromethanesulfonic anhydride:Hunig|s base at −67>C
"Scheme 28# ð83CC74Ł[

STol
O O-TBDMS N i, HCO2Ac, PPh3, O , CH2Cl2
O
O
ii, Hg(OAc)2
N O-TBDMS O iii, dbu
TolS
(20)

O O-TBDMS NHCHO O O-TBDMS NC


(CF3SO2)2O, Pri2NEt
O O
O O
CH2Cl2, –78 °C
NHCHO O-TBDMS O NC O-TBDMS O
(21)
Scheme 39

Kende has prepared the a\b!unsaturated isocyanide "11# by the dehydration of the precursor
formamide with tri~uoromethanesulfonic anhydride:Hunig|s base at −67>C "Equation "39##
ð82TL468Ł[

Bn2N NHCHO (CF3SO2)2O, Pri2NEt Bn2N NC


CH2Cl2, –78 °C
OMe OMe (40)
99%
O O
(22)
619 Isocyanides and their Heteroanalo`ues
"iv# With sulfur!based substituents
The group of van Leusen has also reported the synthesis of 0!"arylthio#alkenyl isocyanides by the
condensation of the lithio anion of "arylthio#methyl isocyanides with TMS!Cl\ followed by addition
of another equivalent of BunLi and the requisite aldehyde at −67>C[ A mixture of "E# and "Z#
isomers was produced "Scheme 39# ð74RTC066Ł[ The paper also discusses the synthesis and use of
diethyl "isocyano"arylthio#methyl#!phosphonate in the preparation of 0!"arylthio#alkenyl
isocyanides[

NC i, BunLi
NC i, BunLi R2 NC
TMS
SR1 ii, TMS-Cl SR1 ii, R2CHO
SR1

Scheme 40

a\b!Unsaturated isocyanides bearing an a!tosyl group are conveniently prepared from the con!
densation of the lithio anion of a!"trimethylsilyl#tosylmethyl isocyanide "TosMIC# with aldehydes
ð71RTC191Ł[ In all the examples given\ an aromatic aldehyde was used "Equation "30##[

NC R NC
THF
R CHO + Li Tos + TMS-OLi (41)
TMS –78 °C to – 30 °C Tos

"v# With nitro`en!based substituents


Meerwein and co!workers have reported that ethyl isocyanoacetate reacts with N\N!dimethyl!
formamide acetal at room temperature to give ethyl 2!dimethylamino!1!isocyanoacrylate in 67)
yield "Equation "31## ð50LA"530#0\ 68LA0333Ł[

NC OEt Me2N NC
+ Me2N (42)
CO2Et OEt CO2Et

The unusual a\b!unsaturated isocyanide "12# was prepared by the mono deprotonation of 0\2!
diisocyanopropane with BunLi at −67>C\ followed by intramolecular cyclization of the resulting
anion and in situ trapping with TMS!Cl "Scheme 30# ð79LA17Ł[

Li
Li Li+ TMS NC
TMS-Cl N
NC NC
N N –
CN NC
(23)

Scheme 41

The addition:elimination of benzylamine to "Z#!methyl!b!bromo!a!isocyanocinnamate gives "E#!


methyl!b!benzylamino!a!isocyanocinnamate "Equation "32## ð77T4356Ł[

Ph CO2Me
Ph CO2Me PhCH2NH2, Et3N
(43)
50% N NC
Br NC
Ph H
Isocyanides 610
2[10[0[2[2 Isocyanides bearing an a\b!aryl or hetaryl substituent

"i# General methods


Although several other methods exist\ the most common method for the preparation of aryl
isocyanides is the dehydration of the appropriate precursor formamide[ The presence of the aryl
ring does not allow for displacement!type reactions commonly found in the preparation of aliphatic
isocyanides[ The general methods of preparation are listed below]
"i# dehydration of formamides\
"ii# the Hofmann carbylamine reaction\
"iii# reduction of isocyanates\ isothiocyanates and isocyanide dihalides\
"iv# deprotonation of aryl imidates and aryl heterocycles\
"v# abnormal Beckmann rearrangements\
"vi# ring cleavage reactions of heterocyclic compounds[
These general methods are discussed in more detail below[
"a# The dehydration of aryl formamides[ The dehydration of aryl formamides is the most widely
used procedure for the synthesis of aryl isocyanides "Equation "33##\ and a large range of dehydrating
reagents have been used[

Ar
–H2O
N CHO Ar NC (44)
H

The reagents of choice are phosgene ð54AG"E#361Ł and diphosgene ð66AG"E#148Ł in the presence
of a tertiary amine[ In a review article by Ugi\ the preparation of over 149 isocyanides is described
by the phosgene method\ many of which are aryl isocyanides ð54AG"E#361\ B!60MI 210!90Ł[ Other
dehydrating reagents that have been used include POCl2 in the presence of a tertiary amine ð52CJC752\
47AG691\ 50OS"30#02\ 55TL770\ 59CB128Ł or secondary amine ð74S399Ł\ PCl4\ P1O4\ ð59CB128Ł\ PPh2Br1
ð57LA"607#13Ł\ PPh2:diethyl azodicarboxylate "dead# ð61AG"E#818Ł\ and PPh2:CCl3:NEt2
ð60AG"E#021Ł[ The use of SOCl1:DMF:Na1CO2 has also found widespread application ð61JOC076Ł[
Miscellaneous dehydrating systems include di!1!pyridyl sul_te:NEt2 ð75TL0814Ł and cyanuric
chloride:K1CO2 ð50AG108Ł[
The treatment of N!aryl thioformamides with cyanogen bromide:NEt2\ has been reported to yield
aryl isocyanides ð53CA"59#4527Ł[
"b# The Hofmann carbylamine reaction[ The treatment of a primary aromatic amine with aque!
ous KOH:CHCl2 under phase transfer conditions leads to the corresponding aryl isocyanide in
reasonable yields ð61AG"E#429\ 61TL0526Ł[ The mechanism of this transformation was discussed in
Section 2[10[0[0[ Other variations have been reported[ Krapcho has described the generation of
dichlorocarbene by thermolysis of sodium trichloroacetate\ followed by its reaction with primary
arylamines to give the isocyanide ð51JOC0978Ł[ Thus\ the reaction is performed under anhydrous
conditions[
The conversion of N!sul_nylarylamines to aryl isocyanides in good yield using CHCl2:KOH:C5H5
has been reported ð66S164Ł[
"c# The reduction of isocyanates\ isothiocyanates and isocyanide dihalides[ Triethylphosphite has
been used in the conversion of aryl isocyanates into aryl isocyanides ð51JOC2540Ł as has 1!phenyl!
2!methyl!0\2\1!oxaphospholidine "Mukaiyama|s reagent# ð54BCJ747Ł[
Baldwin et al[ have reported the preparation of aryl isocyanides by the reduction of the precursor
isocyanate using either diphenyl!t!butylsilyllithium or Cl2SiH:NEt2 ð71CC831Ł[
Aryl isothiocyanates can be converted into aryl isocyanides using a variety of reagents\ including\
triethylphosphine ð0769CB655Ł\ triethylphosphite ð51JOC2540Ł\ triphenyltin hydride ð52JOC0696Ł\
phenylacetyl chloroformamidine ð55CB2052Ł\ and samarium diiodide ð81CL0032Ł[
The transformation of arylisocyanide dihalides into aryl isocyanides has been e}ected with a
number of di}erent reagents\ including phosphines ð51AG737\ 53CA"59#5684Ł\ and potassium iodide
ð53CA"59#5684Ł[ More recently\ the electrochemical reduction of N!aryl isocyanide dichlorides has
been reported to give aryl isocyanides in excellent yields ð81TL3668Ł[
"d# Deprotonation of aryl imidates and aryl heterocycles[ Pornet et al[ have reported that treatment
of aryl imidate ethers with magnesium diisopropylamides yields the corresponding aryl isocyanide
ð54AG"E#691\ 69TL2298\ 60TL856Ł[ In a recent extension of this approach\ it has been disclosed that the
reaction of disubstituted aryl imidate ethers with lithium dialkylamides gives very high yields of
disubstituted aryl isocyanides "Equation "34## ð89CA"001#007364Ł[
611 Isocyanides and their Heteroanalo`ues

R1 R1
LDA, –78 °C
R2 R2 (45)
R3 hexane R3
N OR4 NC

R1, R2 = H, alkyl; R3 = H, alkyl, alkoxy, aryl, aryloxy

LDA = Lithium diisopropylamide

The treatment of benzoxazoles with BunLi at low temperature followed by addition of TMS!Cl\
gives high yields of 1!siloxyaryl isocyanides ð72JOM"135#048Ł[
"e# Abnormal Beckmann rearran`ements[ A number of oxime derivatives have been reported to
give mixtures of cyanides and isocyanides under Beckmann!type conditions[ For example\ treatment
of syn!oximes of aromatic aldehydes with 0\0!diethoxy!0!propene in the presence of BF2 and
HgO gives mixtures of the corresponding aromatic isocyanide "49Ð62) and the cyanides "9Ð12)#
"Equation "35## ð50JOC1191Ł[

OEt BF3, HgO


OEt Ph NC + Ph CN (46)
Ph N
O Et Et2O

Other examples include 2\4!disubstituted!3!hydroxy!benzaldehyde oxime tosylates ð50ZN"B#734Ł


and the transformation of aryl aldoximes to isocyanides using aryl cyanates ð55CB1250Ł[ Werner
and Piquet attempted a Beckmann rearrangement on g!benzil monoxime with benzenesulfonyl
chloride under basic conditions and obtained phenyl isocyanide ð93CB3184Ł[
"f# Rin` cleava`e reactions of heterocyclic compounds[ An interesting thermolytic method has
been described by Wentrup and co!workers whereby simply heating 3!iminoisoxazalones "prepared
from nitroso compounds# gives good yields of heteroaryl isocyanides ð67AG"E#577Ł[ The reactions
of indole with nitroso compounds have also been reported to give isocyanides ð04CB842Ł[
Treatment of quinazoline!2!oxide with Ac1O leads to 1!isocyanobenzonitrile ð50CPB524Ł\ and an
interesting ring cleavage reaction occurs when 1!methylpyridine reacts with dichlorocarbene\ leading
to phenyl isocyanide ð36BSF890Ł[ Several other examples of similar ring cleavage reactions are given
ð47CB0279\ 53JA0245Ł[

"ii# Aryl isocyanides


Ugi has reported the synthesis of a wide range of aryl isocyanides utilizing his phosgene:NEt2
procedure[ Comprehensive details can be found in the references ð54AG"E#361\ B!60MI 210!90Ł[ More
recently\ diphosgene ð66AG"E#148Ł has been utilized in the preparation of benzoisocyanides[ Other
dehydrating reagents that have been employed in the synthesis of aryl isocyanides include\
POCl2:pyridine ð59CB128Ł\ PPh2:CCl3:NEt2 ð60AG"E#021Ł\ PPh2:diethyl azodicarboxylate "dead#
ð61AG"E#818Ł\ POCl2\ P1O4 ð59CB128Ł\ and triphenylphosphine dibromide ð57LA"607#13Ł[ The de!
hydration of the parent formamide with POCl2:Pri1NH has also proved a popular reagent system
ð74S399Ł\ and a practical synthesis of azidophenylisocyanide has been disclosed ð75ZN"B#021Ł[
The Vilsmeier approach developed by Walborsky and co!workers has also been used in the
synthesis of aryl isocyanides ð61JOC076Ł\ and the synthesis of penta~uorophenyl isocyanide has been
reported[ Thus\ dehalogenation of dibromo!N!"penta~uorophenyl#methanimine with magnesium
gave the product in analytically pure form "Equation "36## ð77CB0334Ł[

F F Br F F
Br Mg
F N F NC (47)

F F F F

The deprotonation of ethyl N!phenylformimidate with BunLi yields phenyl isocyanide "Equation
"37## ð69TL2298Ł[ A further development in this area describes the reaction of substituted aryl imidate
ethers with lithium dialkylamides at low temperature to give substituted aryl isocyanides in excellent
yields ð89CA"001#007364Ł[
Isocyanides 612

Ph BunLi, hexane
N OEt Ph NC (48)

Although not a widely used method\ Farrar has described the preparation of 3!chlorophenyl
isocyanide by treatment of the sodium salt of N!"3!chlorophenyl#dichloromethylsulfonamide with
Na1CO2 at 099>C ð59JCS2947Ł[
N\N?!Diaryl!N!hydroxyformamidines give aryl isocyanides on heating to 069>C ð13JCS"014#76\
13JCS"014#1432Ł\ and Ho
 ~e has reported that 4!aryl aminotetrazoles give high yields of aryl isocyanides
upon oxidation with sodium hypobromite or lead tetraacetate ð65AG"E#002Ł[
A number of aryl isocyanides bearing a functionalized ortho!methyl substituent have been
prepared[ Substituents include Cl and I ð73IC850Ł\ CN and CO1Me ð63BCJ0075Ł\ ketone ð68JOC1929Ł\
and amide ð68TL0928Ł[ All these compounds were prepared by deprotonation of o!methyl phenyl
isocyanide with BunLi at low temperature and quenching the anion with the appropriate electrophile
"Scheme 31#[

LDA, DIGLYME, –78 °C Li E+ E

NC NC NC

Scheme 42

Ito and co!workers have described the preparation of o!diisocyanoarenes by dehydration of the
precursor o!di"formamido#arenes using diphosgene ð77S603Ł[ He has also published the synthesis of
the highly hindered 3!"t!butyldimethylsiloxy#!1\5!xylyl isocyanide by dehydration of the precursor
formamide with POCl2:KOBut\ ð59CB128\ 82JOC5655Ł[
Recent interest in the coordination chemistry of multidentate aryl isocyanides has resulted in the
synthesis of a number of novel aryl isocyanides ð82AG"E#549\ 79IC2749Ł[ Thus\ dehydration of the
bisformamide "13# with PPh2:CCl3:Et2N gave the bidentate isocyanide ligand "14# "Equation "38##
ð71IC1067Ł[

O O PPh3, CCl4 O O
(49)
N H H N NEt3
NC CN
OHC CHO
(24) (25)

The trimethylsilyloxy substituted aryl isocyanide "16# has been prepared by treatment of the
precursor benzoxazole "15# with BunLi followed by trapping with TMS!Cl "Scheme 32#
ð73JOM"159#236Ł[
O O O O O O
( )n ( )n ( )n
BunLi TMS-Cl

N N NC CN NC CN
O O OLi OLi O-TMS O-TMS
(26) (27)

Scheme 43

A number of tridentate aryl isocyanide ligands have been synthesized by the dehydration of the
precursor triformamides with diphosgene ð80AG"E#192\ 80CB0572\ 81OM73Ł^ some examples are shown
in "17# and "18#[

N
NC NC
O O
O O O O
CN CN CN CN

(28) (29)
613 Isocyanides and their Heteroanalo`ues
An interesting class of bi! and tetradentate benzoisocyanides has been disclosed by Ito et al[
ð75JOM"292#290Ł[ On treatment of 0\1!dibromoethane with o!lithiomethylphenyl isocyanides\ oxi!
dative dimerization was found to occur\ leading to 0\1!bis"isocyanophenyl#ethanes in good yields[
These intermediates could then be further deprotonated\ and on treatment with one equivalent of
0\1!dibromoethane the cyclic tetra!isocyanide product "29# was isolated "Scheme 33#[

i, LDA, –78 °C i, LDA (4 equiv.), –78 °C

NC Br NC Br
ii, Br NC ii, Br

NC

NC CN

NC

(30)

Scheme 44

"iii# Polycyclic aromatic isocyanides


Ugi and co!workers have reported the preparation of a number of polycyclic aromatic isocyanides
utilizing the dehydration of the precursor formamides with phosgene\ which appears to be the
method of choice "Equation "49##[
Ar
COCl2
N CHO Ar NC (50)
H R3N

Some examples are given in "20#\ "21# and "22#\ and further examples can be found ð54AG"E#361\
B!60MI 210!90Ł[

NC NC
NC
(31) (97%) (32) (97%) (33) (93%)

"iv# Heterocyclic aromatic isocyanides


Wollweber et al[ have reported the preparation of a number of heterocyclic isocyanides by
the thermolysis of iminoisoxazolones[ The latter compounds are conveniently prepared by the
condensation of nitroso compounds with 2!phenylisoxazol!4"3H#!one[ Heating in toluene at 89>C\
followed by removal of the solvent and sublimation then leads to product isocyanides in excellent
yields ð67AG"E#577Ł[ Examples are shown in Scheme 34[
Isocyanides 614
Ph N R

R NC
N –PhCN, –CO2
O O

CN CN
NC

N N
Me2N N N
H Ph

CN NC
CN

NMe Ph
N O
Ph N N N
H Ph Me

Scheme 45

Ugi and co!workers have reported the preparation of a large number of heterocyclic aromatic
isocyanides using his phosgene dehydration protocol\ which again appears to be the method of
choice ð54AG"E#361\ B!60MI 210!90Ł[ The heterocyclic systems include\ furans\ pyridines\ tetrazoles\
quinolines\ benzotriazoles\ benzothiophene and benzothiazoles^ examples are given in Scheme 35[

Ar
COCl2
N CHO Ar NC
H R3N

CN NC
NC
O
N N
(77%) (93%) (71%)
Ph
NC
NC
S
O O2 CN O O
(50%) (60%) (41%)
O NC
S N N
NC N
N N
NC
NC O
(64%) (46%)

Scheme 46

Kozikowski et al[ have disclosed the preparation of the thiophene isocyanide "23# ð80SL543Ł from
the corresponding thiophene amine using the Hofmann carbylamine approach "Equation "40##[
NH2 NC

CHCl3, 50% NaOH


S S
(51)
TEBA, CH2Cl2
NHEt NHEt

(34)
TEBA = Triethylbenzylammonium chloride
615 Isocyanides and their Heteroanalo`ues
The unusual 1\3\5!triisocyanotriazinetris"pentacarbonylchromium# has been reported as a stable
compound "24# ð71CC073Ł[
CCr(CO)5
N

N N

N N N
(OC)5CrC CCr(CO)5
(35)

2[10[1 ISOCYANIDE ANALOGUES WITH A HETEROATOM OTHER THAN NITROGEN


There are no known examples of isocyanide analogues RX1C\ where Xphosphorus\ arsenic\
antimony or bismuth[ The intermediacy of a {phosphaisocyanide| has been implicated when C!
halophosphaalkenes are treated with base at low temperature "Scheme 36# ð80CB1566\ 83CR0302Ł[
The product of the reaction is a phosphaalkyne\ which was suggested to have been formed by
rearrangement of the highly unstable phosphaisocyanide at −74>C[
X
R P R P C R P
Li

Scheme 47

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
References to Volume 3
EXPLANATION OF THE REFERENCE SYSTEM
Throughout this work\ references are designated by a numberÐlettering coding of which the _rst
two numbers denote tens and units of the year of publication\ the next one to three letters denote
the journal\ and the _nal numbers denote the page[ This code appears in the text each time a
reference is quoted^ the advantages of this system are outlined in the Introduction[ The system has
been used previously in {{Comprehensive Heterocyclic Chemistry\|| eds A[ R[ Katritzky and C[ W[
Rees\ Pergamon\ Oxford\ 0873 and is based on that used in the following two monographs] "a# A[ R[
Katritzky and J[ M[ Lagowski\ {{Chemistry of the Heterocyclic N!Oxides\|| Academic Press\
New York\ 0860^ "b# J[ Elguero\ C[ Marzin\ A[ R[ Katritzky and P[ Linda\ {{The Tautomerism of
Heterocycles\|| in {{Advances in Heterocyclic Chemistry\|| Supplement 0\ Academic Press\ New
York\ 0865[
The following additional notes apply]
0[ A list of journal codes in alphabetical order\ together with the journals to which they refer\ is
given immediately following these notes[ Journal names are abbreviated throughout using the
CASSI "Chemical Abstracts Service Source Index# system[
1[ Each volume contains all the references cited in that volume^ no separate lists are given for
individual chapters[
2[ The list of references is arranged in order of "a# year\ "b# journal in alphabetical order of
journal code\ "c# part letter or number if relevant\ "d# volume number if relevant\ "e# page number[
3[ In the reference list the code is followed by "a# the complete literature citation in the con!
ventional manner and "b# the number"s# of the page"s# on which the reference appears\ whether in
the text or in tables\ schemes\ etc[
4[ For nontwentieth!century references the year is given in full in the code[
5[ For journals which are published in separate parts\ the part letter or number is given "when
necessary# in parentheses immediately after the journal code letters[
6[ Journal volume numbers are not included in the code numbers unless more than one volume
was published in the year in question\ in which case the volume number is included in parentheses
immediately after the journal code letters[
7[ Patents are assigned appropriate three!letter codes[
8[ Frequently cited books are assigned codes[
09[ Less common journals and books are given the code {{MI|| for miscellaneous with the whole
code for books pre_xed by the letter {{B!||[
00[ Where journals have changed names\ the same code is used throughout\ e[g[ CB refers to
both Chem[ Ber[ and to Ber[ Dtsch[ Chem[ Ges[

Journal Codes
AAC Antimicrob[ Agents Chemother[
ABC Agric[ Biol[ Chem[
AC Appl[ Catal[
AC"P# Ann[ Chim[ "Paris#
AC"R# Ann[ Chim[ "Rome#
ACH Acta Chim[ Acad[ Sci[ Hung[

616
617 References

ACR Acc[ Chem[ Res[


ACS Acta Chem[ Scand[
ACS"A# Acta Chem[ Scand[\ Ser[ A
ACS"B# Acta Chem[ Scand[\ Ser[ B
AF Arzneim[!Forsch[
AFC Adv[ Fluorine Chem[
AG Angew[ Chem[
AG"E# Angew[ Chem[\ Int[ Ed[ Engl[
AHC Adv[ Heterocycl[ Chem[
AHCS Adv[ Heterocycl[ Chem[ Supplement
AI Anal[ Instrum[
AJC Aust[ J[ Chem[
AK Ark[ Kemi
AKZ Arm[ Khim[ Zh[
AM Adv[ Mater[ "Weinheim\ Ger[#
AMLS Adv[ Mol[ Spectrosc[
AMS Adv[ Mass[ Spectrom[
ANC Anal[ Chem[
ANL Acad[ Naz[ Lncei
ANY Ann[ N[ Y[ Acad[ Sci[
AOC Adv[ Organomet[ Chem[
AP Arch[ Pharm[ "Weinheim\ Ger[#
APO Adv[ Phys[ Org[ Chem[
AQ An[ Quim[
AR Annu[ Rep[ Prog[ Chem[
AR"A# Annu[ Rep[ Prog[ Chem[\ Sect[ A
AR"B# Annu[ Rep[ Prog[ Chem[\ Sect[ B
ARP Annu[ Rev[ Phys[ Chem[
ASI Acta Chim[ Sin[ Engl[ Ed[
ASIN Acta Chim[ Sin[
AX Acta Crystallogr[
AX"A# Acta Crystallogr[\ Part A
AX"B# Acta Crystallogr[\ Part B
B Biochemistry
BAP Bull[ Acad[ Pol[ Sci[\ Ser[ Sci[ Chim[
BAU Bull[ Acad[ Sci[ USSR\ Div[ Chim[ Sci[
BBA Biochim[ Biophys[ Acta
BBR Biochim[ Biophys[ Res[ Commun[
BCJ Bull[ Chem[ Soc[ Jpn[
BEP Belg[ Pat[
BJ Biochem[ J[
BJP Br[ J[ Pharmacol[
BMC Bioorg[ Med[ Chem[ Lett[
BP Biochem[ Biopharmacol[
BPJ Br[ Polym[ J[
BRP Br[ Pat[
BSB Bull[ Soc[ Chim[ Belg[
BSF Bull[ Soc[ Chim[ Fr[
BSF"1# Bull[ Soc[ Chim[ Fr[\ Part 1
C Chimia
CA Chem[ Abstr[
CAN Cancer
CAR Carbohydr[ Res[
CAT Chim[ Acta Turc[
CB Chem[ Ber[
References 618

CBR Chem[ Br[


CC J[ Chem[ Soc[\ Chem[ Commun[
CCA Croat[ Chem[ Acta
CCC Collect[ Czech[ Chem[ Commun[
CCR Coord[ Chem[ Rev[
CE Chem[ Express
CEN Chem[ Eng[ News
CHE Chem[ Heterocycl[ Compd[ "Engl[ Transl[#
CHEC Comp[ Heterocycl[ Chem[
CI"L# Chem[ Ind[ "London#
CI"M# Chem[ Ind[ "Milan#
CJC Can[ J[ Chem[
CJS Can[ J[ Spectrosc[
CL Chem[ Lett[
CLY Chem[ Listy
CM Chem[ Mater[
CMC Comp[ Med[ Chem[
COC Comp[ Org[ Chem[
COMC!I Comp[ Organomet[ Chem[\ 0st edn[
COS Comp[ Org[ Synth[
CP Can[ Pat[
CPB Chem[ Pharm[ Bull[
CPH Chem[ Phys[
CPL Chem[ Phys[ Lett[
CR C[ R[ Hebd[ Seances Acad[ Sci[
CR"A# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ A
CR"B# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ B
CR"C# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ C
CRAC Crit[ Rev[ Anal[ Chem[
CRV Chem[ Rev[
CS Chem[ Scr[
CSC Cryst[ Struct[ Commun[
CSR Chem[ Soc[ Rev[
CT Chem[ Tech[
CZ Chem[!Ztg[
CZP Czech[ Pat[
DIS Diss[ Abstr[
DIS"B# Diss[ Abstr[ Int[ B[
DOK Dokl[ Akad[ Nauk SSSR
DP Dyes Pigm[
E Experientia
EC Educ[ Chem[
EF Energy Fuels
EGP Ger[ "East# Pat[
EJM Eur[ J[ Med[ Chem[
EUP Eur[ Pat[
FCF Forschr[ Chem[ Forsch[
FCR Fluorine Chem[ Rev[
FES Farmaco Ed[ Sci[
FOR Forschr[ Chem[ Org[ Naturst[
FRP Fr[ Pat[
G Gazz[ Chim[ Ital[
GAK Gummi Asbest Kunstst[
GEP Ger[ Pat[
GEP"O# Ger[ Pat[ O}en[
629 References

GSM Gen[ Synth[ Methods


H Heterocycles
HAC Heteroatom Chem[
HC Chem[ Heterocycl[ Compd[
HCA Helv[ Chim[ Acta
HOU Methoden Org[ Chem[ "Houben!Weyl#
HP Hydrocarbon Process
IC Inorg[ Chem[
ICA Inorg[ Chim[ Acta
IEC Ind[ Eng[ Chem[ Res[
IJ Isr[ J[ Chem[
IJC Indian J[ Chem[
IJC"A# Indian J[ Chem[\ Sect[ A
IJC"B# Indian J[ Chem[\ Sect[ B
IJM Int[ J[ Mass Spectrom[ Ion Phys[
IJQ Int[ J[ Quantum Chem[
IJS Int[ J[ Sulfur Chem[
IJS"A# Int[ J[ Sulfur Chem[\ Part A
IJS"B# Int[ J[ Sulfur Chem[\ Part B
IS Inorg[ Synth
IZV Izv[ Akad[ Nauk SSSR Ser[ Khim[
JA J[ Am[ Chem[ Soc[
JAN J[ Antibiot[
JAP Jpn[ Pat[
JAP"K# Jpn[ Kokai
JBC J[ Biol[ Chem[
JC J[ Chromatogr[
JCC J[ Coord[ Chem[
JCE J[ Chem[ Ed[
JCED J[ Chem[ Eng[ Data
JCI J[ Chem[ Inf[ Comput[ Sci[
JCP J[ Chem[ Phys[
JCPB J[ Chim[ Phys[ Physico!Chim[ Biol[
JCR"M# J[ Chem[ Res[ "M#
JCR"S# J[ Chem[ Res[ "S#
JCS J[ Chem[ Soc[
JCS"A# J[ Chem[ Soc[ "A#
JCS"B# J[ Chem[ Soc[ "B#
JCS"C# J[ Chem[ Soc[ "C#
JCS"D# J[ Chem[ Soc[\ Dalton Trans[
JCS"F0# J[ Chem[ Soc[\ Faraday Trans[ 0
JCS"F1# J[ Chem[ Soc[\ Faraday Trans[ 1
JCS"P0# J[ Chem[ Soc[\ Perkin Trans[ 0
JCS"P1# J[ Chem[ Soc[\ Perkin Trans[ 1
JCS"S1# J[ Chem[ Soc[ "Suppl[ 1#
JEC J[ Electroanal[ Chem[ Interfacial Electrochem[
JEM J[ Energy Mater[
JES J[ Electron[ Spectrosc[
JFA J[ Sci[ Food[ Agri[
JFC J[ Fluorine Chem[
JGU J[ Gen[ Chem[ USSR "Engl[ Transl[#
JHC J[ Heterocycl[ Chem[
JIC J[ Indian Chem[ Soc[
JINC J[ Inorg[ Nucl[ Chem[
JLC J[ Liq[ Chromatogr[
References 620

JMAS J[ Mat[ Sci[


JMC J[ Med[ Chem[
JMOC J[ Mol[ Catal[
JMR J[ Magn[ Reson[
JMS J[ Mol[ Sci[
JOC J[ Org[ Chem[
JOM J[ Organomet[ Chem[
JOU J[ Org[ Chem[ USSR "Engl[ Transl[#
JPC J[ Phys[ Chem[
JPJ J[ Pharm[ Soc[ Jpn[
JPO J[ Phys[ Org[ Chem[
JPP J[ Pharm[ Pharmacol[
JPR J[ Prakt[ Chem[
JPS J[ Pharm[ Sci[
JPS"A# J[ Polym[ Sci[\ Polym[ Chem[\ Part A
JPU J[ Phys[ Chem[ USSR "Engl[ Transl[#
JSC J[ Serbochem[ Soc[
JSP J[ Mol[ Spectrosc[
JST J[ Mol[ Struct[
K Kristallogra_ya
KFZ Khim[ Farm[ Zh[
KGS Khim[ Geterotsikl[ Soedin[
KO Kirk!Othmer Encyc[
KPS Khim[ Prir[ Soedin[
L Langmuir
LA Liebigs Ann[ Chem[
LC Liq[ Cryst[
LS Life Sci[
M Monatsh[ Chem[
MAC Macromol[ Chem[
MC Mendeleev Chem[ J[ "Engl[ Transl[#
MCLC Mol[ Cryst[ Liq[ Cryst[
MI Miscellaneous ðbook:journalŁ
MIP Miscellaneous Pat[
MM Macromolecules
MP Mol[ Phys[
MRC Magn[ Reson[ Chem[
N Naturwissenschaften
NAT Nat[
NEP Neth[ Pat[
NJC Nouv[ J[ Chim[
NKK Nippon Kagaku Kaishi "J[ Chem[ Soc[ Jpn[#
NKZ Nippon Kagaku Zasshi
NZJ N[ Z[ J[ Sci[ Technol[
OCS Organomet[ Synth[
OM Organometallics
OMR Org[ Magn[ Reson[
OMS Org[ Mass Spectrom[
OPP Org[ Prep[ Proced[ Int[
OR Org[ React[
OS Org[ Synth[
OSC Org[ Synth[\ Coll[ Vol[
P Phytochemistry
PA Polym[ Age
PAC Pure Appl[ Chem[
621 References

PAS Pol[ Acad[ Sci[


PB Polym[ Bull[
PC Personal Communication
PCS Proc[ Chem[ Soc[
PHA Pharmazi
PHC Prog[ Heterocycl[ Chem[
PIA Proc[ Indian Acad[ Sci[
PIA"A# Proc[ Indian Acad[ Sci[\ Sect[ A
PJC Pol[ J[ Chem[
PJS Pak[ J[ Sci[ Ind[ Res[
PMH Phys[ Methods Heterocycl[ Chem[
PNA Proc[ Natl[ Acad[ Sci[ USA
POL Polyhedron
PP Polym[ Prepr[
PRS Proceed[ Roy[ Soc[
PS Phosphorus Sulfur
QR Q[ Rev[\ Chem[ Soc[
QRS Quart[ Rep[ Sulfur[ Chem[
QSAR Quant[ Struct[ Act[ Relat[ Pharmacol[ Chem[ Biol[
RC Rubber Chem[ Technol[
RCM Rapid Commun[ Mass Spectrom[
RCP Rec[ Chem[ Prog[
RCR Russ[ Chem[ Rev[ "Engl[ Transl[#
RHA Rev[ Heteroatom Chem[
RJ Rubber J[
RP Rev[ Polarogr[
RRC Rev[ Roum[ Chim[
RS Ric[ Sci[
RTC Recl[ Trav[ Chim[ Pays!Bas
RZC Rocz[ Chem[
S Synthesis
SA Spectrochim[ Acta
SA"A# Spectrochim[ Acta\ Part A
SAP S[ Afr[ Pat[
SC Synth[ Commun[
SCI Science
SL Synlett
SM Synth[ Met[
SR Sulfur Reports
SRI Synth[ React[ Inorg[ Metal!Org[ Chem[
SS Sch[ Sci[ Rev[
SST Org[ Compd[ Sulphur\ Selenium\ Tellurium ðR[ Soc[ Chem[ seriesŁ
SUL Sulfur Letters
SZP Swiss Pat[
T Tetrahedron
T"S# Tetrahedron\ Suppl[
TA Tetrahedron Asymmetry
TAL Talanta
TCA Theor[ Chim[ Acta
TCC Top[ Curr[ Chem[
TCM Tetrahedron\ Comp[ Method
TFS Trans[ Faraday Soc[
TH Thesis
TL Tetrahedron Lett[
TS Top[ Stereochem[
References 622

UK Usp[ Khim[
UKZ Ukr[ Khim[ Zh[ "Russ[ Ed[#
UP Unpublished Results
URP USSR Pat[
USP US Pat[
WCH Wiadom[ Chem[
YGK Yuki Gosei Kagaku Kyokaishi
YZ Yakugaku Zasshi "J[ Pharm[ Soc[ Jpn[#
ZAAC Z[ Anorg[ Allg[ Chem[
ZAK Zh[ Anal[ Khim[
ZC Z[ Chem[
ZN Z[ Naturforsch[
ZN"A# Z[ Naturforsch[\ Teil A
ZN"B# Z[ Naturforsch[\ Teil B
ZOB Zh[ Obshch[ Khim[
ZOR Zh[ Org[ Khim[
ZPC HoppeÐSeyler|s Z[ Physiol[ Chem[
ZPK Zh[ Prikl[ Khim[

VOLUME 2 REFERENCES

0799MI 219!90 E[ Howard^ Phil[ Trans[ Roy[ Soc[ London\ 0799\ 193[ 574

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0749LA"64#16 A[ Strecker^ Justus Liebi`s Ann[ Chem[\ 0749\ 64\ 16[ 505

0743JPR"50#59 A[ E[ Williamson^ J[ Prakt[ Chem[\ 0743\ 50\ 59[ 501

0748LA"001#205 W[ Lieke^ Justus Liebi`s Ann[ Chem[\ 0748\ 001\ 205[ 582

0755JPR036 E[ Meyer^ J[ Prakt[ Chem[\ 0755\ 56\ 036[ 582

0756LA"033#003 A[ W[ Hofmann^ Justus Liebi`s Ann[ Chem[\ 0756\ 033\ 003[ 582

0758LA"035#008 A[ Gautier^ Justus Liebi`s Ann[ Chem[\ 0758\ 035\ 008[ 583

0769CB655 A[ W[ Hofmann^ Ber[ Dtsch[ Chem[ Ges[\ 0769\ 2\ 655[ 587\ 588\ 610

0761LA"053#144 F[ Urech^ Justus Liebi`s Ann[ Chem[\ 0761\ 053\ 144[ 504

0762CB109 W[ Weith^ Ber[ Dtsch[ Chem[ Ges[\ 0762\ 5\ 109[ 587

0766CB690 T[ Norton and A[ Oppenheim^ Ber[ Dtsch[ Chem[ Ges[\ 0766\ 09\ 690[ 435

0767LA"080#22 A[ Claus^ Justus Liebi`s Ann[ Chem[\ 0767\ 080\ 22[ 510\ 527

0779CB271 F[ Tiemann^ Ber[ Dtsch[ Chem[ Ges[\ 0779\ 02\ 271[ 505

0770CB0264 R[ Schi}^ Ber[ Dtsch[ Chem[ Ges[\ 0770\ 03\ 0264[ 357
0770CB0534 W[ Mann^ Ber[ Dtsch[ Chem[ Ges[\ 0770\ 03\ 0534[ 501

0772CB1129 T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0772\ 05\ 1129[ 351\ 357

0773CB468 E[ Fischer^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 468[ 349
0773CB842 T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 842[ 357
0773CB0393 A[ W[ Hofmann^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 0393[ 519
0773CB0460 B[ Lach^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 0460[ 507
0773CB0522 T[ Sandmeyer^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 0522[ 553
0773CB0819 A[ W[ Hofmann^ Ber[ Dtsch[ Chem[ Ges[\ 0773\ 06\ 0819[ 519

0774CB1260 E[ Buchner and T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0774\ 07\ 1260[ 208
623 References
0775CB0322 A[ W[ Hofmann^ Ber[ Dtsch[ Chem[ Ges[\ 0775\ 08\ 0322[ 519
0775CB0711 A[ W[ Hofmann^ Ber[ Dtsch[ Chem[ Ges[\ 0775\ 08\ 0711[ 519

0776CB710 E[ Fischer^ Ber[ Dtsch[ Chem[ Ges[\ 0776\ 19\ 710[ 349

0778AC"R#111 A[ Haller and A[ Held^ Ann[ Chim[ "Rome#\ 0778\ 06\ 111[ 503
0778JA78 C[ Palmer^ J[ Am[ Chem[ Soc[\ 0778\ 00\ 78[ 501

0789CB0460 V[ Meyer^ Ber[ Dtsch[ Chem[ Ges[\ 0789\ 12\ 0460[ 435

0781LA"169#156 I[ U[ Nef^ Justus Liebi`s Ann[ Chem[\ 0781\ 169\ 156[ 583

0782CB1942 R[ Rothenburg^ Ber[ Dtsch[ Chem[ Ges[\ 0782\ 15\ 1942[ 344
0782LA"163#201 A[ Michaelis and H[ Siebert^ Justus Liebi`s Ann[ Chem[\ 0782\ 163\ 201[ 507\ 508

0783BSF0956 C[ Moureu^ Bull[ Soc[ Chim[ Fr[\ 0783\ 00\ 0956[ 507
0783CB48 R[ Jay and T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0783\ 16\ 48[ 366
0783CB689 R[ Rothenburg^ Ber[ Dtsch[ Chem[ Ges[\ 0783\ 16\ 689[ 217
0783CB1082 A[ Werner and H[ Buss^ Ber[ Dtsch[ Chem[ Ges[\ 0783\ 16\ 1082[ 572

0784AC"R#178 A[ Berg^ Ann[ Chim[ "Rome#\ 0784\ 2\ 178[ 519


0784CB104 E[ Buchner^ Ber[ Dtsch[ Chem[ Ges[\ 0784\ 17\ 104[ 377
0784CB0571 E[ Bamberger and E[ Renauld^ Ber[ Dtsch[ Chem[ Ges[\ 0784\ 17\ 0571[ 519
0784CB1758 L[ Gattermann^ Ber[ Dtsch[ Chem[ Ges[\ 0784\ 17\ 1758[ 253

0785CB51 G[ Munch^ Ber[ Dtsch[ Chem[ Ges[\ 0785\ 18\ 51[ 505
0785CB0060 H[ Schmidtmann^ Ber[ Dtsch[ Chem[ Ges[\ 0785\ 18\ 0060[ 503
0785CZ89 C[ Pape^ Chem[!Zt`[\ 0785\ 00\ 89[ 504

0787CB1378 T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0787\ 20\ 1378[ 366

0788CB532 A[ Hantzsch and G[ Osswald^ Ber[ Dtsch[ Chem[ Ges[\ 0788\ 21\ 532[ 503
0788CB0455 A[ Michaelis and E[ Kohler^ Ber[ Dtsch[ Chem[ Ges[\ 0788\ 21\ 0455[ 382

99CB1359 T[ Curtius and A[ Lublin^ Ber[ Dtsch[ Chem[ Ges[\ 0899\ 22\ 1359[ 333\ 334

90CR"021#367 E[ E[ Blaise^ C[ R[ Hebd[ Seances Acad[ Sci[\ 0890\ 021\ 367[ 350
90JPR071 A[ Edinger and W[ Arnold^ J[ Prakt[ Chem[\ 0890\ 53\ 071[ 251

91CB264 R[ Mohlau\ M[ Heinze and R[ Zimmermann^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 264[ 252
91CB786 A[ Hantzsch and M[ Lehmann^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 786[ 354\ 355
91CB804 C[ Bulow and E[ Hailer^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 804[ 337
91CB2123 T[ Curtius and H[ Franzen^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 2123[ 333
91CB2536 A[ Einhorn and C[ Mettler^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 2536[ 507
91JCS487 O[ Silberrad^ J[ Chem[ Soc[\ 0891\ 487[ 357
91LA"214#018 L[ Wol}^ Justus Liebi`s Ann[ Chem[\ 0891\ 214\ 018[ 429

92JCS0190 A[ G[ Green and A[ G[ Perkin^ J[ Chem[ Soc[\ 0892\ 0190[ 247


92JPR61 A[ Edinger and J[ C[ Ritsema^ J[ Prakt[ Chem[\ 0892\ 57\ 61[ 287

93CB0150 T[ Curtius and E[ Muller^ Ber[ Dtsch[ Chem[ Ges[\ 0893\ 26\ 0150[ 357
93CB0173 T[ Curtius^ Ber[ Dtsch[ Chem[ Ges[\ 0893\ 26\ 0173[ 357\ 365
93CB2912 R[ Stolle^ Ber[ Dtsch[ Chem[ Ges[\ 0893\ 26\ 2912[ 217
93CB3184 A[ Werner and A[ Piquet^ Ber[ Dtsch[ Chem[ Ges[\ 0893\ 26\ 3184[ 611
93JA0434 W[ A[ Noyes^ J[ Am[ Chem[ Soc[\ 0893\ 15\ 0434[ 501
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93LA"222#0 L[ Wol}^ Justus Liebi`s Ann[ Chem[\ 0893\ 222\ 0[ 429

94CB0624 H[ Staudinger^ Ber[ Dtsch[ Chem[ Ges[\ 0894\ 27\ 0624[ 429\ 420

95CB0959 P[ Friedlander^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0959[ 140
95CB0070 W[ Gulewitsch and T[ Wasmus^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0070[ 505
95CB0262 T[ Curtius and A[ Darapsky^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0262[ 357
95CB0268 T[ Curtius and J[ Thompson^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0268[ 357
95CB0272 T[ Curtius and J[ Thompson^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0272[ 365
95CB0745 A[ J[ Ultee^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0745[ 504
95CB2951 H[ Staudinger^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 2951[ 420

96CB1698 A[ Braun and J[ Tcherniac^ Ber[ Dtsch[ Chem[ Ges[\ 0896\ 39\ 1698[ 508
96JCS0827 N[ T[ M[ Wilsmore^ J[ Chem[ Soc[\ 0896\ 80\ 0827[ 423\ 424
96LA"240#243 C[ Pomeranz^ Justus Liebi`s Ann[ Chem[\ 0896\ 240\ 243[ 501
96LA"245#44 H[ Staudinger^ Justus Liebi`s Ann[ Chem[\ 0896\ 245\ 44[ 450
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References 624
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97CB233 T[ Curtius\ A[ Darapsky and A[ Brockmuhl^ Ber[ Dtsch[ Chem[ Ges[\ 0897\ 30\ 233[ 365
97CB1197 H[ Staudinger and E[ Ott^ Ber[ Dtsch[ Chem[ Ges[\ 0897\ 30\ 1197[ 423\ 430
97CB1814 A[ Skita and R[ Levi^ Ber[ Dtsch[ Chem[ Ges[\ 0897\ 30\ 1814[ 505
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97MI 207!90 L[ Rosenthaler^ Biochem[ Z[\ 0897\ 03\ 127[ 517

98CB1225 G[ Schroeter^ Ber[ Dtsch[ Chem[ Ges[\ 0898\ 31\ 1225[ 429
98CB2245 G[ Schroeter^ Ber[ Dtsch[ Chem[ Ges[\ 0898\ 31\ 2245[ 429
98CB3102 H[ Staudinger and J[ Kubinsky^ Ber[ Dtsch[ Chem[ Ges[\ 0898\ 31\ 3102[ 429\ 420

09CB0913 W[ Dieckmann^ Ber[ Dtsch[ Chem[ Ges[\ 0809\ 32\ 0913[ 219
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00CB1086 H[ Staudinger and O[ Kupfer^ Ber[ Dtsch[ Chem[ Ges[\ 0800\ 33\ 1086[ 352
00JPR011 H[ Franzen and F[ Kraft^ J[ Prakt[ Chem[\ 0800\ 73\ 011[ 336
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00MI 207!90 V[ Grignard^ Compt[ Rend[\ 0800\ 041\ 277[ 503

01CB0724 R[ Lesser and R[ Weiss^ Ber[ Dtsch[ Chem[ Ges[\ 0801\ 34\ 0724[ 145
01LA"283#12 L[ Wol}^ Justus Liebi`s Ann[ Chem[\ 0893\ 283\ 12[ 364\ 429
B!01MI 205!90 H[ Staudinger^ {{Die Ketene\|| Ferdinand Enke\ Stuttgart\ 0801[ 415
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02CB2428 H[ Staudinger\ E[ Anthes and H[ Schneider^ Ber[ Dtsch[ Chem[ Ges[\ 0802\ 35\ 2428[ 423\ 430
02CB3990 J[ Houben and H[ Kau}mann^ Ber[ Dtsch[ Chem[ Ges[\ 0802\ 35\ 3009[ 575
02M0782 A[ Franke^ Monatsh[ Chem[\ 0802\ 23\ 0782[ 501

03MI 207!90 V[ Grignard and E[ Bellet^ Compt[ Rend[\ 0803\ 047\ 346[ 503

04AC"R#17 V[ Grignard\ E[ Bellett and C[ Courtot^ Ann[ Chim[ "Rome#\ 0804\ 2\ 17[ 503
04BSF117 V[ Grignard and C[ Courtot^ Bull[ Soc[ Chim[ Fr[\ 0804\ 06\ 117[ 564
04CB842 W[ Madelung and M[ Tencer^ Ber[ Dtsch[ Chem[ Ges[\ 0804\ 37\ 842[ 611
04JCS159 M[ O[ Forster^ J[ Chem[ Soc[\ 0804\ 159[ 352
04JCS0380 D[ L[ Clibbens and M[ Nierenstein^ J[ Chem[ Soc[\ 0804\ 0380[ 363

05BJ"09#208 H[ D[ Dakin^ Biochem[ J[\ 0805\ 09\ 208[ 519


05CB0272 A[ Albert^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 0272[ 504
05CB0786 H[ Staudinger and J[ Gaule^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 0786[ 352
05CB0812 H[ Staudinger and J[ Goldstein^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 0812[ 352
05CB0867 H[ Staudinger\ J[ Becker and H[ Hirzel^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 0867[ 363\ 364
05CB1586 G[ Schroeter^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 1586[ 429
05PRS121 H[ D[ Dakin\ J[ B[ Cohen\ M[ Daufresne and J[ Kenyon^ Proc[ Roy[ Soc[ "London#\ 0805\
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06BJ"00#68 H[ D[ Dakin^ Biochem[ J[\ 0806\ 00\ 68[ 519

07M139 R[ Scholl and J[ Adler^ Monatsh[ Chem[\ 0807\ 28\ 139[ 507

08CB0638 K[ W[ Rosenmund and E[ Struck^ Ber[ Dtsch[ Chem[ Ges[\ 0808\ 41\ 0638[ 550
08HCA508 H[ Staudinger and J[ Meyer^ Helv[ Chim[ Acta\ 0808\ 1\ 508[ 387
08HCA524 H[ Staudinger and J[ Meyer^ Helv[ Chim[ Acta\ 0808\ 1\ 524[ 444\ 480
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19CB61 H[ Staudinger and J[ Meyer^ Ber[ Dtsch[ Chem[ Ges[\ 0819\ 42\ 61[ 450\ 473\ 480
19HCA722 H[ Staudinger and J[ Siegwart^ Helv[ Chim[ Acta\ 0819\ 2\ 722[ 441
19HCA742 H[ Staudinger\ G[ Rathsam and F[ Kjelsberg^ Helv[ Chim[ Acta\ 0819\ 2\ 742[ 438

10HCA776 H[ Staudinger and E[ Hauser^ Helv[ Chim[ Acta\ 0810\ 3\ 776[ 473
10HCA786 H[ Staudinger and W[ Braunholtz^ Helv[ Chim[ Acta\ 0810\ 3\ 786[ 475

11JCS0537 O[ L[ Brady and G[ P[ McHugh^ J[ Chem[ Soc[\ 0811\ 0537[ 335


11JCS0588 A[ Lapworth and J[ A[ McRae^ J[ Chem[ Soc[\ 0811\ 0588[ 515\ 523

12CB0025 D[ Vorlander\ J[ Osterburg and O[ Meye^ Ber[ Dtsch[ Chem[ Ges[\ 0812\ 45\ 0025[ 341
12CB0061 K[ van Auwers^ Ber[ Dtsch[ Chem[ Ges[\ 0812\ 45\ 0061[ 501
12HCA180 H[ Staudinger\ H[ Schneider\ P[ Schotz and P[ M[ Strong^ Helv[ Chim[ Acta\ 0812\ 5\ 180[ 423
12JA1056 C[ D[ Hurd and C[ Kocour^ J[ Am[ Chem[ Soc[\ 0812\ 34\ 1056[ 424
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13CB0097 D[ Vorlander\ J[ Osterburg and O[ Meye^ Ber[ Dtsch[ Chem[ Ges[\ 0813\ 46\ 0097[ 341
625 References
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15AC"P#4 V[ Grignard and H[ Perrichon^ Ann[ Chimie\ 0815\ 4\ 4[ 564


15BSF0478 V[ Grignard and K[ Ono^ Bull[ Soc[ Chim[ Fr[\ 0815\ 28\ 0478[ 503

16CB713 R[ E[ Lyons and W[ E[ Brandt^ Ber[ Dtsch[ Chem[ Ges[\ 0816\ 59\ 713[ 399
16M60 F[ Holzl\ W[ Hauser and M[ Eckmann^ Monatsh[ Chem[\ 0816\ 37\ 60[ 584

17JCS679 E[ G[ Hartley^ J[ Chem[ Soc[\ 0817\ 679[ 584


17JCS0209 W[ Bradley and R[ Robinson^ J[ Chem[ Soc[\ 0817\ 0209[ 363

18CB1022 N[ Schapiro^ Ber[ Dtsch[ Chem[ Ges[\ 0818\ 51\ 1022[ 333
18CB2937 A[ E[ Tschitschibabin and I[ L[ Knunjanz^ Ber[ Dtsch[ Chem[ Ges[\ 0818\ 51\ 2937[ 252
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29CB691 H[ Lindemann\ A[ Wolter and R[ Groger^ Ber[ Dtsch[ Chem[ Ges[\ 0829\ 52\ 691[ 357
29CB0549 H[ Lindemann and L[ Wiegrebe^ Ber[ Dtsch[ Chem[ Ges[[\ 0829\ 52\ 0549[ 583
29JCS85 F[ D[ Chattaway and L[ H[ Farinholt^ J[ Chem[ Soc[\ 0829\ 85[ 340
29JCS0765 D[ L[ Hammick\ R[ G[ A[ New\ N[ V[ Sidgewick and L[ E[ Sutton^ J[ Chem[ Soc[\ 0829\
0765[ 583

20CB429 R[ E[ Lyons and E[ D[ Scudder^ Ber[ Dtsch[ Chem[ Ges[\ 0820\ 53\ 429[ 399
20IEC241 H[ B[ Hass and J[ R[ Marshall^ Ind[ En`[ Chem[ Res[\ 0820\ 12\ 241[ 501
20JCS0280 W[ Cocker and A[ Lapworth^ J[ Chem[ Soc[\ 0820\ 0280[ 505
20JCS0783 W[ Cocker and A[ Lapworth^ J[ Chem[ Soc[\ 0820\ 0783[ 505
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21BSB085 H[ Wuyts and H[ Koeck^ Bull[ Soc[ Chim[ Bel`[\ 0821\ 30\ 085[ 507
21CB154 A[ Weissberger and H[ Bach^ Ber[ Dtsch[ Chem[ Ges[\ 0821\ 54\ 154[ 357
21HCA143 T[ Reichstein and G[ Trivelli^ Helv[ Chim[ Acta\ 0821\ 04\ 143[ 501
21JA1321 C[ D[ Hurd and M[ F[ Dull^ J[ Am[ Chem[ Soc[\ 0821\ 43\ 1321[ 424\ 430
21JA1770 J[ B[ Conant and P[ D[ Bartlett^ J[ Am[ Chem[ Soc[\ 0821\ 43\ 1770[ 338
21MI 207!90 D[ Biguard^ Compt[ Rend[\ 0821\ 083\ 872[ 504
21RZC169 L[ Szperl and W[ Wiorogorski^ Rocz[ Chem[\ 0821\ 01\ 169[ 271

22CB126 A[ Schonberg\ A[ Stephenson\ H[ Kaltschmitt\ E[ Peterson and H[ Schulten^ Ber[ Dtsch[


Chem[ Ges[\ 0822\ 55\ 126[ 436
22CB300 H[ Meerwein^ Ber[ Dtsch[ Chem[ Ges[\ 0822\ 55\ 300[ 179
22CB0901 F[ Arndt and H[ Scholz^ Ber[ Dtsch[ Chem[ Ges[\ 0822\ 55\ 0901[ 368
22JA3050 F[ C[ Whitmore and G[!H[ Fleming^ J[ Am[ Chem[ Soc[\ 0822\ 44\ 3050[ 501
22JA3188 E[ P[ Kohler and F[ W[ Brown^ J[ Am[ Chem[ Soc[\ 0822\ 44\ 3188[ 501
22JCS252 E[ C[ S[ Jones and J[ Kenner^ J[ Chem[ Soc[\ 0822\ 252[ 354

23CB28 E[ Strack and H[ Schwaneberg^ Ber[ Dtsch[ Chem[ Ges[\ 0823\ 56\ 28[ 501
23CB0651 J[ Braun and W[ Rudolph^ Ber[ Dtsch[ Chem[ Ges[\ 0823\ 56\ 0651[ 508
23JA1984 G[ E[ P[ Smith and F[ W[ Bergstrom^ J[ Am[ Chem[ Soc[\ 0823\ 45\ 1984[ 505
23JA1086 G[ A[ Menge^ J[ Am[ Chem[ Soc[\ 0823\ 45\ 1086[ 505
23JA1270 F[ O[ Rice and A[ L[ Glasebrook^ J[ Am[ Chem[ Soc[\ 0823\ 45\ 1270[ 278
23JPR06 G[ Rohde^ J[ Prakt[ Chem[\ 0823\ 039\ 06[ 505
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24CB749 N[ A[ Preobrashenski\ A[ M[ Poljakowa and W[ A[ Preobrashenski^ Ber[ Dtsch[ Chem[ Ges[\


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57CB166 M[ Schmidt and H[ Schulz^ Chem[ Ber[\ 0857\ 090\ 166[ 260
57CB352 K[ Griesbaum^ Chem[ Ber[\ 0857\ 090\ 352[ 215
57CB484 H[ Schmidbaur and W[ Tronich^ Chem[ Ber[\ 0857\ 090\ 484[ 385
57CB605 A[ Schonberg and E[ Frese^ Chem[ Ber[\ 0857\ 090\ 605[ 251\ 254
57CB843 R[ Aumann and E[ O[ Fischer^ Chem[ Ber[\ 0857\ 090\ 843[ 486
57CB0019 C[ Metzger and R[ Wegler^ Chem[ Ber[\ 0857\ 090\ 0019[ 416
57CB0152 M[ Regitz and J[ Ruter^ Chem[ Ber[\ 0857\ 090\ 0152[ 361
57CB0243 G[ Maier and T[ Sayrac^ Chem[ Ber[\ 0857\ 090\ 0243[ 344
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57RTC0125 H[ E[ Wijers\ C[ H[ D[ Van Ginkel\ P[ J[ W[ Schujil and L[ Brandsma^ Recl[ Trav[ Chim[
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57T0230 Y[ A[ Cheburkov\ N[ M[ Mukhamadaliev and I[ L[ Knunyants^ Tetrahedron\ 0857\ 13\
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57T3174 T[ Metler\ A[ Uchida and S[ I[ Miller^ Tetrahedron\ 0857\ 13\ 3174[ 142
57T4140 G[ Just and K[ Dahl^ Tetrahedron\ 0857\ 13\ 4140[ 573
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57ZC151 R[ Muller^ Z[ Chem[\ 0857\ 7\ 151[ 372

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58AG"E#19 E[ Kuhle\ B[ Anders\ E[ Klauke\ H[ Tarnow and G[ Zumach^ An`ew[ Chem[\ Int[ Ed[ En`l[\
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Obshch[ Khim[\ 0858\ 28\ 356[ 423

69ACS0353 J[ Sletten^ Acta Chem[ Scand[\ 0869\ 13\ 0353[ 243


69ACS2313 J[ Skramstad^ Acta Chem[ Scand[\ 0869\ 13\ 2313[ 519
69ACS2661 A[ J[ Dale and P[ Froyen^ Acta Chim[ Scand[\ 0869\ 13\ 2661[ 217
69AG180 U[ Schollkopf and H[ Frasnelli^ An`ew[ Chem[\ 0869\ 71\ 180[ 363\ 375
69AG"E#290 U[ Schollkopf and H[ Frasnelli^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0869\ 8\ 290[ 363\ 375
69AG"E#347 W[ A[ Boll\ F[ Gerhart\ A[ Nurrenbach and U[ Schollkopf^ An`ew[ Chem[\ Int[ Ed[ En`l[\
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69AJC730 M[ J[ Lacey^ Aust[ J[ Chem[\ 0869\ 12\ 730[ 152
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69BSF3008 J[ Elguero\ R[ Jaquier and C[ Marzin^ Bull[ Soc[ Chim[ Fr[\ 0869\ 3008[ 341
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60ACS2466 J[ Sletten^ Acta Chem[ Scand[\ 0860\ 14\ 2466[ 243


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61T2914 S[ Uemura\ Y[ Ikeda and K[ I[ Ichikawa^ Tetrahedron\ 0861\ 17\ 2914[ 553
61T3320 R[ Leblanc\ E[ Corre\ M[ Soenen!Svilarich\ M[ F[ Chasle and A[ Foucaud^ Tetrahedron\
0861\ 17\ 3320[ 457
61T4086 M[ Eissenfels and M[ Pulst^ Tetrahedron\ 0861\ 17\ 4086[ 62
61T4812 F[ Duus^ Tetrahedron\ 0861\ 17\ 4812[ 233
61TL334 H[ Meier and I[ Menzel^ Tetrahedron Lett[\ 0861\ 334[ 442
61TL376 E[ J[ Corey and I[ Kuwajima^ Tetrahedron Lett[\ 0861\ 02\ 376[ 512\ 539
61TL558 J[ H[ Babler and T[ R[ Mortell^ Tetrahedron Lett[\ 0861\ 558[ 531
61TL0028 J[ Ficini and J[ Pouliquen^ Tetrahedron Lett[\ 0861\ 0028[ 590
61TL0408 J[ Goerdeler and C[ Lindner^ Tetrahedron Lett[\ 0861\ 0408[ 447
61TL0526 W[ P[ Weber and G[ W[ Gokel^ Tetrahedron Lett[\ 0861\ 0526[ 584\ 610
61TL0704 E[ J[ Corey and S[ Terashima^ Tetrahedron Lett[\ 0861\ 0704[ 50
61TL0724 R[ J[ S[ Beer and A[ J[ Poole^ Tetrahedron Lett[\ 0861\ 0724[ 267
61TL0738 A[ Hamada and T[ Takizawa^ Tetrahedron Lett[\ 0861\ 0738[ 439\ 432
61TL0742 S[ C[ Welch and R[ Y[ Wong^ Tetrahedron Lett[\ 0861\ 0742[ 197
61TL1946 M[ L[ Hallensleben^ Tetrahedron Lett[\ 0861\ 02\ 1946[ 508
61TL1258 A[ M[ van Leusen\ B[ E[ Hoogenboom and H[ Siderius^ Tetrahedron Lett[\ 0861\ 1258[ 698
61TL1280 M[ Makosza\ E[ Bialecka and M[ Ludwikow^ Tetrahedron Lett[\ 0861\ 02\ 1280[ 523
61TL1632 K[ Hirai and Y[ Kishida^ Tetrahedron Lett[\ 0861\ 1632[ 46
61TL2332 V[ Dvorak\ J[ Kolc and J[ Michl^ Tetrahedron Lett[\ 0861\ 2332[ 431
61TL2658 E[ J[ Corey and P[ L[ Fuchs^ Tetrahedron Lett[\ 0861\ 2658[ 384
61TL4924 I[ Ojima and T[ Kogure^ Tetrahedron Lett[\ 0861\ 4924[ 01
61TL4036 S[ M[ Hecht and J[ W[ Kozarich^ Tetrahedron Lett[\ 0861\ 02\ 4036[ 355
61TL4102 C[ T[ Pedersen and C[ Lohse^ Tetrahedron Lett[\ 0861\ 4102[ 255
61ZOR543 E[ G[ Lubenets\ T[ N[ Gerasimova and V[ A[ Barkash^ Zh[ Or`[ Khim[\ 0861\ 7\ 543[ 425
61ZOR0711 L[ N[ Markovskii\ T[ N[ Dubinina\ E[ S[ Levchenko\ V[ P[ Kukhar and A[ V[ Kirsanov^ Zh[
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62ACR230 C[ R[ Johnson^ Acc[ Chem[ Res[\ 0862\ 5\ 230[ 268


62ACS1406 R[ Kristensen and J[ Sletten^ Acta Chem[ Scand[\ 0862\ 16\ 1406[ 243
62ACS2770 J[ Sletten and M[ Velsvik^ Acta Chem[ Scand[\ 0862\ 16\ 2770[ 144
62AG473 T[ Kau}man\ A[ Busch\ K[ Habersaat and E[ Koppelmann^ An`ew[ Chem[\ 0862\ 74\ 473[ 393
62AG"E#14 E[ Anders\ E[ Ruch and I[ Ugi^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0862\ 01\ 14[ 420
62AG"E#58 D[ Seebach\ M[ Kolb and B[!T[ Grobel^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0862\ 01\ 58[ 103
62AG"E#044 K[ Burger\ W[ Thenn and E[ Muller^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0862\ 01\ 044[ 579
62AG"E#126 G[ Koszmehl and B[ Bohn^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0862\ 01\ 126[ 383
62AG"E#212 C[ Reichardt and K[ Schagerer^ An`ew[ Chem[ "Int[ Ed[ En`l[#\ 0862\ 74\ 212[ 63\ 693
62AG"E#453 E[ O[ Fischer\ G[ Kreis\ C[ G[ Kreiter\ J[ Muller\ G[ Huttner and H[ Lorenz^ An`ew[ Chem[\
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62AG"E#564 S[ V[ Ponomarev^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0862\ 01\ 564[ 439
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62TL1354 H[ Taguchi\ S[ Tanaka\ H[ Yamamoto and H[ Nozaki^ Tetrahedron Lett[\ 0862\ 1354[ 43
62TL1474 Y[ Leroux and C[ Roman^ Tetrahedron Lett[\ 0862\ 1474[ 103
62TL1656 J[ M[ Conia and C[ Girard^ Tetrahedron Lett[\ 0862\ 1656[ 113
62TL1764 M[ Franck!Neumann and C[ Buchecker^ Tetrahedron Lett[\ 0862\ 1764[ 54\ 432
62TL2424 Y[ Watanabe\ M[ Yamashita\ T[ Mitsudo\ M[ Tanaka and Y[ Takegami^ Tetrahedron Lett[\
0862\ 2424[ 73
62TL2524 J[ Wicha\ A[ Zarecki and M[ Kocor^ Tetrahedron Lett[\ 0862\ 2524[ 183
62TL2616 J[ W[ Lown and M[ H[ Akhtar^ Tetrahedron Lett[\ 0862\ 2616[ 473
62TL2714 J[ C[ Graham^ Tetrahedron Lett[\ 0862\ 2714[ 508
62TL2818 H[ Hogeveen\ R[ M[ Kellogg and K[ A[ Kuindersma^ Tetrahedron Lett[\ 0862\ 2818[ 260
62TL2868 A[ Ferwanah\ W[ Pressler and C[ Reichardt^ Tetrahedron Lett[\ 0862\ 2868[ 65
62TL3922 H[ Braun\ G[ Huber and G[ Kresze^ Tetrahedron Lett[\ 0862\ 3922[ 263
62TL3314 W[ G[ Dauben\ D[ H[ Hart\ J[ Ipaktschl and A[ P[ Kozikowski^ Tetrahedron Lett[\ 0862\
3314[ 383
62TL3388 E[ J[ Corey and G[ W[ J[ Fleet^ Tetrahedron Lett[\ 0862\ 3388[ 67
62TL3422 T[ Okamoto and K[ Shudo^ Tetrahedron Lett[\ 0862\ 3422[ 153
62TL3462 J[ Tsuji\ H[ Takahashi and T[ Kajimoto^ Tetrahedron Lett[\ 0862\ 3462[ 369
62TL3818 D[ A[ Evans and L[ K[ Truesdale^ Tetrahedron Lett[\ 0862\ 3818[ 504\ 505
62TL4926 R[ B[ Miller and B[ F[ Smith^ Tetrahedron Lett[\ 0862\ 4926[ 109
62TL4002 D[ Seebach and M[ Teschner^ Tetrahedron Lett[\ 0862\ 4002[ 24
62TL4056 G[ Buono^ Tetrahedron Lett[\ 0862\ 4056[ 447
62TL4196 A[ M[ van Leusen\ J[ Strating and D[ van Leusen^ Tetrahedron Lett[\ 0862\ 4196[ 368
62ZOB1977 V[ M[ Vodolazskaya and Y[ I[ Baukov^ Zh[ Obshch[ Khim[\ 0862\ 32\ 1977[ 439
62ZOR0606 M[ S[ Korobov\ L[ E[ Nivorozhkin and V[ I[ Minkin^ Zh[ Or`[ Khim[\ 0862\ 8\ 0606 "Chem[
Abstr[\ 0862\ 68\ 014 531#[ 236\ 245

63ACR310 R[ A[ Moss^ Acc[ Chem[ Res[\ 0863\ 6\ 310[ 355


655 References
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63CL0328 R[ Okazaki and N[ Inamoto^ Chem[ Lett[\ 0863\ 0328[ 248
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63CR"167#0042 A[ Gorgues and A[ Le Coq^ C[R[ Hebd[ Seances Acad[ Sci[\ 0863\ 167\ 0042[ 163
63CR"C#148 J[ M[ Decrouen\ D[ Paquer and R[ Pou^ C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ C\ 0863\
168\ 148[ 228
63CR"C#682 J[!L[ Burgot and J[ Vialle^ C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ C\ 0863\ 167\ 682[ 265
63HCA0271 P[ Gilgen\ H[ Heimgartner and H[ Schmid^ Helv[ Chim[ Acta\ 0863\ 46\ 0271[ 568\ 579
63HCA1190 F[ Dayer\ H[ Le¼ Dao\ H[ Gold\ H[ Rode!Gowal and H[ Dahn^ Helv[ Chim[ Acta[\ 0863\ 46\
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63HCA1472 P[ Schiess and P[ Radimerski^ Helv[ Chim[ Acta\ 0863\ 46\ 1472[ 432
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67S347 D[ Masure\ C[ Chuit\ R[ Sauvetre and J[ F[ Normant^ Synthesis\ 0867\ 347[ 56\ 126
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68S116 G[ A[ Olah\ Y[ D[ Vankar and A[ Garcia!Luna^ Synthesis\ 0868\ 116[ 507\ 551
68S155 S[ Zahr and I[ Ugi^ Synthesis\ 0868\ 155[ 59
68S184 G[ I[ Field and W[ J[ Zally^ Synthesis\ 0868\ 184[ 089
68S292 C[ Galli^ Synthesis\ 0868\ 292[ 179\ 185\ 187\ 294
68S245 S[ Cacchi\ F[ La Torre and D[ Misiti^ Synthesis\ 0868\ 245[ 3\ 46\ 004
68S250 G[ Seitz\ H[ Morck\ R[ Schmiedel and R[ Sutrisno^ Synthesis\ 0868\ 250[ 244
68S277 W[ Adam and L[ A[ Arias Encarnacion^ Synthesis\ 0868\ 277[ 00
68S390 A[ McKillop and D[ W[ Young^ Synthesis\ 0868\ 390[ 3\ 004
68S329 H[ Westmijze\ H[ Kleijn and P[ Vermeer^ Synthesis\ 0868\ 329[ 531
68S327 P[ J[ Stang and T[ E[ Fisk^ Synthesis\ 0868\ 327[ 162
68S496 F[ Jung\ D[ Ladjama and J[ J[ Riehl^ Synthesis\ 0868\ 496[ 43
References 674
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68S611 G[ Sosnovsky\ J[ A[ Krogh and S[ G[ Umhoefer^ Synthesis\ 0868\ 611[ 506
68S613 R[ Sterzycki^ Synthesis\ 0868\ 613[ 8\ 012
68S639 H[ Sakurai\ A[ Shirahata\ K[ Sasaka and A[ Hosomi^ Synthesis\ 0868\ 639[ 439
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68T070 B[ Divisia^ Tetrahedron\ 0868\ 24\ 070[ 379\ 370
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71ABC0792 A[ Fujiwara\ T[ Okuda\ S[ Masuda\ Y[ Shiomi\ C[ Miyamoto\ Y[ Sekine\ M[ Tazoe and M[


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71S350 A[ Hirao\ I[ Hattori\ K[ Yamaguchi\ S[ Nakahama and N[ Yamazaki^ Synthesis\ 0871\ 350[ 339
71S479 D[ Ghiringhelli^ Synthesis\ 0871\ 479[ 05\ 021
71S477 M[ N[ Bhattacharjee\ M[ K[ Chaudhuri\ H[ S[ Dasgupta\ N[ Roy and D[ T[ Khathing^
Synthesis\ 0871\ 477[ 3\ 77\ 004
71S480 M[ Yokoyama\ S[ Yoshida and T[ Imamoto^ Synthesis\ 0871\ 480[ 507
71S486 A[ Hercouet\ M[ Corre and Y[ Le Floch^ Synthesis\ 0871\ 486[ 383
71S608 A[ Brandi\ F[ De Sarlo\ A[ Guarna and S[ Speroni^ Synthesis\ 0871\ 608[ 575
71S654 N[ De Kimpe\ R[ Verhe\ L[ De Buyck\ L[ Moens\ P[ Sulmon and N[ Schamp^ Synthesis\
0871\ 654[ 073
71S794 A[ P[ Krapcho^ Synthesis\ 0871\ 794[ 013\ 020
71S718 L[ Ban_\ L[ Colombo\ C[ Gennari\ R[ Annunziata and F[ Cozzi^ Synthesis\ 0871\ 718[ 26
71S804 M[ Nakano\ Y[ Okamoto and H[ Sakurai^ Synthesis\ 0871\ 804[ 539
71S811 A[ Zwierzak and S[ Pilichowska^ Synthesis\ 0871\ 811[ 077
71S0910 S[ Motohashi\ M[ Satomi\ Y[ Fujimoto and T[ Tatsuno^ Synthesis\ 0871\ 0910[ 041\ 043\ 044
71S0980 X[ Huang and C[!C[ Chan^ Synthesis\ 0871\ 0980[ 3\ 77\ 005
71S4497 G[ A[ Lee^ Synthesis\ 0871\ 4497[ 573
71SC04 R[ E[ Gawley and E[ J[ Termine^ Synth[ Commun[\ 0871\ 01\ 04[ 022
71SC14 C[ Botteghi\ G[ Chelucci and M[ Marchetti\ Synth[ Commun[\ 0871\ 01\ 14[ 506\ 508
71SC24 J[ T[ Gupton\ S[ A[ Andrews and C[ Colon^ Synth[ Commun[\ 0871\ 01\ 24[ 153
71SC120 J[ M[ Brittain\ R[ A[ Jones\ J[ S[ Arques and T[ A[ Saliente^ Synth[ Commun[\ 0871\
01\ 120[ 095\ 297
71SC358 J[ L[ Belletire\ D[ R[ Walley and M[ J[ Bast^ Synth[ Commun[\ 0871\ 01\ 358[ 383
71SC384 C[ Stetin\ B[ de Jeso and J[ C[ Pommier^ Synth[ Commun[\ 0871\ 01\ 384[ 396
71SC410 G[ A[ Kraus and M[ E[ Krolski^ Synth[ Commun[\ 0871\ 01\ 410[ 115
71SC684 Y[ F[ Zhou and N[ Z[ Huang^ Synth[ Commun[\ 0871\ 01\ 684[ 198
71SC728 J[ H[ Babler^ Synth[ Commun[\ 0871\ 01\ 728[ 02\ 72
71SC884 T[ L[ Ho and S[!H[ Liu^ Synth[ Commun[\ 0871\ 01\ 884[ 108
71SC0010 S[ Fayed\ M[ Delmas and A[ Gaset^ Synth[ Commun[\ 0871\ 01\ 0010[ 291
71T416 G[ Morel\ M[ A[ LeMoing!Orliac\ S[ Khamsitthideth and A[ Foucaud^ Tetrahedron\ 0871\
27\ 416[ 456\ 463
71T882 S[ Scheibye\ R[ Shabana\ S[!O[ Lawesson and C[ Ro mming^ Tetrahedron\ 0871\ 27\ 882[ 235\ 242
71T0366 A[ Gillon\ D[ Ovadia\ M[ Kapon and S[ Bien^ Tetrahedron\ 0871\ 27\ 0366[ 219
71T0458 L[ Castedo\ R[ Riguera and M[ J[ Rodriguez^ Tetrahedron\ 0871\ 27\ 0458[ 301
71T0562 S[ Rajappa\ M[ D[ Nair\ R[ Sreenivasan and B[ G[ Advani^ Tetrahedron\ 0871\ 27\ 0562[ 250
71T0716 M[ P[ Paradisi and G[ P[ Zecchini^ Tetrahedron\ 0871\ 27\ 0716[ 20
71T0864 P[ W[ Hickmott^ Tetrahedron\ 0871\ 27\ 0864[ 393
71T2244 J[ N[ C[ Hood\ D[ Lloyd\ W[ A[ MacDonald and T[ M[ Shepherd^ Tetrahedron\ 0871\ 27\
2244[ 085\ 499
71T2252 P[ W[ Hickmott^ Tetrahedron\ 0871\ 27\ 2252[ 393
71TL24 S[ O[ Nwaukwa and P[ M[ Keehn^ Tetrahedron Lett[\ 0871\ 12\ 24[ 008
71TL056 I[ Ernest\ R[ Menasse and A[ J[ Main^ Tetrahedron Lett[\ 0871\ 12\ 056[ 54
71TL242 A[ Pelter\ R[ Al!Bayati and W[ Lewis^ Tetrahedron Lett[\ 0871\ 12\ 242[ 136
687 References
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71TL0152 H[ Yamaguchi\ S[ Kametani\ T[ Karakasa\ T[ Saito and S[ Motoki^ Tetrahedron Lett[\ 0871\
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71TL0494 A[ Hulkenberg and J[ J[ Troost^ Tetrahedron Lett[\ 0871\ 12\ 0494[ 507
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71TL0594 L[ Duhamel and J[ Chauvin^ Tetrahedron Lett[\ 0871\ 12\ 0554[ 331
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71TL0510 W[ R[ Jackson and C[ G[ Lovel^ Tetrahedron Lett[\ 0871\ 12\ 0510[ 503
71TL0640 A[ S[ Kende\ B[ Roth and I[ Kubo^ Tetrahedron Lett[\ 0871\ 12\ 0640[ 197
71TL0764 E[ D[ Thorsett^ Tetrahedron Lett[\ 0871\ 12\ 0764[ 357
71TL0834 D[ J[ Ager^ Tetrahedron Lett[\ 0871\ 12\ 0834[ 160
71TL1962 G[ Stork and K[ S[ Atwal^ Tetrahedron Lett[\ 0871\ 12\ 1962[ 10
71TL1966 M[ M[ Midland and Y[ C[ Kwon^ Tetrahedron Lett[\ 0871\ 12\ 1966[ 511
71TL1094 A[ Toshimitsu\ H[ Owada\ S[ Uemura and M[ Okano^ Tetrahedron Lett[\ 0871\ 12\ 1094[ 063
71TL1244 L[ E[ Overman and R[ J[ McCready^ Tetrahedron Lett[\ 0871\ 12\ 1244[ 119
71TL1262 A[ S[ Kende and P[ Fludzinski^ Tetrahedron Lett[\ 0871\ 12\ 1262[ 035
71TL1268 C[ L[ Baumgardner\ J[ R[ Lever and S[ T[ Purrington^ Tetrahedron Lett[\ 0871\ 12\ 1268[ 113
71TL1288 I[ Paterson and H[ A[ Khan^ Tetrahedron Lett[\ 0871\ 12\ 1288[ 45
71TL1396 R[ A[ Raphael\ J[ H[ A[ Stibbard and R[ Tidbury^ Tetrahedron Lett[\ 0871\ 12\ 1396[ 27
71TL1498 M[ A[ McKervey and P[ Ratananukul^ Tetrahedron Lett[\ 0871\ 12\ 1498[ 055
71TL1422 C[ Jennings!White and R[ G[ Almquist^ Tetrahedron Lett[\ 0871\ 12\ 1422[ 079
71TL1512 P[ T[ Lansbury and J[ P[ Vacca^ Tetrahedron Lett[\ 0871\ 12\ 1512[ 198
71TL1700 M[ F[ Ansell\ M[ P[ L[ Caton and P[ C[ North^ Tetrahedron Lett[\ 0871\ 12\ 1700[ 50
71TL1742 N[ De Kimpe\ R[ Verhe\ L[ De Buyck\ N[ Schamp and M[ Charpentier!Morize^ Tetrahedron
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71TL1898 G[ L|abbe\ D[ Sorgeloos and S[ Toppet^ Tetrahedron Lett[\ 0871\ 12\ 1898[ 447
71TL2962 W[ Ando and H[ Tsumaki^ Tetrahedron Lett[\ 0871\ 2962[ 306
71TL2974 J[ Tsuji\ H[ Nagashima and K[ Sato^ Tetrahedron Lett[\ 0871\ 12\ 2974[ 003
71TL2250 C[ Petrier\ A[ L[ Gemal and J[ L[ Luche^ Tetrahedron Lett[\ 0871\ 12\ 2250[ 03
71TL2284 K[ Hattori\ K[ Maruoka and H[ Yamamoto^ Tetrahedron Lett[\ 0871\ 12\ 2284[ 396\ 327
71TL2300 J[ N[ Denis and A[ Krie}^ Tetrahedron Lett[\ 0871\ 12\ 2300[ 63
71TL2432 H[ J[ Bestmann and G[ Schade^ Tetrahedron Lett[\ 0871\ 12\ 2432[ 119
71TL2820 N[ Sayo\ Y[ Kimura and T[ Nakai^ Tetrahedron Lett[\ 0871\ 12\ 2820[ 11
71TL3152 N[ Bluthe\ M[ Malacria and J[ Gore^ Tetrahedron Lett[\ 0871\ 12\ 3152[ 030
71TL3536 R[ V[ Stevens\ K[ T[ Chapman\ C[ A[ Stubbs\ W[ W[ Tam and K[ F[ Albizati^ Tetrahedron
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71TL3554 J[ Brokatzky!Geiger and W[ Eberbach^ Tetrahedron Lett[\ 0871\ 12\ 3554[ 204
71TL3702 N[ Miyoshi\ T[ Yamamoto\ N[ Kambe\ S[ Murai and N[ Sonoda^ Tetrahedron Lett[\ 0871\
12\ 3702[ 27\ 063
71TL3720 A[ De Groot\ M[ P[ Broekhuysen and L[ L[ Doddema^ Tetrahedron Lett[\ 0871\ 12\ 3720[ 43\ 142
71TL3812 M[ Karpf^ Tetrahedron Lett[\ 0871\ 12\ 3812[ 169
71TL4998 N[ R[ Natale^ Tetrahedron Lett[\ 0871\ 12\ 4998[ 108
71TL4920 F[ Leyendecker and M[!T[ Comte^ Tetrahedron Lett[\ 0871\ 12\ 4920[ 054
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71TL4988 H[ S[ Gill and J[ A[ Landgrebe^ Tetrahedron Lett[\ 0871\ 12\ 4988[ 210
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72T194 N[ H[ Werstiuk^ Tetrahedron\ 0872\ 28\ 194[ 10\ 026
72T186 G[ S[ Harris\ D[ Lloyd\ W[ A[ MacDonald and I[ Gosney^ Tetrahedron\ 0872\ 28"1#\ 186[ 499
72T234 V[ V[ Kane\ V[ Singh\ A[ Martin and D[ L[ Doyle^ Tetrahedron\ 0872\ 28\ 234[ 015
72T322 M[ Julia and H[ Mestdagh^ Tetrahedron\ 0872\ 28\ 322[ 308
72T750 G[ M[ Rubottom\ R[ Marrero and J[ M[ Gruber^ Tetrahedron\ 0872\ 28\ 750[ 20\ 43
72T850 M[ T[ Reetz\ I[ Chatziiosi_dis\ H[ Kunzer and H[ Muller!Starke^ Tetrahedron\ 0872\
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72T856 K[ Utimoto\ Y[ Wakabayashi\ T[ Horiie\ M[ Inoue\ Y[ Shishiyama\ M[ Obayashi and
H[ Nozaki^ Tetrahedron\ 0872\ 28\ 856[ 505\ 516\ 522
72T0376 J[ E[ Baldwin and R[ C[ G[ Lopez^ Tetrahedron\ 0872\ 28\ 0376[ 223\ 224
72T0440 M[ Cariou\ G[ Mabon\ G[ Le Guillanton and J[ Simonet^ Tetrahedron\ 0872\ 28\ 0440[ 541\ 543
72T0456 A[ Fadel\ J[ Salaun and J[ M[ Conia^ Tetrahedron\ 0872\ 28\ 0456[ 428
72T0666 E[ Bisagni\ N[ Chi Hung and J[ M[ Lhoste^ Tetrahedron\ 0872\ 28\ 0666[ 331
72T1758 D[ L[ Boger^ Tetrahedron\ 0872\ 28\ 1758[ 302\ 303
72T1878 J[ E[ Baldwin\ A[ E[ Derome and P[ D[ Riordan^ Tetrahedron\ 0872\ 28\ 1878[ 587
72T2196 J[ D[ Albright^ Tetrahedron\ 0872\ 28\ 2196[ 026\ 181\ 516
72T2734 P[ S[ Mariano^ Tetrahedron\ 0872\ 28\ 2734[ 319
72T2770 A[ J[ Floyd\ R[ G[ Kinsman\ Y[ Roshan!Ali and D[ W[ Brown^ Tetrahedron\ 0872\ 28\ 2770[ 558\ 569
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73ACR247 E[ Vedejs^ Acc[ Chem[ Res[\ 0873\ 06\ 247[ 240


73ACR309 A[ P[ Kozikowski^ Acc[ Chem[ Res[\ 0873\ 06\ 309[ 572
73AG"E#47 H[ Werner and W[ Paul^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0873\ 12\ 47[ 264\ 276
73AG"E#58 B[ Giese\ J[ A[ Gonzalez and T[ Witzel^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0873\ 12\ 58[ 510
73AG"E#328 E[ Schaumann\ W[!R[ Forster and G[ Adiwidjaja^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0873\
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73RTC217 J[ Lub and Th[ J[ de Boer^ Recl[ Trav[ Chim[ Pays!Bas\ 0873\ 092\ 217[ 323
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73S26 G[ Friour\ G[ Cahiez and J[ F[ Normant^ Synthesis\ 0873\ 26[ 041
73S35 R[ Verhe\ N[ De Kimpe\ L[ De Buyck and N[ Schamp^ Synthesis\ 0873\ 35[ 24
73S055 R[ A[ J[ Smith and A[ R[ Bin Manas^ Synthesis\ 0873\ 055[ 87
73S117 G[ A[ Olah\ G[ K[ S[ Prakash and M[ Arvanaghi^ Synthesis\ 0873\ 117[ 03\ 89\ 090
73S258 J[ Tsuji^ Synthesis\ 0873\ 258[ 002
73S368 F[ S[ Guziec\ Jr[ and J[ M[ Russo^ Synthesis\ 0873\ 368[ 328
73S493 E[ Ghera\ A[ Plemenitas and Y[ Ben!David^ Synthesis\ 0873\ 493[ 78
73S418 M[ Ramaiah^ Synthesis\ 0873\ 418[ 195\ 105
73S596 G[ Rosini\ R[ Ballini\ P[ Sorrenti and M[ Petrini^ Synthesis\ 0873\ 596[ 080
73S597 A[ G[ Martinezi and M[ O[ Ruiz^ Synthesis\ 597\ 0873[ 46
73S518 J[ G[ Smith^ Synthesis\ 0873\ 518[ 8\ 011
73S552 S[ Mataka\ K[ Uehara\ M[ Tashiro and S[ Sato^ Synthesis\ 0873\ 552[ 152
73S580 M[ Mikolajczyk and P[ Balczewski^ Synthesis\ 0873\ 580[ 086
73S623 B[ Frolisch and R[ Flogaus^ Synthesis\ 0873\ 623[ 041
73S636 L[ Syper and J[ Mlochowski^ Synthesis\ 0873\ 636[ 78\ 85\ 87\ 88\ 097
73S755 K[ S[ Kim\ Y[ K[ Chang\ S[ K[ Bae and C[ S[ Hahn^ Synthesis\ 0873\ 755[ 77
73S830 P[ A[ Harland\ P[ Hodge\ W[ Maughan and E[ Wildsmith^ Synthesis\ 0873\ 830[ 077
73S836 E[ A[ Mistryukov and I[ K[ Korshevets^ Synthesis\ 0873\ 836[ 394
73S844 A[ M[ Maione and A[ Romeo^ Synthesis\ 0873\ 844[ 4
73S880 Z[ N[ Parnes and G[ I[ Bolestova^ Synthesis\ 0873\ 880[ 47\ 100
73S0909 K[ Thangaraj\ P[ C[ Srinivasan and S[ Swaminathan^ Synthesis\ 0873\ 0909[ 033
73S0910 G[ M[ Coppola^ Synthesis\ 0873\ 0910[ 8\ 012
73S0914 W[ Waszkuc\ T[ Janecki and R[ Bodalski^ Synthesis\ 0873\ 0914[ 047
73S0922 U[ Schollkopf and T[ Wintel^ Synthesis\ 0873\ 0922[ 695
73S0927 V[ Dryanska\ C[ Ivanov and R[ Krusteva^ Synthesis\ 0873\ 0927[ 397
73S0937 L[ N[ Prigden and S[ C[ Shilcrat^ Synthesis\ 0873\ 0937[ 200
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03\ 052[ 421
73SC528 R[ Smith and T[ Livinghouse^ Synth[ Commun[\ 0873\ 03\ 528[ 600
73SC632 A[ T[ Au^ Synth[ Commun[\ 0873\ 03\ 632[ 181\ 292\ 200
73SC638 A[ T[ Au^ Synth[ Commun[\ 0873\ 03\ 638[ 181
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73SR22 S[ Motoki and T[ Saito^ Sulfur Reports\ 0873\ 3\ 22[ 269
73T510 M[ Gill^ Tetrahedron\ 0873\ 39\ 510[ 293
73T530 E[ Erdik^ Tetrahedron\ 0873\ 39\ 530[ 01\ 017
73T572 G[ Friour\ A[ Alexakis\ G[ Cahiez and J[ Normant^ Tetrahedron\ 0873\ 39\ 572[ 029
73T782 J[ C[ Jochims\ J[ Lambrecht\ U[ Burkert\ L[ Zsolnai and G[ Huttner^ Tetrahedron\ 0873\
39\ 782[ 445\ 446\ 459\ 475
73T0214 H[ C[ Brown\ P[ K[ Jadhav and M[ C[ Desai^ Tetrahedron\ 0873\ 39\ 0214[ 024
73T1924 E[ Armani\ A[ Dossena\ R[ Marchelli and G[ Casnati^ Tetrahedron\ 0873\ 39\ 1924[ 16\ 043
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74JA3228 E[ J[ Corey\ M[ C[ Desai and T[ A[ Engler^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 3228[ 417
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096\ 3568[ 106
74JA4108 P[ DeShong\ S[ Ramesh\ V[ Elango and J[ J[ Perez^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 4108[ 120\ 292
74JA4285 R[ Haner\ T[ Laube and D[ Seebach^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 4285[ 426
74JA4888 H[ Strutz\ J[ C[ Dewan and R[ R[ Schrock^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 4888[ 402
74JA5604 C[ F[ Jewel\ Jr[\ L[ S[ Liebeskind and M[ Williamson^ J[ Am[ Chem[ Soc[\ 0874\ 096\
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74JA5620 E[ Block and S[ Ahmad^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 5620[ 258
74JA6068 T[ Hirao\ D[ Misu and T[ Agawa^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 6068[ 016
74JA6193 J[ C[ Scaiano\ W[ G[ McGimpsey and H[ L[ Casal^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 6193[ 203
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74JA6856 P[ A[ Ansto}\ P[ D[ Johnson and A[ W[ Hamson^ J[ Am[ Chem[ Soc[\ 0874\ 096\ 6856[ 119
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74JCS"P0#156 A[ J[ Pearson\ Y[!S[ Chen\ C[ R[ Han\ S[!Y[ Hsu and T[ Ray^ J[ Chem[ Soc[\ Perkin Trans[
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74JCS"P0#336 J[ Barluenga\ J[ R[ Fernandez and M[ Yus^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 336[ 47
74JCS"P0#0050 M[ G[ Pettett and A[ B[ Holmes^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 0050[ 256
74JCS"P0#0390 M[ Nitta and T[ Kobayashi^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 0390[ 158
74JCS"P0#0406 R[ M[ Paton\ F[ M[ Robertson\ J[ F[ Ross and J[ Crosby^ J[ Chem[ Soc[\ Perkin Trans[ 0\
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74JCS"P0#0430 C[ M[ Bladon\ I[ E[ G[ Ferguson\ G[ W[ Kirby\ A[ Lochead and D[ C[ McDougall^ J[ Chem[
Soc[\ Perkin Trans[ 0\ 0874\ 0430[ 222\ 224
74JCS"P0#1012 D[ R[ Boyd\ P[ B[ Coulter\ R[ Hamilton\ N[ T[ Thompson\ N[ D[ Sharma and M[ E[ Stubbs^
J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 1012[ 393
74JCS"P0#1074 P[ L[ Coe\ A[ Sellars and J[ C[ Tatlow^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 1074[ 478
74JCS"P0#1082 D[ J[ Buckley and M[ A[ McKervey^ J[ Chem[ Soc[ Perkin Trans[ 0\ 0874\ 1082[ 063\ 123\ 145
74JCS"P0#1396 G[ R[ Clemo and G[ Pattenden^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 1396[ 120
74JCS"P0#1556 D[ H[ R[ Barton\ J[ C[ Blazejewski\ B[ Charpiot\ J[ P[ Finet\ W[ B[ Motherwell\
M[ T[ B[ Papoula and J[ C[ Stanforth^ J[ Chem[ Soc[\ Perkin Trans[ 0\ 0874\ 1556[ 034
74JGU15 A[ A[ Leonov\ V[ Y[ Komarov\ A[ V[ Dogadina\ B[ I[ Ionin and A[ A[ Petrov^ J[ Gen[ Chem[
USSR "En`l[ Transl[#\ 0874\ 44\ 15[ 480
74JMC0926 J[ M[ Muchowski and S[ H[ Unger^ J[ Med[ Chem[\ 0874\ 17\ 0926[ 296
74JMC0721 H[ Cairns\ D[ Cox and J[ L[ Syschitzky^ J[ Med[ Chem[\ 0874\ 17\ 0721[ 186
74JOC21 J[ L[ Kice and L[ Weclas^ J[ Or`[ Chem[\ 0874\ 49\ 21[ 254
74JOC022 M[ S[ Mourad\ R[ S[ Varma and G[ W[ Kabalka^ J[ Or`[ Chem[\ 0874\ 49\ 022[ 315
74JOC024 E[ G[ Lewars and S[ Siddiqi^ J[ Or`[ Chem[\ 0874\ 49\ 024[ 429
74JOC064 D[ Caine\ C[ J[ McCloskey and Van Derveer^ J[ Or`[ Chem[\ 0874\ 49\ 064[ 032
74JOC426 I[ Shimizu\ T[ Sugiura and J[ Tsuji^ J[ Or`[ Chem[\ 0874\ 49\ 426[ 122
74JOC432 W[ W[ Sander and O[ L[ Chapman^ J[ Or`[ Chem[\ 0874\ 49\ 432[ 271
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74LA455 K[ Weinges\ H[ Brachmann\ P[ Stahnecker\ H[ Rodewold\ M[ Nixdorf and H[ Irngartinger^
Liebi`s Ann[ Chem[\ 0874\ 455[ 505
74LA674 U[ Schmidt\ A[ Lieberknecht\ H[ Griesser and H[ Bokens^ Liebi`s Ann[ Chem[\ 0874\
674[ 068\ 073
74LA0714 H[ H[ Wust\ J[ Bardenhagen and U[ Schollkopf^ Liebi`s Ann[ Chem[\ 0874\ 0714[ 608
74LA1294 L[ Capuano and K[ Djokar^ Liebi`s Ann[ Chem[\ 0874\ 1294[ 481\ 482
74M66 E[ Ohler\ M[ El!Badawi and E[ Zbiral^ Monatsh[ Chem[\ 0874\ 005\ 66[ 169
74MAC0644 S[ Asada\ Y[ Kobayashi and S[ Inoue^ Macromol[ Chem[\ 0874\ 075\ 0644[ 517
B!74MI 292!90 T[ L[ Gilchrist^ {{Heterocyclic Chemistry\|| Longman\ Harlow\ 0874[ 093\ 096
74MI 297!90 C[ R[ Johnson^ Aldrichim[ Acta\ 0874\ 07\ 2[ 268
74MI 207!90 C[ A[ Tolman\ R[ J[ McKinney\ W[ C[ Seidel\ J[ D[ Druliner and W[ R[ Stevens^ Advances
in Catalysis\ 0874\ 22\ 0[ 503
74MI 219!90 V[ Jager\ I[ Muller\ R[ Schohe\ M[ Frey\ R[ Ehrler\ B[ Hafele and D[ Schroter^ Lect[
Heterocycl[ Chem[\ 0874\ 6\ 68[ 572
74MI 210!90 Y[ Araki\ N[ Kobayashi\ K[ Watanabe and Y[ Ishido^ J[ Carbohydr[ Chem[\ 0874\ 3\ 454[ 697
74NJC0 E[ Dunach and H[ B[ Kagan^ Nouv[ J[ Chim[\ 0874\ 0[ 523
74OM0826 J[ H[ Freudenberger and R[ R[ Schrock^ Or`anometallics\ 0874\ 3\ 0826[ 405
701 References
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74OPP072 K[ Mai and G[ Patil^ Or`[ Prep[ Proced[ Int[\ 0874\ 06\ 072[ 315
74PS"14#126 M[ Yoshifuji\ K[ Toyota\ N[ Inamoto\ K[ Hirotsu\ T[ Higuchi and S[ Nagase^ Phosphorus
Sulfur\ 0874\ 14\ 126[ 594
74RTC8 J[ L[ Mieloszynski\ C[ G[ Andrieu\ M[ Schneider and D[ Paquer^ Recl[ Trav[ Chim[
Pays!Bas\ 0874\ 093\ 8[ 241
74RTC49 A[ M[ van Leusen^ Rec[ Trav[ Chim[ Pays!Bas\ 0874\ 093\ 49[ 583\ 698
74RTC066 A[ M[ van Leusen\ J[ Wildeman\ J[ Moskal and A[ W[ van Hemert^ Rec[ Trav[ Chim[
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74S49 G[ Friour\ G[ Cahiez and J[ F[ Normant^ Synthesis\ 0874\ 49[ 100\ 162
74S55 A[ Bender\ D[ Gunther\ L[ Willms and R[ Wingen^ Synthesis\ 0874\ 55[ 060
74S87 V[ P[ Litvinov\ V[ Y[ Mortikov\ Y[ A[ Sharanin and A[ M[ Shestopalov^ Synthesis\
0874\ 87[ 545
74S010 M[!C[ Lasne and J[!L[ Ripoll^ Synthesis\ 0874\ 010[ 122
74S048 Y[ Shen\ W[ Cen and Y[ Huang^ Synthesis\ 0874\ 048[ 68\ 163
74S066 D[ Matthies and I[ Malassa^ Synthesis\ 0874\ 066[ 306
74S073 A[ Saednya^ Synthesis\ 0874\ 073[ 507
74S113 M[ Sato\ K[ Sekiguchi\ H[ Ogasawara and C[ Kaneko^ Synthesis\ 0874\ 113[ 432
74S168 T[ Sasaki\ K[ Mori and M[ Ohno^ Synthesis\ 0874\ 168[ 322
74S242 H[ J[ Anderson and C[ E[ Loader^ Synthesis\ 0874\ 242[ 296
74S253 R[ J[ K[ Taylor^ Synthesis\ 0874\ 253[ 01\ 017
74S399 R[ Obrecht\ R[ Herrmann and I[ Ugi^ Synthesis\ 0874\ 399 585\ 588\ 610\ 611
74S395 Y[ Satoh\ T[ Tayano\ H[ Koshino\ S[ Hara and A[ Suzuki^ Synthesis\ 0874\ 395[ 16
74S528 R[ C[ Haddon\ S[ V[ Chichester and S[ L[ Mayo^ Synthesis\ 0874\ 528[ 252
74S532 H[ Ishibashi^ Synthesis\ 0874\ 532[ 138
74S561 F[ Duus^ Synthesis\ 0874\ 561[ 249\ 253
74S568 F[ Texier!Boullet^ Synthesis\ 0874\ 568[ 395
74S643 H[ Moulines\ T[ Nguyen and C[ Wakselman^ Synthesis\ 0874\ 643[ 56
74S655 J[ C[ Depezay\ Y[ Le Merrer and M[ Saniere^ Synthesis\ 0874\ 655[ 100
74S673 F[ A[ Lakhvich\ T[ S[ Khlebnicova and A[ A[ Akhrem^ Synthesis\ 0874\ 673[ 128
74S851 P[ J[ Stang and V[ Dixit^ Synthesis\ 0874\ 851[ 162
74S856 M[ Tanaka and T[!A[ Kobayashi^ Synthesis\ 0874\ 856[ 395
74S858 P[ G[ Baraldi\ G[ P[ Pollini\ V[ Zanirato\ A[ Barco and S[ Benetti^ Synthesis\ 0874\ 858[ 537
74S0007 M[ A[ Pericas\ F[ Serratosa and E[ Valenti^ Synthesis\ 0874\ 0007[ 136\ 439
74SC046 K[ Mai and G[ Patil^ Synth[ Commun[\ 0874\ 04\ 046[ 505
74SC156 D[ Kalvin\ K[ Ramalingram and R[ Woodard^ Synth[ Commun[\ 0874\ 04\ 156[ 693
74SC224 D[ K[ Dutta\ D[ Prajapati\ J[ S[ Sandhu and J[ N[ Barauah^ Synth[ Commun[\ 0874\ 04\ 224[ 306
74SC260 C[ W[ Spangler\ R[ P[ K[ Tan and R[ S[ Gibson^ Synth[ Commun[\ 0874\ 04\ 260[ 48
74SC332 R[ S[ Varma and G[ W[ Kabalka^ Synth[ Commun[\ 0874\ 04\ 332[ 054
74SC362 B[ Rigo\ S[ Jabre\ F[ Maliar and D[ Couturier^ Synth[ Commun[\ 0874\ 04\ 362[ 548
74SC538 R[ M[ Moriarty and I[ Prakash^ Synth[ Commun[\ 0874\ 04\ 538[ 070
74SC648 H[ J[ Liu and I[ S[ Han^ Synth[ Commun[\ 0874\ 04\ 648[ 010
74SC866 R[ G[ Pews and Z[ Lysenko^ Synth[ Commun[\ 0874\ 04\ 866[ 16
74SC880 G[ Mehta and H[ S[ P[ Rao^ Synth[ Commun[\ 0874\ 04\ 880[ 040
74SC0160 J[ V[ Early and N[ W[ Gilman^ Synth[ Commun[\ 0874\ 04\ 0160[ 209
74SC0214 R[ S[ Varma\ M[ Varma and G[ W[ Kabalka^ Synth[ Commun[\ 0874\ 04\ 0214[ 315
74T316 E[ E[ Aboujaoude\ N[ Collignon and P[ Savignac^ Tetrahedron\ 0874\ 30\ 316[ 49
74T588 J[ E[ Baldwin\ R[ H[ Jones\ C[ Najera and M[ Yus^ Tetrahedron\ 0874\ 30\ 588[ 318
74T708 M[ Regitz and R[ Martin^ Tetrahedron\ 0874\ 30\ 708[ 371
74T0000 S[ Rozen and R[ Filler^ Tetrahedron\ 0874\ 30\ 0000[ 037
74T0774 M[ E[ Hassan\ M[ A[ Magraby and M[ A[ Aziz^ Tetrahedron\ 0874\ 30\ 0774[ 228\ 250
74T0820 J[ E[ Baldwin\ H[ S[ Bansal\ J[ Chondrogianni\ L[ D[ Field\ A[ A[ Taha\ V[ Thaller\
D[ Brewer and A[ Taylor^ Tetrahedron\ 0874\ 30\ 0820[ 601
74T1892 J[ M[ Aizpurua\ M[ Juaristi\ B[ Lecea and C[ Palomo^ Tetrahedron\ 0874\ 30\ 1892[ 3\ 004
74T2124 R[ B[ King and L[ Borodinsky^ Tetrahedron\ 0874\ 30\ 2124[ 604
74T3914 B[ Giese and M[ Horler^ Tetrahedron\ 0874\ 30\ 3914[ 510
74T3338 K[ Kojima\ K[ Koyama and S[ Amemiya^ Tetrahedron\ 0874\ 30\ 3338[ 24
74T3616 D[ Liotta^ Tetrahedron\ 0874\ 30\ 3616[ 26\ 062
74T3648 T[ G[ Back and R[ G[ Kerr^ Tetrahedron\ 0874\ 30\ 3648[ 063
74T3660 H[ J[ Reich\ C[ A[ Hoeger and W[ W[ Willis\ Jr[^ Tetrahedron\ 0874\ 30\ 3660[ 066
74T3710 A[ P[ Kozikowski and A[ Ames^ Tetrahedron\ 0874\ 30\ 3710[ 184\ 291\ 294\ 296\ 298
74T3732 F[ S[ Guziec\ L[ J[ San Filippo\ C[ J[ Murphy\ C[ A[ Moustakis and E[ R[ Cullen^ Tetrahedron\
0874\ 30\ 3732[ 281
74T3750 D[ Seebach\ G[ Calderari and P[ Knochel^ Tetrahedron Lett[\ 0874\ 30\ 3750[ 081
74T3770 D[ Liotta\ M[ Saindane\ C[ Barnum and G[ Zima^ Tetrahedron\ 0874\ 30\ 3770[ 063
74T4950 M[ P[ Cava and M[ I[ Levinson^ Tetrahedron\ 0874\ 30\ 4950[ 235\ 244
74T4282 J[ D[ Coyle^ Tetrahedron\ 0874\ 30\ 4282[ 241
74T4534 H[ Nagashima\ K[ Sato and J[ Tsuji^ Tetrahedron\ 0874\ 30\ 4534[ 007
74T4744 P[ L[ Pauson^ Tetrahedron\ 0874\ 30\ 4744[ 107
74T4768 R[ Noyori and Y[ Hayakawa^ Tetrahedron\ 0874\ 30\ 4768[ 018
74TL36 S[!F[ Chen and P[ S[ Mariano^ Tetrahedron Lett[\ 0874\ 15\ 36[ 303
74TL366 I[ K[ Stamos^ Tetrahedron Lett[\ 0874\ 15\ 366[ 524
74TL692 S[ Wol} and W[ C[ Agosta^ Tetrahedron Lett[\ 0874\ 15\ 692[ 130
References 702
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74TL1284 R[ D[ Miller and R[ Hassig^ Tetrahedron Lett[\ 0874\ 15\ 1284[ 544
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74TL2916 K[ Tomioka\ H[ Kawasaki and K[ Koga^ Tetrahedron Lett[\ 0874\ 15\ 2916[ 180
74TL2920 H[ Kawasaki\ K[ Tomioka and K[ Koga^ Tetrahedron Lett[\ 0874\ 15\ 2920[ 180
74TL2270 J[ C[ Carretero and J[ L[ Garcia Ruano^ Tetrahedron Lett[\ 0874\ 15\ 2270[ 584\ 698
74TL2352 T[ Kobayashi\ T[ Sakakura and M[ Tanaka^ Tetrahedron Lett[\ 0874\ 15\ 2352[ 189
74TL2484 C[ Cardellicchio\ V[ Fiandanese\ G[ Marchese and L[ Ronzioni^ Tetrahedron Lett[\ 0874\
29\ 2484[ 174
74TL2502 M[ Pohmakotr and S[ Pisutjaroenpong^ Tetrahedron Lett[\ 0874\ 15\ 2502[ 51
74TL2726 Y[ Tamura\ T[ Yakura\ J[!I[ Haruta and Y[ Kita^ Tetrahedron Lett[\ 0874\ 15\ 2726[ 047
74TL2888 R[ Sauvetre\ J[ P[ Gillet and J[ F[ Normant^ Tetrahedron Lett[\ 0874\ 15\ 2888[ 126
74TL3084 G[ Rousseau and L[ Blanco^ Tetrahedron Lett[\ 0874\ 15\ 3084[ 102
74TL3118 S[ Sato\ I[ Matsuda and Y[ Izumi^ Tetrahedron Lett[\ 0874\ 15\ 3118[ 40\ 191
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74TL3392 B[ Alcaide\ C[ L[ Mardamigo\ R[ Perez!Ossorio\ J[ Plumet and M[ M[ Sanchez^ Tetrahedron
Lett[\ 0874\ 15\ 3392[ 303
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76S300 A[ A[ Kandil\ T[ M[ Porter and K[ N[ Slessor^ Synthesis\ 0876\ 300[ 528
76S341 J[ T[ Wrobel and E[ Hejchman^ Synthesis\ 0876\ 341[ 523
76S492 M[ Fetizon\ P[ Goulaouic and I[ Hanna^ Synthesis\ 0876\ 492[ 054
76S421 N[ Ono\ M[ Fujii and A[ Kaji^ Synthesis\ 0876\ 421[ 35\ 089
76S520 A[ Sera\ H[ Tani\ I[ Nishiguchi and T[ Hirashima^ Synthesis\ 0876\ 520[ 510
76S537 H[!J[ Cristau\ Y[ Beziat\ C[ E[ Niangoran and H[ Christol^ Synthesis\ 0876\ 537[ 085
76S548 M[ Mikolajczyk and P[ Balczewski^ Synthesis\ 0876\ 548[ 24
76S582 A[ Dondoni\ G[ Fantin\ M[ Fogagnolo\ A[ Medici and P[ Pedrini^ Synthesis\ 0876\ 582[ 696\ 603
76S608 F[ Clerici\ A[ Di Mare\ M[ L[ Gelmi and D[ Pocar^ Synthesis\ 0876\ 608[ 327
76S618 M[ Node\ H[ Nagasawa\ Y[ Naniwa and K[ Fuji^ Synthesis\ 0876\ 618[ 36\ 081
76S713 A[ Kubo\ N[ Saito\ N[ Kawakami\ Y[ Matsuyama and T[ Miwa^ Synthesis\ 0876\ 713[ 308
76S720 R[ V[ Ho}man and G[ A[ Buntain^ Synthesis\ 0876\ 720[ 320
76S785 S[ Apparao and R[ R[ Schmidt^ Synthesis\ 0876\ 785[ 156
76S897 D[ R[ Williams\ R[ D[ Gaston and J[ F[ Hoover^ Synthesis\ 0876\ 897[ 60
76S813 K[ Burger\ H[ Neuhauser and M[ Eggersdorfer^ Synthesis\ 0876\ 813[ 579
76S827 R[ Zhang and Y[ Zhou^ Synthesis\ 0876\ 827[ 528
76S887 A[ Dondoni\ G[ Fautin\ M[ Fogagnolo\ A[ Medici and P[ Pedrini^ Synthesis\ 0876\ 887[ 098
76S0901 R[ Mahrwald\ F[ Thiel\ H[ Schick and H[!J[ Palme^ Synthesis\ 0876\ 0901[ 119
76S0922 E[ Campi\ N[ J[ Fitzmaurice and W[ R[ Jackson^ Synthesis\ 0876\ 0922[ 66
76S0932 T[ Mukaiyama and M[ Murakami^ Synthesis\ 0876\ 0932[ 119
76S0944 P[ F[ Schuda\ C[ B[ Ebner and S[ J[ Potlock^ Synthesis\ 0876\ 0944[ 084\ 119
76S0981 M[ Ohno\ S[ Matsuoka and S[ Eguchi^ Synthesis\ 0876\ 0981[ 162
76S0985 T[ Hiiro\ N[ Kambe\ A[ Ogawa\ N[ Miyoshi\ S[ Murai and N[ Sonoda^ Synthesis\ 0876\
0985[ 065
76S0002 J[ Cossy^ Synthesis\ 0876\ 0002[ 021
76S0015 S[ Bernasconi\ G[ Jommi\ S[ Montanari and M[ Sisti^ Synthesis\ 0876\ 0015[ 058
76SC044 B[ C[ Rano and D[ C[ Sarkar^ Synth[ Commun[\ 0876\ 06\ 044[ 50
76SC332 H[ A[ Stefani\ J[ V[ Comasseto and N[ Petragnani^ Synth[ Commun[\ 0876\ 06\ 332[ 066
76SC712 R[ Davis^ Synth[ Commun[\ 0876\ 06\ 712[ 060
76SC842 D[ Y[ Kim and D[ Y[ Oh^ Synth[ Commun[\ 0876\ 06\ 842[ 528
76SC872 H[ J[ Monteiro^ Synth[ Commun[\ 0876\ 06\ 872[ 082
76SC0476 A[ R[ Harris^ Synth[ Commun[\ 0876\ 06\ 0476[ 018
76SC0698 J[ S[ Baum\ D[ A[ Shook\ H[ M[ L[ Davies and H[ D[ Smith^ Synth[ Commun[\ 0876\ 06\
0698[ 082
76T440 D[ H[ R[ Barton\ I[ Fernandez\ C[ S[ Richard and S[ Z[ Zard^ Tetrahedron\ 0876\ 32\ 440[ 316\ 329
76T702 T[ Tanaka\ A[ Hazato\ K[ Bannai\ et al[^ Tetrahedron\ 0876\ 32\ 702[ 081
76T0736 A[ R[ B[ Manas and R[ A[ J[ Smith^ Tetrahedron\ 0876\ 32\ 0736[ 172
76T1598 Y[ G[ Gololobov\ A[ N[ Nesmeyanov\ V[ P[ Lysenko and I[ E[ Boldeskul^ Tetrahedron\
0876\ 32\ 1598[ 267
76T1610 D[ Bernard\ A[ Doutheau and J[ Gore^ Tetrahedron\ 0876\ 32\ 1610[ 129
76T2952 A[ Golebiowski\ U[ Jacobsson and J[ Jurczak^ Tetrahedron\ 0876\ 32\ 2952[ 28
76T2834 M[ E[ Borredon\ M[ Delmas and A[ Gaset^ Tetrahedron\ 0876\ 32\ 2834[ 262
76T2852 F[ P[ Cossio\ M[ C[ Lopez and C[ Palomo^ Tetrahedron\ 0876\ 32\ 2852[ 3\ 005
76T3186 D[ H[ R[ Barton\ Y[ Herve\ P[ Potier and J[ Thierry^ Tetrahedron\ 0876\ 32\ 3186[ 524
76T3370 P[ Gramatica\ P[ Manitto\ D[ Monti and G[ Speranza^ Tetrahedron\ 0876\ 32\ 3370[ 47
76T3514 G[ Petrillo\ M[ Novi\ G[ Garbarino and C[ Dell|Erba^ Tetrahedron\ 0876\ 32\ 3514[ 553
76T4060 A[ R[ Katritzky\ D[ L[ Ostercamp and T[ I[ Yousaf^ Tetrahedron\ 0876\ 32\ 4060[ 395
76T4170 M[ Watanabe\ E[ Shinoda\ Y[ Shimizu\ S[ Furukawa\ T[ Kuraishi and M[ Iwao^ Tetrahedron\
0876\ 32\ 4170[ 209
76TL20 L[ A[ Paquette\ J[ L[ Romine and H[!S[ Lin^ Tetrahedron Lett[\ 0876\ 17\ 20[ 195
76TL192 T[ Machiguchi\ H[ Otani\ Y[ Ishii and T[ Hasegawa^ Tetrahedron Lett[\ 0876\ 17\ 192[ 241
76TL184 S[ L[ Buchwald and S[ J[ LaMaire^ Tetrahedron Lett[\ 0876\ 17\ 184[ 503
76TL234 S[ V[ Ley and P[ R[ Woodward^ Tetrahedron Lett[\ 0876\ 17\ 234[ 086
76TL260 H[ M[ L[ Davies and L[ V[ T[ Crisco^ Tetrahedron Lett[\ 0876\ 17\ 260[ 262
76TL286 E[ Di}erding\ O[ Vandevelde\ B[ Roekens\ T[ T[ Van and L[ Ghosez^ Tetrahedron Lett[\
0876\ 17\ 286[ 313
76TL394 M[!P[ Teulade and P[ Savignac^ Tetrahedron Lett[\ 0876\ 17\ 394[ 38
76TL353 D[ S[ Kemp and J[ S[ Carter^ Tetrahedron Lett[\ 0876\ 17\ 353[ 519
76TL436 P[ Q[ Huang\ S[ Arseniyadis and H[!P[ Husson^ Tetrahedron Lett[\ 0876\ 17\ 436[ 505
76TL448 C[ M[ Moorho} and D[ F[ Schneider^ Tetrahedron Lett[\ 0876\ 17\ 448[ 120
76TL500 P[ K[ Chakravarty\ P[ Combs\ A[ Roth and W[ J[ Greenlee^ Tetrahedron Lett[\ 0876\ 17\
500[ 086
76TL658 B[ Byrne and M[ Karras^ Tetrahedron Lett[\ 0876\ 17\ 658[ 008
76TL770 I[ Kolodiazhnyi^ Tetrahedron Lett[\ 0876\ 17\ 770[ 438
76TL774 H[ Dhimane\ J[!C[ Pommelet\ J[ Chuche\ G[ Lhommet and M[ Haddad^ Tetrahedron Lett[\
0876\ 17\ 774[ 430
76TL802 A[ Padwa\ D[ N[ Kline and J[ Perumattam^ Tetrahedron Lett[\ 0876\ 17\ 802[ 149
76TL878 N[ Simkins^ Tetrahedron Lett[\ 0876\ 17\ 878[ 61
713 References
76TL0900 M[ T[ H[ Liu\ N[ Soundarajan\ S[ M[ Anand and T[ Ibata^ Tetrahedron Lett[\ 0876\ 17\
0900[ 213
76TL0958 D[ Liotta\ D[ Brown\ W[ Hoekstra and R[ Monahan^ Tetrahedron Lett[\ 0876\ 17\ 0958[ 118
76TL0182 Y[ Ito\ S[ Nishimura and M[ Ishikawa^ Tetrahedron Lett[\ 0876\ 17\ 0182[ 397
76TL0500 B[ M[ Trost and D[ J[ Jebaratnam^ Tetrahedron Lett[\ 0876\ 17\ 0500[ 519
76TL0736 A[ R[ Katritzky and S[ Sengupta^ Tetrahedron Lett[\ 0876\ 17\ 0736[ 046
76TL0746 J[ S[ Prasad and L[ S[ Liebeskind^ Tetrahedron Lett[\ 0876\ 17\ 0746[ 162
76TL0782 A[ Takahashi and M[ Shibasaki^ Tetrahedron Lett[\ 0876\ 17\ 0782[ 48\ 119
76TL0802 S[ Kim and S[ S[ Kim^ Tetrahedron Lett[\ 0876\ 17\ 0802[ 72
76TL1942 C[ Cardellicchio\ V[ Fiandanese\ G[ Marchese and L[ Ronzini^ Tetrahedron Lett[\ 0876\ 17\
1942[ 029\ 174\ 295
76TL1976 G[ Stork and N[ A[ Saccomano^ Tetrahedron Lett[\ 0876\ 17\ 1976[ 109
76TL1988 L[ Castedo\ J[ L[ Mascarnenas and M[ Mairino^ Tetrahedron Lett[\ 0876\ 17\ 1988[ 46
76TL1020 J[ Muzart^ Tetrahedron Lett[\ 0876\ 17\ 1020[ 182
76TL1044 L[ L[ Shi\ W[ J[ Xia\ J[ H[ Yang\ X[ Wen and Y[ Z[ Huang^ Tetrahedron Lett[\ 0876\ 17\
1044[ 085\ 120
76TL1064 C[ L[ Willis^ Tetrahedron Lett[\ 0876\ 17\ 1064[ 51
76TL1122 P[ Deshong and D[ R[ Sidler^ Tetrahedron Lett[\ 0877\ 42\ 1122[ 107
76TL1186 R[ Antonioletti\ F[ Bonadies and A[ Scettri^ Tetrahedron Lett[\ 0876\ 17\ 1186[ 134
76TL1236 C[ Petrier and J[ Luche^ Tetrahedron Lett[\ 0876\ 17\ 1236[ 016
76TL1242 D[ Bacos\ J[ P[ Celerier and G[ Lhommet^ Tetrahedron Lett[\ 0876\ 17\ 1242[ 300
76TL1248 E[ Laurent\ B[ Marquet\ R[ Tardivel and H[ Thiebault^ Tetrahedron Lett[\ 0876\ 17\ 1248[ 038
76TL1272 S[ Murahashi and T[ Shiota^ Tetrahedron Lett[\ 0876\ 17\ 1272[ 321
76TL1278 J[ S[ Cha\ J[ E[ Kim\ S[ Y[ Oh\ J[ C[ Lee and K[ W[ Lee^ Tetrahedron Lett[\ 0876\ 17\ 1278[ 02\ 71
76TL1362 P[ H[ Mazzocchi\ C[ R[ King and H[ L[ Ammon^ Tetrahedron Lett[\ 0876\ 17\ 1362[ 81\ 86
76TL1570 U[ Gruseck and M[ Heuschmann^ Tetrahedron Lett[\ 0876\ 17\ 1570[ 110
76TL1742 J[ M[ Fang and M[ Y[ Chen^ Tetrahedron Lett[\ 0876\ 17\ 1742[ 525
76TL1810 A[ R[ De Lera and W[ H[ Okamura^ Tetrahedron Lett[\ 0876\ 17\ 1810[ 53
76TL2910 M[ Makosza and Z[ Owczarczyk^ Tetrahedron Lett[\ 0876\ 17\ 2910[ 88\ 094
76TL2004 Y[ Lin\ D[ Ma and X[ Lu^ Tetrahedron Lett[\ 0876\ 17\ 2004[ 007\ 107
76TL2044 P[ Clawson and D[ A[ Whiting^ Tetrahedron Lett[\ 0876\ 17\ 2044[ 207
76TL2188 R[ L[ Danheiser and S[ Savariar^ Tetrahedron Lett[\ 0876\ 17\ 2188[ 105
76TL2346 J[!F[ Lavallee and P[ Deslongchamps^ Tetrahedron Lett[\ 0876\ 17\ 2346[ 111
76TL2352 T[ D[ Aicher and Y[ Kishi^ Tetrahedron Lett[\ 0876\ 17\ 2352[ 133
76TL2404 K[ Suzuki\ M[ Miyazawa and G[!I[ Tsuchihashi^ Tetrahedron Lett[\ 0876\ 17\ 2404[ 059
76TL2572 J[ Tsuji and M[ Minato^ Tetrahedron Lett[\ 0876\ 17\ 2572[ 002
76TL2630 J[ Bergman and L[ Venemalm^ Tetrahedron Lett[\ 0876\ 17\ 2630[ 298
76TL2776 P[ T[ Meinke\ G[ A[ Kra}t and J[ T[ Spencer^ Tetrahedron Lett[\ 0876\ 17\ 2776[ 283
76TL2830 R[ J[ P[ Corriu\ G[ F[ Lanneau and M[ Perrot^ Tetrahedron Lett[\ 0876\ 17\ 2830[
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76TL3104 C[!M[ Andersson and A[ Hallberg^ Tetrahedron Lett[\ 0876\ 17\ 3104[ 134
76TL3156 W[ D[ Rudorf and R[ Schwarz^ Tetrahedron Lett[\ 0876\ 17\ 3156[ 140
76TL3182 M[ Miyashita\ T[ Suzuki and A[ Yoshikoshi^ Tetrahedron Lett[\ 0876\ 17\ 3182[ 059
76TL3280 S[ Collins and Y[ Hong^ Tetrahedron Lett[\ 0876\ 17\ 3280[ 020
76TL3284 W[ Flitsch\ K[ Hampel and M[ Hohenhorst^ Tetrahedron Lett[\ 0876\ 17\ 3284[ 157
76TL3446 T[ Yamada\ K[ Goto\ Y[ Mitsuda and J[ Tsuji^ Tetrahedron Lett[\ 0876\ 17\ 3446[ 320
76TL3464 J[ S[ Cha\ J[ E[ Kim\ S[ Y[ Oh and J[ D[ Kim^ Tetrahedron Lett[\ 0876\ 17\ 3464[ 71
76TL3534 D[ S[ Kemp and J[ S[ Carter^ Tetrahedron Lett[\ 0876\ 17\ 3534[ 519\ 510
76TL3634 F[ Camps\ J[ Coll\ J[ M[ Moreto and J[ Torras^ Tetrahedron Lett[\ 0876\ 17\ 3634[ 107
76TL3722 W[ Ando\ Y[ Kumamoto and N[ Tokitoh^ Tetrahedron Lett[\ 0876\ 17\ 3722[ 240
76TL3738 Y[ Ito\ M[ Sawamura\ M[ Matsuoka\ Y[ Matsumoto and T[ Hayashi^ Tetrahedron Lett[\
0876\ 17\ 3738[ 696
76TL4970 J[ A[ Marshall and S[ L[ Crooks^ Tetrahedron Lett[\ 0876\ 17\ 4970[ 111
76TL4004 F[ A[ Davis\ J[ Wei\ A[ C[ Sheppard and S[ Gubernick^ Tetrahedron Lett[\ 0876\ 17\ 4004[ 327
76TL4130 E[ J[ Corey and W[!G[ Su^ Tetrahedron Lett[\ 0876\ 17\ 4130[ 111
76TL4250 J[ M[ Aizpurua\ M[ Oiarbide and C[ Palomo^ Tetrahedron Lett[\ 0876\ 17\ 4250[ 051
76TL4258 G[ Cainelli\ D[ Giacomini\ M[ Panunzio\ G[ Martelli and G[ Spunta^ Tetrahedron Lett[\
0876\ 17\ 4258[ 339\ 345
76TL4402 A[ E[ Vougioukas and H[ B[ Kagan^ Tetrahedron Lett[\ 0876\ 17\ 4402[ 504\ 521
76TL4508 R[ O[ Hutchins and M[ C[ Rutledge^ Tetrahedron Lett[\ 0876\ 17\ 4508[ 328
76TL4780 M[ Shimazaki\ H[ Hara\ K[ Suzuki and G[!I[ Tsuchihashi^ Tetrahedron Lett[\ 0876\ 17\ 4780[ 059
76TL5068 P[ Jimonet\ D[ S[ Grierson and H[!P[ Husson^ Tetrahedron Lett[\ 0876\ 17\ 5068[ 527
76TL5120 J[ S[ Cha\ J[ E[ Kim\ M[ S[ Yoon and Y[ S[ Kim^ Tetrahedron Lett[\ 0876\ 17\ 5120[ 71\ 88
76TL5350 F[ Tubery\ D[ S[ Grierson and H[!P[ Husson^ Tetrahedron Lett[\ 0876\ 17\ 5350[ 244
76TL5358 S[!I[ Murahashi and T[ Shiota^ Tetrahedron Lett[\ 0876\ 17\ 5358[ 527
76TL5538 K[ Okuma\ J[!I[ Sakata\ Y[ Tachibana\ T[ Honda and H[ Ohta^ Tetrahedron Lett[\ 0876\ 17\
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77S283 H[ Suga and H[ Miyake^ Synthesis\ 0877\ 283[ 8
77S306 D[ P[ Curran^ Synthesis\ 0877\ 306[ 181
77S378 D[ P[ Curran^ Synthesis\ 0877\ 378[ 181
77S453 M[ Rambaud\ M[ Bakasse\ G[ Duguay and J[ Villieras^ Synthesis\ 0877\ 453[ 109
77S593 A[ Kasahara\ T[ Izumi and N[ Kudou^ Synthesis\ 0877\ 593[ 122
77S586 S[ Canonica\ M[ Ferrari\ G[ Jommi and M[ Sisti^ Synthesis\ 0877\ 586[ 48
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0877\ 33\ 0592[ 083
77T0716 E[ Schaumann^ Tetrahedron\ 0877\ 33\ 0716[ 435\ 436
77T1302 H[ Nishiyama\ K[ Sakuta\ N[ Osaka\ H[ Arai\ M[ Matsumoto and K[ Itoh^ Tetrahedron\
0877\ 33\ 1302[ 552
77T1346 S[ Arseniyadis\ P[ Q[ Huang\ D[ Piveteau and H[ P[ Husson^ Tetrahedron\ 0877\ 33\ 1346[ 311
77T1546 C[ Almansa\ A[ Moyano and F[ Serratosa^ Tetrahedron\ 0877\ 33\ 1546[ 107
77T3046 E[ W[ Colvin\ D[ G[ McGarry and M[ J[ Nugent^ Tetrahedron\ 0877\ 33\ 3046[ 339
77T3196 I[ Paterson^ Tetrahedron\ 0877\ 33\ 3196[ 25\ 013\ 057
77T3336 J[!C[ Guillemin\ J[!M[ Denis\ M[!C[ Lasne and J[!L[ Ripoll^ Tetrahedron\ 0877\ 33\ 3336[ 453
77T3352 M[ Pellet and F[ Huet^ Tetrahedron\ 0877\ 33\ 3352[ 109
77T3542 S[ E[ Drews and G[ H[ P[ Roos^ Tetrahedron\ 0877\ 33\ 3542[ 387
77T4356 K[ Nunami\ K[ Hiramatsu\ K[ Hayashi and K[ Matsumoto^ Tetrahedron\ 0877\ 33\ 4356[ 606\ 619
77T5096 C[ Larpent and H[ Patin^ Tetrahedron\ 0877\ 33\ 5096[ 528
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77TL890 L[ E[ Overman and M[ J[ Sharp^ Tetrahedron Lett[\ 0877\ 18\ 890[ 310
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77TL1750 Z[ Arnold\ G[ V[ Kryshtal\ V[ Kral and D[ Dvorak^ Tetrahedron Lett[\ 0877\ 18\ 1750[ 60
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0877\ 18\ 2638[ 01\ 017
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89MI 292!90 J[ S[ Cha\ J[ C[ Lee\ M[ S[ Yoon\ J[ B[ Seo and J[ M[ Kim^ Bull[ Kor[ Chem[ Soc[\ 0889\ 00\
65[ 71
89MI 293!90 W[ P[ Gri.th and S[ V[ Ley^ Aldrichimica Acta\ 0889\ 12\ 02[ 006
B!89MI 293!91 Y[ Z[ Huang\ L[ L[ Shi\ J[ H[ Yang\ W[ J[ Xiao\ S[ W[ Li and W[ B[ Wang^ in {{Heteroatom
Chemistry\|| ed[ E[ Block\ VCH\ Weinheim\ 0889\ p[ 078[ 085
B!89MI 200!90 P[ K[ Claus^ in {{Sulphenic Acids and their Derivatives\|| ed[ S[ Patai\ Wiley\ New York\
0889\ p[ 612[ 325\ 326
B!89MI 202!90 H[ R[ Hudson^ in {{The Chemistry of Organophosphorus Compounds||\ ed[ F[ R[ Hartley\
Wiley\ Chichester\ 0883\ ch[ 00[ 382
89MI 219!90 A[ Padwa and A[ M[ Scho}stall^ Adv[ Cycloaddition\ 0889\ 1\ 0[ 567
89OM1151 R[ R[ Schrock\ R[ T[ DePue\ J[ Feldman et al^ Or`anometallics\ 0889\ 8\ 1151[ 404
89OM1756 W[ Dragisich\ W[ D[ Wull} and K[ Hoogsteen^ Or`anometallics\ 0889\ 8\ 1756[ 579
89OPP288 L[ E[ Fisher and J[ M[ Muchowski^ Or`[ Prep[ Proced[ Int[\ 0889\ 11\ 288[ 28\ 39\ 067\ 072\ 073
89OPP696 G[ Rosini\ R[ Ballini\ M[ Petrini\ E[ Marotta and P[ Righi^ Or`[ Prep[ Proced[ Int[\ 0889\
11\ 696[ 35\ 080
89OR"27#544 H[ W[ Pinnick^ Or`[ React[\ 0889\ 27\ 544[ 07\ 023
89OR"28#186 T[ T[ Tidwell^ Or`[ React[\ 0889\ 28\ 176[ 5\ 007
89OS"58#047 J[ C[ Towson\ M[ C[ Weismiller\ G[ S[ Lal\ A[ C[ Sheppard and F[ A[ Davis^ Or`[ Synth[\
0889\ 58\ 047[ 060
89OSC"6#16 G[ Ho~e and B[ Lange^ Or`[ Synth[\ Coll[ Vol[\ 0889\ 6\ 16[ 691
89OSC"6#183 P[ G[ Gassman and T[ L[ Guggenheim^ Or`[ Synth[\ Coll[ Vol[\ 0889\ 6\ 183[ 696
89PAC594 G[ Cainelli\ M[ Panunzio\ P[ Andreoli\ G[ Martelli\ G[ Spunta\ D[ Giacomini and E[ Bandini^
Pure Appl[ Chem[\ 0889\ 51\ 594[ 345\ 346\ 347
89PS"38#290 G[ Bertrand\ A[ Igau\ A[ Baceiredo and H[ Grutzmacher^ Phosphorus Sulfur\ 0889\ 38\ 290[ 578
89PS"43#060 J[ Nasser\ E[ About!Jaudet and N[ Collignon^ Phosphorus Sulfur\ 0889\ 43\ 060[ 528
89RTC335 H[ C[ L[ Abbenhuis\ D[ M[ Grove\ P[ van der Sluis\ A[ L[ Spek and G[ van Koten^ Recl[
Trav[ Chim[ Pays!Bas\ 0889\ 098\ 335[ 401
89S0 S[ Servi^ Synthesis\ 0889\ 0[ 29\ 050
89S016 S[ P[ Acharya and R[ A[ Rane^ Synthesis\ 0889\ 016[ 3
89S051 Z[!T[ Huang and X[ Shi^ Synthesis\ 0889\ 051[ 154
89S084 M[ Hojo\ R[ Masuda\ E[ Okada and H[ Yamamoto^ Synthesis\ 0889\ 084[ 154
89S132 N[ G[ Kundhu\ B[ Das and A[ Majumdar^ Synthesis\ 0889\ 132[ 162
89S290 D[ Jacoby\ J[ P[ Celerier\ H[ Petit and G[ Lhommet^ Synthesis\ 0889\ 290[ 385
89S222 D[ Albanese\ D[ Landini and M[ Penso^ Synthesis\ 0889\ 222[ 316\ 329
89S342 W[ S[ Saari and T[ E[ Fisher^ Synthesis\ 0889\ 342[ 39
89S404 A[ M[ Polozov\ N[ A[ Polezhaeva\ A[ H[ Mustaphin\ A[ V[ Khotinen and B[ A[ Arbuzov^
Synthesis\ 0889\ 404[ 199
89S457 J[ Stoelwinder and A[ M[ van Leusen^ Synthesis\ 0889\ 457[ 603\ 605
89S464 T[ Ziegler\ B[ Horsch and F[ E}enberger^ Synthesis\ 0889\ 464[ 517
89S484 N[ De Kimpe and P[ Brunet^ Synthesis\ 0889\ 484[ 041
89S504 H[ Yinglin and H[ Hongwen^ Synthesis\ 0889\ 504[ 068
89S520 M[ Iman\ P[ Bouyssou and J[ Chenault^ Synthesis\ 0889\ 520[ 163
89S535 G[ A[ Olah\ R[ Krishnamurti and G[ K[ S[ Prakash^ Synthesis\ 0889\ 535[ 696
89S566 M[ Shimazaki\ Z[!H[ Huang\ M[ Goto and N[ Suzuki^ Synthesis\ 0889\ 566[ 197
89S583 A[ Kamimura and T[ Nagashima^ Synthesis\ 0889\ 583[ 35
89S644 V[ Blanchot\ M[ Fetizon and I[ Hanna^ Synthesis\ 0889\ 644[ 139\ 134
89S657 Y[ Yamada and H[ Yasuda^ Synthesis\ 0889\ 657[ 516\ 523
89S670 K[ Hiramatsu\ K[ Nunami\ K[ Hayashi and K[ Matsumoto^ Synthesis\ 0889\ 670[ 606
89S730 V[ A[ Petrosyan\ M[ E[ Niyazymbetov\ L[ D[ Konyushkin and V[ P[ Litvinov^ Synthesis\
0889\ 730[ 523
89S746 T[ T[ Tidwell^ Synthesis\ 0889\ 09\ 746[ 5\ 007
89S774 G[ Olah and A[ H[ Wu^ Synthesis\ 0889\ 774[ 384
89S784 G[ Bartoli\ C[ Cimarelli\ G[ Palmieri and M[ Bosco^ Synthesis\ 0889\ 784[ 151\ 152
89S882 J[ K[ F[ Geirsson and A[ D[ Gudmundsdottir^ Synthesis\ 0889\ 882[ 119
89S0992 J[ Barluenga\ L[ Llavona\ M[ Yus and J[ M[ Concellon^ Synthesis\ 0889\ 0992[ 041\ 043
89S0922 Y[!H[ Chang\ B[!J[ Uang\ C[!M[ Wu and T[!H[ Yu^ Synthesis\ 0889\ 0922[ 51
89S0948 S[ R[ Hitchcock\ F[ Perron\ V[ A[ Martin and K[ F[ Albizati^ Synthesis\ 0889\ 0948[ 059
89S0017 J[ C[ Jochims\ S[ Hehl and S[ Herzberger^ Synthesis\ 0889\ 0017[ 576
89S0062 A[ R[ Katritzky\ J[ Borowiecka and W[!Q[ Fan^ Synthesis\ 0889\ 0062[ 31
89SC04 Y[ Z[ Jiang\ P[ Guo and G[ L[ Liu^ Synth[ Commun[\ 0889\ 19\ 04[ 304
89SC60 M[ Adachi and T[ Sugasawa^ Synth[ Commun[\ 0889\ 19\ 60[ 553
89SC020 J[ E[ Hernandez\ V[ Samano and V[ Valdes^ Synth[ Commun[\ 0889\ 19\ 020[ 195
89SC272 C[ Giordano and M[ Villa^ Synth[ Commun[\ 0889\ 19\ 272[ 290
89SC288 M[ Navarro\ W[ F[ De Giovani and J[ R[ Romero^ Synth[ Commun[\ 0889\ 19\ 288[ 6\ 019
89SC598 J[ C[ Cochran and M[ G[ Melville^ Synth[ Commun[\ 0889\ 598[ 80\ 86
89SC526 H[ R[ Kim\ E[ K[ Ryu\ J[ H[ Jung and J[ N[ Kim^ Synth[ Commun[\ 0889\ 19\ 526[ 019\ 183
89SC602 A[ Muza}ar and A[ Brossi^ Synth[ Commun[\ 0889\ 19\ 602[ 242
89SC854 D[ Albanese\ D[ Landini\ M[ Penso and G[ Pozzi^ Synth[ Commun[\ 0889\ 19\ 854[ 532
89SC0984 G[ L[ Larson\ J[ A[ Soderquist and M[ R[ Claudio^ Synth[ Commun[\ 0889\ 19\ 0984[ 161
89SC0554 G[ T[ Crisp and T[ P[ Bubner^ Synth[ Commun[\ 0889\ 19\ 0554[ 160
89SC0832 C[ C[ Fortes and E[ A[ Okina^ Synth[ Commun[\ 0889\ 19\ 0832[ 523
739 References
89SC1980 M[ Baboulene\ A[ Lattes and Z[ Benmaarouf!Khallaayoun^ Synth[ Commun[\ 0889\ 19\ 1980[ 33
89SC1140 B[ Mauze and L[ Miginiac^ Synth[ Commun[\ 0889\ 19\ 1140[ 549
89SC1168 A[ S[ Demir\ N[ Camkerten\ H[ Akgun\ C[ Tanyeli\ A[ S[ Mahasneh and D[ S[ Watt^ Synth[
Commun[\ 0889\ 19\ 1168[ 051
89SC1180 X[ Huang and J!H[ Pi^ Synth[ Commun[\ 0889\ 19\ 1180[ 524
89SC1248 C[ M[ Adams and J[ E[ Schemenaur^ Synth[ Commun[\ 0889\ 19\ 1248[ 313
89SC1342 G[ W[ Kabalka\ R[ D[ Pace and P[ P[ Wadgaonkar^ Synth[ Commun[\ 0889\ 19\ 1342[ 315
89SC1426 A[ Alberola\ J[ M[ Andres\ A[ Gonzalez and R[ Pedrosa^ Synth[ Commun[\ 0889\ 19\
1426[ 141
89SC1454 M[ L[ Scarpati\ A[ Bianco\ L[ Mascitelli and P[ Passacantilli^ Synth[ Commun[\ 0889\ 19\
1454[ 81
89SC1572 A[ Bhattacharya\ J[ M[ Williams\ J[ S[ Amato\ U[ Dolling and E[ J[ J[ Grabowski^ Synth[
Commun[\ 0889\ 19\ 1572[ 020
89SC1872 B[ Contreras\ L[ Duhamel and G[ Ple^ Synth[ Commun[\ 0889\ 19\ 1872[ 52
89SC2952 Y[ Inoue\ K[ Ohuchi\ S[ Imaizumi and H[ Hagiwara^ Synth[ Commun[\ 0889\ 19\ 2952[ 133
89SC2958 K[ F[ Cheng and K[ P[ Chan^ Synth[ Commun[\ 0889\ 19\ 2958[ 298
89SC2974 D[ Brillon^ Synth[ Commun[\ 0889\ 19\ 2974[ 250
89SC2056 A[ Chesney and I[ E[ Marko^ Synth[ Commun[\ 0889\ 19\ 2056[ 33
89SC2148 M[ N[ Kanvinde\ S[ A[ Kulkarni and M[ V[ Paradkar^ Synth[ Commun[\ 0889\ 19\ 2148[ 182
89SC2154 E[ J[ Parish\ S[ Parish and H[ Honda^ Synth[ Commun[\ 0889\ 19\ 2154[ 023
89SC2248 E[ J[ Parish\ H[ Honda and D[ L[ Hileman^ Synth[ Commun[\ 0889\ 2248[ 004
89SL096 J[ C[ Anderson and S[ C[ Smith^ Synlett\ 0889\ 096[ 045
89SL006 D[ Crich and L[ B[ L[ Lim^ Synlett\ 0889\ 006[ 052
89SL044 M[ J[ Calverley^ Synlett\ 0889\ 044[ 28
89SL134 Y[ Ito and M[ Murakami^ Synlett\ 0889\ 134[ 307
89SL171 B[ Lygo and N[ O|Connor^ Synlett\ 0889\ 171[ 060
89SL234 I[ E[ Marko\ A[ Mekhal_a and W[ D[ Ollis^ Synlett\ 0889\ 234[ 183
89SL254 R[ M[ Moriarty\ R[ K[ Vaid and G[ F[ Koser^ Synlett\ 0889\ 254[ 052\ 067
89SL366 A[ Sera\ H[ Yamauchi\ H[ Yamada and K[ Itoh^ Synlett\ 0889\ 366[ 315
89SL592 J[ E[ Baldwin and I[ A[ O|Neil^ Synlett[\ 0889\ 592[ 585\ 602
89SL508 D[ S[ Brown\ M[ J[ Earle\ R[ A[ Fairhurst\ H[ Heaney\ G[ Papageorgiou\ R[ F[ Wilkins and
S[ C[ Eyley^ Synlett\ 0889\ 508[ 075
89SL530 M[ Frank!Neumann\ P[ Chemla and D[ Martina^ Synlett\ 0889\ 530[ 29
89SL614 D[ Enders and A[ Plant^ Synlett\ 0889\ 614[ 07\ 023
89SL624 R[ F[ W[ Jackson\ A[ Wood and M[ J[ Wythes^ Synlett\ 0889\ 624[ 029\ 523
89SUL72 A[ Senning^ Sulfur Letters\ 0889\ 00\ 72[ 269
89T868 J[ Brussee\ W[ T[ Loos\ C[ G[ Kruse and A[ Van der Gen^ Tetrahedron\ 0889\ 35\ 868[ 517
89T876 A[ R[ Katritzky and P[ A[ Harris^ Tetrahedron\ 0889\ 35\ 876[ 075\ 076
89T0680 M[ Tramontini and L[ Angiolini^ Tetrahedron\ 0889\ 35\ 0680[ 073
89T1024 D[ Crich\ K[ A[ Eustace\ S[ M[ Fortt and T[ J[ Ritchie^ Tetrahedron\ 0889\ 35\ 1024[ 181
89T1194 M[ Novi\ G[ Garbarino\ G[ Petrillo and C[ Dell|Erba^ Tetrahedron\ 0889\ 35\ 1194[ 553\ 556
89T2738 H[ Vorbruggen\ B[ D[ Bohn and K[ Krolikiewicz^ Tetrahedron\ 0889\ 35\ 2738[ 313
89T3938 J[ Miittendorf\ H[ Hiemstra and W[ N[ Speckamp^ Tetrahedron\ 0889\ 35\ 3938[ 311
89T3150 H[ Suga and M[ Schlosser^ Tetrahedron\ 0889\ 35\ 3150[ 16
89T3306 S[ Agarwal\ H[ P[ Tiwari and J[ P[ Sharma^ Tetrahedron\ 0889\ 35\ 3306[ 3\ 004
89T4102 Y[ Bessard\ U[ Muller and M[ Schlosser^ Tetrahedron\ 0889\ 35\ 4102[ 384
89T5240 H[ Muratake\ H[ Kumagami and M[ Natsume^ Tetrahedron\ 0889\ 35\ 5240[ 585
89T5490 C[ J[ Moody and R[ J[ Taylor^ Tetrahedron Lett[\ 0889\ 35\ 5490[ 055
89T5512 T[ P[ Kogan\ T[ C[ Somers and M[ C[ Venuti^ Tetrahedron\ 0889\ 35\ 5512[ 209
89T5758 H[ Firouzabadi\ M[ Seddighi\ E[ Mottaghinejad and M[ Bolourchian^ Tetrahedron\ 0889\
35\ 5758[ 4
89T6064 K[ Afarinkia\ C[ W[ Rees and J[ I[ G[ Cadogan^ Tetrahedron\ 0889\ 35\ 6064[ 49
89T6230 P[ E[ O|Bannon and W[ P[ Dailey^ Tetrahedron\ 0889\ 35\ 6230[ 379
89T6302 J[ R[ Hwu and S[ C[ Tsay^ Tetrahedron\ 0889\ 35\ 6302[ 315
89T6360 K[ Nakamura\ T[ Kitayama\ Y[ Inoue and A[ Ohno^ Tetrahedron\ 0889\ 35\ 6360[ 050
89T6458 M[ Miyashita\ B[ Z[ E[ Awen and A[ Yoshikoshi^ Tetrahedron\ 0889\ 35\ 6458[ 324
89T6488 R[ B[ Woodward\ W[ A[ Ayer\ J[ M[ Beaton et al^ Tetrahedron\ 0889\ 35\ 6488[ 230
89T7156 M[ North and G[ Pattenden^ Tetrahedron\ 0889\ 35\ 7156[ 507\ 508
89TL52 D[ Gravel\ L[ Farmer and C[ Ayotte^ Tetrahedron Lett[\ 0889\ 20\ 52[ 26
89TL068 T[ B[ Patrick\ S[ Hosseini and S[ Bains^ Tetrahedron Lett[\ 0889\ 20\ 068[ 16
89TL154 K[ Takeda\ K[ Torii and H[ Ogura^ Tetrahedron Lett[\ 0889\ 20\ 154[ 034
89TL212 M[ B[ Power and A[ R[ Barron^ Tetrahedron Lett[\ 0889\ 20\ 212[ 016
89TL884 C[ W[ Je}ord\ Q[ Tang and J[ Boukouvalas^ Tetrahedron Lett[\ 0889\ 20\ 884[ 296
89TL0138 F[ E}enberger\ B[ Horsch\ S[ Forster and T[ Ziegler^ Tetrahedron Lett[\ 0889\ 20\ 0138[ 517
89TL0254 H[ Vicente\ I[ N[ Rezzano and K[ M[ Smith^ Tetrahedron Lett[\ 0889\ 20\ 0254[ 53
89TL0318 M[ Thiam and F[ Chastrette^ Tetrahedron Lett[\ 0889\ 20\ 0318[ 30
89TL0722 C[ Retherford\ T[!S[ Chou\ R[ M[ Schelkun and P[ Knochel^ Tetrahedron Lett[\ 0889\ 20\
0722[ 190
89TL0866 S[ P[ Tanis\ M[ C[ McMills\ T[ A[ Scahill and D[ A[ Kloosterman^ Tetrahedron Lett[\ 0889\
20\ 0866[ 291
89TL1936 J[ E[ Baldwin and I[ A[ O|Neil^ Tetrahedron Lett[\ 0889\ 20\ 1936[ 585\ 693
89TL1940 J[ E[ Baldwin\ D[ J[ Aldous and I[ A[ O|Neil^ Tetrahedron Lett[\ 0889\ 20\ 1940[ 602
89TL1066 R[ Siedlecka\ J[ Skarzewski and J[ Mlochowski^ Tetrahedron Lett[\ 0889\ 20\ 1066[ 6
References 730
89TL1194 C[ Palomo\ J[ M[ Aizpurua\ M[ C[ Lopez and N[ Aurrekoetxea^ Tetrahedron Lett[\ 0889\
20\ 1194[ 521
89TL1102 I[ Paterson and S[ Osborne^ Tetrahedron Lett[\ 0889\ 20\ 1102[ 136
89TL1166 J[!M[ Vatele\ D[ Dumas and J[ Gore^ Tetrahedron Lett[\ 0889\ 20\ 1166[ 079
89TL1200 M[ Yoshifuji\ K[ Toyota\ Y[ Okamoto and T[ Asakura^ Tetrahedron Lett[\ 0889\ 20\
1200[ 594
89TL1480 J[ Le Roux and M[ Le Corre^ Tetrahedron Lett[\ 0889\ 20\ 1480[ 086
89TL1488 A[ M[ Martre\ G[ Mousset\ R[ Bel Rhlid and H[ Veschambre^ Tetrahedron Lett[\ 0889\ 20\
1488[ 05\ 021
89TL1596 K[ Takehira\ M[ Shimizu\ Y[ Watanabe\ H[ Orita and T[ Hayakawa^ Tetrahedron Lett[\
0889\ 20\ 1596[ 76
89TL1550 J[ F[ Delloria and K[ F[ Sallin^ Tetrahedron Lett[\ 0889\ 20\ 1550[ 387
89TL1794 R[ J[ Ternansky and S[ E[ Draheim^ Tetrahedron Lett[\ 0889\ 20\ 1794[ 528
89TL1864 S[!U[ Park\ T[ R[ Varick and M[ Newcomb^ Tetrahedron Lett[\ 0889\ 20\ 1864[ 510
89TL2018 L[ Duhamel\ J[ Guillemont\ Y[ Le Gallie and G[ Ple^ Tetrahedron Lett[\ 0889\ 20\ 2018[ 54
89TL2322 K[ Jarowicki\ P[ Kocienski\ S[ Marczak and T[ Wilson^ Tetrahedron Lett[\ 0889\ 13\
2322[ 139
89TL2370 G[ Cainelli\ E[ Mezzina and M[ Panunzio^ Tetrahedron Lett[\ 0889\ 20\ 2370[ 347
89TL2460 N[ Tokitoh\ N[ Choi and W[ Ando^ Tetrahedron Lett[\ 0889\ 20\ 2460[ 240\ 440
89TL2468 T[ Umemoto and S[ Ishihara^ Tetrahedron Lett[\ 0889\ 20\ 2468[ 040
89TL2566 R[ S[ Coleman and E[ B[ Grant^ Tetrahedron Lett[\ 0889\ 20\ 2566[ 432
89TL2580 P[ A[ Wender and F[ E[ McDonald^ Tetrahedron Lett[\ 0889\ 20\ 2580[ 169
89TL2746 E[ J[ Corey and P[ Carpino^ Tetrahedron Lett[\ 0889\ 20\ 2746[ 197\ 101
89TL3094 R[ K[ Dieter\ B[ Lagu\ N[ Deo and J[ W[ Dieter^ Tetrahedron Lett[\ 0889\ 20\ 3094[ 017
89TL3318 G[ Markl\ P[ Kreitmeier\ H[ Noth and K[ Polborn^ Tetrahedron Lett[\ 0889\ 20\ 3318[ 595
89TL3356 L[ Chen and L[ Ghosez^ Tetrahedron Lett[\ 0889\ 20\ 3356[ 591
89TL3876 M[ McGuiness and H[ Shechter^ Tetrahedron Lett[\ 0889\ 20\ 3876[ 082\ 361
89TL4992 E[ Block and S[ H[ Zhao^ Tetrahedron Lett[\ 0889\ 20\ 4992[ 226
89TL4928 E[ Lee\ C[ U[ Hur and C[ Park^ Tetrahedron Lett[\ 0889\ 20\ 4928[ 112
89TL4430 P[ C[ Heidt\ S[ C[ Bergneier and W[ H[ Pearson^ Tetrahedron Lett[\ 0889\ 20\ 4430[ 300
89TL4468 Z[ Wang and G[ Zvlichovsky^ Tetrahedron Lett[\ 0889\ 20\ 4468[ 51
89TL4614 K[!P[ Pfeifer and G[ Himbert^ Tetrahedron Lett[\ 0889\ 20\ 4614[ 258
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005\ 047\ 050
89TL4786 Y[ Li and Y[ Z[ Huang^ Tetrahedron Lett[\ 0889\ 20\ 4786[ 085
89TL5034 S[ S[ Murphree\ C[ L[ Muller and A[ Padwa^ Tetrahedron Lett[\ 0889\ 20\ 5034[ 119
89TL5072 F[ Bourdon\ J[!L[ Ripoll and Y[ Vallee^ Tetrahedron Lett[\ 0889\ 20\ 5072[ 240
89TL5198 S[ Matsubara\ H[ Onishi and K[ Utimoto^ Tetrahedron Lett[\ 0889\ 20\ 5198[ 521
89TL5106 J[ S[ Yadav and V[ R[ Gadgil^ Tetrahedron Lett[\ 0889\ 20\ 5106[ 698
89TL5180 C[ J[ Li and D[ N[ Harpp^ Tetrahedron Lett[\ 0889\ 20\ 5180[ 065
89TL5220 G[ Markl and S[ Reithinger^ Tetrahedron Lett[\ 0889\ 20\ 5220[ 598
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89TL6190 B[ L[ Feringa\ O[ J[ Gelling and L[ Meesters^ Tetrahedron Lett[\ 0889\ 20\ 6190[ 110
89TL6208 M[ Rodriguez\ A[ Heitz and J[ Martinez^ Tetrahedron Lett[\ 0889\ 20\ 6208[ 33
89TL6494 M[ Poch\ E[ Valenti\ A[ Moyano and M[ A[ Pericas^ Tetrahedron Lett[\ 0889\ 20\ 6494[ 132
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89TL6460 W[ H[ Pearson and K[ C[ Lin^ Tetrahedron Lett[\ 0889\ 20\ 6460[ 308
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80OM1418 I[ N[ Jung\ B[ R[ Yoo\ M[ E[ Lee and P[ R[ Jones^ Or`anometallics\ 0880\ 09\ 1418[ 491
80OM2194 M[ P[ Arthur\ A[ Baceiredo and G[ Bertrand^ Or`anometallics\ 0880\ 09\ 2194[ 571
80OM2856 H[ Werner\ R[ Weinand\ W[ Knaup\ K[ Peters and H[ G[ Von Schnering^ Or`anometallics\
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80OPP482 A[ Kotali and V[ P[ Vassilios^ Or`[ Prep[ Proced[\ 0880\ 12\ 482[ 318
80OR"39#046 O[ De Lucchi\ U[ Miotti and G[ Modena^ Or`[ React[\ 0880\ 39\ 046[ 05
80POL0042 M[ Lazraq\ C[ Couret\ J[ Escudie and J[ Satge^ Polyhedron\ 0880\ 09\ 0042[ 492
80PS"48#030 N[ Lage\ S[ Masson and A[ Thuillier^ Phosphorus Sulfur\ 0880\ 48\ 030[ 451
80PS"48#308 G[ Himbert\ K[!P[ Pfeifer and C[ E[ Finkele^ Phosphorus Sulfur\ 0880\ 48\ 308[ 258
80PS"59#70 P[ Froyen^ Phosphorus Sulfur\ 0880\ 59\ 70[ 083
80RHA169 T[ Minami and I[ Yamamoto^ Rev[ Heteroatom Chem[\ 0880\ 4\ 169[ 385
80RTC282 D[ van Leusen and A[ M[ van Leusen^ Recl[ Trav[ Chim[ Pays!Bas\ 0880\ 009\ 282[ 607
80RTC391 D[ van Leusen and A[ M[ van Leusen^ Recl[ Trav[ Chim[ Pays!Bas\ 0880\ 009\ 391[ 691\ 602
80S004 A[ Otto and H[ Schick^ Synthesis\ 0880\ 004[ 152
80S065 B[ B[ Kikani\ J[ R[ McKee and M[ Zanger^ Synthesis\ 0880\ 065[ 153
80S070 G[ Zecchi^ Synthesis\ 0880\ 070[ 566\ 567\ 579
80S084 V[ V[ Popic\ S[ M[ Korneev\ V[ A[ Nikoleav and I[ K[ Korobitsyna^ Synthesis\ 0880\ 084[ 082
80S196 M[ G[ Gorbunova\ I[ I[ Gerus and S[ V[ Galushko^ Synthesis\ 0880\ 196[ 154
80S102 K[ Lee and D[ Y[ Oh^ Synthesis\ 0880\ 102[ 120
80S132 T[ R[ Bailey^ Synthesis\ 0880\ 132[ 292
80S290 D[ Villemin and A[ B[ Alloum^ Synthesis\ 0880\ 290[ 140
80S219 Y[ Y[ Belosludtev\ B[ C[ Borer and R[ J[ K[ Taylor^ Synthesis\ 0880\ 219[ 53
80S211 N[ R[ Ayyangar\ R[ J[ Lahoti\ K[ V[ Srinivasan and T[ Daniel^ Synthesis\ 0880\ 211[
172\ 184\ 185\ 294
80S246 E[ Ohler and E[ Zbiral^ Synthesis\ 0880\ 246[ 169
80S372 A[ Colla\ M[ A[ P[ Martins\ G[ Clar and S[ Krimmer^ Synthesis\ 0880\ 372[ 135
80S388 D[ G[ Drueckhammer\ W[ J[ Hennen\ R[ L[ Pederson\ C[ F[ Barbas\ III\ C[ M[ Gautheron\
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80S420 D[ van Leusen and A[ M[ van Leusen^ Synthesis\ 0880\ 420[ 695
80S428 Z[ Zhuangyu\ P[ Yi\ H[ Honwen and K[ Tsi!yu^ Synthesis\ 0880\ 428[ 13
80S432 A[ Reliquet\ R[ Besbes\ F[ Reliquet and J[ C[ Meslin^ Synthesis\ 0880\ 432[ 252
80S598 J[ Becher\ P[ L[ Jo rgensen\ H[ Frydendahl and B[ Falt!Hansen^ Synthesis\ 0880\ 598[ 231
80S518 V[ Jager\ B[ Seidel and E[ Guntrum^ Synthesis\ 0880\ 518[ 147
80S602 S[ Fernandez\ E[ Menendez and V[ Gotor^ Synthesis\ 0880\ 602[ 320
80S649 T[ Sakamoto\ H[ Mori\ M[ Takizawa and Y[ Kikugawa^ Synthesis\ 0880\ 649[ 329\ 555
80S674 R[ Sato and S[ Satoh^ Synthesis\ 0880\ 674[ 225\ 252
80S682 N[ Petragnani and J[ V[ Comasseto^ Synthesis\ 0880\ 682[ 065
80S757 A[ R[ Katritzky\ J[ Pernak and W[ Q[ Fan^ Synthesis\ 0880\ 757[ 609
735 References
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80SL26 J[ Einhorn\ C[ Einhorn and J[!L[ Luche^ Synlett\ 0880\ 26[ 067
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80SL452 A[ Mori\ H[ Ohno\ H[ Nitta\ K[ Tanaka and S[ Inoue^ Synlett\ 0880\ 452[ 518
80SL472 M[ Lakhrissi and Y[ Chapleur^ Synlett\ 0880\ 472[ 384
80SL543 A[ P[ Kozikowski\ A[ H[ Fauq\ W[ Tuckmantel\ S[ O[ Casalotti and K[ E[ Krueger^ Synlett[\
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80SL604 Y[ Ichikawa^ Synlett[\ 0880\ 604[ 585\ 699
80SL805 E[ Schuster\ C[ Hesse and D[ Schumann^ Synlett\ 0880\ 805[ 302
80SUL102 F[ M[ Soliman and M[ M[ Said^ Sulfur Letters\ 0880\ 02\ 102[ 245
80T336 L[ T[ Belen|kii\ D[ B[ Brokhovetski and M[ N[ Kragushi^ Tetrahedron\ 0880\ 36\ 336[ 318
80T864 C[ N[ Eid\ Jr[ and J[ P[ Konopelski^ Tetrahedron\ 0880\ 36\ 864[ 059
80T0098 R[ V[ Ho}man^ Tetrahedron\ 0880\ 36\ 0098[ 052
80T0654 J[ A[ Adams and D[ M[ Spero^ Tetrahedron\ 0880\ 36\ 0654[ 018
80T1572 A[ R[ Katritzky\ S[ Rachwal and G[ J[ Hitchings^ Tetrahedron\ 0880\ 36\ 1572[ 31
80T2196 J[ P[ Begue and D[ Bonnet!Delpon^ Tetrahedron\ 0880\ 36\ 2196[ 037
80T2236 J[ Viala\ P[ Munier and M[ Santelli^ Tetrahedron\ 0880\ 36\ 2236[ 084
80T2642 U[ Hedtmann\ R[ Klintz\ K[ Hobert\ J[ Frelek\ I[ Vlahov and P[ Welzel^ Tetrahedron\ 0880\
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80T3816 A[ C[ Gaumont\ L[ Wazneh and J[ M[ Denis^ Tetrahedron\ 0880\ 36\ 3816[ 226\ 240
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80T5872 K[ Maruoka\ T[ Ooi\ S[ Nagahara and H[ Yamamoto^ Tetrahedron\ 0880\ 36\ 5872[ 23
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80T6602 C[ Bernaus\ J[ Font and P[ de March^ Tetrahedron\ 0880\ 36\ 6602[ 204
80T7476 B[ K[ Sarmah and N[ G[ Barua^ Tetrahedron\ 0880\ 36\ 7476[ 01\ 016
80TA0 P[ J[ Cox and N[ S[ Simpkins^ Tetrahedron Asymmetry\ 0880\ 1\ 0[ 013
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Hirota^ Tetrahedron Lett[\ 0881\ 22\ 5712[ 690\ 693
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82SL248 S[ E[ Denmark and O[ Nicaise^ Synlett\ 0882\ 248[ 30
82SL396 R[ K[ Dieter and C[ W[ Alexander^ Synlett\ 0882\ 396[ 077
82SL316 G[ A[ Olah\ Q[ Liao\ C[ Lee and G[ K[ S[ Prakash^ Synlett\ 0882\ 316[ 022
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82SL488 D[ J[ Aitken\ F[ Vergne\ A[ S[ Phimmanao\ D[ Guillaume and H[!P[ Husson^ Synlett\ 0882\
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82SL653 B[ Lygo^ Synlett[\ 0882\ 653[ 077
82SL796 M[ North^ Synlett\ 0882\ 796[ 29\ 517
82T66 N[ Langlois and A[ Rojas^ Tetrahedron\ 0882\ 38\ 66[ 527
82T066 R[ J[ Mears and A[ Whiting^ Tetrahedron\ 0882\ 38\ 066[ 193
82T854 B[ E[ Rossiter\ M[ Eguchi\ G[ Miao\ M[ N[ Swingle\ A[ E[ Hernandez\ D[ Vickers\
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82T0310 T[ Besson\ M[ Hretani\ G[ Coudert and G[ Guillaumet^ Tetrahedron\ 0882\ 38\ 0310[ 89\ 86
82T0430 M[ Koos and H[ S[ Mosher^ Tetrahedron\ 0882\ 38\ 0430[ 516
82T0710 D[ Enders\ K[ Papadopoulos and E[ Herdtweck^ Tetrahedron\ 0882\ 38\ 0710[ 061
82T0720 K[ Hiroi and M[ Umemura^ Tetrahedron\ 0882\ 38\ 0720[ 523
82T1900 S[ Nakatani\ J[!i[ Yoshida and S[ Isoe^ Tetrahedron\ 0882\ 38\ 1900[ 25\ 054
82T1774 J[ R[ Dormoy and A[ Heymes^ Tetrahedron\ 0882\ 38\ 1774[ 298
82T2798 G[ Cainelli\ M[ Panunzio\ M[ Contento\ D[ Giacomini\ E[ Mezzina and D[ Giovagnoli^
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82T3904 I[ M[ Downie\ M[ J[ Earle\ H[ Heaney and K[ F[ Shuhaibar^ Tetrahedron\ 0882\ 38\ 3904[ 81\ 88\ 090
82T3216 I[ Mico and C[ Najera^ Tetrahedron\ 0882\ 38\ 3216[ 516
82T3812 J[ F[ Gil\ D[ J[ Ramon and M[ Yus^ Tetrahedron\ 0882\ 38\ 3812[ 20\ 050
82T4980 R[ Barhdadi\ J[ Gal\ M[ Heintz\ M[ Troupel and J[ Perichon^ Tetrahedron\ 0882\ 38\ 4980[ 519
82T4042 P[ Molina\ M[ Alajarin\ C[ Lopez!Leonardo and J[ Alcantara^ Tetrahedron\ 0882\ 38\ 4042[ 512
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82TL1164 J[ W[ Faller and L[!L[ Gundersen^ Tetrahedron Lett[\ 0882\ 23\ 1164[ 504
82TL1354 I[ Delamarche and P[ Mosset^ Tetrahedron Lett[\ 0882\ 23\ 1354[ 292
82TL1804 G[ Markl and W[ Bauer^ Tetrahedron Lett[\ 0882\ 23\ 1804[ 596
82TL2408 J[!F[ Lavallee\ R[ Rej\ M[ Courchesne\ D[ Nguyen and G[ Attardo^ Tetrahedron Lett[\ 0882\
23\ 2408[ 78\ 85
82TL2572 R[ H[ Mitchell and V[ S[ Iyer^ Tetrahedron Lett\ 0882\ 23\ 2572[ 209
82TL2584 D[ C[ Chauret and J[ M[ Chong^ Tetrahedron Lett[\ 0882\ 23\ 2584[ 40
82TL2860 F[ A[ Davis\ P[ Zhou and C[ K[ Murphy^ Tetrahedron Lett[\ 0882\ 23\ 2860[ 038
82TL3990 E[ J[ Corey and Z[ Wang^ Tetrahedron Lett[\ 0882\ 23\ 3990[ 518
82TL3370 H[ E[ Morton and M[ R[ Leanna^ Tetrahedron Lett[\ 0882\ 23\ 3370[ 042
82TL3512 I[ Klement\ K[ Lennick\ C[ E[ Tucker and P[ Knochel^ Tetrahedron Lett[\ 0882\ 23\ 3512[
503\ 535\ 554\ 569\ 564
82TL3658 N[ Klempier and H[ Griengl^ Tetrahedron Lett[\ 0882\ 23\ 3512[ 517
82TL4002 J[ S[ Cha\ S[ J[ Min\ J[ M[ Kim and O[ O[ Kwon^ Tetrahedron Lett[\ 0882\ 23\ 4002^ 0883\
24\ 1[ 2\ 003
82TL4348 J[!E[ Backvall and U[ Andreason^ Tetrahedron Lett[\ 0882\ 23\ 4348[ 011
82TL4728 B[ Santiago and A[ I[ Meyers^ Tetrahedron Lett[\ 0882\ 23\ 4728[ 510
82TL4800 F[!T[ Luo and R[!T[ Wang^ Tetrahedron Lett[\ 0882\ 23\ 4800[ 564
82TL4832 M[ Hojo\ M[ Ohkuma\ N[ Ishibashi and A[ Hosomi^ Tetrahedron Lett[\ 0882\ 23\ 4832[ 215
82TL5118 F[ A[ Davis\ R[ E[ Reddy\ J[ M[ Szewczyk and P[ S[ Portonovo^ Tetrahedron Lett[\ 0882\
23\ 5118[ 326
82TL5170 H[ Shoda\ T[ Nakamura\ K[ Tanino and I[ Kuwajima^ Tetrahedron Lett[\ 0882\ 23\ 5170[ 048
82TL5290 B[ Bhatia\ M[ M[ Reddy and J[ Iqbal^ Tetrahedron Lett[\ 0882\ 23\ 5290[ 028
82TL5520 G[ Pandey\ A[ Krishna\ K[ Girija and M[ Karthikeyan^ Tetrahedron Lett[\ 0882\ 23\ 5520[ 033
82TL6978 R[ Antonioletti\ L[ Arista\ F[ Bonadies\ L[ Locati and A[ Scettri^ Tetrahedron Lett[\ 0880\
23\ 6978[ 111\ 292
82TL6180 K[ I[ Booker!Milburn and D[ F[ Thomson^ Tetrahedron Lett[\ 0882\ 23\ 6180[ 113
82TL6224 A[ Trehan\ A[ Vij\ M[ Walia\ G[ Kaur\ R[ D[ Verma and S[ Trehan^ Tetrahedron Lett[\ 0882\
23\ 6224[ 051
82TL6284 M[ T[ Reetz and H[ Haning^ Tetrahedron Lett[\ 0882\ 23\ 6284[ 013
82TL6484 T[ Ishiyama\ H[ Kizaki\ N[ Miyaura and A[ Suzuki^ Tetrahedron Lett[\ 0882\ 23\ 6484[
189\ 185\ 290\ 295\ 200
82TL6694 D[ R[ Williams and E[ L[ McClymont^ Tetrahedron Lett[\ 0882\ 37\ 6694[ 201
82TL6614 Q[ Zhou and A[ Pfaltz^ Tetrahedron Lett[\ 0882\ 23\ 6614[ 017
82TL6644 J[ Cossy and N[ Furet^ Tetrahedron Lett[\ 0882\ 23\ 6644[ 27\ 062
82TL6742 A[ Padwa\ J[ M[ Kassir\ M[ A[ Semones and M[ D[ Weingarten^ Tetrahedron Lett[\ 0882\
23\ 6742[ 219
82TL7046 G[ Mehta and P[ V[ R[ Acharyulu^ Tetrahedron Lett[\ 0882\ 23\ 7046[ 031
82TL7346 Y[ Matano\ N[ Azuma and H[ Suzuki^ Tetrahedron Lett[\ 0882\ 23\ 7346[ 085
82TL7432 M[ M[ Kabat^ Tetrahedron Lett[\ 0882\ 23\ 7432[ 199

83AG"E#229 R[ Kunz and W[ P[ Fehlhammer^ An`ew[ Chem[\ Int[ Ed[ En`l[\ 0883\ 22\ 229[ 605
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83T2718 M[ Barani\ S[ Fioravanti\ M[ A[ Loreto\ L[ Pellacani and P[ A[ Tardella^ Tetrahedron\ 0883\
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83TL192 Y[ Ahn and T[ Cohen^ Tetrahedron Lett[\ 0883\ 24\ 192[ 020
83TL334 S[ R[ Baker\ L[ Crombie and D[ A[ V[ Edwards^ Tetrahedron Lett[\ 0883\ 24\ 334[ 542
83TL842 S[ Braverman\ D[ Grinstein and H[ E[ Gottlieb^ Tetrahedron Lett[\ 0883\ 24\ 842[ 258
83TL0070 J[!P[ Salvi\ N[ Walchshofer and J[ Paris^ Tetrahedron Lett[\ 0883\ 24\ 0070[ 39
83TL0470 H[ Takayanagi^ Tetrahedron Lett[\ 0883\ 24\ 0470[ 535
83TL0666 H[ M[ Moody\ B[ Kaptein\ Q[ B[ Broxterman\ W[ H[ J[ Boesten and J[ Kamphuis^ Tetra!
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83TL1316 P[ C[ B[ Page\ S[ M[ Allin\ E[ W[ Collington and R[ E[ Carr^ Tetrahedron Lett[\ 0883\ 24\
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83TL8240 F[ A[ Davis\ R[ E[ Reddy and P[ S[ Portonovo^ Tetrahedron Lett[\ 0883\ 24\ 8240[ 326

84TL1098 J[ P[ G[ Versleijen\ P[ M[ Faber\ H[ H[ Bodewes\ A[ H[ Braker\ D[ van Leusen and A[ M[


van Leusen^ Tetrahedron Lett[\ 0884\ 25\ 1098[ 601

Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations

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