Mol Divers (2009) 13:71193
DOI 10.1007/s11030-009-9138-8
REVIEW
Controlled microwave heating in modern organic synthesis:
highlights from the 20042008 literature
C. Oliver Kappe Doris Dallinger
Received: 6 January 2009 / Accepted: 27 February 2009 / Published online: 21 April 2009
Springer Science+Business Media B.V. 2009
Abstract Direct and rapid heating by microwave irradia-
tion in combination with sealed vessel processing in many
cases enables reactions to be carried out in a fraction of the
time generally required using conventional conditions. This
makes microwave chemistry an ideal tool for rapid reac-
tion scouting and optimization of conditions, allowing very
rapid progress through hypothesesexperimentresults iter-
ations. The speed at which multiple variations of reaction
conditions can be performed allows a morning discussion
of What should we try? to become an after-lunch discus-
sion of What were the results? Not surprisingly, there-
fore, many scientists both in academia and industry have
turned to microwave synthesis as a front-line methodology
for their projects. In this review, more than 220 published
examples of microwave-assisted synthetic organic transfor-
mations from the 2004 to 2008 literature are discussed. An
additional ca. 500 reaction schemes are presented in the Elec-
tronic Supplementary Material, providing the reader with an
overall number of ca. 930 references in this fast-moving and
exciting field.
Keywords Combinatorial chemistry Enabling technol-
ogies High-temperature reactions Microwave dielectric
heating Organic synthesis
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-009-9138-8) contains supplementary
material, which is available to authorized users.
C. O. Kappe (B) D. Dallinger
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and
Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse
28, 8010 Graz, Austria
e-mail: oliver.kappe@uni-graz.at
1 Introduction
Heating chemical reactions by microwave energy continues
to be a popular theme in the organic and medicinal chemis-
try community. Since the first published reports on the use of
microwave irradiation to carry out organic chemical trans-
formations by the groups of Gedye and Giguere/Majetich
in 1986 [1,2], more than 4,000 articles have been published
in this fast-moving and exciting field, generally referred to
as microwave-assisted organic synthesis (MAOS) (Fig. 1).
In many of the published examples, microwave heating has
been shown to dramatically reduce reaction times, increase
product yields, and enhance product purities by reducing
unwanted side-reactions compared with conventional heat-
ing methods. The advantages of this enabling technology are
exploited not only in organic and medicinal chemistry/drug
discovery, but have also penetrated related fields such as poly-
mer synthesis, material sciences, nanotechnology, and bio-
chemical processes. At least in the field of organic synthesis,
the use of microwave irradiation has become such a popular
technique that it might be assumed that, in a few years, most
synthetic chemists will probably use microwave energy to
heat chemical reactions on a laboratory scale.
Today, several books [312], a number of special issues
of synthetic chemistry journals [1316] and an extensive col-
lection of review articles (>150, see Table 1)[17203] cover
MAOS from every conceivable angle. In 2004 our group
published a review article entitled Controlled microwave
heating in modern organic synthesis in Angewandte Che-
mie [48] that currently is the most cited review in the field,
having received 260 citations in 2008. The present review
provides an update of our original 2004 treatise covering
the literature from April 2004 until the end of 2008. Since
many other review articles [1720] and books [312] already
discuss the basic theory of microwave chemistry and
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72 Mol Divers (2009) 13:71193

1000
Table 1 Review articles and key references in microwave-assisted
900 organic synthesis
800
Microwave theory/dielectric 1721
700
heating
600
Microwave effects 2232,204,205,209
500
Microwave reactors/equipment 17,19,33
400
Technical reviews 3440
300
200
General organic synthesis 34,35,4156
100 Solvent-free conditions 5766
0 Reactions on graphite supports 67,68
Phase-transfer catalysis 6971
19 6
19 7
19 8
19 9
90
19 1
19 2
93
19 4
19 5
19 6
19 7
19 8
20 9
20 0
20 1
20 2
20 3
20 4
20 5
20 6
20 7
08
8
8
8
8

9
9

9
9
9
9
9
9
0
0
0
0
0
0
0
0
19

19

19

Gaseous reagents 72
Fig. 1 Publications on microwave-assisted organic synthesis (1986 Green chemistry 59,7384
2008). Gray bars: Number of articles involving MAOS for seven
Water as solvent 73,8587,206
selected synthetic organic chemistry journals (J Org Chem, Org Lett,
Tetrahedron, Tetrahedron Lett, Synth Commun, Synthesis, and Synlett; Ionic liquids 77,8891
SciFinder Scholar keyword search on microwave). The black bars Passive heating elements 204,207
represent the number of publications (20012008) reporting MAOS Medicinal chemistry/drug 92106,111,117,145,147
experiments in dedicated reactors with adequate process control (ca. 50 discovery
journals, full-text search: microwave). Only those articles dealing Combinatorial chemistry 107116,131
with synthetic organic chemistry were selected
Parallel processing 107,117119,124
Solid-phase synthesis 120125
provide information on equipment and processing techniques
(Table 1), the focus of the current review is to highlight synt- Polymer-supported reagents 126131
hetic applications of MAOS published during the past 5 years. Fluorous synthesis 132134
The review is therefore mainly intended as a resource and Peptide synthesis 135137,208
inspiration for synthetic organic chemists in academia and Enzymatic reactions 138
industry. Carbohydrate chemistry 139142
Organocatalysis 209
Transition-metal catalysis 143155
2 Literature survey Metathesis chemistry 154,155
Multicomponent reactions 132,156158
The present review article highlights selected examples of Heterocycles 58,74,122,127,148,156,159174
controlled microwave heating technology in organic synthe- Cycloadditions 166,175177
sis published between April of 2004 and 2008. The term Natural products 178,179
controlled here refers to the use of a dedicated microwave Photochemistry 180,181
reactor for synthetic chemistry purposes (single- or multi-
Radiochemistry 182186
mode). Therefore, the exact reaction temperature during the
Hyphenated methods 180,181,187
irradiation process has been adequately determined in the
Miscellaneous 188194
original literature source. In terms of processing techniques,
Scale-up 195199
preference is given to transformations in solution phase under
Continuous flow processing 200203
sealed vessel conditions, since this reflects the recent trend in
Energetic aspects 33,37,210
the literature. Among the ca. 950 original publications that
Educational publications 41,211,212
appeared in 2008 describing microwave-assisted reactions
under controlled conditions (Fig. 1), a careful analysis dem- Internet resources 213216
onstrates that in ca. 90% of the cases sealed-vessel processing
in dedicated single-mode microwave instruments has been
employed. A recent survey has found that as much as 30% of presented in a graphical-abstract format, with a minimum of
all published MAOS papers still employ kitchen microwave additional information being discussed in the accompanying
ovens [217], a practice unfavored by most scientific journals text. The arrangement of chemistry examples closely follows
today. the sequence used in our 2005 Wiley-VCH book, where the
The focus of the following microwave literature survey is literature from 2000 to 2004 was covered in a similar for-
on modern synthetic methods of interest to organic/medic- mat [11]. In addition to the ca. 220 schemes/references dis-
inal chemists working in industry or academia. Because of cussed in the main section of this review article, an additional
the volume of the covered material, the information is ca. 500 examples are briefly mentioned in the text with the

123
Mol Divers (2009) 13:71193 73

X C2 H4 (150 psi), [Pd] coupling partner using a gas-loading device. For aryl iodides
K2CO3, Bu 3N, DMF
(1) as coupling partners, 0.02 mol% Pd using an ICP stan-
MW, 125-150 C, 60 min dard and 125 C are required to obtain the coupled products
R1 R1
1 2 2, whereas for aryl bromides (1) 0.5 mol% of the Herrmanns
X = I, Br catalyst and 150 C are necessary. In the next step, styrenes
R1 = Me, OMe, COMe, NH 2 2 are coupled with aryl bromides using a 1:1 molar ratio and
R2 = Me, COMe, OMe, "naphthyl"
Herrmanns catalyst in the same reaction vial to get stilbenes
Br 3. It has to be noted that the less reactive aryl halide has to
be used in the first coupling step in order to reduce the com-
petitive symmetric stilbene formation and thus increase the
R2
R2
product yield.
[Pd], K2CO3
Nicolas Lachance and co-workers form the Merck Frosst
R1 3
MW, 175 C, 15 min
14 examples Centre for Therapeutic Research in Quebec have shown that
(6-72%) imines/enamines 6 can be converted via a microwave-assisted
intramolecular MizorokiHeck reaction to the correspond-
Scheme 1 Synthesis of asymmetrically substituted stilbenes
ing azaindoles 7 in good yields (Scheme 2) [219]. Several
synthesis routes have been investigated, including the one-
corresponding reaction schemes being provided in the Elec- step reaction (route A) of aminopyridines 4 with ketones 5
tronic Supplementary Material. or ketals as well as the one-pot two-step reaction (route B)
leading to azaindoles 7. Using either of the two strategies
2.1 Transition-metal-catalyzed carboncarbon bond a small library of 17 examples was synthesized employing
formation chloro-, bromo-, and iodo-aminopyridines with toleration of
sensitive groups such as ketones and esters.
2.1.1 MizorokiHeck reactions Intramolecular Heck couplings have also been used by
Vasudevan for the construction of cyclic sulfonamides
Nicholas Leadbeater and Chad Kormos from the University (Scheme S1) [220], by Porco for the generation of indanes
of Connecticut have disclosed a one-pot two-step Mizoroki and related polycyclic scaffolds (Scheme S2) [221], by Van
Heck coupling strategy for the preparation of asymmetrically der Eycken for the synthesis of 3-benzazepines (Scheme S3)
substituted stilbenes (Scheme 1) [218]. In the first step, sty- [222], and by Chruma for the synthesis of polyfunctionalized
renes 2 were synthesized selectively by employing ethene as 1-aminoindanes (Scheme S4) [223].

R2
X R2 1. Condensation
N + 2. Heck reaction N R1
NH2 N
O R1 A MW H
4 5 7

X = Cl, Br, I
B B Heck reaction
Condensation X R2 MW
MW N
N R1
H
6

N Cl OEt Pd(PPh3)4, pyridine N

OEt MW, 160 C, 20 min N

NH2
H
81%
+16 related examples
(12-95%)
Scheme 2 Synthesis of 4-, 5-, 6-, and 7-azaindoles

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74 Mol Divers (2009) 13:71193

X
O Pd(OAc)2 , PMP O
O
O TBAB, toluene, (H 2O)

MW, 140-180 C, 10 min

X = Br, I X = Br: 82%; X = I: 91%

+5 related examples
PMP: pentamethylpiperidine
(51-77%)
Scheme 3 Pd-catalyzed spiro cyclizations

NHBoc
BocHN
Pd(OAc)2, ligand
PMP, toluene

N MW, 170 C, 45 min N

OTf CO2Me CO2Me
8 9, 87%, 99% ee
O
PPh2 N
t -Bu
ligand

1: 9-BBN, THF
MW, 100 C, 80 min O
then H2O2, NaOH, 0 C --> rt
N 2: TPAP, NMO, DCM N
N N
MeO2C Boc MeO2C Boc
10 11, 63%
O
9-BBN: 9-borabicyclo[3.3.1]nonane
TPAP: tetrapropylammonium perruthenate
NMO: N-methylmorpholine-N-oxide +
N
N
MeO2C Boc
25%
Scheme 4 Total synthesis of (+)-minfiensine

The Larhed group from Uppsala University has disclosed
the regioselective synthesis of spiro[cyclohexane-1,1 -iso-
benzofurane] derivatives via intramolecular MizorokiHeck
cyclization (Scheme 3) [224]. Five-exo cyclization of o-bro-
mobenzyl cyclohexenyl ethers proceeded at 180 C within
10 min. When o-iodobenzyl cyclohexenyl ethers are emplo-
yed as substrates the addition of 5% of water (v/v) to the sol-
vent system proved to promote the cyclization within 10 min
at 140 C. Conventional heating at 100 C provided the prod-
ucts in similar yields but a reaction time of 18 h is required.
The same group has also reported on selective terminal
Heck arylations of vinyl ethers with aryl chlorides
(Scheme S5) [225], on chelation-controlled diastereoselec-
tive Heck arylations on route to enantiopure 2-aryl-2-methyl
cyclopentanones (Scheme S6) [226], and on regioselective
internal Heck arylations of hydroxyalkyl vinyl ethers
(Scheme S7) [227].
In the course of the multistep synthesis of the Strychnos
alkaloid minfiensine Larry Overman and his group from the
University of California, Irvine, have conducted two reac-
tion sequences with microwave irradiation (Scheme 4) [228].
As a key step, the intramolecular asymmetric Mizoroki
Heck reaction of precursor 8 was performed at 170 C within
45 min and afforded the cyclized product 9 in high yield and
excellent 99% ee. Due to the short reaction times the cat-
alyst loading could be decreased from 20 to 10 mol%. The
employed PHOX ligand proved to be optimal in order to
prevent double-bond migration. In a second-generation total
synthesis of (+)-minfiensine, the hydroboration of scaffold
10 proceeded under microwave heating with 9-borabicyclo
[3.3.1]nonane (9-BBN) in tetrahydrofuran (THF) at 100 C
whereas in refluxing THF no reaction took place. After oxida-
tion of the crude product with tetrapropylammonium
perruthenate/N -methylmorpholine-N -oxide (TPAP/NMO)

123
Mol Divers (2009) 13:71193 75

TfO X O
X
12 L1: X = CH2: 82% conv 100% conv
X = CH2, O [Pd 2 (dba) 3]dba / ligand 97% ee L1: 93% ee
i Pr 2 NEt, THF L2: X = O: 100% conv L2: 97% ee
or + or 99% ee
MW, 70 C, 10-45 min
O O
TfO
O O
13 L1: 94% conv
92% ee
1 2
Ph R R
O
O O
O O O
=
O P N O O O
O
Ph R1 R2
L1: =R1 R2
= t -Bu
ligand L2: R1 = SiMe3 , R 2 = H

Scheme 5 Pd-catalyzed asymmetric Heck reactions

Pd 2(dba)3 , ligands 14-19

O DIPEA, THF O
R
+ ROTf
MW, 120 C, 1-4 h
29 examples
R=aryl,cyclohexenyl (28-98% conv)
(28-98% ee)

PPh2 P(o-Tol)2 P(3,5-Me2-Ph) 2

N N N
(R) Ligands = Ph Ph Ph
S S S
14 15 16

P(o-Tol)2 P(o-Tol) 2 PPh 2

N N N
(S) Ligands = H
S S S
17 18 19

Scheme 6 Asymmetric Heck reactions using phosphine-thiazole ligands

the desired ketone 11 was obtained as major product in 63%
yield. (+)-Minfiensine was synthesized in 15 steps and 6.5%
overall yield with the second-generation protocol.
The use of MizorokiHeck chemistry as one of the key
steps in a natural product synthesis has also been highlighted
by Qin (Scheme S8) [229].
A library of sugar-based phosphate-oxazoline ligands for
use in asymmetric Pd-catalyzed MizorokiHeck couplings
was synthesized by the groups of Oscar Pmies and Mont-
serrat Diguez from Universitat Rovira di Virgili, Tarragona
(Scheme 5) [230]. Performing the MizorokiHeck reactions
of 2,3-dihydrofuran (12, X = O), cyclopentene (12, X = CH2 )
and 4,7-dihydro-1,3-dioxepin 13 with phenyl- or cyclohexe-
nyl triflate employing either ligand L1 or ligand L2 in combi-
nation with a Pd catalyst, provided the corresponding coupled
products in excellent conversions, regio- (up to 98%) and
enantioselectivities. Compared with conventional heating at
50 C (where excellent conversions, regio- and enantioselec-
tivities were also obtained) applying microwave heating at
70 C accelerated the reactions from up to 2.5 days to only
1045 min.
Pher Andersson and co-workers from the Department of
Biochemistry and Organic Chemistry in Uppsala have made
investigations toward the impact of the ligand structure on
the asymmetric MizorokiHeck coupling of 2,3-dihydrofu-
ran with various triflates (Scheme 6) [231]. With all employed
phosphine-thiazole ligands 1419 the regioselectivity was
excellent whereas the enantioselectivity and the reaction rate
were dependent on the substitution patterns of the ligands.
For the coupling with aryl triflates, bulkier substituents in the

123
76
B(OH)2
+ N
O
N
Me
dmphen =
Me
Scheme 7 Oxidative Heck arylations
Ar B(OH)2 R
Br
Ar = 4-MePh, 4-(F 3CO)Ph,
3-NO2 Ph, Ph, 3,4,5-MeOPh,
2-benzof uran, 3-quinoline
R = 2-Me, 4-CH 2-OH, 4-NHAc
Scheme 8 SuzukiMiyaura couplings catalyzed by microencapsulated Pd
2-position of the ligands enhanced the enantioselectivity and
reaction rate: ligand 19 proved to be the best regarding ees
(9498%) and reaction time (1 h) whereas with ligand 17 low
conversions (2830%) and ees (7780%) were obtained. By
employing microwave heating the reactions proceed faster
with constant high enantioselectivities.
A 2004 publication by Mats Larhed and co-workers
describes dioxygen-promoted regioselective oxidative Heck
arylations of electron-rich olefins with arylboronic acids
(Scheme 7) [232]. Controlled microwave heating and increa-
sed oxygen pressure were used to reduce the required reac-
tion time from 18 h (50 C, oxygen balloon) to 1 h (100 C,
3 bar oxygen pressure). The reaction was performed both on a
1 mmol scale in a 25 mL vessel (single-mode microwave cav-
ity) and on a 10 mmol scale in a 300 mL vessel (multimode
microwave reactor) using a continuous flow of oxygen.
Other microwave-assisted MizorokiHeck transforma-
tions have been reported involving simple aryl bromides and
alkenes with low levels of Pd catalysts (500 ppb) (Scheme S9)
[233]. A number of more complex intramolecular examples
have also been disclosed (Schemes S10S12) [234236], for
example, for the total synthesis of the batrachotoxin ring
system (Scheme S13) [237]. A Cu-catalyzed Heck-type cou-
pling of aryl iodides and acrylates has been suggested by
Lamaty (Scheme S14) [238].
2.1.2 SuzukiMiyaura reactions
The progress of microwave-assisted SuzukiMiyaura reac-
tions has been monitored online using FTRaman spectros-
copy by the Leadbeater group (Scheme S15) [239]. The same
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Mol Divers (2009) 13:71193
Pd(OAc) 2, dmphen
O 2 (3 bar), EtCN, NMM O
MW, 100 C, 1h
Me 80%
( / = 93/7)
N N
Me
Bu 4NOAc, Pd EnCat, EtOH
MW
R
A: Batch, 120 C, 10 min Ar
B: Batch, 50 W, 20 min
with cooling 9 examples
C: Flow, 0.1 mL/min, 50 W
with cooling A : purity <10-48%
B : purity 81- >98%
C : purity 91- >98%
group has also reported on the scalability of these reactions
going from a 5 mmol to a 1 mol scale in larger microwave
reactors (Scheme S16) [240].
SuzukiMiyaura couplings using a microencapsulated Pd
catalyst (Pd EnCat) under microwave heating were inves-
tigated by the group of Steven V. Ley at the University of
Cambridge (Scheme 8) [241]. For those compounds giving
low purities under conventional microwave conditions (A),
higher purities could be achieved by performing the reac-
tions at 50 W (reaction temperature did not exceed 76 C)
with simultaneous cooling (compressed air, B) by preventing
otherwise occurring thermal decompositions. Even higher
purities were obtained by conducting the reactions via a flow-
through approach again in combination with cooling (C) due
to shorter reaction times (ca. 1 min) and, therefore, dimin-
ished side-reactions.
Sharma and co-workers have described related Suzuki
Miyaura couplings using Pd EnCat catalysts (Scheme S17)
[242]. Other immobilized forms of Pd catalysts have also
been used in SuzukiMiyaura couplings (Schemes S18 and
S19) [243,244]. For the use of Pd/C in microwave-assisted
SuzukiMiyaura couplings, see Scheme S20 [245].
A series of air- and moisture-stable (N -heterocyclic
carbene) Pd(allyl)Cl complexes has been shown by Steven
P. Nolan and co-workers to catalyze SuzukiMiyaura cross-
coupling reactions of aryl chlorides with boronic acids
(Scheme 9) [246]. This catalytic system is compatible with
microwave conditions, and rapid couplings were observed
within 1.5 min at 120 C. The conventionally heated reac-
tions (60 C) required several hours to reach completion. The
same article also reports on microwave-assisted dehalogen-
ations of aryl chlorides using the same catalytic system.
Mol Divers (2009) 13:71193
Cl (HO)2 B
+
R
R = H, Me, Cl, OMe
IPr =
Scheme 9 SuzukiMiyaura couplings of aryl chlorides
[(t-Bu)2P(OH)] 2PdCl2
R CO2Et K 2CO3, THF
Cl CO2Et MW, 100 C, 30 min
R = Me, i-Pr, Ph
Me CO2Et
O2N
CO2Et
+ B(OH)2
Cl
Scheme 10 SuzukiMiyaura couplings of vinyl chlorides
Similarly, Clarke and co-workers demonstrated that aryl
chlorides couple with boronic acids using Pd complexes
formed from the amine-phosphine ligand dcpmp
(Scheme S21) [247].
A 2004 publication by Nicholas J. Turner and co-workers
from the University of Edinburgh describes the microwave-
assisted Pd-catalyzed cross-coupling of -chloroalkylidene/
arylidene malonates (vinyl chlorides) with boronic acids
in a SuzukiMiyaura-type fashion (Scheme 10) [248]. The
Suzuki arylation reaction was found to proceed with a wide
range of arylboronic acids, including electron-rich, electron-
deficient, and sterically demanding systems. For most
reactions the presence of 1 mol% of the air-stable Pd catalyst
[(t-Bu)2 P(OH)]2 PdCl2 provided a high yield of the desired
-aryl/alkylarylidene malonates. The catalyst was also found
active to promote standard Suzuki reactions of aryl chlorides
under microwave conditions.
The group of Michael F. Greaney from the University of
Edinburgh has described a protocol for the arylation of oxaz-
oles in the 4- or 2-position, respectively, via SuzukiMiya-
ura reactions (Scheme 11) [249]. 2-Aryl-4-trifloyl oxazoles
20 were coupled with a variety of boronic acids, whereas
the coupling at the 2-position was performed with 2-chloro-
4-phenyl oxazole as coupling partner. Both couplings were
conducted at the same reaction conditions (5 mol% PdCl2
(PPh3 )2 , Na2 CO3 , dioxane, 150 C, 20 min). The reaction
was further extended to the one-pot synthesis of dioxazoles.
In the first step, boronic esters were generated in situ via
77
(IPr)Pd(allyl)Cl
NaOt Bu, dioxane
MW, 120 C, 1.5 min R
4 examples
(88-97%)
N N
..
ArB(OH)2
R CO2Et
Ar CO2Et
15 examples
(50-72%)
[(t-Bu)2P(OH)] 2PdCl2 Me CO2Et
O2N
K 2CO3, THF
CO2Et
MW, 100 C, 30 min
77%
the reaction of 20ac with bis(pinacolato)diboron (B2 Pin2 ).
In the next sequence, 1 equiv of 20a, b or c was added to
the reaction mixture together with the reagents needed for
the SuzukiMiyaura coupling (catalyst, base). In this way,
homo- and heterodimeric dioxazoles 21 were obtained.
For a related approach based on Suzuki- or Stille couplings
to 2 -chlorobisthiazoles, see Scheme S22 [250].
Brad Savall and Jill Fontimayor from Johnson & Johnson
Pharmaceutical Research & Development, San Diego, have
synthesized a series of 2-arylbenzimidazoles via Suzuki
Miyaura couplings of unprotected 2-chlorobenzimidazoles
(Scheme 12) [251]. Higher yields could be achieved when
switching from arylboronic acids to aryltrifluoroborate salts
as coupling partners. To overcome the problem with homo-
coupling of pyridylboronic acids, a change in the catalyst
system to PdCl2 (dppf)CH2 Cl2 and the use of aryltrifluorob-
orate salts was advantageous.
For an application of SuzukiMiyaura reactions in the
scaffold decoration of quinazoline heterocycles, see
Scheme S23 [252]. Along similar lines, flavones have been
decorated by Caddick using SuzukiMiyaura and Buchwald
Hartwig chemistry (Scheme S24) [253]. In 2007, Reiig
reported on SuzukiMiyaura couplings of alkenyl nonaflates
with aryl boronic acids (Scheme S25) [254]. For a one-pot
HunsdieckerSuzuki strategy leading to stilbene derivatives,
see Scheme S26 [255].
A report by Barbarella and co-workers from Bologna
reports the rapid preparation of poorly soluble unsubstituted
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78 Mol Divers (2009) 13:71193

RB(OH) 2, PdCl2 (PPh 3)2 R

O Na2CO 3, dioxane O
OTf
Ar N Ar N
MW, 150 C, 20 min
20
Ar = Ph, 4-F-Ph, 4-MeO-Ph 9 examples
R = H, Me, 3-NO2, 4-CF3 , 4-MeO, 3-F (75-94%)

1. PdCl2 (dppf)/dppf, B2 Pin2

KOAc, dioxane
O MW, 150 C, 20 min O O
OTf
N 2. PdCl2(PPh3 )2, K2CO3, N N
Ar 1 Ar 1 Ar 2
dioxane, 20a,b or c 21
20a: Ar 1 = Ph MW, 150 C, 20 min
20b: Ar 1 = 4-F-Ph 3 examples: Ar1 = Ar 2 (58-69%)
20c: Ar 1 = 4-MeO-Ph 1 example : Ar 1 = Ph; Ar 2 = 4-F-Ph, 39%

Scheme 11 SuzukiMiyaura couplings of oxazoles

R2
B(OH)2
R1 X R1
N K2 CO 3, PdCl2 (PPh 3) 2 N R2
or MeCN
Cl +
N R2 N
H BF3K MW, 150 C, 30 min H
X 16 examples
(27-90%)
R1 = H, OMe, CF3, F, Me
R2 = OBn, OMe, Me, Cl, F, CN
X = CH, N
Scheme 12 SuzukiMiyaura coupling of unprotected 2-chlorobenzimidazoles

and modified -quinque and sexithiophenes by extensive
use of microwave-assisted SuzukiMiyaura and Sonogash-
ira cross-couplings, in addition to one-pot borylation/Suzuki
sequences (Scheme 13) [256]. Several of the prepared oli-
gothiophenes show liquid-crystalline properties.
More recently, the same group has revisited the synthesis
of oligothiophenes and has presented a Suzuki coupling pro-
cedure based on the use of a chitosan-supported Pd catalyst
(Scheme S27) [257].
Similar one-pot borylation/Suzuki sequences were used
by Erik van der Eycken and co-workers for the prepara-
tion of bis-2(1H )-pyrazinones (Scheme S28) [258]. Poly-
p-phenylene conjugated polymers based on spirobifluorene
scaffolds were obtained via Suzuki couplings of appropri-
ate bis-boronic acids and p-dibromoarene building blocks
(Scheme S29) [259]. Water-soluble polyacetylenes have been
obtained from diborylethyne and p-diiodoarene synthons
(Scheme S30) [260].
Vincenzo Santagada and his group from Universit di
Napoli Federico II have reported on the synthesis of biphe-
nyls 24 that incorporate an amino acid moiety with the
carboxyl and amino function in ortho-position (Scheme 14)
[261]. These biphenyl scaffolds were synthesized in order
to develop new compounds that are able to induce -hairpin
folding in peptides. Biphenyls 24 were obtained in a single
step by the SuzukiMiyaura coupling of boronic acids 22 and
aniline (m = 0), benzylamine (m = 1) or phenethyl amine
(m = 2) bromides 23 in aqueous N , N -dimethylformamide
(DMF) as solvent and 30 min microwave heating at
150 C.
Along similar lines, 2,2 -binaphthyls have been obtained
by SuzukiMiyaura cross-coupling chemistry. Modest lev-
els of enantioselectivity were obtained by employing chiral
ligands (Scheme S31) [262].
Jung-Nyoung Heo and his group from Korea Research
Institute of Chemical Technology have published a Suzuki
Miyaura coupling/aldol condensation cascade reaction as the
key step in the total synthesis of natural and unnatural
aristolactams (Scheme 15) [263]. In this one-pot synthesis
4-bromoisoindolin-1-one is reacted with various 2-formyl-
phenylboronic acids using Pd(PPh3 )4 as catalyst, Cs2 CO3
as base, and toluene/EtOH as solvent system to construct the
core phenanthrene ring system. Only when 3-thienylboronic
acid is employed a lower product yield of 35% was obtained.
The same research group has also disclosed a cascade
reaction of o-substituted aryl halides and o-formyl or
o-acetyl-arylboronic acidsinvolving first a SuzukiMiya-
ura coupling and a subsequent intramolecular aldol conden-
sationfor the synthesis of phenanthrene derivatives
(Scheme 16) [264]. Crucial for obtaining the phenanthrenes

123
Mol Divers (2009) 13:71193 79

S NIS
S
I
S S

PdCl2 dppf S
KF/alumina (HO) 2B
MW, 80 C, 5 min

1. NIS
S S S S
S 2. 2-thiopheneboronic acid S S
S
PdCl2 dppf, toluene, MeOH
60% MW, 70 C, 10 min 85%

1. NBS
S S S
2. O O S S
S
B B
O O 84%
PdCl 2dppf , toluene, MeOH
MW, 70 C, 10 min

Scheme 13 SuzukiMiyaura cross couplings for oligothiophene synthesis

R4
R3 R5
R5 Pd(PPh 3)4, Cs2CO3 NH2
1 R4 DMF/H2O R2
n COOR mNH2 m
+ MW, 150 C, 30 min COOR1
n
B(OH)2 R3 Br
R2
22 23 24
n = 0, 1, 2 m = 0, 1, 2 18 examples
(15-39%)
Scheme 14 Synthesis of potential -sheet nucleators via SuzukiMiyaura coupling

in high yields is the ratio of the solvent mixture, with tol-
uene/EtOH 2:1 leading to optimum results. When a ketone
is employed as aldol acceptor (R4 = Me) DavePhos as lig-
and has to be used, and a lower temperature of 120 C for
5 min for the Suzuki coupling was necessary, followed by an
additional 10 min at 150 C for the aldol condensation. The
same is true for some aryl halide building blocks (R1 = CO2
Et, CN; X = Cl), where either DavePhos or SPhos has to be
applied in order to prevent side-reactions and to receive the
phenanthrene products in good yields. The reversed approach
was possible as well, where boronate esters are reacted with
2-bromoaryl carboxaldehydes.
In the course of the synthesis of quinazolinone transform-
ing growth factor type I receptor (TGF- RI) inhibitors
29, Hong-yu Li and co-workers from the Lilly Corporate
Center in Indianapolis have disclosed the synthesis of key
intermediate 27 via a one-pot three-component SuzukiMi-
yaura/etherification sequence (Scheme 17) [265]. In order to
prevent side-reactions in the Suzuki coupling of boronic acid
25 and quinazoline 26 (in particular Suzuki reaction at the
2-chloro position of 26), ethylene glycol was employed for
the etherification step at the 2-position of 26. In addition,
product purification was improved by performing the reac-
tion sequence in one pot. The final products 29 were obtained
by amination of scaffold 28, again using microwave heating.
Numerous other applications of microwave-assisted
Suzuki couplings applied to medicinal-chemistry-oriented
target molecules have been reported in the literature
(Schemes S32S36) [266270].
The formation of a 15-membered meta,meta-cyclophane,
biphenomycin B, featuring a key microwave-induced intra-
molecular SuzukiMiyaura reaction step, has been demon-
strated by Renaud Lpine and Jieping Zhu from the Institute
de Chimie des Substances Naturelles (Scheme 18) [271].
Controlled microwave heating has been utilized to increase
the cyclization efficiency in the key CC coupling reaction

123
80 Mol Divers (2009) 13:71193

O
MeO
N R1
O
MeO MeO
Br Pd(PPh3 )4, Cs 2 CO 3 N R1
toluene, EtOH MeO
+
CHO
B(OH) 2 MW, 150 C, 10 min
CHO R3
R2
3
R
R2
R1 = H, Me O
R2 , R 3 = H, Me, OMe, OCH 2O, Cl MeO
N R1
MeO

R3
R2

8 examples
(80-89%)
Scheme 15 Total synthesis of aristolactams

R2
R2
R1 Pd(PPh3 )4
(DavePhos or SPhos)
Cs2 CO3, toluene/EtOH R1
X
+
(OH) 2B O
MW, 120-150 C, 10-15 min R4

R4
R3
18 examples
R3 (52-90%)
X = Br, Cl
R1 = CN, CO2 Me DavePhos SPhos
CO2Et, CONHMe
COMe, SO2Ph
P(Cy) 2 P(Cy) 2
R2 , R 3 = H, OMe Me
Me, CF 3, F N MeO OMe
Me
R4 = H, Me

Scheme 16 SuzukiMiyaura coupling/aldol condensation cascade reaction

of the tripeptide precursor. The study of solvent effect, taking
into account the advantage of best ligandbase combination,
found the toluenewater solvent system in the presence of tet-
rabutylammonium bromide (TBAB) as an additive, to give
best yields (50%) as compared with MeCN and dimethyl sul-
foxide (DMSO) under identical conditions. The choice of 2-
(2 ,6 -dimethoxybiphenyl)dicyclohexylphosphine as the lig-
and, in comparison with ligand-free conditions, has favored
higher efficiency of cyclization in the key SuzukiMiyaura
reaction step.
In a 2006 publication, Nicholas E. Leadbeater and
co-workers from the University of Connecticut have dem-
onstrated the synthesis of functionalized biaryls via Suzuki
Miyaura coupling (Scheme 19) [272]. By using potassium
organotrifluoroborates as an alternative to boronic acids
and ultralow Pd loading (2.5 ppm), efficient coupling with

123
Mol Divers (2009) 13:71193 81

N N
I
N
N N
N PdCl2(dppf), (o-biphenyl)P(t-Bu) 2, K2 CO3
+ Cl ethylene glycol/dioxane
B O
HO OH N N MW, 120 C, 20 min
HO
25 26 N N
27, 72%

N N N N
N N

MsCl, pyridine, amine

O O
rt, 1 h MW, 140 C, 1 h 29
N N N N
Cl R
28, 89% amine = pyridine, morpholine, 4 examples
piperidine, azepine (71-75%)

Scheme 17 One-pot SuzukiMiyaura/etherification reaction

O O
Pd(dba) 2, ligand
O K2 CO 3, TBAB
I O B toluene/H 2 O
H O
N N COOMe
BocHN MW, 110 C, 30 min
H
O O

N O O
Cbz
O
H
N N COOMe
ligand: BocHN
H
O O
MeO
Cy
Cy P PdCl2 50%
2 N
OMe
Cbz
Scheme 18 Intramolecular SuzukiMiyaura reaction leading to macrocycles

[Pd], Na2CO3, TBAB

Y X Y Z H 2 O, EtOH Y Y
R1 + R2 R1 R2
n n MW, 150 C, 5 min n n

26 examples
n = 1, 2 (4-98%)
R1 = H, OMe, Me, CN, OH, NH 2, COMe
R2 = H, Me, CF 3, OMe
X = Cl, Br, I, vinyl-Br
Y = CH 2 , NH, S
Z = BF3 K, vinyl-BF3K
Scheme 19 SuzukiMiyaura couplings with organotrifluoroborates

123
82
R1I+R 2X
H2O 1
Ph 4BNa or Ph R
OR2 MW, 100 C, 1-15 min
R1 I 14 examples
OR3 (37-93%)
R 1 = R2 = Ph, p- tolyl, p-Br-Ph, p-MeO-Ph,
thiophene, m-NO2-Ph, p-Cl-Ph
R 2 = R3 = H, OAc, OCOCF3, OTs
X = Cl, Br, OTs, BF 4
Scheme 20 Catalyst- and base-free Suzuki-type couplings
arylhalides could be performed in 5 min at 150 C under
microwave irradiation.
Closely related work was published simultaneously by
the Kabalka group (Scheme S37) [273], and subsequently
by Najera applying oxime-derived palladacycles as catalysts
(Scheme S38) [274].
Jie Yan and co-workers from Zhejiang University of
Technology have reported on Suzuki-type couplings in water
without the use of catalyst and base (Scheme 20) [275]. Both
symmetrical and unsymmetrical biaryls could be synthe-
sized by coupling of sodium tetraphenylborate with hyper-
valent iodonium salts or iodanes under mild reaction
conditions.
A set of 19 symmetrical and unsymmetrical aryl ketones
was prepared via Suzuki-type coupling of arylboronic acids
with acid chlorides in moderate to high yields under com-
paratively mild reaction conditions (98 C, 10 min) by the
group of Viera Polckov from Comenius University in Bra-
tislava (Scheme 21) [276]. A catalyst screen revealed that
Pd(PPh3 )4 and Cs2 CO3 as catalyst/base system generally
provided the aryl ketones in highest yield under the given
microwave conditions.
Along the same lines the group of Christian Wolf from
Georgetown University, Washington, has reported on the syn-
thesis of benzophenone and acetophenone derivatives via the
Suzuki-type cross-coupling of aromatic and aliphatic acyl
chlorides with boronic acids that thus overcomes the draw-
backs of FriedelCrafts acylations such as harsh conditions,
untunable regiocontrol, and low substrate scope (Scheme 22)
[277]. When using Pd-phosphinous acid (POPd) as catalyst
system in combination with microwave heating, the ketone
products are obtained in good to high yields in 10 min reac-
tion time (versus 1 h at the same temperature under thermal
heating). Importantly, aryl halides in both the acyl chloride
and boronic acid substrate were tolerated.
Additional published examples of microwave-assisted
SuzukiMiyaura couplings involve the scaffold decoration
of 3-chloropyrazolines (Scheme S39) [278] and 3-bromo-
flavones (Scheme S40) [279], or the preparation of oligophe-
nyl derivatives (Scheme S41) [280].
123
Mol Divers (2009) 13:71193
2.1.3 Sonogashira reactions
Hong Liu and co-workers from the Chinese Academy of Sci-
ences, Shanghai, have successfully performed Sonogashira
cross-couplings of terminal alkynes with a variety of aryl
chlorides (Scheme 23) [281]. This Cu-free method proved
to be very general and also both sterically hindered and
electron-rich aryl chlorides can be coupled very efficiently
in addition to electron-neutral and electron-deficient ones
giving the products in high yield and short reaction times.
Furthermore, this protocol can be applied for other Pd-cat-
alyzed CC and CN bond-forming reactions by switching
from PdCl2 (PPh3 )2 to Pd(OAc)2 as catalyst. BuchwaldHar-
twig aminations, Suzuki and Heck coupling were conducted,
delivering the coupled products in excellent yields (9095%).
Selective Sonogashira couplings of het(aryl) bromides
containing a boronic ester functionality with TMS-acetylene
have been described by Wang and co-workers (Scheme S42)
[282].
The Pd-catalyzed synthesis of diaryl acetylenes has
been demonstrated by Ulrik S. Srensen and Esteban
Pombo-Villar from Novartis Pharma AG (Scheme 24) [283].
A direct coupling of activated aryl- and heteroaryl bromides
and iodides with 1-aryl-2-trimethylsilylacetylenes has been
developed for the synthesis of diarylacetylenes, avoiding the
use of Cu(I) iodide as a cocatalyst. Microwave dielectric heat-
ing has shown improvement in reaction yields over the con-
ventional oil bath heating.
Timothy M. Swager and co-workers from MIT have
employed a microwave-assisted double SonogashiraHagi-
hara coupling for the synthesis of rotaxanated-conjugated
sensory polymers (Scheme 25) [284]. Microwave irradiation
of a suitable diiodo rotaxane with a corresponding aryl diacet-
ylene under standard microwave Sonogashira coupling con-
ditions at 115 C for 50 min provided the poly( p-phenylene
ethynylene)s which displayed interesting macromolecular
photophysical properties. Using the microwave approach the
reaction time for the synthesis of the rotaxanated-conjugated
polymer was reduced from 2 days to less than 1 h.
The synthesis of 2-substituted indoles by a one-pot two-
step sequence starting from o-iodoanilines and terminal
alkynes was described by the group of Roberto Sanz from
Universidad de Burgos, Spain (Scheme 26) [285]. The first
step includes a Sonogashira coupling, leading to o-alkyny-
lanilines, which were subsequently cyclized under NaOH
mediation to the 2-substituted indoles. Both steps were per-
formed under microwave heating which had the advantage
of employing less NaOH (4 versus 10 equiv) and reduced
reaction times compared with conventional heating (12 h at
rt for step 1 and up to 6 h at 140 C for step 2). In addition,
an arylthio group can be selectively introduced at the C-3
position in a one-pot three-step procedure.
Mol Divers (2009) 13:71193 83

Pd(PPh3 )4, Cs 2CO3 O

B(OH)2 O toluene
R1 + R2
R1
R2 Cl MW, 98 C, 10 min

19 examples
R1 = H, CF 3, Me, OMe, (CH 3 ) 2, "naphthalene"
(18-93%)
R2 = (het)aryl
Scheme 21 Cross-coupling of arylboronic acids with acid chlorides

O
POPd, K 2CO3
R 2
B(OH)2 R2
O toluene, dioxane R1
+
R1 Cl MW, 80 C, 10 min
7 examples
(61-90%)
R 1 = alkyl, aryl Bu-t
t -Bu
R 2 = H, Br Cl P
Pd OH
HO
P Cl POPd
Bu-t t-Bu

Scheme 22 Pd-phosphinous acid-catalyzed cross-coupling of acyl chlorides

PdCl2(PPh 3) 2, PtBu3,
DBU, Cs2 CO3, DMF
R1 Cl + R2 R1 R2
MW, 150 C, 10 min
R1 = (het)aryl, vinyl 22 examples
R2 = Ph, n-hexyl (76-95%)

NH2 NHPh
R1
or or

HN O Pd(OAc) 2, PtBu3, N O
DBU, Cs 2 CO3, DMF
R1
Cl + or or
R1 MW, 150 C, 10 min

R1 Ph
R1 = OMe, Me or
or
B(OH) 2

R1

7 examples
(90-95%)
Scheme 23 Sonogashira and related cross-coupling reactions with aryl chlorides

Hopkins and Collar have reported a one-pot Sonogash-
ira/heteroannulation strategy for the synthesis of 6-substi-
tuted-5H -pyrrolo[2,3-b]pyrazines (Scheme 27) [286]. The
reaction could either be performed in a two-step protocol,
by first performing a classical Sonogashira coupling on 2-
amino-3-chloropyrazine, followed by base-induced cycliza-
tion (Scheme 27a), or in a one-step method by reacting the
corresponding sulfonamide, N -(3-chloropyrazin-2-yl)-
methanesulfonamide, directly with terminal acetylenes in the
presence of suitable Pd catalyst (3 mol%) (Scheme 27b). The
microwave conditions (150 C, 20 min) tolerated much func-
tional diversity (both electron-withdrawing and electron-
donating substituents). Halogens as well as cyano groups
were also tolerated, along with silyl protecting groups.
Adenosine-based nucleosides 31, which exhibit fluores-
cence in the visible range and that are bridged via a

123
84 Mol Divers (2009) 13:71193

cat, base, solvent

Ar X + Si R Ar
MW, 100-140 C, 2.5-15 min
26 diverse examples
Ar = aryl, 2,3-pyridyl
(5-90%)
R = aryl, 3-pyridyl
X = Br, I
cat: Pd(OAc)2, Pd(OAc)2/P(o-tol)3 , Pd(PPh 3) 2
base: NaOAc/Bu 4NBr, NaOAc/Bu 4NCl, K2CO3/Bu 4NCl, triethylamine
solvent: NMP, DMF, DMA, n-Bu 2O or H 2O/DMF
Scheme 24 Cu-free, Pd-catalyzed Sonogashira-type couplings
1,2,3-triazole moiety between the purine base and the ribose,
were prepared by Morten Grtli and co-workers from the
University of Gothenburg, Sweden (Scheme 28) [287]. To
incorporate the 8-alkynyl functionality for the cyclization
precursor, a Sonogashira reaction between 8-bromoadeno-
sine derivative 30 and various terminal alkynes was
performed under microwave heating. After triflation of the
2 -OH group, the 2 -azide functionality was introduced by
nucleophilic displacement. The displacement and subsequent
intramolecular cyclization via Huisgen [3+2]-cycloaddition
of the alkyne and the 2 -azide was again accomplished under
microwave heating. Since these conditions proved to be
incompatible with the silyl protecting groups, complete
deprotection and subsequent protection with acetic anhy-
dride had to be performed to obtain cyclonucleosides 31 in
R moderate yields. For both synthesis steps better results regard-
ing conversion were achieved with microwave heating.
A couplingisomerization reaction (CIR) of (hetero)aryl
halides with propargyl alcohols 32 under Sonogashira con-
ditions for the synthesis of chalcones 33, was disclosed by
Thomas Mller and Oana Schramm from the University of
Heidelberg (Scheme 29) [288]. The first step in this one-
pot synthesis is a Pd/Cu-catalyzed alkyne coupling followed
by base-catalyzed propargyl alcohol to enone isomerization.
The reaction times could be reduced from 1624 h under
conventional heating to only 1530 min by applying micro-
wave irradiation. In a subsequent publication Mller and Liao
extended this protocol to a couplingisomerizationcoupling
(CIC) sequence for the synthesis of chalcones 36 [289]. The
boronate moiety attached to bromoaryls 34 initially serves
as electron-withdrawing substituent for the CIR and, after
addition of K2 CO3 , (het)aryl bromides 35, and water, this
organometallic group is activated by the alkali base for the
Suzuki coupling sequence.
The same group has also reported on the one-pot reaction
of electron-deficient (hetero)aryl bromides 37, (hetero)aryl
propargyl alcohols 38, and enamino carbonyl compounds 39
or 40, respectively (Scheme 30) [290]. The reaction

N N

O N N O

O O
O
O
O
I I
O

Pd(PPh 3) 4, CuI
H H
i-Pr 2NH, toluene
MW, 115 C, 50 min

N N

O N N O
O O
O
O
O
Ar Ar
n
O
Scheme 25 Sonogashira cross-couplings in supramolecular chemistry

123
Mol Divers (2009) 13:71193 85

1. PdCl2(PPh 3) 2, CuI
R2 I R2
Et2 NH, DMA
+ R 4
MW, 70 C, 10 min R4
R 3
NH R 3 N
R1 2. NaOH, DMA R1
MW, 170-190 C
11 examples
R1 = H, Bn, COMe 10-50 min
(40-88%)
R2 = H, NO 2
R3 = H, F, Cl
R4 = alkyl, (het)aryl
SPh
1. PdCl2(PPh 3) 2, CuI
I
Et2 NH, DMA
+ R4 MW, 70 C, 10 min R4
R 3
NH 2 R 3 N
H
2. NaOH
MW, 140 C, 20 min 3 examples
3. Ph2S2 (68-81%)
MW, 140 C, 20 min
Scheme 26 One-pot Sonogashira coupling NaOH-mediated cyclizations

(a)
Pd(PPh3 )2 Cl2, CuI Ph
N Cl TMG, DMF KOt Bu, NMP N
N
+ H Ph Ph
MW, 150 C, 20 min 70 C N
N NH2 N
N NH2 H
70% 60%

(b) A) Pd(PPh 3) 2Cl2 or PdCl2 (dppf)

CuI, TMG, DMF N
N Cl
B) PdCl2(dppf) R
+ H R LiCl, Na2CO3, DMF
N N
N NHMs H
R = aryl, alkyl MW, 150 C, 20 min
9 examples
(24-65%)
TMG: 1,1,3,3-tetramethylguanidine

Scheme 27 Sonogashira/heteroannulation strategies

proceeds via a couplingisomerizationenamine addition
aldol condensation sequence and furnishes dienes 41 when
enaminones 39 are used or the hydrolyzed products 42 if
-amino crotonamide (40) is applied. Compared to thermal
heating, where dihydropyridines are obtained, an aldol-type
condensation is favored in the second step under microwave
conditions providing cyclohexa-1,3-dienes 41 and cyclohexa-
nones 42, respectively.
In a more recent publication, the Mller group described
the synthesis of 3,4,5-substituted isoxazoles via a one-pot
three-component reaction pathway based on an initial
Sonogashira coupling (Scheme 31) [291]. In the first sequ-
ence, alkynones 43 are obtained by Sonogashira coupling
of acid chlorides with terminal alkynes at room temperature.
After addition of hydroximinoyl chlorides 44 and Et3 N to the
same reaction vessel, alkynones 43 reacted further to the cor-
responding isoxazoles via a 1,3-dipolar cycloaddition with in
situ-generated aromatic nitrile oxides from 44. By employ-
ing microwave heating for the cycloaddition step, reaction
times could be reduced from 3 days to 30 min, while increased
yields of the final products and less by-product formation
(dimerization of nitrile oxides to furoxan oxides) were
observed.
A similar strategy was used by the same authors for the
synthesis of highly fluorescent 3,5- and 1,3,5-substituted pyr-
azoles (Scheme 32) [292]. In the first sequence, alkynones
are obtained by a Sonogashira coupling of acyl chlorides
with terminal alkynes at room temperature. Subsequent addi-
tion of hydrazines, MeOH, and acetic acid under microwave
heating to 150 C for 10 min furnished the pyrazoles regiose-
lectivelydepending on the hydrazine substituents R3 via
a Michael addition/cyclocondensation step. Further scaffold
decoration for one example was accomplished in a one-pot
four-component fashion by performing an additional Suzuki

123
86 Mol Divers (2009) 13:71193

R
Br
N
O O N
N NH 2 O
Si Pd(PPh3)2 Cl2 , CuI, Et 3N, THF O N NH 2
+ R H Si
O O OH N N
MW, 120-150 C, 12.5-20 min N
Si O O OH N
30 Si

R = alkyl, cyclic alkyl, aryl, Si(Me)2t-Bu, C(OEt)3 10 examples

(47-88%)
R
R

N
O O N
N NH 2 O
DMF O N NH 2
Si
+ NaN 3 Si
N
O O OTf N MW, 150 C, 15 min N N
Si O O N3
Si

N
N
NH2
AcO O
N
N

AcO N
31 N N R

5 examples
(17-34%)

Scheme 28 Synthesis of cyclonucleosides

coupling step employing the catalyst system from step one,
again under microwave heating giving a biphenyl substituted
pyrazole.
Cryofluorescent 2,4-disubstituted 3H -1,5-benzodiazepi-
nes have been prepared by the same group using a similar
strategy (Scheme S43) [293].
The desulfitative Sonogashira-type cross-coupling of thi-
oether-functionalized pyrazinones 45 and various terminal
alkynes was disclosed by Erik Van der Eycken from the Uni-
versity of Leuven (Scheme 33) [294]. The reaction proceeded
well for both ethylthio-substituted and resin-linked pyrazi-
nones, although longer reaction times (60 and 90 min) com-
pared with the phenylthio-substituted scaffolds are necessary
for resin-bound reactions. In addition, the desulfitative alky-
nylation was extended to other (het)aryls such as oxazinones,
pyrazines, and phenyl thioesters.
The same group has also reported on desulfitative Suzuki-
type couplings of pyrazinones 45 with boronic acids under
LiebeskindSrogl conditions (Schemes S44 and S45) [295,
296], on Sonogashira couplings starting from the correspond-
ing chloro-substituted pyrazinones (Scheme S46) [297], and
on general CC and CN cross-coupling protocols using
chloro-substituted pyrazinone precursors (Scheme S47)
[298].
Starting from oxazolinethiones and oxazolidinethiones,
desulfitative Sonogashira cross-couplings with terminal
alkynes were realized by Tatibouet under similar conditions
as described in Scheme 33 (Scheme S48) [299].
Additional examples of Sonogashira (Scheme S49) [300]
and bis-Sonogashira couplings (Scheme S50) [301] for the
generation of polyacetylenes have been reported. Pd-cata-
lyzed, Cu-free alkenylations and alkynylations of aryl bro-
mides and iodides were reported by Botta (Scheme S51)
[302]. The use of Au nanoparticles supported on inorganic
oxides (e.g., silica) for Cu-free Sonogashira reactions was
described by Antunes (Scheme S52) [303].
2.1.4 Stille reactions
The synthesis of fully conjugated semiconducting para-phe-
nylene ladder polymers via microwave-assisted Pd-mediated
double Suzuki and Stille-type reactions has been demon-
strated by Ulrich Scherf and co-workers (Scheme 34) [304].

123
Mol Divers (2009) 13:71193 87

PdCl2 (PPh3 )2, CuI, PPh3 O

OH DBU or Et 3N, THF
(het)aryl X + (het)aryl R
R MW, 100-150 C, 15-30 min 33
32
X = Br, I 10 examples
R = Ph, 3-thienyl, n-Pr (62-96%)

1. PdCl2(PPh 3) 2, CuI, PPh 3

O
DBU, THF
R OH R
MW, 120 C, 30 min Ar 1
Br +
O het or Ar 2
B Ar 1
2. (Ar 2 or het)Br (35 ), K2 CO 3, H2 O 36
O 34 MW, 110 C, 20 min 9 examples
(49-76%)
R = H, (Me) 2
Ar1 = Ph, 2-thienyl, 4-MeO-Ph
Ar 2 = Ph, 4-CN-Ph, 4-pyridyl, 4-MeO-Ph

Scheme 29 Sequential couplingisomerizationcoupling reactions

1. CuI, PdCl2(PPh 3) 2,
Et3N, THF Ar 2 Ph
OH MW, 150 C, 15 min
Ar 1 Br + Ar1 Ar1
or
Ar 2 2. 39 or 40, AcOH
37 38 MW, 150 C, 10 min O HN R O O
NMe 2
R 41 42
Ar 1 = 4-NC-Ph, 4-CF3-Ph, O HN
2-pyridyl, 2-pyrimidyl 9 examples 4 examples
(30-74%) (48-70%)
Ar 2 = Ph, 3-thienyl, 4-MeO-Ph
R = alkyl, aryl 39
n-Bu
O HN

Me 2 N
40

Scheme 30 Synthesis of 1-acetyl-2-amino-cyclohexa-1,3-dienes

Compared with the classical thermal protocols, reaction times
were reduced by orders of magnitude and the molecular-
weight distributions of the polymers were changed signifi-
cantly comparing microwave and thermal runs.
Thiophene-based copolymers were obtained by a simi-
lar approach using Stille coupling chemistry (Scheme S53)
[305].
Microwave-assisted Stille cross-couplings for the scaffold
decoration of 2(1H )-pyrazinones (e.g., 45) were described by
the Van der Eycken group (Scheme S54) [306]. Several other
Stille cross-couplings performed under microwave condi-
tions were reported (Schemes S55 and S56) [307,308].
2.1.5 Negishi, Kumada, and related reactions
An application of high-speed Negishi coupling methodology
for the preparation of enantiopure 2,2 -diarylated 1,1 -bina-
phthyls was reported by Martin Putala and co-workers from
the Slovak republic (Scheme 35) [309]. Reaction times as
short as 40 s in some cases were sufficient to achieve complete
conversions in the stereoconservative Negishi coupling of
commercially available 2,2 -diiodo-1,1 -binaphthyl (DIBN)
with arylzinc chlorides. The catalyst loading for typical runs
was 5 mol% of Pd(PPh3 )4 , but could be lowered to 0.5 mol%
in some instances without appreciable reduction of coupling
efficiency. The formed enantiopure 2,2 -diarylated 1,1 -bina-
phthyls are of interest in material sciences application. In the
same article, the corresponding Negishi alkynations using
zinc phenylacetylide and zinc trimethylsilylacetylide were
also described.
Ni- and Pd-catalyzed Kumada-type couplings of aryl Grig-
nard reagents with aryl fluorides have been reported by Dank-
wardt (Scheme S57) [310].
Seganish and DeShong from the University of Maryland
have described rapid, microwave-promoted Hiyama coup-
lings of bis(catechol) silicates with aryl bromides
(Scheme 36) [311]. Suitable reaction conditions entailed the
use of 5 mol% of Pd2 (dba)3 as a Pd source, 5 mol% of
2-(dicyclohexylphosphanyl)biphenyl as ligand, and 1.5
equivalents of tetrabutylammonium fluoride (TBAF) in tet-
rahydrofuran as solvent. Exposure of the reaction mixture to
microwave irradiation at 120 C for 10 min typically provided

123
88 Mol Divers (2009) 13:71193

PdCl2(PPh3)2, CuI 1. PdCl2(PPh3 )2, CuI

O Et3N , THF NEt3, THF
+ R2 rt, 1 h R1
R1 Cl
O R2
rt, 1 h + R2
1 N N
R Cl 2. R 3NHNH 2, MeOH, AcOH
R3
MW, 150 C, 10 min
HO 21 examples
N 44 R 1 = (het)aryl (53-95%)
O
O R 2 = SiMe 3, alkyl, (het)aryl
R3 Cl , Et3 N R1 R3
R 3 = H, Me, aryl
R1
MW, 90 C, 30 min N
R2 R2 O
O 1. PdCl2 (PPh3 )2, CuI
43 NEt 3, THF,
24 examples
(12-78%) Cl + Br rt, 1 h
R1 = cyclic, (het)aryl, alkyl, alkenyl
S
R2 = aryl, alkyl, TMS 2. MeNHNH2, MeOH, AcOH
R3 = (het)aryl MW, 150 C, 10 min
3. p-MePhB(OH) 2, K2CO3
Scheme 31 One-pot three-component isoxazole synthesis PPh 3, H2 O
MW, 150 C, 20 min

good yields of biaryl coupling products for a wide range of S

Me
substrates. The only functional group that was found to fail N N

in the coupling studies was the amino group, probably as a Me

result of catalyst poisoning.
In addition, Hiyama couplings involving aryl- and vinyl-
siloxane derivatives have been described by Clarke
(Scheme S58) [312]. Fluoride-free Hiyama couplings of aryl
bromides/chlorides with arylsiloxanes and vinyl siloxanes
have been reported by Njera (Schemes S59S61) [313315].
2.1.6 Carbonylation reactions
Mats Larhed and co-workers from Uppsala University have
reported on the synthesis of benzamides via aminocarbony-
lations of aryl chlorides, aryl bromides, and aryl iodides
using Mo(CO)6 as solid CO source and water as solvent
(Scheme 37) [316]. Intensive investigations have been made
toward reaction conditions, especially in terms of reagent
ratios. By either using the aryl halide or amine as limit-
ing reagent, accompanied with the proper Pd catalyst, hy-
droxycarbonylations could be suppressed as side-reactions
and even the otherwise unreactive aryl chlorides could be
employed under these conditions.
The Larhed group has also reported on aminocarbonly-
ations using allylamine using a similar set of conditions
(Scheme S62) [317]. Similarly, the Pd-catalyzed hydroxy-
carbonylation of aryl- and vinyl-triflates in water using Mo
(CO)6 as CO source has been described (Scheme S63) [318].
Related hydroxycarbonylation (Scheme S64) [319] and alk-
oxycarbonylation chemistry (Schemes S65 and S66) [320,
321] has been performed by the Leadbeater group using CO
gas in a dedicated microwave reactor.
The Larhed group has also reported on the Pd-catalyzed
carbonylation of both aryl iodides and bromides using sul-
fonamides as nucleophiles (Scheme 38) [322]. Good to excel-
52%
Scheme 32 One-pot three-component synthesis of 1,3,5-trisubstituted
pyrazoles
lent yields of acyl sulfonamide products were achieved by
employing microwave heating for 15 min at 110140 C and
using Mo(CO)6 as the CO source. Utilizing this protocol, a
novel hepatitis C virus NS3 protease inhibitor including acyl
sulfonamide elements was also synthesized.
Mathias Alterman and co-workers from Uppsala Univer-
sity have employed a tandem carbonylationlactone forma-
tion reaction sequence for the synthesis of phthalides
(Scheme 39) [323]. Optimum conditions involved the use of
Mo(CO)6 as a solid source of CO, and Pd(OAc)2 /dppf as a
catalyst (5 mol%) at 180 C. The microwave-assisted carbon-
ylationcyclization method was also applied for the synthesis
of other scaffolds, such as dihydroisocoumarins, dihydrois-
oindones, and phthalimides.
In a related study, intramolecular carbonylation reactions
leading to indanones were described by the Larhed group
(Scheme S67) [324].
The Larhed group also reported on a novel and very fast
gas-free carbonylation method for the preparation of ureas
starting from primary amines (Scheme 40) [325]. Under high-
intensity microwave heating with in situ generation of inter-
mediate isocyanates from Co2 (CO)8 , amines have been
converted to the corresponding ureas within 10-s reaction
times. This method has facilitated the preparation of sym-
metrical and unsymmetrical ureas in good to moderate yields,
respectively.
The group of Maurizio Taddei from Universit degli Studi
di Siena has reported on the rapid synthesis of linear
aldehydes via the hydroformylation of alkenes (Scheme 41)

123
Mol Divers (2009) 13:71193 89

R1 R1
2 Pd(PPh 3)2 Cl2, CuI 2
R N O R N O
Cs2 CO3, DMF
+ H R4
R3
Cl N S MW, 95 C, 45-90 min Cl N
45 R4
13 examples
R1 = p-MeOBn, (CH2 )3 -Ph, CH 2-cyclohexyl (54-88%)
R2 = H, Me, Bn, 4-OMe-Ph
R3 = Et, Ph,
R4 = alkyl, (het)aryl
: mercapto phenylpropionyl AM resin

Scheme 33 Desulfitative Sonogashira-type cross-couplings

R2 R2

R1 O R1 O
Pd(PPh3 )2 Cl2, Na2 CO 3
THF, H 2O
(HO)2 B B(OH)2 + Br Br
MW, 130 C, 11 min
R1 O R1 O

R1 = n-hexyl

R2 R2 n
R2 = n -decyl 61%
Mn = 12 600

Stille precur sor

Me3 Sn SnMe3
S S
ladder-type poly(para-phenylene) materials
(LPPPs)

Scheme 34 Ladder polymers via Suzuki and Stille couplings

Pd(PPh3) 4, THF
I Ar
+ Ar-ZnCl
I MW, 120 C, 0.6-20 min Ar

(R)- or (S)-DIBN 10 examples

>99% ee
(75-99%)
Scheme 35 Negishi couplings for the preparation of enantiopure 2,2 -diarylated 1,1 -binaphthyls

Pd2 (dba) 3, ligand R

+ TBAF, THF
O O HNEt 3 + ArBr Ar
Si MW, 120 C, 10 min
O O
19 examples
(49-93%)
PCy2

ligand =

Scheme 36 Hiyama couplings of bis(catechol) silicates with arylbromides

123
90 Mol Divers (2009) 13:71193

[Pd], Mo(CO) 6, Na 2CO3

H 2O NR 2R 3
R2
X + HN
R1 MW, 110-170 C, 10-30 min R1 O
R3
28 examples
X = I, Br, Cl
(15-99%)
ArI: Pd (OAc) 2
ArBr: Herrmanns palladacycle
ArCl: Herrmanns palladacycle/[(t-Bu) 3PH]BF4

Scheme 37 Aminocarbonylations of aryl halides in water

[Pd], Mo(CO)6 , DBU O

O O
dioxane
O O [326]. By using a special adapter, the microwave reaction
X S 2 S
Ar HN R Ar N R2 vial containing the reaction mixture was filled with syngas
R1 MW, 110-140 C, 15 min
R1 (CO/H2 1:1) up to an internal pressure of 3 bar and was sub-
26 examples
(47-96%)
sequently subjected to microwave heating. The reaction pro-
X = I, Br
R1 = H, Me tocol (Rh-catalyst, Xantphos, [bmim][BF4 ], toluene, 110 C,
R2 = Ph, 4-tolyl, 4-Br-Ph, Me, CF3 46 min) was applicable to differently substituted alkenes to
for X = I: Pd(OAc)2 obtain the linear aldehydes without notable formation of the
for X = Br: Herrmanns palladacycle/Fu salt
branched isomers. Importantly, the ionic liquid was essen-
Scheme 38 Synthesis of acyl sulfonamides via carbonylation reac- tial for the reaction; without it only 60 C could be reached,
tions resulting in incomplete conversion of the alkene.

R2 Mo(CO)6, Pd(OAc)2, dppf R2 O

Br DMAP, DIEA, dioxane
O
OH MW, 180 C, 30 min

R1 R1
R 1 = H, Me 9 examples
R 2 = H, Cl, F, NO 2, OMe (10-92%)
fused aryl

Relat ed Scaf f olds

O O O
O
NH NH

O
180 C, 1 h, 74% 160 C, 30 min, 72% 150 C, 30 min, 70%
Scheme 39 Tandem carbonylationlactone formation reactions

H H
NH 2 Co2 (CO)8, NEt 3, solvent N N

MW, T max = 120 C, 600 s O

84%
solvent: MeCN, DMSO, THF, toluene + 14 related examples

H
NH 2 Co2 (CO) 8, NEt3, MeCN N N
HN(n-Pr)2
MW, Tmax = 110 C, 600 s O

44%
+ 3 related examples
Scheme 40 Co carbonyl-mediated synthesis of ureas

123
Mol Divers (2009) 13:71193
HRh(CO)(PPh3)3, XANTPHOS
bmimBF4, CO/H2, toluene CHO
R R
MW, 110 C, 4-6 min
10 examples
R = alkyl, aryl
(65-95%)
Scheme 41 Hydroformylation of alkenes
The same group has reported that similar catalyst/ligand
systems can also be used for the hydroaminomethylation of
alkenes (Scheme S68) [327].
2.1.7 Asymmetric allylic alkylations
The group of Antonio L. Braga from Universidade Federal
de Santa Maria, has disclosed Pd-catalyzed allylic alkyla-
tions of rac-1,3-diphenyl-2-propenyl acetate with malonates
(Scheme 42) [328]. By applying chiral -seleno amides as
ligands in combination with microwave heating, reaction
times of 24 min were possible compared with 24 h at rt with
only a minimal loss of enantioselectivity (ees up to 94%
were obtained). During optimization studies, two methods
were found to give high yields (method A and B). For lig-
ands with R2 = Ph and R3 = Bn, i-Bu it turned out that the
method applied had a significant influence on the ees; better
values could be reached with method A.
The groups of John A. Porco, Jr. and Scott E. Schaus from
Boston University have reported on the synthesis of aryl ether
C-glycoside derivatives 48 via Pd(0)-mediated allylic sub-
stitution of biscarbonates 46 with phenols 47 (Scheme 43a)
[329]. This reaction was both regio- and stereoselective with
an overall retention of configuration when the enantiomeric
(S, S)-Trost ligand was employed. The protected aryl ether
C-glycosides 49 can be further diversified by Eu(III)-cata-
lyzed Claisen rearrangement where glycosides 49 undergo a
Method A: ligand , [Pd(3-C 3 H 5)Cl] 2
OAc O O
+ R1 R1
Ph Ph
Method B: ligand, [Pd(3 -C 3H 5 )Cl] 2
R 1 = Me, Et
R2 = Ph, p-Cl-Ph, p-MeO-Ph,
2,4,6-Me3 -Ph, Bn
R3 = i-Pr, Bn, i-Bu
Scheme 42 Pd-catalyzed asymmetric allylic alkylations
91
[3,3]-sigmatropic rearrangement and furnish the novel phe-
nol derivatives 50 (Scheme 43b).
2.1.8 Miscellaneous carboncarbon bond-forming reactions
Bruce H. Lipshutz and co-workers from the University of
California Santa Barbara have performed several heteroge-
neous cross-coupling reactions catalyzed by nickel-in-char-
coal (Ni/C) (Scheme 44) [330]. In combination with micro-
wave heating, the CC and CN cross-coupling reactions
[Negishi (a), Suzuki (b), aminations (c), and the coupling
of vinyl alanes with benzylic chlorides (d)] could be accel-
erated from several hours to minutes compared with con-
ventional heating, giving the products in excellent yields.
A reduction of the NiII /C precatalyst with n-BuLi at room
temperature to the active Ni0 /C prior to introduction of the
coupling partners is necessary, except for the Negishi cou-
pling. Here a direct use of NiII /C gives the same results as
with Ni0 /C.
Similar to the chemistry using Ni/C described in
Scheme 44, carboncarbon cross-couplings catalyzed by
activated Ni(II) mounted on graphite (Ni/Cg ) were recently
also reported by the Lipshutz group (Scheme 45) [331]. In
addition to the Suzuki coupling of aryl chlorides and tosy-
lates with boronic acids, vinylalanes and vinylzirconocenes
were reacted with aryl halides and tosylates. Compared with
the corresponding Ni/C-catalyzed reactions, couplings pro-
ceed faster, higher yields are obtained, and cleaner reactions
are afforded with Ni/Cg as catalyst. In some cases, differ-
ent chemoselectivities depending on the used catalyst were
obtained.
Christian Wolf and Rachel Lerebours from Georgetown
University, Washington, DC, have reported on the Pd-phos-
phinous acid-catalyzed conjugate addition of (het)aryl silox-
anes to , -unsaturated substrates in water (Scheme 46)
BSA/KOAc, DCM O O
MW, 300 W, 70 C, 4 min
R1 R1
Ph Ph
BSA/KOAc, MeCN
MW, 30 W, 70 C, 2 min 9 examples
Method A: 30-93%
24-93% ee
Method B: 23-91%
R3 6-94% ee
R 2 Se
NHBz
ligand
123
92
(a)
OCO 2Et
+ HO
OCO2 Et R2
R1 O R1
46 47
1
R = aryl, vinyl, alkynyl
R2 = alkyl, COH, COMe, OMe
halogen, NMe2
(b)
R2
O Eu(fod)3 , PhCl
3
OR MW, 200 C, 30-90 min
R1 O R1
49
R1 = vinyl, 4-COMe-Ph
R 2 = OMe, Ph
R 3 = TBS, CO2 Et
TBS: t -butyldimethylsilyl
fod: 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione
Scheme 43 Scaffold decoration of C-glycosides
[332]. Key to the success of a general method is the
employment of 10 mol% of a Cu co-catalyst [Cu(ACN)4 PF6 ]
additional to 5 mol% of the Pd catalyst POPd1. An advan-
tage of the Pd-phosphinous acid catalyst POPd1 is the air
and water stability that eliminates an inert atmosphere dur-
ing the reaction. With this protocol -substituted ketones,
aldehydes, and nitroalkanes were obtained in high yields.
Even otherwise difficult available -substituted esters and
nitriles can be generated smoothly in this way.
The asymmetric synthesis of ,  -dibenzyl esters 51 from
-benzyl acrylates and diversely substituted boronic acids
was performed by Christopher Frost and co-workers from
the University of Bath (Scheme 47) [333]. Dibenzyl esters
51 were generally obtained in good enantioselectivities via
a tandem Rh-catalyzed conjugate addition-enantioselective
protonation protocol. (S)-BINAP (2, 2 -bis(diphenylphosph-
ino)-1, 1 -binaphthyl) as ligand and B(OH)3 as proton source
proved to be the best combination in terms of yields and en-
antioselectivities in optimization studies.
The same group has also reported on the Rh-catalyzed
addition of organotrialkoxysilanes to -substituted acryl
esters leading to a range of useful products, including 2-alkyl
succinates and -amino acid derivatives (Scheme S69) [334].
For Rh-catalyzed additions of boronic acids to maleimides,
see Scheme S70 [335].
123
Mol Divers (2009) 13:71193
R2
1. Pd 2(dba)3 .CHCl3 , Trost ligand
DCM
MW, 100 C, 15 min O
2. MP-CO 3 or K2 CO3, MeOH, rt, 2-15 h OCO2Et
O
48
20 examples
O O (20-100%)
NH HN
PPh 2 Ph2P
(S,S)-Trost ligand
OH
R2
OR 3
O
50
2 examples
(60-70%)
Comparison studies of microwave versus conventional
heating in the arylation of -ketones with aryl chlorides have
been performed by Steven Nolan and his group (Scheme 48)
[336]. By employing the versatile N -heterocyclic carbene
palladacycle 52 as catalyst, full conversion was reached under
both microwave and conventional conditions. Due to the
higher temperatures (130 C versus 70 C) which can be
reached by microwave heating, the reactions proceeded up
to 60 times faster.
Along the same lines, Pd-catalyzed arylations of bicylic
lactones with aryl bromides have been reported (Scheme S71)
[337].
In the course of a multidimensional reaction screening
of o-alkynyl benzaldehydes with a variety of catalysts and
reactants in order to identify novel chemical transformations
the groups of Aaron Beeler and John Porco Jr. from Bos-
ton University have discovered two new reaction pathways
where microwave heating is employed (Scheme 49) [338]. In
the first reaction o-alkynyl benzaldehyde 53 is reacted with
diethyl malonate in dichloroethane (DCE) under Au(OAc)3
catalysis. Via this cycloisomerization/nucleophilic addition
sequence isochromene 54 was obtained as major product
along with the ring-opened benzylidenemalonate 55. When
MeCN is used as solvent exclusively the ring-opened prod-
uct 55 is obtained in 90% yield. The second novel reaction
Mol Divers (2009) 13:71193 93

(a) NiII/C, PPh3, n-BuLi

R2 dioxane R2
R 1 ZnX + Cl R1
MW, 70-200 C, 15-30 min
X = Cl, I 8 examples
R 1 = alkyl, aryl (75-95%)

(b)
NiII/C, PPh 3, n-BuLi,
LiOH, KF, dioxane
R Cl + Ar B(OH) 2 R Ar
Y Y
MW, 180-200 C, 30-40 min
7 examples
Y = CH, N (80-91%)
R = CN, CF3 , COMe

(c)
NiII/C, dppf, t -BuOLi
R Y
R Y n-BuLi, dioxane
N
X +
N MW, 200 C, 10 min
H
X = Cl, Br, I
Y = CH, N 3 examples (84-91%)
R = H, CF3, CN + 8 related examples (80-95%)

(d)
MeO Me

Cl Me 2Al H
MeO 9
OTs
NiII/C, PPh 3 , n-BuLi MeO Me
THF
MeO H
10
MW, 200 C, 20 min OTs
80%
Scheme 44 Ni-in-charcoal-catalyzed cross-couplings

Ni/C g, PPh3, LiOH,

KF, THF/dioxane
X + (HO)2 B
R1 R2 MW, 180-200 C, 0.7-4.5 h R1 R2

X = Cl, OTs 8 examples

(80-100%)
R 1 = OMe, Ph, Bz, COMe, "naphthyl"
R 2 = H, OMe, COMe, CF3

Scheme 45 Ni-on-graphite-catalyzed cross-couplings

employing microwave heating was the cycloisomerization
with subsequent FriedelCrafts addition and phenol
annulation. This sequence is catalyzed by PtCl2 and fur-
nished tetracycle 56 as product.
Mark Lautens and co-workers from Toronto University
have reported on Pd-catalyzed intramolecular cross-coupling
reactions between aryl iodides and allyl moieties (Scheme 50)
[339]. Various five- to seven-membered carbo- and hetero-
cycles were synthesized applying microwave irradiation at
160 C for only 1 min. Compared with conventional thermal
heating the yields could be improved by up to 40%.
In an extension of the strategy shown in Scheme 50 the
Lautens group has investigated the synthesis of tricyclic het-
erocycles (59 and 60) starting from aryl iodide 57 which
contains two tethered alkyl bromides and a Heck accep-
tor 58 or Zn(CN)2 , respectively. Products 59 are obtained

123
94 Mol Divers (2009) 13:71193

O O

Cu(ACN)4PF6, POPd1
R3
H2O
or + R3 Si(OR4)3 6 examples
MW, 120 C, 4 h (83-96%)
2 or
R
R1
t-Bu t-Bu t-Bu t-Bu R3
1
R = H, Ph O P Cl P O 1 R2
R
R2 = COH, COOt-Bu H Pd Pd H
CN, NO2 O P Cl P O 4 examples
(83-92%)
R3 = (het)aryl t-Bu t-Bu t-Bu t-Bu
R4 = Me, Et POPd1

Scheme 46 Pd(II)-catalyzed conjugate additions

R2
[Rh(acac)(C 2H 4 ) 2 ]
R1 R2 (S)-BINAP, B(OH)3, dioxane
X +
MW, 100 C, 1 h CO2 t Bu
n CO2 tBu B(OH) 2 H
X
X = CH, S R1
n = 0, 1 n
R1 = OMe, SMe, F, "naphthyl" 51
R2 = OMe, SMe, t-Bu, Br, CHO, 3,5-(CF 3) 2 15 examples
Ph, "naphthyl" (67-93%)
Scheme 47 Rh-catalyzed conjugate additionenantioselective protonation

O
O cat 52
R3 R1 R3
R1 NaOt -Bu, THF
+ Cl
Y MW, 130 C, 2 min R2 Y
R2 or , 70 C, 1-2 h
5 examples
R1 = Ph, Me (89-100% conv)
R2 = Et
R3 = Me, CF3 R N N R
Y = CH, N

Pd Cl
R=

N
Me
Me
52

Scheme 48 Pd-catalyzed -ketone arylations

via a norbornene-mediated Pd-catalyzed intramolecular bis-
alkylation/intermolecular alkenylation sequence of 57 and
58 (Scheme 51) [340], whereas tricyclic benzonitriles 60 are
furnished via tandem intramolecular bis-alkylation/intermo-
lecular cyanation applying the same catalytic system [341].
A similar approach has been used by the same group for the
generation of tricyclic mescaline analogs (Scheme S72) [342]
and other tricyclic heterocyclic ring systems (Scheme S73)
[343].
An additional report by the same group has described a
Pd-catalyzed CH functionalization reaction for the synthe-
sis of highly substituted benzonitriles (Scheme 52) [344].
Bicyclic products 61 were obtained in one step by an intramo-
lecular alkylation/cyanation sequence. Both electron-with-

123
Mol Divers (2009) 13:71193 95

(a) MeO (CH2 )5CH 3

O
O MeO
O
(CH 2)5 CH3 EtO OEt
EtO OEt
MeO 54 , 62% O O
Au(OAc) 3, DCE
+
H
MeO MW, 110 C, 15 min
MeO (CH 2) 5CH3
O
53
O
MeO
EtO OEt
O O
55, 20%
(b) OH

(CH 2) 5CH3
MeO OMe MeO (CH 2 )5CH3
MeO
PtCl2, DCE
H O
MeO MeO H
MW, 130 C, 3 h
O MeO O

OMe

(CH 2) 5CH3
MeO
O O
MeO
H
56, 58% MeO OMe
Scheme 49 Multidimensional reaction screening of o-alkynyl benzaldehydes

I Pd 2(dba)3, P(o-tolyl)3
nBuNMe2, MeCN/H2 O
OCO 2Et
R X n R X n
MW, 160 C, 1 min
9 examples
n = 1-3 (56-74%)
X = O, NTs, CH2 O, C(CO2 Et)2
Scheme 50 Pd-catalyzed intramolecular cyclization

drawing and electron-donating o-substituents are tolerated.
Tricyclic benzonitriles can be obtained via a double o-alkyl-
ation/cyanation sequence. Biaryl compounds 62 were syn-
thesized via an intermolecular o-arylation/cyanation
sequence employing electron-deficient aryl bromides. The
reaction conditions regarding ligand, cyanation reagent, and
solvent had to be changed, and when aryl iodides lacking
an o-blocking group were employed, only complex mixtures
of products were received. Important for both strategies is
the norbornene, which is able to initiate the competitive
CH functionalization pathway, so that CC and CCN bond
formation can occur sequentially.
Finally, in a very recent study the Lautens group has dis-
closed Pd-catalyzed norbornene-mediated intramolecular
o-alkylations of aryl iodides with secondary alkyl iodides
and bromides for the synthesis of polycylic heterocycles
(Scheme 53) [345]. These alkylations proceed in a domino
process with subsequent termination steps such as Heck reac-
tions, direct arylations or BuchwaldHartwig aminations in
one-pot forming new CC or CN bonds. In the domino intra-

123
96
I R3
Br Br
m O O n
R1
57
m, n = 1-3
R1 = H, OMe
R2 = H, NHAc
R3 = CO 2t -Bu, CO 2Me, CONHt-Bu
Ph, 2-pyridyl
I CN
Br Br
m MW, 150 C, 4000 s
O O
1
R R1
57
m, n = 1-2
R = H, OMe
Scheme 51 Synthesis of tricyclic symmetrical and unsymmetrical oxo-heterocycles
molecular o-alkylation/Heck reaction tricyclic heterocycles
are formed with separable exo- and endocyclic double-bond
isomers for products with an O-containing five-membered
ring. Pyrrole-, indole-, and thiophene-containing substrates
undergo an intramolecular o-alkylation/direct arylation
sequence delivering tetra- and pentacyclic heterocycles. In
addition, the reaction sequence occurs in a stereospecific
manner which was validated by the use of enantioenriched
substrates where a minimal loss of ee was obtained for phenol
tethered alkyl iodides. However, secondary alkyl bromides
gave the product in more diminished ee.
Pd-catalyzed cyanations of aryl bromides using Zn(CN)2
have been disclosed by Pitts and co-workers (Scheme S74)
[346]. Subsequent work by Wan has shown that nontoxic
K4 [Fe(CN)6 ] can also be employed (Scheme S75) [347].
Pd-catalyzed reductive Ullmann-type homocouplings of
isothiazoles have been studied by Koutentis (Scheme S76)
[348]. Synthetically valuable 1,6-dioxo-2,4-dienes have
been obtained by Pd-catalyzed reductive dimerization from
N -vinylpyridinium tetrafluoroborate salts (Scheme S77)
[349].
Microwave irradiation has been applied successfully to
promote PausonKhand type processes (Schemes S78 and
S79) [350,351]. For an example of a microwave-assisted
Dtz benzannulation, see Scheme S80 [352].
Pd-catalyzed 4-exo-dig cyclocarbopalladations have been
reported as an approach to cyclobutanediols (Scheme S81)
[353] and strained aromatic ring systems (Scheme S82) [354].
The Ru-catalyzed N -directed o-arylation and heteroaryla-
tion of 2-phenylpyridine and 2-phenyloxazolidine with aryl
123
Mol Divers (2009) 13:71193
R2
Pd(OAc)2, PPh3, Cs 2CO3
R2 R3 norbornene, DME
m n
MW, 190 C, 5-20 min O O
R1
58 59
8 examples
(42-85%)
Pd(OAc)2, PPh3, Cs 2CO3
Zn(CN)2, norbornene, DME
m n
n O O
60
4 examples
(56-88%)
bromides has been described by Oi (Scheme S83) [355]. For
examples of Pd-catalyzed phosphonations in the steroid
series, see Scheme S84 [356]. For a report on Pd-catalyzed al-
lylations of aryl bromides with homoallyl alcohols via retro-
allylation, see Scheme S85 [357].
2.2 Transition-metal-catalyzed carbonheteroatom
bond formations
2.2.1 BuchwaldHartwig reactions
Stephen L. Buchwald and his group from Massachusetts
Institute of Technology, Cambridge, have described a fast
protocol for the coupling of (het)aryl nonaflates and amines
(Scheme 54) [358]. An excellent functional group tolerance
was observed for the synthesis of diverse arylamines using
the catalyst systems Pd2 (dba)3 with ligands 63, 64 or 65,
respectively, and the soluble amine bases 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) and 7-methyl-1,5,7-triazabicyclo
[4.4.0]dec-5-ene (MTBD).
Niels Skjaerbaek and co-workers from LEO Pharma,
Denmark, have disclosed an efficient protocol for the synthe-
sis of aryl aminobenzophenone p38 mitogen-activated pro-
tein (MAP) kinase inhibitors using microwave-assisted Pd-
catalyzed aminations (Scheme 55) [359]. Several different
strategies involving halide, triflate, and tosylate leaving
groups were investigated, in addition to an alternative amina-
tion mode (method B). Amination of an electronically diverse
array of aryl halides with a variety of anilines was realized in
Mol Divers (2009) 13:71193 97

X
CN
R1 Pd(OAc)2, PPh3, Cs 2 CO3
norbornene, Zn(CN) 2, DME R1
Br n
Y n MW, 150 C, 4000 s Y
X = I, Br 61
Y = O, NTs 11 examples
R 1 = Me, NO2 , OMe (47-91%)
n = 1-3

Pd(OAc)2, P(2-furyl)3
I Br Cs2 CO 3, norbornene, K 4 [Fe(CN)6 ]3 CN
1 R3
R1 H2 O, MeCN R
+
MW, 130 C, 2 h R2
R2
R3 62
19 examples
R 1 = "naphthyl", Me, Cl, MeO (traces-94%)
R 2 = H, Cl
R 3 = CO2 Me, CHO, MeO, OH, COMe,
Br, SO 2 Me, NO2 , CF3
Scheme 52 Synthesis of polysubstituted aromatic nitriles

R
Me Me
I Pd(OAc) 2, PPh 3
norbornene, Cs 2CO 3, DME
m
I MW, 180 C, 8-11 min
O R O n
n m
3 examples
(12-75%)
m, n = 1, 2
R = CO2t Bu, COEt, Ph

Me
I Pd(OAc) 2, PPh 3 or TFP Me Z
norbornene, Cs 2 CO 3 or K2 CO 3
Z MeCN or DME Y
X
O Y m
MW, 140-160 C, 20 min
n m O n
m, n = 1, 2
6 examples
X = Br, I
Y = N, C (29-90%)
Z = CH, S
Scheme 53 o-Alkylation of aryl iodides with secondary halides

good to excellent yields for most cases, without the necessity
to work under an inert atmosphere.
Henry Q. Zhang and co-workers from Abbott Laborato-
ries, Abbott Park, have shown that 2-chloro pyrimidines 66
can be converted to the corresponding 2-arylamino or 2-
heteroarylamino pyrimidines 67, respectively, via Pd-medi-
ated aminations (Scheme 56) [360]. The reactions were con-
ducted under both Pd-free conventional and microwave heat-
ing as well, furnishing the 2-arylamino pyrimidines in similar
yields as under Pd-catalyzed microwave conditions. How-
ever, when 2-heteroaryl amines are reacted with 66, only the
Pd-catalyzed microwave protocol afforded the desired prod-
ucts. 2-Bromo pyrimidines were also found to react under
these conditions.
An extensive optimization study toward the synthesis of
6-heterocyclic substituted 2-aminoquinolines via Buchwald
Hartwig amination of 6-bromo-2-chloroquinoline with cyclic
amines was conducted by the group of Simon Pyke from the
University of Adelaide (Scheme 57) [361]. Crucial for the
selective amination at the 6-position is the choice of the sol-

123
98 Mol Divers (2009) 13:71193

R2
2 N
R
HN R1 R3
3
R
or Pd 2 (dba)3 , ligand 63, 64, or 65 or
ONf
2 3 DBU or MTBD, toluene NR 2R 3
R1 + HNR R
R1 23 examples
or MW, 115-175 C, 5-45 min (71-99%)
Nf = SO2 (CF2) 3CF3 O
O or
R 1 = (het)aryl R2
R2 N
H2 N
R3 R1 H R3

R2 , R 3 = H, alkyl, (het)aryl

Me Me
PCy 2 Pt-Bu 2
i-Pr i-Pr i-Pr i-Pr
O
PPh 2 PPh2
i-Pr i-Pr
63 64 65
XPhos XantPhos

Scheme 54 Pd-catalyzed amination of aryl nonaflates

O Pd(OAc)2, ligand
O
NaOt -Bu or Cs 2CO3
+ t-BuOH, toluene
R
R
NH2 X MW, 120-160 C, 3-30 min N
H
X = Cl, Br, I 18 examples
OTs, OTf (22-96%)

A O Cl

+ R Pd(OAc)2, ligand O Cl
Me NH2 X NaOt-Bu or Cs2 CO3
X = Br, I, OTf t-BuOH, toluene
R
B O Cl
MW, 150 C, 3-20 min Me N
H
+ R A: 15 examples
Me Br H 2N (51-80%)
i-Pr B: 6 examples
ligand:
(70-79%)
i-Pr

i-Pr PCy 2

Scheme 55 Pd-catalyzed amination reactions

vent. By changing from toluene to benzotrifluoride (BTF) yields were obtained. Under thermal heating BTF proved to
not only can the reaction be performed in the microwave at be superior to toluene with respect to product yields as well.
150 C due to the better microwave absorbance characteris- Gitte Van Baelen and Bert Maes from the University of
tics of BTF compared with toluene, but also higher product Antwerp, Belgium, have developed a protocol that allows

123
Mol Divers (2009) 13:71193 99

Pd(OAc) 2, Xantphos
N Cs2 CO3, dioxane N
R + Ar R
NH 2 Ar
N X MW, 160 C, 40 min N N
H
66 67
R = H, Et, CF3 11 examples
X = Cl, Br (50-83%)
Ar = MeO-Ph, CF3-Ph, quinoline, pyridine
methylpyrazole, benzothiazole
Scheme 56 Pd-catalyzed synthesis of 2-arylaminopyrimidines

R
X
Br Pd(OAc) 2, NaOt Bu, BTF N
+ R X NH
N Cl MW, 150 C, 15-20 min
N Cl

X = N, O, C 4 examples
R = H, Me, Ph, Bn (50-95%)

Scheme 57 Selective BuchwaldHartwig aminations

aq KOH, Pd(OAc)2 /2 ligand

toluene
R Cl + HN O R N O
MW, 100-120 C, 30 min

R = CN, COOMe, COMe DCPB: 58-82%

ligand: DCPB, X-Phos X-Phos: 24-99%
+ 33 related examples
DCPB: 2-(dicyclohexylphosphino)biphenyl
(13-83%)
Scheme 58 Pd-catalyzed amination of aryl chlorides

selective hydrolysis of nitriles to amides or avoids hydro-
lysis of esters and nitriles by employing a toluene/concen-
trated aqueous KOH two-phase system under microwave
conditions (Scheme 58) [362]. Selective hydrolysis can be
achieved by the use of a phase-transfer catalyst (PTC)
whereas no hydrolysis occurs in the absence of a PTC under
otherwise identical conditions. By employing the reaction
conditions discovered in this study for the Pd-catalyzed ami-
nation of aryl chlorides bearing sensitive functional groups
such as nitriles or esters with aliphatic amines, successful
coupling to the corresponding products without the occur-
rence of hydrolysis could be achieved. When primary amines
are employed JohnPhos proved to be a superior ligand. Ani-
lines can be coupled as well, although the yields are rather
low. Heteroaromatics are also suitable substrates for this cou-
pling protocol.
In related work, the Nolan group has reported on Buch-
waldHartwig aminations of unactivated aryl chlorides with
amines using N -heterocyclic carbene containing N -C-palla-
dacycles as catalysts (Scheme S86) [363].
Michael Harmata and co-workers from the University of
Missouri-Columbia have disclosed an efficient protocol for
the Pd-catalyzed N -arylation of enantiopure sulfoximines
with aryl chlorides (Scheme 59) [364]. Optimal results were
achieved by using Pd(OAc)2 as Pd source and rac-BINAP
or P(t-Bu)3 as ligands under microwave irradiation condi-
tions. For aryl chlorides bearing ortho-carbonyl substituents
the corresponding benzothiazines were obtained.

(for suitable ArCl)

Pd(OAc)2 R
BINAP or P(t -Bu) 3 Ar
NH N
Cs2 CO 3, toluene _
+S +S or O
+
Me _ Ph + ArCl Me _ Ph S
O MW, 135 C, 1.5-3 h O N
Ph
14 examples
(31-94%)
Scheme 59 N -Arylation of sulfoximines

123
100 Mol Divers (2009) 13:71193

O
morpholine, proline
Br CuI, K2CO3, DMSO N
O O

N N MW, 140 C, 30 min N N

H H
58%
+ 9 related examples
(30-70%)
Scheme 60 Cu-catalyzed aminations

H2 N NH2

O (CuOTf)2 .C6 H6 , (dba) O R

R Cs 2CO3 , dioxane
Ar N NH Ar N N
+ X Y
Y MW, 150 C, 30 min
68 69
12 examples
Ar = Ph, 4-MeOPh
(35-100%)
R = 4-Me, 4-MeO, 4-CF3 , 4-NO2 , 3-NO 2
X = Br, I
Y = CH, N

Scheme 61 Cu-catalyzed aminations

The Pd-catalyzed N -arylation of o-nitroaryl bromides A set of asymmetrically substituted N ,N  -diarylimidaz-

with anilines was described by Uwe Beifuss and co-workers
in 2005 (Scheme S87) [365]. Nicholas Turner has reported
on a Pd-catalyzed intramolecular amination sequence for the
synthesis of oxindoles (Scheme S88) [366]. Closely related
intramolecular aminations leading to oxindoles have also
been studies by Zhu (Scheme S89) [367]. Pyrazino[1,2-a]
benzimidazol-1(2H )-ones have been obtained in a similar
way (Scheme S90) [368].
A recent report by Liu suggested that N -arylations of aryl
halides with amines can also be carried out using inexpensive
Fe2 O3 as a catalyst in the presence of L-proline (Scheme S91)
[369].
2.2.2 Ullmann condensation reactions
The amination of various functionalized heterocyclic bro-
mides with aliphatic primary and cyclic amines and pyrazole
was disclosed by Vince S. C. Yeh and Paul E. Wiedeman from
Abbott Laboratories (Scheme 60) [370]. Optimization stud-
ies have shown that high conversions to the desired product
could be achieved with the catalyst system CuI/proline which
proved to be very general in the further process. However,
a rather high catalyst (20%) and ligand (40%) loading was
necessary to achieve the aminated products in moderate to
good yields.
The Larhed group has shown that, using microwave irra-
diation, free and protected amino acids can be N -arylated by
aryl bromides in the presence of CuI using water as solvent
(Scheme S92) [371].
olinones 69 was synthesized by Doris Kunz and Thomas
Hafner from Ruprecht-Karls-University Heidelberg via
Cu-catalyzed N -arylation of arylimidazolinones 68 with aryl
iodides or bromides (Scheme 61) [372]. Similar yields can
be achieved by conventional heating at lower temperature
(120 C); however, a longer reaction time of 15 h has to be
applied. The synthesis of symmetrically substituted N ,N  -di-
arylimidazolinones via double N -arylation was less success-
ful since substrate decomposition of imidazolinone occurred
as a side-reaction. Thus only electron-poor aryl halides can
be employed, which furnish the products in moderate yield.
Hong Lui and co-workers from the Shanghai Institute
of Biological Sciences have reported on the Cu-mediated
N -arylation of amines with boronic acids (Scheme 62) [373].
The coupling of various amines with differently substituted
boronic acids under mild conditions and in the absence of
a Pd catalyst led to a small library of 21 arylated prod-
ucts. Importantly, in addition to anilines, this protocol is
applicable to primary and secondary alkyl amines and
nitrogen-containing heterocycles, where a reduced reaction
time of 15 min is sufficient to obtain the coupled products in
4896% yield.
Erik Van der Eycken and co-workers from University of
Leuven performed Cu(II)-mediated scaffold decorations on
the pyrazinone core (Scheme 63) [374]. N -Arylations utiliz-
ing arylboronic acids applying the ChanLam protocol were
successfully conducted under microwave heating with inten-
sive simultaneous cooling at 0 C. Due to prevented
product decomposition, excellent yields could be achieved

123
Mol Divers (2009) 13:71193 101

R1 R2
R1 R2 Cu(OAc)2, DBU
NH 2 + B(OH) 2
MW, 100 C, 30 min N
H
R1 , R 2 = H, OMe, NO2, Cl, Me
17 examples
(29-87%)
+ 4 related examples
(48-96%)

Scheme 62 Cu-mediated N -arylation of amines with boronic acids

H Cu(OAc) 2, Et3 N/Py (1:2)

N O N O
R DCM
+ B(OH) 2
Cl N S MW, 300 W, 0 C, 1 h Cl N S
with cooling
R = H, 3-CF3 , 3-Cl, 3-Br, 3-EtO, 8 examples
4-MeO, 4-PhO, 2-naphtyl (83-97%)

Scheme 63 Cu(II)-mediated N -arylation of amides with boronic acids

Cu/C, 1,10-phenanthroline
Br HO Cs 2CO3, dioxane O
+
MW, 180-220 C, 25-180 min
R1 R2 R1 R2
14 examples
(79-89%)
Scheme 64 Cu-in-charcoal catalyzed diaryl ether synthesis

compared with reactions at rt or elevated temperatures, res-
pectively. High yields could be obtained by using a mixture
of Et3 N/pyridine (1:2) as opposed to Et3 N alone: 93% com-
pared with 69% for R= 3-CF3 .
Numerous examples of microwave-assisted Ullmann
condensations have been additionally reported (Schemes
S93S95) [375377].
2.2.3 Miscellaneous carbonheteroatom bond-forming
reactions
The Lipshutz group has reported on the cross-coupling of
(het)aryl bromides with phenols which was catalyzed by Cu
impregnated into charcoal (Cu/C) (Scheme 64) [378]. If the
aryl bromide substrate was used as the limiting reagent, it was
discovered that active Cu was released from the charcoal into
solution. By simply adjusting the molar ratio to phenol being
the limiting reagent, this problem could be overcome with
the advantage that less Cs2 CO3 base and thus less solvent
could be used. However, longer reaction times were neces-
sary in these cases. When aryl chlorides were employed, the
reaction time under microwave heating turned out to be too
long (8 h) to be of practical use.
In a recent article Lipshutz presented copper + nickel-in-
charcoal (CuNi/C) as a bimetallic heterogeneous catalyst
that promotes a variety of cross-couplings normally cata-
lyzed by Pd, Ni or Cu (Scheme S96) (see also Schemes 44
and 45) [379].
Similar cross-couplings of aryl iodides and alcohols
employing an octanuclear Cu cluster as catalyst were reported
by Guezei (Scheme S97) [380]. Related Cu-catalyzed cou-
plings of aryl halides with phenols have also been described
(Schemes S98S100) [381383]. The Cu-catalyzed conver-
sion of aryl halides to phenols in the presence of L-proline
in high-temperature water has been demonstrated by Lead-
beater (Scheme S101) [384].
Alternatively, John Verkade and Steven Raders from Iowa
State University have reported on the synthesis of diaryl
ethers by the reaction of electron deficient aryl fluorides with
various t-butyldimethylsilyl (TBDMS)-protected phenols
(Scheme 65) [385]. Proazaphosphatrane 70 was utilized as
strong base in this protocol, and compared with conventional
heating, the amount could be reduced from 1050 to only 1
10 mol%, giving the products in comparable high yields. For
NO2 -substituted aryl fluorides toluene was used as solvent
whereas the other aryl fluorides required DMF.
A 24-member benzoxazole library was synthesized by
Robert Batey and co-workers from the University of Toronto
using an automated sequential processing technique
(Scheme 66) [386]. The reaction proceeds in one pot via ini-

123
102 Mol Divers (2009) 13:71193

proazaphosphatrane 70
F TBDMSO toluene or DMF O
R1 + R2 R1 R2
MW, 130-180 C, 0.5-5 h

R 1 = NO2, CN, CO2Et, Me i-Bu 18 examples

R 2 = OMe, CN, Cl, Br, i-Pr, t-Bu N (56-99%)
Bu-i
TBDMS: t-butyldimethylsilyl P i-Bu
N N
N
70

Scheme 65 Synthesis of diaryl ethers without metal catalyst

CuI, 1,10-phenanthroline Br
Br O Cs2CO3, MeCN O
+
NH2 Cl R2 MW, 210 C, 15 min N R2
R 1 R1 H
71
O
R1 = Me, F, CF3,
O O
2
R2
R = alkyl, (het)aryl N
R1
24 examples
(21-97%)
Scheme 66 Cu-catalyzed one-pot benzoxazole synthesis

tial acylation of the aniline building blocks with acid chlo-
rides giving the 2-haloanilide intermediates 71, followed by
Cu-catalyzed intramolecular cyclization of 71 to form the
CO bond of the benzoxazole products. Shorter reaction
times could be achieved by employing microwave heating
compared with conventional heating (15 min at 210 C ver-
sus 24 h at 95 C).
In a related fashion, intramolecular CO coupling has been
used for the synthesis of benzopyranones and isolamellarin
alkaloids (Scheme S102) [387]. N -Substituted benzimidazol-
2-ones have been obtained via intramolecular Cu-catalyzed
amination from the appropriate N -substituted N -(2-halophe-
nyl)ureas (Scheme S103) [388].
Brindaban Ranu and co-workers from the Indian Associa-
tion for the Cultivation of Science in Kolkata have
developed the ligand-free coupling of aryl iodides with thi-
ophenols and alkanethiols under Cu nanoparticle (46 nm)
catalysis (Scheme 67) [389]. The arylsulfide synthesis
proceeded in good to excellent yields and high purities. Com-
pared with conventional heating at 120 C, the reaction times
could be shortened from 1215 h to only 57 min. Other Cu
sources such as metallic Cu, CuI or Cu powder lead to lower
product yields, indicating the key role of Cu nanoparticles in
this CS coupling reaction.
In a 2005 publication, Xifu Liang and co-workers from
LEO Pharma, Denmark, reported on optimization studies
for the synthesis of aryl azides from aryl halides using Cu(I)
catalysis (Scheme 68) [390]. In a first screening several
ligands have been tested, resulting in the selection of 1,
2-diamino ligands 72 and 73. In further optimizations, dif-
ferent solvents and catalyst/ligand ratios have been studied,
reaching full conversion by using EtOH/H2 O as solvent mix-
ture, 10 mol% of CuI, 15 mol% of ligand 73, and irradiation
at 100 C for 30 min.
Chi-Ming Che and co-workers from the University of
Hong Kong have reported on the intra- and intermolecular
hydroamination of unactivated alkenes (Scheme 69) [391].
In a catalyst screening the phosphine Au(I) catalyst combina-
tions (PCy3 )AuCl/AgOTf and (PPh3 )AuCl/AgOTf, respec-
tively, showed the best catalytic activity. By applying micro-
wave heating not only were reaction times reduced (e.g.,
30 h 30 min) but also the amount of catalyst, compared
with conventional heating.
2.3 Other transition-metal-mediated processes
2.3.1 Ring-closing metathesis and cross-metathesis
Daniela Balan and Hans Adolfsson of Stockholm University
have demonstrated that functionalized 2,5-dihydropyrroles
can be obtained by microwave-mediated ruthenium-
catalyzed ring-closing metathesis (RCM) (Scheme 70) [392].
The required bis-olefin precursors 74 were conveniently
obtained from aza-BaylisHillman adducts. Microwave irra-

123
Mol Divers (2009) 13:71193 103

SH S

I R2 Cu nanoparticles R2
K2 CO3, DMF R1
or
+ or
MW, 120 C, 5-7 min S R3
R1
3
R SH
R1
R1 = H, OMe, NH2 , Me, NO 2 17 examples
OH, Br, "naphthyl" (61-98%)
R2 = H, Cl, Me, NH 2
R3 = Ph, alkyl
Scheme 67 Cu nanoparticle-catalyzed aryl-sulfur bond formation

Br NaN 3 , CuI, ligand
EtOH/H 2O
MW, 100 C, 30 min
NH 2
ligand screening:
OH
N CO 2H
N N
H H
NHMe
NHMe
MeHN
NHMe
72 73
Scheme 68 Cu(I)-catalyzed synthesis of aryl azides
diation for 12 min at 100 C of a dilute solution of the diene
with 5 mol% Grubbs II catalyst in dichloromethane (DCM)
produces the desired pyrroles 75 in high yield.
The group of Erik Van der Eycken at the University of
Leuven has employed microwave-enhanced SuzukiMiya-
ura cross-coupling and RCM as the key steps in the six-step
synthesis of so far unknown N -shifted buflavine analogs of
type 79 (Scheme 71) [393]. Particularly the generation of
the rigid, medium-sized ring system by RCM was enhanced
by employing microwave heating for 5 min at 150 C using
3 mol% Grubbs II catalyst.
In 2007 the same group has also reported on the synthesis
of ring-expanded (in addition to N -shifted) buflavine ana-
logs (Scheme 71) [394]. Key steps in both reaction pathways
are the Suzuki coupling of highly electron-rich aryl halides
76 with ortho-substituted boronic acids 77 followed by RCM
for the medium-sized ring construction. The N -shifted bufla-
vine derivatives 79, possessing an eight-membered ring, were
obtained by allylation of biaryls 78 and subsequent RCM
utilizing Grubbs II catalyst. For the preparation of the nine-
membered ring buflavine scaffolds 81, reductive amination
N3 was first performed on the biaryl aldehydes 80 followed by
RCM. The double bond in both derivatives 79 and 81 was
reduced by Pd-catalyzed hydrogenation to obtain the corre-
NH 2 sponding buflavine analogs (not shown).
100% conv
The combination of multicomponent chemistry, RCM,
and Heck coupling chemistry was highlighted by Martin for
the generation of diverse heterocyclic scaffolds following
the concept of diversity-oriented synthesis (DOS) (Scheme
S104) [395].
H Oliver Reiser and his group from the University of
Regensburg have reported on the RCM of a sterically deman-
ding substrate in the context of the total synthesis of tri-
cyclic 5.7.5-sesquiterpene lactones of the guaianolide type
(Scheme 72) [396]. Key to the success for the formation of
the tetrasubstituted double-bond system by RCM was the
combination of microwave heating and sparging an inert gas
through the solution in order to remove the formed ethylene.
An optimized 98% isolated product yield was obtained by
irradiating the bis-olefin precursor in the presence of 15 mol%
of Grubbs II catalyst in toluene for 90 min at reflux tempera-
ture (110 C), while passing a gentle stream of argon through
the solution. Importantly, under sealed vessel microwave
irradiation the RCM failed completely, and starting material
was recovered almost quantitatively.
Paramjit Arora and Ross Chapman from New York Uni-
versity were successful in the solid-phase synthesis of hydro-
gen-bond surrogate (HBS) -helices (artificial -helices
where the N-terminal H bond is replaced by a covalent CC
bond) including the RCM reaction as key step (Scheme 73)
[397]. Compared with conventional heating at 60 C, where
reaction times up to 72 h are required for maximum conver-
sion, under microwave irradiation the RCM could be accel-
erated to 25 min. Three different substituted 13-membered
macrocycles (82) and one 16-membered macrocycle were
obtained in high yields either at 120 C within 2 min when
Grubbs II (GII) catalyst is employed or at 200 C within 5 min
for the HoveydaGrubbs II (HGII). Importantly, in this HBS
approach GII produces the macrocycles in high yields com-
pared with conventional heating, where it showed to be inac-

123
104 Mol Divers (2009) 13:71193

(PCy3)AuCl/AgOTf O
H DCE
N
R1 N R1
MW, 140 C, 30 min
O

R1 = Ph, PhCO, p-Cl-Ph 3 examples

(57-60%)

(PPh3)AuCl/AgOTf
O O
DCE
S NH2 N S
MW, 140 C, 40 min H O
O

93%
+ 5 related examples
(50-97%)
Scheme 69 Phosphine Au(I)-catalyzed hydroamination of alkenes

O A za-Baylis-Hillman

3-HQD (15 mol%) O O allylbromide

Ar H S
Ti(Oi-Pr) 4 (2 mol%) NH K2 CO3, DMF
E R
O O + E
S 4 mol sieves Ar rt
R NH 2 i-PrOH, rt

O O O
O S
S Grubbs II, DCM
N R N
R
E MW, 100 C, 1-2 min
Ar Ar
E
74 75
7 examples
(78-95%)
Scheme 70 2,5-Dihydropyrroles via ring-closing metathesis

tive. Additionally, it was found that a greater variety of amino
acid residues is tolerated, which was also one of the limita-
tions using oil-bath heating.
For related RCM strategies in the solid-phase synthesis of
carbocyclic peptides, see Scheme S105 [398].
A RCM approach was also employed in the generation of
helicenes using Grubbs II catalyst (Schemes S106 and S107)
[399,400], and in the preparation of macrocyclic bispyridi-
nium salts (Scheme S108) [401]. Microwave-assisted RCM
processes have also been employed in the synthesis of com-
plex norbornenes (Scheme S109) [402].
In a 2005 publication Frdric C. Bargiggia and William
V. Murray from Johnson & Johnson Pharmaceuticals have
reported on cross-coupling metathesis between deactivated
olefins (Scheme 74) [403]. By applying microwave irradia-
tion, reaction rates could be enhanced compared to classical
heating, showing superior yields for the HoveydaGrubbs
catalyst 83 than for Grubbs II catalyst. No differences in
yields or selectivities in homo- or heterocouplings, respec-
tively, have been observed by comparison studies of micro-
wave and oil-bath heating.
Stephen Caddick and co-workers from University College
London were successful in the generation of peptidomimet-
ics via stereoselective cross-metathesis (Scheme 75) [404].
By applying Grubbs II catalyst in the reaction of two differ-
ent single amino acids, products which still have the length
of two amino acids but with a modified main chain (lack
of the amide bond) are obtained. This structural feature is
of interest with regard to protein folding and proteinpro-
tein interactions. Notably, for those products which needed
60 min reaction time, the reaction mixture was degassed after
30 min to remove any dissolved ethylene and subsequently
subjected to irradiation for additional 30 min.
For an example of cross-metathesis reactions used for the
construction of dicarba analogs of multicysteine-containing
peptides, see Scheme S110 [405].
Maurizio Botta and his group from the University of Siena,
Italy, have employed microwave-mediated ethylene-alkyne
cross-metathesis using Grubbs II catalyst for the synthe-
sis of enantioenriched 2-substituted butadienes (Scheme 76)
[406]. Importantly, microwave heating was essential for the
fast reaction of enantiomerically enriched alkynes with eth-
ylene (closed vessel saturated with ethylene) under reten-
tion of configuration at the propargylic/allylic position. At
atmospheric pressure no reaction was observed (see also
Scheme S111) [407].

123
Mol Divers (2009) 13:71193 105

OMe
MeO
OMe B(OH) 2 Pd(PPh 3) 4
MeO R2 NaHCO 3, H 2O, DMF
R1
+
R2
R1 MW, 150 C, 15min
Br
76 77
1
R = H, OMe 6 examples
R2 = NO 2, CHO, NHC(O)t Bu (82-93%)

OMe OMe
OMe OMe MeO

Grubbs II, toluene MeO

R1 R1
H
N N MW, 150 C, 5 min R1
N
O O
78 79 O
1
R = H, OMe 2 examples
(68-69%)

OMe OMe MeO

MeO 1. allylamine,TFA, MeO
toluene MeO
R1 MW, 175 C, 3 min R1 Grubbs II, toluene
CHO R1
MW, 150 C, 15 min N
2. Na(CN)BH 3, MeOH N Me
rt, 1.5 h Me
80 3. HCHO, rt, 1.5 h 81
1
R = H, OMe 2 examples 2 examples
(76%) (54-55%)

Scheme 71 Synthesis of N -shifted and ring-expanded buflavine analogues

Et 3 SiO HO O R* O R*
Me H 1. GII or HGII, DCB
H Grubbs II, toluene H 1' Me N Peptide MW,120-200 C, 2-5 min
N N
H
H H O R* O 2. TFA, TIPS, H2 O
MW, 110 C, 90 min rt, 90 min
O O "open vessel" O O
H H
then Bu 4NF R* = protected amino acid side chain
O O
R
98% (dr 1'S/1'R = 71:29) TIPS: triisopropylsilane Peptide
N
R N O H
Scheme 72 Ring-closing metathesis for guaianolide synthesis HN R

HN O

Cyclic -amino carbonyl derivatives were synthesized via 82

a cross metathesis-aza-Michael tandem process by Santos
Fustero and co-workers from Universidad de Valencia
(Scheme 77) [408]. Vinyl ketones are reacted with Cbz-pro-
tected amines to give pyrrolidines (n = 1) and piperidines
(n = 2), respectively, in good to excellent yields. Key to the
success of the reaction sequence was the combination of Hov-
eydaGrubbs (HG) catalyst and BF3 OEt2 as Lewis acid that
activates the cyclization step. By applying microwave heat-
3 examples
(69-84% conv)
Scheme 73 Synthesis of hydrogen-bond surrogate helices via ring-
closing metathesis
ing the reaction time could be dramatically reduced from
4 days (45 C) to only 20 min. Interestingly, under micro-
wave heating an inversion of the selectivity was observed

123
106 Mol Divers (2009) 13:71193

O DCM, catalyst 83 O
1 + 2 1
R R MW, 100 C, 15 min R R2

homo and hetero-cross coupling

R1 = OEt, Et, t-BuO, NH2, NMe2 11 examples

(<5-99%)
2
R = OEt OEt
, P
OEt
O O O O
COOEt, COEt, COOt-Bu, CONH2, CONMe2 Mes N N
Mes
Cl
Cl Ru
Me O

Me

83

Scheme 74 Cross-coupling metathesis between deactivated olefins

Grubbs II
O H
H DCM N R2
N + BocR1
BocR1 R2 MW, 80-100 C, 30-60 min O
10 examples
R1, R2 = amino acids (34-86%)

Scheme 75 Synthesis of peptidomimetics via cross-metathesis

R R
CH2 =CH 2
Grubbs II, toluene
or
MW, 80 C, 2 x 10 min
NHCOCH 3 NHCOCH3

R = H, 3-F, 4-F, 4-Cl, 3-Me

R R

or
NHCOCH3 NHCOCH3
10 examples
95-97% ee
(44-70%)
Scheme 76 Ethylenealkyne cross-metathesis

when -substituted amines 84 were used, giving pyrrolidine
derivatives 85 as major diastereoisomers.
Microwave-assisted cross-metathesis protocols have been
employed in the context of steroid chemistry (Scheme S112)
[409], and in the synthesis of -substituted prolines
(Scheme S113) [410].
Successful enzyme metathesis reactions of homopropar-
gylic homoallylic alcohols leading to functionalized vinylcy-
clopentenols have been reported by Lautens (Scheme S114)
[411]. Enyne metathesis was also used by Porco for the gener-
ation of polycyclic ring systems applying a diversity-oriented
synthesis (DOS) approach (Scheme S115) [412]. In addition
1,5-enyne metathesis transformations were extensively stud-
ied by Campagne for the synthesis of substituted cyclobut-
enes as valuable 1,3-diene units (Scheme S116) [413].
2.3.2 Carbonhydrogen bond activation
Jonathan Ellman and co-workers from the University of
California, Berkeley, have reported on the direct coupling
of azoles 86 with aryl bromides and iodides, respectively, by
Rh-catalyzed CH bond activation (Scheme 78) [414]. Supe-
rior yields could be obtained by using a mixture of the bulky
trialkylphosphines 87a and 87b as ligand compared with
PCy3 due to less hydrodehalogenation. A variety of func-
tional groups in para and meta position was tolerated and
the method was also compatible with different heterocycles.
In order to overcome problemssuch as substrate scope,
functional group tolerance, and practicabilityobserved
in previously published Rh-catalyzed arylations (see
Scheme 78), the groups of Robert Bergman and Jonathan Ell-

123
Mol Divers (2009) 13:71193 107

R2
HG catalyst
O 2 2 O R2
R R BF3 .OEt 2, DCM n
+ NHCbz R1
R1 N
n MW, 100 C, 20 min
Cbz
R1 = Me, n-Pr
7 examples
R2 = H, F
(55-96%)
n = 1, 2

O HG catalyst
BF3 .OEt 2, DCM
+ NHCbz

84 R MW, 100 C, 20 min

R = i-Pr, Ph, 4-MeO-Ph, CF3

O O
R + R
N N
Cbz Cbz
minor 85 major
4 examples
(81-97%)

Scheme 77 Tandem cross-metathesisintramolecular aza-Michael reaction

X [RhCl(coe) 2] 2, 87a,b N
N R
+ i-Pr 2i-BuN, 1,2-DCB
Y MW, 250 C, 40 min Y
R
86
coe: cyclooctene 20 examples
Y = N, O (45-91%)
X = Br, I
R = EW and ED Cy Cy
P P

87a 87b

Scheme 78 Rh-catalyzed arylation of heterocycles

N Rh cat/ligand, i-Pr2i-BuN, THF N

man from the University of California, Berkeley, have subse- + RBr R
quently developed a new protocol for the direct arylation of a X MW, 200 C, 2 h X
variety of heterocycles with aryl bromides employing phos- X = NH, NMe, O 32 examples
phepine ligand 88 (Scheme 79) [415]. This ligand proved to R = (het)aryl (28-100%)

be the most effective in a ligand screen and coordinates to Rh coe: cyclooctene Rh cat/ligand: [RhCl(coe)2]2 /88 or
cod: cyclooctadiene [RhCl(cod)]2/[88H]BF4
in a bidentate P-olefin fashion and thus generates an active
and temperature stable catalyst. For greater practicability of t-Bu
P
the protocol, the air-sensitive ligand 88 can be protected as ligand 88
its HBF4 salt and [RhCl(cod)]2 as air-stable Rh source can be
employed. Thus, reaction mixture preparation in a glovebox
is avoided and only an inert atmosphere in the microwave Scheme 79 Rh(I)-catalyzed arylation of heterocycles employing a
phosphepine ligand
vial is required. In addition, by using THF as low-boiling
solvent, product isolation is simplified.
Kenichiro Itami and co-workers from Nagoya Univer- 1,3-dimethoxybenzene were reacted with p-nitrophenyl
sity have developed Rh complex 89 as a catalyst precur- iodide. For arylated anisole a mixture of regioisomers was
sor for the CH arylation of heteroarenes with aryl iodides obtained (o: p = 29:71), whereas the latter was arylated regio-
(Scheme 80) [416]. Key to the success of the arylation is the specifically at the 4-position in 76% yield. For related exam-
use of P[OCH(CF3 )2 ]3 as ligand due to its strongly -accept- ples involving the CH arylation of heteroarenes involving
ing character. Various five-membered heteroarenes were Rh complexes, see Scheme S117 [417].
selectively arylated either at the 2- (X = S, O) or 3-position The same group recently reported that for electron-defi-
(X = N). To show the generality of this method, anisole and cient N -heterocycles coupling with haloarenes can be

123
108 Mol Divers (2009) 13:71193

Ag2CO3, Rh complex 89
R3 R2 R3 R2
DME, m-xylene
Ar
4 + ArI
R X H MW, 150-200 C, 30 min R4 X
R1 R1
X = S, N, O; for X = N, R1 = Ph 10 examples
R2 = R3 = R4 = H, Me, Et, OMe, thiophene (50-94%)
Ar = (het)aryl
Cl
[(CF3)2CHO]3P Rh P[OCH(CF3)2]3
CO
89

Scheme 80 Rh-catalyzed CH arylations of heteroarenes

NH 2 X NH 2
Pd(OH) 2 /C, CuI
N Cs 2CO3, NMP N
N N
+
N N MW, 160 C, 15-120 min N N R
Bn R Bn
X = I, Br, Cl 12 examples
R = OMe, Me, NH2, CN, NO2, CF3 (42-95%)
"naphthyl"
Scheme 81 Direct CH arylation of adenines

efficiently promoted by KOtBu alone, without the addition R2 Br

of any exogenous transition-metal species (Scheme S118)
[418].
Mouad Alami and co-workers from Universit Paris-Sud
have reported on the direct arylation of adenines under li-
gandless Pd(OH)2 /C catalysis (Scheme 81) [419]. Regiose-
lective coupling at the C8-position was obtained with a
variety of aryl iodides, bromides, and chlorides, although for
aryl chlorides a longer reaction time (12 h) was necessary
compared with the corresponding iodide or bromide deriv-
atives. Advantages of this general protocol are that there is
no need for protecting free NH2 -substituents and that CuI
is used in stoichiometric amounts. -(E)-Bromostyrene as
an example for vinyl halide coupling was also successfully
reacted, giving exclusively the E-isomer in 55% yield.
Along similar lines the Van der Eycken group has
described the Pd-catalyzed direct CH arylation of imidazo
[1,2-a] pyrimidines using aryl bromides (Scheme S119)
[420].
The Pd-catalyzed, Cu-mediated C-2 direct arylation of
5-substituted oxazoles with aryl bromides was disclosed by
Sandrine Piguel and co-workers from the Institut Curie/
CNRS (Scheme 82) [421]. This method shows a high func-
tional group tolerance and in addition the reaction times can
be reduced from hours to minutes when employing micro-
wave heating. In particular, electron-poor oxazoles need only
very short reaction times of 48 min to give the 2,5-diaryl-
oxazoles in higher yields.
The groups of Hideki Yorimitsu and Koichiro Oshima
from Kyoto University have disclosed Pd-catalyzed direct
arylations of 1,4-disubstituted triazoles with aryl chlorides
Pd(OAc) 2 /CuI
N K2 CO3, DMF N
R1 O R1 O R2
MW, 150 C, 4-30 min
R 1 = aryl 17 examples
R 2 = (het)aryl (57-81%)
Scheme 82 Direct CH arylation of oxazoles
(Scheme 83) [422]. Slightly longer reaction times (20
30 min) were required in order to achieve high product yields
when hexyl-substituted triazoles (R1 = n-C6 H13 ) are
employed as precursors. Interestingly, when tricyclohexyl-
phosphine [P(Cy)3 ] is used as ligand, aryl chlorides were
superior compared with aryl bromides and iodides. A solvent
mixture of toluene:DMF (5:1) is crucial for the outcome of
the reaction, since pure toluene cannot be heated to 250 C,
whereas pure DMF afforded the products in lower yields. It
has to be noted that, when performed under identical con-
ditions, this reaction is nearly quantitative under microwave
heating, whereas almost no outcome was observed under con-
ventional conditions.
A protocol for the Pd-catalyzed fluorination of CH bonds
was developed by the group of Melanie S. Sanford at the Uni-
versity of Michigan (Scheme 84) [423]. This reaction pro-
ceeds via a Pd(OAc)2 -catalyzed CH activation/oxidative
fluorination step where an electrophilic fluorinating reagent
(90 or 91) is necessary for successful aromatic and ben-
zylic CF bond formations. Compared with thermal heating,

123
Mol Divers (2009) 13:71193 109

N Pd(OAc)2 , P(c-C6 H 11 )3 , K2CO3 N 2

2
N N R toluene:DMF (5:1) N N R
+ ArCl
R1 MW, 250 C, 15-30 min R1 Ar

17 examples
R 1 = Ph, n-C6 H 13 , 4-pyridyl,
(40-100%)
4-tolyl, HO
Bu
Bu
R 2 = Bn, 4-tolyl
Scheme 83 Direct CH arylation of substituted triazoles

R1 R1

N N
Pd(OAc)2 , 90 or 91
H benzene or MeCN/CF3C 6H 5 F
or or
MW, 100-150 C, 1-4 h
R2 R2

N N
R3 R3 F

R1 = Me, F, Br 11 examples
N N
R2 = 2-F, 2-Me, 2-OMe, 2-CF3 (33-75%)
F BF4 F BF4
2-Cl, 3-CF3 , 3-CO 2Et
R3 = H, OMe 90 91

Scheme 84 Pd-catalyzed CF-couplings

higher yields could be achieved with microwave irradiation
due to shorter reaction times.
Bedford and Betham have disclosed a Pd-catalyzed
one-pot process for the synthesis of carbazoles from 2-chlo-
roanilines and aryl bromides that relies on consecutive ami-
nation and CH activation chemistry (Schemes S120 and
S121) [424,425]. A somewhat related approach was chosen
by Maes to generate 9H --carbolines from 2,3-dichloropyri-
dines and substituted anilines (Scheme S122) [426].
A selective sp2 and benzylic sp3 Pd-catalyzed arylation
in the picoline N -oxide series has been disclosed by Fagnou
(Scheme S123) [427].
2.3.3 Cu-catalyzed azide-acetylene cycloaddition (CuAAC)
The Kappe group has exploited a microwave-assisted ver-
sion of the Cu(I)-catalyzed azide-acetylene ligation process
(CuAAC, click chemistry) for the preparation of 6-(1,2,3-
triazol-1-yl)-dihydropyrimidones (Scheme 85) [428]. Here a
suitable heterocyclic azide intermediate (obtained by micro-
wave-assisted azidation) was treated with phenyl acetylene
in N ,N -dimethylformamide, employing 2 mol% Cu(II) sul-
fate/sodium ascorbate as catalyst precursor. After comple-
tion of the cycloaddition process the triazole product can
be precipitated in high yield (73%) and purity by addition
to ice/water. For the model reaction displayed in Scheme 85
full conversion at room temperature required 1 h. By carrying
out the same reaction utilizing controlled microwave heating
at 80 C, complete conversion was achieved within 1 min. A
library of 27 6-(1,2,3-triazol-1-yl)-dihydropyrimidones was
prepared with four points of diversity.
For certain substrates, Fokin, Van der Eycken, and
co-workers discovered that the azidation and ligation step
can be carried out in a one-pot fashion, thereby simplify-
ing the overall protocol [429]. This procedure eliminates the
need to handle organic azides, as they are generated in situ.
Similarly, triazoles can be obtained directly from amines
in one pot using Cu(II)-catalyzed diazo transfer with trifluo-
romethanesulfonyl azide, coupled with the Cu(I)-catalyzed
CuAAC reaction (Scheme S124) [430]. An alternative in situ
method for azide generation uses the reagent combination
t-BuONO and TMS-N3 (Scheme S125) [431].
The Lipshutz group has shown that copper-in-charcoal
(cf. Scheme 64) is an effective catalyst for CuAAC chemis-
try under microwave conditions (Scheme S126) [432].
The synthesis of 1,2,3-triazoles via Ru-catalyzed aryl
azide-alkyne cycloadditions was described by the group of

123
110 Mol Divers (2009) 13:71193

O Ph O Ph
NaN 3, DMF
EtO NH EtO NH
Br MW, 60 C, 20 min N3
N O N O
H H

O Ph
Ph H Et
CuSO 4, Na ascorbate, DMF O NH
N
N N N O
MW, 80 C, 1 min H
Ph 73%
Scheme 85 Cu(I)-catalyzed azide-acetylene ligations (click chemistry)

R1 R1
N3 [Cp*RuCl]4, DMF N N
+ R2 N
MW, 110 C, 20 min
R2
15 examples
R 1 = H, Me, OMe, Cl, I, COOEt
(43-92%)
R 2 = alkyl, hetaryl

[Cp*RuCl]4: pentamethylcyclopentadienyl ruthenium(II) chloride tetramer

Scheme 86 Ru-catalyzed aryl azidealkyne cycloaddition

R3
O Rh 2 (Oct)4, CHCl 3 O
N N N
N S R2 + N R3 N S R2
MW, 140 C, 15 min
R1 O R1 O

R 1 = aryl, Bn 15 examples
R 2 = aryl (42-88%)
R 3 = aryl, alkyl, alkenyl
Scheme 87 Rh-catalyzed transannulation of 1,2,3-triazoles

Valery Fokin from the Scripps Research Institute (Scheme 86)
[433]. In comparison to the Cu(I)-catalyzed azide-alkyne
cycloaddition where 1,4-disubstituted triazoles are obtained
(see Scheme 85), the Ru-catalyzed version produces 1,5-
regioisomers of 1,2,3-triazoles. [Cp*RuCl]4 proved to be
superior in activity over the original Cp*RuCl(PPh3 )2 cat-
alyst and, in combination with microwave heating higher
yields, cleaner products and shorter reaction times were
accomplished. By-product formation and lower yields were
noticed under conventional heating conditions in an oil
bath.
For an application of the Ru-catalyzed azide-alkyne cyclo-
addition reaction in carbohydrate chemistry, see Scheme
S127 [434].
In subsequent work, the groups of Vladimir Gevorgyan
and Valery Fokin from the University of Illinois and the
Scripps Research Institute have reported on the synthesis
of imidazoles via the transannulation of 1-sulfonyl triazoles
with nitriles using Rh(II) octanoate as catalyst (Scheme 87)
[435]. When applying microwave heating no inert atmo-
sphere is necessary, in contrast to performing the reactions
under conventional heating at 80 C wherein addition
longer reaction times of 1224 h are needed. Furthermore,
the authors were successful in combining the synthesis of
1-sulfonyl triazolesvia the Cu(I)-catalyzed cycloaddition
of sulfonyl azides with alkynesand the transannulation in
a one-pot two-step sequence.
Applications of the CuAAC reaction in the carbohydrate
(Schemes S128 and S129) [436,437], glycodendrimer
(Scheme S130) [438], cyclodextrin (Scheme S131) [439],
glycocyclodextrin (Scheme S132) [440], porphyrine (Scheme
S133) [441], and nucleic acid field (Scheme S134) [442] have
been reported. For the preparation of triazol oligomers using
this approach, see Scheme S135 [443]. The use of chiral acet-
ylene building blocks in the CuAAC reaction has also been
described (Scheme S136) [444].

123
Mol Divers (2009) 13:71193 111

R2
R1 MeO 2C
MeO 2 C R2
MeO 2C R1
MeO 2 C

92 2 examples
(72-90%)
catalyst 94 or 95, DCM
or or
R 3 MW, 50-80 C, 0.5-30 min
MeO 2 C MeO 2C
R3
MeO 2 C MeO 2C
R2 R1 R2
93 1
R 7 examples
t -Bu t-Bu
SbF6 (81-93%)
R 1, R2 = H, Me, Ph P Au NCMe
R 3 = H, NO2 , CN, OMe

94
t-Bu

t-Bu O P AuCl /AgSbF 6

3
95

Scheme 88 Au(I)-catalyzed intramolecular [4 + 2] cycloadditions

2.3.4 Miscellaneous reactions Ts H Ts

N 1. ZnMe 2 , TMSCCH, toluene N

The intramolecular [4 + 2] cycloaddition of alkenyl-(92) and R H 2. TBAF, THF R

aryl-substituted 1,6-enynes 93 was described by the group of
Antonio Echavarren from the Institute of Chemical Research R = 4-MePh, 2-BrPh, 2-naphthyl, 2-f uryl, c-Hex, t-Bu
of Catalonia (ICIQ), Spain (Scheme 88) [445]. The transfor-
mations proceed via catalysis involving cationic Au(I)-com-
[CpRu(Naphth)]PF 6
plexes and furnish bicyclic products from 92 and tricyclic H Ts
ligand, H 2O, acetone N O
derivatives from 93. Heating under microwave conditions
leads to reduced reaction times (hours versus minutes) and MW, 90-115 C, 15-30 min R H
improved yieldsprecatalyst 95 proved to be more reac- 6 examples
tive than 94, especially under room temperature conditions. (73-94%)
Ph
Substrates 93 with m-substituents at the aryl moiety gave
mixtures of regioisomers, whereas other minor by-product Ph2 P N
formation was observed via a 6-endo cyclization path-way.
Ph Ph
The Au-catalyzed rearrangement of allylic acetates was ligand
described by Steven P. Nolan from the same institute
(Scheme S137) [446]. Scheme 89 Synthesis of -amino aldehydes
The synthesis of N -protected -amino aldehydes via an
alkynylation/anti-Markovnikov alkyne hydration sequence Chi-Ming Che and co-workers from the University of
was developed by the groups of Lukas Hintermann and Car- Hong Kong have developed a method for the synthesis of
sten Bolm from RWTH Aachen University (Scheme 89) substituted 1,2-dihydroquinolines and quinolines under Au
[447]. By performing the Ru-catalyzed hydration under catalysis (Scheme 90) [449]. The reaction of anilines 96 with
microwave heating the reaction times could be reduced from alkynes 97 employing the Au(I) catalyst 98/AgOTf combi-
several hours at 55 C to a maximum of 30 min. Addition- nation afforded the corresponding dihydroquinolines 99 via
ally, for most of the derivatives the catalyst loading could be a tandem hydroaminationhydroarylation sequence. By uti-
reduced to 5 mol%, compared with thermal heating, without lizing the proper substituted alkynes 97, products contain-
any decrease in yields. ing multiple alkyne groups can be obtained as well. Under
In related work, the Rh-catalyzed hydrophosphinylation similar conditions, quinolines 101 can be synthesized when
of ethynyl steroids was disclosed by Stockland (Scheme alkynes are reacted with o-acetyl or o-benzoyl substituted
S138) [448]. anilines 100.

123
112 Mol Divers (2009) 13:71193

R1 Au(I) catalyst 98, AgOTf R1 H

NH 2 N
NH 4PF6, MeCN R2
+ R2
MW, 150 C, 25-70 min
96 97 R2
99
R1 = H, OMe, Me, F, Cl, 15 examples
"naphthyl" (42-89%)
R2 = aryl, alkyl N N
R3 = Me, Ph
Au
Cl
98

NH2 Au(I) catalyst 98, AgOTf N R2

NH4 PF6, MeCN
R3 + R2
MW, 150 C, 30 min
O 3
100 101 R
9 examples
(65-94%)
Scheme 90 Dihydroquinoline and quinoline synthesis via tandem hydroaminationhydroarylation

O R
1. (S)-proline (0.5-1 mol%), DMSO OH
O R
+ + MW, 46-49 C, 3-4 h N
H H H
H2N 2. NaBH4
3 examples
R = H, OMe, i-Pr (83-86%; 94-98% ee )

Scheme 91 Asymmetric Mannich reactions

The same group has also disclosed related inter- and intra-
molecular hydroaminations of alkenes using Au catalysis
(Scheme S139) [450], and intermolecular hydroarylations of
alkenes with indoles (Scheme S140) [451]. Late transition
metals have been shown to be efficient catalysts in the
intramolecular hydroamination of C-propargyl vinylogous
amides into pyrroles (Scheme S141) [452].
For a study on Ru-catalyzed isomerizations of alkenols to
alkanones, see Scheme S142 [453]. A Ru-catalyzed cycloiso-
merization of 1,6-dienes has also been described (Scheme
S143) [454]. Pd-catalyzed bisdiene cyclizations have been
reported by Takacs (Scheme S144) [455]. The Pd-catalyzed
regioselective cyanothiolation of alkynes with thiocyanates
has been described by Chung (Scheme S145) [456]. For
examples of Cu(II)-promoted intramolecular carboamina-
tions of olefins, see Scheme S146 [457].
2.4 Organocatalytic transformations
Carsten Bolm and Beln Rodrguez from the University of
Aachen investigated thermal effects in the (S)-proline-cat-
alyzed Mannich reaction (Scheme 91) [458]. By applying
microwave heating with simultaneous cooling, reaction times
and, most importantly, catalyst loadings could be reduced.
Similar results were also achieved by heating in an oil bath for
23 h at the same temperature (4550 C). The corresponding
reduced aminoalcohols could be obtained in excellent yields
and ees.
Sarah Moss and Alexandre Alexakis from the Univer-
sity of Geneva have reinvestigated asymmetric aldol (a),
Mannich (b), and DielsAlder reactions (c) applying organ-
ocatalysis under microwave conditions (Scheme 92) [459].
L-proline (a), N -i-Pr-2R, 2 R-bipyrrolidine [(R, R)-iPBP]
102 (b), and McMillan imidazolidinone 103 (c) were used as
organocatalysts. In all cases the reaction times were reduced
dramatically using microwave heating. Additionally, for the
aldol (a) and Mannich reaction (b) catalyst loadings could be
decreased maintaining the enantioselectivities achieved by
conventional rt experiments.
In a related study, the group of Stefan Brse from the
University of Karlsruhe has performed optimization studies
toward solvent, time, temperature, and catalyst loading for

123
Mol Divers (2009) 13:71193 113

(a)
O O O OH
L-proline, DMSO
+
H Ar Ar
MW, 31-35 C, 15-60 min
5 examples
(38-70%; 64-70% ee)

(b) O
Ph O Ph
(R, R)-i PBP (102), CHCl3
R1 + 1 NO 2
MW, 27-28 C, 1-4 h R
NO2
R2 R2
R 1 = H, Me 3 examples
R 2 = OH, i-Pr, (Me)2 (76-97%; 77-98% ee)
N N
H
102

(c)
MeOH/H 2O, 103
Ph Ph +
+ CHO MW, 65-90 C, 0.5-1 h CHO
CHO Ph
O endo exo
N 79-82%; 78% ee
N
Ph H
.HCl
103

Scheme 92 Organocatalyzed asymmetric reactions

O O MeCN, L-proline
O +
2.5 Rearrangement reactions
R O N N O MW, 60 C, 30 min
2.5.1 Claisen rearrangements
R = H, aryl
CO2 Et
N -Chiral aldehydes were obtained by Trost with minimum
O NH
R CO2Et
loss of chirality by Claisen rearrangement of allyl vinyl ethers
at 140 C within 15 min (Scheme S149) [463]. For a descrip-
9 examples
(54-97%; 52-90% ee) tion of a decarboxylative Claisen rearrangement, see Scheme
S150 [464]. For Claisen rearrangements carried out in ionic
Scheme 93 Synthesis of ,-disubstituted amino aldehydes
liquids, see Scheme S151 [465]. Aza-Claisen rearrangements
under microwave conditions have been discussed by Gonda
(Scheme S152) [466].

the microwave-mediated organocatalytic asymmetric -ami-

nation of disubstituted aldehydes with diethyl azodicarboxyl-
ate (Scheme 93) [460]. Optimum conditions in terms of both
high yield and enantioselectivity proved to be MeCN as sol-
vent, 50 mol% of L-proline as catalyst, reaction temperature
of 60 C, and 30 min reaction time. Importantly, the reaction
time could be decreased from several days to only 30 min by
applying microwave heating compared with room-temper-
ature conditions, with a concomitant increase in yield and
enantioselectivity. In particular, improvements for otherwise
unreactive starting materials bearing electron-withdrawing
R-groups (e.g., F, NO2 , CF3 ) were observed.
For other examples of microwave-assisted organocatalyt-
ic transformations, see Schemes S147 and S148 [461,462].
A detailed study on microwave effects in these reactions has
been published [209].
2.5.2 Domino/tandem Claisen rearrangements
The base-catalyzed intramolecular cyclization of appropri-
ately substituted 4-alkyn-1-ols, followed by in situ Claisen
rearrangement was investigated by Ovaska and co-work-
ers (Scheme 94) [467]. The tandem cyclization-Claisen rear-
rangements were best carried out in DMF or phenetole as
solvent in the presence of 10 mol% MeLi base. In most cases,
the resulting cycloheptanoid ring systems were produced in
high yields in a matter of minutes upon microwave irradiation
at 150200 C. Some of the reactions were also performed
under solvent-free conditions providing similar isolated prod-
uct yields. Several other bicyclo[5.3.0]decane ring systems
were also available from relatively simple acetylenic alcohols
using this strategy.

123
114 Mol Divers (2009) 13:71193

MeLi (or KOt Bu)

DMF or PhOEt or neat H
OH
MW, 150-200 C, 4-30 min
H H O
82%
+ 8 related examples
(65-93%)
Scheme 94 Tandem cyclization/Claisen rearrangements

Me Me
Me OH
O
[3,3] Br
Br Me
Ph3PO, o-xylene
BocO
BocO OH
O MW, 180 C, 20 min
Me BocO
BocO
104 Me
Me Me

OH OR
Me OH Br
Br Me Me
Me formal Me Me
[2+2] OH OMe
HO
OH

HO
HO Me Me HO Me Me
Me Me
HO 105, 55% HO
R = H: artochamin H
R = Me: artochamin I

Me OH OMe

Me Me
HO Me
OH O
Me
HO Me

Me Me HO
artochamin J
artochamin F HO

Scheme 95 Cascade reactions in the total synthesis of artochamins F, H, I, and J

For related cyclizations published by the same group, see
Scheme S153 [468].
K. C. Nicolaou and his group from the Scripps Research
Institute have performed the total synthesis of artochamins
F and HJ applying microwave heating for the key step
(Scheme 95) [469]. After synthesizing stilbene 104, the art-
ochamin skeleton 105 was obtained via a cascade sequence
that required catalytic amounts of Ph3 PO. The cascade reac-
tion incorporated two consecutive Claisen rearrangements,
collapsing of the Boc groups and a formal [2+2] cycloaddi-
tion. Further chemoselective protection of 105 with subse-
quent methylation afforded artochamins H and I and
artochamin J by generation of a benzopyran scaffold. If the t-
butyldimethylsilyl (TBS)-protected stilbene 104 is employed
under the same conditions but without Ph3 PO, the cascade
reaction stops after the Claisen rearrangements, indicating
the need of the unprotected hydroxyl groups for the formal
[2+2] cycloaddition. After debromination and TBS depro-
tection, artochamin F was obtained in 92% yield.
Matthew J. Pelc and Armen Zakarian from Florida State
University have reported on the synthesis of A,G-spiroimine
106 of pinnatoxins (Scheme 96) [470]. Key step in this proce-
dure is a cascade sigmatropic route that integrates the
Claisen and MislowEvans rearrangements. By applying

123
Mol Divers (2009) 13:71193 115

PvO PvO
O
P(EtO)3 , s-collidine
Me(OCH 2CH 2) 2OH
PMBO R OH
O S
MW, 170 C, 20 min
O PMBO
O O
O O
R = p-tolyl 82%

steps A
N
G
OAc

PMBO O
O
106
Scheme 96 Tandem ClaisenMislowEvans rearrangement

Br H
O N + NH2
_
N HN NH Cl H2O
H
H H _
MW, 195 C, 1 min
N N NH Cl
NH2
O N +
Br sceptrin H _
H2N + Cl
Br NH
O HN

HN H
N
N +
H
NH
H _
N Cl
N HN H

O ageliferin
Br
40% (+ 52% s.m.)
Scheme 97 Vinyl cyclobutane rearrangements in total synthesis

microwave heating at 170 C, the reaction time could be
reduced to 20 min compared with 15 h under conventional
heating at 150 C.
A combined microwave-assisted Mitsunobu reaction/
Claisen rearrangement has been reported by Moody (Schemes
S154 and S155) [471,472]. A microwave transformation
involving a tandem HornerWadsworthEmmons olef-
ination/Claisen rearrangement/hydrolysis sequence has
been disclosed by Taylor (Scheme S156) [473]. Pyrroles have
been obtained via an imine condensation/aza-Claisen rear-
rangement/imine-allene cyclization process (Scheme S157)
[474].
2.5.3 Vinylcyclobutanecyclohexene rearrangements
A publication by the group of Phil S. Baran from the Scripps
Research Institute reports the total synthesis of ageliferin, an
antiviral agent with interesting molecular architecture
(Scheme 97) [475]. One minute of microwave irradiation
of sceptrin, another natural product, for 195 C under sealed
vessel conditions provides ageliferin in 40% yield, along with
52% of recovered starting material. Remarkably, if the reac-
tion is performed without microwaves at the same tempera-
ture, only starting material and decomposition products are
observed.

123
116 Mol Divers (2009) 13:71193

R2 DCB
O for 16 h then extraction, removal of solvent, and subse-
R3 CHO 2
R N
N MW, 200-220 C
R1 75 min - 16 h R1
R4
"open vessel"
8 examples
R1 , R 2 = H, Me, Ph (39-87%)
R3 , R 4 = Me, Bn, Ph, "morpholine"
Scheme 98 Stereoselective synthesis of Z -dienes
2.5.4 Miscellaneous rearrangements
Christopher Vanderwal and his group from the University
of California, Irvine, have discovered a new method for the
stereoselective synthesis of Z-, , , -unsaturated amides
(Scheme 98) [476]. Riecke aldehydes (5-amino-2,4-penta-
dienals) rearrange thermally to the corresponding , , , -
unsaturated amides via a pericyclic cascade process.
Excellent Z -selectivity (>20:1) is observed in most of the
cases. Preliminary experiments indicated that the rearrange-
ment rates could be increased by addition of small amounts
of camphorsulfonic acid.
A protocol for the synthesis of substituted pyridines was
disclosed by Barry Trost and Alicia Gutierrez from Stanford
University (Scheme 99) [477]. Ru-catalyzed cycloisomeriza-
tion of primary and secondary propargyl diynols 107 at room
temperature afforded unsaturated ketones and aldehydes 108,
respectively. The , , , -unsaturated aldehydes and
ketones 108 are subsequently reacted with hydroxylamine
hydrochloride to the corresponding pyridines via 1-azatriene
intermediates which undergo an electrocyclizationdehydra-
tion sequence. This last step can be either performed in a one-
pot format for aryl- or unsubstituted aldehydes or ketones
(108, R2 = H, Ph) applying microwave irradiation, or in a
two-step protocol for isopropyl-substituted aldehydes and
ketones (addition of NH2 OH HCl, NaOAc, MeOH, reflux
R3 quent microwave irradiation of the oxime at 220230 C for
40 min4.25 h).
R4
The groups of Domingo Gomez Pardo and Janine Cossy
from ESPCI-ParisTech, France, were successful in the stere-
oselective rearrangement of -amino alcohols via an azirid-
inium intermediate under catalytic conditions (Scheme 100)
[478]. Linear N ,N -dibenzyl -amino alcohols 109 and
N -benzyl prolinol 110 rearranged to -amino alcohols 111
and 3-hydroxypiperidine 112, respectively, by treatment with
0.2 equiv trifluoroacetic anhydride followed by saponifica-
tion with 0.3 equiv NaOH in high yields and excellent ees.
Compared with the traditional method, in which stoichiom-
etric amounts are employed, Et3 N can be omitted from the
procedure. See also Scheme S158 [479].
A re-evaluation of the NewmanKwart rearrangement
under microwave conditions was carried out by Jonathan
D. Moseley and co-workers from AstraZeneca, Bristol
(Scheme 101) [480]. Comparisons of results obtained by
microwave and thermal heating showed no significant differ-
ence, which excluded any microwave effects. Additionally,
a solvent rate effect has been confirmed under both micro-
wave and thermal heating, demonstrating the stabilization
of the polar transition-state intermediate 113 by polar sol-
vents such as formic acid (78% compared with 23% conv.
with N -methyl-2-pyrrolidone (NMP) after 30 min at
140 C).
Microwave irradiation has been used successfully to carry
out Cope rearrangements leading to spiroindane frameworks
[221], Caroll rearrangements (Scheme S159) [481], and var-
ious 6 -electrocyclizations (Scheme S160) [482]. Nazarov
cyclizations have been carried out in ionic liquids in very
short reaction times (Scheme S161) [483]. For examples of
Nazarov cyclizations proceeded by FriedelCrafts acylations
leading to 1-indanones involving arenes and ,-unsaturated
acid chlorides, see Scheme S162 [484]. Alder-ene-type cycli-

O
R1 [CpRu(CH3 CN)3 ]PF6
X OH X R1
acetone, water, rt
R2
107 108 R2
X = C(CO2Me)2 ,C(COMe)2 , O 11 examples
(54-80%)
R 1 = H, Me
R 2 = H, i-Pr, Ph
OH R1
N
NH 2OH.HCl
NaOAc, EtOH R1 N
X X
MW, 150 C, 1-1.5 h R2

R2 3 examples
(75-99%)
Scheme 99 Synthesis of pyridines via a cycloisomerization-6 -cyclization sequence

123
Mol Divers (2009) 13:71193
Bn2N OH
1 1
R 109 1. (CF3 CO)2 O, THF
MW, 180 C, 2 h
or
2. NaOH
OH
N N
Bn
110
R1 = alkyl
Scheme 100 Synthesis of -amino alcohols
O NMe2
S MW, 180-295 C, 20 min
R
R = H, 2-NO2, 3-NO2, 4-NO2, 4-CN, 4-CO2Me, 4-CF3, 2-naph, 4-Br,
4-Cl, 4-Me, 4-F, 4-MeO,3-MeO, 2-MeO
O N
S
R 113
Scheme 101 NewmanKwart rearrangements
zations of enallenes have also been reported under microwave
conditions (Scheme S163) [485]. Phosphonylated isoindoles
have been obtained by rearrangement of o-ethynylbenzyl
-aminophosphonates (Scheme S164) [486]. Morphine has
been rearranged to apomorphine in the presence of MeSO3 H
(Scheme S165) [487].
2.6 Cycloaddition reactions
A one-pot DielsAlder/acylation (or vice versa) sequence for
the synthesis of isoquinol-1-one-8-carboxylic acids 114 has
been developed by the group of Jeffrey Aub from the Uni-
versity of Kansas (Scheme 102) [488]. A set of six dienes
containing an attached secondary amine functionality were
reacted with maleic anhydride (R2 = H) or citraconic anhy-
dride (R2 = Me) at 165 C for 1.5 h to afford the isoquino-
lone products 114 in one step. In addition, the synthesis of
the aminodiene precursors was performed under microwave
conditions as well by displacement of a mesylate with the
corresponding primary amine at 130 C within 1 h in MeCN.
The six carboxylic acid scaffolds obtained by the reaction
with maleic anhydride were further reacted with 12 diverse
amines to generate a 72-member isoquinolone-amide library;
however, this step was performed at room temperature.
117
HO NBn 2
5 examples
(87-98%)
R 111 (up to 99% ee)
or
OH
87%
Bn
112
NMP
S NMe2
O
R
15 examples
(72-99% conv)
Christopher J. Moody and co-workers have employed a
biomimetic hetero-DielsAlderaromatization sequence for
the construction of the pyridine ring in amythiamicin D
(Scheme 103) [489]. The key cycloaddition reaction between
the azadiene and enamine component was carried out by
microwave irradiation at 120 C for 12 h and gave the required
2,3,6-tris(thiazolyl)pyridine intermediate in moderate yield.
Coupling of the remaining building blocks then completed
the first total synthesis of the thiopeptide antibiotic amythi-
amicin D.
The group of Samuel Danishefsky from Columbia
University has reported on an oxidative dearomatization/
transannular DielsAlder sequence as key step in the total
synthesis of ()-11-O-debenzoyltashironin (118) (Scheme
104) [490]. Upon exposure of 115 to a hypervalent iodine
species such as phenyliodine(III) diacetate (PIDA), a mix-
ture of oxidized intermediate 116 and DielsAlder adduct
117 was obtained; however subsequent microwave irradia-
tion of this mixture leads exclusively to the cycloadduct 117
in 65% yield. A following series of deprotections and diaste-
reoselective oxidation steps furnished 11-O-debenzoyltashi-
ronin (118).
The microwave-assisted sidewall functionalization of sin-
gle-wall carbon nanotubes (SWNT) via DielsAlder cyclo-
123
118
2
O
R
+ O
MW, 165 C, 1.5 h
O
NH
R1 = alkyl, cyclic
R1
R = H, Me
DCM
acylation
MW, 165 C
1.5 h
R2
CO2H
O O
N N
R1
Scheme 102 Tandem DielsAlder/acylation sequence
addition with o-quinodimethane has been demonstrated by
Fernando Langa and co-workers from Spain (Scheme 105)
[491]. The required o-quinodimethane was generated in situ
from 4,5-benzo-1,2-oxathiin-2-oxide (sultin) by refluxing in
1,2-dichlorobenzene under open-vessel microwave-irradia-
tion conditions. In the presence of ester-functionalized
SWNTs, cycloadditions takes place within 45 min. Conven-
tional refluxing in 1,2-dichlorobenzene for 3 days leads only
to a low degree of conversion.
Multiwalled carbon nanotubes (MWNT) have been
functionalized using 1,3-dipolar cycloaddition chemistry
(Schemes S166 and S167) [492,493].
DielsAlder reactions involving 2-oxazolidinone dienes
have been reported by Tamariz (Scheme S168) [494].
Xanthones have been prepared by microwave-assisted Diels
Alder reaction of 3-styrylchromones with suitable dieno-
philes (Scheme S169) [495]. Polycyclic oxygen heterocycles
have been obtained by intramolecular DielsAlder cycload-
dition of N -propargyl-N -2-furfurylamines (Scheme S170)
[496], and from 1,3,8-nonatrienes (Scheme S171) [497]. For
examples of aza-DielsAlder reactions leading to 1,3-oxa-
zines (Scheme S172) [498] or polyheterocycles, see Scheme
S173 [499]. Tandem Wittigintramolecular DielsAlder cyc-
loadditions have been used by Dai for the construction of
bicyclic lactones (Scheme S174) [500]. Tandem domino
Knoevenagel DielsAlder strategies have been used for the
preparation of bis-pyrano-1,4-benzoquinones (Scheme S175)
[501]. Anilines have been prepared by DielsAlder addi-
tion of acetylenes to 3-amino-substituted 2H -pyran-2-ones
123
Mol Divers (2009) 13:71193
Diels-Alder
R2 O
DCM O
H O
HN
2
R1
acylation
R2
CO2H
Diels-Alder
H
H
R1
114
7 examples
(54-80%)
(Scheme S176) [502]. Regioselective cycloaddition reactions
between 9-substituted anthracenes and levoglucosenone have
been studies by Suarez (Scheme S177) [503]. Acetylketene
can be generated by microwave-assisted retro-DielsAlder
reaction from 2,2,4-trimethyl-4H -1,3-dioxin-4-one precur-
sor, and has been trapped in situ by a range of alcohols,
aldehydes, and ketones (Scheme S178) [504].
Steven V. Ley and his group from the University of Cam-
bridge have shown that a variety of oligomeric alkynes cyclo-
trimerized in a [2+2+2] manner to the corresponding arenes
without the need of any metal catalyst if microwave heating
is used (Scheme 106) [505]. Furthermore, a flow process was
applied for one example, pumping the sample through a glass
coil in the microwave cavity.
Co, Ni, and Ru-catalyzed [2 + 2 + 2] cyclotrimerization
reactions on both solid phase (Schemes S179 and S180) [506,
507] and solution phase (Schemes S181S183) [508510]
have been described by Deiters and co-workers. Martinez has
disclosed similar transformations mediated by an Ir catalyst
(Scheme S184) [511], whereas the Kotera group has applied
a Rh catalyst in cyclotrimerizations involving 1-alkynyl-2-
deoxyribofuranose (Scheme S185) [512].
For Co2 (CO)8 -mediated intramolecular cycloadditions of
dienynes and related precursors, see Schemes S186S188
[513515].
The groups of Fernando Cossio and Angel Daz-Ortiz
from Universidad de CastillaLa Mancha, Spain, have made
investigations toward the stereochemical outcome for the
[3 + 2] cycloaddition of stabilized azomethine ylides and
Mol Divers (2009) 13:71193 119

S
CO2Me
N
BnO2C N EtO N toluene
+
NHAc
S MW, 120 C, 12 h
N
S
N
S
S CO2Me
BocHN N
O O
S N N
CO2Me
N MeHN NH S
BnO2C N N
N S
steps N S
S Me
O S
N N
S amythiamicin D
HN
N S HN
33 % H
S N N O
BocHN
O

Scheme 103 DielsAlder cycloaddition chemistry in natural product synthesis

OH O
OBn
OBn
PIDA, DCM O
HO
rt, 2 h
OTs OTs
115 116
PIDA: phenyliodine(III) diacetate
O
HO
H
O OBn
O OH
MW, 600 W, 4 min
OTs
O
117, 65% 118
Scheme 104 Oxidative dearomatization/transannular DielsAlder cascade

O less of which the cycloaddition is conducted under micro-

S
wave or conventional heating. Further aromatization of the
O
corresponding pyrrolidines with 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ) in refluxing xylene, again under micro-
SWNT, DCB S wave irradiation, gives pyrrole-2-carboxylate 119 as major
W and 120 as minor product.
MW, "reflux", 45 min N
T In a related cycloaddition approach, Till Opatz and Ines
"open vessel"
Bergner from the University of Mainz have synthesized
Scheme 105 DielsAlder cycloaddition to single-wall carbon 2,3,4,5-tetrasubstituted pyrroles by the reaction of -(alky-
nanotubes lideneamino)nitriles 121 and , -unsaturated nitro
compounds 122 under basic conditions (Scheme 108) [517].
nitrostyrenes (Scheme 107) [516]. By performing the reac- The reaction proceeds via cycloaddition of 121 and 122 with
tions without any solvent, three stereoisomers (endo, exo, subsequent elimination of HCN and HNO2 . Complete reg-
and endo) of the pyrrolidine products are obtained, regard- ioselectivity was achieved when Cs2 CO3 was employed as

123
120 Mol Divers (2009) 13:71193

R4 R3
R3 CN
3 R4 Cs 2 CO 3, DMF
DMF + R
X R1 N R2 R1 R2
NO 2 N
MW, 200 C, 1-28 h MW, 100 C, 2 min H
121 122
R1 1 10 examples
X1 7 examples R = 2-naphthyl, 3,4-(MeO) 2-Ph
(31-56%)
(39-81%) R 2 = Me, Bn, Ph
R 3 = Me, Ph, 1-Cl-Ph, 3,4-(MeO)2-Ph, 4-CN-Ph, -(CH 2)4 -
R 4 = Me, Et, n-pent, Ph
DMF
R1 O Scheme 108 Tetrasubstituted pyrrole synthesis via [3 + 2] cycload-
X2 MW, 200 C, 1 h
dition
87%
R2
X1 = O,S, N-Ts, CH 2 O
X2 = O, CH 2 the nature of the secondary amine plays a crucial role on the
R 1 = H, alkyne DMF
R 2 = alkene, alkyne
O outcome of the reaction (R1 = H, R2 =Ph: 10%; R1 = H,
MW, 200 C, 1 h
R 3 = cyclic alkane R2 = Me: 59%).
78% 1,3-Dipolar cycloaddition reactions of cinnamaldehyde
Scheme 106 Metal-free intramolecular alkyne trimerizations with azomethine ylides generated through decarboxylation of
iminium or oxazolidinone intermediates formed by the reac-
tion of L-proline with cinnamaldehydes have been reported.
base. The only exception being 4-cyanophenyl-substituted The stereoselective reaction provides an efficient access
122 (R3 = 4-CN-Ph); here isomeric mixtures of pyrroles were to the highly functionalized hexahydro-1H -pyrrolizines
obtained. When microwave heating is applied, the reaction (Scheme S189) [519]. An intramolecular 1,3-dipolar cyclo-
time could be reduced from several hours in refluxing THF addition of an azide and acetylene functionality was used
to only 2 min at 100 C. by Van der Eycken as a key step in the synthesis of stega-
In the course of the preparation of a polycyclic pyrrolidine none aza analogs (Scheme S190) [520]. Bimolecular azide-
library, Mark Kurth and co-workers from the University of acetylene cycloadditions have been described by Katritzky
California, Davis, have disclosed an intramolecular azome- (Scheme S191) [521] and Santagada (Scheme S192) [522].
thine ylide 1,3-dipolar cycloaddition as key transformation Generation of nitrile sulfide by microwave-assisted decom-
(Scheme 109) [518]. Fused pyrrolidine scaffolds 126 were position of a suitable precursor followed by trapping of the
obtained in high regio- and stereoselectivity via condensation dipole with a selection of dipolarophiles allows the prepa-
of benzimidazole-carbaldehydes 123 with a secondary amino ration of five-membered S-heterocycles (Schemes S193 and
ester 124 to form the S-shaped ylide 125 and the subsequent S194) [523,524]. Intramolecular [2 + 2] allenic cycloaddi-
intramolecular 1,3-dipolar cycloaddition of 125. Importantly, tion reactions carried out in toluene doped with ionic

O 2N R2 O 2N R2 O 2N R2
R1 N CO 2Me
+ +
+ R1 R1 CO2 Me R1
N CO2 Me N N CO2Me
O2 N MW, 110-120 C, 10-15 min
H H H
"open vessel" endo exo endo'
R2
6 examples
R1 = Ph, 4-Me-Ph, 4-Cl-Ph, 4-OH-Ph (81-87%)
R2 = Ph, 4-MeO-Ph, 4-Cl-Ph for R 1 , R 2 = Ph: endo/exo/endo' 38/43/19

R2 O2 N R2
DDQ, xylene +
R1 CO 2Me R1 N CO2 Me
MW, 140 C, 45 min N
H 119 H 120
"open vessel"
major 6 examples minor
(35-89%) (0-15%)

Scheme 107 Synthesis of pyrroles via [3+2] cycloaddition

123
Mol Divers (2009) 13:71193 121

R1 N xylene, Et3N
CHO + R2
N CO2 Et
R1 N H MW, 130 C, 20 min
.HCl
123 124

R1 = H, Me, Cl, -(CH) 4-

R2 = Me, Bn, Ph

H R1 R2
R1 N N H
+ R2
N N O
N H 1 N
R1 _ CO 2Et R
OEt
126 H
125, S-shaped ylide 6 examples
(10-93%)
Scheme 109 Intramolecular cycloaddition of azomethine ylides

H2 (8 bar), Pt, AcOH ucts. Importantly, the hydrogenation was as stereoselective

R R
as hydrogenations carried out at room temperature.
N MW, 80 C, 20-60 min N
H Similar hydrogenation reactions under microwave con-
R = alkyl, CONH2, COOMe, acetal 14 examples
ditions in a pressurized reactor were disclosed by Vanier
(48-95%) (Scheme S196) [527].
In a 2006 publication, Adolf Gogoll and co-workers from
Scheme 110 Hydrogenation of pyridines Uppsala University have developed the Raney/Ni-catalyzed
reduction of thiolane 127 to N ,N  -dialkyl-3,7-diazabicyclo
nonanes (bispidines) 128 (Scheme 111) [528]. Primary alco-
S S hols, which also serve as reagents and to which the reaction
Raney-Ni, ROH
is limited, proved to be the best solvents. After initial thioac-
MW, 160 C, 55-120 min etal reduction and simultaneous debenzylation, the gener-
N N N N ated secondary amine is alkylated by the alcohol, which was
Bn Bn R R
converted to the corresponding carbonyl compound. Best
127 128
R = prim. alkyl
reaction conditions to reach full conversion turned out to
10 examples
(53-71 %) be 20 mass equiv of Raney/Ni, temperature of 160 C, and
55120 min as reaction time (compared with 2 days under
Scheme 111 Raney nickel reductions conventional reflux heating).
The groups of Vincenzo Calderone and Simona Rappo-
selli from the Universit di Pisa have disclosed the micro-
liquids have been published by Brummond and co-workers
wave-assisted reduction of spiromorpholone 129 with the
(Scheme S195) [525].
borane-dimethyl sulfide complex BH3 SMe2 in the course
of the synthesis of conformationally restricted benzopyrans
2.7 Reductions and hydrogenations 130 by the introduction of a spirocyclic substituent at the C-4
position (Scheme 112) [529].
The group of Maurizio Taddei from the Universit degli Studi In the presence of a proline-based chiral diamine, ketones
di Siena has investigated the preparation of substituted piper- can be reduced in an asymmetric fashion using BH3 SMe2
idines via hydrogenation of the corresponding pyridine deriv- as reducing agent (Scheme S197) [530].
atives (Scheme 110) [526]. For introducing hydrogen into The group of John Spencer from the University of Green-
the microwave vial, a special gas-charging accessory for the wich at Medway, has reported on the reduction of nitroarenes
dedicated microwave instrument was employed. Key to the to anilines mediated by Mo(CO)6 and DBU (Scheme 113)
success of reproducible hydrogenations was the pre-reduc- [531]. The addition of DBU was essential for obtaining the
tion of PtO2 to Pt in acetic acid with hydrogen combined with anilines in high yields due to the facilitated liberation of
microwave heating at 50 C for 15 min. Subsequent addition CO from Mo(CO)6 (33% versus 93% for nitrobenzene). The
of the pyridine building block, charging the vial again with method proved to be chemoselective and tolerates a broad
hydrogen, and heating at 80 C delivered the piperidine prod- range of functional groups. By applying microwave heating

123
122 Mol Divers (2009) 13:71193

N N
O BH 3 .SMe 2 O
Br NH2 Br NH 2
MW, 70 C, 20 min
O O
67%
129
Y
N
O R2
R1 N
H

O Y = CO, CH2
130 R 1 = H, Br
R 2 = COMe, SO2 Me

Scheme 112 Reduction of spiromorpholone

NO2 Mo(CO) 6, DBU, EtOH NH 2

R3 R1 MW, 150 C, 15 - 30 min R3 R1

R2 R2

R1 = H, F, Br, Cl, COMe 15 examples

R2 = H, I, Br, COMe, CH=CH 2 (50-93%)
R3 = H, Me, OMe, Br, CN, CH2 OH
COMe, CONH 2
Scheme 113 Reduction of nitro compounds with Mo(CO)6 and DBU

O OH
6 mol% i-PrOLi
R1 i-PrOH R1
R2 R2
MW, 180 C, 20-30 min

R1 = H, Br, CN, OMe 10 examples

R2 = Me, t-Bu, Ph (86-96% conv)
Scheme 114 Ketone reduction via transfer hydrogenation

to 150 C the reaction time could be reduced from
several hours to 1530 min compared with conventional
heating.
In a related fashion, Alterman and co-workers have shown
that benzylic alcohols can be deoxygenated using a combi-
nation of Mo(CO)6 and Lawesson reagent under microwave
conditions (Scheme S198) [532]. Nitro groups have also been
reduced to amines using SnCl2 or Fe/NH4 Cl as reagents
(Scheme S199) [533].
The group of Hans Adolfsson from Stockholm University
has shown that ketones can be reduced to the corresponding
alcohols via transfer hydrogenation in the absence of a transi-
tion-metal catalyst when catalytic amounts of an alkali alk-
oxide are employed (Scheme 114) [534]. The reaction pro-
ceeded smoothly for a range of aromatic and aliphatic ketones
using lithium isopropoxide (i-PrOLi) as catalyst and i-PrOH
as hydrogen donor. Problematic ketone substrates, e.g., where
R1 = CN or acetylpyridines that show coordination to the
metal catalyst under traditional conditions can be converted to
the alcohols in high yields. In addition, a scale-up from 0.5 to
82 mmol for acetophenone (R1 = H, R2 = Me) was conducted
employing a multimode instrument under the same reaction
conditions, giving the alcohol in similar isolated yield.
In this context, Ru-catalyzed transfer hydrogenations of
1,3-cycloalkanediones with i-PrOH as hydrogen donor have
been described by the Bckvall group (Scheme S200) [535].
Bruce H. Lipshutz and Bryan A. Frieman from the
University of California, Santa Barbara, have made investi-
gations on [{(R)-(-)-DTBM-segphos}CuH] as a hydrosilyla-
tion reagent regarding stability and preparation (Scheme 115)
[536]. This reagent proved to be very stable over several
weeks at room temperature (no decrease in ees) if prepared
by using Cu(OAc)2 H2 O as copper source, and stored as
stock solution in a bottle. Excellent ees and good

123
Mol Divers (2009) 13:71193 123

O
[(DTBM-segphos)CuH]
O and microwave heating (70 C for 40 min) for the hydroge-
PMHS, toluene nation step, the corresponding product 132 was obtained in
MW, 60 C, 10 min excellent yield and selectivity (>99% de) which could not be
reached by conducting the reaction at room temperature and
131 prolonged reaction time.
S/C: 1000:1: 95 % conv
99% ee WolffKishner carbonyl group reductions (HuangMin-
lon modification) (Scheme S202) [301] and LiBH4 -mediated
O double bond reductions (Scheme S203) [539] have both been
Ar
O Ar reported to work efficiently in conjunction with microwave
P
Cu H heating. Azides can be reduced selectively to primary amines
O P
Ar using the CeCl3 7H2 O/NaI system (Scheme S204) [540].
Ar
O -Haloketones have been reduced (dehalogenated) by Zn and
NH4 Cl in ethanol (Scheme S205) [541].
Ar = 3,5-di-tert-butyl-4-methoxy-phenyl

Scheme 115 CuH in a bottle for asymmetric hydrosilylations

2.8 Mitsunobu reactions

conversions were obtained in several asymmetric hydrosi-
lylations at room temperature, but also microwave heating
could be applied for the reduction of enone 131. By using
a substrate/catalyst ratio (S/C) of 1000:1, the reaction time
could be reduced from several hours to only 10 min.
A modified Strykers reagent for achiral conjugate addi-
tions of unsaturated substrates was recently reported by the
same group (Scheme S201) [537].
An asymmetric hydrogenation step within the synthesis
of the C-glycoside analog of -D-galactosyl hydroxylysine
(133) was disclosed by Jan Kihlberg and co-workers from
Ume University (Scheme 116) [538]. Using Burks catalyst
Shahnaz Ghassemi and Kristin Fuchs from Biotage AB, Vir-
ginia, have reported on a general method for the synthesis
of a set of unsymmetric sulfamides in combination with an
alternative method for a Boc-removal strategy (Scheme 117)
[542]. The first step was a one-pot synthesis of Boc-pro-
tected sulfamides, followed by N -alkylation via Mitsunobu
reaction to introduce more diversity. Silica-bonded phenyl-
sulfonic acid (Si-TsOH) was used for Boc removal, which
was possible in 5 min at 100 C for all examples. All synthe-
sis steps have been performed using microwave heating. For
releasing the sulfamides from Si-TsOH, NH3 in MeOH was
used.

OBn OBn OBn OBn

NHCbz H2, Burk's catalyst
O O NHCbz
i-PrOH
BnO OMe OMe
MW, 70 C, 40 min BnO
OBn OBn
O O
OTBDMS OTBDMS
132
Burk's cat.: [(COD)Rh(S,S)Et-DuPHOS]OTf (95%; >99% de)
TBDMS: t-butyldimethylsilyl
Cbz: carbobenzyloxy
6 steps

OH OH
O NHFmoc
HO OH
OH
O
133 NHBoc
(18% over 17 steps)

Scheme 116 Asymmetric hydrogenation using Burks catalyst

123
124 Mol Divers (2009) 13:71193

O O O O O
O O t-BuOH, DCM O R 1R 2 NH S
S 2
S N Cl N N R
Cl NCO 0 C MW, 80 C, 5 min O H
O H R1
5 examples
(55-86%)

Si TsOH
R 3-OH, PPh3, DEAD O O O
O O O
S O
S THF 2 MeCN/DCM O O
N N R
2 N N R Si S O H S
O O R2
H
R1
MW, 80 C, 1-4 min
R3 R1 MW, 100 C, 5 min O H N N
1
R3 R
6 examples 2M NH 3 /MeOH
(44-75%)

O O
H S 2
N N R
1
R3 R
8 examples
(61-92%)

Scheme 117 Synthesis of unsymmetric sulfonamides

OBn
OBn
OBn O OBn
O CO2 Me LiClO 4, DCE BnO
BnO O BnO O
BnO + HO O
O BnO OBn BnO
OBn MW, 100 C, 40 min
AcHN AcHN
O2N NO 2 OMe 72% ( / = 4:1) OMe
134 + 3 related examples

OBn
OBn
NH O HO LiClO4, DCE O
O O O BnO
BnO + BnO O
BnO O CCl3 MW, 100 C, 30 min
O OBn
OBn O
O
O
135 72% ( / = 1.5:1) O O
O
+ 2 related examples

Scheme 118 Glycosylations using LiCLO4 as Lewis acid

2.9 Glycosylation reactions and related
carbohydrate-based transformations
Knud J. Jensen and co-workers from the Royal Veterinary and
Agricultural University, Denmark, have described the micro-
wave promoted synthesis of oligosaccharides (Scheme 118)
[543]. Without the use of a strong Lewis acid, O-glycosy-
lations could be accelerated from up to 31 h to 540 min by
applying microwave heating. Glycosylation reactions have
been performed with trichloroacetimidate (135) or 3,5-dini-
trosalicylate (DISAL, 134) donors, respectively, in the latter
case with -selectivity for sterically hindered alcohols.
The group of Jacquelyn Gervay-Hague from the Univer-
sity of California, Davis, has discovered that microwave
heating can accelerate the -glycosidation of per-O-silylated
galactosyl iodide 136 with ceramide 137 (Scheme 119) [544].
If galactosyl iodide 136 is reacted with ceramide 137 under
conventional heating or at room temperature for 48 h, low
yields are obtained. The authors assume that the unsaturated
side-chain in 137 favors lipid packing which could be over-
come by applying microwave heating, thus obtaining the
glycolipid product in higher yield. With this method, which
normally gives high yields when the reaction is performed
at rt, only the -isomer is obtained, unsaturated fatty acid
side-chains are tolerated, and multiple protectiondeprotec-
tion steps are eliminated.
Brett Bookser and Nicholas Raffaele from Metabasis
Therapeutics have reported on the synthesis of a nucleo-
side library via the Vorbrggen glycosylation and subse-
quent deprotection with NH3 /MeOH (Scheme 120) [545].
They were successful in performing this reaction which is
known to be a two-step synthesis (presilylation of the base

123
Mol Divers (2009) 13:71193 125

O
Peter H. Seeberger from MIT (Scheme 121) [546]. One of the
OTMS C17 H 35 1. TBAI, DIPEA, DCM
TMSO many synthetic steps involves the simultaneous installment
HN OH MW, 120 C, 90 min
O
+ HO C13 H27 of an N -diacetate and O-acetyl functionality in a trisaccha-
TMSO 2. Dowex 50WX8-200
MeOH, rt, 4 h
TMSO I OH ride building block. Microwave irradiation in isopropenyl
136 137 acetate as solvent in the presence of p-TsOH at 90 C for
OH 5 h led to the desired product in 86% yield. This transforma-
HO O
O C 17 H35
tion could not be achieved under a variety of thermal con-
HO HN OH ditions, with only poor yields achieved even after several
HO O C13H 27 days.
OH Bajugam and Flitsch have described the synthesis of gly-
67%
cosylamines from mono-, di-, and trisaccharides via direct
Scheme 119 Synthesis of -linked glycolipids microwave-assisted Kochetkov amination (Scheme 122)
[547]. The reaction was found to be effective with only five-
then reaction with trimethylsilyl triflate activated sugar) in fold excess (w/w) of ammonium carbonate over sugar com-
only one step by applying microwave heating at 130 C for pared with 40- to 50-fold excess needed under thermal
5 min. An additional advantage of the elevated temperature conditions. All transformations were completed within 90 min
is that otherwise insoluble silylated bases were solubilized in dimethylsulfoxide as solvent while maintaining the vessel
under these conditions. For the library synthesis, 48 N -con- temperature at an apparent 40 C, using the heating-while-
taining bases were reacted with -D-ribofuranose 138; out cooling technique.
of these, 32 yielded single isomers, six provided separable A rapid synthesis of carbasugars was reported by Pohl and
mixtures, and seven afforded inseparable regioisomer mix- co-workers from Iowa State University starting from a pro-
tures. Altogether a set of 58 nucleosides were obtained in tected D-glucose (Scheme 123) [548]. Microwave-enhanced
poor to good yields. iodination of the selectively protected glucose precursor took
The synthesis of fully N -differentiated heparin oligosac- place in 1 min in toluene at 60 C in the presence of iodine and
charides has been demonstrated by Gregory J. S. Lohman and triphenylphosphine. Subsequent base-promoted elimination

1. base, BSA
TMSOTf, MeCN
BzO O OAc MW, 130 C, 5 min BzO base
O

2. N(CH2CH2OH)3
BzO OBz MeCN/H2O BzO OBz
138 rt, 30 min
NH3, MeOH
BSA: N ,O -bis(trimethylsilyl)acetamide 50 C, 16 h

base examples
HO O base
OMe NH2
N N N HO OH
N
N N NH2 N N O
H H H
58 examples
H O (3-75%)
N
N N
N
N
N N
NH2 H H

O NH2
N O
HN
N NH2
O N H
H O

Scheme 120 One-step Vorbrggen glycosylation

123
126 Mol Divers (2009) 13:71193

MeO2 C OBn ers in one step and one pot. Unreacted enamine was scav-
OBn AcO
O MeO 2C
AllO O O
BnO +
enged by sulfonic acid A-15, -ketoester by the strongly
OBn Me
AcO AcHN
O O OTBDMS basic anion exchange resin Ambersep and aldehyde by the
(solvent)
aminomethylated (AM) resin. Subsequent oxidation employ-
HO
ing silica-supported pyridinium chlorochromate (PCC)
MeO2 C OBn
OBn afforded the products in good yields. Attachment of the car-
p-TsOH, DMF O O MeO2 C
AllO O
BnO
bohydrate residue onto the -ketoester building block and
MW, 90 C, 5 h OBn
AcO AcNAc O O OTBDMS the amino acid residue onto the aldehyde building block,
AcO
respectively, is also possible.
86 %
Samuel Danishefsky and Xuechen Li from the SloanKet-
Scheme 121 Heparin oligosaccharide synthesis tering Institute for Cancer Research, New York, have investi-
gated the reaction of isonitriles with carboxylic acids to form
OH OH N -formyl amides (Scheme 125) [550]. The reactions proceed
1
R O O (NH4)2CO3, DMSO 1
R O O well under microwave irradiation conditions at 150 C for
HO NH2
HO 3045 min (depending on the substrates), possibly through
R2 OH
MW, 40 C, 90 min R2
35-87%
a 1,3-O N -acyl transfer, whereas at room temperature no
1
reaction could be detected. When glycosyl-linked isonitriles
R = H, Glc
are reacted with aspartate, the reactions occur in an ano-
R2 = OH, NHAc
merically specific way to the corresponding - and N -
Scheme 122 -Glycosylamine synthesis via Kochetkov amination linked glycosyl amino acids. Further transformations of the
N -formyl amides to different amide types are described as
OH I2, PPh3, imidazole I well.
toluene
BnO O BnO O Other examples of microwave-assisted transformations
BnO BnO related to carbohydrate chemistry involve glycosylation reac-
BnO MW, 60 C, 1min
BnO
OMe OMe tions catalyzed by FeCl3 (Scheme S206) [551], or carried
98%
out in a solvent-free manner (Scheme S207) [552], Ferrier
DBU, DMF BnO O
PdCl2, dioxane/H2 O rearrangements (Scheme S208) [553], Fischer glycosylations
BnO
MW, 80 C, 30 min BnO (Scheme S209) [554], glycosylations of N -acetyl glycosam-
OMe MW, 60 C, 5 min
98% ines (Scheme S210) [555], and acetal-exchange-type
O glycosylations from methyl glycosides (Scheme S211) [556].
BnO
BnO
BnO 2.10 Multicomponent reactions
74% OH

Scheme 123 Multistep carbasugar synthesis
of hydrogen iodide in the presence of DBU required 30 min
(DMF, 80 C), and the key Ferrier rearrangement induced
by PdCl2 was also completed within 5 min of microwave
irradiation. The development of this series of microwave-
assisted transformations significantly shortened the time to
form the core carbocyclic structure from a protected glu-
cose.
The groups of Alessandro Dondoni and Alessandro Massi
from Universit di Ferrara, have disclosed the synthesis of
glycosyl amino acids where the carbohydrate and amino
acid residues are linked via a pyridine ring (Scheme 124)
[549]. The synthesis of those C-glycosylmethyl pyridylala-
nines was accomplished by a Hantzsch-type three-compo-
nent cyclocondensation of C-glycosyl or C-galactosyl
acetaldehydes (139), -ketoester 140 that incorporates the
amino acid residue, and enaminoester 141. The purification
was performed using three different polymer-bound scaveng-
A 2005 publication of Markus Follmann and co-workers
from Aventis Pharma described the rapid microwave
three-component coupling reaction of an amine 142, boronic
acid 143, and glyoxylic aldehyde 144, the Petasis reaction
(boronic Mannich reaction) (Scheme 126) [557]. A wide
range of electron-poor anilines and heterocyclic anilines, but
only electron-rich boronic acids, can be employed to obtain
the unnatural N -aryl--amino acids in reasonable yields.
Comparison studies under conventional heating conditions
(heating block, 84 C, 0.54 h) gave identical results for most
of the reactions.
The group of Matthias Beller from the University of Ro-
stock has reported on the three-component reaction of amides
145, aldehydes 146, and dienophiles 147 (AAD reaction)
to give 2-bromo-substituted 1-amido-2-cyclohexene deriva-
tives 148 (Scheme 127) [558]. With this protocol aromatic
amides, sulfonamides, carbamates, and cyclic amides are
well tolerated, the latter providing the products only in mod-
erate yields (3546%). Up to four stereogenic centers are
generated in the AAD sequence and in most cases an all-syn

123
Mol Divers (2009) 13:71193 127

OBn OBn
139
O
BnO CHO
OBn 1. t-BuOH
MW, 120 C, 1.5 h
t-BuO2 C
+ CO 2t-Bu 2. Amberlyst A-15, Ambersep
AM-resin
O 3. PCC on SiO2
MeO2 C NHBoc H2 N Me
PCC: pyridinium chlorochromate
140 141

OBn OBn
O CO2 t-Bu
BnO Me
OBn
N
t-BuO2 C
62% CO2 Me
+ 7 related examples NHBoc
(55-68%)
Scheme 124 Synthesis of carbon-linked glycosyl amino acids

OBn CO2 H O
BnO O O R3
CHCl3
O + + R4 N
NC HN CO2 t-Bu H +
BnO MW, 150 C, 45 min R1 NHR 2
OBn Fmoc Br
O
OBn 145 146 147
BnO
CHO R 1 = OPh, aryl
O
BnO N CO2t -Bu R 1 = R 2 = cyclic O
OBn R2 = H
O NHFmoc R 3, R4 = H, Me
85% R1 NR 2 O
+ 5 related examples Br
(75-85%) toluene N
MW, 120-180 C, 20-40 min R3
Scheme 125 Reaction of carbohydrate-derived isonitriles with car- O
boxylic acids R4
148
O 9 examples
(35-85%)
R 1 NH2 + R2 B(OH) 2 +
H COOH
Scheme 127 Three-component synthesis of 1-amido-2-cyclohexenes
142 143 144

COOH A related and more general protocol for the three-

MeCN/DMF (10:1)
R1 2 component synthesis of aldehydes, amides, and dienophiles
N R
MW, 120 C, 5-10 min H (AAD reaction) was developed by the same group
21 examples (Scheme 128) [559]. Optimization studies revealed that a sol-
(5-95%) ventless microwave protocol (150 C, 20 min) gave a superior
R 1 = 1,4-(F)2 -3-CN-Ph, 1-NO 2 -5-COOMe-Ph, hetaryl, yield (90% versus 61%) for the reaction of acetamide (149),
R 2 = Ph, 4-MeO-Ph, 4-Cl-Ph, hetaryl crotonaldehyde (150), and N -methyl-maleimide (151) in a
50 times shorter reaction time compared with thermal heating
Scheme 126 Petasis reactions of electron-poor aromatic amines at 110 C. The addition of acetic anhydride (Ac2 O) as water
removing reagent proved to be beneficial for the reaction. All
configuration is obtained. By applying -bromo aldehydes ten cyclohexene derivatives are obtained as only one diaste-
146, further scaffold decorations like cross-coupling or car- reomer, namely as the all-syn product, due to the selective
bonylation reactions are possible at the 2-position. endo addition of the dienophile.

123
128 Mol Divers (2009) 13:71193

O products 158 were obtained via an Ugi-type cyclization, lead-

O O
+ +
ing to intermediate 157, Suzuki coupling sequence in a one-
N
NH 2 H pot procedure. Notably, the authors were not successful in
O
performing the reaction sequence in one step nor can the
149 150 151 sequence be reversed (first Suzuki then cyclization).
O A 144-member library of furocoumarins via three-com-
ponent reaction of 4-hydroxycoumarins, isocyanides, and
NH O arylaldehydes was prepared by Jie Wu from VivoQuest Inc.,
Ac2 O, p-TSA NY (Scheme 131) [563]. By applying a microwave protocol
MW, 150 C, 20 min
N (DMF, 150 C, 5 min), reduction in reaction times (24 h
5 min), higher yields, and less by-products were observed
O
90% compared with the conventional synthesis.
+ 9 related examples The synthesis of highly functionalized dibenz[b, f ][1,4]
(26-96%) oxazepin-11(10H )-ones 159 and carboxamides 160, respec-
Scheme 128 Solvent-free synthesis of functionalized 1-amido-2-cy- tively, has been disclosed by Wei-Min Dai and co-workers
clohexenes from Zhejiang University (Scheme 132) [564]. The
oxazepine derivatives 159 and 160 were obtained via a one-
pot/two-sequence Ugi reaction and intramolecular O-aryla-
tion in good to excellent yields. It turned out that for the Ugi
N O
reaction in the synthesis of derivatives 160 the acidity of the
R1 + R2 + TMS-CN
NH2 H employed acid component played an important role, result-
ing in a 49% overall yield for Ar2 = o-Br-Ph with a pKa
152 153 154
of 2.85 and decreased yields for less strong acids. Addition-
R1 = Me, Et, Ph ally, a post-modification of derivatives 159 was conducted via
R2 = alkyl, (het)aryl a Pd-catalyzed intramolecular N -arylation, which furnished
NH2 derivatives 161 containing a 2-oxindole unit.
Sc(OTf)3, MeOH N The groups of Laurent El Kam and Laurence Grimaud
R1 R2
N from Ecole Nationale Suprieure de Techniques Avances in
MW, 140 C, 10 min
Paris have reported on the generation of quinoxaline scaf-
155 folds (Scheme 133) [565]. The reaction sequence consists
12 examples of an Ugi four-component reaction with subsequent Smiles
(27-73%)
rearrangement, leading to intermediate 162. The UgiSmiles
Scheme 129 Synthesis of 3-aminoimidazo[1,2-a]pyridines intermediate 162 further cyclizes to the quinoxaline product
via an intramolecular Ullmann-type coupling. A higher yield
of 62% could be obtained when the UgiSmiles intermedi-
A novel one-step three-component reaction for the syn- ate is isolated prior to the Ullmann-type coupling step. By
thesis of 3-aminoimidazo[1,2-a]pyridines has been demon- applying microwave heating for both steps the reaction time
strated by Christopher Hulme (Scheme 129) [560]. In this can be reduced from 31 h to only 1.8 h.
multicomponent reaction, an aminopyridine 152, aldehyde Tryptophan-derived diketopiperazines with variable side-
153, and TMS-CN 154 are reacted under microwave heating chains have been obtained by Ugi four-component reaction
to give the desired products 155. By using TMS-CN as non- followed by a deprotection/cyclization sequence to generate
classical isonitrile equivalent, no further deprotection steps the diketopiperazine fragment (Scheme S213) [566].
were necessary, making this method applicable for library The group of Peter Andreana from Wayne State Univer-
synthesis. sity, Michigan, has developed a one-pot two-step synthesis
A closely related approach combining the Ugi-type chem- of regiochemically differentiated 1,4-benzodiazepin-3-ones
istry shown in Scheme 129 with a Strecker synthesis leading (Scheme 134) [567]. The first step involves the Ugi four-
to -iminonitriles was disclosed by the same group in 2006 component coupling reaction to form -acylaminoamides,
(Scheme S212) [561]. which are subsequently converted to benzodiazepines by a
Using a related approach, Erin DiMauro and Joseph Ken- reductive (NO2 NH2 ) aza-Michael cyclization employ-
nedy from Amgen have developed a microwave protocol for ing Fe(0)/NH4 Cl in aqueous media as reducing agent. With
the synthesis of a focused library of 3-amino-imidazopyri- bifunctional o-nitrobenzaldehyde 163 exclusively C2, N4,
dines 158 (Scheme 130) [562]. Starting from 2-aminopyr- C5-substituted benzodiazepines 164 are obtained, whereas
idine-5-boronic acid pinacol ester 156 the imidazopyridine with o-nitrobenzylamine 165 the C2, N4-substituted

123
Mol Divers (2009) 13:71193
NH 2 R 1CHO, R2 NC
MgCl2, MeOH
O N
B B
O MW, 160 C, 10-20 min
156
R 1 = (het)aryl, alkyl, H
R 2 = aryl, (cycl)alkyl
R 3 = (het)aryl, Bn
Scheme 130 One-pot cyclization/Suzuki coupling
OH
CHO
R1 + R 2NC + R3
O O
NHR2
O DCM was used. Interestingly, direct conversion to products
DMF
R1
MW, 150 C, 5 min
O O
144 examples
(92-99%)
R 1 = H, Me, Cl, Br, OMe
R 2 = cyclohexyl, p-MeO-Ph, benzyl, t-Bu
R 3 = H, Me, MeO, F, Cl
Scheme 131 Synthesis of furocoumarin libraries
derivatives 166 are formed. The reduction reaction gave higher
yields in shorter times compared with reactions performed
under oil-bath heating. It has to be noted that at higher tem-
peratures either decomposition or a 6-exo aza-Michael cycli-
zation to form 2,5-diketopiperazines occurred.
The same group has demonstrated that small molecule
diversity can be easily obtained in a single-step starting from
standard Ugi multicomponent reaction building blocks
(Scheme 135) [568]. Depending on the solvent and sterics
of the substituents, in particular of the amine and isocya-
nide precursors, three different scaffolds can be generated.
When water is employed as protic solvent either 2,5-dike-
topiperazines 167 via an aza-Michael reaction or 2-azaspi-
ro[4.5]deca-6,9-diene-3,8-diones 168 from a 5-exo Michael
cyclization are obtained due to stabilization of zwitterionic
intermediates by the protic solvent. When the reactions are
performed in aprotic DCM only the acyclic Ugi products,
which are formed in the first reaction step prior to intramo-
lecular cyclizations, could be isolated. If bulky R4 -substi-
129
N
R1
O N
O NHR 2
157
R 3Br, aq K2 CO3 MW, 90 C
Pd(dppf)Cl2 30 min
N
R1
3 N
R
2
158 NHR
14 examples
(42-68%)
tuents (t-Bu, i-Pr, cyclic alkyl) are present, either product
168 or the acyclic Ugi product are accessible, depending on
the amine substitution pattern. The tricyclic lactam product
169 was obtained via an intramolecular thiophene-derived
DielsAlder reaction when thiophene-2-carboxaldehyde in
167169 could only be achieved by microwave irradiation
and not with conventional heating.
R3
Miller and co-workers reported a one-pot protocol for the
preparation of thiazolidin-4-ones by condensation of aro-
matic aldehydes, amines, and mercaptoacetic acid in etha-
nol (Scheme 136) [569]. The optimized procedure involved
microwave irradiation of a mixture of amine hydrochloride,
aldehyde, and mercaptoacetic acid (molar ratio 1:2:3) in the
presence of 1.25 equivalents of N ,N -diisopropylethylamine
(DIEA) base in ethanol at 120 C for 30 min at atmospheric
pressure.
Francesco Risitano and co-workers from Universit Vill.
S. Agata, Italy, have reported on a synthesis of bridgehead az-
iridines with high yields and excellent diastereocontrol by a
three-component reaction of an aldehyde, phenacyl chloride,
and ammonium acetate in acetic acid (Scheme 137) [570]. As
opposed to 23 h for traditional conductive heating, 510 min
of microwave irradiation at 90 C afforded the stereodefined
bridgehead aziridines in 3592% isolated yields.
The group of Shu-Jiang Tu at the Xuzhou Normal Uni-
versity in China has reported on the one-pot four-compo-
nent reaction for the synthesis of tetrahydroquinoline-diones
(Scheme 138) [571]. By reacting aromatic aldehydes 170,
dimedone 171, Meldrums acid 172, and amines 173 under
microwave conditions a new series of N -functionalized quin-
olone products 174 was obtained. Higher yields and shorter
reaction times compared with conventional heating could be
accomplished.
The same group has described a number of related multi-
component reaction (MCR) approaches to heterocycles,
123
130 Mol Divers (2009) 13:71193

Ar1 CHO OH 2
for 159: MeOH 1 Ar
OH MW, 80 C, 20 min R
R1 + Ar2 CO2 H N O
for 160: MeOH
NH2 MW, 60 C, 30 min O
Ar 1
R 2 NC HN
R2

Cl Cl
Ar 2 = Ar 1 =
NO2 NO2

aq. K2CO3 aq. K2 CO 3

MW, 100 C, 10 min MW, 120 C, 10 min

O
NO2
R1 O O
for Ar1 = o-Br-Ph NO2 NO2
N Pd(OAc) 2, BINAP R1 R 1
O
K2CO3 , toluene N N
O O Ar2 O
MW, 150 C, 40 min Ar1 O
N O HN
R2 HN R2
161 159 R2 160
8 examples 8 examples 4 examples
(70-94%) (81-96%) (17-49%)

Scheme 132 One-pot Ugi reaction and intramolecular O-arylation

NH2
NH4 Cl
CHO toluene/H 2O (9:1) O
N
NC
+ I NHp-ClBn
MW, 100 C, 30 min
OH
I 162
NO 2

Cl
NO2
CuI/L-proline MW, 180 C
K3PO 4, MeCN 80 min

O
N
N
p-ClBn

NO2
39 %
Scheme 133 Quinoxaline synthesis via a UgiSmiles sequence

123
Mol Divers (2009) 13:71193 131

H R4
N
NO 2 O Fe, NH 4 Cl, EtOH, H2 O R1 O
R1 + R 2 NH2 + R3 NC + N
HO R4 MW, 150 C, 30-45 min R2
CHO
163 O
164 N R3
H
R1 = CF3, OMe 5 examples
(70-78%)
R2 = aryl, alkyl
R3 = t -Bu, Cy, cyclopentyl, Bn
R4 = H, Bz, ethoxycarbonyl, Me-Bz

H R4
N
NO2 O Fe, NH4 Cl, EtOH, H 2O
O
i-Pr CHO + + R 3 NC +
NH2 HO R 4
MW, 150 C, 30-45 min N O

165 166 HN R 3
i-Pr
2 examples
(85-90%)

Scheme 134 One-pot synthesis of 1,4-benzodiazepin-3-ones

O
R4 R1
N
N
H 2O R3
O R2 O 167
R2 OH 11 examples
(81-98%; dr<20:1)
H 2N R 3
R1 CHO O
R4 NC

H 2O

MW, 200 C, 20 min R2

O N
O
HN R 1 168
R 4 6 examples
(60-95%; dr<3:1)

O R3
DCM R4 N
N
H S O

H
H
169 R2
2 examples
(23-25%; dr<10:1)
Scheme 135 Generation of molecular diversity from Ugi-type multicomponent reactions

involving Hantzsch-type condensations leading to dihydro-
pyridin-2(1H )-ones (Scheme S214) [572], indeno[1,2-b]
quinolines (Schemes S215 and S216) [573,574], furo[3,4-
b]quinolines (Scheme S217) [575], and pyrimido[1,2-a]
quinolines (Scheme S218) [576]. The generation of 4-aza-
fluorenone derivatives (Scheme S219) [577], furo[3 ,4 :5,6]
pyrido[2,3-d]pyrimidines (Scheme S220) [578], and amino-
pyridines (Scheme S221) [579] has also been disclosed by
the same group using MCR strategies.
Michael G. Organ and W. Stacey Bremner have employed
microwave-assisted continuous-flow organic synthesis for
the preparation of heterocyclic compounds via multicom-
ponent reactions utilizing a self-designed capillary system
as reactor (Scheme 139) [580]. The three components are

123
132 Mol Divers (2009) 13:71193

O O
R 1 CHO + R2 NH2 .HCl + HS CO2 H R2 O
CHO + + + R 3NH
1 2
R = aryl R 1
R2 O
R 2 = alkyl O O
170 171 172 173

S O
DIEA, mol sieves, EtOH R1
N O
MW, 30 min R1 R2
"open vessel" EtOH R2
10 examples MW, 100 C, 4-9 min N O
(55-91%) R2
R3
174
Scheme 136 4-Thiazolidinones via multicomponent chemistry 18 examples
(82-96%)

R1 = H, 4-Cl, 2-Cl, 4-MeO, 4-F, 4-Br, 3-NO 2,

each introduced into the microwave cavity through three sep-
arate leads, in equal concentrations and at the same flow
rate. In this way a set of tetrahydropyrazolo[3,4-b]quinolin-
5(6H )-ones 175 and aminofuranes 176, respectively, could
be accomplished in a few seconds and in very good conver-
sions. Importantly, this flow system is an open system which
means that high-boiling and good microwave-absorbing sol-
vents such as DMSO or DMF have to be used to reach higher
temperatures and hence higher conversions.
Valentin Chebanov and co-workers from the National
Academy of Sciences of Ukraine and the University of Graz
have disclosed the microwave-assisted three-component
reaction of 3-substituted 5-aminopyrazoles 177, pyruvic acid
or ethyl pyruvate 178, and aromatic aldehydes 179 (Scheme
140) [581]. By changing the solvent from AcOH, which is
used under conventional conditions, to an EtOH/HCl system,
product isolation was facilitated and no further recrystalliza-
tion was necessary. Compared with classical heating, an 8-
to 12-fold decrease in reaction time was possible and higher
yields could be obtained for the pyrazolopyridine carboxylic
ethyl ester products 180 (R2 = Et).
Related three-component condensation reactions involv-
ing aminoazoles, aldehydes, and -ketoamides leading to
triazolopyrimidines have been described by the same
group (Scheme S222) [582]. A series of polysubstituted
(3 -indolyl)pyrazolo[3,4-b]pyridine and (3 -indolyl)benzo
[H ]quinoline derivatives were synthesized via one-pot mul-
ticomponent condensation of aldehydes, 3-cyanoacetyl in-
doles with 5-aminopyrazoles or naphthylamines (Scheme
S223) [583].
2,4-(Cl) 2, 4-Me, 3,4-(MeO) 2, hetaryl
R2 = Me, H
R3 = Me, cyclopropyl, cyclopentyl, cyclohexyl, 4-MePh
Scheme 138 Synthesis of N -substituted tetrahydroquinoline-diones
The three-component reaction of Meldrums acid (181),
aldehydes 182, and guanidine carbonate (183) for the syn-
thesis of 2-amino-dihydropyrimidines 184 was developed
by Nikolay Yu Gorobets and co-workers from the National
Academy of Sciences of Ukraine (Scheme 141) [584]. The
condensations were performed both under conventional
(120130 C, 2025 min) and microwave heating (150 C,
5 min), showing slightly higher yields for most of the deriva-
tives applying conventional conditions. Importantly, to avoid
high pressure build up in the closed microwave vials due to
CO2 formation, the reaction mixture was stirred for
1015 min at rt before subjecting to microwave irradiation.
The group of Lal Dhar Yadav from the University of
Allahabad, India, has reported on a Biginelli-type reaction
of unprotected aldoses, 2-methyl-2-phenyl-1,3-oxathiolan-
5-one 185 as CH-acidic building block, and urea/thiourea
under acidic Montmorillonite K-10 catalysis and solvent-free
conditions (Scheme 142) [585]. By employing the unpro-
tected aldoses D-xylose (n = 3) and D-glucose (n = 4) a
one-pot protocol was feasible, avoiding protection and depro-
tection steps; furthermore they induce asymmetry to the final
products. Thiosugar-annulated dihydropyrimidines were
obtained via intermolecular domino cyclocondensations with
>95% diastereoselectivity in favor of the cis-isomer.

O H Ph
AcONH4 H
Cl
AcOH, n-PrOH
+ RCHO
MW, 90 C, 10 min R N H N

R
7 examples
(35-92%)
Scheme 137 Multicomponent synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes

123
Mol Divers (2009) 13:71193 133

O
Me O
60L/min flow O
1180 m capillary Me
H
HN DMSO
O N HN
NH 2 R MW, 170 W N N
H
R= OH, OMe, Br, CN, CO2Me, N(CH3 )2
175
6 examples
(71-94%)

60L/min flow
1180 m capillary R2
NC 2 DMF O H
R CHO N
MeO2 C CO2 Me
MW, 180 W R1
R1 MeO 2C CO 2Me
R1 = H, NO 2
176
R2 = H, NO 2, CF3 , CO2 Me, F, Cl, OMe
7 examples
(30-83% conv)

Scheme 139 Synthesis of heterocycles by multicomponent reactions

R1 microwave heating, less by-products are formed and only a

O R3 simple filtration/recrystallization workup is required.
N Me R2
NH2 O Several publications have reported the use of terminal
N
H O O H acetylenes as building blocks in MCRs leading to fused het-
177 178 179 erocycles (Schemes S224S226) [587589].
Pyridine-3,5-dicarbonitrile libraries have been prepared
O O in pseudo-four-component condensations involving malono-
R1 R2
EtOH, HCl nitrile as one of the building blocks (Scheme S227) [590].
N Several other MCR strategies on route to N -heterocycles
MW, 150 C, 10 min
N N using malononitrile as building block have been reported
H R3 (Schemes S228 and S229) [591,592].
180
20 examples
A three-component cascade reaction to yield 3-spirocy-
(35-48%) clopropanated -lactames was reported by de Meijere
(Scheme S230) [593]. Three-component condensations of
R 1 = Me, Ph cyclic amino acid esters, carboxylic acids, and amines pro-
R 2 = H, Et
duced spiroimidazolinones in high yields (Scheme S231)
R 3 = H, 4-Cl, 3-Cl, 2-Cl,
4-MeO, 4-Me, 4-F, 4-Br [594]. The preparation of -aminophosphonates using a
three-component condensation approach has been described
Scheme 140 Synthesis of pyrazolopyridines via a three-component (Scheme S232) [595]. 2-Aminomorpholines have been
approach obtained in a four-component approach starting from 1,2-
aminoalcohols, glyoxal, boronic acids, and amines (Scheme
S233) [596]. For a microwave-assisted Gewald approach to
Chao-Guo Yan and co-workers from Yangzhou Univer- 2-aminothiophenes, see Scheme S234 [597]. One-pot con-
sity have developed a modified Krhnke protocol for the densation of 2-chlorobenzenthiols, chloroacetyl chloride, and
synthesis of pyridines (Scheme 143) [586]. This typically primary amines leads to benzo[b][1,4]thiazin-3(4H )-ones
two-step procedure could be performed in one pot by four- (Scheme S235) [598].
component cyclocondensation of a pyridinium salt 186, aro-
matic aldehydes 187, acetophenones 188, and ammonium 2.11 Alkylation reactions
acetate and leads to polysubstituted pyridines 189. When
acetophenone is replaced by cyclic ketones 190, annulated Thierry Ollevier and Zhiya Li from Universit Laval, Que-
pyridines 191 are obtained in very good yields. By applying bec, have reported on the bismuth-catalyzed Sakurai reaction

123
134 Mol Divers (2009) 13:71193

R 182
O H R
O
NH
. H 2CO3 N
O DMF
H 2N NH 2
Me O N NH 2
O O 183 MW, 150 C, 5 min
Me H

181 184
R = alkyl, aryl 10 examples
(19-45%)
Scheme 141 Synthesis of 2-amino-dihydropyrimidin-4-ones

OH

OH
S
n= 3
O
OH 6 examples
CHO (76-85%)
S R N NH
(CHOH)n Ph O
O X
CH2 OH + Me K-10 clay
185
HO
MW, 90 C, 9-13 min OH
X
OH
H2 N NHR S
n= 4 O
OH 6 examples
n = 3, 4 (77-89%)
X = O, S R N NH
R = H, Ph, Et, MePh
X

Scheme 142 Synthesis of thiosugar-annulated dihydropyrimidines

R1

R1
O
R2 NH 4OAc, AcOH
Me
+N + +
MW, 130 W, 3-4 min
_ CH2 COPh "open vessel" Ph N
Br O H R2
186 187 188 189
4 examples
(53-82%)
R1 = p-Me, p-Cl, p-MeO
R2 = H, p-Me, m-NO2 R

R O
NH 4OAc, AcOH n

+N + 2 + MW, 130 W, 2-4 min

_ CH 2COPh n "open vessel" Ph N
Br O H
186 187 190 191
11 examples R
n = 0, 1, 2 (70-80%)
R = H, p-Me, p-Cl, p -MeO, m-NO2 ,
m -MeO-p-OH

Scheme 143 One-pot synthesis of polysubstituted and annulated pyridines

123
Mol Divers (2009) 13:71193 135

O Bi(OTf)3, MeCN uids (Scheme S238) [603] or under solvent-free conditions

SnBu3
R H
MW, 160 C, 5 min
R = (het)aryl, alkyl
OH
R are reported in Schemes S242 and S243 [607,608]. Camphor-
10 examples
(64-93%)
Scheme 144 Allylation of aldehydes with allylstannane
toward the synthesis of homoallylic alcohols (Scheme 144)
[599]. Several aldehydes were successfully converted to the
corresponding homoallylic alcohols by reaction with 1 equiv
of allyltributylstannane and only 0.5 mol% of Bi(OTf)3 as
catalyst. By microwave irradiation at 160 C for 5 min, the
alcohols were obtained in good to excellent yields without
any by-product formation.
In the course of the synthesis of ()-baccatin III (193),
a precursor of taxol, Takashi Takahashi and his group from
Tokyo Institute of Technology have developed a microwave-
assisted protocol for the key ABC ring construction step
(Scheme 145) [600]. The cyclization of protected cyanohy-
drin 192, which was synthesized in 36 steps completely with
the aid of automated synthesizers, was accomplished by intra-
molecular alkylation in the presence of excess LiN(TMS)2 .
The reaction time could be reduced from 10 h in refluxing
dioxane employing thermal heating to 15 min at 145 C using
microwave irradiation.
Yb(OTf)3 -catalyzed etherifications of benzylic alcohols
with allyl alcohol have been described by Handlon and Guo
(Scheme S236) [601]. Ir-catalyzed monoalkylations of 1,3-
dimethylbarbituric acid with benzyl alcohols were discussed
by Grigg (Scheme S237) [602]. Similarly, the alkylation of
active methylene compounds with alkyl halides in ionic liq-
(Scheme S239) [604] has been described. The allylation of
tetramic acids using allyl bromides in the presence of Et3 N
has been reported (Scheme S240) [605]. For microwave-
assisted N -allylations of 2(1H )-quinolones, see Scheme
S241 [606]. S-Alkylations of thiouracils with benzyl halides
derived chiral imidazolium ionic liquids have been synthe-
sized by N -alkylation of imidazoles with appropriate
camphor-derived alkyl halides (Scheme S244) [609]. Simi-
larly, imidazolium salts have been prepared as N -heterocy-
clic carbene ligand precursors by microwave-assisted
alkylation reactions (Scheme S245) [610].
2.12 Nucleophilic aromatic substitutions
A 2004 report by Amy Takvorian and Andy Combs of Incyte
Corporation discloses the rapid synthesis of 2-amino-substi-
tuted purines by rapid, microwave-assisted nucleophilic aro-
matic substitution (SN2 Ar) (Scheme 146) [611]. Importantly,
the authors describe the use of small-scale reaction vessels
(0.2 mL) for optimization of reaction conditions under opti-
mal reaction concentrations.
Along similar lines, Hong Liu and co-workers from the
Chinese Academy of Sciences have developed a simple pro-
cedure for the synthesis of 2,6,9-substituted purines 195
(Scheme 147) [612]. 2-Chloro-6,9-substituted purines 194
are obtained via an one-pot two-step reaction of 2,6-chloro-
purine with anilines or amines in the first step, followed by N -
alkylation or N -arylation at the 9-position with alkyl halides
or phenyl boronic acid, respectively. In a subsequent reaction
sequence the generated 2-chloro-6,9-substituted purines 194
are further reacted with various amines and anilines under
NaBF4 catalysis to finally provide the 2,6,9-functionalized
purines 195 in low to excellent yields (1399%).

OEE OTs
NC OBOM OEE OBOM
NC
LiN(TMS)2, dioxane
B C
MW, 145 C, 15 min A
H H 49%
TMSO OBn TMSO OBn
192

EE: ethoxyethyl AcO OH

BOM: benzyloxymethyl

HO A B C
D O
H
HO OAc
OBz
()-baccatin III, 193

Scheme 145 Intramolecular alkylation in the synthesis of ()-baccatin III

123
136 Mol Divers (2009) 13:71193

Ph NH
Ph NH R 1 R2 NH, DIPEA, (cat NaI)
N
N MeCN, NMP N
N
1
R N
N N N
F N MW, 220 C, 15 min Bu
Bu R2
7 examples
(50-95% conv)
Scheme 146 2-Amino-substituted purines via nucleophilic aromatic substitution

1. R 1 R2 NH, AcOH
R1 R2
Cl dioxane or DMF N
MW, 150 C, 10 min N
N N N

N 2. R 3 -Br, NaOH, DMF Cl N N

Cl N
H MW, 150 C, 10 min or 3
194 R
PhB(OH)2 , Cu(II)OAc
MS 4, Et3 N 14 examples
(17-94%)
MW, 150 C, 20 min
MW, 180 C R 4R 5 NH, NaBF4
R1 , R 2, R4 , R5 = H, alkyl, cyclic, aryl 5 min DMSO
R3 = Et, Bn, Ph
R1 R2
N

N N
R4 N
N N
R5 R3
195
12 examples
(13-99%)
Scheme 147 Synthesis of 2,6,9-substituted purines via nucleophilic aromatic substitution

R1
O2N HN O 2N
R2
R1
Cl MW, 80-120 C, 5-30 min N
2
HO O HO O R

R 1 , R2 = H, alkyl, cycloalkyl, (aryl)alkyl, aryl 23 examples

(30-99%)
Scheme 148 Nucleophilic aromatic substitution for the generation of 5-nitroanthranilic acid derivatives

The synthesis of N -substituted 5-nitroanthranilic acid Microwave-assisted nucleophilic aromatic substitutions

derivatives was disclosed by Christa Mller and Younis Baqi
from the University of Bonn (Scheme 148) [613]. The ami-
nation of 2-chloro-5-nitrobenzoic acid proceeded smoothly
with a variety of aryl- and alkylamines under catalyst- and
solvent-free microwave conditions. Aliphatic primary and
secondary amines only needed 5 min to give the products in
quantitative yields. In the absence of the NO2 -group in para-
position or the carboxylate in ortho-position, respectively,
no reaction occurred even under harsh reaction conditions
(200 C, 3 h).
have also been reported on halouracils (Scheme S246) [614],
polyfluoropyridine scaffolds (Scheme S247) [615], pentaflu-
orophenyl substrates (Scheme S248) [616], dichloropyri-
dines (Scheme S249) [617], 5-chloropyridazinones (Scheme
S250) [618], 4-chloroquinolines (Scheme S251) [619],
6-chloro-purines (Scheme S252) [620], and 4-chloro-7H -
pyrrolo[2,3-d]pyrimidines (Scheme S253) [621]. A tandem
cross-coupling/nucleophilic aromatic substitution approach
for the synthesis of carbazoles has been described by St. Jean
(Scheme S254) [622].

123
Mol Divers (2009) 13:71193 137

R1 R 1OH
O R 3 NH 2
n-BuOH A
HN
R2 N Cl MW, 150-200 C R2 N Cl R3
8-180 min
196
1
R = Me, Ph, i-Bu
R2 = H, Cl B
R3 = alkyl

R1 R1
OH
C

R2 N N R2 N N
R3 R3
197
28 examples
(28-95%)
Scheme 149 Synthesis of 7-azaindoles

R1

F H2 N R2 F R1
LiClO4 , THF N R2
O H
MW, 75 C, 1.5-3 h OH

198 199
R 1, R 2 = alkyl, aryl
12 examples
( 50-92%)
Scheme 150 Ring-opening of epoxides

2.13 Ring-opening reactions products 199 could be very easily identified by 19 F, 1 H, 13 C

Hartmut Schirok from Bayer HealthCare, has reported on
a short and flexible synthesis of 1,3-substituted 7-azaindoles
197 starting from oxiranes 196 (Scheme 149) [623]. The reac-
tion of epoxides 196 with a variety of substituted primary
amines proceeds via an epoxide-opening (A)/cylization (via
SN Ar, B)/dehydration (C) sequence, which is accelerated by
microwave irradiation. The higher temperature (200 C) was
required for the mono-chloro pyridine derivatives (R2 = H)
since they proved to be less reactive. As opposed to the
conventional heating protocol, no addition of an acid was
required for the dehydration step.
In a 2005 publication, Miquel A. Perics and co-workers
from Universitat de Barcelona have described the investiga-
tion of fluoroepoxide 198 as a new, chiral resolution reagent
(Scheme 150) [624]. By applying microwave heating, the
regioselective ring-opening of this reagent induced by -chi-
ral primary and secondary amines occurred in higher yields
and less byproducts were detected, compared with conven-
tional heating. Because of the use of readily available e-
nantiopure epoxide 198, the resulting diastereomeric amine
NMR and by HPLC.
For closely related examples published by the same group,
see Scheme S255 [625]. Similar epoxide ring-openings with
amines have also been described by Flitsch in the context
of synthesizing 1-aminopropan-2-ols with anti-malaria-para-
site activities (Scheme S256) [626]. The aminolysis of epox-
ides using microwave conditions has been reported by
Lindsay (Scheme S257) [627].
The ring-opening of cyclohexene epoxide with thiophenol
has been described by Pironti and Colonna (Scheme S258)
[628]. Ring-opening of fused epoxides with ammonia pro-
vides cyclic -aminoalcohols in good yields (Scheme S259)
[629]. For the ring-opening of epoxides with N -arylpipera-
zines, see Scheme S260 [630]. The ring-opening of an epox-
ide ring by an internally displayed indole nitrogen was used
in the total synthesis of balasubramide (Scheme S261) [631].
Ring-opening of (S)-N -tosyl-2-isopropylaziridine with
suitable amines provides polydentate chiral amines (Scheme
S262) [632]. -Hydroxyamides have been obtained by ring-
opening of oxazolidin-2,4-diones with NaOMe (Scheme
S263) [633].

123
138 Mol Divers (2009) 13:71193

H O
H 2O (cat AuBr 3)
Me
MW, 200 C, 20 min

R R
10 examples
R = H, OMe, NH 2, OH, OEt, Cl, Me, Br (30-100%)

H
H2O
Br
+ MW, 200 C, 20 min
MeO H 2N
200
Br

Me
201, 87%
MeO
Scheme 151 Hydration of alkynes in superheated water

Aryl pyranosides have been ring-opened by nucleophiles
in the presence of Sc(OTf)3 (Scheme S264) [634]. Cyclic
ureas have been ring-opened under acid catalysis to pro-
duce enantiomerically pure (S)-2-(aminomethyl)-4-phenyl-
butanoic acids (Scheme S265) [635].
2.14 Addition and elimination reactions
2.14.1 Michael additions
The Michael addition of phthalimide and saccharin to acrylic
acid esters in the presence of a ZnO catalyst has been reported
by Zare (Scheme S266) [636].
allylic amides 205 was elaborated where an alkyne was first
hydrozirconated by microwave irradiation, followed by rapid
addition of imines in the presence of dimethyl zinc.
Along similar lines the Zr(IV)-catalyzed hydroboration
of allyl propargyl esters was reported by the Nelson group
(Scheme S267) [639].
Stannylated allylsulfones can be prepared by hydrostan-
nylation of propargyl sulfones using a Mo catalyst (Scheme
S268) [640]. The same group has also reported the Mo-cat-
alyzed hydrostannation of simple alkynes with tributyltin
hydride (Schemes S269 and S270) [641,642].
2.14.3 Addition to alkenes

2.14.2 Addition to alkynes
Anil Vasudevan and Mary K. Verzal at Abbott Laborato-
ries have found that terminal acetylenes can be hydrated
under neutral, metal-free conditions using water as solvent
(Scheme 151) [637]. While typically this reaction requires
a catalyst such as AuBr3 , employing microwave-irradiated
superheated water allowed this chemistry to proceed without
any catalyst in distilled water. Extension of this methodology
led to a one-pot conversion of alkynes to imines (hydroam-
ination, e.g., 200201).
The group of Peter Wipf at the University of Pittsburgh has
reported in 2004 that the hydrozirconation of alkynes (e.g.,
202) with zirconocene hydrochloride (203) can be greatly
accelerated by microwave irradiation (Scheme 152) [638]. A
synthetically useful one-pot method for the preparation of
Ketophosphine-boranes have been prepared by the neat addi-
tion of boranephosphine complexes to activated olefins
(Scheme S271) [643]. Similarly, the microwave-assisted
addition of sodium bisulfite to activated olefins has been
reported by Crawley and co-workers (Scheme S272) [644].
-Hydroxy--amino acids can be synthesized by conjugate
addition of chiral amines to methacryloxy acrylates (Scheme
S273) [645].
2.14.4 Addition to nitriles
Bagley and co-workers have described the preparation of
primary thioamides by treatment of nitriles with ammonium
sulfide in methanol solution (Scheme 153) [646]. While the
reaction with electron-deficient aromatic nitriles proceeds
at room temperature, other aromatic and aliphatic nitriles

123
Mol Divers (2009) 13:71193 139

R H
Cp 2ZrHCl (203 ), toluene I

MW, 60 C, 30 min R

202; R = Me, Et then I2, THF 204

1. Cp 2ZrHCl, toluene
R1 NP(O)Ph2 MW, 60-80 C, 1-45 min
+
R2 Ar 2. Me2 Zn, -78 C to 0 C
3. imine, MW, 100 C, 1-15 min
Ar = Ph, p-MeO2 C-Ph
NHP(O)Ph 2

Ar R1
R2

205
8 examples
(60-95%)
Scheme 152 Hydrozirconationtransmetalationaldimine addition sequence

(NH4)2S, MeOH S H TCT, DCM, pyridine or TEA

N O R NC
R
R C N R NH2 MW, 50-100 C, 3-10 min
MW, 80-130 C, 15-30 min 15 examples
R = alkyl, aryl
10 examples (75-98%)
(35-98%) Cl

TCT = N N
Scheme 153 Preparation of primary thioamides
Cl N Cl

require microwave heating at 80130 C for 1530 min to Scheme 154 Synthesis of isonitriles
furnish the thioamides in moderate to high yields. This pro-
tocol avoids the use of hydrogen sulfide gas under high pres-
sure, proceeds in the absence of base and provides thioamides tert-butanesulfenic acid from tert-butanesulfinyl-protected
usually without the need for chromatographic purification. imines has been reported by Ellman (Scheme S275) [649].
Similarly, amidines have been obtained by addition of
ammonia to nitriles (Scheme S274) [647].
2.15 Substitution reactions

2.14.5 Elimination reactions
A recent publication by Andrea Porcheddu, Giampaolo
Giacomelli, and Marghareta Salaris from the University of
Sassari describes a simple and efficient method for the syn-
thesis of both aliphatic and aromatic isonitriles in high yields
(Scheme 154) [648]. By employing 1.33.0 equivalents of a
cheap dehydration agent such as 2,4,6-trichloro[1,3,5]
triazine (cyanuric chloride, TCT) aliphatic and aromatic for-
mamides have been transformed to their corresponding isoni-
triles in high yields at 50100 C within 310 min of
controlled microwave irradiation.
A one-pot method for the synthesis of nitriles from alde-
hydes via a microwave-assisted concerted elimination of
Rajender S. Varma and Yuhong Ju from the US Environmen-
tal Protection Agency have reported a double N -alkylation
by alkyl dihalides of aniline derivatives for the synthesis of
N -aryl azacycloalkanes (Scheme 155) [650]. By applying
microwave irradiation at 120 C for 20 min it was possible to
significantly improve the yields, compared with conventional
heating, which is related to the elimination of side-reactions.
This green chemistry approach uses very mild basic aque-
ous conditions which tolerates not only a variety of functional
groups but also simplifies the isolation of the either solid or
liquid products by the occurring phase separation.
The same authors have subsequently reported on the direct
syntheses of 4,5-dihydro-pyrazole, pyrazolidine, and 1,2-
dihydrophthalazine derivatives by double alkylation of

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140 Mol Divers (2009) 13:71193

R
X(CH 2) nX
R
Selectfluor O O
O O
NH2 K2CO3 , H 2 O
N (CH2 )n
MeCN
1
MW, 120 C, 20 min R1 R2 R R2
MW, 82 C, 10 min
F
R = H, Me, Et, Br, COMe, COOEt, NH 2 11 examples
R1 = Me, Ph "open vessel"
X = Cl, Br, I (42-96%) 70-86%
n = 3, 4, 5, 6 R2 = Ph, OEt, NMe2

Scheme 155 Synthesis of N -aryl azacycloalkanes Scheme 157 Electrophilic fluorination of 1,3-dicarbonyl compounds

hydrazine compounds with alkyl dihalides or tosylates
(Scheme 156) [651]. Using water as solvent, the reaction
could be performed under microwave heating at 120 C for
20 min without the need of a phase transfer catalyst, making
this protocol more environmentally friendly.
The same group has also presented the preparation of
azides, thiocyanates, and sulfones in aqueous medium by
nucleophilic displacement of halides or tosylates by the
appropriate nucleophile (Scheme S276) [652]. Displacement
of iodide with amino acid esters was used for the synthesis
of [CH2 NH] amide bond surrogates (Scheme S277) [653].
A recent publication by Ji-Chang Xiao and Jeanne M.
Shreeve from the University of Idaho describes the rapid
electrophilic fluorination of 1,3-dicarbonyl compounds using
Selectfluor
as fluorinating agent (Scheme 157) [654]. By
employing 1 equivalent of Selectfluor
under neutral reac-
tion conditions the 2-monofluorinated products were
obtained. Treatment of 1,3-dicarbonyls with 3 equivalents of
Selectfluor in the presence of tetrabutylammonium hydrox-
ide (TBAH) as base, difluorination can be achieved in a single
reaction step, also resulting in high yields.
Deoxyfluorinations of aminoalcohols without solvent
using N ,N -diethyl-, -difluorobenzylamine (DFBA) as
reagent have been reported by Hara and co-workers (Scheme
S278) [655]. Deoxyfluorinations of 3-deoxy-D-manno-2-oc-
turosonic acid using N ,N -diethyl-, -difluoro-(m-methyl-
benzyl)amine (DFMBA) as reagent have been studied by
Fukase (Scheme S279) [656]. Similar deoxyfluorinations of
primary alcohols can also be achieved using TBAFHF as
reagent (Scheme S280) [657]. Applying Et3 N3HF as
reagent, epoxides can be efficiently ring-opened to fluoro-
alcohols (Scheme S281) [658].
Nucleophilic substitution of chiral mesylates by Cs phen-
oxylates in the presence of 18-crown-6 provided the corre-
sponding aryl ether as a pure stereoisomer (Scheme S282)
Mg (turnings)
I2, THF
ArX ArMgX
MW, 100-170 C, 1 h
OH
PhCHO
MW, 100 C, 30 min Ar
+
H , H 2O
16 examples
(51-99%)
Scheme 158 Grignard reaction of aryl chlorides
[659]. Purines have been used as nucleophiles in substitution
reactions (Scheme S283) [660]. The cyanation of alkyl chlo-
rides with NaCN in MeCN has been demonstrated (Scheme
S284) [661]. For microwave-assisted Chichibabin reactions,
see Scheme S285 [662].
2.16 Organometallic transformations (Mg, Zn, Ti)
Mats Larhed and co-workers from Uppsala University, Swe-
den, have described a safe, productive, and reproducible labo-
ratory-scale protocol for fast generation of Grignard reagents
from reluctant aryl chlorides and bromides under controlled
microwave heating (Scheme 158) [663]. The Grignard
reagents prepared in this way have been used as precur-
sors to promote a subsequent microwave-assisted Kumada
coupling, toward the synthesis of novel human immune-defi-
ciency virus-1 (HIV-1) protease inhibitor. The microwave-
induced (150 C for 1 h) Grignard formation in most of the
aryl chlorides was initiated using only catalytic amounts of
iodine as the sole activator.
Paul Knochel and Stefan Wunderlich from Ludwig-Max-
imilians-Universitt, Munich, have reported on the direct
zincation of highly functionalized aryl and heteroaryl deriva-
tives using the complex base (tmp)2 Zn 2MgCl2 2LiCl

H Br Br Cl
Cl N K2CO3, H2O
NH2 N
MW, 120 C, 20 min N

+ 15 related examples
(60-89%)
Scheme 156 Cyclocondensation of hydrazine derivatives with alkyl dihalides or ditosylates

123
Mol Divers (2009) 13:71193 141

R1 R1
2 (tmp)2 Zn*2MgCl2*2LiCl R 2
Zn
R
THF
2
R3 MW, 80-120 C, 1-5 h R3
R4 R4

R 1 = H, CN, CO2Et, CO2 Me, CONEt 2 13 examples

R 2 = H, F, COPh, CO2 Et
R 3 = H, CO2Me
R 4 = H, Cl, Br, F, CN, CO2Et

tmp: 2,2,6,6-tetramethylpiperidyl
Scheme 159 High-temperature zincation of functionalized (het)aromatics

(Scheme 159) [664]. With microwave heating a tremendous O Zn, THF O

time saving could be achieved; e.g. for derivatives with Br XR 1 BrZn XR1
MW, 100 C, 5 min
R1 = CO2 Et, R2 = R3 = H, R4 = Cl, Br the reaction
XR1 = Ot-Bu, NBn2
time could be reduced from 110 h at 25 C to 2 h at 80 C.
Interestingly, for substrates with R1 = CO2 Et, CONEt2 , R2 Br Pd(PPh 3) 4, THF
R2 = R3 = R4 = H microwave heating is crucial since Y Z MW, 120 C, 5 min

under oil-bath heating at the same temperature a very low Y, Z = CH, N

yield is obtained (1020% versus >90%). Importantly, sen- O
sitive functional groups are well tolerated under the reaction 2 XR1
R
conditions. This zincation protocol was further successfully Y Z
applied to heterocyclic systems such as pyridines, benzothio- 18 examples
phene or benzofuran. In a postderivatization step, the bis-zin- (18-98%)

cated species were further transformed via Cu-mediated or Scheme 160 -Arylation of esters using Reformatsky reagents
Pd-catalyzed reactions.
Mark G. Moloney and co-workers from Oxford Univer- Zn, I 2, THF EtO 2C CO 2Et
EtO2 C CO 2Et R2
sity have reported the Pd-catalyzed -arylation of esters and + Me
Me Br MW, 100 C, 10-35 min R1
amides with organozinc reagents in a one-pot fashion R1
R 2

(Scheme 160) [665]. The required Reformatsky reagents R1 = Me, Ph, p-MeOPh 206a; R2 = CO2t -Bu
8 examples
p-ClPh 206b; R2 = CN
were readily prepared by microwave irradiation of the corre- (34-99%)

sponding bromoacetate or bromoacetamide with Zn in THF
for 5 min at 100 C. Addition of this Reformatsky reagent
to the coupling partner, an aryl bromide and the relevant
catalyst/ligand in THF followed by further irradiation for
510 min at 120 C provided the arylacetic esters or amides
in good yields.
More recently, a reexamination of the reactivity of
Reformatsky reagents in conjugate additions was performed
by the same group. t-Butyl 2-bromopropionate 206a and 2-
bromopropionitrile 206b were used as Reformatsky reagent
precursors in the reaction with , -unsaturated malonate
esters under both microwave and conventional conditions
(Scheme 161) [666]. Compared with thermal heating, the
protocol could be simplified when microwave irradiation is
applied. The Reformatsky reagents are formed in situ when
activated Zn, iodine, precursors 206a and 206b, respectively,
and malonates in THF are microwave heated. Bromopro-
pionitrile 206b showed increased reactivity compared with
the thermal approach, whereas bromopropionate 206a gave
higher yields only when being activated (R1 = p-ClPh).
Scheme 161 Reformatsky conjugate additions
The groups of Antonio Braga and Ludger Wessjohann
from Universidade Federal de Santa Maria, Brazil, and the
Leibniz Institute of Plant Biochemistry, Germany, have
reported on the arylation of aromatic aldehydes via aryl-
zinc addition using an aziridine-based ligand (Scheme 162)
[667]. Employing microwave heating, the reactive arylzinc
species are generated from aryl boronic acids and Et2 Zn in
only 10 min followed by the addition of the aldehyde and lig-
and and further microwave heating for 5 min. The reaction
time can be reduced from 1 day conventionally to only 15 min
under microwave conditions. A key feature of this method is
that both enantiomers of the product can be obtained selec-
tively using only one enantiomer of the ligand by interchang-
ing the functional groups of the boronic acids and aldehydes.
Enantioselective addition of aromatic aldehydes to Et2 Zn
catalyzed by chiral aminonaphthols was described by Flp
(Scheme S286) [668]. Similar results were obtained by

123
142 Mol Divers (2009) 13:71193

1. toluene
O Cp2TiMe2
MW, 60 C, 10 min OH toluene / THF
O O
Ar1 B(OH)2 + Et2 Zn R R
2
2. Ar CHO, ligand Ar1 Ar2
O MW, 120-150 C, 0.5-3 h O
MW, 60 C, 5 min
6 examples 5 examples
(88-98%, 70-98% ee) (20-82%)
Ar 1, Ar 2 = Ph, o-MePh, p -MePh,
p-ClPh, o-ClPh
R = OEt, OCH 2Ph, OCH 2C 6H 4-4-OMe, NMe 2, HN
Trit: triphenylmethyl
ligand
Ph Scheme 163 Petasis olefination of unsymmetrical oxalates
Ph
H
OH
N
Trit
O
R
low valent Ti, THF
Scheme 162 Enantioselective arylation of aromatic aldehydes R
2
MW, 110 C, 10 min
R

R = H, aryl, alkyl 5 examples

Espinet using Me2 Zn and chiral -aminoalcohols (Scheme S287)
[669].
The synthesis of pyruvate-based enol ethers and enam-
ines via the Petasis olefination has been demonstrated by
Timothy Gallagher and co-workers from the University of
Bristol (Scheme 163) [670]. The olefination of unsymmetri-
cal oxalates is highly regioselective by employing the Peta-
sis reagent and is dramatically improved when microwave
heating is applied. Shorter reaction times and higher yields
are achieved by irradiating in toluene/THF for 0.53 h at
120150 C.
Other microwave-assisted Petasis olefinations have been
described in the recent literature (Scheme S288) [671]. For
examples of microwave-assisted Wittig olefinations, see
Schemes S289S291 [672674]. novel protocol include aliphatic and aromatic aldehydes
Nicolai Stuhr-Hansen from the University of Copenha-
gen has reported on a microwave-induced high-yielding syn-
thesis of alkenes by McMurry coupling of aldehydes and
ketones with low-valent titanium (Scheme 164) [675]. For
all the aldehydes and ketones studied, including sulfur end- Johnson utilized successive reductive aminations and Suzuki
capped analogues, within 10 min of microwave heating, even
at low-energy microwave conditions, complete conversion
and above 80% yields of corresponding alkenes were rea-
lized. With microwave heating, the corresponding alkenes
have been produced much faster with higher yields as
compared with conventional heating, and in some cases
without damaging the sensitive tert-butyl sulfur protecting
groups.
2.17 Reductive aminations
A team from Medivir Ltd. in the UK has described a fast pro-
tocol for the direct reductive amination of aldehydes which
uses dibutyltin dichloride as catalyst in the presence of
phenylsilane as reductant (Scheme 165) [676]. Best results
are obtained utilizing 10 mol% of dibutyltin dichloride as
a catalyst and 2 equivalents of phenylsilane as the reducing
agent, employing THF as solvent and sealed vessel micro-
(82-93%)
Scheme 164 Synthesis of alkenes by McMurry reaction
O R
2
R3 PhSiH3, Bu2SnCl2 R2 R3
+ N N
R1 H MW, 100 C, 7 min
H R1 H
20 examples
(41-93%)
Scheme 165 Direct reductive amination of aldehydes
wave heating at 100 C for 7 min. Suitable reactants for this
building blocks on the one hand, and anilines, and secondary
and primary amines on the other. Work-up typically involves
extraction or cation exchange methods.
Steve Coats and a group of researchers from Johnson and
cross-coupling reactions to prepare a 192-member library of
tropanylidene benzamides (Scheme 166) [677]. This series
of tropanylidene opioid agonists proved extremely tolerant
of structural variation while maintaining excellent opioid
activity. For the solution-phase preparation of functionalized
tropanylidenes those authors simply dispensed 1,2-dichloro-
ethane (DCE) solutions of the bromo NH precursor to a set
of microwave vials, added the aldehydes (3 equiv.) and a solu-
tion of sodium triacetoxy borohydride in dimethylformamide
(2 equiv.), and subjected the mixture to microwave irradia-
tion for 6 min at 120 C. Quenching the reductive amination
with water and subsequent concentration allowed to directly
perform a microwave-assisted Suzuki reaction on the crude
products.
A related two-step procedure for the preparation of
N -alkylated glycine methyl esters from glycine methyl ester
and aldehydes was described by Santagada and co-workers
(Scheme S292) [678].

123
Mol Divers (2009) 13:71193 143

O
O

NHEt R1CHO, NaBH(OAc)3 NHEt

DCE, DMF, AcOH Br
Br

MW, 120 C, 6 min

then evaporation N
N
H R1
O

R2B(OH)2, Pd(PPh3)4 NHEt

2
K2CO3, DMF, H2O R

192 examples
MW, 180 C, 10 min (purified by HPLC)
N

R1
Scheme 166 Reductive aminations in combination with Suzuki-type couplings in library synthesis

R3 Pd/C (1.7 mol%) O O DABAL-Me 3, THF O

H2 O + H N
NH R OMe R N
MW, 130 C, 5-16 m in
R1 R2
R1 R2 MW, 50 W, 5-60 min
6 examples R = Ph, Cy, propenyl 9 examples
DABAL-Me 3 (52-98%)
R1 , R 2 = alkyl, Ph (56-100%)
Me3 Al N N AlMe3
R3 = alkyl, H

Scheme 167 Retro-reductive aminations

Scheme 168 Synthesis of tertiary amides from esters

Microwave-promoted direct transformations of amines to

ketones have been disclosed by Akira Miyazawa and co-
workers from the AIST-Institute in Japan (Scheme 167) [679].
By using water as an oxygen source and catalytic amounts
of Pd/C, the retro-reductive amination of mono- or di-sec-
alkylamines to the corresponding ketones was performed
very efficiently. This new and green method provides the
ketones in a high selectivity and faster rate compared with
other methods which use late transition-metal oxidants (e.g.,
KMnO4 , Pb(OAc)4 ) in large amounts and strong bases such
as n-butyllithium.
A special case of reductive amination was described by
Kann in the preparation of P-chirogenic -amino phosphine
boranes starting from the corresponding P-chirogenic alde-
hydes, amines, and NaBH(OAc)3 (Scheme S293) [680].
2.18 Ester and amide formation
Simon Woodward and co-workers from the University of
Nottingham have demonstrated the direct coupling of cyclic
secondary amines with esters employing the air-stable tri-
methylaluminum source DABAL-Me3 for the preparation of
tertiary amides (Scheme 168) [681]. Microwave heating at
130 C for 516 min afforded the amides in good to excel-
lent yields, with the longer reaction times necessary for more
hindered amineester pairs. Weinreb amides can be also pre-
pared in good yields by using a one-pot in situ deprotonation
with NaH to liberate the free N -methoxy-N -methylamine
followed by the coupling step.
Benzoic acid amides have been obtained by direct, sol-
vent-free amidation of benzoic acid with a variety of amines
(Scheme S294) [682]. Similar results have been disclosed
using acetic acid (Scheme S295) [683]. Benzoic acid amides
have also been obtained by solvent-free Ritter reaction
involving the reaction of benzylic alcohols with benzonitr-
iles catalyzed by Nafion NR50 (Scheme S296) [684]. Sali-
cylamides have been obtained via BCl3 -mediated coupling
of phenols with isocyanates (Scheme S297) [685]. Succin-
imides can be prepared from succinic anhydrides and
hydrazines using water as solvent (Scheme S298) [686], or
by treatment with amines under solvent-free conditions
(Scheme S299) [687]. Hydroxamic acids can be formed
directly from esters and hydroxylamine under microwave
conditions (Scheme S300) [688]. Sterically hindered amino

123
144
R CO 2Et
Bu3 SnH, AIBN, toluene
Br
R N Ar MW, 100-105 C, 3.5 h
Moc "open vessel"
207
R = H, OMe
Ar = (het)aryl
EtO2 C
R R
5-exo-trig
Ar
N N
R R
Moc
7 examples
(25-89%)
Scheme 169 Synthesis of 2-arylindoles via tandem radical cyclization
acids such as N -benzylaminoisobutyric acid can be incorpo-
rated into dipeptides under microwave irradiation in the pres-
ence of zinc dust (Scheme S301) [689]. Similar results can be
obtained with benzotriazol-activated N -protected amino
acids (Schemes S302 and S303) [690,691]. Sulfonamides
have been obtained directly from sulfonic acids and amines
using 2,4,6-trichloro-[1,3,5]triazine as dehydrating agent
(Scheme S304) [692]. Alternatively, the treatment of
sulfonylchlorides with N -arylpiperidines in the presence of
Et3 N base has also been reported (Scheme S305) [693].
Radical cyclizations of N -allyl-2-nitroanilines to yield
substituted 1,2,3,4-tetrahydroquinoxalines have been
described by Beifuss (Schemes S309 and S310) [700,701].
Ester bonds have been formed starting from benzotriazol-
activated N -protected amino acids and terpene alcohols
(Scheme S306) [694]. Carboxylic acid esters can be transe-
sterified with methanol (and other alcohols) using Sc(OTf)3
as a catalyst (Scheme S307) [695].
2.19 Radical reactions
The synthesis of 2-arylindoles 209 via tandem radical cycli-
zation of the corresponding acrylates 207 and subsequent
oxidation was reported by the group of Oliver Reiser from
the University of Regensburg, Germany (Scheme 169) [696].
In the first step of the synthesis, acrylates 207 are transformed
to 2-arylindolines 208 by a tributyltin-hydride-mediated rad-
ical cyclization involving a 1,6-H transfer followed by a
5-exo ring-closure under open-vessel microwave conditions.
For the aromatization step, DDQ proved to be the oxida-
tion reagent of choice and 2-arylindoles were obtained in
good yields. For both procedures, higher yields and reduced
reaction times could be achieved when applying microwave
heating.
123
Mol Divers (2009) 13:71193
R CO2 Et R CO 2Et
1,6-H
H
R N Ar R N Ar
Moc Moc
EtO 2 C EtO2 C
DDQ, toluene R
Ar Ar
MW, 120 C, 4 h R N
208 Moc 209 Moc
6 examples
(55-69%)
John Walton and co-workers from the University of
St. Andrews have reported on the use of O-phenyl oxime
ethers as precursors for iminyl radicals en route for N -het-
erocycle synthesis (Scheme 170) [697]. Microwave irradi-
ation was employed for the thermolysis of functionalized
O-phenyl oximes 210 generating the iminyl radicals 211
followed by cyclization to the corresponding heterocycles.
For the synthesis of dihydropyrroles 212, toluene is used as
solvent whereas a non-H-atom donor solvent such as t-butyl-
benzene has to be employed for cyclizations onto aromatic
radical acceptors for the synthesis of quinolines, phenanthri-
dines (213, X = CH), benzonaphthiridines (213, X = N), and
indolopyridines. For both protocols the ionic liquid emimPF6
needs to be used in order to reach the 160 C reaction tem-
perature. With this method, no initiator is necessary and, in
combination with microwave heating, cleaner product mix-
tures and shortened reaction times can be achieved; see also
Scheme S308 [698].
An efficient one-pot sequence comprising a homolytic
aromatic substitution followed by an ionic HornerWads-
worthEmmons olefination for the production of a small
library of , -unsaturated oxindoles was disclosed by Arm-
ido Studer and co-workers from The Philipps-Universitt
Marburg (Scheme 171) [699]. Suitable 2,2,6,6-tetramethyl-
pipedinyloxy (TEMPO)-derived alkoxyamine precursors
were exposed to microwave irradiation in DMF for 2 min to
generate an oxindole intermediate via a radical reaction path-
way (intramolecular homolytic aromatic substitution). After
addition of KOt-Bu base and a suitable aromatic aldehyde
the mixture was exposed again to microwave irradiation at
180 C for 6 min to provide the , -unsaturated oxindoles
in moderate to high overall yields.
Radical addition reactions of diphenylphosphine sulfide to
olefins have been reported (Scheme S311) [702]. A related
Mol Divers (2009) 13:71193 145

R2 R2 R2
R3
PhO toluene, emimPF6
3
N R3 N R
N
MW, 160 C, 15 min 1
1 R
R R1
210 211 212
R 1 = Me, esters, aryl 5 examples
(70-82%)
R 2, R 3 = H, Me, alkyl
R 4 = H, Br, CN, OMe
X = CH, N
R4
R4

X t-BuPh, emimPF6 X

N 213
N MW, 160 C, 30 min
OPh
210 9 examples
(62-76%)
+ 5 related examples
(46-69%)

Scheme 170 Synthesis of N -heterocycles via iminyl radicals

O O
EtO O
P Me Me
EtO N N
DMF O
O
P
N MW, 180 C, 2 min EtO
OEt

81%

O Me
N
KOt-Bu, ArCHO Ar
MW, 180 C, 6 min

8 examples
(43-87%)
Scheme 171 Homolytic aromatic substitution/HornerWadsworthEmmons olefinations

publication describes the radical addition of phosphorous O 1. TFA, DCM

hydrides to bis-olefines (Scheme S312) [703]. Bergmann
cyclizations leading to poly-N -heterocycles assisted by
microwave irradiation at high temperatures have been
described (Scheme S313) [704]. Microwave irradiation of
N -(alkoxy) thiazole-2(3H )-thiones generates alkoxy radi-
cals which have been used by Hartung and co-workers for
additions, -fragmentations, and remote functionalizations
(Scheme S314) [705].
2.20 Protection/deprotection chemistry
A. Ganesan and his group from the University of South-
ampton have demonstrated a rapid method for the deprotec-
tion of N -Boc-protected amines using microwave irradiation
(Scheme 172) [706]. The procedure utilizes 5 equiv. of triflu-
oroacetic acid (TFA) and DCM as solvent. The protected
MW, 60 C, 30 min R
R NH 2
N Ot-Bu
H 2. Amberlyst A-21, rt, 30 min
12 examples
(28-99%)
Scheme 172 Rapid deprotection of N -Boc amines
amines are heated at 60 C for 30 min in the cleavage cock-
tail. The free-base amines can be rapidly isolated by scaveng-
ing the crude reaction mixture with basic Amberlyst A-221
ion-exchange resin.
N -Boc deprotections of lactams were reported using SiO2
as support under solvent-free conditions (Scheme S315)
[707]. An aqueous N -Boc deprotection of a dipeptide was
used in the synthesis of the Schllkopf chiral auxiliary
(Scheme S316) [708].

123
146 Mol Divers (2009) 13:71193

OH OS
HO Me3N.SO3, Et3N, MeCN SO

N N
HO OH MW, 100 C, 20 min SO OS
O O
85%
+ 3 related examples
S = SO3Na (54-87%)

HO SO
H H
HOH2C SOH2C
O H SO3.py, pyridine O H
HO O SO O
MW, 120 C, 10 min
HO OH SO OS
HO SO
72%
+ 2 related examples
(84-94%)
Scheme 173 Synthesis of highly sulfated organic scaffolds

Umesh Desai and co-workers from Virginia Commonwe-

alth University have disclosed the sulfation of polyhydroxyl O HCl/EtOH O
scaffolds (Scheme 173) [709]. This otherwise troublesome Br 14 C Br 14 C
OH MW, 110 C, 30 min OEt
reaction proceeded well under microwave heating 9.88 mCi
employing either Me3 N SO3 (69 equiv./OH) and Et3 N
(10 equiv./OH) as base or SO3 py (612 equiv./OH) and O O

pyridine (10 equiv./OH), respectively, giving the per-sulfated O Me

Me OEt O
products in high yields and short reaction times. With this EtOH/NaOEt EtO 14 C HCl/H2O
OEt
method a range of functional groups are tolerated (amides, MW, 65 C, 16 min MW, 130 C, 10 min
O
esters, aldehydes), alcoholic and phenolic OH-groups are sul-
fated equally well, and the products are obtained in high O
purities. Me 14 C
OEt
The selective monodecarboxylation of a chiral substituted
O
dimethylmalonate was achieved by Schaus using microwave 73%
(7.17 mCi)
heating in DMSO containing small amounts of water
(Scheme S317) [710]. In the carbohydrate field, a similar Scheme 174 Synthesis of radio-labeled levulinic acid
transformation was reported by Linker using LiI in DMSO
(Scheme S318) [711]. In the total synthesis of mersicarpine
the selective mono-decarboxylation of a dimethylmalonate
unit was accomplished by Kerr employing LiCl in DMF
(Scheme S319) [712].
2.21 Preparation of isotope-labeled compounds
Pyridine- and solvent-free acetylation of nucleosides
employing Ac2 O in combination with molecular sieves have
The synthesis of [1-14 C]levulinic acid has been demonstrated
been reported by Sa and Meier (Scheme S320) [713]. The
by Steen K. Johansen and co-workers from Denmark (Scheme
transprotection of aryl methyl ethers to aryl benzoates using
174) [717]. In all three of the synthetic steps, starting from
benzoyl chloride in combination with hexabutylguanidini-
bromo[1-14 C]acetic acid, microwave heating was used in
um chloride hydrochloride as reagent has been disclosed
order to accelerate the reactions, allowing the total prep-
by Gras (Scheme S321) [714]. Phenols can be rapidly pro-
aration to proceed in less than 1 h. The labeled levulinic
tected with a 4-methoxybenzyl protection group by treatment
acid was subsequently transformed into (5Z )-4-bromo-5-
with 4-methoxybenzyl chloride in DMF in the presence of
(bromomethylene)-2(5H )-furanone in a bromination/oxida-
K2 CO3 applying microwave irradiation (or ultrasound)
tion sequence (not shown), a potent quorum sensing inhibitor.
(Scheme S322) [715]. Acetal and ketal formation can be effi-
Deuterated anilines can be prepared by selective deutera-
ciently performed using In(OTf)3 as a catalyst (Scheme
tion of anilines in o- and p-position using 1 equiv. conc. HCl
S323) [716].
in D2 O (Scheme S324) [718].

123
Mol Divers (2009) 13:71193 147

(a) O LnX2, THF OH OH

1 2 R1 R1
R R MW, 180 C 2 2
R R
1 2
5-60 min
R , R = alkyl, aryl, H 23 examples
(16-99%)

(b)
LnX2, THF O O
O ( )n
( )n ( )n
MW, 180 C
I 10-30 min
214 215
n = 1, 2, 3 12 examples
(0-99%) (0-95%)
Scheme 175 Exploring SmBr2 -, SmI2 -, and YbI2 -mediated reactions

O O O
(CHO) n
PSSA/H 2O O

O MW, 120 C, 30 min O

85%
+ 11 related examples
PSSA: polystyrenesulfonic acid (30-84%)
Scheme 176 Tandem bis-aldol reaction of ketones

2.22 Miscellaneous transformations
Gran Hilmersson and co-workers from Gteborg University
have investigated the use of lanthanide(II) halides (LnX2 =
SmBr2 , SmI2 , YbI2 ) in microwave-assisted reduction and
reductive coupling reactions without the use of a co-sol-
vent for a variety of functional groups such as , -unsat-
urated esters, aldehydes, ketones, imines, and alkyl halides
(Scheme 175) [719]. A strong influence on the direction of
the reactions was found to be the redox potential of the LnX2
reagent, i.e., SmBr2 induced mainly the pinacol-coupling of
ketones (reaction a) or the intramolecular reductive coupling,
respectively, (215, reaction b) while the weaker YbI2 affor-
ded mainly the reduction products (214, reaction b).
In order to attach a 1,3-dioxane moiety to ketones, Raj-
ender Varma and Vivek Polshettiwar from the National Risk
Management Research Laboratory, Ohio, have performed
tandem bis-aldol reactions of ketones with paraformaldehyde
(Scheme 176) [720]. This one-pot protocol can be considered
as ecofriendly, since polymer-supported polystyrenesulfonic
acid (PSSA) and water as solvent are employed. Further-
more, phase separation under hot conditions occurred for
most of the examples, thus facilitating the purification step
(only decantation is needed).
Chiral N -Boc- and Cbz-protected (-aminoacyl)benzo-
triazoles react with ethyl (triphenylphosphoranylidene)ace-
tate to produce chiral phosphorus ylides (Scheme S325)
[721]. A one-pot intramolecular aldol process to synthesize
bicyclo[2.2.2]oct-5-en-2-ones has been developed in which
a cyclic or acyclic ketone is reacted with a cyclic enone in
the presence of strong acid (Scheme S326) [722]. FeBr3 -pro-
moted oxidations of diarylalkynes to the corresponding dike-
tones in DMSO as solvent have been reported (Scheme S327)
[723]. For Pb(OAc)4 -promoted domino transformation lead-
ing to complex oxygen heterocycles, see Scheme S328 [724].
Microwave-assisted FriedelCrafts acylations catalyzed by
BCl3 have been discussed by Zhang (Scheme S329) [725].
For the oxidation of Hantzsch-type dihydropyridines to pyr-
idines with MnO2 see Scheme S330 [726]. Cyclic amidines
can be obtained from the corresponding lactams and amines
using TiCl4 as a reagent (Scheme S331) [727]. The construc-
tion of substituted phenanthrenes via intramolecular conden-
sation of 2 -methylbiphenyl-2-carbaldehydes using a mild
base at 200 C has been described (Scheme S332) [728].
CuBr-catalyzed homologation of alk-1-ynes with parafor-
maldehyde and N ,N -dicyclohexylamine afforded the
corresponding allenes (Scheme S333) [729]. MoritaBaylis
Hillman reactions have been performed in water/ionic liquid
medium catalyzed by 1,4-diazabicyclo[2.2.2]octane
(DABCO) (Scheme S334) [730]. For an example of a micro-
wave-assisted Grob fragmentation used in the synthesis of
lamellarin alkaloids, see Scheme S335 [731].

123
148 Mol Divers (2009) 13:71193

R1 PaalKnorr reactions involving a specific set of 1,4-dicar-

O
Mg3 N2, MeOH HN
R2
R1
O MW, 120 C, 1-8 h R2
R1 = Me, t -Bu, Ph 6 examples
(72-99%)
R2 = alkyl, aryl
Scheme 177 Synthesis of pyrroles using magnesium nitride as ammo-
nia source
2.23 Heterocycle synthesis
2.23.1 Three-membered heterocycles with one heteroatom
Aziridine-fused 2-azabicyclo[2.2.1]hept-5-en-3-ones have
been obtained by cycloaddition of azides to the bicyclohep-
tene core (Scheme S336) [732].
2.23.2 Four-membered heterocycles with one heteroatom
-Lactams have been obtained by [2+2] cycloaddition of ket-
enes with imines under microwave conditions (Schemes S337
and S338) [733,734].
2.23.3 Five-membered heterocycles with one heteroatom
2.23.3.1 Pyrroles
The group of Steven Ley from the University of Cambridge
has reported on the synthesis of substituted pyrroles from
the corresponding 1,4-dicarbonyl compounds via the Paal
Knorr reaction (Scheme 177) [735]. Magnesium nitride
(Mg3 N2 ) was used as source of ammonia which is generated
in situ by the reaction of Mg3 N2 with protic solvents such as
MeOH. Reaction times were typically 1 h, the only exception
being the derivative with R1 = R2 = t-Bu where 8 h irra-
diation was necessary to achieve complete conversion. With
respect to scale-up and library synthesis the authors prepared
pyrroles under thermal heating at 80 C as well. Here, a 24-h
reaction time is necessary for providing the products in good
to excellent yields.
bonyl compounds and amines under microwave conditions
have been reported by Werner and Brummond (Scheme S339)
[736]. The same strategy has also been used to prepare N -
phenylpyrroles using aniline (Scheme S340) [737]. 3,
4-Disubstituted pyrroles have also been obtained by Piloty
Robinson synthesis (Scheme S341) [738]. For an alternative
microwave-assisted pyrrole synthesis, see Scheme S342
[739].
The synthesis of indolizinones via a thermally induced
cycloisomerization of tertiary propargylic alcohols was
described by Ikyon Kim and co-workers from the Korea
Research Institute of Chemical Technology (Scheme 178)
[740]. Heating the starting materials in EtOH to 150 C with-
out the addition of a catalyst afforded the indolizinones in
excellent yields. Compared with conventional heating in re-
fluxing EtOH the reactions could be accelerated from 24
36 h to only 2030 min (the longer reaction time is necessary
when R2 = t-Bu) with similar isolated product yields.
A microwave-assisted Fischer indole synthesis using
ZnCl2 in triethylene glycol as reaction medium has been
reported by Lipinska (Schemes S343 and S344) [741,742].
Indoles have also been obtained by reaction of (2-amino-
benzyl) triphenylphosphonium bromide with aromatic alde-
hydes or , -unsaturated aldehydes (Scheme S345) [743],
and by Pd-catalyzed intramolecular cyclization of N -vinyl-
2-chloroanilines (Scheme S346) [744]. Isoindoles have been
obtained by microwave irradiation of o-substituted aryl-
oximes in the presence of Ac2 O which undergo a sp3
CH activated cyclization (Scheme S347) [745].
2.23.3.2 Furans
Alain Wagner, Rachid Baati, and co-workers from Universit
Louis Pasteur have disclosed the synthesis of 4-keto-4,5,6,
7-tetrahydrobenzofurans via an intramolecular cyclization
of triketones (Scheme 179) [746]. Key to the success was
the employment of 4 equiv. TMS-Cl in MeOH as a source
of anhydrous HCl. In general excellent product yields are
obtained; only for 1,3-dicarbonyls with an amide function-
ality was a lower yield (56%) of the corresponding oxazole
achieved. Whereas acyclic and seven-membered triketones

R1 OH
R1 O
EtOH

N R2 MW, 150 C, 20-30 min N

R2
R1 = Me, Et, Ph, py 12 examples
R2 = alkyl, cyclic alkyl, (het)aryl (100%)
Scheme 178 Catalyst-free cycloisomerization approach to indolizinones

123
Mol Divers (2009) 13:71193 149

O O

TMSCl, MeOH
Me Me
O O
Me O MW, 90 C, 8 min Me
100%
+ 10 related examples
(56-100%)
Scheme 179 Synthesis of 4-keto-4,5,6,7-tetrahydrobenzofurans

O O OH
O
+ NaH, DME CF3
R F3 C OEt R X
X MW, 160 C, 10 min
216
12 examples
(61-95%)

O OH
H
N Si-TsOH, EtOH
CF3 + NH 2
R X MW, 160 C, 5 min
Me
R = Me, dimethyl, Et, Cy, CN, OMe, F
X = C, N
Me

N N
CF 3
R X
217
12 examples
(42-95%)
Scheme 180 Synthesis of 1,5-diarylpyrazoles

furnished the products in high yields, five-membered trike-
tones were completely unreactive and only starting material
was recovered.
A closely related strategy developed by Mulzer uses HCl
in EtOH to form a furan ring from a 1,4-dicarbonyl compo-
nent as part of the total synthesis of providencin (Scheme
S348) [747]. Benzofurans have been obtained in one-pot
from o-bromophenols and ketones using Pd-catalyzed eno-
late arylation chemistry (Scheme S349) [748].
2.23.4 Five-membered heterocycles with two heteroatoms
2.23.4.1 Pyrazoles
Paul Humphries and Jennifer Finefield from Pfizer have
described the two-step synthesis of pyrazoles using micro-
wave heating for both steps (Scheme 180) [749]. In the first
step, the enol ketone precursor 216 was prepared from aryl
methyl ketones and ethyl trifluoroacetate. For the second
step, enole ketones were reacted with 4-methylphenyl hydra-
zine and silica-supported p-toluenesulfonic acid (Si-TsOH)
to give the corresponding pyrazoles 217 in good to excel-
lent yields. Compared with standard p-TsOH, higher yields
could be achieved using Si-TsOH and additionally the reac-
tion work-up was simplified.
For an application of this strategy to the generation of
analogs of the pyrazole cyclooxygenase-2 (COX-2) inhibi-
tor Celecoxib, see Scheme S350 [750].
In a related fashion, the condensation of hydrazines with
-cyano-acetophenones produced 5-aminopyrazoles
(Scheme S351) [751]. A multistep microwave approach for
the synthesis of N -pyrazole ureas including the preparation
of the p38 inhibitor BIRB 796 was disclosed by Bagley and
co-workers (Scheme S352) [752]. Alternative pyrazole syn-
thesis involving hydrazine building blocks have been reported
(Schemes S353S356) [753756].
2.23.4.2 Imidazoles
A simple, high-yielding synthesis of 2,4,5-trisubstituted imi-
dazoles of type 218 from 1,2-diketones and aldehydes in
the presence of ammonium acetate was recently reported by

123
150 Mol Divers (2009) 13:71193

R1 H tuted imidazo[1,2-a]pyridine derivatives via a one-pot,

O NH4OAc, AcOH R1 N
O
+ R3 three-step cyclization/Suzuki coupling/Pd-catalyzed hetero-
MW, 180 C, 5 min N
R2 O H R3 R2 arylation sequence (Scheme 183) [759]. In previous optimi-
218 zation studies, the best conditions for a one-pot, two-step
R1, R2, R3 = alkyl, (het)aryl
13 examples Suzuki reaction/heteroarylation starting from 6-bromoimi-
(76-99%)
dazo[1,2-a]pyridine were evaluated. Pd(OAc)2 /PPh3 proved
for R1, R2, R3 = Me to be superior to Pd(PPh3 )4 as catalyst system for the reac-
Ph
PhCH2Cl, TEA
MeCN Me N
tion sequence; in addition it is essential to perform the Suzuki
Me coupling as first step. In the three-step sequence, 2-amino-5-
MW, 180 C, 5 min
Me N+ bromopyridine was reacted with -halogenocarbonyls 219 to
_
Cl Ph 6-bromoimidazo[1,2-]pyridine derivatives followed by the
43% Suzuki coupling and heteroarylation in the same pot, giving
lepidiline B the products in somewhat lower yields compared with the
Scheme 181 One-pot imidazole synthesis
two-step sequence.
Using a somewhat related strategy, Erik Van der Eycken
and Denis Ermolatev from the University of Leuven pre-
R1 O R1 N pared 1-substituted and 1-unsubstituted 2-aminoimidazoles
H2N MeCN
+ NAc NHAc of type 221 and 223 (Scheme 184) [760]. By a cycloconden-
R2 Br H2N MW, 100 C, 10 min R 2 N
sation sequence of 2-aminopyrimidines with -bromo car-
H
bonyl compounds at 150 C imidazopyrimidinium salts 220
R1 = alkyl, aryl 19 examples
(92-99%) are obtained as intermediates which undergo cleavage using
R2 = H, Me, Ph
hydrazine hydrate furnishing 1-substituted 2-aminoimidaz-
1. H2SO4, MeOH/H 2O oles 221. However, is the cyclocondensation step performed
or EtOH R1 N at 80 C, 2-hydroxy-2,3-dihydroimidazopyrimidinium salts
MW, 100 C, 10 min NH2 222 are formed that can be subsequently cleaved with hydra-
R2 N
2. KOH in MeOH H zine hydrate to give the 1-unsubstituted 2-aminoimidazoles
223. The cleavage step for the formation of products 223
19 examples is proposed to proceed via a Dimroth-type rearrangement
(88-98%)
with an in situ generation of 2-amino-5-hydroxyimidazoli-
Scheme 182 Synthesis of substituted 2-aminoimidazoles dine. See also Scheme S357 [761].
Comparison studies of thermal versus microwave heat-
ing in the synthesis of 2,4-disubstituted 5-aminoimidazoles
Scott E. Wolkenberg and co-workers from Merck (Scheme 226 have been conducted by Yulin Lam and co-workers from
181) [757]. Utilizing microwave irradiation, alkyl-, aryl-, and National University of Singapore (Scheme 185) [762].
heteroaryl-substituted imidazoles are formed in very high Higher yields and considerable rate enhancements (up to ca.
yields ranging from 7699%. Further microwave-assisted 130 times for the overall reaction) could be achieved by
alkylation of 2,4,5-trimethylimidazole with benzyl chloride applying microwave heating for all three synthetic steps. The
in the presence of base led to the alkaloid lepidiline B in 43% synthesis of 5-aminoimidazole scaffolds 226 was performed
overall yield. in parallel employing a multivessel rotor system, making the
The synthesis of mono- and disubstituted 2-aminoimid- protocol amenable for high-throughput synthesis.
azoles by the reaction of diverse -haloketones with N - 1,3-Diarylimidazolinium chlorides useful as precursors
acetylguanidine was reported by Yulin Lam and co-work- to N -heterocyclic carbene ligands can be synthesized effi-
ers from the National University of Singapore (Scheme 182) ciently by condensation of N ,N  -diarylethylenediamines
[758]. In the first reaction step, the corresponding dihydrochlorides with triethyl orthoformate (Scheme S358)
imidazol-2-acetamides were obtained in excellent yields. [763]. Similar results can be achieved using carboxylic acids
Further deacylation with H2 SO4 and MeOH/H2 O (1:1) or instead of orthoformate in the presence of pyridine (Scheme
EtOH, respectively, and subsequent formation of the free S359) [764]. 2-Substituted benzimidazoles have been
amine with 5 M KOH in MeOH furnished the 2-aminoim- obtained by SnCl2 -mediated reduction/condensation of
idazole products, again in high yields. The overall reaction o-nitro anilines with carboxylic acids (Scheme S360) [765],
time could be cut down to only 20 min compared with several or by the condensation of aromatic 1,2-diamines with aro-
days under conventional room-temperature conditions. matic aldehydes in the presence of SiO2 (Scheme S361) [766].
Sabine Berteina-Raboin and co-workers from Universit Similar approaches were used for the generation of xanthines
d Orlans were successful in the synthesis of 2,3,6-trisubsti- (Scheme S362) [767].

123
Mol Divers (2009) 13:71193 151

O
1. X 219
R1
NH2 K2CO3, dioxane/EtOH N
MW, 150 C, 20 min R1
N 2 N
Br R
2. R2B(OH)2, Pd(OAc)2/PPh3
MW, 150 C, 20 min N
6 examples
3.
N Br (32-51%)

MW, 150 C, 2 h X = Cl, Br

R1 = H, Ph, p-F-Ph
R2 = (het)aryl
Scheme 183 Synthesis of polysubstituted imidazo[1,2-a]pyridines

N N
N
Br 1
1 N NHR 1
N N R MeCN MeCN N N R
+ Br 222
220 OH
MW, 150 C, 25 min Br MW, 80 C, 30 min 2
R3
R2 R3 R
2 R3
R
N2H4, MeCN N2H4, MeCN
MW, 100 C, 5 min O MW, 100 C, 10 min

N R2 R2
N
H2 N 221 1
R HN 223
N R3 N R3
H
R1
12 examples
15 examples (54-98%)
(46-95%)
R1 = alkyl, Cy, aryl R1 = H, alkyl, cyclic alkyl, hetaryl
R2 = H, aryl, alkyl R2 = H, alkyl, aryl
R3 = H, aryl R3 = (het)aryl, amidyl

Scheme 184 Synthesis of 2-aminoimidazoles from 2-aminopyrimidines

S H 2O S
1 EtO P SH
R C N
MW, 80 C, 10 min R1 NH 2
OEt
224
10 examples
(82-99%)
R 1 = alkyl, aryl
R 2 = Ph, CO2 Et
MW, 80 C PhCH 2 Br
10 min CHCl3
NH2.HCl

R2 R2 CN
N
pyridine, CHCl3
R1 S NH.HBr
H2 N N MW, 60 C, 5 min
H
R1
226 225
15 examples 12 examples
(83-98%) (81-100%)
Scheme 185 Parallel synthesis of 2,4-disubstituted 5-aminoimidazoles

123
152 Mol Divers (2009) 13:71193

SH O O neat S
1
R + 2 R1 R2
R OEt MW, 240 C, 4 min
NH 2 N

R1 = H, Cl 10 examples
(93-99%)
R2 = alkyl, (het)aryl
Scheme 186 One-pot solvent-free synthesis of 2-aryl and 2-alkylbenzothiazoles

2.23.4.3 Isoxazoles O K2CO 3, BuOH R1 N

NH
R1 CN + H 2N
N R2 MW, 150 C, 1-14 h N
Isoxazolidinyl analogs have been prepared via a cycloaddi- H
R2
tion approach using nitrones and allyl alcohol (Schemes S363 R1, R 2 = aryl, hetaryl 12 examples
and S364) [768,769] or acrylate building blocks (Scheme (34-83%)
S365) [770]. Scheme 187 One-step synthesis of 3,5-disubstituted 1,2,4-triazoles

2.23.4.4 Oxazoles 2.23.5.2 1,2,4-Triazoles

The group of Peter Wipf has described a one-pot oxazole
synthesis via base-catalyzed condensation of oximes and acid
chlorides at 180 C (Scheme S366) [771]. Benzoxazoles have
been obtained by acid-catalyzed cyclization of N -acetylated
o-aminophenols at 200 C (Scheme S367) [772].
2.23.4.5 Thiazoles
A recent publication by Edward R. Biehl and co-workers
from the South Methodist University, Texas, describes an
improved and ecofriendly synthesis of 2-alkyl and aryl-
substituted benzothiazoles (Scheme 186) [773]. As opposed
to conventional heating, under controlled microwave heating
the neat reaction of aromatic and aliphatic -ketoesters and
o-aminothiophenols proceeded faster and in higher yields.
It was also possible to scale up selected reactions to give
multigram quantities with similar high yields.
For an alternative Mn(III)-promoted benzothiazole syn-
thesis starting from thioformanilides, see Scheme S368 [774].
Endothiopeptides have been converted directly to thia-
zoles in the presence of 1.5 equiv. TMS-Cl in MeCN (Scheme
S369) [775]. For examples of Hantzsch thiazole syntheses,
see Schemes S370 and S371 [776,777].
A recent publication by Kap-Sun Yeung and co-workers from
BristolMyers Squibb describes a convenient and efficient
one step, base-catalyzed synthesis of 3,5-disubstituted 1,2,4-
triazoles by the condensation of a nitrile and a hydrazide
(Scheme 187) [779]. Under the reaction conditions, a diverse
range of functionality and heterocycles are tolerated. The
reactivity of the nitrile partner is relatively insensitive to elec-
tronic effects.
The condensation of hydrazides with 3,6-dichloropyrida-
zines furnishes [1,2,4]triazolo[4,3-b]pyridazines via a
similar mechanistic pathway (Scheme S373) [780].
2.23.5.3 1,2,4-Oxadiazoles
Mehdi Adib and co-workers from University of Tehran have
disclosed a three-component, one-pot reaction of nitriles,
where the hydroxylamine generated in situ further reacted
with aldehydes to give 1,2,4-oxadiazoles (Scheme 188)
[781]. First the nitrile and hydroxylamine were reacted at
100 C for 1 min, then subsequent addition of aldehyde and
irradiation at 150 C for 3 min under solvent-free conditions
gave oxadiazoles in excellent yields.
A related approach to 3,5,-diamino-1,2,4-oxadiazoles has
been described by Kurz and co-workers (Scheme S374)
[782].

2.23.5 Five-membered heterocycles with three heteroatoms 2.23.5.4 1,3,4-Oxadiazoles

2.23.5.1 1,2,3-Triazoles 1,3,4-Oxadiazoles have been obtained by treatment of tet-

Triazolo[4,5-b]pyridin-5-ones can be obtained by [3 + 2]
cycloaddition of NaN3 to 5-benzenesulfonyl-3,4-dihydro-1
H -pyridin-2-one in DMF (Scheme S372) [778]. For other
examples of 1,2,3-triazole syntheses, see Sect. 2.3.3.
razoles with acetic anhydride at high temperatures (Scheme
S375) [783]. Heterocyclic sulfonylureas such as [1,2,5]thi-
adiazolo[3,4-b]pyrazines can be obtained by condensation of
the corresponding o-diaminohetarenes with sulfamide
(Scheme S376) [784].

123
Mol Divers (2009) 13:71193 153

AcOH (cat) NH2 cyclization of dienaminoesters was reported by Vounatsos

Ar1 C N NH2OH Ar1
MW, 100 C, 1 min
NOH
Ar1 = Ph, 4-tolyl, 3-Cl-Ph
Ar1
2 Guan-Wu Wang from the University of Science and
Ar CHO N
N
MW, 150 C, 3 min Ar2
O ducting the reaction under solvent-free conditions with p-
Ar2 = Ph, 4-tolyl, 4-Cl-Ph, 12 examples
4-MeO-Ph, 3-Cl-Ph (92-97%)
Scheme 188 One-pot synthesis of 1,2,4-oxadiazoles
2.23.6 Five-membered heterocycles with four heteroatoms
5-Substituted-tetrazoles can be prepared in a one-pot fashion
by in situ generation of nitriles from aldehydes and ammo-
nia in THF at room temperature, followed by cycloaddition
with NaN3 /ZnBr2 (Scheme S377) [785]. For related exam-
ples, see Scheme S378 [786].
2.23.7 Six-membered heterocycles with one heteroatom
2.23.7.1 Pyridines
The group of C. Oliver Kappe from the University of Graz has
described a multicomponent, one-pot, two-step pathway to
3,5,6-substituted 2-pyridones (Scheme 189) [787]. In the first
step equimolar mixtures of a CH-acidic carbonyl compound
and N ,N -dimethylformamide dimethyl acetal (DMFDMA)
were reacted to form the corresponding enamines, either
at room temperature or under microwave conditions. After
addition of a methylene active nitrile (1 equiv.), 2-propanol
as solvent, and catalytic amounts of piperidine base, the reac-
tion mixture was heated to 100 C for 5 min under microwave
conditions. In most cases, the desired heterocyclic product
precipitated directly after cooling of the reaction mixture and
could be collected by filtration.
An alternative method to access 3-bromo-2(1H )-pyridi-
nones involving the N -bromosuccinimide (NBS)-mediated
(Scheme S379) [788].
The synthesis of polysubstituted quinolines applying the
Friedlnder condensation was disclosed by the group of
Technology of China, Hefei (Scheme 190) [789]. By con-
toluene sulfonic acid ( p-TsOH) as catalyst, the quinoline
products could be obtained in excellent yields through a sim-
ple work-up procedure. Identical results were achieved per-
forming the reactions under conventional heating at the same
temperature, but with prolonged reaction times.
Alternatively, quinolines have been prepared by conden-
sation of 2-aminoaryl ketones with phenylacetylene in the
presence of In(OTf)3 [790].
The group of Shujiang Tu from Xuzhou Normal Univer-
sity has reported on the synthesis of a series of pyrido[2,3-
d]pyrimidine-4,7-diones (Scheme 191) [791]. By reacting
isoxazoles 227 with 2,6-diaminopyridinone 228 or naphtha-
lene-2-amine, pyridopyrimidines 229 and 230 with a
hydroxyiminoethyl substituent at the 6-position are obtained,
whereas 6-benzamide functionalized products 232 are
generated by the reaction of oxazolones 231 with 2,6-di-
aminopyridinone. The authors propose a Michael addition,
cyclization, and ring-opening reaction sequence, where the
acetic acid acts as both solvent and catalyst.
An efficient multistep synthesis of biologically active
4-aryl-3-alkenyl-substituted quinolin-2-(1H )-ones has been
demonstrated by the Kappe group (Scheme 192) [792]. All
the synthetic transformations (six steps) required for the syn-
thesis of the desired target quinolin-2-(1H )-ones have been
carried out under controlled microwave heating. The key
steps in the synthesis include a sequential Pd-catalyzed
Suzuki/Heck scaffold decoration method to allow introduc-
tion of substituents late in the synthetic scheme and facilitate
preparation of 2(1H )-quinolinone analogues with a greater
diversity for potentially generating combinatorial libraries.
Related cyclizations of activated malonic esters and ani-
lines leading to 4-hydroxy-2(1H )quinolones have been

R2 OMe R2 Me
+ Me neat N
MeO N Me
R1 O rt/MW, 100-170 C R1 O
Me
5-10 min
R3

CN R2 R3

neat/i-PrOH
R1 N O
H
MW, 100 C, 5 min
18 examples
(27-85%)
Scheme 189 Multicomponent synthesis of 2-pyridones

123
154 Mol Divers (2009) 13:71193

R3

R2 R2
O R4
R3
O p-TsOH

R1 NH2 MW, 100 C, 0.5-4 min N R4

R1
6 examples
R1 = H, Br (92-96%)
R2 = p-F-Ph, Me, H
R3 = CO2 Et
R4 = Me
R3 , R 4 = cyclic
Scheme 190 Quinolines via Friedlnder annulation

O O Ar Me
O O
DMF, AcOH
N + HN HN NOH

Me H2N N NH2 MW, 140 C H2N N N O

Ar 7-10 min H
227 229
228
14 examples
(78-90%)

H
N O
H2N DMF, AcOH
Me
227 + MW, 140 C
6-8 min Ar NOH
230
8 examples
(76-87%)

O Ar H
O O DMF, AcOH N Ph
Ph + 228 HN
N MW, 140 C O
6-9 min H2N N N O
Ar 231 H
232
9 examples
(83-91%)
Scheme 191 Synthesis of pyrido[2,3-d]pyrimidine-dione derivatives

described by Rivkin (Scheme S380) [793]. The same app-
roach was also used for the preparation of the correspond-
ing aza-analogs starting from -aminoazines (Scheme S381)
[794], or bis(pentafluorophenyl)imidodicarbonate (Scheme
S382) [795].
Fused pyridines have been obtained by PictetSpengler
heterocyclization using DMSO at high temperatures as a
formaldehyde source (Scheme S383) [796], and by conden-
sation of thiazolidine precursors with Meldrums acid
derivatives (Scheme S384) [797]. A one-pot synthesis of 2,
3-dihydro-1H -pyrrolo[3,2-c]quinolines from substituted
2-iodoanilines and 2,3-dihydro-1H -pyrrole using Pd catal-
ysis was reported by Hu (Scheme S385) [798]. For addi-
tional preparations of pyridine and quinoline heterocycles,
see Schemes S386S388 [799801].
2.23.7.2 Pyranes
Utilizing the microwave protocol shown in Scheme 193,
George W. Kabalka and Arjun R. Mereddy from the Uni-
versity of Tennessee were able to synthesize a variety of
functionalized flavones and chromones in very high yields
by the cyclization of 1-(2-hydroxyaryl)-1,3-propanediones
(Scheme 193) [802].
A related flavone synthesis by Seijas employs solvent-free
conditions (Scheme S389) [803]. Coumarin libraries have
been generated from activated phenols and -ketoesters using
a similar approach (Scheme S390) [804]. Fused -pyrones
have been obtained by Lewis-acid-catalyzed regiocontrolled
6-endo-dig cyclization of 2-(2-arylethynyl)heteroaryl esters
(Scheme S391) [805].

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Mol Divers (2009) 13:71193 155

F3 C F3 C CF3 P4O10 in MeSO3H

CH 2(COCl) 2 O O
(Eatons Reagent)
NH 2 DCM N N
H H MW, 120 C, 20 min

OH Cl 1.2 equiv ArB(OH) 2

F3 C 1. POCl3, dioxane F3 C 0.5 mol% Pd(OAc)2 , PPh3
MW, 120 C, 20 min Et3 N, DME/H 2O (3:1)
N O 2. MeSO3 H, EtOH N O MW, 150 C, 30 min
H MW, 120 C, 25 min H
65% 72%

Cl
Cl Cl

OMe
OMe ethyl acrylate OMe
F3 C Br Pd(PPh3 )4
F3C F3 C CO2 Et
NBS, MeCN Et 3N, DMF
MW, 100 C, 1 h N O MW, 150 C, 45 min
N O H N O
H H
97%
91% 90%

Scheme 192 Multistep synthesis of functionalized 4-arylquinolin-2(1H )-ones

O O O
X 3 CuCl2 , EtOH X
R

R1 OH MW, 80 C, 5 min R1 O R3
2
R R2
R 1 = H, Me, OH 12 examples
R 2 = H, OH (86-98%)
R 3 = Ph, 4-NO 2-Ph, Me, CF3
X = H, Cl, Br, OH
Scheme 193 Synthesis of flavones and chromones

2.23.8 Six-membered heterocycles with two heteroatoms
2.23.8.1 Pyrimidines
Eric Wellner and co-workers from Active Biotech AB have
made extensive use of microwave chemistry in the prepara-
tion of cyclic thioureas and guanidines (Scheme 194) [806].
Utilizing MAOS it was possible to assemble all intermedi-
ates and target molecules without any need for activation or
protecting groups, cutting reaction and workup times to a
minimum.
Mohammad Movassaghi and Matthew D. Hill from MIT
have developed a protocol for the synthesis of quinazolines
233 via electrophilic activation of secondary amides utiliz-
ing 2-chloropyridine (2-ClPyr) in combination with Tf2 O
and subsequent reaction with weakly nucleophilic nitriles
(Scheme 195) [807]. Whereas electron-rich N -vinyl and aryl
amides afforded the corresponding pyrimidine derivatives at
room temperature, microwave heating to 140 C was neces-
sary for less reactive substrates. Additionally, one example
was presented where a primary amide was employed instead
of the nitrile under the same microwave conditions giving the
quinazoline (R1 = Ph, R2 = H, R3 = OMe, R4 =c C6 H11 )
in 74% yield.
For alternative synthetic approaches to quinazolines, see
Schemes S392 and S393 [808,809].
In a subsequent publication the same authors reported a
comparative study of oil-bath and microwave heating for the
synthesis of quinazolines 234 and pyridine 235 (Scheme 196)
[810]. Microwave irradiation proved to be beneficial for elec-
tron-deficient and sterically hindered amides or for weak
nucleophiles. Improved yields could be achieved with micro-
wave heating at 140 C for 20 min compared with oil-bath
heating under otherwise identical conditions. At lower tem-
peratures of 75 C no difference in the reaction outcome was
observed, however 3070% lower yields were obtained.

123
156 Mol Divers (2009) 13:71193

NH 2 NaH, DMA NH2 1. CS2, EtOH, rt

Ar-F + HO ArO
MW, 170 C, 4 min 2. MW, 140 C, 4 min
NH 2 NH2

R 1-X, MeCN + X
NH NH
ArO S 20 examples
ArO SR1 (52-94%)
NH MW, 130-160 C, 9-14 min NH
6 examples
(36-79%)

for R1 = Me, X = CF 3COO

+ CF3 COO
NH
R 2CH2 NH2, MeCN R2 12 examples
ArO NH (32-93%)
NH
MW, 160 C, 35 min
Scheme 194 Preparation and reactions of cyclic thioureas

R2 R2
R3 R3
N R4
Tf2O, 2-ClPyr, DCM N
HN
1. -78 C --> rt, 15 min
R1 O 2. MW, 140 C, 20 min R1 N R4
233
R1 = cyclic, alkyl, aryl 9 examples
(61-88%)
R2, R3 = H, CF3, OMe
R4 = cyclic, alkyl, aryl
Scheme 195 Single-step synthesis of pyrimidine derivatives

R2
R2
HN
N
+ N cHx
R1 O
R1 N cHx

R1 = Ph, t -Bu 234

R2 = CF3, OMe Tf2O, 2-ClPyr, DCM 2 examples
(61-86%)
-78 C --> 0C: 5 min
0 C --> rt: 5 min
MW, 140 C, 20 min
S S
HN N
+ OSiPh3
Ph O Ph
235, 76%
Scheme 196 Single-step synthesis of azaheterocycles

A microwave-assisted rapid and highly selective method
for the synthesis of new pyrazolo[1,5-a]pyrimidines has been
demonstrated by Li Ming and co-workers from the Qing-
dao University of Science and Technology (Scheme 197)
[811]. The synthesis of 12 new pyrazolo[1,5-a]pyrimidines
has been performed by the reaction of 5-amino-1H -pyra-
zoles with a variety of enaminones under microwave irradia-
tion. Under controlled microwave heating, the synthesis has
shown the same high regioselectivity as in the case of conven-
tional heating; however, the yields with microwave heating
were improved by 1020% and the reaction rates enhanced
from 10 to 100 times.
For a related approach to pyrazolo[1,5-a]pyrimidines
starting from 1,3-dicarbonyl compounds and 5-amino-1H -
pyrazoles, see Schemes S394 and S395 [812,755].
A simple, efficient, and high-yielding synthesis of quinaz-
olin-4-ylamines and thieno[3,2-d]pyridin-4-ylamines based
on the condensation of appropriately functionalized N  -(2-
cyanophenyl)-N ,N -dimethylformamidines and primary ami-
nes has been reported by Han and co-workers (Scheme 198)

123
Mol Divers (2009) 13:71193 157

R2
R1
N NH2
N
O H
AcOH
N(CH3)2 N N
MW, 120 C, 20 min
R1 N
R2
12 examples
(82-95%)
Scheme 197 Synthesis of pyrazolo[1,5-a]pyrimidines

R (thio)cyanates proved to give higher product yields compared

HN N with aliphatic ones. In addition, the products could be easily
R NH2
CN N isolated by precipitation and filtration due to the employed
MeCN, AcOH DMSO/H2 O solvent mixture.
N NMe2
MW, 160 C, 10 min For alternative syntheses of quinazolin-4-ones from anthra-
X nilic acid, amines, and carboxylic acid derivatives, see
X 20 examples Schemes S396S399 [815818].
(83-97%)
Pyrimidines have been synthesized in one step from
R ketones and formamidine using p-TsOH as a catalyst
R NH2
CN HN N (Scheme S400) [819], and from enones and benzamidines
MeCN, AcOH
N NMe2 (Scheme S401) [820]. Related approaches starting from
S N ureas (Scheme S402) [821], enaminomethylene malonates
MW, 160 C, 10 min S
(Scheme S403) [822], and benzamidines have also been dis-
3 examples closed (Scheme S404) [823]. Pyrazolo[1,5-a]pyrimidines
(78-96%) and 1,2,4-triazolo[1,5-a]pyrimidines were synthesized as
novel carbohybrids by condensation of 2-C-formyl glycals
Scheme 198 Aminoquinazoline synthesis
with 3-aminopyrazoles and 3-amino-1,2,4-triazoles (Scheme
S405) [824].

[813]. Optimization of the reaction parameters resulted in the

use of MeCN/acetic acid as solvent mixture and utilization
of 1.2 equiv. of the corresponding amine. In general, micro-
wave heating to 160 C for 10 min provided excellent product
yields.
A small library of 2,4(1H ,3H )-quinazolinediones (X = O)
and 2-thioxoquinazolines (X = S) was prepared via the reac-
tion of substituted methyl anthranilate with diverse iso(thio)
cyanates without the addition of catalyst, ligand or base by
Hong Liu and co-workers from the Chinese Academy of Sci-
ences in Shanghai (Scheme 199) [814]. Aryl-substituted iso
2.23.8.2 Pyrazines
The manganese(IV) dioxide-catalyzed synthesis of quinox-
alines has been demonstrated by So Yeon Kim and co-work-
ers from Seoul National University (Scheme 200) [825]. The
quinoxalines were obtained from a variety of -hydroxyke-
tones by trapping with aromatic or aliphatic 1,2-diamines
under solventless microwave conditions for 1 min at 70 C.
By applying the same protocol, also benzimidazoles from
aldehydes and 1,2-diaminobenzene were prepared.

O O
R2 NCX R2
OMe DMSO, H 2 O N
R1 R1
NH 2 MW, 120 C, 20 min N X
H

R 1 = H, 5-F, 4,5-(MeO)2 34 examples

(13-92%)
R 2 = alkyl, aryl
X = O, S
Scheme 199 Synthesis of quinazolinediones and thioxoquinazolines

123
158 Mol Divers (2009) 13:71193

cat. MnO 2
OH H 2N 4 mol sieves N
+
R O H 2N MW, 70 C, 1 min R N
7 examples
R = aryl, alkyl (15-81%)

cat. MnO 2
H 2N N
O 4 mol sieves
R
+
R H N
H 2N MW, 70 C, 1 min H
R = Ph: 35%
R = Bu: 24%
Scheme 200 Synthesis of quinoxalines

H
R1 NH2 Br R3 DBU R1 N R3
+
MW, 190 C, 6 min
R2 NH2 EtO O R2 N O
H
236 237 238
R 1, R 2 = H, Me 12 examples
R 3 = alkyl, Ph (70-98%)
Scheme 201 Synthesis of quinoxalinones

O
MeOPCl2, NEt3 , IL H
CO 2H
toluene N
R R R
NH N
MW, 145 C, 1 h
H
O
R = H, OTBDMS, 4 examples
OBn, Ot-Bu Me (86-97%)
O IL
N
P + 12 related examples
O OMe (81-97%)
N
OMe
Me

Scheme 202 Synthesis of symmetrical and unsymmetrical 2,5-diketopiperazines

Sukanta Kamila and Edward R. Biehl from the South-
ern Methodist University, Dallas, have reported on the syn-
thesis of potentially biologically active quinoxalin-2-ones
(Scheme 201) [826]. Symmetrical 1,2-diaminobenzenes 236
were reacted with ethyl 2-bromoalkyl/phenyl acetates 237
and DBU as base under solvent-free microwave conditions
to give quinoxalinones 238 in good to excellent yields.
The phosphorous-promoted coupling of unprotected
amino acids toward the one-step synthesis of 2,5-diketopi-
perazines was disclosed by Stefan Brse and his group from
Karlsruhe University (Scheme 202) [827]. Symmetrical and
unsymmetrical 2,5-diketopiperazines are generated by the
condensation of amino acids with methyldichlorophosphite
in toluene. The ionic liquid (IL) 1,3-dimethylimidazolium
dimethyl phosphate needs to be used as a heating aid in order
to reach the 145 C. Unsymmetrical derivatives are obtained
by the combination of proline, sarcosine, indoline-, and
octahydroindolecarboxylic acids without the formation of
any by-products (1.2 equiv. excess of one amino acid is cru-
cial in this case). Advantages of this protocol are excellent
yields, complete retention of the stereochemistry, tolerance
of base-stable protecting groups, and a simple work-up pro-
cedure (only filtration).
2.23.8.3 Pyridazines
Polysubstituted pyridazines have been synthesized by cycli-
zation of 1,4-dicarbonyl compounds with hydrazine followed
by oxidation with DDQ (Scheme S406) [828]. Fused and
polycyclic pyridazine analogs have been generated by cyclo-
addition chemistry (Schemes S407 and S408) [829,830].
3,6-Di(pyridin-2-yl)pyridazines can be obtained by cycload-
dition of suitable dienophiles to 3,6-disubstituted tetrazines

123
Mol Divers (2009) 13:71193 159

OH Br R2 DBU, NMP The same product class was synthesized by the Dai group
1 +
R using a slightly different approach (Scheme 204) [834]. The
CO2 Et MW, 180 C, 3 min
X NH2 first step was a reductive N -alkylation of substituted 2-ami-
nophenols with aromatic aldehydes to obtain the N -alkylated
R2 = Et, n-Pr, i-Pr
anilines 239. Regioselective O-alkylation of 239 with 2-bro-
X = CH, N O R2 moalkanoates furnished acyclic intermediates which showed
1
R spontaneous cyclization to 1,4-benzoxazines 240. Higher
X N
H
O
temperatures (180200 C) for the second step were neces-
20 examples sary when electron-withdrawing groups were present at the
(13-82%) C6-position (R1 = NO2 , Cl).
Highly functionalized benzoxazine derivatives 242 were
Scheme 203 Regioselective synthesis of 3,4-dihydro-3-oxo-2H -1,4-
benzoxazines
obtained in yet a different approach by the same group via
a one-pot Ugi four-component reaction of 2-aminophenols,
in a cycloaddition-cycloreversion pathway (Scheme S409) aromatic aldehydes, -bromoalkanoic acids, and isocyanides,
[831]. and subsequent base-catalyzed O-alkylation of 241 (Scheme
205) [835]. By additional postmodification of scaffolds 243
through CuI-catalyzed intramolecular amidations, a novel
2.23.8.4 Oxazines class of heterocyclic derivatives could be achieved.

A 2005 publication by Wei-Min Dai and co-workers from
Hong Kong University of Science and Technology describes
a regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-
oxo-2H -1,4-benzoxazines (Scheme 203) [832]. The use of
a base such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
is critical for achieving a regioselective O-alkylation of
2-aminophenols with 2-bromoalkanoates to give an acyclic
intermediate, which subsequently undergoes an intramolec-
ular amidation reaction to furnish the desired 2-alkyl-3,4-
dihydro-3-oxo-2H -1,4-benzoxazines. The desired products
possessing alkyl, aryl, halogen, nitro, sulfonyl group, and ring
structures have been prepared in 1382% yields, respectively.
Microwave heating was necessary to induce annulation
reaction, for acyclic intermediates bearing an electron-with-
drawing group. For a different approach to 3,4-dihydro-3-
oxo-2H -1,4-benzoxazines, see Scheme S410 [833].
2.23.9 Larger heterocyclic and polycyclic ring systems
The one-pot total synthesis of the quinazolinobenzodiazepine
alkaloid sclerotigenin via a novel microwave-assisted dom-
ino reaction was reported by Ji-Feng Liu and colleagues from
ArQule Inc., Woburn, Massachusetts (Scheme 206) [836].
The alkaloid was obtained in 55% yield by condensation of
two equivalents of anthranilic acid with N -Boc-glycine in
the presence of triphenyl phosphite using pyridine as solvent
and microwave heating at 230 C for 20 min. Related prod-
ucts were obtained employing substituted anthranilic acids
and other amino acids as starting materials (R1 = H). The
authors also developed a three-component one-pot sequential
modification that allowed the preparation of related alkaloids
having different substituents on the aromatic rings, starting
from two different anthranilic acid derivatives.

2
R CHO
OH OH
NaBH(OAc)3, THF
R1 R1
NH2 MW, 80 C, 3 min NH

R1 = H, 5-Me, 4,5-(CH2)4-, 4-NO2, 4-Cl

239 R2
9 examples
R2 = 2-furyl, Ph, 4-MeO-Ph, 3-pyridinyl (58-91%)

R3CH(Br)CO2Et
O R3
K2CO3, DMF/H2O 1
R
MW, 80-200 C, 15-45 min N O
2
R3 = H, Me, Et, n-Pr 240
R
28 examples
(51-98%)
Scheme 204 Multistep synthesis of 1,4-benzoxazine scaffolds

123
160 Mol Divers (2009) 13:71193

(a) Br
OH
R3
OH Br R3 MeOH N O
+ R2 CHO + + R 4 NC R1
MW, 80 C, 20 min O
NH 2 HO O R2
R1
HN
R4
R1 = H, 4-Cl, 4-Me, 5-Me, 4,5-(CH 2) 4- 241
R2 = (het)aryl
R3 = H, Me
R4 = Cy, Bn O R3
K2CO3, H 2O
MW, 120 C, 15-20 min N O
R1
2 O
R
HN
R4
242
(b) 14 examples
O O (52-90%)

CuI, K3 PO 4, DMF
1 N O N O
R MW, 150 C, 35-50 min R1
O O
HN N
Br Bn
Bn
243 3 examples
R 1 = 7-Me, 6-Me, 6-Cl (80-93%)

Scheme 205 One-pot Ugi four-component reaction and intramolecular O-alkylation

CO2 H R1
Boc P(OPh) 3, pyridine
+ HO2 C N
NH2 H
MW, 230 C, 20 min

N
O
N NH
R1
R1 = H: sclerotigenin, 55%
Scheme 206 Synthesis of quinazolinobenzodiazepines

The groups of Nobutaka Fujii and Hiroaki Ohno from
Kyoto University have developed a Cu(I)-catalyzed domino
three-component coupling/indole formation/N -arylation pro-
tocol for the synthesis of indole-fused 1,4-diazepines
(Scheme 207) [837]. The first step toward the indole-fused
tetracyclic scaffolds is a Mannich-type reaction of 2-ethy-
nylanilines, o-bromobenzylamines, and paraformaldehyde,
followed by the indole formation, subsequent deprotection
of the N -mesyl group by addition of MeONa, and the final
N -arylation. In addition to the fused benzodiazepines, het-
erocycle-fused 1,4-diazepines with a pyridine or thiophene
moiety were also prepared.
The synthesis of complex macrodiolides involving micro-
wave-accelerated transesterification of chiral, nonracemic,
hydroxy esters has been demonstrated by John A. Porco Jr.
and co-workers at Boston University (Scheme 208) [838].
Dramatic accelerations in cyclodimerizations of monomeric
units containing ethers and amino acid subunits have been
seen under microwave heating with a fluorous tin oxide cat-
alyst, affording optimal yields. Cyclodimerizations studied

123
Mol Divers (2009) 13:71193 161

1. (HCHO)n, CuI, dioxane

1 R2HN MW, 170 C, 20-40 min
R +
NHMs Br X
2. MeONa
MW, 170 C, 20 min

R1 = H, Me, CO2Me, CF3

R2 = Me, Bn, allyl
R1
X = CH, N
N 2
N R
X

8 examples
(23-85%)
Scheme 207 Synthesis of indole-fused 1,4-diazepines

CO2Me
solid-phase route (Scheme 209) [852]. Both natural and non-
Me natural AHLs could be obtained in high purities and short
NHTs OH reaction times. Among the two libraries, a set of nonnative
O AHLs has been found to have high inhibitory affinity for
cat (10 mol%) NHTs
NHTs PhCl (0.03 M) bacterial quorum sensing. See also Scheme S424 [853].
O Me
HO OMe Justin K. Murray and Samuel H. Gellman from the Uni-
+
MW, 225-235 C
Me O 20 min O versity of WisconsinMadison have evaluated the effects
Me
of microwave heating on the solid-phase synthesis of high-
cat: [[CF3(CF2 )5 CH2 CH 2] 2 SnO] n O
NHTs purity -peptides (Scheme 210) [854]. They showed that by
O
NHTs microwave irradiation using an automated microwave
O Me peptide synthesizer, 14-helical -peptides, especially those
containing the structure-promoting residue trans-2-amino-
Scheme 208 Synthesis of complex macrodiolides by cyclodimeriza-
tion of hydroxy esters cyclohexanecarboxylic acid (ACHC), can be obtained in a
purity superior to that of both conventional heating and stan-
dard solid-phase peptide synthesis (SPPS). For shorter pep-
tides (i.e., the hexamer) microwave heating and conventional
under microwave heating indicated an initial dependence heating gave the same results.
of macrodiolide formation on microwave power. Use of a For the synthesis of a 15-kD -peptide tetramer, see
rapid cyclodimerization process under microwave incubation Scheme S425 [855]. The preparation of other -peptides
has been demonstrated to prepare a 127-member library of using microwave heating has been reported (Scheme S426)
diverse macrodiolides with high levels of macrocyclic ring, [856].
stereochemical, and functional diversity. Microwave technology was also used in the synthesis of
Other synthetic transformation leading to larger hetero- difficult -peptide sequences (Schemes S427S429)
cyclic or polycyclic ring systems have been described in [857859], of glycopeptides (Scheme S430) [860], for the
Schemes S411S423 [839851]. preparation of peptoids (Scheme S431) [861] and -peptides
(Scheme S432) [862], pseudopeptides (Scheme S433) [863],
and for the generation of N -glycosyl amino acids (in solu-
2.24 Combinatorial and high-throughput synthesis tion phase) (Scheme S434) [864]. The issue of racemization
methods and aspartamide formation was extensively investigated by
Collins (Scheme S435) [865]. For a critical discussion of
2.24.1 Solid-phase organic synthesis microwave-assisted solid-phase peptide synthesis methods,
see Ref. [208].
Helen E. Blackwell and co-workers from the University of A 2004 publication by Helen E. Blackwell reports the mul-
Wisconsin-Madison have described the synthesis of N -acyl tistep synthesis of a spatially addressed pyrimidine library on
L-homoserine lactones (AHLs) via a microwave-assisted planar membrane supports (SPOT synthesis) (Scheme 211)

123
162 Mol Divers (2009) 13:71193

O 1. DIC, HOBt, CHCl3 / DMF O

2x
S MW, 50 C, 10 min S
NH2 + HO N
2. DMF H NH2
HN
Fmoc MW, 150 C, 6 min

O O
O
O R1 OH 1. 2 x DIC, CHCl3 / DMF R1 N
S MW, 50 C, 10 min H H O
N + or
H 2. CNBr, TFA, CHCl3/H2O or
NH2
MW, 60 C, 30 min O O
O
O O O
2
R2 OH R N
H H O

R1, R2 = aryl, alkyl 11 examples of natural AHLs

(62-80%)

15 examples of non-natural AHLs

(47-81%)

Scheme 209 Solid-phase synthesis of natural and nonnatural AHLs

NH2 NH NH2 CO2 H

CO2 H

O O O O O O O O O
O
N N N N N N N N OH
H 2N N H H H H H
H H H H

Standard SPPS Oil Bath, MW Irradiation,

Conditions LiCl in NMP LiCl in NMP
deprotection: 15 min deprotection: 15 min, 60C deprotection: 4 min, 60C
couplings: 90 min, DMF couplings: 90 min, 60 C, DMF except couplings: 6 min, 50 C, DMF except
ACHC2+5: 0.8 M LiCl in NMP ACHC2+5: 6 min, 45 C, 0.8 M LiCl in NMP

Purity = 21 % 53 % 88 %
Scheme 210 Synthesis of 14-helical -peptides

[866]. For all of the three steps of the synthesis microwave
irradiation was used to speed up the chemistry on the planar
support. Importantly, microwave irradiation did not impact
on the integrity of the cellulose support and the chemistry
could easily be scaled up employing other (nonplanar) types
of cellulose supports.
A similar support strategy (SPOT synthesis) was used by
the same group to construct deazalumazine dyes (Scheme
S436) [867], a small molecule array based on the Ugi four-
component reaction (Scheme S437) [868], and a selection
of diketopiperazines again based on Ugi chemistry (Scheme
S438) [869]. For examples of a Ugi four-component
condensation performed on a Rink amide resin, see Scheme
S439 [870].
Angelo Carotti and his group from University of Bari
have developed a multistep solid-phase synthesis of Imatinib
which acts as a selective tyrosine kinase inhibitor (Scheme
212) [871]. By applying microwave heating in five steps of
the synthesis (preparation of linker 244, nucleophilic substi-
tution, reduction of the nitro group, formation of guanidine,
and final cyclization) the total process could be accelerated.
Key steps were the guanylation of aniline 245 where a higher
yield and purity of product 246 could be obtained under
microwave irradiation, and the final cyclization to resin-
bound Imatinib where the reaction time could be reduced
from 20 h to 50 min. Additionally, resin stability was ensured
due to the shorter reaction time.
A specially engineered linker for microwave-assisted solid-
phase organic synthesis was developed by Dai and co-workers
(Scheme S440) [872]. The alkylation of N -acyl-sulfonamide
linkers (Scheme S441) [873] and microwave-assisted cleav-
age reactions have also been reported (Scheme S442) [874].

123
Mol Divers (2009) 13:71193
OH 1. TsCl, DMF, rt, 30 min
2.
O
R1
W ang Me
300 cm 2 sheets KOt Bu, DMSO
HO MW, 10 min
1.
O
R1
R3
R2 KOtBu, DMA
MW, 30 min
O
40 examples 2. TFA cleavage
Scheme 211 SPOT synthesis of pyrimidines on planar cellulose supports
Koichi Fukase and co-workers from Osaka University
have reported the solid-phase synthesis of indol-2-ones (four
diversity points) via a radical cyclization pathway (Scheme
213) [875]. The key cyclization step was carried out by using
Bu3 SnH and 2, 2 -azobisisobutyronitrile (AIBN) in DMF
under microwave irradiation conditions, providing a small
library of 40 compounds. Interestingly, the related radical
cyclization in solution phase was considerable less effective.
By applying a catch and release strategy, the group of
Giampaolo Giacomelli from Universit degli Studi di Sassari
has synthesized a set of 1-alkyl-4-imidazolecarboxylates
(Scheme 214) [876]. The resin-bound isocyanoacrylate 247
was prepared under microwave conditions in only 20 min, com-
pared with 36 h of oil-bath heating. For the next step, resin
247 was reacted with a set of amines under open-vessel micro-
wave conditions to give imidazolecarboxylates 248 in excel-
lent yields and high purities. Furthermore, the solid support
could be recycled and used successfully for three to four
cycles.
Other microwave-assisted transformations performed on a
solid support include Suzuki cross-couplings (Scheme S443)
[877], peptide macrocyclizations by nucleophilic aromatic
substitution (Scheme S444) [878], the Nicholas reaction
(Scheme S445) [879], the Pd-catalyzed deoxygenation of
multifunctionalized phenols (Scheme S446) [880], the prepa-
ration of 2,5-diketopiperazines (Scheme S447) [881], benzo-
furans (Scheme S448) [882], benzimidazoles (Scheme S449)
[883], Knoevenagel condensations (Scheme S450) [884], and
Fmoc deprotections and amide bond formations (Scheme
S451) [885].
163
O
R2
H
O
R1
KOH, H 2O
Me
MW, 20 min
O 6 examples
NH 2+ Cl R3
NH2 N N
R1
R2
HO 12 examples
2.24.2 Soluble-polymer-supported synthesis
The synthesis of thiohydantoin fused tetrahydro--carbo-
lines has been investigated by the group of Chung-Ming Sun
at National Chiao Tung University (Scheme 215) [886]. A
soluble polymer-supported strategy using polyethylene gly-
col (PEG) resin combined with a traceless cyclative cleavage
step was applied to achieve products 249 in high stereoselec-
tivity. By employing microwave heating the thermodynami-
cally stable trans diastereomers were obtained preferentially.
A series of related articles by the same group highlights
the efficiency of using PEG-derived soluble supports for het-
erocyclic synthesis (Scheme S452) [887].
A cycloalkane-based thermomorphic system for perform-
ing Pd-catalyzed cross-coupling reactions has been
developed by Chiba (Scheme S453) [888]. The use of sub-
strates with cycloalkane-soluble tags facilitates separation
of the desired products and the homogeneous Pd catalyst via
simple liquidliquid extraction, thereby eliminating the need
for a catalyst removal process.
2.24.3 Fluorous synthesis
A 2004 publication by Wei Zhang and co-workers describes
a new strategy to improve the efficiency of Suzuki coupling
reactions by combining rapid microwave synthesis with flu-
orous separation techniques (F-SPE) (Scheme 216) [889].
Aryl perfluorooctylsulfonates 250 as precursors for Suzuki-
type couplings were readily prepared from phenols and
123
164 Mol Divers (2009) 13:71193

CHO
CHO
NaH, DMF
P Cl
MW, 120 C, 5 min P O OMe
HO OMe
244

CHO
CHO
Me N NH
Cl
P O OMe
O
1. DIPEA, DMF
N MW, 100 C, 5 min

2. SnCl2, DMF
Me MW, 100 C, 5 min
NO2
N
N O N
Me
O N 1. bis( N-alloc)methylthiopseudourea
Me HgCl2, TEA, DMF, 0 C, 10 min N
N
2. MW, 80 C, 5 min Me
Me 3. Pd(PPh3 )4 , PhSiH 3, DCM, 1 h HN NH
NH 2
NH 2
245 246
O

N
N
N
H H 1. nitrobenzene, BEMP (or DBU)
N N N N MW, 120 C, 50 min
Me
N O 2. TFA/DCM, 1 h
Me
overall yield 65%
purity >90 %
N
Imatinib

Scheme 212 Multistep solid-phase synthesis of Imatinib

commercially available perfluorooctylsulfonylfluoride. Sub-
sequent Suzuki reaction with aryl boronic acids in the
presence of a suitable Pd catalyst provided the desired biaryls
251 in high yield. Work-up simply involved filtration of the
reaction mixture through a fluorous solid-phase extraction
cartridge (F-SPE).
In 2005 the same group reported on a solution-phase syn-
thesis of biaryl substituted proline analogs by a three-compo-
nent 1,3-dipolar cycloaddition and a Suzuki coupling
(Scheme 217) [890]. Use of controlled microwave irradiation
in both steps and perfluoroalkylsulfonyl protected hydroxy-
benzaldehydes has enhanced both the reaction and separation
processes for the synthesis of bicyclic proline analogs.
A fluorous analog of Lawessons reagent has been devel-
oped for the thionation of carbonyl compounds (Scheme S454)
[891]. A fluorous organicinorganic hybrid support for Pd
nanoparticles has been described for use in Heck reactions
(Scheme S455) [892].
2.24.4 Task-specific ionic liquids
Extensive studies by Jean-Pierre Bazureau and co-workers
have demonstrated the usefulness of specifically designed
ionic liquids as supports in organic synthesis. Examples
include multicomponent reactions such as the Biginelli or
Hantzsch synthesis (Scheme S456) [893]. The same group
has subsequently extended this concept to the synthesis of
polyhydroquinolines (Scheme S457) [894]. Other research-
ers have described similar ionic liquid-based approaches for
the Gewald synthesis of 2-aminothiazoles (Scheme S458)
[895].

123
Mol Divers (2009) 13:71193 165

O
R4
2
HN
R
Br R3

NH-Fmoc
Cl R1 NaH, DMF
H
N

PS-Rink O

CONH 2
O
R4 1. Bu3 SnH, AIBN, DMF
H N MW, 170 C, 45 min
N R2
O
Br R 3 N
2. TFA, DCM, rt, 30 min R2
O
R4
R1
R3
R1
40 examples
(45-100%, >66% purity)

Scheme 213 Solid-phase synthesis of indol-2-ones via radical cyclization

EtO OEt
O R 1OC
CSA (cat), DMF
+ NC NC
N Me R1 MW, 80 C, 20 min N
H Me
247
R1OC
H 2N R 2, n-BuOH N
+
MW, 114 C, 2 cycles of 30 min
N N Me
H
R2
R1 = OMe, OBn, sec alkyl amines 248
R2 = pr im-, sec -or t er t-alkyl 18 examples
(80-98%)
Scheme 214 Synthesis of 1-alkyl-4-imidazolecarboxylates

O O
H DCC, DMAP, DCM H
HO PEG OH HO PEG O
MW, 100 W, 20 min
NH NH NH NH
Boc Boc 2

2
R1CHO, CF3COOH O R -NCS, Et3N O
H
H ClCH2CH2Cl
DCM
PEG O 2
R N
MW, 100 W, 20 min MW, 200 W, 30 min N NH
HN NH
S H R1
R1 = alkyl, aryl R1 2 R2 = alkyl, aryl
249
cis:trans ~ 1:1 15 examples
(84-98%)

Scheme 215 Synthesis of tetracyclic -carbolines

123
166 Mol Divers (2009) 13:71193

HO C 8F17 SO 2F, K2CO3, DMF C 8F17 O

S
R1 O O R1
70 C, 5 h
250

ArB(OH) 2, PdCl2 (dppf ), K2 CO 3 Ar

toluene, acetone, H 2O R1

MW, 100-150 C, 10 min 251

12 examples
(74-95%)
Scheme 216 Fluorous Suzuki-type coupling reactions

1
O H R CO 2 R
O
R1 R3 N NH
R2 DMF, Et3N
CHO
OR + + R3 N
H 2N H
O
O C 8 F17 O2 SO
MW, 150 C, 15 min R2
O
(40-75%)
OSO2 C 8 F17
O H R1 CO 2R

R3 N NH
R 4 PhB(OH)2 , PdCl2 (dppf)
K3PO4 , toluene/acetone/H 2O H
O
R2
MW, 120 C, 12 min

15 examples
(19-79%) R4

Scheme 217 Fluorous synthesis of biaryl-substituted proline analogs

2.24.5 Polymer-supported reagents Met hod A

HBTU, PS-BEMP, MeCN
MW, 160 C, 15 min R2
An expeditious synthesis of 1,2,4-oxadiazoles has been dem-
onstrated by Yin Wang and co-workers at Abbott Labs O
+
NOH N
N
(Scheme 218) [896]. The synthesis of 1,2,4-oxadiazoles from R 1
OH R 2
NH 2
Method B R 1 O
i) PS-PPh3, CCl3CN
a variety of readily available carboxylic acids and amidox- 15 examples
R1 , R 2 = alkyl, aryl ii) DIEA, THF (77-99%)
imes using solid-phase reagents and catalysts has been
i) MW, 100 C, 5 min
devised in two approaches with high yields and simplifica-
ii) MW, 150 C, 15 min
tion of purification process. Microwave technology has been
utilized for a rapid optimization of reaction conditions with Scheme 218 Synthesis of 1,2,4-oxadiazoles using polymer-supported
reduction in reaction times from hours to minutes. reagents
In a related work, the same group has reported on the gen-
eration of 1,3,4-oxadiazoles via condensation of acid hydra-
zides and carboxylic acids employing trichloroacetonitrile 5-substituted-2-amino-1,3,4-oxadiazoles and their corre-
in combination with polymer-supported PPh3 as reagents sponding thiadiazole analogues (Scheme 219) [899]. A one-
(Scheme S459) [897]. The same reagent combination was pot preparation of the 2-aminosulfonylated analogs through
also used in the synthesis of triazolopyridines by the same a three-component coupling of an acylhydrazine, an isocya-
authors (Scheme S460) [898]. nate, and sulfonyl chloride promoted by a polymer-supported
Along similar lines, Steven Ley and co-workers from the phosphazine base (PS-BEMP) under microwave heating is
University of Cambridge have reported on a symbiotic com- also described.
bination of solid-supported reagents and microwave-assisted The synthesis of highly substituted benzoxazoles employ-
organic synthesis to rapidly generate compound libraries of ing solid-supported reagents was developed by Maurizio

123
Mol Divers (2009) 13:71193 167

N C N
O N N
H H R2
N N DMF R1 X N
R1 N R2 H
H MW, 140 C, 1 h
X
10 examples
X = O, S (64-88%)

N N
P
N N
O N N
H H R2
1 N N 2 MeCN, R 3SO 2Cl R1 X N X = O: 51 examples (49-93%)
R N R
H X = S: 32 examples (65-98%)
X O S O
MW, 150 C, 15-20 min
R3
One pot procedure; X = O; R 2 = p-tolyl: 22 examples (42-80%)

Scheme 219 Preparation of 1,3,4-oxadiazoles using polymer-supported reagents

O
R1 O
O R1 R2 R
2
R2
HO 3
HO R3 R O R3
N O O
+ +
1
S N Me H2N MW, 300 W, 10 min R N R1 N
H H
252 253 254 255
1
R = aryl
R2 = H, NO2
2
R3 = H, Cl, Me TsOH R
3
toluene R N
R1
MW, 180 C, 10 min O

19 examples
(24-99%)

Scheme 220 One-pot two-step synthesis of benzoxazoles

Botta and his group from Universit di Siena, Italy
(Scheme 220) [900]. In the first step solid-supported reagents
252 were reacted neat with 2-aminophenols 253 to give the
uncyclized mono- and diacylated intermediates 254 and 255.
Subsequent addition of toluene and polymer-bound p-tolu-
enesulfonic acid to catalyze the cyclodehydration and irradi-
ation at 180 C for 10 min gave the benzoxazole derivatives
in moderate to excellent yields. Importantly, the products are
obtained in high purity only by final filtration from the poly-
mer-supported reagents. By combining a parallel synthesizer
for evaporation and filtration/washing steps and microwave
heating the small library was produced in short time and ren-
ders the protocol amenable for automation.
Wolfgang Lindner and co-workers from the University
of Vienna have reported on the nucleophilic halide/azide
exchange of pre-activated silica gels 256 (Scheme 221) [901].
By applying microwave heating the reaction time could be
reduced from 48 h at 80 C to only 5 min at 125 C. For the
azidopropyl-modified silica support 257a 87%, and for the
11-azidoundecyl silica 257b even quantitative, conversion
was obtained. The azido-modified silica supports were then
subjected to click chemistry with alkyne-functionalized Cin-
chona alkaloids 258 and 259, respectively, in order to produce
an effective chiral stationary phase for HPLC enantiomer
separation.
Esterification reactions using a Mukaiyama-type sup-
ported reagent were described by the Taddei group (Scheme
S461) [902]. A similar supported reagent was used by Cro-
signani for the preparation of a 2-oxazoline library (Scheme
S462) [903]. In a related study, a polymer-supported carbodi-
imide was employed to prepare a library of imidazothiazol-
3-ones and imidazothiazine-4-ones (Scheme S463) [904],
in the generation of a 3,4-dehydroproline amide discovery
library (Scheme S464) [905], and for the synthesis of car-
boxamide libraries containing oxepines and pyrans (Scheme
S465) [906]. Resin-bound isocyanates were prepared as
amine scavengers by Bradley using microwave heating
(Scheme S466) [907].

123
168 Mol Divers (2009) 13:71193

MeO NaN3, DMSO MeO

O Si O Si
X MW, 125 C, 5 min MeO N3
MeO n
n
256
n = 2, X = Cl 257a: n = 2: 87% conv
n = 10, X = Br 257b: n = 10: quantitative conv

258 N N
259
OR O
N or N

O
MeO
CuI, DIPEA, MeCN
O Si N N
rt, 48 h MeO N
n Cinchona
Ligands
R = H, C(O)N(H)t-Bu,
NO2

N
O H
NO2
Scheme 221 Synthesis of azido-modified silica gels

2.24.6 Polymer-supported catalysts
Andreas Kirschning and co-workers from Hannover Univer-
sity [908] and a team from Abbott Laboratories [909] have
reported very efficient Suzuki coupling reactions involving
immobilized Pd catalysts (Scheme 222). The methods can
be used to couple a range of aryl halides and triflates with
boronic acids in solvents such as water or ethanol. The Han-
nover team has used a novel type of solid Pd(II)-precata-
lyst that can easily be prepared from 4-pyridine-aldoxime
and Na2 PdCl4 (catalyst 260), whereas the Abbott researchers
employed polyethylene-supported FibreCat Pd catalysts (cat-
alysts 261263) under similar conditions.
The same type of FibreCat Pd catalysts were also
employed in BuchwaldHartwig aminations (Scheme S467)
[910], and in intramolecular Heck cyclizations (Scheme
S468) [911]. Wang reported the use of an immobilized Pd
catalyst for performing cross-couplings of sodium tetraphen-
ylborate with aryl halides in water (Scheme S469) [912].
For additional examples of Suzuki reactions performed with
immobilized Pd catalysts see Scheme 8.
The groups of Andreas Kirschning (Universitt Hannover)
and Karol Grela (Polish Academy of Science) have devel-
oped the Ru-catalyst 264 for various metathesis reactions
(Scheme 223) [913]. The Ru-complex is noncovalently (ion
exchange) immobilized on glasspolymer composite
Raschig rings, which has the advantage of easy removal and
reactivation after the reaction. By applying microwave heat-
ing, the reaction could be enhanced from 2 h to 4 min but with
slightly reduced isolated yields. Additionally to the batch
protocol, the olefin metathesis was also performed under
PASSflow continuous flow conditions, however, a diminished
recyclability of 264 (six cycles versus two) was observed. A
similar type Raschig ring Pd catalyst was developed by the
same group for Suzuki cross-couplings (Scheme S470) [914].
The concept of performing microwave chemistry (for
example, Suzuki cross-couplings) in Pd-coated microcapil-
laries has been introduced by Organ (Scheme S471) [915].

123
Mol Divers (2009) 13:71193 169

A: catalyst 260 (1 mol%)

K2 CO 3, TBAB, H2 O
R MW, 120 C, 20 min R
Ar-X + (HO)2 B Ar
B: catalysts 261- 263 (3 mol%)
X = Br, I, OTf, Cl K2 CO 3, EtOH A: 31 examples
MW, 110-120 C, 10-25 min (48-100%)
B: 13 examples
(50-98%)

OH
N
P P P
N
O O Cl
Pd Pd Pd Pd
Cl AcO Me AcO Me (t-Bu)3P Cl
Cl O O
n
catalyst 260 catalyst 261 (FC 1001) catalyst 262 (FC 1007) catalyst 263 (FC 1032)

Scheme 222 Suzuki couplings utilizing immobilized Pd catalysts

CO2Et catalyst 264, DCM CO2Et 2.24.7 Polymer-supported scavengers

CO2Et MW, 60 C, 4 min CO2Et
Xiaoguang Lei and John A. Porco Jr. from Boston University
71%
have demonstrated the usefulness of a thermally stable poly-
mer-supported anthracene derivative (265) for scavenging
MesN NMes : Raschig ring dienophiles under microwave conditions (Scheme 224)
Cl [922]. This strategy was successfully used to rapidly seques-
Ru
Cl
SO3 ter reactive dienophiles from reaction mixtures containing
O flavenoid DielsAlder cycloadducts (267) prepared by micro-
NHEt2
wave-assisted DielsAlder cycloaddition from flavenoid
264
+ dienes (266).
Extensive work by the Ley group has demonstrated the
Scheme 223 Ru-catalyst on Raschig rings for olefin metathesis usefulness of tagged reagents and scavengers when applied
in conjunction with microwave heating (Scheme S478) [923].

A variety of other transformations have been reported by the

same group using metal films on glass capillaries in flow for-
mat (Scheme S472) [916]. A similar approach was chosen
by Ondruschka applying Pd on porous glass for Suzuki and
Heck chemistry (Scheme S473) [917]. Cu and Pd-containing
perovskites were shown to be useful catalysts for Ullmann
and Sonogashira couplings (Scheme S474) [918]. A Pd cat-
alyst based on modified starch has been shown to be active
in Sonogashira cross-couplings (Scheme S475) [919]. Sim-
ilarly, the use of Pd-N -heterocyclic carbene ligands grafted
onto silica in CC coupling chemistry has been demonstrated
(Scheme S476) [920].
A polymer-supported BEMP base was used for the ionic
immobilization of carboxylic acid derivative possessing a Su-
zuki-active bromide functionality. The Suzuki reaction was
carried out under microwave conditions directly on the ionic
complex (Scheme S477) [921].
3 Conclusion and outlook
The diverse examples provided in Sect. 2 and in the Sup-
porting Information of this review make it obvious that most
types of chemical transformations requiring heat can be car-
ried out successfully under microwave conditions. This does
not necessarily imply that dramatic rate enhancements com-
pared with a classical, thermal process will be observed in all
cases, but the convenience of using microwave technology
should make this nonclassical heating method a standard tool
in the laboratory within a few years.
In our 2004 review article we posed the question: so why
isnt everybody using microwaves? [48]. Browsing through
synthetic chemistry journals one can often not help of think-
ing: this reaction would run much better under microwave
conditions. Putting the total number of publications in the

123
170 Mol Divers (2009) 13:71193

Me O
H O
O O N O H
O Me H 2N Ph N Ph N
O N

O O
O PS

toluene DCE
100 C, 12 h MW, 150 C, 15-40 min
10 examples with different
265 , 1.09 mmol/g dienophiles (alkene, alkynes)

O
1.
Me O H
Et N , DCE Me
OMe Et N H
O OMe
MeO O MW, 150 C, 10 min O H
O
MeO
2. PS-scavenger, DCE
266 MW, 150 C, 20 min
OMe O 267
OMe O

Scheme 224 Resin-bound dienophile scavengers

field of synthetic organic chemistry in perspective to the References

number on papers using MAOS, it is clear that the major-
ity of chemists have not accepted this enabling technology
yet. Closer inspection of Fig. 1, in fact, reveals that the annual
percentage growth in the number of publications has recently
(20072008) fallen to only 14%.
One of the major drawbacks of this relatively new tech-
nology is still equipment cost. While prices for dedicated
microwave reactors for organic synthesis have come down
considerably since their first introduction in the late 1990s,
the current price range for microwave reactors is still many
times higher than that of conventional heating equipment.
This fact has severely limited the penetration of microwave
synthesis in academic laboratories around the world. It can
only be hoped that this situation will change over the next sev-
eral years and less expensive equipment will become avail-
able. Another cause is probably related to the fact that many
chemists are extremely conservative and are reluctant to
accept radical changes in technology [924]. Other factors
may include unanswered questions relating to the existence
of special microwave effects, and the scalability, and
overall energy efficiency of this method. The next 510 years
will tell if MAOS will ultimately be accepted by the majority
of chemists in both academia and industry.
Acknowledgements The authors would like to thank all members
of the Kappe research group who have participated in the microwave
literature meetings during 20052008 for their contributions. Fund-
ing for this project was provided, in part, by Biotage AB and www.
organic-chemistry.org.
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