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Introduction:

Tertiary amine oxides possess the gross chemical structure shown below, in
which a tetravalent nitrogen is substituted with three alkyl or aryl substituents
and is datively bonded to an oxygen atom (Scheme 1). The term “amine
oxide” has been used in the literature to describe a variety of chemical
structures. In this article only amine oxides in which the nitrogen is sp 3
hybridised and R1, R2 and R3 is equivalent to either an alkyl, functionalised
alkyl or vinyl group will be considered. Structures containing either sp2
hybridised nitrogen atoms (heteroaromatic amine oxides) or in which R is
equivalent to hydrogen, or heteroatoms such as nitrogen, oxygen or sulfur will
not be discussed.
Scheme 1.
R1 R1
R2 N O or R2 N O R1, R2, R3 = Alkyl, functionalised alkyl, vinyl
R3 R3

Amine oxides have been studied since the end of the nineteenth century
(PIN). Many of the initial investigations into amine oxides were prompted as a
result of the isolation of novel amine oxides from animal tissues or plant
extracts (ALB 1), (CUL). Indeed, trimethylamine oxide (TMAO) was first
isolated from the muscle of the shark Acanthius vulgaris in 1909 (SUW), and
has subsequently been shown to be present in the muscular tissue, liver,
kidneys and sex glands of most crustaceans, cephalopods and marine
vertebrates (HEN). One of the primary causes for the decomposition of fish (at
the market place) is an increase in the bacteria responsible for the reduction
of TMAO to trimethylamine (LOV). The first alkaloid N-oxide, iodinin (CLE)
was reported in 1938, but it was not until 1943 when White and Hill (WHI)
isolated the antibiotic aspergillic acid from aspergillus flavis that interest in the
field expanded. More than two hundred naturally occurring aromatic and
aliphatic amine oxides have been reported to date (ALB 1). However, this
value may not accurately reflect the total number that actually exist. During
the process of extraction, purification and analysis of new natural products, it
is possible that any amine oxide present may be reduced to the parent tertiary
amine or undergo rearrangement to a more stable chemical entity.
A number of characteristic features associated with tertiary amine oxides
occur as a direct consequence of their highly polar nature. They are often
crystalline materials and are frequently isolated as mono or dihydrates. The
hygroscopic character of amine oxides is typified by anhydrous TMAO which
absorbs ca. 1% water/minute @ 80% humidity (SOD). Both sublimation and
azeotropic drying from DMF or toluene have been employed to dehydrate
TMAO dihydrate. Tertiary amine N-oxides are often soluble in water, alcohols
and dipolar aprotic solvents. They display limited solubility in non-polar
organic solvents such as toluene (KOS). Although amine oxides are
considerably weaker bases than their parent tertiary amines, they readily
react with acids to produce stable hydroxyammonium salts. The pK a values of
these conjugate acids have been estimated to be in the region of 4-5 (NYL).
The structure of tertiary amine oxides was the subject of debate within the
chemical literature for some years. A number of spectroscopic techniques
have been employed to study the physical nature of these compounds. X-ray
crystallography has confirmed the tetrahedral arrangement of the oxygen
atom and the three carbon substituents around the nitrogen atom. The
nitrogen-oxygen bond length was first determined by Lister and Sutton (LIS),
during an electron diffraction study of TMAO. Their value of 1.36 ± 0.03 Å,
equal to the sum of the normal single bond radii correlates very closely to N-O
bond distances determined by X-ray diffraction. A variety of amine oxide
structures have been determined by X-ray crystallographic studies (LIS),
(LAL), (BRE), (BRO), (CHA), (CIG), (MAI), (MAI 1), (MAI 2), (NUB), (PAJ),
(PIR), (ONE), (ONE 2), (ONE 3), (ONE 4), (ONE 5). The reported N-O bond
distances extend from a minimum value of 1.366 Å to an upper limit of 1.41 Å.
The experimental evidence suggesting that amine oxides are stabilised
through hydrogen bonding to the amine oxide oxygen is well supported by X-
ray crystallographic data. X-ray structures in which the amine oxide oxygen is
intermolecularly hydrogen bonded to water (CIG), ethanol (BRE) and d- -
bromo- -camphorsulfonic acid (PIR) have been published. Hydrogen bonding
to an internal acidic proton is evident in the crystal structure of N,N-dimethyl
ethanolamine N-oxide (MAI 2). The X-ray structure of the complex formed
between N-methyl morpholine N-oxide and trans cyclohexane diol (MAI)
demonstrates that the N-oxide oxygen can simultaneously hydrogen bond to
two separate alcohol moieties. Extensive studies have been carried out on the
structure of proline and pipecolic acid derived N-oxides by the O‟Neil group
(ONE), (ONE 2), (ONE 3), (ONE 4), (ONE 5). The simultaneous
intramolecular hydrogen bonding of an N-oxide to two amide residues has
also been reported (ONE 3). Both inter and intramolecular hydrogen bonding
result in a decrease in the N-O bond length by 0.01 - 0.03Å.
Further evidence of tertiary amine N-oxide structure has come from studies of
transition metal complexes (ALS), (KID), LUH). The use of simple aliphatic
amine oxides as ligands for transition metals in synthetic inorganic chemistry
has received increasing attention during recent years. In contrast to the large
number of well documented heteroaromatic amine oxide transition metal
complexes, tertiary amine N-oxide complexes are more difficult to form and
are less stable. X-ray structures in which the amine oxide oxygen is
complexed to ruthenium(II), copper(II) and manganese(III) have been
reported (BRO), (NUB), (PAJ).
The highly polar nature of tertiary amine N-oxides is exemplified by the large
value of their dipole moment. Typical values for simple simple tertiary amine
oxides lie in the region of 4.5-5.0 Debyes (COO), (LIN). Heteroaromatic amine
oxides, such as pyridine N-oxide have a lower dipole moment (~ 4.2 Debyes)
as a consequence of their ability to exist in resonance stabilised structures.
The dipole moment of similar polar bonds e.g. P=O, S=O, 3.5 D. and 3.0 D.
respectively, are considerably lower than those of amine oxides. The
difference arises from the fact that both the phosphorus and sulfur can
participate in d -p orbital overlap. The nitrogen in an amine oxide is unable
to participate in this orbital overlap, so exists solely in the highly polar, single
bonded form.
Additional evidence of the strong electron donor character of amine oxides is
evident from the interaction of TMAO with SO2 and BF3. Reaction of
anhydrous TMAO with SO2 (CRA), (BUR) yields the extremely stable
zwitterionic oxide adduct Me3NOSO2. Similarly, reaction of BF3 (BUR 2) with
anhydrous TMAO produces a stable betaine Me3NOBF3 (Scheme 2).
Scheme 2.
BF3 SO2
Me3N O BF3 Me3N O Me3N O SO2

A number of infra-red studies of tertiary amine oxides have been undertaken


by Zundel and co-workers (BOH), (BRZ), (BRZ 2), (BRZ 3), (BRZ 4), (KEI),
(OH). The N-O bond exhibits a stretching mode absorption at 940-970 cm-1 in
the infra-red spectrum and a vibrational absorption at 460 cm -1 in the far infra-
red. Both infra-red and far infra-red have been used to demonstrate that in
solution tertiary amine oxides strongly hydrogen bond to either inter or
intramolecular hydrogen bond donors such as alcohols, amides and acids
(SAF), (BUE). The strength of the hydrogen bond is directly related to the pK a
of the acidic proton.

N-Oxide stability:

Simple acyclic tertiary amine oxides are generally stable at room temperature,
although the presence of a propargylic or allylic substituents can allow a [2,3]
Meisenheimer rearrangement to occur. In these cases the stability of the
amine oxide is substrate and solvent specific.
The stability of cyclic N-oxides is dependent upon the ring size of the parent
tertiary amine. The amine oxides of N-substituted aziridines are extremely
strained dipolar species, and have thus far have proven too reactive to isolate.
Baldwin and coworkers (BAL) have recorded the NMR spectrum of N-tert-
butylaziridine N-oxide at low temperature. They are prepared by the direct
oxidation of the parent aziridine. The reverse Cope elimination cannot be
used to prepare aziridine N-oxides. The decomposition of aziridine N-oxides
has been shown to proceed through two stereochemically distinct pathways.
In general, the presence of a suitably positioned -hydrogen atom favours
decomposition via a Cope elimination. The second pathway involves
elimination of a nitroso moiety with concomitant olefin formation.
Decomposition through both pathways may arise with sterically demanding
aziridine substitution patterns (Scheme ).
Scheme

Cope
O O elimination
+ N OH
N N
R R
R

Furthermore, Baldwin investigated the oxidation of cis and trans 1,2,3-


trimethylaziridines. Both isomers yielded the same hydroxylamine, indicating
that oxidation of the cis aziridine yielded the cis N-oxide.
O3, CH2Cl2
O3, CH2Cl2
-75oC O O
-75oC
NMe N N MeN
Me Me

Me OH
N
Me
Peltzer and co-workers (HEI) have also investigated the decomposition of N-
alkyl aziridine N-oxides. Penkett (PEN) has reported that the oxidation of
bicyclic aziridines gives a mixture of nitrones and oximes, presumably via the
intermediacy of the aziridine N-oxide. Intriguingly, aziridine N-oxides have
been postulated as intermediates in the reverse Cope elimination of allenic
hydroxylamines, as shown in Scheme (DUM), (DUM 2).
Scheme
OH
H O O
HN
C N HN
R1 R1
R1
R2 O
R2 R2 O

Like aziridine N oxides, most azetidine N-oxides are unstable compounds


which readily undergo fragmentation, depending upon the substrate structure.
To date, the only examples of stable azetidine N-oxides have been reported
by the O‟Neil group (ONE 16) (vide infra).
Most of the azetidine N-oxide that have been reported undergo further
reaction via Cope elimination or Meisenheimer rearrangement at room
temperature, to give a variety of products (KUI), (KUI 2), (KUI 3), (YON),
(YON 2) (Scheme).
Scheme
N
O
N THF, rt O

CO2Me
N H 57% N
Me CO2Me Me H

The N-oxides of 5,6 and larger ring tertiary amines are generally stable at
room temperature in the absence of an allylic or propargylic substituent, which
again allows for the possibility of a Meisenheimer rearrangement.
The axial versus equatorial conformational preference of the nitrogen oxygen
bond of N-methyl piperidine N-oxide and N-methyl morpholine N-oxide, has
been estimated independently by Shovo and Katritzky respectively to be
90:10 (SHV), (SHV 1), (COOK) (Scheme).
Scheme
O Me
N Me N O
X X

X = O, CH2
90% axial 10% equatorial

Kawazoe and Tsuda (KAW) have shown that substitution to nitrogen in N-


methyl piperidines can dramatically alter the ratio of isomeric N-oxides
produced during H2O2 oxidation. For example, the axial N-oxide predominates
over its equatorial isomer by a factor of 81:19, upon treatment of 2-methyl-N-
methyl piperidine with H2O2. However, the equatorial N-oxide is the major
product formed during the oxidation of cis-2-ethyl-6-methyl-N-methyl
piperidine. The ratio was found to be 64:36. Clearly, increasing the steric bulk
at the centres adjacent to nitrogen favours equatorial attack during N-oxide
formation (Scheme ).
Scheme

O Me
H2O2 +
N Me N Me
N Me
Me O
Me
81 : 29

O Me
H2O2 + Et
Et N Me N Me
Et N Me
Me O
Me
36 : 64

Chiral amine N-oxides:

As a consequence of their tetrahedral nature and configurational stablility,


tertiary amine N-oxides possessing three different carbon substituents can
exist as enantiomers. Optically active amine oxides have traditionally been
prepared by resolution with an optically pure acid derived from the “chiral
pool.” Both d- -bromo- -camphorsulfonic (JME) and dibenzoyltartaric acids
(BER), (GOL) have been successfully used for this purpose. Goldberg and
Lam (GOL) have resolved the enantiomers of cis-N-methyl-N-neopentyl-4-
methyl-cyclohexane N-oxide using dibenzoyltartaric acid (Scheme ).
Scheme
Me Me Me
(-)-Dibenzoyltartaric acid Me O O Me
H
N N N

(-)-(S)-cis (-)-(R)-trans
[ ]D = -2.87o [ ]D = +2.90o
The use of chiral HPLC to resolve racemic tertiary amine N-oxides has been
reported (HAD). Other methods for the synthesis of chiral amine oxides will be
discussed in the relevant sections of this review.
The ee of amine oxides can be determined by NMR, when a chiral shift
reagent is employed. Pirkle and co-workers have reported the use of (S)-
2,2,2-trifluoro-(1-naphthyl)ethanol and (S)-(+)-2,2,2-trifluorophenylethanol for
the determination of both the ee and the absolute configuration of N,N-dialkyl-
N-arylamine N-oxides (PIR). Toga and co-workers have reported the use of
the chiral shift reagents (-) and (+)-4,4‟,6,6‟-tetrachloro-2,2‟-
bis(hydroxydiphenylmethyl)-biphenyl for the measurement of the enantiomeric
purity of N-ethyl-N-methyl-p-toluidine N-oxide (TOD). More recently the
addition of (R)-BINOL as a chiral solvating agent has enabled the use of 1H-
NMR to accurately determine the ee of amine oxides (WEN).

The synthesis of tertiary amine N-oxides has been described in a number of


previous reviews. (ALB 2), (CUL), (FRE), (DOS), (ROB). Tertiary amine N-
oxides are substrates in a number of important reactions, including the Cope
elimination (COP), (AST), (ACE); the Meisenheimer rearrangement (PIN 2),
(JOH), (MUC) and the Polonovski reaction (GRI), (POL). They have also
found use as ligands in asymmetric synthesis (MAL), in the conversion of
halides to aldehydes (FRA), (SUZ), (GOD) and as oxidants in a number of
metal-mediated reactions. These include the osmium mediated cis
hydroxylation of alkenes (VAN), (VAN 1), (MCK) (SCH), (AHR), (JAC), the
ruthenium-mediated oxidation of alcohols to aldehydes; (Podlech, J., Science
of Synthesis, (2006) 25, p41), (SHA), (GRIF), (GRIF 2), the oxidation of
alkylboranes (SOD 2), iron mediated oxidations (PEA) and the Pauson Khand
reaction (GEI), (GIB), (PAU), (SCH 1), (SCH 2), (SCH 3). Amine N-oxides
have been used as enzyme inhibitors (CER) and as haptens for antibodies
(LI).
Industrially tertiary amine N-oxides are widely used as “amphoteric
surfactants” (GOR), (SIN), (PIA), (KUS). They are also found in cosmetic
products and have been used as solvents for cellulose (LOU).

The aim of this review is to describe the major methods of preparation of


tertiary amine oxides.

There are three principal methods for the synthesis of tertiary amine N-oxides:

Method 1. The reaction of hydroxylamines with alkyl halides.


Method 2. The oxidation of the parent tertiary amine.
Method 3. The reverse Cope cyclisation.

Of these three methods, the direct oxidation of tertiary amines is by far the
most commonly used in synthesis. Furthermore, hydrogen peroxide (H 2O2)
and meta-chloroperoxybenzoic acid (m-CPBA) are the most widely used
oxidants in this transformation. The reverse Cope cyclisation is generally used
for the synthesis of functionalised pyrrolidines, piperidines, morpholines and
related bicyclic systems.
Method 1: The reaction of hydroxylamines with alkylating agents:

The preparation of tertiary amine N-oxides from the reaction of


hydroxylamines with alkyl halides was first reported by Dunstan and Goulding
at the turn of the century (DUN). This is not a commonly used method for the
synthesis of tertiary amine N-oxides, probably due to the paucity of methods
for the preparation of the precursor hydroxylamines (SOS reference). A more
recent investigation of this method of amine oxide synthesis was successful,
although the yields were variable (JON). The reaction of O-methyl-N,N-
dimethylhydroxylamine with methyl iodide led directly to the isolation of the
trimethylamine oxide, presumably through an intermediate ammonium
species (Scheme ).
Scheme .
Me Me Me Me
MeI
N OMe N Me N O
Me Me O Me I Me

Tertiary amine N-oxides have also been prepared in excellent yield from O-
silylated hydroxylamines in a similar manner. When the O-silyl hydroxylamine
() was treated with a large excess of MeI and CsF in MeOH, the
corresponding amine oxides were isolated in up to 86% (Scheme 3) (LAN),
(FAL).
Scheme 3.

MeI (20eq)
CsF (5.7eq)
Me MeOH Me
N O SiPh2tBu N O
86% Me

Shvo has shown that the methylation of a number of 4-tert-butyl piperidine


derivatives gave the corresponding N-oxides in modest yields, after aqueous
hydrolysis of the salts. When the O-benzoylhydroxylamine was used, this
procedure gave two isomeric N-oxides in a cis:trans ratio of 65:35 in 80%
overall yield (Scheme )(SHV).
Scheme
1. MeI or MeOTf Me
N OR 2. H2O N O
t-Bu t-Bu

R=H 15%
= CH2Ph 40%
= COPh 80% cis:trans 65:35
Interestingly, when this method was applied to 1,4-bis(benzoyloxy)piperazine,
the product bis-N-oxide was formed as 55:45 cis:trans mixture (Scheme ).
Direct oxidation of 1,4-N,N-dimethyl piperazine gives the trans isomer as the
sole product (vide infra).
Scheme
O
N Me
O N

Me Cis
1. MeOTf
2 (PhCO2)2O N OCOPh 2. H2O
NH
PhOCO N +
HN
72% O
N Me
Me N

O
Trans

cis:trans 55:45
Preparation of 1,4-N,N-dimethylpiperazine N,N-dioxide:
1,4-Bis(benzoyloxy)piperazine (16.3g, 0.05 mol) and methyl fluorosulfonate
(12.5 g, 0.11 mol) in dichloromethane (50 mL) were stirred at room
temperature for 10 h to give a white precipitate; 32.5 g (100%); NMR (CDCI3
3.55 (s, 8H), 7.5 (m, 6H), 8.05 (m, 4H). The above product (30 g) was
dissolved in water (30 mL) and the mixture stirred for 15 h at room
temperature. After the benzoic acid was filtered off, a saturated solution of
picric acid in water was added to the filtrate to the point of complete
precipitation. The free amine oxide was obtained by decomposing the picrate
salt on Amberlite 400 (BDH) in methanol solution. A mixture of the cis and
trans N-oxides in the ratio of 55/45 was obtained (72%).

Method 2. The oxidation of tertiary amines:


The most common method for the preparation of tertiary amine oxides is via
treatment of the requisite tertiary amine with an oxidant. A wide variety of
oxidants have been used and they will be discussed individually. Of the
reagents available, hydrogen peroxide and meta-chloroperoxybenzoic acid
(m-CPBA) are the most commonly used.

Variation 1: Hydrogen Peroxide:


The oxidation of tertiary amines is usually carried out with commercially
available hydrogen peroxide in either aqueous or alcoholic solution. In the
absence of a catalyst the reaction is slow and frequently leads to low yields of
products containing various amounts of H2O2, necessitating further
purification (MEI 1), (MEI 2), (COP). When using H2O2 as an oxidant, it is
CRITICAL to ensure that any excess hydrogen peroxide is destroyed by
the use of manganese dioxide or platinum foil before work-up, otherwise
explosive decomposition may occur. For example, the oxidation of DABCO
with H2O2 yields DABCO-di-N-oxide diperhydrate, in which the N-oxides are
each hydrogen bonded to a molecule of H2O2 (Scheme).
Scheme
O H
H O
O
N H2O2
N
N N
95%
O DABCO-diperhydrate
O H
H O

This material has been investigated as an oxidant in its own right, but:
“DABCO diperhydrate has been found to be very unstable, decomposing
violently in the presence of trace amounts of transition metal salts which are
sometimes present on „clean‟ glassware and stirrer bars” (HEA). The
mechanism of the reaction of H2O2 with tertiary amines has been investigated
by Oswald and Guertin (OSW). They demonstrated that the oxidation
proceeds through an initially formed trialkylammonium complex, R 3N.H2O2.
This hydrogen bonded complex, which can be isolated, then decomposes
yielding the amine oxide and water.
Heteroaromatic amines are not normally oxidised by H2O2, except in the
presence of a catalyst or activating agent (THE), (COPE), (ZHU), (TAY),
(MOS).

N,N-Dimethylcyclohexylmethylamine-N-oxide: (BAU)
To 31 g. (0.22 mole) of N,N-dimethylcyclohexylmethylamine 125 g (1.09
moles) of 30% hydrogen peroxide was added with shaking while maintaining
the temperature between 35-40ºC. The completion of the reaction was
gauged by the complete solution of the amine, requiring 48-72 h of shaking
depending on the amount of tertiary amine being oxidized. The excess
hydrogen peroxide was decomposed with a small amount of platinum
oxide shaken in the solution overnight. The solution was filtered and the
water was evaporated at 35-40ºC under reduced pressure, giving 28.3g
(83%) of semi-solid N,N-dimethylcyclohexylmethylamine oxide.

Organic Synthesis procedures for the preparation of N,N-


dimethyldodecylamine oxide (SHE) and N-methylmorpholine N-oxide (VAN)
using H2O2 have been reported
Shvo has reported a general procedure for the oxidation of a number of 4-tert-
butyl N-alkyl piperidine derivatives using H2O2 (SHV) (Scheme).
Scheme
O R
N R H2O2, acetone
N R N O
t-Bu
t-Bu t-Bu
trans cis

% trans
R = Me 95
= Et 95
= CH(CH3)2 95
= PhCH2 95
= t-Bu 100

General method for oxidation of 4-tert-butyl N-alkyl piperidines (SHV):


To a solution of the amine in acetone (0.25 M) was added a 30% aqueous
solution of H2O2. The molar ratio of amine to H2O2 was 1:2.5. Usually the
oxidation was complete after 24 h at 25 ºC (disappearance of amine as
monitored by TLC). Excess oxidant was decomposed with MnO2 to
negative KI test. The solvents were removed under vacuum (60 ºC), and the
residue was flash evaporated several times with benzene. The crude product
was washed with pentane to remove residual amine and dissolved in
chloroform, and the mixture was dried (MgSO4), filtered, and evaporated
(crude yields were 90-95%). Picrates were prepared in aqueous solutions and
usually crystallized from chloroform. Separations of isomers were effected
either by fractional crystallization of the picrates or by chromatography on
basic alumina (11-111).

There are numerous examples in the literature, which utilize H2O2 to convert
tertiary amines into their N-oxides. Selected examples are given below.
Woodward reported the synthesis of the bis-N oxide shown in Scheme ().
Thermolysis resulted in a double Cope elimination to give triquinacene (WOO)
Scheme
30% aq. H2O2 125-140oC
H H H H H
H MeOH 10-30mm

O O 79% overall
Me2N NMe2 N N H
Me Me Me Me

Shvo and Kaufmann (SHV) observed that the oxidation of cis-8-methyl-8-


azabicyclo[4.3.0] nonane with H2O2 at 25ºC generated a mixture (88:12) of
stereoisomers. They concluded that the major isomer was produced as a
result of oxidation occurring on the more sterically shielded face of the
molecule (Scheme ).
Scheme
H2O2, 25oC
N H N H N H

N N N
O Me Me O
Me
88% 12%

LaLonde and coworkers have described the synthesis of N-oxide () by


oxidation of the di-deuterated precursor with H2O2. No oxidation of the furan
ring was observed. Subsequent treatment with Ac2O gave the mono-
deuterated enamine, indicating that the Polonovski reaction had occurred with
trans-diaxial elimination of acetic acid (LAL) (Scheme ).
Scheme ()
D Me
Me D O H
H2O2, EtOH Me Ac2O, CHCl3
N D
N D
72% H 90% N
Me Me Me
O D
O
O

There are many examples of N-oxides which possess substituents containing


a triple or double bond. H2O2 can be used to carry out a selective oxidation of
the tertiary amine, provided an excess of the oxidant is not used. If the
unsaturation is allylic to the amine oxide then frequently these compounds
undergo a [2,3] Meisenheimer rearrangement. Examples of propargylic amine
N-oxides (CRA2), (SZA), (SZA 1) and allylic amine N-oxides (TAK) are known
(Scheme ).
Scheme
H2O2
R = H, CH3 , neat or DMF

N N N
O R O C

R R

O NEt2
H2O2,

NEt2 96%

A note of caution when using H2O2 as an oxidant in the preparation of amine


oxides is necessary. Usually, the reagent is used as an aqueous solution, and
this can lead to unwanted side reactions. Koskinen and coworkers (KOS),
(LOU) investigated the oxidation and subsequent Polonovski reaction of the
piperidine derivative shown in Scheme (). When m-CPBA was used to
prepare the amine oxide, the product was the -amino ester nitrile as shown.
When H2O2 was used as the oxidant, the same synthetic sequence gave the
-amino nitrile (). This was rationalised by hydrolysis of the methyl ester in the
presence of H2O2. Subsequent elimination in the Polonovski reaction now
occurred by loss of CO2.
Scheme ()

1. m-CPBA
KCN
2. TFAA, CH2Cl2

N H N N 50% overall N CN
OCOCF3
CO2Me CO2Me CO2Me CO2Me

CF3CO2 CF3CO2

1. H2O2
KCN
2. TFAA, CH2Cl2
N N N
OCOCF3 55% overall N
O
CO2Me H
CN
O CF3CO2
CF3CO2
Procedures employing H2O2 in the presence of a variety of catalysts to effect
the oxidation of tertiary amine to the N-oxides products have also been
reported. These include, vanadium silicate molecular sieves (PRO), and a
Mg-Al-OtBu hydrotalcite catalyst (BMC). Interestingly, carbon dioxide has
been reported to catalyse the oxidation of tertiary and secondary amines with
H2O2 to yield amine oxides and nitrones respectively (BHA).

Variation 2: Alkyl hydroperoxides:


A number of independent studies investigating the oxidation of tertiary amines
with alkylperoxides have been published (KUH), (SHE 1). Although simple
organic hydroperoxides do oxidise tertiary amines, the yields are low and the
reaction conditions are vigorous. Tertiary amines react with organic
hydroperoxides in the presence of catalytic amounts of group (V) and (VI)
transition metals to give the amine oxides in excellent yields (Scheme ).
Scheme
R1 T. M. (Ln)n R1
R2 N + R4 OOH R2 N O + R4OH
R3 R3

Sheng and Zajacek (SHE 1) demonstrated that three experimental variables


affected the reaction: transition metal catalyst, hydroperoxide
reactivity/stability and solvent. From their results on the oxidation of N,N-
dimethyldodecylamine they concluded that vanadium based catalysts and in
particular VO(acac)2 were the most active. Mo(CO)6 effected oxidation, but at
an appreciably slower rate. Tungsten, niobium and tantalum compounds were
poorer catalysts still, whilst chromium, cobalt, manganese and iron complexes
did not effect oxidation. An examination of three different hydroperoxides, t-
butyl, cumene and amylene revealed that both the amylene and cumene
hydroperoxides were more reactive with regards to amine oxidation. These
more reactive hydroperoxides allow the reactions to be run at lower
temperatures. However, tert-butyl hydroperoxide (TBHP) showed greater
resistance towards decomposition, and consequently can be used more
effectively than the other hydroperoxides when higher reaction temperatures
are required. The effect of solvent on the reaction rate was examined. The
absence of solvent severely retarded the rate of reaction and lowered the
yield of amine oxide. In comparison to THF, Et2O and acetone, the use of
protic solvents such as MeOH, or tert-butanol decreased the rate of reaction.
This effect may occur as a result of hydrogen bonding between the alcohols
and the hydroperoxide or the amine. Again, since many alkyl peroxides are
explosive, excess alkyl peroxide MUST be destroyed prior to work up of
the reaction.

Preparation of N,N-dimethyldodecylamine N-oxide (SHE 1):

A solution of 21 g (0.1 mole) of practical grade N,N-dimethyldodecylamine,


9.2 g (0.1 mole) of tert-butyl hydroperoxide (94% purity), 0.05 g of vanadium
oxyacetylacetonate, and 27 g of tert-butyl alcohol was added to a round-
bottom flask equipped with a thermometer and reflux condensor. The reaction
was refluxed at 90ºC for 15 min and cooled. The hydroperoxide was
determined by iodometric titration. There was complete conversion of the
hydroperoxide. The amine oxide was determined by standard hydrochloric
acid titration after reaction of the excess amine with methyl iodide. The
titration analysis showed a 97% yield of amine oxide. The titration was
confirmed by NMR analysis. For the NMR analysis, dichloromethane was
used as an internal standard and TMS as the reference compound. The
methyl groups on the nitrogen of the amine and the oxide appeared at 7.87
and 6.8. The solvent was flash evaporated and gave 21 g of solid, mp 123-
125 ºC. The solid was triturated with 50 mL of pentane, filtered, and dried
under vacuum. This yielded 17.7 g (80% yield) of anhydrous amine oxide, mp
128-130 ºC. The infra-red and NMR spectra were identical with those of an
authentic sample. An organic synthesis procedure for the preparation of this
compound has also been reported (SHE 2).

The oxidation of N-methyl anabasine is notable because it possesses an N-


methyl piperidine and a pyridine ring. Selective oxidation of the N-methyl
piperidine was achieved by using tert-butyl hydroperoxide in the presence of
MoCl5, giving a mixture of the two diastereoisomeric N-oxides (MUS).
Interestingly, the use of m-CPBA, gave a higher yield, but with a reduced level
of diastereoselectivity (Scheme).
Scheme
H H
H
N + N
N
Me O Me Me O
N N
N

MoCl5 /TBHP 51% 1:4


m-CPBA 81% 1:2

Alumina supported MoO3 has also been used to oxidise tertiary amines to
their N-oxides (JAI).

The use of titanium alkoxide complexes such as Ti(OiPr)4 to catalyse the


TBHP-mediated oxidation of tertiary amines was initially reported by Kuhnen
(KUH). Subsequently, Sharpless and co-workers developed an extremely
effective procedure for the kinetic resolution of racemic -hydroxyamines, via
enantioselective N-oxide formation (MIY). Under the reaction conditions, the
faster reacting enantiomeric alcohol is converted into its N-oxide. In the
example shown, treatment of racemic alcohol with diisopropyl tartrate (1.2
eqs) and Ti(OiPr)4 (2 eqs) in dichloromethane, followed by the addition of tert-
butyl hydroperoxide (0.6 eqs) at -20°C, gave the alcohol in 37% and the N-
oxide in 59%.

1. (+)-DIPT
CH2Cl2, Ti(OiPr)4
2. TBHP, -20oC OH OH
OH
+
N N N
Ph Ph Ph
O
37% (95% e.e.) 59% (63% e.e.)

Kinetic resolution of dimethyl ( -hydroxydecyl)-1-amine (MIY):

A 50 mL, one-necked round-bottomed flask equipped with a Teflon-coated


magnetic stir bar was oven dried and flushed with nitrogen while cooling.
Addition of -hydroxyamine (404 mg, 2.01 mmol) and (+)-DIPT (570 mg, 2.43
mmol, 1.21 equiv) was followed by brief flushing with nitrogen. The flask was
then charged with 20 mL of CH2Cl2 followed by Ti(O-i-Pr)4 (1.20 mL, 4.09
mmol, 2.04 equiv). The mixture was stirred for 30 min at rt. After this aging
period, the flask was cooled, while stirring, in a dry ice/CCl4 bath (ca. -20ºC).
To this solution was added 0.6 equiv of tert-butyl hydroperoxide (365 L,
1.2mmol, 3.29 M solution in toluene). After stirring for 2 h at -20ºC, the
reaction was quenched by adding 20 mL of diethyl ether, 0.8 mL of H2O, and
0.8 mL of a 40% NaOH solution. This mixture was vigorously stirred for 4-5 h
at rt, yielding a gelatinuous precipitate which was filtered through a pad of
Celite. The precipitate was stirred vigorously in refluxing CHCl3, for 5 min
before filtering it again through the Celite pad. The combined filtrates were
concentrated to leave a pale, yellow, viscous oil, which was dried under high
vacuum. This oil was triturated in 20 mL of n-hexane. The clear supernatant
solution was filtered and the filtrand was washed with 20 mL of n-hexane. The
filtered solid is the optically active N-oxide of dimethyl( -hydroxydecyl)amine
(233 mg, 53.5%). The hexane extracts were diluted with 5 mL of ether,
washed with water (ca. 200 L x 2), and dried over anhydrous Na2SO4. The
solvent was evaporated to afford 144 mg (35.7%) of (-)-( -
hydroxydecyl)amine as an oil: Chiral shift study indicated that the recovered
-hydroxyamine had a 91% ee.

Variation 3: Peracids:
A wide range of organic peracids, such as peracetic, perbenzoic and
monoperphthalic can be used to effect the oxidation of tertiary amines to
amine oxides (SWE). In 1970, Craig and Purushothaman reported a
procedure for the preparation of tertiary amine oxides with meta-
chloroperbenzoic acid (m-CPBA). m-CPBA is now used extensively for the
oxidation of tertiary amines (CRA 1). It is tolerant of a wide range of functional
groups such as alcohols, esters, amides, carboxylic acids and alkenes. The
oxidation can be performed at low temperature (-78°C) in a range of solvents
and gives reproducible, high yields of products (Scheme ).
Scheme

R m-CPBA R
O R R N O
R N
Cl O N R R
R
O H R
+

Cl CO2H

General Procedure for oxidation of amines with m-CPBA: (CRA 1)


A solution of 1.0 mol of m-chloroperoxybenzoic acid in chloroform was added
gradually at 0-5°C to an ice-cooled, stirred solution of 1.0 mol of the amine in
chloroform. Stirring was continued for a total of 3 h, during which the mixture
was allowed to come to rt. The solution was passed through a column of
alkaline alumina (100-200 mesh, ca. 20 times the weight of the combined
starting materials), and traces of unreacted amine were removed by washing
with chloroform. Elution with methanol-chloroform (1:3) then gave the amine
N-oxide in the yield stated in the table below, after crystallization from alcohol-
ether or acetone-hexane. All compounds had the melting points reported in
the literature, and gave single spots on tlc.

Amine N-oxide Yield, %

Trimethylamine N-oxide 96
Tribenzylamine N-oxide 96
Dimethylaniline N-oxide 94
Nicotine N-oxide 98
Nicotine N,N-dioxide 98
Codeine N-oxide 98
Morphine N-oxide 86

To date, the only examples of stable azetidine N-oxides have been reported
by the O‟Neil group (ONE 16). Simple derivatives of azetidine-2-carboxylic
acid have been shown to undergo a highly diastereoselective oxidation with
m-CPBA to yield the cis N-oxide. The N-oxides are presumably stabilized by
hydrogen bonding to the side chain group. Interestingly the N-oxide derived
from N-benzyl 2-hydroxymethyl azetidine undergoes clean rearrangement, on
gentle heating to the oxazine derivative shown, presumably via a Cope
elimination.

O
CO2H mCPBA
CH2Cl2 O
N N H
60% O
Ph Ph

OH
mCPBA
OH CH Cl O
2 2 O
N N H
O Quantitative N Ph
63%
Ph Ph

Subsequent to the original observation of Siemion (SIE), the synthesis of


chiral amine oxide derivatives of proline has been described by the O‟Neil
group. Treatment of N-benzylproline with m-CPBA gives a 69% yield of the
syn N-oxide (ONE) (Scheme ).
Scheme

mCPBA, CH2Cl2
K2CO3
N CO2H N CO2H
69% O
Ph
Ph
The reaction is general for derivatives of proline that have a hydrogen bond
donor group such as primary and secondary amides and alcohols in place of
the carboxylic acid (ONE 2). In all cases a highly diastereoselective syn
oxidation occurs (Scheme ).
Scheme
mCPBA, CH2Cl2
K2CO3

N 96% N
Bn Bn O OH
OH

The oxidation of proline substrates bearing two hydrogen bond donor groups
also proceeds with very high diastereoselectivity (ONE 3) (Scheme ).
Scheme

mCPBA, CH2Cl2 O
K2CO3
O N
N N t-Bu
94% O
NHt-Bu H
CONH2 O N H
H

The group went on to report the use of chiral amine oxides prepared using
this method in the BH3 mediated reduction of ketones (ONE 4). Subsequently
related proline N-oxide catalysts have been used in a number of
enantioselective transformations, including cyanohydrin formation (CHE 1),
(CHE 2), (SHE 1), (SHE 2), (QIN), the Strecker reaction (HUA), the aza-Henry
reaction (ZHO), the allylation of ketones (ZHA), the allylation of -ketoesters
(ZHE) and the reaction of allyltrichlorosilane with aldehydes (JOH).
The preparation of optically active tertiary amine oxides by the asymmetric
oxidation of unsymmetrical amines has met with limited success. Two
peracids from the chiral pool, (+)-mono-percamphor acid (LON) and (-)-O,O-
dibenzoyl-D-pertartaric acid have been used for this purpose. Oxidation of
trans-N-crotyl-N-methyl-p-toluidine with (R,R)-O,O-dibenzoylpertartaric acid
(MOR) in CHCl3 at -70ºC gave (+)-trans-N-crotyl-N-methyl-p-toluidine N-oxide
with a specific rotation of [a]D -78.4º, which equates to an ee of 16%!
Aurcih and co-workers have reported the synthesis of annulated pyrrolidine N-
oxides by oxidation of the parent tertiary amines with m-CPBA (AUR).
The oxidation of pipecolic acid derivatives bearing a hydrogen bond donor
group in the side chain, with m-CPBA, has been reported to give the syn N-
oxide derivatives with high diastereoselectivity (ONE 5) (Scheme ).
Scheme
m-CPBA, CH2Cl2
m-CPBA, CH2Cl2

N CO2H N N
N CO2H 91%
53% Bn O OH
Bn O Bn OH
Bn

The oxidation of piperazine derivatives bearing hydrogen bond donor


substituents on both nitrogens, with m-CPBA, yields piperazine bis-N-oxides,
in which both N-oxide oxygens are axial, and hydrogen bonded to the amide
NH in the side chains, resulting in a conformationally rigid structure (ONE 17)
(Scheme ).
Scheme
O R R
m-CPBA (2eqs)
H N H
MeO2C N N CO2Me O N CO2Me
N H
N
O O O
N
R = H, 63%
= Me, 72% MeO2C N O
H
= i-Pr, 77%
= i-Bu, 74% R
= Ph, 75%
= Bn, 81%
The use of chiral allylic amine oxides in the preparation of chiral allylic
alcohols has been investigated by a number of groups. Again m-CPBA is the
oxidant of choice in converting the tertiary amine to its N-oxide (REE), (END),
(DAV), (DAV 1), (BUS), (BLA) (Scheme )
Scheme
O
R CO2Et
Bn2N CO2Et m-CPBA Bn2N CO2Et [2,3]

70-80% ONBn2
R R

R = Me, Bn, I-Bu, t-BuMe2SiOCH2

The selective oxidation of a tertiary amine in the presence of a vinyl chloride


was reported by Lansbury (LAN) (Scheme ).
Scheme
Ph
Cl 1.m-CPBA Cl O N
2. [2,3] Me

Ph
N
Me

Shamma has described the synthesis of the 10 membered ring N-oxide of


protopine, by oxidation of protopine with m-CPBA (GOZ) (Scheme ). No
Baeyer Villiger products were observed.
Scheme
O O
O
Me
N m-CPBA, CHCl3 N Me
O O
O O
O 87% O

O O

Perhaps one of the most elegant synthetic uses of N-oxides has been in the
total synthesis of the clinically important anti-cancer drug vinblastine. This
biomimetically inspired work starts with the conversion of catharanthine into
its N-oxide by the use of m-CPBA. Subsequent treatment of the N-oxide with
trifluoroacetic anhydride in the presence of vindoline, followed by addition of
NaBH4 gave a modest yield of vinblastine (Scheme) (KUT)
Scheme
O
N m-CPBA N
Catharanthine
N-oxide
N N
H CO2Me H CO2Me
Catharanthine

1. (CF3CO)2O N

2.
H
MeO N OAc
N Me
HO CO2Me
Me 3. NaBH4
Vindoline
N
H N
MeO2C OH

H Me
Vinblastine
MeO N OAc
Me
MeO2C OH

Variation 4: Molecular oxygen:

Molecular oxygen has been shown to oxidise tertiary amines to amine oxides
under transition metal catalysis or under conditions of high temperature and
pressure. Treatment of an aqueous solution of NMe3 and RuCl3 with
pressurised oxygen at 100°C, gave a 50% yield of trimethylamine oxide (RIL).
The oxidation of dimethyldodecylamine was also described. As a
consequence of the reaction mechanism, in which the tertiary amine acts as a
sacrificial reductant of the in situ oxidised ruthenium, the overall yield is limited
to 50%.
In the absence of a metal catalyst, high yields of amine oxide can be obtained
(RIL 2). In a typical procedure, aqueous NMe3 was shaken under 71 bar air at
100°C for 64 hours, after which time >95% conversion to the amine oxide had
occurred. A radical mechanism has been proposed. Using this procedure the
N-oxides of N,N-dimethyldodecylamine, N-methylmorpholine, N,N-
dimethylaniline, N,N-dimethylbenzylamine, NMe3 and NEt3 were prepared in
poor to good yields (16-95%)
The use of molecular oxygen in the presence of an aldehyde and Fe 2O3 has
been reported to convert several tertiary amines to tertiary amine oxides in
reasonable yield (WAN).
Variation 5: Ozone:

The action of ozone on nucleophiles, such as tertiary amines has been


discussed at length by Bailey (BAI). Although high yields of simple trialkyl
amine oxides (>90%) have been obtained, amine oxide formation is often
accompanied by side chain oxidation by-products. The mechanism of amine
oxide formation is proposed to involve initial nucleophilic attack of the amine
nitrogen onto the terminal oxygen of the electrophilic ozone, giving a
zwitterionic adduct. Although no direct evidence exists to support this
structure, corroborative evidence indicates its presence to be highly plausible.
Loss of molecular oxygen from the adduct yields the tertiary amine oxide
(Scheme ).
Scheme

Bu3N O O O Bu3N O O O Bu3N O + O2

The side chain oxidation products are believed to arise from an intramolecular
Polonovski-type reaction. The tertiary amine-ozone adduct can undergo
intramolecular proton abstraction to generate a highly reactive iminium ion.
Subsequent decomposition of the iminium ion accounts for the formation of
the numerous by-products. The use of methanol or chloroform as solvent
suppresses unwanted side-chain oxidation. These solvents effectively solvate
the highly polar adduct, thereby decreasing the rate of -proton abstraction.
N-Aryl-N-alkyl tertiary amines undergo only side-chain oxidation, upon
treatment with ozone. The increased acidity of the protons to nitrogen is
believed to favor proton abstraction over amine oxide formation (Scheme ).
Scheme
O O
H
Bu2N O
Bu2N + HO O O
H Pr
Pr
In cases where the formation of an iminium ion is not possible the use of
ozone is highly effective. This is highlighted by the oxidation of quinuclidine to
quinuclidine N-oxide (QNO). Formation of an iminium ion would violate Bredt‟s
rule, and clean oxidation is observed. This method has the advantage that the
quinuclidine N-oxide is generated in a totally anhydrous state (ONE 6)
(Scheme ).
Scheme

O3
Et2O, -78oC

N 95% N
N
O
Preparation of quinuclidine N-oxide (QNO)(ONE 6):
A stirred solution of quinuclidine (3.0 g, 27 mmol) in Et 2O (50 mL) was cooled
to -78 C. O3 (3-4% in O2) was passed through the solution for 3 h (during
which time a precipitate formed), before purging with N2 for 5 min. The
mixture was allowed to warm to ambient temperature, before removing the
Et2O in vacuo affording QNO (3.26 g, 95%) as a white solid to be used
immediately or stored over P2O5 under a vacuum.
1
H NMR (400MHz, CDCl3) 3.50-3.40 (6H, m, 3 x N(O)CH2); 2.10-1.90 (7H,
m, 3 x N(O)CH2CH2 and CH2CH); 13C NMR (100MHz, CDCl3) 63.51, 26.96,
20.42. νmax (nujol) 2935, 1574, 939cm-1. m/z (CI) 128.10752 ([M+H]+),
C7H14NO requires 128.10754.

Variation 6: Oxaziridines:

Zajac jr, Walters and Darcey (ZAJ) have reported the preparation of amine
oxides by the oxidation of tertiary amines with 2-phenylsulfonyl-3-
phenyloxaziridines (Davis‟ reagent). They found that tertiary amines more
basic than pyridine (NEt3, N-methylpiperidine and quinuclidine) were rapidly
oxidised by Davis‟ reagent to their amine oxide in greater than 95% yield. The
sulfonimine by-product was easily removed by re-crystallisation or
chromatography. The oxidation was selective for non-aromatic tertiary amines
(pyridine did not undergo oxidation) and selective oxidation of the quinuclidine
nitrogen in quinine was observed. (Scheme ).
Scheme

CHCl3
R1 O R1
R2 N + N CHPh R2 N O + N CHPh
PhO2S PhO2S
R3 > 95% R3

Kerr has reported the use of Davis‟ reagent in the synthesis of polymer
supported N-methylmorpholine N-oxide (KER). The oxaziridine displayed total
chemoselectivity in the presence of potentially sensitive functionality such as
alkenes, secondary alcohols and heteroaromatic tertiary amines.

Variation 7: Dimethyldioxirane:

Dimethyldioxirane (DMDO) is an efficient and clean reagent for the


preparation of tertiary amine oxides from tertiary amines (FER). The reagent
is tolerant of alkenes present in the substrates (Scheme ). Reactions were
carried out by dropwise addition of the indicated excess of DMDO solution in
acetone, to the amine maintained at 0 °C, and the corresponding N-oxides
were isolated as pure compounds in nearly quantitative yields. The exceptions
were dibenzylmethylamine and tribenzylamine, which gave poor yields of the
N-oxide product.
Scheme
Acetone O
R1 O O R1
R2 N + R2 N O +
Me Me
R3 > 95% R3
Me Me

DMDO (eqs) DMDO (eqs)

Bu3N 1.2

Ph Ph
2 N 1.2
N

Ph
Ph
2-5 1.2
Ph N N

Ph
Ph 2
Ph N N
1-5

Ph

Ph 1.2
Ph
2 N
N

N O N 1.2
2

The mildness of the method is highlighted by the work of Thomas and co-
workers (CHR), who have recently reported a procedure for the preparation of
tricarbonylchromium (0) complexes of ortho-substituted styrenes. Treatment
of the complexes with 1.2 eqs of DMDO at -78°C, followed by warming to
room temperature gave the styrene derivatives in 48-69% yield. The DMDO is
believed to have oxidised the amine to its amine oxide, which then underwent
Cope elimination to give the vinyl substituent. It is of note that neither the
DMDO or the in situ generated amine oxides attack the oxidation sensitive
tricarbonylchromium (0) moiety (Scheme ).
Scheme
O O
Cr(CO)3 Cr(CO)3 Cr(CO)3
H Me Me Me2N O r.t.

Me Me
E NMe2 -78oC E H E

Variation 8: Magnesium monoperoxyphthalate (MMPP):

Magnesium monoperoxyphthalate (MMPP) has been reported to oxidise N,N-


dimethylaniline to its N-oxide (HEA). Balasubramanian has also used it to
convert allenic amines to the corresponding N-oxides. These undergo a
Meisenheimer rearrangement to yield indoles after cyclisation (BAL) (Scheme
).
Scheme
R MMPP R
R O
MeOH-H2O N
N [2,3] N
10-1 O

C R = Me, 80% C
= Et, 82%
= Bn, 63%
[3,3]

R
N
O

N
R

Variation 9: HOF.CH3CN:

HOF.CH3CN has been used for the conversion of tertiary amines to the
corresponding N-oxides (Scheme ). The reaction is high yielding, but suffers
from the drawback of having to handle fluorine to prepare the reagent (SHA).
Scheme ().
Amine % Yield amine oxide

Bu3N 82

C8H17
95
Me N
C8H17

Me N 95

Ph
85
Et N
Bn

85
N
Ph

Variation 10: Biomimetic hydroperoxides:

The in vivo N-oxidation of amines in animals is a function of hepatic


flavomonooxygenases. Bruice and Ball (BAL1) have provided evidence for the
involvement of the enzyme bound 4a-hydroperoxyflavin (4a-FlEtOOH) in this
process. The reaction of 4a-FlEtOOH with N,N-diethylaniline and N,N-
dimethylbenzylamine in absolute and oxygen free tert-butanol, at very high
amine concentrations, gave the flavin pseudobase and the corresponding
amine oxide in excellent yield. This reaction gave the amine N-oxides of N-
methylpiperidine, N,N-dimethylbenzylamine, N-methylmorpholine, N,N-
dimethylaniline and NEt3, all in quantitative yield. The mechanism of oxidation
was shown to proceed through nucleophilic displacement by the amine on the
terminal oxygen of the hydroperoxide.
Scheme
Me
Me
Me N N O NR3
Me N N O
N
Me N Me N
O Me N Me
Et O O NR3 O
O Et O
H H
The synthesis and oxygen transfer properties of two structurally unrelated 4a-
hydroperoxyflavin mimics have been reported. In 1980 Ganem, Biloski and
Heggs (GAN) described the results of their investigation into the oxidation of
tertiary amines with 2-hydroperoxyhexafluoro-2-propanol (HPHI), prepared
from H2O2 and hexafluoropropan-2-one. Addition of 1 equiv of HPHI to a
solution of the tertiary amine in CH2Cl2 gave the amine oxide in excellent yield
after 15 minutes. The authors noted that although the oxidations could be
conducted in a range of solvents, hydrogen bonding solvents diminished the
rate considerably (Scheme ). Substrates used included; N,N-
dimethylbenzylamine, N-methylmorpholine, N,N-diethylphenylamine and N,N-
diallyl-O-methyl-tyrosine methyl ester. All N-oxide products were formed in
>90%.
Scheme

OH CH2Cl2, 0oC - r.t. OH


R R
R N F3C CF3 R N O + F3C CF3
+
R OOH R OH
> 90%

Baumstark and Chrisope (BAU) have shown that 3-bromo-4,5-dihydro-5-


hydroperoxy-4,4-dimethyl-3,5-diphenyl-3H-pyrazole rapidly oxidises tertiary
amines under mild conditions to the corresponding amine oxides in high yield
(>90%). The rate of oxidation was found to be proportional to the
nucleophilicity of the amine: Et3N>BnNMe2>NMO>PhNMe2. The authors
argued that the observation that a phenyl substituent on the amine greatly
slows the rate of oxidation, rules out a single electron transfer mechanism.
They favour nucleophilic displacement by nitrogen of the terminal oxygen
atom of the hydroperoxide. This process may be assisted by intramolecular
hydrogen bonding to the nearest nitrogen atom of the azo group (Scheme )
Scheme

Me Me Me Me
CDCl3, 34oC R Ph Ph
R Ph Ph
R N O +
R N + Br OH
Br OOH > 90% R N N
R N N

Bäckvall has used a flavin to catalyse the oxidation of tertiary amines with
H2O2. The reactions were rapid and high yielding (>85%) (Scheme). (BER)
Scheme
H Me
N N O

NMe
N
Et
O
MeOH, air R
R
R N + H2O2 R N O
R R
> 85%
Substrates for this reaction included N-methyl morpholine, N,N-
dimethyldodecylamine, N,N-dimethylmethylcyclohexylamine, N,N-
dimethylbenzylamine, N,N-dimethylcycloheptylamine, N-methylpiperidine and
NEt3.

Variation 11: Enzymatic transformations:


The synthesis of a range of chiral amine oxides using bovine serum albumin
as a catalyst, in the presence of a variety of oxidants has been reported
(COL) (HAD). Oxidants used in this reaction include m-CPBA, NaIO4, H2O2
and oxone. Chemical yields of product were variable, ranging from 13-100%,
as were the ees of the product N-oxides which ranged from 4-67% (Scheme ).
Scheme
Bovine serum
albumin
R1 oxidant (2eq)
R1
R2 N R2 N O
R3 R3
(1eq)

R1 = Me
R2 = Bn, Ph, p-Tol
R3 = Et, Pr, iPr, Bu, C5H12

Pig liver esterase (PLE) has been used as an efficient catalyst for the
desymmetrization of prochiral tertiary amine N-oxides diacetates. It was
demonstrated that they were hydrolyzed by PLE efficiently to afford N-
chirogenic tertiary amine oxides in up to 99% ee, in moderate to good yields
(Scheme )(SUZ).
Scheme
OAc OH OH
O O O
PLE, pH 7.2, 25oC
N N + N

OAc OAc OH
X X X

% Yield (e.e) %

X = 2-NO2 74 (99) 12

= 3-NO2 33 (92) 10

= 4-NO2 31 (6) 2

= 2-OMe 49 (88) 18

= 3-OMe 36 (36) 19

= 4-OMe 50 (13) 10

= 2-Cl 64 (89) 21

= 4-Cl 30 (8) 9

= 2-F 60 (88) 15
Method 3: Reverse Cope cyclisation:

The reverse Cope cyclisation (COO) has recently emerged as a powerful


method for the stereocontrolled synthesis of tertiary amine N-oxides. As the
name suggests, this process is the reverse of the classical Cope elimination.
The Cope elimination was first reported in 1900 (MAM), however, it was not
until the late 1940s that Cope studied the reaction in detail, and it came to
prominence (COP), (ASH). Although Cope was probably aware of the
reversibility of the elimination reaction, the first genuine report of a reverse
Cope cyclisation was not until 1976 (HOU), when House serendipitously
observed the formation of hydroxylamine () from the dioxime () (Scheme ).
Scheme

NH2OH. HCl, NaOAc


aq. dioxane,
H
N N O H
H O
O O N N
OH OH

7%

N N
O OH

Subsequently, Ciganek (CIG, (CIG 1), (CIG 2) and Oppolzer (OPP) delineated
the mechanism and scope of the reaction, and they have shown that it is best
considered as a 2 + 2 + 2n process proceeding through a planar, five
centered transition state (Scheme ).
Scheme

R1 R1
R2
N N
R2
R R O
O H

Holmes has investigated the reverse Cope cyclisation of hydroxylamines onto


alkynes. The initial product of this reaction is a N-protonated amine oxide.
These normally rearrange to the more stable nitrone, which can then be
ustilised in further transformations (FOX). Holmes has described the total
synthesis of (-) histrionicotoxin (WIL) using this methodology (Scheme ).
Scheme
PhCH3, 80oC, 6h
OTBDPS OTBDPS
X X
NH N X
OTBDPS N
O OH O H O 85%
O O

The addition of simple hydroxylamines to -unsaturated sulfones, nitriles


and nitro compounds has been reported as a route into functionalised
hydroxylamines (ONE 7). Again, the initial product of the reaction is a
protonated amine N-oxide which rearranges to give the hydroxylamine. The
stereochemistry of the products strongly suggested that the reaction is
concerted.
In general, the reverse Cope elimination has been used for the synthesis of
pyrrolidine, piperidine, morpholine and their annulated ring system amine
oxides. The formation of smaller or larger ring systems has not been reported.
The reaction has been somewhat limited by the paucity of methods available
for the synthesis of the precursor hydroxylamines (SOS REFERENCE
HERE). The reverse Cope cyclisation has been the subject of an excellent
review by Knight and Cooper (COO).

Ciganek utilised the reduction of nitrones in the preparation of the requisite


hydroxylamines for the synthesis of functionalised pyrrolidine N-oxides (CIG).

Preparation of 1,2-dimethyl-4,4-diphenylpyrrolidine-1-N-oxide (CIG):

Ph
Ph
Ph Ph Ph
LiAlH4, THF 20oC, <15min
Ph
O
89% N Me
N HN
OH Me O

To a solution of 1.31 g (4.9 mmol) of nitrone in 10 mL of THF was added


below 0 °C 4 mL (4.0 mmol) of 1 M LiAlH4 in THF. The mixture was stirred in
an ice bath for 1 h, and a solution of 1.0 mL of H 2O in 10 mL of THF was
added slowly below 0°C. Dichloromethane and MgSO4 were added, and the
mixture was stirred for 15 min and filtered. The solids were washed several
times with CH2Cl2, and the filtrates were concentrated under vacuum at 25 “C
to give 1.17 g (89%) of essentially pure title compound: „H NMR 6 7.1-7.4 (m,
10 H), 4.6 (d, J = 12 Hz, 1 H), 4.4 (d, J = 12 Hz, 1 HI, 3.5 (m, 1 H), 3.2 (s, 3
H), 2.8-3.0 (m, 2 HI, 3.9 (d, J = 7 Hz, 3 HI. A sample crystallized from MeCN
contained one molecule of H2O, mp 130-131 ºC.
Knight and co-workers have shown that the addition of both lithiated sulfones
(WHE) and sulfoxides (HAN) into nitrones gives functionalized
hydroxylamines, which undergo reverse Cope cyclisation to give
functionalized pyrrolidine N-oxides.
Bagley has reported that thermolysis of diastereoisomeric mixtures of
pyrrolidine N-oxides, produced by use of the reverse Cope cyclisation leads to
a highly diastereoselective isomerisation to give cis-2,5 disubstituted
pyrrolidine N-oxides (BAG). The groups of O‟Neil (ONE 8) and Jäger (PAL),
(PAL 2) have reported the ring opening of epoxides with simple
hydroxylamines as a concise route to highly functionalized unsaturated
hydroxylamines. These rapidly undergo reverse Cope elimination to give
chiral pyrrolidine N-oxides (Scheme ).
Scheme
BnNHOH.HCl HO OH HO OH
OH K2CO3, MeOH

O N 63% Me N
HO Bn O Bn

Preparation of 1-benzyl-(2S)methyl-(1S)-N-oxy-pyrrolidine-(3R),(4S)-diol:
()(CLEA)
To a solution of 1,(2S)-oxiranyl-prop-2-en-(1R)-ol, (0.30g, 3.06 mmol) in
methanol, 3 mL, was added N-benzyl hydroxylamine.hydrochloride (0.39g,
2.45 mmol, 0.8 eq) and potassium carbonate (2.53g, 18.36 mmol, 6 eq), the
resultant solution was flushed with dry nitrogen and allowed to stir at room
temperature for 4 days. The solvent was removed in vacuo and the resulting
brown oil was purified by flash column chromatography, by gradient elution,
dichloromethane containing 2% methanol to 1:1 dichloromethane:methanol, to
yield the desired compound as a colourless oil, which on vigorous drying on a
high vacuum line solidified to a white solid, (0.35g, 63%). m.pt. 148˚C. dec;
[ ]D +15.9˚ (c, 0.52, MeOH); max (KBr)/cm-1, 3220 (OH), 2910, (C-H), 1090
(N-O); H (300 MHz, CD3OD), 1.48 (3H, d, J 6.4 Hz, H3CCH), 3.35-350 (2H,
m, H3CCH and NCH(b)HCH(OH)), 4.10 (1H, m, CHCH(OH), 4.30 (2H, s,
PhCH2N), 4.40 (1H, m, NCH(a)HCH(OH), 7.40 (5H, s, Ph).

The ring opening of N-tosyl aziridines with hydroxylamines, in the presence of


BF3.OEt2 has also been examined and gives amino functionalized pyrrolidine
and piperidine N-oxides after reverse Cope cyclisation (ONE 9).

Various annulated pyrrolidine N-oxides have been prepared using the reverse
Cope cyclisation. Examples are given in Scheme (). The first three examples
are all taken from the seminal work of Ciganek (CIG 2) and illustrate the
diversity of structures that can be prepared using this approach. The fourth
example was reported by Knight and co-workers, and provides a rapid route
to a highly functionalized pyrrolidine N-oxide (HAN 2).
Scheme
Ph Ph Ph
Ph
O
THF, Et2O, rt 1. CHCl3, 65oC, 18h
N
O MeN 2. 18d, 20oC Me
N N OH
OH 80% Me
H > 90%
N N
Bn Bn

25oC O O
OH
N + N
N 82% Me Me
Me
9:1

PhSO2CH2Li
O O -78oC, THF O O 20oC, 1-5h O O

PhO2S PhO2S
N N CH2R
N
O R R Me O
Me OH

R = H, 1h, 83%
= Me, 1h, 83%
= Ph, 5h, 88%
= 2-furyl, 2h, 88%

The reduction of oximes with NaCNBH3 also provides a route into


hydroxylamines, which undergo reverse Cope cyclisation to give pyrrolizidine
N-oxides shown ( Scheme ) (CIG 2).
Scheme
H

N
OH
NaCNBH3, pH 4 Me
+
NH
NOH H
HO

H N
H OH
Me
+
N N
O Me O Me
Me Me

Preparation of cis- and trans-3,5-dimethylhexahydropyrrolizine-N-oxide


(CIG 2):
A mixture of 2.69 g (17.6 mmol) of 1,8-nonadien-5-one oxime, 3.8 g (62
mmol) of NaCNBH3, 20 drops of 0.01% methyl orange in EtOH, and 20 mL of
MeOH was cooled to 10°C, and a mixture of 16 mL of conc. HCl and 84 mL of
MeOH was added at a rate to keep the indicator pink. The cooling bath was
removed after 30 min, and stirring and HCl addition were continued for 2.5 h.
Concentrated HCl (10 mL) was added (CAUTION; HCN evolution), and the
mixture was concentrated to dryness. The residue was made basic with
NH4OH and extracted with CHCl3. The solution was allowed to stand at rt for
2 d at which time ca. 10% of uncyclized hydroxylamines remained. The
solvent was removed at rt to give 3.02 g of the N-oxides, which were reduced
immediately with Cl3SiSiCl3.

Transannular reverse Cope cyclisations give rise to a number of synthetically


useful ring systems as shown in Scheme. Again, the first example in Scheme
() was reported by Ciganek. In the second example, the
azabicyclo[3.2.1]octane was prepared in excellent yield by simply heating the
precursor hydroxylamine in CHCl3 (LAM), (KAR), (LEE) (Scheme ).
Scheme

Ph Ph
CHCl3, , 72h
Me N Me
Ph N Me
OH 42% O
NaCNBH3

NOH Ph
Ph
CHCl3, , 72h
Me N
N Me
OH 42% O Me

Me OH
Me N Me
CHCl3, 2h, 60oC Me O

100%

Piperidine N-oxides have also been synthesized using the reverse Cope
cyclisation. Ciganek prepared the simple piperidine N-oxide by initial Cope
elimination of the azepine N-oxide shown in Scheme () to generate the
required hydroxylamine (CIG). Not surprisingly, the related diphenyl
substituted precursor underwent reverse Cope cyclisation under milder
conditions. O‟Neil and co-workers have described the synthesis of a number
of polyhydroxylated piperidine N-oxides by the reverse Cope cyclisation. The
precursor hydroxylamines were prepared by ring opening of epoxides with
simple hydroxylamine derivatives also shown in Scheme () (ONE 10).
Scheme
160oC
Cope
elimination 61oC, CHCl3

N N Me
N 63% Me
Me O H O
Me O

Ph Ph
CHCl3, 25oC Ph
Ph

N N Me
88%
Me O
Me OH

RNHOH.HCl
Et3N, MeOH OH OH
OH HO HO
20oC, 24-72h , CHCl3, 48-120h
O
60-85% N 51-82% N Me
R OH R O

R = Me, Bn

The synthesis of a hydroxylamine by the oxidation of a tertiary amine bearing


a cyanoethyl group was first reported by Nagasawa (NAG). This route was
developed by the O‟Neil group (ONE 11) into a mild and general procedure for
the synthesis of functionalized hydroxylamines. This methodology was then
combined with a reverse Cope cyclisation to give a rapid route to
functionalized morpholines (ONE 12) (Scheme ).
Scheme
Cope
m-CPBA, CH2Cl2 elimination
N N
N
O O OH O
O
NC
CN

, MeOH, N2
95%

N
O O
Me

More functionalized morpholine N-oxides have been prepared from


derivatives of ephedrine and pseudoephedrine (Scheme ) (ONE 13). Fused
pyrrolidine N-oxides have also been prepared using this approach (ONE 14).

Synthesis of (2S,3S,4R,5R)-3,4,5-trimethyl-2-phenyl-morpholine-4-oxide
and (2S,3S,4S,5S)-3,4,5-trimethyl-2-phenyl-morpholine 4-oxide (ONE 13).
Me
Ph O Ph O
O
N
NC Ph Me N Me Me N Me
O O

A stirred solution of propionitrile, (4.80 g, 18.58 mmol), in dry dichloromethane


(100 mL) was cooled to –78oC and m-CPBA (3.52 g, 20.44 mmol, 1.1 eq) and
potassium carbonate (3.85 g, 27.87 mmol, 1.5 eq) were added. The solution
was stirred for 3 h and then allowed to come to rt, under a nitrogen
atmosphere, then after complete consumption of the starting material the
resulting suspension was filtered, and the filtrate washed with
dichloromethane. The solvent was removed in vacuo, the residue taken up in
methanol (150 mL), then heated to reflux for 3 d under a nitrogen atmosphere.
The solvent was removed in vacuo and the residue purified by flash column
chromatography, eluting with 20% methanol in ethyl acetate, to give the title
compounds in a 3:2 ratio, as gummy yellow solids (3.38g, 82%).
Data for () ; [ ]D = + 32 0 (c= 0.1, CH2Cl2); max(nujol) / cm-1, 2908, (CH), 987
(N+-O-)
Data for () ; [ ]D = + 70 0 (c= 0.01, CH2Cl2); max(nujol) / cm-1, 2908, (CH).

-Hydroxy amine N-oxides:

Ciganek has reported the synthesis of an -hydroxy amine oxide using a


reverse Cope cyclisation (CIG 1). The product was characterised by X-ray
crystallography (Scheme ). Remarkably, this N-oxide could be sublimed at
under vacuum at 160ºC without decomposition!
Scheme
Ph
Ph
O
MeNHOH N
Ph Ph
EtOH, rt 51%
Ph Me
Ph
CHO O
HO N H +
Me Ph
Ph 45%

HO N Me
Me O
More recently, Knight and co-workers have described the synthesis of a
number of anomeric amine oxides, again utilising the reverse Cope cyclisation
(BAI) (Scheme ).
Scheme
MeNHOH.HCl (2.5eq)
K2CO3 (10eq), hexanes
O O H
60oC, 4h
OH
N O
89%
H

Enamine N-oxides:

Enamine N-oxides are a relatively unknown functional group in which the one
of the groups on the nitrogen is a vinyl substituent. The direct preparation of
these compounds by the oxidation of the parent enamine fails, and alternative
methods for their synthesis have to be employed. Ciganek has reported the
synthesis of two enamine N-oxides via the addition of dimethyl hydroxylamine
and 1-hydroxypiperidine to ethoxyacetylene (CIG 1) (Scheme ).
Scheme

O OEt
OEt
NMe2
Me2NOH
N OEt
OEt N
O
OH

Krouwer (KRO) and O‟Neil (ONE 15) have reported routes to these
compounds, which rely on the elimination of HCl from -chloro amine oxides
and TsOH from -tosyl amine oxides respectively.

O O
Cl NMe2 NMe2 t-BuOK, THF
OTs
-78oC - rt
t-BuOK, t-BuOH

60% N 80% N
O O

N,N-Dimethyl-1-cyclohexenylamine N-oxide (KRO). To a stirred solution


containing 2.24 g (20.0 mmol) of potassium tert-butoxide in 40 mL of tert-butyl
alcohol was added dropwise a solution containing 2.14 g (10.0 mmol) of the -
chloro amine oxide hydrochloride in 20 mL of tert-butyl alcohol. The order of
addition did not affect the yield of product. A fine precipitate formed during the
addition. The reaction mixture was stirred for several hours and aliquoted into
ten equal portions. Lyophilization and sublimation of an aliquot gave, typically,
70-85 mg (50-60%) of product as a deliquescent, white, crystalline solid: mp
94.5-96ºC; decomposition temp, 160ºC; Picrate of (): mp 122-123.5ºC. Anal.
Calcd for C14H18N4O8: C, 45.41; H, 4.90; N, 15.13. Found: C, 45.29; H, 4.81;
N, 15.04.
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Peracids:
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Ozone:
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Oxaziridines:
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DMDO
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MMPP:
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(BAL) Balasubramanian, T.; Balasubramanian, K. K., J. Chem. Soc., Chem.
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HOF. CH3CN:
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Biomimetic:
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Enzyme:
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Reverse Cope:

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-Hydroxy N-oxides:

(CIG 1) Ciganek, E., J. Org. Chem., (1990) 55, 3007.


(BAI) Bainbridge, N. P.; Currie, A. C.; Cooper, N. J.; Muir, J. C.; Knight, D. W.;
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Enamine N-oxides:

(CIG 1) Ciganek, E.; Read Jr, J. M.; Calabrese, J. C., J. Org. Chem., (1995)
60, 5795.
(KRO) Krouwer, J. S.; Richmond, J. P., J. Org. Chem., (1978) 43, 2464.
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