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
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
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
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
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
(-)-(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).
There are three principal methods for the synthesis of tertiary amine N-oxides:
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:
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
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%).
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.
% trans
R = Me 95
= Et 95
= CH(CH3)2 95
= PhCH2 95
= t-Bu 100
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
N N N
O Me Me O
Me
88% 12%
N N N
O R O C
R R
O NEt2
H2O2,
NEt2 96%
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).
Alumina supported MoO3 has also been used to oxidise tertiary amines to
their N-oxides (JAI).
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.)
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
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
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
70-80% ONBn2
R R
Ph
N
Me
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
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 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:
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
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
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.
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:
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
Ph
Ph
Ph Ph Ph
LiAlH4, THF 20oC, <15min
Ph
O
89% N Me
N HN
OH Me O
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).
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%
N
OH
NaCNBH3, pH 4 Me
+
NH
NOH H
HO
H N
H OH
Me
+
N N
O Me O Me
Me Me
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
, MeOH, N2
95%
N
O O
Me
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
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
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