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 sp3 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.

or R1, R2, R3 = Alkyl, functionalised alkyl, vinylR2 N

R1

O

R3

R2 N

R1

R3

O

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 pKa 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.

Me3N O

SO2BF3Me3N O SO2Me3N O BF3

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 pKa 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

N

O

R NOH

R

Cope eliminationO

NR

+

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.

NMe

O3, CH2Cl2-75oC

N

O

MeMeNN

O

Me

O3, CH2Cl2-75oC

NOH

Me

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

OR2

HNC

OH

R1 R1

R2

N

H O

O

O

HN

R1

R2

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

NMe

N

O

HCO2Me

THF, rt

57% NMe

N

CO2Me

O

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

X

N

O

Me

X = O, CH2

X

N

Me

O

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

N Me

Me

H2O2 N Me

Me

O

+N Me

O

Me

81 : 29

N Me

Me

H2O2 N Me

Me

O

+ N Me

O

Me

36 : 64

EtEtEt

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

HN

Me

N

Me O

Me

N

O Me(-)-Dibenzoyltartaric acid

(-)-(S)-cis

[ ]D = -2.87o

(-)-(R)-trans

[ ]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 (H2O2) 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 .

N OMe

Me

Me

MeI Me

N

Me

Me

O Me IN O

Me

Me

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.

N OMe

SiPh2tBu

MeI (20eq) CsF (5.7eq)

MeOH

86%N O

Me

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

N ORt-Bu

1. MeI or MeOTf

2. H2O N Ot-Bu

Me

cis:trans 65:35

R = H 15%

= CH2Ph 40%

= COPh 80%

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

HN

NH 2 (PhCO2)2O

N

NPhOCO

OCOPh

1. MeOTf

2. H2O

72%

N

N

Me

O

MeO

N

N

O

O

MeMe

Cis

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

N

N H2O2

N

N

O

O

H OO H

H OO H

DABCO-diperhydrate95%

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, R3N.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

N Rt-Bu

% trans

R = Me 95

= Et 95

= CH(CH3)2 95

= PhCH2 95

= t-Bu 100

N Rt-Bu

H2O2, acetoneO

N Ot-Bu

R

trans cis

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

HH

Me2N NMe2

30% aq. H2O2

MeOHHH

N N

Me Me Me Me

OO

125-140oC

10-30mm

79% overall

HH

H

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

N

N H

Me

H2O2, 25oC

N

N H

N

N H

O MeMe O

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 ()

N

D

D

Me

Me

O

H2O2, EtOH N

OD

H

DMe

Me

O

Ac2O, CHCl3

N

HMe

D

Me

O

90%72%

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

NEt2

H2O2,

96%

O NEt2

N

R

H2O2

R = H, CH3

N

O R

, neat or DMF

N

O

R

C

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 ()

N

CO2Me

1. m-CPBA

2. TFAA, CH2Cl2

N

CO2Me

CF3CO2

KCN

N

CO2Me

CN

N

CO2Me

1. H2O2

2. TFAA, CH2Cl2

CF3CO2

KCN

N

CN

OCOCF3

H

NOCOCF3

O

OH

N

CO2Me

CF3CO2

N

CF3CO2

50% overall

55% overall

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

N

R1

R2

R3

+ R4 OOH

T. M. (Ln)n

N

R1

R2

R3O + R4OH

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

N

NMe

H

N

N

H

O MeN

N

H

Me O

+

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%.

PhN

OH

1. (+)-DIPT

CH2Cl2, Ti(OiPr)4

2. TBHP, -20oC

PhN

OH

PhN

OH

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

N

R

R

RCl

O

OO

H

N R

R

R

N

R

R

R

O

Cl CO2H

+

m-CPBA

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.

N

CO2H

Ph

mCPBA

CH2Cl2

60%N

Ph

OH

O

O

N

Ph

OH

N

Ph

OH

O

N

O

OH

PhQuantitative

mCPBA

CH2Cl2

63%

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

N CO2H

Ph

N CO2H

O

Ph

mCPBA, CH2Cl2K2CO3

69%

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

NBn

OH

N

OHBn O

mCPBA, CH2Cl2K2CO3

96%

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

Scheme

N

NHt-Bu

mCPBA, CH2Cl2K2CO3

94%

O

CONH2

N

O

O

O

N

H

t-Bu

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

N CO2H

Bn

m-CPBA, CH2Cl2

53%N CO2H

Bn O

N

Bn

m-CPBA, CH2Cl2

91%N

Bn OOH OH

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

N

N

O

NH

CO2Me

O

HNMeO2C

R

N

N

NH

O

NH

O

CO2Me

MeO2C

R

R

OO

m-CPBA (2eqs)

R = H, 63% = Me, 72% = i-Pr, 77% = i-Bu, 74% = 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

Bn2N CO2Et

R

m-CPBA Bn2N CO2Et

R

O

[2,3]

70-80%

R CO2Et

ONBn2

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

Cl

N

Me

Ph

1.m-CPBA2. [2,3]

Cl O N

Ph

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

ON

O

O

Me

O

m-CPBA, CHCl3

87%

O

ON

O

O

O

O

Me

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

NH

N

CO2MeNH

N

CO2Me

O

m-CPBA

NMe

N

MeO OAc

MeO2C OH

Me

NH

N

OH

Me

H

NMe

N

H

OAc

HO CO2Me

MeO

1. (CF3CO)2O

2.

3. NaBH4

MeO2C

Vinblastine

Vindoline

Catharanthine

CatharanthineN-oxide

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 Fe2O3 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 O O OBu3N OBu3N + 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

Bu2N

H

O

OO

Pr

Bu2N

H

PrHO O O+

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

N

O3

Et2O, -78oC

95% N

O

N

Preparation of quinuclidine N-oxide (QNO)(ONE 6): A stirred solution of quinuclidine (3.0 g, 27 mmol) in Et2O (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. 1H 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

R2 N

R1

R3

OR2 N

R1

R3

O

N CHPhPhO2S

+ N CHPhPhO2S

+

CHCl3

> 95%

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

R2 N

R1

R3

OR2 N

R1

R3

+ +

Acetone

> 95%

OO

Me Me

Me Me

O

N

Ph

N

Ph

Ph

N

Ph

Ph

Ph

N

Ph

N

N

Ph

N

Ph

N

Ph

N

Ph

O N

Bu3N

DMDO (eqs)

1.2

2

2-5

1-5

2

2

DMDO (eqs)

1.2

1.2

2

1.2

1.2

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

Cr(CO)3

E

H

NMe2

Me

Me Me

OO

-78oC

Cr(CO)3

E

Me2N O

H

Me

Cr(CO)3

E

r.t.

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

N

R MMPP

MeOH-H2O

10-1

C

N

C

R O

[2,3]O

N

R

[3,3]

NO

R

N

R

R = Me, 80% = Et, 82% = Bn, 63%

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 ().

Bu3N

Me N

C8H17

C8H17

Me N

Amine % Yield amine oxide

N

Ph

Et N

Ph

Bn

82

95

95

85

85

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

N

N

N

NMe

Me

O

OO

Et

Me

Me

OH

N

N

N

NMe

Me

O

OO

Et

Me

Me

H

NR3

NR3O

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

N

R

R

R

F3C

OH

OOH

CF3+

CH2Cl2, 0oC - r.t.

N

R

R

R

O F3C

OH

OH

CF3+

> 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

N

R

R

R+

NN

Me Me

Ph

OOH

Ph

Br

CDCl3, 34oC

N

R

R

R

O +

NN

Me Me

Ph

OH

Ph

Br> 90%

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

N

R

R

R

+ H2O2

NEt

HN

NMe

MeN O

O

MeOH, air

N

R

R

R

O

> 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 serumalbumin

oxidant (2eq)

R1 = Me

R2 = Bn, Ph, p-Tol

R3 = Et, Pr, iPr, Bu, C5H12

(1eq)

R2 N

R1

R3

OR2 N

R1

R3

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

X

N

O

OAc

OAc

PLE, pH 7.2, 25oC

X

N

O

OH

OAc

+

X

N

O

OH

OH

X = 2-NO2

= 3-NO2

= 4-NO2

= 2-OMe

= 3-OMe

= 4-OMe

= 2-Cl

= 4-Cl

= 2-F

% Yield (e.e)

74 (99)

33 (92)

31 (6)

49 (88)

36 (36)

50 (13)

64 (89)

30 (8)

60 (88)

%

12

10

2

18

19

10

21

9

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

NN

NO

HN

NO

N

OH

OH OH

HO

OO

NH2OH. HCl, NaOAc

aq. dioxane,

7%

H

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

N

R O H

R1

R2 N

OR

R2R1

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

X

O

NH OTBDPS

OH

PhCH3, 80oC, 6h

N

O

X

OTBDPS

H ON

O

X

OTBDPS

O85%

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):

N

PhPh

O

LiAlH4, THFPh

Ph

HNOH

N

Ph

Ph

Me

OMe

20oC, <15min

89%

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 H2O 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

OH

O

BnNHOH.HCl

K2CO3, MeOH

N

HO OH

HO BnN

OHHO

Me63%

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

NOH

N

H

O

Me

THF, Et2O, rt

80%

NBn

MeN

PhPh

OH

1. CHCl3, 65oC, 18h

2. 18d, 20oC

> 90%

N

NBn

Ph

PhO

Me

N

OH

Me

N

O

Me

25oC

82%

N

O

Me+

9:1

OO

N

O R

PhSO2CH2Li

-78oC, THF OO

RN

Me OH

PhO2S

20oC, 1-5h OO

N CH2R

OMe

PhO2S

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

NOH

NaCNBH3, pH 4

NH

HO

N

H

Me

OH

N

H

OH

Me

+

N

Me MeO

H

N

MeO

H

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

NOH

Ph

NaCNBH3

NOH

Ph

Me

NOH

Ph

Me

N

O

Ph

Me Me

N

O

Ph

Me

Me

NMe

Me OHMe

N

Me OCHCl3, 2h, 60oC

100%

CHCl3, , 72h

42%

CHCl3, , 72h

42%

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

N

Me O

160oC

Cope

elimination

N

Me O H

61oC, CHCl3

63%N Me

OMe

OH

O

RNHOH.HCl

Et3N, MeOH

20oC, 24-72h

60-85%

OHHO

N

R OH

OHHO

N Me

R O

, CHCl3, 48-120h

51-82%

R = Me, Bn

N

Ph

Ph

Me OH

CHCl3, 25oC

88%N Me

OMe

Ph

Ph

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

N

O

CN

m-CPBA, CH2Cl2N

OO

NC

Copeelimination

N

OOH

N

OO

Me

, MeOH, N2

95%

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).

N

O

Me Me

O

Ph

N

O

Me Me

O

Ph

NO

Me

PhNC

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

CHO

Ph

Ph

MeNHOHEtOH, rt

Ph

Ph

NMe

OHHO

Ph

Ph

NO

Me

+

N

O

Me

Ph

Ph

Me

HO

51%

45%

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

O

OH

MeNHOH.HCl (2.5eq)

K2CO3 (10eq), hexanes

60oC, 4h

89%

O

N

H

H

O

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

Me2NOHN

OH

OEt

OEt

NMe2

O OEt

N

OOEt

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.

Cl NMe2

O

t-BuOK, t-BuOH

60%

NMe2

O

N

O

OTs

N

O

t-BuOK, THF

-78oC - rt

80%

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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