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Revision as of 21:16, 9 February 2012

The Neber rearrangement is the reaction of activated oximes or N,N,N-trimethyl hydrazonium salts with base to afford azirines. Subsequent transformations of the azirine ring may produce α-amino ketones or ketals. Although the rearrangement is sometimes complicated by side reactions, it is one of a small number of methods for the synthesis of azirines.[1]


During an investigation of the reactivity of O-sulfonyl and O-acyl ketoximes, Neber discovered that in the presence of base, O-sulfonyl ketoximes rearrange with the loss of sulfonic acid to afford azirines.[2] Azirines are susceptible to nucleophilic addition and hydrolysis, and may thereby be converted into α-amino ketones or ketals (Eq. 1).


Many of the mechanistic details of the Neber rearrangement remain ambiguous. At least three distinct mechanistic pathways are feasible, and it is unlikely that all rearrangements can be described by a single mechanism. The vast majority of Neber rearrangements are insensitive to the configuration of the starting oxime: both geometric isomers of a given oxime usually react with base to afford the same constitutional isomer of azirine.[3] The site selectivity of the rearrangement can be effectively controlled using anion-stabilizing groups in the starting material; however, the role of steric hindrance in site selectivity is more ambiguous and is difficult to predict.[4]

Mechanism and Stereochemistry

Proposed Mechanisms

The mechanism of the Neber rearrangment has not been firmly established, and it is likely that different rearrangements proceed via different mechanisms. Three pathways have been advanced for the mechanism of the rearrangement (Eq. 2). Pathway A, supported by a deuterium incorporation study, involves concerted deprotonation and displacement of the leaving group.[5] A lack of deuterium incorporation into the product suggested that an intermediate aza-allyl anion was not involved in the mechanism.


Pathways B and C involve an intermediate aza-allyl anion, formed via full deprotonation of the starting material. By analogy to the conversion of vinyl azides to azirines, pathway B involving a vinyl nitrene intermediate has been proposed. Although azirines have been shown to form vinyl nitrenes reversibly,[6] these intermediates are unlikely in both Neber rearrangements and reactions of vinyl azides in light of more recent evidence.[7][8]

The barrier to rotation about the carbon-nitrogen bond of vinyl azides is low.[7] It has been proposed that the aza-allyl anion implicated in the Neber rearrangement possesses a similarly low barrier to rotation about the carbon-nitrogen bond. Considering the lack of sensitivity of the reaction to the configuration of the oxime, facile rotation about this bond seems to be a prerequisite for pathway C, which involves direct conversion of the aza-allyl anion to an azirine.

Enantioselective Variants

In the presence of a chiral phase transfer catalyst (PTC) and base, O-sulfonyl oximes rearrange with high enantioselectivity (Eq. 3).[9] This result argues against pathway B, since tight association of the vinyl nitrene and PTC in the enantiodetermining step is unlikely. Pathway C is more consistent with the observed enantioselectivity, as the tetraalkylammonium cation is likely to associate with the aza-allyl anion.


Scope and Limitations

Aldoximes and hydrazonium salts of aldehydes do not react to form azirines in the presence of base and form nitriles instead.[10] However, ketone-derived oximes and hydrazonium salts exhibit broad scope in the Neber rearrangement. The choice of leaving group seems to have little effect on the yield of the reaction. The few direct comparisons that are available illustrate that either O-sulfonyl oximes or N,N,N-trimethyl hydrazonium salts may be used interchangeably with success (Eq. 4).[11]


When the desired site of deprotonation is unstabilized, N,N,N-trimethyl hydrazonium salts are more commonly employed than oxime derivatives (Eq. 5).[12] Hydride or alkoxide bases are most commonly used in this context.


Relatively weak bases may be used with O-sulfonyl oximes when the substrate contains an anion-stabilizing group, such as a phenyl ring (Eq. 6).[13] When two anion-stabilizing groups are present, cyclization commonly occurs at near-neutral conditions, even when the leaving group is poor.[14]


Mitsunobu conditions are effective for the in situ activation and rearrangement of oximes containing anion-stabilizing groups (Eq. 7).[13]


The initial products of the Neber rearrangement are azirines, but these strained heterocycles may be converted to other products through hydrolysis or nucleophilic addition. Acidic hydrolysis of azirines yields α-amino ketones. O-sulfonyl oximes are most commonly employed when α-amino ketones are the target, and isolation of the hydrochloride salt of the α-amino ketone is typical (Eq. 8).[15] Self-condensation of basic α-amino ketones to form dihydropyrazines and pyrazines (after air-mediated oxidation) can be a problematic side reaction for this class of rearrangements.[16]


Azirines in the presence of alkoxide/alcohol mixtures may react further to afford α-amino ketals. Only methyl or ethyl ketals are accessible using this method,[17] but aside from this limitation, the scope of ketal formation is roughly the same as that of α-amino ketone formation. Intermediate treatment with anhydrous acid followed by treatment with base is sometimes employed in this context (Eq. 9).[18]


Neber rearrangements may be subject to the formation of side products. In addition to the pyrazine side products mentioned previously, phenyl azirines may form indoles via insertion of a vinyl nitrene into an aromatic C-H bond (Eq. 10).[13]


Synthetic Applications

The Neber rearrangement has seen some application for the synthesis of α-amino ketones in natural products. For instance, a Neber rearrangement was used as a key step in the synthesis of a precursor to dragmacidin F (Eq. 11).[19]


Comparison to Other Methods

A small number of alternative approaches for the synthesis of azirines have been developed. Thermal[20] and photochemical[21] reactions of vinyl azides afford aziridines (Eq. 12). In some cases preparation of the vinyl azide is more inconvenient than preparation of the corresponding oxime, but the use of vinyl azides obviates the need for base as in the Neber rearrangement.


Both thermal and photochemical rearrangements of isoxazoles may afford acyl azirines, which can be converted to the corresponding oxazoles by treatment with base (Eq. 13).[22]


Oximes may be converted to aziridines with lithium aluminum hydride or Grignard reagents (Eq. 14).[23] The leaving group in these reactions is an O-metal species, and the aziridine product is formed via nucleophilic addition to an intermediate azirine.


Experimental Conditions and Procedure

Typical Conditions

Care should be taken when handling oxime tosylates, as shock and thermal sensitivity of these compounds has been reported.[24]

Oxime tosylates are often prepared via treatment of the oxime with tosyl chloride in pyridine; however, stronger bases may be employed to avoid Beckmann rearrangement of the oxime tosylate. To prepare N,N,N-trimethyl hydrazonium salts, the corresponding dimethyl hydrazone is reacted with methyl iodide. Unstabilized oximes are typically subjected to rearrangement in protic solvents using alkoxide bases. Aprotic solvents are more common in reactions of substrates containing anion-stabilizing groups. Bulky alkoxides (isopropoxide) or hydride bases are most commonly used to effect rearrangements of N,N,N-trimethyl hydrazonium salts.

Example Procedure[25]


To a stirred solution of quinidine (162 mg, 0.449 mmol) in dry toluene (90 mL), a solution of ethyl 3-(4-tolylsulfonyloximino)butanoate (201 mg, 0.672 mmol) in dry toluene (10 mL) was added dropwise at 0 °C. After 24 h aq HCl (50 mL, 0.05 M) was added and the resulting mixture was extracted with Et2O (3 × 50 mL). The combined organic layers were washed with brine, then were dried over MgSO4, and concentrated under vacuum to give the crude 2H-azirine ester (116 mg). Purification by bulb-to-bulb distillation at 80 °C (1 mm Hg) yielded 37.0 mg (0.291 mmol, 43%) of ethyl (–)-3-methyl-2H-azirine-2-carboxylate as a colorless liquid, 100% pure by GLC, 91.0:9.0 er): α20D – 65.7 (c 0.6, CHCl3); IR (CCl4) 1795, 1730, 1190 cm–1; 1H NMR (CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 2.42 (s, 1H), 2.52 (s, 3H), 4.17 (q, J = 7.1 Hz, 2H); HRMS (m/z): [M+] calcd for C6H9NO2, 127.0633; found, 127.0633.


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