Ketones Neber rearrangement

One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

A ketoxime tosylate 1 can be converted into an a-amino ketone 2 via the Neber rearrangement by treatment with a base—e.g. using an ethoxide or pyridine. Substituent R is usually aryl, but may as well be alkyl or H substituent R can be alkyl or aryl, but not H. 

An a-amino ketone, obtained by the Neber rearrangement, can be further converted into an oxime tosylate, and then subjected to the Neber conditions a ,a -diamino ketones can be prepared by this route. 

The Neber rearrangement was discovered in 1926 during the investigation of the Beckmann rearrangement. It was reported that treatment of ketoxime tosylate 517 with potassium ethoxide followed by acetic and hydrochloric acid produced a-amino ketones 518 (equation 231). 

The Neber rearrangement is usually performed with ketoxime tosylates but ketone trimethylhydrazonium halides (519), iV,iV-dichloro-5ec-alkyl amines (520), N-chloroimines (521) and A-chloroimidates (522) may also be precursors for the reaction. Only the Neber rearrangement of oxime derivatives will be analysed in this chapter. 

Generally, the Neber rearrangement is a base-catalysed conversion of 0-acylated ketoximes 523 (but not aldoximes) to a-amino ketones 525 via an isolable 2//-azirine intermediate 524 (equation 232). The azirine itself may be used as a valuable synthetic tooP and the Neber rearrangement is commonly used to produce it. 

The Neber rearrangement has been used as a valuable synthetic tool to introduce an a-amino group relative to a ketone and it has been used as a key step in the synthesis of a large array of heterocycles, including imidazoles, oxazoles, isoquinolines and pyrazines and has been reviewed long ago °° . ... 

The Neber rearrangement of oxime sulfonates has been considered to proceed via a nitrene pathway or an anion pathway. If the latter mechanism is operative, the use of a certain chiral base might result in the discrimination of two enantiotropic a-protons to furnish optically active a-amino ketones. Verification of this hypothesis was provided by realizing the asymmetric Neber rearrangement of simple oxime sulfonate 83,... 

An interesting formation of a cyclic imine with a three-membered ring (31) was encountered in the pyrolysis of azidostyrene.188 Compounds of this type are also considered as intermediates in the Neber rearrangement of tosyloxyimino-ketones. 

The Neber rearrangement involves the base-catalyzed conversion of oxime tosylates, quaternary salts of hydrazones or /V-chloroimines to a-amino ketones via isolable azirine intermediates (equation... 

In the synthesis of various heterocycles from a-amino ketones, pyrazine formation can be a complicating side reaction due to the tendency of the a-amino ketone to dimerize. One way of avoiding this problem would be to generate the a-amino ketone in a protected form, specifically, as an a-amino acetal. Such derivatives allow the manipulation of the amino moiety as desired. Accordingly, the azirine intermediates derived from oxime tosylates by the Neber rearrangement are subsequently treated with acidic ethanol to furnish the corresponding a-amino acetals (equation 65). ° ... 

The Neber rearrangement of dimethylhydrazone quaternary salts to a-amino ketones is a well-studied reaction. However, when this reaction is carried out at temperatures below those of normal Neber condi-... 

O Brien, C. The rearrangement of ketoxime 0-sulfonates to amino ketones (The Neber rearrangement). Chem. Rev. 1964, 64, 81-90. 

The hexahydrothianaphthoxazines 38 and 39 were synthesised from the commercially available ketone 58, which was readily converted into the tosyloxime 60 in two steps. Neber rearrangement of 60 with potassium tert-butoxide afforded the desired amino-ketone 61. The amino ketone 61 was readily acylated with chloroacetyl chloride. Reduction of the keto-chloroacetamide 62 with sodium borohydride gave only the trans isomer. The proton on Cl gave a doublet at 8 4.6 ppm with a coupling constant of 7.2 Hz indicating a di-axial coupling. The cis-compound would have a couplings constant of about 3.5 Hz. 

Neber rearrangement. Formation of a-amino ketones by treatment of sulfonic esters of ketoximes with potassium ethoxide, followed by hydrolysis. 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

The Neber rearrangement is the transition of an oxime / -toluenesulfonate into an amino ketone under the influence of an alkoxide, e.g. ... 

A methylene group adjacent to the oxime group is essential for occurrence of the Neber rearrangement. In oximes of unsymmetrical ketones it is the... 

Fewer mechanistic details are available for the Neber rearrangement than for the closely related Favorskii and Ramberg-Backlund reactions. Oxime tosylates, when treated initially with base and then with water, yield a-amino-ketones, viz-... 

Oximes which are treated with tosyl chloride can also be used as substrates in the Neber rearrangement to a-amino ketones. The mixture shown in eq 26 was further subjected to reductive amination to 3ueld 14% of the CNS-active cis-lV,A(-dimethylated a-amino alcohol. 

This reaction was first reported by Neber et al. in 1926. It is the transformation of a ketoxime 0-arylsulfonate into an Q -amino ketone involving the deprotonation of an a-methylene hydrogen by a base and the subsequent acidic hydrolysis of the resulting azirine intermediate. Therefore, this reaction is generally known as the Neber rearrangement or... 

The net conversion of a ketone into an a-aminoketone via the oxime is known as the Neber rearrangement. 

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