The Neber Rearrangement

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- 

The presence of a gamma-hydrogen atom is essential and when more than one appropriate gamma carbon is available, the amino-group is substituted for the more acidic hydrogen, irrespective of the stereochemical relationship between the oxime tosylate and the hydrogen atom In the only stereo- 

Under varying reaction conditions, a number of three-membered ring inter- 

The alternative scheme of Hatch and Cram seems more likely, the nitrene arising from a 1,3-elimination and being partially stabilised by the adjacent double bond, viz. 

There is obviously great need for a more thorough mechanistic study. The nature of the nitrene (e.g. singlet or triplet), if one is in fact an intermediate, is unknown. The 1,3-elimination may be a stepwise process. 

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Important synthetic paths to azirines and aziridines involve bond reorganization, or internal addition, of vinylnitrenes. Indeed, the vinylnitrene-azirine equilibrium has been demonstrated in the case of trans-2-methyl-3-phenyl-l-azirine, which at 110 °C racemizes 2000 times faster than it rearranges to 2-methylindole (80CC1252). Created in the Neber rearrangement or by decomposition of vinyl azides, the nitrene can cyclize to the p -carbon to give azirines (Scheme 4 Section 5.04.4.1). 

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. 

Unlike the Beckmann rearrangement, the outcome of the Neber rearrangement does not depend on the configuration of the starting oxime derivative E- as well as Z-oxime yield the same product. If the starting oxime derivative contains two different a-methylene groups, the reaction pathway is not determined by the configuration of the oxime, but rather by the relative acidity of the a-methylene protons the more acidic proton is abstracted preferentially. ... 

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 has for example found application in natural product synthesis. 

Isolation of an Intermediate. It is sometimes possible to isolate an intermediate from a reaction mixture by stopping the reaction after a short time or by the use of very mild conditions. For example, in the Neber rearrangement (18-12)... 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Both oximes (10) and their ester (11) or ether derivatives can be used in the classical Beckmann rearrangement and the reaction usually proceeds under acidic or neutral conditions (although basic conditions may also be used). In sharp contrast, only 0-oxime esters can be used as starting materials for the Neber rearrangement and basic conditions are always necessary. The Neber rearrangement is not stereospecific, as the stereochemistry of the starting material E or Z) does not influence the outcome of the reaction. In... 

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). 

Although both the Beckmann and Neber reactions can use oxime derivatives as starting materials, O-unsubstituted oximes cannot undergo the Neber rearrangement. The latter occurs only in strongly alkaline reaction conditions while the former can also proceed in both acid and basic media. As a consequence, the Neber rearrangement will only be a possible side reaction of base-induced Beckmann rearrangements. 

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. 

Both cyclic and acyclic ketoximes may be used in this transformation and the reaction is usually performed in an alcohol solution containing equimolar quantities of alkoxide. For a successful reaction, the starting material usually contains at least an a-methylene group but the presence of only one a-hydrogen may suffice. When treated with base the 0-acylated aldoximes do not react via the Neber rearrangement and instead they undergo an E2 elimination to cyanides or isocyanides. 

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 °° . ... 

Asymmetric induction in the Neber rearrangement was also obtained under phase-transfer conditions with chiral quaternary ammonium bromides 544 as catalysts (equation 243). Moderate enantioselectivities (30-70% ee, 60-95% yield) were observed, but there is still an opportunity for extending the full synthetic utility of this classical rearrangement. 

Azirines are prepared by base-catalyzed cycloelimination of imine derivatives, e.g. as isolable intermediates in the Neber rearrangement (87 — 88) (77JA1514). 

Nitro groups attached to the benzene ring of chromans or chromanones may be reduced catalytically to give the amines but 3-aminochromanones (698) are usually obtained from the oxime (697) of the chromanone by the Neber rearrangement. The free bases are rather unstable (69JMC277). 

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