Neber rearrangement synthesis

Morrow, D. F., Butler, M. E. Stereoselectivity in the Neber rearrangement-synthesis of a steroidal spiroazirine. J. Heterocycl. Chem. 1964,... 

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... 

The Neber rearrangement has for example found application in natural product synthesis. 

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 °° . ... 

Similar Neber rearrangements were used to produce 528, an intermediate for an efficient synthesis of 2-imidazol-2-yl acetates 530 (equation 234). Condensation of the a-amino ketals 528 with imidates 529, followed by cyclization in refluxing acidic dioxane, yielded 2-imidazol-2-yl acetates 530 in a one-pot reaction. 

During the total synthesis of Dragmacidin F (537) from quinic acid, Stoltz and col-leagues applied a high-yield late-stage Neber rearrangement to introduce in a completely enantioselective manner an amino group into a complex framework (equation 238). 

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). ° ... 

A new variant of the Neber rearrangement has been reported recently which involves the treatment of amidoxime-O-tosylate (120) with sodium methoxide affording 2-amino-1-aziridine (121), a useful intermediate for the synthesis of a large array of heterocyclic compounds. None of possible pyrazolone (122) or cyanamide (123) derivatives were detected in the reaction mixture (Scheme 28). ° ... 

The chemoenzymatic synthesis of a Ps adrenergic receptor agonist was developed by J.Y.L. Chung and co-workers. The key chiral 3-pyridylethanolamine intermediate was prepared via the Neber rearrangement of the ketoxime tosylate derived from 3-acetylpyridine. The oxime formation and the tosylation were carried out in a one-pot process using pyridine as the solvent. The solution of the ketoxime tosylate in ethanol was then cooled to 10 °C and potassium ethoxide was added. After the TsOK salt was removed from the reaction mixture, HCI gas was bubbled through the solution until the pH reached 2 and the 3-pyridylaminomethyl ketal was isolated as its di-HCI salt. 

The synthesis of optically active 3-amino-2/-/-azirines was carried out using a modified Neber rearrangement in the laboratory of I.P. Piskunova. The optically active amidoximes were acylated using mesyl chloride to give 0-mesyl derivatives that upon treatment with sodium methoxide afforded the desired product with high diastereoselectivity. 

Hyatt, J. A. Neber rearrangement of amidoxime sulfonates. Synthesis of 2-amino-1-azirines. J. Org. Chem. 1981,46, 3953-3955. 

The initial intent to cover the subject exhaustively had to be abandoned because of the overwhelming amount of relevant literature. The following reactions are not covered but are briefly discussed, with references to reviews and seminal papers, in the section on Comparison with Other Methods reactions of carbanions and enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters, and nitroso and nitro compounds reactions of enolates with diazonium salts, including the Japp-Klingemann reaction the diazo transfer reaction except as it interferes with the synthesis of azides the animation of boranes and the Neber rearrangement. 

MeC6H4S02) and treated with base to yield (299) as the sole product. This new variant of the Neber rearrangement provides the first synthesis of unsubstituted amino-azirines and has also been shown to proceed for the formation of (299 = PhS02). 

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