Tosyl ketoxime

Alternatively, oximes may be converted to O-substituted oximes (typically O-tosyl oximes) making the rearrangement much easier. Sometimes, these oxime derivatives rearrange spontaneously under the condition of their formation and cannot be isolated. Usually, O -tosyl ketoximes rearrange smoothly with exclusive anti migration. Relative to the acid-promoted Beckmann rearrangement, the rearrangement of O -tosyl oximes is much milder and specific. 

Tosyl ketoximes generally rearrange smoothly and with exclusive anti migration whoi dissdved in polar media a typical example is depicted in equation (10). The tosyl derivatives frequently rearrange under the conditions of their formation (equation 11), and the mildness and specificity of diis procedure recommend it for use with acid-sensitive substrates (equation 12). ... 

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. 

The ketoxime derivatives, required as starting materials, can be prepared from the appropriate aromatic, aliphatic or heterocyclic ketone. Aldoximes (where R is H) do not undergo the rearrangement reaction, but rather an elimination of toluenesulfonic acid to yield a nitrile. With ketoxime tosylates a Beckmann rearrangement may be observed as a side-reaction. 

Azirines can be prepared in optically enriched form by the asymmetric Neber reaction mediated by Cinchona alkaloids. Thus, ketoxime tosylates 173, derived from 3-oxocarhoxylic esters, are converted to the azirine carboxylic esters 174 in the presence of a large excess of potassium carbonate and a catalytic amount of quinidine. The asymmetric bias is believed to be conferred on the substrate by strong hydrogen bonding via the catalyst hydroxyl group <96JA8491>. 

An efficient synthesis of 2Ff-azirines 6 substituted with a phosphate group is described. Its key step is an alkaloid catalyzed Neber reaction of -ketoxime tosylates 5 (equation 3) . Similarly, azirines containing an ester group in position 2 were obtained from tosy-lated oximes . A novel approach to substituted 2Ff-azirines using benzotriazole (Bt) methodology was recently presented. The reaction of benzotriazole oxime tosylates formed from the oxime 7 and TsCl with aqueous KOH yielded 2-(benzotriazol-l-yl)-2H-azirines. 

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. 

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. 

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