2//-Azirine intermediate, Neber rearrangements

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. 

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

In a reinvoetigation of the Neber rearrangement 77 of oxiiiu-toeyl tes to aminoketonee it has been conclusively demonstrated that a l-azirine is an intermediate ( q. 70). When the reaction was run under slightly different conditions, an unstable aUtoxyaesridine v-i obtained. 2.105... 

RCH2CH(NCl2)R , where the product is also RCH(NH2)COR The mechanism of the Neber rearrangement is via an azirine intermediate 19 ... 

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). ° ... 

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... 

Although it has been proposed that this reaction is initiated by an alkoxide addition to C=N double bond followed by the loss of tosyloxy group to form a nitrene intermediate, which inserts to the of-carbon to form an alkoxy ethylenimine, more experimental evidence indicates that the Neber rearrangement involves an initial base-induced elimination of the more acidic a-proton accompanied by the loss of the tosyloxy group to give azirine... 

Finally, a synthesis of 2i/-pyrido[l,2-Z>]-as-triazines was reported, exploiting an intercepted Neber rearrangement. For this reaction, the trimethylhydrazonium iodides (40) were treated with KO/-Bu to presumably form the intermediate azirines. Rather than hydrolyzing these intermediates, the azirines were instead intercepted with 1-aminopyridinium salts (39) to directly furnish the heterocyclic products (41) in moderate yields. 

A Neber route to substituted indoles 532, complementary to the Fischer indole synthesis, was recently developed (equation 235). Formation of azirine 531 from the oxime was smoothly induced, for example using MsCl/DBU or DIAD/BU3P or PhsP, and the intermediate was isolated. Thermal rearrangement of the azirine (40 to 170 °C, depending on the azirine structure) produced the indoles 532 directly in usually good yields (84-88% from the azirine). 

The Neber route has been noted to be mildly influenced by the introduction of chiral auxiliaries. Thus, rearrangement of the tosyl oxime 860 (formed in situ from the oxime 859) in the presence of catalytic amounts of the chiral quaternary ammonium bromide 858 led to the formation of enantiomerically enriched amino ketone 863, which is presumed to arise from the preferential formation of the intermediate 2//-azirine 862. Association of the cationic chiral auxiliary with an anionic intermediate (i.e, 861) has been invoked to rationalize the stereochemical outcome (Scheme 215) <2002JA7640>. 

The Neber rearrangement650-653 is a method for preparing a-amino ketones by base-catalyzed intramolecular rearrangement of ketoxime O-sulfonates. The intermediate azirine,654-656 which can be isolated, can also lead to aziridine derivatives when the base is lithium aluminum hydride657 or a Grignard reagent (the Hoch-Campbell reaction)658,659 (Eq. 190). 

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