2//-Azirine intermediate, Neber

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 2//-azirine may be optically active and therefore be regarded as a chiral building block for enatioselective synthesis. This opens a wide field of investigation and recently efforts have been made to produce optically pure azirines. Considering the anionic displacement as the main pathway (and not the nitrene pathway), the Neber reaction may be modified to serve as a synthetic tool for the production of optically active 2//-azirine intermediates. 

Azirines have also been shown to be likely intermediates in the Campbell aziridine synthesis.62 This reaction is analogous to the Neber reaction in which the intermediate azirine is hydrolyzed to the aminoketone. Here the proposed azirine intermediate prepared from oxime (144) reacts with a Grignard reagent to give the aziridine (145). 

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). ° ... 

The foregoing reaction is probably initiated by nucleophilic addition of the iY-imines to the 2H-azirines to form 36 which may undergo homo-1,5-dipolar cyclization or ring opening followed by cyclization of 1,6-dipoles 37. This novel heterocyclic system was first prepared by the reaction of pyridine N-imines with a-chlorocinnamates, in which azirine intermediates were postulated.164 As a variation, use of azirine intermediates generated in situ from acetophenone oxime O-tosylate or dimethylhydrazone methiodide under the Neber reaction conditions also produces the pyrido[l,2-/>]triazines... 

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... 

These intermediates with benzyhnagnesinm bromides gave 2-benzyl-2/7-azirines 8 in 50-80% yields, bnt potassinm phthahmide and sodium salt of benzenethiol converted them into the corresponding azirines 9 and 10 in good yields (equation 4). Similar Neber-type cyclization of a-hthio oxime ethers to highly reactive azirines was recently reported. ... 

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). 

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... 

Neber and co-workers undoubtedly synthesized the first authentic 1-azirine in 1932 while studying the reaction of oxime -toluene-sulfonates with base to give aminoketones. Neber observed that while trying to prepare the p-toluenesulfonate derivatives of oximes (21), pyridine was a sufficiently strong base to convert the intermediate p-toluenesulfonates (22) into the aziridines (23).10,11 Azirines (24) could then be prepared by treating 23 with sodium carbonate. 

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>. 

From mechanistic studies on the Neber reaction, the 2//-azirine has been shown to be a distinct intermediate formed by ring closure of a vinyl nitrene. The evidence for the vinyl nitrene has resulted from the reported lack of steieospecificity in converting the ( )- and (Z)-isomers of 0-tosyloximes to the same a-amino ketone. Although a vinyl nitrene has been suggested as a possible intermediate in the thermal and photochemical preparations of the azirine ring, direct evidence for such a species is lacking. In this context, the configurational stereospecificity in a modified Neber reaction has been studied with oxime... 

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). 

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... 

It is also important to note that several intermediates in this sequence have been isolated and characterized, further bolstering the mechanistic interpretation. Neber isolated an azirine of type which has been conclusively corroborated. In fact, there are many reports which do not hydrolyse the azirine to the aminoketone, but rather isolate these moieties in good yields (vide supra). Intermediates of type 13 have been isolated, after alkoxide addition to the azirine. Furthermore, the azirine was shown to be non-isomerizing under the reaction conditions," allowing predictable application of this reaction. Finally, it was shown that when two ionizable a-centers are present, deprotonation occurs at the most acidic site. ... 

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. 

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