Azirines, Neber rearrangement

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... 

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... 

Another significant preparative pathway to the 2i/-azirine system is the Neber rearrangement of oxime sulfonates. The presence of strong electron-withdrawing groups in the a-position to the oxime increases the acidity of those protons, and thus favors the cycloelimination reaction under mild conditions. The Neber reaction occurs either through an internal concerted nucleophilic displacement or via a vinyl nitrene (Scheme 213) <2001EJ02401>. 

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 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. 

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). 

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... 

Perhaps the most widespread variation of the Neber rearrangement is its utility in preparing 2//-azirines. The first reported isolation of such a product (18), albeit in a special case, was reported by Neber in his seminal studies of this reaction, Since then, numerous reports have appeared which prepare these moieties in good yields under predictably selective conditions, usually... 

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. 

The Neber rearrangement of oxime 0-sulfonates to 2//-azirines (or a-amino ketones, after aqueous acid workup) has been reviewed, together with the modified Neber , involving /V,/V,A-trimethylhydrazonium iodides.With an excess of base, the a-amino acetal can be formed from the 2//-azirine via the unstable 2-alkoxy aziridine. 

It should be remembered that the historically first pathway to 2H-azirines is the Neber rearrangement, in which oxime sulfonates of type 17 are transformed to a-aminoketones 18 by interaction with base, for example ... 

Taber and Tian have employed the Neber protocol to prepare a-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-... 

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). 

---