Oximes Neber reaction

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

An entirely different approach to the synthesis of 2H-azirinecarboxylic esters involves a modified Neber reaction of oxime tosylates derived from -keto esters (Scheme 15) [26]. 

A possible extension of the modified Neber reaction would be the synthesis of sulfonyl-substituted 2ff-azirines following the chemistry shown in Scheme 17 [27]. Unexpectedly, the oxime derived from -keto sulfones could not be converted into the oxime tosylate. Therefore, a different route to these requisite starting materials was designed, viz., via the corresponding sulfides 30 which were then oxidized with peracid to the sulfones 31. 

The lipase-catalyzed resolution of (2/ , 35 )-3-methyl-3-phenyl-2-aziridine-methanol ( )-H by using the low-temperature method gave synthetically useful (2/ ,35 )-ll and its acetate (2S, iR)- a with (25 )-selectivity E = 55 at —40°C), while a similar reaction of (2/ , 3f )-3-methyl-3-phenyl-2-aziridinemethanol ( )-12 gave (25,35 )-12 and its acetate (2/ ,3/ )-12a with (2/ )-selectivity E = 73 at —20°C) (Scheme 2). Compound ( )-ll was prepared conveniently via diastereos-elective addition of MeMgBr to t-butyl 3-phenyl-2//-azirine-2-carboxylate, which was successfully prepared by the Neber reaction of oxime tosylate of t-butyl... 

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. 

Although both the Beckmann and Neber reactions can use oxime derivatives as starting materials, O-unsubstituted oximes cannot undergo the Neber rearrangement. The latter occurs only in strongly alkaline reaction conditions while the former can also proceed in both acid and basic media. As a consequence, the Neber rearrangement will only be a possible side reaction of base-induced Beckmann rearrangements. 

Neber reaction produces the corresponding 3-aminothiochroman-4-one.62 Similar reactions have been conducted on the [Pg.70]

One of the best known reactions of 1-azirines is the acid/catalyzed hydrolysis to aminoketones. Since the Neber reaction also accomplishes this same synthetic end, this reaction may appear to have little practical value. This is not the situation because with the Neber reaction there is no control over the aminoketone that will be obtained from a given ketone. For example, when oxime (127) derived from benzyl methyl ketone (126) is subjected to the Neber reaction aminoketone 128 is obtained.59 The amino function is substituted for the most acidic a-hydrogen. The isomeric aminoketone (132) that could not be prepared by the Neber reaction can be formed by the hydrolysis of 1-azirine (131). The synthesis of this 1-azirine has been accomplished from allyl benzene (129) through vinyl azide (130) using iodine azide.22... 

Hydrolysis of 2-unsubstituted 1-azirines is a potentially valuable method for the preparation of aminoaldehydes. The application of the Neber reaction to oxime tosylates derived from aldehydes does not give the aminoaldehydes.59 Instead, nitriles are produced by elimination. 

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). 

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>. 

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 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... 

The / -toluenesulphonate esters of 2-, 3- and 4-acetylpyridine oximes undergo the Neber reaction 2. 

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... 

Unlike the Beckmann rearrangement, the outcome of the Neber rearrangement does not depend on the configuration of the starting oxime derivative E- as well as Z-oxime yield the same product. If the starting oxime derivative contains two different a-methylene groups, the reaction pathway is not determined by the configuration of the oxime, but rather by the relative acidity of the a-methylene protons the more acidic proton is abstracted preferentially. ... 

Both oximes (10) and their ester (11) or ether derivatives can be used in the classical Beckmann rearrangement and the reaction usually proceeds under acidic or neutral conditions (although basic conditions may also be used). In sharp contrast, only 0-oxime esters can be used as starting materials for the Neber rearrangement and basic conditions are always necessary. The Neber rearrangement is not stereospecific, as the stereochemistry of the starting material E or Z) does not influence the outcome of the reaction. In... 

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. 

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. 

It was discussed by Neber and co-workers (294-298) that some oximes (34) can be rearranged to a-amino ketones (36). The oxime was first converted into its /7-toluenesulfonic ester (35), which rearranged with sodium or potassium ethoxide to produce the amino ketone, which in most cases underwent further condensation to the dihydropyrazine (or pyrazine). The mechanism has been studied carefully in the reaction of 2,4-dinitrobenzyl methyl ketone and the unstable intermediate isolated from the reaction has been assigned (299, 300) the structure (37). The method was not always successful but literature preparations (294-298) are recorded in Table II.6. 

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 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 Neber rearrangement of oxime sulphonate esters (equation 28) is a useful method for the synthesis of a-aminoketones78. The reaction is base catalysed and involves abstraction of the most acidic proton a to the oxime functional group, as exemplified by the exclusive formation of compound 40 in this rearrangement (equation 29). 

Fewer mechanistic details are available for the Neber rearrangement than for the closely related Favorskii and Ramberg-Backlund reactions. Oxime tosylates, when treated initially with base and then with water, yield a-amino-ketones, viz-... 

This reaction, like all Neber rearrangements, is limited by availability of the appropriate oxime tosylate. Substrates in which the aryl group contain an electron-donating function are unstable, since they have a propensity to undergo Beckmann rearrangement. However, this difficulty can be resolved by subsequent conversion of the a-amino acetals. For example, catalytic hydrogenation of 2,2-diethoxy-2-(p-bromophenyl)ethylaraine yields the known parent compound, 2,2-diethoxy-2-phenylethylamine These two a-amino acetals readily undergo hydrolysis and should be protected from moisture. 

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