Neber reaction

In addition to the present method, 2H-azirines can be prepared by using a modified Neber reaction,or by heating 4,5-dihydro-l,2,5-oxazaphospholes. 1... 

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]. 

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 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]. 

Interestingly, certain chiral tertiary bases, viz., the Cinchona alkaloids, result in an asymmetric 1,3-elimination to give enantiomerically enriched azirine esters 29 (Scheme 15). The best results were obtained with quinidine in toluene as the solvent at a rather high dilution (2 mg mL ) at 0 °C. In an alcoholic solvent no asymmetric conversion was observed. It is of importance to note that the pseudoenantiomers of the alkaloid bases gave opposite antipodes of the azirine ester, whereby quinidine leads to the predominant formation of the (k)-enan-tiomer (ee = -80%). To explain this asymmetric Neber reaction, it is suggested... 

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. 

Palacios et al. utilized the modified Neber reaction for the preparation of 2ff-azirine-2-phosphonates 33 as shown in Scheme 18 [28 a]. The use of quini-dine and dihydroquinidine as the chiral base resulted in moderate chirality transfer (20-52% ee). Similarly, 2-phosphinoyl-2H-azirines could be obtained by the Neber 1,3-elimination reaction [28bj. 

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... 

The Neber reaction of 1 with the hydrazone salts in tetrahydrofuran containing potassium /m-butoxide gave 5 (77JOC2514), where azirines... 

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 reaction has found application as an important synthetic tool, particularly in the synthesis of heterocycles. 

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. 

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. 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

The previous strategy has been applied to the synthesis of other enantiomerically enriched 2/7-azirines. Palacios and coworkers developed the alkaloid-mediated Neber reaction to produce enantiomerically enriched 2/7-azirines containing a phosphorus substituent in the C(2) position. 

Naphthoquinone, 2-methyl- 56,70 Neber reaction, 57, 87 Neopentylbromide, 58, 145 NEOPENTYL PHENYL SULFIDE, 58,... 

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

The Neber reaction generally does not lend itself as a useful method for the synthesis of 1 -azirines. The above reaction is probably successful because of the strong electron-withdrawing substituent which increases the acidity of the a-hydrogens and allows the ring closure to occur under mild conditions. Nevertheless, a few azirines have been prepared by related Neber reactions. 

Smith and Most13 developed a modified Neber reaction for the synthesis of aminoketones which was used successfully by Parcell for the synthesis of 3,3-dimethyl-2-phenyl-l-azirine (26).14... 

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... 

---