Thermal isomerization of isoxazole

MNDO results suggest that the activation energies are similar for the gas phase thermal isomerization of isoxazole to oxazole via either a nitrile ylide or a keteneimine, through an azirine intermediate. The first step is rate limiting, which is in good agreement with experimental results (90JPO611). 

Computational studies on the mechanisms of thermal isomerization of isoxazole and 5-methylisoxazole have been reported.162... 

In the photochemical isomerization of isoxazoles, we have evidence for the presence of the azirine as the intermediate of this reaction. The azirine is stable and it is the actual first photoproduct of the reaction, as in the reaction of r-butylfuran derivatives. The fact that it is able to interconvert both photochemically and thermally into the oxazole could be an accident. In the case of 3,5-diphenylisoxazole, the cleavage of the O—N bond should be nearly concerted with N—C4 bond formation (8IBCJ1293) nevertheless, the formation of the biradical intermediate cannot be excluded. The results of calculations are in agreement with the formation of the azirine [9911(50)1115]. The excited singlet state can convert into a Dewar isomer or into the triplet state. The conversion into the triplet state is favored, allowing the formation of the biradical intermediate. The same results [99H(50)1115] were obtained using as substrate 3-phenyl-5-methylisoxazole (68ACR353) and... 

For isoxazoles the first step is the fission of the weak NO bond to give the diradical 69 which is in equilibrium with the vinylnitrene 70. Recyclization now gives the substituted 27/-azirine 71 which, via the carbonyl-stabilized nitrile ylide 72, can give the oxazole 73. In some cases the 27/-azirine, which is formed both photochemically and thermally, has been isolated, in other cases it is transformed rapidly into the oxazole. Thermal isomerization of 4-nitro-3-phenylisoxazole derivatives to 4-nitro-2-phenyloxazoles works well by heating in xylene at 155 C in the presence of FeCl3Si02 <1998JOC6050>. 

Further work by Adembri et al. describes the irradiation of 5-hydrazino-isoxazoles 291a-b under nitrogen, which gives a mixture of products analogous to that obtained by thermal isomerization 5-methylaminopyrazol-3-ones 292a-b, 4-aminopyrazol-3-ones 293a-b, and l,2,4-triazin-6-ones 294 -b (78TL4439). 

Numerous synthetically relevant ring transformations of isoxazoles are known. For example the iV-isoxazolyl thiourea 23 isomerizes thermally to give 1,2,4-thiadiazole 24 ... 

Isoxazoles largely undergo photochemical isomerization to azirines, which sometimes undergo a further thermal or photochemical reaction. 3,4,5-Triarylisoxazole (529) formed the 2,3-diphenyl-3-benzoylazirine (530) which underwent further reaction to the oxazole (531) 72JA1199). A small amount of the corresponding benzoyl ketenimine was also obtained. 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

Upon UV irradiation, the heteroaromatic isoxazoles 35 rearrange similarly—most likely via azirines (293)159—to afford, by photocleavage of 293, nitrilylides (294)140,160 and finally the isomeric 1,3-oxazoles 295.1S7 However, ethyl 5-aminoisoxazole-4-carboxylate (34) isomerizes by another pathway. Similar to some thermal reactions,161 reorganization of the nitrile function in 295 affords the vinylamine 296157 (Scheme 80). Similar results are known for benzisoxazoles.162... 

Azirines and Aziridines.— The photolysis and thermolysis of the azido ester (143) to the azirine (144) was described by Hassner and Fowler in 1968. A study of isomeric compounds (145) has now been described, leading to the tautomeric isomer (146) of the antibiotic azirinomycin (147). 3,5-Dimethylaminoisoxazoles (148) have been prepared by the addition of hydroxylamine to phosgene iminium salts. The photoisomerization of the 4-substituted isoxazoles (148) to the azirines (149) is already known, and a paper has now described the near-quantitative thermal... 

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