Isoxazoles ring fission

Isoxazoles are readily reduced, usually with concomitant ring fission. Thus, solvent-dependent hydrogenolysis of 3,5-diphenylisoxazole in the presence of palladium on charcoal resulted in open-chain products (347) and (348) (87T3983). 

Isoxazoles are readily reduced, usually with concomitant ring fission (e.g. 262 -> 263). They behave as masked 1,3-diketones <79AHC(25)147>. 1,2-Benzisoxazoles are easily reduced to various products (Scheme 28) (67AHC(8)277). Chemical or catalytic reduction of oxazoles invariably cleaves the heterocyclic ring (Scheme 29) (74AHC(17)99). For similar reactions of thiazoles, see Section 4.02.1.5.1. 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

Isoxazoles are photolabile. The first step in the reaction is believed to be fission of the N—O bond with formation of a diradical which may recyclize. In the case of the isoxazolopyridine (4) the reaction is rationalized as taking place via a 2ZZ-azirine (5) and a carbenoid structure (6) before formation of an oxazole ring (7). A high pressure mercury lamp is used, and the reaction can be run on a preparative scale (79CB3282). Photolysis of the isoxazole (8), which is fused to an azine ring with a different order of its azole heteroatoms, also leads to oxazole formation (10) (78CPB2497), but in this instance another type of intermediate is postulated (9). 

The reaction of 3-unsubstituted isoxazoles with bases, leading to ring opening, has been known for almost 90 years, and has many applications. The mechanism of the reactions with hydroxide ion has been studied by Italian workers.156 157 The reactions showed second-order kinetics (first-order in base and in substrate) and the UV spectra of reaction mixtures showed sharp isosbestic points, indicating the transformation of reactants into products without formation of an intermediate. A primary deuterium isotope effect indicated that fission of the C3—H bond was rate-determining. 

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