Ring transformations leading to isoxazoles

Ring transformations of heterocycles leading to isoxazoles have been briefly reviewed (79AHC(25)147). The heterocycles undergoing such transformations may be divided into three classes. 

The fragmentation pattern of isoxazoles on electron impact has been well studied. It has been used as an important tool for the structural assignment of isoxazoles obtained from the reaction of chromones with hydroxylamine 79MI41600, 77JOC1356). For example, the structures of the isoxazoles (387) and (388) were assigned on the basis of their fragmentation patterns. Ions at mje 121 (100%) and mje 93 (19.8%) were expected, and indeed observed, for the isoxazole (388), and an ion at mje 132 (39.5% ) was similarly predicted and observed for the isoxazole (387). 

The reaction of hydroxylamine with 2-substituted chromones (392) where R = Me, Ph (76MI41601) or CO2H (79MI41600) gave exclusively 5-(o-hydroxyphenyl)isoxazoles (393). 

The reaction of flavylium salts (403a) with hydroxylamine in pyridine gave 2,5-dihy-droisoxazoles (404) in an analogous manner (75T2884). Pyrimidines have also been converted into isoxazoles, and the reaction of the pyrimidines (405) with hydroxylamine hydrochloride gave the isoxazoles (338). 

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Reactions in which the CCC unit is part of a ring, with attack by hydroxyl-amine leading to a labile acyclic intermediate which recyclizes to form an isoxazole, are classified as ring transformations (Section II,B,4). 

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. 

Continuation of the study of ring transformations of l,3-oxazin-4-ones has led to the discovery of new routes to 5-acetyl-pyrimidinones (313) (Scheme 75 path a), 1,2,4-oxadiazoles (314) (path b), and isoxazoles (315) (path In buffered hydroxylamine hydrochloride solution, nucleophilic ring-opening of the oxazinone (path a) leads ultimately to oxadiazole (314). In contrast, hydroxylamine hydrochloride effects protonation of the oxazinone ring (316) and subsequent ring-opening and ring-closure to the isoxazoles (315), as illustrated in path (c). 

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