3- Halo-5-substituted isoxazoles

Highly regioselective tandem syntheses of 3-halo-5-substituted isoxazoles 3 have been developed from l-copper(I)-alkynes and dihaloformaldoximes under base-free conditions. This methodology inhibits the formation of halonitrile oxides precluding 1,3-dipolar cycloadditions (1,3-DC) (14OL6140). 

Reaction of a 1,3-diketone with hydroxylamine gives an isoxazole 50 via the isolable monoxime 48 and 5-hydroxydihydroisoxazole 49 (Scheme 34). Various modifications of this procedure involving other 1,3-dielectrophiles are known the examples can be represented by the reaction of alkynyl ketone 51 with hydroxylamine hydrochloride leading to the 3-substituted isoxazole 52 (Scheme 35) <2000J(P1)2311 >, and the electrophilic cyclization of O-methyl oximes 53 allowing access to a variety of 3,5-disubstituted-4-halo- or -4-selenoisoxazoles 54 under mild reaction conditions (Scheme 36) <20050L5203>. 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

Isoxazoles are quatemized by iodoalkanes or dialkyl sulfates. Electrophilic substitutions such as halo-genation, nitration, sulfonation, Vilsmeier-Haack formylation and acetoxymercuration, occur at the 4-position, provided this position is unsubstituted. As with oxazole, the pyridine-like N-atom impedes electrophilic substitution, so that isoxazoles are less reactive than furans but more reactive than benzene. 

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