Electrophilic reagents, reactions with isoxazoles

Isoxazoles are known at present to undergo the following electrophilic substitution reactions nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, and mercuration. Repeated attempts to effect the Friedel-Crafts reaction in the isoxazole series in the authors laboratory failed. The isoxazole nucleus seems not active enough to react with weak electrophilic reagents. 

Both - and -alkylazolium ions, like the 2- and 4-alkylazoles themselves, can also react with electrophilic reagents without initial complete deprotonation. They undergo the same types of reactions as the alkylazoles but under milder conditions, and these reactions can often be catalyzed by piperidine. Thus, in quaternized pyrazoles, 5-methyl groups react with benzaldehyde to give styryl derivatives. The methyl groups in quaternized isoxazoles are also reactive, and here piperidine is sufficient as catalyst (Scheme 124). 

Isoxazoles are very weak bases. The Ka of isoxazole is -2.97. Protonation occurs at the N-atom. Reactions with electrophilic reagents... 

Zhdankin et al. reported the iodine(III) catalyzed oxidative cycloaddition of aldoximes 60 with alkenes and alkynes to prepare isoxazoles and isoxazolines. The active hypervalent iodine(III) species was generated in situ by the oxidation of catalytic 3,5-dimethyliodobenzene using Oxone as an inexpensive and environmentally safe terminal oxidant in aqueous 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). This activated iodine(III) promoted the oxidation of the corresponding aldoximes efficiently affording nitrile oxides 61, which upon cycloaddition reaction with various alk5mes 62 and alkenes 64 resulted in isoxazoles 63 and isoxazolines 65, respectively in moderate-to-excellent yields (up to 92%). In this oxidative conversion, HFIP is believed to increase the electrophilicity of I(III) reagent (Scheme 11) [27]. 

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