Isothiazoles ring cleavage

Friedel-Crafts acylation usually fails (72AHC(14)43), but 3-substituted l-methyl-2,1-benzisothiazole 2,2-dioxides can be acetylated at the 5-position (73JHC249). l-Methyl-2,1-benzisothiazol-3-one can be chlorsulfonated at the 5-position (78JHC529). Vilsmeier-Haack formylation causes cleavage of the isothiazole ring (80JCR(S)197). 

To further illustrate the diversity of hydrolytic opening reactions, we turn our attention to an isothiazole ring as found in the antipsychotic agent ziprasidone (11.129). This drug is subject to various reactions of oxidation and reduction, but also undergoes hydrolytic cleavage of the C=N bond of the isothiazole ring. Evidence for this reaction was afforded by detection of radioactive metabolite 11.130, a sulfonamide, in the urine of patients dosed... 

Cleavage of isothiazoles during lithiation was discussed in Section III,B, and a related example is provided by the fission of the isothiazole ring of an isothiazolo[5,4-6][l,4]benzothiazine during alkylation with sodium hydride and alkyl halide.123... 

In halo isothiazoles the order of activity for nucleophilic displacement is 5 > 4 > 3. Attempts to displace the 3-halo in 1,2-benzisothiazoles leads to ring cleavage, whereas the 3-halo group in 2,1-benzisothiazoles is displaced <84CHEC-I(6)l3l>. The relative reactivities of the chloro groups in a 3,4-dichloroisothiazole have been explored (see Section 3.05.7.7). 

Quaternization of isothiazole increases the tendency for nucleophilic ring cleavage. Accordingly, 2-phenylisothiazolium bromides 291 reacted with benzylamine or... 

The P4 isothiazole -> thiazole transposition is thus mechanistically quite similar to the analogous pyrazole imidazole isomerization. Scheme 14 shows that both reactions involve competition between ring cleavage to yield a nitrile cleavage product and to transposition involving an isocyanide intermediate. 

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