Unified Gold-Catalyzed Cyclization Approach Towards Isothiazoles from Propargylic Sulfinamides

Abstract

Isothiazoles are valuable heterocycles in agrochemical and pharmaceutical research, yet they remain synthetically less accessible than their isoxazole counterparts. We report here a gold-catalyzed cyclization of propargylic N-tert-butanesulfinamides that provides direct and efficient access to isothiazoles under mild conditions. The transformation proceeds through an unusual cascade: cationic gold activation of the alkyne triggers a 5-endo-dig ring closure with sulfur as the nucleophile followed by irreversible loss of the tert-butyl group and dehydrative aromatization. The substrate scope encompasses a range of alkyl and aryl substituents, affording isothiazoles in yields of up to 79%. Reaction monitoring and isolation of key intermediates establish that the cyclic sulfinamide is a direct precursor to the aromatic product and that protic solvents, particularly acetic acid, facilitate the cascade of events, dramatically reducing reaction times. A complementary base-catalyzed pathway from CF₃-substituted substrates selectively delivers cyclic sulfoximines, demonstrating that both heterocyclic classes are accessible from a common precursor by simply switching the activation mode. These results originate from a serendipitous observation made during insecticide research at Syngenta and have broader implications for the design of sulfur-containing heterocyclic scaffolds.