Acid-catalyzed divergent synthesis of 2-substituted 1,3-benzazoles with antioxidant and mitochondrial protective effects

Abstract

An efficient and divergent acid-catalyzed annulation of alkyl/arylmethyl thiooxamates with o-aminoaryl precursors has been developed for the synthesis of 2-substituted 1,3-benzazoles. The transformation proceeds under mild conditions, demonstrates broad functional group tolerance, and affords benzimidazole, benzoxazole, and benzothiazole derivatives in good yields. A plausible mechanism has been proposed, in which initial protonation is followed by condensation and subsequent intramolecular cyclization via desulfurization, leading to the formation of benzazoles without external oxidants or metal catalysts. A library of 44 benzazole derivatives was synthesized and evaluated for mitochondrial protective and antioxidant activities. Among them, compounds 4i and 4n showed notable mitochondrial stabilization and reduced oxidative stress in cellular models. These findings provide a versatile synthetic route to benzazole scaffolds and identify new compounds with favorable antioxidant and organelle-protective properties.