Access to Substituted Tricyclic Heteroarenes by an Oxidative Cyclization Reaction and Their Antifungal Performance.

: Fungal pathogens are increasingly developing concerning resistance against the currently available antifungal drugs, which creates a constant demand for new antifungal agents. : Here, we report the synthesis of C3,N4-substituted triazole derivatives containing a N4-(2-((4-methoxybenzyl)thio)phenyl) group. By selectively removing the 4-methoxybenzyl group, we were able to access the free thiol analogs which, under oxidative conditions, undergo a cyclization reaction yielding a C5-substituted benzo[4,5]thiazolo[2,3-][1,2,4]triazole. We were able to show a broad functional group tolerance for the preparation of the triazole derivatives, as well as the tricyclic heteroarenes prepared thereof. Mechanistic investigations suggest that the oxidative cyclization reaction proceeds via an ionic pathway involving a disulfide intermediate. Isolation of the disulfide intermediate and resubjecting it to the reaction conditions shows that the presence of acid significantly increases its rate of conversion to the corresponding benzo[4,5]thiazolo[2,3-][1,2,4]triazole. Antifungal testing of both the novel triazoles and the benzo[4,5]thiazolo[2,3-][1,2,4]triazoles was carried out with (SC5314) and a clinical strain of (OK01). : Most of the novel sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-][1,2,4]triazoles showed activity against (SC5314) and the emerging pathogen (OK01). : A series of new sulfur-containing triazoles and benzo[4,5]thiazolo[2,3-][1,2,4]triazoles were synthesized. Antifungal testing revealed modest activity against (SC5314) and (OK01).