Work

Diazacyclobutenes as Reactive Intermediates: The Cascade Cyclization of Thiolated Ene-ynes and Azodicarboxylates to Provide Tetrahydroindoles

Year: 2025

Type: article

Abstract: We describe a new one-pot synthesis to access richly functionalized tetrahydroindoles and related fused pyrroles. The key to this transformation is a robust cascade cyclization between ene-yne sulfides and azodicarboxylates involving diazacyclobutene formation primed for rapid electrocyclic ring opening to an α-iminothioimidate intermediate, followed by cyclization and aromatization to yield the N -heterocycles in good yields. This tactic represents a significant departure from conventional approaches to the tetrahydroindole motif, which typically involve either staging the 140-year-old Paal–Knorr cyclization or leveraging transition metal catalysis. Further synthetic applications demonstrated that this method can be used for the late-stage functionalization of complex bioactive molecules or natural product-like structures in an efficient manner. The mechanism of the cyclization event leading to the heterocyclic products was probed computationally and is more consistent with a polar process instead of a concerted aza-Nazarov cyclization. The products can be leveraged in a mechanistically interesting desulfination reaction or converted to highly substituted indoles under mild conditions.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.5c00705