Multi-site thiolation enables rapid and precise synthesis of 2-pyridone thioethers

Abstract

The direct and selective functionalization of 2-pyridones remains a fundamental challenge in synthetic chemistry. While conventional strategies targeting the C=C double bond offer some solutions, achieving broad site-selectivity and site-diversity continues to be limited. Reported methods have largely focused on single-position modifications, and site-selective multi-functionalization remains an attractive goal. Herein, we report I₂- and Ru₃(CO)₁₂/I₂-catalyzed strategies enabling multi-site thiolation of 2-pyridones with disulfides. This approach allows for selective C5-thiolation, C3-thiolation, as well as C3,C5- and C3,C6-dithiolation, under tunable and controllable reaction conditions. These transformations proceed with excellent regioselectivity, broad substrate scope, and good functional group tolerance. Furthermore, late-stage modifications and product derivatization demonstrate the synthetic utility and versatility of this protocol. Mechanistic investigations suggest that the mono-thiolation proceeds via a radical pathway involving thiyl radicals, while the di-thiolation likely follows a chelation-assisted ruthenation pathway. Overall, this work provides a robust platform for site-specific and multi-site functionalization of 2-pyridones, paving the way for rapid construction of structurally diverse sulfur-containing heterocycles.