Molecular skeleton remodeling represents a pivotal strategy in medicinal chemistry for optimizing the physicochemical profiles of lead compounds. Pyridine is a privileged scaffold in drug discovery. However, its conversion into alternative heterocyclic systems involves modifications of multiple chemical bonds and atoms, which remain inaccessible to current single-atom skeletal editing methods. Herein, we report a skeletal remodeling strategy that enables the conversion of pyridines to anilines through a Lewis acid-catalyzed carbon atom insertion and nitrogen atom transposition under ambient conditions (rt, air). These aniline intermediates can serve as universal intermediates for the synthesis of diverse fused heterocycles (such as quinoline, indole, and carbazole), thereby enabling direct modification of pyridine-containing drug candidates. This methodology demonstrates broad applicability across complex pyridine derivatives and commercial drugs, underscoring its potential for efficient pharmaceutical diversification.
Zhao et al. (Sun,) studied this question.