Skeletal Remodeling of Pyridines Through Nitrogen Atom Transposition
Chunxiu Jing, Hui‐Mei Jiang, Qiuling Yan, Fan Huang, Jialu Sun, Liping Xu, Hao Wei
Abstract
Heterocyclic replacements are crucial tools in medicinal chemistry, enhancing the physicochemical properties of lead compounds. Pyridine, a core structural motif in numerous drug candidates, often serves as a key heterocyclic scaffold. Nonetheless, a universally applicable synthetic strategy for the direct conversion of pyridines into a diverse array of other heterocycles has yet to be established. In this study, we present a skeletal remodeling strategy that enables the transformation of pyridines into corresponding anilines via Lewis acid-catalyzed nitrogen atom transposition. These anilines can subsequently serve as versatile intermediates for accessing a variety of heterocyclic structures, thereby facilitating the rapid synthesis of novel bioactive analogs. DFT calculations indicate that the Lewis acid catalyst not only aids in the formation of pyridinium salts, enhances nucleophilic addition and nitrogen release. This methodology demonstrates considerable utility across a range of complex pyridine derivatives and several commercially available drugs, highlighting its potential for pharmaceutical diversification.