C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates
Shun Li, Juan Tang, Yonglin Shi, Meixin Yan, Yihua Fu, Zhishan Su, Jiaqi Xu, Weichao Xue, Xueli Zheng, Yicen Ge, Ruixiang Li, Hua Chen, Haiyan Fu
Abstract
Regioselective C–H functionalization of pyridines remains a persistent challenge due to their inherent electronically deficient properties. In this report, we present a strategy for the selective pyridine C3-H thiolation, selenylation, and fluorination under mild conditions via classic N−2,4-dinitrophenyl Zincke imine intermediates. Radical inhibition and trapping experiments, as well as DFT theoretical calculations, indicated that the thiolation and selenylation proceeds through a radical addition-elimination pathway, whereas fluorination via a two-electron electrophilic substitution pathway. The pre-installed electron-deficient activating N-DNP group plays a crucial and positive role, with the additional benefit of recyclability. The practicability of this protocol was demonstrated in the gram-scale synthesis and the late-stage modification of pharmaceutically relevant pyridines. Regioselective C–H functionalization of pyridines remains a persistent challenge due to their inherent electronically deficient properties. Here, the authors present a strategy for the selective pyridine C3-H thiolation, selenylation, and fluorination under mild conditions via classic N-2,4-dinitrophenyl Zincke imine intermediates.