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C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates
oleh: 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
Format: | Article |
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Diterbitkan: | Nature Portfolio 2024-08-01 |
Deskripsi
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.