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 () and Haiyan Fu ()
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Shun Li: Sichuan University
Juan Tang: Sichuan University
Yonglin Shi: Sichuan University
Meixin Yan: Sichuan University
Yihua Fu: Sichuan University
Zhishan Su: Sichuan University
Jiaqi Xu: Sichuan University
Weichao Xue: Sichuan University
Xueli Zheng: Sichuan University
Yicen Ge: Chengdu University of Technology
Ruixiang Li: Sichuan University
Hua Chen: Sichuan University
Haiyan Fu: Sichuan University

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51452-0

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