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C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2024. "C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51452-0
    DOI: 10.1038/s41467-024-51452-0
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    References listed on IDEAS

    as
    1. Baptiste Joalland & Yuanyuan Shi & Alexander Kamasah & Arthur G. Suits & Alexander M. Mebel, 2014. "Roaming dynamics in radical addition–elimination reactions," Nature Communications, Nature, vol. 5(1), pages 1-6, September.
    2. Guo-Quan Sun & Peng Yu & Wen Zhang & Wei Zhang & Yi Wang & Li-Li Liao & Zhen Zhang & Li Li & Zhipeng Lu & Da-Gang Yu & Song Lin, 2023. "Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations," Nature, Nature, vol. 615(7950), pages 67-72, March.
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