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Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations

Author

Listed:
  • Guo-Quan Sun

    (Sichuan University)

  • Peng Yu

    (Cornell University)

  • Wen Zhang

    (Cornell University)

  • Wei Zhang

    (Sichuan University)

  • Yi Wang

    (Cornell University)

  • Li-Li Liao

    (Sichuan University)

  • Zhen Zhang

    (Sichuan University)

  • Li Li

    (Sichuan University)

  • Zhipeng Lu

    (Cornell University)

  • Da-Gang Yu

    (Sichuan University
    Beijing National Laboratory for Molecular Sciences)

  • Song Lin

    (Cornell University)

Abstract

Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active compounds1,2. Site-selective C–H functionalization would provide a direct way of making these medicinally active products3–5. For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation6–8. Here we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO2. The choice of the electrolysis setup gives rise to divergent site selectivity: a divided electrochemical cell leads to C5 carboxylation, whereas an undivided cell promotes C4 carboxylation. The undivided-cell reaction is proposed to operate through a paired-electrolysis mechanism9,10, in which both cathodic and anodic events play critical roles in altering the site selectivity. Specifically, anodically generated iodine preferentially reacts with a key radical anion intermediate in the C4-carboxylation pathway through hydrogen-atom transfer, thus diverting the reaction selectivity by means of the Curtin–Hammett principle11. The scope of the transformation was expanded to a wide range of N-heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7950:d:10.1038_s41586-022-05667-0
    DOI: 10.1038/s41586-022-05667-0
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    Cited by:

    1. Wen-Jie Kang & Yanbin Zhang & Bo Li & Hao Guo, 2024. "Electrophotocatalytic hydrogenation of imines and reductive functionalization of aryl halides," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Zhiwei Zhao & Ranran Zhang & Yaowen Liu & Zile Zhu & Qiuyan Wang & Youai Qiu, 2024. "Electrochemical C−H deuteration of pyridine derivatives with D2O," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    3. 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.

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