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Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

Author

Listed:
  • Chaodong Wang

    (Zhejiang University of Technology)

  • Zhi Chen

    (Zhejiang University of Technology)

  • Jie Sun

    (Zhejiang University of Technology)

  • Luwei Tong

    (Zhejiang University of Technology)

  • Wenjian Wang

    (Zhejiang University of Technology)

  • Shengjie Song

    (Zhejiang University of Technology)

  • Jianjun Li

    (Zhejiang University of Technology
    Zhejiang University of Technology)

Abstract

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.

Suggested Citation

  • Chaodong Wang & Zhi Chen & Jie Sun & Luwei Tong & Wenjian Wang & Shengjie Song & Jianjun Li, 2024. "Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49337-3
    DOI: 10.1038/s41467-024-49337-3
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    References listed on IDEAS

    as
    1. Hui Chen & Wenjing Fan & Xiang-Ai Yuan & Shouyun Yu, 2019. "Site-selective remote C(sp3)–H heteroarylation of amides via organic photoredox catalysis," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    2. Nian Li & Jinhang Li & Mingzhe Qin & Jiajun Li & Jie Han & Chengjian Zhu & Weipeng Li & Jin Xie, 2022. "Highly selective single and multiple deuteration of unactivated C(sp3)-H bonds," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Gilbert J. Choi & Qilei Zhu & David C. Miller & Carol J. Gu & Robert R. Knowles, 2016. "Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer," Nature, Nature, vol. 539(7628), pages 268-271, November.
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