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Overcoming limitations in Chan-Lam amination with alkylboronic esters via aminyl radical substitution

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  • Huanyu Xiao

    (Nanchang University)

  • Panting Cao

    (Nanchang University)

  • Wenhui Xiong

    (Nanchang University)

  • Tao Yang

    (Nanchang University)

Abstract

Chan-Lam coupling represents one of the most reliable methods for constructing C(sp2)−N bonds under mild conditions. However, application of this technology as a general platform for C(sp3)−N bond assembly remains a longstanding challenge due to the inherent limitation in boron-to-copper transmetalation. In contrast to the conventional two-electron process, the rapid capture of alkyl radicals by copper(II) complex affording the reactive high-valent copper(III) intermediate, has become a key part of the emerging approaches to forge C(sp3)−N bonds. Here, we report an N-alkylation protocol that overcomes the limitations of Chan-Lam coupling by using versatile alkylboronic pinacol esters (APEs) as radical precursors via aminyl radical-mediated boron abstraction. This distinct approach enables a versatile N-alkylation applicable to a wide range of APEs and N-nucleophiles with diverse functional groups. Synthetic utility of this protocol is further demonstrated by its ease of scalability, sequential N-alkylation of substrate with multiple reactive sites, and the late-stage modification of several complex bioactive materials.

Suggested Citation

  • Huanyu Xiao & Panting Cao & Wenhui Xiong & Tao Yang, 2025. "Overcoming limitations in Chan-Lam amination with alkylboronic esters via aminyl radical substitution," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64155-x
    DOI: 10.1038/s41467-025-64155-x
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    References listed on IDEAS

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    1. Yufan Liang & Xiaheng Zhang & David W. C. MacMillan, 2018. "Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis," Nature, Nature, vol. 559(7712), pages 83-88, July.
    2. Changlei Zhu & Jiaxin Lin & Xiaoguang Bao & Jingjing Wu, 2025. "Development of N-centered radical scavengers that enables photoredox-catalyzed transition-metal-free radical amination of alkyl pinacol boronates," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    3. Ji-Jun Chen & Jia-Heng Fang & Xuan-Yi Du & Jia-Yong Zhang & Jun-Qian Bian & Fu-Li Wang & Cheng Luan & Wei-Long Liu & Ji-Ren Liu & Xiao-Yang Dong & Zhong-Liang Li & Qiang-Shuai Gu & Zhe Dong & Xin-Yuan, 2023. "Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines," Nature, Nature, vol. 618(7964), pages 294-300, June.
    4. Caiyou Chen & Jonas C. Peters & Gregory C. Fu, 2021. "Photoinduced copper-catalysed asymmetric amidation via ligand cooperativity," Nature, Nature, vol. 596(7871), pages 250-256, August.
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