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Skeletal editing of 4-arylpyrimidines into diverse nitrogen heteroaromatics via four-atom synthons

Author

Listed:
  • Shun Li

    (Sichuan University
    Leshan Normal University)

  • Yonglin Shi

    (Sichuan University)

  • Juan Tang

    (Sichuan University
    Leshan Normal University)

  • Meixin Yan

    (Sichuan University)

  • Shunyao Huang

    (Sichuan University)

  • Tingying Dou

    (Sichuan University)

  • Shenxiang Wang

    (Sichuan University)

  • Xinchao Jin

    (Sichuan University)

  • Zhishan Su

    (Sichuan University)

  • Weidong Jiang

    (Sichuan University of Science and Engineering)

  • Jiaqi Xu

    (Sichuan University)

  • Xueli Zheng

    (Sichuan University)

  • Ruixiang Li

    (Sichuan University)

  • Hua Chen

    (Sichuan University)

  • Weichao Xue

    (Sichuan University)

  • Haiyan Fu

    (Sichuan University)

Abstract

Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. We present here a distinct scaffold hopping strategy for the skeletal editing of pyrimidines into a wide range of heteroarenes through the addition of nucleophiles, ring-opening, fragmentation, and ring-closing (ANROFRC) processes. This method features the in situ generation of a vinamidinium salt intermediate, which serves as a unique N-C-C-C four-atom (A4) synthon that reacts with A1 and A2 synthons. Mechanistic studies reveal that C4-aryl substituents play a crucial role in stabilizing the vinamidinium salt intermediate. This work provides a powerful tool for the systematic construction and modification of nitrogen heterocycles, thereby expanding conventional molecular editing techniques.

Suggested Citation

  • Shun Li & Yonglin Shi & Juan Tang & Meixin Yan & Shunyao Huang & Tingying Dou & Shenxiang Wang & Xinchao Jin & Zhishan Su & Weidong Jiang & Jiaqi Xu & Xueli Zheng & Ruixiang Li & Hua Chen & Weichao Xu, 2025. "Skeletal editing of 4-arylpyrimidines into diverse nitrogen heteroaromatics via four-atom synthons," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62547-7
    DOI: 10.1038/s41467-025-62547-7
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    References listed on IDEAS

    as
    1. Shuai Liu & Xu Cheng, 2022. "Insertion of ammonia into alkenes to build aromatic N-heterocycles," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    2. Jisoo Woo & Colin Stein & Alec H. Christian & Mark D. Levin, 2023. "Carbon-to-nitrogen single-atom transmutation of azaarenes," Nature, Nature, vol. 623(7985), pages 77-82, November.
    3. Benjamin J. H. Uhlenbruck & Celena M. Josephitis & Louis Lescure & Robert S. Paton & Andrew McNally, 2024. "A deconstruction–reconstruction strategy for pyrimidine diversification," Nature, Nature, vol. 631(8019), pages 87-93, July.
    Full references (including those not matched with items on IDEAS)

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