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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月2日

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  • 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 Xue,
  • Haiyan Fu

摘要

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.