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

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 () and Haiyan Fu ()
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Shun Li: Sichuan University
Yonglin Shi: Sichuan University
Juan Tang: Sichuan 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

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62547-7

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