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

作者：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 · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-62547-7 · 被引用次数：15 · 研究领域：Catalytic C–H Functionalization Methods、Synthesis and Catalytic Reactions、Radical Photochemical Reactions

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. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. Here, the authors report a 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 processes.