Li Jinghao, Tang Pengcheng, Fan Yang, Lu Hongjian
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, China.
School of Chemistry and Chemical Engineering, Guizhou University, Guiyang, Guizhou, China.
Science. 2025 Jul 17;389(6757):275-281. doi: 10.1126/science.adl4755.
Given the prevalence of nitrogen-containing heterocycles in bioactive molecules, inserting a nitrogen atom into a saturated ring offers a powerful yet underdeveloped scaffold-hopping strategy for expanding drug-like chemical space. In this study, we present a skeletal editing method that directly inserts a nitrogen atom into pyrrolidine rings, converting them into tetrahydropyridazine scaffolds under mild, operationally simple conditions with readily available -diphenylphosphinyl hydroxylamine. This method features broad substrate scope and functional group compatibility, enabling late-stage editing of complex molecules. Furthermore, simple redox manipulation of the tetrahydropyridazines grants access to saturated piperidazines and aromatic pyridazines-nitrogen-rich scaffolds that are highly valued in medicinal chemistry but typically difficult to synthesize. Overall, this work establishes a versatile platform for nitrogen-based skeletal editing of saturated pyrrolidines, expanding the synthetic toolkit for medicinal chemistry.
