A research team led by Professor Lu Hongjian from the School of Chemistry and Chemical Engineering at Nanjing University recently achieves precise insertion of nitrogen atom into the pyrrolidine skeleton. Their findings were published on Science.

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 O-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.

Fig. N-Atom Insertion Strategies in N-Heterocycles. (A) US FDA-Approved new small molecule drugs (2013?2023). (B) N-atom insertion into aromatic N-heterocylces. (C) N-atom insertion into saturated pyrrolidines. (D) Natural products or drug molecules containing tetrahydropyridazine and its redox congeners.

Source: Skeletal editing of pyrrolidines by nitrogen-atom insertion | Science