Skeletal editing of pyrrolidines by nitrogen-atom insertion

Abstract

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 <i>O</i>-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.