Ligand-controlled regiodivergent and enantioselective C–H cyanation of secondary amines

Aliphatic amines, such as N,N-dialkyl secondary amines, represent important scaffolds in bioactive molecules, driving significant interest in their regio- and stereoselective C-H functionalisation. While hydrogen atom transfer (HAT) provides a powerful radical-based approach to elaborate such amines, achieving controllable, regio-divergent, and enantioselective functionalisation across different N-alkyl groups remains challenging. Herein, we report a Cu-catalyzed α'/β-regiodivergent and β-enantioselective cyanation of secondary amine-derived ureas through tunable 1,4'/1,5-HAT. The utilization of a sterically demanding ligand L14 enables the excellent α'-selective C-H cyanation at the N-methyl position, while two developed ligands (L24 and L41) promote the β-chirality construction at the other N-alkyl group. The approach is demonstrated for a broad scope of ureas with wide functional group compatibility. Experimental and computational studies reveal two distinct reaction pathways regarding the different reactive sites (α'/β) and the choice of ligands could significantly influence the selectivity in HAT process.