Ligand-Controlled Regiodivergent and Enantioselective C-H Cyanation of Secondary Amines

Aliphatic amines, such as N,N-dialkyl secondary amines, are important chemical entities in biologically active compounds. The regio- and stereoselective C-H functionalisation of acyclic secondary amines are therefore of great interest and importance. Among the possible approaches, the radical-mediated C-H functionalisation of amines via hydrogen atom transfer (HAT) has emerged as powerful strategy to access elaborated amines. However, despite recent advances, the controllable regio-divergent and enantioselective C-H bond transformation of secondary amines at different N-alkyl groups has remained underdeveloped due to the challenging controllable HAT. Herein, we report a Cu-catalysed α'/β-regiodivergent and β-enantioselective cyanation of secondary amine-derived ureas through ligand-controlled adjustable 1,4’/1,5-hydrogen atom transfer. The utilization of a sterically demanding ligand enables the excellent α’-selective C–H cyanation at the N-methyl position, while two novel developed ligands with relatively less steric congestion promote the concise β-chirality construction at the other N-alkyl group. The approach is demonstrated for a broad scope of ureas with wide functional group compatibility including aryl, alkenyl, and alkynyl groups. Mechanistic studies indicate that the copper catalyst coordinating with different sterically hindered ligands could significantly influence the HAT and the radical trapping process