Mechanistic Insights into Copper-Catalyzed Asymmetric Cyanation of Allylic C–H Bonds

Direct C-H bond functionalization has emerged as one of the most powerful and practical strategies for the modification of drug molecules. We have recently disclosed a Cu/NFAS (NFAS = <i>N</i>-fluoroalkyl sufonamide) catalytic system that exhibits high site-, regio-, and enantioselectivity for the direct cyanation of allylic C-H bonds. Here, we present a mechanistic investigation of this catalyst system, including the elucidation of side reactions involved in the transformation. This work focuses on an in-depth analysis of the catalytic cycle based on kinetic studies by NMR spectroscopy and characterization of the catalyst speciation by EPR and UV-vis spectroscopy. These studies indicate that a fraction of NFAS is sacrificed to the side reactions of the Cu(II)-bounded <i>N</i>-centered radical (Cu(II)-NCR) species for the generation of silylated sulfonamides and (CN)₂. The data also show a great dependence of the reaction yield and selectivity (hydrogen atom abstraction or HAA over side reactions) on the structure of the Cu(II)-NCR species. Kinetic studies and DFT calculations further reveal that oxidation of the CuCN species by NFAS, HAA process, and cyanation of Cu(II)-NCRs with TMSCN have comparable energy barriers, which collectively determine the rate of the overall C-H cyanation reaction.