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 = N-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 N-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.