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.