Asymmetric Radical Allylic Cyanation of Electron-Deficient Alkenes with a Low Copper Catalyst Loading: Development...

The first copper-catalyzed enantioselective allylic C-H cyanation of electron-deficient alkenes was established herein. With a sequential catalytic hydrogenation in a one-pot fashion, the current method provides easy access to structurally diverse γ-cyanated carbonyls in good yields with excellent enantioselectivity, which are difficult to synthesize by the previously reported methods. Additional mechanistic investigations of the controlling experiments, kinetic study, isotopic effect, and DFT calculations revealed a new reaction pathway. We found that the previously reported Cu(II)-bound N-centered radical (NCR) undergoes dissociation in polar solvents to generate a free NCR species. This free sulfonamidyl radical, derived from the NF reagent, has a greater hydrogen-atom abstraction (HAA) ability, which is crucial for the successful allylic C-H abstraction of electron-deficient alkenes. Although the off-cycle existed to quench free NCR species by the extra Cu(I) catalyst, this side reaction can be effectively suppressed by reducing the catalyst concentration. Therefore, highly selective and efficient allylic C-H cyanation of electron-deficient alkenes could be achieved by using a low catalyst loading (0.25 mol %). These findings highlight the method to adjust the interaction between the copper(II) intermediate and free NCRs, which opens a window to carry out asymmetric C-H bond functionalization reactions across a range of substrate types.