Mechanistic Model for Enantioselective Intramolecular Alkene Cyanoamidation via Palladium-Catalyzed C-CN Bond Activation

Article abstract of DOI:10.1021/acs.joc.7b00196

We studied key aspects of the mechanism of Pd-catalyzed C-CN bond activation and intramolecular enantioselective alkene cyanoamidation. An Abboud-Abraham-Kamlet-Taft (AAKT) linear solvation energy relationship (LSER) model for enantioselectivity was established. We investigated the impact of Lewis acid (BPh₃), Lewis base (DMPU), and no additives. BPh₃ additive led to diminished enantioselectivity and differing results in ¹³CN crossover experiments, initial rate kinetics, and natural abundance ¹²C/¹³C kinetic isotope effect measurements. We propose two catalytic mechanisms to account for our experimental results. We propose that the DMPU/nonadditive pathway passes through a κ²-phosphoramidite-stabilized Pd⁺ intermediate, resulting in high enantioselectivity. BPh₃ prevents the dissociation of CN^-, leading to a less rigid κ²-phosphoramidite-neutral Pd intermediate.