Mechanistic insights into the stereocontrolling non-covalent π interactions in Pd-catalyzed redox-relay Heck arylation reaction†

Abstract

The mechanism and origin of enantioselectivity of palladium-catalyzed redox-relay Heck arylation of 1,1-disubstituted homoallylic alcohols were investigated computationally. The computed mechanism consists of an initial migratory insertion, followed by a β-hydride elimination, and a subsequent re-insertion/elimination process to yield an enol intermediate, which tautomerizes to the more stable carbonyl product. Results from DFT calculations suggest that the key enantiodetermining step is the reinsertion of an alkene intermediate into the Pd–H bond, but not the initial migratory insertion of the substrate into the Pd-Aryl species. By comparing two chiral pyridine oxazoline ligands with a focus on the phenyl versus tert-butyl substituent effects, a plethora of attractive non-covalent π interactions, including CH–π interaction, lone pair–π interaction and T-shaped π–π interaction, are identified to play a key role in enabling high enantioselectivity of this reaction. This work provides mechanistic insights into the comprehensive understanding of this catalytic cascade, and highlights the significant role played by non-covalent π interactions in its enantiocontrol.