Unveiling the Mechanistic Role of Chiral Palladacycles in Pd(II)-Catalyzed Enantioselective C(sp3)-H Functionalization

Palladium-catalyzed enantioselective C(sp3)-H functionalization reactions has attracted considerable attention due to its ability for the synthesis of enantiomerically enriched molecules and stimulation of novel retrosynthetic disconnections. Understanding the reaction mechanism, especially the stereochemical process of the reaction, is crucial for the rational design of more efficient catalytic systems. Previously, we developed a Pd(II)/sulfoxide-2-hydroxypridine (SOHP) catalytic system for asymmetric C(sp3)-H functionalization reactions. In this study, our focus is on unraveling the chemistry of chiral palladacycles involved in the Pd(II)-catalyzed enantioselective C(sp3)-H functionalization. We have isolated key palladacycle intermediates involved in the enantioselective β-C(sp3)-H arylation of carboxylic acids catalyzed by the Pd(II)/SOHP system. These palladacycles, exhibiting ligand-induced chirality, provided a significant opportunity to investigate the stereochemical process and the ligand effect in this asymmetric C-H functionalization. Our investigation revealed that the C(sp3)-H palladation step is irreversible, representing the enantioselectivity-determining step to form diastereomeric palladacycles. Ligand exchange experiments and DFT calculations provided insights into the chiral induction in palladacycle formation and the preservation of chirality in the functionalization step. This work highlights the value of chiral palladacycle chemistry in offering mechanistic insights into the Pd(II)-catalyzed asymmetric C(sp3)-H functionalization reactions.