Mechanistic Study of Enantioselective Pd-Catalyzed C(sp3)–H Activation of Thioethers Involving Two Distinct Stereomodels

Enantioselective C­(sp3)–H activation has gained considerable attention from the synthetic chemistry community. Despite the intense interest in these reactions, the mechanisms responsible for enantioselection are still vague. In the course of the development of aryl thioether-directed-C­(sp3)–H arylation, we noticed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3-pentylsulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral β-center) were entirely insensitive. Quantitative structure-selectivity relationship (QSSR) analyses of directing group and ligand substitution and the development of a class of mono-N-acetyl protected amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up to 99:1) for thioether-directed-C­(sp3)–H arylation. Key to the realization of this method was the exploitation of transient chirality at sulfur, which relays stereochemical information from the ligand backbone to enantiotopic carbons of the substrate in a rate- and enantiodetermining cyclometallation deprotonation. The absolute stereochemistry of the products for these two substrates were revealed to be opposite. Density functional theory (DFT) evaluation of all possible diastereomeric transition states confirmed initial premises that guided rational ligand and directing group design. The implications of this study will assist in the further development of enantioselective C­(sp3)–H activation, namely by highlighting the noninnocence of directing groups, distal steric influences, and the delicate interplay between steric Pauli repulsion and London dispersion in enantioinduction.