Understanding the Activity and Enantioselectivity of Acetyl-Protected Aminoethyl Quinoline Ligands in Palladium-Catalyzed β-C(sp3)-H Bond Arylation Reactions.

Abstract

Chiral acetyl-protected aminoalkyl quinoline (APAQ) ligands were recently discovered to afford highly active and enantioselective palladium catalysts for the arylation of methylene C(sp3)-H bonds, and herein, we investigate the origins of these heightened properties. Unprecedented amide-bridged APAQ-Pd dimers were predicted by density functional theory (DFT) calculations and were confirmed by single-crystal X-ray diffraction studies. Comparison of structural features between APAQ-Pd complexes and an acetyl-protected aminoethylpyridine APAPy-Pd complex strongly suggests that the high activity of the former originates from the presence of the quinoline ring, which slows the formation of the off-cycle palladium dimer. Furthermore, steric topographic maps for a representative subset of monomeric, monoligated palladium complexes allowed us to draw a unique parallel between the three-dimensional structures of these catalysts and their reported asymmetric induction in β-C(sp3)-H bond arylation reactions. Finally, cooperative noncovalent interactions present between the APAQ ligand and the substrate were identified as a crucial factor for imparting selectivity between chemically equivalent methylenic C(sp3)-H bonds prior to concerted metalation deprotonation activation.