How Does Palladium–Amino Acid Cooperative Catalysis Enable Regio- and Stereoselective C(sp3)–H Functionalization in Aldehydes and Ketones? A DFT Mechanistic Study

Abstract

Density functional theory computations have elucidated the detailed mechanism and intriguing selectivities of C(sp3)–H activation and arylation of aldehydes and ketones promoted by palladium–amino acid cooperative catalysis. The amino acid cocatalyst takes up the carbonyl substrate by a condensation reaction to form an imine–acid, which acts as a transient directing reagent and metathesizes with Pd(OAc)2 (the precatalyst) to initiate active Pd(II) complexes. The reaction then proceeds through C–H bond activation, oxidative addition of Pd(II) by iodobenzene, and reductive elimination from Pd(IV) completing C–C bond formation, followed by ligand exchange to regenerate the active Pd(II) catalyst and release the arylated imine–acid which continues on hydrolysis to give the final product and regenerate the amino acid cocatalyst. The C–H activation step via concerted metalation–deprotonation (CMD), which is rate- and selectivity-determining, favors palladacyclic transition states with a minimum chelate ring str...