Method Development and Mechanistic Insights into Palladium-Catalyzed C–CN Bond Activation and Iridium–Catalyzed Sequential C–O/C–H Bond Activation Reactions

Abstract

Two organometallic methods were developed and the mechanisms were investigated using experiments and computations. The first transformation was the cyanoamidation of alkenes by palladium-catalyzed C–CN bond activation. We used an Abboud-Abraham-Kamlet-Taft linear solvation energy relationship to model the relationship between the solvent and enantioselectivity. We also investigated the effect of the Lewis base DMPU, Lewis acid BPh3, and no additive on the rate and enantioselectivity of the reaction. 13CN crossover experiments were used to probe the possibility of a cationic palladium intermediate and natural abundance kinetic isotope experiments were used to determine the turnover-limiting step of the reaction. Computational methods were used to model the mechanism of the reaction and form a hypothesis for how 13CN crossover occurs. Our computational results suggest that crossover occurs during isomerization post-migratory insertion and that the enantiodetermining step occurs at a neutral palladium complex. The second transformation investigated was the sterics-selective acylation of arenes by iridium-catalyzed sequential C–O/C–H bond activation. Acylation of electron rich arenes using phenyl salicylates was found to proceed at the most sterically accessible site, contrary to Friedel-Crafts acylation. Mechanistic insights were obtained using initial rates kinetics, phosphine concentration experiments, computational modeling, and kinetic isotope effect experiments. The mechanistic results suggest that C–H activation is turnover-limiting and that the reaction is under thermodynamic equilibrium. A substrate scope of the arene found that electron rich arenes were acylated to a greater extent than electron poor arenes. Also, arenes with multiple sites of similar sterics were acylated at the more electron rich site. The reaction also tolerates many functional groups on the phenyl salicylate substrate. A mechanism was postulated wherein the C–H activation of the arene proceeds by concerted metallation deprotonation. This reaction represents the first direct sterics-controlled acylation of arenes by C–H activation at a single metal catalyst.