Mechanism and Selectivity Control in Ni- and Pd-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bond Activation

Abstract

Transition-metal-catalyzed C-O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C-O bond activation and functionalization methods.Toward the rational design of C-O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C(sp²)-O and C(sp³)-O bond activations. We found that the nickel catalyst cleaves the benzylic and allylic C(sp³)-O bonds via two general mechanisms: the stereoinvertive S_N2 back-side attack model and the stereoretentive chelation-assisted model. These two models control the stereochemistry in a wide array of stereospecific Ni-catalyzed cross-coupling reactions with benzylic or allylic alcohol derivatives. Because of the catalyst distortion, the ligands can differentiate the competing stereospecific C(sp³)-O bond activations. The PCy₃ ligand interacts with nickel mainly through σ-donation, and the Ni(PCy₃) catalyst can undergo facile bending of the substrate-nickel-ligand angle, which favors the stereoretentive benzylic C-O bond activation. The N-heterocyclic carbene SIMes ligand has additional d(metal)-p(ligand) back-donation with nickel, which leads to an extra energy penalty for the same angle bending. This results in the preference of stereoinvertive benzylic C-O bond activation under Ni/SIMes catalysis. In addition to ligand control, a Lewis acid can increase the selectivity for stereoinvertive C(sp³)-O activation by stabilizing the S_N2 back-side attack transition state. The oxygen leaving group complexes with the MgI₂ Lewis acid in the stereoinvertive activation, leading to the exclusive stereoinvertive Kumada coupling of benzylic ethers. We also identified that the competing C(sp³)-O bond activation models have noticeable differences in charge separation. This leads to the solvent polarity control of the stereospecificity in C(sp³)-O activations. Low-polarity solvents favor the neutral stereoretentive C-O bond activation, while high-polarity solvents favor the zwitterionic stereoinvertive cleavage.In sharp contrast to the nickel catalysts, the C(sp²)-O bond activation under palladium catalysis mainly proceeds via the classic three-membered ring oxidative addition mechanism instead of the chelation-assisted mechanism. This is due to the lower oxophilicity of palladium, which disfavors the oxygen coordination in the chelation-assisted-type activation. The three-membered ring activation model selectively cleaves the weak C-O bond, resulting in the exclusive chemoselectivity of acyl C-O bond activation in Pd-catalyzed cross-coupling reactions with aryl carboxylic acid derivatives. This explains the overall acylation in the Pd-catalyzed Suzuki-Miyaura coupling with aryl esters. In collaboration with the Szostak group, we revealed that the three-membered ring model applies in the Pd-catalyzed C-O bond activation of carboxylic acid anhydride, which stimulated the development of a series of Pd-catalyzed decarbonylative functionalizations of aryl carboxylic acids.