On the Mechanism of the Palladium-Catalyzed β-Arylation of Ester Enolates

The palladium-catalyzed beta-arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the alpha/beta-arylation reactions of ortho- and meta-fluorobromobenzene was described. Selective beta-arylation was observed for the reaction of o-fluorobromobenzene with a range of biarylphosphine ligands, whereas alpha-arylation was predominantly observed with m-fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of alpha-/beta-arylated products. Next, the effect of the substitution pattern of the aryl bromide reactant was studied with DavePhos as the ligand. We showed that electronic factors played a major role in the alpha/beta-arylation selectivity, with electron-withdrawing substituents favoring beta-arylation. Kinetic and deuterium-labeling experiments suggested that the rate-limiting step of beta-arylation with DavePhos as the ligand was the palladium-enolate-to-homoenolate isomerization, which occurs by a beta H-elimination, olefin-rotation, and olefin-insertion sequence. A dimeric oxidative-addition complex, which was shown to be catalytically competent, was isolated and structurally characterized. A common mechanism for alpha- and beta-arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to beta-arylation was kinetically favored over the pathway leading to a-arylation, with the palladiumenolate-to-homoenolate isomerization being the rate-limiting step of the beta-arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate-limiting step changed with PCy3 and PtBu3 ligands, and with the latter, a-arylation became kinetically favored. The trend in selectivity observed experimentally with differently substituted aryl bromides agreed well with that observed from the calculations. The presence of electron-withdrawing groups on these bromides mainly affected the a-arylation pathway by disfavoring C-C reductive elimination. The higher activity of the ligands of the biaryldialkylphosphine ligands compared to their corresponding trialkylphosphines could be attributed to stabilizing interactions between the biaryl backbone of the ligands and the metal center, thereby preventing deactivation of the beta-arylation pathway.