RESUMEN
The palladium-catalyzed ß-arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the α/ß-arylation reactions of ortho- and meta-fluorobromobenzene was described. Selective ß-arylation was observed for the reaction of o-fluorobromobenzene with a range of biarylphosphine ligands, whereas α-arylation was predominantly observed with m-fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of α-/ß-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 α/ß-arylation selectivity, with electron-withdrawing substituents favoring ß-arylation. Kinetic and deuterium-labeling experiments suggested that the rate-limiting step of ß-arylation with DavePhos as the ligand was the palladium-enolate-to-homoenolate isomerization, which occurs by a ß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 α- and ß-arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to ß-arylation was kinetically favored over the pathway leading to α-arylation, with the palladium-enolate-to-homoenolate isomerization being the rate-limiting step of the ß-arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate-limiting step changed with PCy(3) and PtBu(3) ligands, and with the latter, α-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 α-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 ß-arylation pathway.
RESUMEN
Transition-metal-catalyzed C-H activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non-acidic C-H bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.