Computational study on Pd-catalyzed ipso,meta-dimethylation of ortho-substituted iodoarenes: mechanisms and the role of the base

Abstract

Density functional theory (DFT) calculations were performed to study Pd-catalyzed ipso,meta-dimethylation reactions of ortho-substituted iodoarenes. In the presence of K₂CO₃, aryl-I oxidative addition on Pd(0) catalysts can generate an arylpalladium(II) intermediate, which undergoes two sequential processes of C–H activation, CH₃–I oxidative addition (Ar–C reductive elimination/CH₃–I oxidative addition/Ar–C oxidative addition), and Ar–C reductive elimination to generate a dimethylated intermediate. Then hydrogen transfer, C-hydride reductive elimination, and ligand exchange can take place to generate 2,6-dimethylanisole 3b. With KOAc as the base, 2,3-dihydrobenzofuran 4b can be obtained via aryl-I oxidative addition, two sequential processes of C–H activation/Ar–C reductive elimination/CH₃–I oxidative addition/Ar–C oxidative addition/Ar–C reductive elimination, the third C–H activation, reductive elimination, and ligand exchange, respectively. The competition between the third C–H activation and the hydrogen transfer from the dimethylated intermediate determines the selectivity of the reaction. The hydrogen transfer is generally superior to the third C–H activation due to the stronger reactivity of the methyl group in methanol than a normal methyl group. When K₂CO₃ is used, such an electronic effect is dominant. However, when KOAc is employed, its different structure and properties compared to K₂CO₃ make the ligand exchange step highly endergonic, thereby rendering subsequent hydrogen transfer unfavorable and leading to 2,3-dihydrobenzofuran 4b as the final product.