Organometallic-Free Catalytic Cross-Electrophile Methylation of Aryl Halides

Abstract The “Magic Methyl Effect” stands for the welcoming effect of the methyl group in enhancing the potency of drug precursors. To date, no catalytic chemical route for methylation of aryl halides that excludes organometallic species is known. In this report, we introduce an organometallic-free cross electrophile methylation of aryl halides based on the generation of a methyl anion achieved under chemical conditions. It successfully methylated several strong bonds, such as CAr–Br, CAr–Cl, and CAr–F. This catalytic protocol was further diversified by preparing methyl derivatives of various clinically used antidepressants and antipsychotic drugs. Furthermore, we have demonstrated that the methylated product of one such drug molecule has significantly superior suppressive effects on neural activity as compared to the clinically active nonmethylated parent drug.