Acetone Derivatives for Nickel‐Catalyzed Methylation, Trideuteromethylation, and ¹³ C‐Methylation of (Hetero)Aryl Chlorides

The development of low-cost, readily available, and broadly applicable reagents for the methylation, trideuteromethylation, and ¹³C-methylation of aryl chlorides is crucial. Using acetone and its isotopic derivatives as feedstocks, we have prepared the methylating, trideuteromethylating, and ¹³C-methylating agents TDTP (2-(1,5,5-trimethyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridine), TDTP-CD₃, and TDTP-¹³CH₃. Under nickel catalysis and without any additional redox reagent, these reagents efficiently methylate a wide range of (hetero)aryl chlorides, chlorine-containing complex molecules and phenolic derivatives, showing efficient functional-group tolerance and scalability; they, therefore, hold great promise for drug discovery and complex molecule synthesis. Mechanistic studies indicate that the reaction begins with nickel-catalyzed generation of a methyl radical, followed by radical cross-coupling.