Ruthenium-Catalyzed Monoselective C–H Methylation and d(3)-Methylation of Arenes

[Image: see text] Site-selective installation of C–Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C–H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d(3)-methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity.