Late-Stage 4-Methylation of [6,5]-Fused Arenes

Late-stage methylation of [6,5]-fused bicyclic arenes is a transformation of considerable importance in medicinal chemistry, yet the selective C4-methylation of these privileged scaffolds without directing groups has remained elusive. Here we report a relay strategy for the late-stage 4-methylation of [6,5]-fused arenes that couples temporary C3 iodination with a Catellani-type peri-methylation/ipso-H-termination sequence proceeding through an unusual six-membered palladacycle. A rationally designed thio-cycloolefin ligand bearing an N-acetyl pendant accelerates the peri-C–H activation step while suppressing competing C,C reductive-elimination pathways, thereby enabling selective C4-methylation. Inexpensive trimethyl (or trideuteromethyl) phosphate serves as a bifunctional reagent that delivers both the methyl electrophile and the hydrogen nucleophile, providing convenient access to both CH3- and CD3-labelled products. The protocol accommodates indoles, 7-azaindoles, indolizines, benzothiophenes, and benzofurans, and was applied to the late-stage methylation of drug molecules and to 1 mmol-scale synthesis. Mechanistic studies corroborate the six-membered palladacycle intermediate and identify the hydride source of the ipso-H-termination.