Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Aryl­boronic Esters

A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methyl­arene involve strong nucleo­philes or strong and often toxic electro­philes. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and hetero­aryl­boronic esters with the mild, nontoxic reagent trimethyl­phosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C–H borylation and this methylation with trimethyl­phosphate provides a new approach to the functionalization of inert C–H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO­(OMe)₃ with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electro­phile enables selective reaction with an aryl­copper intermediate, rather than nucleo­philic groups on the aryl­boronate, and binding of tert-butoxide to the boronate inhibits reaction of the electro­phile with the tert-butoxide activator to form methyl ether.