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

Abstract

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.

Scheme 1.. Research Design

Scheme 2.. Scope of Arylboronic Esters That Undergo Methylation with PO(OMe)₃^a

^aConditions: 1 (1.0 equiv), PO(OMe)₃ (1.1 equiv), CuI (5−10 mol %), LiI (20 mol%), LiO^tBu (1.1 equiv), DMI (0.66M), 50 °C. Isolated yields are reported. For cases of MeOTs and MeI, yields were determined by crude ¹H NMR or ¹⁹F NMR. ^bDetermined by crude ¹H NMR.

Scheme 3.. Scope of Heteroarylboronic Esters That Undergo Methylation with PO(OMe)₃^a

^aConditions: 3 (1.0 equiv), PO(OMe)₃ (1.1 equiv), CuI (10 mol%), LiI (20 mol %), LiO^tBu (1.1 equiv), DMI (0.66M), 50 °C. Isolated yields are reported. ^bReaction performed at 2 mmol scale. ^cCuI (20 mol%) was used.

Scheme 4.. Late-Stage Site-Selective C−H Methylation of Biologically Active Molecules^a

^aSee SI for details.

Scheme 5.. Reaction with 200 mmol of Arylboronate

Scheme 6.. Stoichiometric Reactions Potentially Occurring in the Catalytic System

^aReactivity comparison of MeI and PO(OMe)₃ with ArCu. ^bMeI generation from PO(OMe)₃ and LiI. ^cReaction of 4-FPhBpin with LiO^tBu.

Scheme 7.. Kinetic Order of the Methylation Reaction

Scheme 8.. Proposed Reaction Mechanism