Formaldehyde hydrazone as a methyl reagent for nickel-catalyzed cross-coupling methylation of aryl and heteroaryl electrophiles

Methyl groups play a vital role in pharmaceuticals, where their installation onto aryl and heteroaryl moieties of drug candidates can often enhance drug-target interactions. This phenomenon, termed the “magic methyl effect”, has become an important tool for improving therapeutic potency during the lead optimization stages of drug development. Herein, we report a methodology for the methylation of various phenols (as tosylates) and aryl halides via a hydrazone-mediated Ni-catalyzed cross-coupling reaction, employing formaldehyde hydrazone as the methyl reagent. The reaction delivers moderate to good yields across a structurally diverse set of aryl and heteroaryl electrophiles. Experimental and computational investigations support the proposed reaction mechanism. Methyl groups play a vital role in pharmaceuticals, where their installation onto aryl and heteroaryl moieties of drug candidates can often enhance drug-target interactions. Here, the authors report the methylation of phenols (as tosylates) and aryl halides via a hydrazone-mediated Ni catalyzed cross-coupling reaction, employing formaldehyde hydrazone as the methyl reagent.