Nickel-Catalyzed Cross-Coupling Methylation of Aryl and Heteroaryl Electrophiles via Hydrazone Umpolung

Methyl groups play a vital role in pharmaceutical substrates, where their installation onto aryl and heteroaryl moieties can often lead to enhanced drug-target interactions. This phenomenon has been termed the “magic methyl effect”, and it has become an important tool for the improvement of therapeutic potency during lead optimization stages in drug development. Herein, we report a new methodology for the methylation of various phenols as tosylates as well as aryl halides via a hydrazone-mediated Ni-catalyzed cross-coupling by introducing a new bench-stable methylating reagent in the form of formaldehyde hydrazone. The reaction produces moderate to good yields on a structurally diverse set of aryl and heteroaryl electrophiles. Experimental and computational investigations were carried out to support the proposed mechanism for this reaction.