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Formaldehyde hydrazone as a methyl reagent for nickel-catalyzed cross-coupling methylation of aryl and heteroaryl
Daliah Farajat1, Léa Philippe1, Faraz Alaghemand1
1Department of Chemistry, and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada.
Abstract:
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.
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