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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月20日

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  • Daliah Farajat,
  • Léa Philippe,
  • Faraz Alaghemand,
  • Anastasiia Afanasenko,
  • Durbis J. Castillo-Pazos,
  • Juan D. Lasso,
  • Yiram Kim,
  • Evan F. W. Chen,
  • Joaquín Barroso-Flores,
  • Rustam Z. Khaliullin,
  • Chao-Jun Li

摘要

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.