Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
Drug Substance Development, Celgene Corporation, Summit, New Jersey 07901, United States.
J Am Chem Soc. 2020 Apr 22;142(16):7683-7689. doi: 10.1021/jacs.0c02805. Epub 2020 Apr 10.
Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.
有机卤化物的甲基化是一种很有价值的转化反应，但通常需要苛刻的反应条件或试剂。我们报告了一种使用镍/光氧化还原催化的（杂）芳基氯化物甲基化的自由基方法，其中三甲基原甲酸酯，一种常见的实验室溶剂，用作甲基源。该方法允许（杂）芳基氯化物和酰氯在早期和晚期进行甲基化，具有广泛的官能团兼容性。机理研究表明，三甲基原甲酸酯通过氯介导的氢原子转移生成的叔自由基的β断裂，作为甲基自由基的来源。
