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C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling
Science ( IF 56.9 ) Pub Date : 2021-04-23 , DOI: 10.1126/science.abh2623
Aristidis Vasilopoulos 1 , Shane W Krska 2 , Shannon S Stahl 1
Affiliation  

The “magic methyl” effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)–H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light–initiated triplet energy transfer promotes homolysis of the O–O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C–H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.



中文翻译:

过氧化物光敏和 Ni 介导的自由基偶联使 C(sp3)-H 甲基化成为可能

“神奇的甲基”效应描述了与添加单个甲基相关的候选药物的效力、选择性和/或代谢稳定性的变化。我们报告了一种合成方法,该方法能够直接甲基化多种类药物分子和药物结构单元中的 C(sp 3 )-H 键。可见光引发的三重态能量转移促进二重态中 O-O 键的均-丁基或过氧化二异丙苯在温和条件下。生成的烷氧基自由基经历不同的反应性,要么从底物 C-H 键转移氢原子,要么通过 β-甲基断裂产生甲基自由基。这些步骤的相对速率可以通过改变反应条件或过氧化物取代基来调整,以优化由镍介导的底物和甲基自由基的交叉偶联产生的甲基化产物的产率。

更新日期:2021-04-22
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