C(sp<sup>3</sup>)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

doi:10.1126/science.abh2623

GSTDTAP > 气候变化

DOI	10.1126/science.abh2623
	C(sp³)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling
	Aristidis Vasilopoulos; Shane W. Krska; Shannon S. Stahl
	2021-04-23
发表期刊	Science
出版年	2021
英文摘要	In pharmaceutical research, swapping out hydrogens for methyl groups is a frequent strategy to optimize small-molecule properties. Vasilopoulos et al. report a versatile, convenient, and comparatively safe method for methylation of carbon centers adjacent to nitrogen or aryl rings. Under carefully optimized conditions, di-tert-butyl peroxide plays a dual role as oxidant and methyl source. Cleaving the O–O bond through photosensitization produces butoxyl radicals, some of which cleave substrate C–H bonds, whereas others release methyl radicals that a nickel catalyst delivers to those activated substrates. Science , this issue p. [398][1] 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. [1]: /lookup/doi/10.1126/science.abh2623
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/324081
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Aristidis Vasilopoulos,Shane W. Krska,Shannon S. Stahl. C(sp³)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling[J]. Science,2021.
APA	Aristidis Vasilopoulos,Shane W. Krska,&Shannon S. Stahl.(2021).C(sp³)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling.Science.
MLA	Aristidis Vasilopoulos,et al."C(sp³)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling".Science (2021).