C(sp3)-H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling.
Science
; 372(6540): 398-403, 2021 04 23.
Article
in En
| MEDLINE
| ID: mdl-33888639
ABSTRACT
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 ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peroxides
/
Benzyl Compounds
/
Carbon
/
Free Radicals
/
Hydrogen
/
Nickel
Language:
En
Journal:
Science
Year:
2021
Type:
Article
Affiliation country:
United States