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Synfacts 2025; 21(01): 50
DOI: 10.1055/a-2467-4975
Metals in Synthesis

Nickel-Catalyzed Tertiary C(sp3)–H Bond Methylation Enabled by Photochemically Activated Alkyl Peroxides

Contributor(s):
Martin Oestreich 
,
Hendrik F. T. Klare 
,
Daniel Brösamlen 
Tan J-F, Kang YC, Hartwig JF *. University of California, Berkeley, USA
Catalytic Undirected Methylation of Unactivated C(sp3)−H Bonds Suitable for Complex Molecules.

Nat. Commun. 2024;
15: 8307
DOI: 10.1038/s41467-024-52245-1
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Keywords

C(sp3)−H bond methylation - iridium photocatalysis - magic methyl effect - nickel catalysis - peroxides

Significance

The installation of a methyl group on a drug candidate can significantly boost its potency, which is widely known as the ‘magic methyl effect’. Hartwig and co-workers have now disclosed a nickel-catalyzed, site-selective, undirected methylation of unactivated tertiary C(sp3)−H bonds using photochemically activated alkyl peroxides as methylating agents.


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Comment

Mechanistic studies support the shown mechanism. The addition of acetylacetone was found to be crucial for this transformation, as it regenerates the catalytically active nickel(II) catalyst and thus improves the turnover of the reaction. This method features broad functional group tolerance and is suitable for the late-stage methylation of complex molecules.


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Publication History

Article published online:
20 December 2024

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