Bioinspired transfer methylation enabled by a photoactive reagent
Radical methylation ranks among the most important yet challenging transformations in chemistry and biology, which often involves small and unstable radical intermediates, such as the methyl radical, and results in low reactivity and poor selectivity. Herein, we report a photoactive, biomimetic reagent to address some facets of these challenges by leveraging a bulky and stabilised α-aminomethyl radical, which can offer enhanced control over radical generation and transfer. Our bioinspired transfer methylation protocol enables direct and selective C(sp<sup>2</sup>)-H methylation across a wide spectrum of heteroarenes, from simple scaffolds to complex drug molecules, including the thus far elusive C4-methylation of free quinolines. Mechanistic studies reveal that the unique α-aminomethyl radical intermediate undergoes an addition-elimination sequence reminiscent of natural methyltransferases and yields balanced reactivity and selectivity.
Authors
- Zheng Hu (ORCID: https://orcid.org/0000-0002-4847-899X)
- Weiqiu Liang
- Chao‐Jun Li (ORCID: https://orcid.org/0000-0002-3859-8824)
- Zhihan Zhang (ORCID: https://orcid.org/0000-0002-1758-3914)
- Z. Y. Yuan (ORCID: https://orcid.org/0009-0007-7160-9955)
- Liqiang Tan (ORCID: https://orcid.org/0000-0002-8330-1401)
- Jianbin Li (ORCID: https://orcid.org/0000-0003-4956-7625)
- Ding Zhang (ORCID: https://orcid.org/0000-0002-1876-5090)
- Zhibo Liu (ORCID: https://orcid.org/0000-0002-5587-4165)
Institutions
- Peking University (CN)
- Central China Normal University (CN)
- Centre in Green Chemistry and Catalysis (CA)
- Beijing National Laboratory for Molecular Sciences (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-18
- DOI
- https://doi.org/10.1038/s41467-025-61857-0
- Citations
- 1
- Primary Topic
- Radical Photochemical Reactions
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- McGill University
- Canada Research Chairs
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Dalian University of Technology
- Fonds Québécois de la Recherche sur la Nature et les Technologies
- Chinese University of Hong Kong
- University of Illinois at Urbana-Champaign
- University of North Carolina at Chapel Hill
- Natural Sciences and Engineering Research Council of Canada