康 · 学术 | Reaction of the Day No. 1736

来源：市场资讯

（来源：康龙化成）

Isotope-Labeled Methanol-Derived O-Alkylisoureas as Versatile and Practical Agents for d3-Methylation, 13C-Methylation, and 13CD3-Methylation

Weikang Xiong1, Zhenyu Li1, Fei Li2, Yanan Liu2, Jiameng Zhang1, Tengfei Kang1, Dong Xue1

1 Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, Institute of New Concept Sensors and Molecular Materials, and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, Shaanxi, China

2 Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China

—Angew.Chem.Int.Ed.,2026,e7843825,doi.org/10.1002/anie.7843825

Recommended by Xiaoxu Wang_MC3

KEY WORDS: 13CD3-methylation, 13C-methylation,d3-methylation (反应类型), O-alkylisourea, MDIC-d3, MDIC-13CD3 MDIC-13C (原料), Isotope-Labeled methylation targets (产物)

ABSTRACT: Herein, methyl-d3-N,N’-diisopropylcarbamimidate (MDIC-d3), methyl-13C-N,N’-diisopropylcarbamimidate (MDIC-13C) and methyl-13C-d3-N,N’-diisopropylcarbamimidate (MDIC-13CD3), synthesized via reaction of diisopropylcarbodiimide with the corresponding stable isotope labelled methanols, have been developed for the efficient d3-methylation, 13C-methylation and 13CD3-methylation of complex molecules bearing several possible reactive sites with good selectivity, high-level deuterium and 13C incorporation, and good functional group tolerance under external base-free conditions. Additionally, these reagents can also be employed for the highly efficient isotope-labeled methylation of arenes via palladium-catalyzed Suzuki–Miyaura type cross-coupling.

Trideuteromethylation of organic acids (selected examples)

Trideuteromethylation of phenols, thiols, sulfonamides, and amides (selected examples)

13C-Methylation and 13CD3-methylation. (selected examples)

Suzuki-Miyaura-type trideuteromethylation. (selected examples)

Summary and Comments

In summary, Prof. Dong Xue and Weikang Xiong et al. developed isotopically labeled methanol-derived O-alkylisoureas (MDIC-d3, MDIC-13C and MDIC-13CD3) as cheap, practical and efficient methylating agents. These reagents can successfully enable nucleophilic substitution under mild, external base-free conditions, as well as palladium-catalyzed Suzuki–Miyaura type cross-coupling, facilitating efficient incorporation of CD3, 13CH3, and 13CD3 into complex molecules. The method supports the formation of C─O, C─N, C─S, and C─C bonds, providing avaluable approach for medicinal chemistry. Further more, these reagents are readily scalable and exhibit excellent chemoselectivity and functional group compatibility with substrates bearing multiplereactivesites, demonstrating great potential for future industrial applications.