Acetone Derivatives for Nickel-Catalyzed Methylation, Trideuteromethylation, and 13C-Methylation of (Hetero)aryl Chlorides

Jingsheng Li; Yi Xiao; Zhenyu Li; Yonggang Yan; Geyang Song; Gang Li; Jianyang Dong; Chao Wang; Tengfei Kang; Dong Xue

doi:10.1002/anie.202511648

Acetone Derivatives for Nickel-Catalyzed Methylation, Trideuteromethylation, and 13C-Methylation of (Hetero)aryl Chlorides

Angew Chem Int Ed Engl. 2025 Jun 30:e202511648. doi: 10.1002/anie.202511648. Online ahead of print.

Authors

Jingsheng Li¹, Yi Xiao¹, Zhenyu Li², Yonggang Yan³, Geyang Song³, Gang Li³, Jianyang Dong³, Chao Wang³, Tengfei Kang³, Dong Xue⁴

Affiliations

¹ Shaanxi Normal University, Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, CHINA.
² Shaanxi Normal University, Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, 710119, CHINA.
³ Shaanxi Normal University, Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, 710119, Xi'an, CHINA.
⁴ Shaanxi Normal University, School of Chemistry and Chemical Engineering, west changan street, 710062, Xi'an, CHINA.

PMID: 40588435
DOI: 10.1002/anie.202511648

Abstract

The development of low-cost, readily available, and broadly applicable reagents for the methylation, trideuteromethylation, and 13C-methylation of aryl chlorides is crucial. Using acetone and its isotopic derivatives as feedstocks, we have prepared the methylating, trideuteromethylating, and 13C-methylating agents TDTP (2-(1,5,5-trimethyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridine), TDTP-CD3, and TDTP-¹3CH3. Under nickel catalysis and without any additional redox reagent, these reagents efficiently methylate a wide range of (hetero)aryl chlorides, chlorine-containing complex molecules and phenolic derivatives, showing efficient functional-group tolerance and scalability; they therefore hold great promise for drug discovery and complex molecule synthesis. Mechanistic studies indicate that the reaction begins with nickel-catalyzed generation of a methyl radical, followed by radical cross-coupling.

Keywords: Homogeneous catalysis * Isotopes * Methylation * Nickel * Synthetic methods.