康 · 学术 | Reaction of the Day No. 1719

Electrochemical C(sp3)–C(sp3) Cross-coupling of Alcohols

Yanwei Wang1, Yushi Jiang1, Weikang Qi1 & Youai Qiu1,2,3*

1State Key Laboratory and Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, Haihe Laboratory of Sustainable Chemical Transformations, Academy for Advanced Interdisciplinary Studies, College of Chemistry, Nankai University, Tianjin, China. 2State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China. 3Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, China

—Nat. Syn., 2026, doi: org/10.1038/s44160-026-01128-y.

Recommended by Bingbing Chang_MC5

KEY WORDS: Electro chemistry,C(sp3)–C(sp3) cross-coupling, dehydroxylation, Ni catalysis, late-stage functionalization (反应类型), C(sp3)–C(sp3) (成键类型), alcohols (原料), alkane (产物), DMF (其他)

ABSTRACT: The preparation of C(sp3)–C(sp3) bonds is of great importance for the construction of molecular frameworks found in pharmaceuticals and natural products. Alkyl alcohols, which are commercially available and naturally abundant alkylation precursors, offer direct conversion into C(sp3)-rich molecules by C(sp3)–C(sp3) cross-coupling, however, such transformations remain challenging in synthesis due to the inertness of the C(sp3)–O bond. Here Prof. Youai Qiu et al. report a modular, versatile and selective electrochemical strategy that achieves C(sp3)–C(sp3) cross-coupling of alkyl alcohols by means of a doubly dehydroxylative cross-coupling process under nickel catalysis. The highly selective cross-coupling strategy eliminates the need for prefunctionalization of alcohols, providing a general platform for the modification of hydroxyl-containing bioactive molecules. This protocol demonstrates good functional group compatibility and is well-suited for late-stage functionalization, with the potential to streamline the synthesis of pharmaceuticals and drug analogues that would typically necessitate multi-step processes.

Cross-coupling for C(sp3)?C(sp3) bond formation using alkyl alcohols. a. Commercially available alkyl precursors used in cross-coupling reactions.

b, Representative in situ activation modes of alcohols. c, This work: electrochemical C(sp3)–C(sp3) cross-coupling of alcohols.

Optimization studies and substrate scope of (trideutero)methylation with MeOH/CD3OD (selected examples)

General substrate scope of other alcohols (selected examples)

Applications for the electrochemical dehydroxylative cross-coupling Strategy (selected examples)

Proposed mechanism

Summary and Comments

Prof. Youai Qiu et al. have successfully developed an electrochemical doubly dehydroxylative strategy that enables the highly selective construction of C(sp3)–C(sp3) bonds across a diverse range of alkyl alcohols. The liberated deoxy by-product (DMF) shows no deleterious effects on the subsequent coupling process. Furthermore, the protons released during the activation step are rapidly consumed at the cathode via hydrogen evolution, which substantially mitigates the detrimental influence of a strongly acidic environment on the Ni-catalysed cross-coupling process. The method demonstrates excellent substrate generality, successfully realizing dehydroxylative cross-couplings between primary–primary, primary–secondary, secondary–secondary and tertiary–primary alcohols. When using deuterated methanol as a coupling component, the approach enables the highly efficient synthesis of a wide array of trideuteromethylated molecules. The synthetic utility has been further demonstrated through the expedited synthesis of three bioactive molecules. This method represents a promising solution for forming C(sp3)–C(sp3) linkages in organic synthesis and drug discovery.