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Contra-electronegativity transmetallation unlocks alkene carbomagnesiation to access quaternary stereocentres

Nature Chemistry (2026)Cite this article

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Abstract

Grignard reagents—cornerstones of synthetic chemistry—are hindered by enduring limitations in accessing complex architectures, which poses a persistent synthetic bottleneck. Meanwhile, quaternary carbon (stereo)centres, ubiquitous in bioactive molecules and natural products, remain formidable synthetic targets despite decades of research. Here we introduce a nickel-catalysed carbomagnesiation strategy that simultaneously overcomes these challenges through a rare contra-electronegativity transmetallation (Ni to Mg). This approach enables the efficient and modular synthesis of β-quaternary Grignard reagents via carbomagnesiation of 1,1-disubstituted alkenes and 1,3-dienes, employing aryl triflate and PhMgBr as carbon and magnesium sources, respectively. The resulting organomagnesium reagents undergo one-pot reactions with diverse electrophiles, delivering stereochemically complex quaternary centres with high precision. Mechanistically, bulky N-heterocyclic carbene (NHC)-based catalysts divert classical cross-coupling pathways, enforcing a counterintuitive Ni-to-Mg transmetallation that defies conventional electronegativity trends while achieving exceptional regio- and enantiocontrol. This contra-electronegativity transmetallation demonstrates substantial potential to advance carbometallation reactions and open new avenues for cross-coupling chemistry.

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Fig. 1: Unexpected contra-electronegativity transmetallation unlocks alkene carbomagnesiation to access quaternary stereocentres.
Fig. 2: Gram-scale reactions and synthetic applications.
Fig. 3: Control experiments and proposed catalytic cycles.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition no. 2417329 (12d). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this Paper.

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Acknowledgements

This work is supported by the National Key R&D Program of China (2022YFA1503702), the National Natural Science Foundation of China (22325110, 92256303, 22171280), the Strategic Priority Research Program of the CAS (XDB0610000, XDA0540000), and the CAS Youth Interdisciplinary Team (JCTD-2021-11). We thank Y. Wang for helpful discussion of the manuscript.

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Author notes

  1. Bo Sun

    Present address: Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China

  2. These authors contributed equally: Xiaodong Ye, Bo Sun.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Xiaodong Ye, Bo Sun & Shi-Liang Shi

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  1. Xiaodong Ye
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  2. Bo Sun
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  3. Shi-Liang Shi
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Contributions

S.-L.S. conceived and directed the projects. X.Y. and B.S. performed the experiments. All authors analysed the data. S.-L.S. and B.S. wrote the manuscript.

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Correspondence to Shi-Liang Shi.

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Nature Chemistry thanks David Nelson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Tables 1–5 and Fig. 1

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Reaction profile—Fig. 3d

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Ye, X., Sun, B. & Shi, SL. Contra-electronegativity transmetallation unlocks alkene carbomagnesiation to access quaternary stereocentres. Nat. Chem. (2026). https://doi.org/10.1038/s41557-026-02073-1

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