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Modular arene functionalization by differential 1,2-diborylation

Nature volume 644, pages 102–108 (2025) Cite this article

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Abstract

Aromatic rings, also known as arenes, containing two or more adjacent different substituents are ubiquitously found in small-molecule drugs1. Strategies that can rapidly introduce diverse vicinal substituents to readily available precursors would greatly benefit the generation of analogues of biologically active compounds2, which, however, remain challenging to realize so far. The existing approaches for preparing vicinal difunctionalized arenes lack modularity, regioselectivity or generality. Here we report a nickel-catalysed arene vicinal diborylation method that can directly install two chemically differentiated boryl groups in a regioselective and site-selective manner using readily available aryl triflates or chlorides as substrates. This reaction operates under simple and mild conditions and is scalable. It also shows a broad substrate scope and excellent functional group tolerance. Given that each boryl group can be independently transformed into various functional groups, this method offers a modular, regioselective and divergent approach to access diverse vicinal difunctionalized arenes, showing promise for constructing analogue libraries. The combined experimental and computational mechanistic studies reveal a highly unusual reaction pathway, involving the formation of a dearomatized gem-diboryl species and 1,2-boron migration. The site-selectivity and regioselectivity of this reaction are proposed to be controlled by steric interactions of the boryl groups with the nickel catalyst. The mechanistic insights gained in this investigation could have broad implications on developing other boron-mediated functionalization reactions.

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Fig. 1: Construction of vicinal difunctionalized arenes.
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Fig. 2: Reaction discovery and condition optimization.
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Fig. 3: Substrate scope of vicinal diborylation of aryl triflates.
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Fig. 4: Substrate scope of vicinal diborylation of aryl chlorides.
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Fig. 5: Synthetic applications.
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Data availability

All of the data generated or analysed during this study are included in this article and its Supplementary Information. Crystallographic data for the structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 2415595 (3a). These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service; www.ccdc.cam.ac.uk/structures.

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Acknowledgements

University of Chicago and National Institute of General Medical Sciences (R01GM124414 to G.D., R35GM128779 to P.L.) are acknowledged for research support. We thank H. Han (Northwestern University) for X-ray crystallography. J. Kurutz (University of Chicago) and J. Schneider (University of Chicago) are acknowledged for nuclear magnetic resonance and electron paramagnetic resonance experiments. M. Levin (University of Chicago), Y. Ping (Harvard University) and R. Zhang (University of Chicago) are thanked for helpful discussions. Computational studies were performed at the Center for Research Computing at the University of Pittsburgh and the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) programme, supported by National Science Foundation award numbers OAC-2117681 and OAC-2138259.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Jingfeng Huo, Melody J. Tang, Ya Su, Shengkun Hu & Guangbin Dong

  2. Modeling and Informatics, Merck & Co., Inc., Rahway, NJ, USA

    Yue Fu

  3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Peng Liu

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Contributions

G.D. and J.H. conceived and designed the experiments. J.H., M.J.T., Y.S. and S.H. performed the experiments and analysed the data. Y.F. and P.L. conceived and designed the computational studies. Y.F. performed the computational studies. J.H., Y.F., P.L. and G.D. prepared the manuscript together.

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Correspondence to Yue Fu, Peng Liu or Guangbin Dong.

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Extended data figures and tables

Extended Data Fig. 1 Selected experimental mechanistic studies.

a, Control experiment under the dark condition. b, Stoichiometric reaction and catalytic reaction based on aryl-Ni(II) complex 22. c, KIE studies. d, Generation of gem-diborylated products 24 from vinyl triflate or chloride 23. dr, diastereomeric ratio.

Extended Data Fig. 2 Selected computational mechanistic studies.

a, Free-energy profile of the Ni-catalysed diborylation of o-tolyl triflate 1a. b, Proposed catalytic cycle based on the computational studies. c, Regioselectivity in boron 1,2-shift. All energies were calculated at the M06/SDD–6-311+G(d,p), SMD(cyclohexane)//B3LYP-D3/LANL2DZ–6-31G(d) level of theory. L, ligand.

Supplementary information

Supplementary Information (download PDF )

Supplementary Information, including the following sections: 1. General information; 2. Reaction optimization; 3. Substrate scope; 4. Synthetic applications; 5. Mechanistic studies; 6. Computational studies; 7. X-ray data; 8. NMR spectra; and 9. References.

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Huo, J., Fu, Y., Tang, M.J. et al. Modular arene functionalization by differential 1,2-diborylation. Nature 644, 102–108 (2025). https://doi.org/10.1038/s41586-025-09284-5

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