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A radical approach for the selective C–H borylation of azines

Nature volume 595, pages 677–683 (2021)Cite this article

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Abstract

Boron functional groups are often introduced in place of aromatic carbon–hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments1,2,3. Current approaches based on transition-metal-catalysed activation of carbon–hydrogen bonds are effective for the borylation of many (hetero)aromatic derivatives4,5 but show narrow applicability to azines (nitrogen-containing aromatic heterocycles), which are key components of many pharmaceutical and agrochemical products6. Here we report an azine borylation strategy using stable and inexpensive amine-borane7 reagents. Photocatalysis converts these low-molecular-weight materials into highly reactive boryl radicals8 that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp2 carbon–boron bond assembly, where the elementary steps of transition-metal-mediated carbon–hydrogen bond activation and reductive elimination from azine-organometallic intermediates are replaced by a direct, Minisci9-style, radical addition. The strongly nucleophilic character of the amine-boryl radicals enables predictable and site-selective carbon–boron bond formation by targeting the azine’s most activated position, including the challenging sites adjacent to the basic nitrogen atom. This approach enables access to aromatic sites that elude current strategies based on carbon–hydrogen bond activation, and has led to borylated materials that would otherwise be difficult to prepare. We have applied this process to the introduction of amine-borane functionalities to complex and industrially relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.

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Fig. 1: Strategies for azine C–H borylation.
Fig. 2: Substrate scope for the radical C–H borylation of azines.
Fig. 3: Diversification of the azine amine-boranes by oxidation, Suzuki cross-coupling, Chan–Lam amination and Chan–Lam etherification.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

D.L. thanks the EPSRC for a fellowship (EP/P004997/1) and the European Research Council for a research grant (758427); J.H.K. thanks Marie Curie Actions for a fellowship (842422). The Chemical Capabilities team of Janssen Research and Development (Toledo) is acknowledged for technical support.

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Authors and Affiliations

  1. Department of Chemistry, University of Manchester, Manchester, UK

    Ji Hye Kim, Timothée Constantin, Marco Simonetti & Daniele Leonori

  2. Discovery Chemistry, Janssen Research and Development, Toledo, Spain

    Josep Llaveria

  3. Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia

    Nadeem S. Sheikh

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Contributions

J.H.K. and D.L. designed the project; J.H.K., T.C., M.S. and J.L. performed the experiments; N.S.S. performed the computational studies; and all the authors analysed the results and wrote the paper.

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Correspondence to Daniele Leonori.

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Kim, J.H., Constantin, T., Simonetti, M. et al. A radical approach for the selective C–H borylation of azines. Nature 595, 677–683 (2021). https://doi.org/10.1038/s41586-021-03637-6

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