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Boryl radical-mediated halogen-atom transfer enables arylation of alkyl halides with electrophilic and nucleophilic coupling partners

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Abstract

Traditional metal-catalysed cross-couplings of alkyl halides for C(sp3)–C(sp2) bond formation are often challenging to achieve. Processes where the alkyl halide is initially converted into a radical species can provide valuable complementarity. So far, these strategies are almost exclusively orchestrated by silicon-based reagents, which can be expensive, have low atom economy and are sensitive to steric factors. Here we report the use of the stable Lewis acid–Lewis base complex Me3N–BH3, which, upon conversion into its corresponding amine-ligated boryl radical, enables nickel- and copper-catalysed cross-coupling of alkyl iodides and bromides with electrophilic aryl bromides and nucleophilic aryl boronic acids. Mechanistically, this method uses the amine borane radical’s propensity to activate halides via halogen-atom transfer through highly polarized transition states. This reactivity features mild conditions and broad tolerability of functional groups and engages sterically hindered alkyl halides.

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Fig. 1: Cross-coupling of alkyl halides via radical intermediates requires activation via XAT.
Fig. 2: Mechanistic analysis and development of nickel-catalysed cross-coupling between alky halides and aryl bromides via boryl radical-mediated XAT.
Fig. 3: Substrate scope for the cross-coupling of alkyl iodides and bromides with aryl bromides.
Fig. 4: Mechanistic analysis and development of copper-catalysed cross-coupling between alky halides and aryl boronic acids via boryl radical-mediated XAT.

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Data availability

The authors declare that all relevant data supporting the findings of this study, including experimental procedures, compound characterization, computational study details, NMR spectra and other spectroscopic analysis, are available within the paper and its Supplementary Information.

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Acknowledgements

C. Vermeeren (RWTH Aachen University) is acknowledged for help with the purification of some of the products. J. Liu is acknowledged for the help in the preparation of some starting materials. Computations were performed with computing resources granted by RWTH Aachen University under project RWTH1268.

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Authors and Affiliations

  1. Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany

    Zhenhua Zhang & Daniele Leonori

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

    Michael J. Tilby

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  1. Zhenhua Zhang
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  2. Michael J. Tilby
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  3. Daniele Leonori
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Contributions

D.L. and Z.Z. designed the project; Z.Z. performed the synthetic experiments; M.J.T. performed the computational studies; all authors analysed and discussed the results and wrote the paper.

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Correspondence to Daniele Leonori.

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Nature Synthesis thanks Jia-Rong Chen, Ignacio Funes-Ardoiz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary Figs. 1–14, Table 1, experimental details, characterization data and computational analysis details.

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Coordinates (xyz) of the computational section.

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Zhang, Z., Tilby, M.J. & Leonori, D. Boryl radical-mediated halogen-atom transfer enables arylation of alkyl halides with electrophilic and nucleophilic coupling partners. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00587-5

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