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Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

Nature Catalysis volume 4, pages 623–630 (2021)Cite this article

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Abstract

Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues.

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Fig. 1: Relevance and assembly of sp3 C–N bonds.
Fig. 2: Development of a coupling between alkyl iodides and N-nucleophiles by merging XAT and copper catalysis.
Fig. 3: Scope of the N-nucleophilic partner for the amination of iodide 1.
Fig. 4: Scope of the secondary alkyl iodide partner for the amination with N-nucleophile 2.
Fig. 5: Late-stage N-alkylations of complex and biologically active materials.

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The data supporting the findings of this study are available within the paper and its Supplementary Information or from the authors upon reasonable request.

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Acknowledgements

D.L. thanks EPSRC for a fellowship (EP/P004997/1) and a research grant (EP/T016019/1) and the European Research Council for a research grant (758427). We thank W. Ashworth, P. Gillespie and S. Wells for performing safety studies. We thank M. Johansson (AstraZeneca) for useful discussions.

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Author notes

  1. These authors contributed equally: Bartosz Górski, Anne-Laure Barthelemy.

Authors and Affiliations

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

    Bartosz Górski, Anne-Laure Barthelemy, Fabio Juliá & Daniele Leonori

  2. Early Chemical Development, Pharmaceutical Sciences R&D, AstraZeneca, Macclesfield, UK

    James J. Douglas

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Contributions

F.J. and D.L. designed the project and directed the work. B.G. and A.-L.B. performed all the synthetic and mechanistic experiments. J.J.D performed the scale-up experiments. All authors analysed the results and wrote the manuscript.

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Correspondence to Fabio Juliá or Daniele Leonori.

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Peer review information Nature Catalysis thanks Michael Doyle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary methods, discussion, Tables 1–8, Figs. 1–30 and references.

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Górski, B., Barthelemy, AL., Douglas, J.J. et al. Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer. Nat Catal 4, 623–630 (2021). https://doi.org/10.1038/s41929-021-00652-8

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