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Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes

Nature Chemistry volume 15, pages 685–693 (2023)Cite this article

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Abstract

Catalytic borylations of sp3 C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C–H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C–H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C–H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C–B bond.

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Fig. 1: State of the borylation of alkyl C–H bonds, applications of BCPs and routes for their synthesis relevant to this study.
Fig. 2: Conversion of the boryl group of 3-boryl-bicyclo-[1.1.1]-pentanes and 3-boryl-bicyclo-[2.1.1]-hexanes into various functional groups.
Fig. 3: Competition experiments and measurement of 1JC–H coupling constants.
Fig. 4: Mechanistic experiments.
Fig. 5: DFT studies.

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Complete experimental procedures, computational details and compound characterization data are available in the Supplementary Information. Atomic coordinates of optimized structures are available as Supplementary Data 1.

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Acknowledgements

This work was supported by the NIGMS of the NIH under R35GM130387. I.F.Y. and J.L.M. gratefully acknowledge the National Science Foundation Graduate Research Fellowship Program and the UC Berkeley Graduate Research Fellowship Program for support under DGE 1752814 and DGE 2146752. We thank H. Celik and A. Lund and UC Berkeley’s NMR facility in the College of Chemistry (CoC-NMR) for spectroscopic assistance, in particular for assistance and advice in acquiring J-resolved spectra. Instruments in the CoC-NMR are supported in part by NIH S10OD024998. We thank K. Durkin and D. Small and UC Berkeley’s Molecular Graphics and Computation Facility (MGCF) for assistance and resources for the computations. The MGCF is supported in part by NIH S10OD023532. We thank the QB3/Chemistry Mass Spectrometry Facility for assistance in obtaining high-resolution mass spectrometry data. We wish to thank T. W. Butcher and E. D. Kalkman for helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, CA, USA

    Isaac F. Yu, Jenna L. Manske & John F. Hartwig

  2. Janssen Research and Development, Toledo, Spain

    Alejandro Diéguez-Vázquez & Antonio Misale

  3. The Institute of High Technologies, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine

    Alexander E. Pashenko, Pavel K. Mykhailiuk, Sergey V. Ryabukhin & Dmitriy M. Volochnyuk

  4. Enamine Ltd, Kyiv, Ukraine

    Alexander E. Pashenko, Pavel K. Mykhailiuk, Sergey V. Ryabukhin & Dmitriy M. Volochnyuk

  5. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine

    Alexander E. Pashenko, Sergey V. Ryabukhin & Dmitriy M. Volochnyuk

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Contributions

J.F.H., A.M. and D.M.V. conceived and created an initial design of the research. I.F.Y., J.L.M., A.M. and A.D-v. performed the synthetic experiments. I.F.Y. conducted the computational and kinetic studies. J.L.M. conducted the competition studies. I.F.Y., A.M., A.E.P., P.K.M., S.V.R. and D.M.V. selected and prepared the bicyclic reagents used in this study. I.F.Y., J.L.M., A.M., D.M.V. and J.F.H. designed and analysed the experiments and prepared the initial paper. All authors contributed to or approved the final version of the paper.

Corresponding authors

Correspondence to Antonio Misale, Dmitriy M. Volochnyuk or John F. Hartwig.

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Competing interests

A.E.P., P.K.M., S.V.R. and D.M.V. are employees of Enamine, which is a chemical supplier of reagents used in the studies in this paper. All other authors declare no competing interests.

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Supplementary Information

Supplementary Figs. 1–20, Tables 1–3 and Discussion.

Supplementary Data 1

Atomic coordinates of optimized structures from DFT calculations.

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Yu, I.F., Manske, J.L., Diéguez-Vázquez, A. et al. Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes. Nat. Chem. 15, 685–693 (2023). https://doi.org/10.1038/s41557-023-01159-4

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