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Iterative reactions of transient boronic acids enable sequential C–C bond formation

Nature Chemistry volume 8, pages 360–367 (2016)Cite this article

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Abstract

The ability to form multiple carbon–carbon bonds in a controlled sequence and thus rapidly build molecular complexity in an iterative fashion is an important goal in modern chemical synthesis. In recent times, transition-metal-catalysed coupling reactions have dominated in the development of C–C bond forming processes. A desire to reduce the reliance on precious metals and a need to obtain products with very low levels of metal impurities has brought a renewed focus on metal-free coupling processes. Here, we report the in situ preparation of reactive allylic and benzylic boronic acids, obtained by reacting flow-generated diazo compounds with boronic acids, and their application in controlled iterative C–C bond forming reactions is described. Thus far we have shown the formation of up to three C–C bonds in a sequence including the final trapping of a reactive boronic acid species with an aldehyde to generate a range of new chemical structures.

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Figure 1: Previous work on boronic acids–diazo coupling and development of an iterative reaction strategy.
Figure 2: Iterative strategy for the sequential addition of three diazo species.
Figure 3: Synthesis of bakuchiol precursor 11p using an iterative coupling method.
Figure 4: Sequencial interception of boronic acid species and final reaction with aldehydes.

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Acknowledgements

The authors acknowledge Pfizer (C.B., D.M.A. and D.C.B.), the Studienstiftung des deutschen Volkes (German National Academic Foundation, F.F.), the Alexander-von-Humboldt foundation (A.H.), Erasmus+ (M.S.), the Swiss National Science Foundation (D.N.T.) and the EPSRC (S.V.L., grants nos. EP/K009494/1 and EP/M004120/1) for financial support. The authors thank J.M. Hawkins for discussions and R.M. Turner for providing assistance throughout the development of the research programme.

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Author notes

  1. Claudio Battilocchio and Florian Feist: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, Innovative Technology Centre, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW

    Claudio Battilocchio, Florian Feist, Andreas Hafner, Meike Simon, Duc N. Tran, Daniel M. Allwood & Steven V. Ley

  2. Pfizer Worldwide Medicinal Chemistry, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK

    David C. Blakemore

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  1. Claudio Battilocchio
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Contributions

C.B., D.N.T. and S.V.L. conceived the project. C.B., A.H. and S.V.L. designed the experiments. C.B., F.F., A.H., M.S. and D.N.T. performed the experiments. D.M.A. analysed the data and prepared the supporting information. D.C.B. provided crucial information for the development of the project. C.B., A.H. and S.V.L. wrote the paper.

Corresponding authors

Correspondence to Claudio Battilocchio or Steven V. Ley.

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The authors declare no competing financial interests.

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Battilocchio, C., Feist, F., Hafner, A. et al. Iterative reactions of transient boronic acids enable sequential C–C bond formation. Nature Chem 8, 360–367 (2016). https://doi.org/10.1038/nchem.2439

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