Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

Abstract

Transition-metal-catalysed cross-coupling reactions, particularly those mediated by palladium, are some of the most broadly used chemical transformations. The fundamental reaction steps of such cross-couplings typically include oxidative addition, transmetallation, carbopalladation of a π-bond and/or reductive elimination. Herein, we describe an unprecedented fundamental reaction step: a C–C σ-bond carbopalladation. Specifically, an aryl palladium(ii) complex interacts with a σ-bond of a strained bicyclo[1.1.0]butyl boronate complex to enable addition of the aryl palladium(ii) species and an organoboronic ester substituent across a C–C σ-bond. The overall process couples readily available aryl triflates and organoboronic esters across a cyclobutane unit with total diastereocontrol. The pharmaceutically relevant 1,1,3-trisubstituted cyclobutane products are decorated with an array of modular building blocks, including a boronic ester that can be readily derivatized.

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Fig. 1: Previous palladium-mediated cross-coupling reactions involving organoboron reagents, and our reaction design.
Fig. 2: Applications of the distal cross-coupling reaction.
Fig. 3: Proposed catalytic cycle for the distal cross-coupling.

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for compounds 5, 7, 15 and 35 are available free of charge from the Cambridge Crystallographic Date Centre (www.ccdc.cam.ac.uk) under reference numbers 1835072, 1847415, 1835073 and 1847416, respectively.

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Acknowledgements

This work was supported by the EPSRC (EP/I038071/1), H2020 ERC (670668) and the Bayer Science and Education Foundation (Otto–Bayer Fellowship; T.B.). The authors thank E. L. Myers (NUI Galway) and A. Noble for helpful discussions, E. Denton for technical support and H. A. Sparkes for X-ray analysis.

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Authors

Contributions

V.K.A. and A.F. conceived the project. A.F. designed and conducted the experiments and analysed the data. T.B. first synthesized compound 5. V.K.A. and A.F. prepared the manuscript.

Corresponding author

Correspondence to Varinder K. Aggarwal.

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The authors declare no competing interests.

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Supplementary information

Supplementary information

Supplementary experimental details and compound characterization data

Crystallographic data

CIF for compound 5; CDCC reference 1835072

Crystallographic data

CIF for compound 7; CDCC reference 1847415

Crystallographic data

CIF for compound 15; CDCC reference 1835073

Crystallographic data

CIF for compound 35; CDCC reference 1847416

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Fawcett, A., Biberger, T. & Aggarwal, V.K. Carbopalladation of C–C σ-bonds enabled by strained boronate complexes. Nature Chem 11, 117–122 (2019). https://doi.org/10.1038/s41557-018-0181-x

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