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Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals

Nature Chemistry volume 10, pages 724–731 (2018)Cite this article

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Abstract

Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C–H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C–H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C–H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(ii)-catalysed C–H arylation of N–chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades.

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Fig. 1: Ru(ii)-catalysed C–H arylation of DG-containing arenes with aryl (pseudo)halides.
Fig. 2: Kinetic evidence that supports the involvement of a bis-cycloruthenated intermediate in the Ru-catalysed C–H arylation of DG-containing arenes with aryl (pseudo)halides.
Fig. 3: Detection, isolation and reactivity of the bis-cycloruthenated complex Ru5.
Fig. 4: Cycloruthenated complexes as a superior class of catalysts for the C–H arylation of DG-containing arenes with aryl (pseudo)halides.
Fig. 5: Substrate scope of the C–H arylation with respect to the aryl (pseudo)halide-containing drugs.
Fig. 6: Substrate scope of the C–H arylation with respect to the DG-containing drugs and C–H arylation between DG-containing drugs and aryl (pseudo)halide-containing drugs.

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Acknowledgements

We gratefully acknowledge the Engineering and Physical Sciences Research Council (EPSRC, EP/L014017/2 and EP/K039547/1) for funding and the European Research Council for a Starting Grant (to I.L.).

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  1. These authors contributed equally: Marco Simonetti, Diego M. Cannas.

Authors and Affiliations

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

    Marco Simonetti, Diego M. Cannas, Xavier Just-Baringo, Iñigo J. Vitorica-Yrezabal & Igor Larrosa

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Contributions

M.S. and I.L. conceived the work and prepared the manuscript. M.S., D.M.C. and I.L. designed the experiments. M.S. and D.M.C. performed the experiments and analysed the data. X.J.-B., M.S. and D.M.C. prepared the Supplementary Information. I.J.V.-Y. acquired the X-ray of Ru5.

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Correspondence to Igor Larrosa.

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A patent protecting the findings disclosed in this manuscript has been filed by the University of Manchester (application number 1807672.9).

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Supplementary information

Supplementary Information

Experimental procedures for the mechanistic studies; general procedures for the synthesis of ruthenium complexes, starting materials and new products; the experimental procedure for the 10 g-scale synthesis of A12; NMR characterization for the new products and X-ray crystallography data for Ru5

Crystallographic data

CIF for compound Ru5; CCDC reference: 1567316

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Simonetti, M., Cannas, D.M., Just-Baringo, X. et al. Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals. Nature Chem 10, 724–731 (2018). https://doi.org/10.1038/s41557-018-0062-3

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