Catalytic C(sp3)–H bond activation in tertiary alkylamines

Abstract

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C–H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)–H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(ii)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)–H functionalization. A simple ligand for Pd(ii) orchestrates the C–H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines.

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Fig. 1: Design plan towards γ-C(sp3)–H arylation of tertiary alkylamines.
Fig. 2: The γ-C(sp3)–H arylation of tertiary alkylamines.
Fig. 3: Applications and further advances of the γ-C–H arylation of tertiary alkylamines.

Data availability

The data that support the findings of this study are available within the paper and its supplementary information files. Raw data are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis. We thank I. Michaelides (AstraZeneca) and M. Grayson (University of Bath) for useful discussion. We are grateful to La Caixa Foundation and the Cambridge European Trust (J.R.) and the Gates Cambridge Trust (N.J.F.) for scholarships, the EPSRC (EP/N031792/1), the Leverhulme Trust (RPG-2016-370 to M.N.), Mitsubishi (H.A.), H2020 Marie Curie Actions (702462 to M.N. and 656455 to M.E.B.) and the Royal Society for a Wolfson Merit Award (to M.J.G.)

Author information

J.R., M.N. and M.J.G. conceived the project. J.R., M.N., H.A. and M.E.B. designed and performed the synthetic experiments. J.R. and N.J.F. designed and performed the computational studies. J.R., M.N., H.A., N.J.F. and M.J.G. prepared the manuscript.

Correspondence to Matthew J. Gaunt.

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Supplementary information

Supplementary information

Details of the materials and methods, experimental procedures, mechanistic studies, optimization studies, computational data and compound characterization data, including 1H NMR spectra, 13C NMR spectra and MS data.

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Rodrigalvarez, J., Nappi, M., Azuma, H. et al. Catalytic C(sp3)–H bond activation in tertiary alkylamines. Nat. Chem. 12, 76–81 (2020). https://doi.org/10.1038/s41557-019-0393-8

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