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A general carbonyl alkylative amination for tertiary amine synthesis

Nature volume 581, pages 415–420 (2020)Cite this article

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Abstract

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3,4,5,6,7,8,9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a ‘higher order’ variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10,11,12,13,14. However, despite extensive efforts, the successful realization of a ‘carbonyl alkylative amination’ has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.

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Fig. 1: Evolution of a strategy for carbonyl alkylative amination.
Fig. 2: Scope of the amine component in carbonyl alkylative amination.
Fig. 3: Scope of the carbonyl alkylative amination reaction.
Fig. 4: One-step synthesis of complex tertiary alkylamines via carbonyl alkylative amination and its comparison with related methods.

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Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, optimization studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in the Supplementary Information. Raw data are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge the Swiss National Science Foundation (R.K.), the Gates Cambridge Trust (N.J.F.), the EPSRC (W.G.W.) and the Royal Society (for a Wolfson Merit Award, M.J.G.).

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Author notes

  1. These authors contributed equally: Nils J. Flodén, William G. Whitehurst

Authors and Affiliations

  1. Department of Chemistry, University of Cambridge, Cambridge, UK

    Roopender Kumar, Nils J. Flodén, William G. Whitehurst & Matthew J. Gaunt

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Contributions

R.K., N.J.F., W.G.W. and M.J.G. conceived the project; R.K., N.J.F. and W.G.W. conducted and analysed the experiments; and R.K., N.J.F., W.G.W. and M.J.G. wrote the manuscript. N.J.F. and W.G.W. contributed equally to the project and are listed alphabetically.

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Correspondence to Matthew J. Gaunt.

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Supplementary information

Supplementary Information 1

This file contains Materials and Methods, Supplementary Text, Supplementary Figures 1 to 9 and Supplementary Tables 1 to 2.

Supplementary Information 2

This file contains Supplementary Comparative Experimental Information, Supplementary Literature Overview and Supplementary Figures 1 to 3. information.

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Kumar, R., Flodén, N.J., Whitehurst, W.G. et al. A general carbonyl alkylative amination for tertiary amine synthesis. Nature 581, 415–420 (2020). https://doi.org/10.1038/s41586-020-2213-0

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