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Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation

Nature volume 561, pages 522–527 (2018)Cite this article

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Abstract

There is evidence to suggest that increasing the level of saturation (that is, the number of sp3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines4,5,6,7. In particular, processes that transform accessible feedstocks into sp3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp3)–C(sp3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.

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Fig. 1: Evolution of a strategy for the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 2: Scope of the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 3: Studies towards understanding the mechanism of the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 4: Expanding the scope of the multicomponent photocatalytic synthesis of tertiary alkylamines.

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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. 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 Materials. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1819790.

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Acknowledgements

We thank A. Bond for X-ray crystallographic analysis, the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis, and M. Nappi, J. C. K. Chu and T. Hunt (AstraZeneca) for useful discussion. We acknowledge the Herschel Smith Scholarship Scheme and AstraZeneca for studentships (to A.T. and D.R., respectively) and the Royal Society for a Wolfson Merit Award (M.J.G.).

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

    Aaron Trowbridge, Dominik Reich & Matthew J. Gaunt

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Contributions

M.J.G., A.T. and D.R. designed the experiments. A.T. and D.R. performed and analysed the experiments. M.J.G., A.T. and D.R prepared the manuscript.

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Correspondence to Matthew J. Gaunt.

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Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Figs. 1–5, Supplementary Tables 1–2, Supplementary References and 1H and 13C NMR Spectral Data.

Supplementary Data

This file contains the crystallographic information.

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Trowbridge, A., Reich, D. & Gaunt, M.J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018). https://doi.org/10.1038/s41586-018-0537-9

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