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A general alkene aminoarylation enabled by N-centred radical reactivity of sulfinamides

Nature Chemistry volume 16, pages 599–606 (2024)Cite this article

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Abstract

Arylethylamines are popular structural elements in bioactive molecules but are often made through a linear series of synthetic steps. A modular protocol to assemble arylethylamines from alkenes in one step would represent a useful advance in discovery chemistry, though current limitations preclude a generally applicable method. In this work we disclose an aminoarylation of alkenes using aryl sulfinamide reagents as bifunctional amine and arene donors. This reaction features excellent regioselectivity and diastereoselectivity on a variety of activated and unactivated substrates. Using a weakly oxidizing photocatalyst, a nitrogen radical is generated under mild conditions and adds to an alkene to form a new C–N bond. A desulfinylative aryl migration event known as a Smiles–Truce rearrangement follows to form a new C–C bond. In this manner, arylethylamines can be rapidly assembled from abundant alkene feedstocks. Moreover, chiral information from the sulfinamide can be transferred via rearrangement to a new carbon stereocentre in the product, thus advancing the development of traceless asymmetric alkene difunctionalization.

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Fig. 1: Alkene aminoarylation to synthesize biologically active molecules.
Fig. 2: Considerations informing reaction design and depiction of first success.
Fig. 3: Proposed mechanism and key experiments.
Fig. 4: Examples of synthetic utility and stereocontrol.

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Data availability

All data in support of the findings of this study are available within the Article and its Supplementary Information. X-ray crystallographic data for compound 2u are freely available from the Cambridge Crystallographic Data Center (CCDC 2150974).

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Acknowledgements

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM144286. We thank the University of Michigan for additional funding and J. W. Kampf for collecting and analysing X-ray crystallography data.

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Authors and Affiliations

  1. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

    Efrey A. Noten, Cody H. Ng, Robert M. Wolesensky & Corey R. J. Stephenson

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Contributions

E.A.N. and C.R.J.S. conceived the project, and E.A.N. executed the initial reaction discovery. E.A.N., C.H.N. and R.M.W. conducted the experiments and analysis. E.A.N. wrote the paper with input from C.R.J.S., C.H.N. and R.M.W.

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Correspondence to Corey R. J. Stephenson.

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Nature Chemistry thanks Robert Stockman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–200, experimental procedures and details, characterization data, NMR spectra, chiral high-performance liquid chromatography and supercritical fluid chromatography traces and X-ray crystallographic data.

Supplementary Data 1

Crystallographic data for compound 2u. CCDC reference 2150974.

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Noten, E.A., Ng, C.H., Wolesensky, R.M. et al. A general alkene aminoarylation enabled by N-centred radical reactivity of sulfinamides. Nat. Chem. 16, 599–606 (2024). https://doi.org/10.1038/s41557-023-01404-w

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