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Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

Nature Catalysis volume 1, pages 120–126 (2018)Cite this article

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Abstract

Amines are a quintessential moiety in bioactive molecules, pharmaceuticals and organic materials. Transition-metal-catalysed C–N coupling of aryl electrophiles has been established as a powerful and reliable method for amine synthesis. However, the analogous C–N coupling of alkyl electrophiles is largely under-developed due to the decomposition of metal alkyl intermediates by β-hydrogen elimination and difficulty in C(sp3)–N reductive elimination. Here, we provide a general strategy for amination of alkyl electrophiles by merging photoredox and copper catalysis. Photoredox catalysis allows the use of alkyl redox-active esters, recently established as a superior class of alkyl electrophiles, whereas copper catalysis enables C(sp3)–N cross-coupling. Decarboxylative amination can be used for the synthesis of a diverse set of alkyl anilines with high chemoselectivity and functional-group compatibility. Rapid functionalization of amino acids, natural products and drugs is demonstrated.

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Fig. 1: Reaction development.
Fig. 2: Synthetic applications.
Fig. 3: Control reactions. 
Fig. 4: Reactions of copper amine complexes with a redox-active ester.

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Acknowledgements

This work is supported by the NoNoMeCat Marie Skłodowska-Curie training network funded by the European Union under the Horizon 2020 Programme (675020-MSCA-ITN-2015-ETN). We thank R. Scopelliti (École Polytechnique Fédérale de Lausanne) for assistance with X-ray crystallography of 9a.

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Authors and Affiliations

  1. Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Runze Mao, Adrian Frey, Jonathan Balon & Xile Hu

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  2. Adrian Frey
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Contributions

R.M. and X.H. conceived and designed the study. R.M. designed and optimized the synthetic method, and studied the scope, application and mechanism. A.F. and J.B. contributed to the scope and application. R.M. and X.H. wrote the manuscript. X.H. directed the research.

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Correspondence to Xile Hu.

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Supplementary Information

Supplementary Methods, Supplementary Tables 1–10, Supplementary Figures 1–100, Supplementary References.

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Mao, R., Frey, A., Balon, J. et al. Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis. Nat Catal 1, 120–126 (2018). https://doi.org/10.1038/s41929-017-0023-z

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