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Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis

Nature volume 559, pages 83–88 (2018)Cite this article

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Abstract

Over the past three decades, considerable progress has been made in the development of methods to construct sp2 carbon–nitrogen (C–N) bonds using palladium, copper or nickel catalysis1,2. However, the incorporation of alkyl substrates to form sp3 C–N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C–N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C–N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

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Fig. 1: Decarboxylative nitrogen-nucleophile fragment coupling.
Fig. 2: Catalytic cycles and control experiments.
Fig. 3: Decarboxylative C–N couplings of 3-chloroindazole with a range of alkyl carboxylic acids.
Fig. 4: Decarboxylative C–N couplings of cyclohexyl carboxylic acid with various nitrogen nucleophiles.
Fig. 5: Sequential C–N couplings and comparisons with nucleophilic substitutions.

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Acknowledgements

This research was supported by the National Institutes of Health National Institute of General Medical Sciences (R01 GM103558-03) and gifts from Merck, Bristol-Myers Squibb, Eli Lilly, Genentech and Johnson & Johnson. X.Z. is grateful for a postdoctoral fellowship from the Shanghai Institute of Organic Chemistry. We thank C. Liu and Y. Y. Loh for assistance in preparing this manuscript.

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Nature thanks S. Bagley and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: Yufan Liang, Xiaheng Zhang.

Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    Yufan Liang, Xiaheng Zhang & David W. C. MacMillan

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  1. Yufan Liang
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Contributions

Y.L. and X.Z. performed and analysed the experiments. Y.L., X.Z. and D.W.C.M. designed the experiments. Y.L., X.Z. and D.W.C.M. prepared the manuscript.

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Correspondence to David W. C. MacMillan.

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Extended data figures and tables

Extended Data Fig. 1 Decarboxylative sp3 C–N couplings with a series of secondary alkyl acids.

An array of secondary alkyl carboxylic acids can be cross-coupled with 3-chloroindazole. The protocol provides the product as a single regioisomer in all cases. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. d.r., diastereomeric ratio. #d.r. was determined by 1H NMR.

Extended Data Fig. 2 Decarboxylative sp3 C–N couplings with a series of nitrogen heterocycles.

Various nitrogen heterocycles, including indazoles, azaindoles, indoles and pyrazoles, can cross-couple with carboxylic acids with good efficiency. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. *Single regioisomer.

Extended Data Fig. 3 Decarboxylative sp3 C–N couplings with a series of nitrogen nucleophiles.

Various nitrogen nucleophiles, including nitrogen heterocycles, anilines, sulfonamides and amides, can cross-couple with carboxylic acids with good efficiency. All yields are isolated unless otherwise noted. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. #Yield was determined by 19F NMR with an internal standard. &Yield was determined by gas-chromatography analysis with an internal standard. *Single regioisomer.

Extended Data Fig. 4 Decarboxylative sp3 C–N couplings with a series of pharmaceutical compounds.

Several drug molecules can cross-couple with carboxylic acids with good efficiency. All yields are isolated. All reactions were replicated at least twice for consistency. See Supplementary Information for full experimental details. *Single regioisomer.

Supplementary information

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Liang, Y., Zhang, X. & MacMillan, D.W.C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018). https://doi.org/10.1038/s41586-018-0234-8

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