Letter | Published:

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

Naturevolume 559pages8388 (2018) | Download Citation


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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  1. 1.

    Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

  2. 2.

    Bhunia, S., Pawar, G. G., Kumar, S. V., Jiang, Y. & Ma, D. Selected copper-based reactions for C–N, C–O, C–S, and C–C bond formation. Angew. Chem. Int. Ed. 56, 16136–16179 (2017).

  3. 3.

    Knölker, H.-J. (ed.) The Alkaloids: Chemistry and Biology Vol. 70 (Elsevier, San Diego, 2011).

  4. 4.

    Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

  5. 5.

    Ćirić-Marjanović, G. Recent advances in polyaniline research: polymerization mechanisms, structural aspects, properties and applications. Synth. Met. 177, 1–47 (2013).

  6. 6.

    Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development. Chem. Soc. Rev. 43, 3525–3550 (2014).

  7. 7.

    Qiao, J. X. & Lam, P. Y. S. Copper-promoted carbon–heteroatom bond cross-coupling with boronic acids and derivatives. Synthesis 2011, 829–856 (2011).

  8. 8.

    Salvatore, R. N., Yoon, C. H. & Jung, K. W. Synthesis of secondary amines. Tetrahedron 57, 7785–7811 (2001).

  9. 9.

    Swamy, K. C. K., Kumar, N. N. B., Balaraman, E. & Kumar, K. V. P. P. Mitsunobu and related reactions: advances and applications. Chem. Rev. 109, 2551–2651 (2009).

  10. 10.

    Abdel-Magid, A. F. & Mehrman, S. J. A review on the use of sodium triacetoxyborohydride in the reductive amination of ketones and aldehydes. Org. Process Res. Dev. 10, 971–1031 (2006).

  11. 11.

    Huang, L., Arndt, M., Gooßen, K., Heydt, H. & Gooßen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).

  12. 12.

    Matier, C. D., Schwaben, J., Peters, J. C. & Fu, G. C. Copper-catalyzed alkylation of aliphatic amines induced by visible light. J. Am. Chem. Soc. 139, 17707–17710 (2017).

  13. 13.

    Peacock, D. M., Roos, C. B. & Hartwig, J. F. Palladium-catalyzed cross coupling of secondary and tertiary alkyl bromides with a nitrogen nucleophile. ACS Cent. Sci. 2, 647–652 (2016).

  14. 14.

    Curtius, T. 20. Hydrazide und azide organischer säuren I. Abhandlung. J. Prakt. Chem. 50, 275–294 (1894).

  15. 15.

    Shaw, M. H., Twilton, J. & MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).

  16. 16.

    Twilton, J., Le, C., Zhang, P., Shaw, M. H., Evans, R. W. & MacMillan, D. W. C. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

  17. 17.

    Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp3-carbons with aryl halides. Science 345, 437–440 (2014).

  18. 18.

    Zhang, X. & MacMillan, D. W. C. Alcohols as latent coupling fragments for metallaphotoredox catalysis: sp3–sp2 cross-coupling of oxalates with aryl halides. J. Am. Chem. Soc. 138, 13862–13865 (2016).

  19. 19.

    Zhao, W., Wurz, R. P., Peters, J. C. & Fu, G. C. Photoinduced, copper-catalyzed decarboxylative C–N coupling to generate protected amines: an alternative to the Curtius rearrangement. J. Am. Chem. Soc. 139, 12153–12156 (2017).

  20. 20.

    Mao, R., Frey, A., Balon, J. & Hu, X. Decarboxylative C(sp 3)–N cross-coupling via synergistic photoredox and copper catalysis. Nat. Catal. 1, 120–126 (2018).

  21. 21.

    Lowry, M. S. et al. Single-layer electroluminescent devices and photoinduced hydrogen production from an ionic iridium(III) complex. Chem. Mater. 17, 5712–5719 (2005).

  22. 22.

    Sanna, G., Pilo, M. I., Zoroddu, M. A. & Seeber, R. Electrochemical and spectroelectrochemical study of copper complexes with 1,10-phenanthrolines. Inorg. Chim. Acta 208, 153–158 (1993).

  23. 23.

    He, Z., Bae, M., Wu, J. & Jamison, T. F. Synthesis of highly functionalized polycyclic quinoxaline derivatives using visible-light photoredox catalysis. Angew. Chem. Int. Ed. 53, 14451–14455 (2014).

  24. 24.

    Minisci, F., Vismara, E., Fontana, F. & Barbosa, M. C. N. A new general method of homolytic alkylation of protonated heteroaromatic bases by carboxylic acids and iodosobenzene diacetate. Tetrahedr. Lett. 30, 4569–4572 (1989).

  25. 25.

    Tran, B. L., Li, B., Driess, M. & Hartwig, J. F. Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes. J. Am. Chem. Soc. 136, 2555–2563 (2014).

  26. 26.

    Stepan, A. F. et al. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J. Med. Chem. 55, 3414–3424 (2012).

  27. 27.

    Afagh, N. A. & Yudin, A. K. Chemoselectivity and the curious reactivity preferences of functional groups. Angew. Chem. Int. Ed. 49, 262–310 (2010).

  28. 28.

    Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456–463 (1988).

  29. 29.

    Lõkov, M. et al. On the basicity of conjugated nitrogen heterocycles in different media. Eur. J. Org. Chem. 4475–4489 (2017).

  30. 30.

    Le, C. C. et al. A general small-scale reactor to enable standardization and acceleration of photocatalytic reactions. ACS Cent. Sci. 3, 647–653 (2017).

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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.


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

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


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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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to David W. C. MacMillan.

Extended data figures and tables

  1. 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.

  2. 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.

  3. 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.

  4. 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

  1. Supplementary Information

    This file contains supplementary information 1-10

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