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A general carbonyl alkylative amination for tertiary amine synthesis

Abstract

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3,4,5,6,7,8,9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a ‘higher order’ variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10,11,12,13,14. However, despite extensive efforts, the successful realization of a ‘carbonyl alkylative amination’ has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines.

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Fig. 1: Evolution of a strategy for carbonyl alkylative amination.
Fig. 2: Scope of the amine component in carbonyl alkylative amination.
Fig. 3: Scope of the carbonyl alkylative amination reaction.
Fig. 4: One-step synthesis of complex tertiary alkylamines via carbonyl alkylative amination and its comparison with related methods.

Data availability

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 Information. Raw data are available from the corresponding author on reasonable request.

References

  1. 1.

    Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    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).

    CAS  Article  Google Scholar 

  4. 4.

    Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010).

    CAS  Article  PubMed  Google Scholar 

  5. 5.

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

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Pirnot, M. T., Wang, Y.-M. & Buchwald, S. L. Copper hydride catalyzed hydroamination of alkenes and alkynes. Angew. Chem. Int. Ed. 55, 48–57 (2016).

    CAS  Article  Google Scholar 

  7. 7.

    Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727–730 (2017).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Grogan, G. Synthesis of chiral amines using redox biocatalysis. Curr. Opin. Chem. Biol. 43, 15–22 (2018).

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Friestad, G. K. Addition of carbon-centered radicals to imines and related compounds. Tetrahedron 57, 5461–5496 (2001).

    CAS  Article  Google Scholar 

  11. 11.

    Reiber, H. G. & Stewart, T. D. The tetra alkyl methylene immonium salts. J. Am. Chem. Soc. 62, 3026–3030 (1940).

    CAS  Article  Google Scholar 

  12. 12.

    Paukstelis, J. W. & Cook, A. G. in Enamines: Synthesis, Structure and Reactions 2nd edn (ed. Cook, A. G.) Ch. 6, 275–346 (Marcel Dekker, 1988).

  13. 13.

    Bloch, R. Additions of organometallic reagents to C=N bonds: reactivity and selectivity. Chem. Rev. 98, 1407–1438 (1998).

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kaiser, E. M. Lithium: annual survey covering the year 1975. J. Organomet. Chem. 130, 1–131 (1977).

    CAS  Article  Google Scholar 

  15. 15.

    Werner, V., Ellwart, M., Wagner, A. J. & Knochel, P. Preparation of tertiary amines by the reaction of iminium ions derived from unsymmetrical aminals with zinc and magnesium organometallics. Org. Lett. 17, 2026–2029 (2015).

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Saidi, M. R. & Nazari, M. Aminoalkylation with aldehydes mediated by solid lithium perchlorate. Monatsh. Chem. 135, 309–312 (2004).

    CAS  Article  Google Scholar 

  17. 17.

    Agosti, A., Britto, S. & Renaud, P. An efficient method to convert lactams and amides into 2,2-dialkylated amines. Org. Lett. 10, 1417–1420 (2008).

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Haurena, C., LeGall, E., Sengmany, S. & Martens, T. Chiral amines in the diastereoselective Mannich-related multicomponent synthesis of diarylmethylamines, 1,2-diarylethylamines, and β-arylethylamines. Tetrahedron 66, 9902–9911 (2010).

    CAS  Article  Google Scholar 

  19. 19.

    Wu, P., Givskov, M. & Nielsen, T. E. Reactivity and synthetic applications of multicomponent Petasis reactions. Chem. Rev. 119, 11245–11290 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Aschwanden, P. & Carreira, E. M. in Acetylene Chemistry: Chemistry, Biology and Material Science (eds Diederich, F., Stang, P. J. & Tywinski, R. R.) (Wiley, 2005).

  21. 21.

    Lauder, K., Toscani, A., Scalacci, N. & Castagnolo, D. Synthesis and reactivity of propargylamines in organic chemistry. Chem. Rev. 117, 14091–14200 (2017).

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Heinz, C. et al. Ni-catalyzed carbon–carbon bond-forming reductive amination. J. Am. Chem. Soc. 140, 2292–2300 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Chen, T.-Y., Tsutsumi, R., Montgomery, T. P., Volchkov, I. & Krische, M. J. Ruthenium-catalyzed C–C coupling of amino alcohols with dienes via transfer hydrogenation: redox-triggered imine addition and related hydroaminoalkylations. J. Am. Chem. Soc. 137, 1798–1801 (2015).

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Miyabe, H., Yoshioka, E. & Kohtani, S. Progress in intermolecular carbon radical addition to imine derivatives. Curr. Org. Chem. 14, 1254–1264 (2010).

    CAS  Article  Google Scholar 

  25. 25.

    Friestad, G. K. Radical additions to chiral hydrazones: stereoselectivity and functional group compatibility. Top. Curr. Chem. 320, 61–91 (2011).

    Article  CAS  Google Scholar 

  26. 26.

    Tauber, J., Imbri, D. & Opatz, T. Radical addition to iminium ions and cationic heterocycles. Molecules 19, 16190–16222 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Russell, G. A., Yao, C.-F., Rajaratnam, R. & Kim, B. H. Promotion of electron transfer by protonation of nitrogen-centered free radicals. The addition of radicals to iminium ions. J. Am. Chem. Soc. 113, 373–375 (1991).

    CAS  Article  Google Scholar 

  28. 28.

    Baguley, P. A. & Walton, J. C. Flight from the tyranny of tin: the quest for practical radical sources free from metal encumbrances. Angew. Chem. Int. Ed. 37, 3072–3082 (1998).

    CAS  Article  Google Scholar 

  29. 29.

    Chatgilialoglu, C., Ferreri, C., Landais, Y. & Timokhin, V. I. Thirty years of (TMS) 3SiH: a milestone in radical-based synthetic chemistry. Chem. Rev. 118, 6516–6572 (2018).

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Le, C., Chen, T. Q., Liang, T., Zhang, P. & MacMillan, D. W. C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes. Science 360, 1010–1014 (2018).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Cheng, Y., Mück-Lichtenfeld, C. & Studer, A. Metal-free radical borylation of alkyl and aryl iodides. Angew. Chem. Int. Ed. 57, 16832–16836 (2018).

    CAS  Article  Google Scholar 

  32. 32.

    Bahamonde, A. & Melchiorre, P. Mechanism of the stereoselective α-alkylation of aldehydes driven by the photochemical activity of enamines. J. Am. Chem. Soc. 138, 8019–8030 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Fawcett, A. et al. Photoinduced decarboxylative borylation of carboxylic acids. Science 357, 283–286 (2017).

    ADS  CAS  Article  PubMed  Google Scholar 

  34. 34.

    Lei, L. et al. Systematic study on alkyl iodide initiators in living radical polymerization with organic catalysts. Macromolecules 47, 6610–6618 (2014).

    ADS  CAS  Article  Google Scholar 

  35. 35.

    Bosma, R. et al. Route to prolonged residence time at the histamine H1 receptor: growing from desloratadine to rupatadine. J. Med. Chem. 62, 6630–6644 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. Deuterium- and tritium-labelled compounds: applications in the life sciences. Angew. Chem. Int. Ed. 57, 1758–1784 (2018).

    CAS  Article  Google Scholar 

  37. 37.

    Trowbridge, A., Reich, D. & Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018).

    ADS  CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the Swiss National Science Foundation (R.K.), the Gates Cambridge Trust (N.J.F.), the EPSRC (W.G.W.) and the Royal Society (for a Wolfson Merit Award, M.J.G.).

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Authors

Contributions

R.K., N.J.F., W.G.W. and M.J.G. conceived the project; R.K., N.J.F. and W.G.W. conducted and analysed the experiments; and R.K., N.J.F., W.G.W. and M.J.G. wrote the manuscript. N.J.F. and W.G.W. contributed equally to the project and are listed alphabetically.

Corresponding author

Correspondence to Matthew J. Gaunt.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information 1

This file contains Materials and Methods, Supplementary Text, Supplementary Figures 1 to 9 and Supplementary Tables 1 to 2.

Supplementary Information 2

This file contains Supplementary Comparative Experimental Information, Supplementary Literature Overview and Supplementary Figures 1 to 3. information.

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Kumar, R., Flodén, N.J., Whitehurst, W.G. et al. A general carbonyl alkylative amination for tertiary amine synthesis. Nature 581, 415–420 (2020). https://doi.org/10.1038/s41586-020-2213-0

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