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Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation

Nature volume 561, pages 522–527 (2018)Cite this article

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Abstract

There is evidence to suggest that increasing the level of saturation (that is, the number of sp3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines4,5,6,7. In particular, processes that transform accessible feedstocks into sp3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp3)–C(sp3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.

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Fig. 1: Evolution of a strategy for the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 2: Scope of the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 3: Studies towards understanding the mechanism of the multicomponent photocatalytic synthesis of tertiary alkylamines.
Fig. 4: Expanding the scope of the multicomponent photocatalytic synthesis of tertiary alkylamines.

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Data availability

The data that support the findings of this study are available within the paper and its supplementary information files. Raw data are available from the corresponding author on reasonable request. 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 Materials. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1819790.

References

  1. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines. Science 349, 62–66 (2015).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. Johnston, C. P., Smith, R. T., Allmendinger, S. & MacMillan, D. W. C. Metallophotoredox-catalysed sp 3 –sp 3 cross-coupling of carboxylic acids with alkyl halides. Nature 536, 322–325 (2016).

    Article  ADS  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Mayol-Llinàs, J., Nelson, A., Farnaby, W. & Ayscough, A. Assessing molecular scaffolds for CNS drug discovery. Drug Discov. Today 22, 965–969 (2017).

    Article  Google Scholar 

  9. Lahmy, V., Long, R., Morin, D., Villard, V. & Maurice, T. Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2–73, a tetrahydrofuran derivative, in Aβ25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front. Cell. Neurosci. 8, 463 (2015).

    Article  Google Scholar 

  10. Marciano, D. P. et al. The therapeutic potential of nuclear receptor modulators for treatment of metabolic disorders: PPARγ, RORs, Rev-erbs. Cell Metab. 19, 193–208 (2014).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Kalck, P. & Urrutigoïty, M. Tandem hydroaminomethylation reaction to synthesize amines from alkenes. Chem. Rev. 118, 3833–3861 (2018).

    Article  CAS  Google Scholar 

  14. Herzon, S. B. & Hartwig, J. F. Hydroaminoalkylation of unactivated olefins with dialkylamines. J. Am. Chem. Soc. 130, 14940–14941 (2008).

    Article  CAS  Google Scholar 

  15. Perez, F., Oda, S., Geary, L. M. & Krische, M. J. Ruthenium catalyzed transfer hydrogenation for C–C bond formation: hydrohydroxyalkylation and hydroaminoalkylation via reactant redox pairs. Top. Curr. Chem. 374, 35 (2016).

    Article  Google Scholar 

  16. Renaud, P. & Giraud, L. 1-Amino- and 1-amidoalkyl radicals: generation and stereoselective reactions. Synthesis 1996, 913–926 (1996).

    Article  Google Scholar 

  17. Mariano, P. S. Electron-transfer mechanisms in photochemical transformations of iminium salts. Acc. Chem. Res. 16, 130–137 (1983).

    Article  CAS  Google Scholar 

  18. Chu, L., Ohta, C., Zuo, Z. & MacMillan, D. W. C. Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin. J. Am. Chem. Soc. 136, 10886–10889 (2014).

    Article  CAS  Google Scholar 

  19. Nakajima, K., Miyake, Y. & Nishibayashi, Y. Synthetic utilization of α-amino radicals and related species in visible light photoredox catalysis. Acc. Chem. Res. 49, 1946–1956 (2016).

    Article  CAS  Google Scholar 

  20. Thullen, S. M. & Rovis, T. A mild hydroaminoalkylation of conjugated dienes using a unified cobalt and photoredox catalytic system. J. Am. Chem. Soc. 139, 15504–15508 (2017).

    Article  CAS  Google Scholar 

  21. Andrieux, C. P. & Savéant, J. M. Electrodimerization: II. Reduction mechanism of immonium cations. J. Electroanal. Chem. 26, 223–235 (1970).

    Article  CAS  Google Scholar 

  22. Lee, K. N. & Ngai, M.-Y. Recent developments in transition-metal photoredox-catalysed reactions of carbonyl derivatives. Chem. Commun. 53, 13093–13112 (2017).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Capacci, A. G., Malinowski, J. T., McAlpine, M. J., Kuhne, J. & MacMillan, D. W. C. Direct, enantioselective α-alkylation of aldehydes using simple olefins. Nat. Chem. 9, 1073–1077 (2017).

    Article  CAS  Google Scholar 

  25. Dai, X. et al. The coupling of tertiary amines and acrylate derivatives via visible-light photoredox catalysis. J. Org. Chem. 79, 7212–7219 (2014).

    Article  CAS  Google Scholar 

  26. Guo, X. & Wenger, O. S. Reductive amination by photoredox catalysis and polarity-matched hydrogen atom transfer. Angew. Chem. Int. Ed. 57, 2469–2473 (2018).

    Article  CAS  Google Scholar 

  27. Flamigni, L., Barbieri, A., Sabatini, C., Ventura, B. & Barigelletti, F. Photochemistry and photophysics of coordination compounds: iridium. Top. Curr. Chem. 281, 143–203 (2007).

    Article  CAS  Google Scholar 

  28. Yu, P. et al. Enantioselective C–H bond functionalization triggered by radical trifluoromethylation of unactivated alkene. Angew. Chem. Int. Ed. 53, 11890–11894 (2014).

    Article  CAS  Google Scholar 

  29. Wayner, D. D. M., Dannenberg, J. J. & Griller, D. Oxidation potentials of α-aminoalkyl radicals: bond dissociation energies for related radical cations. Chem. Phys. Lett. 131, 189–191 (1986).

    Article  ADS  CAS  Google Scholar 

  30. Simons, F. E. R. Advances in H1-antihistamines. N. Engl. J. Med. 351, 2203–2217 (2004).

    Article  CAS  Google Scholar 

  31. Hager, A., Vrielink, N., Hager, D., Lefranc, J. & Trauner, D. Synthetic approaches towards alkaloids bearing α-tertiary amines. Nat. Prod. Rep. 33, 491–522 (2016).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Bond for X-ray crystallographic analysis, the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis, and M. Nappi, J. C. K. Chu and T. Hunt (AstraZeneca) for useful discussion. We acknowledge the Herschel Smith Scholarship Scheme and AstraZeneca for studentships (to A.T. and D.R., respectively) and the Royal Society for a Wolfson Merit Award (M.J.G.).

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  1. Department of Chemistry, University of Cambridge, Cambridge, UK

    Aaron Trowbridge, Dominik Reich & Matthew J. Gaunt

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  1. Aaron Trowbridge
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Contributions

M.J.G., A.T. and D.R. designed the experiments. A.T. and D.R. performed and analysed the experiments. M.J.G., A.T. and D.R prepared the manuscript.

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Correspondence to Matthew J. Gaunt.

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Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Figs. 1–5, Supplementary Tables 1–2, Supplementary References and 1H and 13C NMR Spectral Data.

Supplementary Data

This file contains the crystallographic information.

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Trowbridge, A., Reich, D. & Gaunt, M.J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018). https://doi.org/10.1038/s41586-018-0537-9

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