Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A photochemical dehydrogenative strategy for aniline synthesis

Nature volume 584, pages 75–81 (2020)Cite this article

Subjects

Abstract

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3,4,5,6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C–H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon–nitrogen (C–N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C–N coupling protocol by preparing commercial medicines and by the late-stage amination–aromatization of natural products, steroids and terpene feedstocks.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cross-coupling strategies for aniline synthesis.
Fig. 2: Scope of the amine partner in the dehydrogenative amination.
Fig. 3: Scope of the cyclohexanone partner in the dehydrogenative amination.
Fig. 4: Synthesis of complex anilines.

Similar content being viewed by others

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

    Article  CAS  Google Scholar 

  2. Campos, K. R. et al. The importance of synthetic chemistry in the pharmaceutical industry. Science 363, eaat0805 (2019).

  3. Hartwig, J. F. Carbon–heteroatom bond-forming reductive eliminations of amines, ethers, and sulfides. Acc. Chem. Res. 31, 852–860 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. West, M. J., Fyfe, J. W. B., Vantourout, J. C. & Watson, A. J. B. Mechanistic development and recent applications of the Chan–Lam amination. Chem. Rev. 119, 12491–12523 (2019).

    Article  CAS  Google Scholar 

  6. Beletskaya, I. P. & Cheprakov, V. A. Copper in cross-coupling reactions: the post-Ullmann chemistry. Coord. Chem. Rev. 248, 2337–2364 (2004).

    Article  CAS  Google Scholar 

  7. MacMillan, D. W. C. The advent and development of organocatalysis. Nature 455, 304–308 (2008).

    Article  ADS  CAS  Google Scholar 

  8. Crawley, M. L. & Trost, B. M. Applications Of Transition Metal Catalysis In Drug Discovery And Development: An Industrial Perspective (John Wiley & Sons, 2012).

  9. Hartwig, J. F. Carbon–heteroatom bond formation catalyzed by organometallic complexes. Nature 455, 314–322 (2008).

    Article  ADS  CAS  Google Scholar 

  10. Olah, G. A. Friedel-Crafts And Related Reactions (Wiley, 1963).

  11. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C-H activation for the construction of C-B bonds. Chem. Rev. 110, 890–931 (2010).

    Article  CAS  Google Scholar 

  12. Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C-H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    Article  ADS  CAS  Google Scholar 

  13. Ruffoni, A. et al. Practical and regioselective amination of arenes using alkylamines. Nat. Chem. 11, 426–433 (2019).

    Article  CAS  Google Scholar 

  14. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    Article  CAS  Google Scholar 

  15. Johnsson, K., Allemann, R. K., Widmer, H. & Benner, S. A. Synthesis, structure and activity of artificial, rationally designed catalytic polypeptides. Nature 365, 530–532 (1993).

    Article  ADS  CAS  Google Scholar 

  16. Grondal, C., Jeanty, M. & Enders, D. Organocatalytic cascade reactions as a new tool in total synthesis. Nat. Chem. 2, 167–178 (2010).

    Article  CAS  Google Scholar 

  17. Silvi, M. & Melchiorre, P. Enhancing the potential of enantioselective organocatalysis with light. Nature 554, 41–49 (2018).

    Article  ADS  CAS  Google Scholar 

  18. Izawa, Y., Pun, D. & Stahl, S. S. Palladium-catalyzed aerobic dehydrogenation of substituted cyclohexanones to phenols. Science 333, 209–213 (2011).

    Article  ADS  CAS  Google Scholar 

  19. Koizumi, Y. et al. Selective synthesis of primary anilines from NH3 and cyclohexanones by utilizing preferential adsorption of styrene on the Pd nanoparticle surface. Angew. Chem. Int. Ed. 58, 10893–10897 (2019).

    Article  CAS  Google Scholar 

  20. Hong, W. P., Iosub, A. V. & Stahl, S. S. Pd-catalyzed Semmler–Wolff reactions for the conversion of substituted cyclohexenone oximes to primary anilines. J. Am. Chem. Soc. 135, 13664–13667 (2013).

    Article  CAS  Google Scholar 

  21. Li, Y., Wang, D., Zhang, L. & Luo, S. Redox property of enamines. J. Org. Chem. 84, 12071–12090 (2019).

    Article  CAS  Google Scholar 

  22. Pirnot, M. T., Rankic, D. A., Martin, D. B. C. & MacMillan, D. W. C. Photoredox activation for the direct β-arylation of ketones and aldehydes. Science 339, 1593–1596 (2013).

    Article  ADS  CAS  Google Scholar 

  23. West, J. G., Huang, D. & Sorensen, E. J. Acceptorless dehydrogenation of small molecules through cooperative base metal catalysis. Nat. Commun. 6, 10093 (2015).

    Article  ADS  Google Scholar 

  24. Sun, X., Chen, J. & Ritter, T. Catalytic dehydrogenative decarboxyolefination of carboxylic acids. Nat. Chem. 10, 1229–1233 (2018).

    Article  CAS  Google Scholar 

  25. Weiss, M. E., Kreis, L. M., Lauber, A. & Carreira, E. M. Cobalt-catalyzed coupling of alkyl iodides with alkenes: deprotonation of hydridocobalt enables turnover. Angew. Chem. Int. Ed. 50, 11125–11128 (2011).

    Article  CAS  Google Scholar 

  26. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  Google Scholar 

  27. Nicholas, A. M. P. & Arnold, D. R. Thermochemical parameters for organic radicals and radical ions. Part 1. The estimation of the pKa of radical cations based on thermochemical calculations. Can. J. Chem. 60, 2165–2179 (1982).

    Article  CAS  Google Scholar 

  28. Gridnev, A. A. & Ittel, S. D. Catalytic chain transfer in free-radical polymerizations. Chem. Rev. 101, 3611–3660 (2001).

    Article  CAS  Google Scholar 

  29. Dempsey, J. L., Brunschwig, B. S., Winkler, J. R. & Gray, H. B. Hydrogen evolution catalyzed by cobaloximes. Acc. Chem. Res. 42, 1995–2004 (2009).

    Article  CAS  Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. Santanilla, A. B. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).

    Article  ADS  Google Scholar 

  32. Park, N. H., Vinogradova, E. V., Surry, D. S. & Buchwald, S. L. Design of new ligands for the palladium-catalyzed arylation of α-branched secondary amines. Angew. Chem. Int. Ed. 54, 8259–8262 (2015).

    Article  CAS  Google Scholar 

  33. Morris, S. A., Wang, J. & Zheng, N. The prowess of photogenerated amine radical cations in cascade reactions: from carbocycles to heterocycles. Acc. Chem. Res. 49, 1957–1968 (2016).

    Article  CAS  Google Scholar 

  34. Brusoe, A. T. & Hartwig, J. F. Palladium-catalyzed arylation of fluoroalkylamines. J. Am. Chem. Soc. 137, 8460–8468 (2015).

    Article  CAS  Google Scholar 

  35. Dobrikov, G. M. et al. Synthesis and anti-enterovirus activity of new analogues of MDL-860. Bioorg. Med. Chem. Lett. 27, 4540–4543 (2017).

    Article  CAS  Google Scholar 

  36. Sulur, M. et al. Development of scalable manufacturing routes to AZD1981. Application of the Semmler–Wolff aromatisation for synthesis of the indole-4-amide core. Org. Process Res. Dev. 16, 1746–1753 (2012).

    Article  CAS  Google Scholar 

  37. Zhao, Y., Yim, W.-L., Tan, C. K. & Yeung, Y.-Y. An unexpected oxidation of unactivated methylene C–H using DIB/TBHP protocol. Org. Lett. 13, 4308–4311 (2011).

    Article  CAS  Google Scholar 

  38. Cooke, J., Glover, B. N., Lawrence, R. M., Sharp, M. J. & Tymoschenko, M. F. WO 02/066418 (Glaxo-SmithKline, 2002).

  39. See, Y. Y., Dang, T. T., Chen, A. & Seayad, A. M. Concise synthesis of vesnarinone and its analogues by using Pd-catalyzed C–N bond-forming reactions. Eur. J. Org. Chem. 2014, 7405–7412 (2014).

Download references

Acknowledgements

D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and the European Research Council for a research grant (758427). S.U.D. thanks the Marie Curie Actions for a Fellowship (791349).

Author information

Authors and Affiliations

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

    Shashikant U. Dighe, Fabio Juliá, Alberto Luridiana & Daniele Leonori

  2. Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK

    James J. Douglas

Authors
  1. Shashikant U. Dighe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Juliá
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Luridiana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James J. Douglas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniele Leonori
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.U.D. and D.L. designed the project. S.U.D., F.J. and A.L. performed all experiments. All the authors analysed the results. D.L., F.J. and J.J.D. wrote the manuscript.

Corresponding author

Correspondence to Daniele Leonori.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Edward Anderson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

The Supplementary Information file contains the following sections: (1) general experimental details; (2) starting material synthesis; (3) reaction optimization; (4) pictures of reaction set-up; (5) substrate scope; (6) mechanistic considerations; (7) NMR spectra; and (8) references.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

U. Dighe, S., Juliá, F., Luridiana, A. et al. A photochemical dehydrogenative strategy for aniline synthesis. Nature 584, 75–81 (2020). https://doi.org/10.1038/s41586-020-2539-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-020-2539-7

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing