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.

Multicomponent alkene azidoarylation by anion-mediated dual catalysis

Abstract

Molecules that contain the β-arylethylamine motif have applications in the modulation of pain, treatment of neurological disorders and management of opioid addiction, among others, making it a privileged scaffold in drug discovery1,2. De novo methods for their assembly are reliant on transformations that convert a small class of feedstocks into the target compounds via time-consuming multistep syntheses3,4,5. Synthetic invention can drive the investigation of the chemical space around this scaffold to further expand its capabilities in biology6,7,8,9. Here we report the development of a dual catalysis platform that enables a multicomponent coupling of alkenes, aryl electrophiles and a simple nitrogen nucleophile, providing single-step access to synthetically versatile and functionally diverse β-arylethylamines. Driven by visible light, two discrete copper catalysts orchestrate aryl-radical formation and azido-group transfer, which underpin an alkene azidoarylation process. The process shows broad scope in alkene and aryl components and an azide anion performs a multifaceted role both as a nitrogen source and in mediating the redox-neutral dual catalysis via inner-sphere electron transfer10,11. The synthetic capabilities of this anion-mediated alkene functionalization process are likely to be of use in a variety of pharmaceutically relevant and wider synthetic applications.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Background and concept.
Fig. 2: Development of alkene azidoarylation reaction.
Fig. 3: Scope of alkene azidoarylation reaction.
Fig. 4: Alkene azidoarylation as a powerful method to explore the chemical space around the Akt inhibitor CCT128930.
Fig. 5: Mechanistic investigation of the alkene azidoarylation reaction.

Data availability

Materials and methods, optimization studies, experimental procedures, mechanistic studies, 1H NMR, 13C NMR and 19F NMR spectra, and high-resolution mass spectrometry, infrared, ultraviolet–visible and cyclic voltammetry data are available in the Supplementary Information. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under the reference numbers CCDC 2027142, CCDC 2027143 and CCDC 2032989. Raw data are available from the corresponding author on reasonable request.

References

  1. 1.

    Freeman, S. & Alder, J. F. Arylethylamine psychotropic recreational drugs: a chemical perspective. Eur. J. Med. Chem. 37, 527–539 (2002).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Dalley, J. W. & Everitt, B. J. Dopamine receptors in the learning, memory and drug reward circuitry. Semin. Cell Dev. Biol. 20, 403–410 (2009).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Barton, D. H. R., Bracho, R. D. & Widdowson, D. A. A new β-arylethylamine synthesis by aryl aldehyde homologation. J. Chem. Soc. Chem. Commun. 781a–781a (1973).

  4. 4.

    Schulze, M. Synthesis of 2-arylethylamines by the curtius rearrangement. Synth. Commun. 40, 1461–1476 (2010).

    CAS  Article  Google Scholar 

  5. 5.

    Bracher, F. Methods for arylethylation of amines and heteroarenes. SynOpen 02, 0096–0104 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Müller, T. E., Hultzsch, K. C., Yus, M., Foubelo, F. & Tada, M. Hydroamination: direct addition of amines to alkenes and alkynes. Chem. Rev. 108, 3795–3892 (2008).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Nguyen, T. M., Manohar, N. & Nicewicz, D. A. Anti-Markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: direct access to phenethylamine derivatives. Angew. Chem. Int. Edn 53, 6198–6201 (2014).

    CAS  Article  Google Scholar 

  8. 8.

    Boyington, A. J., Seath, C. P., Zearfoss, A. M., Xu, Z. & Jui, N. T. Catalytic strategy for regioselective arylethylamine synthesis. J. Am. Chem. Soc. 141, 4147–4153 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Estrada, J. G., Williams, W. L., Ting, S. I. & Doyle, A. G. Role of electron-deficient olefin ligands in a Ni-catalyzed aziridine cross-coupling to generate quaternary carbons. J. Am. Chem. Soc. 142, 8928–8937 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Haim, A. Role of the bridging ligand in inner-sphere electron-transfer reactions. Acc. Chem. Res. 8, 264–272 (1975).

    CAS  Article  Google Scholar 

  11. 11.

    Rorabacher, D. B. Electron transfer by copper centers. Chem. Rev. 104, 651–698 (2004).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Zeng, W. & Chemler, S. R. Copper(II)-catalyzed enantioselective intramolecular carboamination of alkenes. J. Am. Chem. Soc. 129, 12948–12949 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Zhang, G., Cui, L., Wang, Y. & Zhang, L. Homogeneous gold-catalyzed oxidative carboheterofunctionalization of alkenes. J. Am. Chem. Soc. 132, 1474–1475 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Brenzovich, W. E. Jr et al. Gold-catalyzed intramolecular aminoarylation of alkenes: C–C bond formation through bimolecular reductive elimination. Angew. Chem. Int. Edn 49, 5519–5522 (2010).

    CAS  Article  Google Scholar 

  15. 15.

    Schultz, D. M. & Wolfe, J. P. Recent developments in palladium-catalyzed alkene aminoarylation reactions for the synthesis of nitrogen heterocycles. Synthesis 44, 351–361 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Yang, H.-B., Pathipati, S. R. & Selander, N. Nickel-catalyzed 1,2-aminoarylation of oxime ester-tethered alkenes with boronic acids. ACS Catal. 7, 8441–8445 (2017).

    CAS  Article  Google Scholar 

  17. 17.

    Lerchen, A., Knecht, T., Daniliuc, C. G. & Glorius, F. Unnatural amino acid synthesis enabled by the regioselective cobalt(III)-catalyzed intermolecular carboamination of alkenes. Angew. Chem. Int. Edn 55, 15166–15170 (2016).

    CAS  Article  Google Scholar 

  18. 18.

    Liu, Z. et al. Catalytic intermolecular carboamination of unactivated alkenes via directed aminopalladation. J. Am. Chem. Soc. 139, 11261–11270 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    van der Puyl, V. A., Derosa, J. & Engle, K. M. Directed, nickel-catalyzed umpolung 1,2-carboamination of alkenyl carbonyl compounds. ACS Catal. 9, 224–229 (2019).

    Article  CAS  Google Scholar 

  20. 20.

    Jiang, H. & Studer, A. Intermolecular radical carboamination of alkenes. Chem. Soc. Rev. 49, 1790–1811 (2020).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Monos, T. M., McAtee, R. C. & Stephenson, C. R. J. Arylsulfonylacetamides as bifunctional reagents for alkene aminoarylation. Science 361, 1369–1373 (2018).

    CAS  PubMed  Article  ADS  Google Scholar 

  22. 22.

    Wang, D. et al. Asymmetric copper-catalyzed intermolecular aminoarylation of styrenes: efficient access to optical 2,2-diarylethylamines. J. Am. Chem. Soc. 139, 6811–6814 (2017).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Heinrich, M. R., Blank, O. & Wölfel, S. Reductive carbodiazenylation of nonactivated olefins via aryl diazonium salts. Org. Lett. 8, 3323–3325 (2006).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Fumagalli, G., Boyd, S. & Greaney, M. F. Oxyarylation and aminoarylation of styrenes using photoredox catalysis. Org. Lett. 15, 4398–4401 (2013).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    PrasadHari, D., Hering, T. & König, B. The photoredox-catalyzed meerwein addition reaction: intermolecular amino-arylation of alkenes. Angew. Chem. Int. Edn 53, 725–728 (2014).

    CAS  Article  Google Scholar 

  26. 26.

    Cativiela, C. & Díaz-de-Villegas, M. D. Recent progress on the stereoselective synthesis of acyclic quaternary α-amino acids. Tetrahedron Asymmetry 18, 569–623 (2007).

    CAS  Article  Google Scholar 

  27. 27.

    Venkatraman, J., Shankaramma, S. C. & Balaram, P. Design of folded peptides. Chem. Rev. 101, 3131–3152 (2001).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    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).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Clayden, J., Donnard, M., Lefranc, J. & Tetlow, D. J. Quaternary centres bearing nitrogen (α-tertiary amines) as products of molecular rearrangements. Chem. Commun. 47, 4624–4639 (2011).

    CAS  Article  Google Scholar 

  30. 30.

    Leggans, E. K., Barker, T. J., Duncan, K. K. & Boger, D. L. Iron(III)/NaBH4-mediated additions to unactivated alkenes: synthesis of novel 20′-vinblastine analogues. Org. Lett. 14, 1428–1431 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Huang, X., Bergsten, T. M. & Groves, J. T. Manganese-catalyzed late-stage aliphatic C–H azidation. J. Am. Chem. Soc. 137, 5300–5303 (2015).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Bunescu, A., Ha, T. M., Wang, Q. & Zhu, J. Copper-catalyzed three-component carboazidation of alkenes with acetonitrile and sodium azide. Angew. Chem. Int. Edn 56, 10555–10558 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Fu, N., Sauer, G. S., Saha, A., Loo, A. & Lin, S. Metal-catalyzed electrochemical diazidation of alkenes. Science 357, 575–579 (2017).

    CAS  PubMed  Article  ADS  Google Scholar 

  34. 34.

    Heinrich, M. R. Intermolecular olefin functionalisation involving aryl radicals generated from arenediazonium salts. Chem. Eur. J. 15, 820–833 (2009).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Fischer, H. & Radom, L. Factors controlling the addition of carbon-centered radicals to alkenes—an experimental and theoretical perspective. Angew. Chem. Int. Edn 40, 1340–1371 (2001).

    CAS  Article  Google Scholar 

  36. 36.

    Odian, G.in Principles of Polymerization (ed. Odian, G.) 198–349 (Wiley, 2004); https://doi.org/10.1002/047147875X.ch3.

  37. 37.

    Tang, W. et al. Understanding atom transfer radical polymerization: effect of ligand and initiator structures on the equilibrium constants. J. Am. Chem. Soc. 130, 10702–10713 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Qiu, J., Matyjaszewski, K., Thouin, L. & Amatore, C. Cyclic voltammetric studies of copper complexes catalyzing atom transfer radical polymerization. Macromol. Chem. Phys. 201, 1625–1631 (2000).

    CAS  Article  Google Scholar 

  39. 39.

    Caldwell, J. J. et al. Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J. Med. Chem. 51, 2147–2157 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Addie, M. et al. Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J. Med. Chem. 56, 2059–2073 (2013).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Goel, P. et al. Recent advancement of piperidine moiety in treatment of cancer—a review. Eur. J. Med. Chem. 157, 480–502 (2018).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Suh, S.-E. et al. Site-selective copper-catalyzed azidation of benzylic C–H bonds. J. Am. Chem. Soc. 142, 11388–11393 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Alfassi, Z. B., Harriman, A., Huie, R. E., Mosseri, S. & Neta, P. The redox potential of the azide/azidyl couple. J. Phys. Chem. 91, 2120–2122 (1987).

    CAS  Article  Google Scholar 

  44. 44.

    Pavlishchuk, V. V. & Addison, A. W. Conversion constants for redox potentials measured versus different reference electrodes in acetonitrile solutions at 25 °C. Inorg. Chim. Acta 298, 97–102 (2000).

    CAS  Article  Google Scholar 

  45. 45.

    Bard, A. Standard Potentials in Aqueous Solution (Routledge, 1985).

  46. 46.

    Zhou, J. & Fu, G. C. Cross-couplings of unactivated secondary alkyl halides: room-temperature nickel-catalyzed Negishi reactions of alkyl bromides and iodides. J. Am. Chem. Soc. 125, 14726–14727 (2003).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Wang, Z., Yin, H. & Fu, G. C. Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563, 379–383 (2018).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

Download references

Acknowledgements

We thank the Herchel Smith Fund at the University of Cambridge for a postdoctoral fellowship to A.B., the AstraZeneca–University of Cambridge PhD programme for studentship (Y.A.) and the Royal Society for Wolfson Merit Award to M.J.G.

Author information

Affiliations

Authors

Contributions

A.B. and M.J.G. conceived the project. A.B. and Y.A. conducted the experiments. A.B., Y.A. and M.J.G. analysed and interpreted the results. A.B., Y.A. and M.J.G. wrote the manuscript.

Corresponding author

Correspondence to Matthew J. Gaunt.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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

Supplementary information

Supplementary Information

This file contains Supplementary Text, Materials and Methods, Figs. 1–40, Tables 1–10 and Refs. 1–155.

Peer Review File

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bunescu, A., Abdelhamid, Y. & Gaunt, M.J. Multicomponent alkene azidoarylation by anion-mediated dual catalysis. Nature 598, 597–603 (2021). https://doi.org/10.1038/s41586-021-03980-8

Download citation

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

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