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Alkyne–azide click reaction catalyzed by metallic copper under ultrasound

Abstract

This protocol is for the ultrasound (US)-assisted 1,3-dipolar cycloaddition reaction of azides and alkynes using metallic copper (Cu) as the catalyst. The azido group is a willing participant in this kind of organic reaction and its coupling with alkynes is substantially improved in the presence of Cu(I). This protocol does not require additional ligands and proceeds with excellent yields. The Cu-catalyzed azide–alkyne cycloaddition (CuAAC) is generally recognized as the most striking example of 'click chemistry'. Reactions involving metals represent the favorite domain of sonochemistry because US favors mechanical depassivation and enhances both mass transfer and electron transfer from the metal to the organic acceptor. The reaction rate increases still further when simultaneous US and microwave irradiation are applied. The US-assisted click synthesis has been applied for the preparation of a wide range of 1,4-disubstituted 1,2,3-triazole derivatives starting both from small molecules and oligomers such as cyclodextrins (CDs). Using this efficient and greener protocol, all the adducts can be synthesized in 2–4 h (including work-up and excluding characterization). Click chemistry has been shown to be able to directly link chemistry to biology, thus becoming a true interdisciplinary reaction with extremely wide applicability.

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Figure 1: Examples of copper-catalyzed azide–alkyne cycloaddition (CuAAC) with phenylacetylene under ultrasound (US) irradiation.
Figure 2: Ultrasound (US) reactor.
Figure 3: Septa for horn probe.
Figure 4
Figure 5: Complete assembling of high-intensity ultrasound (US) device (probe system with the titanium horn and the electronic generator) and a silicon oil bath on a heating plate.
Figure 6: Combined ultrasound (US)/microwave (MW) system.
Figure 7
Figure 8
Figure 9: The reaction in progress.
Figure 10: Note the complete reaction setup (horn, septa and internal temperature probe).

References

  1. Huisgen, R. 1,3-Dipolar cycloaddition. Introduction, survey, mechanism. In 1,3-Dipolar Cycloaddition Chemistry (ed. Padwa, A.) 1–176 (Wiley, New York, 1984).

    Google Scholar 

  2. Padwa, A. Intermolecular 1,3-dipolar cycloaddition. In Comprehensive Organic Synthesis Vol. 4 (eds. Trost, B.M. & Fleming, I.) 1069–1109 (Pergamon, Oxford, UK, 1994).

    Google Scholar 

  3. Rostovtsev, V.V. et al. A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective 'ligation' of azides and terminal alkynes. Angew. Chem. Int. Ed. 41, 2596–2599 (2002).

    CAS  Article  Google Scholar 

  4. Tornoe, C.W., Christensen, C. & Meldal, M. Peptidotriazoles on solid phase: 1,2,30-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 67, 3057–3064 (2002).

    CAS  Article  Google Scholar 

  5. Inglis, A.J. et al. Ultrafast click conjugation of macromolecular building blocks at ambient temperature. Angew. Chem. Int. Ed. 48, 2411–2414 (2009).

    CAS  Article  Google Scholar 

  6. Kele, P. et al. Dual labeling of biomolecules by using click chemistry: a sequential approach. Angew. Chem. Int. Ed. 48, 344–347 (2009).

    CAS  Article  Google Scholar 

  7. Sletten, E.M. & Bertozzi, C.R. Biorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew. Chem. Int. Ed. 48, 6974–6998 (2009).

    CAS  Article  Google Scholar 

  8. Kharas, M.G. et al. Ablation of PI3 K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL + leukemia cells. J. Clin. Invest. 118, 3038–3050 (2008).

    CAS  Article  Google Scholar 

  9. Limsirichaikul, S. et al. A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU). Nucleic Acids Res. 37, e31 (2009).

    Article  Google Scholar 

  10. Chehrehasa, F. et al. EdU, a new thymidine analogue for labeling proliferating cells in the nervous system. J. Neurosci. Methods 177, 122–130 (2009).

    CAS  Article  Google Scholar 

  11. Jao, C.Y. & Salic, A. Exploring RNA transcription and turnover in vivo by using click chemistry. Proc. Natl. Acad. Sci. USA 105, 15779–15784 (2008).

    CAS  Article  Google Scholar 

  12. Kostiuk, M.A. et al. Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analogue. FASEB J. 22, 721–732 (2008).

    CAS  Article  Google Scholar 

  13. Martin, D.D. et al. Rapid detection, discovery, and identification of post-translationally myristoylated proteins during apoptosis using a bio-orthogonal azidomyristate analog. FASEB J. 22, 797–806 (2008).

    CAS  Article  Google Scholar 

  14. Agnew, H.D. et al. Iterative in situ click chemistry creates antibody-like protein-capture agents. Angew. Chem. Int. Ed. 48, 4944–4948 (2009).

    CAS  Article  Google Scholar 

  15. Wang, Z. et al. Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes. Diabetes 58, 309–317 (2009).

    CAS  Article  Google Scholar 

  16. Rowan, A.S. et al. Nucleoside triphosphate mimicry: a sugar triazolyl nucleoside as an ATP-competitive inhibitor of B. anthracis pantothenate kinase. Org. Biomol. Chem. 7, 4029–4036 (2009).

    CAS  Article  Google Scholar 

  17. Le Droumaguet, B. & Velonia, K. Click chemistry: a powerful tool to create polymer-based macromolecular chimeras. Macromol. Rapid Commun. 29, 1073–1089 (2008).

    CAS  Article  Google Scholar 

  18. Agard, N.J., Prescher, J.A. & Bertozzi, C.R. A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. J. Am. Chem. Soc. 126, 15046–15047 (2004).

    CAS  Article  Google Scholar 

  19. Becer, C.R., Hoogenboom, R. & Schubert, U.S. Click chemistry beyond metal-catalyzed cycloaddition. Angew. Chem. Int. Ed. 48, 4900–4908 (2009).

    CAS  Article  Google Scholar 

  20. Himo, F. et al. Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc. 127, 210–216 (2005).

    CAS  Article  Google Scholar 

  21. Gommermann, N., Gehrig, A. & Knochel, P. Enantioselective synthesis of chiral α-aminoalkyl-1,2,3-triazoles using a three-component reaction. Synlett 2796–2798 (2005).

  22. Pachòn, L.D., van Maarseveen, J.H. & Rothenberg, G. Click chemistry: Copper clusters catalyse the cycloaddition of azides with terminal alkynes. Adv. Synth. Catal. 347, 811–815 (2005).

    Article  Google Scholar 

  23. Moses, J.E. & Moorhouse, A.D. The growing applications of click chemistry. Chem. Soc. Rev. 36, 1249–1262 (2007).

    CAS  Article  Google Scholar 

  24. Lipshutz, B.H. & Taft, B.R. Heterogeneous copper-in-charcoal-catalyzed click chemistry. Angew. Chem. Int. Ed. 118, 8415–8418 (2006).

    Article  Google Scholar 

  25. Cintas, P. et al. Improved protocols for microwave-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloadditions. Collect. Czech. Chem. Commun. 72, 1014–1024 (2007).

    CAS  Article  Google Scholar 

  26. van Dijk, M. et al. Synthesis and characterization of biodegradable peptide-based polymers prepared by microwave-assisted click chemistry. Biomacromolecules 9, 2834–2843 (2008).

    CAS  Article  Google Scholar 

  27. Appukkuttan, P. et al. A microwave-assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles via a copper(I)-catalyzed three-component reaction. Org. Lett. 6, 4223–4225 (2004).

    CAS  Article  Google Scholar 

  28. Sreedhar, B. & Surendra Reddy, P. Sonochemical synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous medium. Synth. Commun. 37, 805–812 (2007).

    CAS  Article  Google Scholar 

  29. Cintas, P. & Luche, J.-L. Organometallic sonochemistry. In Synthetic Organic Sonochemistry (ed. Luche, J.-L.) 165–234 (Plenum Press, New York, 1998).

    Google Scholar 

  30. Tuulmets, A., Kaubi, K. & Heinoja, K. Influence of sonication on Grignard reagent formation. Ultrason. Sonochem. 2, 75–78 (1995).

    Article  Google Scholar 

  31. Kappe, C.O., Dallinger, D. & Murphree, S.S. Practical Microwave Synthesis for Organic Chemists. Strategies, Instruments, and Protocols (Wiley-VCH, Weinheim, Germany, 2009).

    Google Scholar 

  32. Cravotto, G. & Cintas, P. Power ultrasound in organic synthesis: moving cavitational chemistry from academia to innovative and large-scale applications. Chem. Soc. Rev. 35, 180–196 (2006).

    CAS  Article  Google Scholar 

  33. Cravotto, G. & Cintas, P. The combined use of microwaves and ultrasound: new tools in process chemistry and organic synthesis. Chem. Eur. J. 13, 1902–1909 (2007).

    CAS  Article  Google Scholar 

  34. Cravotto, G., Fokin, V.V., Garella, D., Binello, A., Boffa, L. & Barge, A. Ultrasound-promoted copper-catalyzed azide-alkyne cycloaddition. J. Comb. Chem. 12, 13–15 (2010).

    CAS  Article  Google Scholar 

  35. Santos, H.M., Lodeiro, C. & Capelo-Martinez, J.-L. in Ultrasound in Chemistry. Analytical Applications (ed. Capelo-Martinez, J.-L.) Ch. 1 (Wiley-VCH, Weinheim, Germany, 2009).

  36. Mason, T.J . Practical Sonochemistry. User's Guide to Applications in Chemistry and Chemical Engineering (Ellis Horwood, London, 1991).

  37. Cravotto, G., Omiccioli, G. & Stevanato, L. An improved sonochemical reactor Ultrason. Sonochem. 12, 213–217 (2005).

    CAS  Article  Google Scholar 

  38. Mourer, M. et al. Click chemistry as an efficient tool to access β-cyclodextrin dimers. Tetrahedron 64, 7159–7163 (2008).

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by the University of Turin and the Regione Piemonte (NanoSAFE—2004 and NanoIGT Project—2007).

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All authors contributed extensively to the work presented in this paper. P.C. designed experiments and contributed to the preparation of the manuscript; A.B. and S.T. carried out all the analysis and the purifications giving the NMR attributions; L.B. carried out all the experiments optimizing the equipments set up; and G.C. supervised all the work and wrote the manuscript.

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Correspondence to Giancarlo Cravotto.

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Cintas, P., Barge, A., Tagliapietra, S. et al. Alkyne–azide click reaction catalyzed by metallic copper under ultrasound. Nat Protoc 5, 607–616 (2010). https://doi.org/10.1038/nprot.2010.1

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