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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References
Huisgen, R. 1,3-Dipolar cycloaddition. Introduction, survey, mechanism. In 1,3-Dipolar Cycloaddition Chemistry (ed. Padwa, A.) 1–176 (Wiley, New York, 1984).
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).
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).
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).
Inglis, A.J. et al. Ultrafast click conjugation of macromolecular building blocks at ambient temperature. Angew. Chem. Int. Ed. 48, 2411–2414 (2009).
Kele, P. et al. Dual labeling of biomolecules by using click chemistry: a sequential approach. Angew. Chem. Int. Ed. 48, 344–347 (2009).
Sletten, E.M. & Bertozzi, C.R. Biorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew. Chem. Int. Ed. 48, 6974–6998 (2009).
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).
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).
Chehrehasa, F. et al. EdU, a new thymidine analogue for labeling proliferating cells in the nervous system. J. Neurosci. Methods 177, 122–130 (2009).
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).
Kostiuk, M.A. et al. Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analogue. FASEB J. 22, 721–732 (2008).
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).
Agnew, H.D. et al. Iterative in situ click chemistry creates antibody-like protein-capture agents. Angew. Chem. Int. Ed. 48, 4944–4948 (2009).
Wang, Z. et al. Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes. Diabetes 58, 309–317 (2009).
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).
Le Droumaguet, B. & Velonia, K. Click chemistry: a powerful tool to create polymer-based macromolecular chimeras. Macromol. Rapid Commun. 29, 1073–1089 (2008).
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).
Becer, C.R., Hoogenboom, R. & Schubert, U.S. Click chemistry beyond metal-catalyzed cycloaddition. Angew. Chem. Int. Ed. 48, 4900–4908 (2009).
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).
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).
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).
Moses, J.E. & Moorhouse, A.D. The growing applications of click chemistry. Chem. Soc. Rev. 36, 1249–1262 (2007).
Lipshutz, B.H. & Taft, B.R. Heterogeneous copper-in-charcoal-catalyzed click chemistry. Angew. Chem. Int. Ed. 118, 8415–8418 (2006).
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).
van Dijk, M. et al. Synthesis and characterization of biodegradable peptide-based polymers prepared by microwave-assisted click chemistry. Biomacromolecules 9, 2834–2843 (2008).
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).
Sreedhar, B. & Surendra Reddy, P. Sonochemical synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous medium. Synth. Commun. 37, 805–812 (2007).
Cintas, P. & Luche, J.-L. Organometallic sonochemistry. In Synthetic Organic Sonochemistry (ed. Luche, J.-L.) 165–234 (Plenum Press, New York, 1998).
Tuulmets, A., Kaubi, K. & Heinoja, K. Influence of sonication on Grignard reagent formation. Ultrason. Sonochem. 2, 75–78 (1995).
Kappe, C.O., Dallinger, D. & Murphree, S.S. Practical Microwave Synthesis for Organic Chemists. Strategies, Instruments, and Protocols (Wiley-VCH, Weinheim, Germany, 2009).
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).
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).
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).
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).
Mason, T.J . Practical Sonochemistry. User's Guide to Applications in Chemistry and Chemical Engineering (Ellis Horwood, London, 1991).
Cravotto, G., Omiccioli, G. & Stevanato, L. An improved sonochemical reactor Ultrason. Sonochem. 12, 213–217 (2005).
Mourer, M. et al. Click chemistry as an efficient tool to access β-cyclodextrin dimers. Tetrahedron 64, 7159–7163 (2008).
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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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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DOI: https://doi.org/10.1038/nprot.2010.1
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