Copper(II)/Copper(I)-Catalyzed Aza-Michael Addition/Click Reaction of in Situ Generated r-Azidohydrazones: Synthesis of Novel Pyrazolone-Triazole Framework Orazio A. Attanasi, Gianfranco Favi,* Paolino Filippone, Fabio Mantellini, Giada Moscatelli, and Francesca R. Perrulli Istituto di Chimica Organica, UniVersita ` degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino (PU), Italy gianfranco.faVi@uniurb.it Received November 16, 2009 ABSTRACT A one-pot Cu(II)-catalyzed aza-Michael addition of trimethylsilyl azide to 1,2-diaza-1,3-dienes and Cu(I)-catalyzed 1,3-dipolar cycloaddition of in situ generated r-azidohydrazones with alkynes is reported. This process combining two consecutive steps with recycling of the catalyst (Cu(OAc) 2 ·H 2 O) represents a useful protocol for the smooth synthesis of novel pyrazolone-triazole derivatives. Nitrogen-containing heterocycles (azaheterocycles) occur in a wide variety of natural and biologically active compounds. 1 From a recent survey of GMP bulk reactions run in a research facility (Pfizer-Groton) it is estimated that over 90% of pharmaceutical have at least one nitrogen atom in their structure and about one reaction out of seven in the pharmaceutical industry involves the formation of a carbon-nitrogen bond. 2 For these reasons, efficient methods for the synthesis of nitrogen-containing molecules merits further investigations. Surprisingly, little attention has been focused on the copper- promoted C-N bond formation-based protocols. 3 Among them, undoubtedly, “click reaction” 4 and in particular Huisgen [3 + 2] cycloaddition 5 has emerged as a “near perfect” (very fast, selective, high-yield, and wide scope) carbon-nitrogen bond forming reaction toward the synthesis of N-substituted 1,2,3- triazoles. This process that occurs between organic azides and alkynes is significantly accelerated by Cu(I) catalysis, 6 and it offers easy access to the 1,4-disubstituted isomer. 1,2,3-Triazoles have found numerous applications ranging from chemical and combinatorial synthesis, bioconjugation and biology, to material science, especially polymer and dendrimer synthesis. 7 Despite (1) See, for example: The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 2000; Vol. 54;and others in this series. (2) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337–2347. (b) Duggers, R. W.; Ragan, J. A.; Brown Ripin, D. H. Org. Process Res. DeV. 2005, 9, 253–258. (3) For a review on copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis, see: Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054–3131. (4) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. (5) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 1-177. (6) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3062. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (7) For general reviews on the chemistry of 1,2,3-triazoles, see: (a) Fan, W.-Q.; Katritzky, A. R. ComprehensiVe Heterocyclic Chemistry II; Katritz- ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, 1986; Vol. 4, pp 1-126. For some applications in organic synthesis, see: (b) Dichtel, W. R.; Miljanic, O. S.; Spruel, J. M.; Health, J. R.; Stoddart, J. F. J. Am. Chem. Soc. 2006, 128, 10388–10390. In combinatorial chemistry, see: (c) Rodriguez-Loaiza, P.; Lo ¨ber, S.; Hu ¨bner, H.; Gmeiner, P. J. Comb. Chem. 2006, 8, 252–261. In bioconjugation, see: (d) Cavalli, S.; Tipton, A. R.; Ovarhand, M.; Kros, A. Chem. Commun. 2006, 3193– 3195. In materials and surface science, see: (e) Such, G. K.; Quinn, J. F.; Quinn, A.; Tjipto, E.; Caruso, F. J. Am. Chem. Soc. 2006, 128, 9318–9319. ORGANIC LETTERS 2010 Vol. 12, No. 3 468-471 10.1021/ol902642z  2010 American Chemical Society Published on Web 12/31/2009