10.1021/ol201409j r 2011 American Chemical Society Published on Web 06/06/2011 ORGANIC LETTERS 2011 Vol. 13, No. 13 3542–3545 Consecutive Condensation, CN and NN Bond Formations: A Copper- Catalyzed One-Pot Three-Component Synthesis of 2H-Indazole Manian Rajesh Kumar, Ahbyeol Park, Namjin Park, and Sunwoo Lee* Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju, 500-757, Republic of Korea sunwoo@chonnam.ac.kr Received May 25, 2011 ABSTRACT 2H-Indazoles are synthesized using copper-catalyzed, one-pot, three-component reactions of 2-bromobenzaldehydes, primary amines, and sodium azide. A copper catalyst plays the key role in the formation of CN and NN bonds. This method has a broad substrate scope with a high tolerance for a variety of functional groups. Over the past decade, researchers have been interested in the structure of indazoles in the field of drug discovery because indazoles act as efficient bioisosteres of indoles and benzimidazoles. 1 The indazole unit has been found in pharmaceutical materials with a broad range of biological properties, including antitumor activity, 2 HIV protease inhibition, 3 antimicrobial activity, 4 and anti-inflammatory activity. 5 A variety of synthetic methods for the production of indazoles have been reported. However, most studies have attempted to obtain the thermodynamically favored 1H-indazole, whereas much less attention has been paid to efficient methods of synthesizing 2H-indazole. 6 Recently, a number of important biologically active compounds bearing 2H-indazole have been shown to have potent affinity for 5-HT 1A receptors, 7 estrogen receptor β, 8 and high affinity to the imidazoline I 2 receptor. 9 Considering the potent bioactivities of compounds pos- sessing a 2H-indazole core, the development of new stra- tegies for the efficient synthesis of 2H-indazole is needed. 10 Recently, four newly developed approaches have been (1) (a) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 4073. (b) Clutterbuck, L. A.; Posada, C. G.; Visintin, C.; Riddal, D. R.; Lancaster, B.; Gane, P. J.; Garthwaite, J.; Selwood, D. L. J. Med. Chem. 2009, 52, 2694. (2) (a) Baraldi, P. G.; Balboni, G.; Pavani, M. G.; Spalluto, G.; Tabrizi, M. A.; Clercq, E.; De.; Balzarini, J.; Bando, T.; Sugiyama, H.; Romagnoli, R. J. Med. Chem. 2001, 44, 2536. (b) Qian, S.; Cao, J.; Yan, Y.; Sun, M.; Zhu, H.; Hu, Y.; He, Q.; Yang, B. Mol. Cell. Biochem. 2010, 345, 13. (3) Han, W.; Pelletier, J. C.; Hodge, C. N. Bioorg. Med. Chem. Lett. 1998, 8, 3615. (4) Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.; Levin, J.; Sparankle, K. G.; Fedder, M. E.; Almassy, R.; Appelt, K.; Yager, K. M. J. Med. Chem. 2003, 46, 5663. (5) Picciola, G.; Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M. Farmaco Ed. Sci. 1981, 36, 1037. (6) (a) Molina, P.; Arques, A.; Vinader, M. V. Tetrahedron Lett. 1989, 30, 6237. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (c) Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197. (d) Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett. 1999, 40, 2747. (e) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519. (7) Andreonati, S.; Sava, V.; Makan, S.; Kolodeev, G. Pharmazie 1999, 54, 99. (8) Angelis, M. D.; Stossi, F.; Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2005, 48, 1132. (9) Saczewski, F.; Saczewski, J.; Hudson, A. L.; Tyacke, R. J.; Nutt, D. J.; Man, J.; Tabin, P. Eur. J. Pharm. Sci. 2003, 20, 201. (10) The derivatization of 2H-indazoles has been reported. See: (a) Slade, D. J.; Pelz, N. F.; Bodnar, W.; Lampe, J. W.; Watson, P. S. J. Org. Chem. 2009, 74, 6331. (b) Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12, 224.