Synthesis of Polysubstituted Imidazo[1,2-a]pyridines via Microwave-Assisted One-Pot Cyclization/Suzuki Coupling/ Palladium-Catalyzed Heteroarylation Jamal Koubachi, ²,‡ Saı ¨d El Kazzouli, ²,‡ Sabine Berteina-Raboin,* ,² Abderrahim Mouaddib, ‡ and Ge ´rald Guillaumet ² Institut de Chimie Organique et Analytique, UMR CNRS 6005, UniVersite ´ d’Orle ´ ans, BP 6759, 45067 Orle ´ ans Cedex 2, France, and Faculte ´ des Sciences et Te ´ chniques de Be ´ ni-Mellal, UniVersite ´ Cadi-Ayyad, BP 523, 23000 Be ´ ni-Mellal, Morocco sabine.berteina-raboin@uniV-orleans.fr ReceiVed June 13, 2007 A new and efficient method for the synthesis of 2,3,6-trisubstituted imidazo[1,2-a]pyridine derivatives using a microwave-assisted one-pot, two-step Suzuki/heteroarylation or one-pot, three-step cyclization/ Suzuki/heteroarylation was developed. Polysubstituted compounds are obtained in good yield from 2-amino-5-halogenopyridines, 2-halogenocarbonyl derivatives, boronic acids, and heteroaryl bromides. Introduction Imidazo[1,2-a]pyridine derivatives have been shown to exhibit a diverse range of therapeutic properties such as melatonin receptor ligands, 1 antiviral, 2 antiulcer, 3 antibacterial, 4 antifungal, 5 agonist of benzodiazepine receptor, 6 calcium channel blocker, 7 -amyloid formation inhibitor, 8 or ligand for detecting ² Universite ´ d’Orle ´ans. ‡ Universite ´ Cadi-Ayyad. (1) Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.; Delagrange, P.; Caignard, D.-H. PCT, Int. Appl. WO 027474, 2006; Chem. Abstr. 2006, 144, 254132. (2) (a) Elhakmoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache, Y.; Chapat, J. P. Bioorg. Med. Chem. Lett. 1994, 4, 1937. (b) Gueiffier, A.; Lhassani, M.; Elhakmoui, A.; Snoeck, R.; Andrei, G.; Chavignion, O.; Teulade, J. C.; Kerbal, A.; Essassi, M.; Debouzy, J. C.; Witurowo, J. P.; Blache, Y.; Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med. Chem. 1996, 39, 2856. (c) Lhassani, M.; Chavignion, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. J. Med. Chem. 1999, 34, 271. (d) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J. Org. Chem. 1997, 62, 3453. (e) Pan, S.; Wang, G.; Shinazi, R. F.; Zhao, K. Tetrahedron Lett. 1998, 39, 2695. (f) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50. (g) Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2003, 46, 1449. (3) (a) Kaminsky, J. J.; Doweyko, A. M. J. Med. Chem. 1999, 40, 427. (b) Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn, D. J.; Elliot, A. J.; Lovey, R. G.; Guzik, H.; Chui, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem. 1989, 32, 1686. (4) (a) Rival, Y.; Grassy, G.; Michael, G. J. Med. Chem. 1992, 40, 1170. (b) Rewankar, G. R.; Matthews, J. R.; Robins, R. K. J. Med. Chem. 1975, 18, 1253. (5) Beeswick, P. J.; Campbell, I. B.; Naylor, A. PCT. Int. Appl. WO 9631 509, 1996; Chem. Abstr. 1997, 126, 8117j. Abiegnente, E. Act. Chim. Therap. 1991, 18, 1253. (6) (a) Tully, W. R.; Guardner, C. R.; Gillespie, R. J.; Westwood, R. J. Med. Chem 1991, 34, 2060. (b) G. Trapani, M. Franco, A. Latrofa, L. Ricciardi, A. Carotti, M. Serra, E. Sanna, G. Biggio, G. Liso, J. Med. Chem. 1999, 42, 3934. (c) G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G. Genchi, E. Sanna, F. Tuveri, E. Gagetti, G. Biggio, G. Liso, J. Med. Chem. 1997, 40, 3109. (7) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.; Moore, J. B., Jr. J. Med. Chem. 1991, 34, 2060. SCHEME 1. Heteroarylation on 6-Chloroimidazo[1,2-a]pyridines 1 and 2 7650 J. Org. Chem. 2007, 72, 7650-7655 10.1021/jo0712603 CCC: $37.00 © 2007 American Chemical Society Published on Web 09/05/2007