10.1021/ol200508x r 2011 American Chemical Society Published on Web 03/29/2011 ORGANIC LETTERS 2011 Vol. 13, No. 9 2286–2289 A Base Promoted Cyclization of N-Propargylaminopyridines. Synthesis of Imidazo[1,2-a]pyridine Derivatives Suren Husinec, † Rade Markovic, ‡ Milos Petkovic, § Veselin Nasufovic, § and Vladimir Savic* ,§ Institute of Chemistry, Technology and Metallurgy, Centre for Chemistry, P.O. Box 815, Njegoseva 12, 11000 Belgrade, Serbia, University of Belgrade, Faculty of Chemistry, Studentski Trg 12-16, 11000 Belgrade, Serbia, and University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia vladimir.savic@pharmacy.bg.ac.rs Received March 1, 2011 ABSTRACT A base promoted cyclization of the protected N-propargylaminopyridines was shown to be an efficient method for the preparation of imidazo[1,2-a] pyridine derivatives. The reactions were carried out with a small excess of base, at room temperature or slightly above producing the heterocyclic products in moderate to good yields. The stereoelectronic properties of substituents on the pyridine ring were shown to influence the cyclization process. The imidazo[1,2-a]pyridine scaffold (Figure 1) is present in a large number of compounds showing an impressive variety of biological properties. 1 It is also a core structure of several drugs such as zolpidem (hypnotic), alpidem (anxiolytic), and zolimidine (antiulcer). A number of synthetic methods have been designed for the preparation of this heterocyclic skeleton with majority of them relying on the formation of the imidazole ring. 2 The most common process involves the condensation of 2-aminopyridines with R-halocarbonyl compounds, either in solution 3aÀc or in the solid phase. 3dÀh Perhaps, a more versatile method, producing the 3-ami- no derivatives, involves three-component coupling trans- formations. 4 Condensation reactions of aldehydes, 2-ami- nopyridine, and isocyanides is usually carried out in the presence of acidic catalysts, either protic or Lewis acids. In † Institute of Chemistry, Technology and Metallurgy. ‡ University of Belgrade, Faculty of Chemistry. § University of Belgrade, Faculty of Pharmacy. (1) For selected recent examples of biological activity, see: Antibiotic activity: (a) Lhassani, M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271. Antiinflammatory activity:(b) Rupert, K. C.; Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.; Olini, G. C.; Fahmy, B.; Siekierka, J. Bioorg. Med. Chem. Lett. 2003, 13, 347. Antibacterial activity:(c) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170. Bradykinin B2 receptor antagonists:(d) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K.; Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.; Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 564. Antiulcer activity: (f) Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H. Chem. Pharm. Bull. 1992, 40, 371. Cyclin dependent kinase inhibitors:(g) Hamdouchi, C.; Zhong, B.; Mendoza, J.; Collins, E.; Jaramillo, C.; De Diego, J. E.; Robertson, D.; Spencer, C. D.; Anderson, B. D.; Watkins, S. A.; Zhanga, F.; Brooks, H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1943. GABA receptor agonists:(h) Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J. M.; Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis, R. T.; Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S. M.; Pike, A.; Brown, N.; Wafford, K. A.; Marshall, G.; Castro, J. L.; Atack, J. R. J. Med. Chem. 2006, 49, 35. Benzodiazepine receptor agonists:(i) Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934. (2) For selected recent examples, see: (a) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem. 2010, 8, 3631. (b) Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079. (c) DiMauro, E. F.; Kennedy, J. M. J. Org. Chem. 2007, 72, 1013. (d) Aginagalde, M.; Vara, Y.; Arrieta, A.; Zangi, R.; Cebolla, V. L.; Delgado-Camon, A.; Cossio, F. P. J. Org. Chem. 2010, 75, 2776. (e) Adib, M.; Mohamadi, A.; Sheikhi, E.; Ansari, S.; Bijanzadeh, H. Synlett 2010, 1606. (f) Kiselyov, A. S. Tetrahedron Lett. 2006, 47, 2941. (g) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4487. (h) Dai, W.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2005, 70, 6647.