Domino 6-endo-dig Cyclization/Halogenation Reactions: Three-Component Synthesis of 1,3-Disubstituted 4-Haloimidazo[1,2-a:4,5-c′]dipyridines

Abstract

A regiocontrolled 6-endo-dig cyclization of 3-ethynylimidazo[1,2-a]pyridine-2-carbonitriles promoted by Grignard reagent in the presence of iodine has been developed. We optimized the reaction conditions to allow the straightforward synthesis of 1,3-disubstituted 4-iodoimidazo[1,2-a:4,5-c′]dipyridines. Finally, the reactivity of the 4-iodo position toward various metal-catalyzed coupling reactions (Suzuki–Miyaura­, Sonogashira, etc.) or cyanation was successfully evaluated.

Key words

heterocycles - polycycles - cyclizations - Suzuki–Miyaura reactions - Sonogashira reactions - cyanations

• References

• 1a For a review on biological activities, see: Enguehard-Gueiffier C, Gueiffier A. Mini-Rev. Med. Chem. 2007; 7: 888

For recent examples see:
• 1b Jose G, Kumara TH. S, Nagendrappa G, Sowmya HB. V, Sriram D, Yogeeswari P, Sridevi JP, Guru Row TN, Hosamani AA, Ganapathy PS. S, Chandrika N, Narendra LV. Eur. J. Med. Chem. 2015; 89: 616
• 1c Moraski GC, Miller PA, Bailey MA, Ollinger J, Parish T, Boshoff HI, Cho S, Anderson JR, Mulugeta S, Franzblau SG, Miller MJ. ACS Infect. Dis. 2015; 1: 85
• 1d Kamal A, Kumar GB, Nayak VL, Reddy VS, Shaik AB, Reddy R, Reddy MK. MedChemComm 2015; 6: 606
• 2 For a review on functionalization of imidazo[1,2-a]pyridine, see: Koubachi J, El Kazzouli S, Bousmina M, Guillaumet G. Eur. J. Org. Chem. 2014; 5119
• 3 Oudot R, Costes P, Allouchi H, Pouvreau M, Abarbri M, Gueiffier A, Enguehard-Gueiffier C. Tetrahedron 2011; 67: 9576
• 4 Cartwright MW, Convery L, Kraynck T, Sandford G, Yufit DS, Howard JA. K, Christopher JA, Miller DD. Tetrahedron 2010; 66: 519
• 5 Frolov AN. Russ. J. Org. Chem. 2006; 883
• 6 Andaloussi M, Chezal JM, Moreau E, Lartigue C, El Laghdach A, Teulade JC, Chavignon O. Heterocycles 2005; 65: 1071
• 7 Dubbaka SR, Kienle M, Mayr H, Knochel P. Angew. Chem. Int. Ed. 2007; 46: 9093
• 8 Enguehard-Gueiffier C, Thery I, Gueiffier A, Buchwald SL. Tetrahedron 2006; 62: 6042