Synthesis of 3-aminoimidazo[1,2-a]pyridines via three-component reaction in the 2,2,2-trifluoroethanol-water two-phase systems

Document Type : Original Article


Department of Chemistry, Faculty of Science, Babol Noshirvani University of Technology, Babol, Iran


An efficient synthesis of 3-aminoimidazo[1,2-a]pyridines via three-component reaction from aromatic aldehydes, 2-aminopyridines and isonitriles at room temperature in water/2,2,2-trifluoroethanol two-phase systems is described. In this methodology equivalent or better yield was obtained in the two-phase systems when compared to pure 2,2,2-trifluoroethanol for reaction. The use of the two-phase system also reduces the consumption of CF3CH2OH by 75% leading to a significant reduction in cost as well as toxicity of the reaction media. The strong hydrogen bond donation properties can also eliminate the need for Lewis acid catalyst, further simplifying the procedure. High yield, short reaction time, simple work up without need to column chromatography and use of mild and environmental friendliness conditions are some of benefits of the present method in synthesis of this biologically compounds.


[1] D. Rideout, R. Breslow "Hydrophobic acceleration of Diels-Alder reactions" J. Am. Chem. Soc. 102 (1980) 7816.
[2] D. Chaturvedi, N.C. Barua "Recent developments on carbon-carbon bond forming reactions in water" Current Organic Synthesis 9 (2012) 17.
[3] R.N. Butler, A.G. Coyne, W.J. Cunningham, E.M. Moloney "Water and organic synthesis: A focus on the in-water and on-water border. Reversal of the in-water Breslow hydrophobic enhancement of the normal endo-effect on crossing to on-water conditions for Huisgen cycloadditions with increasingly insoluble organic liquid and solid 2π-dipolarophiles" J. Org. Chem. 78 (2013) 3276.
[4] I.A.  Shuklov, N.V. Dubrovina, A. Boerner "Fluorinated alcohols as solvents, cosolvents and additives in homogeneous catalysis" Synthesis 2007 (2007) 2925.
[5] S. Khaksar "Fluorinated alcohols: A magic medium for the synthesis of heterocyclic compounds" J. Fluorine Chem. 172 (2015) 51. 
[6] N. Weisner, M.G. Khaledi "Organic synthesis in fluoroalcohol-water two-phase systems" Green Chem. 18 (2016) 681. 
[7] S. E. Koubachi, M. Bousmina, G. Guillaumet "Functionalization of imidazo[1,2‐a]pyridines by means of metal‐catalyzed cross‐coupling reactions" Eur. J. Org. Chem. 2014 (2014) 5119.
[8] K. Pericherla, P. Kaswan, K. Pandey, A. Kumar "Recent developments in the synthesis of imidazo[1,2-a]pyridines" Synthesis 47 (2015) 887.
[9] R. Goel, V. Luxami, D. Paul "Synthetic approaches and functionalizations of imidazo[1,2-a]pyrimidines: an overview of the decade" RSC Adv. 5 (2015) 81608.
[10] A. Shaabani, E. Soleimani, A. Maleki "Ionic liquid promoted one-pot synthesis of 3-aminoimidazo[1,2-a]pyridines" Tetrahedron Lett. 47 (2006) 3031.
[11] M. Adib, M. Mahdavi, M.A. Noghani, P. Mirzaei "Catalyst-free three-component reaction between 2-aminopyridines (or 2-aminothiazoles), aldehydes, and isocyanides in water" Tetrahedron Lett. 48 (2007) 7263.
[12] A. Shaabani, E. Soleimani, A. Sarvary, A.H. Rezayan, A. Maleki "Tin (II) chloride dihydrate catalyzed Groebke condensation: An efficient protocol for the synthesis of 3-aminoimidazo[1,2-a]pyridines and  pyrazines" Chin. J. Chem. 27 (2009) 369.
[13] A.T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain, A. Agarwal, S.K. Guchhait, C.N. Kundu, U.C. Banerjee, P.V. Bhara "N-Fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIα and induce apoptosis in G1/S phase" J. Med. Chem. 54 (2011) 5013.
[14] M.L. Bode, D. Gravestock, S.S. Moleele, C.W. Westhuyzen, S.C. Pelly, P.A. Steenkamp, H.C. Hoppe, T. Khan, L.A. Nkabinde "Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors" Bioorg. Med. Chem. 19 (2011) 4227.
[15] A. Maleki, S. Javanshir, M. Naimabadi "Facile synthesis of imidazo[1,2-a]pyridines via a one-pot three-component reaction under solvent-free mechanochemical ball-milling conditions" RSC Adv. 4 (2014) 30229.
[16] M. Naeimabadi, S. Javanshir, A. Maleki, M.G. Dekamin "MCM-41-SO3H-catalyzed synthesis of highly substituted 3-amino-imidazo[1,2-a]pyridines or pyrazines via the Groebke-Blackburn-Bienaymé multicomponent reaction under grinding conditions at ambient temperature" Scientia Iranica C 23 (2016) 2724.
[17] A.L. Rousseau, P. Matlaba, C.J. Parkinson "Multicomponent synthesis of imidazo[1,2-a]pyridines using catalytic zinc chloride" Tetrahedron Lett. 48 (2007) 4079.