Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Efficient Synthesis and Characterization of 6-substituted-N-p-tolyl-imidazo[1,2- a]pyridine-8-carboxamide: A Promising Scaffold for Drug Development

Author(s): Keval Bhatt, Dhara Patel*, Mrudangsinh Rathod, Ashish Patel and Drashti Shah

Volume 27, Issue 22, 2023

Published on: 21 December, 2023

Page: [1978 - 1984] Pages: 7

DOI: 10.2174/0113852728269243231206044929

Price: $65

Abstract

Imidazo[1,2-a]pyridine is a highly significant fused bicyclic heterocycle widely utilized in medicinal chemistry, and it holds a prominent position as a "drug prejudice" framework because of its extensive applications. Numerous approaches have been documented for the synthesis of imidazo[1,2-a]pyridines, with a particular focus on functionalizing these compounds. In this research, we have presented an effective multi-step synthesis method for producing imidazo[1,2-a]pyridines, achieving impressive yields ranging from 93% to 97%. The synthesized compounds were subjected to thorough characterization using various spectral analysis techniques, including FTIR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. Overall, this synthetic strategy possesses desirable features for the synthesis of imidazo[1,2-a]pyridines and their derivatives, including high product purity, accessible starting materials, broad substrate scope, scalability, and transformability. These characteristics make it a promising approach for further development and potential application in the synthesis of valuable therapeutic compounds.

« Previous Next »
Graphical Abstract

[1]
Sunderhaus, J.D.; Dockendorff, C.; Martin, S.F. Synthesis of diverse heterocyclic scaffolds via tandem additions to imine derivatives and ring-forming reactions. Tetrahedron, 2009, 65(33), 6454-6469.
[http://dx.doi.org/10.1016/j.tet.2009.05.009] [PMID: 20625454]
[2]
Yan, R.; Huang, G.; Yan, H.; Yang, S.; Gao, X.; Zhou, K.; Ma, C. Iron(II)-catalyzed denitration reaction: Synthesis of 3-methyl-2-arylimidazo[1,2-a]pyridine derivatives from aminopyridines and 2-methylnitroolefins. Synlett, 2012, 23(20), 2961-2964.
[http://dx.doi.org/10.1055/s-0032-1317685]
[3]
Patel, A.; Shah, D.; Patel, N.; Patel, K.; Soni, N.; Nagani, A.; Parikh, V.; Shah, H.; Bambharoliya, T. Benzimidazole as ubiquitous structural fragment: An update on development of its green synthetic approaches. Mini Rev. Org. Chem., 2021, 18(8), 1064-1085.
[http://dx.doi.org/10.2174/1570193X17999201211194908]
[4]
Patel, A.; Shah, J.; Patel, K.; Patel, K.; Patel, H.; Dobaria, D.; Shah, U.; Patel, M.; Chokshi, A.; Patel, S.; Parekh, N.; Shah, H.; Patel, H.; Bambharoliya, T. Ultrasound-assisted one-pot synthesis of tetrahydropyrimidne derivatives through biginelli condensation: A catalyst free green chemistry approach. Lett. Org. Chem., 2021, 18(9), 749-756.
[http://dx.doi.org/10.2174/1570178617999201105162851]
[5]
Wan, J.; Zheng, C.J.; Fung, M.K.; Liu, X.K.; Lee, C.S.; Zhang, X.H. Multifunctional electron-transporting indolizine derivatives for highly efficient blue fluorescence, orange phosphorescence host and two-color based white OLEDs. J. Mater. Chem., 2012, 22(10), 4502-4510.
[http://dx.doi.org/10.1039/c2jm14904d]
[6]
Song, G.; Zhang, Y.; Li, X. Rhodium and iridium complexes of abnormal N-heterocyclic carbenes derived from imidazo[1,2-a]pyridine. Organometallics, 2008, 27(8), 1936-1943.
[http://dx.doi.org/10.1021/om800109a]
[7]
John, A.; Shaikh, M.M.; Ghosh, P. Palladium complexes of abnormal N-heterocyclic carbenes as precatalysts for the much preferred Cu-free and amine-free Sonogashira coupling in air in a mixed-aqueous medium. Dalton Trans., 2009, 47(47), 10581-10591.
[http://dx.doi.org/10.1039/b913068c] [PMID: 20023883]
[8]
Enguehard-Gueiffier, C.; Gueiffier, A. Recent progress in the pharmacology of imidazo[1,2-a]pyridines. Mini Rev. Med. Chem., 2007, 7(9), 888-899.
[http://dx.doi.org/10.2174/138955707781662645] [PMID: 17897079]
[9]
Balalaie, S.; Zolfigol, M.; Derakhshan-Panah, F.; Rominger, F. A convenient method for the synthesis of imidazo[1,2-a]pyridines with a new approach. Synlett, 2018, 29(1), 89-93.
[http://dx.doi.org/10.1055/s-0036-1590906]
[10]
Chattopadhyay, B.; Gevorgyan, V. Transition-metal-catalyzed denitrogenative transannulation: Converting triazoles into other heterocyclic systems. Angew. Chem. Int. Ed., 2012, 51(4), 862-872.
[http://dx.doi.org/10.1002/anie.201104807] [PMID: 22121072]
[11]
Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem. Rev., 2006, 106(1), 17-89.
[http://dx.doi.org/10.1021/cr0505728] [PMID: 16402771]
[12]
Rival, Y.; Grassy, G.; Michel, G. Synthesis and antibacterial activity of some imidazo[1,2-a]pyrimidine derivatives. Chem. Pharm. Bull., 1992, 40(5), 1170-1176.
[http://dx.doi.org/10.1248/cpb.40.1170] [PMID: 1394630]
[13]
Fisher, M.H.; Lusi, A. Imidazo[1,2-a]pyridine anthelmintic and antifungal agents. J. Med. Chem., 1972, 15(9), 982-985.
[http://dx.doi.org/10.1021/jm00279a026] [PMID: 5065787]
[14]
Rival, Y.; Grassy, G.; Taudou, A.; Ecalle, R. Antifungal activity in vitro of some imidazo[1,2-a]pyrimidine derivatives. Eur. J. Med. Chem., 1991, 26(1), 13-18.
[http://dx.doi.org/10.1016/0223-5234(91)90208-5]
[15]
Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B.A.; Vance, L. 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imid azo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity. J. Med. Chem., 1999, 42(1), 50-59.
[http://dx.doi.org/10.1021/jm9810405] [PMID: 9888832]
[16]
Kaminski, J.J.; Doweyko, A.M. Antiulcer agents. 6. Analysis of the in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2-a]pyridines and related analogues using comparative molecular field analysis and hypothetical active site lattice methodologies. J. Med. Chem., 1997, 40(4), 427-436.
[http://dx.doi.org/10.1021/jm950700s] [PMID: 9046332]
[17]
Rupert, K.C.; Henry, J.R.; Dodd, J.H.; Wadsworth, S.A.; Cavender, D.E.; Olini, G.C.; Fahmy, B.; Siekierka, J.J. Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2003, 13(3), 347-350.
[http://dx.doi.org/10.1016/S0960-894X(02)01020-X] [PMID: 12565927]
[18]
Goel, R.; Luxami, V.; Paul, K. Imidazo[1,2-a]pyridines: Promising drug candidate for antitumor therapy. Curr. Top. Med. Chem., 2016, 16(30), 3590-3616.
[http://dx.doi.org/10.2174/1568026616666160414122644] [PMID: 27086790]
[19]
Badawey, E.; Kappe, T. Benzimidazole condensed ring system. IX. Potential antineoplastics. New synthesis of some pyrido[1,2-α]benzimidazoles and related derivative. Eur. J. Med. Chem., 1995, 30(4), 327-332.
[http://dx.doi.org/10.1016/0223-5234(96)88241-9]
[20]
Hranjec, M.; Kralj, M.; Piantanida, I.; Sedić, M.; Šuman, L.; Pavelić, K.; Karminski-Zamola, G. Novel cyano- and amidino-substituted derivatives of styryl-2-benzimidazoles and benzimidazo[1,2-a]quinolines. Synthesis, photochemical synthesis, DNA binding, and antitumor evaluation, part 3. J. Med. Chem., 2007, 50(23), 5696-5711.
[http://dx.doi.org/10.1021/jm070876h] [PMID: 17935309]
[21]
Kotovskaya, S.K.; Baskakova, Z.M.; Charushin, V.N.; Chupakhin, O.N.; Belanov, E.F.; Bormotov, N.I.; Balakhnin, S.M.; Serova, O.A. Synthesis and antiviral activity of fluorinated pyrido[1,2-a]benzimidazoles. Pharm. Chem. J., 2005, 39(11), 574-578.
[http://dx.doi.org/10.1007/s11094-006-0023-9]
[22]
Lhassani, M.; Chavignon, O.; Chezal, J.M.; Teulade, J.C.; Chapat, J.P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Synthesis and antiviral activity of imidazo[1,2-a]pyridines. Eur. J. Med. Chem., 1999, 34(3), 271-274.
[http://dx.doi.org/10.1016/S0223-5234(99)80061-0]
[23]
Humphries, A.C.; Gancia, E.; Gilligan, M.T.; Goodacre, S.; Hallett, D.; Merchant, K.J.; Thomas, S.R. 8-fluoroimidazo[1,2-a]pyridine: Synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABAA receptor. Bioorg. Med. Chem. Lett., 2006, 16(6), 1518-1522.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.037] [PMID: 16386901]
[24]
Fuchs, K.; Romig, M.; Mendla, K.; Briem, H.; Fechteler, K. Novel betaamyloid inhibitors, method for producing the same and the use thereof as medicaments. W.O. Patent 2002014313, 2002.
[25]
Davey, D.; Erhardt, P.W.; Lumma, W.C., Jr; Wiggins, J.; Sullivan, M.; Pang, D.; Cantor, E. Cardiotonic agents. 1. Novel 8-aryl substituted imidazo[1,2-a]- and [1,5-a]pyridines and imidazo[1,5-a]pyridinones as potential positive inotropic agents. J. Med. Chem., 1987, 30(8), 1337-1342.
[http://dx.doi.org/10.1021/jm00391a012] [PMID: 3039131]
[26]
Fookes, C.J.R.; Pham, T.Q.; Mattner, F.; Greguric, I.; Loc’h, C.; Liu, X.; Berghofer, P.; Shepherd, R.; Gregoire, M.C.; Katsifis, A. Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography. J. Med. Chem., 2008, 51(13), 3700-3712.
[http://dx.doi.org/10.1021/jm7014556] [PMID: 18557607]
[27]
Langer, S.Z.; Arbilla, S.; Benavides, J.; Scatton, B. Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes. Adv. Biochem. Psychopharmacol., 1990, 46, 61-72.
[PMID: 1981304]
[28]
Xiang, T.; Cai, Y.; Hong, Z.; Pan, J. Efficacy and safety of Zolpidem in the treatment of insomnia disorder for one month: A meta-analysis of a randomized controlled trial. Sleep Med., 2021, 87, 250-256.
[http://dx.doi.org/10.1016/j.sleep.2021.09.005] [PMID: 34688027]
[29]
Mizushige, K.; Ueda, T.; Yukiiri, K.; Suzuki, H. Olprinone: A phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. Cardiovasc. Drug Rev., 2002, 20(3), 163-174.
[http://dx.doi.org/10.1111/j.1527-3466.2002.tb00085.x] [PMID: 12397365]
[30]
Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.; Murmann, W. Derivatives of imidazole. I. Synthesis and reactions of imidazo[1,2-α]pyridines with analgesic, antiinflammatory, antipyretic, and anticonvulsant activity. J. Med. Chem., 1965, 8(3), 305-312.
[http://dx.doi.org/10.1021/jm00327a007] [PMID: 14329509]
[31]
Gudmundsson, K.; Boggs, S.D. Chemical compounds. W.O. Patent 2006026703, 2006.
[32]
Koo, H.L.; DuPont, H.L. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr. Opin. Gastroenterol., 2010, 26(1), 17-25.
[http://dx.doi.org/10.1097/MOG.0b013e328333dc8d] [PMID: 19881343]
[33]
Kurteva, V. Recent progress in metal-free direct synthesis of imidazo[1,2-a] pyridines. ACS Omega, 2021, 6(51), 35173-35185.
[http://dx.doi.org/10.1021/acsomega.1c03476] [PMID: 34984250]
[34]
Ghosh, P.; Ganguly, B.; Kar, B.; Dwivedi, S.; Das, S. Green procedure for highly efficient, rapid synthesis of imidazo[1,2-a]pyridine and its late stage functionalization. Synth. Commun., 2018, 48(9), 1076-1084.
[http://dx.doi.org/10.1080/00397911.2018.1434893]
[35]
Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W. CuI-catalyzed aerobic oxidative α-aminaton cyclization of ketones to access aryl or alkenyl-substituted imidazoheterocycles. J. Org. Chem., 2013, 78(24), 12494-12504.
[http://dx.doi.org/10.1021/jo402134x] [PMID: 24256374]
[36]
Okai, H.; Tanimoto, K.; Ohkado, R.; Iida, H. Multicomponent synthesis of imidazo[1,2-a]pyridines: Aerobic oxidative formation of C–N and C–S bonds by flavin–iodine-coupled organocatalysis. Org. Lett., 2020, 22(20), 8002-8006.
[http://dx.doi.org/10.1021/acs.orglett.0c02929] [PMID: 33006477]
[37]
Roslan, I.I.; Ng, K.H.; Wu, J.E.; Chuah, G.K.; Jaenicke, S. Synthesis of disubstituted 3-phenylimidazo[1,2-a]pyridines via a 2-aminopyridine/cbrcl3 α-bromination shuttle. J. Org. Chem., 2016, 81(19), 9167-9174.
[http://dx.doi.org/10.1021/acs.joc.6b01714] [PMID: 27606896]
[38]
Wu, Z.; Pan, Y.; Zhou, X. Synthesis of 3-arylimidazo[1,2-a]pyridines by a catalyst-free cascade process. Synthesis, 2011, 14, 2255-2260.
[39]
Wang, Y.; Frett, B.; Li, H. Efficient access to 2,3-diarylimidazo[1,2-a]pyridines via a one-pot, ligand-free, palladium-catalyzed three-component reaction under microwave irradiation. Org. Lett., 2014, 16(11), 3016-3019.
[http://dx.doi.org/10.1021/ol501136e] [PMID: 24854606]
[40]
Huo, C.; Tang, J.; Xie, H.; Wang, Y.; Dong, J. CBr4 mediated oxidative c–n bond formation: Applied in the synthesis of imidazo[1,2-α]pyridines and Imidazo[1,2-α]pyrimidines. Org. Lett., 2016, 18(5), 1016-1019.
[http://dx.doi.org/10.1021/acs.orglett.6b00137] [PMID: 26882001]
[41]
Zhang, Y.; Chen, R.; Wang, Z.; Wang, L.; Ma, Y. I2-catalyzed three-component consecutive reaction for the synthesis of 3-aroylimidazo[1,2-a]-n-heterocycles. J. Org. Chem., 2021, 86(9), 6239-6246.
[http://dx.doi.org/10.1021/acs.joc.1c00023] [PMID: 33835809]
[42]
Iazzetti, A.; Cacchi, S.; Ciogli, A.; Demitri, N.; Fabrizi, G.; Ghirga, F.; Goggiamani, A.; Lamba, D. Copper-catalyzed C-N bond formation via C-H functionalization: Facile synthesis of multisubstituted imidazo[1,2-a]pyridines from n-(2-pyridinyl)enaminones. Synthesis, 2018, 50(17), 3513-3519.
[http://dx.doi.org/10.1055/s-0037-1610071]
[43]
Zhang, J.; Yang, H.; Zhang, Y.; Zhang, J.; Wu, Q. Synthesis of C3-cyanomethylated imidazo[1,2-a]pyridines via ultrasound-promoted three-component reaction under catalyst- and oxidant-free conditions. Synlett, 2022, 33(3), 264-268.
[http://dx.doi.org/10.1055/a-1704-4822]
[44]
Tian, X.; Song, L.; Rudolph, M.; Wang, Q.; Song, X.; Rominger, F.; Hashmi, A.S.K. N-pyridinyl sulfilimines as a source for α-imino gold carbenes: Access to 2-amino-substituted N-fused imidazoles. Org. Lett., 2019, 21(6), 1598-1601.
[http://dx.doi.org/10.1021/acs.orglett.9b00140] [PMID: 30807195]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy