Microwave assisted, sequential two-step, one-pot synthesis of novel imidazo[1,2-a] pyrimidine containing tri/tetrasubstituted imidazole derivatives

A series of novel imidazo[1,2-a]pyrimidine containing tri/tetrasubstituted imidazole derivatives (1-10) has been synthesized via sequential two-step, one-pot, multicomponent reaction using imidazo[1,2-a]pyrimidine-2-carbaldehyde, benzil, primary amines, and ammonium acetate catalyzed by p-toluenesulfonic acid under microwave-assisted conditions. The results showed that target compounds can be obtained from a wide range of primary amines bearing different functional groups with moderate to good yields (46%-80%) under optimum reaction conditions. This method provides a green protocol for imidazo[1,2-a]pyrimidine containing tri/ tetrasubstituted imidazole derivatives due to ethyl alcohol as a green solvent, microwave irradiation as a greener heating method and one-pot multicomponent reaction as a green technique. The synthesized compounds have been elucidated using various spectroscopic tools such as $FT-IR, ^{1}H NMR, ^{13}C NMR, and MS.$

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1. Vitaku E, Smith DT, Njardarson JT. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. Journal of Medicinal Chemistry 2014; 57: 10257-10274. doi: 10.1021/jm501100b
2. Wang LM, Wang YH, Tian H, Yao YF, Shao JH et al. Ytterbium triflate as an efficient catalyst for one-pot synthesis of substituted imidazoles through three-component condensation of benzil, aldehydes and ammonium acetate. Journal of Fluorine Chemistry 2006; 127: 1570- 1573. doi: 10.1016/j.jfluchem.2006.08.005
3. Sharma GVM, Ramesh A, Singh A, Srikanth G, Jayaram GV et al. Imidazole derivatives show anticancer potential by inducing apoptosis and cellular senescence. Medicinal Chemistry Communications 2014; 5: 1751-1760. doi: 10.1039/c4md00277f
4. Fang Y, Yuan R, Ge W, Wang Y, Liu G et al. Synthesis and biological evaluation of 1,2,4,5-tetrasubstituted imidazoles. Research on Chemical Intermediates 2017; 43: 4413-4421. doi: 10.1007/s11164-017-2886-7
5. Ghorbani-Vaghei R, Izadkhah V, Mahmoodi J, Karamian R, Khoei MA. The synthesis of imidazoles and evaluation of their antioxidant and antifungal activities. Monatshefte für Chemie-Chemical Monthly 2018; 149: 1447-1452. doi: 10.1007/s00706-018-2167-1(0123456789
6. Mader M, De Dios A, Shih C, Bonjouklian R, Li T et al. Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38a MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorganic & Medicinal Chemistry Letters 2008; 18: 179-183. doi: 10.1016/j.bmcl.2007.10.106
7. Takle AK, Brown MJ, Davies S, Dean DK, Francis G et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorganic & Medicinal Chemistry Letters 2006; 16: 378-381. doi: 10.1016/j.bmcl.2005.09.072
8. Rossi R, Angelici G, Casotti G, Manzini C, Lessi M. Catalytic synthesis of 1,2,4,5-tetrasubstituted 1H-imidazole derivatives: State of the art. Advanced Synthesis & Catalysis 2019; 361: 2737-2803. doi: 10.1002/adsc.201801381
9. Esmaeilpour M, Javidi J, Zandi M. One-pot synthesis of multisubstituted imidazoles under solvent-free conditions and microwave irradiation using Fe3O4@SiO2–imid–PMAn magnetic porous nanospheres as a recyclable catalyst. New Journal of Chemistry 2015; 39: 3388-3398. doi: 10.1039/c5nj00050e
10. Bahrami K, Khodaei MM, Nejati A. One-pot synthesis of 1,2,4,5-tetrasubstituted and 2,4,5-trisubstituted imidazoles by zinc oxide as efficient and reusable catalyst Monatshefte für Chemie-Chemical Monthly 2011; 142: 159-162. doi: 10.1007/s00706-010-0428-8
11. Kumar D, Kommi DN, Bollineni N, Patel AR, Chakraborti AK. Catalytic procedures for multicomponent synthesis of imidazoles: selectivity control during the competitive formation of tri- and tetrasubstituted imidazoles. Green Chemistry 2012; 14: 2038-2049. doi: 10.1039/c2gc35277j
12. Green MD, Long TE. Designing imidazole-based ionic liquids and ionic liquid monomers for emerging technologies. Polymer Reviews 2009; 49: 291-314. doi: 10.1080/15583720903288914
13. Moosavi-Zare AR, Asgari Z, Zare A, Zolfigol MA, Shekouhy M. One pot synthesis of 1,2,4,5-tetrasubstitutedimidazoles catalyzed by trityl chloride in neutral media. RSC Advances 2014; 4: 60636- 60639. doi: 10.1039/c4ra10589c
14. Abrahams SL, Hazen RJ, Batson AG, Phillips AP. Trifenagrel: A chemically novel platelet aggregation inhibitor. Journal of Pharmacology and Experimental Therapeutics 1989; 249: 359-365.
15. Higuera NL, Peña-Solórzano D, Ochoa-Puentes C. Urea–zinc chloride eutectic mixture-mediated one-pot synthesis of ımidazoles: efficient and ecofriendly access to trifenagrel. Synlett 2019; 30: 225-229. doi: 10.1055/s-0037-1610679
16. Zhou JP, Ding YW, Zhang HB, Xu L, Dai Y. Synthesis and anti-inflammatory activity of imidazo[1,2-a]pyrimidine derivatives. Chinese Chemical Letters 2008; 19: 669-672. doi: 10.1016/j.cclet.2008.04.020
17. Spitzer WA, Victor F, Don Pollock G, Scott Hayes J. Imidazo[l,2-a]pyrimidines and imidazo[l,2-a]pyrazines: the role of nitrogen position in inotropic activity. Journal of Medicinal Chemistry 1988; 31: 1590-1595. doi: 10.1021/jm00403a018
18. Aeluri R, Alla M, Polepalli S, Jain N. Synthesis and antiproliferative activity of imidazo[1,2-a]pyrimidine Mannich bases. European Journal of Medicinal Chemistry 2015; 100: 18-23. doi: /10.1016/j.ejmech.2015.05.037
19. Mantipally M, Gangireddya MR, Gundla R, Badavath VN, Mandhaa SR et al. Rational design, molecular docking and synthesis of novel homopiperazine linked imidazo[1,2-a]pyrimidine derivatives as potent cytotoxic and antimicrobial agents. Bioorganic & Medicinal Chemistry Letters 2019; 29: 2248-2253. doi: 10.1016/j.bmcl.2019.06.031
20. Rupert KC, Henry JR, Dodd JH, Wadsworth SA, Cavender DE et al. Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorganic & Medicinal Chemistry Letters 2003; 13: 347-350. doi: 10.1016/S0960-894X(02)01020-X
21. Moog C, Wick A, Le Ber P, Kirn A, Aubertin AM. Bicyclic imidazo derivatives, a new class of highly selective inhibitors for the human immunodeficiency virus type 1. Antiviral Research 1994; 24 (4):275-288. doi: 10.1016/0166-3542(94)90075-2
22. Goel R, Luxami V, Paul K. Synthetic approaches and functionalizations of imidazo[1,2-a]pyrimidines: An overview of the decade. RSC Advances 2015; 5: 81608-81637. doi: 10.1039/c5ra14795f
23. Verma P, Pal S, Chauhan S, Mishra A, Sinha I et al. Starch functionalized magnetite nanoparticles: A green, biocatalyst for one-pot multicomponent synthesis of imidazopyrimidine derivatives in aqueous medium under ultrasound irradiation Journal of Molecular Structure 2020; 1203: 127410. doi: 10.1016/j.molstruc.2019.127410
24. Clements-Jewery S, Danswan G, Gardner CR, Matharu SS, Murdoch R et al. (Imidazo[l,2-a]pyrimidin-2-yl)phenylmethanones and related compounds as potential nonsedative anxiolytics. Journal of Medicinal Chemistry 1988; 31: 1220-1226. doi: 10.1021/jm00401a025
25. Feely M, Boyland P, Picardo A, Cox A, Gent JP. Lack of anticonvulsant tolerance with RU 32698 and Ro 17-1812. European Journal of Pharmacology 1989; 164 (2): 377-380. doi: 10.1016/0014-2999(89)90482-2
26. Tully WR, Gardner CR, Gillespie RJ, Westwood R. 2-(Oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as agonists and inverse agonists at benzodiazepine receptors. Journal of Medicinal Chemistry 1991; 34: 2060-2067. doi: 10.1021/jm00111a021
27. Güngör T. Preparation of novel imidazo[1,2-a]pyrimidine derived schiff bases at conventional and microwave heating conditions. Journal of Balıkesir University Institute of Science and Technology 2020; 22 (2): 428-438. doi: 10.25092/baunfbed.707673
28. Güngör T. One pot, multicomponent protocol for the synthesis of novel imidazo[1,2-a]pyrimidine-based pyran analogs: A potential biological scaffold. Monatshefte für Chemi-Chemical Monthly 2020; 151: 781-789. doi: 10.1007/s00706-020-02601-w
29. Singh H, Rajput JK. Co(II) anchored glutaraldehyde crosslinked magnetic chitosan nanoparticles (MCS) for synthesis of 2,4,5‐trisubstituted and 1,2,4,5‐tetrasubstituted imidazoles. Applied Organometallic Chemistry 2018; 32: e3989. doi: 10.1002/aoc.3989
30. Wolkenberg SE, Wisnoski DD, Leister WH, Wang Y, Zhao Z et al. Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation. Organic Letters 2004; 6: 1453-1456. doi: 10.1021/ol049682b
31. Arafa WAA. An eco-compatible pathway to the synthesis of mono and bis-multisubstituted imidazoles over novel reusable ionic liquids: An efficient and green sonochemical process. RSC Advances 2018; 8: 16392–16399. doi: 10.1039/c8ra02755b
32. Heravi MM, Derikvand F, Haghighi M. Highly efficient, four component, one-pot synthesis of tetrasubstituted imidazoles using a catalytic amount of $FeCl_3.6H_2O$. Monatshefte für Chemie 2008; 139: 31-33. doi: 10.1007/s00706-007-0736-9
33. Karimi-Jaberi Z, Barekat M. One-pot synthesis of tri- and tetra-substituted imidazoles using sodium dihydrogen phosphate under solventfree conditions. Chinese Chemical Letters 2010; 21: 1183-1186. doi: 10.1016/j.cclet.2010.06.012
34. Shoar RH, Rahimzadeh G, Derikvand F, Farzaneh M. Four-component, one-pot synthesis of tetra-substituted imidazoles using a catalytic amount of MCM-41 or p-TsOH, Synthetic Communications 2010; 40: 1270-1275. doi: 10.1080/00397910903068204
35. Xu F, Wang N, Tian Y, Li G. Simple and efficient method for the synthesis of highly substituted imidazoles catalyzed by benzotriazole. Journal of Heterocyclic Chemistry 2013; 50: 668-675. doi: 10.1002/jhet.1818
36. Kurumurthy C, Kumar G S, Reddy GM, Nagender P, Rao PS et al. A facile strategy for the synthesis of highly substituted imidazole using tetrabutyl mmoniumbromide as catalyst. Research on Chemical Intermediates 2012; 38: 359-365. doi: 10.1007/s11164-011-0352-5
37. Nejatianfar M, Akhlaghinia B, Jahanshahi R. Cu(II) immobilized on guanidinated epibromohydrinfunctionalized $γ‐Fe_2 O_3@TiO_2 (γ‐Fe_2O_3@TiO_2‐EG‐Cu(II)):$ A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles. Applied Organometallic Chemistry 2018; 32: e4095. doi: 10.1002/aoc.4095
38. Khalafi-Nezhad A, Shekouhy M, Sharghi H, Aboonajmi J, Zare A. A new more atom-efficient multi-component approach to tetrasubstituted imidazoles: one-pot condensation of nitriles, amines and benzoin. RSC Advances 2016; 6: 67281–67289. doi: 10.1039/c6ra11171h
39. Kappe CO, Dallinger D. Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Molecular Diversity 2009; 13: 71-193. doi: 10.1007/s11030-009-9138-8
40. Moseley JD, Kappe CO. A critical assessment of the greenness and energy efficiency of microwave-assisted organic synthesis. Green Chemistry 2011; 13: 794-806. doi: 10.1039/c0gc00823k
41. Gedye R, Smith F, Westaway K, Ali H, Baldisera L et al. The use of microwave ovens for rapid organic synthesis. Tetrahedron Letters 1986; 27: 279-282. doi:10.1016/S0040-4039(00)83996-9
42. Giguere RJ, Bray TL, Duncan SM, Majetich G. Application of commercial microwave ovens to organic synthesis. Tetrahedron Letters 1986; 27: 4945-4948. doi: 10.1016/S0040-4039(00)85103-5
43. Lidstrom P, Tierney J, Wathey B, Westman J. Microwave assisted organic synthesis-a review. Tetrahedron 2001; 57: 9225-9283. doi: 10.1016/S0040-4020(01)00906-1
44. Taha NI, Tapabashi NO, El-Subeyhi MN. Green synthesis of new tetra schiff bases and bis-azo bis-schiff bases derived from 2,6-diaminopyridine as promising photosensitizers. International Journal of Organic Chemistry 2018; 8: 309-318. doi: 10.4236/ ijoc.2018.83023
45. Shaikh M, Wagare D, Farooqui M, Durrani A. Microwave assisted synthesis of novel schiff bases of pyrazolyl carbaldehyde and triazole in PEG-400. Polycyclic Aromatic Compounds 2019; 1-6. doi: 10.1080/10406638.2018.1544154
46. Zhou JF, Song YZ, Yang YL, Zhu YL, Tu SJ. One‐step synthesis of 2‐aryl‐4,5‐diphenylimidazoles under microwave irradiation. Synthetic Communications 2005; 35: 1369-1373. doi: 10.1081/SCC-200057281
47. Wu L, Jıng X, Zhu H, Lıu Y, Yan C. One-pot synthesis of polysubstituted imidazoles from arylaldehydes in water catalyzed by NHC using microwave irradiation. Journal of the Chilean Chemical Society 2012; 57: 1204-1207. doi: 10.4067/S0717-97072012000300002
48. Bhaskaruni SVHS, Maddila S, Gangu KK, Jonnalagadda SB. Review on multi-component green synthesis of N-containing heterocycles using mixed oxides as heterogeneous catalysts Arabian Journal of Chemistry 2020; 13: 1142-1178. doi: /10.1016/j.arabjc.2017.09.016
49. Binh Nguyen T, Anh Nguyen L, Corbin M, Retailleau P, Ermolenko L et al. Toward the synthesis of Sceptrin and Benzosceptrin: Solvent effect in stereo- and regioselective [2+2] photodimerization and easy access to the fully substituted benzobutane. European Journal of Organic Chemistry 2018: 5861-5868. doi: 10.1002/ejoc.201800458.
50. Kumar BRP, Sharma GK, Srinath S, Noor M, Suresh B et al. Microwave-assisted, solvent-free, parallel syntheses and elucidation of reaction mechanism for the formation of some novel tetraaryl imidazoles of biological interest. Journal of Heterocyclic Chemistry 2009; 46: 278-284. doi: 10.1002/jhet.68