Efficient and environmentally sustainable domino protocol for the synthesis of diversified dispiroheterocycles using 1-Butyl-3-methylimidazolium bromide [bmim]Br

Document Type : Research Article


1 Department Of Chemistry, Dr.Babasaheb Ambedkar Marathawada University, Aurangabad

2 Department of Chemistry, Dr.Babasaheb Ambedkar Marathwada University, Aurangabad

3 Department of Chemistry, Dr.Babasaheb Ambedkar Marathawada University, Aurangabad

4 Department of Chemistry, Shivaji Art, Commerce and Science College, Kannad, Aurangabad 431103, Maharashtra, India


An environmentally benign, simple, and efficient procedure has been developed for the construct of some symmetrical dispiroheterocycles derivatives by the reaction of the variety of 6-amino-2-thiouracil/6-aminouracil /2-amino-1,3,4-thiadiazole, isatins and p-toluidine in the presence of 1-Butyl-3-methylimidazolium bromide ([bmim]Br) as a solvent as well as catalyst at room temperature. In this study, a variety of bis-spiro-indoline-chromenes, pyranopyranes, imidazo-pyridines, pyrido-pyrimidines and pyridines were obtained with excellent yields within short reaction time and without chromatographic separation. Furthermore, the green catalytic system can be recycled specific times with no decreases in yields and reaction rates.


Main Subjects

[1]         K. Verma, Y.K. Tailor, S. Khandelwal, E. Rushell, M. Agarwal, M. Kumar, Efficient and environmentally sustainable domino protocol for the synthesis of diversified spiroheterocycles with privileged heterocyclic substructures using bio-organic catalyst in aqueous medium., Mol. Divers. 24 (2020) 1355–1365. https://doi.org/10.1007/s11030-019-09999-4.
[2]         P. Slobbe, E. Ruijter, R.V.A. Orru, Recent applications of multicomponent reactions in medicinal chemistry, Medchemcomm. 3 (2012) 1189. https://doi.org/10.1039/c2md20089a.
[3]         L. Weber, The Application of Multi-Component Reactions in Drug Discovery, Curr. Med. Chem. 9 (2002) 2085–2093. https://doi.org/10.2174/0929867023368719.
[4]         C.K. Jadhav, A.S. Nipate, A. V. Chate, V.S. Dofe, J.N. Sangshetti, V.M. Khedkar, C.H. Gill, Rapid Construction of Substituted Dihydrothiophene Ureidoformamides at Room Temperature Using Diisopropyl Ethyl Ammonium Acetate: A Green Perspective, ACS Omega. 5 (2020) 29055–29067. https://doi.org/10.1021/acsomega.0c03575.
[5]         C.K. Jadhav, A.S. Nipate, A. V. Chate, V.D. Songire, A.P. Patil, C.H. Gill, Efficient Rapid Access to Biginelli for the Multicomponent Synthesis of 1,2,3,4-Tetrahydropyrimidines in Room-Temperature Diisopropyl Ethyl Ammonium Acetate, ACS Omega. 4 (2019) 22313–22324. https://doi.org/10.1021/acsomega.9b02286.
[6]         L.Z. Fekri, M. Nikpassand, R. Maleki, 1,4-Diazabicyclo [2.2.2] octanium diacetate: As an effective, new and reusable catalyst for the synthesis of benzo[d]imidazole, J. Mol. Liq. 222 (2016) 77–81. https://doi.org/10.1016/j.molliq.2016.07.009.
[7]         M. Nikpassand, L. Fekri, S. Sahrapeima, S. Shariati, Synthesis of Bis Coumarinyl Methanes Using Fe3O4@SiO2@KIT-6 as an Efficient and Reusable Catalyst, Lett. Org. Chem. 13 (2016) 578–584. https://doi.org/10.2174/1570178613666160927111534.
[8]         X.-B. Chen, S.-L. Xiong, Z.-X. Xie, Y.-C. Wang, W. Liu, Three-Component One-Pot Synthesis of Highly Functionalized Bis-Indole Derivatives, ACS Omega. 4 (2019) 11832–11837. https://doi.org/10.1021/acsomega.9b01159.
[9]         Y. Hayashi, Pot economy and one-pot synthesis, Chem. Sci. 7 (2016) 866–880. https://doi.org/10.1039/C5SC02913A.
[10]       Z. El Asri, Y. Génisson, F. Guillen, O. Baslé, N. Isambert, M. del Mar Sanchez Duque, S. Ladeira, J. Rodriguez, T. Constantieux, J.-C. Plaquevent, Multicomponent reactions in ionic liquids: convenient and ecocompatible access to the 2,6-DABCO core, Green Chem. 13 (2011) 2549. https://doi.org/10.1039/c1gc15635g.
[11]       E. Rushell, Y.K. Tailor, S. Khandewal, K. Verma, M. Agarwal, M. Kumar, Deep eutectic solvent promoted synthesis of structurally diverse hybrid molecules with privileged heterocyclic substructures, New J. Chem. 43 (2019) 12462–12467. https://doi.org/10.1039/C9NJ02694K.
[12]       S.K. Singh, K.N. Singh, Eco-friendly and facile one-pot multicomponent synthesis of acridinediones in water under microwave, J. Heterocycl. Chem. 48 (2011) 69–73. https://doi.org/10.1002/jhet.508.
[13]       M. Nikpassand, S. Atrchian, Chemical Review and Letters DFT study of azo linkage effect on homoaromatization of some 1,4-dihydropryridines, Chem Rev Lett. 3 (2020) 53–60. https://doi.org/10.22034/crl.2020.220974.1038.
[14]       L. R. Melo, W. A. Silva, Ionic Liquid in Multicomponent Reactions: A Brief Review, Curr. Green Chem. 3 (2016) 120–132. https://doi.org/10.2174/2213346103666160530143059.
[15]       A.J. Greer, J. Jacquemin, C. Hardacre, Industrial Applications of Ionic Liquids, Molecules. 25 (2020) 5207. https://doi.org/10.3390/molecules25215207.
[16]       I.R. Siddiqui, D. Kumar, S. Shamim, Ionic Liquid Promoted Multicomponent Reaction: A Good Strategy for the Eco-Compatible Synthesis of Functionalized Pyrroles, J. Heterocycl. Chem. 50 (2013) E111–E115. https://doi.org/10.1002/jhet.1085.
[17]       A.A. Abdelhamid, H.A. Salah, A.A. Marzouk, Synthesis of imidazole derivatives: Ester and hydrazide compounds with antioxidant activity using ionic liquid as an efficient catalyst, J. Heterocycl. Chem. 57 (2020) 676–685. https://doi.org/10.1002/jhet.3808.
[18]       S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, [Bmim]BF 4 ionic liquid: An efficient reaction medium for the one-pot multi-component synthesis of 2-amino-4,6-diphenylpyridine-3-carbonitrile derivatives, J. Saudi Chem. Soc. 20 (2016) 517–522. https://doi.org/10.1016/j.jscs.2012.07.011.
[19]       B. Jiang, T. Rajale, W. Wever, S.-J. Tu, G. Li, Multicomponent Reactions for the Synthesis of Heterocycles, Chem. - An Asian J. 5 (2010) 2318–2335. https://doi.org/10.1002/asia.201000310.
[20]       J.E. Biggs-Houck, A. Younai, J.T. Shaw, Recent advances in multicomponent reactions for diversity-oriented synthesis, Curr. Opin. Chem. Biol. 14 (2010) 371–382. https://doi.org/10.1016/j.cbpa.2010.03.003.
[21]       A.M. Shahi, M. Nikpassand, L.Z. Fekri, Acidic Ionic Liquid-catalyzed Synthesis of Pyrano[4,3-b]pyran-5(4H)-ones using 4,4,4-trifluoro-1-phenylbutane-1,3-dione as a Building Block, Curr. Org. Synth. 17 (2020) 648–653. https://doi.org/10.2174/1570179417666200520111536.
[22]       A.M. Shahi, M. Nikpassand, L.Z. Fekri, An Efficient and Green Synthesis of New Benzo[ f ]chromenes Using 1,4-Disulfo-1,4-diazoniabicyclo[2.2.2]octane Chloride as a Novel Medium, Org. Prep. Proced. Int. 51 (2019) 521–529. https://doi.org/10.1080/00304948.2019.1666637.
[23]       H. Taherkhorsand, M. Nikpassand, One-pot Synthesis of Novel 2-pyrazolo-3-phenyl-1,3-thiazolidine-4-ones Using DSDABCOC as an Effective Media, Comb. Chem. High Throughput Screen. 21 (2018) 65–69. https://doi.org/10.2174/1386207321666180124094055.
[24]       Z. Gharib, M. Nikpassand, 3,3-(Butane-1,4-diyl)bis(1,2-dimethyl-1H-imidazole-3-ium)bromide–cerium(IV) ammonium nitrate: A novel reagent for mild synthesis of 12-aryldibenzo[i,b]pyrano[4,3-b]chromenone of benzyl alcohols, Russ. J. Gen. Chem. 86 (2016) 2759–2767. https://doi.org/10.1134/S1070363216120379.
[25]       C. Zhou, J. Min, Z. Liu, A. Young, H. Deshazer, T. Gao, Y.-T. Chang, N.R. Kallenbach, Synthesis and biological evaluation of novel 1,3,5-triazine derivatives as antimicrobial agents, Bioorg. Med. Chem. Lett. 18 (2008) 1308–1311. https://doi.org/10.1016/j.bmcl.2008.01.031.
[26]       N.C. Desai, A.H. Makwana, K.M. Rajpara, Synthesis and study of 1,3,5-triazine based thiazole derivatives as antimicrobial agents, J. Saudi Chem. Soc. 20 (2016) S334–S341. https://doi.org/10.1016/j.jscs.2012.12.004.
[27]       V. Dubey, M. Pathak, H.R. Bhat, U.P. Singh, Design, Facile Synthesis, and Antibacterial Activity of Hybrid 1,3,4-thiadiazole-1,3,5-triazine Derivatives Tethered via -S- Bridge, Chem. Biol. Drug Des. 80 (2012) 598–604. https://doi.org/10.1111/j.1747-0285.2012.01433.x.
[28]       R.P. Modh, E. De Clercq, C. Pannecouque, K.H. Chikhalia, Design, synthesis, antimicrobial activity and anti-HIV activity evaluation of novel hybrid quinazoline–triazine derivatives, J. Enzyme Inhib. Med. Chem. 29 (2014) 100–108. https://doi.org/10.3109/14756366.2012.755622.
[29]       K.M. Al-Zaydi, H.H. Khalil, A. El-Faham, S.N. Khattab, Synthesis, characterization and evaluation of 1,3,5-triazine aminobenzoic acid derivatives for their antimicrobial activity, Chem. Cent. J. 11 (2017) 39. https://doi.org/10.1186/s13065-017-0267-3.
[30]       W. Yan, Y. Zhao, J. He, Anti‑breast cancer activity of selected 1,3,5‑triazines via modulation of EGFR‑TK., Mol. Med. Rep. 18 (2018) 4175–4184. https://doi.org/10.3892/mmr.2018.9426.
[31]       M. Venkatraj, I.G. Salado, J. Heeres, J. Joossens, P.J. Lewi, G. Caljon, L. Maes, P. Van der Veken, K. Augustyns, Novel triazine dimers with potent antitrypanosomal activity., Eur. J. Med. Chem. 143 (2018) 306–319. https://doi.org/10.1016/j.ejmech.2017.11.075.
[32]       H.R. Bhat, U.P. Singh, P. Gahtori, S.K. Ghosh, K. Gogoi, A. Prakash, R.K. Singh, 4-Aminoquinoline-1,3,5-triazine: Design, synthesis, in vitro antimalarial activity and docking studies, New J. Chem. 37 (2013) 2654. https://doi.org/10.1039/c3nj00317e.
[33]       H.H. Al Rasheed, A.M. Malebari, K.A. Dahlous, D. Fayne, A. El-Faham, Synthesis, Anti-proliferative Activity, and Molecular Docking Study of New Series of 1,3-5-Triazine Schiff Base Derivatives, Molecules. 25 (2020) 4065. https://doi.org/10.3390/molecules25184065.
[34]       N. Lolak, S. Akocak, S. Bua, C.T. Supuran, Design, synthesis and biological evaluation of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as potent carbonic anhydrase IX inhibitors, Bioorg. Chem. 82 (2019) 117–122. https://doi.org/10.1016/j.bioorg.2018.10.005.
[35]       G.B. Bennett, R.B. Mason, L.J. Alden, J.B. Roach, Synthesis and antiinflammatory activity of trisubstituted pyrimidines and triazines, J. Med. Chem. 21 (1978) 623–628. https://doi.org/10.1021/jm00205a006.
[36]       E. Havránková, J. Csöllei, P. Pazdera, New Approach for the One-Pot Synthesis of 1,3,5-Triazine Derivatives: Application of Cu(I) Supported on a Weakly Acidic Cation-Exchanger Resin in a Comparative Study, Molecules. 24 (2019) 3586. https://doi.org/10.3390/molecules24193586.
[37]       R. Santosh, P. Paul, M.K. Selvam, C. Raril, P.M. Krishna, J.G. Manjunatha, G.K. Nagaraja, One-Pot Synthesis of Pyrimido[4,5-d]pyrimidine Derivatives and Investigation of Their Antibacterial, Antioxidant, DNA-Binding and Voltammetric Characteristics, ChemistrySelect. 4 (2019) 990–996. https://doi.org/10.1002/slct.201803416.
[38]       Y. Diao, X. Fang, P. Song, M. Lai, L. Tong, Y. Hao, D. Dou, Y. Liu, J. Ding, Z. Zhao, H. Xie, H. Li, Discovery and Biological evaluation of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as potent Bruton’s tyrosine kinase inhibitors, Bioorg. Med. Chem. 27 (2019) 3390–3395. https://doi.org/10.1016/j.bmc.2019.06.023.
[39]       T. Venkatesh, Y.D. Bodke, A.R.S. J, Facile CAN catalyzed one pot synthesis of novel indol-5,8-pyrimido[4,5-d]pyrimidine derivatives and their pharmacological study, Chem. Data Collect. 25 (2020) 100335. https://doi.org/10.1016/j.cdc.2019.100335.
[40]       P. Sharma, N. Rane, V.. Gurram, Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents, Bioorg. Med. Chem. Lett. 14 (2004) 4185–4190. https://doi.org/10.1016/j.bmcl.2004.06.014.
[41]       V.J. Ram, A. Goel, S. Sarkhel, P.R. Maulik, A Convenient Synthesis and Hepatoprotective Activity of Imidazo[1,2- c ]pyrimido[5,4- e ]pyrimidine, Tetraazaacenaphthene and Tetraazaphenalene from Cyclic Ketene Aminals Through Tandem Addition-Cyclization Reactions ‡ ‡CDRI communication number 5986., Bioorg. Med. Chem. 10 (2002) 1275–1280. https://doi.org/10.1016/S0968-0896(01)00423-0.
[42]       P. Perlíková, M. Hocek, Pyrrolo[2,3- d ]pyrimidine (7-deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides, Med. Res. Rev. 37 (2017) 1429–1460. https://doi.org/10.1002/med.21465.
[43]       L. Suresh, P. Sagar Vijay Kumar, Y. Poornachandra, C. Ganesh Kumar, G.V.P. Chandramouli, Design, synthesis and evaluation of novel pyrazolo-pyrimido[4,5- d ]pyrimidine derivatives as potent antibacterial and biofilm inhibitors, Bioorg. Med. Chem. Lett. 27 (2017) 1451–1457. https://doi.org/10.1016/j.bmcl.2017.01.087.
[44]       A.Y. Aksinenko, T. V. Goreva, T.A. Epishina, S. V. Trepalin, V.B. Sokolov, Synthesis of bis(trifluoromethyl)pyrimido[4,5-d]pyrimidine-2,4-diones and evaluation of their antibacterial and antifungal activities, J. Fluor. Chem. 188 (2016) 191–195. https://doi.org/10.1016/j.jfluchem.2016.06.019.
[45]       A.R. Suresh Babu, D. Gavaskar, R. Raghunathan, A facile synthesis of novel ferrocene grafted spiro-indenoquinoxaline pyrrolizidines via one-pot multicomponent [3+2] cycloaddition of azomethine ylides, Tetrahedron Lett. 53 (2012) 6676–6681. https://doi.org/10.1016/j.tetlet.2012.09.104.
[46]       M. Zhang, W. Yang, K. Li, K. Sun, J. Ding, L. Yang, C. Zhu, Facile Synthesis of Dispiroheterocycles through One-Pot [3+2] Cycloaddition, and Their Antiviral Activity, Synthesis (Stuttg). 51 (2019) 3847–3858. https://doi.org/10.1055/s-0037-1611900.
[47]       K. Martina, S. Tagliapietra, V. V. Veselov, G. Cravotto, Green Protocols in Heterocycle Syntheses via 1,3-Dipolar Cycloadditions, Front. Chem. 7 (2019) 1–21. https://doi.org/10.3389/fchem.2019.00095.
[48]       A. V. Chate, S.P. Kamdi, A.N. Bhagat, C.K. Jadhav, A. Nipte, A.P. Sarkate, S. V. Tiwari, C.H. Gill, Design, Synthesis and SAR Study of Novel Spiro [Pyrimido[5,4-b]Quinoline-10,5′-Pyrrolo[2,3-d]Pyrimidine] Derivatives as Promising Anticancer Agents, J. Heterocycl. Chem. 55 (2018) 2297–2302. https://doi.org/10.1002/jhet.3286.
[49]       V.S. Dofe, A.P. Sarkate, Z.M. Shaikh, C.K. Jadhav, A.S. Nipte, C.H. Gill, Ultrasound-assisted Synthesis of Novel Pyrazole and Pyrimidine Derivatives as Antimicrobial Agents, J. Heterocycl. Chem. 55 (2018) 756–762. https://doi.org/10.1002/jhet.3105.
[50]       A.S. Nipate, C.K. Jadhav, A. V. Chate, K.S. Taur, C.H. Gill, β‐Cyclodextrin catalyzed access to fused 1,8‐dihydroimidazo[2,3‐ b ]indoles via one‐pot multicomponent cascade in aqueous ethanol: Supramolecular approach toward sustainability, J. Heterocycl. Chem. 57 (2020) 820–829. https://doi.org/10.1002/jhet.3828.
[51]       A. V. Chate, A.S. Kulkarni, C.K. Jadhav, A.S. Nipte, G.M. Bondle, Multicomponent reactions and supramolecular catalyst: A perfect synergy for eco‐compatible synthesis of pyrido[2,3‐ d ]pyrimidines in water, J. Heterocycl. Chem. 57 (2020) 2184–2193. https://doi.org/10.1002/jhet.3938.
[52]       C.K. Jadhav, A.S. Nipate, A. V. Chate, A.P. Patil, C.H. Gill, Ionic liquid catalyzed one‐pot multi‐component synthesis of fused <scp>pyridine derivatives</scp> : <scp>A strategy</scp> for green and sustainable chemistry, J. Heterocycl. Chem. 57 (2020) 4291–4303. https://doi.org/10.1002/jhet.4135.
[53]       C.K. Jadhav, A.S. Nipate, A. V. Chate, P.M. Kamble, G.A. Kadam, V.S. Dofe, V.M. Khedkar, C.H. Gill, Room temperature ionic liquid promoted improved and rapid synthesis of highly functionalized imidazole and evaluation of their inhibitory activity against human cancer cells, J. Chinese Chem. Soc. (2021) jccs.202000468. https://doi.org/10.1002/jccs.202000468.