Outline
Comptes Rendus

Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones
Comptes Rendus. Chimie, Volume 15 (2012) no. 6, pp. 504-510.

Abstract

A simple, green and catalyst free one pot synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones via a multicomponent reaction between thiazolidine-2, 4-dione (TZD), aromatic aldehyde and urea analogues is described. The ionic liquid has been used as a solvent as well as catalyst for this reaction. This reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, simple experimental workup procedure and no by-products.

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DOI: 10.1016/j.crci.2012.04.002
Keywords: Tetrahydro-thiazolo[5, 4-d]pyrimidine-2, 5-diones, One pot synthesis, Catalyst free, Ionic liquid

Prashant Singh 1, 2; Kamlesh Kumari 3; Monica Dubey 3; Vijay K. Vishvakarma 2; Gopal K. Mehrotra 3; Narender D. Pandey 3; Ramesh Chandra 4

1 A.R.S.D. College, University of Delhi, New Delhi 110021, India
2 Department of Applied Chemistry, BBA University, Lucknow, UP, India
3 Department of Chemistry, MNNIT Allahabad, UP, India
4 ACBR, University of Delhi, New Delhi 110007, India
@article{CRCHIM_2012__15_6_504_0,
     author = {Prashant Singh and Kamlesh Kumari and Monica Dubey and Vijay K. Vishvakarma and Gopal K. Mehrotra and Narender D. Pandey and Ramesh Chandra},
     title = {Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones},
     journal = {Comptes Rendus. Chimie},
     pages = {504--510},
     publisher = {Elsevier},
     volume = {15},
     number = {6},
     year = {2012},
     doi = {10.1016/j.crci.2012.04.002},
     language = {en},
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%A Kamlesh Kumari
%A Monica Dubey
%A Vijay K. Vishvakarma
%A Gopal K. Mehrotra
%A Narender D. Pandey
%A Ramesh Chandra
%T Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones
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Prashant Singh; Kamlesh Kumari; Monica Dubey; Vijay K. Vishvakarma; Gopal K. Mehrotra; Narender D. Pandey; Ramesh Chandra. Ionic liquid catalyzed synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones. Comptes Rendus. Chimie, Volume 15 (2012) no. 6, pp. 504-510. doi : 10.1016/j.crci.2012.04.002. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.1016/j.crci.2012.04.002/

Version originale du texte intégral

1 Introduction

Heterocyclic compounds bearing nitrogen and sulphur have long been the prime focus of synthetic chemistry research due to their broad spectrum of applications in biological, pharmaceutical, and material areas [1,2]. Mainly, thiazolidines containing ketonic group have attracted much attention due to their interesting and unique properties such as protein-nucleic acid interactions, antiviral activity and antidiabetic activity. However, to our knowledge, a few methods were developed to construct polysubstituted thiazolones. Here over, some of these protocols have not been entirely satisfactory because of drawbacks such as low yields, long reaction time and cumbersome experimental processes [3,4]. One pot syntheses are emerging as useful tools for synthesizing small drug-like molecules with several degrees of structural diversity [5–10]. Pioneering work by several research groups in this area has already established the versatility and uniqueness of one pot multicomponent coupling protocols as a powerful methodology for the synthesis of diverse structure scaffolds required in the search of novel therapeutic molecules [11–14].

Thiazolidinone derivatives have been extensively used in drug discovery. They are reported to have anticonvulsant, antibacterial, antiviral and antidiabetic properties. For example, pioglitazone and rosiglitazone were launched recently for type-II diabetes mellitus [15–19]. Presence of these moieties in organic molecules imparts them with the extensive range of biological and pharmacological properties, such as antidiabetic, anticancerous and antimicrobial activities. Moreover, these compounds are also useful as conducting materials. Many of the methods reported for the synthesis of organic compounds are associated with the use of hazardous organic solvents, long reaction time, and lack of general applicability. Thus, we developed a simple one pot synthesis of novel 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones under catalyst free conditions.

2 Experimental

In a typical experiment, thiazolidine-2, 4-dione (10 mmol), aromatic aldehydes (10 mmol) and thiourea (11 mmol) in ionic liquid {[bmim]Br} (15 mL) was stirred at room temperature (80 °C) for the appropriate time. The completion of the reaction was monitored by thin layer chromatography (ethyl acetate: n-hexane: 20: 80). After the completion of reactions, the compound was isolated from the reaction mixture by the addition of ethyl ether (three times × 30 mL) and further washed with brine solution (three times × 30 mL). Then ethyl ether was evaporated under reduced pressure to afford the corresponding product. Structural assignments of the products are based on their 1H NMR, 13C NMR, FT-IR and mass analysis. The analysis of complete spectral and compositional data revealed the formation of corresponding derivatives in 85–95% yield. The ionic liquid used for the transformation was recovered and used for the further reactions.

3 Result and discussion

Thiazolidine-2,4-dione (1) reacts with benzaldehyde (2a) and thiourea (3a) to afford the product 7-Phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-dione (4a) in excellent yield (Scheme 1, 94%). The reaction of thiazolidine-2,4-dione (1) with benzaldehyde (2a) and thiourea could rapidly form (A) after dehydration. Further dehydration of A will occur and coupling processes to afford the target compound (4a). Screening of the reaction conditions was established suitable solvents, the mole ratio of reactants as well as temperature for the desired MCRs (Table 1). It was exciting that the chosen solvents such as dioxane, N,N–dimethylformamide (DMF), acetonitrile (CH3CN), dimethylsulfoxide (DMSO), toluene, etc. were suitable for the MCRs (Table 1, entries 1–10). Ionic liquid {[bmim]Br} proved to be the best among them (Table 1, entry 10), while under solvent free conditions, a complex result was obtained (Table 1, entry 5). To modulate the ratio of reactants and improve the yield, we examined various ratios of thiazolidine-2, 4-dione (1), benzaldehyde (2a) and thiourea (3a) by using ionic liquid {[bmim]Br} as a solvent (Table 1, entries 10–15). The best result obtained when the ratio of thiazolidine-2, 4-diones (1), benzaldehyde (2a) and phenol (3a) is 1:1:1.1 to afford the product 4a i.e. entry 12. Further, optimization of temperature was done (Table 1, entries 16–18) and we found the best yield was obtained at 80 °C (entry 17).

Scheme 1

Mechanism for the synthesis of 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones.

Table 1

Optimization of reaction conditions (solvent, mole ratio and temperature of the reactants) for the catalyst free multicomponent reactionsa.

S. no.SolventMole ratio (1:2a:3a)t (h)Temp (°C)Yield (%)
1Dioxane1:1:163065
2CH3CN1:1:173064
3DMF1:1:1143065
4Toluene1:1:183050
5None1:1:11830Complex
6DMSO1:1:1163055
7THF1:1:183070
8[NEt3][Ac]1:1:143080
9[bmim][Cl]1:1:143078
10[bmim][Br]1:1:12.53080
11[bmim][Br]1:1:1.12.53084
12[bmim][Br]1:1:1.22.53080
13[bmim][Br]1:1:1.32.53075
14[bmim][Br]1:1:0.92.53072
15[bmim][Br]1:1:0.82.53062
16[bmim][Br]1:1:1.12.54585
17[bmim][Br]1:1:1.12.56090
18[bmim][Br]1:1:1.12.58094

With the optimized condition in hand, we examine the scope of the multicomponent reaction (Table 2, entries 1–16). We are pleased to find that the reaction proceeded smoothly, and the desired products were afforded in excellent yields. Meaningfully, the substituted group on the thiazolidine ring could not be selectively induced by changing the addition order of the aromatic aldehyde and urea/thiourea under the same employed conditions. The ionic liquid used for the transformation was recovered and used for further reactions and gave good yield for further reactions as shown in Table 3. The mechanism has been justifiesd through a semi-empirical calculation on the basis of their energy and the same have incorporated in the manuscript as Table 4.

Table 2

Catalyst free one pot synthesis of 9-phenyl-3,9-dihydro-chromeno [2,3-d] thiazol-2-one via MCRs between thiazolidine-2,4-dione, aromatic aldehyde, urea derivative.

S. no.Reactant2Reactant3ProductCompound numbert (h)Yield (%)
14a2.594
24b3.090
34c2.092
44d2.092
54e3.095
64f3.593
74g4.588
84h5.084
94i6.086
104j7.582
114k6.094
124l6.092
134m6.090
144n6.090
154o6.588
164p6.584
Table 3

Optimization of the activity of ionic liquid for the synthesis of 4a after reuse.

S. no.No. of cycleYield (%)
1I95
2II94
3III94
4IV92
5V92
Table 4

Optimization and various parameters of the synthesized compounds.

Thermodynamic properties
CompoundSingle point energy (kcal/mol)Optimization energy (kcal/mol)Total E (Kcal/mol)Entropy (Kcal/mol/deg)Total Free E (Kcal/mol)H (Kcal/mol/deg)
16604.98612.66844.3670.071622.8790.0137
26681.34717.28350.6400.06929.9360.0120
318193.48136.564129.9070.095101.3920.0326
416901.23821.288113.4790.09983.7220.0338

4 Conclusion

In conclusion, a series of biologically and pharmacologically 7-phenyl-1,4,6,7-tetrahydro-thiazolo[5,4-d]pyrimidine-2,5-diones have been synthesized via one pot three component condensation of aromatic aldehyde, urea/thiourea, and thiazolidine-2,4-dione in excellent yields within a short reaction time. The advantages offered by ionic liquid as a solvent versus known organic solvent are:

  • • the ionic liquid has high vapor pressure;
  • • highly stable;
  • • reusable;
  • • environmentally benign.

The exploration of ionic liquid for other multicomponent reactions leading to biologically active compounds is underway.

Analytical data of the few selected compounds.

C. no.Data
4aIR (ν in cm−1) 3154.21, 2946.72, 2864.15, 1742.20, 1695.46, 1461.08, 1356.26, 1245.70, 1179.92, 807.37, 652.48; 1H NMR (300 MHz, d-DMSO) δ 8.45 (s, 1H of NH), 7.00–7.19 (m, 5H), δ 4.58 (s, 1H of benzylic proton), 2.54 (s, 1H of NH), 1.98 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (184.6), carbonyl carbon (165.1), aromatic carbon (129.3, 125.7, 120.1), δ for alkenic carbon (113.0, 110.5), benzylic carbon (65.8), HRMS (M+ ion peak) 263.0154.
4bIR (ν in cm−1) 3165.43, 2932.45, 2874.32, 1741.05, 1699.46, 1459.52, 1368.06, 1246.98, 1162.01, 816.09, 665.97; 1H NMR (300 MHz, d-DMSO) δ 8.14 (s, 1H of NH), 6.98–7.20 (m, 5H), δ 4.46 (s, 1H of benzylic proton), 2.79 (s, 1H of NH), 1.95 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (182.0), carbonyl carbon (163.4), aromatic carbon (130.1, 123.0, 119.1), δ for alkenic carbon (113.9, 111.6), benzylic carbon (66.0), HRMS (M+ ion peak) 247.3248.
4cIR (ν in cm−1) 3165.48, 2932.45, 2872.45, 1746.89, 1699.05, 1469.15, 1378.65, 1260.65, 1170.05, 812.65, 666.01; 1H NMR (300 MHz, d-DMSO) δ 8.65 (s, 1H of NH), 7.01-7.29 (m, 4H), δ 4.65 (s, 1H of benzylic proton), 2.36 (s, 1H of NH), 2.09 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (179.3), carbonyl carbon (162.3), aromatic carbon (131.4, 126.8, 121.7), δ for alkenic carbon (116.5, 111.0), benzylic carbon (62.2), HRMS (M+ ion peak) 308.4565.
4dIR (ν in cm−1) 3189.13, 2945.65, 2879.03, 1726.78, 1679.09, 1446.46, 1362.19, 1239.62, 1180.49, 812.36, 666.03; 1H NMR (300 MHz, d-DMSO) δ 8.49 (s, 1H of NH), 7.05–7.35 (m, 4H), δ 4.62 (s, 1H of benzylic proton), 2.63 (s, 1H of NH), 2.00 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (180.4), carbonyl carbon (161.0), aromatic carbon (131.0, 124.9, 121.8), δ for alkenic carbon (114.7, 111.7), benzylic carbon (66.9), HRMS (M+ ion peak) 292.8706.
4eIR (ν in cm−1) 3123.35, 2922.33, 2846.72, 1716.29, 1666.13, 1476.43, 1365.08, 1246.35, 1182.69, 832.35; 1H NMR (300 MHz, d-DMSO) δ 8.26 (s, 1H of NH), 6.79–7.33 (m, 4H), δ 4.46 (s, 1H of benzylic proton), 2.60 (s, 1H of NH), 2.32 (s, 3H of methyl), 1.89 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (185.6), carbonyl carbon (167.0), aromatic carbon (130.0, 125.0, 121.7), δ for alkenic carbon (112.6, 111.7), benzylic carbon (63.1), HRMS (M+ ion peak) 239.5987.
4fIR (ν in cm−1) 3102.32, 2978.29, 2878.45, 1732.49, 1702.23, 1465.78, 1321.22, 1246.08, 1145.65, 845.38, 615.95; 1H NMR (300 MHz, d-DMSO) δ 8.11 (s, 1H of NH), 6.83–7.29 (m, 4H), δ 4.62 (s, 1H of benzylic proton), 2.46 (s, 1H of NH), 2.12 (s, 3H of methyl), 1.86 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (188.0), carbonyl carbon (164.9), aromatic carbon (131.0, 126.4, 124.4), δ for alkenic carbon (115.7, 113.9), benzylic carbon (60.6), HRMS (M+ ion peak) 277.6598.
4gIR (ν in cm−1) 3202.15, 2938.46, 2873.09, 1739.15, 1738.45, 1489.15, 1375.17, 1260.19, 1154.28, 836.97, 666.67; 1H NMR (300 MHz, d-DMSO) δ 8.23 (s, 1H of NH), 6.88–7.10 (m, 4H), δ 4.32 (s, 1H of benzylic proton), 2.35 (s, 1H of NH), 1.89 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (181.6), carbonyl carbon (166.5), aromatic carbon (128.4, 126.3, 122.7), δ for alkenic carbon (115.1, 111.2), benzylic carbon (61.0), HRMS (M+ ion peak) 297.8977.
4hIR (ν in cm−1) 3208.65, 2945.68, 2879.46, 1719.18, 1689.39, 1461.08, 1354.72, 1298.15, 1183.36, 835.79, 679.15; 1H NMR (300 MHz, d-DMSO) δ 8.32 (s, 1H of NH), 7.00–7.19 (m, 4H), δ 4.18 (s, 1H of benzylic proton), 2.24 (s, 1H of NH), 1.84 (s, 1H of NH); 13C NMR (75 MHz, d-DMSO) δ for thiourea carbon (186.0), carbonyl carbon (160.9), aromatic carbon (124.7, 122.0, 119.3), δ for alkenic carbon (111.7, 108.7), benzylic carbon (61.1), HRMS (M+ ion peak) 281.0350.

Acknowledgement

We gratefully acknowledge financial support from University Grant Commission (UGC) and Department of Science and Technology, India.


References

[1] M. Manouchehr; L. Azam; T. Mohammad Reza Ultrason. Sonochem, 18 (2011), p. 45

[2] K. Ajeet; S. Prashant; S. Amit; D. Arnab; C. Ramesh; M. Subho Cat. Comm, 10 (2008), p. 17

[3] A. Uwe; G. Dirk; S. Enrico; T. Kerstin; L.P. Michael Bioorg. Med. Chem, 13 (2005), p. 4402

[4] M. Laura; B. Sylvain; S. Estibaliz; O. Aurelio Tet. Lett, 51 (2010), p. 6041

[5] A. Hemaka; H.Z. Rajapakse; B.Y. Mary; T.M. Bryan Tet. Lett., 47 (2006), p. 4827

[6] M. Dirk; A. Fatih; Li. Jun; R.F.S. Sven Bioorg. Med. Chem, 15 (2007), p. 7311

[7] Z. Jian; Z. Yongmin; Z. Xia; Z. Jing; Z.Li. He; Y. Xin-Shan; Z. Xiao-Lian Bioorg. Med. Chem, 16 (2008), p. 1605

[8] H. Zhou; T.P. Loh Tet. Lett., 50 (2009), p. 4368

[9] S. Paolo; C. Damiano; G. Giuseppe; C. Ornella Tet. Lett., 51 (2010), p. 4801

[10] J.L. Han; C.W. Ong Tet. Lett., 61 (2005), p. 1693

[11] E. Hossein; H. Gholam; D. Saman; V. Mohammad Chinese Chem. Lett., 21 (2010), p. 1423

[12] S.J. Yan; Y.J. Liu; Y.L. Chen; L. Liu; J. Lin Bioorg. Med. Chem, 20 (2010), p. 5225

[13] K. Toyoharu; H. Sho; T. Hiroshi; K. Shigeo Tetrahedron Lett, 49 (2008), p. 4349

[14] S.D. Sharma; H. Parasa; K. Dilip Tet. Lett., 49 (2008), p. 2216

[15] K. Srinivas; V.N. Srinivasu; D.O. Vuppalapati; L. Biradar J. Mol. Cat. A: Chem, 266 (2007), p. 109

[16] Li. Ji-Tai; Xin-Li. Zhai; C. Guo-Feng Ultrason. Sonochem., 17 (2010), p. 356

[17] L.M. Zhen; H.Z. Yi; S.L. Yi; X.P. Si Chinese Chem. Lett, 19 (2008), p. 915

[18] A. Davoodnia; M. Bakavoli; M. Soleimany; H. Behmadi Chinese Chem. Lett., 19 (2008), p. 685

[19] A. Tadashi; M. Sumiko; N. Yasutaka; T. Toshio; K. Mitsuo Tetrahedron Lett, 46 (2005), p. 4875


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