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Journal of Chemistry
Volume 2013 (2013), Article ID 325268, 5 pages
http://dx.doi.org/10.1155/2013/325268
Research Article

Al(NO3)3 · 9H2O: An Efficient Catalyst for the One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Both under Reflux or Solvent-Free Conditions

Department of Chemistry, Semnan University, P.O. Box 35195-363, Semnan, Iran

Received 23 January 2012; Accepted 30 May 2012

Academic Editor: Kotaro Satoh

Copyright © 2013 Eskandar Kolvari and Maryam Mirzaeeyan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Al(NO3)3 · 9H2O efficiently catalyzes the three-component Biginelli reaction between an aldehyde, a β-dicarbonyl compound, and urea or thiourea in refluxing ethanol and solvent-free (SF) conditions to afford the corresponding dihydropyrimidinones in high yields. The advantages of this method involve the easy procedure, the environmentally friendly process, and the low cost of the Lewis acid catalyst.

1. Introduction

In 1893, the Italian chemist Pietro Biginelli reported a cyclocondensation reaction between ethylacetoacetate, benzaldehyde, and urea to obtain a heterocyclic system of 3,4-dihydropyrimidinones (DHPMs), which is known as Biginelli reaction [1]. Dihydropyrimidinones are known to exhibit a wide range of biological activities such as antiviral, antitumor, and antibacterial andante-inflammatory activities [2]. In addition, these compounds have emerged as potential calcium channel blockers, antihypertensive [3]. Furthermore, pyrimidin unit is found in many marine natural products including batzelladine alkaloids, which have been found to be HIVgp-120-CD4 inhibitors [4]. Hence, the Biginelli reaction continues to attract the attention of organic chemists interested in finding milder and more efficient procedures for the synthesis of dihydropyrimidinones [57]. Synthetic strategies for the dihydropyrimidinone nucleus involve both one-pot and multistep approaches [8, 9]. At present, several general methods are known for the preparation of dihydropyrimidinones, using various Lewis and protic acids such as BF3·OEt2 [10], ZrCl4 [11, 12], Sc(OTf)3 [13], zeolites [1416], SbCl3 [17], CuCl2·2H2O [18] trichloroisocyanuric acid (TCCA) [19], RuCl3 [20], silica sulfuric acid (SSA) [21], and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) [22]. However, some of these procedures suffer from disadvantages such as unsatisfactory yields, cumbersome product isolation procedures, and environmental pollution.

Therefore, there still exists a need for versatile, simple, and environmentally friendly processes whereby DHPMs may be formed under milder and practical conditions.

2. Experimental

2.1. General

Chemicals were purchased from Merck, Aldrich, and Acros companies and were used without further purification. All yields refer to isolated products. The purity determination of the substrates and reaction monitoring were accompanied by thin-layer chromatography (TLC) and visualized under ultraviolet (UV) light. Melting points were determined using Electrothermal 9100 instrument in open capillaries and are uncorrected. All compounds are well known and were identified by comparison of the spectroscopic data with those of the authentic samples.

2.2. Typical Reaction for the Synthesis of Biginelli Compounds in Refluxing Ethanol

A solution of ethyl acetoacetate (2 mmol, 210 mg), benzaldehyde (2 mmol, 212 mg), urea (3 mmol, 180 mg), and Al(NO3)3·9H2O (0.3 mmol, 112 mg) in 95% ethanol (5 mL) was heated under reflux for 7 h. On cooling, the product crystallized from the solution. The pure solid, 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one, (92%, 479 mg, mp 202–204°C) was filtered, washed with cold ethanol ( mL), and dried under vacuum.

2.3. Typical Reaction for the Synthesis of Biginelli Compounds in Solvent-Free Conditions

A mixture of ethyl acetoacetate (2 mmol, 210 mg), benzaldehyde (2 mmol, 212 mg), urea (3 mmol, 180 mg), and Al(NO3)3·9H2O (0.3 mmol, 112 mg) was heated under solvent-free conditions for 30 min at 80°C. After completion of reaction, hot ethanol (5 mL) added to reaction mixture. On cooling, the product spontaneously crystallized from the solution. The pure solid, 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one, (97%, 505 mg, mp 202–204°C) was filtered, washed with cold ethanol ( mL) and dried under vacuum.

3. Results and Discussion

In continuation of our work on the development of useful synthetic methodologies [2325], we have observed that aluminum nitrate is an effective catalyst for the synthesis of Biginelli compounds (Figure 1). As a model reaction, we started to study the three-component aluminum nitrate catalyzed Biginelli condensation by examining the conditions required for the reaction involving benzaldehyde, urea, and ethyl acetoacetate to afford the corresponding 3,4-dihydropyrimidinone in refluxing ethanol.

325268.fig.001
Figure 1: Aluminum nitrate-catalyzed synthesis of 3,4-dihydropyrimidin-2-ones/thiones.

Initially, we turned our attention toward screening appropriate concentration of aluminum nitrate (Table 1). In the first stage, we carried out the model reaction in absence of any catalyst (entry 1, Table 1) for which the yield of product was negligible. Afterward, we selected 5 mol% aluminum nitrate to catalyze the model reaction and found that the desired 3,4-dihydropyridinone was obtained in 70% yield. The reaction worked well when the amount of Al(NO3)3·9H2O was increased from 10 to 15 mol%, but 15 mol% of Al(NO3)3·9H2O gave highest yield, and larger amount of catalyst did not improve the yields to a greater extent.

tab1
Table 1: Influence amount of aluminum nitrate on the yield of ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in refluxing ethanola.

After investigation of the influence of catalyst amount on the yield of the reaction, various solvents including CH3CN, EtOH, MeOH, Acetone, CHCl3, EtOH/H2O (1 : 1), and H2O were tested and compared with solvent-free conditions (Table 2). As can be seen in Table 2, among the different solvents, ethanol gave the highest yield (Table 2, entry 2), whereas water did not yield good results in aluminum nitrate-catalyzed Biginelli reaction (Table 2, entry 7). Also, addition of catalytic amount of sodium dodecyl sulfate (SDS) only improved yield of product up to 5%. In addition, we prepared Al(DS)3 by reaction of aluminum nitrate with SDS according to reported procedure [26] and used it as catalyst in the model reaction in water as solvent under the reflux condition, but Al(DS)3 did not improve yield of reaction in our hand. We finally identified ethanol as the most efficient solvent for aluminum nitrate-catalyzed Biginelli reaction. To investigate the versatility as well as the capacity of our method, the reactions were examined in solvent-free conditions.

tab2
Table 2: Synthesis of ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in the presence of Al(NO3)3·9H2O in various solvents under reflux and solvent-free conditionsa.

In solvent-free conditions, the yield increased, and the reaction time decreased (Table 2, entry 12). In addition, at low temperature and long reaction times only smaller amounts of the desired products were obtained (Table 3, entry 1).

tab3
Table 3: Influence of temperature on the solvent-free synthesis of ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in the presence of Al(NO3)3·9H2Oa.

After optimizing the reaction conditions, various aromatic aldehydes carrying either electron-releasing or electron-withdrawing substituents in the ortho, meta, and para positions afforded good to excellent yields of the products both in refluxing ethanol and solvent-free conditions. An important feature of this procedure is that despite the high oxidizing potential of aluminum nitrate, functional groups such as ethers and hydroxy survive under the reaction conditions. Thiourea was used with similar success to provide the corresponding 3,4-dihydropyrimidin-2(1H)-thiones which are also of interest with regard to their biological activities (Table 4, entries 3, 8) [27].

tab4
Table 4: Synthesis of various dihydropyrimidinones catalyzed by Al (NO3)3·9H2O in refluxing ethanol (I) and solvent-free conditions at 80°C .

We can reach a better conclusion by comparing the performance of the present work with some other recent reports available in the literature, as illustrated in Table 5.

tab5
Table 5: Biginelli synthesis of 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one: Al(NO3)3·9H2O in comparison with some recent reports.

The mechanism of Biginelli reaction has been investigated thoroughly [33]. According to Kappe [34], the first step in the mechanism is believed to be the condensation between the aldehyde and urea. The iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH2 to give the cyclized product (Figure 2).

325268.fig.002
Figure 2: Proposed mechanism for the aluminum nitrate-catalyzed Biginelli reaction.

4. Conclusions

In conclusion, the present procedure provides an efficient and improved modification of the Biginelli reaction. Mild reaction conditions, operational simplicity and easy work-up, good to excellent yields, cheap and nontoxic catalyst, and short reaction times (in solvent-free conditions) are features of this new procedure.

Acknowledgments

The authors gratefully acknowledge the financial support received for this research work from the Research Council of Semnan University. Also they acknowledge Professor Mohammad Ali Zolfigol and Professor Ardeshir Khazaei for their generous support.

References

  1. P. G. Biginelli, “Ueber aldehyduramide des acetessigäthers. II,” Berichte der Deutschen Chemischen Gesellschaft, vol. 24, no. 2, pp. 2962–2967, 1891. View at Publisher · View at Google Scholar
  2. C. O. Kappe, “Biologically active dihydropyrimidones of the Biginelli-type—a literature survey,” European Journal of Medicinal Chemistry, vol. 35, no. 12, pp. 1043–1052, 2000. View at Publisher · View at Google Scholar
  3. C. O. Kappe, “4-aryldihydropyrimidines via the Biginelli condensation: aza-analogs of nifedipine-type calcium channel modulators,” Molecules, vol. 3, no. 1, pp. 1–9, 1998. View at Google Scholar · View at Scopus
  4. K. Folkers, H. J. Harwood, and J. Johnson, “Hydrogenation of cyclic ureides under elevated temperatures and pressures. I.1 2-Keto-1,2,3,4-tetrahydropyrimidines,” Journal of the American Chemical Society, vol. 56, no. 5, pp. 1180–1185, 1934. View at Publisher · View at Google Scholar
  5. I. T. Phucho, A. Nongpiur, S. Tumtin, R. Nongrum, and R. L. Nongkhlaw, “Recent progress in the chemistry of dihydropyrimidinones,” Rasayan Journal of Chemistry, vol. 2, no. 3, pp. 662–676, 2009. View at Google Scholar · View at Scopus
  6. A. Saini, S. Kumar, and J. S. Sandhu, “Biginelli reaction,” Journal of the Indian Chemical Society, vol. 84, no. 10, pp. 959–970, 2007. View at Google Scholar · View at Scopus
  7. C. O. Kappe, “100 years of the Biginelli dihydropyrimidine synthesis,” Tetrahedron, vol. 49, no. 32, pp. 6937–6963, 1993. View at Publisher · View at Google Scholar · View at Scopus
  8. P. Wipf and A. Cunningham, “A solid phase protocol of the Biginelli dihydropyrimidine synthesis suitable for combinatorial chemistry,” Tetrahedron Letters, vol. 36, no. 43, pp. 7819–7822, 1995. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Studer, P. Jeger, P. Wipf, and D. P. Curran, “Fluorous synthesis: fluorous protocols for the ugi and Biginelli multicomponent condensations,” Journal of Organic Chemistry, vol. 62, no. 9, pp. 2917–2924, 1997. View at Google Scholar · View at Scopus
  10. E. H. Hu, D. R. Sidler, and U.-H. Dolling, “Note unprecedented catalytic three component one-pot condensation reaction:  an efficient synthesis of 5-Alkoxycarbonyl- 4-aryl-3,4-dihydropyrimidin-2(1H)-ones,” The Journal of Organic Chemistry, vol. 63, no. 10, pp. 3454–3457, 1998. View at Publisher · View at Google Scholar
  11. C. V. Reddy, M. Mahesh, P. V. K. Raju, T. R. Babu, and V. V. N. Reddy, “Zirconium(IV) chloride catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones,” Tetrahedron Letters, vol. 43, no. 14, pp. 2657–2659, 2002. View at Publisher · View at Google Scholar · View at Scopus
  12. J. C. Rodríguez-Domínguez, D. Bernardi, and G. Kirsch, “ZrCl4 or ZrOCl2 under neat conditions: optimized green alternatives for the Biginelli reaction,” Tetrahedron Letters, vol. 48, no. 33, pp. 5777–5780, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. K. S. De and R. A. Gibbs, “Scandium(III) triflate as an efficient and reusable catalyst for synthesis of 3,4Dihydropyrimidin2(1H)ones,” Synthetic Communications, vol. 35, no. 20, pp. 2645–2651, 2005. View at Publisher · View at Google Scholar
  14. M. G. Kulkarni, S. W. Chavhan, M. P. Shinde et al., “Zeolite catalyzed solvent-free one-pot synthesis of dihydropyrimidin-2(1H)- ones—a practical synthesis of monastrol,” Beilstein Journal of Organic Chemistry, vol. 5, article 4, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. V. Radha Rani, N. Srinivas, M. Radha Kishan, S. J. Kulkarni, and K. V. Raghavan, “Zeolite-catalyzed cyclocondensation reaction for the selective synthesis of 3,4-dihydropyrimidin-2(1H)-ones,” Green Chemistry, vol. 3, no. 6, pp. 305–306, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Tajbakhsh, B. Mohajerani, M. M. Heravi, and A. N. Ahmadi, “Natural HEU type zeolite catalyzed Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-2(1H) one derivatives,” Journal of Molecular Catalysis A, vol. 236, no. 1-2, pp. 216–219, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. I. Cepanec, M. Litvić, M. Filipan-Litvić, and I. Grüngold, “Antimony(III) chloride-catalysed Biginelli reaction: a versatile method for the synthesis of dihydropyrimidinones through a different reaction mechanism,” Tetrahedron, vol. 63, no. 48, pp. 11822–11827, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. F. Xu, J. J. Wang, and Y. P. Tian, “New procedure for one pot synthesis of 3,4 dihydropyrimidin 2(1H) ones by Biginelli reaction,” Synthetic Communications, vol. 38, no. 8, pp. 1299–1310, 2008. View at Publisher · View at Google Scholar
  19. F. Shirini, M. A. Zolfigol, and E. Mollarazi, “Solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones using trichloroisocyanuric acid,” Letters in Organic Chemistry, vol. 2, no. 8, pp. 718–720, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. S. K. De and R. A. Gibbs, “Ruthenium(III) chloride-catalyzed one-pot synthesis of 3,4- dihydropyrimidin-2-(1H)-ones under solvent-free conditions,” Synthesis, no. 11, pp. 1748–1750, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. P. Salehi, M. Dabiri, M. A. Zolfigol, and M. A. Bodaghi Fard, “Silica sulfuric acid: an efficient and reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones,” Tetrahedron Letters, vol. 44, no. 14, pp. 2889–2891, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. S. F. Hojati, M. Gholizadeh, M. Haghdoust, and F. Shafiezadeh, “1,3-dichloro-5,5-dimethylhydantoin as a novel and efficient homogeneous catalyst in Biginelli reaction,” Bulletin of the Korean Chemical Society, vol. 31, no. 11, pp. 3238–3240, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. M. A. Zolfigol, P. Salehi, A. Ghaderi, and M. Shiri, “A catalytic and green procedure for Friedlander quinoline synthesis in aqueous media,” Catalysis Communications, vol. 8, no. 8, pp. 1214–1218, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. M. A. Zolfigol and M. Safaiee, “Synthesis of 1,4-dihydropyridines under solvent-free conditions,” Synlett, no. 5, pp. 827–828, 2004. View at Google Scholar · View at Scopus
  25. A. Khazaei, M. A. Zolfigol, E. Kolvari, N. Koukabi, H. Soltani, and L. S. Bayani, “Electrophilic bromination of alkenes, alkynes, and aromatic amines with iodic acid/potassium bromide under mild conditions,” Synthetic Communications, vol. 40, no. 19, pp. 2954–2962, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. M. A. Zolfigol, P. Salehi, M. Shiri, and Z. Tanbakouchian, “A new catalytic method for the preparation of bis-indolyl and tris-indolyl methanes in aqueous media,” Catalysis Communications, vol. 8, no. 2, pp. 173–178, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Dondoni, A. Massi, and S. Sabbatini, “Improved synthesis and preparative scale resolution of racemic monastrol,” Tetrahedron Letters, vol. 43, no. 34, pp. 5913–5916, 2002. View at Publisher · View at Google Scholar · View at Scopus
  28. S. D. Salim and K. G. kamanchi, “Sulfated tungstate: an alternative, eco-friendly catalyst for Biginelli reaction,” Catalysis Communications, vol. 12, no. 12, pp. 1153–1156, 2011. View at Publisher · View at Google Scholar
  29. M. Zeinali-Dastmalbaf, A. Davoodnia, M. M. Heravi, N. Tavakoli-Hoseini, A. Khojastehnezhad, and H. A. Zamani, “Silica gel-supported polyphosphoric acid (PPA-SiO2) catalyzed one-pot multi-component synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and—thiones: an efficient method for the Biginelli reaction,” Bulletin of the Korean Chemical Society, vol. 32, no. 2, pp. 656–658, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. H. A. Oskooie, M. M. Heravi, N. Karimi, and M. H. Monjezy, “FeCl3 immobilized in Al-MCM 41: an efficient catalyst system for the Biginelli reaction,” Synthetic Communications, vol. 41, no. 6, pp. 826–831, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. A. R. Hajipour, L. Khazdooz, and A. Zarei, “Brønsted acidic ionic liquid-catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones under solvent-free conditions,” Synthetic Communications, vol. 41, no. 15, pp. 2200–2208, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. O. Rosati, M. Curini, F. Montanari, M. Nocchetti, and S. Genovese, “α-zirconium sulfophenylphosphonate as a catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives under solvent free conditions,” Catalysis Letters, vol. 141, no. 6, pp. 850–853, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. C. O. Kappe, “Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog,” Accounts of Chemical Research, vol. 33, no. 12, pp. 879–888, 2000. View at Publisher · View at Google Scholar
  34. C. O. Kappe, “A reexamination of the mechanism of the Biginelli dihydropyrimidine synthesis. Support for an N-acyliminium ion intermediate,” The Journal of Organic Chemistry, vol. 62, no. 21, pp. 7201–7204, 1997. View at Publisher · View at Google Scholar