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Print version ISSN 0103-5053
J. Braz. Chem. Soc. vol.15 no.2 São Paulo Mar./Apr. 2004
Dennis RussowskyI, *; Fabrício A. LopesI; Victor S. S. da SilvaI; Karen F. S. CantoI; Marcelo G. Montes D'OcaII; Marla N. GodoiII
IInstituto de Química, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre - RS, Brazil
IIDepartamento de Química, Fundação Universidade do Rio Grande 96201-900, Rio Grande - RS, Brazil
The ability of SnCl2.2H2O as catalyst to promote the Biginelli three-component condensation reaction from a diversity of aromatic aldehydes, ethyl acetoacetate and urea or thiourea is described. The reaction was carried out in acetonitrile or ethanol as solvents in neutral media and represents an improvement of the classical Biginelli protocol and an advantage in comparison with FeCl3.6H2O, NiCl2.6H2O and CoCl2.6H2O which were used with HCl as co-catalyst. The synthesis of 3,4-dihydropyrimidinones was achieved in good to excelent yields.
Keywords: Biginelli reaction, multicomponent reaction, dihydropyrimidinones, tin(II) chloride hydrate, Lewis acid
Neste trabalho é descrita a habilidade do SnCl2.2H2O como catalisador na reação de Biginelli tricomponente. Uma variedade de aldeídos aromáticos mono- e dissubstituidos foi utilizada na condensação com acetoacetato de etila e uréia ou tiouréia. A reação foi efetuada em etanol ou acetonitrila como solventes em meio neutro e os resultados representam um melhoramento com relação ao procedimento clássico de Biginelli e uma vantagem com relação ao uso de FeCl3.6H2O, NiCl2.6H2O e CoCl2.6H2O que são utilizados juntamente com HCl como co-catalisador. A síntese das 3,4-diidropirimidinonas foi conseguida em bons rendimentos.
The multicomponent reactions (MCRs) are one of the most important protocols in organic synthesis and medicinal chemistry.1 The diversity, efficiency and rapid access to small and highly functionalized organic molecules makes this approach of central current interest in the construction of combinatorial libraries and optimization in drug discovery process.2
The 3,4-dihydropyrimidin-2(1H)-ones (DHPMs1, Figure 1) have recently emerged as important target molecules due to their therapeutic and pharmacological properties3 such as antiviral,4 antimitotic,5 anticarcinogenic,6 antihypertensive7 and noteworthy, as calcium channel modulators.8 Additionally, their particular structure has been found in natural marine alkaloid batzelladine A and B which are the first low molecular weight natural products reported in the literature to inhibit the binding of HIV gp-120 to CD4 cells, so disclosing a new field towards the development of AIDS therapy.9 Also, due to the close related structure of DHPMs with the known dihydropyridine calcium channel modulators of the Hantzsch-type (DHPs - 2, Figure 1), an intensive research has been devoted to synthesize the dihydropyrimidinone nucleus and this subject was recently reviewed.10
The original one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones was firstly reported by Pietro Biginelli in 1893 performing the three-component cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea under Brönsted acid catalysis.11 However, this reaction suffers from the harsh conditions, high reaction times and frequently low yields. Among the diversity of available methodologies in the literature that use lithium salts,12 TMSI,13 reactions performed under ionic liquids,14 solid phase,15 polymer-supported,16 heterogeneous catalysis by silicas17 and montmorillonites18 or activation by ultrasound19 and microwave20 energies as synthetic protocols to prepare DHPMs, special attention has been dedicated to Lewis acids catalysis.
Recently, BF3.OEt2 complex was shown to be an excellent promoter of the three-component reaction21 but anhydrous conditions were required. High yields of DHPMs were obtained using metals halides, such as NiCl2.6H2O and FeCl3.6H2O,22 CoCl2.6H2O,23 BiCl3,24 In(III)-halides,25 and ZrCl4,26 or lanthanide halides such as LaCl3.7H2O,27 and CeCl3.7H2O28 as Lewis acid catalysts. Metal triflates, such as Zn(OTf)2,29 Cu(OTf)2,30 Bi(OTf)3,31 and Sc(OTf)332 or lanthanide triflates as Yb(OTf)3,32 and La(OTf)3.33 were also reported.
Results and Discussion
In connection with our research on the use of SnCl2.2H2O in multicomponent Mannich reaction,34 we would like to disclose here our preliminary results employing this catalyst as a new and mild Lewis acid which, to our best knowledge, has not yet been reported promote the multicomponent Biginelli reaction (Scheme 1, Table 1). It should be noted, that SnCl2.2H2O was used as the sole promoter agent in neutral media while for the others previously reported hydrates of metallic halides such as Fe(III), Ni(II) and Co(II) a catalytic amount of conc. HCl was needed as a Brönsted acid co-catalyst.
To evaluate the ability of SnCl2.2H2O as catalyst in this reaction, we performed the three component condensation reaction of benzaldehyde (3a), ethyl acetoacetate (4) and urea (5a) in EtOH and CH3CN as solvents. To establish the optimal conditions, we carried out a set of experiments varying the reaction time, amounts of the catalysts and the quantities of urea.
The best condition to prepare the dihydropyrimidinone 6a were achieved when 20 mol% of SnCl2.2H2O, 1 equivalent of both aldehyde 3a and ethyl acetoacetate (4) and 1.2 equivalents of urea (5a) were mixed under reflux for 6 hours, affording the desired product in good yield (>90%, Entry 1, Table 1). This condition was applied to a series of substituted aromatic aldehydes 3b-m with urea (5a) affording the desired products 6b-m.
The ability of SnCl2.2H2O to promote the Biginelli reaction in EtOH was comparable to those performed in CH3CN, affording good yields in all cases (Entries 2-26). The reactions of aldehydes 3a and 3d with thiourea (5b) also afforded the desired products in good yields for both the solvents (entries 27-30). Apparently, for the employed rection conditions (reflux for 6 hours) the nature of the substituents does not affect significantly the yield of the reactions. The product 6c, which has an electron-donanting substituent attached at C-4 position of the aromatic ring was produced in 98% yield while the dihydropyrimidinone 6l with an electron-withdrawing group yielded 96% (see entries 6 and 24, respectively).
The 1H NMR and 13C NMR data of compounds 6a-o were compatible with the proposed structures as well as the melting points were in accordance with those reported in the literature.
A general procedure for the synthesis of 3,4-dihydropyrimidinones is described as follow: a 50 cm3 round-bottom flask was charged with 3.6 mmol of urea or thiourea, 3.0 mmol of the aldehyde, 3.0 mmol of ethyl acetoacetate, 0.6 mmol of SnCl2.2H2O and 4.0 cm3 of ethanol (or acetonitrile). The mixture was heated to reflux for 6 hours period under magnetic stirrer. The solution was cooled to room temperature and 10 cm3 of cold water was added, the mixture was additionally stirred for 15 minutes. The resulting solid was filtered under suction, washed with cold ethanol (3 cm3) and recrystalized from hot ethanol to afford the product.
In some cases (compounds 6c, 6d and 6g, entries 5, 7 and 13, respectively), the crude isolated solid compound was dried under vacuum pump and shown essentially the same purity as the recrystallized sample.
Although different mechanistic pathways have been previously proposed,35, 36 we believe that the reaction may proceed through an initially N-acylimine 7 formed from aldehyde 3 and urea 5 (Scheme 2).
The coordination of the lone-pair of the nitrogen atom in the N-acylimine 7 with the Lewis acid could lead to the in situ formation of an N-carbamoyliminium ion 7a, which is sufficiently electrophilic to react with the enol form of ethyl acetoacetate 4 affording the open chain intermediate 8. Further intramolecular cyclization, with lost of H2O, produce the 2,3-dihydropyrimidin-2-(1H)-ones 6.
Spectroscopic evidences for such mechanism from 1H NMR and 13C NMR studies were reported by Kappe, supporting the intervenience of a N-carbamoyliminium ion as a possible intermediate.37
In summary, we have demonstrated the ability of SnCl2.2H2O as a new and mild Lewis acid promoter in the multicomponent Biginelli reaction. Besides its simplicity, neutral reaction conditions and use of commercial solvents without previous purifications or drying, this method was effective with a variety of substituted aromatic aldehydes independently of the nature of the substituents in the aromatic ring, representing an improvement to the classical Biginelli's methodology.
The authors would like to acknowledge the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) for the financial support. F. A. L. acknowledges FAPERGS for the fellowship.
1. Weber, L.; Drug. Disc. Today 2002, 7, 143; Domling, A.; Curr. Opin. Chem. Biol. 2002, 6, 306. [ Links ]
2 . Dolle, R. E.; Nelson, K. H.; J. Comb. Chem. 1999, 1, 235; [ Links ]Thompson, L. A.; Ellman, J. A.; Chem. Rev. 1996, 96, 555; Gordon, E. M.; Gallop, M. A.; Patel, D. V.; Acc. Chem. Res.1996, 29, 144.
3. For an interesting review see: Kappe, C. O.; Eur. J. Med. Chem. 2000, 35, 1043. [ Links ]
4. Hurst, E. W.; Hull, R.; J. Med. Pharm. Chem. 1961, 3, 215. [ Links ]
5. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. I.; Mitchison, T. J.; Science 1999, 286, 971. [ Links ]
6. Kato, T.; Jpn.Kokay Tokkyo Koho 59 190,974 1984, (CA 102:132067). [ Links ]
7. Atwal, K.S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O'Reilly, B. C.; J. Med. Chem. 1991, 34, 806; [ Links ]Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O'Reilley, B. C.; Schwartz, J.; Malley, M. F.; J. Med. Chem. 1992, 35, 3254.
8. For a review of aza-analogs of Nifedipine calcium channel modulators see: Kape, C. O.; Molecules 1998, 3, 1; [ Links ]Jauk, B.; Pernat, T.; Kappe, C. O.; Molecules 2000, 5, 227.
9. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; Debrossi, C.; Mai, S.; Truneh, a.; Faulkner, D. J.; Carte, B.; Breen. A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts, B. C. M.; J. Org. Chem. 1995, 60, 1182. [ Links ]
10. For recent reviews see: Kappe C. O.; QSAR. Comb. Sci. 2003, 22, 630; Kappe, C. O.; Acc.Chem.Res. 2000, 33, 879; [ Links ]Kappe, C. O.; Tetrahedron 1993, 49, 6937.
11. Biginelli, P.; Gazz. Chim. Ital. 1893, 23, 360. [ Links ]
12. LiBr: Maiti, G.; Kundu, P.; Guin, C.; Tetrahedron Lett. 2003, 44, 2757; [ Links ]LiClO4: Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.; Ramalingam, T.; Synthesis 2001, 1341.
13. Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Yadav, J. S.; Synlett 2003, 858. [ Links ]
14. Peng, J.; Deng, Y.; Tetrahedron Lett. 2001, 42, 5917. [ Links ]
15. Kappe, C. O.; Biorg. Med. Chem. Lett. 2000, 10, 49. [ Links ]
16. Dondoni, A.; Massi, A.; Tetrahedron Lett. 2001, 42, 7975; [ Links ]Xia, M.; Wang, Y-G.; Tetrahedron Lett. 2002, 43, 7703.
17. Silica/Fe: Martínez, S.; Meseguer, M.; Casas, L.; Rodríguez, E.; Molins, E.; Moreno-Manas, M.; Roig, A.; Sabastián, R. M.; Vallribera, A.; Tetrahedron 2003, 59, 1553; [ Links ]Silica/H2SO4: Salchi, P.; Dabiri, M.; Zolfigol, M. A.; Fard, M. A. B.; Tetrahedron Lett. 2003, 44, 2889.
18. Bigi, F.; Cartini, S.; Frullanti, B.; Maggi, R.; Sartoti, G.; Tetrahedron Lett. 1999, 40, 3465; [ Links ]Lin, H.; Ding, J.; Chen, X.; Zhang, Z.; Molecules 2000, 5, 1240.
19. Li, J-T.; Han, J-F.; Yang, J-H.; Li, T-S.; Ultrason. Sonochem. 2003, 10, 119. [ Links ]
20. For reviews see: Eynde, J. J. V.; Mayenee, A.; Molecules 2003, 8, 381; Stadler, A.; Yousefi, B. H.; Dallinger, D.; Walla, P.; Van der Eycken, E.; Kaval, N.; Kappe, C. O.; Org. Process Res.Dev. 2003, 7, 707; [ Links ]Stadler A.; Kappe, C. O.; J. Comb. Chem. 2001, 3, 624; Kappe, C.O.; Kumar, D.; Varma, R. S.; Synthesis 1999, 1799.
21. Hu, E. H.; Sidler, D. R.; Dolling, U. H.; J. Org. Chem. 1998, 63, 3454. [ Links ]
22. Lu, J; Ma, H.; Synlett 2000, 63; Lu, J.; Bai, Y.; Synthesis 2002, 466. [ Links ]
23. Lu, J.; Bai, Y-J.; Guo, Y-H.; Wang, Z-J.; Ma, H-R.; Chinese J. Chem. 2002, 20, 681. [ Links ]
24. Ramalinda, P. K.; Vijayalakashmi, K. T. N. B.; Synlett 2001, 863. [ Links ]
25. InCl3: Ranu, B. C.; Hajra, A.; Jana, U.; J. Org. Chem. 2000, 65, 6270; [ Links ]InBr3: Fu, N-Y.; Yuan, Y-F.; Cao, Z.; Wang, S. W.; Wang, J-T.; Peppe, C.; Tetrahedron 2002, 58, 4801; Fu, N-Y.; Yuan, Y-F.; Pang, M-L.; Wang, J-T.; Peppe, C.; J. Oragnomet. Chem. 2003, 672, 52.
26. Reddy, Ch-V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N.; Tetrahedron Lett. 2002, 43, 2657. [ Links ]
27. Lu, J.; Bay, Y.; Wang, Z.; Yang, B.; Ma. H.; Tetrahedron Lett. 2000, 41, 9075. [ Links ]
28. Bose, D. S.; Fatima, L.; Mereyala, H. B.; J. Org. Chem. 2003, 68, 587. [ Links ]
29. Xu, H.; Wang, Y-G.; Chinese J. Chem. 2003, 21, 327. [ Links ]
30. Paraskar, A. S.; Dewkar, G. K.; Sudalai, A.; Tetrahedron Lett. 2003, 44, 3305. [ Links ]
31. Varala, R.; Alam, M. M.; Adapa, S. R.; Synlett 2003, 67. [ Links ]
32. Ma, Y.; Qian, C.; Wang, L.; Yuang, M.; J. Org. Chem. 2000, 65, 3864. [ Links ]
33. Chen, R-F.; Qian, C-T.; Chinese J. Chem. 2002, 20, 427. [ Links ]
34. Russowsky, D.; Mancilha, F. S.; Abstracts of the 26ª Reaunião Anual da Sociedade Brasileira de Química, Poços de Caldas, Brazil, 2003. [ Links ]
35. Folkers, K.; Johnson, T. B.; J. Am. Chem. Soc. 1933, 55, 3784. [ Links ]
36. Sweet, F.; Fissekis, J. D.; J. Am. Chem. Soc. 1973, 55, 8741. [ Links ]
37. Kappe, C. O.; J. Org. Chem. 1997, 62, 7201. [ Links ]
38. Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D.; Tetrahedron Lett. 2001, 42, 7873. [ Links ]
Received: January 14, 2004
Published on the web: April 20, 2004