Research interest in 3,4-dihydropyrimidin-2-(1H)-ones (‘Biginelli compounds’,DHPMs),has surged rapidly,owing to the pharmacological properties ^{[1, 2, 3, 4, 5]} associated with many derivatives of this privileged hetero-cyclic core. The biological activity ^[1] of these Biginelli compounds includes antiviral,antitumor, antibacterial and anti-inflammatory properties. In addition,some functionalized DHPMs have emerged as potent calcium channel blockers ^[2],antihypertensive agents ^[3],and neuropeptide Y (NPY) antagonists ^[4]. Several recently isolated marine alkaloids ^[5] with interesting biological activity also contain the dihydropyrimidinone- 5-carboxylate core. Their applications in the field of drug research have stimulated the development of a wide range of synthetic methods for their preparation and chemical transformations. Out of the five major bases in nucleic acids,three (i.e. cytosine,uracil,and thymine) are pyrimidine derivatives,which are found in DNA and RNA ^{[6, 7, 8]}. Because of their involvement as bases in DNA and RNA,they have become very important in the world of synthetic organic chemistry. The best-known method for making DHPMs is the classical Biginelli synthesis ^[9]. Although it has been known for more than a century,it is still the most useful method for the preparation of this class of compounds. The simple and direct method for the synthesis of DHPMs reported by Biginelli in 1893 involves a one-pot condensation of an aldehyde,a β-diketone and urea under strong acidic conditions ^[9]. However,this method suffers from low yields,especially in the cases of some substituted (hetero) aromatic aldehydes ^[10]. To enhance the efficiency of the Biginelli reaction,various catalysts have been studied. In an attempt to prepare DHPMs,different types of acidic catalysts such as H₂SO₄ ^[11],BF₃^.EtOH/CuCl ^[12],LaCl₃^.H₂O with catalytic amount of concentrated HCl ^[13],CeCl₃^.7H₂O ^[14],InCl₃ ^[15],Fe₃O₄@mesoporous SBA-15 ^[16],nickel chloride ^[17], Cu(OTf)₂ ^[18],Iron(III) tosylate ^[19],LiClO₄^[20],LiBr ^[21],InBr₃ ^[22],CAN/HCl ^[23],FeCl₃^.6H₂O/HCl ^[24],TMSI ^[25],CdCl₂ ^[26], CuCl₂^.2H₂O-HCl ^[27],and ZnBr₂ ^[28] have been used. However,in spite of their potential utility many of the existing methods suffer from some drawbacks,such as the use of strong acidic conditions, long reaction times,tedious workup procedures,environmental disposal difficulties,and lowyields of the products. Here,weutilized silica gel-supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate as an inexpensive mediator for the Biginelli reaction ^[29].

All solvents and reagents were purchased from Aldrich or Merck with high-grade quality and used without any purification. Melting points were determined on electrothermal apparatus using open capillaries and are uncorrected. Thin-layer chromatography was accomplished on 0.2-mm precoated plates of silica gel (Merck). Visualization was made with UV light (254 nm and 365 nm). ¹H NMR and ₁₃C NMR spectra were recorded in DMSO-d6 solutions on a Bruker FX 400 Q spectrometer operating at 400 (¹H) and 100 (¹³C) MHz.

General procedure for the synthesis of 3,4-dihydropyrimidin-2- (1H)-ones: A mixture of aldehyde 1 (1 mmol),ethyl acetoacetate 2 (1.1 mmol),urea (or thiourea) 3 (1.5 mmol),silica gel-supported Lpyrrolidine- 2-carboxylic acid-4-hydrogen sulfate (212 mg),and ethanol (10 mL) was charged into a 25 mL round bottom flask. The mixture was refluxed for 6 h. The reaction was monitored by TLC analysis using n-hexane/acetone (8:2) as eluent. After completion of the reaction,the solid materials were filtered off and the solvent (ethanol) of the filtrate was evaporated. After cooling,20 mL of water was added to the mixture and filtered. The filtrate was dissolved in hot ethanol (25 mL) and the insoluble materials were filtered off. Then,the filtrate was concentrated and dried to obtain the corresponding 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs). The crude product was crystallized from water/ethanol mixture (1:1).

Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4a): ¹H NMR (400 MHz,DMSO-d6): δ 9.16 (s,1H),7.68 (s,1H),7.13 (d,2H,J = 8.4 Hz),6.87 (d,2H, J = 8.4 Hz),5.08-5.07 (s,1H),3.97 (q,2H,J = 7.2 Hz),3.71 (s,3H), 2.23 (s,3H),1.09 (t,3H,J = 7.2 Hz).

Ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4d): ¹H NMR (400 MHz,DMSO-d6): δ 9.26 (s, 1H),7.78 (s,1H),7.39-7.22 (m,4H),5.13-5.12 (s,1H),3.97 (q,2H, J = 7.2 Hz),2.23 (s,3H),1.08 (t,3H,J = 7.2 Hz).

Ethyl 4-(4-p-tolyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4e): ¹H NMR (400 MHz,DMSO-d6): δ 9.16 (s, 1H),7.96 (s,1H),7.11 (s,4H),5.09 (s,1H),3.97 (q,2H, J = 7.2 Hz), 2.25 (s,3H),2.23 (s,3H),1.09 (t,3H,J = 7.2 Hz). ¹³C NMR (100 MHz, DMSO-d6): δ 165.8,152.7,148.6,142.4,136.8,129.3,126.6,99.9, 59.6,54.1,21.1,18.2,14.5.

Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4g): ¹H NMR (400 MHz,DMSO-d6): δ 9.26 (s, 1H),7.78 (s,1H),7.39-7.22 (m,4H),5.13 (s,1H),3.97 (q,2H, J = 7.2 Hz),2.23 (s,3H),1.08 (t,3H,J = 7.2 Hz).

Ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4h): ¹H NMR (400 MHz,DMSO-d6):δ 9.16 (s,1H),7.68 (s,1H),6.89-6.69 (m,3H),5.08 (s,1H),3.99 (q, 2H,J = 7 .2 Hz),3.73-3.7 (s,6H),2.23 (s,3H),1.09 (t,3H,J = 7.2 Hz).

Ethyl 4-phenyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4i): ¹H NMR (400 MHz,DMSO-d6): δ 10.34 (s,1H), 9.66 (s,1H),7.35-7.21 (m,5H),5.16 (s,1H),4 (q,2H,J = 7.2 Hz), 2.27 (s,3H),1.09 (t,3H,J = 7.2 Hz).

Ethyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4j): ¹H NMR (400 MHz,DMSO-d6): δ 10.39 (s,1H),9.68 (s,1H),7.42 (d,2H,J = 6.8 Hz),7.22 (d,2H, J = 6.8 Hz),5.16 (s,1H),4 (q,2H,J = 7.2 Hz),2.3 (s,3H),1.09 (t,3H, J = 7.2 Hz). ¹³C NMR (100 MHz,DMSO-d6): δ 174.7,165.4,145.8, 142.8,132.7,129,128.8,100.7,60.1,53.9,17.7,14.5.

Ethyl 4-(4-p-tolyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylate (4k): ¹H NMR (400 MHz,DMSO-d6): δ10.30 (s,1H),9.62 (s,1H),7.15-7.08 (m,4H),5.13-5.12 (s,1H),4.00 (q, 2H,J = 7.2 Hz),2.28 (s,3H),2.25 (s,3H),1.1 (t,3H,J = 7.2 Hz). ¹³C NMR (100 MHz,DMSO-d6): δ 174.6,165.6,145.3,141.1,137.4, 129.5,126.8,126.5,101.3,60,54.3,21.1,17.6,14.5.

¹H NMR and ¹³C NMR spectra of compounds are supplied in Supporting information.

The present work describes our endeavors to develop a simple, economical and highly efficient strategy for the synthesis of dihydropyrimidinones and/or thiones through a three-component one-pot condensation of an aldehyde,ethyl acetoacetate and urea or thiourea using supported L-pyrrolidine-2-carboxylic acid-4- hydrogen sulfate on silica gel as a catalyst in ethanol under reflux conditions.

Initially,in order to determine the optimal loading of the catalyst,p-chlorobenzaldehyde was combined with ethyl acetoacetate and urea in the presence of different amounts of supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate on silica gel to afford the corresponding DHPM (4g) (Table 1).

Table 1

Table 1 Synthesis of 4g promoted by different amounts of supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate on silica gel as catalyst.a

Table 1 Synthesis of 4g promoted by different amounts of supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate on silica gel as catalyst.a

As results shown in Table 1,the highest yield of corresponding DHPM could be achieved using 0.212 g of supported L-pyrrolidine- 2-carboxylic acid-4-hydrogen sulfate on silica gel per mmol of aldehyde. No conversion was observed in the blank run (without catalyst,entry 1,Table 1),indicating that the presence of catalyst is necessary for the formation of dihydropyrimidinones and/or thiones. Also the effects of temperature on the outcome of the reaction were studied. To this end,the reaction of p-methoxybenzaldehyde with urea and ethyl acetoacetate in the presence of supported L-pyrrolidine-2-carboxylic acid-4- hydrogen sulfate on silica gel was conducted at different temperatures (Fig. 1).

Fig. 1

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Fig. 1. Preparation of ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate in gradient temperature.

Encouraged by these optimized reaction conditions [aldehyde (1 mmol),ethyl acetoacetate (1.1 mmol),urea/thiourea (1.5 mmol) and catalyst (0.212 g),under refluxing],the reaction of ethyl acetoacetate,and urea/thiourea with different aromatic aldehydes in the presence of a catalytic amount of silica gel-supported Lpyrrolidine- 2-carboxylic acid-4-hydrogen sulfate was investigated (Scheme 1).

Scheme 1

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Scheme 1. General reaction scheme for the synthesis of DHPMs.

The results for the preparation of substituted dihydropyrimidinones and/or thiones 4a-l are summarized in Table 2.

Table 1

Table 2 Synthesis of dihydropyrimidine-ones or -thiones (DHPMs) via combination of aromatic aldehydes,ethyl acetoacetate and urea or thiourea in presence of catalytic amount of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel) in ethanol under reflux conditions.a

Table 2 Synthesis of dihydropyrimidine-ones or -thiones (DHPMs) via combination of aromatic aldehydes,ethyl acetoacetate and urea or thiourea in presence of catalytic amount of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel) in ethanol under reflux conditions.a

Several 3,4-dihydropyrimidin-2-(1H)-ones were successfully synthesized in high yield by following the above procedure. Aromatic aldehydes bearing both electron-donating and electronwithdrawing groups readily undergo the transformation,giving fair yields of corresponding Biginelli compounds. Also 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 activity.

The proposed mechanism for the Biginelli reaction is outlined in Scheme 2.

Scheme 2

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Scheme 2. Mechanism for the Biginelli reaction catalyzed by L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel).

In order to assess the capability of the present methodology in comparison to the reported procedures for the preparation of 3,4-dihydropyrimidin-2-(1H)-ones or thiones,we compared our results of the preparation of ethyl 6-methyl-2-oxo- 4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (as typical examples) with the best from the literature as shown in Table 3.

Table 3

Table 3 Comparison of the catalytic efficiency of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate supported on silica gel with that of reported catalysts in the preparation of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate.

Table 3 Comparison of the catalytic efficiency of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate supported on silica gel with that of reported catalysts in the preparation of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate.

In summary,the present work provides an efficient and improved modification of the Biginelli reaction. Mild reaction conditions,ease of work up,high yields and eco-friendliness are the features of this new procedure. In all cases the pure products were isolated by simple filtration without use of any chromatography or cumbersome reaction workup procedures. The catalyst was easily separated from the reaction mixture by filtration.

Financial support to this work by the Ilam University,Ilam,Iran is gratefully acknowledged.

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2013.05.033.