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Journal of the Chilean Chemical Society

versión On-line ISSN 0717-9707

J. Chil. Chem. Soc. vol.59 no.1 Concepción mar. 2014 





Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
* e-mail:


A series of 3,4-dihydropyrimidin-2(1H)-one(thione) derivatives was synthesized using Co(NO3)2.6H2O in solvent-free condition. Avoiding organic solvents during the chemical reactions leading to an economic approach is effective. The reaction is characterized by high efficiency, short reaction time, high yields, simple experimental procedure, availability of catalyst and environmentally friendly reaction conditions.

Keywords: Dihydropyrimidinone, Dihydropyrimidinthione, Cobalt(II)Nitrate, Solvent-free, One-pot synthesis



Synthesis of 3,4-dihydropyrimidine-2(1H)-Ones (DHPMs) through one-pot reaction of aromatic aldehyde, urea and ethyl acetoacetate in acid ethanol solution was initiated by Biginelli in 18931. These compounds occupied an important place in medicinal and synthetic organic chemistry, mainly because of their wide range of biological activities2.

Notably, monastrol (1) is the only cell-permeable molecule that blocks normal bipolar spindle assembly in mammalian cells causing cell cycle arrest3, and is considered a lead for the development of new anticancer drugs4, while the appropriately functionalized DHPM analogs have emerged as orally active antihypertensive agents (2, 4)5.

Many biological activities such as anticancer, antifungal, anti HIV have been exhibited using the representatives such as batzelladines, ptilomycalines (3) and crambescidines (Fig. 1)6.


<<Fig. 1>>

The Biginelli method was developed7 and many catalysts such as CaF2 8, Sr(OTf)2 9, PPh3 10, tetrabutylammonium bromide (TBAB)11, copper(II) sulfamate12, phenyl phosphonic acid13, γ-Fe2O3/CuO (on the nanoscale)14 and so on have been used in the Biginelli reaction. Also microwave irradiation15, ultrasound irradiation16 and/or ionic liquids17 have been used. However, many of these methods suffer from drawbacks such as the use of expensive reagents, strong acidic conditions, long reaction times and use of expensive and poisonous solvents. Therefore, the introduction of a more efficient and milder methods accompanied with higher yields are in demand yet. In recent years with the development of green chemistry technology, multi components reactions under solvent-free conditions with a solid catalyst are considered as an important subject18. Solid acids have emerged as potential alternate catalysts to the common liquid acids due to their safe natures, enhanced selectivity, requirements in catalytic amounts and easier work up19.

Solid catalysts are harmless to the environment due to safety, no corrosion and reduction of the amount of waste residuals. So many reactions in organic chemistry of the solid catalyst are used. Following our interest in producing 3,4-dihydropyrimidine-2(1H)-ones 20, a study to revisit this reaction in a parallel combinatorial fashion using Co(NO3)2.6H2O in a solvent-free synthesis approach was initiated.


Chemicals were purchased from Merck, Fluka and Aldrich chemical companies. Melting points were determined using a Barnstead/Electothermal (BI) capillary apparatus and are uncorrected. IR spectra were recorded from KBr discs on a JASCO FT-IR-680. 1H NMR spectra were recorded with Brucker ultrasheilld NMR 400 machines. NMR spectra were obtained on solution in DMSO-d6 using TMS as internal standard.

General procedure for the synthesis of 3,4-dihydropyriinidin-2(1H)-ones(thiones)

A mixture of aldehyde (1.0 mmol), β-dicarbonyl (1.0 mmol), Co(NO3)2.6H2O (0.15 mmol) and urea or thiourea (1.5 mmol) was magnetically stirred at 80 °C in solvent-free condition. After completion of the reaction, as indicated by TLC (EtOAc/n-hexane, 1:4), the reaction mixture was filtered and the residue recrystallized from ethanol to afford the pure product. All products were characterized by mp, IR and 1H NMR spectra. The physical and spectroscopic data of new compounds is given bellow:

Methyl 4-(2,6-dichlorophenyl)-6-methyl-2-oxo-1,2,3,4 tetrahydropy-rimidine-5-carboxylate (8q): Mp: 292-294 ˚C; Rf = 0.43 (n-hexane:ethyl acetate = 4:1); IR (, cm-1): 3320, 3227, 2976, 1698, 1652, 1661, 1577, 1497, 1284, 1236; 1H NMR (400 MHz, DMSO-d6) δ(ppm) : 2.06 (s, 3H), 2.19 (s, 3H), 6.18 (s, 1H), 7.26 (t, 1H, J = 7.6 Hz ), 7.40 (d, 2H, J = 8.0 Hz), 7.62 (s, 1H), 9.25 (s, 1H); Anal. Calcd. for C13H12Cl2N2O3: C, 49.54; H, 3.84; Cl, 22.50; N, 8.89; O, 15.23; found: C 49.45, H 3.90, N 8.80.

Methyl 4-(2-bromophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimi-dine-5-carboxylate (8r): Mp: 249-251 ˚C; Rf = 0.33 (n-hexane:ethyl acetate = 4:1); IR (, cm-1): 3363, 3249, 2929, 1703, 1623, 1458, 1381, 1229; 1H NMR (400 MHz, DMSO-d6) δ (ppm) : 2.05 (s, 3H), 2.34 (s, 3H), 5.63 (s, 1H), 7.20 (t, 1H, J = 6.0 Hz ), 7.26 (d, 1H, J = 6.4 Hz), 7.37 (t, 1H, J = 7.2 Hz ), 7.61 (d, 1H, J = 7.2 Hz), 7.71 (s, 1H), 9.30 (s, 1H); Anal. Calcd. for C13H13BrN2O3: C, 48.02; H, 4.03; Br, 24.57; N, 8.62; O, 14.76; found: C 47.93, H 4.10, N 8.54.

Methyl 4-(2,4-dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (8y): Mp: 214-215 ˚C; Rf = 0.50 (n-hexane:ethyl acetate = 4:1); IR (, cm-1): 3406, 3179, 2949, 1678, 1652, 1563, 1464, 1203; 1H NMR (400 MHz, DMSO-d6) δ(ppm) : 2.30 (s, 3H), 3.34 (s, 3H), 5.58 (s, 1H), 7.28 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 8.0 Hz ), 7.58 (s, 1H, J = 7.2 Hz), 9.65 (s, 1H), 10.45 (s, 1H); Anal. Calcd. for C13H12Cl2N2O2S: C, 47.14; H, 3.65; Cl, 21.41; N, 8.46; O, 9.66; S, 9.68; found: C 47.03, H 3.72, N 8.39.

Methyl 4-(3-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropy-rimidine-5-carboxylate (8z): Mp: 248-249 ˚C; Rf = 0.35 (n-hexane:ethyl acetate = 4:1); IR (, cm-1): 3316, 3176, 2968, 1678, 1662, 1574, 1434, 1385, 1285; 1H NMR (400 MHz, DMSO-d6) δ(ppm) : 2.29 (s, 3H), 3.56 (s, 3H), 5.17 (s, 1H), 7.17-7.36 (m, 4H), 9.71 (s, 1H), 10.45 (s, 1H); Anal. Calcd. for C13H-13ClN2O2S: C, 52.61; H, 4.42; Cl, 11.95; N, 9.44; O, 10.78; S, 10.80; found: C 52.53, H 4.50, N 9.37.


In this paper, we report synthesis of the dihydropyrimidinones and dihydropyrimidinthiones using cobalt nitrate hexahydrate as catalyst at 80 °C in solvent-free condition (Scheme 1).


Scheme 1. Synthesis of DHPMs 8a-x.

Effect of catalyst concentration and solvent

The catalyst concentration was varied over a range of 5-25 mol% of Co(NO3)2.6H2O on the basis of the total volume of the reaction mixture. Table 1 shows the effect of catalyst concentration on the reaction of benzaldehyde, ethylacetoacetate and urea. The yield of the corresponding dihydropyrimidinone increased with increasing catalyst concentration from 5 to 15 mol%. Further addition of catalyst had no noticeable effect on the yield. This was due to over an obvious concentration, there have an excess of catalyst sites beyond what is actually required by the reactant substrates, and the additional catalyst does not increase the rate of the reaction. The refore, in all further reactions 15 mol% were used.

Table 1. Investigation of catalyst effects in the synthesis of 5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropy-rimidin-2(1H)-one under solvent-free conditionsa

bIsolated yields

Then, the solvent effect in the condensation of benzaldehyde (1 mmol), urea (1.5 mmol) and ethyl acetoacetate (1mmol) in the presence of Co(NO3)2.6H2O (0.15 mmol) as a model has been studied. As shown in Table 2, among the tested solvents, such as ethanol, methanol, acetonitrile, water, chloroform and a solvent-free system, the best result was obtained after 40 min under solvent-free conditions in excellent yield (90%).

Table 2. Solvent effect on the reaction of benzaldehyde, urea and ethyl acetoacetate catalyzed by Co(NO3)2.6H2O.


a Isolated yields
b At 80 0C

We began our studies with the reaction of benzaldehyde (5a), ethylacetoacetate (6a) and urea (7a) as a model reaction. For this purpose, various parameters such as molar ratio of reactants, catalyst and reaction temperature were optimized. The results showed that use of 1mmol benzaldehyde, 1 mmol ethylacetoacetate, 1.5 mmol of urea or thiourea and 1.5 mmol catalyst under solvent-free condition at 80 °C, the product of dihydropyrimidinone (thiones) with 90% efficiency was achieved. Then under this condition, dihydropyrimidinones and dihydropyrimidinthiones by various aromatic and aliphatic aldehydes were synthesized. The results were presented in table 3. As shown, various aromatic aldehydes bearing either electron-releasing or electron-withdrawing substituents can lead to high yields. The use of methyl acetoacetate or acetylacetone as 1,3-dicarbonyl moiety in place of ethyl acetoacetate also gave similar results (Table 3, entries 16-21, 25-27). Furthermore, substrate with two formyl group (entry 10) was produced the corresponding bis-dihydropyrimidinone in short time and excellent yield (Scheme 2).

Table 3. Synthesis of 3,4-dihydropyrimidin-2-(1H)-ones(thiones) Catalyzed by Co(NO3)2.6H2O under solvent-free Conditionsa


a Reaction conditions: aldehyde (1 mmol), β-dicarbonyl (1 mmol), urea or thiourea (1.5 mmol), Co(NO3)2.6H2O (0.15 mmol), 80 °C; b Isolated yield


Scheme 2. Synthesis of ethyl-4-(3-(5-(ethoxycarbonyl)-1,2,3,4-

The reactions of acid-sensitive substrates such as 2-thiophenecarbaldehyde and cinnamaldehyde also proceeded well to give the dihydropyrimidinone without any side products (entry 11 and 12). However, aliphatic aldehydes such as butanal, as observed previously, reacted over longer times with a reduced yield (entry 13, 80 min time, 35% yield) compared with the aromatic compounds under our reaction conditions20.

To use of Co(NO3)2.6H2O in large scale synthesis especially in chemical laboratory, a typical reaction was performed for synthesis of 8a with tenfold amounts of reactants and catalyst with respect to one mentioned in the experimental section. The result showed that the yield of 87% in these conditions that is comparable with one in table 3.

Three possible mechanisms are proposed for Biginelli reaction according to the literature but generally accepted reaction mechanism includes the acid-catalyzed formation of C-N bond from the benzaldehyde and urea (pathway A, Scheme 3)36. According to reported results the pathway A is characteristic for the Brensted type of catalysts whereas Lewis acid type of catalysts follows the pathway B (ureido-crotonate mechanism)37. For clarifying the role of the catalyst, three separated reactions were performed (pathways A-C, Scheme 3) under the optimized reaction conditions (15 mol% of cobalt(II) nitrate at 80 °C in condition and reflux temperature in acetonitrile during 30 min and 20 h, respectively). The prolonged heating of benzaldebyde and ethyl acetoacetate (pathway C) or benzaldehyde and urea (pathway A) did not undergo the expected reactions to yield of products whereas the reaction of ethyl acetoacetate and urea furnished the ureido-crotonate (pathway B). These observations clearly indicate that Biginelli reaction catalyzed by cobalt(II) nitrate proceeds predominately.


Scheme 3. Three proposed possible mechanisms for Biginelli reaction.

Comparative results

In order to show the ability of our method with respect to previous reports, our result for synthesis of 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-ones (8a) in comparison to other methods for preparation of this compound have been summarized in table 4. As shown in table 4, the yield/time ratio of the present method is better or comparable with the other reported results.

Table 4. Comparison of efficiency of various catalysts in synthesis of 5-(Ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-ones

a Values refer to yield(%)/time(h)
b Amount of catalysts are in mol%


In summary, we have described an improved procedure for the synthesis of dihydropyrimidinones and dihydropyrimidinthiones using cobalt(II) nitrate hexahydrate as heterogeneous catalyst. For clarifying the role of the catalyst, three separated reactions were performed that the results clearly indicated that the reaction catalyzed by Co(NO3)2 proceeds predominately through ureido-crotonate intermediate, which this achievement well supports the necessity of Lewis type catalyst for the Biginelli reaction. The mild reaction conditions, rapid conversion, high yields, simple experimental procedure, availability of catalyst are some notable advantages of the present method. Moreover, compatibility with the environment, more efficiency and easy separation after synthesis are considered as another advantages of this catalyst loading. Most importantly, absence of organic solvents in this method contributes it to the development of green technology.


We are grateful to the Yasouj University for financial assistance.



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(Received: May 14, 2013 - Accepted: December 14, 2013)