Abstract: In this study, a variety of 3, 4-dihydropyrimidin-2(1H)-ones derivatives were synthesized via three-component Biginelli reaction. The quaternary ammonium-treated clay -catalyzed process proved to be simple, efficient, and environmentally friendly

Sedigheh Jahanbakhshi

Soheil Sayyahi

Zahra Dehghani

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International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
A green and efficient method for the preparation of 3, 4-
dihydropyrimidin-2(1H)-ones using quaternary ammonium- 
treated clay in water 
 
Soheil Sayyahi*1, Sedigheh Jahanbakhshi2, Zahra Dehghani2  
 
1Chemistry Department, Mahshahr Branch, Islamic Azad University, 
Mahshahr 63519, Iran, E-mail: sayyahi.soheil@gmail.com 
 
2 Chemistry Department, Omidieh Branch, Islamic Azad University, Omidieh, 
Iran 
 
 
Abstract: In this study, a variety of 3, 4-dihydropyrimidin-2(1H)-ones 
derivatives were synthesized via three-component Biginelli reaction. The 
quaternary ammonium- treated clay -catalyzed process proved to be simple, 
efficient, and environmentally friendly. 
 
Keywords: Organoclay, 3, 4-dihydropyrimidin-2(1H)-ones, Multicomponent Reactions, 
Biginelli reaction  
 
  
Introduction 
 
Clays, nanoparticles with layered structures and hydrophilic nature are used as Brønsted and/or Lewis 
acids, or as bases to catalyze various types of organic reactions [1]. Otherwise, hydrophobic 
modification of the clay intra-surface allows many organic guest molecules to be easily intercalated 
[2]. In the modification of clay by ion exchange, the interlayer accessible compensating cations can be 
exchanged with a wide variety of hydrated inorganic cations or organic cations including those of 
amines, quaternary ammonium salts or ionic liquid, and also oxonium, sulfonium, phosphonium and 
more complex cationic species such as methylene blue and cationic dyestuffs [3]. 
Multicomponent Reactions (MCRs) are broadly defined, as “one-pot” processes that combine three or 
more substrates either simultaneously or through a sequential-addition procedure that does not involve 
any change of solvent. By minimizing the number of synthetic operations while maximizing the 
buildup of structural and functional complexity, these highly step economical reactions are particularly 
appealing in the context of target-oriented synthesis [4]. 
A literature survey showed that the Biginelli dihydropyrimidine synthesis as a MCR [5-7], attract a 
high attention because of its ability for the preparation of compounds with potential biological and 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
pharmaceutical properties. 3,4-Dihydropyrimidin-2(1H)-one derivatives (DHPMs) are one of these 
compounds which can be synthesized by cyclocondensation reaction of aldehyde, urea and an easily 
enolizable carbonyl compound [8,9]. 
Although various methods are reported for the synthesis of DHPMs, but only few examples were 
developed with the aim of replacing conventional toxic and polluting Bronsted and Lewis acid 
catalysts with reusable solid acid heterogeneous catalysts, for the development of eco-friendly 
processes with reduced environmental impact [10-12]. 
Herein; as part of our continues effort to develop green and new catalyst systems with reduce 
environmental impact [13-16]; we decided to investigate the application of organophilic clay as a 
catalyst for synthesis of various 3, 4-dihydropyrimidin-2(1H)-ones in water. 
 
Results and discussion 
 
Modification of clay by ion exchange makes hydrophilicity decrease and enhances the organophilicity 
in the interlayers of clay [17]. Therefore, treated clay may play an efficient role in the synthesis of 
DHPMs.  
The catalyst was prepared by the cation exchange of Na+ with cetyltrimethylammonium (CTAB) and 
characterized with FT-IR spectroscopy. In the spectrum of CTAB treated clay (Fig. 1), NCH3 (C-H) 
stretching vibration observed at 3042 cm−1. Furthermore, the 2940 and 2850 cm-1 peaks correspond to 
asymmetric and symmetric vibration of methylene group. This confirms the successful exchange of 
CTAB with sodium ions in the clay structure. 
 
 
 
 
 
 
 
 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
 
Figure 1 The FT-IR spectra of a) Clay, b) Treated-clay 
 
 
 
 
Also, the thermogravimetric analysis (TGA) of the organocatalyst was performed with a TGA/DSC 
simultaneous thermal analyzer apparatus, using a nitrogen atmosphere (Fig. 2). TGA thermogram 
exhibits a 40 % weight loss in the range of 220-240 °C which is due to breakdown of organic cations in 
the organocatalyst. 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
 
Figure 2 TGA curve of CTAB-modified clay 
 
Optimization of the reaction condition was carried out employing benzaldehyde as the substrate and 
the best result obtained by refluxing mixture of 1 mmol aldehyde, 1 mmol acetylacetone, 1.5 mmol 
urea and 0.5 g catalyst in water (Table 1). To examine the scope and versatility of this method, the 
reaction was reinvestigated with various types of arylaldehyde bearing different electron-withdrawing 
and electron-donating substituted under the same reaction conditions (Scheme 1). In all case, the 
desired 3, 4-dihydropyrimidin-2(1H)-one has produced in appropriate time and high yield (Table 2).  
 
 
 
 
 
 
 
 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
Table 1 Optimization of experimental conditions for synthesis of DHPMs 
Entry Catalyst Temperature Time 
(h) 
Result 
     
1 CTAB-modified clay (0.02 g) 
 
reflux 0.5  Not completed, 44% 
Yield 2 CTAB-modified clay (0.04 g) 
 
reflux 0.5  Not completed, 77% 
Yield 3 CTAB-modified clay (0.05 g) 
 
reflux 0.5  Completed, 89% Yield 
4 CTAB-modified clay (0.05 g) 
 
r.t 0.5  Not completed, 35% 
Yield 5 Clay reflux 0.5  No reaction 
Reaction Conditions: Benzaldehyde (1 mmol), acetylacetone (1mmol), urea (1.5 mmol)  
 
 
 
Scheme 1 Synthesis of DHPMs 
 
Table 2 Synthesis of 3, 4-dihydropyrimidin-2(1H)-ones catalyzed by CTAB-modified clay 
 
Entry R R1 Time (h) Yield 
(%)a,b 4a H CH3 0.5 89 
4b 4-NO2 CH3 0.75 91 
4c 3-NO2 CH3 1.0 92 
4d 4-OH CH3 0.75 87 
4e 2-MeO CH3 1.0 88 
4f 4-Cl CH3 0.5 85 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
4g 2-Cl CH3 1.0  88 
4h 4-CH3 CH3 0.5 89 
4i H EtO 0.75 89 
4j 4-F EtO 0.75 85 
4k 4-CH3 EtO 0.5 90 
4l 4-MeO EtO 0.75 87 
 
 
4m 4-Cl EtO 0.5 90 
4n 2-Cl EtO 0.75 86 
4o 4-NMe2 EtO 0.75 84 
 
a Products are known and were identified by comparison of their physical and spectral data with those 
of authentic samples [18-22].  
b Isolated yields. 
 
With the increasing interest in human health and environmental protection, more attention is being 
paid to green chemistry. With this view we used benzaldehyde as a model and studied the recyclability 
and reusability of the catalyst. After completion of the reaction the separated catalyst was washed with 
hot ethanol and dried (Fig. 3). The catalyst was used for several subsequent cycles. To our surprise 
negligible depression in the performance of the catalyst was observed in the following cycles. 
 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
 
 
Figure 3 Reusability of catalyst 
 
According to the obtained results, it is assumed that the reactants are brought together in between 
CTAB tails as organophilic regions and make a micro-vessel which accelerates the reaction (Fig 4). 
 
 
Fig 4 Schematic illustration of the reaction 
 
Experimental 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
 
General information 
Natural Na+-montmorolite clay was provided from Khorasan Mines, Iran (XRF analysis: 
SiO2=51.2%,Al2O3=10.7%, CaO=12.8) and was ground, sieved (200-mesh), washed with water and 
dried in 80°C for 2h before using. All chemicals were purchased from Merck Chemical Company. The 
purity determination of the products and reaction monitoring was accomplished by TLC on polygram 
SILG/UV 254 plates. IR spectra were recorded on BomemMB-Series 1998 FT-IR spectrometer. 1H 
NMR and 13C NMR spectra were taken on a 400 MHz Brucker spectrometer. GLC analyses were 
performed on a Shimadzu GC-12 a chromatograph equipped with a 3-m Thermon-1000 column. 
 
General Procedure for the preparation of organoclay 
Cetyltrimethyl ammonium bromide (1.5 mmol, 0.546 g) was dissolved in 100 ml of 0.01 M HCl 
solution and stirred at 80 °C until a clear solution was obtained. Then, montmorolite (1.0 g g) was 
added to salt solution and vigorous stirring was continued for another 6.0 h. The precipitate formed 
was recovered by filtration and dispersed in hot water by mechanical stirring during 1 h. The later 
process was repeated twice to get chloride free organoclay. The final precipitate was thoroughly dried 
in an oven at 60°C for 24 h to obtain the CTAB modified organoclay. 
 
General Procedure for the preparation of 3, 4-dihydropyrimidin-2(1H)-ones 
A mixture of aromatic aldehyde (1mmol), acetylacetone or ethylacetoacetate (1 mmol), urea (1.5 
mmol) and 0.5 g organoclay in 5 mL water was stirring under reflux condition for appropriate time 
(Table 1). After completion of the reaction that was monitored by TLC, the reaction mixture was 
cooled. The obtained was washed with water (3×10), dissolved in hot ethanol and filtered to remove 
the catalyst. The combined filtrates were evaporated under reduced pressure to dryness to give desired 
product. The solid crude products were recrystallized from ethanol.  
 
 
Conclusion 
 
In conclusion, we have reported here the use of CTAB-modified clay as an efficient catalyst in the 
synthesis of 3, 4-dihydropyrimidin-2(1H)-ones in water. This environmentally benign protocol offers 
 
International Journal of Heterocyclic Chemistry, Vol. 1, No. 2 pp. 50-59 © Ahvaz Branch, Islamic Azad University 
 
several advantages such as a green and cost-effective procedure, short reaction time, easy work-up, 
recovery, and reusability of heterogeneous catalyst and high yield of the products. 
 
Acknowledgements. We are grateful to the Islamic Azad University, Mahshahr Branch for support of 
this work. 
 
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A green and efficient method for the preparation of 3, 4- dihydropyrimidin-2(1H)-ones using quaternary ammonium- treated clay in water

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A green and efficient method for the preparation of 3, 4- dihydropyrimidin-2(1H)-ones using quaternary ammonium- treated clay in water

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