H2SO4-Silica Catalyzed One-Pot and Efficient Synthesis of Dihydropyrimidinones Under Solvent-Free Conditions

H2SO4-Silica efficiently catalyzes the three-component condensation reaction of aldehydes, 1,3-dicarbonyl compounds and urea/thiourea under solvent free conditions to afford the corresponding dihydropyrimidinones and thio-derivatives in high yields. Compared to the classical Biginelli reaction conditions, this new method consistently has the advantage of giving good yields and requiring short reaction times.


Introduction
Dihydropyrimidinone derivatives (DHPMs) have attracted considerable interest in recent years because of their promising activities as calcium channel blockers, antihypertensive agents and R-1a-antagonists [1][2] .Moreover, several alkaloids containing the dihydropyrimidine unit have been isolated from marine sources, which also exhibit interesting biological properties 3 .Thus, synthesis of this heterocyclic nucleus is of much current importance.The simple and direct method for the synthesis of dihydropyrimidinones was first reported by Biginelli in 1893, involving a one-pot condensation of an aldehyde, β-ketoester and urea under strongly acidic conditions 4 .However, it suffers from low yields (20-50%) of products.Therefore, in the recent years several improved methodologies mainly using Lewis acids [5][6][7][8] , triflates [9][10][11][12] , microwave irradiations [13][14] , ionic liquids [15][16] , clay 17 , silica-sulfuric acid 18 , silica supported sodium hydrogen sulfate 19 , heteropoly acids 20 , iodine-alumina system 21 , poly(4-vinylpyridine-co-divinylbenzene)-Cu(II) complex 22 , iodotrimethylsilane 23 , solid super acid 24 , ion-exchange resins 25 , L-proline 26 , polyoxometallates 27 , LaCl 3 -graphite 28 trifluoroacetic acid 29 and thiamine hydrochloride 30 have been reported in the literature.However, many of these methods are associated with expensive and toxic reagents, stoichiometric amount of catalyst, unsatisfactory yields, incompatibility with other functional groups and involve difficult product isolation procedures.Thus, there is still a need for a simple and general procedure for one-pot synthesis of dihydropyrimidinone and thiones under mild conditions.
In recent years, use of eco-friendly applicable industrial and green catalysts has been of interest.Thus, green chemistry has been defined as a set of principles that reduces or eliminates the use or generation of hazardous substances throughout the entire life of chemical materials 31 .

Experimental
Chemicals were purchased from Fluka and Merck chemical companies.Silica gel 60, 0.063-0.200mm was applied as support.The structures of known compounds were identified by comparison of their spectral data with those in the authentic samples.The 1 H NMR (250 MHz) was run on a Bruker Avance DPX-250 FT-NMR spectrometer (δ in ppm).H 2 SO 4 -Silica was prepared according to our previously reported method 32 .

General procedure for the preparation of DHPMs
A mixture of aldehyde (2 mmol), ethyl acetoacetate or acetylacetone (2 mmol), urea or thiourea (3 mmol) and H 2 SO 4 -Silica (0.15 mmol) was stirred at 50-55 °C under solvent-free conditions.The reaction mixture was left stirring and the progress of the reaction was monitored by TLC using cyclohexane/ethylacetate (7:3) as eluent.After completion of the reaction, the mixture was cooled to room temperature and poured on to ice-water (20 mL).The resulting solid product was filtered and washed with water (2×5 mL) and then recrystalized from ethanol to give the pure products.

Results and Discussion
Noting recent reports on the use of sulfuric acid immobilized on silica (H 2 SO 4 -Silica) [33][34][35] and in continuation of our research to develop new reagent for organic transformation 32,[36][37] , we now wish to report a three component Biginelli-type reaction by this catalyst.The Biginelli reaction was carried out with urea, ethyl acetoacetate or acetylacetone, aldehydes and a catalytic amount of H 2 SO 4 -Silica as a non-toxic, inexpensive and easily available catalyst, under solvent-free conditions at 50-55 °C.The reaction mixture was converted to the corresponding DHPMs and the products were obtained in good to high yields under solvent free conditions (Scheme 1).

Scheme 1
To optimize the reaction conditions, we tried to convert a mixture of benzaldehyde, ethyl acetoacetate and urea to its corresponding DHPMs under solvent-free conditions, in various solvents and also various catalytic amounts of H 2 SO 4 -Silica (Table 1).As shown in Table 1, in comparison to conventional methods in solution the yield of the reaction under solvent-free conditions is higher and the reaction time is shorter.It is remarkable to note that the condensation proceeded with a low catalyst concentration (7.5 mol% of H 2 SO 4 -Silica) and gave 3,4-dihydropyrimidin-2(1H)-ones in good yield.Higher amounts of the catalyst did not improve the yields.In a control experiment, we observed that the reaction does not take place in the absence of H 2 SO 4 -Silica.
Therefore, we employed the above conditions for the conversion of various aldehydes to the corresponding DHPMs under solvent-free conditions at 50-55 °C.Under the given reaction conditions several aromatic aldehydes containing electron donating as well as electron withdrawing groups with diverse substitution pattern were effectively cyclized to give DHPMs.The results are summarized in Table 2.As can be seen from Table 2, aldehydes, 1,3-dicarbonyl compounds and urea or thiourea in the presence of a catalytic amount of H 2 SO 4 -Silica gave the corresponding dihydropyrimidinones and thioderivatives in good yields under solvent-free conditions.In most cases, after completion of reaction and washing with H 2 O the crude products were purified by recrystallization from ethanol.An important feature of this method is that aromatic aldehydes carrying either electron-donating or electron-withdrawing groups afforded good yields of products in high purity.

Conclusion
In conclusion, we have demonstrated a very simple, efficient, and practical method for the synthesis of dihydropyrimidinones and thioderivatives through a one-pot, three-component condensation of aldehydes, 1,3-dicarbonyl compounds and urea or thiourea catalyzed by H 2 SO 4 -Silica under solvent-free conditions.The main features of our new reaction are as follows: (1) The simplicity of the system; (2) the condensation reaction could be performed exclusively using cheap, commercially available chemicals; (3) easy separation of products from the reaction mixture (4) The method is cost-effective and environmentally benign.

Table 1 .
Effect of solvent and catalyst amounts of H 2 SO 4 -Silica on the yield of the DHPMs a a benzaldehyde/ ethyl acetoacetate /Urea (1:1:1.5 mmol).bTheyieldsrefer to isolated pure products.cThereaction was carried out under reflux conditions

Table 2 .
H 2 SO 4 -Silica catalyzed Biginelli reaction under solvent free conditions a bThe yields refer to isolated pure products