Synthesis of arylidene dihydropyrimidinones and thiones catalyzed by iron ( III ) phosphate

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Introduction
Pyrimidinones are used in various pharmaceutical and biochemical fields. 1,2Therefore, an interest for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivations is tremendously increasing. 3One of the most important functionalized pyrimidinones is fused derivatives with an arylidene group.These heterocyclic compounds are significant intermediates for the preparation of many biologically active products.For example, some of them show a broad-spectrum antitumor activity. 4cause of the various therapeutic utility of arylidene heterobicyclicpyrimidinones, a number of synthesis routs for these derivatives were developed. 5In most cases, using strong Brönsted acid such as HCl or base such as sodium alkoxide or potassium hydroxide was necessary for the progress of the reaction. 6,7More useful procedures are three-component condensation with aromatic aldehydes, cyclopentanone, and urea or thiourea in presence of stoichiometric amounts of TMSCl 8 and YbCl3. 9herefore, we wish to report the synthesis of arylidene heterobicyclicpyrimidinones and thiones using FePO4 10,11 in the presence of arylaldehydes, cyclopentanone, and urea or thiourea.Moreover, this approach is known as an important economical and environmentally benign process in synthesis chemistry, because it decreases the number of reaction steps, energy consumption and waste (Scheme 1).

Results and Discussion
To optimize the reaction conditions, the reaction of benzaldehyde, cyclopentanone, and urea was selected as a model reaction in presence of catalytic amount of FePO4.The best result was obtained when the reaction was carried in a 2:1.1:1.2 mole ratio of benzaldehyde, cyclopentanone, and urea in the presence of FePO4 (20 mol %) under solvent-free condition at 110 °C for 4.0 h.In a catalyst free reaction, without FePO4, no desired product was obtained in 4.0 h.But, very low yield (20%) was resulted after 48 h.To use these optimized conditions (benzaldehyde (2 mmol), cyclopentanone (1.1 mmol), urea (1.2 mmol), and FePO4 (20 mol %) under solvent-free condition at 110 °C for 4.0 h.), the reaction between various aromatic aldehydes and cyclopentatone in presence of urea and thiourea was investigated (Table 1).It was found that all the reactions proceeded smoothly to give the corresponding arylidene heterobicyclicpyrimidinones and thiones in high yields.Both aromatic aldehydes bearing electron-donating and electron withdrawing groups gave excellent yields.The mildness of the procedure makes it very selective, as it tolerates a variety of functionalities, including; N(Me)2, Cl, Me, NO2 and isopropyl groups.Also, this procedure was equally effective for thiourea. Solvent-free

Scheme 2. Proposed mechanism for the synthesis of arylidenepyrimidinones and thiones using FePO4
To show advantages of this catalytic method with those of previously reported, the results of the formation of 7-benzylidene-4-phenyl-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (4a) were compared for a variety of catalysts (Table 2).From the results given in this Table 2, our method is evident, regarding the catalyst amounts, and high yield which are very important in chemical industry especially when it is combined with easy separation and reusability of the catalyst, and good yield.

Conclusions
FePO4 was used as an inexpensive, easily available, non-corrosive and environmentally benign catalyst for the synthesis of arylidene heterobicyclicpyrimidinones by one-pot three component condensation reactions.Using solvent-free conditions, non-toxic and inexpensive materials, simple and clean work-up and high yields of the products are the advantages of this method.Three new derivatives of arylidene heterobicyclicpyrimidinones (entries 8-10; Table 1) were also synthesized by this new protocol.

Experimental
Melting points were measured by using the capillary tube method with an electro thermal 9200 apparatus.IR spectra were recorded on Perkin Elmer FT-IR spectrometer did scanning between 4000-400 cm -1 . 1 HNMR and 13 CNMR spectra were obtained on Bruker DRX-300 MHz NMR instrument.Analytical TLC of all reactions was performed on Merck precoated plates (silica gel 60 F-254 on aluminium).

General procedure for the synthesis of arylidene heterobicyclicpyrimidinones using FePO4
A mixture of the aldehyde (2.0 mmol, 4a, 4e 0.212 g; 4b, 4f 0.280 g; 4c 0.302 g; 4d 0.240 g; 4h 0.296 g; 4i 0.302 g 4j 0.298 g), cyclopentanone (1.1 mmol, 0.084 g), urea or thiourea (1.2 mmol, 0.072 g or 0.0913 g) and FePO4 (20 mol%, 0.0302 g) was heated in an oil bath at 110 °C for the specified times.The reaction was followed by TLC (ethyl acetate/cyclohexane, 50:50).After completion of the reaction, hot ethanol (15 ml) was added and the catalyst was filtered off.Then the liquor was cooled to room temperature to form solid product.The solid product was collected by filtration, washed with water and then washed with ethanol to afford the pure product.The reusability of the catalyst was also studied.At the end of the reaction, the catalyst was filtered off, washed by ethanol or dichloromethane, and dried at 80 °C.Then the catalyst was subjected for three runs.After three runs, the catalytic activity of the catalyst was almost the same as those of the freshly used catalyst (Table 3).

Table 1 .
Synthesis of arylidenepyrimidinones and thiones using FePO4