A Simple and Green Protocol for the Synthesis of 3,4-dihydropyrimidin-2(1H)-ones Using 11-Molybdo-1-vanado phosphoric Acid as a Catalyst Under Ultrasound Irradiation

A one-pot three-component reaction of ethyl acetoacetate, aldehydes and urea has efficiently been carried out in the presence of 11-molybdo-1-vanadophosphoric acid in ethanol at room temperature under ultrasound irradiation to form the corresponding 3,4-dihydropyrimidin 2(1H)-ones in high yields. The 11-molybdo-1-vanadophosphoric acid (H4PMo11V1O40) was prepared and characterized by FT-IR spectroscopy, TG-DTA analysis and XRD analysis techniques. The presence of Keggin structure and incorporation of vanadium into the Keggin structure of synthesized H4PMo11V1O40 catalyst was confirmed by FT-IR and powder XRD analysis techniques. TG-DTA analysis results indicated that H4PMo11V1O40 catalyst was thermally stable up to the temperature 434 °C. The present catalytic system is recyclable and can be reused without greater loss of reactivity.


Introduction
Heteropoly acids (HPAs) are complex proton acids that exhibit a wide range of molecular sizes, compositions, and molecular architectures [1]. HPAs are widely used as homogeneous and heterogeneous acid and oxidation catalysts due to their high thermal stability, strong acidity and strong oxidizing ability [2]. Among various HPA structural classes, the Keggin-type HPAs are the most studied class within polyoxometalates, because of their unique properties such as welldefined structure, Bronsted acidity, possibility to modify their acid-base and redox properties by changing their counter-cations, heteroatoms and framework polyatoms [3,4]. Nowadays, catalysis by HPAs is a potential area due to their high catalytic activities and reactivity, ease of handling, allow cleaner reactions in comparison to conventional catalysts, non-toxicity and experimental simplicity and hence they are generally recognized as clean, safe and green catalysts [5].
Ultrasound irradiation has been considered as an environmentally benign approach which is being used more and more in organic synthesis during the last three decades [6]. A large number of organic reactions can be carried out in higher yields, shorter reaction time and milder conditions under ultrasound irradiation [7]. Moreover, this method is more convenient and can be easily controlled as compared to traditional methods [8].
In the present work, we describe the preparation of 11-molybdo-1-vanadophosphoric acid using etherate method and its characterization by FT-IR spectroscopy, TG-DTA analysis and XRD analysis techniques. The prepared 11-molybdo-1-vanadophosphoric acid catalyst was applied for the synthesis of 3,4dihydropyrimidin 2(1H)-one derivatives by onepot three-component reaction of ethyl acetoacetate, aldehydes and urea under ultrasound irradiation.

Characterization of 11-molybdo-1vanadophosphoric acid H4[PMo11V1O40] 30H2O
The H4PMo11V1O40 catalyst was characterized using FT-IR spectroscopic analysis, TGA analysis and powder XRD analysis techniques to confirm Keggin structure and incorporation of vanadium into the Keggin structure.

TG-DTA Analysis
The thermal stability of the H4PMo11V1O40 catalyst was examined by TG-DTA analysis and the TG-DTA graphs are depicted in Fig. 2 (a) and 2 (b). The initial weight loss of about 11.6% in the TGA data of H4PMo11V1O40 up to a temperature of 120 °C corresponds to the loss of free and adsorbed water. A gradual mass loss of about 2.7% up to 450 °C, which was attributed to the decomposition of Keggin units and to the evolution of protonic water, the so-called constitution water. observed. At 434 °C, exothermic peak is observed which is attributed to the decomposition of compound in a mixture of anhydride oxide [26]. The above TG -DTA results strongly supports that H4PMo11V1O40 catalyst was thermally stable up to the temperature 434 °C.

Powder XRD Analysis
As shown in Fig. 3, the X-ray diffraction pattern of the H4PMo11V1O40 catalyst was distributed in four ranges of 2θ, which are 6°-12°, 16°-23° and 25°-30°, revealing that the synthesized H4PMo11V1O40 catalyst belong to the Keggin-type HPAs [27,28]. XRD pattern of H4PMo11V1O40 catalyst reflects its secondary structure, which strongly depends upon its environments. The variation in the intensities should be due to the replacement of framework molybdenum by vanadium and the hydration. Catalyst.

Catalytic activity
To find out the suitable conditions for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones, a series of experiments were performed with the standard reaction of benzaldehyde (1 mmol), ethylacetoacetate (1 mmol) and urea (1.5 mmol) in presence of H4PMo11V1O40 as a model reaction. At the onset study, we try to optimize the model reaction mentioned above by detecting the efficiency of several classic solvents chosen as the medium for comparison under ultrasonic irradiation or without ultrasonic irradiation. Among the tested solvents such as toluene, dichloromethane, acetonitrile, ethanol, methanol and water the formation of product was more facile and proceeded to give not only in high yield but also with high reaction rate in ethanol (93 yield in 25 min) under ultrasonic irradiation (Table 1,  entry 4). In order to verify the effect of ultrasound irradiation, the reaction was also performed in mentioned solvents by high stirring alone under silent condition ( Table 1). As shown in Table 1, in all cases, the experimental results show that the yields of the products are lower than sonication and required higher reaction times. Based on the results of this study, it's clear that the ultrasonic technique represented a better procedure in terms of time and yields. In order to optimize concentration of H4PMo11V1O40, the model reaction was carried out under sonication using different concentration of H4PMo11V1O40 (Table 2). It was found that the best results were obtained with 0.10 g of the H4PMo11V1O40 catalyst (yield = 93%) under ultrasonic irradiation (Table 2, entry 6). Using lower amount of catalyst resulted in lower yields, while higher amount of catalyst did not affect the reaction times and yields and in the absence of catalyst, the yield of the product was not found.
After optimization of the reaction conditions, we studied the reaction of ethylacetoacetate and urea with various aldehydes in presence of H4PMo11V1O40 catalyst. The results are summarized in Table 3. Several aromatic aldehydes with either electron-donating or electron-withdrawing groups attached to the aromatic ring reacted smoothly and the desired products were obtained in good to excellent yields.

Recyclability of the catalyst
The reusability of the catalyst was checked by separating the H4PMo11V1O40 catalyst from the reaction mixture by simple filtration and drying in a vacuum oven at room temperature for 4 h followed by drying at 120 °C in an air oven prior to reuse. As a typical example, the catalyst H4PMo11V1O40 showed conversion of 90% in the first run, which decreased to about 86% in the 2nd run and 81% in the 3rd run respectively.

Characterization Techniques
FT-IR spectra were obtained with a Bruker, Germany (Model 3000 Hyperion microscope with vertex 80 FT-IR system) spectrometer. XRD patterns were obtained with a Philips X'pert MPD System instrument using Cu Kα radiation. The TG-DTA measurements of the samples were made with the Thermal Analyzer (Perkin Elmer, Model Diamond TG-DTA) with about 10 mg of sample in a platinum crucible at a heating rate of 10 °C min -1 in an air atmosphere. 1 H NMR spectra were recorded on a Bruker Avance 400 and 13 C NMR were recorded on a Bruker DRX-300 instrument using TMS as an internal reference. Mass spectra were recorded on Waters UPLC-TQD Mass spectrometer using electrospray ionization technique. The uncorrected melting points of compounds were taken in an open capillary in a paraffin bath.

2.2.
Preparation of 11-molybdo-1vanadophosphoric acid H4[PMo11V1O40] 30H2O Na2HPO4 (7.1 g, 0.050 mol) was dissolved in water (100 mL) and mixed with sodium metavanadate (6.1 g, 0.050 mol) that had been dissolved by boiling in water (100 mL). The mixture was cooled and acidified to a red colour with concentrated sulphuric acid (5 mL). To this mixture was added a solution of Na2MoO4. 2H2O (133 g, 0.55 mol) dissolved in water (200 mL). Finally, concentrated sulphuric acid (85 mL) was added slowly with vigorous stirring of the solution. With this addition the dark red colour changed to lighter red. The heteropoly acid was then extracted with diethyl ether (400 mL) after the water solution was cooled. In this extraction the heteropoly etherate was present in the middle layer; the aqueous layer (bottom) was yellow and probably contained vanadyl species. After separation, a stream of air was passed through the heteropoly etherate layer to free it of diethyl ether. The orange solid that remained was dissolved in water (50 mL), concentrated to the first appearance of crystals in a vacuum desiccator over concentrated sulphuric acid, and then allowed to crystallize further. The orange crystals that formed were filtered, washed with water, and air-dried (28 g, 23%). The amount of water of crystallization varied slightly from sample to sample [25].
Further the reaction mass was irradiated under ultrasonic irradiation at room temperature for appropriate time, as shown in Table 4.2.3. After completion of the reaction as indicated by TLC, the crude product was washed with ice-cold water and stirred well. The catalyst is soluble in water and was separated from the reaction mixture. The solid obtained was recrystallized from hot ethanol to afford the corresponding pure product.

Conclusions
In summary, this article describes preparation of vanadium substituted Keggin-type 11-molybdo-1-vanadophosphoric acid (H4PMo11V1O40) and its characterization using FT-IR, TG-DTA and Powder XRD techniques. The FT-IR and powder XRD analysis techniques confirm presence of Keggin structure and the vanadium incorporation into the Keggin structure of H4PMo11V1O40 catalyst. TG -DTA results suggest that H4PMo11V1O40 catalysts were thermally stable up to the temperature 434 °C. It was demonstrated here that H4PMo11V1O40 catalyzed one-pot threecomponent reaction of ethyl acetoacetate, aldehydes and urea under ultrasound irradiation provides an efficient, mild, clean and inexpensive route to obtain 3,4-dihydropyrimidin 2(1H)-ones. The protocol developed using H4PMo11V1O40 catalyst offers several advantages, including shorter reaction times, easy work-up, low toxicity and reusability of catalyst and it obeys the green chemistry conditions. We believe that this method is a useful and attractive alternative to the existing methods for the synthesis of 3,4-dihydropyrimidin 2(1H)-ones.