Tungsten-substituted molybdophosphoric acid impregnated with kaolin: effective catalysts for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones via biginelli reaction

Abstract

A series of highly reusable heterogeneous catalysts (10–25 wt% PMo₇W₅/kaolin), consisting of tungsten-substituted molybdophosphoric acid, H₃PMo₇W₅O₄₀·24H₂O (PMo₇W₅) impregnated with acid treated kaolin clay was synthesized by the wetness impregnation method. The newly synthesized catalyst was fully characterized using inductively coupled plasma-atomic emission spectroscopy (ICP-AES), Fourier transform infrared (FT-IR), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) analysis and thermal analysis (TG-DTA). The synthesized materials were shown to be efficient in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones via Biginelli reaction under solvent-free conditions. The obtained results indicate that 20% PMo₇W₅/kaolin catalyst showed remarkably enhanced catalytic activity compared to the bulk PMo₇W₅ catalyst, and also the (10 and 15%) PMo₇W₅ catalyst supported on kaolin clay.

---

1. Introduction

Heteropoly acids (HPA) are well known as environmentally benign and economically feasible alternatives to traditional acid catalysts due to their Brönsted acidity, high proton mobility and relatively better stability.^1–4 One of the important structural subclass of HPAs is the Keggin anion, which is typically represented by the general formula XM₁₂O₄₀,^x−8 where X is the central atom (Si, P, B, Zr etc.), x is its oxidation state, and M is the metal ion (Mo⁶⁺or W⁶⁺).^5–7 The M⁶⁺ ions can be replaced by many other metal ions, e.g., V⁵⁺, Co²⁺, Zn²⁺, Ni²⁺ etc.^8–12 The Keggin anion is composed of a central tetrahedral XO₄ surrounded by 12 edge and corner sharing metal-oxygen octahedra MO₆. The octahedra are arranged in four M₃O₁₃ groups. Each group is formed by three octahedra sharing edges and having a mutual oxygen atom which is also shared with the central tetrahedral XO₄.^13,14 The catalytic properties of Keggin type heteropoly acids can be tuned by changing their central heteroatoms, framework poly-atoms, and charge-compensating cations because the substitution of these atoms changes their acid and redox properties.^15–17 It is well known that the acid strength of tungstophosphoric acid (H₃PW₁₂O₄₀·nH₂O) is greater than that of molybdophosphoric acid (H₃PMo₁₂O₄₀·nH₂O). Therefore, it can be projected that replacement of molybdenum (Mo) by tungsten (W) in the peripheral metal atom positions of the anions can increase the acid strength of the heteropoly acids, giving high catalytic activity for acid-catalyzed reactions.^18,19 Extremely low surface area, poor stability and rapid deactivation are the major problems associated with heteropoly acids.²⁰ Hence, it is imperative to employ an appropriate support to distribute the heteropoly acid.^21–25

Kaolin, a clay mineral which is abundant on the earth, it is composed of abundantly 1 : 1 clay mineral Al₂Si₂O₅(OH)₄ structure per alumina-silicate producing bulky congested particles of SiO₄ tetrahedral sheets and AlO₂(OH)₄ octahedral sheets.^26,27 Kaolin clay are promising supports due to their common fascinating features, such as their inherent acidity, excellent thermal stability and easily controlled structural morphology.²⁸ Therefore, the acidified-kaolin with larger specific surface area is widely used as a very good catalyst carrier.²⁹ Actually, heteropoly acid-impregnated solid acids have caused great interests in many fields.^30,31

3,4-Dihydropyrimidin-2-(1H)-ones (DHPM) are of significant interest in industry as well as in academia because of their promising biological and pharmacological activities such as antitumor, antibacterial, antiviral and anti-inflammatory activities.^32,33 DHPM also have some other interesting pharmacological properties of being calcium channel modulators, anti-HIV in some natural products containing the DHPM skeleton and anti-cancer by inhibiting kinesin motor protein.^34,35 Therefore, development of new, efficient and convenient protocols that lead to substituted DHPMs is of considerable attention. This has led to the recent disclosure of several one-pot methodologies for the synthesis of DHPM derivatives such as [bmim] [FeCl₄],³⁶ [bmim]BF₄-immobilized Cu(II) acetylacetonate,³⁷ piperidinium triflate³⁸ and ammonium carbonate.³⁹ However, some of existing methods associated with certain limitations such as environmental pollution caused by utilization of organic solvents, long reaction time, exotic reaction conditions and expensive catalysts. Therefore, it is crucial to further develop an efficient and convenient method to construct such significant scaffold (Scheme 1).

Scheme 1 Synthesis of tungsten-substituted molybdophosphoric acid, H₃[PMo₇W₅O₄₀]·24H₂O.

Encouraged by the intense ongoing research activity in the field of heterogeneous acid catalysis and in pursuit of our continuous interest in the area of catalysis by supported heteropoly acids.⁴⁰ Herein, we wish to report a simple, green and efficient protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using series of tungsten-substituted molybdophosphoric acid (H₃PMo₇W₅O₄₀·24H₂O) impregnated with kaolin clay catalysts through Biginelli reaction (Scheme 2).

Scheme 2 Preparation of the series of catalysts having 10–25% loading of H₃[PMo₇W₅O₄₀]·24H₂O on kaolin clay support.

2. Experimental section

2.1 Materials and general characterization

Disodium phosphate (Na₂HPO₄), Sodium molybdate (Na₂MoO₄·2H₂O) sodium tungstate (Na₂WO₄·2H₂O) and kaolin clay (kaolin-product code: 15160) were purchased from MOLYCHEM in India and used without further purification. All the chemicals and solvents involved in the organic synthesis were purchased from Merck, Sigma Aldrich and Alfa Aesar.

Element content was measured on an ARCOS, Simultaneous ICP Spectrometer inductively coupled plasma atomic emission spectroscopy (ICP-AES). The Fourier-transform infrared spectroscopy (FTIR) spectrum was performed on a Bruker ALPHA (Eco-ATR) spectrophotometer. The materials were characterized by X-ray powder diffraction (XRD) using a Bruker AXS Company, D8 ADVANCE diffractometer (Germany). Scanning electron microscopy (SEM) images were obtained using a FEI Nova NanoSEM 450 combined with a Bruker XFlash 6I30 instrument for energy-dispersive X-ray spectroscopy (EDX), with a scanning electron electrode at 15 kV. Transmission electron microscopy (TEM) images were collected using a (HR-TEM: Jeol/JEM 2100) operated at an accelerating voltage of 200 kV. Nitrogen adsorption–desorption isotherms were measured with a NOVA Station A instrument at 77 K. The surface area calculated by the Brunauer–Emmett–Teller (BET) method and pore size distribution derived from adsorption branches of the isotherms using the distribution Barrett–Joyner–Halenda (BJH) method. The thermal stability of the sample was carried out using simultaneous thermogravimetry (TG) and differential thermal analysis (DTA) technique, measurements were performed using a SHIMADZU, DTG-60H simultaneous DTA-TG apparatus. The progress of the reaction monitored by thin-layer chromatography on Merck's silica plates and imagining accomplished by iodine/ultraviolet light. Melting points of all the synthesized analogues were resolute in open capillary tube and are uncorrected. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance 400 Spectrometer in DMSO and CDCl₃. Chemical shifts are expressed in δ parts per million relative to tetramethylsilane (TMS) as the internal standard. All yields refer to the isolated products.

2.2 Catalyst preparation

2.2.1 Preparation of H₃[PMo₇W₅O₄₀]·24H₂O (PMo₇W₅). HPA with general formula H₃[PMo₇W₅O₄₀]·24H₂O, was synthesized using the procedure reported by Huixiong.¹⁸ Briefly, Disodium phosphate (0.63 g, Na₂HPO₄) and desired amount of Sodium molybdate (7.48 g, Na₂MoO₄·2H₂O) were dissolved in distilled water. The obtained solution was stirred at 90 °C. After being stirred for 30 min, aqueous solution of sodium tungstate (7.28 g, Na₂WO₄·2H₂O) was added to the above heated solution. Subsequently, sulfuric acid (H₂SO₄) solution was added drop wise until the solution pH value reached about 1.5–2. The resulting mixture was heated at 90 °C for 6 h. Finally, the solution was cooled and extracted with diethyl ether in sulfuric acid environment. The powder H₃[PMo₇W₅O₄₀]·24H₂O was obtained after concentrated etherate solution was dried in vacuum.

2.2.2 Preparation of PMo₇W₅/kaolin. PMo₇W₅ impregnated-kaolin catalysts were prepared according to literature procedures with small modifications.²¹ In a typical synthesis of 10% PMo₇W₅/kaolin, 0.5 g of PMo₇W₅ dissolved in 0.1 mol L⁻¹ HCl solution was added into the flask containing 4.5 g of kaolin and stirred for 4 hours at room temperature. The resulting mixture was heated to 80 °C until complete evaporation of the liquid part. Then solid residue calcined in an oven at 200 K for 5 h. A series of PMo₇W₅/kaolin (10, 15, 20, 25 wt%) were prepared using the same method.

2.2.3 General procedure of the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. In a typical experiment, a mixture of aromatic aldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (3.2 mmol) and 20% PMo₇W₅/kaolin (0.1 g) was stirred at 80 °C under solvent-free conditions for suitable time as indicated by thin-layer chromatography. After completion of reaction, the reaction mixture was diluted using hot ethanol (10.0 mL) and filtered for catalyst separation. The crude product was obtained by solvent evaporation under reduced pressure and recrystallized from ethanol. The recovered catalyst was washed with ethanol (10 mL) and dried overnight for further reuse. The physical data (Melting point, IR and H¹ & C¹³NMR) of known compounds (see S5†) were found to be identical with those reported in the various literature.

3. Result and discussion

3.1 Catalyst characterization

3.1.1 ICP-AES analysis. The results of ICP-AES elemental analysis revealed that the atomic ratio of P/Mo/W is nearly maintained 1.05 : 6.68 : 5.18 which corresponds to the formula H₃[PMo₇W₅O₄₀]·24H₂O (PMo₇W₅).^18,40

3.1.2 FT-IR spectroscopy. Primarily, FT-IR spectroscopy was used to confirm the successful functionalization of the PMo₇W₅/kaolin catalyst (Fig. 1). For bulk PMo₇W₅, characteristic bands exhibiting at 1061 (P–O_a in central tetrahedral), 960 (terminal M=O_d), 873 (M–O_b–M), and 757 cm⁻¹ (M–O_c–M) are accorded with asymmetric vibrations in Keggin unit.¹⁷ In the FT-IR spectrum of kaolin, absorptions at 748 cm⁻¹ and 789 cm⁻¹ are attributed to Si–O–Al vibrations and the band at 915 cm⁻¹ is assigned to Al-OH bending vibrations. The peak at 1007 cm⁻¹ is assigned to Si–O–Si in-plane vibrations and at 1113 cm⁻¹ is assigned to asymmetric Si–O–Si stretching vibrations.²⁶ The spectrum of PMo₇W₅/kaolin with different percentages of PMo₇W₅ showed two bands at 938 and 910 cm⁻¹, which might be attributed to the (terminal M=O_d) and (M–O_b–M), respectively. However, the bands at 1061 and 757 cm⁻¹ were not prominent due to overlapping with the strong bands of silica in the kaolin support.²¹

Fig. 1 FT-IR analysis of bulk PMo₇W₅, kaolin and PMo₇W₅/kaolin composites.

3.1.3 XRD analysis. Fine dispersion of PMo₇W₅ on the kaolin support was confirmed by XRD analysis. Fig. 2 shows the XRD patterns of PMo₇W₅, kaolin support and PMo₇W₅/kaolin composites (with PMo₇W₅ loading from 10, 15, 20 and 25%). Unsupported PMo₇W₅ showed the characteristic XRD peaks of the Keggin structure mainly exist in four ranges of 2θ = 7–10°, 18–23°, 25–30° and 31–37° (ref. ¹⁷) On the other hand, several prominent peaks of kaolin detected at about 2θ = 12.36°, 20.44°, 21.42°, 25.10°, 35.03°, 38.48° and 62.38°. The peak at 2θ = 12.36° is the distinctive XRD form of kaolin.⁴¹ Interestingly, 10, 15, 20 and 25% PMo₇W₅/kaolin catalyst exhibited no characteristic peaks of PMo₇W₅ but showed almost the same XRD pattern as kaolin, indicating the retention of the original characteristics of kaolin clay.⁴² The above results strongly supports that PMo₇W₅ was finely and molecularly dispersed on the kaolin support in the PMo₇W₅/kaolin catalyst.^28,43

Fig. 2 XRD patterns of bulk PMo₇W₅, kaolin and PMo₇W₅/kaolin composites.

3.1.4 SEM and TEM analysis. The surface morphology and texture of produced samples was investigated using SEM and TEM analysis (Fig. 3a–d). As seen in Fig. 3a, the irregularly shaped particles with rough, flaky edges were observed for bulk PMo₇W₅ sample. The SEM images of kaolin and 20% PMo₇W₅/kaolin are shown in Fig. 3b and c respectively. These images clearly show that the surface morphology of supported catalyst is almost identical to that of pure kaolin. No change in surface morphology of the catalyst demonstrate that PMo₇W₅ species are well dispersed inside the hexagonal pores.⁴¹ Further, no separate crystallites of bulk phase of PMo₇W₅ were found in 20% PMo₇W₅/Kaolin.

Fig. 3 FE-SEM images of bulk PMo₇W₅ (a), kaolin (b), 20% PMo₇W₅/kaolin (c) and TEM images of 20% PMo₇W₅/kaolin (d).

The TEM images of 20% PMo₇W₅/kaolin (Fig. 3d) shows that most of the hexagonal pores covered with dark colored fine particles. This indicates uniform dispersion of PMo₇W₅ inside the hexagonal pores of kaolin clay support.

3.1.5 EDX analysis and mapping images. The chemical constitution of bulk PMo₇W₅ and 20% PMo₇W₅/kaolin were evidenced by EDX analysis as depicted in Fig. S2.† The results of newly prepared PMo₇W₅ confirms the presence of P, Mo and W (Fig. S1-a†). Moreover, the EDX results of 20% PMo₇W₅/kaolin (Fig. S2-b†) showed the presence of P, Mo and W elements of PMo₇ W₅ and Si, Al and O of kaolin clay. Which strongly indicates the successfully formation of 20% PMo₇W₅/kaolin.⁴²

Additionally, EDS mapping images proved a uniform distribution of W, Mo and P in the desired PMo₇W₅ catalyst system (Fig. 4a). The elemental mapping of Fig. 4b depicted the construction of a well-dispersed composite material of P, Mo, W, Si, Al and O in the synthesized 20% PMo₇W₅/kaolin catalyst, which is in moral contract with FT-IR, XRD and SEM results.

Fig. 4 Elemental mapping images of (a) bulk PMo₇W₅ (b) 20% PMo₇W₅/kaolin catalyst.

3.1.6 BET analysis. The specific surface area is an important representative of a catalyst. The specific surface area, pore diameter, and pore volume of the catalysts were determined by BET and BJH methods. The specific surface area of the PMo₇W₅, kaolin support and 20% PMo₇W₅/kaolin catalysts were 5.3801, 16.093 and 6.199 m² g⁻¹, respectively (Table 1). The porosities of these catalysts was investigated by N₂ adsorption/desorption measurement. N₂ adsorption/desorption isotherm are the type IV in nature according to the IUPAC classification. The bulk PMo₇W₅ exhibit a well expressed H4 hysteresis loop (Fig. 5a), whereas, parent kaolin clay and 20% PMo₇W₅/kaolin catalyst exhibit H3 hysteresis loop (Fig. 5b and c) in the range of 0.4–1.0 P/P₀ at high relative pressure, which is typical for mesoporous materials. As demonstrated in Table 1, the pore diameter of the PMo₇W₅, kaolin support and 20% PMo₇W₅/kaolin catalyst were 10.409, 15.850, and 3.882 nm respectively. Also pore volume (0.014–0.070 cm³ g⁻¹) of the catalysts were calculated using the BJH method (see Fig. S3-a–c†).^26,44,45

Table 1 Textural properties of the prepared catalyst

Entry	Samples	SBET (m^2 g^−1)	Dpore (nm)	Vpore (cm^3 g^−1)
1	PMo7W5	5.3801	10.409	0.014
2	Kaolin clay	16.093	15.850	0.070
3	20% PMo7W5/kaolin	6.199	3.882	0.036

---

Fig. 5 N₂ adsorption–desorption isotherms of (a) PMo₇W₅ (b) kaolin support (c) 20% PMo₇W₅/kaolin.

The study proven that the surface area of 20% PMo₇W₅/kaolin catalyst slightly increased but not more than that of kaolin support.⁴⁶ This could primarily due to deposition and incorporation of PMo₇W₅ catalyst into the pores of kaolin support.⁴⁷

3.1.7 TG-DT analysis. The thermal stability of bulk PMo₇W₅ and 20% PMo₇W₅/kaolin examined by the thermogravimetric (TG) and differential thermal analysis (DTA). The hydrated solids usually obtained with a large amount of water of crystallization. Generally, three types of crystallographic water molecule could be distinguishes in the hydrated solid (Fig. 6a).^48,49 The TG curve for bulk PMo₇W₅ shows the total weight loss of 16.01% below 460 °C indicating that 24 water molecules calculated were lost. The first mass loss stage, free crystalized water, 10.20% of the total sample mass was lost and an endothermic peak appeared at 95 °C for 15-water molecule. The second mass lost for H⁺ -combined water, about 3.27% of the total sample mass was loss and endothermic peak appeared at 147 °C for 4.9 water molecule. The structure water, 2.5% of the total sample mass loss and DTA curve shows the exothermic peak at 467 °C, which demonstrate stability of Keggin unit and these third mass losses for oxide mixture.

Fig. 6 TG-DT analysis of (a) PMo₇W₅ and (b) 20% PMo₇W₅/kaolin catalyst.

The TG-DTA of supported PMo₇W₅ on kaolin showed the mass loss of about 3.51% up to 430 °C temperature corresponds to dehydration of surface and interlayer water molecules (Fig. 6b). The gradual mass loss about 7.19% within the temperature range 430 °C to 750 °C, which indicates an increase in the thermal stability of bulk PMo₇W₅ on kaolin clay support.⁴⁰ This might be due to formation of intermolecular bonding interaction between kaolin and bulk PMo₇W₅. The above result reveals that strong chemical interaction between kaolin and PMo₇W₅ catalyst.

3.2 Catalytic activity

Our initial studies were focused on the optimization of the reaction conditions for the synthesis of ethyl 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives. Benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol) and urea (3.2 mmol) were chosen as substrates for model reaction (Scheme 3).

Scheme 3 Synthesis of ethyl 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a–n) by using 20% PMo₇W₅/kaolin catalyst.

Various amounts of PMo₇W₅/kaolin were used to study the effect of the composition of the catalyst on the conversion and obtained results are summarized in Table 2. Pure kaolin showed extremely low catalytic activity in terms of the reaction time and the yield of the desired product (Table 2, entry 1). Bulk PMo₇W₅ gave a moderate yield of the product but only after an extended reaction time (Table 2, entry 2). It was observed that both yield of the product and reaction time were improved upon increasing the catalyst loading up to 20% w/w (Table 2, entries 3, 4, and 5). Further, an increase in PMo₇W₅ catalyst loading above 20% w/w on kaolin support have no effect on yield of product and reaction time due to leaching of catalyst from the support (Table 2, entry 6). The increase in activity of the 20% PMo₇W₅/kaolin catalyst was due to high dispersion of PMo₇W₅ catalyst on kaolin support. This would lead to an increase in its surface area and the number of active sites compared with the bulk PMo₇W₅ catalyst. Hence, 20% PMo₇W₅/kaolin catalyst was found to be optimal amount and adequate to push the reaction forward.

Table 2 Effect of H₃PMo₇W₅O₄₀·24H₂O loading on support kaolin for the synthesis of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a)^a

Entry	Catalyst	Time^b (min)	Yield^c (%)
a Reaction conditions: benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (3.2 mmol) and PMo7W5/kaolin catalyst.b Reaction progress monitored by TLC.c Isolated yields.
1	Pure kaolin	120	45
2	Bulk H3PMo7W5O40·24H2O	55	60
3	10% PMo7W5/kaolin	35	68
4	15% PMo7W5/kaolin	20	85
5	20% PMo7W5/kaolin	08	95
6	25% PMo7W5/kaolin	08	95

---

The determination of appropriate amount of the catalyst for catalyzing the reaction is another critical parameter in terms of reaction efficiency. To find appropriate amount of catalyst, the model reaction was carried out in the presence of different amounts (25, 50, 70, 100 and 125 mg) of 20% PMo₇W₅/kaolin and obtained results are summarized in Table 3. When the amount of 20% PMo₇W₅/kaolin increases gradually, product yield also increases (Table 3, entries 1–5). The obtained results demonstrates that 100 mg amount of 20% PMo₇W₅/kaolin catalyst gave 95% yield of product at 80 °C (Table 3, entry 5). Additional increase in the amount (125 mg) of 20% PMo₇W₅/kaolin does not increase in the yield of the product (Table 3, entry 5). This may be due to overtiredness of the catalytic site or accomplishment of the maximum conversion efficiency of the catalyst. It is also important to note that at 60 and 70 °C low to moderate conversion observed, whereas at 80 °C excellent conversion of starting material were seen (Table 3, entry 5 versus entries 7 and 8). The effectiveness of model reaction also studied without using any catalyst. Where, trace amount of the product obtained after a long period (Table 3, entry 1).

Table 3 Effect of temperature and amount of catalyst on ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a)^a

Entry	Catalyst (mg)	Temp. °C	Time^b	Yield^c (%)
a Reaction conditions: benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (3.2 mmol) and 20% PMo7W5/kaolin catalyst.b Reaction progress monitored by TLC.c Isolated yields.
1	0	80	24 h	Trace
2	25	80	8 min	65
3	50	80	8 min	70
4	70	80	8 min	82
5	100	80	8 min	95
6	125	80	8 min	95
7	100	70	8 min	65
8	100	60	8 min	45

---

Further, the efficiency of 20% PMo₇W₅/kaolin was investigated by using 100 mg of 20% PMo₇W₅/kaolin in various organic solvents (Table 4). Initially, the model reaction was carried out in ethanol and water at reflux temperature the moderate yield were obtained (Table 4, entries 1, 2). When the methanol, acetonitrile, dichloromethane were used as solvent at reflux temperature and DMF at 80 °C, it gave lower yields of product (Table 4, entries 3–6). None of the above solvents demonstrates the advantage of time and yield instead of solvent-free condition (Table 4, entry 7). Therefore, solvent-free condition was superior in terms of cost and it is environmentally benign to promote further derivatives (Table 5).

Table 4 Effect of different solvents on the ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a)^a

Entry	Catalyst (mg)	Temp. °C	Solvent	Time^b	Yield^c (%)
a Reaction conditions: benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (3.2 mmol) and 20% PMo7W5/kaolin catalyst.b Reaction progress monitored by TLC.c Isolated yields.
1	100	Reflux	EtOH	15 min	72
2	100	Reflux	H2O	10 min	68
3	100	Reflux	MeOH	25 min	62
4	100	Reflux	CH3CN	45 min	45
5	100	80	DMF	65 min	55
6	100	Reflux	CH2Cl2	30 min	59
7	100	80	Solvent-free	8 min	95

---

Table 5 Synthesis of ethyl 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a–n) by using 20% PMo₇W₅/kaolin catalyst^a,b

a Reaction conditions: aldehydes (4a–n) (3 mmol), ethyl acetoacetate (3 mmol), and urea (3.2 mmol) in 20% PMo₇W₅/kaolin (0.1 g) stirred at 80 °C.b Isolated yields.

---

A comparative study was performed for the use of 20% PMo₇W₅/kaolin with some of the reported catalysts for the synthesis of 6-methyl-2-oxo-4-aryl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Table 6). Reaction with different catalysts required a higher amount of catalyst and longer reaction times compared with 20% PMo₇W₅/kaolin in solvent-free systems. In most methods, the reaction was achieved in solvent such as ethanol, acetic acid and dioxane. Thus, 20% PMo₇W₅/kaolin encouraged the reactions more effectively than the other catalysts and should be considered as one of the top choices for selecting an economically convenient, user-friendly catalyst.

Table 6 Biginelli reaction of benzaldehyde, ethyl acetoacetate and urea with different catalysts^a

Entry	Catalyst	Condition	Time	Yield^b (%) Ref
a Reaction conditions: benzaldehydes (3 mmol), ethyl acetoacetate (3 mmol), and urea (3.2 mmol) in 20% PMo7W5/kaolin (0.1 g) stirred at 80 °C.b Isolated yields.
1	p-Sulfonic acid calixarenes	EtOH, reflux	8 h	69 (ref. ^50)
2	NH4H2PO4/MCM-41	Solvent-free, 100 °C	6 h	72 (ref. ^51)
3	[Et3NH] [HSO4]	Solvent-free, 100 °C	1 h	75 (ref. ^52)
4	12-Tungstophosphoric acid	Reflux, acetic acid	6 h	98 (ref. ^53)
5	[Btto][p-TSA]	Solvent-free, 90 °C	30 min	96 (ref. ^54)
6	Fe3O4/PAA-SO3H	Solvent-free, rt	2 h	90 (ref. ^55)
7	SnCl2/nano SiO2	EtOH, reflux	40 min	94 (ref. ^56)
8	Bentonite/PS-SO3H	Solvent-free, 120 °C	30 min	89 (ref. ^57)
9	Fe3O4@SBA-15	EtOH, 90 °C	6 h	85 (ref. ^58)
10	PS-PEG-SO3H	Dioxane & 2-propanol, 80 °C	10 h	80 (ref. ^59)
11	20% PMo7W5/kaolin	Solvent-free, 80 °C	8 min	95 (this work)

---

3.3 Recycling of the catalyst

One of the most important features of the present methodology is the recyclability of the catalyst. It was observed that the 20% PMo₇W₅/kaolin catalyst could be reused multiple times. For this purpose, the same model reaction was performed again studied under the optimized conditions (Table 7). After reaction completion, the reaction mixture was diluted using hot ethanol and filtered for catalyst separation, the solid catalyst was washed with ethanol several times, dried and calcined at 200 °C for 5 h and reused for subsequent reaction. The results (Fig. 8) revealed that the catalyst exhibited good catalytic activity up to six consecutive cycles.

Table 7 Recycling and reuse of the catalyst^a

Entry	Number of recycle	Yield (%)^b
a Reaction conditions: benzaldehyde (3 mmol), ethyl acetoacetate (3 mmol), urea (3.2 mmol) and 20% PMo7W5/kaolin catalyst, time 8 min.b Isolated yields.
1	1	95
2	2	95
3	3	94
4	4	90
5	5	90
6	6	88

---

The FT-IR and XRD spectra of the recovered 20% PMo₇W₅/kaolin (after six cycles) were matched with those of the fresh sample. As documented in Fig. 7, the FT-IR showed two bands at 938 and 910 cm⁻¹ were found to similar of fresh 20% PMo₇W₅/kaolin (Fig. 7a verses Fig. 1). XRD spectra displayed by the recovered 20% PMo₇W₅/kaolin catalyst at 2θ = 20.12°, 21.97°, 23.65, 25.63°, 35.53° and 59.32° were found to be almost similar to the fresh one (Fig. 7b verses Fig. 2).

Fig. 7 FT-IR (a) and XRD (b) analysis of recovered 20% PMo₇W₅/kaolin catalyst.

Fig. 8 Recyclability test of 20% PMo₇W₅/kaolin catalyst on model reaction.

3.4 Plausible reaction mechanism

The possible reaction pathway for the Biginelli three-component condensation mediated by 20%PMo₇W₅/kaolin was depicted in Scheme 4. The first step involves nucleophilic attack of urea (3) on the electron deficient carbon of aldehyde (1). Here, electrophilicity of carbonyl group of aldehyde increased due to Brönsted and Lewis acidic nature of 20% PMo₇W₅/kaolin, which leads to formation of N-acyliminium ion intermediate (a). Interception of this iminium ion intermediate by activated 1,3-dicarbonyl compound (2) produces an open-chain ureide (b) which subsequently undergoes cyclization and dehydration to afford the corresponding dihydropyrimidinones.

Scheme 4 Proposed mechanism for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones.

4. Conclusion

In conclusion, we have successfully synthesis a series of tungsten-substituted molybdophosphoric acid (H₃PMo₇W₅O₄₀·24H₂O) catalyst impregnated with acidified kaolin clay. The catalytic activity of PMo₇W₅/kaolin was probed through one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones via Biginelli reaction. The 20% PMo₇W₅/kaolin showed higher catalytic activity than the bulk PMo₇W₅ catalyst, as well as the 10% and 15% PMo₇W₅/kaolin. The effects of various parameters such as catalyst loading, amount of catalyst, effect of solvents, influence of temperature on the rate of reaction, comparison of different catalyst was discussed in detail. The 20% PMo₇W₅/kaolin catalyst shows very high conversion rates in short reaction times. This catalyst was recovered easily from reaction mixture and reused at least six times without significant loss of its catalytic activity. Therefore, the newly synthesised 20% PMo₇W₅/kaolin could be used as a promising heterogeneous catalyst for a wide range of multifunctional applications.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The author DSA is gratefully acknowledges the University Grant Commission (UGC), New Delhi (India) for senior research fellowship (SRF). SGS is thankful to Dr Babasaheb Ambedkar Marathwada University, Aurangabad (MS), India (STAT/VI/RG/DEPT/2019-20/337-38) and UGC-DST SAP for financial assistance. We are also thankful to Department of Chemistry, Dr Babasaheb Ambedkar Marathwada University, Aurangabad (MS), India for providing laboratory facility.

Notes and references

1. H. R. Gurav, K. Y. Nandiwale and V. V. Bokade, J. Phys. Org. Chem., 2014, 27, 121–127.
2. R. Chen, J. Xin, D. Yan, H. Dong, X. Lu and S. Zhang, ChemSusChem, 2019, 12, 2715–2724.
3. J. L. Horan, A. Genupur, H. Ren, B. J. Sikora, M.-C. Kuo, F. Meng, S. F. Dec, G. M. Haugen, M. A. Yandrasits, S. J. Hamrock, M. H. Frey and A. M. Herring, ChemSusChem, 2009, 2, 226–229.
4. J. Li, X. Wang, W. Zhu and F. Cao, ChemSusChem, 2009, 2, 177–183.
5. N. L. Mulik, P. S. Niphadkar, K. V. Pandhare and V. V. Bokade, ChemistrySelect, 2018, 3, 832–836.
6. R. Chaudhary and M. Datta, J. Anal. Sci., Methods Instrum., 2013, 03, 193–201.
7. M. M. Heravi, M. Mirzaei, S. Y. S. Beheshtiha, V. Zadsirjan, F. Mashayekh Ameli and M. Bazargan, Appl. Organomet. Chem., 2018, 32, 1–10.
8. E. G. Zhizhina, Y. A. Rodikova, O. Y. Podyacheva and Z. P. Pai, Z. Anorg. Allg. Chem., 2018, 644, 869–876.
9. N. C. Coronel, M. J. da Silva, S. O. Ferreira, R. C. da Silva and R. Natalino, ChemistrySelect, 2019, 4, 302–310.
10. W.-S. Che, H.-H. Gai, W.-B. Hao and R.-H. Ma, Synth. React. Inorg., Met.-Org., Synth. React. Inorg., Met.-Org., Nano-Met. Chem., 2014, 44, 649–655.
11. S. Bencedira, O. Bechiri, M. Djenouhat and M. Boulkra, Arabian J. Sci. Eng., 2020, 45, 4669–4681.
12. S. Tang, W. Wu, Z. Fu, S. Zou, Y. Liu, H. Zhao, S. R. Kirk and D. Yin, ChemCatChem, 2015, 7, 2637–2645.
13. C. L. Hill and C. M. Prosser-McCartha, Coord. Chem. Rev., 1995, 143, 407–455.
14. J. Xu, R. W. Gable and C. Ritchie, Acta Crystallogr., 2018, 74, 1384–1389.
15. M. Chamack, A. R. Mahjoub and H. Aghayan, Chem. Eng. J., 2014, 255, 686–694.
16. H. Fakhri, A. R. Mahjoub and H. Aghayan, J. Radioanal. Nucl. Chem., 2019, 321, 449–461.
17. H. Aghayan, A. R. Khanchi, T. Yousefi and H. Ghasemi, J. Nucl. Mater., 2017, 496, 207–214.
18. H. Wu, M. Zhou, Y. Qu, H. Li and H. Yin, Chin. J. Chem. Eng., 2009, 17, 200–206.
19. I. V. Kozhevnikov, Chem. Rev., 1998, 98, 171–198.
20. A. D. Newman, D. R. Brown, P. Siril, A. F. Lee and K. Wilson, Phys. Chem. Chem. Phys., 2006, 8, 2893.
21. L. H. O. Pires, A. N. de Oliveira, N. Alex Jr, R. S. Angelica, C. E. F. da Costa, J. R. Zamian, L. A. S. do Nascimento and G. N. R. Filho, Appl. Catal., B, 2014, 160–161, 122–128.
22. T. Suppan, M. K. Kunjunni, A. Barik and R. R. Bhattacharjee, ChemistrySelect, 2018, 3, 1275–1281.
23. L. Muraleedharan, Bellundagere, M. Chandrashekara, Bangalore, S. J. Prakash, Yajnavalkya and S. Bhat, ChemistrySelect, 2018, 3, 801–808.
24. A. E. R. S. Khder, H. M. A. Hassan and M. S. El-Shall, Appl. Catal., A, 2012, 411–412, 77–86.
25. D. S. Park, B. K. Kwak, N. D. Kim, J. R. Park, J. H. Cho, S. Oh and J. Yi, ChemCatChem, 2012, 4, 836–843.
26. A. G. Olaremu, J. Miner. Mater. Charact. Eng., 2015, 03, 353–361.
27. S. Yahaya, S. S. Jikan, N. A. Badarulzaman and A. D. Adamu, Path Sci., 2017, 3, 1001–1004.
28. S. Attique, M. Batool, M. I. Jalees, K. Shehzad, U. Farooq, Z. Khan, F. Ashraf and A. T. Shah, Turk. J. Chem., 2018, 42, 684–693.
29. J. P. Nguetnkam, R. Kamga, F. Villiéras, G. E. Ekodeck, A. Razafitianamaharavo and J. Yvon, J. Colloid Interface Sci., 2005, 289, 104–115.
30. S. K. Kundu, J. Mondal and A. Bhaumik, Dalton Trans., 2013, 42, 10515–10524.
31. L. Chen, B. Nohair, D. Zhao and S. Kaliaguine, ChemCatChem, 2018, 10, 1918–1925.
32. K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A. Hedberg and B. C. O'Reilly, J. Med. Chem., 1991, 34, 806–811.
33. J. Azizian, M. K. Mohammadi, O. Firuzi, B. Mirza and R. Miri, Chem. Biol. Drug Des., 2010, 75, 375–380.
34. A. T. Khan, M. Lal, S. Ali and M. M. Khan, Tetrahedron Lett., 2011, 52, 5327–5332.
35. C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043–1052.
36. X. Chen and Y. Peng, Catal. Lett., 2008, 122, 310–313.
37. S. L. Jain, J. K. Joseph and B. Sain, Catal. Lett., 2007, 115, 52–55.
38. C. Ramalingan, S. J. Park, I. S. Lee and Y. W. Kwak, Tetrahedron, 2010, 66, 2987–2994.
39. F. Tamaddon, Z. Razmi and A. A. Jafari, Tetrahedron Lett., 2010, 51, 1187–1189.
40. D. S. Aher, K. R. Khillare, L. D. Chavan and S. G. Shankarwar, ChemistrySelect, 2020, 5, 7320–7331.
41. O. D. S. Lacerda, R. M. Cavalcanti, T. M. de Matos, R. S. Angélica, G. N. da Rocha Filho and I. D. C. L. Barros, Fuel, 2013, 108, 604–611.
42. L. V. Chopda and P. N. Dave, ChemistrySelect, 2020, 5, 2395–2400.
43. D. S. Aher, K. R. Khillare, L. D. Chavan and S. G. Shankarwar, ChemistrySelect, 2020, 5, 7320–7331.
44. L. Rozic, B. Grbic, S. Petrovic, N. Radic, L. Damjanovic and Z. Vukovic, Mater. Chem. Phys., 2015, 167, 42–48.
45. A. B. Gawade, M. S. Tiwari and G. D. Yadav, ACS Sustainable Chem. Eng., 2016, 4, 4113–4123.
46. V. V. Bokade and G. D. Yadav, Appl. Clay Sci., 2011, 53, 263–271.
47. G. Yadav, J. Catal., 2003, 217, 88–99.
48. Z. Xie, H. Wu, Q. Wu and L. Ai, RSC Adv., 2018, 8, 13984–13988.
49. H. Cai, X. Wu, Q. Wu and W. Yan, Dalton Trans., 2016, 45, 14238–14242.
50. D. L. Da Silva, S. A. Fernandes, A. A. Sabino and A. De Fa, Tetrahedron Lett., 2011, 52, 6328–6330.
51. R. Tayebee and M. Ghadamgahi, Arabian J. Chem., 2017, 10, S757–S764.
52. H. Khabazzadeh, E. T. Kermani and T. Jazinizadeh, Arabian J. Chem., 2012, 5, 485–488.
53. M. M. Heravi, F. Derikvand and F. F. Bamoharram, J. Mol. Catal. A: Chem., 2005, 242, 173–175.
54. Y. Zhang, B. Wang, X. Zhang, J. Huang and C. Liu, Molecules, 2015, 20, 3811–3820.
55. F. Zamani and E. Izadi, Catal. Commun., 2013, 42, 104–108.
56. J. Safaei Ghomi, R. Teymuri and A. Ziarati, Monatsh. Chem., 2013, 144, 1865–1870.
57. R. J. Kalbasi, A. R. Massah and B. Daneshvarnejad, Appl. Clay Sci., 2012, 55, 1–9.
58. J. Mondal, T. Sen and A. Bhaumik, Dalton Trans., 2012, 41, 6173.
59. Z.-J. Quan, Y.-X. Da, Z. Zhang and X.-C. Wang, Catal. Commun., 2009, 10, 1146–1148.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra09811f

---