Fe3O4@SiO2@ADMPT/H6P2W18O62: a novel Wells–Dawson heteropolyacid-based magnetic inorganic–organic nanohybrid material as potent Lewis acid catalyst for the efficient synthesis of 1,4-dihydopyridines

ABSTRACT A novel Wells–Dawson heteropolyacid-based magnetic Inorganic–organic nanohybrid, Fe3O4@SiO2@ADMPT/H6P2W18O62, was fabricated and used as a green, efficient, eco-friendly, and highly recyclable catalyst for the one-pot and multi-component synthesis of 1,4-Dihydopyridine (1,4-DHP) derivatives from the reaction of various aromatic aldehydes with ethyl acetoacetate and ammonium acetate with good to excellent yields and in a short span of time. The nanohybrid catalyst was prepared by the chemical anchoring of Wells–Dawson heteropolyacid H6P2W18O62 onto the surface of functionalized Fe3O4 nanoparticles with 2,4-bis(3,5-dimethylpyrazol)-triazine (ADMPT) linker. These nanocatalysts were identified by using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), infrared spectroscopy (IR) and vibrating sample magnetometer (VSM). This protocol is developed as a safe, cost-effective and convenient alternate method for the synthesis of 1,4-DHP derivatives utilizing an eco-friendly, and a highly reusable catalyst. GRAPHICAL ABSTRACT


Introduction
Nitrogen-containing heterocycles often play important roles as the scaffolds of biological compounds. Among them, the pyridine infrastructure is one of the most common heterocycles found in functional products, pharmaceuticals, and natural materials (1,2). In particular, 1 ,4 -Dihydopyridines (1 ,4 -DHPs) have attracted much attention because they include a great family of medicinally active compositions with various therapeutic and pharmacological properties such as MDR reversal (3), vasodilation (4), HIV protease inhibition (5), radioprotection (6), bronchodilator, antitumor, and also hepatoprotective activities (7). Moreover, recent studies have shown that these compounds have various medicinal applications such as neuroprotectants, compounds with platelet antiaggregatory, cerebral anti-ischemic agents, and chemosensitizers (8). Due to their wide range of pharmacological activity and applications, a number of methods have been reported for their synthesis. More than a century ago the first 1,4-DHPs were obtained by Hantzsch multi-component reaction (9). The classical Hantzsch method includes the one-pot condensation of various aldehydes with ethyl acetoacetate and ammonia either in acetic acid at room temperature or by refluxing in alcohols for a long time (10). This method suffers from harsh reaction conditions, long reaction times, and very low yields of products.
Therefore, several modified methods have been developed for the synthesis of dihydropyridine derivatives by using conventional heating (11), ionic liquid (12), HY-Zeolite (13), molecular iodine (14), polymers (15), cerium(IV) ammonium nitrate (16), metal triflates (17), and silica perchloric acid (18). L-proline and derivatives (19), montmorillonite K-10 (20), Ni nanoparticles (21), P-TSA (22), and ultrasound and microwave irradiation (23). Although many of these methods have considerable advantages, some of these methods suffer from the limited scope, such as the use of high temperatures, long reaction times, drastic reaction conditions, environmentally harmful catalysts, difficult work-up procedures, expensive metal precursors, unsatisfactory yields, and a large amount of volatile organic solvents. Moreover, the main disadvantage of most used procedures is that the use of catalyst was destroyed in the work-up process and cannot be reused or recovered.
Nanoparticles have coordination sites and high surface-to-volume ratio, in comparison with other bulk analogs, which provide many of active sites per unit area (24). Among the different magnetic nanoparticles, Fe 3 O 4 nanoparticles have recently emerged as good supports for the immobilization of core-shell metal nanoparticles and they are certainly the most extensively studied. Due to the potential applications of magnetic Fe 3 O 4 nanoparticles (Fe 3 O 4 MNPs) in catalysis and biomedicine, they have attracted much attention as a significant family of separation materials in chemistry and material sciences (25). The properties of Fe 3 O 4 nanoparticles such as paramagnetic and insoluble, enable the catalyst to be simply separated from the reaction medium by an external permanent magnet. In general, in order to prepare a suitable surface for the modification of magnetic nanoparticles and also to avoid direct contact between them, a coating of the surface with silica shell is necessary. A silica surface can be functionalized with diverse organic groups for desirable aims such as applications as an adsorbent, enzyme immobilization, and catalysis support (26). Due to the considerable properties of Fe 3 O 4 MNPs like greater selectivity, operational simplicity, noncorrosive nature, environmentally benign, moisture insensitive, and ease of isolation, they are used as an efficient catalyst in many organic reactions.
Heteropoly compounds are useful and versatile in organic transformations because of their super acidic and redox properties (27). Among them, heteropolyacids (HPAs) are more active catalysts than conventional mineral acids. The use of HPAs as catalysts is an area of interest in catalysis, which has been studied recently. In addition to the problems related to the environmental and potential hazards of mineral acids and their handling and disposal, the chemist's attention has been attracted to the development of alternative processes using solid acid catalysts (28). Because the HPAs have many advantages in comparison to conventional inorganic acids and are environmentally and economically attractive in both industrial and academic settings, these compounds provide green alternatives to homogeneous catalysts in the industrial manufacture of chemicals and in organic reactions (29). They also have many advantages over homogeneous liquid acid catalysts: higher thermal stabilities and acid strengths; they are cheap, noncorrosive, reusable, and environmentally benign and need less waste disposal (30). The major disadvantages of HPAs such as high solubility in aqueous solution, low surface area, and continuous leakage during operation limit the scope of their practical applications. To overcome these limitations, heterogenization of the heteropolyacid through immobilization onto supports, with a high surface area, is recommended. Among the HPAs, the Wells-Dawson heteropolyacids (WD HPAs) have superacidity and a considerable stability both in solid and in the solution state (31). The structure of the WD HPAs (H 6 P 2 W 18 O 62 . 24H 2 O) including a close-packed structure of octahedral WO 6 surrounding a central P atom, two same "half units" PW 9 are linked through the oxygen atoms (32). Because of the distinctive features of the WD HPAs, such as higher reactivity and greater selectivity in acid catalyzed reactions, they had been the target of many research groups during the last years (33)(34)(35).
As part of our current studies on the development of efficient methods for the preparation of biologically active compounds (36)(37)(38)(39)(40)(41)(42)(43)(44), in this paper, Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 as a new inorganic-organic hybrid nanocatalyst was prepared, characterized, and used as an effective catalyst in the synthesis of 1,4-DHPs 4 via one-pot reaction of various aromatic aldehydes 1, ethyl acetoacetate 2, and ammonium acetate 3 with good to high yield in ethanol (Scheme 1). To the best of our knowledge, there are no examples of the use of WD HPAs as the catalyst for the synthesis of 1,4-DHP derivatives.

Materials and instrumentation
All starting materials and reagents were obtained from commercial sources and were used without further purification. All solvents were dried and distilled under a nitrogen atmosphere, within standard methods. The progress of the reactions was monitored by thin-layer chromatography (TLC) on silica gel 60 F 254 plates. Fourier transform infrared (FT-IR) spectra from 250 to 4000 cm −1 were registered using a Perkin-Elmer 781 FT-IR spectrometer, using KBr pellets. NMR spectra were determined on a Bruker DRX-400-Advance and Bruker DRX-300-Advance instrument using DMSO-d 6 or CDCl 3 as the solvent with TMS as the internal standard. The morphology and size of the nanostructures was observed on an XL-30 scanning electron microscope (SEM) (Philips, Netherlands) and on an EM 10C Transmission Electron Microscope (TEM). X-ray powder diffraction analysis (XRD) measurements were obtained on a STADI P diffractometer (STOE, Germany) using Cu K α radiation with a scanning rate of 3°min −1 in the 2θ range between 10°and 80°. Melting points were measured by using the capillary tube method with a Yanagimoto micro melting point apparatus. Magnetic susceptibility measurements were carried out using a vibrating sample magnetometer (VSM, Meghnatis Daghigh Kavir Company, Iran) in the magnetic field at room temperature. The preparation and characterization of the heteropolyacid catalyst H 6 P 2 W 18 O 62 , was performed following the previously reported procedures (45).

Synthesis of Fe 3 O 4 and Fe 3 O 4 @SiO 2
Fe 3 O 4 magnetic nanoparticles were prepared according to a previous report (48). Briefly, FeCl 3 .6H 2 O (10.4 g) and FeCl 2 .4H 2 O (4.0 g) were dissolved in 100 mL of deionized water, degassed with nitrogen gas for 15 min, and heated to 80°C. Then, 15 mL of NH 3 (32% solution) was added dropwise to the solution. After 15 min, the solid was separated by a magnet and washed three times with water, acetone and dichloromethane.
The interlayers of SiO 2 were prepared through a modified Stober method (49). 1.5 g Fe 3 O 4 particles were dispersed in a mixture of deionized water (30 mL), ethanol (120 mL) and concentrated ammonia aqueous solution (25 wt%, 3.8 ml) by ultrasonication for 15 min. Then, 5 mL of tetraethyl orthosilicate (TEOS) was added dropwise. After stirring for 12 h, the products were collected and washed by deionized water and methanol to eliminate excess reactants and then collected by an external magnet. Finally, the Fe 3 O 4 @SiO 2 particles were dried at room temperature for 24 h.

Functionalizing of silica-coated magnetite nanoparticles Fe 3 O 4 @SiO 2 with ADMPT (Fe 3 O 4 @SiO 2 @ADMPT)
For the synthesis of triazine-functionalized Fe 3 O 4 @SiO 2 , in the first step, 0.50 g of the Fe 3 O 4 @SiO 2 was suspended in dry toluene (50 ml). Then, 1.46 g of ADMPT was added and refluxed for 48 h. After this time, the dark solid was removed from the solvent by a strong magnet, washed with deionized water and ethanol, and subsequently dried at room temperature. FT-IR spectroscopy showed ADMPT anchored onto Fe 3 O 4 @SiO 2 . A schematic diagram for the synthesis of Fe 3 O 4 @SiO 2 @ADMPT is shown in Scheme 2.

Immobilization of Wells-Dawson heteropolyacid on Fe 3 O 4 @SiO 2 @ADMPT (Fe 3 O 4 @SiO 2 @ADMPT/ HPA)
For the immobilization of H 6 P 2 W 18 O 62 on Fe 3 O 4 @SiO 2 @ADMPT, 1.0 g of Fe 3 O 4 @SiO 2 @ADMPT was added to the suspension of 0.6 g of H 6 P 2 W 18 O 62 in methanol (50 ml) and the reaction mixture was refluxed for 4 h. Then, the heterogeneous catalyst was separated by an external magnetic field and extracted by using methanol as a solvent in a Soxhlet extractor. After overnight, catalyst was dried at room temperature. A schematic for the preparation of Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 nanocatalyst is shown in Scheme 3. In first step, the scheme shows grafting of ADMPT onto Fe 3 O 4 @SiO 2 via condensation of ethoxy and hydroxyl groups of the linker and support, respectively; then, the H 6 P 2 W 18 O 62 was anchored to Fe 3 O 4 @SiO 2 @ADMPT through electrostatic interaction in the second step.
General procedure for the synthesis of 1,4-DHPs by using Fe 3  ( Table 3). After completion of the reaction confirmed by TLC (eluent: n-hexane/EtOAc; 8:2), solid catalyst was separated by an external magnet and the solution was cooled to room temperature and extracted with 15 ml water and dichloromethane (3 × 10 mL) and dried with anhydrous Na 2 SO 4 , then the products were purified by recrystallized from ethanol, gave the pure products in 87-98% yields based on the starting aldehyde. The products were characterized by IR, 1 H NMR and via comparison of their melting points with the previous reported.  (50). The absorption bands around 950-998 and 1070-1100 cm −1 are related to W = O and P-O bonds, respectively. The vibration bands at 912 and 776 cm −1 were assigned to the "inter" and "intra" W-O-W bridges, respectively ( Figure 1).

Results and discussion
ADMPT was used to modify the Fe 3 O 4 @SiO 2 nanoparticles in refluxing toluene. The triazine-functionalized magnetic nanoparticles have been synthesized by direct reaction of the surface hydroxyl groups of Fe 3 O 4 @SiO 2 and the ethoxy groups of ADMPT. A schematic diagram for this synthesis route is illustrated in Scheme 2. Figure 2 shows the FT-IR spectrums of Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 in comparison with Fe 3 O 4 , Fe 3 O 4 @SiO 2 and Fe 3 O 4 @SiO 2 @ADMPT. Fe 3 O 4 nanoparticles were synthesized according to the co-precipitation method, and their formation was confirmed by IR spectroscopy (Figure 2). The strong and broad band that observed at 569 cm −1 is ascribed

X-ray diffraction study
The crystalline structures of the Fe 3 O 4 nanoparticles and magnetic hybrids were determined by powder Xray diffraction (XRD). As it can be seen in Figure 3, the patterns show peaks at 2θ = 30.06, 35.45, 43.2, 53.54, 57.16, 62.72, and 73.99, which correspond to d220, d311, d400, d422, d511, d440, and d533, respectively, and confirms that the Fe 3 O 4 structure has remained intact after functionalization by ADMPT and Immobilization of Wells-Dawson heteropolyacid on Fe 3 O 4 @SiO 2 @ADMPT did not decompose or convert to Fe 2 O 3 . Furthermore, the broad peaks in XRD pattern show that the Fe 3 O 4 particles are nanosize. The diameter of magnetite nanoparticles was also determined from X-ray line broadening using the Scherrer formula (D = 0.9λ/βcosθ, where D is the average crystalline size, λ is the X-ray wavelength used, β is the angular line width at half maximum intensity, and θ is the Bragg's angle). For the (311) reflection the average crystalline size of the Fe 3 O 4 NPs was obtained to be around 13 nm.

VSM analysis
The magnetic properties of the hybrids consisting a magnetite component were demonstrated using a VSM. Figure 4 shows the magnetic hysteresis loops of the

SEM and TEM study
The size and morphology details of the nanocatalyst were achieved by SEM measurement (Figure 5) Figure 6 and indicates that the Fe 3 O 4 @SiO 2 composites made as supports for the catalyst had a regular coreshell structures and good spherical morphologies.

Investigation of the catalyst activity
In this work, we have synthesized 1,4-DHPs 4 via one-pot, the three-component reaction of aromatic aldehydes 1, ethyl acetoacetate 2, and ammonium acetate 3 in the presence of catalytic amounts of the Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 nanocatalyst in ethanol at 70°C.

Effect of catalyst concentration on the catalytic efficiency
At the outset of our work, to optimize the reaction conditions, a model reaction was carried out by starting from benzaldehyde 1a (1 mmol 1, entry 2). Therefore, 20 mg of catalyst was found to be the optimal amount and sufficient to produce the best yield of products. As can be seen from Table 1, by decreasing and increasing the amount of nanocatalyst, the yield of the product was not improved (entry 1, 3, and 4, respectively).    (5 mg), produced 92% yield of product after a short time of 35 min (entry 2). The triazine-functionalized Fe 3 O 4 @SiO 2 , Fe 3 O 4 @SiO 2 @ADMPT, and Fe 3 O 4 @SiO 2 were also catalytically active; the results showed that the Fe 3 O 4 @SiO 2 @ADMPT led to 33% of product after 420 min and the Fe 3 O 4 @SiO 2 produced 21% of product after 600 min (entries 6 and 7, respectively). Although the components of the nanohybrid showed trace catalytic activity, Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 gave the best yield in the desired organic synthesis (entry 2). Clearly, grafting the heteropolyacid onto the modified solid material Fe 3 O 4 @SiO 2 @ADMPT drastically increased its catalytic activity toward the organic reaction.

Effect of reaction media on the catalytic efficiency
For optimizing the reaction conditions, we examined the model reaction in the presence 20 mg of Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 as a nanomagnetic catalyst in various solvents at 70°C (Table 2). Solvents such as water, ethanol were screened in the desired reaction. As shown in Table 2, 1,4-DHP 4a was formed in all cases, but the highest yield for these product was achieved in ethanol (Entries 2 and 3). We prefer to use ethanol as a green solvent in these reactions.       To evaluate the generality of the present protocol for the synthesis of 1,4-DHPs 4, we investigated the reaction by using a wide range of diverse aromatic aldehydes carrying either electron-donating, electron-withdrawing, and halogen groups on their aromatic rings under optimized conditions and gave the corresponding products in best yields in short reaction times based on the Hantzsch procedure ( Table 3). As shown in Table 3, the nature of aromatic aldehyde has significant effect on these reaction; when the electron-withdrawing substituents are present in benzaldehyde, the reaction rate increases, whereas the effect is the reverse in the case of benzaldehyde with strong electron-donating substituents such as -OCH 3 and -OH, of course with lower yields. The structures of all the products were characterized by FT-IR and 1 H NMR spectral analysis and their melting points.

Reusability of the catalyst
From industrial point of view, the reusability of the catalyst is very important in the large scale synthetic processes. A major drawback of free heteropolyacid is the separation and recovery of the catalyst after completion the reaction. Heterogenization of the H 6 P 2 W 18 O 62 via anchoring to Fe 3 O 4 @SiO 2 @ADMPT is an attractive strategy that allowing simple separation of the catalyst from the reaction mixture. Moreover, recyclability and reusability of the catalyst reduce amount of wastage and production of wasteful materials; both are important factors in green chemistry. To investigate the reusability of the Fe 3 O 4 @SiO 2 @ADMPT/H 6 P 2 W 18 O 62 nanocatalyst, after completion the reaction, it was easily separated from the products by an external magnet and washed thoroughly with chloroform to remove undesired materials, dried, and activated to reuse for another condensation reaction. As illustrated in Figure 8, it revealed nearly no loss of activity after five successive runs. The results showed that the catalyst could be a satisfactory catalyst for this reaction with good reusability and high activity.

Conclusion
This work has explained the preparation of functionalized magnetic nanomaterials by reacting 2,4-bis(3,5dimethylpyrazol)-triazine (ADMPT) modified silicacoated magnetite nanoparticles with Wells-Dawson diphosphooctadecatungstic acid (H 6 P 2 W 18 O 62 ·24H 2 O) and fabrication of a novel organicinorganic nanohybrid catalyst has been the target of this research. This catalytic system as a straightforward and efficient method was used in an environmentally friendly route to prepare a variety of 1,4-dihydropyridines from the reaction of different aryl aldehydes, ethyl acetoacetate, and ammonium acetate. Compared with a homogenous catalyst, easy separation by magnet was a valuable advantage that means low costs in industrial applications. Magnetic recyclability, mild reaction conditions, and environmental friendliness may be its superior characteristics for green chemistry. Moreover, the advantages such as excellent product yields, shorter reaction times, simplicity of the reaction, the use of non-toxic and inexpensive materials, the easy procedures to carry out the reaction make this protocol as an attractive and useful methodology, among the other methods reported in the literature, for the synthesis of 1,4-DHPs.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
The authors are grateful to the University of Kashan for supporting this work by [Grant Number 573600/2].