Mo@GAA-Fe3O4 MNPs: a highly efficient and environmentally friendly heterogeneous magnetic nanocatalyst for the synthesis of polyhydroquinoline derivatives

Polyhydroquinolines were efficiently obtained from a sequential four-component reaction between dimedone or 1,3-cyclohexandione, ethyl acetoacetate, or methyl acetoacetate as a β-ketoester, aldehydes, and ammonium acetate, under the catalysis of Mo@GAA-Fe3O4 MNPs as a green, effective, recyclable, and environmentally friendly nanocatalyst. Due to its magnetic nature the prepared catalyst can be easily separated from the reaction mixture by an external magnet and reused several times without significant changes in catalytic activity and reaction efficiency. The catalyst was characterized using energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM).


Introduction
In recent decades, the preparation of environmentally friendly catalysts with recoverability and reusability are the main challenges amongst researchers in organic chemistry. Chemical reactions can be accelerated in the presence of homogeneous or heterogeneous catalysts, each of which has its advantages and disadvantages. Homogeneous catalysts, due to the greater interaction with the substrates compared to their heterogeneous counterparts, can generate a uniform layer with the starting materials in the organic solvent of the reaction which increases their activity and selectivity during the corresponding reaction. [1][2][3][4][5][6] However, the main problem when using these catalysts is related to the difficulty in separating and reusing them, which can be largely solved by using heterogeneous types. Heterogeneous catalysts, despite their lower efficiency, can exhibit suitable recyclability by centrifugation or ltration and can be reused several times without a signicant decrease in their catalytic behavior. Functionalization of the heterogeneous supports via a strong connection with homogeneous catalysts increase their efficiency while maintaining their simplicity in recovery and separation. 7 Nanocatalysts exhibit high catalytic activity, which is provided by their large surface area, and this signicantly increases the contact between reactants and catalyst. 8,9 Nowadays, remarkable attention has been paid to the use of magnetic nanoparticles (MNPs), as a bridge between homogeneous and heterogeneous catalysts, by scientic and industrial researchers because of their potential importance in modern chemical research. 10 Some excellent physical and chemical features of MNPs such as separation by an external magnet, superparamagnetism, high surface area, and strong adsorption ability 11 have expanded their utilization in the removal of heavy metal ions in wastewater, [12][13][14] catalysis, 15 and drug delivery. 16 However, some of the MNPs features such as a tendency to oxidize and accumulate during reactions, high initial chemical activity, and high surface area to volume ratio will reduce their catalytic activity and magnetic nature during the reaction period. 17,18 Thus, to overcome this drawback and increase their chemical stability for the special application, functionalization and modication of their surface with organic or inorganic supports are necessary.
Molybdenum as a d-block transition metal has various oxidation states from -I to +VI and it has a signicant role in the life evolution. Despite the little amount of molybdenum on the earth's crust, it could be known as an oxotransferases for the active places and cofactors of several enzymes that catalyzes the oxygen and electron transfer reactions on the layers of nitrogen, carbon, and sulfur. 19,20 Mo(VI) is one of the main oxidation states that obtains a formal double bond between the metal and the oxo ligand via the donating s and p bonds. There is a wide range of reports on the fabricated complexes using dioxomolybdenum(VI) obtained from varying the type and denticity of the remaining anionic ligands. [21][22][23][24] Among those, MoO 2 (acac) 2 is one of the most famous and major dioxomolybdenum(VI) complexes used as a catalyst for the organic transformations including epoxidation of alkenes and the oxidation of suldes. 25,26 Also, the coordination of molybdenum complexes by the organic groups (including oxygen, nitrogen, and sulfur) stabilized on the surfaces of magnetic nanoparticles has been used in many catalytic systems. [27][28][29][30] Multicomponent reactions (MCRs), as a versatile synthetic strategy, combine at least three or more reactants 31-34 via a single synthetic operation to generate several covalent bonds into structurally complex organic molecules containing most atoms of the available starting materials. 35 Currently, MCRs are taken into consideration in the sustainable synthetic strategies, via which we can easily generate high compatibility with green chemistry due to their unique advantages, such as concomitant step economy, mild conditions, atom economy, and high convergence. Over the past decades and due to their various important applications in combinatorial chemistry, 36 agrochemistry, 37 medicinal chemistry, 38-40 polymer chemistry, 31 and natural product synthesis, 41 MCRs have received considerable attention among organic chemists.
1,4-Dihydropyridine (1,4-DHP) core as an important class of nitrogen-containing heterocycles found in the nature have attracted considerable synthetic efforts over the past decade because of their diversity of biological functions, including antitubercular, 42 neuroprotectant, 43 antimicrobial, 44 insecticidal, 45 antiviral, 46 antihypertension, 47 anticancer, 48 and antioxidant 49,50 activities. Amongst them, polyhydroquinoline derivatives are very interesting heterocyclic molecules due to their pharmacological properties such as anti-inammatory, antimalarial, antibacterial, anti-asthmatic, and tyrosine kinase inhibiting agents. [51][52][53] Many procedures have been developed for the preparation of polyhydroquinolines using catalysts such as ionic liquids, 54 microwaves, 55 reuxing at high temperature, 56 metal triates, 57 ceric ammonium nitrate (CAN), 58 77 Although most of these procedures offer distinct merits, some of these procedures suffer from one or more limitations, such as generating a large amount of waste, low yields of the desired product, poor recovery of the catalyst, long reaction times, and hard reaction conditions. Therefore, to avoid these limitation based on the green chemistry protocols, the discovery of simple, efficient, versatile, and environmentally friendly processes for the synthesis of polyhydroquinolines is still favored.

Experimental
All of the chemical substances used in this work were purchased from Merck, Aldrich, and Fluka Chemical Companies and used without further purication. Melting points of the products were determined with an Electrothermal 9100 apparatus.
Energy-dispersive X-ray spectroscopy (EDX) was carried out on a FE-SEM (MIRA III, Detector of SAMX, France). Powder X-ray diffraction (XRD) was performed using Cu-Ka radiation (l ¼ 1.54Å) on a Philips-PW1730 in the 2q range of 10 -80 . Thermogravimetric analyses (TGA) were performed using a Linseis SATPT 100 thermoanalyzer at a heating rate of 10 C min À1 under nitrogen atmosphere over a temperature range of 25-700 C. The Fourier-transform infrared (FT-IR) spectra were recorded on a Perkin Elmer PXI spectrum, using pellets of the materials diluted with KBr in the range of 400-4000 cm À1 . The magnetic features of the catalyst were determined using a vibrating sample magnetometer (VSM; MDK Co. Kashan, Iran) in the magnetic eld range of À15 000 Oe to 15 000 Oe at room temperature. Scanning electron microscopy (SEM) images were recorded using an SEM-LEO 1430VP analyzer. Transmission electron microscopy (TEM) was utilized on a Zeiss-EM 900 instrument.

Synthesis of Fe 3 O 4 nanoparticles (MNPs)
In the rst step, a solution of FeCl 2 $4H 2 O (0.86 g) and FeCl 3 -$6H 2 O (2.36 g) were dissolved in deionized water (40 mL). The mixture was heated to 90 C, and mechanical stirring was done for 30 min under an argon atmosphere. Then, 10 mL of ammonia solution (25%) was added dropwise to the resulting mixture and stirred for another 20 min under argon ow. The precipitates were washed with distilled water and collected using a magnet. The product was dried under vacuum conditions.

Synthesis of Fe 3 O 4 @SiO 2 (SCMNPs)
In a typical method, 1.0 g of obtained Fe 3 O 4 nanoparticles was dispersed in a mixture of 60 mL ethanol, 20 mL deionized water, and 2 mL ammonia solution (25%) by sonication for 10 min. Then, 0.45 mL of tetraethylorthosilicate (TEOS) was added into the reaction system, sonicated for another 10 min, and stirred at ambient temperature for 14 h. The resultant precipitate was magnetically collected by a permanent magnetic eld, washed three times with a mixture of ethanol and water (1 : 1), and dried in a vacuum oven.

Functionalization of SCMNPs by 3aminopropyltriethoxysilane (Amp@SCMNPs)
1 g of core-shell Fe 3 O 4 @SiO 2 nanoparticles was suspended in 20 mL of dry toluene by ultrasonication. Aer treatment for 20 min, 2 mL of 3-aminopropyltriethoxysilane (Amp) was added to the solution and reuxed under an argon atmosphere. Aer 24 h, the Amp@SCMNPs were collected using a permanent magnet, washed with ethanol and distilled water several times, and then dried under vacuum.

Functionalization of Amp@SCMNPs by glutaraldehyde (imine@SCMNPs)
2 g of prepared Amp@SCMNPs nanoparticles was added to 100 mL ethanol and dispersed for 30 min under ultrasonic irradiation. Then, 4 mmol of glutaraldehyde was added into the reaction solution and reuxed for 24 h. The prepared solid product (imine@SCMNPs) was then magnetically isolated and washed several times with ethanol to remove unreacted glutaraldehyde; nally, it was dried under vacuum.

Synthesis of GAA/imine@SCMNPs
1 g of the obtained imine@SCMNPs was dispersed in 25 mL DMF by the ultrasonic bath for 30 min. Then, 0.85 mmol of guanidineacetic acid (GAA) was added to the reaction solution. Aer the stirrer process for 8 h, the resulting substance was separated by a permanent magnet, rinsed with ethanol several times, and dried under vacuum.

Synthesis of Mo@GAA-Fe 3 O 4 MNPs
MoO 2 (acac) 2 was prepared using the literature method. 78 2 g of GAA/imine@SCMNPs were added into 150 mL ethanol and a solution of MoO 2 (acac) 2 (4 mmol) in 70 mL ethanol was added to this reaction solution and reuxed for 12 h. Aer magnetic separation, the resulting solid product was washed with dichloromethane to remove the unreacted MoO 2 (acac) 2 and was dried under vacuum (Scheme 1).

General procedure for the preparation of polyhydroquinolines
Firstly, Mo@GAA-Fe 3 O 4 MNPs (10 mg) was poured into the reaction mixture of dimedone or 1,3-cyclohexandione (1 mmol), ethyl acetoacetate, or methyl acetoacetate (1 mmol), aldehydes (1 mmol), and ammonium acetate (1.2 mmol), and the reaction mixture was heated for a specic time. Upon completion of the reaction, the catalyst was easily extracted using an external magnetic eld; the resulting product was collected by ltration, rinsed, and recrystallized with ethanol to give pure polyhydroquinolines. stretching vibrations, which conrmed the successful covalent attachment of 3-aminopropyltriethoxysilane (Amp) to the SCMNPs surface. Also, vibrations at 796 and 853 cm À1 were probably attributed to the asymmetric stretching and in plane bending of Si-O-Si group, respectively. In about the imi-ne@SCMNPs, the peak at 1636 cm À1 is assigned to the    Fig. 2. All samples underwent a small weight loss below 200 C due to water thermodesorption from the surface (drying). Another weight loss up to 700 C was found in TGA curve of SCMNPs, which can be related to the release of hydroxyl ions from the nanoparticles and volatilization. In the TGA curves of GAA/imine@SCMNPs and Mo@GAA-Fe 3 O 4 MNPs, another weight loss can be seen up to 650 C, which can be attributed to the decomposition of the functionalized organic groups.

XRD analysis of Mo@GAA-Fe 3 O 4 MNPs
Identication of the crystalline materials using X-ray is one of the most common and important analysis techniques. As the Xray region is located between gamma and ultraviolet, useful data could be obtained from this spectral region including the crystalline structure, the material type, and the nanoparticle size. The XRD patterns for Fe 3    crystalline structure of the above-mentioned products. It is necessary to mention that the XRD pattern of recovered Mo@GAA-Fe 3 O 4 MNPs aer the rst recovery and reuse do not show any change in crystalline structure.

VSM analysis of Mo@GAA-Fe 3 O 4 MNPs
Magnetic properties and the behavior of the achieved nanoparticles are investigated by the VSM analysis. An external magnetic eld is applied to evaluate the magnetization ability of the magnetic nanoparticles. The VSM analysis of the synthesized (a) Fe 3 O 4 , (b) SCMNPs, and (c) Mo@GAA-Fe 3 O 4 MNPs were shown in Fig. 4. The saturation magnetization values (M s ) of magnetic materials revealed signicant differences, which are 50.63 and 47.16 emu g À1 for bare Fe 3 O 4 and SCMNPs, respectively, while for catalyst, the difference is 28.99 emu g À1 . As can be seen, the value of M s for the catalyst decreased, which can be attributed to the functionalization of the Fe 3 O 4 core by silica layers, organic molecules, and metal groups.

SEM analysis of Mo@GAA-Fe 3 O 4 MNPs
The obtained images from the SEM technique could be used to study the morphology, uniformity, and physical properties of nanoparticle surfaces. High magnications are obtained by this device to precisely investigate the material details. As shown in

TEM analysis of Mo@GAA-Fe 3 O 4 MNPs
In TEM analysis, a focused electron beam is used for obtaining the images. In this technique, some information from the inner structure could be obtained by transmitting a high-energy electron beam through a thin sample. Fig. 6 shows the TEM image of Mo@GAA-Fe 3 O 4 MNPs. TEM images indicate that the diameter of the obtained catalyst is about 28-35 nm and it has a nearly spherical morphology with a narrow particle size distribution.

EDX and elemental mapping analysis of Mo@GAA-Fe 3 O 4 MNPs
One of the main techniques to identify the elemental composition of the sample or a part of it is the EDX analysis. The EDX spectra of the GAA/imine@SCMNPs and Mo@GAA-Fe 3 O 4 MNPs is shown in Fig. 7a and b, respectively. In the case of GAA/ imine@SCMNPs, the presence of carbon, nitrogen, oxygen, iron, and silicon was conrmed (Fig. 7a). Also in Fig. 7b, the presence of the molybdenum element indicates coordination of Mo with nitrogen and oxygen electron pairs and thus the successful synthesis of the Mo@GAA-Fe 3 O 4 MNPs. In addition, Fig. 8 shows the elemental map of the Mo@GAA-Fe 3 O 4 MNPs nanocatalyst, which exhibits the presence of C, N, O, Fe, Si, and Mo elements.
The catalytic activity of the Mo@GAA-Fe 3 O 4 MNPs was surveyed in the preparation of polyhydroquinoline derivatives. Firstly, the condensation reaction of dimedone, ethyl acetoacetate, 4-chlorobenzaldehyde, and ammonium acetate in the presence of Mo@GAA-Fe 3 O 4 MNPs was chosen as a model reaction. To optimize the reaction conditions, the synthesis of polyhydroquinolines we studied under various reaction conditions, including solvent, temperature, and the amount of catalyst. To optimize the reaction solvent, H 2 O, EtOH, THF, CH 2 Cl 2 , CH 3 CN, toluene, cyclohexane, and solvent-free conditions were tested (Entries 1-8). The results are summarized in Table 1, showing that carrying out the reaction in the absence of solvent led to the formation of the desired product 5p in the highest yield (Entry 8). However, a good yield of the product was     8 and 10-12). These observations showed that carrying out the reaction in the absence of the catalyst gave any yield for the desired product (Entry 9). The reaction in presence of 5 mg of the catalyst provided a good yield of the product (Entry 10), while 10, 15, and 20 mg gave excellent-to-high yields of the corresponding product (Entries 8 and 11-12). It was found that using 10 mg of the Mo@GAA-Fe 3 O 4 MNPs is appropriate to carry out the reaction under solvent-free conditions with a 96% yield. Aerward, the inuence of temperature on the model reaction was investigated.
The reaction was carried out under different temperatures (25,40,60,80,90, and 100 C) (Entries 8 and [13][14][15][16][17], and the best result was achieved at 90 C under solvent-free conditions (Entry 8). Finally, when the model reaction was done in the existence of 10 mg of imine@SCMNPs, GAA/imine@SCMNPs MNPs by free electron pair of nitrogen with the molybdenum complex increased the catalytic activity. Utilizing the optimal reaction conditions, various polyhydroquinolines were prepared by the four-component reaction of dimedone, or 1,3-cyclohexandione, ethyl acetoacetate or methyl acetoacetate, a wide range of aldehydes, and ammonium acetate ( Table 2). Aromatic aldehydes with electron-donating or electron-withdrawing groups tolerate smooth transformation to the corresponding products without the formation of byproducts at better yields and in short reaction times. The reaction was also carried out with aliphatic aldehyde instead of aromatic aldehyde but did not afford the title products in considerable amounts (5y). Scheme 3 Proposed mechanism for the synthesis of polyhydroquinoline derivatives. Aer completion of the reaction as indicated by thin layer chromatography (TLC), the catalyst precipitate was easily ltered off from the product using an external magnetic eld, washed with water/ethanol (1 : 1) to eliminate the residual product, dried under the vacuum oven, and reused under the same experimental conditions. The recycled catalyst was reused with a negligible reduction in catalytic activity and the product yield for six runs (Fig. 9). The yields of the product 5p for each of the six runs were 96, 96, 95, 94, 94, and 93%, respectively.
To show the merits of the Mo@GAA-Fe 3 O 4 MNPs in comparison with previously reported catalysts in the literature for the synthesis of polyhydroquinoline derivatives, some of the results are tabulated in Table 3. As indicated in Table 3, the low catalyst loading of Mo@GAA-Fe 3 O 4 MNPs can develop a suitable methodology in terms of the reaction times and yields, green chemistry, and compatibility with the environment.

Conclusion
In summary, the Mo@GAA-Fe 3 O 4 MNPs were synthesized as an effective, recyclable, and environmentally friendly heterogeneous magnetic nanocatalyst that catalyzed the synthesis of biologically and pharmacologically interesting functionalized polyhydroquinoline derivatives under solvent-free conditions. The catalyst can be magnetically recovered from the reaction media by an external magnet and reused several times without any signicant changes in the reaction efficiency. Moreover, high yields of products, short reaction times, lower loading of the catalyst, clean procedure, easy work-up, and heterogeneous reaction conditions are several advantages of this straightforward and efficient strategy.

Conflicts of interest
There are no conicts to declare.