Zr@IL-Fe3O4 MNPs as an efficient and green heterogeneous magnetic nanocatalyst for the one-pot three-component synthesis of highly substituted pyran derivatives under solvent-free conditions

The present study was conducted to synthesize Zr@IL-Fe3O4 MNPs as a new magnetically recoverable heterogeneous catalyst, which was then characterized by Fourier transform infrared (FT-IR) spectroscopy, energy dispersive X-ray spectroscopy (EDX), vibrating sample magnetometry (VSM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. The catalytic behavior of the Zr@IL-Fe3O4 MNPs was efficiently used for the synthesis of highly substituted pyran derivatives via a one-pot three-component condensation of 4-hydroxycoumarin/dimedone, malononitrile, and arylaldehydes under solvent-free conditions. This new methodology demonstrated some important features, including short reaction times, excellent yields, lower loading of the catalyst, easy work-up, and recyclability of the catalyst for a minimum of six times without any noticeable decrease in catalytic activity.


Introduction
Magnetite (Fe 3 O 4 ) core-shell nanocomposites are the most extensively surveyed magnetic nanoparticles (MNPs) and have been utilized for various applications, including medical diagnosis, color imaging, information storage, catalysis, and microwave absorption. [1][2][3][4][5] MNPs, as a signicant type of separable material, have recently attracted a great deal of interest among researchers for the synthesis of organic compounds and in materials science owing to their high surface area, high stability, and low toxicity. [6][7][8] The high chemical reactivity and large surface area to volume ratio of magnetic nanoparticles has made them highly sensitive to oxidation and accumulation, respectively. One of the basic ways to overcome these problems and also to achieve further functionalization is to coat the surface of MNPs with organic or inorganic supports. 9,10 Recently, efficient catalytic systems have been used as functionalized MNPs in several chemical developments. [11][12][13][14][15][16][17][18][19][20] With regard to the high value of the magnetic catalysts employed in organic transformations and the precious materials synthesized by them, the simple recovery of the catalysts because of their strong magnetic elds and the capability to reuse them several times with a negligible decrease in their magnetic nature are two salient features in catalytic processes. 21,22 Chromenes are interesting oxygen-containing heterocyclic molecules with a wide range of biological and pharmaceutical properties, such as antitubercular, 23 molluscicidal, 24 antifungal, 25 antiproliferative, and antitumor 26 activities. In addition, chromenes act as acetylcholinesterase inhibitors, 27 as antagonists against antiapoptotic Bcl-2 protein, 28 and as Src kinase inhibitors. 29 Moreover, some of these compounds, as cognitive enhancers, can be employed for the treatment of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. 30 Pyrano [3,2-c]coumarins are derivatives of chromenes, which have drawn attention of the scientic community over the last decades. The most important route for their preparation is the one-pot three-component condensation of 4-hydroxycoumarin with aldehyde and malononitrile in the presence of a catalyst. Several strategies for the construction of these types of coumarins have been reported under various conditions, such as H 6 44 Even though most of these methods offer distinct advantages, some of them have one or more limitations, such as low yields of the desired product, generation of a large amount of waste, long reaction times, poor recovery of the catalyst, and hard reaction conditions. Therefore, to avoid these limitations based on green chemistry protocols, the discovery of efficient, simple, versatile, and environmentally friendly processes for the preparation of highly substituted pyran derivatives is still favored.

Experimental
All the pure chemical substances were obtained from Merck, Fluka, and Aldrich, chemical companies. The melting points of the heterocyclic compounds were recorded on an Electrothermal-9100 apparatus. Fourier transform infrared (FT-IR) spectra were recorded on a PerkinElmer PXI spectrometer in the range of 400-4000 cm À1 on KBr wafers. Magnetic susceptibility measurements by vibrating sample magnetometry were taken on a VSM system (MDK Co. Kashan, Iran), in the magnetic eld range of À15 000-15 000 Oe at room temperature. X-ray diffraction (XRD) patterns of the samples were measured using a Philips-pw1730 system in the 2q range of 10 -80 with Cu-Ka radiation (l ¼ 1.54Å). Thermogravimetric analysis was recorded on a Linseis SATPT 100 thermoanalyzer under a N 2 atmosphere at a heating rate of 10 C min À1 over a temperature range of 25 C-650 C. Energy dispersive X-ray spectroscopy (EDX) of the as-prepared magnetic nanoparticles was performed on an FE-SEM (MIRA III, Detector from SAMX, France). Field emission electron microscopy (FESEM) images were obtained to survey the catalyst morphology utilizing an SEM-LEO 1430VP instrument. Transmission electron microscopy (TEM) images were recorded using a Zeiss-EM 900 instrument.
General procedure for synthesis of dihydropyrano [3,2-c] chromene derivatives A mixture of 4-hydroxycoumarin (1 mmol), malononitrile (1.2 mmol), aldehyde (1 mmol), and Zr@IL-Fe 3 O 4 MNPs (20 mg) was stirred and heated in an oil-bath under solvent-free conditions. At the end of the reaction, as monitored by TLC (eluent: EtOAc : nhexane), the catalyst was separated with an external magnetic eld and the residue solid was washed with distilled water and recrystallized via EtOH in order to obtain the pure product 4.
General procedure for synthesis of the 4H-benzo-[b]-pyran derivatives A combination of dimedone (1 mmol), malononitrile (1.2 mmol), aldehyde (1 mmol), and Zr@IL-Fe 3 O 4 MNPs (20 mg) was stirred and heated in an oil-bath under solvent-free conditions. At the end of the reaction, as monitored by TLC (eluent: EtOAc : n-hexane), the catalyst was separated using an external magnetic eld and the residue solid was washed with distilled water and recrystallized via EtOH to obtain the pure product 6.

Preparation of the Fe 3 O 4 MNPs
Primarily, a mixture containing 0.86 g FeCl 2 $4H 2 O and 2.36 g FeCl 3 $6H 2 O was added to the 40 mL deionized water under argon ow. The mixture was then stirred at 90 C under an argon atmosphere until the salts dissolved completely. Subsequently, 10 mL ammonia solution (25%) was added drop-wise to the reaction mixture and stirred at this temperature for another 20 min under an argon ow. The black precipitates were isolated with the help of a permanent magnet and rinsed with distilled water followed by being dried in an oven.

Preparation of the Fe 3 O 4 @SiO 2 (SCMNPs)
In a typical process, 60 mL ethanol, 20 mL deionized water, 2 mL ammonia solution (25%), and 1.0 g of the obtained Fe 3 O 4 nanoparticles were placed into a 250 mL round-bottom ask and sonicated for 10 min. Aerwards, 0.45 mL tetraethylorthosilicate (TEOS) was added to the reaction solution and sonicated for another 10 min. The resulting dispersion was stirred for 14 h at ambient temperature and collected from the reaction solution with magnetic decantation. The dispersion was rinsed several times with a mixture of ethanol and water (1 : 1) and dried under vacuum.

Preparation of the Amp@SCMNPs
First, 1 g SCMNPs was dispersed in 20 mL dry toluene with the aid of ultrasonication for 30 min and 2 mL 3-aminopropyltriethoxysilane (Amp) was added into the resulting solution. The resulting mixture was reuxed under vigorous stirring for 24 h under an argon atmosphere and separated with magnetic decantation in the presence of a permanent magnetic eld. The precipitates were rinsed three times with water and ethanol and dried under a vacuum oven.

Preparation of the ThAl/Amp@SCMNPs
First, 1 g of dispersed Amp@SCMNPs nanoparticles was added to a 30 mL hot methanolic solution containing 5 mmol of 2,5-thiophene-dicarboxaldehyde (ThAl) and stirred under reux for 12 h in a water bath. The achieved precipitates (ThAl/ Amp@SCMNPs) were isolated via magnetic decantation, rinsed with ethanol several times to eliminate the excess chemicals, and dried under a vacuum oven.

Preparation of the IL/ThAl@SCMNPs
First, 1 g of the prepared ThAl/Amp@SCMNPs was added to the reaction solution containing 50 mL of EtOH and dispersed by sonication for 30 min. Aer this period of time, 5 mmol isoleucine was poured in to the reaction vessel and reuxed for 12 h under stirring. The residue precipitates (IL/ ThAl@SCMNPs) were collected using a permanent magnetic eld, rinsed three times with ethanol, and dried in a vacuum oven.

Preparation of the Zr@IL-Fe 3 O 4 MNPs
First, 0.34 g ZrCl 4 was added into the reaction solution containing 1 g of dispersed IL/ThAl@SCMNP nanoparticles in 80 mL ethanol and stirred vigorously for 12 h. Then, the precipitates were isolated by magnetic decantation in the presence of a permanent magnetic eld. The residue solid (Zr@IL-Fe 3 O 4 MNPs) was rinsed three times with water and ethanol and dried under a vacuum oven. Scheme 1 exhibits all the stages for the synthesized catalyst.       The presence of C-H stretching modes, which were assigned to the 3aminopropyltriethoxysilane in the FT-IR of Amp@SCMNPs, was conrmed by the stretching vibrations at about 2935 cm À1 . Two peaks for asymmetric stretching (799 cm À1 ) and in-plane bending (891 cm À1 ) of the Si-O-Si group can be observed in the related spectrum. Moreover, the characteristic peaks at around 3246 and 3432 cm À1 were assigned to the stretching vibrations of NH 2 groups, indicating the successful covalent attachment of Amp to the silica layer surface. The presence of 2,5-thiophene-dicarboxaldehyde in the FT-IR of ThAl/ Amp@SCMNPs was conrmed with C]C stretching and ring stretching at about 1462 and 1405 cm À1 , respectively. In the FT-IR spectrum of IL/ThAl@SCMNPs, the peaks for C-N (1451 cm À1 ) and COO (1653 cm À1 ) stretching vibrations could be observed. The characteristic peak at about 3000 to 3400 cm À1 was assigned to the acidic OH stretching vibrations, suggesting that the isoleucine was successfully attached to the ThAl/ Amp@SCMNP surface. The FT-IR spectra of the Zr@IL-Fe 3 O 4 MNPs showed a frequency shi for certain bonds, indicating the coordination of the zirconia with the desired bonds.

EDX analysis
Energy dispersive X-ray (EDX) analysis was employed to obtain information on the element distribution in the structure of IL/ ThAl@SCMNPs (a) and Zr@IL-Fe 3 O 4 MNPs (b) (Fig. 2). In the case of IL/ThAl@SCMNPs, the presence of C, N, O, Fe, Si, and S signals conrmed the loading of the functional groups on the surface of the magnetic nanoparticles. Based on the EDX analysis of the Zr@IL-Fe 3 O 4 MNPs and the presence of the zirconia element, it could be concluded that the catalyst had been successfully synthesized. Also, the elemental map of the Zr@IL-Fe 3 O 4 MNP nanocatalyst exhibited the presence of C, N, O, Fe, Si, and Zr elements (Fig. 3). Morever, the content of Zr in Zr@IL-Fe 3 O 4 MNPs (4.6% of Zr anchored on the catalyst) was determined by inductively coupled plasma atomic emission spectrometry.

VSM analysis
The magnetic features of the Fe 3 O 4 MNPs, SCMNPs, and Zr@IL-Fe 3 O 4 MNPs were determined by vibrating sample magnetometry (VSM) at ambient temperature (Fig. 4). The saturation magnetization (Ms) quantity of the Fe 3 O 4 MNPs was obtained as 50.63 emu g À1 . For the SCMNPs, the quantity of the saturation magnetization was 48.40 emu g À1 , which was lower than that of the Fe 3 O 4 MNPs. Furthermore, the saturation magnetization quantity (Ms) was 34.83 for Zr@IL-Fe 3 O 4 MNPs. These

TGA analysis
As shown in Fig. 6, the thermal stability of the Fe 3 O 4 MNPs (a), SCMNPs (b), ThAl/Amp@SCMNPs (c), IL/ThAl@SCMNPs (d), and Zr@IL-Fe 3 O 4 MNPs (e) were examined through thermogravimetric analysis (TGA) with a heating rate of 10 C min À1 under a nitrogen stream. In all the samples, the weight loss below 250 C was attributed to water thermodesorption from the surface (drying). The TGA graph of the SCMNPs exhibited a weight loss up to 650 C due to decomposition of the hydroxyl ions on the surface of the magnetic nanoparticles and volatilization. In the TGA curves of the ThAl/Amp@SCMNPs and IL/ThAl@SCMNPs, another weight loss could be seen in the range between 335 C to 440 C, which could be attributed to the decomposition of the organic groups graed on to the surface of the magnetic nanoparticles. Additionally, a two-step weight loss of the Zr@IL-Fe 3 O 4 MNPs in the range between 340 C to 560 C could be ascribed to the decomposition of the organic parts and metal groups.

TEM analysis
The TEM micrograph of the Zr@IL-Fe 3 O 4 MNPs is demonstrated in Fig. 7. Based on this image, the obtained catalyst had Scheme 2 Synthesis of highly substituted pyran derivatives using the Zr@IL-Fe 3 O 4 MNPs.     a mean diameter of roughly 35 nm and the particles indicated a nearly spherical morphology with a narrow size distribution.   In this research, we report our outcomes for the preparation of highly substituted pyran derivatives using Zr@IL-Fe 3 O 4 MNPs as a novel, effective, and reusable heterogeneous magnetic nanocatalyst under solvent-free conditions (Scheme 2).

SEM analysis
To acquire the optimized reaction conditions for the preparation of polyfunctionalized dihydropyrano[3,2-c]chromene (4) derivatives, the reaction among 4-hydroxycoumarin (1 mmol), malononitrile (1.2 mmol), and benzaldehyde (1 mmol) was analyzed under various conditions, for instance, different temperatures, amounts of catalyst, and solvent (Table 1). To discover the effect of the solvent, the reaction performance was carried out with various solvents, such as CH 3 CN, H 2 O, EtOH, CH 2 Cl 2 , and toluene ( Table 1, entries 1-5). The investigations into the selected solvents showed that in the presence of CH 3 CN, the desired product was achieved in good yields in short reaction times (Table 1, entry 1). Once the model reaction was applied in the rest of the above-mentioned solvents, the reaction proceeded rapidly for producing the target product (4a) in excellent yields (Table 1, entry 6). In our study, the inuence of the catalyst concentration on the model reaction was also surveyed at 10, 15, 20, and 25 mg to examine their performance under solvent-free conditions ( Table 1, entries 6 and 7-9). Among the tested concentrations under solvent-free conditions, the best outcome belonged to the existence of 20 mg of Zr@IL-Fe 3 O 4 MNPs (Table 1, entry 6). Any decrease or increase in the concentration of the catalyst did not improve the reaction times or product yields (Table 1, entries 7-9). To illustrate the effect of temperature on the completion of the reaction in the presence of 20 mg of catalyst under solvent-free conditions, various temperatures from 25 C to 120 C were evaluated (Table 1, entries 6 and 10-16). As shown in Table 1, using 20 mg of the Zr@IL-Fe 3 O 4 MNPs under solvent-free conditions at 100 C resulted in the highest yield of the desired product in a short reaction time (Table 1, entry 6). It is noteworthy that when the model reaction was performed at a temperature below 100 C, low-to-high yields of the product were achieved ( Table 1, entries [9][10][11][12][13][14]. It was also found that at a higher temperature than 100 C, the reaction yield could be obtained at relatively low values (Table 1, entries [15][16]. In order to popularize the optimum conditions and determine the priority and the acceptability of the method, various derivatives of dihydropyrano [3,2-c]chromene (4a-q) were achieved with high purity in high-to-excellent yields from the one-pot condensation of 4-hydroxycoumarin (1), malononitrile (2), and a wide range of aromatic aldehydes containing electronwithdrawing as well as electron-donating groups (3) in the presence of Zr@IL-Fe 3 O 4 MNPs under solvent-free conditions ( Table 2).
In addition, to expand the use of the prepared magnetic nanocatalyst for other reactions related to this classication, a series of polyfunctionalized 4H-benzo-[b]-pyran complexes (6a-n) were prepared from the reaction mixture of dimedone (5), malononitrile (2), and the aryl aldehydes (3) under the optimized reaction conditions mentioned above (Table 3), which is described in the following: The proposed mechanism for the preparation of the 2amino-4H-chromene derivatives began with the Knoevenagel condensation reaction between malononitrile 2 and aldehyde 3, among which the carbonyl functional group of the aldehyde was activated with the Zr groups of the catalyst. Subsequently, releasing a molecule of water created alkylidene malononitrile   To evaluate the reusability of Zr@IL-Fe 3 O 4 MNPs, as one of the specied merits of it, a curve of the catalyst performance was prepared for the three-component reaction of 4-hydroxycoumarin, malononitrile, and 4-chlorobenzaldehyde as a model reaction (Fig. 9). At the end of the reaction, a hot mixture of ethyl acetate and ethanol was poured into a ask containing the obtained product. The ask was then placed on a stirrer and aer complete dissolution of the product, the reaction solution was decanted with an external magnet into a beaker and the catalyst remained in the reaction vessel. The recovered Zr@IL-Fe 3 O 4 MNPs were rinsed with ethanol, dried, and reused without a signicant reduction in their activity for at least six runs of the reaction. Table 4 shows the efficiency of the Zr@IL-Fe 3 O 4 MNPs as a catalyst in the preparation of 2-amino-4-(4-chlorophenyl)-5oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile compared with some other introduced homogeneous and heterogeneous catalysts. Although all of the mentioned catalysts can partially accelerate the reaction, the present catalytic system had further advantages; for instance, easy work-up procedures, simple recovery of the catalyst, low reaction times, and low catalyst loading.

Conclusion
In summary, we described an effective procedure for the synthesis of highly substituted pyran derivatives via a one-pot three-component condensation of 4-hydroxycoumarin (1)/ dimedone (5), malononitrile (2), and arylaldehydes (3) using a Zr@IL-Fe 3 O 4 MNP heterogeneous magnetic nanocatalyst under solvent-free conditions. The catalyst was characterized via Fourier transform infrared (FT-IR) spectroscopy, energy dispersive X-ray spectroscopy (EDX), vibrating sample magnetometry (VSM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) techniques. The important features of the suggested strategy include a high efficiency of the catalyst, reusability of the catalyst through the use of an external magnetic eld, high-to-excellent yields of the products, and short reaction times.