Tandem Preparation of Furo[3,2-c]Coumarin Derivations Using Nano-Sized Fe3O4/N-GQDs Composite as a Magnetic Nanocatalyst

INTRODUCTION
Furo[3,2-c]coumarin scaffolds are one of the famous heterocyclic compounds due to their potential and wide spectrum of biological activities including anticancer [1], antibacterial [2], antifungal [3], immunotoxicity [4], anticholinesterase [5], and anti-HIV [6]. Therefore, these compounds are attractive targets in organic and medicinal chemistry. The preparation of bioactive heterocyclic compounds from available starting substances via one-pot multicomponent reactions (MCRs) has gained remarkable interest in both synthetic and medicinal chemists [7]. MCRs are extremely well suited for diversity-oriented synthesis and lead to the connection of three or more starting substances in a single process with high atom economy and bond-forming efficiency [8-10]. The possibility of accomplishing MCRs under mild conditions with a natural catalyst such as amino acids could improve their effectiveness from cost-effectiveness and ecological points of view [11].Several methods have been reported for the preparation of the trans-furo[3,2-c]coumarin scaffolds using diverse catalysts, for instance, pyridine or a mixture of acetic acid/ammonium acetate [12], ionic liquid [BMIm]OH [13], palladium(II) trifluoroacetate [14], copper(II) bromide [15], N-methylimidazolium [16], and triethylamine [17]. Some of these synthesis methods have specific disadvantages: long reaction times, using toxic materials, and specific conditions. 
In recent decades, several categories of carbon nanomaterials such as graphene quantum dots (GQDs) have been developed due to their exceptional physicochemical attributes [18]. GQDs reveal many interesting attributes. These attributes have their origins in their distinguished structure features [19]. Moreover, the presence of functional groups (e.g. hydroxyl and carboxyl) on the edge of GQDs structures can be used as bonding agents to the substrate or coating materials. On the other hand, some reports indicated that heteroatom doping of GQDs such as nitrogen, sulfur, and phosphorus can successfully increase more active sites owing to the modulated bandgap [20-22]. Also, retrieving these carbon nanostructures from the reaction environment could be modified with diverse materials such as nanomaterials, organic compounds, polymers, etc. [23]. Among them, magnetic nanostructures are of sharp interest to investigators due to their outstanding magnetic attributes [24]. Moreover, structural comparative studies indicate that magnetically attributes of metal oxide nanocomposites were superior to bulk form [25, 26]. N- GQDs/Fe3O4 nanocomposite is one of the most practical soft-magnetic compounds due to its low price, nontoxicity, chemical stability, and high resistance to erosion [27-29].
Herein we reported the use of Fe3O4/N-GQDs nanocomposites as a catalyst for the preparation of furo[3,2-c]coumarin derivatives using a multicomponent reaction of 2,4′-dibromoacetophenone, various benzaldehydes, and 4-hydroxycoumarin under microwave irradiation conditions in ethanol.

MATERIALS AND METHODS
Materials
The chemicals were purchased straight from ACROS Company in high purity. All of the chemicals were applied without further purification. The as-prepared products were characterized by melting point, FT-IR, and 1H/13C NMR. All melting points were measured in capillary tubes on a Boetius melting point microscope. Also, an investigation of FT-IR was recorded on a WQF-510 spectrometer 550 Nicolet. In addition, 1H/13C NMR was investigated on Bruker Avance-400 MHz spectrometers in the presence of chloroform-d as solvents (TMS is an internal standard).

Preparation of Fe3O4 nanoparticles
1.4 g of FeSO4.7H2O and 2 g of Fe2(SO4)3 were dissolved in 100 ml of double-distilled water. The concentrated ammonium hydroxide solution (25%) was added dropwise to adjust the pH= 10. The mixture was continually stirred at 60 °C for 1 hour at room temperature. The solid nanoparticles were collected by an external magnet, washed with distilled water (4×20 ml), and then dried at 40 °C for 4 hours under vacuum.

Preparation of Fe3O4@N-GQDs nanoparticles
The mixture of 1 g of citric acid, 0.4 ml of ethylenediamine, and 50 ml of double-distilled water was stirred for 2 minutes at room temperature to form a clear homogeneous mixture. Then, the 1 g of as-prepared Fe3O4 magnetic nanocomposite was poured into the above mixture and sonicated for 1 min to make a homogeneous mixture. Afterward, the mixture was put in a 150 ml Teflon Lined stainless steel autoclave and placed in the electric oven at 180 °C for 9 hours under hydrothermal conditions. At completion, the magnetic solid was collected by external magnetic and washed with dry ethanol (4×20 ml). The separated solid, finally, dried at 60 °C for 24 hours under vacuum conditions.

Preparation of furo[3,2-c]coumarin derivatives using Fe3O4@N-GQDs nanoparticles as a catalyst
An equivalent mixture of 2,4′-dibromoacetophenone and pyridine was stirred (1 min). After that, 4-hydroxycoumarin (1 mmol), various benzaldehyde (1 mmol), Fe3O4@N-GQDs nanoparticles (0.30 g), and ethanol (10 ml) was added to the above mixture. The mixture was stirred. Next, the reaction was continuted under microwave conditions. The reaction progress was checked out by thin-layer chromatography (TLC). After completion, the crude products were washed with ethanol. To give a pure product, the recrystallization from ethanol was done.  

RESULTS AND DISCUSSION
The XRD graphs of pure magnetic Fe3O4 and Fe3O4/N-GQDs nanocomposite were indicated in Fig. 1. As presented in Fig. 1a, diffraction angles (2θ) for magnetic nanoparticles evident at ~ 35.7°, 38°, 43.4°, 53.8°, 57.3°, and 62.9° can be indexed to (220), (311), (222), (400), (422), (511), and (440) plans, according to Fe3O4 cubic spinel structure (JCPDS Card No. 85-1436). In the case of the final graph, a broad peak at 2θ= 24° (002 plane) can be related to the amorphous structure of N-GQDs. According to the final graph, all Bragg peaks of nano-sized Fe3O4 particles and N-GQDs are seen at the same time and the Fe3O4/N-GQDs phase compositions did not change.
The surface functional groups of pure Fe3O4 magnetic and Fe3O4/N-GQDs nanocomposites were confirmed by FT-IR spectroscopy (Fig. 2). Absorption peak at 590 cm-1 is related to Fe-O. Also, absorbance peaks at 1628 cm-1 and 3410 cm-1 related to OH bending and stretching vibration, respectively, due to absorbed H2O by the surface of nanoparticles (Fig. 2a). As compared with pure Fe3O4 spectra, the new bands at 1680 cm-1, 1550 cm-1, and 1388 cm-1 were corresponded to stretching vibration peaks of C=O, C=C, and C-O/C-N, respectively. In addition, a peak located at 3385 cm-1 is related to the vibration of -OH stretching. Also, absorbance peaks approximately at 3198 cm-1 and 2920 cm-1 were related to =CHsp2 and -CHsp3 (Fig. 2b).
The investigation of surface morphology and particle size was done by the FE-SEM method. Moreover, the purity of Fe3O4 and Fe3O4/N-GQDs nanocomposites was studied by EDX analysis. The results of the investigation of morphology and element distribution were revealed in Fig. 3 and Fig. 4, respectively. Fig. 3a reveals the formation of Fe3O4 nanoparticles. According to the Fig. 3b, N-GQDs completely cover the surface of the Fe3O4 nanoparticles. From Fig. 4a, results show that as-prepared nanoparticles contain just two elements: Fe (43.30 %) and O (56.70 %). Besides, the final EDX data confirm not only the presence of the Fe3O4 nanoparticles but also the formation of the carbon (12.52) and nitrogen (7.55) in the final nanostructure (Fe3O4/N-GQDs nanocomposites). 
To determine the optimal conditions for the preparation of the furo[3,2-c]coumarin derivatives, we developed the effect of temperature, solvent, and catalyst amount on the model reaction of 2,4′-dibromoacetophenone (1 mmol), benzaldehyde (1 mmol), and 4-hydroxycoumarin (1 mmol). The model reactions were done using various catalysts: acetic acid, tosylic acid, piperidine, and triethylamine. When the reaction was done in the presence of Fe3O4/N-GQDs nanocomposite (0.30 g) as the nanocatalyst, the product could be obtained in good yield. Some reactions were investigated in the presence of various solvents such as water, acetonitrile, dimethylformamide, and ethanol. The best data were observed under microwave conditions in ethanol. It was found that the reaction gave satisfying data in the presence of nanocom Fe3O4/N-GQDs nanocomposite (0.30 g) which gave excellent yields of products (Table 1). With these hopeful data in hand, we turned to study the scope of the reaction using various benzaldehydes as substrates under the optimized reaction conditions (Table 2). It was revealed that aromatic aldehydes with electron-withdrawing groups reacted faster than those with electron-releasing groups. Meanwhile, it has been observed that better yields are obtained with substrates having electron-withdrawing groups.
Fig. 5 revealed the reasonable mechanism for the preparation of furo[3,2-c]coumarin derivatives in the presence of Fe3O4/N-GQDs nanocomposite. Based on our studies of mechanism, the reaction starts with a Knoevenagel condensation between benzaldehyde and 4-hydroxycoumarin to form the intermediate (I) on the active sites of Fe3O4/N-GQDs nanocomposite, which are chiefly responsible for the catalytic activity. Then, the Michael addition of pyridinium ylide with enones affords a zwitterionic intermediate and followed by cyclization affords the titled product. The final step is a SN2 substitution reaction. The stereochemistry of the SN2 reaction required a nucleophilic enolate attack from the back side of the electrophilic carbon atom bearing the leaving pyridinium group. Thus, the furo[3,2-c]coumarin is formed as the only product [17].  

CONCLUSION
We provide a straightforward and environmentally friendly protocol for the preparation of the furo[3,2-c]coumarin derivations catalyzed by Fe3O4/N-GQDs nanocomposite as a magnetic catalyst. The remarkable catalytic activity was greatly related to uniformity and available active sites on the surface of the catalyst. Then, Fe3O4 nanoparticles were decorated with N-GQDs. It is found that the joining of N-GQDs and Fe3O4 has a remarkable impact on catalytic activity improvement. Therefore, the tandem multicomponent reactions protocol has some benefits, for instance, good yield reaction (up to 90%), low reaction times (20 min), and low-cost and available catalysts. Moreover, using mild conditions led to an increased reaction rate and saved energy. In addition, the present approach can be used for the design of libraries and diversity-oriented synthesis and has potential for biological applications and drug discovery.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interests regarding the publication of this manuscript.