Copper(II) Anchored on Amine-Functionalized MMT: A Highly Efficient Catalytic System for the One-Pot Synthesis of Bispyrano [2,3-c]pyrazole Derivatives

In this study, preparation of pyridine-2-carboimine copper complex immobilized on amine-functionalized nanoclay montmorillonite K10 was reported. The products were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diﬀraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and thermogravimetric analysis (TGA). The catalytic activity of this new nanocatalyst, as a natural, renewable, inexpensive, and heterogeneous catalyst, was very eﬀective for the four-component condensation reaction of hydrazine hydrate (or phenyl hydrazine), malononitrile, β -ketoester, and terephthalaldehyde (or isophthalaldehyde) toward the synthesis of multisubstituted bispyrano[2,3-c]pyrazole derivatives. From the viewpoint of green chemistry, the advantages of this approach are accessibility, simplicity, and high yields synthesis. The catalyst was recycled and reused four times without signiﬁcant loss of activity.


Introduction
Today, multicomponent reactions (MCRs) are powerful strategies in organic and medicinal chemistry. Reactions with three or more reactants lead to the products under mild conditions, excellent yield, low costs, high selectivity, and shorter reaction times. Literature shows that there are many reported applications of multicomponent reactions for the synthesis of organic compounds such as Biginelli and Hantzsch reactions [1][2][3][4][5][6][7].
To the best of our knowledge, limited articles have been reported on the synthesis of bispyrano pyrazole through homogeneous catalysis [15]. ere are several disadvantages of homogeneous catalysis including the labor-intensive separation process and recycling. Based on the mentioned issue for homogeneous catalysis, heterogeneous catalysts have become increasingly attractive to scientists. Heterogeneous catalysis has allowed researchers to develop various inorganic-organic functional materials by modifying inorganic hosts with organic molecules. For example, clay minerals constitute a versatile source of inorganic support for the fabrication of advanced inorganic-organic hybrid materials due to their remarkable structural and chemical diversities [16].
Reviewing the existing methods for synthesis of bispyrano [2,3-c]pyrazole derivatives shows that they suffer from prolonged reaction times and the use of nonrecyclable catalysts [17][18][19][20][21][22]. Considering the disadvantages associated with earlier reported protocols and the increasing importance of pyranopyrazoles derivatives in pharmaceutical chemistry, there is still a need to develop an efficient, low cost, and ecofriendly protocol for the synthesis of bispyrano [2,3-c]pyrazole derivatives under green solid catalytic conditions.
Montmorillonite K10 (MMT K10) has been used due to its potential in absorbing water and other molecules, physicochemical properties, and catalysis activity. MMT K10 as an inorganic solid has been used in organic synthesis as a catalyst and catalysis support. In comparison to the bulk supports, MMT K10 nanoclay offers a large number of potential active sites for the reactants as a result of a large surface-area-to-volume ratio, which eventually results in higher yields [23][24][25][26][27][28][29][30][31]. Here, we used MMT K10 as a support to provide a new and highly efficient heterogeneous catalytic system consisting of anchored Cu(OAc) 2 by modified imine (MMT-n-Pr-NH�Py) as a linker for the synthesis of bispyranopyrazole derivatives (Scheme 1).

Chemicals and Apparatus.
All chemicals were purchased from Merck, Aldrich, and Sigma Chemical Companies. Melting points were determined on an electrothermal MK 3 apparatus using an open-glass capillary and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively. FTIR spectra were obtained with KBr pellets in the range 400-4000 cm −1 with a Perkin-Elmer 550 spectrometer. Nanostructures were characterized using a Holland Philips Xpert X-ray diffraction (XRD) diffractometer (CuK, radiation, λ � 0.154056 nm), at a scanning speed of 2°/min from 10°to 100°(2θ). e surface morphology of chitosan-based materials was analyzed by field emission scanning electron microscopy (SEM) (EVO LS 10, Zeiss, Carl Zeiss, Germany).

Catalyst Preparation.
According to the previously reported method, the amine-modified montmorillonite (MMT-(CH 2 ) 3 -NH 2 ) was prepared as follows: 2 g MMT K10 was added to a 15 mL solution of 3-aminopropyltrimethoxysilane (4.8 mmol) in n-hexane and the mixture was stirred at room temperature for 3 h. en, the solvent was removed by filtration, and amine-modified montmorillonite was washed with n-hexane, eventually drying under vacuum [32]. Covalent attachment of functional organic groups on the montmorillonite surface has advantages over physisorption and cation exchange. Such compounds would benefit from much higher chemical stability as the guest species would be irreversibly bound to the structure. Grafting is the most viable route for the covalent immobilization of organic functional groups over the surface of montmorillonite [16].

General Procedure for the Synthesis of Bispyrano[2,3-c] pyrazole Derivatives in the Presence of MMT-[(CH 2 ) 3 -NH�CHPy]-Cu(II).
A mixture of terephthalaldehyde or isophthalaldehyde (1 mmol), hydrazine hydrate or phenyl hydrazine (2 mmol), β-ketoester (2 mmol), and malononitrile (2 mmol) in the presence of MMT-[(CH 2 ) 3 -NH�CHPy]-Cu(II) (0.01 g) was stirred under reflux conditions for the appropriate time. After completion, as indicated by TLC, the reaction mixture was filtered to separate the catalyst. e filtrate was cooled, and large amounts of a precipitate are formed. e products were purified by recrystallization in hot ethanol. e recovered catalyst was dried and reused for subsequent runs. All the products were characterized by IR, 1 H NMR, and 13 C NMR and identified by the comparison of the spectral data with those reported in the literature [15].
When a heterogeneous catalyst is used, the recyclability of the catalyst is an important issue. To test this, a series of four consecutive runs of the model reaction with the MMT-[(CH 2 ) 3 -NH�CHPy]-Cu(II) catalyst were carried out. e results are shown in Figure 1.  (Figure 2(d)), the C�N stretching frequency is at a lower wavelength of 1624 cm −1 that confirms C�N bond is coordinated to copper through the lone pair of nitrogen in the Schiff base [33]. e XRD spectrum of the catalyst is shown in Figure 3. Figure 3(a) shows powder X-ray diffraction (P-XRD) patterns of MMT K10. As can be seen, the positions and relative intensities of all the peaks coincide well with standard XRD patterns that are mainly in the amorphous form. Some peaks which are caused by impurities such as feldspar, cristobalite, and quartz have been detected in all samples of MMT K10. After grafting APTES to the MMT, the distances between the interlayers of MMT-(CH 2 ) 3 -NH 2 were different from MMT K10 (Figure 3(b)). It indicated that the grafting APTES with montmorillonite (MMT-(CH 2 ) 3 -NH 2 ) increases the distance between sheets and changes the montmorillonite structures (d-spacing MMT-(CH 2 ) 3 -NH 2 � 11 and d-spacing MMT K10 � 9.64). Following the synthesis of the new catalyst, the characteristic Bragg's peaks were obtained at the same 2θ values which indicate that MMT-(CH 2 ) 3 -NH 2 crystal structure remains stable (Figures 3(c) and 3(d)) [34]. e corresponding EDX analysis confirmed the presence of Cu on the catalyst (8 wt% loadings). During the conversion of MMT-[(CH 2 ) 3 -NH�CHPy] to MMT-[(CH 2 ) 3 -NH�CHPy]-Cu(II), a clear change in sample color was observed (khaki to green), which could be attributed to the presence of copper in the sample (Figure 4).    (Figure 5(d)) when compared to MMT K10 ( Figure 5(a)).
After identifying and proving the catalyst structure, further exploration of the catalytic activity of MMT-[(CH 2 ) 3 -NH�CHPy]-Cu(II) for the synthesis of bispyranopyrazoles derivatives was performed (Scheme 1, model reaction).
Initially, we tested the effect of catalyst amounts in H 2 O-EtOH solvent, and results are summarized in Table 1. Our results showed that with increasing the catalyst from 0.00 g to 0.02 g, reaction yield improved from 40% to 95% (    Table 2. Eventually, the role of temperature was examined. As indicated in Table 2, increasing the temperature until reflux resulted in a 95% yield (Table 2, entry 4). As temperature increases up to 100°C, the obtained yield was not changed, so the reaction followed at reflux. In view of these results, we selected the optimized reaction conditions to determine the scope of the model reaction. A wide range of β-ketoesters was subjected to react with terephthalaldehyde (or isophthalaldehyde), hydrazine hydrate (or phenyl hydrazine), and malononitrile in the presence of 0.01 g of the catalyst under reflux condition to generate bispyrano [2,3-c]pyrazole derivatives. e results are summarized in Table 3.
Generally, as given in Table 3, terephthalaldehyde gives a better yield rather than isophthalaldehyde. According to the mechanism of the reaction, steric prevention is the reason for this issue (Table 3, entries 5, 6, 9, and 10). Different β-ketoesters were used to prepare bispyrano[2,3-c]pyrazole derivatives. When methoxy groups exist instead of ethoxy groups, the reaction is done in a shorter time (Table 3, entries 1, 2, 3, and 4). In addition, it is important to note that when phenyl acetoacetate was used, the yield decreased and the reaction became longer (Table 3, entries 1, 2, 5, and 6). As   Journal of Chemistry one additional interesting result, it can be reported that in the case of phenylhydrazine, the reaction is slower than the corresponding hydrazine hydrate (Table 3,

Conclusions
We have developed a new and efficient catalyst for the synthesis of bispyrano[2,3-c]pyrazole derivatives. e catalyst has been recycled and reused five times for the reaction without losing its activity.
is catalyst is environmentally friendly, has a simple synthesis and workup procedure and high synthesis yield, and has a short reaction time.
Data Availability e products that are used to provide the data supporting the findings of this study were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and thermogravimetric analysis (TGA).  Journal of Chemistry 9