An Attractive and Efficient Procedure for Synthesis of Heterocyclic Structures: MNPs-Bis(2-Hydroxyethyl)-Guanidine-Ni Nanocomposite as a Novel and Green Nanomagnetic Catalyst for Multicomponent Reactions

Abstract Now, in this paper, we report the successful fabrication of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocatalyst and study its catalytic behavior for the synthesis of pyrano[2,3-c]pyrazoles and highly functionalized piperidines. The Structure of the as-fabricated MNPs-guanidine-bis(ethanol)-Ni nanomaterial was fully characterized by advanced microscopic and spectroscopic methods, such as FT-IR, SEM, TEM, EDX, TGA, VSM, XRD and ICP-OES. With aryl aldehydes, ethyl acetoacetate, and aniline or malononitrile and hydrazine hydrate as the reactive species, the created MNPs-bis(2-hydroxyethyl)-guanidine-Ni catalytic agent acts as a promising candidate to deliver numerous pharmaceutically relevant highly functionalized piperidines and pyrano[2,3-c]pyrazoles scaffolds. The developed methodology comes with a host of advantageous features, such as gentle reaction conditions, a broad substrate range, great product yields, and a brief reaction time. Additionally, the Ni nanocatalyst could be easily recovered by a simple magnetic separation and recycled at least 8 times without deterioration in catalytic activity.

Catalysts are substances that increase the rate of chemical reactions but are not used in the reaction. 10Catalysts are very important both in industrial applications and in biological processes. 11Although the reaction rate can be significantly increased by increasing the temperature, but since the increase in temperature is associated with energy consumption, such a measure would not be economically viable. 12,13On the other hand, many materials are sensitive to heat and decompose due to heat.Therefore, the most appropriate way is to use suitable catalysts to accelerate chemical reactions.Since catalysts are used in chemical processes and remain intact, isolating and retrieving them is often not easy and accessible. 14Therefore, designing catalysts that are easy to recycle has been a valuable goal for scientists and provides the necessary and sufficient incentive to invent and discover new catalysts.Catalysts are also classified into two categories based on their phase composition: homogeneous and inhomogeneous.Heterogeneous catalysts are more useful than conventional homogeneous catalysts because of their easy removal from the reaction medium by simple separation and reusability, which is essential in green synthesis. 15ue to the high active level and the many active centers in nanocatalysts, these catalysts show improved reactivity.One of the goals in the field of nanocatalysts is the use of nanocrystals due to the high active surface of these structures. 16With the creation of more active centers and surface area, an important improvement in the activity, selectivity, efficiency and stability of nanocatalysts is observed. 17,18However, separating these nanocatalysts from the reaction mixture is not easy, and conventional separations such as filtration are not effective due to the size of the nanocatalysts.0][21] To overcome this problem, the use of magnetic nanoparticles seems to be a suitable solution.Magnetic nanoparticles have high catalytic activity and show a high degree of chemical stability.3][24] Magnetic nanoparticles are well known and can be used as a suitable support for functionalization with metals, organo-catalysts and Nheterocyclic carbon and chiral catalysts. 386][27][28] The most important of magnetic nanoparticle-based catalysts is that they can be easily separated from the reaction medium using an external magnetic field. 29Now, in this paper, we report the successful fabrication of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocatalyst and study its catalytic behavior for the synthesis of pyrano[2,3-c]pyrazoles and highly functionalized piperidines.

Result and discussion
The details of the fabrication of Ni complex immobilized on the surface of silica-coated magnetic nanoparticles modified with guanidine-bis ethanol (prepared via the ring-opening reaction of MNPs-guanidine with epoxide) are listed in Scheme 1. 30 The Structure of the as-fabricated MNPs-guanidine-bis(ethanol)-Ni nanomaterial was fully characterized by FT-IR spectroscopy, SEM, TEM, EDX, TGA, VSM, XRD, and ICP-OES.

Characterization
FT-IR spectroscopy of MNPs-guanidine and MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanomaterial are shown in Figure 2. A clear band at 585 cm À1 related to Fe-O bond and successful fabrication Fe 3 O 4 NPs. 31The free ligand exhibits an (C-N) stretch peak at 1629 cm À1 while in the Ni complex, this band shifts to lower frequency and appears at 1616 cm À1 because of coordination of the nitrogen with the metal.
Furthermore, the elemental composition of the MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanomaterial was confirmed using EDS analysis as depicted in Figure 3.The presence of Fe, O, Si, N, C, and Ni peaks in EDS analysis confirmed the successful fabrication of Ni complex immobilized on the surface of silica-coated magnetic nanoparticles modified with MNPs-bis(2-hydroxyethyl)guanidine.The morphology of the MNPs-bis(2-hydroxyethyl)-guanidine-Ni catalyst was investigated using SEM and TEM analysis.SEM and TEM images of the catalyst at different magnifications were also recorded (Figure 3).These SEM and TEM images confirmed that the particles are made up in nanometer range.
X-ray diffraction (XRD) is an effective spectra technique to the better reorganization of the major properties of the magnetite structures.In fact, the formation of magnetite crystal phase in the nanomagnetic catalyst in aggregate powder form can be as well identified by the X-ray  311), ( 400), ( 422), ( 511) and (440) crystallographic faces of magnetite (in good agreement with the standard Fe 3 O 4 XRD spectrum reported in literature). 40This analysis clearly affirmed this theme that the surface modification and conjugation of the Fe 3 O 4 nanoparticles did not lead to phase change.In addition, the appearance of a new characteristic peak at 2h ¼ 34.2 is related to Ni species, that confirm the successful complexation of organic functionalities on modified support with the metal ions.
Thermogravimetric analysis (TGA) is an effective and fascinating spectra technique to investigate the thermal stability of the immobilized catalyst relative to that of magnetic nanocatalysts.The overlaid TGA curve of MNPs-bis(2-hydroxyethyl)-guanidine-Ni catalyst is displayed in Figure 5.The catalyst lost its solvent molecules (about 8%) in the first scenario (below 200 C).Organic groups have been reported to desorb at temperatures above 260 C. In the curve of MNPs-bis(2-hydroxyethyl)-guanidine-Ni, a weight percentage loss about 24% is also observed, which is attributed to the breakdown of the bond between Ni and ligand.As the result of this  analysis, it can be concluded that the well grafting of Ni complex on the surface of silica-coated magnetic nanoparticles modified with bis(2-hydroxyethyl)-guanidine is verified.
The magnetic property of the catalyst was investigated by vibrating sample magnetometer (VSM) at ambient temperature.The curves of magnetization for the MNPs-bis(2-hydroxyethyl)guanidine-Ni catalyst are depicted in Figure 6.As shown on Figure 6, the saturation magnetization of the MNPs-bis(2-hydroxyethyl)-guanidine-Ni was found to be at about 54.63 emu/g.Atomic absorption spectroscopy (AAS) of the catalyst showed that the amount of Ni loaded on the surface of silica-coated magnetic Fe 3 O 4 nanoparticles is about 15 Â 10 À5 mmol g À1 .Also, the Ni amount was measured by atomic absorption spectroscopy (AAS), which the results were very close to ICP-OES method (15.21 Â 10 À5 mmol g À1 ).All together, these analyses are indicative of the successful immobilization of Ni complex on the surface of silica-coated magnetic nanoparticles modified with guanidine-bis ethanol (prepared via the ring-opening reaction of MNPsguanidine with epoxide).After the characterization of the MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite, the activity of this nanomagnetic bromine catalyst was evaluated in the synthesis of highly substituted piperidines and pyrano[2,3-c]pyrazoles.Initially, the effect of a series of parameters such as catalyst loading, solvent and temperature was studied on the model condensation of benzaldehyde (2 mmol), ethyl acetoacetate (1 mmol) and aniline (2 mmol).The results of these experiments are summarized in Table 1.The presence of catalyst was very vital for the performance of the reaction, because the model product was not performed in the absence of catalyst (Table 1, Entry 1).An increase in the quantity of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite, from 3 to 15 mg increased the product yield slightly from 65% to 94% (Table 1, Entries 2-6).A series of solvents was tested to find the best medium for the performance of reactions.After comprehensive experiments, the mixture of H 2 O:EtOH (1:1) was selected as the standardized medium for the further investigations.Therefore, the utilization of 15 mg of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite in H 2 O:EtOH (1:1) at 80 C is considered as the standardized conditions for the synthesis of highly substituted piperidines and pyrano[2,3-c]pyrazoles.The results are listed in Tables 2 and 3. A broad range of aromatic aldehydes were successfully employed to prepare the corresponding highly substituted piperidines and pyrano[2,3-c]pyrazoles in excellent yields.Most importantly, aromatic aldehydes carrying either electron-donating or electron-withdrawing substituents all reacted very well, giving excellent yields.][34][35] Based on previous studies a Plausible Mechanism for the synthesis of highly substituted piperidines over the catalysis of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite was proposed in Scheme 2.
Based on previous studies a Plausible Mechanism for the synthesis of pyrano[2,3-c]pyrazoles over the catalysis of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite is proposed in Scheme 3. In this process the Ni-complex acts as a Lewis acid catalyst for activation of carbonyl compounds.
Magnetic separation is a more attractive and simple technique than the filtration or centrifugation techniques as it prevents the loss of the nanocatalyst and increases the reusability of the nanocatalyst.In this respect, the reusability of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite was investigated in the synthesis of products 4a and 9b.After completion of the reaction, the isolated MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite was washed with ethyl acetate, oven dried and then directly used for the next cycle reaction without further purification.As shown in Figure 7, the recovered Ni nanocatalyst could be reused 8 times without any significant loss of its activity.
To the insolubility of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocomposite during the organic transformations, the hot filtration test was conducted.The results, suggesting that the catalyst species are heterogeneous in nature and the reaction did not process after catalyst filtration at all.
Magnetization curve of reused MNPs-bis(2-hydroxyethyl)-guanidine-Ni after 8 runs is illustrated in Figure 8.According to the magnetization curves, the saturation of the MNPs-bis(2-hydroxyethyl)-guanidine-Ni catalyst was about 45.78 emu/g.Scanning Electron Microscope (SEM) of MNPs-bis(2-hydroxyethyl)-guanidine-Ni nanocatalyst catalyst after 8 runs is shown in Figure 8.The SEM image illustrate that there was no significant change in the morphology and dispersion of the particles.The FT-IR and EDX analysis of reused catalyst ware compared to that of the fresh one.Surprisingly, after the eighth run, the elemental and chemical composition of the reused nanomaterial were nearly identical to that of the fresh one Figure 8. ICP-OES was employed to determine the exact Ni content of nanomaterial (after 8 times), which it was found to be 15.07 Â 10 À5 mol/g.

Comparison
The comparison catalytic efficiency of MNPs-bis(2-hydroxyethyl)-guanidine-Ni in the reported synthesize in the literature is summarized in Table 4.As can be seen, the previous catalytic methods suffered from multiple disadvantages, including using toxic solvents, high temperature, and catalyst loading However, our method shows better catalytic activity without the mentioned shortcomings.

Conclusion
We have developed a novel and highly active nanomagnetic catalyst via the immobilization of Ni complex on the surface of silica-coated magnetic nanoparticles modified with guanidine-bis ethanol (prepared via the ring-opening reaction of MNPs-guanidine with epoxide) and have studied its catalytic activity in the synthesis of pyrano[2,3-c]pyrazoles and highly functionalized piperidines.The Structure of the as-fabricated MNPs-guanidine-bis(ethanol)-Ni nanomaterial was fully characterized by FT-IR spectroscopy, SEM, TEM, EDX, TGA, VSM, XRD and ICP-OES.This catalytic system presented a number of attractive advantages such as green procedure, short reaction time, excellent yields, and simple work-up, ease of separation, as well as the ability to tolerate a wide variety of substitutions in the reagents.

Experimental
Chemicals were purchased from Fisher and Merck.The reagents and solvents used in this work were obtained from Sigma-Aldrich, Fluka or Merck and used without further purification.The infrared spectra (IR) of samples were recorded in KBr disks using a NICOLET impact 410 spectrometer. 1HNMR and 13 CNMR spectra were recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz respectively.Nanostructures were characterized using a Holland Philips X, pert X-ray powder diffraction (XRD) diffractometer (Co Ka, radiation¼ 0.154056 nm), at a scanning speed of 2 min À1 from 10 to 80 .Scanning electron microscope (SEM) was performed on a FEI Quanta 200 SEM operated at a 20 kV accelerating voltage.The thermogravimetric analysis (TGA) curves are recorded using a PL-STA 1500 device manufactured by Thermal Sciences.The magnetic measurements were carried out in a vibrating sample magnetometer (VSM, BHV-55, Riken, Japan) at room temperature.

Preparation of the magnetic Fe 3 O 4 -nanoparticles
The mixture of FeCl 3 .6H 2 O (5.838 g, 0.0216 mol) and FeCl 2 .4H 2 O (2.147 g, 0.0108 mol) were dissolved in 100 mL of deionized water in a three-necked bottom (250 mL) under N 2 atmosphere.After that, under rapid mechanical stirring, 10 mL of NH 3 was added into the solution within 30 min with vigorous mechanical stirring.After being rapidly stirred for 30 min, the resultant black dispersion was heated to 80 C for 30 min.The obtained black precipitate was isolated by magnetic decantation, washed with double-distilled water until neutrality, and further washed twice with ethanol and dried at room temperature. 29eparation of the Fe 3 O 4 @SiO 2 Then the obtained Fe 3 O 4 MNPs (2 g) were dispersed in 20 mL of water by sonication for 30 min, and then 2-propanol (200 mL) was added to the reaction mixture.The reaction mixture was stirred using a magnetic stirrer at room temperature.Under continuous stirring, PEG (5.36 g), water (20 mL), ammonia solution (10 mL, 28 wt.%) and 2 mL of tetraethyl orthosilicate (TEOS) were respectively added into the suspension and continuously reacted for 36 h under stirring at room temperature.Then the product (Fe 3 O 4 @SiO 2 ) was isolated with an external magnet and washed two times with ethanol and distilled water. 40

Preparation of MNPs -CPTMS
The obtained Fe 3 O 4 @SiO 2 nanoparticles (1.5 g) was dispersed in 250 mL ethanol/water (volume ratio, 1:1) by sonication for 30 min, and then CPTMS (2.5 mL) was added to the mixture reaction.The reaction mixture was stirred using mechanical stirring under N 2 atmosphere at 40 C for 6 h.then, the nanoparticles were re-dispersed in ethanol by sonication for 5 times and separated through magnetic decantation.The nanoparticles product (Fe 3 O 4 @SiO 2-CPTMS) was dried at room temperature. 41

Preparation of MNPs-Guanidine
The propylcholoro-functionalized Fe 3 O 4 (1.5 g) were dispersed in toluene (50 mL) by ultrasonic bath for 10 min.guanidine (1.80 g) (fabricated from the reaction of 2,4,6-trichloro-1,3,5-triazine and ethane-1,2-diamine in the presence of potassium carbonate) was added and stirred at reflux temperature for 10 h under N 2 atmosphere.Then, the prepared Fe 3 O 4 @SiO 2 -guanidine nanocomposite was separated by magnetic decantation and washed three times with ethanol to remove the unattached substrates.The resulting product was dried at room temperature. 41

Table 4 . 38 4
Comparison of the present methodology with other reported catalyst for the synthesis of product 4a.@ATSM-Co(II) 120 92 PbCr x Fe 12-x O 19 (x ¼ 0.5

Table 1 .
Optimization of reaction conditions for the synthesis of highly substituted piperidines over the catalysis of MNPsbis(2-hydroxyethyl)-guanidine-Ni nanocomposite.
a Isolated yield.Bold values signifies optimized conditions.
a Isolated yield.