Fe3O4@SiO2-NH2 Nanocomposite as a Robust and Effective Catalyst for the One-pot Synthesis of Polysubstituted Dihydropyridines

A practical, simple and efficient method for the synthesis of polysubstituted dihydropyridines was described via multicomponent reactions of aldehydes, arylamines, dimethyl acetylenedicarboxylate and malononitrile/ethyl acetoacetate in the presence of Fe3O4@SiO2-NH2 nanocomposites. The present methodology provides a novel and efficient method for the synthesis of dihydropyridine derivatives with some advantages, such as excellent yields, short reaction times, recoverability and low catalyst loading. The nanomagnetic catalyst could be readily recovered using an external magnet and reused several times without any significant loss in activity. The catalyst was fully characterized by FT-IR, SEM, XRD, EDX and VSM analysis.


Introduction
Substituted dihydropyridone derivatives are an important class of nitrogen heterocyclic compounds due to a variety of biological and pharmacological activities 1 such as: antihypertension, 2 antioxidant, 3,4 anticancer 5 and antitumor activity. 6However, there are many methods for the synthesis of dihydropyridines.Among various dihydropyridine structures, some of them have medicinal properties such as: nicardipine 1 and nifedipine 2, 7 isradipine 3 and niguldipine 4, 8 which exhibit dihydropyridine moiety (Figure 1).Consequently, synthesis of highly functionalized dihydropyridine derivatives, with the aim of developing new drug molecules has been an active area of research.Recently, much attention has been paid to the development of new methodologies for the preparation of dihydropyridines.The main synthetic routes for the preparation of substituted dihydropyridines are Hantzsch method via the cyclocondensation of an aldehyde, β-ketoester and ammonia, 9 regioselective [4+2] cycloaddition of 1aryl-4-phenyl-1-azadienes and allenic esters for the synthesis of N-aryl-1,4-DHPs, 10 and a multi-component reaction of alkyl amines, ethyl propiolate, and benzal- Recently, a few methods have been reported for the syntheses of polysubstituted dihydropyridines via fourcomponent reactions of aldehydes, arylamines, acetylenedicarboxylates and malononitrile/ethyl acetoacetate using Et 3 N, 12 NaOH, 13 (NH 4 ) 2 HPO 4 . 14n the modern science, one of the growing and important fields is nanotechnology.Because of different physical and chemical properties of nano-sized catalysts compared to bulk material, they attract interests in different researcher areas. 15Since the particles are small in size, the surface area exposed to the reactant is maximized so allowing more reactions to occur at the same time, hence the process is accelerated. 16agnetic nanoparticles show a great potential as catalysts because of their large surface area and the large ratio of atoms available at the surface to perform the chemical transformation of substrates. 17,18However, the bare Fe 3 O 4 nanoparticles have high reactivity and easily undergo degradation upon direct exposure to certain environments, leading to poor stability and dispersity.Therefore, the surface of magnetic nanoparticles should be modified to improve the dispersity and biocompatibility, which could significantly facilitate its utilization.
Fe 3 O 4 @SiO 2 -NH 2 nanocomposites are one of the most important supported magnetite nanostructures which have received great attention due to their significant properties and potential applications in various fields. 19This kind of catalyst is eco-friendly, non-toxic, non-volatile and can be recycled several times without loss of activity in the reaction.The use of these nanoparticles follows the principles of green chemistry.
Recently, functionalized Fe 3 O 4 nanocatalysts were applied as a robust and effective catalyst in many organic reactions, such as: Knoevenagel condensation and Michael addition, 20 Suzuki and Heck cross-coupling, 21 asymmetric aldol reaction, 22 Suzuki coupling, 23 asymmetric hydrogenation of aromatic ketones, 24 acetalization reaction, 25 reduction of nitro aromatic compounds, 26 cyanosilylation of carbonyl compounds, 27 Henry reaction, 28 enantioselective direct-addition of terminal alkynes to imines. 29n continuation of the progress of the synthetic approach to the synthesis of heterocyclic compounds using reusable nanocatalysts and multi-component reactions, [30][31][32][33][34] herein we report a simple, efficient, mild and practical method for the synthesis of polysubstituted dihydropyridines via a four-component coupling reaction in the presence of Fe 3 O 4 @SiO 2 -NH 2 nanocomposite as a green and environmentally benign nanocatalyst in ethanol as solvent at room temperature (Scheme 1).

Results and Discussion
The chemical purity of the samples as well as their stoichiometry was tested by energy dispersive X-ray spectroscopy (EDX) studies.The EDX spectrum given in Figure 2a shows the presence of Fe and O as the only elementary components of Fe 3 O 4 NPs.EDX spectrum of Fe 3 O 4 @SiO 2 in Figure 2b shows the elemental composition of core-shell nanocomposite to be Fe, Si and O. EDX Scanning electron microscopy (SEM) images of the prepared nanostructures are shown in Figure 3. Figure 3a shows that the Fe 3 O 4 nanoparticles are cubic in shape with an average size about 15 nm. Figure 3b (Fe 3 O 4 @SiO 2 ) and Figure 3c (Fe 3 O 4 @SiO 2 -NH 2 ) show that both are apparently of similar shape, but approximate size of aminofunctionalization silica-coated magnetite nanocomposite is more than r of the Fe 3 O 4 @SiO 2 core-shell nanocomposite.
The structures of Fe 3 O 4 (a), Fe 3 O 4 @SiO 2 (b) and Fe 3 O 4 @SiO 2 -NH 2 (c) were analyzed by X-ray diffraction (XRD) spectroscopy (Figure 4).XRD diagram of the bare Fe 3 O 4 NPs displayed patterns consistent with the patterns of spinel ferrites (Figure 4a).The same peaks were observed in both of the Fe 3 O 4 @SiO 2 (Figure 4b) and Fe 3 O 4 @SiO 2 -NH 2 (Figure 4c) XRD patterns, indicating retention of the crystalline spinel ferrite core structure during the coating process.The average MNPs core diame- , where β FWHM (full-width at half-maximum or half-width) is in radian and θ is the position of the maximum of diffraction peak, K is the so-called shape factor, which usually takes a value of about 0.9, and λ is the Xray wavelength (1.5406 Å for Cu Kα).
The FT-IR spectra of Fe 3 O 4 , Fe 3 O 4 @SiO 2 and Fe 3 O 4 @SiO 2 -NH 2 nanostructures are shown in Figure 5.For the bare magnetic nanoparticle (Figure 5a) the vibration band at 567 cm -1 is the typical IR absorbance induced by structure Fe-O vibration.In the case of Fe 3 O 4 @SiO 2 nanocomposite (Figure 5b), the band at 1072 cm -1 is corresponding to Si-O-Si antisymmetric stretching vibrations, being indicative of the existence of SiO 2 on the nanoparticles.Fe 3 O 4 @SiO 2 -NH 2 can be ascribed to the stretching and deformation vibrations of SiO 2 , reflecting the coating of amino group on the Fe 3 O 4 @SiO 2 core-shell nanocomposite surfaces.Successful aminopropyl functionalization of the silica layer on Fe 3 O 4 @SiO 2 was also evidenced by the absorption at 1478 cm -1 attributed to bending vibrations of amino groups.The absorption peaks in the region 2800-3025 cm -1 were associated with the stretching vibration of methylene groups of Fe 3 O 4 @SiO 2 -NH 2 (Figure 5c).The results verified the formation of a silica shell on the Fe 3 O 4 surface and the amino-functionalization of the silica shell.
The magnetic properties of the uncoated magnetic iron oxide (Fe 3 O 4 ), Fe 3 O 4 @SiO 2 , and Fe 3 O 4 @SiO 2 -NH 2 were measured by vibrating sample magnetometer, VSM, at room temperature (Figure 6).The hysteresis loops that are characteristic of superparamagnetic behavior can be clearly observed for all the nanostructures.Superparamagnetism is the responsiveness to an applied magnetic field without retaining any magnetism after removal of the applied magnetic field.From M versus H curves, the saturation magnetization value (Ms) of uncoated Fe 3 O 4 NPs was found to be 47.12 emu g -1 .For Fe 3 O 4 @SiO 2 and Fe 3 O 4 @SiO 2 -NH 2 , the magnetizations obtained at the same field were 41.23 and 32.42 emu g -1 , respectively, lower than that of uncoated Fe 3 O 4 .These results indicated that the magnetization of Fe 3 O 4 decreased considerably with the increase of SiO 2 and aminopropyl groups.This is mainly attributed to the existence of nonmagnetic materials on the surface of the nanoparticles.Firstly, to obtain the best reaction conditions for the synthesis of polysubstituted dihydropyridine 5a, the model study was carried out in the presence of various catalytic systems including homogenous and heterogeneous catalysts.As can be seen from Table 1, among the various catalysts, Fe 3 O 4 @SiO 2 -NH 2 core-shell nanostructures were found to be the most effective catalyst for the synthesis of polysubstituted dihydropyridine 5a at room temperature.
To find the optimized amount of the catalyst, the preparation of dihydropyridine 5a was carried out using different amounts of Fe 3 O 4 @SiO 2 -NH 2 as the catalyst (0.002, 0.005, 0.01, 0.02, 0.03 g).The best result was obtained by using 0.01 g of Fe 3 O 4 @SiO 2 -NH 2 nanocomposites at room temperature.
In continuation of this research, to select the appropriate solvent, various solvents such as, dichloromethane, DMF, water, toluene and ethanol were used in the model reaction in the presence of Fe 3 O 4 @SiO 2 -NH 2 at room   The substrate scope of this protocol for the synthesis of a variety of polysubstituted dihydropyridines was studied next by applying various amines and aldehydes to the reaction (Scheme 1 and Table 3).As shown in Table 3, aniline derivatives, including those bearing electron-donating or electron-withdrawing as well as sterically demanding substituents, reacted very well to afford the desired products 5a-t in excellent yields over short reaction times.Also, various arylamines with electron-releasing groups such  as methoxy and methyl groups reacted in short reaction times and giving products with higher yields than those with electron-withdrawing groups such as NO 2 and Cl.
In addition, aryl aldehydes with electron-withdrawing groups such as NO 2 , Cl and Br reacted very smoothly to produce highly functionalized dihydropyridines in relatively short reaction times in comparison with aryl aldehydes bearing electron-donating groups, but sterically hindered aldehydes reacted more slowly compared to unhindered aldehydes.
As the results in Table 3 show, Fe 3 O 4 @SiO 2 -NH 2 proved to be a useful nanomagnetic heterogeneous acid nanocatalyst for green synthesis of polysubstituted dihydropyridines in excellent yields.
][14] It is likely that NH 2 groups on the surfaces of nanoparticles act as a Brønsted base and cause the dehydrogenation of substrates.First, the Knoevenagel condensation of malononitrile/ethyl acetoacetate is suggested to give the intermediate A. Then, a nucleophilic attack of arlymine to dimethyl acetylenedicarboxylate leads to the formation of intermediate B. Michael addition of intermediate B to A forms the intermediate C which undergoes an intramolecular cyclization which is catalyzed by Brønsted basic (-NH 2 ) functionalized Fe 3 O 4 core-shell nanoparticles.In the last step, the intermediate D is tautomerized to the product 4.

1. General
Chemicals were purchased from the Sigma-Aldrich and Merck in high purity.All of the materials were of commercial reagent grade and were used without further purification.All melting points are uncorrected and were determined in capillary tube on Boetius melting point microscope.NMR spectra were obtained on a Bruker DRX-400 MHz spectrometer ( 1 H NMR at 400 Hz, 13 C NMR at 100 Hz) with CDCl 3 as the solvent, using TMS as an internal standard.Chemical shifts (δ) are given in ppm and coupling constants (J) in Hz.FT-IR spectrum was recorded on Magna-IR, spectrometer 550.The elemental analyses (C, H, N) were obtained from a Carlo Erba Model EA 1108 analyzer.Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer of X'pert Company with monochromatic Cu Kα radiation (λ = 1.5406Å).Microscopic morphology of the products was visualized by SEM (LEO 1455VP).The mass spectra were recorded on a Joel D-30 instrument at an ionization potential of 70 eV.Magnetic properties were obtained on a BHV-55 vibrating sample magnetometer (VSM) made by MDK, I. R. Iran.The compositional analysis was done by energy dispersive analysis of X-ray (EDX, Kevex, Delta Class I).

2. Preparation of Fe 3 O 4 Nanoparticles
Fe 3 O 4 NPs were prepared according to a procedure previously reported by Hu et al 35  Ghasemzadeh and Abdollahi-Basir: Fe 3 O 4 @SiO 2 -NH 2 Nanocomposite as a Robust ... l (100 mL, 1.2 mM) in an ultrasonic bath (30 min).Then, aqueous NaOH (150 mL, 1.25 M) was added under vigorous stirring and a black precipitate was immediately formed.The resulting solution was heated at 80 °C with rapid mechanical stirring under N 2 atmosphere (2 h).The black products were centrifuged, filtered off and washed with deionized water and ethanol several times, and finally dried at 60 °C for 12 h.

Preparation of Fe 3 O 4 @SiO 2 Nanoparticles
Fe 3 O 4 @SiO 2 core-shell nanoparticles were prepared via modified Stöber sol-gel process. 3630 mg as-prepared Fe 3 O 4 submicrospheres were ultrasonically dispersed in a solution containing 160 mL ethanol, 40 mL water and 10 mL concentrated ammonia (28 wt%).Then, 0.4 mL TEOS was added dropwise to the solution under sonication, followed by mechanical stirring for 3 h at room temperature.Subsequently, the resulting particles were separated using a magnet and washed with deionized water and ethanol.This step was repeated several times before drying at 60 °C for 12 h.

4. Preparation of Fe 3 O 4 @SiO 2 -NH 2
Fe 3 O 4 @SiO 2 -NH 2 MNPs were prepared according to a previously reported procedure by Jiahong Wang et al. 37 Amino-functionalized Fe 3 O 4 @SiO 2 nanocomposite was prepared by surface functionalization of Fe 3 O 4 @Si-O 2 nanocomposite using (3-aminopropyl)triethoxysilane (APTES). 2 g of Fe 3 O 4 @SiO 2 nanocomposite and 50 mL of toluene were added to a 250 mL three-necked flask and then ultrasonically dispersed for 15 min.4 mL of APTES (Sigma) was then added into the flask, and the mixture was refluxed at 110 °C with continuous stirring for 12 h under a nitrogen flow (40 mL/min).The resulting functionalized Fe 3 O 4 @SiO 2 was gathered by filtration followed by washing with ethanol and acetone several times and drying at 50 °C under vacuum for 12 h.The materials obtained are referred to as Fe 3 O 4 @SiO 2 -NH 2 nanocomposite (Scheme 2).

5. General Procedure for the Synthesis of 1,4-Dihydropyridine Derivatives 5a-t
A solution of aldehyde (1 mmol), malononitrile/ethylcyanoacetate (1 mmol) and Fe 3 O 4 @SiO 2 -NH 2 Scheme 4. Preparation of amino functionalized silica-coated magnetite nanocomposites Ghasemzadeh and Abdollahi-Basir: Fe 3 O 4 @SiO 2 -NH 2 Nanocomposite as a Robust ... NPs (0.01 g) were stirred in 5 mL of ethanol at room temperature.Then, a solution of aromatic amine (1 mmol) and acetylenedicarboxylate (1 mmol) in 5 mL ethanol was added to it.The resulting mixture was stirred until the reaction was completed as indicated by thin-layer chromatography (TLC), then the catalyst was separated by an external magnet, the solid obtained was filtered and washed well with cold ethanol.The crude product was crystallized from hot ethanol to afford the pure product in high yield.
All of the products were characterized and identified with m.p., 1 H, 13 C NMR and FT-IR spectroscopy techniques.Spectral data of the new products are given below.

6. Catalyst Recovery
After completion of the reaction, the catalyst was separated using an external magnet and then was washed three to four times with chloroform and ethyl acetate and then dried at 50 °C for 10 h.The separated catalyst was used for six cycles with a slightly decreased activity as shown in Table 4.

Conclusions
In summary, here we describe an efficient method for the synthesis of polysubstituted dihydropyridines through a one-pot four-component reaction of aldehydes, aryl amines, dimethyl acetylenedicarboxylate and malononitrile/ethyl acetoacetate using Fe 3 O 4 @SiO 2 -NH 2 nanocomposites at room temperature.This method offers several advantages including high yields, short reaction times, simple work-up procedure, mild and green reaction conditions, ease of separation, recyclability and reusing of the magnetic nanocatalyst.

Scheme 3 .
Scheme 3. The proposed mechanism for the synthesis of dihydropyridines by Fe 3 O 4 @SiO 2 -NH 2 NPs

Table 1 .
Yields and reaction times for the preparation of 1,4-dihydropyridine 5a in the presence of various catalysts.a
. As shown in Table2, we found that ethanol is the most efficient solvent for the synthesis of polysubstituted dihydropyridine 5a, giving the product in 94% yield (Table2, entry 6).

Table 2 .
The effect of solvents/reaction times on the yield of dihy- bIsolated yield.