Design and Preparation of Copper(II)-Mesalamine Complex Functionalized on Silica-Coated Magnetite Nanoparticles and Study of Its Catalytic Properties for Green and Multicomponent Synthesis of Highly Substituted 4H-Chromenes and Pyridines.

In the present study, a green and ecofriendly nanocatalyst was synthesized through functionalization of 2,4,6-trichloro-1,3,5-triazine (TCT) and mesalamine on silica-coated magnetic nanoparticles (MNPs), then coordination with Cu2+ without agglomeration, consecutively. The silica-coated MNPs functionalized with the Cu(*II)-mesalamine complex was (Fe3O4@SiO2@NH2-TCT-mesalamine-Cu(II) MNPs) completely characterized by FT-IR, XRD, EDX, FESEM, TEM, VSM, TGA, and BET analyses. Afterward, the activity of the novel catalyst was investigated in the synthesis of chromene heterocycles, which were an important group of organic compounds. The activity of Fe3O4@SiO2@NH2-TCT-mesalamine-Cu(II) MNPs as a high-performance heterogeneous nanocatalyst was evaluated for the synthesis of 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles and 2-amino-4H-chromenes via aromatic aldehydes, malononitrile, and enolizable C-H acids (resorcinol, 2-hydroxynaphthalene-1,4-dione, and benzenethiol) in ethanol under reflux conditions. Fe3O4@SiO2-TCT-mesalamine-Cu(II) could be quickly separated using an external magnet and reused nine times without a remarkable reduction of its catalytic activity.

Introduction

Magnetic nanoparticles (MNPs) and cleaner production methods are applied in a wide field of chemical sciences.[1−4] MNPs can be recovered through a simple separation process using an external magnetic field.[5−9] Another advantage of magnetic nanocatalysts is that by changing the size, shape, or composition of MNPs, their properties and characteristics can be controlled, which facilitates their wide range of applications in various fields.[10] To achieve greater stability and to create a suitable substrate for different types of catalysts, various methods have been used to change the surface of MNPs and then stabilize the catalysts on them. It can be noted that the surface of nanoparticles is covered by different layers that create a suitable substrate for catalyst stabilization and are comparable to unstabilized catalysts.[11] In addition to increasing the stability of catalysts under harsh conditions, these methods maintain their catalytic properties during the washing process, which leads to an increase in the number of reuses. Moreover, various methods have been developed to stabilize organic surfactants with long organic (carbon) chains on the surface of MNPs that make them easily soluble in non-polar solvents (such as n hexane, toluene, chloroform, etc.) using dispersion and suspension. It is important to note that surface modification methods must be easy to implement for industrial applications.[12]

Over the past few decades, many new multicomponent reactions (three- and four-component reactions) have been introduced.[13−16] To date, with the increasing benefits of biologically active molecules, the application of these reactions to the production of pharmacological molecules in industry has increased.[17] The advantages of this method compared to other methods are the use of available materials, low cost, simple working method, and so on.[18,19] This method is one of the main existing methods to synthesize heterocyclic compounds such as chromene and pyridine scaffolds via the cyclocondensation of aldehyde, malononitrile, and phenol or thiol under various conditions.

Nitrogen-containing heterocyclic compounds are widely present in drugs and biologically active compounds, thus incorporation of multiple structural units of this type into a candidate drug molecule can improve biological activity and pharmacological properties[20−24] (Scheme ). One of the important nitrogen containing compounds was synthesized by Hantzsch in order to carry out multicomponent reactions. Hantzsch synthesized pyridine by reacting ethyl acetoacetate, aldehyde, and ammonia with a cyclic density.[25] Demand for the pyridine structure and its derivatives has continued to increase over the past 50 years due to the presence of pyridine in many bioactive compounds.[26] Although pyridine derivatives have been of little commercial importance for decades, attention to these systems has increased since the 1930s due to the importance of compounds such as niacin,[27] which is used in the treatment of skin and neurological diseases. Vinyl pyridine was discovered in 1940 and was used as a component of latex. Other derivatives such as 2-picoline were also considered due to their use in elastic latex derivatives.[28]

Scheme 1

Potent Biologically Active Highly Substituted Pyridines

In 1904, Houben reported 2H-chromene synthesis from the reaction of coumarin in the presence of magnesium alkyl halide.[29] 1-Benzopyrans have a bone structure of chromane, 2H-chromene, and 4H-chromene (Scheme ).

Scheme 2

Chromane, 4H-Chromene, and 2H-Chromene

Chromenes and pyridines show anticoagulant, anticancer, diuretic, spasmolytic, and diuretic activities and are of pharmacological and biological importance.[30−32] These heterocycles are also applied in the treatment of the diseases including schizophrenia, parkinson’s, hypertension, and alzheimer’s.[33] A number of chromene derivatives can inhibit the growth of bacteria and show good antimicrobial properties against various bacteria. For example, the literature has shown that these compounds show good selective structures against P-putida(34) (Scheme ).

Scheme 3

Examples of Chromene with Selective Structures against P-Putida

In general, it seems that Knoevenagel condensation occurred in the reaction of an aldehyde with malononitrile to form arylidine(alkylidine)malononitrile for synthesis of these heterocycles. With the addition of the third component (enolizable C single bond H acids such as Kojic acid, barbituric acid, dimedone, 2-hydroxy-1,4-naphthoquinone-4-hydroxy coumarin, α- and β-naphthol, and resorcinol), chromene derivatives are synthesized.[35] In previous literature, many routes were reported for the preparation of chromenes using different catalysts, such as H6P2W18O62·18H2O,[36] silica-grafted ionic liquids,[37] ionic liquids,[38] α-Fe2O3 nanoparticles,[39] Mg/La-mixed metal oxides,[40] C16H33N(CH3)3Br,[41] and (NH4)2HPO4.[42]

In accordance with the abovementioned significance, 2-amino-4-(4-arylphenyl)-4H-chromene-3-carbonitrile and 2-amino-4-aryl-6-(arylthio)pyridine-3,5-dicarbonitriles were synthesized using a condensation reaction between various aldehydes, malononitrile and 2-hydroxynaphthalene-1,4-dione, resorcinol, and benzenethiol in the presence of Fe3O4@SiO2-TCT-mesalamine–Cu(II) MNPs as a magnetically heterogeneous catalyst in ethanol under reflux conditions (Scheme ). Synthesis method of the Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) catalyst reported here has advantages over most of the previous methods, such as a simple work-up procedure, a shorter reaction time, higher reusability of the catalyst, clean reaction, progress in the reaction rate, and best yields.

Scheme 4

Synthesis of 2-Amino-(4-arylphenyl)-4H-chromene-3-carbonitrile and 2-Amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitrile Derivatives Catalyzed by Fe3O4@SiO2@NH2-TCT-Mesalamine–Cu(II) MNPs

Results and Discussion

Silica-coated MNPs functionalized with the Cu(II)–mesalamine complex as a simple, efficient, recyclable, and environmentally friendly nanomagnetic catalyst were prepared by cheap, simple, and readily available chemicals (Scheme ). The catalyst was characterized using FT-IR spectroscopy, X-ray diffraction (XRD), energy-dispersive X-ray (EDX) spectrometry, FESEM, TEM, VSM, TGA, and Brunauer–Emmet–Teller (BET) analyses.

Scheme 5

Synthesis of Fe3O4@SiO2@NH2-TCT-Mesalamine–Cu(II) MNPs

The FT-IR spectra of the nanocatalyst recorded step by step in the range 400–4000 cm–1 are shown in Figure . Figure a–f shows absorption bands at ∼637 cm–1 attributed to the FeO vibrations. The existence of OH and NH stretching vibrations is shown as a broad peak (3000–3500 cm–1). New broad bands attributed to the existence of acidic OH were observed in the range of 2700–3700 cm–1 (Figure e). Figure b–f shows bands at 1090, 800, and 470 cm–1 attributed to the symmetric and asymmetric stretching vibrations of the Si–O groups, which confirm the Si-modification of the MNPs. Immobilization of mesalamine on the surface of the NPs was evidenced by the presence of the characteristic overlapped acidic O–H stretching band of the O–H group in the spectrum shown in Fig. 1e. Finally, synthesis of the ligand and its copper(II) complex was confirmed by the absorption band at 469 cm–1 attributed to the Cu–O stretching vibrations (Figure f).

Figure 1

FT-IR spectra of Fe3O4 (a), Fe3O4@SiO2 (b), Fe3O4@SiO2@NH2 (c), Fe3O4@SiO2@NH2@TCT (d), Fe3O4@SiO2@NH2@TCT-mesalamine (e), Fe3O4@SiO2@NH2@ TCT-mesalamine–Cu(II) (f), and mesalamine (g).

Figure 2

XRD patterns of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

The crystallinity and the size of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) were determined by XRD analysis (Figure ). Intense Bragg’s peaks were observed at 2θ = 30.6, 37.4, 44.5, 58.4, and 63.2°, which correspond to the (220), (311), (400), (422), (511), and (440) planes, respectively. These peaks are related to the crystal planes in the Fe3O4 lattice and are in agreement with the standard XRD pattern of cubic Fe3O4 (JCPDS 88-0866).[43]

The elemental composition of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was investigated by EDX and elemental mapping analysis (Figures and 4). The achieved data from EDX and elemental mapping confirmed the presence of O, N, C, Fe, Si, and Cu elements in the catalyst with an appropriate dispersity.

Figure 3

EDX patterns of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

Figure 4

Elemental mapping analysis of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

For investigating the morphology, the particle size and particle aggregation mode of the Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) nanoparticles were studied using the FESEM and TEM images (Figures and 6). The average size of the coated particles was less than 82 nm, and sphere-like shape was changed due to the complex coating. From the TEM image, the nanometer-sized nature and the core–shell structure of the Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) nanoparticles were obvious.

Figure 5

FESEM analysis of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

Figure 6

TEM analysis of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

The magnetic behavior of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was also investigated by VSM and compared to that of intermediates (Fe3O4@SiO2@NH2@TCT-mesalamine) obtained in the synthetic pathway (Figure ). The specific saturation magnetization values (Ms) of Fe3O4@SiO2@NH2@TCT-mesalamine and Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) are measured to be 34 and 18 emu g–1, respectively. This decrease is due to the newly coated layer and affirms the favored synthesis of the nanomagnetic catalyst.

Figure 7

VSM analysis of (e) Fe3O4@SiO2@NH2@TCT-mesalamine and (g) Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

TGA analysis was used to investigate the thermal stability of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) and confirm the immobilized functionalized groups on the surface of the nanoparticles (Figure ). Three consecutive steps occur in the thermal range 25–800 °C. The weight loss below 180 °C (about 2%) can be attributed to the evaporation of the solvents, which were employed during the course of catalyst preparation. The weight loss from 150 to 350 and 400 to 550 °C (about 28%) can be attributed to the decomposition of the organic layer immobilized on Fe3O4@SiO2.

Figure 8

TGA analysis curves of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

The surface area was calculated using the BET method at a temperature of 77 °K, the linear slope of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was 47.052 m2/g, the quantity adsorbed in this BET surface area was 10.811 cm3 (STP) g–1, the total pore volume was 0.2643 cm3 g–1, and the mean pore diameter was 22.471 nm (Figure ).

Figure 9

(a) BET plot of the nitrogen adsorption–desorption isotherms of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II), (b) BET plot of nitrogen adsorption, (c) t-plot, and (d) Langmuir-plot of catalyst activity of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II).

After full characterization of the novel Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II), we study the catalytic activity for condensation reactions among the aldehydes, malononitrile, enolizable C–H acids (2-hydroxynaphthalene-1,4-dione, resorcinol, and benzenethiol) to synthesize various derivatives of chromenes and 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles under EtOH and reflux conditions (Scheme ). At first, for determining the optimal reaction conditions for synthesis of desired compounds, the substrates 4-nitrobenzaldehyde, malononitrile, and 2-hydroxynaphthalene-1,4-dione are mixed together (Table ). In the absence of the catalyst at room temperature, there is trace product formation even after 180 min (Table , entry 1). The optimal results of the process yield and the rate for the selected model reaction were obtained when the reaction was carried out under reflux conditions using a catalyst loading of 0.07 g in EtOH (entry 6).

Table 1

Study of Optimization of Reaction Conditions for Synthesis of 2-Amino-4H-chromenesa

entry	catalyst (g)	solvent	time (min)	yield (%)b
1	no catalyst	solvent-free	180	tracec
2	0.005	EtOH	120	35
3	0.01	EtOH	90	55
4	0.03	EtOH	70	68
5	0.05	EtOH	60	76
6	0.07	EtOH	30	96
7	0.1	EtOH	30	91
8	0.15	EtOH	35	86
9	0.07	H2O	45	65
10	0.07	H2O/EtOH (1:1)	60	55
11	0.07	CH3OH	180	61
12	0.07	CH2Cl2	240	51
13	0.07	CH3CN	240	35
14	0.07	toluene	260	38
15	0.07	DMF	150	43

Reaction conditions: 4-nitrobenzaldehyde (1 mmol), 2-hydroxynaphthalene-1,4-dione (1 mmol), malononitrile (1 mmol), various solvents (2 mL).

Isolated yield.

Room temperature.

The catalytic activity of the other intermediates of the Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was investigated using a model reaction for 60 min and the results are shown in Table . For this purpose, a reaction between the substrates 4-nitrobenzaldehyde, malononitrile, and 2-hydroxynaphthalene-1,4-dione in ethanol under reflux conditions was carried out. The best results were obtained in the presence of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II), which confirms its strong catalytic properties for the formation of a desired product (96%, entry 6). This is probably due to the presence of Cu coated on the surface of Fe3O4@SiO2@NH2@TCT-mesalamine. The obtained results for the Fe3O4@SiO2@NH2@TCT-mesalamine, Fe3O4@SiO2@NH2@TCT, Fe3O4@SiO2@NH2, Fe3O4@SiO2, and Fe3O4 were 73, 65, 53, 41, and 41%, respectively. By using CuCl2·2H2O as a Lewis acid catalyst, moderate yields can be obtained for the desired product (Table , entry 7).

Table 2

Catalytic Activity of the Other Intermediates of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

entry	catalyst	yield (%)a
1	Fe3O4	41
2	Fe3O4@SiO2	41
3	Fe3O4@SiO2@NH2	53
4	Fe3O4@SiO2@NH2@TCT	65
5	Fe3O4@SiO2@NH2@TCT-mesalamine	73
6	Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)	96
7	CuCl2·2H2O	49

Isolated yield.

Afterward, using the optimized reaction conditions, the scope and generality of the reaction were investigated using a diverse series of aromatic aldehydes carrying different substituent groups and various enolizable C–H acids (2-hydroxynaphthalene-1,4-dione, resorcinol, and benzenethiol) (Table ). All desired products were synthesized in short reaction times with high to excellent yields.

Table 3

Synthesis of Desired Products Using Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) under Reflux Conditionsa

Reaction conditions: aldehyde (1 mmol), malononitrile (1 mmol), enolizable C–H acids (1 mmol), nanocatalyst (0.07 gr), EtOH, reflux conditions.

The recyclability and reusability of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) for the synthesis of desired products were examined using a previously reported model reaction (Table ). After the completion of each run, the catalyst was washed with hot ethanol and stirred, then it was separated using an external magnet. The recovered nanocatalyst was reused for nine successive runs with no significant loss of activity (Figure ).

Figure 10

Recyclability and reusability of the catalyst.

The recovered Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was also characterized by SEM. The SEM image of the reused catalyst after nine runs shows that the catalyst retained its nanosize during the course of the reaction (Figure ). These results indicate that Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) exhibited excellent reusability in the synthesis of chromene derivatives.

Figure 11

SEM of the reused Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)

On the basis of above experimental observation and literature reports, a tentative mechanism is proposed in Scheme .[13] The reaction seems to be initiated by the effect of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) on malononitrile (A) and various aldehydes (B) to generate product (C) via Knoevenagel condensation. Addition of various phenols (D) by Michael addition to the Knoevenagel product (C) gave intermediate (E). In the final step, the enolization of intermediate (E) occurs giving the intermediate (F) that under intramolecular nucleophilic cyclization gives the final product. Then, the catalyst was separated by magnetic field for reuse.

Scheme 6

Probable Mechanism for the Formation of 2-Amino-4H-chromenes Derivatives

The other catalysts reported in previous literature for the synthesis of 2-amino-4H-chromenes have been compared with the present catalyst (temperatures, solvents, and catalysts), and the results are summarized in Table . The Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) catalyst synthesized in this work presents advantages over most of the catalysts reported in the literature including a simple work-up procedure, a shorter reaction time, higher reusability, clean reaction, progress in the reaction rate, and best yields. Therefore, the synthesized Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) was found to be a highly efficient catalyst for the formation of 2-amino-4H-chromene derivatives.

Table 4

Comparison of Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) with Other Catalysts Reported in the Literature for the Preparation of 2-Amino-4H-chromenes

entry	catalyst	reaction condition	time	yield
1	Fe(HSO4)3	0.1 mmol; refluxed in MeCN	4 h	83%[44]
2	Mg/Al-HT	15 wt %; H2O, 60 °C	2 h	95%[46]
3	PdRu/graphene oxide	water–ethanol (2:1), 80 °C	12 min	95%[47]
4	NaPTS solution	microwave	10–30 min	82–94%[48]
5	Pd@GO	10 mg; EtOH, 80 °C	15 min	92%[49]
6	TPOP-2	40 mg; solvent-free, 80 °C	5 h	87%[50]
7	VO2(L)](NHET3)	acetonitrile, 50 °C	45–50 min	85–97%[51]
8	tungstic acid-SBA-15	30 mg; H2O, 100 °C	12 h	86%[50]
9	Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II)	EtOH, reflux	15–45 min	86–95% (this work)

Experimental Section

Preparation of the Catalyst

Fe3O4 nanoparticles were synthesized by the coprecipitation method, as reported in the literature.[44] In 120 mL deionized water were added FeCl3·6H2O (0.97 g) and Fe2(SO4)3 (0.9 g) at 80 °C under N2 gas atmosphere for 10 min. Then, ammonia solution (10 mL, 25% aqueous) was added dropwise at 80 °C under a nitrogen gas atmosphere. The black Fe3O4 was stirred under a N2 gas atmosphere for 30 min. The reaction mixture was then allowed to cool at room temperature and the resulting black precipitate was separated using an external magnet and washed several times with distilled water. Magnetic iron nanoparticles were isolated and dried at room temperature for 24 h. Coating of Fe3O4 MNPs was achieved by the sol–gel approach, as reported in the literature.[45] 1 g MNPs in a mixture of 100 mL ethanol was dispersed for 30 min by sonication. Then, 3 mmol 3-(trimethoxysilyl)-1-propanamine was added to the MNPs under stirring, and the reaction mixture was refluxed under N2 for 12 h. Fe3O4@SiO2@n-pr-NH2 was filtered, washed twice with EtOH, and dried in a vacuum at 50 °C. 1 g Fe3O4@SiO2@n-pr-NH2 in a mixture of ethanol and water (80:20 mL) was dispersed for 30 min by sonication. 2 mL tetraethyl orthosilicate (TEOS) and 25% NH4OH (2 mL) were added to the suspended solid nanoparticles under stirring, and the reaction mixture was refluxed under nitrogen for 6 h. Fe3O4@SiO2 was filtered, washed twice with EtOH, and dried in a vacuum at 50 °C. Fe3O4@SiO2 (1 gr) in dry toluene was sonicated for 30 min. Then, TCT (5 mmol), NEt3 (5 mmol), and THF (10 mL) were added to the reaction mixture and stirred for 24 h at room temperature under a nitrogen gas atmosphere. The resulting catalyst was washed several times with ethanol and dried under vacuum at room temperature. In the next step, mesalamine (6 mmol) and EtOH (10 mL) were added to the reaction mixture and stirred for 24 h at room temperature under reflux conditions and under a nitrogen gas atmosphere. Finally, 1 g of Fe3O4@SiO2@NH2@TCT-mesalamine was dispersed in dry toluene for 30 min, then Cu(NO3)2·3H2O (5 mmol) was added and refluxed for 48 h. The product was separated by the external magnetic field, washed three times with deionized water and ethanol, and dried under vacuum for 24 h at room temperature.

General Procedure for Synthesis of 2-Amino-4-(4-arylphenyl)-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile

Various aromatic aldehyde (1 mmol), malononitrile (1 mmol), hydroxynaphthalene-1,4-dione, resorcinol (1 mmol), and Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) (0.07 g) were mixed in ethanol (5 mL) under reflux conditions appropriate times. After completion of the reaction, 5 mL of ethanol (95%) was added to the reaction mixture to dissolve the thick paste substance. The catalyst was easily collected using a magnet and washed and dried for reuse in subsequent reactions. The pure products were obtained from the reaction mixture by recrystallization from ethanol, and the melting point of the synthetic products was measured to compare with those of the reference samples.

General Procedure for Synthesis of 2-Amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles

To a mixture of aromatic aldehyde (1.0 mmol), malononitrile (1 mmol), and benzenethiol (1.0 mmol) was added the catalyst Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) (0.07 g) under reflux conditions in ethanol (5 mL) at an appropriate time. After the completion of the reaction (the progress of the reaction was monitored by TLC), the magnetic catalyst was separated from the mixture using an external magnet and reused. The reaction mixture was filtered and the obtained solid was washed with cold H2O. The collected product was recrystallized in EtOH.

Conclusions

In the present research, novel silicacoated MNPs with mesalamine as a linker functionalized by the Cu(II)–mesalamine complex was obtained and structurally characterized by XRD, EDX, TGA, FT-IR, VSM, ICP, BET, FESEM, mapping, and TEM analysis. Afterward, Fe3O4@SiO2@NH2@TCT-mesalamine–Cu(II) as a green and recoverable catalyst was used for the synthesis of chromenes and pyridine moieties under reflux conditions in ethanol. Mild and simple synthesis, short reaction times, no usage of column chromatography, excellent yields of desired products, and easy work-up procedure are advantages of the current method.