Nano-Fe3O4–Supported, Hydrogensulfate Ionic Liquid–Catalyzed, One-Pot Synthesis of Polysubstituted Pyridines

Abstract Anchoring 1-methyl-3-(triethoxysilylpropyl) imidazolium chloride onto silica-coated magnetic Fe3O4 particles afforded the corresponding supported ionic liquid. Exchanging the Cl− anion by treating with H2SO4 gave Brønsted ionic liquid 1-methyl-3-(triethoxysilylpropyl) imidazolium hydrogensulfate. The synthesized catalyst was characterized by various techniques such as infrared, x-ray diffraction, scanning electron microscopy, thermogravimetric analysis, and elemental analyses. The results indicated that the prepared catalyst had a nanostructure. The catalytic activity of the supported ionic liquid was examined in the synthesis of the polysubstituted pyridines by reaction of aromatic aldehydes with acetophenones and ammonium acetate in moderate to good yields under solvent-free conditions. The catalyst can be easily recovered by applying an external magnetic field and reused for at least seven runs without deterioration in catalytic activity. GRAPHICAL ABSTRACT


Characterization of the Catalyst
The external surface of magnetite nanoparticles was coated with silica (Fe 3 O 4 @ SiO 2 ) to improve the chemical stability and prevent further aggregation of MNPs. 1-Methy-3-(trimethoxysilylpropyl) imidazolium chloride was anchored onto solid support via treatment with silanol groups of Fe 3  are observed that confirm the structure of the catalyst, which is in good agreement with the reported FT-IR data. [36][37][38] For MNP-[pmim]HSO 4 (e), the appearance of the O=S ¼ O asymmetric and symmetric stretching modes lie in 1133 and 1076 cm À1 respectively together with the broad OH stretching absorption around 2800 to 3380 cm À1 , confirming the exchange of Cl À ions with HSO 4 À ions. Crystalline structure of MNP-[pmim]HSO 4 was characterized by X-ray diffraction (XRD) in Fig. 2
The particle sizes of MNP-[pmim]HSO 4 and MNP@SiO 2 were evaluated using scanning electron microscopy (SEM). The SEM images (Fig. 6) showed floccules without having a regular structure. On the other hand, the shape of these particles was mostly spherical and the surface of them was not smooth, which resulted in an increase in the surface areas of these particles. In these cases, average diameter of      The loading level of IL (0.99 mmol=g) was determined based on the chloride content in MNP-[pmim]Cl by titration method. [40] The evaluated loading by titration method was in good agreement with the results obtained from TGA and conventional elemental analysis. After characterization of the catalyst (MNP-[pmim]HSO 4 ), the catalytic activity of the catalyst was investigated in the one-pot synthesis of 2,4,6-triarylpyridines.

Synthesis of Triaryl Pyridines Catalyzed by MNP-[pmim]HSO 4
The three-component process of benzaldehyde (1 mmol), acetophenone (2 mmol), and NH 4 OAc (1.3 mmol) was chosen as a model reaction to optimize the reaction conditions such as molar ratio of the catalyst, temperature, and solvent (Table 1). Three separated reactions were examined in the absence of any catalyst and in the presence of MNP and MNP-[pmim]Cl. The results of these studies showed that trace amount of the desired product was formed ( . Increasing the amount of catalyst does not improve the yield of the product any further but decreasing the amount of catalyst leads to decrease in the product yield. Because the best solvent from green chemistry point of view is no solvent, combination of solvent-free conditions with a multicomponent reaction has been shown to be a powerful strategy for making complex molecular structures, and we chose it as optimal reaction condition (entry 9).
To establish the generality of this method, synthesis of various triarylpyridines was studied using different aldehydes and acetophenones under optimized reaction conditions ( Table 2).
As is clear from Table 2, aromatic and heteroaromatic aldehydes were tolerated well in this reaction and varieties of aldehydes with electron-donating or electronwithdrawing groups on the aromatic ring had little effect on the reaction rate. Desired products were formed in good yields ( Table 2, entries 1-8 and 13-16). Heteroaromatic aldehydes also tolerate the condensation reaction to afford the corresponding pyridines in good yields (Table 2, entries 10-12).
A plausible mechanism for the formation of 2,4,6-triphenylpyridines catalyzed by MNP-[pmim]HSO 4 is shown in Fig. 7. The first step of the process involves Knoevenagel condensation of aldehyde with acetophenone to form the corresponding chalcone (A). The reaction proceeds through Michael addition of second molecule of acetophenone to (A) followed by nucleophilic attack of ammonium acetate to the carbonyl group of adduct (B) and intramolecular cyclization by loss of water molecular to produce dihydropyridines (C). Aromatization and oxidation of dihydropyridines (C) by air under the reaction conditions give pyridines as final products. Recovery and reuse of a catalyst is highly preferable for a catalytic process. In this regard the recyclability of MNP-([pmim]HSO 4 was investigated in the model reaction of benzaldehyde, acetophenone, and ammonium acetate under optimized reaction conditions. After completion of the reaction, EtOAc was added and the whole amount of MNP-[pmim]HSO 4 was simply separated from the product by an external magnet. The recovered catalyst was washed with ethyl acetate, dried at room temperature, and reused for the next reaction. The magnetic property of MNP-[pmim]HSO 4 facilitates the efficient recovery of the catalyst from the reaction mixture during workup procedure, and the catalyst was recycled and reused for seven consecutive trials without significant loss of its catalytic activity (Fig. 8).
The recyclability test was stopped after seven runs. Comparison of the scanning eletron microscopy (SEM) image and FT-IR spectra of used catalyst ( Fig. 9)

ONE-POT SYNTHESIS OF POLYSUBSTITUTED PYRIDINES 1971
EXPERIMENTAL Materials were purchased from Merck and Aldrich Chemical Companies and used without further purification. All the solvents were distilled, dried, and purified by standard procedures. The samples were analyzed using a FT-IR vector 22 spectrometer (Bruker Vector in KBr matrix). NMR spectra were recorded on a Bruker DRX-400 Avance instrument (400.1 MHz for 1 H, 100.6 MHz for 13 C) with dimethylsulfoxide (DMSO) as the solvent. Chemical shifts (d) are given in parts per million (ppm) relative to tetramethylsilane (TMS), and coupling constants (J) are reported in hertz (Hz). Mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heraeus CHNS=O-Rapid analyzer. Thermogravimetric analysis (TGA) was recorded on a Stanton Redcraft STA-780 (London, UK). X-ray diffraction (XRD) was carried out on a Philips Xpert Pro diffractometer using Cu Ka source (k ¼ 1.5418 Å). FESEM images were obtained on a Hitachi S-1460 field-emission scanning electron microscope using an AC voltage of 15 kV. Melting points were measured on an Electrothermal 9100 apparatus.

General Procedure for the Synthesis of Catalyst
Silica-coated magnetite nanoparticles (Fe 3 O 4 @SiO 2 ) were prepared according to the reported method. [38,41] Then ionic liquid of 1-methy-3-(trimethoxysilylpropyl) imidazolium chloride ([pmim]Cl) was synthesized according to the reported method. [42] In the next step for anchoring of ([pmim]Cl on the silica-coated magnetite nanoparticles, [pmim]Cl (0.5 gr, 1.3 mmol) was dissolved in 25 ml of dry toluene and treated with 1 g of previously prepared Fe 3 O 4 @SiO 2 . After heating the slurry at 90°C for 16 h, the resulting solid was then separated by an external magnet and washed with 100 ml of dichloromethane. Afterward, the unreacted ionic liquid was removed by extraction for 24 h with boiling dichloromethane (soxhlet extraction) and the material (MNP-[pmim]Cl) was dried under high vacuum. At the end for exchanging the Cl À anion, MNP[pmim]Cl (1 g) was suspended in 20 ml of dry CH 2 Cl 2 . During vigorous stirring, concentrated H 2 SO 4 (1.3 mmol 98%) was introduced drop by drop at 0°C. Then the mixture was warmed up to the room temperature and refluxed for 48 h. The mixture General Procedure for the Synthesis of Triarylpyridines MNP-([pmim]HSO 4 ) (0.012 gr, 1.2 mol%) was added to a mixture of aldehyde (1.0 mmol), acetophenone (2.0 mmol), and ammonium acetate (1.3 mmol) and the resulting mixture was stirred at 100°C for the specific period of time. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, EtOAc (10 ml) was added to the cooled reaction mixture. The catalyst was separated by an external magnet, washed with EtOAC, dried, and reused for a consecutive run under the same reaction conditions. Evaporation of the organic solvent under reduced pressure gave the crude products. Pure products were obtained by recrystallization by aqueous EtOH. The products were characterized by IR, 1 H NMR, and 13 C NMR spectra.
To show the merit of the present protocol for the synthesis of the triarylpyridines, we have compared our results with some of the reported in the literature (Table 3). Although all the methods are effective, the present procedure comparatively affords good yield of the product with reusability for at least 7 consecutive runs without loss of activity.

CONCLUSION
In summary, we successfully synthesized a supported IL of 1-methyl-3-(trimethoxysilylpropyl) imidazolium hydrogensulfate (MNP-[pmim]HSO 4 ) from readily available starting materials. It was applied as a magnetically recyclable heterogeneous catalyst for the one-pot, three-component synthesis of triarylpyridines. This catalyst efficiently promoted the condensation of aromatic aldehydes and acetophenone with ammonium acetate, leading to corresponding pyridines in moderate to good yields under solvent-free conditions. Product separation and catalyst recycling are easy and simple with the assistance of an external magnet. The catalyst can be recovered and reused for seven cycles without significant degradation in activity.

SUPPLEMENTAL MATERIAL
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