Synthesis of thiazolidine derivatives via multicomponent reaction in the presence of Fe 3 O 4 @ SiO 2 -SO 3 H nanoparticles as a heterogeneous catalyst

A novel and convenient procedure for the synthesis of thiazolidine derivatives has been described. The reaction of primary alkylamines, isothiocyanates and maleic anhydride in the presence of magnetically supported sulfuric acid on Fe 3 O 4 @SiO 2 nanoparticles ( MNPs@SiO 2 -SO 3 H ) as a heterogeneous catalyst led to synthesis of thiazolidine derivatives. The desired products were obtained in moderate to good yields. Important Advantages of this method are easy and fast catalyst separation, simple purification procedure, facile procedure and mild condition. The synthesized products were fully characterized by FT-IR, 1 H-and 13 C-NMR and elemental analyses. The structure of MNPs@SiO 2 -SO 3 H was identified by scanning electron microscopy ( SEM ), transmission electron microscopy ( TEM ), thermogravimetric analysis ( TGA ) and x-ray powder diffraction ( XRD ).


Introduction
Nowadays, due to the increasing pollution of the environment and its devastating effects on human life, the development of methods based on eco-friendly materials and green chemical methods has attracted much attention.Therefore, the development of chemical processes with the use of green catalysts, chemicals, solvents, and atomic efficiency processes appear as a theme for innovation in green chemistry.2][3][4][5][6][7][8] Magnetic nanoparticles (MNPs) have received great interest because of their potential applications in cell separation, 9 magnetic resonance imaging, 10 drug delivery systems, 11 protein separation 12 and cancer treatments through hyperthermia. 13The MNP surface without modifications does not have the proper capabilities to create strong covalent bonds with other molecules.However, the reactivity of MNPs can be improved by coating them with a silica layer.The resulting silica shell can easily be modified by various functional groups through covalent bonding. 14,15e3O4 nanoparticles is being vigorously studied because of its attractive features such as ease to recover, high surface area, super paramagnetism, low toxicity and their potential applications in various fields. 16Fe3O4 nanoparticles are easily prepared and susceptive for accept a wide range of functional group on its surface.They can be recycled from the solution by an external magnetic field.So, this separation method is much more effective than other methods. 17Synthesis of magnetic core-shell structures by coating a SiO2 shell around is an interesting topic in Fe3O4 nanoparticle 18 heterogeneous catalysts show higher catalytic activities than their counter parts because of their solubility in reaction media, which increases catalytic site accessibility for the substrate. 191][22][23][24][25][26][27] Significant progress has been made in MCRs over the last decade and there has been much effort to improve the new MCR. 28In these reactions, numerous new bonds can be formed in a one-pot reaction that does not require the separation of intermediate products.Strecker was the first chemist to use MCRs to synthesize amino acids. 291][32][33][34][35][36][37][38][39][40] Thiazolidines are one of the compounds synthesized in recent years using MCRs.Thiazolidines, which represent an important class of heterocycles, have attracted considerable researches in recent years because of their broad utility.Thiazolidinones have received much attention and have been found in variety of biologically active compounds.These heterocycles show an effective and strong activities as an antimicrobial, [41][42][43] antidiarrheal, 44,45 antidiabetic, 46 antihistaminic, 47,48 anticancer, 49 antifungal, 50 and anti-HIV. 51Since the use of more effective pharmaceutical and industrial compounds is a continuous need of modern societies, the synthesis of new pharmaceutical compounds is a major task for chemists.
As part of our current study on the multicomponent reactions and synthesis of heterocycles, [52][53][54] here we report an efficient, novel and green synthesis of thiazolidine derivatives by tandem reaction of amines, isothiocyanates and maleic anhydride in the presence of MNPs@SiO2-SO3H as a catalyst.

Results and Discussion
Here, We set our minds to a simple and well-organized route for the synthesis of thiazolidine derivatives by a tandem reaction of amines, isothiocyanates and maleic anhydride in the presence of MNPs@SiO2-SO3H.© ARKAT USA, Inc At first, the reaction was carried out by benzylamine (1e 1 mmol), phenylisothiocyanate (2e 1 mmol) and maleic anhydride (3e 1 mmol) in EtOH at room temperature.It was noticable that in the absence of any catalyst no product was formed.Then, various catalysts such as BF3, nano Fe3O4, ZnO, and CuO as well as MNPs@SiO2-SO3H were tested.As can be seen in Table 1, the best results obtained by MNPs@SiO2-SO3H.Thus, MNPs@SiO2-SO3H was selected as more suitable catalyst.In the next step, to improve the efficiency and optimization of the reaction, the effect of solvents was examined.Among the examined solvents, the yield is significantly increased by DMF as solvent (Table 1).Model reaction conditions: 1e (1.0 mmol), 2e (1.0 mmol), 3e (1.0 mmol), catalyst (20 mg) and solvent (2 mL). a Isolated yields.
b Optimized reaction conditions.
In the end, the effect of amount of catalyst was studied.Various amounts of catalyst was tested and the results are given in Table 2.The yield of product 4e 55 improved when the amount of catalyst increased from 10 mg to 30 mg however, amounts greater than 30 mg of catalyst had no significant influence in this conversion.Thus, optimal amount of MNPs@SiO2-SO3H found 30 mg which resulted in a 67% yield of product 4e after 8 h at room temperature.The optimized reaction conditions were selected using 30 mg MNPs@SiO2-SO3H, 1 mmol of 1, 1 mmol of 2 and 1 mmol of 3 in DMF at room temperature.Then, we applied the optimized reaction conditions to the synthesis of thiazolidine derivatives from reaction of the various primary amines, isothiocyanates and maleic anhydride.As described in Table 3, 4methoxyphenyl isothiocyanate reacted well in this reaction with good yield and had higher yields than p-tolyl isothiocyanate and phenyl isothiocyanate.Aromatic amines with a Cl group in the para position had higher yields than ortho position.Aliphatic amines are not suitable substrates for this reaction.The synthesized products 4a-h were completely characterized by their IR, 1 H NMR, 13 C NMR spectra and elemental analyses data.In the IR spectrum of 4a, absorption bands at 1727 and 1710 cm -1 (C=O) are the most significant stretching frequencies.In 1 H NMR spectrum of 4a, multiplet signal at δ 3.01-3.15ppm related to one CH2 group.One singlet signal at 3.76 ppm and one broad signal at 4.40 ppm are related to methyl of methoxy and CH2 groups, respectively.The aromatic protons appeared at δ 6.89-7.35ppm.In The 1 Hdecoupled 13 C NMR spectrum of 4a were observed 15 distinct resonances in agreement with the proposed structure.The characteristic signals for two carbonyl groups were observed at δ = 171.6 and 173.3 ppm.
][58][59] Prepared catalyst was estimated using SEM (Figure 1).SEM analysis of the synthesized catalyst shows that nano particles are uniform dispersed and spherical.TGA of Fe3O4@SiO2-SO3H reported in Figure 3.The primary weight loss of the catalyst under 100 °C (about 2%) is presumably affected by the contained water and solvent.From 150 to 400℃, decomposition of the SiO2 and SO3H groups took place.The results of TGA illustrated that there is SO3H groups in the magnetite nanoparticles with weight is around 15%.Throughout the TGA demonstrated that SO3H groups existed on the surface of magnetite nanoparticles.The reusability of Fe3O4@SiO2-SO3H, in the synthesis of compound 4e was evaluated.After each reaction, the catalyst was separated out using an external permanent magnet, washed with ethyl acetate and dichloromethane to remove any organic impurities.It was then dried at 80 °C and reused for the next cycle, without further activation.It is found that the Fe3O4@SiO2-SO3H could be reused for seven consecutive reactions (Figure 5).

Conclusions
In summary, the synthesis of the thiazolidine derivatives by reaction thiourea intermediate with maleic anhydride was successfully achieved using MNPs@SiO2-SO3H as a catalyst.The advantages of this work are high yield of the desired product, under mild conditions, easy synthesis of the catalyst, available starting materials, and short reaction times.

Experimental Section
General.All chemicals and solvents were purchased from Merck (Germany) and Fluka (Switzerland) and were used without further purification.IR Spectra were obtained on a Perkin-Elmer Spectrum RXI FT-IR spectrometer.SEM image was observed using Tescan MIRA [III] instruments.TEM image recorded using CM120 Philips instruments.XRD was recorded at room temperature with a Philips PW1730.TGA was performed using TA Q600 with a heating rate of 10 °C min -1 over a temperature range of 25-800 °C.VSM data were obtained on a LBKFB. 1 H and 13 C-NMR Spectra were obtained on Bruker AMX-300 MHz spectrometer at 300 and 75.5 MHz, respectively.TMS as internal standard.Also Melting points were recorded with an Electrothermal 9200 apparatus.Elemental analyses were measured with using a Perkin-Elmer 2004 series [II] CHN elemental analyzer.
General procedure for synthesis of Fe3O4 MNPs. 5 mmol FeCl3.6H2O and 2.5 mmol FeCl2.4H2Osalts were dissolved in 100 mL deionized water.The mixture was stirred at 85 °C for 1 h under vigorous stirring.In the next step, 30 ml NH4OH solution (25%, w/w) was added to it.PH reaches to 10.This solution was stirred mechanically for 8 h under reflux.The resulting black dispersion was collected by an external magnet and was washed with ethanol three times and then dried at 80 °C for 10 h.General procedure for surface modification of Fe3O4 by tetraethylorthosilicate. Coating of a layer of silica on the surface of the Fe3O4 nanoparticles were performed by a modified Stober method.The obtained magnetic nanoparticle was dispersed in ethanol by sonication then heated for 1 h at 40 °C.Finally, tetraethyl orthosilicate (TEOS, 10 mL) was added to the reaction vessel, and the mixture was stirred mechanically for 24 h.The silica-coated nanoparticles were collected by a magnet.Product was washed five times with EtOH, diethyl ether and dried at 80 °C in vacuum for 4 h.General procedure for synthesis of Fe3O4@SiO2 coated with chlorosulfonic acid.Chlorosulfonic acid (0.638 g, 5.5 mmol) was dissolved in CH2Cl2 (10 mL) and added to 1 g of the former suspension of Fe3O4@SiO2 nanoparticles.The mixture was stirred for 30 min at room temperature.Then residue was collected by a magnet, followed by washing several times with 50 ml diethyl ether and it was dried at room temperature to obtain Fe3O4@SiO2@SO3H.General procedure for the synthesis of Compounds 4a-h.Primary amine 1 (1 mmol) was added to phenylisothiocyanate 2 (1 mmol) at room temperature and stirred for 20 min.Next, maleic anhydride 3 (1 mmol), MNPs@SiO2-SO3H (30 mg) and DMF (5 ml) were added to the mixture and stirring was continued for 8 h.After completion of the reaction (monitored by TLC), the catalyst was collected with external magnet, followed by washing the nanoparticles three times with ethanol.Solvent was removed under reduced pressure.The crude product was washed with EtOH to give the pure products 4a-h.

Table 1 .
Results of the Synthesis of 4e under Different Reaction Conditions.

Table 2 .
Optimization and comparison of various amounts of MNPs@SiO2-SO3H.

Table 3 .
Synthesis of thiazolidine derivatives a Isolated yields