Nano-kaolin/Ti(IV)/Fe3O4: a natural based magnetic nano-catalyst for the synthesis of coumarins

INTRODUCTION    
Coumarin is a heterocyclic compound that plays an important role in the field of natural products and synthetic organic chemistry [1]. Coumarins are also a member of the benzopyrone family [2]. These compounds have shown various biological activities such as analgesic, antimicrobial, antimalarial, antioxidant, anti-inflammatory, anticancer, antituberculosis and anti-HIV properties [3]. In addition, coumarins are used in various industries such as perfumery, cosmetics, food industry and dispersed fluorescent and laser dyes [4-6]. Coumarins are synthesized in several various methods, such as Reformatsky [7], Wittig [8-9], Knoevenagel [10-11], Perkin [12], and Pechmann reaction [13]. One of the widely used methods for the synthesis of coumarin is the Pechmann reaction, which involves the condensation reaction between phenols and β- ketoesters by various types of acidic catalyst [14-15]. The catalysts including H2SO4 [13], P2O5 [16-17], AlCl3 [18], CF3COOH [19], starch-SO3H [20], SnCl4-SiO2 [21], NbCl5 [22], Nano-CuFe2O4 [23], ZrCl4 [24], [Et3NH]+[HSO4]- [25] and [Hmim]+[HO3SCH2SO3]- [26] have been applied for the preparation of these compounds. The drawbacks of these protocols are high price of catalyst, long reaction time and required large amounts of catalyst, which lead to environmental pollution.
Kaolin is a clay mineral, part of the group of industrial minerals with the chemical composition Al2Si2O5(OH)4. It is a layered silicate mineral, with one tetrahedral sheet of silica (SiO4) linked through oxygen atoms to one octahedral sheet of alumina (AlO6) octahedral [27-29]. The various physical attributes of kaolin mineral have made it useful in various ways industrially and these include paints, ceramics, rubber, paper, medicine, petroleum and glass industries [30]. One of main usege of kaolin is catalyst role in the chemical industry [31]. Magnetic nanoparticles are a category of nanoparticle that can be manipulated using magnetic fields. Such particles generally include of two components, a magnetic material, often iron, nickel and cobalt, and a chemical component that has functionality [32-34]. Among them, magnetic nanoparticles (Fe3O4) have been the focus of much research recently because advantages such as high stability, low toxicity and easy separation from reaction media [35]. In this work, we wish to report application of nano-kaolin/Ti(IV)/Fe3O4 [28] for synthesis of coumarines via pechmann reaction include of  the condensation reaction of β-keto esters with phenols.

MATERIALS AND METHODS
All compounds were purchased from Merck, Aldrich and Fluka chemical companies and used without any additional purification. FT-IR spectra were run on a Bruker, Equinox 55 spectrometer. A Bruker (DRX-400 Avance) NMR was used to record the NMR spectra. Melting points were determined by a Buchi melting point B-540 B.V.CHI apparatus. 

Preparation of Fe3O4 NPs
A mixture of FeCl3.6H2O (2.7 g, 10 mmol) and FeCl2.4H2O (1 g, 5 mmol) in deionized water (25 mL) was warmed until 80 °C. Then 17 ml of NH3 (30%) was added slowly and the mixture was stirred with mechanical stirrer for 30 minutes. Then black magnetic nanoparticles were collected by using an external magnet and washed three times with deionized water. Finally Fe3O4 NPs were dried at 80 °C for 4 hours.

Preparation of nano-kaolin/Ti(Ⅳ) 
At first, 1 ml of TiCl4 was added drop wise to a mixture of nano-kaolin (2 g) in 10 ml of dichloromethane In a beaker. the mixture stirred by using a mechanical stirrer for 1 h at room temperature. The resulting suspension was filtered and washed with dichloromethane and dried at room temperature.

Preparation of nano-kaolin/Ti(Ⅳ )/Fe3O4
the mixture of nano-kaolin/Ti(IV) (2 g) and dichloromethane (10 mL) were dispersed in the ultrasonic irradiation bath for 30 minutes. Then, nano-Fe3O4 (1 g) was added to the mixture. Again, compound placed for 40 minutes in the ultrasonic irradiation bath to disperse the particles. The resulting suspension was collected by using external magnet and washed with dichloromethane and dried at room temperature.

General procedure for the synthesis of coumarines 
The mixture of phenol (1 mmol), ethyl acetoacetate (1 mmol) and nano-kaolin/Ti(IV)/Fe3O4 (0.03 g)  was warmed at 100 ºC In a sand bath and stirred by using a mechanical stirring motor with a speed of 50 rpm . The advance of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was dissolved in ethanol and the catalyst was separated by an external magnet. Finally, The reaction mixture was were purified using column chromatography on silica gel and recrystallized from hot ethanol to afford pure coumarin derivatives.  

RESULTS AND DISCUSSION
Nano-kaolin/Ti(IV)/Fe3O4 was generally prepared as a magnetic nano-catalyst in two-steps process. At first, TiCl4 was added to the mixture of nano-Kaolin and CH2Cl2. The resulted white powder (nano-kaolin/Ti(IV)) was added to the suspension of nano Fe3O4 in CH2Cl2 under ultrasonic condition to formation of nano-kaolin/Ti(IV)/Fe3O4 as a brown magnetic powder. 
The particles size of the nano-kaolin/Ti4+/Fe3O4 was studied using field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) and were less than 100 nm (Fig. 1).
Energy-dispersive X-ray spectroscopy (EDS) was used to determine the percentage of elements in the nano-kaolin/Ti4+/Fe3O4. (Fig. 2) The percentage of Fe, Si, Al, Ti, Cl, O and K in nano-kaolin/Ti4+/Fe3O4 was 37.4, 25.5, 12.6, 11.0, 8.2, 4.2 and 1.2 respectively.
The thermal stability (TG–DTA) of nano-kaolin/Ti4+/Fe3O4 was studied by thermo-gravimetric analysis (TGA) in a temperature range of 50-800 °C (Fig. 3). According to the figure 4, at 100-250 ºC, 4% of catalyst weight was reduced, which can be related to the removal of moisture and bonded water. Also, the catalyst has lost 80% of its weight in the range of 250-600 ºC probably due to collapse of the Kaolin network. According to the TGA curve, this catalyst is stable to 230 °C and is suitable for reactions that were carried out at temperatures below 230 °C.
The vibrating sample magnetometer (VSM) pattern of catalyst at room temperature shows, the coercivity value is zero and there was no hysteresis loop and remanence that confirm the catalytic superparamagnetic property (Fig. 4). The saturation magnetization (Ms) values of Fe3O4 and the nano-kaolin/Ti4+/Fe3O4 were 50 and 23 emu g-1, respectively. Although the magnetization of catalyst is lower than Fe3O4, the catalyst can be easily separated from the solution with an external magnet.
The X-ray diffraction (XRD) of nano-kaolin/Ti4+/Fe3O4 is shown in Figure 5. According to the XRD pattern, signals at 2θ equal to 13º, 20º, 25º, 41º, 46º, 61º and 68º indicates the presence of kaolin. The four signals in 2θ = 21º, 27º, 39º and 50º show the existence of SiO2. Also, the signals in 2θ =31º, 36º, 44º, 58º and 63º are related to Fe3O4. Presumably, three other peaks in 2θ of 37°, 43° and 55° revealed that Ti was bonded to Kaolin and Fe3O4.
After characterization of nano-kaolin/Ti(IV)/Fe3O4, its catalytic activity was investigated for the synthesis of coumarin derivatives by using Pechmann condensation between phenols and β-ketoester. To select optimization conditions, the reaction of ethyl acetoacetate and resorcinol as a model reaction was studied in various conditions. As shown in Table 1, entry 14, the best conditions for the synthesis of coumarines under solvent-free conditions are using 0.03 g of catalyst at 120 °C.
With the optimized reaction conditions for the model reaction, 7-hydroxy-2H-chromen-2-one derivatives were explored by the reaction of phenolic derivatives with a range of β-ketoester and the results are summarized in Table 1.  The nature of the substituent on β-ketoester and phenols have a considerable effect on the time and yield of the reaction. β-Ketoesters with electron withdrawing group and phenol with electron releasing group reacts in shorter time with higher yield. The product structure were characterized by using melting point, FT-IR, and 1H-NMR spectra.
The reusability of the catalyst was also investigated on the model reaction in the presence of nano-kaolin/Ti(IV)/Fe3O4 at 120 ºC under solvent-free conditions. That way, catalyst was separated by using an external magnet, washing with ethanol and drying at room temperature. The results indicated that the catalyst nano-kaolin/Ti(IV)/Fe3O4 can be reused for four times without considerable loss at its catalytic activity (Table 1).  
The suggested mechanism for the synthesis of coumarines is shown in Fig. 6. In this reaction, the Ti(IV) cation in catalyst doing as a Lewis acid and activates carbonyl groups in substrates.
The efficiency of nano-kaolin/Ti(IV)/Fe3O4 catalyst in Pechmann reaction was compared with other reported ones (Table 3). The results shows, one of the best catalysts for the synthesis of coumarin in solvent-free conditions is nano-kaolin/Ti(IV)/Fe3O4 with short reaction time and high yield.

CONCLUSION
In conclusion, we have reported the preparation and description of nano-kaolin/Ti(IV)/Fe3O4 as an efficient and magnetically recyclable heterogeneous catalyst. This catalyst was applied to synthesize of coumarine derivatives via Pechmann condensation reaction of phenols and β-ketoester under solvent-free condition at 120 °C. Several main advantages of this protocol includes  high yields, short reaction times, mild reaction conditions, simple work-up procedure and easy separation with reusability of the catalyst
Conflicts of interest

CONFLICT OF INTEREST
The authors declare that there are no conflicts of interest regarding the publication of this manuscript.

Acknowledgements
The Research Council of  Yazd University is gratefully acknowledged for the financial support for this work.