Copper-iron oxide based catalysts have been widely used due to their biocompatibility, insensitivity to air and humidity, and easy removal from the reaction mixture with an external magnetic field [1-7]. In addition, they are a new type of functionalized products which can be largely used in biotechnology and nanotechnology [8,9]. Poly(ethylene oxide) (PEO) is a significant biocompatible polymeric material widely used for multipurpose applications and coating agents. Due to their excellent properties such as hydrophilicity nontoxicity, nonimmunogenicity, flexibility, introducing many new protocols is of prime importance for preparing PEO-coated MNPs [10,11].
Dihydropyrimidines are important bioactive heterocyclic compounds which have analgesic, antiviral, antimicrobial, and anti-inﬂammatory effects, which are produced by condensing urea, thiourea, β-ketoesters or aryl aldehydes [12-15]. In recent years, design and synthesis of economical, universal, and recyclable catalysts for preparing DHPMs has been of central importance. In this regard, a variety of different catalysts and reaction modifications have been successfully employed to develop the existing array of DHPMs [16-18].
However, most of these reported procedures, unavoidably suffer from some characteristics such as strong acidic conditions, long and expensive procedures in tedious work-up, needing excessive amounts of hazardous chemical reagents, toxic solvents, complex handling, poor yields of the products, and failures in the synthetic method. In continuation of our efforts in the progress and optimization of green synthetic procedures [5-9,19], this research reports a novel strategy for the synthesis of magnetic poly(ethylene oxide)-coated copper ferrite nanoparticles-supported sulfonic acid (CuFe2O4@PEO-SO3H) which is used as a catalyst for the synthesis of dihydropyrimidines (4a-l) (Scheme 1). This study offers a green protocol due to the use of a recyclable nanocatalyst and ethanol as a solvent at room temperature under mild and safe conditions.
As far as we know, it is the first time for the synthesis, characterization, and application of CuFe2O4@PEO-SO3H nanocomposite as an effective, green and eco-friendly nanocatalyst in the synthesis of dihydropyrimidine derivatives.
All chemicals and solvents were obtained from Merck, and used directly without any further purification. Melting points (mp) were determined on an Electrothermal 9100 apparatus. FT-IR spectra were recorded using Shimadzu IR-470 spectrometer (KBr pellets). 1H and 13C NMR spectra were obtained at 250 and 62.5 MHz, respectively, on a Bruker DRX-250. The morphology and structure of the nanocatalyst were examined by field emission scanning electron microscope (FE-SEM, Hitachi S-4800). The energy-dispersive X-ray (EDX) spectroscopy was applied to show the elemental composition of the nanocatalyst. The magnetic properties of the samples were investigated by a vibrating sample magnetometer (Meghnatis Kavir Kashan Co., Iran). X-ray diffraction patterns were performed by X’ Pert Pro X-ray diffractometer (40 mA, 40 kV).
Preparation of CuFe2O4
Copper ferrite nanoparticles were prepared using the conventional co-precipitation technique by Cu(NO3)2·3H2O and Fe(NO3)3·9H2O under argon atmosphere. Using a typical procedure, 1.5 g (6.15 mmol) Cu(NO3)2.3H2O and 5.01 g (12.3 mmol) Fe(NO3)3.9H2O were dissolved in 100 mL deionized water and stirred under argon atmosphere at room temperate. Then an alkaline solution contains 4.0 g NaOH in 20 mL deionized water was added dropwise during 10 minutes via syringe pump to the above solution under magnetic stirring. Upon the addition of alkaline solution, copper ferrite nanoparticles were formed as a black precipitate. The reaction mixture was heated to 90 °C under stirring for additional 5 h. Having magnetic properties, CuFe2O4 nanoparticles were separated using an external magnetic field and washed by 15 mL deionized water and then 15 mL EtOH, four times by each of these solvents. Then, the residue was dried for 24 h at 80 °C in air oven. Finally, the dried nanoparticles were calcinated for 5 h at 700 °C.
Preparation of CuFe2O4@PEO nanocomposite
The CuFe2O4 nanoparticles (3 g) were added to the 250-mL flask and dispersed in 30 mL of water for 10 minutes. Then, 1.5 g of dissolved PEO in 60 mL water was gradually added and again stirred under ultrasonic bath for 2 h. After the addition of PEO over a period of 2 h, the mixture was magnetically stirred for 2 h at 80 °C. After the evaporation of water and the formation of brown gel, CuFe2O4@PEO was separated by a magnetic bar and dried in a vacuum oven at 60 °C.
Preparation of CuFe2O4@PEO-SO3H nanocatalyst
A suction flask (500 mL filter flask), equipped with a constant pressure dropping-funnel and gas outlet tube connected to a vacuum system, contained an adsorbing alkaline solution. CuFe2O4@PEO (3 g) in CH2Cl2 (60 mL) was added into the flask and then was sonicated for 15 minutes until all the mixture was dispersed. Then, a solution of chlorosulfonic acid (HSO3Cl) (1.5 mL) in 30 mL 1,2-dichloroethane was added dropwise for 30 minutes at 0 °C under stirring. After the addition of HSO3Cl solution, the mixture was stirred for additional 90 minutes for removing any residual of HCl. By using an external magnet, CuFe2O4@PEO-SO3H was easily separated from the reaction medium and washed several times with CH2Cl2. Finally, CuFe2O4@PEO-SO3H was dried in a vacuum at 60 °C (Scheme 2).
General procedure for the synthesis of DHPM derivatives (4a-l)
In general, a mixture of an aryl aldehyde (3 mmol), a β-ketoester (3 mmol), urea or thiourea (3.15 mmol) and CuFe2O4@PEO-SO3H (0.012 g) were added to 6 mL absolute ethanol and stirred at 25°C. At the end of the reaction, which was monitored by thin-layer chromatography, the used catalyst was separated using an external magnetic field. Then, the purification of the crude product was carried out by recrystallization from hot ethanol, without any more purification.
RESULTS AND DISCUSSION
After the preparation of the nanocomposite catalyst, it was characterized by conventional analyses. Initially, FT-IR spectroscopy confirmed its preparation. Fig. 1 presents the FT-IR spectrum of the CuFe2O4@PEO-SO3H magnetic catalyst which confirms the preparation of the expected product. In Fig. 1a, the peak about 2852 and 2923 cm-1 is attributable to C–H in PEO. In Fig. 1b, the peak at 584 cm-1 is assignable to the Fe–O–Fe vibration of magnetite phase which can be obviously seen. In Fig. 1c, the wide and strong peak at near 3440 cm-1 can be attributed to O–H in PEO. In Fig. 1d, the stretching vibrations of C–H observed at 2852 and 2923 cm-1 confirm the successful composition of the PEO onto the surfaces of CuFe2O4 nanoparticles. The S=O absorption band at 1124 cm-1 proves the functionalization of SO3H groups on the CuFe2O4@PEO surface.
As shown in Fig. 2, the FE-SEM images of synthesized CuFe2O4@PEO-SO3H confirm that the average size of CuFe2O4@PEO-OSO3H nanoparticles is about 35 nm.
Energy dispersive X-ray analysis (EDX) of the sample was conducted for the determination and characterization of the elements constituting the catalyst. As shown in the Fig. 3, there are mainly Fe, Cu, S and O atoms in the nanocomposite. Therefore, EDX analysis data indicated the presence of PEO and SO3H in the prepared sample.
The EDX analysis for the CuFe2O4@PEO-SO3H nanoparticles was shown in Fig. 4. In addition to the conventional SEM images, EDX mapping presented a significant picture of the distribution of the elements on the surface. This set of maps clearly illustrates the presence of all elemens in the selected area of the nanostructure texture, e.g. iron, copper, sulfur, and carbon.
In TEM image shown in Fig. 5, each CuFe2O4 core was made from small primary nanocrystals with a diameter of about 10 nm surrounded by PEO-SO3H shells with a thickness of nearly 20 nm. The prepared nanocatalyst shows a semispherical morphology and agglomerated structure.
The magnetization curve for the magnetic nanoparticles was recorded with vibrating sample magnetometer (VSM) at room temperature. It is remarkable to know that the magnetic nanoparticles (MNPs) have sufficient magnetic properties to be used in various applications. The results of magnetization measurements of nanoparticles was described in Fig. 6. Furthermore, the magnetic properties of CuFe2O4 MNPs were studied at 298 K using a vibrating sample magnetometer (VSM) that the magnetic hysteresis S-shape loops appeared and the saturation magnetization (Ms) was 20 emu/g. The saturation magnetization gradually reduced due to the covering of magnetite core with nonmagnetic PEO layers and the surface functionalized with sulfonic acid groups.
Fig. 7 shows the XRD measurements performed with PEO coated CuFe2O4 for identifying the crystal phases present in the samples. The XRD pattern of the CuFe2O4@PEO-SO3H indicates all the major peaks corresponding to CuFe2O4. The diffraction angles (2 theta) of 31.21, 36.07, 44.15, 54.39 and 63.85 can be assigned to 2 2 0, 3 1 1, 0 0 4, 2 2 4, 3 3 3, and 4 4 0 planes, respectively, which are in accordance with the CuFe2O4 reference pattern (JCPDS# 77–0010) . Moreover, XRD patterns of CuFe2O4@PEO-SO3H showed a peak around 2θ= 25 which is related to PEO-SO3H polymer (The symbol *) confirming the formation of PEO-SO3H on the surface of CuFe2O4.
To study the catalytic ability of CuFe2O4@PEO-SO3H, a pilot reaction was performed via the reaction of 3 mmol of β-diketone, 3 mmol of aromatic aldehyde, and 3.15 mmol of urea or thiourea. First, the effect of different amounts of the catalyst on the reaction yield was determined. As the results show in Table 1, the synthesis of 4a in 98% yield was completed after 20 minutes at room temperature in 4 mL of ethanol using 0.012 g of the CuFe2O4@PEO-SO3H as the catalyst. In order to prove the capability of ethanol, a number of solvents with various polarity values including MeOH, H2O, MeCN, and DMF were investigated by the model reaction in the presence of CuFe2O4@PEO-SO3H. The results revealed that EtOH is the best solvent for this work in the presence of 0.012 g of the CuFe2O4@PEO-SO3H catalyst at room temperature.
The generality of the CuFe2O4@PEO-SO3H nanocatalyst for the synthesis of DHPMs was evaluated by synthesizing several products under optimized conditions. A ratio of 2:2:2.1 mmol of an aromatic aldehyde, β-ketoester, urea or thiourea and 0.015 g of nanocatalyst in EtOH (6 mL) as a choice green solvent were stirred at room temperature and resulted in high yields of products. As shown in Table (2), the results of this study demonstrate that electron-rich and electron-deficient aldehydes operated successfully and underwent the Biginelli condensation reaction. Substituents with electron-withdrawing groups generated the products with larger amounts and fast reaction time than electron-donating groups. For example, 4-chlorobanzaldehyde gave a higher yield compared to 4-methoxybenzaldehyde. Additionally, the para-substituted group had less steric hindrance than ortho- or meta-position (Table 2, entries 1, 6, 7, 9 and 11).
As presented in Table 3, various types of catalysts in several solvents were examined to confirm the efficiency of CuFe2O4@PEO-SO3H for the synthesis of dihydropyrimidine derivatives (4a). The obtained results proved that the synthesis of (4a) using CuFe2O4@PEO-SO3H was performed at lower temperature. Another significant advantage of this nanocatalyst is that it can be recovered and reused efficiently for several times.
After the completion of the reaction, in order for further evaluating the recoverability of this nanocatalyst, it was separated and collected by an external magnet, washed with EtOH, and H2O, and dried . Then, it was reused in the next reactions in the same ratio of catalyst and other reaction conditions. As shown in Fig. 8, the experiments clearly indicate that the prepared catalyst, CuFe2O4@PEO-SO3H, is highly stable at least within six repeated runs.
The Biginelli reaction mechanism is still under debate, without any agreement on the actual pathway. At least, three mechanisms have been offered for the Biginelli reaction, which include iminium, enamine, and Knoevenagel mechanisms. The plausible mechanism for the synthesis of DHPMs (4a-l) is shown in Scheme 3. The first step, like Mannich condensation reaction, is the condensation of an aldehyde with a urea or thiourea, utilizing the nanocatalyst at room temperature. The obtained iminium (6) reacts as an electrophile in the nucleophilic addition of the β- ketoester carbanion (5) (generated from 1 attached via anion form of the catalyst) for the synthesis of intermediate (7). Then, the product (8) was achieved by condensation reaction between ketone carbonyl group of the resulting adduct with the NH2 group of urea. At the end, the products 4 were achieved by an imine-enamine tautomerization of (8) .
In this work, for the first time, CuFe2O4@PEO-SO3H was synthesized and its application as a magnetic nanocatalyst in the multicomponent synthesis of dihydropyrimidine derivatives was reported. The catalyst was synthesized through an easy process under mild conditions and then characterized by FT-IR spectra, EDX, VSM, XRD analyses, TEM and SEM images. Then, the effective synthesis of dihydropyrimidine derivatives were prepared with a number of aromatic aldehydes, β-ketoester, urea or thiourea with catalytic amount of the magnetically recoverable CuFe2O4@PEO-SO3H nanocatalyst in ethanol as a green solvent. It is notable that in most reported studies, this reaction was conducted under reflux condition during long reaction times; however, in this work, all the reactions were carried out at room temperature and with high yields of products.
The authors gratefully acknowledge the partial support from the Research Council of the Iran University of Science and Technology.
Ali Bodaghi: https://orcid.org/0000-0003-2194-1793
CONFLICT OF INTEREST
The authors declare no conflict of interest.