Green multicomponent synthesis of four different classes of six-membered N-containing and O-containing heterocycles catalyzed by an efficient chitosan-based magnetic bionanocomposite

Materials and methods

All the solvents, chemicals and reagents were purchased from Merck, Fluka and Aldrich. Thin layer chromatography (TLC) was performed using Silica gel 60 F₂₅₄ (Merck) plates. Compounds were visualized with UV light (254 nm). Melting points were measured on an electrothermal 9100 apparatus and are uncorrected. FT-IR spectra were recorded on a Shimadzu FT-IR 8400 instrument with samples prepared as KBr disks. ¹H NMR spectra were recorded on a Bruker DRX-500 Avance spectrometer at 500 MHz in DMSO-d₆ as the solvent. SEM micrographs and energy-dispersive X-ray (EDX) spectra were taken using a Tescan-Vega II microscope. Thermal analysis was conducted on a Bahr-STA 504 instrument under argon atmosphere. VSM was measured on a Magnetic Daghigh Daneshpajouh Co., Iran, vibrating sample magnetometer.

Preparation of CuFe₂O₄/chitosan magnetic bionanocomposite

The CuFe₂O₄/chitosan nanocomposite was prepared by a two-step process. First, CuFe₂O₄ magnetic nanoparticles were synthesized via a previously reported method [29]. Briefly, CuFe₂O₄ nanoparticles were prepared by thermal decomposition of Cu(NO₃)₂ and Fe(NO₃)₃ in water in the presence of sodium hydroxide. Fe(NO₃)₃·9H₂O (3.34 g, 8.2 mmol) and Cu(NO₃)₂·3H₂O (1 g, 4.1 mmol) were dissolved in 75 mL of distilled water. Then, 3 g (75 mmol) of NaOH dissolved in 15 mL of water was added over a 10 min period resulting in a formation of a reddish-black precipitate was formed. The reaction mixture was warmed to 90°C, stirred under ultrasonic irradiation for 2 h and then cooled to room temperature. Magnetic particles so formed were separated using an external magnet, washed with distilled water (3×30 mL) dried in air oven overnight at 80°C, ground in a mortar and pestle, heated in a furnace at 700°C for 5 h (step up temperature 2°C/min) and finally cooled to room temperature. The synthesized ferrite nanopowder (20 wt%) was added gradually to a chitosan polymer solution (1.5% chitosan in 1% aqueous acetic acid) and stirred at room temperature for 6 h. Ammonia solution was added dropwise to neutralize the solution and the resultant gel separated from the reaction mixture using a permanent magnet, washed several times with distilled water, and vacuum dried at 50°C for 12 h to obtain the chitosan-supported magnetic nanoparticles.

General procedure for the synthesis of 5-ethoxycarbonyl-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans (6a–k) and 2-amino-7,7-dimethyl-5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (7a–j)

A solution of an arylaldehyde (1 mmol), malononitrile (1 mmol), ethylacetoacetate (1 mmol) for (6a–k) and dimedone (1 mmol) for (7a–j), containing CuFe₂O₄/chitosan (0.01 g) was stirred in 5 mL ethanol at room temperature until the completion of the reaction [monitored by TLC using mobile phase ethylacetate/n-hexane; 1:3 for (6a–k) and ethylacetate/n-hexane; 1:4 for (7a–j)]. After completion of the reaction, the catalyst was simply removed from reaction mixture with an external magnet without any need for filtration or other typical separation procedures. Products solidified at room temperature in ethanol. The solid product was recovered by filtration and recrystallized from ethanol. The reaction mixture has been left for a while (container openings was covered to prevent solvent vaporization). After some hours/days crystals or precipitates appeared. All the products were known compounds that were identified by comparison of their physical data (melting points) with data reported for authentic samples. Furthermore, some selected spectral data of the products was provided in the supplementary information file.

General procedure for the synthesis of 2-amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinolines (8a–j) and ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(aryl)-5(6H)-oxoquinolin-3-carboxylate (9a–l)

A mixture of aryl aldehyde (1 mmol), malononitrile (1 mmol) for (8a–j) and ethyl acetoacetate (1 mmol) for (9a–l), dimedone (1 mmol) for (8a–j) and dimedone/cyclohexane-1,3-dione (1 mmol) for (9a–l), ammonium acetate (1.5 mmol) containing CuFe₂O₄/chitosan (0.01 g) was stirred in 5 mL ethanol at room temperature until the completion of the reaction (monitored by TLC). After completion of the reaction, the catalyst was simply removed from reaction mixture with an external magnet. Then, the reaction mixture was further purified by recrystallization in hot ethanol. All the products were known compounds that were identified by comparison of their physical data (melting points) with data reported for authentic samples. Furthermore, some selected spectral data of the products was provided in the supplementary information file.

Characterization of the nanocatalyst

The FT-IR spectrum of the synthesized magnetic bionanocomposite is shown in Fig. S1. In the FT-IR spectrum of CuFe₂O₄/chitosan, absorption band at 3431 cm⁻¹ referred to stretching band of OH and NH groups of chitosan that bind to the copper ferrite nano particles and shift to lower frequency. It is also referred to O–H of nanoparticles. The absorption bands around 1059 cm⁻¹ showed the stretch vibration of C–O bond and the 598 cm⁻¹ band represented the Fe–O group of CuFe₂O₄. EDX analysis was performed for determination of the elements constitutes catalyst (Fig. S2). It showed that there was mainly C, Fe, Cu and O atoms in the bionanocomposite structure. Field-emission scanning electron microscopy (FE-SEM) images are used to investigate the surface structure of the nanocomposite. As it is seen in Fig. 1, distribution of the nanoparticles on the chitosan surface is obvious. Furthermore, FE-SEM image of CuFe₂O₄ confirmed its accordance with nanoparticles incorporated in the catalyst nanostructure (Fig. S3). TG curve of CuFe₂O₄/chitosan shows first weight loss at about 100°C due to evaporation of adsorbed water in the sample (Fig. S4). TG curve shows no weight loss up to about 300°C. The nanocomposite is stable to above temperature and is suitable for organic reactions.

Fig. 1:

FE-SEM image of CuFe₂O₄/chitosan nanocomposite.

Application of the catalyst in the synthesis of N- and O-heterocycles

The first catalytic application of this magnetic bionanocomposite has been reported by our research group recently [23]. To optimize the reaction conditions for the synthesis of 2-amino-4H-pyrans (6) and 2-amino-4H-chromens (7), the three-component reactions of 4-chlorobenzaldehyde, malononitrile and ethylacetoacetate or dimedone in the presence of CuFe₂O₄/chitosan was selected as test reactions under various conditions at room temperature, to give the products 6j and 7i. Only ethanol, water or solvent-free conditions were tested and ethanol found to be the best choice for the reactions (Table 1).

To optimize the synthesis of 2-amino-3-cyano-5-oxo-1,4,5,6,7,8-hexahydroquinoline 8 and 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate derivatives 9, four-component reaction of 4-chlorobenzaldehyde, malononitrile (8)/ethylacetoacetate (9), dimedone and ammonium acetate in the presence of CuFe₂O₄/chitosan was selected as test reaction under various conditions at room temperature, to give the product 8b and 9b. Only ethanol, water or solvent-free conditions were tested and ethanol found to be the best choice for all reactions (Table 2).

As indicated in the Tables 3 and 4, after optimization of the reactions conditions, various aldehydes were used in every method to get diversities of O- and N-heterocycles. High-to-excellent yields and relatively short reaction times were obtained for almost all of the starting materials including either electron-withdrawing or electron-releasing substituents. Melting points of the products could be found in Table S1.

Catalyst recyclability

Catalyst recyclability was investigated in all four model-reactions (Fig. 2). After every run, catalyst was recovered using an external magnet, then washed with ethanol and dried. Magnetic bionanocomposite catalyst can be successfully reused in at least seven cycles with only small reduction in activity.

Fig. 2:

Catalyst recyclability.