Ultrasound-assisted synthesis of β-amino ketones via a Mannich reaction catalyzed by Fe₃O₄ magnetite nanoparticles as an efficient, recyclable and heterogeneous catalyst

2.1 Materials and apparatus

All chemicals were purchased from Fluka and Merck (Darmstadt, Germany). For mixing chemicals, a universal Ultrasonic DSA100-SK₂ was used. SEM images were obtained with a XI-300 scanning electron microscope (Philips, Japan). IR spectra were determined on a Shimadzo FTIR-470 spectrophotometer. ¹H and ¹³C NMR spectra were recorded on 300 MHz Bruker DRX-500 spectrometers with solutions in CDCl₃ in the presence of tetramethylsilane as internal standard. X-ray diffractometer pattern of synthesized MNPs was obtained with an X-ray diffractometer (JCPDS No. 19-629). Melting points were obtained by a thermo scientific 9100 apparatus. For separation of magnetic catalyst from the solution a Nd–Fe–B strong magnet (10 × 5 × 4 cm, 1.4 Tesla) was used and magnetic properties were analyzed using a vibrating sample magnetometer (VSM, LDJ 9600).

For the synthesis of β-aminocarbonyl compounds, a mixture of benzaldehyde (2.5 mmol), aniline (2.5 mmol), cyclohexanone or acetophenone (3.0 mmol) and MNPs (1.0–1.5 mg mL⁻¹) was sonicated in ethanol (3.0 mL) at room temperature for 30–75 min and the reaction products were monitored with TLC. After completion of the reaction, the products which connected to MNPs were separated from the solution with a permanent magnet. Finally, the reaction product was eluted from the MNPs with hot ethanol and the catalyst was removed by a permanent magnet. Then, in order to crystallize the product, the ethanolic solution containing product was kept at room temperature. Finally, the collected product was filtrated and washed via ethanol (95%).

2.2 Synthesis of Fe₃O₄ MNPs

Fe₃O₄ MNPs were chemically synthesized with a little modification in the methodology already described in the literature (Faraji et al., 2010). Briefly, 6.3 g FeCl₃.6H₂O, 4.0 g FeCl₂.4H₂O and 1.7 mL HCl (12 mol L⁻¹) were dissolved in 50 mL of deionized water in a beaker in order to prepare the stock solution of ferrous and ferric chloride. After that, the solution was degassed with argon gas and heated to 80 °C in a reactor. Simultaneously, 250 mL of a 1.5 mol L⁻¹ ammonia solution was slowly added to the solution under argon gas protection and vigorous stirring (1000 rpm). During the process, the solution temperature was kept constant at 80 °C and argon gas was purged to prevent the intrusion of oxygen. After completion of the reaction, the obtained precipitate of Fe₃O₄ MNPs was separated from the reaction medium by the magnetic field, and then was washed four times with 500 mL doubly distilled water. Finally, the obtained Fe₃O₄ MNPs were resuspended in 500 mL of degassed deionized water. The concentration of obtained Fe₃O₄ MNPs was 6.2 mg mL⁻¹.

2.3 General procedure for the synthesis of β-aminocarbonyl compounds using cyclohexanone

Under the optimum conditions, a mixture of benzaldehyde (2.5 mmol), aniline (2.5 mmol), cyclohexanone (3 mmol) and MNPs (4.0 mg) was sonicated in ethanol (3.0 ml) at room temperature for 45 min. The reaction products were monitored by TLC. After completion of the reaction, products were separated from solution and characterized by FTIR, ¹H NMR and ¹³C NMR and were identified by comparison of the spectral data and melting points with those reported in the literature. To show the generality and scope of this new protocol, different aromatic aldehydes and aromatic amines were used as bearing electron-withdrawing and electron-donating groups in addition to cyclohexanone. The reaction gave the corresponding products in good to excellent yields. The effects of electron-withdrawing and electron-donating substituent are summarized in Table 1.

The anti- and syn-isomers were identified by the coupling constants (J) of the vicinal protons adjacent to C⚌O and NH in ¹H NMR spectra (Loh et al., 2000). The coupling constants for anti-isomers are reported to be bigger than those of syn-isomers (Ranu et al., 2002).

Probably, interaction between MNP catalyst and the transition state in this reaction conduces to the formation of anti- or syn-isomer (Bigdeli et al., 2007; Wu et al., 2007). A plausible mechanism is shown in Fig. 2. If hydrogen bonding occurs among MNPs, imine and enol form of cyclohexanone, the aryl and phenyl group would be anti- to each other, so there is minimum steric repulsion between methylene groups in cyclohexanones and the aryl group, as well as MNPs and H. Therefore, this transition state conduces to anti-isomer. Because complete anti-selectivity is observed, it can be concluded that powerful hydrogen bonding exists between MNPs, imine and enol form of cyclohexanon.

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Figure 2

Possible mechanism.

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2.4 General procedure for the synthesis of β-aminocarbonyl compounds using acetophenone

Under the optimum conditions, the one-pot, three-component Mannich reaction using acetophenone was also studied. Hence, a mixture of benzaldehyde (2.5 mmol), aniline (2.5 mmol), acetophenone (3 mmol) and MNPs (6.0 mg) was sonicated in ethanol (3 ml) at room temperature for 75 min. The reaction was monitored by TLC. It was found that the corresponding β-amino carbonyl compounds were formed in good to moderate yields. The results are summarized in Table 2.

According to the results, acetophenone was less reactive than cyclohexanone and required a greater quantity of catalyst and longer reaction times to achieve the desired products.

2.5 Characterization of the MNPs

Characterization of synthesized Fe₃O₄ MNPs was done using FTIR, XRD and SEM methods (Fig. 3). It is most important that Fe₃O₄ MNPs should possess a sufficient magnetic and super paramagnetism property for magnetic carrier technology (MCT) practical application. Fe₃O₄ MNPs exhibited typical super paramagnetic behavior due to not exhibiting hysteresis, remanence and coercivity. The large saturation magnetization of Fe₃O₄ MNPs was 76 emu/g, which is sufficient for magnetic separation with a conventional magnet. The SEM image of the prepared MNPs is shown in Fig. 3a. Based on the SEM image, the Fe₃O₄ surface morphology analysis demonstrated the agglomeration of many ultrafine particles with a diameter of about 40 nm. As shown in Fig. 3b, the XRD analysis of Fe₃O₄ MNPs indicated peaks with 2θ at 29.72, 35.57, 43.17, 57.15 and 62.77 which are characteristic peaks of Fe₃O₄, indicating the purity of the synthesized Fe₃O₄.

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Figure 3

Characterization of the Fe₃O₄ MNPs. (a) SEM image of the Fe₃O₄ MNPs, (b) XRD pattern of the synthesized Fe₃O₄ MNPs.

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3.1 Method development

In the proposed procedure, to establish the optimum conditions and achieve maximum yield, various parameters affecting the synthesis of β-amino carbonyl were studied using the Taguchi orthogonal array design (OAD). The Taguchi method is a type of fractional factorial design in which orthogonal array is used to assign the selected factors to a serial of experimental combinations (Shariati and Golshekan, 2011). The results of the OAD experiments can be treated by the analysis of variance (ANOVA). In ANOVA, the effects of different factors on the response function can be evaluated by computing F-ratio (variances ratio) and percent contribution (PC) values for each factor (Roy, 1990; Zhu and Ju, 2004). In all optimizing experiments 2.5 mmol benzaldehyde, 2.5 mmol aniline, 3.0 mmol cyclohexanone or acetophenone were mixed and glass tubes with 5.0 mL volumes were used for optimization.

3.2 Experimental design and data analysis

The effects of four experimental parameters including type of solvent, temperature, amount of MNPs and reaction time on the synthesis of β-amino carbonyl compounds were studied at four levels using Taguchi OA₁₆ design. The used levels and the OA₁₆ (4⁴) matrix that were employed to assign the considered factors are shown in Tables 3 and 4, respectively.

The designing of table was done via experimental design 7.0 software. For increasing the precision of the optimization process, each trial was repeated twice (n = 32) using cyclohexanone or acetophenone. The sequence of each experiment was randomized to avoid any personal or subjective bias. Analysis of variance (ANOVA) was used to assess the OA design results. For ANOVA calculations, yield of product was used and the results of the sum of squares (SS) for different variables were calculated.

The mean values of the four levels of each parameter revealed how the yield changes with variation of the level of each factor. Fig. 4 shows the mean yield as a function of the levels of the studied parameter. For cyclohexanone, maximum yield of reaction was obtained at ethanol solvent, 25 °C temperature, 4.0 mg of the Fe₃O₄ MNPs and 45 min reaction time and for acetophenone the maximum yield of reaction was obtained at ethanol, 25 °C, 6.0 mg of the Fe₃O₄ MNPs and 75 min. The ANOVA results (Tables 5a and 5b) showed that the most important parameter contributing to the reaction efficiency was the amount of MNPs.

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Figure 4

The response graph illustrating the variation of the mean yield values plotted against various reaction parameters.

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