Introduction

In recent years, applying heterogeneous catalysts in organic synthesis is become popular because they are removable from the reaction media by simple filtration and reusable. In addition, to achieve high activity in heterogeneous catalysts, composite nanoparticles are the logical strategy because of a large surface to volume ratio, thus increasing catalytic activity. Furthermore, magnetic nanoparticles, especially supported magnetic nanocatalysts, have attracted considerable interest in both academic and industrial researches because they are viable alternatives to conventional materials, readily available, simple separation by an external magnet and high degree of chemical stability in various organic and inorganic solvents [1–10].

Dihydropyridines are privileged heterocyclic ring systems because of their broad and significant pharmacological properties and they are also analogues of NADH coenzymes. 1,4-Dihydropyridine derivatives have applications as calcium channel blockers for the treatment of cardiovascular diseases including hypertension. They are also used as antidiabetic agents, anti-tumor, geroprotective, anti-therosclerotic, and bronchodilator [11–14]. The first molecules of 1,4-dihydropyridines were reported by Hantzch in 1882. It is a one-pot four component synthesis of 1,4-dihydropyridine by two molecules of ethyl acetoacetate, aldehyde and ammonia. This procedure does not need any additives and the reaction was done either at reflux in alcohol or in acetic acid; furthermore, the reaction suffer from long reaction times and low-yields of products [15]. Due to significance of dihydropyridine derivatives in the synthesis of various class of drugs several synthesis procedures have been presented such as use of microwaves [16, 17], high temperature at reflux [18–22], ionic liquid [23], SiO2/HClO4 [24], SiO2/NaHSO4 [25], I2 [26], Bakers’ yeast [27], metal triflates [28], tetrabutylammonium hydrogen sulfate [29], organocatalysts [30], PTSA [31], iron trifluoroacetate [32], TMSCl [33] and Ni nanoparticles [34].

Some of the above-mentioned methods for the synthesis of 1,4-dihydropyridine derivatives have one or more negative points such as expensive reagents, tedious work-up, moisture sensitive, toxic and harsh reaction conditions, thus developing an efficient protocol with a powerful catalyst for the synthesis of 1,4-dihydropyridine is still of prime importance. On the other hand, catalysis is a key part of green chemistry, and one of the fundamental needed challenges facing chemists now is to design and apply of eco-friendly catalysts [35–38]. A stable and green catalyst is defined as low preparation cost, high activity, great selectivity, high stability, efficient recovery, and good recyclability [39].

In continuation of our recent works to applying heterogeneous nanocatalysts in organic synthesis [40–44], herein, we wish to report Fe3O4@chitosan as a green heterogeneous catalyst for the synthesis of 1,4-dihydropyridine derivatives 4a–4ai via a one-pot four-component Hantzsch condensation reaction using various aromatic aldehyde (1) 5,5-dimethyl-1,3-cyclohexanedione (dimedone) or 1,3-cyclohexandione (2) ethyl acetoacetate or methyl acetoacetate (3) and ammonium acetate in ethanol in good to excellent yields at room temperature (Scheme 1). The main advantages of this protocol are using ethanol as a green solvent, inexpensive catalyst and easy preparation, mild reaction conditions, high yields, easy work-up, simple filtration and ability of reusing catalyst.

Scheme 1
scheme 1

One-pot four-component reaction synthesis of 1,4-dihydropyridine derivatives 4a–4ai

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Experimental

General

All solvents, chemicals and reagents were purchased from Merck, Fluka and Aldrich. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. The scanning electron microscopy (SEM) images were obtained on a Seron AIS 2100. Fourier transform infrared (FT–IR) spectra were recorded using Perkin-Elmer spectrometer; using pellets of the nanomaterials diluted with KBr. The 1H NMR spectra were recorded on Bruker DRX-300 Avance spectrometer at 300.13 MHz. The elemental analyses were performed with an Elementar Analysensysteme GmbH VarioEL.

Preparation of Fe3O4@chitosan nanocomposite

First, 1 g of chitosan powder was added into a 100 mL of 0.1 M acetic acid and the mixture was stirred to form a 1 % (w/v) clear chitosan solution. Then, the homogeneous solution was filtered through a synthetic cloth to remove any undissolved materials and degassed by keeping the solution into vacuum oven for 3 h to remove the trapped air bubbles. After that, 2 mL of glycolic acid and calculated amount of Fe3O4 nanoparticles [black powder, average particle size 30 nm (TEM), purity 99 % and specific surface area 55 m2/g] were dispersed in the chitosan solution by stirring at room temperature and then it was sonicated for 1 h. The resulting solution was stirred overnight at room temperature. After that, the resulted gel separated from the reaction mixture by a permanent magnet, washed several times with EtOH, and dried on a ceramic plate at room temperature during 48 h to obtain the chitosan-supported magnetite nanoparticles.

Synthesis of dihydropyridine derivatives

A mixture of an aldehyde (1.0 mmol), dimedone or 1,3-cyclohexanedione (1.0 mmol), ethyl acetoacetate or methyl acetoacetate (1.0 mmol) and ammonium acetate (1.0 mmol) in 5 mL of EtOH was stirred at room temperature in the presence of a catalytic amount of Fe3O4@chitosan (0.03 g) for the appropriate times to obtain dihydropyridines derivatives. After completion of the reaction, as indicated by thin layer chromatography (TLC) (n-hexane/ethyl acetate 3/1), the catalyst was separated magnetically from the reaction mixture, washed with ethanol, and used for subsequent reactions after drying. Pure dihydropyridines 4a–4ai was afforded by evaporation of the solvent, followed by recrystallization from EtOH.

Spectral data of the product 4ai

IR (KBr) (υmax cm−1) = 3,274, 3,207, 2,960, 1,701, 1,647, 1,604, 1,492, 1,379, 1,215, 1,072. 1H NMR (300 MHz, CDCl3): δH (ppm) = 1.04 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.27 (t, 3H, J = 7.1 Hz, CH3), 2.22–2.34 (m, 4H, 2CH2), 2.38 (s, 3H, CH3), 4.16 (q, 2H, J = 7.1 Hz, OCH2), 5.42 (s, 1H, CH), 6.19 (br s, 1H, NH), 6.84 (d, 2H, J = 1.8 Hz, H–Ar), 7.03 (t, 1H, J = 2.1 Hz, H–Ar). Anal. Calcd for C19H23NO3S: C, 66.06; H, 6.71; N, 4.05. Found: C, 67.11; H, 6.63; N, 3.94.

Results and discussion

The Fe3O4@chitosan nanocatalyst was first prepared by a sol–gel method modified in our previous reports [42]. Then, it was characterized by SEM analysis. The particle size was studied by SEM and the identification of Fe3O4@chitosan morphology was based on the analysis of SEM images. The obtained SEM images of nanoparticles clearly showed that Fe3O4 nanoparticles were properly supported on chitosan.

To optimize the reaction conditions, we checked the four-component condensation reaction of dimedone (1 mmol), ethyl acetoacetate (1 mmol), 4-chlorobenzaldehyde (1 mmol) and ammonium acetate (1 mmol) in the presence of different catalytic amounts of Fe3O4@chitosan at room temperature in 5 mL of EtOH, as a model reaction. It was found that 0.03 g of catalyst was enough to catalyze the reaction to produce high yields of dihydropyridines derivatives. As shown in Table 1 (Entries 1–4), using 0.03 g of the catalyst was enough to progress the reaction and an increment of the catalyst amount did not improve the yields. In the second stage the effect of solvent was studied. As can be seen from Table 1 (Entries 5–9), it was found that EtOH is the best solvent for this reaction to produce high yields in short reaction time in comparison with other polar, non-polar, protic and aprotic solvents.

Table 1 Optimization of the reaction conditions in the model reaction
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To study the generality of this method, different types of starting material were reacted in the synthesis of 1,4-dihydropyridines. As illustrated in Table 2, aromatic aldehyde with both electron withdrawing groups and electron donating groups react well to give the products in good to excellent yields. As it predicted starting from aldehyde with electron withdrawing groups (such as nitro group) the condensation reaction occurs in the lower time in comparison with electron donating groups (such as alkoxyl group).

Table 2 Synthesis of dihydropyridine derivatives 4a–4ai in the presence of Fe3O4@chitosan
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As shown in Scheme 2, the proposed mechanism of this reaction could be in two forms. In step 2 and 2′ which are Knoevenagel reaction involves coupling of aldehyde with active methylene compound. Furthermore, in step 3 and 3′ a Michael addition of intermediates gives the target products.

Scheme 2
scheme 2

Two proposed mechanistic routes of the reaction

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In addition, the reusability of this heterogeneous nanocatalyst is one of its important plus point and also this potency leads us to use it in commercial and industrial applications. One of the natural ability of this heterogeneous catalyst that makes it special is easy separation from the reaction media by an external magnetic bar. By washing with acetone or ethanol and drying it at room temperature it can be reused several times. As indicated in Table 3, the reusability of the present composite nanocatalyst is examined in the model reaction.

Table 3 Reusability studies of the nanocatalyst on the model reaction
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Conclusion

In summary, Fe3O4@chitosan was prepared and used as a green, magnetically recyclable and efficient composite nanocatalyst for the synthesis of chemically and biologically important dihydropyridine derivatives by a simple, clean, eco-friendly and inexpensive method. This protocol can be applied in large-scale and industrial synthesis of heterocyclic compounds, because it can be simple recovered and reused several times without significant decreasing in its catalytic activity.