Scholarly article on topic 'Efficient one-pot four-component synthesis of 1,4-dihydropyridines promoted by magnetite/chitosan as a magnetically recyclable heterogeneous nanocatalyst'

Efficient one-pot four-component synthesis of 1,4-dihydropyridines promoted by magnetite/chitosan as a magnetically recyclable heterogeneous nanocatalyst Academic research paper on "Chemical sciences"

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J Nanostruct Chem
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Academic research paper on topic "Efficient one-pot four-component synthesis of 1,4-dihydropyridines promoted by magnetite/chitosan as a magnetically recyclable heterogeneous nanocatalyst"

J Nanostruct Chem

DOI 10.1007/s40097-014-0140-z


Efficient one-pot four-component synthesis of 1,4-dihydropyridines promoted by magnetite/chitosan as a magnetically recyclable heterogeneous nanocatalyst

Ali Maleki • Maryam Kamalzare • Morteza Aghaei

Received: 6 October 2014/Accepted: 28 November 2014

© The Author(s) 2014. This article is published with open access at

Abstract 1,4-Dihydropyridines are synthesized from various aromatic aldehyde, dimedone or 1,3-cyclohex-andione, ethyl acetoacetate or methyl acetoacetate and ammonium acetate catalyzed by magnetite/chitosan at room temperature under mild reaction conditions. This process offers an easy and efficient synthesis of 1,4-dihy-dropyridine derivatives in high yields. The benefits of this protocol are simplicity, nontoxicity, low cost, simple workup, and an environmentally benign nature. The catalyst is recovered by filtration and reused at least five times without significant loss in catalytic activity.

Keywords Nanocatalyst • Multicomponent reactions • Chitosan • Fe3O4 • 1,4-dihydropyridine • Heterogeneous


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

A. Maleki (&) • M. Kamalzare • M. Aghaei Catalysts and Organic Synthesis Research Laboratory, Department of Chemistry, Iran University of Science and Technology, 16846-13114 Tehran, Iran e-mail:

Published online: 10 December 2014

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 Han-tzch 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


O Ar O

+ + + NH4OAc Fe3O4@chitosan ^

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

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-cy-clohexandione (2) ethyl acetoacetate or methyl acetoace-tate (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.



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 m /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-sup-ported 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)

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 H 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

Table 1 Optimization of the reaction conditions in the model reaction

Entry Catalyst Amount of catalyst (g) Solvent Time (min) Yielda (%)

1 Fe3O4@chitosan 0.01 EtOH 180 Trace

2 Fe3O4@chitosan 0.02 EtOH 120 51

3 Fe3O4@chitosan 0.03 EtOH 70 90

4 Fe3O4@chitosan 0.04 EtOH 70 90

5 Fe3O4@chitosan 0.03 MeOH 70 74

6 Fe3O4@chitosan 0.03 EtOAc 75 79

7 Fe3O4@chitosan 0.03 CH2Cl2 70 82

8 Fe3O4@chitosan 0.03 CH3CN 70 87

9 Fe3O4@chitosan 0.03 n-hexane 140 Trace

10 Fe3O4 0.03 EtOH 120 Trace

11 chitosan 0.03 EtOH 120 Trace

12 - - EtOH 150 Trace

a Isolated yield

Table 2 Synthesis of dihydropyridine derivatives 4a-4ai in the presence of Fe3O4@chitosan


Time (min) Yield (%)a

Mp (°C)



207-209 207-209 [45]

242-244 243-245 [46]

235-236 234-236 [47]

258-260 258-260 [48]

257-259 258-259 [49]

247-249 [47]

257-258 255-257 [46]

Table 2 continued

Entry Product

Time (min) Yield (%)a Mp (°C)

Observed Reported

245-246 243-245 [50]

233-235 233-235 [45]

175-176 174-176 [34]

212-214 204-206 [51]

196-198 201-203 [49]

245-248 244-246 [52]

235-237 237-238 [23]

Table 2 continued

Entry Product

Time (min) Yield (%)a Mp (°C)

Observed Reported

249-250 252 [53]

235-237 [54]

236-237 236.6-237 [55]

186-188 188-189 [56]

189-191 193-195 [26]

288-290 [53]

Table 2 continued

Entry Product

Time (min) Yield (%)a Mp (°C)

Observed Reported

256-258 257-259 [47]

272-273 271-273 [56]

254-256 252-254 [57]

263-265 263-264 [58]

248-250 250-252 [57]

256-258 258 [59]

Table 2 continued

Entry Product

Time (min) Yield (%)a Mp (°C)

Observed Reported

221-223 223-224 [57]

215-217 219-221 [55]

233-234 238-240 [57]

250-252 248-251 [53]

250-252 256-257 [53]

221-223 [52]

208-211 208-211 [52]

Table 2 continued

Entry Product Time (min) Yield (%)a Mp (°C)

Observed Reported

34 1 91 97 237-239 238-240 [57]

o Y Cl j o

--- N' H 4ah

35 / S. o ? ° H 4ai 85 93 222-224 223-225 [45]

a Isolated yield

(n-hexane/ethyl acetate 3/1), the catalyst was separated magnetically from the reaction mixture, washed with eth-anol, 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) (tmax 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): dH (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 C19-H23NO3S: 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 Fe3-O4@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-chlorobenzalde-hyde (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.

To study the generality of this method, different types of starting material were reacted in the synthesis of 1,4-di-hydropyridines. 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).

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.

In addition, the reusability of this heterogeneous nano-catalyst 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

Scheme 2 Two proposed mechanistic routes of the reaction

Table 3 Reusability studies of the nanocatalyst on the model reaction

Run Fresh 1 2 3 4 5

Isolated yield (%) 90 90 90 89 89 87

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.


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.

Acknowledgments The authors gratefully acknowledge the partial support from the Research Council of the Iran University of Science and Technology.

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


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