In recent years,magnetic nanoparticles (MNPs) have emerged as attractive solid supports for immobilization of homogeneous catalysts ^{[1, 2]},because these MNPs can be well dispersed in the reaction mixtures without magnetic field providing large surface for readily access of substrate molecules. More significantly,after completing the reactions,the MNPs supported catalysts can be isolated efficiently from the product solution through a simple magnetic separation process thereby eliminating the requirement of catalyst filtration and centrifugation ^{[3, 4]}. Magnetic nanoparticles have obtained a considerable interest in recent years ^{[5, 6, 7, 8, 9]}. Ni-Zn ferrites are one of the most versatile magnetic materials as they have high saturation magnetization,high Curie temperature, chemical stability and relatively high permeability ^[10]. Calcium hydroxyapatite,the major component of bone and teeth,isof significant interest in many areas because of ion-exchangeability, adsorption capacity and acid-base properties. Because of good chemicalstability,high surface area and easy synthesis, hydroxyapatite coated magnetic nanoparticle has recently been used as heterogonous catalytic supports ^{[11, 12]}.

Base-catalyzed reactions,such as Michael,Knoevenagel,and aldol reactions,esterification of carboxylic acid with alcohol, transesterification of fatty oils with alcohol,and isomerization of olefins,are important for academic research and industrial production ^[13]. Although homogeneous bases are widely used catalysts for these reactions,separation of the catalysts from the reaction mixtures presents a particularly energy demanding high environmental load. Thus,heterogeneous catalytic processes are anticipated to resolve the loading ^[14]. During the efforts to explore stable base catalysts,we have found that Cs₂CO₃supported on Al₂O₃gives excellent results for some base-catalyzed reactions, such as Michael addition and dimerization of glycerine ^[15]. Furthermore,hydroxyapatite supported cesium carbonate has been used as a recyclable solid base catalyst for the Knoevenagel condensation in water ^[16].

Pyranopyrazoles are an important class of heterocyclic compounds. They find applications as pharmaceutical ingredients and biodegradable agrochemicals ^[17]. Vasukiet al.^[18] reported an efficient four-component reaction protocol for the synthesis of pyranopyrazole derivatives in the presence of a catalytic quantity of bases such as piperidine,pyrrolidine,morpholine and triethylamine at an ambient temperature.

In continuation of our previous works on the applications of reusable catalystsinorganic reactions ^{[19, 20, 21]},here we report the new efficient and green synthesis of pyranopyrazoles using Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ as a basic catalyst (Scheme 1). To the best of our knowledge,this is the first report on the synthesis, characterization and catalytic performance ofaNi_0.5Zn_0.5Fe₂O₄@ Hap-Cs₂CO₃catalyst.

Scheme 1

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Scheme 1.Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3 catalyzed the synthesis of pyranopyrazoles.

The Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ was prepared according to the reported procedure byMassart with minor modifications ^[22]. Coating of a layer of hydroxyapatite on the surface of the Ni_0.5Zn_0.5Fe₂O₄nanoparticles was achieved by premixing (ultrasonic) a dispersion of the nanoparticles (8% w/w,25 mL) obtained with ethanol for 2 h at 60℃.Then 25 mL 0.3 mol/L (NH4)2HPO4 and 0.1 g CTAB mixed solution was added. Under the 800 W ultrasonic a pH 10.5 was maintained by addition of NH4OH.25 mL 0.5 mol/L Ca(NO₃)₂ was added dropwise by constant pressure funnel. The whole Ca/P mole ratio of the mixture was 1.67. The prepared mixture aged 24 h after the reaction finished,and then the precipitation was washed with deionized water until the pH was neutral with the assistance of the permanent magnet. The dried composite particles were obtained after the products were dried for 24 h in a vacuum drying oven. Then the magnetic powder was placed in a crucible and heated under air atmosphere at 300℃ for 2 h.

Cesium carbonate (1.1 g) was charged in the round-bottom flask,and water (100 mL) was added. Then,Ni_0.5Zn_0.5Fe₂O₄@Hap (2.0 g) was added to the solution,and the mixture was stirred for 4 h. The solid was filtered,washed with water and dried overnight first at 100℃ and later at 700℃ in a muffle furnace for 1 h.

General procedure for the synthesis of 5-cyano-1,4-dihydropyrano^{[2, 3, c]}pyrazoles 5a-5p by Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃: typically,to a mixture of hydrazine hydrate 1a or phenylhydrazine 2a(2 mmol),ethyl-3-alkyl-3-oxopropanoate2(2 mmol),aromatic aldehyde 3a-p(2 mmol) and malonitrile 4(2 mmol) was added the catalyst (0.03 g) at room temperature in 50:50 water/ethanol. The reaction mixture was vigorously stirred for the period of time denoted in Table 1. During the procedure,the reaction was monitored by TLC. Upon completion,Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ could be placed on the side wall of the reaction vessel with the aid of an external magnet,and water was removed from the mixture to leave a residue (including the product and the catalyst). Then,the product was dissolved in ethanol and the catalyst easily separated from the product with the aid of an external magnet onto the reaction vessel,followed by decantation of the product solution. Then,the solution was concentrated,dried at room temperature and recrystallized from ethanol. All the products were identified by comparingtheir spectral data with those of authentic samples ^{[23, 24, 25]}.

Table 1

Table 1 Comparison of different solvents and catalysts for synthesis of pyranopyrazole (5a).a

Table 1 Comparison of different solvents and catalysts for synthesis of pyranopyrazole (5a).a

The one-pot synthesis of pyranopyrazoles was achieved by the four-component condensation of hydrazine hydrate 1a or phenylhydrazine 1b,ethyl-3-alkyl-3-oxopropanoate 2,aromatic aldehydes 3a-p and malononitrile 4 in the presence of Ni_0.5Zn_0.5-Fe₂O₄@Hap-Cs₂CO₃as a heterogeneous basic catalyst (Scheme 1). Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ nanocrystallites were prepared according to the reported procedure by Massart with minor modifications: fine particles are precipitated in an alkaline solution ^[22]. Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃nanocrystallites were characterized by FT-IR (Fig. 1),TEM (Fig. 2),SEM (Fig. 3) and XRD (Fig. 4). FT-IR spectra of Ni_0.5Zn_0.5Fe₂O₄,Ni_0.5Zn_0.5Fe₂O₄@Hap,Cs₂CO₃, Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃at 100℃ and 700℃ are compared in Fig. 1. In the FT-IR spectrum of Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ (Fig. 1(d)),most of the bands of Ni_0.5Zn_0.5Fe₂O₄ (Fig. 1(a)), Ni_0.5Zn_0.5Fe₂O₄@Hap (Fig. 1(b)) andCs₂CO₃ (Fig. 1(c)) with a slight shift for some of them,are observable,which shows Cs₂CO₃ has been adsorbed well on the Hap surface. The adsorption band at 3580 cm^-1 represented the stretching vibration mode of the lattice OH^- . The bands at 1095,1041,and 962 cm^-1 characterized the stretching mode of phosphate(PO₄^3- ,P-O),while the bands at 606, 569,and 476 cm^-1 exhibited the bending mode of phosphate (PO₄^3- ,P-O). Those are the major characteristic bands of Hap. Also, Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃has typical absorbance ofCO₃^2- at 1540 cm^-1 for both dried and calcined samples,which are assigned to carbonate^[26]. As shown in Fig. 1(d) and (e),the corresponding bands for cesium carbonate are present at 100℃ and 700℃.

Fig. 1

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Fig. 1. The FTIR spectra of: (a) Ni0.5Zn0.5Fe2O4; (b) Ni0.5Zn0.5Fe2O4@Hap; (c) Cs2CO3; (d) Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3at 1008C and (e) Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3at 7008C.

The particle size of nanocatalyst was investigated by TEM technique. The TEM photograph of sample (Fig. 2) shows average size of Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ magnetic nanocatalyst is approximately between 40and 50 nm in the diameter. Also,the morphological features were studied by SEM technique. The SEM image of Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃(Fig. 3)demonstrates that these modified hydroxyapatite magnetic nanoparticles are almost spherical,narrowly distributed and well dispersed.

Fig. 2

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Fig. 2. TEM image of Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3nanoparticles.

Fig. 3

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Fig. 3. SEM image of Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3nanoparticles

To confirm Ni_0.5Zn_0.5Fe₂O₄ formation in the synthesized magnetic nanoparticles,the XRD pattern of the samples was studied. The XRD patterns (Fig. 4) indicate that these nanoparticles have the spinel structure,with all the major peaks matching the standard pattern of bulk Ni_0.5Zn_0.5Fe₂O₄ (JCPDS 08-0234). Furthermore,the presence of hydroxyapatite was confirmed inFig. 4 (pattern 2). The related peak for the cesium carbonate was not detected in the XRD pattern of the catalyst. It is probably may be due to overlapping with hydroxyapatite peaks. Additionally,XRDrelated peaks for cesium carbonate are very weak ^[15]. However, the presence of cesium carbonate has been confirmed by FT-IR spectrum (Fig. 1) and X-ray fluorescence (XRF) analysis. XRF analysis showed that the amount of cesium in the samples was 10.42 wt%.

Fig. 4

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Fig. 4. XRD patterns of Ni0.5Zn0.5Fe2O4. (1) Ni0.5Zn0.5Fe2O4; (2) Ni0.5Zn0.5Fe2O4@Hap and (3) Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3

At first,the synthesis of compound5awas selected as a model reaction to optimize the reaction conditions. The reaction was carried out by mixing hydrazine hydrate (2 mmol),ethyl-3-oxopropanoate (2 mmol),benzaldehyde (2 mmol) and malononitrile (2 mmol) at room temperature under neat conditions. The model reaction was examined in the different solvents such as ClCH₂CH₂Cl,EtOH,MeOH,MeCN,CHCl₃,H₂O and as well as 50:50 water/ethanol (Table 1). No product was obtained in the absence of the catalyst (entry 1),indicating that the catalyst is necessary for the reaction. Also,bare Ni_0.5Zn_0.5Fe₂O₄ nanoparticles for the reaction as well as the hydroxyapatite coated Ni_0.5Zn_0.5Fe₂O₄ nanoparticles have been used for catalysis (entries 2,3). As shown, yields of the reactions are very low. Furthermore,yield of the reaction in the polar solvents was more than non-polar solvents (entries 4-11),we believe which due to the anionic structure generation and hydrogen bonding formation of cesium carbonate in the polar solvents,the reaction could be carried out with better yields. Also,among these polar solvents,50:50 water/ethanolat room temperature showed the best results (entry 7). Increasing the reaction temperature did not improve the yield (entries5-7).

Then,to find the optimum quantity of Ni_0.5Zn_0.5Fe₂O₄@Hap- Cs₂CO₃,the model reaction was carried out under the previously mentioned conditions using different amounts of catalyst (Table 2). Raising the amount of the catalyst increased the yield of the product 5a(entries2-4). Using 0.03 g of catalyst resulted in the highest yield in 10 min (entry 4). Increasing the amount of the catalyst beyond this value did not increase the yield of the reaction noticeably (entries 5,6).

Table 2

Table 2 Comparison of the amount of Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3and yields for the synthesis of pyranopyrazole (5a).

Table 2 Comparison of the amount of Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3and yields for the synthesis of pyranopyrazole (5a).

Using these optimized reaction conditions,the scope and efficiency of this approach was explored for the synthesis of a wide variety of 5-cyano-1,4-dihydropyrano^{[2, 3, c]}pyrazoles and the obtained results are summarized in Table 3. All the reactions, delivered good product yields and accommodated a wide range of aromatic aldehydes bearing both electron-donating and electronwithdrawing substituents. In all cases,the obtained product was isolated by a very simple work-up.

Table 3

Table 3 Preparation of 5-cyano-1,4-dihydropyrano[2, 3, c]pyrazoles using Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3(0.03 g) as catalyst.a

Table 3 Preparation of 5-cyano-1,4-dihydropyrano[2, 3, c]pyrazoles using Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3(0.03 g) as catalyst.a

From the view point of green chemistry,good recovery and reusability of the catalyst are highly preferable. For this purpose, the same model reaction was again studied under optimized conditions. After the completion of the reaction,the reaction mixture was then separated by an external magnet. Then the product was dissolved in ethanol and the catalyst easily separated by an external magnet.The catalyst was washed with diethyl ether, dried at 60℃ under vacuum for 1 h,and reused for a similar reaction. As shown in Fig. 5,the catalyst could be reused at least six times without significant loss of its activity.The weight of the recovered catalyst is the same as the amount of the fresh catalyst that was used the first time in the reaction.

Fig. 5

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Fig. 5. Reusability test of the catalyst. Reaction conditions: hydrazine hydrate (2 mmol),ethyl-3-oxopropanoate (2 mmol),benzaldehyde (2 mmol),malononitrile (2 mmol) and Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3 nanocatalyst (0.03 g) at room temperature and reaction time (10 min).

The FT-IR spectra of catalyst before use (fresh) and after reuse five times (recovered) were studied. As shown in Fig. 6,the FT-IR spectrum of the recovered nanocatalyst showed whichstructure of catalyst remained almost the same after five-run reuse. In addition, the weight of the recovered catalyst is the same as the amount of the fresh catalyst that was used the first time in the reaction.

Fig. 6

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Fig. 6. FT-IR spectrum of (a) fresh and (b) recovered (after five times) Ni0.5Zn0.5Fe2O4@Hap-Cs2CO3.

We have introduced Ni_0.5Zn_0.5Fe₂O₄@Hap-Cs₂CO₃ as a new, efficient,reusable and green nanocatalyst for the synthesis of 5-cyano-1,4-dihydropyrano^{[2, 3, c]}pyrazoles at room temperature in water/ethanol. The catalyst could be recycled after a very simple work-up (with the aid of an external magnet),and reused at least six runs without significant loss of its catalytic activity. The present method requires small amounts of inexpensive catalyst. The mild reaction conditions,high yields,short reaction times,easy work-up,and absence of any volatile and hazardous organic solvents are some advantages of this protocol. With regard to observed satisfactory catalytic properties,it is expected that it can be potential substitute for some commercial catalysts.

The authors are grateful toIslamic Azad University,Bandar Abbas Branch for financial support.