Ultrasound mediated green synthesis of pyrano[2,3-c]pyrazoles by using Mn doped ZrO₂

2.1 Preparation of catalyst

Manganese oxide loaded on zirconia (1, 2 & 4 wt% Mn/ZrO₂) catalysts was prepared by wet impregnation method (Chetty et al., 2012a,b). Typically, an appropriate wt% amount of manganese nitrate [Mn(NO₃)₂ (Alfa Aesar)] solution was added to 2.0 g of support (ZrO₂, Catalyst support, Alfa Aesar) and the mixture was stirred at 40 °C for 8 h. Then the catalyst was dried in an oven at 110–130 °C for 12 h, followed by their calcination in the presence of air, at 450 °C for 3 h to acquire the w/w catalyst. The catalyst characterization details are provided in Electronic Supporting Information (ESI-I).

2.2 General procedure for the synthesis of pyrano[2,3-c]pyrazole-3-carboxylate and pyrano[2,3-c]pyrazole-5-carbonitrile derivatives under silent conditions

A flask containing a mixture of malononitrile (1 mmol), aromatic aldehyde (1 mmol), dimethylacetylenedicarboxylate/ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol) and 2% Mn/ZrO₂ (30 mg) in aqueous ethanol (1:1, v/v 10 mL) was employed and stirred at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered, and the solvent was evaporated to obtain the pure product (Scheme 1) without further recrystallization.

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Scheme 1 Synthesis of pyrano[2,3-c]pyrazoles-3-carboxylate derivatives.

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2.3 General procedure for the synthesis of pyrano[2,3-c]pyrazole-3-carboxylate and pyrano[2,3-c]pyrazole-5-carbonitrile derivatives under ultrasound irradiation

A mixture of dimethylacetylenedicarboxylate/ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), malononitrile (1 mmol), aromatic aldehyde (1 mmol) and 2% Mn/ZrO₂ (30 mg) in aqueous ethanol (1:1, v/v 10 mL) was irradiated with ultrasound at 40 kHz at room temperature within 10 min. After completion of the reaction as observed by TLC, the solution was filtered to separate the catalyst. The filtrate was concentrated under reduced pressure to afford the pure product. The structures of the resulting products were established on the basis of their physical properties and spectral data.

2.4 Physical data for the pyrano[2,3-c]pyrazole-3-carboxylate derivatives (5a–g)

2.5 Physical data for the pyrano[2,3-c]pyrazole-5-carbonitrile derivatives (7a–g)

3.1 Nitrogen adsorption analysis

The N₂ adsorption/desorption isotherms and corresponding pore size distribution of the Mn doped zirconia catalyst are shown in Fig. 1. The isotherm is a typical type IV isotherm with the presence of a hysteresis loop (H2 type), which indicates the presence of mesopores in the material. The pore size distribution and specific area were calculated from the Barrett–Joyner–Halenda (BJH adsorption) and Brunauer–Emmett–Teller methods, respectively. The BET surface area calculated from this isotherm is 194.56 m² g⁻¹. The pore volume estimated for this sample is 0.563 cm³ g⁻¹.

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Figure 1 N₂ adsorption and desorption spectra of 2% Mn/ZrO₂ catalyst.

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3.2 Powder X-ray diffraction analysis

An X-ray diffractogram of the calcined prepared Mn/ZrO₂ catalyst is depicted in Fig. 2. The narrow line widths indicate a high crystallinity of the material. ZrO₂ displayed diffraction peaks at 2θ = 28.45, 31.53, 35.25, 50.55 and 60.23 corresponding to (1 1 1), (0 0 2), (0 2 2), (1 1 3) planes representing various phases. The d-spacings at 2θ peaks of 25.27, 34.79, 38.83, 55.21, and 66.12 for Mn₂O₃ respectively. It is in good agreement with the JCPDS file no. 41-1442. From the XRD image it is evident that Mn₂O₃ is the major phase in this catalyst. There is a formation of other phase, i.e. Mn₃O₄ observed. The d-spacings at 2θ angles of 16.02, 26.17, 33.12, 45.47, 49.88 and 57.73 for Mn₃O₄ correspond to the JCPDS file no. 18-0803 for Mn₃O₄ phase.

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Figure 2 XRD spectrum of 2% Mn/ZrO₂ catalyst.

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3.3 TEM analysis

The size and morphology of Mn doped ZrO₂ were analyzed by transmission electron microscopy (TEM) (Fig. 3). The result shows that the catalyst consists of spherical particles with the crystallite size between 12 and 23 nm for manganese oxide particles which could be agglomerated on the zirconia surface. Due to the relatively low doping of Mn, we did not observe many MnO₂ particles. The image revealed that the ZrO₂ existed as uneven elliptical shaped particles.

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Figure 3 TEM micrograph of 2% Mn/ZrO₂ catalyst.

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3.4 SEM analysis

Fig. 4 reveals the SEM images of MnO₂ doped ZrO₂ catalyst. MnO₂ particles were observed as tiny particles homogeneously distributed on the surface of ZrO₂. The manganese oxide particles are evidenced as hexagonally shaped. The catalyst appeared crystalline in nature. Due to the low loading of manganese there were a low number of particles observed. The SEM–EDX confirms the data from ICP elemental analysis. Furthermore, the morphology of the catalyst from the SEM images noticeably points to the crystallinity and homogeneity of the sample.

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Figure 4 SEM micrograph of 2% Mn/ZrO₂ catalyst.

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3.5 Optimization procedure

In order to synthesize pyranopyrazole derivatives, we have examined the multicomponent reaction of dimethylacetylenedicarboxylate/ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), malononitrile (1 mmol) and aromatic aldehyde (1 mmol) in aqueous ethanol (1:1, v/v) in the presence of catalytic amount of 2% Mn/ZrO₂ (30 mg) by using ultrasound irradiation at room temperature (Scheme 1).

Firstly, the effect of various solvents (non-polar, protic and aprotic) on the formation of pyranopyrazoles was investigated in the presence of catalyst under silent and ultrasonification (Table 1). Under solvent free conditions, the reaction did not take place, even in the presence of catalyst at prolonged reaction time (Table 1, entry 1). In non-polar solvents such as 1,4-dioxane, n-hexane and toluene, the reaction did not proceed (Table 1, entries 2–4). Further, low yields were obtained using polar aprotic solvents such as THF, and DMF (Table 1, entries 5 and 6). In the case of polar protic solvents such as methanol, ethanol and water (Table 1, entries 7–9), the yield of the desired products was good; however, an excellent yield was afforded using H₂O and EtOH (1:1, v/v) as the solvent (Table 1, entry 10). The efficiency of methanol and ethanol relative to water was also investigated. Although comparable yields were observed (Table 1), aqueous ethanol had a marginal advantage, thus proving to be best medium for the reaction. A highly polar solvent which dissipates heat faster may provide optimum conditions for the formation of intermediates, and their conversion to final products on the catalyst surface. Therefore, the reaction was optimized using a cheap, safe, and environmentally benign reaction medium as opposed to the other synthetic solvents. An aqueous ethanol could also be used as the best solvent for the synthesis.

Next, the model reaction for the synthesis of pyranopyrazoles was carried out in the absence and presence of different catalysts at different reaction temperature under magnetic stirring and ultrasonication by using aqueous ethanol as solvent (Table 2). When, the reaction neither at room temperature nor at heating condition proceeds even for a prolonged reaction time without catalyst (Table 2, entries 1 and 2). This indicates that the catalyst is necessary for this conversion. However, the starting materials were screened by different acidic catalysts such as FeCl₂ and ZnCl₂ at RT in aqueous ethanolic media and gave trace yields under both conditions, with the product yield obtained in less reaction time using ultrasonication (Table 2, entries 3 and 4). Further, the reaction was performed using the organic and inorganic bases such as Et₃N, NaOH, K₂CO₃, and Na₂CO₃. In the presence of these bases after 3 h, only low amount of the product was observed under silent conditions. The yield of the product was considerably increased within shorter reaction time under ultrasound irradiation (Table 2, entries 5–8). Thereafter, the reaction was performed in the presence of an ionic liquid like (Bmim)BF₄ to obtain moderate yields at RT condition, but the product was obtained at 1.5 h under ultrasound irradiation (Table 2, entry 9). Further heterogeneous pure oxides, such as Al₂O_3, SiO₂ and ZrO₂ were employed as catalysts under both conditions. The reaction gave moderate to good yields and reduced the reaction times. Fascinatingly, by using the ZrO₂ as catalyst, an ample improvement in yield was observed (Table 1, entries 10–12). Based on the positive results obtained with zirconia, reactivity for various metal supported ZrO₂ catalysts, such as 2% Ag/ZrO₂ and 2% Mn/ZrO₂ was screened. These mixed oxide catalyzed reactions gave improved yields (78% and 83%) within 1.0 h reaction time under normal condition and yields (85% and 98%) within 10 min reaction time under ultrasonication (Table 1, entries 13 and 14). Tremendously, when Mn supported on ZrO₂ was used as catalyst, the reaction progressed impressively recording an excellent 98% yield of pyranopyrazoles at RT within 10 min reaction time under ultrasonication (Table 2, entry 14). This study endorses that ultrasonication method with aqueous ethanol as solvent media is the best for one-pot, four-component reactions to achieve excellent yields.

It was perceived that the optimal the amount of catalyst loading in the synthesis of desired products, we started the study by treating a mixture of dimethylacetylenedicarboxylate/ethyl acetoacetate, hydrazine hydrate, malononitrile, and aromatic aldehyde in the presence of various amounts of Mn/ZrO₂ catalyst in aqueous ethanol under ultrasonication to afford the target protocols. The results of this study are described in Table 3. It is noted that, when the amount of catalyst was lower, the yield of the product decreased, whereas raising the catalyst concentration did not lead to a pronounced increase in the product yield. During our optimization studies, 30 mg of 2% Mn doped ZrO₂ gave the best result in terms of time of completion and the product was obtained in 98% yield (Table 3).

To assess the versatility of this method a series of aromatic aldehydes were studied under the optimum reaction conditions; the results are listed in Table 4. In all cases, the reactions gave the products in good to excellent yields in very short reaction times. Fascinatingly, a variety of aryl aldehydes bearing both electron-releasing and electron-withdrawing (o, m and p functional) groups have apparently no obvious effect on the yields obtained and the reaction time under the optimal conditions, and afforded the pyrano[2,3-c]pyrazole-3-carboxylate/pyrano[2,3-c]pyrazole-5-carbonitrile derivatives (5a–g and 7a–g) in good to excellent yield in all the cases (Table 4). Structures of all the products (5a–g and 7a–g) were established and confirmed on the basis of their spectral data, ¹H NMR, ¹³C NMR, ¹⁵N NMR (GHSQC) and HRMS.

According to our results, the probable mechanism to account for the reaction was suggested (Scheme 1). The reaction mechanism displays the tandem sequence of Mn/ZrO₂ catalyzed through ultrasound irradiation reactions proposed to explain formation of the pyranopyrazoles. In the first step, 2-arylidenemalononitrile (3) is formed by a fast Knoevenagel condensation of malononitrile (1) with arylaldehyde (2) catalyzed by the Mn/ZrO₂ under ultrasound irradiation. The second step involves formation of 1H-pyrazol-3-carboxylate (6) by reaction of hydrazine hydrate (5) with ester compound (4). In the third step, a Michael addition of 3–7 in the presence of the catalyst under ultrasound irradiation produces the intermediate. Intramolecular cyclization and subsequently tautomerization afford the desired pyranopyrazole derivatives.

3.6 Reusability of the catalyst

Recovery and reuse of catalysts is a significant facet of green chemistry and makes it useful for commercial applications. Thus, the reusability of the catalyst was tested in the synthesis of pyranopyrazoles. Excitingly, after each reaction, the catalyst was filtered and the recovered catalyst was washed with hot ethanol (2 × 10 mL), which was then dried at 110 °C under reduced pressure for 2–3 h. The recycled catalyst was used for the subsequent runs repeating the same procedure. The reusability of the catalyst was evaluated in the synthesis of pyrano[2,3-c]pyrazole-3-carboxylate/pyrano[2,3-c]pyrazole-5-carbonitrile derivatives (5a–g and 7a–g). The recovered catalyst was employed in six consecutive runs, and the decrease in activity was marginal (Fig. 5).

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Figure 5 Recyclability of 2% Mn/ZrO₂ catalyst.

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