An extremely efficient catalytic protocol for the synthesis of a series of pyranopyrazole derivatives developed in a one-pot four-component approach in the presence of ZnO nanoparticles as heterogeneous catalyst using water as a green solvent is reported. Greenness of the process is well instituted as water is exploited both as reaction media and medium for synthesis of catalyst. The ZnO nanoparticles exhibited excellent catalytic activity, and the proposed methodology is capable of providing the desired products in good yield (85–90%) and short reaction time. After reaction course, ZnO nanoparticles can be recycled and reused without any apparent loss of activity which makes this process cost effective and hence ecofriendly. All the synthesized compounds have been characterized on the basis of elemental analysis, IR, 1H NMR, and 13C NMR spectral studies.
Multicomponent reactions (MCRs) occupy an interesting position in organic synthesis because of their atom economy, simple procedures, and convergent character [
Catalysis has played a vital role in the success of the industry [
In recent years, in biological field, the potential utility of ZnO nanoparticle in the treatment of cancer has been reported by many researchers. Owing to numerous advantages associated with this ecofriendly nature, it has been explored as a powerful catalyst for several organic transformations [
Pyrazole derivatives constitute an interesting class of heterocycles due to their synthetic versatility and effective biological activities [
Hence, in continuation of our work to develop ecofriendly techniques for heterocyclic synthesis [
The process described here offers rapid facile one-pot synthesis of pyranopyrazole derivatives using easily recyclable ZnO nanoparticles. This process is cost effective and eco-friendly as it is one-pot synthesis with easy work-up and does not require harsh reagents. To the best of our knowledge, there is no report available in the literature describing the use of ZnO nanoparticles as catalysts for the synthesis of pyranopyrazole carboxyethylester derivatives. The effectiveness of the process was studied by comparing the results obtained with and without catalyst under normal conditions.
Reagents and solvents were obtained from commercial sources and used without further purification. Melting points were determined on a Toshniwal apparatus. The spectral analyses of synthesized compounds have been carried out at SAIF, Punjab University, Chandigarh. Purity of all compounds was checked by TLC using “G” coated glass plates and benzene: ethyl acetate (8 : 2) as eluent. IR spectra were recorded in KBr on a Perkin Elmer Infrared RXI FTIR spectrophotometer, and 1H NMR spectra were recorded on Bruker Avance II 400 NMR spectrometer using DMSO-d6 and CDCl3 as solvent and tetramethylsilane (TMS) as internal reference standard. The obtained products were identified from their spectral (1H NMR, 13C NMR, and IR) data. The microwave-assisted reactions were carried out in a Catalysts Systems Scientific Multimode MW oven attached with a magnetic stirrer and reflux condenser, operating at 700 W generating 2450 MHz frequency.
ZnO nanoparticles were synthesized by two different methods.
ZnO nanorods are prepared according to a literature method developed by Pacholski et al. [
Zinc acetate and hydrazine hydrate were mixed in a molar ratio of 1 : 4 in water under stirring. Hydrazine readily reacted with zinc acetate to form a slurry-like precipitate of the hybrid complex between them. The stirring of the slurry was continued for 15 min, and then the mixture was subjected to microwave irradiation at 150 W microwave power for 10 min. The slurry became clear with a white precipitate at the bottom. The precipitate was filtered off, washed with absolute ethanol and distilled water several times and then dried in vacuum at
A mixture of hydrazine hydrate
Nano-ZnO catalyzed synthesis of pyrano[2,3-
Entry | Ar | Time (min.) | Yield (%) | M.P. (°C) |
---|---|---|---|---|
Ethyl-6-amino-1,4-dihydro-4-(3,4-dimethoxyphenyl)-3-methylpyrano[2,3- |
3,4-Dimethoxy |
60 | 90 | 135 |
| ||||
Ethyl-6-amino-1,4-dihydro-4-(3-methoxyphenyl)-3-methylpyrano[2,3- |
3-Methoxyphenyl | 55 | 85 | 120 |
| ||||
Ethyl-6-amino-1,4-dihydro-4-(3,4,5-trimethoxyphenyl)-3-methylpyrano[2,3- |
3,4,5-Trimethoxy |
55 | 86 | 160 |
| ||||
Ethyl-6-amino-4-(4-chlorophenyl)-1,4-dihydro-3-methylpyrano[2,3- |
4-Chlorophenyl | 60 | 87 | 140 |
| ||||
Ethyl-6-amino-1,4-dihydro-4-(4-methoxyphenyl)-3-methylpyrano[2,3- |
4-methoxyphenyl | 55 | 89 | 130 |
| ||||
Ethyl-6-amino-1,4-dihydro-3-methyl-4-(5-methylfuran-2-yl)pyrano[2,3- |
3-methyl-2-furyl | 60 | 86 | 142 |
| ||||
Ethyl-6-amino-1,4-dihydro-3-methyl-4-(thiophen-2-yl)pyrano[2,3- |
2-thienyl | 55 | 87 | 115 |
| ||||
Ethyl-6-amino-1,4-dihydro-3-methyl-4-(pyridin-3-yl)pyrano[2,3- |
3-pyridyl | 60 | 85 | 125 |
| ||||
Ethyl-6-amino-1,4-dihydro-4-(2-hydroxyphenyl)-3-methylpyrano[2,3- |
2-Hydroxyphenyl | 60 | 87 | 143 |
| ||||
Ethyl-6-amino-1,4-dihydro-4-(3-hydroxy-4-methoxy phenyl)-3-methylpyrano[2,3- |
3-hydroxy, 4-methoxyphenyl | 60 | 85 | 145 |
Reaction conditions: hydrazine hydrate
Recyclability of ZnO nanoparticles.
To examine the reusability, the catalyst was recovered by filtration from the reaction mixture after dilution with ethyl acetate, washed with methanol, and reused as such for subsequent experiments (up to three cycles) under similar reaction conditions. The observed fact that yields of the product remained comparable in these experiments (Figure
An environ-economic synthesis of ethyl-6-amino-1, 4-dihydro-3-methyl-4-substituted pyrano[2,3-
We have extensively studied the reaction using various catalysts such as alum, Montmorillonite-K10 clay, P2O5, acidic alumina, silica, Montmorillonite-KSF clay, glacial acetic acid, and ZnO nanoparticles (Table
Screening of catalysts for one-pot condensation of ethyl cyanoacetate, hydrazine hydrate, 4-methoxy benzaldehyde, and methyl acetoacetate.
Entry | Catalyst | Catalyst |
Yield |
Time |
---|---|---|---|---|
|
Alum | 3 | 66 | 110 |
|
ZnO nps | 9 | 89 | 60 |
|
Mont K10 | 7 | 75 | 80 |
|
P2O5 | 5 | 68 | 110 |
|
Acidic alumina | 7 | 63 | 100 |
|
Silica | 12 | 69 | 100 |
|
Mont KSF | 7 | 58 | 90 |
|
Glacial acetic acid | 12 | 60 | 90 |
Reaction conditions: hydrazine hydrate
Effect of solvent on the reaction of ethyl cyanoacetate, hydrazine hydrate, 4-methoxy benzaldehyde, and methyl acetoacetate under stirring at room temperature.
Entry | Solvent | Time (min) | Yield (%) |
---|---|---|---|
|
Ethanol | 90 | 62 |
|
Methanol | 80 | 68 |
|
Water | 60 | 89 |
Reaction conditions: hydrazine hydrate
Comparison of catalytic activity of ZnO nanoparticles in the synthesis of compound
Entry | Conditions | Types of catalysts | Reaction time (hrs/min.) | Yield (%) |
---|---|---|---|---|
|
Stirring (25°C) | No catalyst | 8 hrs | Traces |
Stirring (25°C) | Nano-ZnO | 60 min | 89 | |
|
No catalyst | 6 hrs | Traces | |
|
Nano-ZnO | 40 min | 55 |
Encouraged by these results, we have extended this reaction to variously substituted aromatic aldehydes under similar conditions using ZnO nanoparticle as a catalyst to furnish the respective pyranopyrazole derivatives in excellent yields (85–90%) without the formation of any side products. Further, we have emphasized the amount of ZnO nanoparticle to be used in this reaction. We found that the yields were obviously affected by the amount of ZnO nanoparticles loaded. When 3, 6, 9, and 12 mol% of ZnO nanoparticles was used, the yields were 75%, 82.06%, 89%, and 89%, respectively. Therefore, 9 mol% of ZnO nano particles were sufficient to push the reaction forward, and, further, increasing the amount of ZnO nanoparticles did not increase the yields (Table
Optimization of the ZnO nanoparticle catalyzed model reaction for synthesis of
Entry | Catalyst (mol %) | Yield (%) |
---|---|---|
|
3 | 75 |
|
6 | 82 |
|
9 | 89 |
The above results indicate that ZnO nanoparticle was essential in the reaction and the best results were obtained when the reaction was carried out with 9 mol% of ZnO nanoparticles at room temperature.
The proposed mechanism for the formation of the product would be as follows. The ZnO nanoparticle facilitates the Knoevenagel type coupling through Lewis acid sites (Zn+2) coordinated to the oxygen of carbonyl groups of methylacetoacetate. On the other hand, ZnO nanoparticles can activate ethylcyanoacetate so that deprotonation of the C–H bond occurs in the presence of Lewis basic sites (O−2). As a result, the formation of pyranopyrazole derivatives proceeds by activation of reactants through both Lewis acids and basic sites of ZnO nanoparticles. The reaction occurs via initial formation of arylidene ethylcyanoacetate by the Knoevenagel condensation between aromatic aldehyde and ethyl cyanoacetate and pyrazolone by the reaction of methyl acetoacetate and hydrazine hydrate. Finally, the Michael addition of pyrazolone to arylidene ethylcyanoacetate followed by cyclization and tautomerization yields pyranopyrazole.
The synthesis of ZnO nanoparticles was carried out in distilled water for its inherent advantages as it is simple, cost effective, environmentally benign, and easily scaled up for large scale synthesis, and in this method there is no need to use high pressure, high temperature, and toxic chemicals. Additionally, water served as a suitable solvent for the current transformation as well.
Reusability (and hence recyclability) is one of the important properties of this catalyst. The catalyst could be recycled easily, simply by solvent extraction of the product from the reaction mixture using ethyl acetate. The catalyst retained optimum activity till three cycles after which drop in yield was observed (Figure
The nanostructure of ZnO nanoparticle has been studied at room temperature by using X-ray diffraction pattern. Figure
XRD Pattern of ZnO nanoparticles.
The spectroscopic characterization data of the synthesized compounds are given below.
We have demonstrated a highly efficient green catalytic approach for the four-component one-pot synthesis of pyranopyrazole derivatives catalyzed effectively by ZnO nanoparticles. ZnO nanoparticles are well characterized by XRD technique. This method offers several advantages including avoidance of harmful organic solvents, high yield, short reaction time, simple work-up procedure, ease of separation, and recyclability of the catalyst.
The authors are thankful to the Dean and to the Head of the Department of Science and Humanities at FET, MITS, for providing necessary research facilities in the department. Financial assistance from FET, MITS, is gratefully acknowledged. They are also thankful to SAIF Punjab University, Chandigarh, for the spectral and elemental analyses.