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Nanomagnetic CoFe2O4@SiO2-EA-H3PO4 as a zwitterionic catalyst for the synthesis of bioactive pyrazolopyranopyrimidines and dihydropyrano[2,3-c]pyrazoles

Ali Mirzaie a, Lotfi Shiri *a, Mosstafa Kazemi a, Nourkhoda Sadeghifard b and Vahab Hassan Kaviar b
aDepartment of Chemistry, Faculty of Basic Sciences, Ilam University, P. O. Box 69315-516, Ilam, Iran. E-mail: l.shiri@ilam.ac.ir
bClinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran

Received 19th October 2023 , Accepted 21st January 2024

First published on 5th February 2024


Abstract

This study presents the development of a phosphoric acid-based zwitterionic catalyst immobilized on CoFe2O4 nanoparticles [CoFe2O4@SiO2-EA-H3PO4]. The structure of the nanocatalyst CoFe2O4@SiO2-EA-H3PO4 was identified by applying several spectroscopic techniques, i.e. FT-IR, SEM, TEM, XRD, EDX, elemental Mapping, VSM, TGA, and BET techniques. The catalytic efficiency of CoFe2O4@SiO2-EA-H3PO4 was evaluated in the water-based multicomponent synthesis of pyrazolopyranopyrimidine and dihydropyrano[2,3-c]pyrazole derivatives. Subsequently, an exploration of the antibacterial properties of the compounds was conducted. The catalytic system offers several advantages, encompassing high efficiency, brief reaction duration, uncomplicated operation, and facile recycling of the catalyst.


1. Introduction

Multicomponent reactions (MCRs) represent an exceedingly efficient approach for conducting diversity-oriented synthesis in the field of organic chemistry.1–3 In this sense, MCRs are recognized for their ability to create complex molecules in a single-pot reaction with high yields, short reaction times, minimal waste, and low purification costs. This makes MCRs a powerful tool used to construct novel and structurally diverse compounds.4,5

Compounds that include a nitrogen atom in their heterocyclic structure possess a variety of biological activities and pharmacological properties.6–8 Pyrazolopyranopyrimidine and dihydropyrano[2,3-c]pyrazoles exhibit notable promise in the realms of organic synthesis and medicine, owing to their prospective role as fundamental building blocks for pharmaceutical compounds.9 As a result, in order to synthesize such compounds, numerous techniques have been developed.6,10

Green catalysis, a subset of green chemistry, emphasizes the pressing need to develop and utilize catalysts that are environmentally friendly.12,13 In this regard, an ideal catalyst should be cost-effective, highly active, efficient, selective, stable, easily recoverable, and recyclable.14 Moreover, hybrid organic–inorganic materials have attracted considerable attention as heterogeneous catalysts in the field of organic synthesis.15 In recent years, there has been an increase in using heterogeneous catalysts due to their ability to be separated from the reaction mixture with ease, despite the potential lower activity as compared to homogeneous catalysts.16,17 Furthermore, the use of magnetic nanoparticles and their coated analogues has gained popularity due to their various advantages, i.e. effortless separation with the help of an external magnet, low toxicity, a highly active surface, easy recovery, and remarkable stability.18

Phosphoric acid stands out as one of the most crucial industrial catalysts, finding extensive application in a diverse range of organic transformations since 2004.19 Notably, various methods have been applied aiming to recycle phosphoric acid in these transformations.20 However, these methods are very costly and complex. It is worth mentioning that zwitterions are an efficient class of catalysts that include two different ions in their structure.21 As a part of our continuing efforts toward the development of solid acid catalysts, an efficient method is described for the preparation of a novel phosphoric acid-based zwitterionic catalyst immobilized on CoFe2O4 MNPs as the catalyst for the synthesis of important N-containing heterocycles in water and at room temperature.22 The overuse of antibiotics in the market has led to various health issues, including antibiotic resistance; therefore, discovering new drugs to combat microbial infections is crucial.23 The synthesized compounds were evaluated for their antibacterial properties against both Gram-negative and Gram-positive bacteria in our research.

2. Experimental

2.1. General methods

The chemicals and solvents utilized in this study were obtained from Merck and Sigma-Aldrich Chemical Companies and were used as received.

2.2. Typical method for the synthesis of the CoFe2O4@SiO2-EA-H3PO4 nanomagnetic catalyst

The CoFe2O4@SiO2 core–shell was synthesized using the method that has been previously documented.24 In the subsequent step, 1.5 g of nanoparticles obtained from the previous step were dispersed in 50 mL of H2O for 10 min. The dispersion was then combined with 2 g of 2-chloroethylamine hydrochloride, followed by the addition of 1.5 g of NaHCO3. The mixture was subjected to reflux temperature for 24 h and 2 h, respectively. The resulting CoFe2O4@SiO2-EA product was extracted using a magnet, rinsed with DI water and, then, dried. In the concluding step, the CoFe2O4@SiO2-EA-MNP was dispersed in 10 mL of CH2Cl2 using ultrasound for 10 min. Subsequently, 1.5 mL of phosphoric acid was added dropwise to the reaction mixture, followed by stirring at room temperature. After 12 h, the nanoparticles were extracted with a magnet, washed with CH2Cl2 and EtOH, and then dried to produce the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst outlined in Scheme 1.
image file: d3na00900a-s1.tif
Scheme 1 Stepwise synthesis of CoFe2O4@SiO2-EA-H3PO4.

2.3. The production of pyrazolopyranopyrimidines and dihydropyrano[2,3-c]pyrazole over the catalysis of CoFe2O4@SiO2-EA-H3PO4

A thoroughly stirred mixture comprising 1 mmol of ethyl acetoacetate and 1 mmol of hydrazine hydrate was supplemented with 1 mmol of barbituric acid or malononitrile, 1 mmol of aromatic aldehyde, and 20 mg of the catalyst. The reaction was monitored using TLC (applying n-hexane/ethyl acetate (1[thin space (1/6-em)]:[thin space (1/6-em)]2) as eluent) and, then, the mixture was diluted with hot ethanol. Subsequently, the catalyst was effortlessly removed using a magnet. Following that, the resulting substance which was subjected to recrystallization, using ethanol, was purified and, then, dried in an oven. The identification of the known compounds was done by comparing their melting points with those of authentic samples. Moreover, in certain instances, the analysis was conducted using FT-IR, 1H NMR, and 13C NMR, as illustrated in ESI Fig. S1–S33.

2.4. Antibacterial activity

The cup plate technique was used to test the in vitro antimicrobial activity of the synthesized derivatives against Gram-negative Escherichia coli ATCC-25922 and Gram-positive Staphylococcus aureus ATCC-25923. The minimum inhibitory concentration (MIC) of the compounds was determined using the broth micro-dilution method, wherein concentrations of 1000 and 5000 μg were tested for all derivatives. The compounds exhibiting antibacterial activity were selected for MIC determination.

3. Results and discussion

Following the synthesis of CoFe2O4@SiO2-EA-H3PO4, the structure of the nanomagnetic catalyst was verified through the utilization of FT-IR, SEM, TEM, XRD, EDX, elemental Mapping, VSM, TGA, and BET techniques.

3.1. Characterization of CoFe2O4@SiO2-EA-H3PO4

3.1.1. FT-IR studies. The FT-IR spectra of CoFe2O4, CoFe2O4@SiO2, CoFe2O4@SiO2-EA, and CoFe2O4@SiO2-EA-H3PO4 MNPs are presented in Fig. 1. The Fe–O and O–H bands were identified through the observation of stretching vibrations at 590 cm−1 and 3383 cm−1, respectively, confirming the successful synthesis of CoFe2O4 MNP (Fig. 1A). The verification of the SiO2 content on the surface of CoFe2O4@SiO2 MNPs is confirmed by the stretching frequencies detected at 1089 cm−1 (Fig. 1B). The grafting of 2-chloroethylamine on the CoFe2O4@SiO2 surface is verified by distinct peaks for methylene groups (CH2) at 2897–2949 cm−1 and a broadening peak at 3435 cm−1 for the NH2 group (Fig. 1C). Furthermore, the broad peak at around 3000–3700 cm−1 corresponds to the ammonium content of the catalyst, while symmetric and asymmetric PO stretching modes are observed at 1200 cm−1 (Fig. 1D).
image file: d3na00900a-f1.tif
Fig. 1 FT-IR spectra of CoFe2O4 (A), CoFe2O4@SiO2 (B), CoFe2O4@SiO2-EA (C), and CoFe2O4@SiO2-EA-H3PO4 (D).
3.1.2. Scanning electron microscopy (SEM) studies. The SEM image of CoFe2O4@SiO2-EA-H3PO4 MNPs is shown in Fig. 2. The obtained images indicate that the nanoparticles are spherical and fall within the size range of nanomaterials.
image file: d3na00900a-f2.tif
Fig. 2 SEM image of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst.
3.1.3. Transmission electron microscopy (TEM) studies. Transmission electron microscopy (TEM) was used to examine the morphology, size and shape of the CoFe2O4@SiO2-EA-H3PO4 MNPs. The TEM images indicate that the catalyst has a spherical form and a core–shell structure, with the average particle size at around 15–20 nm which is illustrated in Fig. 3. Furthermore, the TEM results were consistent with those obtained from SEM images.
image file: d3na00900a-f3.tif
Fig. 3 TEM micrograph of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst.
3.1.4. XRD analysis. Fig. 4 depicts the XRD pattern of CoFe2O4@SiO2-EA-H3PO4 MNPs. The plots exhibit six peaks at 2θ = 30.21°, 35.76°, 43.36°, 54.06°, 57.61° and 63.16°, which correspond to the standard plot of CoFe2O4 MNPs.25 The findings validate that the CoFe2O4 crystal structure remains unaltered even after the addition of organic and inorganic layers onto its surface. Through the application of Debye–Scherrer's calculation, it has been established that the nanoparticles exhibit a dimension of approximately 17.43 nm, aligning closely with the findings from TEM analysis.
image file: d3na00900a-f4.tif
Fig. 4 XRD patterns of CoFe2O4@SiO2-EA-H3PO4 MNPs.
3.1.5. EDX analysis. To determine the elemental composition of the CoFe2O4@SiO2-EA-H3PO4 catalyst, EDX spectroscopy was employed. The analysis confirmed the presence of Fe, Co, O, Si, C, P, and N elements, as predicted (Fig. 5).
image file: d3na00900a-f5.tif
Fig. 5 EDX spectrum of CoFe2O4@SiO2-EA-H3PO4 MNPs.
3.1.6. EDX elemental mapping analysis. EDX mapping imaging was used to examine the elemental composition of the CoFe2O4@SiO2-EA-H3PO4 MNP catalyst. The analysis revealed a significant amount of cobalt, iron, silicon, and oxygen elements in the CoFe2O4@SiO2 material. Significantly, the distribution of carbon, nitrogen, and phosphorus confirmed the presence of the desired zwitterion functionalities (EA-H3PO4) on the nanomagnetic support surface, as illustrated in Fig. 6.
image file: d3na00900a-f6.tif
Fig. 6 Displaying the scattering of elements in CoFe2O4@SiO2-EA-H3PO4 MNPs.
3.1.7. VSM analysis. The VSM technique was utilized to examine the magnetic characteristics of CoFe2O4, CoFe2O4@SiO2, and CoFe2O4@SiO2-EA-H3PO4 MNPs (as shown in Fig. 7). The magnetic potency of each material was assessed and determined to be 53 emu g−1, 35 emu g−1 and 9 emu g−1, respectively. This decrease in saturation magnetization indicates successful incorporation of the amorphous silica phase and organic functionalities onto the CoFe2O4 surface.
image file: d3na00900a-f7.tif
Fig. 7 VSM analysis of CoFe2O4 MNPs (blue curve), CoFe2O4@SiO2 (gray curve) and CoFe2O4@SiO2-EA-H3PO4 (yellow curve) nanocatalysts.
3.1.8. TGA analysis. Fig. 8 displays the TGA curve for the CoFe2O4@SiO2-EA-H3PO4 catalyst, revealing three distinct phases of weight loss. The initial mass reduction at room temperature up to approximately 200 °C is attributed to the elimination of residual solvents from the catalyst preparation process. Furthermore, the significant mass decrease observed between 200 and 590 °C, encompassing the second and third stages of weight loss, is likely attributed to the decomposition of both organic and inorganic components associated with the CoFe2O4 nanoparticles.
image file: d3na00900a-f8.tif
Fig. 8 TGA curve of CoFe2O4@SiO2-EA-H3PO4 MNPs.
3.1.9. N2 adsorption/desorption analysis. The surface area and pore volume of CoFe2O4@SiO2-EA-H3PO4 were studied applying the Brunauer–Emmett–Teller (BET) method (Fig. 9). The BET specific surface area (SSA) and total pore volume (TPV) were ascertained to be 110.31 m2 g−1 and 2.36 cm3 g−1, respectively, which indicate a high surface area for catalysis applications.
image file: d3na00900a-f9.tif
Fig. 9 N2 adsorption/desorption isotherms of CoFe2O4@SiO2-EA-H3PO4 MNPs.

3.2. Catalysis study

Our research endeavors center around the development of efficient synthetic pathways for heterocycles, employing magnetic nanoparticle catalysts. Using CoFe2O4@SiO2-EA-H3PO4 MNPs as the catalyst, a one-pot, four-component reaction was conducted that involved ethylacetoacetate, hydrazine hydrate, barbituric acid, and aromatic aldehydes to produce pyrazolopyranopyrimidines. The reaction conditions were optimized through studying the model reaction while using 4-chlorobenzaldehyde and varying the solvent type and amount of the catalyst. The best reaction conditions were achieved using 20 mg of the catalyst in H2O solvent at room temperature (entry 3, Table 1).
Table 1 Effect of different amounts of catalyst and solvent on the model reactiona

image file: d3na00900a-u1.tif

Entry Catalyst Amount of catalyst (mg) Solvent (mL) Time (min) Yieldb (%)
a Reaction conditions: ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol) and barbituric acid (1.0 mmol) catalyst (g) and solvent (2 mL). b Optimum conditions.
1 CoFe2O4@SiO2-EA-H3PO4 10 H2O 5 80
2 CoFe2O4@SiO2-EA-H3PO4 15 H2O 5 85
3 CoFe 2 O 4 @SiO 2 -EA-H 3 PO 4 20 H 2 O 5 98
4 CoFe2O4@SiO2-EA-H3PO4 30 H2O 5 98
5 CoFe2O4@SiO2-EA-H3PO4 20 EtOH 15 80
6 CoFe2O4@SiO2-EA-H3PO4 20 H2O/EtOH (1[thin space (1/6-em)]:[thin space (1/6-em)]1) 15 85
7 CoFe2O4@SiO2-EA-H3PO4 20 DMF 15 80
8 CoFe2O4@SiO2-EA-H3PO4 20 CH3CN 15 75
9 CoFe2O4@SiO2-EA-H3PO4 20 EtOAC 20 50
10 CoFe2O4@SiO2-EA 20 H2O 20 76
11 CoFe2O4@SiO2 20 H2O 20 60
12 CoFe2O4 20 H2O 20 50
13 H2O 60 10


Table 2 presents the results of synthesizing pyrazolopyranopyrimidine derivatives using different benzaldehyde and barbituric acid combinations under optimized reaction conditions, resulting in good yields and short reaction times. The synthesis of these derivatives was influenced by both electron-withdrawing and electron-releasing groups. The synthesized derivatives using benzaldehydes, featuring electron-withdrawing groups, exhibited shorter synthesis times and higher yields in comparison to those with electron-donating groups.

Table 2 Synthesis of pyrazolopyranopyrimidine derivatives catalyzed by CoFe2O4@SiO2-EA-H3PO4a

image file: d3na00900a-u2.tif

Entry Ar R X Product Time (min) Yieldb (%) MP (°C)
a Reaction conditions: ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), benzaldehyde (1.0 mmol), barbituric acid (1.0 mmol) and catalyst (20 mg) in 2 mL H2O. b Isolated yield.
1 C6H5 H O image file: d3na00900a-u3.tif 10 98 214–216 (ref. 10)
2 4-ClC6H4 H O image file: d3na00900a-u4.tif 5 98 216–218 (ref. 10)
3 2-ClC6H4 H O image file: d3na00900a-u5.tif 10 96 228–230 (ref. 10)
4 4-MeC6H4 H O image file: d3na00900a-u6.tif 15 85 200–202 (ref. 10)
5 2-OMeC6H4 H O image file: d3na00900a-u7.tif 20 91 230–231 (ref. 10)
6 4-OMeC6H4 H O image file: d3na00900a-u8.tif 15 97 225–227 (ref. 10)
7 2-ClC6H4 H S image file: d3na00900a-u9.tif 10 85 170–172 (ref. 10)
8 4-NO2C6H4 H S image file: d3na00900a-u10.tif 5 85 230–232 (ref. 26)
9 4-OMeC6H4 H S image file: d3na00900a-u11.tif 15 86 226–228 (ref. 10)
10 C6H5 CH3 O image file: d3na00900a-u12.tif 25 86 192–194 (ref. 10)
11 4-ClC6H4 CH3 O image file: d3na00900a-u13.tif 20 87 200–202 (ref. 10)
12 4-MeC6H4 CH3 O image file: d3na00900a-u14.tif 25 82 173–175 (ref. 10)


To explore the scope of the reaction, malononitrile was used in place of barbituric acid to synthesize dihydropyrano[2,3-c]pyrazole products. The optimal reaction conditions, previously established for pyrazolopyranopyrimidines, were applied to synthesize various dihydropyrano[2,3-c]pyrazole compounds, as detailed in Table 3. The findings indicate that the catalyst employed in this study consistently produces dihydropyrano[2,3-c]pyrazole products with exceptional yields and rapid reaction times.

Table 3 Synthesis of dihydropyrano[2,3-c]pyrazoles catalyzed by CoFe2O4@SiO2-EA-H3PO4a

image file: d3na00900a-u15.tif

Entry Ar Product Time (min) Yieldb (%) MP (°C)
a Reaction conditions: ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), benzaldehyde (1.0 mmol), malononitrile (1.0 mmol) and catalyst (20 mg) in 2 mL water. b Isolated yield.
1 C6H5 image file: d3na00900a-u16.tif 10 98 244–246 (ref. 11)
2 4-ClC6H4 image file: d3na00900a-u17.tif 5 98 232–234 (ref. 11)
3 2-ClC6H4 image file: d3na00900a-u18.tif 10 96 245–247 (ref. 27)
4 4-MeC6H4 image file: d3na00900a-u19.tif 15 85 195–197 (ref. 28)
5 2-OMeC6H4 image file: d3na00900a-u20.tif 25 91 221–223 (ref. 29)
6 4-OMeC6H4 image file: d3na00900a-u21.tif 20 97 211–213 (ref. 28)
7 4-OHC6H4 image file: d3na00900a-u22.tif 25 85 224–226 (ref. 11)
8 3-OHC6H4 image file: d3na00900a-u23.tif 15 85 246–248 (ref. 30)
9 4-N(Me)2C6H4 image file: d3na00900a-u24.tif 30 86 170–172 (ref. 28)
10 3-NO2 C6H4 image file: d3na00900a-u25.tif 15 86 233–235 (ref. 11)
11 4-NO2 C6H4 image file: d3na00900a-u26.tif 5 87 249–251 (ref. 11)
12 4-Br C6H4 image file: d3na00900a-u27.tif 10 82 247–249 (ref. 11)


3.3. Plausible mechanism for the synthesis of pyrazolopyranopyrimidine and dihydropyrano[2,3-c]pyrazoles

A plausible mechanism for the synthesis of pyrazolopyranopyrimidine, based on the previously reported reactions, is shown in Scheme 2. Initially, the condensation of ethyl acetoacetate with hydrazine resulted in the formation of pyrazole (I), which can subsequently be converted to its corresponding enolate form (II). In the presence of the nanocatalyst, Knoevenagel condensation takes place between benzaldehyde and barbituric acid, leading to the formation of intermediate (III). Subsequently, compound (II) reacts with intermediate (III) through a Michael addition, resulting in the formation of intermediate (IV). Ultimately, through the reaction of the intramolecular intermediate (IV) and the elimination of a water molecule, compound 5a was synthesized. The mechanism for the formation of dihydropyrano[2,3-c]pyrazoles closely parallels the synthesis mechanism of pyrazolopyranopyrimidine, with the substitution of malononitrile for barbituric acid.30
image file: d3na00900a-s2.tif
Scheme 2 A possible mechanism for the synthesis of pyrazolopyranopyrimidine and dihydropyrano[2,3-c]pyrazoles catalyzed by the CoFe2O4@SiO2-EA-H3PO4 nanocomposite.

3.4. Antibacterial activity

Table 4 and Fig. 8 show the antibacterial results of pyrazolopyranopyrimidine derivatives, with compounds 6b, 6c, 6e, 6f and 6k being the most active antibacterial agents. The structure–activity relationship revealed that amide groups at the pyrimidine ring contribute to the antibacterial activity. It should be mentioned that chlorine and methoxide derivatives increased the antibacterial properties of the compound. In addition, the substitution of barbituric acid with thiobarbituric acid or dimethylbarbituric acid decreased the antibacterial properties of pyrazolopyranopyrimidine with similar derivatives. The antibacterial activity of the dihydropyrano[2,3-c]pyrazole derivatives against Gram-positive and Gram-negative bacteria was evaluated as shown in Table 5, wherein no significant effect was observed against the tested strains. The substitution of barbituric acid with malononitrile resulted in the elimination of the antibacterial effect observed in the targeted derivatives (Fig. 10).
Table 4 Antibacterial activity results for compounds (6a–6l)
Minimum inhibitory concentration (MIC = μg mL−1)
Compound 6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l
Test organism S. aureus 625 156.2 156.2 >2500 312.5 312.5 625 >2500 1250 >2500 312.5 >2500
E. coli >2500 1250 >2500 >2500 1250 1250 1250 1250 1250 >2500 1250 >2500


Table 5 Antibacterial activity results for compounds (7a–7l)
Minimum inhibitory concentration (MIC = μg mL−1)
Compound 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l
Test organism S. aureus >2500 >2500 >2500 >2500 >2500 >2500 >2500 >2500 >2500 >2500 >2500 >2500
E. coli



image file: d3na00900a-f10.tif
Fig. 10 The antibacterial activity of synthesized derivatives against Gram positive bacteria (S. aureus).

3.5. Catalyst recycling and reusing test

The model reaction was used to examine the recovery and recyclability of CoFe2O4@SiO2-EA-H3PO4 MNPs. Upon completion of the reaction, an external magnetic field was applied to facilitate the separation of the catalyst from the reaction mixture. The catalyst was subsequently washed with EtOH, dried, and reused in subsequent reactions.

This catalyst showed little deactivation after six uses, which is an important aspect of green chemistry. The reactions were conducted under optimal conditions, the results of which are presented in Fig. 11. To evaluate the durability and reusability potential of the CoFe2O4@SiO2-EA-H3PO4 particles, some specific analyses were used applying FT-IR, SEM, VSM, TGA, and BET (Fig. 12).


image file: d3na00900a-f11.tif
Fig. 11 Recyclability of CoFe2O4@SiO2-EA-H3PO4 for the synthesis of pyrazolopyranopyrimidine derivatives.

image file: d3na00900a-f12.tif
Fig. 12 (a) FT-IR, (b) SEM, (c) BET, (d) VSM TGA and (e) TGA of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst after 6 runs.

The results of the various tests conducted on the recycled catalyst confirm that the catalytic components attached to the CoFe2O4 support and its morphology remain stable throughout the reaction and recycling process. The N2 adsorption/desorption isotherms of the regenerated catalyst reveal a BET specific surface area (SSA) and total pore volume (TPV) of approximately SSA = 96.64 m2 g−1 and 1.98 cm3 g−1, respectively. These values indicate a minimal decrease as compared to the fresh catalyst, affirming its stability throughout the catalytic process.

3.6. Hot-filtration and leaching test

In order to investigate the heterogeneity of the catalyst in the reaction medium, a hot filtration test was performed on the model reaction. The catalyst was separated using a magnet at the midway point of the reaction and, then, the resulting filtrate solution was employed to resume the process. Following the hot filtration experiment, no change in the yield of the product was witnessed, which is comparable to the catalyst-free reaction conditions. In addition, ICP-OES analysis of the filtrate solution showed that there was almost no phosphor leaching into the reaction medium. These results indicate the heterogeneous nature and no leakage of the catalyst in the course of the reaction.

3.7. Comparison

In order to investigate the activity of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst in synthesizing pyrazolopyranopyrimidine, this system was compared to previous studies concerning the model reaction (product 6b), the results of which are illustrated in Table 6. These results demonstrate that the utilization of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst for the synthesis of pyrazolopyranopyrimidine offers advantages such as high yield, reduced reaction time, and lower temperature as compared to other catalysts.
Table 6 Comparison of the activity of the CoFe2O4@SiO2-EA-H3PO4 nanocatalyst with other catalysts for the synthesis of pyrazolopyranopyrimidine
Entry Catalyst Conditions Time (min) Yield (%)
1 TiO2 NWs 10 mol%, H2O/EtOH, reflux 60 95 (ref. 31)
2 SBA-Pr-SO3H H2O, reflux 10 92 (ref. 32)
3 Oleic acid EtOH/reflux 15 78 (ref. 33)
4 Meglumine 0.1 mmol, H2O, rt 15 92 (ref. 34)
5 ABCO 20 mol%, H2O, reflux 20 99 (ref. 35)
6 HPA-FHNTs 30 mg, H2O, reflux 35 95 (ref. 36)
7 MWCNTs/CO2H 5 mg, H2O/EtOH, reflux 80 92 (ref. 10)
8 Choline chloride/urea 20 mol%, EtOH, reflux 60 78 (ref. 37)
9 CoFe2O4@SiO2-PA-CCGuanidine 30 mg, H2O, rt 15 97 (ref. 10)
10 MWCNTs/guanidine/Ni(II) 5 mg, EtOH, ultrasound 5 95 (ref. 37)
11 CoFe2O4@SiO2-EA-H3PO4 20 mg, water, rt 5 98 [this work]


4 Conclusion

In conclusion, this study demonstrated that the CoFe2O4@SiO2-EA-H3PO4 nanocomposite is an efficient and highly reusable nanomagnetic catalyst for the synthesis of pyrazolopyranopyrimidines and dihydropyrano[2,3-c]pyrazole via a one-pot four-component reaction under mild conditions with minimal energy consumption. Some of the important advantages of this catalytic system are as follows: high reusability of the nanocatalyst, high purity and yield of the products, environmentally friendly conditions and simple operation.

Author contributions

Ali Mirzaie (the PhD student) performed the practical laboratory work as part of his PhD thesis. Lotfi Shiri (Supervisor, PhD) designed and coordinated the study, devised the concept, edited the final version of the manuscript, and submitted the manuscript for publication. Mosstafa Kazemi (Adviser, PhD) edited the final version of the manuscript draft. Nourkhoda Sadeghifard performed the antibacterial activity examination. Vahab Hassan Kaviar performed the antibacterial activity examination.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors are grateful to the IIam University Research Council for financial support to carry out this work.

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Footnote

Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3na00900a

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