Poly(acrylic acid)/Fe3O4 supported on MIL-100(Cr) MOF as a novel and magnetic nanocatalyst for the synthesis of Pyrido[2,3-d]Pyrimidines

In the current work, a convenient and simple approach for preparing poly (acrylic acid)/Fe3O4 supported on MIL-100(Cr) for the synthesis of pyrido [2,3-d]pyrimidine derivatives via the three-component one-pot reaction of 1,3-indandione, 6-amino uracil, and aromatic aldehydes is reported. The effectiveness of this new magnetic nanocatalyst was proved. The results showed this nanocatalyst's moderate to high yield under reflux conditions. SEM, TEM, IR, EDX, XRD, BET, and TGA were used to characterize the structure of the synthesized nanocatalyst. This synthetic protocol offers various advantages, including cost-saving, excellent yields in short reaction times (67–98%), low catalyst loading, and catalyst reusability.


Introduction
Metal-organic frameworks (MOFs) as a unique class of porous materials, are used as catalysts, heavy-metal adsorption, and gas storage and separation [1,2,3,4]. MOFs present various properties depending on the type of their ligands and their surface functional groups. Functional groups in these frameworks could be firstly available in organic ligand structures, or functional groups could be created within the MOFs structure after their synthesis [5]. To obtain the following objectives, Cr-based MOFs should have improved adsorption, water, thermal stability, and larger surface area in the reaction processes [6,7].
Multicomponent reactions (MCRs) and related one-pot synthesis (such as tandem, cascade, and domino reactions) are vital in developing novel methodologies in organic catalysis and synthesis because of their countless applications, especially in pharmaceutical works [8,9,10,11,12,13]. Hence, complex purification phases are avoided, and time and reagents and solvents are saved [14,15]. Pyrimidine cores, as main categories of heterocyclic and bioactive molecules, have been recently the subject of intense research in pharmaceutical studies. This great attention is attributed to their broad pharmacological and therapeutic properties, including anti-inflammatory [16], anticancer [17], antimicrobial [18], or antihistaminic activities [19].
One of these materials is pyrido [2,3-d] pyrimidine. This compound is considered an important group of heterocyclic compounds annulated uracil because of their various medicinal applications, like anticonvulsants, antibacterials, and anti-aggressive activities, antileishmanial, antifolate, anti-inflammatory, antimicrobial, and inhibition of cyclindependent kinases [20,21].
We review the studies on synthetic approaches to produce these compounds in the following. Shi et al. (2008) presented pyrimidine derivative synthesis in ionic liquid [bmim]Br, and they obtained 75-93% of yields [22]. Khurana et al. (2012) reported an approach for synthesizing these systems. They used 20 mol% InCl 3 (20 mol%) as a catalyst in water and gained 87-90% of product yields [23]. We recently presented various synthesis methods for many products that utilize nanocatalysts [24,25,26,27,28]. The current work presents a simple method for fabricating Poly (acrylic acid)/Fe 3 O 4 Supported on MIL-100(Cr) (Fe 3 O 4 @PAA@MIL-100(Cr)) as an efficient and robust catalyst. It is an environmentally benign, highly reusable, and heterogeneous catalyst with high catalytic activity for synthesizing pyrido [2,3-d]pyrimidine derivatives through a one-pot three-component condensation reaction of aromatic aldehydes, 1,3-indandione, and 6-amino uracil in EtOH under reflux conditions (Scheme 1).

Preparation of Fe 3 O 4 -PAA
Fe 3 O 4 @PAA nanocomposite was prepared according to a method reported by Tian Jin et al [29]. Typically, we added 0.6 g PAA to a mix of 0.75 g FeCl 3 .6H 2 O in 40 mL ethylene glycol, followed by stirring the solution at ambient temperature for 30 min. Afterward, NaOAc (2.5 g) was added to the solution and it was placed in a 50 mL Teflon-lined stainless steel autoclave at of 200 C for 24 h. Then, the resulting residue was rinsed three times using ethanol and deionized water and dispersed in ethanol (40 mL).

Synthesis of Fe 3 O 4 @PAA@MIL-100(Cr)
Briefly, trimesic acid (1.05 g) and CrO 3 (0.5 g) were dissolved in H 2 O (2 mL) and HF (0.2 g). In the next step, it was mixed with an as-prepared Fe 3 O 4 @PAA solution (10 mL). The obtained solution was stirred for 2 h at 80 C. Lastly, the synthesized Fe 3 O 4 @PAA@MIL-100(Cr) was rinsed using ethanol, and dried at 100 C (Scheme 2). The mixture of Fe 3 O 4 @PAA@MIL-100(Cr) (0.008 g), 1,3-indandione (1 mmol), aromatic aldehyde (1 mmol), and 6-amino uracil (1 mmol) in ethanol (5 mL) was refluxed for 30 min. The mixture was cooled to room temperature when the reaction (which was TLC-monitored) was completed, and the resulting solid was subsequently dissolved in dichloromethane. A straightforward filtering was used to isolate the catalyst, which was insoluble in CH 2 Cl 2 . M. p., FT-IR, 1 H NMR and 13 C NMR spectroscopy methods were performed to characterize and identify of all the products.
The spectral data of some products are provided, as below.

Results and discussion
Using EDX, FE-SEM, TEM, FT-IR, BET, TGA, and XRD techniques, the Fe 3 O 4 @PAA@MIL-100(Cr) nanostructure was studied in the main experiments. A magnetic core with a strong inclination between the ligand and the receptor and through the specific gravity absorption of       Scanning electron microscopy was used to visualize the results of the SEM examination for each stage of the catalyst synthesis. This examination appeared that Fe 3 O 4 is composed of moderately uniform circular particles (Figure 1a). [30]. According to literature, the SEM image of MIL-100(Cr) showed that this structure has a typical octahedral shape (Figure 1b) Figure 4 represents the FT-IR spectrum of Fe 3 O 4 @PAA@MIL-100(Cr). The absorption band at 550 cm À1 is due to the Fe-O stretching vibration [33]. The peaks in 1412 and 1566 cm À1 are due to C-O and C¼O stretching vibrations of PAA, respectively. Besides, the stretching vibration of OH groups of PAA was observed at 3460 cm À1 . The vibration bands as characteristics of framework (O-C-O) groups appeared near 1709 and 1383 cm À1 , confirming the tricarboxylate coordination in the MIL-100(Cr) framework. The peak at 1452 cm À1 is attributed to the C¼C bond vibration in tricarboxylate rings. Intense bands at about 3282 and 1641 cm À1 proved the presence of water molecules in the Fe 3 O 4 @-PAA@MIL-100(Cr) [34].
Thermal gravimetric analysis (TGA) was used to measure the mass reduction caused by heating under a nitrogen gas stream ( Figure 5). Fe 3 O 4 @PAA@MIL-100(Cr) structure depicts two stages of weight loss. At temperatures between 300 and 400 C, organic molecules from the composite including PAA are destroyed. The second case is in the 400-850 C range, which is attributed to destructing metal-organic framework (MIL-100(Cr)) in the Fe 3 O 4 @PAA@MIL-100(Cr) structure.  This work a Based on the three-component reaction of 4-chlorobenzaldehyde, 1,3indandione, and 6-amino uracil. Figure 11. Reusability of the Fe 3 O 4 @PAA@MIL-100(Cr) catalyst.
Nitrogen adsorption using the BET technique was applied to determine the surface area of the Fe 3 O 4 @PAA@MIl-100(Cr). As shown by BET analysis for Fe 3 O 4 @PAA@MIL-100(Cr), the available surface area was 1248 m 2 g À1 . The cavity volume in the Fe 3 O 4 @PAA@MIL-100(Cr) was 0.8112 cm 3 gr À1 (Figure 7a). Figure 7b indicates the desorptionadsorption isotherm for Fe 3 O 4 @PAA@MIL-100(Cr) as a type I sorption isotherm. The average pore diameter of the nanocarrier, as determined by the findings of the BJH study, was 1.23 nm, confirming the presence of porosity in the MOF (Figure 7c).
In continue, the condensation reaction of 4-chlorobenzaldehyde, 1,3indandione, and 6-amino uracil was chosen as a model study to optimize the reaction and examine the effects of the catalyst, reactants, and solvent on the of synthesis of pyrido [2,3-d]pyrimidine derivatives (Scheme 3).
Initially, the effect of various solvents and solvent-free conditions were examined when we used Fe 3 O 4 @PAA@MIL-100(Cr) as a catalyst in the preparation of pyrido [2,3-d]pyrimidine 4d. As can be observed, the solvent significantly affects the reaction rate ( Figure 8). Ethanol afforded the best results (98% of yield) under reflux conditions for this multicomponent reaction.
In continue, the significance of the prepared catalyst in comparison to other catalysts was studied. Existing catalysts such as MgO, CuI, Fe 3 O 4 , MIL-100(Cr), and Fe 3 O 4 @PAA@MIL-100(Cr) were all applied under reflux conditions while utilizing ethanol as a solvent. According to Figure 9, Fe 3 O 4 @PAA@MIL-100(Cr) was the best catalyst regarding the reaction time and obtained product yield.
The study model was discussed in the following using various quantities of Fe 3 O 4 @PAA@MIL-100(Cr) nanocatalyst. The optimal concentration of Fe 3 O 4 @PAA@MIL-100(Cr) was found at 0.008 g ( Figure 10). As indicated, the reaction duration and yield were not altered by a quantity greater than 0.008 g.
We studied the scope of this research by synthesizing pyrido [2,3d]pyrimidine derivatives using various aromatic aldehydes comprising electron-donating and electron-withdrawing groups in the presence of 0.008 g of Fe 3 O 4 @PAA@MIL-100(Cr) nanocomposite. According to Table 1, prolonged reaction time is required by aryl aldehydes with electron-donating groups to afford the corresponding products. However, the aryl aldehydes with withdrawing groups reacted faster to produce pyrido [2,3-d]pyrimidines. According to the mechanism pathway (Scheme 4), the first step of the mechanism is the Knoevenagel condensation between 1,3-indandione and aromatic aldehyde. Obliviously, the presence of electron-withdrawing groups on the benzaldehydes leads to a faster reaction due to more electrophilicity of the carbon group of the carbonyl. While using Fe 3 O 4 @-PAA@MIL-100(Cr) as a catalyst serves as a Lewis acid catalyst and causes to increase in electrophilicity of the carbonyl groups of aldehydes. The synergic effects of both electron-withdrawing groups and Lewis acidity of Fe 3 O 4 @PAA@MIL-100(Cr) increase the rate of the reaction. However, against the electron-withdrawing groups, the existence of electron-donating groups causes to decrease in the speed of the reaction, because of a slower nucleophilic attack on carbonyl groups of aldehydes.
We compared the usability and efficiency of our catalyst to synthesize pyrido [2,3-d]pyrimidine derivatives and other catalysts reported previously. According to Table 2, Fe 3 O 4 @PAA@MIL-100(Cr) outperformed other catalysts in saving energy, time, and superior yields of the products ( Table 2).

Reuse of catalyst
The catalyst reusability is well known as the key characteristic feature. Here, we assessed the retrievability of the Fe 3 O 4 @PAA@MIL-100(Cr) on the reaction of 4-chlorobenzaldehyde 1,3-indandione, and 6amino uracil. As shown in Figure 11, the catalytic activity of Fe 3 O 4 @-PAA@MIL-100(Cr) reduced from 98% in the fresh run to 85% after 7 runs.
Scheme 4 shows the plausible mechanism to prepare pyrido [2,3-d] pyrimidines in the presence of Fe 3 O 4 @PAA@MIL-100(Cr) nanostructure as the catalyst. When there are Lewis acidic sites over the catalyst surface, the reactants may undergo reaction within a shorter time. The results were examined experimentally based on the literature [37,38]. Fe 3 O 4 and MIL-101(Cr) are thought to function as Lewis acids that, through a potent coordination bond, boost the electrophilicity of the carbonyl groups of 1,3-indandione and aldehyde [39,40]. In the first step, it is assumed that, electron pairs of the carbonyl groups of the 1, 3-indandione and aryl aldehydes were interacted with the catalyst to improve the electrophilicity features of the functional groups (formation of intermediates A and B). In addition, the intermediate (

Conclusio
In summary, we prepared and characterized Fe 3 O 4 @PAA@MIL-100(Cr) magnetic nano-catalyst as a magnetically recyclable, green and bio-friendly catalyst. This catalyst was applied to synthesize pyrido [2,3d]pyrimidine derivatives via a three-component reaction of 1,3-indandione, 6-amino uracil, and aromatic aldehydes. By this approach, some benefits including great yields in short reaction time, high atom economy, and mild reaction conditions were provided.

Author contribution statement
Mohammad Ali Ghasemzadeh: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Boshra Mirhosseini-Eshkevari: Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.

Funding statement
This work was supported by the Research Affairs Office of the Islamic Azad University, Qom Branch, Qom, I. R. Iran (grant number 2019-2898).

Data availability statement
Data will be made available on request.

Declaration of interests statement
The authors declare no conflict of interest.

Additional information
No additional information is available for this paper.