Three-Dimensional Walnut-Like, Hierarchically Zn-MOF Microsphere: One-Pot Synthesis, Characterization And Its Application as a Green Catalyst For The Asymmetric Hantzsch Synthesis of Polyhydroquinolines


 A three-dimensional walnut-like, microsphere Zn-based MOFs system was designed and synthesized via hydrothermal reaction of zinc salt with 4,6-diamino-2-pyrimidinethiol as a tridentate ligand. Besides, Zn ions were coordinated to the ligand’s functional groups to give a novel Zn-MOF microsphere material. Afterward, the resultant material was thoroughly characterized by various analysis and physico-chemical methods; including, FT-IR, XRD, TGA, EDX, X-ray mapping, SEM, TEM, and BET analysis. The Zn-MOF microspheres were utilized in the Hantzsch reaction for selective synthesis of asymmetric polyhydroquinolines, using various aromatic aldehydes. Our strategy provides a way for controlled synthesis of the hierarchically nanoporous Zn-MOF microspheres with well-defined morphology, structure, and excellent catalytic properties, resulting in having a promising heterogeneous catalyst for a selective synthesis with good yields in the short reaction time and a low limit of steric hindrance and electronic effects. Besides, the heterogeneity of the catalyst is further tested with hot filtration and also the reusability results point.


Introduction
Porous materials with large speci c surface areas and other unique properties have gained increasing attention [1]. During the last two decades, it has been revealed that Metal-organic frameworks (MOFs) have extensive applications in drugs delivery, absorption, and desorption of substances, biomedicines, and catalysis due to their desired morphology, high surface area, stability, active metal sites, and controllable pore size [2][3][4][5][6][7]. Among them, coordination polymer microspheres have drawn great attention for their potential applications in many elds especially in the catalytic synthesis of various organic and bioorganic molecules via organic transformations [8][9][10][11]. They can be regarded as a novel class of crystalline porous compounds formed by the strong bonding of metal ions or clusters to polytopic organic ligands, giving rise to extended networks [9,12]. Since traditional microspheres have some drawbacks, i.e. higher product costs because of expensive excipients or sophisticated equipment and stricter quality control [13,14], the nanoporous microspheres with low density and high speci c surface area have become a pragmatic manner to address the existing problems [15][16][17][18].
Recently, some speci c efforts have been made to design effective microsphere catalysts with external pores on the surface or internal pores in the core (which can be regarded as the main difference between porous microspheres and traditional microspheres), instead of using traditional microsphere catalysts based on expensive metals [1,8,[19][20][21][22][23]. Besides, porosity is very signi cant in measuring the capacity e ciency of the catalysts. Moreover, the applied porous microspheres have been based on the porous structure, i.e. the amount, diameter, the structure of the pores, etc., which can be controlled by chemical and physical techniques [24,25]. Among all of the transition metal-based catalysts used in organic transformations, Zinc has gained great attention due to its precious properties such as low cost, nontoxicity, good availability, and being ecofriendly. Therefore, many studies have shown the implementation of catalytic systems based on Zn using various linkers in organic reactions [26][27][28][29][30][31].
The asymmetric reaction of an aldehyde, two components of β-keto esters, and a nitrogen donor is known as Hantzsch method which generates chiral dihydropyridines. Besides, they have been regarded as useful precursors to many compounds of biological and pharmaceutical interest, i.e. different natural products [32]. When transition metal catalysts are present, Polyhydroquinolines with the functionalized aromatic rings can be generated from this reaction [33][34][35][36]. Among various catalysts developed so far, the e ciency of the catalytic systems is generally limited by their low yield, use of volatile organic solvents, harsh reaction condition, aggregation tendency as well as poor mechanical properties, high catalyst loading, tedious workup procedure, and separation of catalyst residue from the reaction mixture [32].
Although this method is practically useful for the synthesis of interesting pharmaceutical products, its selectivity and substrate scope still need to be improved [32,37,38]. We propose to develop a novel selective heterogeneous catalytic system for the recognition of the polyhydroquinoline derivatives to facilitate the screening of the catalysts for this asymmetric reaction.
In this work, we studied the hydrothermal synthesis of novel Zn-based nanoporous microspheres, by the reaction of zinc nitrate hexahydrate salt with 4,6-Diamino-2-pyrimidinethiol containing amine, thiol, and pyrimidine functional groups. We found out that Zn-MOFs can be used as a rapid catalyst for the synthesize the polyhydroquinolines with excellent yields. It represents a new method for the clean and rapid synthesis of asymmetric dihydropyridines. Herein, these results are reported.

Materials
All reagents and solvents were purchased from Merck and used without additional puri cation.

Synthesis of nanoporous Zn-MOF microspheres
To prepare Zn-MOF porous microspheres, 4,6-Diamino-2-pyrimidinethiol (1 mmol) was dissolved in water (2 mL) and, then, it was added to a solution of DMF (12 mL) containing 2 mmol of Zn(NO 3 ) 2 .6H 2 O salt through 20 minutes of stirring at 80 ºC until reaching a clear solution. Afterward, the white suspension was transferred into a Te on lined autoclave reactor and heated at 160 ºC for 24 h (Scheme1), which then cooled to the room temperature at a gradient of 40°C per hour. Subsequently, the target Zn-MOF microsphere yellow powder was obtained after the sonication in ethyl acetate.

General procedure for the catalytic synthesis of polyhydroquinolines
A mixture of Substituted aromatic aldehyde (1.0 mmol) ethyl acetoacetate (1 mmol), and dimedone (1 mmol), were stirred with Ammonium acetate as a green NH 3 source (1.2 mmol), and Zn-MOF microspheres (8 mg) in PEG-400 (2 mL) for 70-180 min at 80°C. Completion of the following reaction has been analyzed via TLC. Subsequent to cooling at room temperature, the catalyst was separated using simple ltration and the resultant mixture's preparation was extracted using Ethyl acetate and water derivation to gather unre ned polyhydroquinoline product, which was further puri ed through recrystallization in ethanol.

Results And Discussions
This study reports the synthesis of nanoporous Zn-MOF microspheres to develop an e cient and novel heterogeneous catalyst to synthesize polyhydroquinolines as an important dihydropyridine-containing scaffold via Hantzsch reaction. The resulting samples were characterized using various techniques.

Synthesis and characterization of the catalyst
The heterogeneous Zn-MOF microsphere catalyst was successfully prepared by hydrothermal reaction of Zn(NO 3 ) 2 .6H 2 O and 4,6-Diamino-2-pyrimidinethiol, using the deprotonation of amine and thiol groups.
Afterward, metal coordination bonding to the Zn ions was made to give a novel Zn-based microsphere catalyst. This newly synthesized nanoporous microsphere catalyst was fully characterized by various techniques; including, FT-IR, XRD, TGA, EDX, X-ray mapping, SEM, TEM and BET analysis. The results obtained from these techniques con rmed the successful preparation of this novel catalyst.

Structural and chemical composition analysis
The changes in the chemical features during the synthesis of the composite were measured by FT-IR, spectroscopy. Figure   The crystalline phases of nanoporous Zn-MOF microspheres were examined by X-ray diffraction (XRD) analysis as shown in Fig. 2 [39][40][41]. Based on the XRD results, we can also observe that the Zn-MOF microspheres obtained from zinc nitrate show sharp characteristic peaks, suggesting the high crystalline nature of the obtained nanoporous Zn-MOF microspheres.
To estimate the mass ratios and the thermal stability of nanoporous Zn-MOF microspheres, the TGA-DSC technique was employed. Fig. 3. represents TGA (Maroon line) and DSC (Blue line) curves of Zn-MOF microspheres at the temperature range of 25-1500 ℃. In the TGA curve, the weight loss which was occurred below 200°C was attributed to the release of the physically adsorbed moisture and water and organic solvents from the sample [42]. The next weight loss (10.61% ) in the region of 200-800 C can be associated with the decomposition of 4,6-Diamino-2-pyrimidinethiol ligand [43,44]. In addition, the weight loss at 450 C indicates the decomposition of the framework. A basic point about the nature of the Zn-MOF catalyst is the thermal stability of the catalyst up to 200 C; therefore, this catalyst can be used under various catalytic reaction conditions up to 200 C.
As shown in gure 4, energy dispersive X-ray (EDX) analysis was applied to determine the chemical composition of nanoporous Zn-MOF microspheres. The results indicate the presence of 53.25 W% of Zn species in the obtained nanoporous Zn-MOF microsphere catalyst. In addition, the presence of carbon (10.70 W%), nitrogen (9.11 W%) sulfur (13.97 W%) and oxygen (12.97 W%) elements in the prepared nanoporous material was also con rmed by these measurements. These observations support the high purity of the prepared Zn-MOF microspheres.
The uniform distribution of the index elements (C, S, N, O, and Zn) of the obtained nanoporous material is observed at the X-ray mapping analysis (Fig. 5). In addition, the uniform distribution of the Zn element shows that it has evenly coordinated to N and S elements, indicating the presence of ligand in the obtained frameworks, and the uniform incorporation of the activated Zn catalytic species with S and N groups showing that an excellent catalytic surface has been formed.
The surface morphology of the prepared nanoporous material was assessed by scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) analysis. The FE-SEM images for pure nanoporous Zn-MOF microspheres are presented in Fig. 6. A closer look at the SEM images of the obtained nanoporous material indicates that the Zn-MOF has been formed in uniform three-dimensional walnut-like hierarchically nanoporous microparticle morphology, which can be attributed to a proper bonding in-between the metal and linker. Moreover, the SEM images show that these Zn-MOF microparticles are composed of a collection of nanoparticles having a mean particle size of 23-27 nm.
The results indicate that the Zn-MOF microspheres have been formed in a uniform manner. Besides, there is no indication of agglomeration of the particles and also this feature optimizes the catalytic properties of the samples.
By applying the transmission electron microscopy technique, high-quality images from the synthesized crystalline nanoporous Zn-MOF microspheres were obtained ( Figure 7). As can be seen, the synthesized Zn-MOF microspheres exhibit characteristic yolk-shell structure and a clear gap existed between the shell and the core, con rming that the core is a solid sphere. Particle size distribution histogram of the asprepared microspheres gave distribution dimensions across a range from 90 to 170 nm, with an average size of 130 nm (Figure 7). The porosity and surface characteristics of nanoporous Zn-MOF microspheres were explored by the N 2 adsorption/desorption analysis (Fig. 8). The obtained results are illustrated in Figure 8. Zn-MOF microspheres exhibited a Brunauer-Emmett-Teller (BET) surface area of 63.33 m 2 .g −1 and the pore volumes and pore size distribution of nanoporous Zn-MOF microspheres are calculated by BJH analysis, as the values are 0.088 cm 3 .g −1 , and 1.22 nm, respectively.

Catalytic Study
After the successful characterization of the synthesized Zn-MOF microsphere, We applied these nanoporous materials as a novel catalyst for the multicomponent synthesis of polyhydroquinolines under diverse conditions (Table 1). We optimized conditions of the reaction for Hantzsch synthesis of dihydropyridine scaffolds using para-chlorobenzaldehyde, dimedone, ethyl acetoacetate, and ammonium acetate as a model reaction. Afterward, various parameters of the reaction, including the amount of catalyst, solvent, and temperature, were evaluated for the model reaction, the results of which are summarized in Table 1. When there is no catalyst in the reaction, no reaction takes place ( Table 1, entry 1). In this sense, it is worth mentioning that the existence of Zn-MOF microsphere is required for this type of Hantzsch reaction. The reaction proceeds faster by increasing the catalyst amount up to 10 mg.
According to the results, 10 mg of the catalyst is required for the reaction. Using smaller amounts of the catalyst will cause the reaction to be incomplete (Table 1, entry 4 & 5). Increasing the amount of catalyst by more than 10 mg does not affect the e ciency percentage (Table 1, entry 7). Additionally, the catalytic effect of 4,6-diamino-2-pyrimidinethiol and Zn(NO 3 ) 2 .6H 2 O was investigated on the model reaction. It was observed that they cannot e ciently catalyze the reaction and, as a result, the product is obtained in low yields in 85 min. Among the various solvents used in the reaction, the results indicate that the PEG-400 as a solvent which showed a higher e ciency, as compared to all solvents tested with 96% isolated yield, may serve as both the solvent and the phase transfer catalyst in this type of reaction (Table 1, entry 6).
Finally, the reaction was performed at different temperatures, and the low temperature continued with lower e ciency (Table 1, entry 6, [12][13][14]. Regarding the optimization studies, the optimum conditions for this reaction are 10 mg of Zn-MOF in the PEG-400 at 80°C (Table 1, entry 6). After optimizing the reaction conditions, we explored the scope of the reaction with various electrondonating and electron-withdrawing groups of aldehydes. In all cases, the products were made in high yields ( Table 2). Although the results indicate that ortho and/or meta-substituted aryl aldehydes react slowly, as compared to the para isomers, electron-releasing and electron-withdrawing groups give an excellent yield of product. Table 2 Hantzsch synthesis of polyhydroquinoline derivatives in the presence of Zn-MOF in PEG-400 at 80 °C. It is worth noting that an appropriate mechanism for the polyhydroquinoline derivatives' synthesis reaction, catalyzed by nanoporous Zn-MOF microspheres, was proposed (Scheme 2) [32]. Firstly, the reaction was granted to start through deprotonation of the dimedone which underwent Knoevenagel condensation reaction with an aldehyde to form an α,β-unsaturated compound. Subsequently, the Michael addition of imine (which was achieved from the combination of NH 3 with ethyl acetoacetate) on the α,β-unsaturated carbonyl compounds, followed by cyclization reaction, generated a six-membered ring. Finally, the dehydration gave the nal polyhydroquinoline products (Scheme 2) [32].

Catalyst Reusability Studies:
Recyclability of the heterogeneous catalyst put an end to the use of harmful and costly metal catalysts while decreasing the cost of products. These factors are of crucial importance from an economical point of view. Recyclability of the nanoporous Zn-MOF microsphere was investigated in the model reaction.
The catalyst was separated after completion of the reaction, washed with ethyl acetate and acetone and, then, dried at 70°C. The dried catalyst was reused for the next cycle. The recycled catalyst was employed in the four sequential cycles; the yield of the reaction was decreased moderately after the fourth run of the reaction, as illustrated in Fig. 9.

Hot Filtration
The hot ltration test was another analysis to approve the heterogeneous nature of the nanoporous Zn-MOF microspheres in the Hantzsch synthesis of polyhydroquinolines. On this basis, the model reaction was studied again under the optimized reaction condition. After 43 min (59 % conversion), the Zn-MOF was removed from the reaction by simple ltration. Afterward, the rest of the reaction was stirred in the absence of the catalyst for a further 43 min. The obtained results show that the Zn-based MOF played a catalytic role in the reaction without the Zn leaching into the solution or framework degradation.

Comparison
In the last part of our studies, to demonstrate the pro t of nanoporous Zn-MOF microspheres as a heterogeneous catalyst in Hantzsch reaction, our resultant and reaction conditions were compared with those of the reported acid, base, and metal catalysts in the synthesis of polyhydroquinolines (Table 3). As depicted in Table 3, the nanoporous Zn-MOF microspheres are the most e cient catalysts to synthesize polyhydroquinolines. Signi cantly, most of the reported methods toil from the absence of commonness for the condensation reactions of the deactivated aldehydes. In addition, the reported synthetic paths have some limitations, such as requiring extreme temperature or long duration, large amounts of the catalyst, and most importantly, the use of hazardous solvents to give excellent yields. Promising results obtained in the presence of Zn-MOF microspheres should be ascribed to the nanoporous structure of the catalyst. The two roles of PEG-400 (solvent and phase transfer catalyst) avouch the better contact between the catalyst and the reactants and, thus, substantially raising the catalytic activity and stability of the catalyst.

Conclusion
In conclusion, we have reported an e cient and novel three-dimensional walnut-like, nanoporous Zn-MOF microsphere catalytic system by hydrothermal method. It was able to accelerate the asymmetric Hantzsch reaction with various aryl aldehydes including electron-donor and electron-acceptor groups for in situ production of polyhydroquinolines. The present protocol gives an excellent yield of the product within a short reaction time, by easy workup and no need for further puri cation of the product. The novelty, simple synthesis procedure, no use of harmful solvents, facile ltration, high yield, and, especially, reusability are some of the advantages of the developed catalyst.

Con icts of interest
There are no con icts of interest with this research work.       Recyclability of the nanoporous Zn-MOF microspheres.

Supplementary Files
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