Microporous hierarchically Zn-MOF as an efficient catalyst for the Hantzsch synthesis of polyhydroquinolines

A three-dimensional walnut-like Zn-based MOF microsphere 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 functional groups of the ligand to give a novel Zn-MOF microsphere material. Afterward, the resultant material was thoroughly characterized using 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 a selective synthesis of asymmetric polyhydroquinolines, using various aromatic aldehydes. Our strategy aims at providing a controlled synthesis of hierarchically nanoporous Zn-MOF microspheres with a well-defined morphology, structure, and excellent catalytic properties. Besides, it would result in having a promising heterogeneous catalyst for a selective synthesis with good yields, short reaction time, a low limit of steric hindrance and electronic effects. Moreover, the heterogeneity of the catalyst is further tested with hot filtration and also the reusability results point.

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 36,42 . Although this method is practically useful for the synthesis of interesting pharmaceutical products, its selectivity and substrate scope still need to be improved 36,43,44 . 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 also found out that Zn-MOFs can be used as a rapid catalyst to synthesize the polyhydroquinolines with excellent yields. It represents a new method for a clean and rapid synthesis of asymmetric dihydropyridines. Herein, these results are reported.

Experimental
Materials. All reagents and solvents were purchased from Merck and used without additional purification.

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 °C until reaching a clear solution. Afterward, the white suspension was transferred into a Teflon lined autoclave reactor and heated at 160 °C for 24 h (Scheme 1), which was 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 the substituted aromatic aldehyde (1.0 mmol), ethyl acetoacetate (1 mmol) and dimedone (1 mmol) was 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 filtration. Besides, the resultant mixture was extracted using Ethyl acetate and water derivation to gather unrefined polyhydroquinoline product, which was further purified through recrystallization in ethanol.

Results and discussions
This study reports the synthesis of nanoporous Zn-MOF microspheres to develop an efficient and novel heterogeneous catalyst to synthesize polyhydroquinolines as an important dihydropyridine-containing scaffold via Hantzsch reaction. The resulting samples were characterized using various techniques. Structural and chemical composition analysis. The changes in the chemical features during the synthesis of the composite were measured by FT-IR spectroscopy. Figure 1 shows the FT-IR spectra of (a) 4,6-Diamino-2-pyrimidinethiol, (b) Zn(NO 3 ) 2 .6H 2 O and (c) nanoporous Zn-MOF microspheres, respectively. Regarding the FT-IR spectrum of the 4,6-Diamino-2-pyrimidinethiol ( Fig. 1a), the bands at 3339 cm −1 and 3435 cm −1 are attributed to the stretching vibration of N-H bonds of the free NH 2 groups while those at 1523 cm −1 are related to the C=C group of the pyrimidine ring. The Amine bands disappeared in the FT-IR spectra of Zn-MOF microspheres ( Fig. 1c), indicating that the NH 2 groups have been deprotonated and coordinated to the Zn atoms. Moreover, the bending vibration of NH 2 at 1638 cm −1 in the Zn-MOF microspheres shows a shift towards higher frequencies as compared to the primary sample. This shift can be assigned to the presence of Zn ions in MOF structure and the reduction of the single bond nature of the amine and thiol groups, which confirms the successful complexion of Zn ions with the N and S atoms in the framework. The strong C=C stretching vibration band at 1468 cm −1 and C-N stretch band at 1102 cm −1 provide shreds of evidence confirming the successful synthesis of the final MOF (Fig. 1c). To estimate the mass ratios and the thermal stability of nanoporous Zn-MOF microspheres, the TGA-DSC technique was employed. Figure 3 represents TGA (Maroon line) and DSC (Blue line) curves of Zn-MOF microspheres at the temperature range of 25-1500 °C. Regarding the TGA curve, the weight loss which was occurred below 200 °C was attributed to the release of the physically adsorbed moisture, water and organic solvents from  As shown in Fig. 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 confirmed by these measurements. These observations support the high purity of the prepared Zn-MOF microspheres.

Synthesis and characterization
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. Besides, the uniform incorporation of the activated Zn catalytic species with S and N groups shows 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) analyses. 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 a uniform, three-dimensional, walnut-like and 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   By applying the transmission electron microscopy technique, high quality images from the synthesized crystalline nanoporous Zn-MOF microspheres were obtained (Fig. 7). Evidently, the synthesized Zn-MOF microspheres showed characteristics of crystalline spherical structure, referring to the fact that the optioned material is a solid sphere. Particle size distribution histogram of the as-prepared microspheres gave distribution dimensions across a range from 90 to 170 nm, with an average size of 130 nm (Fig. 7).
The porosity and surface characteristics of nanoporous Zn-MOF microspheres were explored by the N 2 adsorption/desorption analysis. The obtained results are illustrated in Fig. 8. Accordingly, Zn-MOF microspheres exhibited a Brunauer-Emmett-Teller (BET) surface area of 63.33 m 2 g −1 . Besides, the pore volumes and pore size distribution of nanoporous Zn-MOF microspheres are calculated by BJH analysis, as 0.088 cm 3 g −1 and 1.22 nm, belonging to the range of micropores materials.

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). Moreover, we optimized conditions of the reaction for Hantzsch synthesis of dihydropyridine scaffolds using para-chlorobenzaldehyde, dimedone, ethyl acetoacetate, and ammonium acetate as the model reaction. Afterwards, 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. Besides, using smaller amounts of the catalyst will cause the reaction to be incomplete (Table 1,

entry 4 & 5).
Increasing the amount of the catalyst by more than 10 mg does not affect the efficiency 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 efficiently catalyze the reaction and, as a result, the product is obtained in low yields in 85 min. Among various solvents used in the reaction, the results indicate that the PEG-400 which showed a higher efficiency, as compared to all solvents tested with 96% of 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, significantly, we observed that low temperature continued  After optimizing the reaction conditions, we explored the scope of the reaction with various electron-donating 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 the product.
It is worth noting that an appropriate mechanism for the synthesis reaction of polyhydroquinoline derivatives, catalyzed by nanoporous Zn-MOF microspheres, was proposed (Scheme 2) 36 . 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 was followed by cyclization reaction, generating a six-membered ring. Finally, the dehydration gave the final polyhydroquinoline products (Scheme 2) 36 .

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. Moreover, 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. Furthermore, we aimed at investigating the FT-IR spectrum of the reused microporous Zn-MOF catalyst (Fig. 10). Evidently, the stability of as-prepared catalyst is confirmed due to the fact that, almost all of the characteristic peaks are the same as the fresh catalyst.

Hot filtration
The hot filtration 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 filtration. Afterwards, the rest of the reaction was stirred in the absence of the catalyst

Comparison
In the last part of our studies, to demonstrate the profit 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 efficient catalysts to synthesize polyhydroquinolines. Significantly, 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.

Conclusion
In conclusion, we have reported an efficient and novel three-dimensional walnut-like, microporous Zn-MOF microsphere catalytic system by hydrothermal method. Significantly, we were 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