Sulfonated Pyromellitic Dianhydride-functionalized MCM-41: A Multifunctional Hybrid Catalyst for Melting-assisted Solvent-free Synthesis of Bioactive

This study introduces a practical approach to fabricate a novel hybrid catalyst of namely sulfonated pyromellitic dianhydride-aminopropyl silane-functionalized MCM-41 (MCM-41-APS-PMDA-SO 3 H). Various microscopic, spectroscopic methods and techniques such as FTIR, TGA, XRD, FESEM, and EDX were used to conrm its structural characteristics. The eciency of the new MCM-41-APS-PMDA-SO 3 H organosilica nanomaterials, as a heterogenous nanocatalyst, was evaluated in promoting the synthesis of biologically active 3,4-dihydropyrimidin-2-(1H)-one derivatives under solvent-free conditions. It is not only a nanoporous material for enriching reactants with high surface area provided, but also possesses great acidic sites to activate carbonyl groups. Furthermore, favored reusability of the new introduced hybrid organosilica with negligible loss of its activity, easy and quick isolation of the products are the main advantages of this procedure.


Introduction
In recent decades, the synthesis and use of mesoporous structures have received much attention. The M41S family consists mainly of silica, SiO 2 . Silica has certain advantages as support like high chemical and thermal stability, has a large number of silanol (Si-OH) groups and simplicity of operation. MCM-41 became the most attractive member of the M41S family due to with ordered structure and its special properties such as exceptionally high surface area (> 1000 m 2 g − 1 ), narrow pore-size distribution (1.5-10 nm), and having a hexagonal arrays of cylindrical mesopores [1][2][3][4] . These properties have made MCM-41 known as a support for of metal oxides 5 , heteropoly acids 6 , complexes 7 , drug delivery systems [8][9][10][11][12] , candidate for sensors 13 , degradation inhibitor in polymer dielectrics 14 , adsorption of organic pollutants 15 , and solid supports to immobilize catalysts [16][17][18][19] . However, the acid strength of the pure MCM-41 is relatively weak, which hinders its catalysis applications. Modi cation of its surface can lead to the formation of a solid acid with high uniformity, which is regularly modi ed by covalent anchoring of various organic particles in a mesoporous material or replacing of Si atoms by other tetra-, tri-and divalent metals such as Al, B, Fe, Mn, Zn, etc 10,20−35 . It is expected that the use of MCM-41 as catalyst support for the sulfonated pyromellitic dianhydride may greatly enhance the catalytic capabilities of designed catalyst components.
During the last few years, solvent-free organic synthesis (SFOS) of biologically activated molecules has been an effective tool for the rapid generation of various compound collections. In fact, the SFOS obviously include the formation of a liquid phase reaction. This melting mentions the eutectic mixture with temperature fusion below the melting points of the reactants. These solvent-free protocols have the advantage of including the following: the products are su ciently pure which does not require further puri cation or recrystallization; the reactions are sometimes rapid as compared to using solvent conditions; functional group protection-deprotection can be avoided and sometimes the use of solventfree conditions is more affordable 36,37 . Furthermore, the use of multicomponent reactions (MCRs) allow to achieved maximum diversity molecules in a single and simple synthetic procedure [38][39][40][41] . The synthesis of high-value chemical compounds to produce a library of small molecules enhances the concerted growth of solvent-free and MCRs as a signi cant tool 42 .
In past few decades, dihydropyrimidinones (DHPMs) and their derivatives, an important class of heterocycle compounds, have stimulated interest in medicinal chemistry due to diverse biological activity [43][44][45] . Heterocycle compounds containing pyrimidine moiety in the ring nucleus have a signi cant presence in natural products such as vitamin B 1 and synthetic organic compounds, such as barbituric acid and veranal which are used as hypnotics 46 . Several methods have been developed for the synthesis of DHPMs 47 . A considerable type of catalysts to date have been reported to promote classical synthesis of DHPMs by Biginelli reaction in an elegant manner [48][49][50] . Among these catalysts system, immobilized catalyst moiety onto the large area surface of solid polymeric supports, in particular silica can improve the synthetic procedure [51][52][53][54] . In continuation of our ongoing efforts towards expanding e cient and novel heterogeneous catalysts for different MCRs [55][56][57][58][59][60] . We wish herein to introduce, preparation and curve of MCM-41-APS-PMDA-SO 3 H shows three steps of weight loss. In the rst step, 10% weight loss between room temperature and 150 °C belongs to absorbed water held in the pores of nanomaterial. While the second weight loss between 150-350 ºC is due to decomposition of the organically modi ed framework. Also, the third weight loss (17%) between 380-600 ºC was related to decomposition of silanol groups. These results also indicate that pyromellitic dianhydride has been conjuncted onto the surface of MCM-41.  The systematic reaction parameters like solvent, catalyst loading and temperature were optimized. The results are summarized in Table 1. The results of using different protic and aprotic solvents showed that the reaction in solvent-free conditions at 80 C proceeded with acceptable e ciency (95 % yield) in 35 min, which encouraged us to perform this reaction in solvent-free conditions (Table 1, entry 11). Remarkably, the model reaction was investigated in the presence of 15 mg of catalyst 1 in solvent-free conditions at 80 °C, the favorable product was gained with quantitative e ciency (Entry 11). Subsequently, by further reducing the amount of catalyst, a lower yield of the favorable product was gained under similar conditions even in over a longer time. To our delight, it was found that 15 mg of catalyst 1 in solvent-free conditions at 80 C as optimizing conditions were su cient to promote the model reaction e ciently. Indeed, the results strongly con rmed the role of MCM-41-APS-PMDA-SO 3 H (1) to promote the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Therefore, optimized conditions have been developed using different aromatic aldehydes to synthesize other derivatives of favorable products 5.
The results are given in Table 2.
Noticeably, the desired products were gained in high to excellent yields. Actually, electron-withdrawing groups of the aromatic ring of aldehydes 3 generally react faster compared to the electron-donating groups. These results clearly con rm the suitable catalytic activity of the MCM-41-APS-PMDA-SO3H (1) hybrid nanomaterials to promote the biginelli condensation of a wide range of aldehydes with ethyl acetoacetate and urea. According to above standpoints, the following mechanism can be proposed for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones synthesis condensation (Scheme 3). After completing the reaction, the introduced catalyst was separated, washed several times, and dried then reused in the reaction without any reduction inactivity. The catalyst was used for four cycles in reaction with very little activity reduction (approx. 10%). The results are shown in Fig. 6.
To illustrate the catalytic activity of the new MCM-41-APS-PMDA-SO 3 H organosilica nanomaterials as a heterogenous nanocatalyst, its e ciency has been compared with some of the previously reported catalysts for the preparation of 5a (Table 3). The results illustrate that this study is actually superior to other cases in terms of reaction time, product performance, amount of catalyst, non-toxicity, non-use of intermediate and expensive transition metals, and the obtained e ciency for the catalyst recycling.

Experimental Section
General Information All chemicals are purchased from Merck or Aldrich. Melting points were speci ed using an Electrothermal 9100 device and are unmodi ed. Characterization of new hybrid nanocatalyst 1 was performed by FESEM TESCAN-MIRA3, EDX Numerix DXP-X10P, Shimadzu FT-IR-8400S and TGA Bahr Company STA 504. The XRD pattern of the catalyst was obtained using TW 1800 diffractometer with Cu Ka radiation (λ = 1.54050 Å). The analytical thin layer chromatography (TLC) experiments was performed using Merck 0.2 mm silica gel 60F-254Al-plates. All compounds well characterized by IR and 1 H NMR (500 MHz, Bruker DRX-500 Avance spectrometers in DMSO).
General procedure for preparation of the MCM-41 Nano ordered mesoporous silica MCM-41 were prepared by hydrothermal synthesis conforming to the known method. 33 . 2.70 g of diethyl amine was dissolved in 42 mL deionized water at room temperature. The mixture was stirred for 10 min, then 1.47 g of cetyltrimethylammonium bromide (CTAB) was added and the surfactant solution was stirred for 30 min until a clear solution was gained. Next, 2.10 g tetraethyl orthosilicate (TEOS) was gently added and by drop wise addition of HCl solution (1 M), the pH of the mixture was xed at 8.5 to gain the nal precipitate. The resulting mixture was stirred for 2 h, next the resulting white precipitate was ltered and washed with 100 ml of water. Then it was dried at 45 ° C for 12 h and nally, the sample was calcined at 550 °C with the rate of 2 °C/min for 5 h.  Table 2. The advance of the reactions was checked out by TLC (Eluent: EtOAc: n-hexane, 1:3). At the end of the reaction, 96% EtOH (5 mL) was added to the mixture. The heterogeneous catalyst was then separated by ltration and allowed to cool ltrate over time to give pure crystals of the desired 3,4-dihydropyrimidinones. The separated catalyst was suspended in ethanol (1 mL), for 30 min and ltered off, heated in an oven at 60 °C for 1.5 h and then reused for successive runs.

Conclusions
In summary, we have developed an e cient, practical synthetic methodology for the preparation of 3,4dihydropyrimidin-2(1H)-ones using sulfonated pyromellitic dianhydride-functionalized MCM-41 (MCM-41-APS-PMDA-SO 3 H), as a heterogeneous multifunctional hybrid catalyst, under solvent-free conditions. High catalytic performance, favored reusability of the newly introduced hybrid organosilica with negligible loss of its activity, compatibility with various functional groups and easy and quick isolation of the products are the main advantages of this procedure. Further works to expand and apply MCM-41-APS-PMDA-SO 3 H nanomaterials in organic synthesis and transformation is ongoing in our laboratory and would be presented in due courses.