Sulfamic acid pyromellitic diamide-functionalized MCM-41 as a multifunctional hybrid catalyst for melting-assisted solvent-free synthesis of bioactive 3,4-dihydropyrimidin-2-(1H)-ones

This study introduces a practical approach to fabricate a novel hybrid acidic catalyst, namely sulfamic acid pyromellitic diamide-functionalized MCM-41 (MCM-41-APS-PMDA-NHSO3H). Various techniques such as FTIR, TGA, XRD, BET, FESEM, and EDX were used to confirm its structural characteristics. The efficiency of the new MCM-41-APS-PMDA-NHSO3H organosilica nanomaterials, as a heterogenous nanocatalyst, was examined in the synthesis of biologically active 3,4-dihydropyrimidin-2-(1H)-one derivatives under solvent-free conditions. It was found that the nanoporous MCM-41-APS-PMDA-NHSO3H, demonstrating acidic nature and high surface area, can activate all the Biginelli reaction components to afford desired 3,4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions in short reaction time. Furthermore, easy and quick isolation of the new introduced hybrid organosilica from the reaction mixture as well as its reusability with negligible loss of activity in at least five consecutive runs are another advantages of this green protocol.

In the past few decades, dihydropyrimidinones (DHPMs) and their derivatives, as an important class of heterocyclic compounds, have stimulated interest in medicinal chemistry due to their diverse biological activities [48][49][50][51] . Theses pyrimidine-containing heterocycles are present significantly in natural products or synthetic organic compounds such as natural marine polycyclic guanidine alkaloids, the kinesin Eg5 inhibitor Monastrol, BACE-1 inhibitor to prevent Alzheimer's disease, bioprobes and fluorescent sensors [51][52][53][54][55] . Due to important properties of DHMPs, different methods using Brønsted or Lewis acids catalysts have been developed for the synthesis of DHPMs by the Biginelli reaction in recent years [55][56][57][58][59] . Among these catalytic systems, the immobilization of the catalytic active centers on a wide range of solid polymer supports, especially silica, can improve the efficiency of the relevant method [59][60][61][62][63] . In continuation of our ongoing efforts towards developing of more efficient heterogeneous catalysts for different MCRs [63][64][65][66][67][68][69][70] , we wish herein to introduce preparation and characterization of the new hybrid sulfamic acid pyromellitic diamide-functionalized MCM-41 (MCM-41-APS-PMDA-NHSO 3 H) nanomaterials. Also, its catalytic activity was investigated in the three-component synthesis of 3,4-dihydropyrimidin-2-(1H)-one derivatives from aromatic aldehydes, ethyl acetoacetate and urea (Scheme 1). To the best of our knowledge, there is not any report for the use of sulfamic acid pyromellitic diamide grafted on the surface of MCM-41, as a heterogeneous nanocatalyst, for the synthesis of Biginelli 3,4-dihydropyrimidin-2-(1H)-one derivatives.  Fig. 1. The nano-ordered MCM-41 shows a band in the 3443 cm −1 region that is due to the presence of both Si-OH and OH groups of the adsorbed water molecules on its surface ( Fig. 1a) 71 . Furthermore, the band corresponded to Si-O-Si bonds for MCM-41 and all subsequent modifications are observed around 1228-1062 cm −1 . Also, the signals in the regions of 1600 cm −1 and 2883 cm −1 are attributed to the symmetric vibrations of NH 2 and the asymmetric vibrations of C-H of 3-APTS, respectively (Fig. 1b). On the other hand, the decrease in signal intensity of the OH groups of MCM-41 surface confirms that the MCM-41 substrate has been modified by the covalent bonding of the 3-APTS linker. In addition, the observed broad band at 3604-2923, 1716 and 1569 cm −1 are attributed to the stretching vibrations of the pyromellitic acid and its amide derivative (Fig. 1c). Also, the characteristic band observed at 1365 and 1066 cm −1 are assigned to the asymmetric and symmetric S=O stretching vibration of the SO 3 H group (Fig. 1d).

Results and discussion
Also, the morphology and textural properties of the MCM-41and MCM-41-APS-PMDA-NHSO 3 H (1) were examined using field emission scanning electron microscopy (FESEM). As shown in Fig On the other hand, the thermogravimetric analysis (TGA) of the MCM-41-APS-PMDA-NHSO 3 H (1) are shown in Fig. 3. The TGA curve of MCM-41-APS-PMDA-NHSO 3 H shows three distinct steps of weight loss. In the first step, 10% weight loss between 50 °C and 150 °C can be attributed to the absorbed water or solvent molecules held in the pores of the MCM-41-APS-PMDA-NHSO 3 H nanomaterial. The second weight loss between 150 and 350 °C is due to decomposition of the grafted organic N-carbonyl sulfamic acid pyromellitic diamide moiety. Also, the third weight loss (17%) between 380 and 600 °C can be related to the conversion of silanol (Si-OH) groups to siloxane (Si-O-Si) bridges. These results also indicate that the N-carbonyl sulfamic acid pyromellitic diamide moiety has successfully been grafted onto the surface of MCM-41.
According to the above results and observations, the following mechanism can be proposed for the synthesis of As a part of our study, the heterogeneous solid acid catalyst 1 was separated from the model reaction mixture after its completion, washed several times with EtOH, and then dried in an oven at 60 °C for 1.5 h. The recycled catalyst 1 was reused in four consecutive model reaction under optimized conditions. The results are shown in   To illustrate the merits of catalytic activity of the new MCM-41-APS-PMDA-NHSO 3 H organosilica nanomaterials, as a heterogeneous solid acid, its efficiency 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 desired product yield, amount of catalyst loading, reaction time, working under solvent-free conditions, avoiding of the use of corrosive or expensive reagents and transition metals, and the reusability of the catalyst for at least five consecutive runs. General procedure for preparation of the MCM-41. Nano-ordered mesoporous silica MCM-41 was prepared by the hydrothermal synthesis and according to known reported method 86 . 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 obtained mixture was stirred for 30 min until a clear solution was produced. Next, 2.10 g tetraethyl orthosilicate (TEOS) was gently added and by dropwise addition of HCl solution (1 M), the pH of the mixture was fixed at 8.5 to afford the final precipitate. The resulting mixture was stirred for 2 h and then the resulting white precipitate was filtered and washed with 100 mL of distilled water. Afterward, the obtained white solid was dried at 45 °C for 12 h and finally the sample was calcined at 550 °C with the rate of 2 °C/min for 5 h.

General procedure for preparation of the MCM-41-APS-PMDA-NHSO 3 H (1). In a 200 mL round
button flask, (3-aminopropyl) triethoxysilane (3-APTS, 0.15 mmol, d = 0.946 g/mL) was added to a mixture of MCM-41 (0.15 g) in dry toluene (15 mL) under stirring and reflux conditions. After 8 h, the obtained white MCM-41-APS solid was filtered, and washed with toluene and CHCl 3 several times to remove any excess of the 3-APTS linker. The MCM-41-APS-NH 2 solid was heated in an oven at 80 °C for 8 h. Next, dried MCM-41-APS-NH 2 solid (0.15 g) and pyromellitic dianhydride (0.15 g) were dispersed in dry THF (30 mL) and the obtained mixture was stirred at r.t for 1 h. Following this, triethylamine (TEA, 0.10 g) was added to the obtained mixture. Then the mixture was stirred at r.t for 24 h under N 2 atmosphere. Afterward, the obtained solid was filtered off and washed with toluene and EtOH (2 mL), respectively, for several times. The as-prepared solid having an anhydride functional group was first dispersed in dry toluene (20 mL) and then triethylamine (0.10 g) and sulfamic acid (0.10 g) were added. The obtained mixture was stirred under N 2 atmosphere and reflux conditions   Table 2. The progress of the reactions was monitored by TLC (Eluent: EtOAc: n-hexane, 1:3). After completion of the reaction, 96% EtOH (3 mL) was added to the mixture. The heterogeneous catalyst was then separated by filtration and the filtrate was allowed to cool over time to give pure crystals of the desired 3,4-dihydropyrimidinones 5a-k. The separated catalyst was suspended in EtOH (2 mL) and stirred at r.t for 30 min. Then, it was filtered off and dried in an oven at 60 °C for 1.5 h to be used for next runs.

Conclusions
In summary, we have developed an efficient and practical synthetic methodology for the preparation of 3,4-dihydropyrimidin-2(1H)-ones using sulfamic acid pyromellitic diamide-functionalized MCM-41 (MCM-41-APS-PMDA-NHSO 3 H), as a heterogeneous multifunctional hybrid catalyst, under solvent-free conditions. Low catalyst loading, high to quantitative yield of the desired products and compatibility with various functional groups as well as easy and quick isolation of the products from the reaction mixture and reusability of the novel solid acidic hybrid organosilica with negligible loss of its activity are the main advantages of this procedure. Further works to expand and apply MCM-41-APS-PMDA-NHSO 3 H nanomaterials in different organic transformations is ongoing in our laboratory and would be presented in due courses.