Novel magnetic propylsulfonic acid-anchored isocyanurate-based periodic mesoporous organosilica (Iron oxide@PMO-ICS-PrSO3H) as a highly efficient and reusable nanoreactor for the sustainable synthesis of imidazopyrimidine derivatives

In this study, preparation and characterization of a new magnetic propylsulfonic acid-anchored isocyanurate bridging periodic mesoporous organosilica (Iron oxide@PMO-ICS-PrSO3H) is described. The iron oxide@PMO-ICS-PrSO3H nanomaterials were characterized by Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy and field emission scanning electron microscopy as well as thermogravimetric analysis, N2 adsorption–desorption isotherms and vibrating sample magnetometer techniques. Indeed, the new obtained materials are the first example of the magnetic thermally stable isocyanurate-based mesoporous organosilica solid acid. Furthermore, the catalytic activity of the Iron oxide@PMO-ICS-PrSO3H nanomaterials, as a novel and highly efficient recoverable nanoreactor, was investigated for the sustainable heteroannulation synthesis of imidazopyrimidine derivatives through the Traube–Schwarz multicomponent reaction of 2-aminobenzoimidazole, C‒H acids and diverse aromatic aldehydes. The advantages of this green protocol are low catalyst loading, high to quantitative yields, short reaction times and the catalyst recyclability for at least four consecutive runs.

On the other hand, the inclusion of magnetic nanoparticles (MNPs) in the modified materials allows convenient and cost-effective separation to be conveniently performed by an external magnetic field instead of centrifugation and filtration steps. Furthermore, MNPs enhance the reaction rates by local heating through induction as well as providing appropriate surface area. Also, they show synergistic effects in combination to other catalytic species or centers, due to the catalytic performance of magnetic materials, including Fe, Ni, or Co-based ones 27,[48][49][50][51][52][53][54] . Therefore, the synergistic effects of both PMO-based organosilicas and magnetic components for designing and application of new materials would be very desirable. To the best of our knowledge, a little efforts have been made for designing of magneic PMO materials [54][55][56] , especially thermally stable isocyanurate-based mesoporous organosilica solid acid which are in high demand for promoting of organic reactions at elevated temperatures. On the other hand, development of simple synthetic procedures for the synthesis of complex and diversityoriented organic molecules from readily available substrates is an important challenge in organic and medicinal chemistry. This can be achieved through multicomponent reactions (MCRs) strategy as a powerful process for the synthesis of molecules useful for pharmaceuticals, biological studies, secret communication and electronic including heterocyclic scaffolds 57-62 as well as fabrication of new task-specific materials such as drug delivery systems, nanocomposites, polymers, supramolecular systems and molecular machines [63][64][65][66][67][68] . In MCRs, three or more reactants simultaneously combine together in one reaction vessel to form a final product with high bond forming index such as imidazopyrimidine derivatives [69][70][71][72][73][74][75][76][77] . Indeed, imidazopyrimidine derivatives show a diverse range of biological and pharmacological activities such as CK2 inhibitor as well as for the treatment of anxiety disorders and ulcers, etc. (Fig. 1) [78][79][80][81][82] .
Because of the importance of imidazopyrimidine scaffold, different homogeneous or heterogeneous acidic catalytic systems have been investigated to promote multicomponent condensation of 2-aminobenzoimidazole, aromatic aldehydes and C-H acids such as dimedone/malononitrile or relevant synthons.  94 , molecular iodine 95 , polyethylene glycol methacrylate-grafted dicationic imidazolium-based ionic liquid 96 and NaHSO 4 modified phenylene bridged periodic mesoporous organosilica magnetic nanoparticles 55 . In spite of their merits, the existing methodologies have drawbacks such as low to moderate yields, difficulties in the catalyst recovery and product isolation, toxic or expensive catalysts, lengthy reaction times, the use of volatile organic solvents or significant amounts of waste materials production 97 . Therefore, development of new methodologies and introducing green catalysts to overcome the aforementioned drawbacks is still favorable. To address limitations and disadvantages associated with these catalytic systems, preparation and catalytic application of magnetic isocyanurate-based propylsulfonic acid periodic mesoporous organosilica (Iron oxide@PMO-ICS-PrSO 3 H), as a novel and highly efficient heterogeneous mesoporous catalyst, would be very desirable. In continuation of our research interest to develop and improve novel and efficient catalysts for different MCRs or organic transformations 34,35,51,52,73,74,89,98,99 , we wish herein to report the application of Iron oxide@PMO-ICS-PrSO 3 H (1), as a novel recyclable catalyst, for the synthesis of imidazopyrimidine derivatives through the Traube-Schwarz multicomponent reaction under solvent-free conditions. To the best of our knowledge, there is no report on the use of Iron oxide@PMO-ICS-PrSO 3 H, as a nanao-architectured heterogeneous and recoverable catalyst, for different organic transformations (Scheme 1).

Results and discussion
characterization of the iron oxide@pMo-icS-prSo 3 H nanomaterials (1). After preparation of the magnetic isocyanurate-based propylsulfonic acid periodic mesoporous organosilica (Iron oxide@PMO-ICS-PrSO 3 H) nanocatalyst (1), its composition, structure, morphology and textural properties was properly characterized by different methods and techniques. The FT-IR spectra of both magnetic Iron oxide@PMO-ICS (B) and Iron oxide@PMO-ICS-PrSO 3 H (1) nanomaterials have been compared in Fig. 2. As it can be seen in Fig. 2   www.nature.com/scientificreports/ in the range of 260-800 °C, is attributed to the removing of organic functional groups including propylenesulfonic acid and 1,3,5-tris(1,3-propylen) isocyanurate moiety incorporated in the material framework ( Fig. 3). Furthermore, the composition of Iron oxide@PMO-ICS-PrSO 3 H mesoporous catalyst (1) was characterized by energy-dispersive X-ray (EDX) spectroscopy. As shown in Fig On the other hand, Fig. 5 shows the N 2 adsorption-desorption isotherms and pore size distributions (Barrett-Joyner-Halenda, BJH) of the Iron oxide@PMO-ICS-PrSO 3 H mesoporous materials (1). The Iron oxide@ PMO-ICS-PrSO 3 H itself displays a type IV isotherm, with an H 3 hysteresis loop. This analysis demonstrated that the BET specific surface area of the mesoporous materials 1 is close to 175.05 m 2 /g and it exhibits BJH average pore diameter and total pore volume equal to 7.41 nm and 0.32 cm 3 /g, respectively.
Moreover, the total acidity of Iron oxide@PMO-ICS-PrSO 3 H solid acid (1) was calculated through pH analysis of a precisely weighed sample of the material after ion exchange with saturated solution of NaCl. The results demonstrated that the loading of H + on the solid surface is 2.0 mmol.g −1 . On the other hand, low-angle XRD patterns of Iron oxide@PMO-ICS-PrSO 3 H solid acid (1) shows one sharp peak at 2θ = ~ 0.95 which confirms the presence and preservation of mesoporous framework of the PMO-ICS organosilica as well as its periodicity (Fig. 6).
Furthermore, the morphology of the catalyst (1) was characterized by field emission scanning electron microscopy (FESEM). The FESEM images of Iron oxide@PMO-ICS-PrSO 3 H powder (1) illustrated well-ordered structure of PMO-ICS and almost uniform distribution of propylenesulfonic acid functional group and iron oxide particles with average particle sizes of about 14-32 nm (Fig. 7).
Furthermore, TEM images illustrated the structural order and the morphology of Iron oxide@PMO-ICS-PrSO 3 H nanocatalyst (1) as well as presence of well distributed iron oxide nanoparticles confined inside of its mesoporous channels (Fig. 8).
Also, the saturation magnetic properties of Iron oxide@PMO-ICS-PrSO 3 H mesoporous materials (1) were evaluated using VSM technique at room temperature. According to the obtained results shown in Fig. 9, the saturation magnetization of the Iron oxide@PMO-ICS-PrSO 3 H mesoporous materials was determined to be  www.nature.com/scientificreports/ 35 emu/g which is lower than that of the parent superparamagnetic iron oxide (55 emu/g) but is sufficiently high for practical applications 100,101 . investigation of the catalytic activity of the iron oxide@pMo-prSo 3 H nanocatalyst (1) for the synthesis of imidazopyrimidine derivatives 6a-g or 7a-g. In this step, the catalytic activity of the Iron oxide@PMO-PrSO 3 H nanocatalyst (1) was investigated for the synthesis of imidazopyrimidine derivatives. Therefore, the reaction of 2-aminobenzoimidazole (2) and 4-chlorobenzaldehyde (3a) with dimedone (4) was selected as the model reaction. The obtained results from optimization experiments illustrated that both the catalyst loading and temperature strongly affect the reaction progress which have been summarized in Table 1. Indeed, only a trace amount of the desired product, 12-(4-chlorophenyl)-3,3-dimethyl-3,4,5,12tetrahydrobenzo [4,5] (Table 1, entries 6-7). Furthermore, 12-(4-chlorophenyl)-3,3-dimethyl-1,2,3,4,5,12-hexahydrobenzo [4,5]imidazo [2,1-b] quinazolin-1-one (6a) was obtained in lower yields when the model reaction was investigated using 10 mg loading of Iron oxide@PMO-ICS-PrSO 3 H (1) in other solvents such as EtOH/H 2 O or THF under reflux conditions ( Table 1, entries 8-9). Moreover, lower yields of the desired product 6a was obtained in the presence of Iron oxide@PMO-ICS, Iron oxide@PMO-ICS-PrSH, iron oxide, or pure PMO-ICS under similar reaction conditions (10 mg catalyst loading, solvent-free conditions, 80 °C, Table 1, entries 10-13). These findings indicate that the catalytic activity of Iron oxide@PMO-ICS-PrSO 3 H is mainly related to the existence of significant synergic effect of sulfonic acid groups (-SO 3 H) along with iron oxide in this mesoporous catalyst. Furthermore, the Sheldon test was performed to show the heterogeneous nature of the magnetic catalyst 1 and verify possible leaching of the propylsulfonic acid groups to the reaction mixture 102 . Thus, the catalyst 1 was isolated from the reaction mixture by an external magnet after 5 min heating at 80 °C (10 mg catalyst loading) and the remaining mixture was heated for further 10 min. Indeed, only 57% of the desired product 6a was isolated.
In the next step, the activity of the Iron oxide@PMO-ICS-PrSO 3 H catalyst 1 in the synthesis of imidazopyrimidines derivatives was further investigated to other aromatic aldehydes 3b-h or malononitrile C-H acid 5 using optimized conditions (10 mg Iron oxide@PMO-ICS-PrSO 3 H loading under solvent-free conditions at 80 °C). Indeed, different derivatives of imidazopyrimidine were prepared in high to excellent yields via the condensation of 2-aminobenzimidazole (2), aromatic aldehydes 3a-g, dimedone (4) or malononitrile (5) under optimal reaction conditions. As data in Table 2 show, various aromatic carbocyclic or heterocyclic aldehydes including both electron-withdrawing and electron-donating group were involved in the optimal reaction conditions to afford the desired products 6-7 in high to excellent yields ( Table 2). In all studied cases, the reaction proceeded smoothly and the desired products were obtained without remaining any intermediates after reaction times indicated in Table 2. The obtained products were identified by the comparison of their spectral data and melting points with those reported for the valid samples.
According to the obtained results, a plausible mechanism for the synthesis of imidazopyrimidine derivatives 6a-g and 7a-g catalyzed by the Iron oxide@PMO-ICS-PrSO 3 H nanocatalyst (1) is outlined in Scheme 2. At the first step, aldehydes 3 can be activated by the Iron oxide@PMO-ICS-PrSO 3 H magnetic solid acid mainly through -PrSO 3 H groups to afford the Knoevenagel condensation product of aldehydes 3 and dimedone (4) or Table 1. Optimization of the conditions for the model reaction in the synthesis of imidazopyrimidine derivative 6a.
the recyclability of the iron oxide@pMo-icS-prSo 3 H catalyst (1) in the synthesis of imidazopyrimidine derivatives. In this part of our study, the recyclability of the Iron oxide@PMO-ICS-PrSO 3 H catalyst (1) in the model reaction was investigated under optimized conditions. The catalyst was easily recovered from the reaction mixture by an external magnet in each run, then washed with water and EtOH and finally dried at 100 °C for 2 h before next run (Fig. 10). During the recycling experiments with the reactants of model reaction under the same reaction conditions, no significant change in the activity of the catalyst (1) was observed for at least five successive runs, which clearly demonstrates the stability of the catalyst in synthesis of imidazopyrimidine derivatives under optimized conditions. Finally, to demonstrate the merits of the newly developed solid acid catalyst 1 in the synthesis of imidazopyrimidine derivatives, the present protocol has been compared with other methods and published reports. Table 3 summarizes these data. experimental section General information. All chemicals and reagents were supplied by Aldrich or Merck chemical companies.
Benzaldehyde was used as a fresh distilled sample and other aldehydes were used without further purification. Commercial Merck silica gel 60 coated with flourescent indicator F254 on aluminium plates were used in thin layer chromatography (TLC) experiments to monitor the progress of reactions. Transmission electron microscope, TEM (Zeiss EM10C, Germany) was used to obtain TEM images. A MIRA3 instrument of TESCAN Company, Czech Republic was used to obtain field emission scanning electron microscopy (FESEM) images. XRD patterns were obtained using an X-ray powder X'Pert Pro PANalytical diffractometer with CuKα radiation source. Thermal gravimetric analysis (TGA) was accomplished by means of a Bahr company STA 504 instrument. An ASAP 2020 micromeritics equipment was used to determine the BET specific surface area of the catalyst. FTIR spectra were obtained using KBr disks on a Shimadzu FT IR-8400S spectrometer. Melting points were determined using a digital melting point Electrothermal 9,100 apparatus and are uncorrected. 1 H NMR (500 MHz) spectra were obtained using a Bruker DRX-500 AVANCE spectrometer in DMSO at ambient temperature. VSM analysis was performed using a Lakeshore 7,410 series instrument.
General procedure for the preparation of magnetic isocyanurate-based periodic mesoporous organosilica (iron oxide@pMo-icS) nanomaterials (B). Isocyanurate-based periodic mesoporous organosilica (PMO-ICS) nanomaterials (A) were prepared according to the procedure described in our previous publications 34,98 . After that, PMO-ICS (A, 2.0 g) was dispersed in toluene (20 mL) and stirred for 20 min at room temperature. Then, FeCl 2 .4H 2 O (2.0 g) and FeCl 3 .6H 2 O (4.0 g) were added to the obtained mixture under nitrogen atmosphere. The reaction mixture was then heated in an oil bath at 80 °C for 1 h. Next, aqueous NH 3 (25% w/v, 20 mL) solution was added dropwise to the reaction mixture over 30 min and the reaction allowed to proceed further for 1 h at 80 °C. Then the obtained solid was washed with deionized H 2 O/EtOH (50:50 v/v, 40 mL) and dried at 100 °C for 1 h.
General procedure for the preparation of magnetic isocyanorate-based propylsulfonic acid periodic mesoporous organosilica (iron oxide@pMo-icS-prSo 3 H) nanomaterials (1). Iron oxide@PMO-ICS (B, 2.0 g) was dispersed in toluene (10 mL). Then, 0.4 mL of the 3-[(trimethoxysilyl) propyl] thiol was slowly added to the mixture and stirred at room temperature for 24 h to afford Iron oxide@PMO-ICS-PrSH (C). The resulting solid was filtered, washed by distilled water and dried under vacuum for 1 h. Finally, 1.0 g of Iron oxide@PMO-ICS-PrSH (C) was dispersed in deionized H 2 O (4 mL) and H 2 O 2 (6 mL) was slowly added to the above mixture stirred at room temperature for 24 h. The obtained black solid (Iron oxide@PMO-ICS-PrSO 3 H, 1) was filtered off and washed with deionized water twice (15 mL) and then dried at 100 °C for 2 h.
General procedure for the synthesis of imidazopyrimidine derivatives 6/7 a-g catalyzed by Iron oxide@pMo-icS-prSo 3 H nanomaterials (1). Iron oxide@PMO-ICS-PrSO 3 H (1, 10 mg) was added to a mixture of 2-aminobenzoimidazole (2, 1 mmol, 0.133 mg), aromatic aldehyde (3, 1 mmol), and dimedone or malononitrile (4-5, 1 mmol). The obtained reaction mixture was stirred under solvent-free conditions at 80 °C for the proper times indicated in Table 2. The progress of the reaction was monitored by TLC (EtOAc: n-hexane, 1:3). After completion of the reaction, DMF (2 mL) was added and the reaction mixture was heated to dissolve organic materials. The magnetic nanocatalyst 1 was then collected by an external magnet. After that, distilled water (5 mL) was added to the DMF solution and the obtained precipitate was filtered off and washed using n-hexane (2 mL) to afford pure products. The obtained powders were then dried in an oven at 80 °C for 1 h.