Synthesis of SCMNPs@imine/SO3H magnetic nanocatalyst by chlorosulfonic acid as sulfonating agents and their application for the preparation of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one and 1,8-dioxooctahydroxanthene derivatives

In this survey, new recoverable sulfonated magnetic nanocatalysts (SCMNPs@imine/SO3H) was synthesized by covalent attachment of a Schiff base ligand on the surface of SCMNPs@APTES/sucanh through reaction with 4-[(Pyridin-2-ylmethylene)-amino]-phenol and subsequent reaction with chlorosulfonic acid. The synthesized nanocatalyst was characterized by several techniques such as FTIR, TGA, VSM, XRD, UV–vis and EDX analysis. The nanocatalyst was evaluated in the preparation of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one and 1,8-dioxooctahydroxanthene derivatives with pharmacologically and biologically remarkable activity. 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one and 1,8-dioxooctahydroxanthene derivatives were respectively prepared via one-pot, three-component reactions of 2-naphthol, dimedone and aldehydes, as well as the reaction between dimedone and aldehydes in the presence of SCMNPs@imine/SO3H under solvent-free conditions. The merits of this synthesis are high-to-excellent yields, short reaction time, mild basic conditions and high catalytic activity. Also, the SCMNPs@imine/SO3H with suitable magnetic strength can be easily separated from the reaction solution using an external magnetic field.


Introduction
During the last decades, magnetic nanoparticles (MNPs) have attracted the attention of researchers due to their particular features in terms of catalytic activity like high dispersion, high reactivity, highly stability, durability in the catalytic processes and effective separation without any significant changes in their activity [1][2][3][4][5]. To avoid reducing the efficiency of these unique characteristics, magnetic nanoparticles have been modified with organic or inorganic layers such as silica, polymer, carbon, zeolite, and metal oxides [6][7][8][9][10]. Additionally, magnetic nanoparticles can be used in adsorption of heavy metals, proteins, drug delivery, dyes, beneficial supports, biosensors, hyperthermia activity for cancer treatment and environmental remediation [11][12][13][14][15][16].
Multicomponent reactions (MCRs) are well-appointed techniques to design the product in a single pot from three or more substrates with high yield for accessing a vast number of synthetic and pharmaceutically relevant compounds [17]. This illustrative method has many advantages such as selectivity, efficiency, high reaction rates, high variability, simplicity, low costs, and environmentally friendly properties [18]. Xanthenes have a broad spectrum of approved biological and pharmaceutical activities; e.g., they have been used as anti-inflammatory [19], antibacterial [20], antiviral [21] agents, and as antagonists for inhibiting the action of zoxalamine [22]. Moreover, xanthene derivatives have also been applied in laser technology [23], pH sensitive fluorescent materials [24] and photodynamic therapy [25]. The one-pot multi-component condensation reaction between 2-naphthol, dimedone, arylaldehydes and, also, between dimedone and arylaldehydes, have been used as the Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.

Experimental General
All of the chemicals, reagents, and solvents used in our research work were entirely purchased from Merck and Fluka Chemical Companies. Melting points were done on a Büchi B-545 apparatus. FT-IR spectra were measured through the method of KBr pellets in the range 400-4000 cm −1 with a Shimadzu IR-470 spectrometer. TGA spectra were characterized using a TGA thermoanalyzer (PerkinElmer) instrument. VSM analyses of the samples were characterized by a Lakeshore 7407 at room temperature. Energy-dispersive analysis of x-ray (EDX) was provided on an ESEM, Philips, and XL30. X-ray powder diffraction (XRD) patterns of samples were obtained using a Siemens D-5000 x-ray diffractometer.

Catalyst synthesis
Preparation of the Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 MNPs) First, FeCl 3 ·6H 2 O (4.8g) and FeCl 2 ·4H 2 O (1.7g) were dispersed in 100 ml of deionized water containing 0.9 ml of concentrated HCl and sonicated for 30 min. Then, 250 ml of NaOH solution (1.5 M) was added slowly to the reaction solution and the reaction mixture was stirred for 30 min with a magnetic stirrer in the absence of temperature. The formed black magnetic nanoparticles were collected by a powerful magnet, washed several times with 150 ml deionized water, and dried under vacuum at 60°C for 15h.

Preparation of the silica-coated Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 @SCMNPs)
A mixture of 50 ml ethanol, 8 ml deionized water, and 3 ml concentrated aqueous ammonia (25 wt %) was added to about 1g of the synthesized Fe 3 O 4 magnetic nanoparticles and the contents of the reaction vessel were ultrasonicated for 15 min. After the time required for the reaction passed, 0.6 ml of tetraethylorthosilicate (TEOS) was added to the reaction vessel and ultrasonication was done again for 15 min. To achieve the target product, the contents of the reaction vessel were mechanically stirred at 80°C for 12h. After the passage of the desired time, the precipitates of silica-coated magnetic nanoparticles were separated using an external magnetic field that were then washed with ethanol (3×10 ml) and dried in the absence of temperature under vacuum.
Preparation of the silica-coated Fe 3 O 4 magnetic nanoparticles bonded propyl chloride (SCMNPs@APTESi) Following the successful coating procedure of the magnetic nanoparticles, 1g of SC@ Fe 3 O 4 MNPs was added to the reaction vessel containing 20 ml dry toluene and dispersed with the aid of ultrasonication for 30 min. Next, a certain amount of aminopropyltriethoxysilane (APTESi) (2 ml) was added dropwise to the reaction solution and refluxed under argon atmosphere with vigorous stirring for 24h. After the appearance of the bright solid magnetic nanoparticles in the reaction vessel, the desired product was magnetically separated from the solution, consecutively washed with ethanol, and then dried in a vacuum oven at 50°C.

Preparation of the SCMNPs@APTES/sucanh
The prepared SCMNPs@APTESi (2 g) was added to the reaction vessel containing 100 ml of dry toluene and dispersed for 30 min with sonication. After dispersing the magnetic nanoparticles in the desired solvent, more succinicanhydride (3 mmol) and triethylamine (3.5 mmol) were poured to the reaction solution and the resulting mixture was refluxed for 36h with stirring. The residue solid (SCMNPs@APTES/sucanh) was extracted using an appropriate magnet, consecutively washed with ethanol, and dried in a vacuum oven.
Preparation of the 4-[(Pyridin-2-ylmethylene)-amino]-phenol Iminopyridine was prepared using procedure reported in literature [33]. A mixture of Pyridine-2-carbaldehyde (1 mmol), 4-aminophenol (1 mmol), and MeOH (10 ml) was stirred magnetically under reflux conditions for 3h. After this period and completion of the reaction, as controlled by thin-layer chromatography (TLC), the solution was cooled to room temperature, and the resulting yellow crystals were separated by filtration. The solid residue was rinsed several times with methanol and dried under vacuum.

Preparation of the SCMNPs@APTES/imine
To a dispersed solutions of SCMNPs@APTES/sucanh (2g) in dry DMF (10 ml) was added a solution of iminopyridine (0.2 g), NaH (0.006g) and DMF (7 ml), and the mixture was refluxed under vigorous stirring for 24h. The obtained Schiff base immobilized on SCMNPs@APTES/sucanh was extracted with magnetic decantation in the presence of the powerful magnetic field that was consecutively washed with DMF and dried in a vacuum oven.
Preparation of the SCMNPs@imine/SO 3 H 2g of SCMNPs@APTES/imine was dispersed in 50 ml dry dichloromethane with the aid of ultrasonication for 15 min and 10 mmol chlorosulfonic acid was added dropwise into the resulting solution. The resulting mixture was stirred vigorously for 6h and after collecting sediments in the bottom of the container, the sediments were separated with magnetic decantation in the presence of the powerful magnetic field. The resultant SCMNPs@imine/SO 3 H was rinsed twice with water and ethanol and dried at 60°C for 17h under a vacuum oven. All stages of the SCMNPs@imine/SO 3 H synthesis are exhibited in scheme 1.
General process for the preparation of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives (4) The condensation of 2-naphthol (1 mmol), dimedone (1 mmol), and 3-nitrobenzaldehyde (1 mmol) was tested in the presence of SCMNPs@imine/SO 3 H (10 mg) at 90°C under solvent-free conditions. After solidification of the reaction solution and in order to ensure its completion, the reaction mixture was controlled by the TLC. After viewing the product spot on TLC, the reaction solution was cooled to 25°C and the catalyst was separated by an external magnet and the solid residue was achieved from the reaction container by recrystallization from aqueous ethanol (90%).
General process for the preparation of 1,8-dioxooctahydroxanthene derivatives (5) The condensation of dimedone (1 mmol) and aldehyde (1 mmol) was tested in the presence of SCMNPs@imine/SO 3 H (10 mg) at 90°C under solvent-free conditions. After solidification of the reaction solution and in order to ensure its completion, the reaction mixture was controlled by the TLC. After viewing the product spot on TLC, the reaction solution was cooled to 25°C and the catalyst was separated by an external magnet and the solid residue was achieved from the reaction container by recrystallization from aqueous ethanol (90%).

Results and discussion
Catalyst characterization FTIR analysis of SCMNPs@imine/SO 3 H   Thermal analysis of SCMNPs@imine/SO 3 H The thermal behaviors of MNPs, SCMNPs@APTES/sucanh, SCMNPs@APTES/imine and SCMNPs@imine/SO 3 H are studied by Thermogravimetric analysis (TGA). As shown in all thermogram in figure 6, the mass loss up to the temperature of 250°C is correlated with the evaporation of the adsorbed water molecules. Moreover, TGA data for SCMNPs@APTES/sucanh, SCMNPs@APTES/imine and SCMNPs@imine/SO 3 H samples exhibit 2 mass loss at the temperature up to 600°C because of losing functional groups around the MNPs core.  In order to show the semiconductor property of the synthesized SCMNPs@imine/SO 3 H, the energy band gap of the catalyst was plotted using the Tauc relation. The energy band gap of semiconductors is between 0 to 3 eV. On the other hand, according to the exhibited diagram in figure 7, the band gap of the catalyst was obtained at 2.53 eV, confirming the semiconductor of the synthesized SCMNPs@imine/SO 3 H.
To optimize the reaction conditions, we conducted the condensation of 2-naphthol (1), dimedone (2) and 3-nitrobenzaldehyde (3) as a model reaction for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a] xanthen-11-one derivatives in the presence of SCMNPs@imine/SO 3 H (10 mg) in different solvents (EtOH, H 2 O, THF, and EtOAc) and also under solvent-free condition (table 2, Entries 1-4). The results showed that the best optimal condition was obtained in the absence of solvent (table 2, Entry 5). To determine the effect of temperature on the model reaction, the reaction was carried out in a range of various temperatures, including 25, 70, 80, 90, 100, 110 and 120°C, in the presence of 10 mg of SCMNPs@imine/SO 3 H catalyst under solvent-free conditions (table 2, entries 5-11). Increasing the reaction temperature to 120°C made no obvious difference in the product yield (table 2, Entries 9-11). To optimize the amount of magnetic     a Reaction conditions: 2-naphthol (1 mmol), dimedone (1 mmol), 3-nitrobenzaldehyde (1 mmol), and required amount of the catalysts. b The yields refer to the isolated product.         SCMNPs@imine/SO 3 H is superior with respect to the reported catalysts in terms of saving time, energy, and high yields of the products. After optimizing the reaction parameters such as solvent, temperature and catalyst loading, we have synthesized different derivatives of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives (4a-k) from a variety of substrates including aldehydes, 2-naphthol, and dimedone in the presence of 10 mg of SCMNPs@imine/SO 3 H as catalyst. As clearly shown in table 3, the aryl aldehydes with both electronwithdrawing and electron-donating substituents proceeded smoothly and afforded the corresponding products with high purity in good yields.
Also, we focused on a rapid and efficient one-pot three-component synthesis of 1,8-dioxooctahydroxanthenes via the condensation of dimedone with 4-chlorobenzaldehyde in the presence of SCMNPs@imine/SO 3 H as a model reaction. For optimization of the reaction conditions, various conditions using various concentration of catalyst at different temperatures under solvent-free conditions were investigated (table 4). We found that the best result was obtained using 1 mmol aldehyde, 1 mmol dimedone and 10 mg SCMNPs@imine/SO 3 H at 90°C under solvent-free conditions (table 4, Entry 5). To highlight the advantages of our developed procedures, we have compared our result obtained from the synthesis of 1,8-dioxooctahydroxanthenes catalyzed with SCMNPs@imine/SO 3 H with the previously reported catalysts in the literature. As shown in this table, this method is superior in the term of saving time, energy, and high yields of the products.
Under the optimal conditions and to establish the effectiveness and the acceptability of the method, we surveyed the procedure with a variety of simple readily available substrates. As presented in table 5, wide ranges of aromatic aldehydes containing electron-withdrawing and electron-donating groups were condensed with dimedone under the optimal conditions with high yields and very short reaction times.
An effective characteristic of the SCMNPs@imine/SO 3 H is the ease with which it can be separated from the reaction mixtures by an external magnetic field. Thus, the recyclability of the SCMNPs@imine/SO 3 H in the model reaction between 2-naphthol, dimedone and 3-nitrobenzaldehyde, also, between dimedone and 4-chlorobenzaldehyde were tested. After completion of the reaction and separation of the catalyst from the mixture, ethanol was added and the catalyst was rinsed several times. The washed catalyst was dried before being reused in the next run of the same model reaction. As figure 8 shows, the catalytic activity of the SCMNPs@imine/SO 3 H was not significantly changed at least 6 runs consecutive recycling in the same model reactions.

Conclusion
Results show that functional groups have been supported on the Fe 3 O 4 MNPs surfaces and a heterogeneous magnetic nanocatalyst is formed (SCMNPs@imine/SO 3 H). Then the SCMNPs@imine/SO 3 H, as a nontoxic, efficient and green catalyst, has been used for one pot synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo [a]xanthen-11-one and 1,8-dioxooctahydroxanthene derivatives under solvent free conditions with good to high yield and short reaction times. The SCMNPs@imine/SO 3 H was extracted using a permanent magnetic field and reused efficiently for the six runs without any significant decrease in catalytic activities.