Green Synthesis of 1H-Benzo[d]Imidazol-2-yl-4-(Aryldiazenyl)Phenol and Bis Benzo[d]Imidazoles Using Fe3O4@Silicapropyl@Vanillin/Thiamin Nanoparticles

Abstract Fe3O4@Silicapropyl@Vanillin/Thiamin nanoparticles were synthesized by a simple immobilization method using cheap and natural materials. The nanocatalyst was analyzed by XRD, FT-IR, FE-SEM, TEM, VSM and TGA techniques and was applied as a new, effective and magnetically recoverable solid acid for the synthesis of azo-linked benzo[d]imidazoles or bis benzo[d]imidazoles via the reaction of corresponding aldehydes and 1,2-diaminobenzene in water as green solvent. At the end of reaction, the catalyst could be separated by filtration of mixture in the presence of an external magnet and recycled for 7 consecutive runs, without significant decrease in efficiency. This avenue for the synthesis of benzo[d]imidazoles has advantages such as simplicity in operation, and green aspect by avoiding toxic conventional catalysts and solvents. Graphical Abstract


Introduction
Benzoimidazole is a heterocyclic organic aromatic compound. This compound consists of two fused rings, including benzene and imidazole. 1 Benzimidazole derivatives are very important due to their applications in various industries. Some of them, are used in the treatment of skin diseases and respiratory diseases. 2 Others, can act as antibiotics, fungicides, anti-radiation, anti-diabetics, antihypertensive, herbicidal, anti-HIV, anti-cancer, analgesics, antipyretics, antihistamines, antioxidant, anti-malarial, anti-infective and anti-inflammatory. 3,4 Pimobendan is one of the drugs that have a benzimidazole structure and increases calcium sensitivity and inhibits phosphodiesterase (PDE) activity in cardiomyocytes (myocardial infarction). It can effect on insulin levels. 5 Tetrahydroimidazo [1,4,5]benzodiazepine-2-(1H)-one 1 (Figure 1), is used in the treatment of HIV and is more selective. 6 Benzoimidazole and its derivatives are present in RNA. Some of them, are found in the photosynthesis of plants. 7 Omeprazole 2, a derivative of benzimidazole, is used to treat duodenal ulcers. 8 The benzimidazole derivative 3 is known as an anticoagulant. 9 Benzimidazole compounds protect the skin from ultraviolet rays. Therefore, they are used in the health industry. They are used in the textile industry as moisturizers, emulsifiers, foaming agents and dispersants. A number of amino benzimidazoles are used to make sulfuro azo dyes in the textile industry. 10 The first benzimidazole (2,6-dimethylbenzimidazole) was synthesized in 1872 by Huberker via reduction of 2-nitro-4-methyl acetanilide. Later, Ladenberg synthesized a similar compound by refluxing of 3,4-diaminotoluene with acetic acid. Despite of the importance of benzimidazoles in pharmaceutical, agricultural, industrial, etc., it has limited two methods for the synthesis of them. The first method is the condensation of 1,2-diaminobenzene with carboxylic acids or their derivatives (nitriles, imidates or orthoesters) which often requires strong acidic conditions and sometimes high temperatures or microwave irradiation. The second method is the condensation reaction of orthophenylenediamine with aldehydes in acidic conditions. [11][12][13][14] Nanoparticles have been applied in many interesting fields including bio-nanoscience, optics, electronics, drug delivery, medicine, solar cells and catalysts. [15][16][17][18][19] Among all nanoparticle types, magnetic (Fe 3 O 4 ) has attracted more attentions because of its unique magnetic properties, low toxicity, facile magnetically removal, chemically modifiable surface and biocompatibility. 20-22 Therefore, applications of these magnetic nanoparticles (MNPs) have been developed in magnetic resonance imaging, contrasting reagents, cancer treatment, targeted drug delivery, tissue repairing, magnetic storage media, biosensing, magnetic inks for jet printing, and catalysis. 23 However, having anisotropic dipolar attraction, MNPs trend to be aggregated easily in aqueous solutions. 24 In order to prevent them from self-aggregation and oxidation, MNPs are shielded by a suitable coating through surface functionalization using organic/bio molecules. 25 The existence of hydroxyl functional groups on silica shell surface supply suitable sites for possible conjugation of varies function scaffolds. Therefore, synthesis of Fe 3 O 4 @SiO 2 nanostructures is of interest. Thiamin, also known as thiamin or vitamin B 1 , is a vitamin found in food and manufactured as a dietary supplement and medication. Its low cost, abundance, hydrophilicity, biodegradability and good solubility in water have grabbed profound attention. Moreover, the presence of amine and hydroxyl functional groups provides suitable structure to conjunction to various organic, bioorganic and inorganic material.
In the continuation of our interest to synthesize heterocyclic and pharmaceutically active compounds and to the preparation of new organic-inorganic and organometallic catalysts, [26][27][28][29][30] herein, we decided first to synthesize a novel separable and heterogeneous Fe 3 O 4 @SiO 2 @vanillin/thiamin magnetic nanoparticles ( Figure 2) and applied it as a green, effective and new nanocatalyst and bronsted acid for the synthesis of 1H-benzo[d]imidazol-2-yl-4-(aryldiazenyl)phenol derivatives

Synthesis and characterization
For the synthesis of Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin, initially, Fe 3 O 4 Nps were prepared based on our previous work. Fe 3 O 4 MNPs were covered by a silica layer to prevent the oxidation of nano magnetic. (Z)-3-((4-((2-hydroxy-4-methoxybenzylidene)amino)-2-methylpyrimidin-5yl)methyl)-5-(2-hydroxyethyl)-4-methylthiazol-3-ium (vanillin/thiamin) was synthesized based on routine method for imine synthesis via the reaction between 1 mmol of vanillin and 1 mmol of thiamin (vitamin B1). Then, the hydroxy groups of phenol in vanillin/thiamin treated with Cl moiety of Fe 3 O 4 @Silicapropyl-Cl to synthesize Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin ( Figure 2). To the best of knowledge, this is the first report for the synthesis of Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin. The entry of vitamins into the structure of nanocatalysts has not been done in this way before. As a result, it increases the biological properties of nanocatalysts.
In the FT-IR spectrum of synthesized Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin NPs (Figure 3), the adsorption peak at 3500 cm À1 , 1382 cm À1 , 1016 cm À1 and 568 cm À1 are corresponded to O-H stretching, C-N stretching, C-O stretching and Fe-O stretching vibrations, in order. The other peaks at 1660 cm À1 , 1612 cm À1 , 1477 cm À1 are related to C ¼ N or C ¼ C aromatic stretching vibrations and stretching vibrations of Si-O-Si are appeared at 1149 cm À1 and 777 cm À1 . CH 2   overlapped with nano-Fe 3 O 4 . Using the Scherrer's equation, the mean diameter of nanoparticles was calculated 33 nm.
for CuKa), k is the wavelength of X-ray, b is the full width at half maximum (FWHM), and ⍜ is the diffraction angle.
As shown in Figure 6, the presence of elements as carbon, iron, silica, nitrogen, sulfur and oxygen has proven the synthesis of Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin. The atom % and weight % of elements are shown in Table 1.
The TGA-DTG analysis showed the stability of nanocatalyst and the presence of organic moiety in the structure of this catalyst. There are three weight loss steps in this curve. The first step is related to a weight loss up to 113 C due to the dehydration process and elimination of solvent (35.6%). The second and the third weight loss is at the range of 253-524 C is related to the elimination of vanillin and thiamin (vitamin B1) anchored on to the surface of Nps (Figure 7).
The vibrating sample magnetometry (VSM) analysis of Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin were investigated at room temperature under nitrogen atmosphere. As can be seen in Figure 8, the saturation magnetization (Ms) values for the Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin is 14 emu/g. Magnetization curves show that the nanocatalysts is superparamagnetic.

Catalytic application
Initially, we control the optimized conditions for the condensation of 1,2-diaminobenzene and azolinked salicylaldehyde as a model reaction. As shown in Table 2, various catalysts have different results (reaction time and yield) for the synthesis of sample product (Table 2, entries 2-11). The reaction in the absence of catalyst lead to no product after 24 hours ( Table 2, entry 1). The effect of  Table 2, entries [11][12][13][14][15]. Increasing the catalyst amount up to 0.05 g is sufficient to push the reaction forward. The higher amount of catalyst has no efficiency for the reaction time (Table 2, entries 12, 16 and17).
With the optimized reaction parameters, the synthesis of various derivatives of 1H-benzo[d]imidazol-2-yl-4-(aryldiazenyl)phenol and bis benzo[d]imidazoles were checked. As shown in Table 3, All of starting material were treated with 1,2-diaminobenzene in this condition with high yield and short reaction time.
For comparison of this work with literature, synthesis of 5a was selected as model reaction. The results are summarized in Table 4. This synthesized nanocatalyst lead to synthesis of new derivatives of benzo[d]imidazoles in shorter reaction time and higher yield in nontoxic solvent instead of CHCl 3 , DMF, toluene and 1,4-dioxane. The catalyst is nanodimension and low quantity of it is enough for reaction promotion. Another benefit is that the catalyst is magnetically recoverable.
The reusability of catalyst was assessed. The catalyst is magnetically recoverable for 7 runs without the decrease in efficiency. The SEM and TEM image of reused catalyst in the 7th run was released in Figure 9 and Table 5.

Material and method
The XRD, TEM, SEM and TGA analysis for synthesized MNPs were analyzed on X-PRTPRO (Netherlands) X-ray diffraction (XRD), TEM Jeol model 3010, Philips XL 30 scanning electron microscope (SEM, Netherlands) and Q600 (made in America) instrument, respectively. FT-IR      7c -6 1 2 9 5 a Isolated yield. b The reactions were carried out in the presence of 0.05 g of Fe 3 O 4 @Silicapropyl@Vanillin/Thiamin in 10 mL water.

General procedure for the synthesis of benzo[d]imidazoles
In a flask, 1.0 mmol of aldehyde (1a: 0.285 g; 1 b: 0.260 g; 1c: 0.260 g; 1d: 0.226 g; 1e: 0.257 g; 2a: 0.298 g; 2 b: 0.312 g; 2c: 0.328 g; 3a: 0.358 g; 3 b: 0.372 g; 3c: 0.384 g), 1 mmol of 1,2-diamino benzene (0.108 g) and 0.05 g Fe 3 O 4 @SiO 2 -pr@vanillin/thiamin MNPs were stirred at room temperature in 10 mL of distilled water for required reaction time as shown in Table 3. At the end of the reaction, the resulting mixture was filtered in the presence of an efficient magnetic bar to separate the catalyst. The crude products were recrystallized from ethanol. All of synthesized products were identified by comparison of mp, IR and NMR.

Conclusion
In conclusion, a new catalytic approach for the synthesis of benzo[d]imidazoles has been developed. This method offers several advantages, such as simple work-up and purification procedure without the use of any chromatographic method, mild reaction conditions, use of inexpensive and commercially available starting materials, recyclability and reusability of the catalyst, high product yields and short reaction time. So we think that this procedure could be considered a new and useful addition to the present methodologies in this area.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
Financial support from the Research Council of Payame Noor University of Rasht branch is sincerely acknowledged.