MnO2 Nanoparticles as Efficient Oxidant for Ultrasound-Assisted Synthesis of 2-substituted Benzimidazoles under Mild Conditions

In this article, a novel method for synthesis of 2-substituted benzimidazoles using MnO2 nanoparticles as a convenient oxidant agent in ethanol-water (1:1) as solvent under ultrasound irradiation was demonstrated. In this protocol the desired products were purely obtained in high yields. The main advantages of this research are: mild procedure, simplicity of method, easily work-up, high yields, and short reaction times. The MnO2 nanoparticles were synthesized through a solid-state reaction route using simple strarting materials. Furthermore, their structure was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR).


INTRODUCTION
The benzimidazole ring system is an important class of bioactive molecules in modern drug discovery and pharmaceutical. Benzimidazole and its derivatives have been applied as anti-parasitic, fungicide, anti-histaminic, anti-tumor,

EXPERIMENTAL Materials and Apparatus
All commercially available reagents were used without further purification and purchased from the Merck Chemical Company in high purity. The used solvents were purified by standard procedure. IR spectra were recorded as KBr pellets on a Perkin-Elmer 781 spectrophotometer and an Impact 400 Nicolet FT-IR spectrophotometer. 1 H NMR and 13 C NMR were recorded in DMSO and CDCl 3 solvents on a Bruker DRX-400 spectrometer with tetramethylsilane as internal reference. The BANDELIN ultrasonic HD 3200 with probe model KE 76, 6 mm diameter, was used to produce ultrasonic irradiation and homogenizing the reaction mixture. X-ray diffraction (XRD) analysis of the MnO 2 nanoparticles was conducted on a Rigaku D/max-2000 X-ray powder diffractometer with a CuKa radiation (40 kV, 250 mA) scanned over the 2 h range of 10-90 o . Melting points obtained with a Yanagimoto micro melting point apparatus are uncorrected. The purity determination of the substrates and reaction monitoring were accomplished by TLC on silica-gel polygram SILG/UV 254 plates (from Merck Company). O with a mole ratio of 1:1.2 were mixed and well ground in a mortar at room temperature. In the grinding process, the solid-state reaction took place, accompanying with the hydrated water releasing gradually from the starting materials. Ground for 40 min, the wet mixture was transferred to a thermostatic water bath of 80 • C for several hours, and then a dry mixture was obtained. The mixture was washed with distilled water to remove the dissoluble substances, and dried in an oven at 110 • C for 10 h, and then a white MnC 2 O 4 precursor was obtained. The precursor was calcined in atmosphere at 400 • C in a muffle furnace at 10 h for oxidative decomposition. Afterwards, the calcined product (manganese oxide) was subjected to acid-treatment in 2 mol L −1 H 2 SO 4 solution at 80 • C for 2 h under magnetic stirring, in order to increase its degree of oxidation. After that, the product was washed thoroughly with distilled water, filtered, and dried at 105 • C, and then a final product (MnO 2 material) was obtained.

General Procedure for the Synthesis of Benzimidazoles from o-Phenylenediamine
To a mixture of an aromatic aldehydes (1 mmol), o-phenylenediamine (1 mmol) and 0.017 g (20 mol%) of MnO 2 nanoparticles were added to EtOH/H 2 O (1:1) as solvent, then ultrasonic probe was directly immersed in the reactor. The progress of the reactions was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and MnO 2 nanoparticles were collected by filtration. Then, the reaction mixture was added drop wise into a mixture of water and ice, so the crude solid were filtered off and washed with water. The product was purified by recrystallization from methanol/H 2 O (1:1). They were characterized by comparison of their physical and spectral data with those of authentic samples.

RESULTS AND DISCUSSION
In this article, a convenient method and efficient oxidant agent for the synthesis of 2-substituted benzimidazoles are described. We studied the model reaction involving o-phenylenediamine and aryl aldehyde derivatives 1a-n in a 1:1 mole ratio to afford the 2-substituted benzimidazole derivatives 2a-n (Scheme 1). Initially, we prepared MnO 2 nanoparticles according to the procedure reported by Yuan et al. (34) and it was successfully used as oxidizing agent in the synthesis of benzimidazole derivatives. The FT-IR spectra of MnO 2 nanoparticles are shown in Figure 1.
The oxides and hydroxides of metal nanoparticles generally gives absorption peak in the finger print region, i.e., below wavelength of 1000 nm arising from inter-atomic vibrations. Herein, the band at 527 cm −1 could be attributed to Mn-O stretching vibrations mode in MnO 6 octahedral (35). From the above results it was concluded that the synthesized nanomaterial was manganese oxide. The band at the 3428 cm −1 should be attributed to the -OH stretching vibration in KBr pellet, and the band at the 1630 cm −1 is usually related to the interaction of -OH with Mn atoms.
X-ray diffraction (XRD) pattern of the mechanochemically synthesized MnO 2 is shown in Figure 2. The diffraction angle and intensity of the characteristic peaks of the samples is consistent with that of the standard JCPDS card no. 14-0644. Also the XRD spectrum consists with the characteristics peaks of MnO 2 nanoparticles at 22.153 (1 0 1), 37.014 (2 1 0), 42.424 (2 1 1), and 55.982 (4 0 2), which are similar to the γ-MnO 2 reported in the literature (36). The value of 17 nm was calculated from XRD data for average particle size of this crystalline MnO 2 using Scherrer's equation (37).  As well as, scanning electron microscopy (SEM) micrograph of the MnO 2 nanoparticles is shown in Figure 3. It can be observed that the particles are almost 35.5-46.3 nm.
In order to the optimization of this procedure, the reaction was carried out for synthesis of 4-chlorobenzimidazole by using different solvents and various      Table 1 and Table 2, respectively. As can be seen in Table 1, the best solvent in the reaction was obtained H 2 O/EtOH (1:1) in optimum amount of 20 mol% MnO 2 nanoparticles as oxidative agent. The reaction was initially accomplished without oxidative agent, and it was obtained any product ( Table 2, entry 1). However, the sonochemical synthesis of benzimidazole derivatives using MnO 2 nanoparticles as an oxidant agent (20 mol%) were obtained the best result (Table 2, entry 4). Using lower amount of oxidant agent resulted in lower yields, while higher amounts did not affect on the reaction times and yields.

Synthesis of Benzimidazoles Catalyzed by MnO 2 NPs 497
In continuation of this research, the effect of various powers of ultrasonic irradiation has been investigated. First, it was synthesized 4chlorobenzimidazole as model reaction in order to optimize the best suited reaction conditions. It was observed that the reaction in the presence of MnO 2 as oxidant agent and ultrasonic irradiation with power 55 W were afforded the best result as obtained product with 85% isolated yield during 4 min ( Table 3, entry 4).
The effects of ultrasonic irradiation observed during organic reactions are due to cavitations. In the case of volatile molecules cavities are believed to act as a microreactor as the volatile molecules enter the microbubbles and the high temperature and the pressure produced during cavitations break their chemical bonds thus reacting with other species (38)(39)(40).
At last, the reaction of o-phenylenediamine with various aryl aldehydes was carried out according to the general experimental procedure. In all the cases, the corresponding benzimidazoles were obtained in good to high yields and short reaction times. The similar products are summarized in Table 4.
It was generally observed that the presence of electron withdrawing groups in the aromatic ring of benzaldehye enhances the reaction yield with reduced reaction time. This result can be attributed to higher electrophilicity of the carbonyl carbon in the presence of electron withdrawing substituent which is an essential condition for first step of condensation. On the other hand, the aromatic aldehydes with electron donating groups in this reaction were relatively Scheme 2: The proposed mechanism for preparation of benzimidazoles using MnO 2 nanoparticles.  produced the benzimidazoles in high yield and short reaction times due to the stabilization of intermediate benzimidazoline by these substituents. The proposed mechanism for preparation of benzimidazole using MnO 2 nanoparticles. First, the condensation of o-phenylenediamine and aryl aldehydes leads to the formation of unstable intermediate benzimidazoline with removal of a H 2 O molecule. Then, the reaction proceeds in the presence of MnO 2 nanoparticles using a radical mechanism, in accordance to the a, b, c, and d steps and removal of Mn(OH) 2 , the benzimidazole can be prepared (Scheme 2).

CONCLUSIONS
We described preparation and application of MnO 2 nanoparticles as a readily available, inexpensive, and efficient oxidant agent for the one-pot synthesis of benzimidazole derivatives. They were prepared by using of ophenylenediamine with various aromatic aldehydes in water/ethanol as solvent at 50 W under sonication. The advantages of this procedure are operational simplicity, high product yields, short reaction time, availability of catalyst and cost effective.