Nanocrystalline magnesium oxide as solid base catalyst in the presence of iodine promoted one-pot synthesis of 2-substituted benzimidazole derivatives under mild conditions

Abstract

An efficient single-step procedure for the synthesis of 2-substituted benzimidazole derivatives by nanocrystalline magnesium oxide as solid base catalyst under acetonitrile solvent at room temperature has been developed. The worldwide availability, larger scale synthesis, higher yields and shorter reaction times are the advantages of the present method.

Keywords:

• o-phenylenediamine
• benzimidazole
• aldehydes
• nano MgO
• iodine

1. Introduction

Benzimidazole moiety is a structural isostere of naturally occurring nucleotides; hence, it has been extensively utilised as a drug scaffold in the medicinal chemistry. Several promising anti-tumour active agents were found to contain the benzimidazole ring system. They were found to exert their anti-tumour activity by acting mainly as topoisomerases inhibitors,[1–3] anti-angiogenic agents,[4–6] and alkylating agents.[7–9] In addition, the benzimidazole moiety is found in various synthetic pharmaceuticals displaying a broad spectrum of biological activity including anti-ulcer, anti-tumour and anti-viral effects.[10] In the last years, it has been demonstrated that several bi- and ter-benzimidazole derivatives act as topoisomerase inhibitors.

Nanocrystalline oxides are of immense interest to scientist due to their enriched surface chemistry and high surface area. Ultrafine nanocrystallines of alkaline earth metal oxide, such as magnesium oxide, have many applications as catalyst,[11–13] refractory materials,[14] optically transparent ceramic windows,[15,16] etc. In the field of catalyst, MgO has strong basic properties those are associated with catalysts by base in many organic reactions.[17] Asymmetric Henry and Michael reaction,[18] synthesis of organic carbonates,[19] aldol condensation,[20] etc., are some of the well-studied reactions those are catalysed by MgO nanoparticles. In recent years, I₂ has also been used extensively as a synthetic reagent due to its inherent properties of low toxicity, electrophilicity and easy handling.[21]

In continuation of our ongoing research on synthesis of benzimidazoles,[22] herein we wish to report the use of nanocrystallines MgO and I₂ as convenient, mild and efficient reagent for the preparation of benzimidazoles from o-phenylenediamine and aryl aldehydes in acetonitrile solvent at room temperature.

2. Results and discussion

Detailed studies on the reaction of o-phenylenediamine with aryl aldehydes to form 2-substituted benzimidazoles have shown that this nucleophilic addition and condensation reactions are influenced to a considerable extent by the reagent as shown in Scheme 1 and Table 1. To find the effect of solvent on this reaction, several solvents including acetonitrile, dichloromethane, chloroform and methanol were investigated during the course of this study. After screening different solvents, it was found that the best solvent is acetonitrile in this reaction (Table 1, entry 1).

Table 1. Optimisation of solvent effect on the reaction^a.

Entry	Solvent	Time (min)	Yield (%)^b
1	Acetonitrile	30	95
2	Methanol	52	45
3	Chloroform	61	32
4	Dichloromethane	68	28

^aReaction of benzaldehyde with o-phenylenediamine in presence of different solvents.

^bIsolated yields.

Scheme 1. Synthesis of 2-substituted benzimidazoles from o-phenylenediamine and aryl aldehydes in the presence of nanocrystalline MgO/I₂.

A comparison of the catalytic effect of nano MgO with commercial MgO in the reaction was reported in Table 2. As can be seen in the table, nanocrystalline MgO displays a substantial activity in this reaction (Scheme 1) than the commercial MgO under the same condition. Therefore, in this regard, the nanocrystalline MgO should be having more reactive sites than commercial MgO (irregular morphology with a surface area of 27 m²/g) and consequently higher agent activity. In addition to the above mentioned and with attention to the special structure of nanocrystalline MgO, it seems that the organic species should be able to diffuse faster on the surface of this solid agent rather than the commercial MgO.

Table 2. Survey of nanocatalyst effect in the reaction.

Entry	Reagent	Time (min)	Yield (%)
1	MgO	47	23
2	Nanocrystalline MgO	30	95

The crystallinity and sizes of nano MgO were evaluated by X-ray diffraction (XRD) technique before and after used as a catalyst (Figure 1). The obtained crystallite sizes were between 12.8 and 17.5 nm that were determined by the use of the Scherrer equation, indicative of the nanocrystalline structure of the prepared MgO. Also, it was studied the XRD pattern of catalyst after six consecutive cycles for the synthesis of benzimidazoles. As can be seen in the figure, the crystallinity and sizes of catalyst were retained during the reaction process. This result can be confirmed by the proposed reaction mechanism.

Figure 1. XRD pattern of MgO nanocrystalline: (a) before using and (b) after six trials.

The surface area of MgO nanocrystallines was approximately 116 m²·g⁻¹. The pore volume and pore size were also calculated from the N₂ adsorption result; the pore size was approximately 21.1 nm and the pore volume was approximately 0.69 cm³·g⁻¹. The theoretical particle size was also calculated from the surface area, assuming spherical particles, from the equation,(1) where D_BET is the equivalent particle diameter in nanometres, ρ is the density of the material in g·cm⁻³ and S is the specific surface area in m²·g⁻¹. The particle size calculated from Equation (1) was 14.4 nm, which confirmed the nanostructure of the MgO sample.[23] The transmission electron microscopic (TEM) image of MgO is shown in Figure 2. As can be seen, the sample has a nanocrystalline structure with a plate-like shape. Also, dispersity and surface morphology of the catalyst were studied by scanning electron microscopy (SEM) technique (Figure 3). The SEM analysis displayed that the MgO has a morphology of well-dispersed nanosheets.

Figure 2. TEM image of nanocrystalline MgO.

Figure 3. SEM image of nanocrystalline MgO.

Subsequent efforts were focused on optimising conditions to form the benzimidazole by using different amounts of nanocrystalline magnesium oxide at room temperature (Table 3).

Table 3. Optimising amount of nanocrystalline MgO.

Entry	Amount of nanocrystalline MgO/g	Time (min)	Yield (%)
1	0.1	30	68
2	0.14	30	77
3	0.16	30	86
4	0.18	30	95
5	0.2	30	95

As indicated in the table, the reaction showed an improvement in yield when using 0.18 g nanocrystalline MgO as an agent at room temperature (entry 4 in Table 3). A ratio of 1:1.2:1:1 of nanocrystalline MgO/I₂/aryl aldehyde/1,2-phenylendiamine was found to be the optimum amount for the reaction.

Regarding the mechanism of reaction, it probably involves the formation of [MgOI]⁺I⁻ by the reaction of nano MgO with iodine molecule, which then reacts with the cyclic hydrobenzimidazoles 1 to afford intermediate 2 followed by the abstraction of hydrogen to yield the corresponding benzimidazoles (Scheme 2).

Scheme 2. Proposed mechanism for synthesis of 2-substituted benzimidazole derivatives using nanocrystalline MgO system.

In ascertain and limitation of this methodology, the reaction of o-phenylenediamine with various aldehydes in the presence of nano MgO/I₂ occurred. The results are summarised in Table 4. From the table, it was seen that the beneficial and useful benzimidazole derivatives were obtained from different aldehydes in optimised reaction conditions in excellent yields and short reaction times. The nanocrystalline MgO as a heterogeneous catalyst could be recycled through simple filtration after the reaction. Then, the recovered catalyst was used in the reaction by several runs (Figure 4). However, the results indicate that the product yields were slightly decreased in the reaction processes. Moreover, reusability of the catalyst can be another interesting eco-friendly aspect of this reaction.

Table 4. Reaction of various aryl aldehydes with o-phenylenediamine.

Entry	Substrate	Product^a	Time (min)	Yield (%)^b
1			35	94
2			30	95
3			29	93
4			32	94
5			33	92
6			27	95
7			28	96
8			29	97
9			35	94
10			34	95
11			32	93
12			35	93
13			31	94
14			35	92
15			36	95
16			33	94

^aAll compounds are known and their physical and spectroscopic data were in good agreement with those of authentic samples.

^bYields refer to pure isolated products.

Figure 4. Yields obtained by recycled nano MgO catalyst.

The structure of products has been confirmed by physical and spectroscopic data such as infrared (IR), hydrogen nuclear magnetic resonance (¹H NMR) and carbon nuclear magnetic resonance (¹³C NMR). In the IR spectra, the stretching frequency of aromatic C=C is formed in the region and ν = 1429–1600 cm⁻¹. The stretching vibration of C–H in the alkyl groups was appeared at region and ν = 2903–3059 cm⁻¹. In the ¹H NMR spectra, one proton of N–H has chemical shift in δ = 7.1–15.2 ppm. The signals around δ = 6.84–9.1 ppm are assigned by protons of CH=CH of aromatic rings. In the ¹³C NMR spectra, one carbon of C=N has chemical shift in δ = 148.9–151 ppm.

3. Experimental section

3.1. Materials

All the materials were of commercial reagent grade. The aromatic aldehydes and o-phenylenediamine were purified by standard procedures and the purity was determined by thin layer chromatography (TLC).

3.2. Apparatus

The IR spectra were recorded as KBr pellets on a Perkin-Elmer 781 spectrophotometer and an Impact 400 Nicolet Fourier transform infrared spectrophotometer. The ¹H NMR and ¹³C NMR were recorded in dimethylesulfoxide (DMSO) solvent on a Bruker DRX-400 spectrometer with tetramethylsilane as internal reference. The melting points obtained with a Yanagimoto micro melting-point apparatus are uncorrected. The XRD analysis was performed with an X-ray diffractometer (PAnalytical X’Pert-Pro) using a Cu–Ka monochromatic radiation source and a Ni filter. The TEM was performed with a Jeol JEM- 2100UHR, operated at 200 kV. The purity determination of the substrates and reaction monitoring were accomplished by TLC on silica-gel polygram SILG/UV 254 plates (from Merck Company).

3.3. Preparation of nanocrystalline MgO

Nanocrystalline MgO was prepared by means of a procedure reported elsewhere.[23] In short, poly(vinyl alcohol) (PVA, MW 70,000) was dissolved in water at 90 °C under vigorous stirring to form a transparent solution. Mg(NO₃)₂ 6H₂O was dissolved in water containing PVA. The metal ion-to-PVA monomer unit molar ratio was chosen as 1:3. Aqueous ammonia (25% w/w) was added drop wise at room temperature to the resulting viscous liquid mixture, with rapid stirring, to achieve careful pH adjustment to 10.5. After precipitation, the slurry was stirred for another 30 min and then heated under reflux at 80 °C for 20 h under continuous stirring. The mixture was cooled to room temperature, filtered and washed with hot deionised water for effective removal of the PVA. The final product was dried at 80 °C for 24 h and calcined at 700 °C.

3.4. General experimental procedure for the tandem reaction

In a round-bottomed flask (50 mL) equipped with a magnetic stirrer, a solution of o-phenylenediamine (1.0 mmol), and aryl aldehyde (1.0 mmol) in MeCN (5 mL) was prepared. Nanocrystalline MgO (5.0 mmol) and solid I₂ (3 mmol) were added and the mixture was stirred at room temperature for the time indicated in Table 4. The progress of the reaction was monitored by TLC (eluent: ether–EtOAc, 8:4). When the starting materials had completely disappeared, the mixture was quenched by adding H₂O (10 mL), extracted with CHCl₃ (4 × 12 mL) and the combined extracts were dried in CaCl₂. The filtrate was evaporated and the corresponding benzimidazole was obtained as the only product (Table 4). The selected characterisation data for some of the prepared benzimidazoles are given below.

2-(3-Methoxyphenyl)-benzimidazole: yellow solid; mp = 200–202 °C (mp = 205–206 °C);[24] IR (KBr)/ ν (cm⁻¹) 3437 (NH), 1596 (C=N), 1541, 1464 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 3.9 (3H, s, Me), 7.05 (1H, m, Ar), 7.19 (2H, m, Ar), 7.45 (1H, s, Ar), 7.59 (2H, m Ar), 7.74 (2H, m, Ar), 12.9 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 56.0, 114.0, 115.2, 116.5, 117.8, 124.5, 130.5, 132.6, 139, 152.2, 159.1.

2-Phenyl-benzimidazole: pale yellow solid; mp. = 289–290 °C (mp = 288–290 °C);[25] IR(KBr)/ν (cm⁻¹) 3446 (NH), 1622 (C=N),1590, 1445 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.19 (2H, m, Ar), 7.48–7.64 (5H, m, Ar), 8.17 (2H, m, Ar), 12.9 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 111.1, 118.6, 121.9, 126.2, 128.6, 129.5, 130.0, 134.8, 143.5, 151.0; MS: m/z: 193 ([M-H]⁺, 100%).

2-(4-Chlorophenyl)-benzimidazole: yellow solid; mp = 290–291 °C, (mp = 291–293 °C);[26] IR (KBr)/ ν (cm⁻¹) 3442 (NH), 1598 (C=N), 1580, 1429 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.2 (2H, m, Ar), 7.50–7.89 (6H, m, Ar), 13 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 113.5, 123.7, 127.6, 128.3, 129.4, 133.4, 138.9, 151.8; MS: m/z: 229.0 (M+H)⁺.

2-(4-Bromophenyl)-benzimidazole: pale yellow solid; mp = 292–293 °C (mp = 250–252 °C);[24] IR (KBr)/ ν (cm⁻¹) 3449 (NH), 1628 (C=N), 1598, 1456 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.53 (2H, m, Ar), 7.83 (2H, m, Ar), 7.95 (2H, d, Ar, J = 4.8 Hz), 8.28 (2H, d, Ar, J = 4.8 Hz); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 102.5, 121.5, 141.6, 127, 128.1, 130.4, 138.2, 150.2.

2-(2-Chlorophenyl)-benzimidazole: yellow solid; mp = 231–233 °C, (mp = 232–234 °C);[27] IR (KBr)/ ν (cm⁻¹) 3444 (NH), 1591 (C=N), 1575, 1440 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.2 (2H, m, Ar), 7.50–7.89 (6H, m, Ar), 12.9 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 116.0, 122.7, 127.9, 130.4, 130.8, 131.6, 132.2, 132.5, 139.5, 149.6; MS: m/z: 228.5 (M⁺).

2-(2,3-Dichlorophenyl)-benzimidazole: yellow solid; mp = 224–226 °C, (mp = 224–226 °C);[22] IR (KBr)/ ν (cm⁻¹) 3095 (NH), 1624 (C=N), 1540, 1433 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.2 (2H, m, Ar), 7.53 (1H, m, Ar), 7.64 (2H, m, Ar), 7.82 (2H, m, Ar), 12.8 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 115.9, 122.9, 128.9, 130.5, 131.3, 132.1, 132.9, 133.2, 139.3, 149.1.

2-(3-Nitrophenyl)-benzimidazole: yellow solid; mp = 309–310 °C, (mp = 310–311 °C);[25] IR (KBr)/ ν(cm⁻¹) 3308 (NH). 1630 (C=N), 1531, 1482 (C=C, Ar); ¹H NMR (DMSO, 400MHz)/ δ ppm: 7.47 (2H, m, Ar), 7.79 (2H, m, Ar), 7.92–7.95 (1H, m, Ar), 8.1–8.9 (2H, m, Ar), 9.1 (1H, s, Ar), 10.1 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 113.3, 121.2, 122.7, 125.2, 130.3, 132.1, 133.6, 139, 147.5, 152.7; MS: m/z: 238 ([M-H]⁺, 100%).

2-(4-Nitrophenyl)-benzimidazole: pale yellow solid; mp = 307–309 °C (mp = 312–314 °C);[28] IR (KBr)/ ν (cm⁻¹) 3421 (NH), 1606 (C = N), 1524, 1451 (C = C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.51–7.54 (2H, m, Ar), 7.83 (2H, m, Ar), 8.47 (2H, d, Ar, J = 8.4 Hz), 8.48–8.64 (2H, d, Ar, J = 8.4 Hz), 8.4 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 114.5, 121.7, 127.9, 128.7, 130.5, 137.2, 140.9, 152.8; MS: m/z: 239 (M⁺).

2-(2-Hydroxyphenyl)-benzimidazole: white solid; mp = 238–240 °C (mp = 240–242 °C);[29] IR (KBr)/ ν (cm⁻¹) 3325 (OH), 3055 (NH), 1593 (C=N), 1530, 1491 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 6.99–7.05 (2H, m, Ar), 7.27 (2H, m, Ar), 7.37 (1H, t, Ar), 7.66 (2H, m, Ar), 8.06 (1H, m, Ar), 13.19 (1H, s, OH), 13.19 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 112.1, 113.1, 117.7, 119.6, 123.3, 126.7, 132.2, 141.2, 152.2, 158.6; MS: m/z: 210 (M⁺).

2-(N,N-dimethylphenyl)-benzimidazole: yellow solid; mp = 293–295 °C (mp = 294.2–296.3 °C);[30] IR (KBr)/ ν (cm⁻¹) 3391 (NH), 1605 (C=N), 1518, 1459 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 6.84 (2H, d, Ar, J = 7.8 Hz), 7.43 (2H, m, Ar), 7.70 (2H, m, Ar), 8.21 (2H, d, Ar, J = 7.8 Hz), 15,2 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 39.5, 107.8, 111.8, 113.2, 125.1, 129.1, 131.5, 149.8, 153.2.

2-(4-Hydroxyphenyl)-benzimidazole; white solid; m.p = 254–255 °C (mp = 254.1–256.6 °C);[30] IR (KBr)/ ν (cm⁻¹) 3383 (OH), 3202 (NH), 1668 (C=N), 1600, 1457 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 6.91–7.50 (4H, m, Ar), 7.73–8.21 (4H, m, Ar), 9.7 (1H, s, OH), 15.2 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 113.0, 114.0, 116.9, 126.0, 131.6, 132, 149.9, 160.7.

2-(4-Methylphenyl)-benzimidazole: white solid; mp = 260–261 °C, (mp = 261–263 °C);[27] IR (KBr)/ ν (cm⁻¹) 3429 (NH), 1620 (C=N), 1587, 1433 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 2.36 (3, s, Me) 7.18 (2H, m, Ar), 7.34 (2H, d, Ar, J = 8.0 Hz), 7.57 (2H, m, Ar), 8.06 (2H, d, Ar, J = 8.0 Hz), 12.8 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 21.4, 115.5, 122.4, 125.9, 127.9, 130, 139, 140.0, 151.9.

2-(2-Nitrophenyl)-benzimidazole: pale yellow solid; mp = 212–214 °C (mp = 209–210 °C);[28] IR (KBr)/ ν (cm⁻¹) 3428 (NH), 1622 (C=N), 1530, 1458 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 7.54–7.57 (2H, m, Ar), 7.85–7.87 (2H, m, Ar), 7.99 (1H, t, Ar), 8.05 (1H, m, Ar), 8.12 (1H, d, Ar, J = 7.6 Hz), 8.37 (1H, d, Ar, J = 8.0 Hz), 13 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 114.5, 121.7, 127.9, 128.7, 130.5, 137.2, 140.9, 152.8. MS: m/z: 239 (M⁺).

2-(3-Hydroxyphenyl)-benzimidazole: yellow solid; mp = 245–247 °C, (mp = 245–247 °C);[22] IR (KBr)/ ν (cm⁻¹) 3434 (OH), 3243 (NH), 1588 (C=N), 1541, 1445 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 6.9 (1H, d, Ar, J = 5.6 Hz), 7.18 (2H, m, Ar), 7.33 (1H, t, Ar), 7.59 (4H, d, Ar, J = 6.6 Hz), 12.9 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 113.9, 115.6, 117.6, 117.8, 122.6, 130.5, 131.9, 139.9, 151.9, 158.3.

2-(2,5-Dimethoxyphenyl)-benzimidazole: yellow solid; mp = 197–198 °C, (mp = 197–198 °C);[22] IR (KBr)/ ν (cm⁻¹) 3408 (NH), 1622 (C=N), 1511, 1458 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 4.02 (3H, s, Me), 3.85 (3H, s, Me) 7.33 (2H, d, Ar, J = 6.0 Hz), 7.55 (2H, m, Ar), 7.89 (2H, m, Ar), 8.02 (1H, s, Ar), 15 (1H, s, NH); ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 56.7, 57.0, 11.2, 114.4, 114.6, 114.6, 122.2, 126.3, 131.7, 146.1, 152.6, 153.8.

2-(4-Methoxyphenyl)-benzimidazole: yellow solid; mp = 229–230 °C, (mp = 229.2–231.1 °C);[30] IR (KBr)/ ν (cm⁻¹) 3344 (NH), 1608 (C=N), 1506, 1461 (C=C, Ar); ¹H NMR (DMSO, 400 MHz)/ δ ppm: 3.89 (3H, s, Me), 7.2 (2H, d, Ar, J = 8.0 Hz), 7.52 (2H, m, Ar), 7.79 (2H, m, Ar), 8.38 (2H, d, Ar, J = 8.0 Hz), 15.3 (1H, s, NH).; ¹³C NMR (DMSO, 100 MHz)/ δ ppm: 56.2, 114.1, 115.3, 115.5, 126.0, 130.6, 132, 148.9, 163.6.

4. Conclusion

We have reported an efficient and novel method for the synthesis of 2-substituted benzimidazoles from o-phenylenediamine and aryl aldehydes in the presence of nanocrystalline MgO/I₂ in CH₃CN. The corresponding products have been obtained in excellent yields, high purity and short reaction times. The obtained benzimidazoles have been characterised by physical and spectroscopic data such as UV, IR, ¹H NMR and ¹³C NMR spectroscopy.

Acknowledgements

The authors are grateful to University of Kashan for supporting this work by Grant No. 159148/10.