ISRN Organic ChemistryVolume 2013 (2013), Article ID 453682, 7 pageshttp://dx.doi.org/10.1155/2013/453682

Research Article

A Simple, Efficient Synthesis of 2-Aryl Benzimidazoles Using Silica Supported Periodic Acid Catalyst and Evaluation of Anticancer Activity

Vyankat A. Sontakke,¹ Sougata Ghosh,² Pravin P. Lawande,¹ Balu A. Chopade,² and Vaishali S. Shinde¹

¹Garware Research Centre, Department of Chemistry, University of Pune, Pune 411007, India²Institute of Bioinformatics and Biotechnology, University of Pune, Pune 411007, India

Received 14 March 2013; Accepted 3 April 2013

Academic Editors: D. K. Chand, G. Gattuso, and J. C. Menéndez

Copyright © 2013 Vyankat A. Sontakke et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

A new, efficient method for the synthesis of 2-aryl substituted benzimidazole by using silica supported periodic acid (H₅IO₆-SiO₂) as a catalyst has been developed. The salient feature of the present method includes mild reaction condition, short reaction time, high yield and easy workup procedure. The synthesized benzimidazoles exhibited potent anticancer activity against MCF7 and HL60 cell lines.

1. Introduction

The benzimidazole nucleus is commonly present in a large number of natural products as well as pharmacologically active compounds [1]. It shows a wide spectrum of biological and pharmacological properties such as antifungal [2], antimicrobial [3], anthelmintic [4, 5], antiviral [6, 7], topoisomerase inhibition [8] and anticancer activities [9]. Some of their derivatives are marketed as antifungal drug (Carbendazim) [10], anthelmintic drug (Mebendazole and Thiabendazole) [11], antipsychotic drug (Pimozide) [12] and antiulcer agent (Omeprazole) [13]. Owing to their interesting pharmacological properties, great attention has been paid to the synthesis of benzimidazoles. Two main synthetic methods were well known in the literature. The most common method is direct condensation of 1,2-phenylenediamine and carboxylic acids [14, 15] or their derivatives [16], that require strong acidic conditions and sometimes need high temperature or the use of microwave [17]. The other synthetic route involves a two-step procedure that includes the cyclo-dehydrogenation of aniline Schiff’s bases, which are often generated in situ from the condensation of 1,2-phenylenediamines and aldehydes [18], followed by oxidation with stoichiometric amount of oxidants, such as MnO₂ [19], Oxone [20], NaHSO₃ [21, 22], I₂/KI/K₂CO₃/H₂O [23] or catalytic use of CAN [24] and AIKIT-5 [25]. More recently, 2-alkyl substituted benzimidazoles are synthesized by using hexafluorophosphoric acid under microwave condition [26].

There is renewed interest in the silica supported catalyzed reactions [27]. These reactions have relatively shorter reaction time with high yield and cleaner chemistry. Moreover, the catalyst is easily separated from reaction mixture by simple filtration. There are very few reports involving solid supported catalyzed reaction for synthesis of benzimidazole derivatives. Jacob et al. [28] synthesized 1,2-disubstituted benzimidazoles by silica supported ZnCl₂ catalyst that was found to be of poor yield. Patil et al. [29] developed a method for synthesis of 2-alkyl benzimidazoles using silica supported HBF₄. Paul and Basu [30] described the synthesis of 1,2-disubstituted benzimidazoles by using silica gel soaked with Fe₂(SO₄)₃·xH₂O. Recently, Kumar et al. [31] reported silica supported HClO₄ catalyzed synthesis of benzimidazoles.

Periodic acid is an easily available hypervalent iodine reagent which is used in the oxidation of various functional groups [32, 33]. However, there are no reported efforts for the synthesis of benzimidazoles by using periodic acid. In this paper, we report an efficient and facile synthesis of 2-aryl benzimidazoles by using silica supported periodic acid (H₅IO₆-SiO₂) as a catalyst (Scheme 1). Further, all synthesized derivatives were screened for anticancer activity against two cancer cell lines, namely, MCF7 and HL60.

Scheme 1: Synthesis of 2-aryl benzimidazole.

2. Result and Discussion

Herein, we used unprecedented silica supported periodic acid (H₅IO₆-SiO₂) as catalyst for synthesis of 2-aryl benzimidazole derivatives. In our initial experiments, we choose 1,2-phenylenediamine (1 mmol) and m-nitrobenzaldehyde (1 mmol) as a model reaction for optimization of catalyst and reaction conditions. The results are summarized in Table 1. The use of 20 mol% of H₅IO₆ catalyst supported on silica resulted in 95% of desired product, 5 g in 15 min at room temperature (Table 1, entry 1). Inferior yields were obtained on lowering the catalyst loading at room temperature (Table 1, entries 2 and 3). Even, on increasing temperature, the yield was not improved (Table 1, entries 6 to 8). In control experiments, the poor yields were found in the absence of H₅IO₆ (Table 1, entries 5 and 10) at room temperature and 60°C even after prolonged time (10 h). Further, the reactions were carried out with only H₅IO₆ without silica support at room temperature and 60°C (Table 1, entries 4 and 9) where the yield was not found to be more than 35%. These results confirmed that H₅IO₆ supported on silica significantly increased the efficacy of catalysts which may be attributed to the increase in available surface area. Thus, we found optimized conditions as the 1,2-phenylenediamine (1 mmol), aldehyde (1 mmol) and H₅IO₆ (0.20 mmol supported on silica) in acetonitrile (ACN) at room temperature.

Table 1: Reaction of 1 and 4g under various conditionsa.

Entry
Catalyst (mol %) on silica
Temp.b
Time
Yield (%)c

1
H₅IO₆ (20)
rt
15 min
95

2
H₅IO₆ (15)
rt
15 min
70

3
H₅IO₆ (10)
rt
15 min
45

4
H₅IO₆ (20)d
rt
10 h
28

5
SiO₂
rt
10 h
12

6
H₅IO₆ (20)
60°C
15 min
94

7
H₅IO₆ (15)
60°C
15 min
67

8
H₅IO₆ (10)
60°C
15 min
47

9
H₅IO₆ (20)d
60°C
10 h
35

10
SiO₂
60°C
10 h
16

1,2-phenylenediamine 1 mmol, m-nitrobenzaldehyde 1 mmol catalyst (0.20 mmol supported on silica) in ACN. bRoom temperature was 30–35°C. cYields are measured after purification. dH₅IO₆ which is not supported on silica.

Feasibility of the methodology was examined for a series of aryl/heteroaryl aldehydes bearing electron donating as well as electron withdrawing groups under the optimized reaction conditions and corresponding products were obtained in good to excellent yields (Table 2). Presence of electron withdrawing group in aldehyde system fastened the reaction (entries 5f–5h) while opposite effect was observed for electron donating substituents and hindered aldehydes (entries 5b and 5h). We have not observed any remarkable change in the reaction time for the different substituted diamines. The reaction underwent smoothly even with aldehyde bearing two functional groups (entries 5c, 5h, 6c & 7c) and afforded corresponding products in good yields (entry 5h). The reaction was carried out with substituted 1,2-phenylenediamine (entries 6a–6e and 7a–7c) and afforded 2,5-substituted benzimidazoles in moderate to good yields. Using these reaction conditions exclusively formation of 2-substituted benzimidazoles was observed. The products were characterized by their physical and spectral data. Thus, Table 2 illustrates generality and efficiency of this method for the synthesis of benzimidazoles.

Table 2: Synthesis and anticancer activity of 2-aryl benzimidazoles against MCF7 and HL60 cell lines.

Entry
R
R₁
Reaction time (min)
Yielda
IC₅₀ (M)b

MCF7
HL60

5a
H

20
94
35.67
30.73

5b
H

30
90
27.63
28.68

5c
H

18
95
21.81
24.74

5d
H

20
84
27.11
26.71

5e
H

12
89
27.00
25.28

5f
H

16
90
26.25
25.03

5g
H

15
95
24.41
26.33

5h
H

19
78
29.67
26.52

5i
H

20
82
30.42
29.55

6a
COOH

12
91
22.20
24.88

6b
COOH

30
70
23.28
25.09

6c
COOH

18
90
24.51
25.78

6d
COOH

17
78
25.30
30.32

6e
COOH

15
88
17.65
22.10

7a
PhCO

17
91
17.32
19.64

7b
PhCO

22
89
17.32
19.88

7c
PhCO

12
94
17.45
18.13

8
Bisbenzimidazole
35
80
17.44
30.69

Cisplatin
40.45
41.08

1,2-phenylenediamine 1 mmol, m-nitrobenzaldehyde 1 mmol catalyst (0.20 mmol supported on silica) in ACN. Isolated yields after purification. bIC₅₀ 50% inhibition concentration in M.

We have also extended same methodology for the synthesis of bisbenzimidazole (8) derivative by using 1,2-phenylenediamine, aryl aldehyde (2 : 1) affording compound 8 in 80% yield (Scheme 2).

Scheme 2: Synthesis of bisbenzimidazole.

Although the exact mechanism is not clear, a proposed mechanism for the formation of benzimidazole is shown in Scheme 3. The actual oxidant is H₅IO₆-SiO₂ and not SiO₂ as confirmed by our controlled experiments (Table 1). The acidic site of catalyst is anticipated for oxidation [34].

Scheme 3: Plausible mechanism towards the formation of 2-aryl benzimidazole.

3. Anticancer Activity

All the synthesized benzimidazoles were tested for their anticancer activity against two cell lines MCF7 (human breast adenocarcinoma) and HL60 (human promyelocytic leukemia) by MTT colorimetric assay using cisplatin as a standard anticancer drug. The results are expressed as IC₅₀ in μM and summarized in Table 2. Anticancer activity varies with substitution at 5-position of benzimidazole ring. The benzoyl substituted benzimidazole (7a–7c) showed the highest potency against two cell lines, while carboxyl substituted compounds (6a and 6b) were moderately potent (with the exception of 6c), as compared to unsubstituted benzimidazole (5a–5c). Dichloro derivatives (5c and 6c) exhibited more activity as compared to monochloro derivatives (5d and 6d) against MCF7 and HL60. Substitution of nitro group (5e–5g) showed moderate and mostly similar effect for the given cell lines. Compound 5b with phenolic −OH group (IC₅₀ 27.63 μM for MCF7 and 28.68 μM for HL60) was comparable to 5h (IC₅₀ 29.67 μM for MCF7 and 26.52 μM for HL60) which has additional methoxy group at p-position. Replacing ring carbon of benzene ring with nitrogen atom as in 5i (IC₅₀ 30.42 μM) showed better activity against MCF7 when compared with 5a (IC₅₀ 35.67 μM), but same compound did not show substantial difference in activity against HL60. Bis-benzimidazole (8) was found to be more active for MCF7 (IC₅₀ 17.45 μM) than HL60 (IC₅₀ 30.69 μM). All the tested compounds are found to be more effective against both cell lines as compared to cisplatin.

4. Conclusion

We have developed a short and efficient method for the synthesis of 2-aryl benzimidazoles from 1,2-phenylenediamines and aryl aldehydes using H₅IO₆-SiO₂ as catalyst. The mild reaction condition, low cost, easy workup procedure and good to excellent yields as well as the scope for using wide substrates make our methodology a valuable contribution to the existing processes for synthesis of benzimidazole derivatives. Among 18 derivatives, newly synthesized 5-substituted derivatives exhibited excellent activity against MCF7 and HL60 cell lines. The overall activities for all the derivatives tested were found in micromolar range. The current study provides better insight into the designing of more potent anticancer agents in the future.

5. Experimental Section

All reactions were performed in open atmosphere with unpurified reagents and distilled solvents. Periodic acid was purchased from Spectrochem. Acetonitrile and silica (230–400) were purchased from Sigma Aldrich. Thin-layer chromatography (TLC) was performed using 0.25 mm silica gel coated plates. Column chromatography was performed using the hexane: ethylacetate solvent and silica gel (60–120 meshes). ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on Varian Mercury instrument with DMSO-d ₆ or D₂O as the solvents. Chemical shifts were reported in δ unit (ppm) with reference to TMS as an internal standard, and J values were given in Hertz. Melting points were determined on Thomas Hoover capillary melting point apparatus and are uncorrected. IR spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer in KBr disc and expressed in cm⁻¹. Elemental analysis was carried out with Thermo-Electron Corporation CHNS analyzer Flash-EA 1112.

5.1. Cell Culture

Two cancer cell lines, MCF7 (human breast adenocarcinoma) and HL60 (human promyelocytic leukemia), were obtained from National Center for Cell Sciences, India. MCF7 was cultured in DMEM medium [35] while HL60 cells were cultured in a humidified atmosphere (37°C, 5% CO₂) in RPMI1640 medium supplemented with 10% fetal bovine serum.

5.2. MTT Assay

Test compounds were evaluated for anticancer activity against two cancer cell lines using cisplatin as standard anticancer drug. The compounds were evaluated in vitro at a concentration range of 10 μM to 100 μM. The MTT colorimetric assay was used to determine growth inhibition. 100 μL of cell suspension (5 × 10⁶ cells) were plated in 96-well plates and allowed to attach for 24 h. The compounds were dissolved in 0.5% DMSO. Cells were exposed in triplicate wells to these derivatives at various concentrations for 48 h. After 48 h, 20 μL MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution (5 mg/mL) was added to each well. After 1 h of incubation, the solution was centrifuged for 5 min under 4000 rpm, and the medium was discarded carefully. The formazan precipitate was dissolved in DMSO (200 μL), then shaken by oscillator. The absorbance at 570 nm was determined on a microplate reader (Bio-Rad Model 3350, Japan). The absorbance values were used to calculate % inhibition at various concentrations and IC₅₀ values.

5.3. Procedure for Synthesis of Silica Supported H₅IO₆ Catalyst (H₅IO₆-SiO₂)

H₅IO₆ (2.50 g, 10.96 mmol) was dissolved in 15 mL of hot water (70°C) in a 50 mL round-bottomed flask. To the hot solution was added silica gel (230–400 meshes, 10 g) with vigorous stirring. The resultant H₅IO₆ (resultant mixture contains 20 wt% of H₅IO₆) supported with silica gel was dried in oven at 100°C for 12 h to obtain a white free flow powder. The reagent can be stored for 4 months with negligible loss of activity.

5.4. General Procedure for Synthesis of Benzimidazoles (5a–5i, 6a–6e and 7a–7c)

A typical procedure is as follows. A mixture of 1,2-phenylenediamine (108 mg, 1.0 mmol), m-nitrobenzaldehyde (151 mg, 1.0 mmol) in acetonitrile (3.0 mL) was taken, and H₅IO₆ (45 mg, 20 mmol% supported on silica 210 mg) was added at room temperature. The reaction was stirred at room temperature for 15 minutes. After completion of the reaction (monitored by TLC), filter the reaction mixture over celite. The filtrate was evaporated under vacuum and subsequently dried to afford crude product which was purified by column chromatography using hexane/ethylacetate as eluent to afford pure benzimidazole 5g (227 mg, 95%).

5.5. Procedure for Synthesis of Bisbenzimidazole (8)

A mixture of 1,2-phenylenediamine (216 mg, 2.0 mmol), p-phthalaldehyde (134 mg, 1.0 mmol) in acetonitrile (3.0 mL) was taken, and H₅IO₆ (90 mg, 40 mol% supported on silica 420 mg) was added at room temperature. The reaction was stirred at room temperature for 35 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was filtered over celite. The filtrate was evaporated under vacuum and subsequently dried to afford crude product which was purified by column chromatography using hexane/ethylacetate as eluent to afford pure benzimidazole 8 (250 mg, 80%). The spectral data are in full agreement with data reported in the literature. Spectral data of compounds are given below.

5.5.1. 2-Phenyl-1H-benzoimidazole (5a)

White solid; mp 291–293°C; (lit. [21, 22] mp 290-291°C); IR (cm⁻¹, KBr): 3044, 1622, 1587, 1537, 1458, 1439, 1407, 1312, 1274; ¹H NMR (300 MHz, DMSO-d ₆): δ 12.91 (brs, 1H), 8.15 (d, J = 7.0 Hz, 2H), 7.55–7.47 (m, 5H), 7.19 (brs, 2H); ¹³C  NMR (75 MHz, DMSO-d ₆): δ 151.2, 143.7, 134.9, 130.1, 129.8, 128.9, 126.4, 122.4, 121.6, 118.8, 111.3; (Found: C, 80.39; H, 5.18; N, 14.38. Cal for C₁₃H₁₀N₂: C, 80.42; H, 5.19; N, 14.42%).

5.5.2. 2-(1H-Benzo[d]imidazol-2-yl) Phenol (5b)

White solid; mp 235–237°C; (lit. [21, 22] mp 236-237°C); IR (cm⁻¹, KBr): 3327, 3057, 2332, 1635, 1280, 1037, 840, 729; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.21 (brs, 2H), 8.07 (d, J = 7.7 Hz, 1H), 7.67 (brs, 2H), 7.28–7.40 (m, 3H), 6.99–7.06 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 158.0, 151.7, 131.6, 126.2, 122.7, 119.0, 117.1, 112.5; (Found: C, 74.25; H, 4.78; N, 13.31. Cal for C₁₃H₁₀N₂O: C, 74.27; H, 4.79; N, 13.33%).

5.5.3. 2-(2,6-Dichlorophenyl)-1H-benzimidazole (5c)

White solid; mp 274–276°C; (lit. [36] mp 275-276°C); IR (cm⁻¹, KBr): 3368, 3297, 1558, 1431, 1369, 1265, 1132, 735; ¹H NMR (300 MHz, DMSO-d ₆): δ 12.90 (brs, 1H), 7.53–7.71 (m, 5H), 7.20–7.29 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 146.7, 143.1, 135.0, 134.0, 132.3, 130.5, 128.3, 122.8, 121.6, 119.2, 111.6; (Found: C, 59.33; H, 3.05; N, 10.62. Cal for C₁₃H₈Cl₂N₂: C, 59.34; H, 3.06; N, 10.65%).

5.5.4. 2-(4-Chlorophenyl)-1H-benzimidazole (5d)

White solid; mp 288–291°C; (lit. [25] 287–289°C); IR (cm⁻¹, KBr) 3433, 3055, 1427, 1273, 1091, 829, 744; ¹H NMR (300 MHz, DMSO-d ₆,): δ 13.00 (brs, 1H), 8.23 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 5.9 Hz, 2H), 7.21 (brs, 2H); 13C NMR (75 MHz, DMSO-d ₆): δ 150.2, 143.7, 134.5, 129.1, 129.0, 128.1, 122.4, 118.9, 111.5; (Found: C, 68.27; H, 3.95; N, 12.21. Cal for C₁₃H₉ClN₂: C, 68.28; H, 3.97; N, 12.25%).

5.5.5. 2-(4-Nitrophenyl)-1H-benzo[d]imidazole (5e)

Yellow solid; mp 300–302°C; (lit. [21, 22] mp 299–301°C); IR (cm⁻¹, KBr): 3335, 2912, 1602, 1514, 1435, 1340, 1103, 856, 746; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.39 (brs, 1H), 8.38–8.27 (m, 4H), 7.61 (s, 2H), 7.22–7.20 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 148.8, 147.5, 142.7, 135.9, 127.2, 124.1, 124.0, 122.8; (Found: C, 65.25; H, 3.75; N, 17.52. Cal for C₁₃H₉N₃O₂: C, 65.27; H, 3.79; N, 17.56%).

5.5.6. 2-(2-Nitrophenyl)-1H-benzo[d]imidazole (5f)

Yellow solid; mp 209–211°C; (lit. [25] 208–210°C); IR (cm⁻¹, KBr): 3410, 3078, 2686, 1525, 1348, 1078, 972, 746; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.07 (brs, 1H), 7.96–8.04 (m, 2H), 7.83–7.89 (m, 1H), 7.72–7.78 (m, 1H), 7.60–7.63 (m, 2H), 7.23–7.26 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 148.9, 147.2, 132.5, 131.4, 130.8, 130.8, 128.6, 124.2, 122.4, 119.1, 111.5; (Found: C, 65.26; H, 3.74; N, 17.53. Cal for C₁₃H₉N₃O₂: C, 65.27; H, 3.79; N, 17.56%).

5.5.7. 2-(3-Nitrophenyl)-1H-benzimidazole (5g)

Yellow solid; mp 205–207°C; (lit. [21, 22] mp 205-206°C); IR (cm⁻¹, KBr): 3371, 3088, 1587, 1518, 1473, 1429, 1346, 1274; ¹H NMR (300 MHz, DMSO-d ₆) δ 13.29 (s, 1H), 9.01 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 6.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 148.9, 148.2, 143.5, 134.9, 132.3, 131.6, 130.5, 124.0, 123.1, 122.0, 120.7, 119.1, 111.5; (Found: C, 66.26; H, 3.75, N; 17.55. Cal for C₁₃H₉N₃O₂: C, 65.27; H, 3.79; N, 17.56%).

5.5.8. 5-(1H-Benzo[d]imidazol-2-yl)-2-methoxyphenol (5h)

Yellow solid; mp: 218–220°C; IR (cm⁻¹, KBr): 3273, 2926, 1500, 1450, 1265, 1033, 910, 736; ¹H NMR (300 MHz, DMSO-d ₆): δ 12.65 (s, 1H), 9.31 (s, 1H), 7.52–7.63 (m, 4H), 7.13–7.19 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 151.5, 149.3, 146.6, 139.9, 122.8, 121.6, 117.9, 114.4, 113.7, 112.0, 55.6; (Found: C, 69.91; H, 4.99; N, 11.65. Cal for C₁₄H₁₂N₂O₂: C, 69.99; H, 5.03; N, 11.66%).

5.5.9. 2-(Pyridine-2-yl)-1H-benzo[d)imidazole (5i)

Yellow solid; mp 218–220°C; IR (cm⁻¹, KBr): 3057, 2667, 1595, 1444, 1315, 1280, 1122, 850, 744, 615; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.11 (brs, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.02 (t, J = 7.7 Hz, 1H), 7.49–7.69 (m, 3H), 7.21–7.24 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 151.2, 150.1, 148.3, 138.3, 125.6, 123.6, 122.0, 116.2; (Found: C, 78.80; H, 4.60; N, 21.51. Cal for C₁₂H₉N₃: C, 78.83; H, 4.65; N, 21.52%).

5.5.10. 2-Phenyl-1H-benzo[d]imidazole-5-carboxylic Acid (6a)

White solid; mp 301–303°C; IR (cm⁻¹, KBr): 3405, 1680, 1621, 1450, 981, 770; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.18 (brs, 1H), 12.79 (brs, 1H), 8.19 (m, 3H), 7. 84 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 15.2 Hz, 1H), 7.58–7.48 (m, 3H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 193.2, 167.8, 153.5, 134.5, 130.4, 129.5, 129.2, 129.0, 128.5, 126.7, 124.6, 123.6, 117.1, 114.6; (Found: C, 70.55; H, 4.24; N, 11.72. Cal for C₁₄H₁₀N₂O₂: C, 70.58; H, 4.23; N, 11.76%).

5.5.11. 2-(2-Hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic Acid (6b)

White solid; mp 301–303°C; IR (cm⁻¹, KBr): 3319, 3059, 1681, 1633, 1491, 1261, 1130, 748; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.43 (brs, 1H), 12.84 (brs, 2H), 8.27 (brs, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.90 (brs, 1H), 7.72 (brs, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 168.3, 158.0, 153.9, 132.9, 132.0, 129.1, 127.3, 125.5, 124.6, 120.1, 117.6, 112.8; (Found: C, 66.16; H, 3.93; N, 10.09. Cal for C₁₄H₁₀N₂O₃: C, 66.14; H, 3.96; N, 11.02%).

5.5.12. 2-(2,6-Dichlorophenyl)-1H-benzo[d]imidazole-5-carboxylic Acid (6c)

White solid; mp 304–306°C; IR (cm⁻¹, KBr): 3171, 1915, 1668, 1622, 1433, 1315, 779; ¹H NMR (300 MHz, DMSO-d ₆): 13.12 (brs, 1H), 12.64 (brs, 1H), 8.28–8.17 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.72–7.57 (m, 4H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 167.7, 167.3, 134.9, 134.6, 132.6, 132.3, 130.0, 129.7, 128.4, 128.1; (Found: C, 54.71; H, 2.59; N, 9.14. Cal for C₁₄H₈Cl₂N₂O₂: C, 54.75; H, 2.63; N, 9.12%).

5.5.13. 2-(4-Chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic Acid (6d)

White solid; mp 194–196°C; IR (cm⁻¹, KBr): 3090, 2821, 1907, 1676, 1624, 1425, 1319, 1026, 947, 835, 731; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.30 (brs, 1H), 12.77 (brs, 1H), 8.19 (m, 3H), 7.84 (brs, 1H), 7.65 (m, 3H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 167.8, 152.4, 135.0, 129.1, 128.4, 128.4, 124.7, 123.8, 122.4, 119.9; (Found: C, 61.65; H, 3.31; N, 10.25. Cal for C₁₄H₉ClN₂O₂: C, 61.66; H, 3.33; N, 10.27%).

5.5.14. 2-(4-Nitrophenyl)-1H-benzo[d]imidazole-5-carboxylic Acid (6e)

Yellow solid; mp 272–274°C; IR (cm⁻¹, KBr): 3338, 2949, 1699, 1604, 1514, 1348, 1213, 853, 774; ¹H NMR (300 MHz, DMSO-d ₆,): δ 13.38 (s, 2H), 8.39 (s, 4H), 8.20 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 168.0, 151.5, 148.4, 142.3, 139.5, 135.4, 131.8, 128.9, 128.0, 125.6, 124.5, 117.9, 115.3; (Found: C, 59.32; H, 3.15; N, 14.81. Cal for C₁₄H₉N₃O₄: C, 59.37; H, 3.20; N, 14.84%).

5.5.15. Phenyl(2-phenyl-1H-benzo[d]imidazol-5-yl)methanone (7a)

Yellow solid; mp 221-222°C; IR (cm⁻¹, KBr): 3375, 3061, 1645, 1572, 1321, 902, 707; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.30 (s, 1H), 8.20 (d, J = 6.2 Hz, 2H), 7.94 (brs, 1H), 7.76–7.54 (m, 10H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 195.5, 138.0, 132.0, 130.9, 130.4, 129.4, 129.0, 128.3, 126.6, 124.2; (Found: C, 80.43; H, 4.65; N, 9.31. Cal for C₂₀H₁₄N₂O: C, 80.52; H, 4.73; N, 9.39%).

5.5.16. 2-(2-Hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methanone (7b)

Light yellow solid; mp 227–229°C; IR (cm⁻¹, KBr): 3298, 3057, 1919, 1726, 1614, 1450, 1294, 981, 786; ¹H NMR (300 MHz, DMSO-d ₆): δ 12.91 (brs, 2H), 8.10 (d, J = 8.1 Hz, 1H), 8.08 (brs, 1H), 7.81–7.75 (m, 4H), 7.69 (m, 1H), 7.58 (m, 2H), 7.42 (m, 1H), 7.08–7.02 (m, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 196.5, 158.0, 154.3, 138.3, 133.0, 132.8, 131.9, 130.0, 129.0, 127.4, 135.3, 120.2, 117.7, 113.0; (Found: C, 76.41; H, 4.42; N, 8.88. Cal for C₂₀H₁₄N₂O₂: C, 76.42; H, 4.49; N, 8.91%).

5.5.17. 2-(2,6-Dichlorophenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methanone (7c)

White solid; mp 164–166°C; IR (cm⁻¹, KBr): 3059, 1734, 1651, 1431, 1317, 970,788; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.29 (brs, 1H), 8.05 (brs, 1H), 7.74 (m, 3H), 7.70–7.64 (m, 5H), 7.58 (t, J = 7.6 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 195.7, 148.9, 137.8, 134.8, 132.6, 132.0, 129.9, 129.4, 128.3, 120.0; (Found: C, 65.38; H, 3.25; N, 7.70. Cal for C₂₀H₁₂Cl₂N₂O: C, 65.41; H, 3.29; N, 7.63%).

5.5.18. 2-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazole (8)

White solid; mp 245–247°C; IR (cm⁻¹, KBr): 3061, 1626, 1440, 1317, 1118, 966, 846, 740; ¹H NMR (300 MHz, DMSO-d ₆): δ 13.01 (brs, 2H), 8.33 (s, 4H), 7.61 (s, 4H), 7.23-7.20 (m, 4H); ¹³C NMR (75 MHz, DMSO-d ₆): δ 150.3, 138.9, 130.7, 127.0, 122.6, 115.1; (Found: C, 77.31; H, 4.54; N, 17.98. Cal for C₂₀H₁₄N₄: C, 77.40; H, 4.55; N, 18.05%).

Acknowledgments

The authors are grateful to Professor M. S. Wadia and Professor Dilip D. Dhavale for helpful discussions. Vaishali S. Shinde and Vyankat A. Sontakke are thankful to Department of Science and Technology (DST), New Delhi, for the financial support and Junior Research Fellowship (SR/S1/OC-89/2009), respectively. S. Ghosh thanks Council of Scientific and Industrial Research (CSIR), Government of India, for Senior Research Fellowship (09/137(0516)/2012-EMR-I).

References

G. Balboni, C. Trapella, Y. Sasaki et al., “Influence of the side chain next to C-terminal benzimidazole in opioid pseudopeptides containing the Dmt-Tic pharmacophore,” Journal of Medicinal Chemistry, vol. 52, no. 17, pp. 5556–5559, 2009.

W. A. Maxwell and G. Brody, “Antifungal activity of selected benzimidazole compounds,” Applied microbiology, vol. 21, no. 5, pp. 944–945, 1971.

D. Sharma, B. Narasimhan, P. Kumar, and A. Jalbout, “Synthesis and QSAR evaluation of 2-(substituted phenyl)-1H-benzimidazoles and [2-(substituted phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanones,” European Journal of Medicinal Chemistry, vol. 44, no. 3, pp. 1119–1127, 2009.

A. A. Farahat, E. Paliakov, A. Kumar et al., “Exploration of larger central ring linkers in furamidine analogues: synthesis and evaluation of their DNA binding, antiparasitic and fluorescence properties,” Bioorganic & Medicinal Chemistry, vol. 19, no. 7, pp. 2156–2167, 2011.

D. Valdez-Padilla, S. Rodríguez-Morales, A. Hernández-Campos et al., “Synthesis and antiprotozoal activity of novel 1-methylbenzimidazole derivatives,” Bioorganic & Medicinal Chemistry, vol. 17, no. 4, pp. 1724–1730, 2009.

Y. F. Li, G. F. Wang, P. L. He et al., “Synthesis and anti-hepatitis B virus activity of novel benzimidazole derivatives,” Journal of Medicinal Chemistry, vol. 49, no. 15, pp. 4790–4794, 2006.

H. Banie, A. Sinha, R. J. Thomas, J. C. Sircar, and M. L. Richards, “2-phenylimidazopyridines, a new series of golgi compounds with potent antiviral activity,” Journal of Medicinal Chemistry, vol. 50, no. 24, pp. 5984–5993, 2007.

P. S. Charifson, A. L. Grillot, T. H. Grossman et al., “Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships,” Journal of Medicinal Chemistry, vol. 51, no. 17, pp. 5243–5263, 2008.

J. Chen, Z. Wang, C. M. Li et al., “Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents,” Journal of Medicinal Chemistry, vol. 53, no. 20, pp. 7414–7427, 2010.

H. Göker, C. Kuş, D. W. Boykin, S. Yıldız, and N. Altanlar, “Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species,” Bioorganic & Medicinal Chemistry, vol. 10, no. 8, pp. 2589–2596, 2002.

G. N. Vázquez, L. Yépez, A. H. Campos, et al., “Synthesis and antiparasitic activity of albendazole and mebendazole analogues,” Bioorganic & Medicinal Chemistry, vol. 11, no. 21, pp. 4615–4622, 2003.

K. J. Spivak and Z. Amit, “Effects of pimozide on appetitive behavior and locomotor activity: dissimilarity of effects when compared to extinction,” Physiology & Behavior, vol. 36, no. 3, pp. 457–463, 1986.

P. Lindberg, P. Nordberg, T. Alminger, et al., “The mechanism of action of the gastric acid secretion inhibitor omeprazole,” Journal of Medicinal Chemistry, vol. 29, no. 8, pp. 1327–1329, 1986.

S. B. Mohan, T. P. Behera, and B. V. V. Ravi Kumar, “Microwave irradiation versus conventional method: synthesis of benzimidazolyl chalcone derivatives,” International Journal of ChemTech Research, vol. 2, no. 3, pp. 1634–1637, 2010.

A. K. Tiwari and A. Mishra, “Synthesis and antiviral activity of N-substituted-2-subastituted benzimidazole derivatives,” Indian Journal of Chemistry B, vol. 45, pp. 489–493, 2006.

R. J. Perry and B. D. Wilson, “A novel palladium-catalyzed synthesis of 2-arylbenzimidazoles,” Journal of Organic Chemistry, vol. 58, no. 25, pp. 7016–7021, 1993.

K. Bourgrin, A. Loupy, and M. Soufiaoui, “Trois nouvelles voies de synthèse des dérivés 1, 3-azoliques sous micro-ondes,” Tetrahedron, vol. 54, no. 28, pp. 8055–8064, 1998.

V. R. Ruiz, A. Corma, and M. J. Sabater, “New route for the synthesis of benzimidazoles by a one-pot multistep process with mono and bifunctional solid catalysts,” Tetrahedron, vol. 66, no. 3, pp. 730–735, 2010.

I. Bhatnagar and M. V. George, “Oxidation with metal oxides-II: oxidation of chalcone phenylhydrazones, pyrazolines, o-aminobenzylidine anils and o-hydroxy benzylidine anils with manganese dioxide,” Tetrahedron, vol. 24, no. 3, pp. 1293–1298, 1968.

P. L. Beaulieu, B. Haché, and E. Von Moos, “A practical oxone-mediated, high-throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines and aldehydes and its application to preparative scale synthesis,” Synthesis, no. 11, pp. 1683–1692, 2003.

M. A. Weidner-Wells, K. A. Ohemeng, V. N. Nguyen et al., “Amidino benzimidazole inhibitors of bacterial two-component systems,” Bioorganic and Medicinal Chemistry Letters, vol. 11, no. 12, pp. 1545–1548, 2001.

S. E. López, J. Restrepo, B. Pérez, S. Ortiz, and J. Salazar, “One pot microwave promoted synthesis of 2-aryl-1H-benzimidazoles using sodium hydrogen sulfite,” Bulletin of the Korean Chemical Society, vol. 30, no. 7, pp. 1628–1630, 2009.

P. Gogoi and D. Konwar, “An efficient and one-pot synthesis of imidazolines and benzimidazoles via anaerobic oxidation of carbon-nitrogen bonds in water,” Tetrahedron Letters, vol. 47, no. 1, pp. 79–82, 2006.

K. Bahrami, M. M. Khodaei, and F. Naali, “Mild and highly efficient method for the synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles,” Journal of Organic Chemistry, vol. 73, no. 17, pp. 6835–6837, 2008.

M. A. Chari, D. Shobha, E. R. Kenawy, S. S. Al-Deyab, B. V. Subba Reddy, and A. Vinu, “Nanoporous aluminosilicate catalyst with 3D cage-type porous structure as an efficient catalyst for the synthesis of benzimidazole derivatives,” Tetrahedron Letters, vol. 51, no. 39, pp. 5195–5199, 2010.

C. Mukhopadhyay, S. Ghosh, S. Sengupta (Bandyopadhyay), and S. Deb, “Synthesis of 2-alkyl substituted benzimidazoles under microwave irradiation: anti-proliferative effect of some representative compounds on human histiocytic lymphoma cell U937,” RSC Advances, vol. 1, no. 6, pp. 1033–1037, 2011.

K. Wilson and J. H. Clark, “Solid acids and their use as environmentally friendly catalysts in organic synthesis,” Pure and Applied Chemistry, vol. 72, no. 7, pp. 1313–1319, 2000.

R. G. Jacob, L. G. Dutra, C. S. Radatz, S. R. Mendes, G. Perin, and E. J. Lenardão, “Synthesis of 1,2-disubstitued benzimidazoles using SiO₂/ZnCl₂,” Tetrahedron Letters, vol. 50, no. 13, pp. 1495–1497, 2009.

A. V. Patil, B. P. Bandgar, and S. H. Lee, “Silica supported fluoroboric acid: an efficient and reusable heterogeneous catalyst for facile synthesis of 2-aliphatic benzothiazoles, benzoxazoles, benzimidazoles and imidazo[4,5-b]pyridines,” Bulletin of the Korean Chemical Society, vol. 31, no. 6, pp. 1719–1722, 2010.

S. Paul and B. Basu, “Highly selective synthesis of libraries of 1, 2-disubstituted benzimidazoles using silica gel soaked with ferric sulfate,” Tetrahedron Letters, vol. 53, no. 32, pp. 4130–4133, 2012.

D. Kumar, D. N. Kommi, R. Chebolu, S. K. Garg, R. Kumar, and A. K. Chakraborti, “Selectivity control during the solid supported protic acids catalysed synthesis of 1, 2-disubstituted benzimidazoles and mechanistic insight to rationalize selectivity,” RSC Advances, vol. 3, pp. 91–98, 2013.

S. Yamazaki, “Chromium(VI) oxide-catalyzed benzylic oxidation with periodic acid,” Organic Letters, vol. 1, no. 13, pp. 2129–2132, 1999.

L. Xu, J. Cheng, and M. L. Trudell, “Chromium(VI) oxide catalyzed oxidation of sulfides to sulfones with periodic acid,” Journal of Organic Chemistry, vol. 68, no. 13, pp. 5388–5391, 2003.

A. K. M. L. Rahman, M. Kumashiro, and T. Ishihara, “Direct synthesis of formic acid by partial oxidation of methane on H-ZSM-5 solid acid catalyst,” Catalysis Communications, vol. 12, no. 13, pp. 1198–1200, 2011.

V. U. Pawar, S. Ghosh, B. A. Chopade, and V. S. Shinde, “Design and synthesis of harzialactone analogues: promising anticancer agents,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 24, pp. 7243–7245, 2010.

M. Shen and T. G. Driver, “Iron(II) bromide-catalyzed synthesis of benzimidazoles from aryl azides,” Organic Letters, vol. 10, no. 15, pp. 3367–3370, 2008.