INTRODUCTION

Benzimidazole core is present in some marketed drugs. Examples are Albendazole (used to treat infec­tions caused by dog and pork tapeworms), Veliparib (a potential anticancer drug acting as a PARP inhibi­tor), Nocodazole (antineoplastic agent), Adibenden (potential phosphodiesterase inhibitor), and Lerisetron (5-HT3 antagonist) (Fig. 1). In addition, various benz­imidazole derivatives were reported to exhibit a wide variety of biological activities, including antimicrobial [1], anticancer [2], anti-inflammatory [3], antioxidant [4], antidiabetic [5], anti-HIV [6], and anticonvulsant [7] activities. Moreover, 1,2,3-triazole and its deriva­tives have attracted considerable attention over the past few decades due to their chemotherapeutical value as antimicrobial [8], anti-inflammatory [9], anticonvulsant [10], anticancer [11], anti-HIV [12], and anti-tubercular agents [13].

Fig. 1.
figure 1

Representative marketed drugs containing a benzimidazole nucleus.

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On the other hand, recent green chemistry methods have gained popularity as a nonconventional technique for rapid organic synthesis. There is increasing interest in the use of microwave irradiation in organic synthesis due to several advantages like mild conditions, clean reac­tions, convenient operation, high selectivity, simple workup, spontaneity of the reaction process, and environ­mental friendliness. As part of our ongoing research program, the above listed facts encouraged us to design and synthesize a novel series of benzimid­azole derivatives, 1-[(1-aryl-1H-1,2,3-triazol-4-yl)­methyl]-2-(pyridin-3-yl)-1H-benzimidazoles, under microwave irradiation and evaluate them for antimi­crobial activity.

RESULTS AND DISCUSSION

The synthetic route to novel 1,2,3-triazole-tethered 2-pyridinylbenzimidazole derivatives is shown in Scheme 1. The key starting material was 2-(pyridine-3-yl)-1H-benzimidazole (1) which was prepared as per literature procedure by the reaction of o-phenylene­diamine with pyridine-3-carbaldehyde. Compound 1 was alkylated with propargyl bromide in DMF using K2CO3 as a base under micro­wave irradiation at 180 W for 4 min to afford 1-(prop-2-yn-1-yl)-2-(pyridin-3-yl)-1H-benzimidazole (2) in 94% yield.

Scheme
scheme 1

1.

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The synthesis of compound 4a via copper-catalyzed azide–alkyne cycloaddition of 2 and phenyl azide (3a) was selected as a model process (Scheme 2). Initially, the reaction of 2 and 3a was carried out in the presence of copper(I) iodide in four different solvents like tri­ethyl­amine (TEA), ethyl(diisopropyl)amine (DIPEA), DMF, and DMSO. The maximum yield of 4a (68%) was obtained in TEA at room temperature. In our effort to increase the yield, the model reaction was carried out under microwave irradiation, other conditions being equal. Surprisingly, a remarkable improvement in the yield from 68% to 94% was observed. En­couraged by this result, we studied the effect of micro­wave power and performed a series of experiments at 100, 180, 360, and 480 W. As expected, the highest yield within the shortest reaction time was obtained in the reaction performed at an MW power of 360 W (Table 1, entry no. 9).

Scheme
scheme 2

2.

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Table 1. Optimization of the conditions for the synthesis of compound 4a
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Next, the scope and generality of the described reac­tion were examined by reacting 1-(prop-2-yn-1-yl)-2-(pyridin-3-yl)-1H-benzimidazole (2) with dif­fer­ently substituted aryl azides 3a–3j under the optimized conditions. The results showed that both electron-donating and electron-withdrawing substituents in the aryl azide were well tolerated, and the corresponding products 4a–4j were obtained in good yields.

Antimicrobial activity. Compounds 4a–4j were tested in vitro against four bacterial strains, namely B. faecalis, S. aureus, K. pneumoniae, and E. coli, using ampicillin as a standard antibacterial drug. The anti­bacterial activity was determined using the cup plate agar diffusion method by measuring the zone of inhibition in mm at a concentration of 100 μg/mL in DMSO. Compounds 4e–4h and 4j demonstrated good activity, while the others were weakly or moderately active. Compounds 4a–4j were also tested for their in vitro antifungal activity against A. niger and C. meta­psilosis using griseofulvin as a standard drug. The antifungal activity was evaluated by the cup plate agar diffusion method by measuring the zone of inhibition in mm at a concentration of 500 μg/mL in DMSO. Compounds 4e, 4i, 4h, and 4j demonstrated a good activity against the tested fungi.

EXPERIMENTAL

The melting points were determined in open capil­lary tubes and are uncorrected. The purity of the isolated compounds was checked by TLC using pre­coated silica gel 60 UV254 plates (Merck). Microwave-assisted reactions were carried out in a Milestone multi-SYNTH microwave system. The IR spectra were recorded in KBr on a Shimadzu FT-IR-8400s spectrom­eter. The 1H and 13C NMR spectra were measured on a Bruker Avance II 400 MHz spectrometer using CDCl3 as a solvent and tetramethylsilane as an internal standard. The mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer.

General procedure for the preparation of 1-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]-2-(pyridin-3-yl)-1H-benzimidazoles 4a–4j. A mixture of 1-(prop-2-yn-1-yl)-2-(pyridin-3-yl)-1H-benzimidazole (2, 1 mmol), aryl azide 3a–3j (1.2 mmol), and copper(I) iodide (2 mmol) in triethylamine (3 ml) was subjected to microwave irradiation at 360 W for 6–8 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into ice water, and a solid product slowly precipitated. It was filtered off, washed with water, dried, and purified by column chromatography using n-hexane–ethyl acetate (8:2) as an eluent.

1-[(1-Phenyl-1H-1,2,3-triazol-4-yl)methyl]-2-(pyri­din-3-yl)-1H-benzimidazole (4a). Yield 94%, off-white solid, mp 129–131°C. IR spectrum, ν, cm–1: 1421, 1589, 1649. 1H NMR spectrum, δ, ppm: 5.65 s (2H, NCH2), 7.26–7.32 m (2H, Harom), 7.47–7.66 m (4H, Harom), 7.70–7.74 m (2H, Harom), 7.86 d (2H, J = 8.0 Hz, Harom), 8.42–8.45 m (1H, Harom), 8.78 d (1H, J = 2.4 Hz, Harom), 8.93 s (1H, 5-H, triazole), 9.17 s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.9, 111.2, 119.3, 120.1, 122.0, 122.4, 123.0, 128.8, 129.8, 135.6, 136.4, 136.8, 142.6, 143.4, 149.8, 150.7. Mass spec­trum: m/z 353 (Irel 100%) [M + H]+. Found, %: C 71.52; H 4.53; N 23.82. C21H16N6. Calculated, %: C 71.57; H 4.58; N 23.85.

1-{[1-(4-Methylphenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4b). Yield 92%, off-white solid, mp 148–150°C. IR spec­trum, ν, cm–1: 1422, 1591, 1652. 1H NMR spectrum, δ, ppm: 2.41 s (3H, CH3), 5.66 s (2H, NCH2), 7.22– 7.26 m (2H, Harom), 7.48–7.62 m (3H, Harom), 7.69–7.73 m (2H, Harom), 7.86 d (2H, J = 8.0 Hz, Harom), 8.41–8.44 m (1H, Harom), 8.79 d (1H, J = 2.4 Hz, Harom), 8.91 s (1H, 5-H, triazole), 9.70 s (1H, Harom). 13C NMR spectrum, δC, ppm: 25.1, 39.7, 111.2, 118.9, 120.4, 121.9, 122.6, 123.0, 126.7, 128.5, 129.8, 135.6, 136.4, 136.7, 142.6, 143.5, 149.8, 150.6. Mass spec­trum: m/z 367 (Irel 100%) [M + H]+. Found, %: C 72.08; H 4.93; N 22.92. C22H18N6. Calculated, %: C 72.11; H 4.95; N 22.94.

1-{[1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4c). Yield 92%, off-white solid, mp 143–145°C. IR spec­trum, ν, cm–1: 1423, 1589, 1654. 1H NMR spectrum, δ, ppm: 3.81 s (3H, OCH3), 5.63 s (2H, NCH2), 7.11– 7.13 d (2H, J = 8.4 Hz, Harom), 7.29 m (2H, Harom), 7.74–7.77 m (4H, Harom), 7.70–7.74 m (2H, Harom), 8.46 d (1H, J = 9.8 Hz, Harom), 8.82 s (1H, 5-H, triazole), 9.55 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.9, 55.5, 111.2, 114.8, 119.3, 121.8, 121.9, 122.4, 122.9, 129.7, 136.8, 143.2, 150.7, 159.3. Mass spectrum: m/z 383 (Irel 100%) [M + H]+. Found, %: C 69.12; H 4.72; N 21.95. C22H18N6O. Calculated, %: C 69.10; H 4.74; N 21.98.

1-{[1-(2-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4d). Yield 90%, off-white solid, mp 162–164°C. IR spec­trum, ν, cm–1: 1425, 1590, 1648. 1H NMR spectrum, δ, ppm: 3.83 s (3H, OCH3), 5.66 s (2H, NCH2), 7.09– 7.13 m (1H, Harom), 7.26–7.33 m (3H, Harom), 7.50–7.79 m (5H, Harom), 8.48–8.51 m (1H, Harom), 8.60 s (1H, 5-H, triazole), 8.78 d (1H, J = 3.6 Hz, Harom), 9.19 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.8, 56.1, 111.3, 113.0, 119.3, 120.8, 122.4, 122.9, 123.7, 125.4, 125.6, 125.9, 126.4, 130.8, 135.6, 136.9, 142.0, 142.6, 149.8, 150.4, 150.5, 151.5. Mass spec­trum: m/z 383 (Irel 100%) [M + H]+. Found, %: C 69.12; H 4.72; N 21.95. C22H18N6O. Calculated, %: C 69.10; H 4.74; N 21.98.

1-{[1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4e). Yield 93%, off-white solid, mp 125–127°C. IR spec­trum, ν, cm–1: 1424, 1592, 1654. 1H NMR spectrum, δ, ppm: 5.66 s (2H, NCH2), 7.26–7.33 m (2H, Harom), 7.65–7.72 m (5H, Harom), 7.91 d (2H, J = 8.8 Hz, Harom), 8.43 d (1H, J = 8.0 Hz, Harom), 8.80 br.s (1H, Harom), 8.94 s (1H, 5-H, triazole), 9.15 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.7, 111.3, 119.3, 121.8, 122.0, 122.4, 123.0, 124.8, 129.0, 129.8, 133.0, 135.1, 136.8, 142.6, 143.6, 149.7, 153.0. Mass spectrum: m/z 387 (Irel 100%) [M + H]+. Found, %: C 65.22; H 3.88; N 21.70. C21H15ClN6. Calculated, %: C 65.20; H 3.91; N 21.73.

1-{[1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4f). Yield 89%, off-white solid, mp 152–154°C. IR spec­trum, ν, cm–1: 1420, 1588, 1656. 1H NMR spectrum, δ, ppm: 5.69 s (2H, NCH2), 7.26–7.33 m (2H, Harom), 7.63–7.73 m (3H, Harom), 8.18 d (2H, J = 8.4 Hz, Harom), 8.39–8.46 m (3H, Harom), 8.78 br.s (1H, Harom), 9.11 s (1H, 5-H, triazole), 9.35 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.8, 111.1, 119.3, 120.6, 122.4, 122.4, 123.0, 125.5, 129.5, 129.7, 133.0, 135.6, 136.8, 140.6, 142.6, 144.1, 146.7, 149.7, 150.5. Mass spectrum: m/z 398 (Irel 100%) [M + H]+. Found, %: C 63.42; H 3.83; N 24.69. C21H15N7O2. Calculated, %: C 63.47; H 3.80; N 24.67.

1-{[1-(2-Nitrophenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4g). Yield 90%, off-white solid, mp 148–150°C. IR spec­trum, ν, cm–1: 1424, 1589, 1653. 1H NMR spectrum, δ, ppm: 5.69 s (2H, NCH2), 7.28–7.34 m (2H, Harom), 7.33–7.96 m (6H, Harom), 8.21 d (1H, J = 8.4 Hz, Harom), 8.42 d (1H, J = 6.8 Hz, Harom), 8.80 br.s (1H, Harom), 8.81 s (1H, 5-H, triazole), 9.32 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.9, 111.2, 119.4, 120.6, 122.4, 123.0, 125.2, 125.5, 127.7, 128.9, 129.7, 131.3, 132.7, 134.4, 136.5, 140.5, 143.1, 143.9, 146.9, 149.6, 150.7. Mass spectrum: m/z 398 (Irel 100%) [M + H]+. Found, %: C 63.42; H 3.83; N 24.69. C21H15N7O2. Calculated, %: C 63.47; H 3.80; N 24.67.

1-{[1-(2-Chloro-4-nitrophenyl)-1H-1,2,3-triazol-4-yl]methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4h). Yield 88%, off-white solid, mp 137–139°C. IR spectrum, ν, cm–1: 1422, 1593, 1655. 1H NMR spec­trum, δ, ppm: 5.73 s (2H, NCH2), 7.27–7.33 m (2H, Harom), 7.33–7.78 m (3H, Harom), 7.98 d (1H, J = 8.8 Hz, Harom), 8.36–8.45 m (2H, Harom), 8.62 d (1H, J = 2.6 Hz, Harom), 8.78 br.s (1H, Harom), 8.81 s (1H, 5-H, triazole), 9.16 br.s (1H, Harom). 13C NMR spec­trum, δC, ppm: 40.1, 111.2, 119.3, 122.5, 123.0, 123.5, 125.2, 125.8, 126.1, 129.7, 129.2, 132.1, 135.6, 136.8, 138.8, 142.4, 142.8, 146.5, 148.2, 149.7, 150.5. Mass spectrum: m/z 432 (Irel 100%) [M + H]+. Found, %: C 58.40; H 3.24; N 22.65. C21H14ClN7O2. Calculat­ed, %: C 58.41; H 3.27; N 22.70.

1-{[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4i). Yield 90%, off-white solid, mp 135–137°C. IR spec­trum, ν, cm–1: 1422, 1590, 1652. 1H NMR spectrum, δ, ppm: 5.67 s (2H, NCH2), 7.15–7.18 m (2H, Harom), 7.62–7.67 m (5H, Harom), 7.83 d (2H, J = 8.8 Hz, Harom), 8.41 d (1H, J = 8.0 Hz, Harom), 8.78 br.s (1H, Harom), 8.93 s (1H, 5-H, triazole), 9.12 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.7, 111.3, 117.8, 119.2, 121.6, 122.1, 122.5, 123.4, 125.2, 128.7, 128.7, 133.0, 135.4, 136.5, 142.2, 143.5, 149.7, 153.1. Mass spec­trum: m/z 373 (Irel 100%) [M + H]+. Found, %: C 68.13; H 4.05; N 22.65. C21H15FN6. Calculated, %: C 68.10; H 4.08; N 22.69.

1-{[1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl]­methyl}-2-(pyridin-3-yl)-1H-benzimidazole (4j). Yield 89%, off-white solid, mp 126–128°C. IR spec­trum, ν, cm–1: 1421, 1589, 1649. 1H NMR spectrum, δ, ppm: 5.66 s (2H, NCH2), 7.22–7.27 m (2H, Harom), 7.65–7.72 m (5H, Harom), 7.90 d (2H, J = 8.4 Hz, Harom), 8.41 d (1H, J = 8.0 Hz, Harom), 8.80 br.s (1H, Harom), 8.93 s (1H, 5-H, triazole), 9.15 br.s (1H, Harom). 13C NMR spectrum, δC, ppm: 39.7, 111.2, 119.3, 121.9, 122.2, 122.7, 123.2, 125.1, 128.6, 129.8, 132.9, 135.1, 136.8, 142.5, 143.6, 149.8, 153.2; Mass spectrum, m/z 431/433 (Irel 100%) [M + H]+. Found, %: C 58.46; H 3.48; N 19.52. C21H15BrN6. Calculated, %: C 58.48; H 3.51; N 19.49.

CONCLUSIONS

A novel series of 1,2,3-triazole-tethered 2-pyridinyl­benzimidazole derivatives have been synthesized with high efficiency by click reaction under microwave irradiation. The described procedure proved to be simple and easy-to-perform, and it provided high yields within a short time.