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.
The benzimidazole nucleus is commonly present in a large number of natural products as well as pharmacologically active compounds [
There is renewed interest in the silica supported catalyzed reactions [
Periodic acid is an easily available hypervalent iodine reagent which is used in the oxidation of various functional groups [
Synthesis of 2-aryl benzimidazole.
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
Reaction of
| ||||
| ||||
Entry | Catalyst (mol %) on silica | Temp.b | Time | Yield (%)c |
| ||||
|
H5IO6 (20) | rt | 15 min | 95 |
|
H5IO6 (15) | rt | 15 min | 70 |
|
H5IO6 (10) | rt | 15 min | 45 |
|
H5IO6 (20)d | rt | 10 h | 28 |
|
SiO2 | rt | 10 h | 12 |
|
H5IO6 (20) | 60°C | 15 min | 94 |
|
H5IO6 (15) | 60°C | 15 min | 67 |
|
H5IO6 (10) | 60°C | 15 min | 47 |
|
H5IO6 (20)d | 60°C | 10 h | 35 |
|
SiO2 | 60°C | 10 h | 16 |
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
Synthesis and anticancer activity of 2-aryl benzimidazoles against MCF7 and HL60 cell lines.
Entry | R | R1 | Reaction time (min) | Yielda | IC50 ( |
|
---|---|---|---|---|---|---|
MCF7 | HL60 | |||||
|
H |
|
20 | 94 | 35.67 | 30.73 |
|
H |
|
30 | 90 | 27.63 | 28.68 |
|
H |
|
18 | 95 | 21.81 | 24.74 |
|
H |
|
20 | 84 | 27.11 | 26.71 |
|
H |
|
12 | 89 | 27.00 | 25.28 |
|
H |
|
16 | 90 | 26.25 | 25.03 |
|
H |
|
15 | 95 | 24.41 | 26.33 |
|
H |
|
19 | 78 | 29.67 | 26.52 |
|
H |
|
20 | 82 | 30.42 | 29.55 |
|
COOH |
|
12 | 91 | 22.20 | 24.88 |
|
COOH |
|
30 | 70 | 23.28 | 25.09 |
|
COOH |
|
18 | 90 | 24.51 | 25.78 |
|
COOH |
|
17 | 78 | 25.30 | 30.32 |
|
COOH |
|
15 | 88 | 17.65 | 22.10 |
|
PhCO |
|
17 | 91 | 17.32 | 19.64 |
|
PhCO |
|
22 | 89 | 17.32 | 19.88 |
|
PhCO |
|
12 | 94 | 17.45 | 18.13 |
|
Bisbenzimidazole | 35 | 80 | 17.44 | 30.69 | |
| ||||||
Cisplatin | 40.45 | 41.08 |
bIC50 50% inhibition concentration in
We have also extended same methodology for the synthesis of bisbenzimidazole (
Synthesis of bisbenzimidazole.
Although the exact mechanism is not clear, a proposed mechanism for the formation of benzimidazole is shown in Scheme
Plausible mechanism towards the formation of 2-aryl benzimidazole.
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
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.
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-
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 [
Test compounds were evaluated for anticancer activity against two cancer cell lines using cisplatin as standard anticancer drug. The compounds were evaluated
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.
A typical procedure is as follows. A mixture of 1,2-phenylenediamine (108 mg, 1.0 mmol),
A mixture of 1,2-phenylenediamine (216 mg, 2.0 mmol),
White solid; mp 291–293°C; (lit. [
White solid; mp 235–237°C; (lit. [
White solid; mp 274–276°C; (lit. [
White solid; mp 288–291°C; (lit. [
Yellow solid; mp 300–302°C; (lit. [
Yellow solid; mp 209–211°C; (lit. [
Yellow solid; mp 205–207°C; (lit. [
Yellow solid; mp: 218–220°C; IR (cm−1, KBr): 3273, 2926, 1500, 1450, 1265, 1033, 910, 736; 1H NMR (300 MHz, DMSO-
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-
White solid; mp 301–303°C; IR (cm−1, KBr): 3405, 1680, 1621, 1450, 981, 770; 1H NMR (300 MHz, DMSO-
White solid; mp 301–303°C; IR (cm−1, KBr): 3319, 3059, 1681, 1633, 1491, 1261, 1130, 748; 1H NMR (300 MHz, DMSO-
White solid; mp 304–306°C; IR (cm−1, KBr): 3171, 1915, 1668, 1622, 1433, 1315, 779; 1H NMR (300 MHz, DMSO-
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-
Yellow solid; mp 272–274°C; IR (cm−1, KBr): 3338, 2949, 1699, 1604, 1514, 1348, 1213, 853, 774; 1H NMR (300 MHz, DMSO-
Yellow solid; mp 221-222°C; IR (cm−1, KBr): 3375, 3061, 1645, 1572, 1321, 902, 707; 1H NMR (300 MHz, DMSO-
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-
White solid; mp 164–166°C; IR (cm−1, KBr): 3059, 1734, 1651, 1431, 1317, 970,788; 1H NMR (300 MHz, DMSO-
White solid; mp 245–247°C; IR (cm−1, KBr): 3061, 1626, 1440, 1317, 1118, 966, 846, 740; 1H NMR (300 MHz, DMSO-
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).