INTRODUCTION:

Benzimidazole is an aromatic heterocyclic compound. It is an important pharmacophore and a privileged structure in medicinal chemistry. Benzimidazole nucleus a constituent of vitamin-B₁₂, exhibits a wide range of biological activities^1,2. Benzimidazole derivatives are structural isosters of naturally existing nucleotides, which allow them to interact easily with the biopolymers of the living system. The incorporation of an imidazole nucleus, a biologically accepted pharmacophore, in the benzimidazole molecule has made it a versatile heterocycle possessing wide spectrum of biological activities including antimicrobial^3-7, antiproliferative^8,9, anti-inflammatory^10,11, sunscreen¹², antidiabetic¹³, spasmolytic¹⁴, antihypertensive¹⁵, and antiviral¹⁶. Acid hydrazides have also been used as important intermediates in synthesis of various heterocyclic compounds^17-19 such as 1,2,4-triazoles, 1,3,4-thiadiazoles, 1,3,4-oxadiazoles, 1,2,4,5-tetrazines, that possess diverse pharmacological properties. Microwave irradiation using commercial oven has emerged as an important synthetic tool to accelerate organic reactions, because the high heating efficiency with remarkable rate enhancement and dramatic reduction in reaction time.

In view of above mentioned facts, and in continuation of our work in the synthesis of biologically and chemically valuable compounds^5,20-21 it was felt worthwhile to prepare novel [2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-yl]acetic acid(substituted-benzylidene)hydrazides (7a-g) and 5-[2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-ylmethyl]-[1,3,4]-oxadiazole-2-thiol(8) adopting both conventional and microwave induced methods.

MATERIAL AND METHODS:

Instrumentation:

Melting points of the compounds were determined with an electro thermal melting point apparatus (Seatal Scientific Ltd.) and are uncorrected. Reactions under microwave assisted conditions were carried out using Q Pro-M microwave sample preparation system. Microwaves were generated by magnetron at a frequency of 2450 MHz having an output energy range of 100-500 W and a fiber optic sensor for temperature control. The reactions were monitored by thin layer chromatography (TLC) using silica gel-G coated Al-plates (0.5mm thickness, Merck) and spots were visualized by exposing dry plates to UV light or iodine vapours. Mannich bases were purified by column chromatography using suitable solvents mixture as eluant. IR spectra (υ in cm^-1) were recorded on FT-IR spectrometer using KBr pallets, ¹H NMR (δ in ppm) spectra were recorded on 200 MHz / 400 MHz instrument using CDCl₃ or DMSO-d₆ as the solvent, TMS as the internal reference and mass spectra were acquired on a Jeol TMS D-300 spectrometer operating at 70 eV. The C; H and N elemental analysis of compounds were achieved. The analytical data obtained was found to be in good agreement with the calculated values.

Chemistry:

Synthesis of 1H-benzimidazole-2-thiol (2):

o-Phenylene diamine (0.019 mol) and water (3 mL) were added to solution of sodium hydroxide (0.022 mol) in ethanol (20 mL) and carbon disulfide (0.022 mol). The mixture was heated under reflux for 3 h. Charcoal was then added cautiously and the mixture was further refluxed for 10 min. The charcoal was removed by filtration. The filtrate was heated to 60-70 °C and quenched with warm water (70 °C, 20 mL) and then 50% acetic acid (9 mL) was added. The product was separated on cooling in the refrigerator for 3 h and re-crystallized using alcohol as solvent.

Synthesis of 2-[(2,4-dinitrophenyl)sulphanyl]-1H-benzimidazole (4):

Conventional method: 2,4-Dinitrochlorobenzene (3, 0.04 mol) was added to a solution of 2-mercaptobenzimidazole (2, 0.04 mole) and potassium hydroxide (0.04 mole) dissolved in ethanol and water. The reaction mixture was stirred using magnetic stirrer for about 30 min and then refluxed on water bath for 2 h. The solvent was removed and the residue was poured in ice cold water. The product that resulted was filtered, washed thoroughly with small portions of ice-cold water and purified by re-crystallization. Microwave assisted method: The reaction under microwave irradiation (MWI) conditions was completed within 2.0min. whereas similar reaction under conventional heating on steam bath (80-100 °C) gave poor yields with comparatively longer reaction time period (2 h) demonstrating that the effect of microwave irradiation facilitates the polarization of molecules under irradiation causing rapid reaction to occur. This is in consistent with reaction mechanism, which involves polar transition state. Under microwave irradiation conditions the yield of 4 was high (89-94 %), where as using conventional methods the yield was comparatively low (68-85 %).

Synthesis of [2-(2,4-dinitrophenylsulphanyl) benzimidazol-1-yl]acetic acid ethyl ester (5):

Conventional method: Ethyl chloroacetate (1.225gm, 0.01 mole) 1-H-benzimidazole-2-yl-(2,4-dinitrophenyl)sulphide (3.16 gm, 0.01 moles) and anhydrous potassium carbonate in ethanol were refluxed on hot water bath for about 20hrs. Completion of reaction was monitored by TLC, the excess solvent was distilled off and the residue was poured into ice coldwater. The compound thus obtained was recrystallised from ethyl acetate-petroleum ether brown coloured crystals (3.02gm, 75%) m.p. 78-81°C. Anal. Calcd for C₁₇H₁₄N₄O₆S: C, 50.74; H, 3.51; N, 13.92; Found: C, 49.01; H, 3.75; N, 13.85%; Mol. Wt.: 402.38. IR (KBr): υ (cm^-1) 1744 (C=O),1610 (C=N), 1520 & 1350 (NO₂), 734 (C-S-C); ¹HNMR: δ1.25 (s, 3H, J = 7Hz); 4.10 (q, 2H, J = 7Hz) 4.62 (s, 2H, N-CH₂-CO); 7.25-7.53 (m, 4H); 7.79 (d, 1H, J = 7.5 Hz); 8.39 (d, 1H, J = 7.5 Hz); 8.79 (s, 1H); MS: m/z: 403 [M+H].

Microwave irradiation method:

1-H-benzimidazole-2-yl-(2,4-dinitrophenyl)sulphide (1.58gm, 0.005 mole) and ethyl chloroacetate (0.61gm, 0.005 mole) in dimethylformamide (5ml) in presence of anhydrous potassium carbonate (0.5gm) were placed in a conical flask inside a microwave oven and irradiated (360 W) for 6.0 min. up on completion of the reaction (monitored by TLC), the reaction mixture was allowed to attain room temperature and treated with water and recrystallized from ethyl acetate and petroleum ether to furnish the title compound (1.81gm 90 %), m.p. 78-81°C.

Synthesis of 2-{2-[(2,4-dinitrophenyl)sulphanyl]-1H-benzimidazol-1-yl]ethanohydrazides (6).

Conventional method:

In the solution of [2-(2,4-dinitrophenylsulfanyl) benzimidazol-1-yl]acetic acid ethyl ester (8.04 gm, 0.02 mole) in methanol, and hydrazine hydrate (1.8 ml) was added drop wise and heated for 7-9 hrs till TLC (ethyl acetate:hexane, 4:1) showed complete conversion. The solvent was then distilled off and residue was poured into ice cold water to yield a solid which was collected by filtration and re-crystallized from chloroform to give the 2-{2-[(2,4-dinitrophenyl)sulphanyl]-1H-benzimidazol-1-yl]ethanohydrazide (4.65 gm, 60%) m.p. 150-152 °C. Anal. Calcd for C₁₅H₁₂N₆O₅S: C, 46.39; H, 3.11; N, 21.64; Found: C, 46.21; H, 3.05; N, 21.85%. IR (KBr): υ (cm^-1) 3350 and 3375 (NH and NH₂), 1688 (C=O).

Microwave irradiation method:

[2-(2,4-dinitrophenylsulfanyl)-benzimidazol-1-yl]acetic acid ethyl ester (8.04 gm, 0.02 mole) and hydrazine hydrate (1.8 ml) in methanol were placed in a conical flask inside a microwave oven and irradiated (360 W) for 3.0 min. up on completion of the reaction (monitored by TLC), the reaction mixture was allowed to attain room temperature and treated with water. The formed precipitate was filtered off and re-crystallized from chloroform to give the 2-{2-[(2,4-dinitrophenyl) sulphanyl]-1H-benzimidazol-1-yl]ethanohydrazide (90%).

Synthesis of [2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-yl]acetic acid(substituted-benzylidene)hydrazides (7a-g).

General procedure:

A mixture of compound [2-(2,4-dinitrophenylsulfanyl) benzimidazol-1-yl]acetic acid hydrazide (0.005 mole), the appropriate aromatic or heterocyclic aldehyde, namely, benzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, p-methoxybenzaldehyde, or 2-furancarboxaldehyde (0.005 mole), absolute ethanol (20 ml) and 4 drops glacial acetic acid was heated under refluxed for 3-4 hours. Then the reaction mixture was concentrated, cooled to room temperature and poured into ice water. The formed precipitate was filtered off, washed with water and ethanol, and purified by ethanol re-crystallization technique to give the title compounds 7a-g.

Synthesis of [2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-yl]acetic acid benzylidenehydrazide (7a):

1.49 gm, (63 %), m.p.165 °C. Anal. Calcd for C₂₂H₁₆N₆O₅S: C, 55.46; H, 3.38; N, 17.64; Found: C, 55.24; H, 3.34; N, 17.96% Mol. Wt.: 476.47. IR (KBr): υ (cm^-1) 3285 (NH), 1660 (C=O), 1620 (C=N), 1535 & 1340 (NO₂), 724 (C-S-C); ¹HNMR: δ 4.32 (s, 2H, N-CH₂-CO); 7.25-7.65 (m, 9H); 7.75 (d, 1H, J = 7.5Hz); 8.15 (s, 1H, -CH=N); 8.32 (d, 1H, J = 7.5Hz); 8.75 (s, 1H); 9.24 (s, 1H, -NH); MS: molecular ion (M⁺) peak at m/z 477 (m+H).

Synthesis of 2[2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]acetic acid (2-chlorobenzylidene) hydrazide (7b):

1.53gm, 60 %, m.p. 133-135 °C. Anal. Calcd for C₂₂H₁₅ClN₆O₅S: C, 51.72; H, 2.96; N, 16.45; Found: C, 51.64; H, 2.84; N, 16.26; Mol. Wt.: 510.91. IR (KBr): υ (cm^-1) 3315 (NH), 1665 (C=O), 1625 (C=N), 1530 & 1335 (NO₂), 735 (C-S-C); ¹HNMR: d 4.35 (s, 2H, N-CH₂-CO); 7.10-7.50 (m, 8H); 7.60 (d, 1H J = 7.5Hz); 8.10 (s, 1H, -CH=N); 8.42 (d, 1H, J = 7.5Hz); 8.88 (s, 1H); 9.26 (s, 1H, -NH).

Synthesis of [2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]-acetic acid (3-chlorobenzylidene) hydrazide (7c):

1.58 gm, 62 %), m.p.140-142 °C. Anal. Calcd for C₂₂H₁₅ClN₆O₅S: C, 51.72; H, 2.96; N, 16.45; Found: C, 51.64; H, 2.84; N, 16.26; OMol. Wt.: 510.91. IR (KBr): υ (cm^-1) 3280 (NH), 1670 (C=O), 1630 (C=N), 1540 & 1350 (NO₂), 734 (C-S-C); ¹HNMR: d 4.42 (s, 2H, N-CH₂-CO); 7.15-7.40 (m, 8H); 7.65 (d, 1H J = 7.5Hz); 8.16 (s, 1H, -CH=N); 8.36 (d, 1H); 8.86 (s, 1H,); 9.28 (s, 1H, -NH).

Synthesis of [2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]-acetic acid (2-nitrobenzylidene) hydrazide (7d):

1.56 gm, 60 %), m.p.170-172 °C. Anal. Calcd for C₂₂H₁₅N₇O₇S: C, 50.67; H, 2.90; N, 18.80; Found: C, 50.24; H, 2.76; N, 17.96; Mol. Wt.: 521.46. ¹HNMR: d 4.45 (s, 2H, N-CH₂-CO); 7.25-7.96 (m, 8H); 8.24 (s, 1H, -CH=N); 8.42 (d, 2H,); 8.85 (s, 1H,); 9.42 (s, 1H, -NH); MS: molecular ion (M⁺) peak at m/z 522 (m+H)

Synthesis of [2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]-acetic acid (3-nitrobenzylidene) hydrazide (7e):

1.58 gm, 61 %), m.p.161-163 °C. Anal. Calcd for C₂₂H₁₅N₇O₇S: C, 50.67; H, 2.90; N, 18.80; Found: C, 50.24; H, 2.76; N, 17.96; Mol. Wt.: 521.46. IR (KBr): υ (cm^-1) 3350 (NH), 1650 (C=O), 1630 (C=N), 1535 & 1357 (NO₂), 744 (C-S-C); ¹HNMR: d 4.47 (s, 2H, N-CH₂-CO); 7.30-7.72 (m, 6H); 7.95-8.15 (m, 2H); 8.24 (s, 1H, -CH=N); 8.26 (d, 1H); 8.58 (s, 1H); 8.88 (s, 1H); 9.46 (s, 1H, -NH).

Synthesis of [2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]-acetic acid (4-methoxybenzylidene) hydrazide (7f):

1.53gm, 60 %), m.p. 120-123 °C. Anal. Calcd for C₂₃H₁₈N₆O₆S: C, 54.54; H, 3.58; N, 16.59; Found: C, 50.24; H, 2.76; N, 17.96; IR (KBr): υ (cm^-1) 3250 (NH), 1650 (C=O), 1615 (C=N), 1545 & 1355 (NO₂), 738 (C-S-C); ¹HNMR: d 3.56 (s, 3H, -OCH₃); 4.63 (s, 2H, N-CH₂-CO); 6.76 (d, 2H); 7.35-7.78 (m, 7H); 8.24 (s, 1H, -CH=N); 8.36 (d, 1H); 8.88 (s, 1H,); 9.41 (s, 1H, -NH); MS: molecular ion (M⁺) peak at m/z 507 (m+H).

Synthesis of [2-(2,4-dinitrophenylsulfanyl) benzoimidazol-1-yl]acetic acid furan-2-ylmethylenehydrazide(7g):

1.58 gm, 62 %), m.p.144-146 °C. Anal. Calcd for C₂₀H₁₄N₆O₆S: C, 51.50; H, 3.03; N, 18.02; Found: C, 51.46; H, 3.14; N, 18.26; Mol. Wt.: 466.41. IR (KBr): υ (cm^-1) 3295 (NH), 1670 (C=O), 1620 (C=N), 1530 & 1335 (NO₂), 744 (C-S-C); ¹HNMR: d 4.53 (s, 2H, N-CH₂-CO); 6.75-7.00 (m, 2H); 7.26-7.74 (m, 6H); 7.82 (s, 1H, -CH=N); 8.34 (d, 1H); 8.87 (s, 1H,); 9.34 (s, 1H, -NH); MS: molecular ion (M⁺) peak at m/z 467 (m+H).

Synthesis of 5-[2-(2,4-dinitrophenylsulfanyl) benzimidazol-1-ylmethyl]-[1,3,4]oxadiazole-2-thiol (8):

A mixture of 2-{2-[(2,4-dinitrophenyl)-sulphanyl]-1H-benzimidazol-1-yl]-ethanohydrazide (0.01 mole), potassium hydroxide (0.84 gm, 0.015 mole) and carbon disulphide (20 ml) in ethanol (200 ml) was heated under reflux for 8 hours. Then it was concentrated, acidified with dilute hydrochloric acid and the resulting solid was collected, washed with water and re-crystallized to give 5-[2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-ylmethyl]-[1,3,4]oxadiazole-2-thiol m.p. 200 °C. Anal. Calcd for C₁₆H₁₀N₆O₅S₂, C, 44.65; H, 2.34; N, 19.53; Found: C, 44.21; H, 2.05; N, 19.85. IR (KBr): υ (cm^-1) 3375 (NH), 1688 (C=O) 1620 (C=N), 1535 & 1340 (NO₂), 1370 (C=S), 1100 (C-O-C). ¹HNMR: (200 MHz,) d(ppm) 4.13 (s, 2H, N-CH₂-CO); 7.29-7.69 (m, 5H, Ar); 8.16 (s, br, 1H, NH); 8.35 (d, 1H); 8.85 (s, 1H); MS: molecular ion (M⁺) peak at m/z 431 (m+H).

RESULTS AND DISCUSION:

1H-Benzimidazole-2-thiol (2) was prepared by refluxing respective o-phenylenediamine (1) with carbon disulphide in ethanol-water solution of sodium hydroxide. It was treated with 2,4-dinitrochlorobenzene (3) in presence of a base by conventional and microwave induced methods afford to 2-[(2,4-dinitrophenyl)sulphanyl]-1H-benzimidazole (4). Formation of the compounds 4 was evidenced by absence of C=S absorption band at 1200 cm^-1, NHabsorption band at ~ 3300 cm^-1and appearance of new absorption bands at 1520 and 1350 cm^-1 pertaining to NO₂ group in IR spectra. ¹H NMR spectra of compound 4 showed signals at δ (ppm) 7.25-7.53 (m, 4H, Ar), 7.79 (d, 1H, J = 7.5 Hz), 8.39 (d, 1H, J = 7.5 Hz); 8.39 (s, 1H); 13.5 (s, br, 1H, benzimidazole NH) conform the formation of 1H-benzimidazole-2-yl-(2,4-dinitrophenyl)sulphide (4).

Reagents and conditions: (i) a) Conventional method: Ethyl Chloroacetate, K₂CO₃, ethanol, reflux, 20 hrs; b) Microwave method: Ethyl Chloroacetate, K₂CO₃,DMF, 6.0 min (ii) a) Conventional method: Hydrazine hydrate, methanol, reflux, 1 h. b) Microwave method: Hydrazine hydrate, 1,4-dioxane, 2 min.

Reagents and conditions: (i) Ethanol, acetic acid, reflux (ii) R₁-CHO, CS₂, NaOH, aq. methanol, reflux

[2-(2,4-Dinitrophenylsulphanyl)-1H-benzimidazol-1-yl] acetic acid hydrazide has been treated with carbon disulphide and potassium hydroxide in methanol, to give 5-[2-(2,4-dinitrophenylsulfanyl)benzimidazol-1-ylmethyl]-[1,3,4]-oxadiazole-2-thiol (8) with melting point 200 °C. The compound thus obtained was characterized as 8 using its analytical analysis and spectral data.

ACKNOWLEDGMENTS:

The authors are thankful to the Management of C.K.M. Arts and Science College for providing amenities and also thankful to Indian Institute of Chemical Technology, Hyderabad for Spectral support.

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Received on 26.12.2013 Modified on 12.01.2014

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