A fast, high efficiency and environmentally friendly procedure for the synthesis of 2-aryl benzim-idazole derivatives has been reported. Reaction between 1,2-phenylenediamine derivatives and arylidene malononitrile under aqueous media and also solvent-free conditions generates 2-aryl benzimidazole derivatives with a high yield.
In recent years, significant attentions have been considered to the organic reaction under aqueous media, particularly from the viewpoint of green chemistry [
In view of the biological importance of benzimidazoles, there have been growing interests in the development of efficient, fast, simple and environment friendly synthetic methods for the preparation of these molecules. Several procedures have been reported for the synthesis of 2-substituted benzimidazoles: Condensation of 1,2- phenylenediamines with carboxylic acids, acid chlorides, nitriles, imidates and orthoesters under strong acidic conditions, sometimes combined with very high temperatures or useing microwave irradiation, [
In order to further development of synthetic route of benzimidazoles under green reaction conditions, here, we devoted our effort for the synthesis of 2-aryl benzimidazole derivatives in water as a green solvent as well as solvent-free conditions (Scheme 1).
In this work, we report a highly efficient, and environmentally benign procedure for the reaction of 1,2-pheny- lenediamine derivatives 1 with arylidenemalononitrile 2 in aqueous medium as a green solvent to produce benzimidazole derivatives 3. Also, in continuation of our goal towards performing of this reaction under another green condition, we have developed reaction between reactants under solvent-free condition using thermal heating method after grinding. Arylidenemalononitrile 2 was reacted with 1,2-phenylenediamine derivatives in the presence of water to produce the related products 3 with excellent yields. We initially employed 1,2-phenyl- nediamine 1a (1 mmol) and arylidenemalononitrile 2a (2 mmol) in water at room temperature as a model reaction. In this condition the reaction wasn’t complete after 14 hours (
Scheme 1. Synthesis of 2-aryl benzimidazole derivatives.
Entry | Solvent | Tem. [˚C] | Time [min] | Yield [%]b |
1 | H2O | 25 | 14h | 40 c |
2 | H2O | 50 | 5 | 75 |
3 | H2O | 50 | 10 | 79 |
4 | H2O | 50 | 15 | 83 |
5 | H2O | 50 | 20 | 83 |
6 | H2O | 75 | 5 | 80 |
7 | H2O | 75 | 10 | 86 |
8 | H2O | 75 | 15 | 89 |
9 | H2O | 75 | 20 | 92 |
10 | H2O | 75 | 30 | 92 |
11 | H2O | 90 | 10 | 88 |
12 | H2O | 90 | 20 | 90 |
13 | H2O | 90 | 30 | 90 |
14 | EtOH | reflux | 20 | 91 |
15 | MeOH | reflux | 20 | 89 |
16 | Acetone | reflux | 20 | 70 |
17 | DMSO | 50 | 20 | 85 |
18 | THF | 50 | 20 | 77 |
19 | CHCl3 | reflux | 20 | 65 |
20 | No solvent | 75 | 20 | 79 |
21 | No solvent | 90 | 20 | 82 |
22 | No solvent | 90 | 30 | 87 |
aReaction condition: 1,2-phenylenediamine 1a (1 mmol) and arylidenemalononitrile 2a (2 mmol); bIsolated yield. cyield based on TLC analysis.
3a (
In continuation of this study, we are interested in solvent-free conditions as another green procedure by using grinding method. Thus, we have synthesized a series of 2-substituted benzimidazoles 3a-p by the reaction of reactants under this method on heating. Therefore, the reaction of arylidenemalononitrile 2a and 1,2-phenylne- diamine 1a proceeded successfully in an open vial through grinding of two components together and then heating at 90˚C for 30 min. This reaction started immediately after heating, with liquification of the mixture, followed by solidification of the mixture of reaction. By comparing the reaction time and yields of entries 20 to 22 in
Compound | Ar | R1 | R2 | M.p. (lit. m. p.)/[˚C] | H2Oa | Solvent-freeb | Ref. | |
Yield [%]c | Yield [%]c | |||||||
3a | C6H5 | H | H | 287-289 (288-290) | 92 | 87 | [ | |
3b | 2-Cl-C6H4 | H | H | 231-233 (233-234) | 86 | 87 | [ | |
3c | 4-Cl-C6H4 | H | H | 291-293 (287-289) | 89 | 88 | [ | |
3d | 3-NO2-C6H4 | H | H | 204-207 (205) | 88 | 87 | [ | |
3e | 4-NO2-C6H4 | H | H | 325-327 (328) | 90 | 91 | [ | |
3f | 3-MeO-C6H4 | H | H | 202-205 (201-204) | 86 | 83 | [ | |
3g | 4-MeO-C6H4 | H | H | 223-226 (225) | 93 | 90 | [ | |
3h | 4-Me-C6H4 | H | H | 275-276 (278) | 92 | 90 | [ | |
3i | 4-Br-C6H4 | H | H | 299-300 (298) | 85 | 87 | [ | |
3j | 2-C4H4S | H | H | 330-333 (330) | 90 | 88 | [ | |
3k | C6H5 | Me | H | 240-242 (241-242) | 93 | 91 | [ | |
3l | 2-Cl-C6H4 | Me | H | 104-106 (106-108) | 87 | 88 | [ | |
3m | 4-Cl-C6H4 | Me | H | 225-227 (224) | 90 | 89 | [ | |
3n | C6H5 | Me | Me | 251-252 (244-247) | 85 | 87 | [ | |
3o | 2-C4H4S | Me | Me | 240-242 | 93 | 91 | [ | |
3p | 3-MeO-C6H4 | Me | Me | 240-243 | 93 | 90 | [ |
aReaction condition: 1,2-phenylenediamine derivatives 1 (1 mmol), arylidene malononitrile 2 (2 mmol), water (5 ml) under 75˚C and 20 min; bReaction condition: 1,2-phenylenediamine derivatives 1 (1 mmol), arylidene malononitrile 2 (2 mmol), grinding heating at 90˚C for 30 min; cIsolated yield.
electron-donating and electron-deficient groups were suitable for this reaction because the products were obtained in excellent yields. In addition, a heterocyclic arylidenemalononitrile such as 2-(thiophen-2-ylmethylene) malononitrile could react with 1,2-phenylenediamine and 4,5-dimethyl-1,2-phenylenediamine to afford the corresponding benzimidazole (
In summary, we have reported green and highly efficient method for the synthesis of 2-aryl benzimidazoles in water as well as under solvent-free and catalyst-free conditions. The main advantages of these procedures are environmentally friendly, the operational simplicity, short reaction times, simple work-up procedures and high yields.
Scheme 2. Plausible mechanism for the formation of products 3a-p.
1,2-phenylenediamine derivatives, malononitrile and aldehyde derivatives were purchased from the Merck and Fulka companies and were used without further purification. Melting points were determined on Electrothermal 9100 apparatus. 1H NMR spectra was recorded on a Bruker Avance 300 MHz employing tetramethylsilane as an internal standard.
1,2-phenylenediamine (1 mmol) was dissolved in 5 ml water at 75˚C. Then, arylidenemalononitrile (2 mmol) was added to this solution, and immediately the reaction mixture liquefied and resolidified. The reaction was monitored by TLC (petroleum ether: Ethyl Acetate (8:2)) till the disappearance of the starting arylidene malononitrile. After cooling the resultant reaction mixture, recrystalization in ethanol-water and finally pure 2-aryl bezimidazole was filtered out.
Arylidenemalononitrile (2 mmol) and 1,2-phenylenediamine (1 mmol) were mixed thoroughly with glass stirrer and heated at 90˚C. The reaction mixture liquefied and resolidified in 30 min. Completion of the reaction was checked by TLC (petroleum ether: Ethyl Acetate (8:2)). After cooling the resultant semi-solid reaction mixture, crystallization was performed in ethanol-water and 2-aryl bezimidazole was filtered out.
2-Phenylbenzimidazole [
2-(2-Cholorophenyl) benzimidazole [
2-(4-Chlorophenyl) benzimidazole [
2-(3-Nitrophenyl) benzimidazole [
2-(3-Methoxyphenyl) benzimidazole [
2-(4-Methoxyphenyl) benzimidazole [
2-(Thiophen-2-yl) benzoimidazole [
5,6-Dimethyl-2-phenylbenzoimidazole [
2-(3-Methoxyphenyl)-5,6-dimethylbenzoimidazole [
AzizollahHabibi,YousefValizadeh,MarjanMollazadeh,AbdolaliAlizadeh, (2015) Green and High Efficient Synthesis of 2-Aryl Benzimidazoles: Reaction of Arylidene Malononitrile and 1,2-Phenylenediamine Derivatives in Water or Solvent-Free Conditions. International Journal of Organic Chemistry,05,256-263. doi: 10.4236/ijoc.2015.54025