Trifluoroacetic Acid as an Efficient Catalyst for the Room Temperature Synthesis of 2-Aryl-1-arylmethyl-1 H-1 , 3-benzimidazoles in Aqueous Media

Trifluoroacetic acid (TFA) is introduced as a commercially available, inexpensive and effective catalyst for the selective and ecocompatible synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles via condensation reaction of o-phenylenediamine derivatives and aromatic aldehydes in ethanol/water at room temperature.


Introduction
The benzimidazole core is classified by medicinal chemists as one of the 'privileged substructures' for drug design, in light of the affinity they display towards a variety of enzymes and protein receptors 1 .They have emerged as potent non nucleoside inhibitors of HIV-1 reverse transcriptase 2 and specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) 3 .Appropriately functionalized 1,2-disubstituted benzimidazoles are used as agonists against c-butyric acid A receptor (GABAA) 4 .Moreover, they display potent thrombin inhibitory activity 5 and antibacterial activity against gram-positive bacteria 6 .
Among the transformations leading to benzimidazoles 7 , the reaction of o-phenylenediamine with aldehydes in the presence of acidic catalysts under various reaction conditions is of great importance 8 .This is due to the fact of one-pot nature and simplicity of the procedures and their usefulness for the creation of diverse chemical libraries of potentially 'drug-like' molecules for biological screening 9 .However, a few really simple and efficient protocols are exist 8f-g most of these methods have several drawbacks such as low yields, use of expensive reagents, a special oxidation process or long reaction times, tedious work-up procedures, occurrence of several side reactions and poor selectivity.Therefore, the search continues for a better catalyst for the synthesis of benzimidazoles in terms of operational simplicity, economic viability and in particular, with greater selectivity.TFA is the simplest perfluorinated carboxylic acid which is commercially available.TFA is a versatile solvent for acid stable compounds in NMR spectroscopy and also used as a calibrant in mass spectrometry.Because of its interesting properties, such as low toxicity, solubility in water and organic solvents, and strength, TFA is considered to be a special reagent for highly sensitive microsequencing of proteins 10 , as well as a special catalyst for promotion of numerous organic reactions 11 , Furthermore, because of high oxidative resistance and also due to its ability to dissolve considerable amounts of molecular oxygen, oxidation of organic substrates in the media of TFA has been well documented 12 .
As a part of our ongoing programs on the studying of catalytic ability of TFA 11a , here we introduced TFA as a new inexpensive and commercially available catalyst for the room temperature chemoselective synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazole derivatives in aqueous media via the condensation reaction of o-phenylenediamines 1 and aromatic aldehydes 2 (Scheme 1).

Experimental
A mixture of o-phenylenediamine derivatives 1 (1 mmol), aromatic aldehyde 2 (2 mmol), and TFA (0.3 mmol) in 5 mL of water/ethanol mixture (1/2), was stirred in a round bottomed flask at room temperature for the appropriate time (c.f.Table 2).The progress of the reaction was followed by TLC.After completion of the reaction, the precipitates were filtered, washed with water (2 × 10 mL) and air dried to afford the desired product.Finally the crude product was recrystallized from ethanol.All compounds 3 gave satisfactory spectroscopic data in accordance with their proposed structures 7-8 .

Results and Discussion
Initially, condensation of o-phenylenediamine and benzaldehyde was performed with different molar ratio of TFA, solvents and temperatures to optimize the reaction conditions.As shown in Table 1, a mixture of 30 mol% of TFA in H 2 O/ethanol (1:2) created the best reaction media and afforded the corresponding benzimidazole 3a with optimum yields among the conditions tested.

b Calculated from GC chromatogram of reaction mixtures
There is an urgent need to develop alternative solvents and technologies because of pressure from governmental organizations and other regulatory bodies to protect the environment.Use of green solvents such as water showed both economical and synthetic advantages.Thus, however some tested solvent and conditions such as acetonitrile at 80 o C (Table 1, entry 4) and reflux chloroform (Table 1, entry 5) were effectively performed benzimidazole 3a, we decided to investigate the reaction in water/ethanol (1/2) media.Consequently several aromatic aldehydes with different substituents on the aromatic ring were subjected to the condensation reaction.In all cases, the reactions were clean and complete within 15-60 min.All products, except 3m are known compounds and were characterized by 1 H NMR spectroscopy and/or comparison of their physical properties with those of authentic samples.New product 3m is unambiguously characterized by its 1 H-, 13 C NMR and mass spectroscopic data.
On careful analysis of Table 2 we can say that our methodology is quite a general one being applicable to reactions with substitutions in the diamine (with H, Me and Cl).However, aldehydes bearing electron-donating substituents gave more desired benzimidazoles (Table 2, entries 1-5 and 9-16) than electron-withdrawing substituents (Table 2, entries 6-8).
The chemoselectivity of the procedure was examined by analysis of 1 H NMR spectra of reaction mixtures.When the reactions were completed the product mixtures 3 and 4 (if it has been created) were washed with water, dried and used for 1 H NMR analysis without further purification.In almost all cases, 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles 3 are the sole product and signals indicating of monosubstituted benzimidazoles 4 were not detected on the 1 H NMR spectra.However, in the cases that both product 3 and 4 were formed (Table 2, entries 3, 6, 7, 8, 15), their ratio determined by division of area of corresponding signals in 1 H NMR spectra of mixtures.Table 2 shown, using this procedure there is no clear relation between electron-withdrawing and releasing nature of substituent of aldehydes with the ratio of their corresponding benzimidazoles 3 and 4.

Conclusion
In summary, we have reported a new and effective methodology for the selective and ecocompatible preparation of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles via condensation reaction of o-phenylenediamine derivatives and aromatic aldehydes using commercially available, inexpensive TFA as an organocatalyst at room temperature.The use of ethanol/water as the reaction media, mild reaction conditions, operational and experimental simplicity suggest good prospects for the applicability of this process.

Table 1 .
Effect of TFA molar ratio and reaction conditions on the condensation of o-phenylenediamine (1 mmol) with benzaldehyde (2 mmol) to produce 3a a a Compound 4a was not obtained.