Facile and efficient one-pot synthesis of benzimidazoles using lanthanum chloride

Background We report the synthesis of benzimidazoles using lanthanum chloride as an efficient catalyst. One-pot synthesis of 2-substituted benzimidazole derivatives from o-phenylenediamine and a variety of aldehydes were developed under mild reaction conditions. Results We have examined the effect of different solvents using the same reaction conditions. The yield of the product varied with the nature of the solvents, and better conversion and easy isolation of products were found with acetonitrile. In a similar manner, the reaction with o-phenylenediamine and 3,4,5-trimethoxybenzaldehyde was carried out without any solvents. The observation shows that the reaction was not brought into completion, even after starting for a period of 9 h, and the reaction mixture showed a number of spots in thin-layer chromatography. Conclusions In conclusion, lanthanum chloride has been employed as a novel and efficient catalyst for the synthesis of benzimidazoles in good yields from o-phenylenediamine and a wide variety of aldehydes. All of the reactions were carried out in the presence of lanthanum chloride (10 mol%) in acetonitrile at room temperature.


Background
Benzimidazole nucleus is found in a variety of naturally occurring compounds such as vitamin B12 and its derivatives; it is structurally similar to purine bases. Benzimidazoles and its derivatives represent one of the most biologically active classes of compounds, possessing a wide spectrum of activities, and these are well documented in the literature. They show selective nonpeptide luteinizing hormone-releasing hormone antagonist, lymphocytespecific kinase inhibitor, N-methyl-D-aspartate antagonist, 5-liopoxygenase inhibitor, NS5B polymerase inhibitor (Figure 1), neuropeptide YY1 receptor antagonist, nonpeptide thrombin inhibitor, γ-aminobutyric acid receptor, factor Xa inhibitor, and poly (ADP-ribose) polymerase inhibitor. DNA-minor groove-binding agents possess antitumor activity, topoisomerase I inhibitors, angiotensin II inhibitors, and proliferation inhibitors. Several benzimidazole derivatives find applications that include antimicrobial, antihypertensive, anticancer antiulcer, antifungal, antihistamine activity, herbicides, and other veterinary applications as promising drugs in different therapeutic categories. The benzimidazole moieties express a significant activity against several viruses such as HIV, herpes (HSV-1), RNA influenza, human cytomegalovirus, selective angiotensin II inhibitors, and 5-HT3 antagonists. In addition, benzimidazoles are very impotent intermediates in synthetic routes and serve as ligands for asymmetric catalysts [1][2][3][4][5][6][7][8]. The high profile of biological applications of the benzimidazole compounds has prompted the emergence of extensive studies of their syntheses. In this context, numerous efforts have been made to synthesize benzimidazole derivatives. One of the most common methods for the preparation of benzimidazole derivatives involves the condensation of an o-phenylenediamine and carbonyl compounds such as aldehydes and acid derivatives. The condensation of o-phenylenediamine with carboxylic acid often requires strong acidic conditions and high temperatures [9,10]. The other method involves the oxidative cyclodehydrogenation of Schiff bases, which is generated from o-phenylenediamine and aldehydes in the presence of various catalysts. This is the most popular approach in general for the synthesis of benzimidazole derivatives. The catalysts used are CAN, K 3 PO 4 , oxone, sulfamic acid, DDQ, PhI (OAc) 2 , iodine, and KHSO 4 [11][12][13][14][15][16][17]. In addition, several catalysts such as metal halides and metal oxychlorides, [18][19][20][21][22] metal oxides, PTSA, metal triflates, air, [23][24][25][26][27][28][29][30] ionic liquid, heteropoly acid, BDSB [31][32][33], proline, solid-supported catalysts, polymer-supported catalysts [34,35], and microwave-promoted [36][37][38][39] and clayzic [40] reactions have been reported in the literature. Unfortunately, many of these methods suffer from drawbacks such as drastic reaction conditions, low yields, tedious workup procedures, and co-occurrence of several side reactions. As a consequence, the introduction of an efficient and mild method is still needed to overcome these limitations.

Methods
Melting points were recorded on a Buchi R-535 apparatus (BUCHI Labortechnik AG, Flawi, Switzerland) and were uncorrected. Infrared (IR) spectra were recorded on a PerkinElmer FT-IR 240-c spectrophotometer (PerkinElmer Instruments, Branford, CT, USA) using KBr discs. Hydrogen-1 nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Gemini-200 spectrometer (Varian Medical Systems, Palo Alto, CA, USA) in CDCl 3 using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 (Thermo Fisher Scientific, Waltham, MA, USA) mass spectrometer operating at 70 eV.
We have examined the effect of different solvents using the same reaction conditions, as shown in Table 1. The yield of the product varied with the nature of the solvents; better conversion and easy isolation of products were found with acetonitrile. Acetonitrile dissolves a wide range of ionic and nonpolar compounds. In a similar manner, the reaction with o-phenylenediamine and 3,4,5-trimethoxybenzaldehyde was carried out without any solvents. The observation shows that the reaction was not brought into completion, even after starting for a period of 9 h, and the reaction mixture showed a number of spots in thin-layer chromatography (TLC).
In a similar manner, a comparative study on the role and requirement of the catalyst for condensation has been carried out, and the obtained results are clearly shown in Table 2. The reactants for this reaction are also o-phenylenediamine and 3,4,5-trimethoxybenzaldehyde in acetonitrile. From our observation, a catalytic amount  (10 mol%) of LaCl 3 was enough to complete the conversion of aldehyde and o-phenylenediamine into the required condensation product.
A blank experiment was carried out with o-phenylenediamine and 3,4,5-trimethoxybenzaldehyde in the absence of the catalyst LaCl 3 , and the required 3,4,5trimethoxybenzimidazole product was not found even after stirring for 15 h. Finally, it was decided that the suitable conditions for condensation is in a solvent and in the presence of an activator or promoter. As shown in Table 3, aromatic, heteroaromatic, α-unsaturated and β-unsaturated aldehydes, and aliphatic aldehydes were reacted very well to afford the corresponding products of benzimidazole derivatives in very good to excellent yields. In general, the aromatic aldehydes having electron-donating groups and heteroaromatic compounds are reacting a little faster when compared with other aldehydes. In a similar manner, the aliphatic aldehydes and aromatic aldehydes containing electronwithdrawing groups are reacting comparatively a little slower in terms of conversion as well as yields, benzaldehyde and OPD, in the presence of the catalyst Lacl 3 . In general, all the reactions were completed within 2 to 4 h, and the obtained yields were 85% to 95%.

General procedure
A mixture of o-phenylenediamine (1.0 mmol) and aldehyde (1.2 mmol) in the presence of lanthanum chloride (10 mol%) was stirred in acetonitrile (5 ml) at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The crude products were purified by column chromatography. All the products were identified by their 1 H NMR, IR, and mass spectroscopy data.

Conclusions
In conclusion, lanthanum chloride has been employed as a novel and efficient catalyst for the synthesis of benzimidazoles in good yields from o-phenylenediamine and a wide variety of aldehydes. All the reactions were carried out at room temperature while using the catalyst lanthanum chloride in 10 mol%. The reaction conditions were very mild, and the isolation of products was also very easy.