Direct conversion of alkyl halides into benzimidazoles using pyridine-N -oxide and 1,2-diaminobenzenes

Benzimidazole heterocycles were obtained from halogenated compounds and aromatic 1,2-diamines. A mild oxidizing reagent such as pyridine N -oxide (PyO) is required to produce the benzimidazole core. The method is solvent free and provides products without the need for chromatography. Good yields, moderate reaction temperature, fast reaction rates are important advantages of this procedure.


Introduction
Many important biological compounds contain the benzimidazole skeleton. 1Benzimidazoles are valuable pharmacophores in compounds employed for the treatment of various human and animal diseases. 2,3 nzimidazole derivatives are used as anti-inflammatory analgesic agents, 4 giardicidal drugs, 5 phosphorylase inhibitors, 6 HIV-1 RT inhibitors, 7 anti-hypertensive agents, 8 histamine H3 receptor ligands, 9 antibacterial and antifungal agents, 10 anti-ulcer drugs 11 and anti-tumour agents. 12Only benzimidazoles substituted at positions 1, 2 and 5 of the core reveal high antimicrobial activity. 13any benzimidazole derivatives form complexes with transition metal cations and also have interesting pharmacological properties. 14,15Silver(I) complexes containing V-shaped bis-benzimidazole ligands exhibit antioxidant activity and DNA-binding properties. 16Benzimidazole-based copper and zinc complexes display analgesic, antipyretic, anti-inflammatory, 17 antitumor 18 and nuclease activity. 19,20 ome of the d10 transition metal coordination polymers based on bis(benzimidazole) ligands show luminescent properties 21 and cobalt(II) benzimidazole complexes have been used as catalysts in polymerization reactions. 224][25][26][27][28] The major drawbacks of these procedures are severe dehydrating reaction conditions, high temperature, considerable reaction time up to one day, and very strong acid catalysts.
Domino Mitsunobu reactions, 29 intramolecular cyclization of o-bromoaryl derivatives using copper(II) oxide nanoparticles in DMSO, 30 and the intramolecular cyclocondensation of the common arylamino oximes in the presence of methanesulfonyl chloride and triethylamine 31 can also be used to produce benzimidazole derivatives.However, all these synthetic routes require expensive metal catalysts, toxic solvents and a long reaction time up to 50 hours.
Reductive cyclization of o-nitroarylamines with aldehydes using sodium dithionite 32,33 or formic acid, iron powder and NH4Cl 34 leads to benzimidazole derivatives.These procedures use a large amount of reducing agent which leads to waste at the end of the synthesis.
Oxidative methods have also been implemented for benzimidazole preparation from Schiff bases of aldehydes and ortho-phenylenediamines.The oxidizing agent carries out dehydrocyclization of an imine intermediate.Some of the most employed oxidants are hypervalent iodine, 35 hydrogen peroxide, 36 Oxone, 37 air, 38 lead tetraacetate, 39 potassium ferricyanide, 40 nitrogen dioxide and ozone, 41 zirconyl chloride octahydrate/ montmorillonite K-10, 42 .These procedures have important drawbacks such as laborious workup, difficult benzimidazole purification, toxic byproducts containing heavy metals and low yields.
Recently, a patent described a method for benzimidazole preparation starting from o-aminoanilines, organic halides, DMSO and copper halide and sodium bicarbonate as catalysts.The protocol employs huge amounts of hazardous organic solvents and the reaction needs one day to produce the benzimidazoles. 43

Results and Discussion
We accomplished the synthesis of benzimidazole derivatives starting from a benzylic halide and a 1,2phenylenediamine.This is the first method of synthesis of benzimidazoles from organic halides by means of pyridine N-oxide (PyO) involving a one-pot reaction without catalyst or solvent (Scheme 1).

Scheme 1 One-pot three component process for benzimidazole synthesis.
To establish optimal experimental conditions for synthesis of the benzimidazole derivatives, we first studied the reaction between o-phenylenediamine, 1-(bromomethyl)-4-methylbenzene and pyridine N-oxide to obtain 2-(p-tolyl)-1H-benzimidazole.The reaction was conducted at different temperatures and stoichiometry of reactants and reagent to establish a yield of product and a reaction time, Table 1.
Optimal conditions were found to be an equimolar ration of reactants with 2.5 eq of PyO, which at 105 °C gave the best yield of 78% after 2 hours (Table 1, entry 6 ).Mechanistically, it is reasonable to postulate that 4-methylbenzyl bromide is transformed into 4methylbenzaldehyde (A) by means of PyO (Scheme 2), akin to a Kornblum reaction achieved under mild conditions. 44The condensation reaction between 4 Using the optimal condition for 2-(p-tolyl)-1H-benzimidazole synthesis a number of benzimidazoles were prepared.In general, the yields obtained were high (Table 2).The experimental conditions such as the molar ratio of reactants, temperature, the nature of reagents, amine and organic halide, and the reaction time influence the amount of benzimidazole product.
Electron-withdrawing groups attached to the aromatic ring of the bromide such as a nitro substituent, increase the electrophilic character of the primary carbon atom, increasing the rate of alkylation with PyO and facilitatating the formation of the aldehyde intermediate.Similarly, electron-donating groups on the aromatic ring of the diamine of the o-phenylenediamine such as alkyl, methoxy and halogen substituents increase amine nucleophilicity , resulting in an increase in the rate of formation of the intermediate Schiff base and the subsequent intramolecular cyclization to afford the 2,3-dihydro-1H-benzoimidazole derivative.Moreover, the reducing strength of the 2,3-dihydro-1H-benzoimidazole derivative increases and the oxidation reaction with PyO occurs more easily in the presence of an electron-donating group.In both cases the reaction yield of the benzimidazole product increases notably (Table 2, entries 4, 5 and 10).
The method that we have developed uses a benzylic bromide and an aromatic 1,2-diamine in stoichiometric ratio.The method provides an alternative route for benzimidazole preparation in a dry medium by a convergent reaction.The benzimidazole products were easily purified by recrystallization from solvents such as ethanol-water mixtures.Moreover toxic hydrogen bromide is not released during the reaction but is trapped by the pyridine generated during the process.

Conclusions
A new procedure for conversion of benzyl bromides into benzimidazole derivatives was developed.
Benzimidazoles were synthesized by a one-pot three-component reaction starting from benzyl bromides, ophenylenediamines and pyridine N-oxide.The synthesis does not require catalysts and solvents.The procedure constitutes an alternative to current methods that all use either hazardous catalysts or toxic organic solvents as reaction media and separation of benzimidazoles by chromatographic techniques.Important benefits of the method are also a significantly short reaction time, moderate temperature, and lower energy consumption than in the other methods.

Experimental Section
General.Organic bromides, ortho-phenylenediamine, pyridine N-oxide are commercial compounds.The synthesized products were identified by TLC (EtOAc-petroleum ether) and 1 H-NMR.The 1 H-NMR spectra were recorded on a BRUKER ARX instrument (300 MHz).DMSO-d6 was used as the solvent and tetramethylsilane as an internal standard.The melting points were determined on a Gallenkamp digital melting point apparatus.

Table 2 .
Continued a Isolated and unoptimized yields.