Developments towards regioselective synthesis of 1,2-disubstituted benzimidazoles

1,2-Disubstituted benzimidazoles play an important role in several areas and particularly as drug discovery targets. Herein, several methods to assemble these structures are reviewed, from the classical approaches to the more recently developed metal-catalyzed intramolecular amination process, the cascade arylamination/condensation reaction and polymer-supported benzimidazole assembly under microwave conditions.     

A one-pot tandem synthesis of various 1,2-disubstituted benzimidazoles

A facile method to synthesize various 1,2-disubstituted benzimidazoles is developed. It is suggested that formation of a Meisenheimer adduct between the substrate, amine, and solvent aids the N-arylation process. The generality of the protocol is demonstrated by the efficient reactions involving numerous substituents ranging from electron-withdrawing groups to electron-donating groups.     

Copper-catalyzed synthesis of 1,2-disubstituted benzimidazoles from imidoyl chlorides

A strategy for the synthesis of 1,2-disubstituted benzimidazoles has been developed and a variety of 1,2-disubstituted benzimidazoles were obtained from imidoyl chlorides and o-haloanilines via copper(I)-catalyzed reaction in moderate yields.     

Glyoxylic acid as catalyst： A simple selective synthesis of 1,2-disubstituted benzimidazoles in aqueous media

Glyoxylic acid （5 mol%） performs as a novel highly water-soluble catalyst for the synthesis of 2-aryl-l-arylmethyl-lH- benzimidazoles from a wide range of substituted o-phenylenediamines and various substituted aldehydes in good to excellent isolated yields （85-95%） using water as solvent at ambient temperature. The remarkable advantages offered by this method are easily and inexpensive available catalyst, simple procedure, mild conditions, much faster （20--40 rain） reactions and excellent yields of products.     

One-pot sequential synthesis of 1,2-disubstituted benzimidazoles under metal-free conditions

An easy and inexpensive method has been developed to access 1,2-disubstituted benzimidazoles following a one-pot sequential coupling/reduction/cyclization process under metal-free neutral conditions.     

Chemoselective synthesis of 1,2-disubstituted benzimidazoles in lactic acid without additive

Lactic acid is recognised as a biocompatible medium for the chemoselective synthesis of the 1,2-disubstituted benzimidazole scaffold via a direct one-pot cyclocondensation of o-phenylenediamine with aldehydes. Various 1,2-disubstituted benzimidazole derivatives were successfully synthesised with high selectivity with good to excellent yields without any additional catalyst or additive. Most products could be isolated by a simple filtration after completion of the reactions. Satisfactory results were also obtained from multi-gram scale reactions.     

Highly selective synthesis of libraries of 1,2-disubstituted benzimidazoles using silica gel soaked with ferric sulfate

An efficient and highly selective synthesis of functionalized 1,2-benzimidazoles has been developed under solvent-free conditions at ambient temperature using eco-friendly ferric sulfate soaked with silica [iron(III)sulfate-silica]. Recycling of the solid support up to six runs was investigated with appreciable yield and selectivity of the product.     

A facile and highly chemoselective synthesis of 1,2-disubstituted benzimidazoles using hierarchical nanoporous material

A highly ordered nanoporous aluminosilicate (MMZ_Y) is prepared and employed as a catalyst for the synthesis of benzimidazoles from 1,2-diaminobenzene and aromatic aldehydes. In all the cases, the reactions are highly chemoselective and afford 1,2-disubstituted benzimidazoles in excellent yield. The catalyst was characterized by electron microscopy and X-ray methods and its other advantages like functional tolerance, mildness of the reaction conditions, easy separation, and reusability are also highlighted.     

Nano indium oxide: an efficient catalyst for the synthesis of 1,2-disubstituted benzimidazoles in aqueous media

Synthesis of 1,2-disubstituted benzimidazoles has been developed by the condensation of diamine with aldehydes using nano In₂O₃ as an efficient catalyst under mild reaction conditions in aqueous media. The procedure is applicable to aryl, aliphatic, heteroaryl aldehydes. In₂O₃ nanoparticles are recyclable without the loss of significant catalytic activity.     

Zn-proline catalyzed direct aldol reaction in aqueous media

Zn complexes of proline, lysine and arginine are efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in aqueous medium, giving quantitative yields and enantiomeric excesses up to 56% with 5 mol% of the catalysts at room temperature.     

Diastereoselective and enantioselective synthesis of 1,2-disubstituted cycloalkanecarboxaldehydes

A highly useful method for diastereoselective and enantioselective synthesis of trans- and cis-1,2-disubstituted cycloalkanecarboxaldehydes (trans- and cis-10), useful chiral synthons having asymmetric tertiary and quaternary carbon atoms in vicinal positions in their rings, is devised starting from cycloalkenecarboxal-dehydes (5) t-Leucine t-butyl ester (2, R=Bu^t), a highly effective chiral auxiliary reagent in the present method, can be recovered for recycling without any loss of optical purity Some mechanistic explanations on the stereochemical courses of the reactions are presented     

Efficient electrochemical synthesis of pyrido[1,2-a]benzimidazoles

Electrochemical reduction of N-(2-nitroaryl)pyridinium chlorides in alcohol—dilute HCl mixtures gave pyrido[1,2-a]benzimidazoles in high yields in both divided and undivided cells. According to cyclic voltammetry measurements and DFT calculations (B3LYP/6-31+G(d)), the reaction involves intermediate formation of the corresponding hydroxylamine derivative followed by its heterocyclization.     

Catalyst-free one-pot synthesis of benzimidazoles from 1,2-diaminoarenes and alcohols

A new and efficient protocol is described for the one-pot synthesis of benzimidazoles from a variety of aryl alcohols and 1,2-diaminoarenes. The yields were ranging from moderate to excellent. Moreover, the present method is utilizing alcohols instead of aldehydes and the reactions are carried out under solvent- and catalyst-free conditions, offering an environmentally benign process.     

A regio- and stereoselective synthesis of 1,2-disubstituted vinylsilanes

The alkylcopper reagents prepared from RMgBr and CuBr react with trimethylsilylacetylene to give regio- and stereo-selectivity 1-trimethylsilyl-1(Z)-alkenylcopper adducts. Hydrolysis affords 1-trimethylsilyl-1(E)-alkenes exclusively. Alkylation, acylation, halogenation, and stannylation proceed stereoselectively to afford synthetically useful intermediates. Homopropargylation of alkyl 1-trimethylsilyl-1(Z)-alkenylcuprates provided better yield than that of the original vinylcopper reagents.     

Regiodirected synthesis of polyfluoro-alkylated pyrimido[1,2-a]benzimidazoles

Conditions have been found for the regiodirected cyclization of 2-aminobenzimidazoles using ethyl 3-oxo-3-polyfluoroalkyl-2-ethoxymethylidenepropionates at the ethoxymethylidenefluoroacyl fragment to give ethyl pyrimidobenzimidazole-3-carboxylates.     

A simple regioselective synthesis of pyrimido[1,2-a]benzimidazoles

2-Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2-a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.     

Acetoxymercuration of acylferrocenes a novel synthesis of 1,2-disubstituted ferrocenes

Acetoxymercuration of a series of acylferrocenes has been found to produce appreciable amounts of 1,2- as well as 1,1′-mercurated products. The mercurated derivatives were readily converted into a variety of other unsymmetrical 1,2- and 1,1′-disubstituted ferrocenes. The 1,2-orientation of substituents was inferred by spectra data, and was confirmed by a comparison of products from the mercuration reactions with analogous products obtained from the 2-lithiation of [(dimethylamino)methyl]ferrocene. Both 2-(methoxycarbonyl)biferrocene and 2-acetylbiferrocene have been obtained from mixed Ullmann reactions of iodoferrocene with 2-iodo-1-(methoxycarbonyl)ferrocene and 2-iodo-1-acetylferrocene, respectively.