Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.     

Synthèse chimiosélective des benzimidazoles sur silice traitée par le chlorure du thionyle

Chemoselective synthesis of benzimidazoles in good yield was achieved with a variety of aldehydes in heterogeneous media. This efficient procedure has been developed for the condensation of ortho-phenylene-diamine with aldehydes by silica-supported thionyl chloride in dichloromethane at ambient temperature.     

Metal-free selective synthesis of 2-substituted benzimidazoles catalyzed by Brönsted acidic ionic liquid: Convenient access to one-pot synthesis of N-alkylated 1,2-disubstituted benzimidazoles

A novel efficient method for the selective synthesis of 2-substituted benzimidazoles is described through condensation reaction of o-phenylenediamines with a wide rang of aliphatic, aromatic and heteroaromatic aldehyde substrates using Brönsted acidic ionic liquid as a reusable catalyst under metal-free conditions at ambient temperature. Notably, Dodecylimidazolium hydrogen sulfate ([DodecIm][HSO₄]) is the most efficient catalyst for good to excellent yields of the corresponding products (up to 98%). Subsequently, this protocol was successfully applied for the preparation of N-alkylated 1,2-disubstituted benzimidazoles in high to excellent yields via sequential one-pot reaction. In addition, catalysts are recycled at least four times without significant loss in activity.     

1,2,3-benzotriazines. I. The synthesis of some benzimidazo [1,2-c][1,2,3]-benzotriazines and naphth[1′,2,(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine

A number of substituted benzimidazo[1, 2-c][1,2,3]benzotriazines were prepared by the diazotization of the appropriate 2-(o-aminophenyl)benzimidazoles. Diazotization of 2-(o-aminophenyl)naphth[1,2-d]imidazole yielded a new heterocyclic ring system. Various methods of preparation of 2 - (o-aminophenyl)benzimidazoles were investigated. The condensation of o-phenylenediamines with anthranilic acids, in the presence of polyphosphoric acid, provided a convenient route to 2-(o-aminophenyl)benzimidazoles but in several cases the products were contaminated with considerable amounts of 6-(o-aminophenyl)benzimidazo[1,2 -c]quinazolines. 2 - (o-Aminophenyl)benzimidazoles were also obtained by the catalytic hydrogenation of 2-(o-nitrophenyl)benzimidazoles which resulted from the condensation of an o-phenylenediamine with an o-nitrobenzaldehyde in ethanol, nitrobenzene or acetic acid. When the condensation was carried out in nitrobenzene, small amounts of 2-(o-aminophenyl)benzimidazoles were also formed. The Weidenhagen synthesis, which involves the reaction of an aromatic diamine with an aldehyde in the presence of copper acetate and subsequent decomposition of the cuprous salt of the benzimidazole, yielded 2-(o-aminophenyl)benzimidazoles instead of the expected 2-(o-nitrophenyl)benzimidazoles when the decomposition was carried out in ethanol. When the cuprous salt was treated with hydrogen sulfide in dilute hydrochloric acid, a mixture of amino- and nitrobenzimidazoles resulted. The ultraviolet and infrared spectra of all the compounds prepared were examined.     

An efficient and reusable heterogeneous catalyst Animal Bone Meal for facile synthesis of benzimidazoles, benzoxazoles, and benzothiazoles

A library of benzimidazoles, benzoxazoles, and benzothiazoles was efficiently synthesized by condensation of o-phenylenediamine, o-aminophenol, and o-aminothiophenol respectively with aromatic aldehydes in the presence of catalytic amounts of Animal Bone Meal (ABM) and Lewis acids doped ABMs. Reactions were conducted under reflux conditions in air. The remarkable features of this new protocol are high conversion, short reaction times, and cleaner reaction profiles, straightforward procedure, and reduction in catalyst toxicity.     

Tungstate sulfuric acid: preparation, characterization, and application in catalytic synthesis of novel benzimidazoles

Tungstate sulfuric acid (TSA) was prepared, characterized, and applied for direct synthesis of novel and known benzimidazoles through a condensation reaction of o-phenylenediamines with orthoesters under solvent-free conditions. TSA was characterized by powdered X-ray diffraction (XRD), X-ray fluorescence (XRF), and FTIR spectroscopy. This novel and eco-friendly method is very cheap and has many advantages such as excellent yields, recyclable and eco-friendly catalyst, and simple work-up procedure.     

Synthesis of some 1- and 2-carboxyalkyl substituted benzimidazoles and their derivatives

Mono- and disubstituted benzimidazoles were synthesized during alkaline hydrolysis or reactions with ethyl chloroacetate of 1-phenyl substituted 4-(1H-benzimidazol-2-yl)-2-pyrrolidinones. The properties of the synthesized ethyl-[2-(1-(substituted phenyl)-5-oxopyrrolidinyl-3-yl)-1H-benzimidazolyl]ethanoates have been investigated and their benzimidazolium chlorides, 1-carboxymethylbenzimidazoles, condensation products of 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-yl}acetohydrazide with various aromatic aldehydes and aliphatic ketones have been obtained.     

Mass spectral study on thiazolo[3,2-a]benzimidazoles. Studies on heterocyclic compounds. IV

Condensation of α-halocarbonyl compounds and 2-mercaptobenzimidazole gives thiazolo-[3,2-a]benzimidazoles. This condensation occurred at the mercapto group of the benzimidazole followed by cyclization to form the thiazole ring. This was confirmed by the examination of the mass spectra of 2- and 3-methylthiazolo[3,2-a]benzimidazoles, 2- and 3-phenylthiazolo[3,2-a]-benzimidazoles, and their derivatives.     

Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted benzimidazoles from o-phenylenediamines and DMF derivatives

A facile, general, and economical synthesis of diversely functionalized benzimidazoles and 2-substituted benzimidazoles has been realized via the imidazolium chloride-catalyzed cyclization of o-phenylenediamines with DMF derivatives. This protocol shows a broad substrate scope for aliphatic, aromatic, and heteroaromatic amides. A series of benzimidazoles and 2-substituted benzimidazoles have been obtained in moderate to excellent yields.     

Synthesis of seven- and eight-membered [1,2-a] alicyclic ring-fused benzimidazoles and 3-aziridinylazepino[1,2-a]benzimidazolequinone as a potential antitumour agent

Azepino and azocino[1,2-a]benzimidazoles were obtained either by treatment of 1-nitrophenyl-2-azacycloalkanes via a one-pot catalytic hydrogenation/acetylation or by treatment of the acetamides generated in the latter reaction with performic acid. This represents the first facile synthesis of eight-membered [1,2-a] alicyclic ring-fused benzimidazoles. 3-Methoxy-azepino[1,2-a]benzimidazole was elaborated to the novel potential cytotoxin, 3-(N-aziridinyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole-1,4-dione. The synthesis included clarification of the reactivity of methoxy-substituted benzimidazoles towards nitration.     

A Rapid and Convenient Synthesis of Derivatives of Imidazoles under Microwave Irradiation

An efficient and a quick microwave‐assisted synthesis of benzimidazoles and trisubstituted imidazoles was developed. Three benzimidazoles were obtained as a result of the condensation of 1,2‐phenylenediamine with carboxylic acids and acetoacetic ester without catalyst. A series of trisubstituted imidazoles were synthesized by condensation of benzil, aromatic aldehyde and ammonium acetate in the presence of glacial acetic acid.     

Convenient Routes to Substituted Benzimidazoles and Imidazolo[4,5-b]pyridines Using Nitrobenzene as Oxidant

Various substituted benzimidazoles and imidazolo[4,5-b] pyridines 5a-c have been prepared by condensation of appropriate diamines and aldehydes in nitrobenzene. This method has been utilized to synthesize compounds 5f-h, which are analogues of the DNA binding fluorochrome Hoechst 33258.     

Cyclization of aromatic aldehydes and phenylenediamines under reduced pressure: A convenient,environmentally friendly,and simple procedure for benzimidazole precursors

The condensation of phenylenediamines with aromatic aldehydes in the presence of catalysts to obtain benzimidazoles under harsh condition is achieved by various reported conditions. The present work demonstrates a convenient, environmentally friendly, and simple procedure to obtain benzimidazoles through the cyclization between phenylenediamines and aromatic aldehydes under reduced pressure. By simply adding aromatic aldehydes to diaminobenzene derivatives and allowing the stoichiometric reaction at room temperature under reduced pressure at 66.6?Pa, the dehydrogenation leads to benzimidazoles with the yield as high as 80–90%. In addition, the purging of H₂ gas to benzimidazoles results in the hydrogenation of imidazole to obtain the intermediate benzimidazolidine form. This confirms how the cyclization relies on the reduced pressure. This synthesis pathway not only gives the aromatic aldehydes with high yield under the mild condition but also the selection of benzaldehydes with reactive functional groups leads to the precursors for other chemical modifications and polymerizations.     

CN bond formation and cyclization: A straightforward and metal-free synthesis of N-1-alkyl-2-unsubstituted benzimidazoles

A straightforward and metal-free synthesis of N-1-alkyl-2-unsubstituted benzimidazoles from the corresponding o-fluoro aryl formamidines and primary amines using microwave irradiation is described. The displacement of -F by the primary amine and cyclization to form the corresponding benzimidazoles took place in one pot.     

Simple and Convenient One‐Pot Synthesis of Benzimidazoles and Benzoxazoles using N,N‐Dimethylchlorosulfitemethaniminium Chloride as Condensing Agent

N,N‐Dimethylchlorosulfitemethaniminium chloride (SOCl₂‐DMF) has been found to be an efficient reagent for the one‐pot synthesis of benzimidazoles and benzoxazoles in excellent yield by condensation of carboxylic acids with o‐phenylenediamine/2‐amino‐phenol.     

Simple and Efficient One-Pot Synthesis of 2-Substituted Benzimidazoles from θ-Diaminoarene and Aryl Aldehydes

An easy and efficient one-pot condensation method for the synthesis of substituted benzimidazoles from θ-phenylenediamines with aryl aldehydes using urea hydrogen peroxide (UHP) and I₂ in dimethylsulfoxide (DMSO) provides wide substrate scope with good to excellent yields and simple and quick isolation of the products.     

The synthesis of 2-chloro-1-(β-D-ribofuranosyl)benzimidazole and certain related derivatives

The synthesis of 2-chloro-1-(β-D-ribofuranosyl)benzimidazole (4b) has been accomplished by a condensation of 2-chloro-1-trimethylsilylbenzimidazole (1) with 2,3,5-tri-O-acetyl-D-ribofuranosyl bromide (2) followed by subsequent deacetylation. Nucleophilic displacement of the 2-chloro group has furnished several interesting 2-substituted-1-(β-D-ribofuranosyl)benzimidazoles. 1-(β-D-Ribofuranosyl)benzimidazole (5) and 1-(β-D-ribofuranosyl)benzimidazole-2-thione (6) were prepared from 4b and 6 was also prepared by condensation of 2 with silylated benzimidazole- 2-thione (3). Alkylation of 6 furnished certain 2-alkylthio-1-(β-D-ribofuranosyl)benzimidazoles and oxidation of 6 with alkaline hydrogen peroxide produced 1-(β-D-ribofuranosyl)benzimidazole-2-one (9). The assignment of anomeric configuration for all nucleosides reported is discussed.     

Simple and Mild Protocol for Synthesis of 1,2-Disubstitued Benzimidazoles Using SBA-15-Supported Poly(4-styrenesulfonyl(perfluorobutylsulfonyl)imide) Catalyst

Abstract

A simple method for the synthesis of several 1,2-disubstituted benzimidazoles catalyzed by strongly acidic SBA-15-supported poly(4-styrenesulfonyl-(perfluorobutylsulfonyl)imide) is described. The protocol furnished the products in moderate yield and good selectivity in the condensation of o-phenylenediamine with structurally diverse aldehydes under mild conditions.     

N,N′-Di(3-amino-4-nitrophenyl)piperazine and related poly(benzimidazoles)

New poly(benzimidazoles) containing piperazine rings have been prepared via the reductive polyheterocyclization of poly(o-nitroamides) synthesized through the interaction of the new monomer N, N′-di(3-amino-4-nitrophenyl)piperazine with dichlorides of aromatic dicarboxylic acids. The relationship between the characteristics of poly(o-nitroamides) and poly(benzimidazoles) and their chemical structure has been studied.     

Recent Trends in the Synthesis of Benzimidazoles From o‐Phenylenediamine via Nanoparticles and Green Strategies Using Transition Metal Catalysts

Benzimidazole is a heterocyclic moiety of immense importance as it acts as a primary “biolinker” in diverse synthetic routes to obtain bioactive compounds. Substituted benzimidazoles are known to possess a varied range of pharmacological applications, namely, anti‐cancer, anti‐diabetic, anti‐inflammatory, and antiviral like anti‐HIV and anti‐fungal. A number of reviews covering the important aspects of benzimidazoles such as pharmacological activities, SAR studies, and well‐known methods of synthesis have appeared in the literature. However, green synthetic methods particularly using transition metal (TM) catalysts and their nanoparticles, although being more viable and extensively applied by researchers in the present scenario, have not been exclusively and expansively reviewed. Besides this, the vital precursors required for knitting the skeleton of benzimidazole are mainly o‐aryldiamines. The conventional synthesis generally involved the condensation of these diamines with carbonyl/carboxylic acid derivatives either via high temperature heating or via adding strong acids, mostly resulting in poor yields or mixtures. However, recent trends are replacing these conditions by mild and green conditions through TM catalysts. Therefore, the current review emphasizes on the recent trends adopted in the synthesis of benzimidazoles using condensation reaction of o‐phenylenediamines and various aldehydes/ester/amide/alcohols with TM in a catalytic role in nanoform and under environmentally benign green conditions.