Benzimidazole 3-oxides aldehydes

Aldehydes have been used to condense with o-phenylenediamines, o-nitroanilines, or ethylene diamines to afford benzimidazoles and imidazolines. Either an oxidation or a reduction process may be required during the annelation depending on the oxidation state of the starting material. To prepare imidazolines or benzimidazoles from aldehydes and diamines under anaerobic conditions, the system I2/KI/K2CO3/H2O can be used to oxidize a C-N single bond to a double bond (Scheme 302) <2006TL79>. Oxidant K3Fe(CN)5 has also been used to promote similar processes... 

Apart from the chemistry of the 4-hydroxy derivative (see p. 126) relatively little investigation in this area has been conducted. Thiocoumarin-3-carbonyl compounds have proved to be effective precursors for the synthesis of the pharmaceutically useful 3-(2-benzimidazolyl) derivatives. Thus, on interaction of the 3-carboxamide with o-phenylenediamine or the 3-aldehyde with o-nitroanilines, the above benzimidazoles or their TV-oxides are formed. 

The electrochemical generation of a nitrilimine provides an entrance to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydra-zones. The same reaction was used for annelation of various heterocyclic systems,86 e.g., substituted pyridines, quinolines, isoquinolines, indoles, imidazoles, benzimidazoles, and benzotriazoles. 

The reaction of 1,2-diaminonitrobenzenes with aldehydes is a widely accepted synthetic route to nitrobenzimidazoles [57, 62,63,66, 350,372-383], This reaction passes sequentially through a stage of the formation of azomethines (Schiff s base) and benzimidazolines. On oxidation the latter forms the corresponding benzimidazole derivatives (Scheme 2.44). 

Alkyl and fused aryl substituents (as in benzimidazoles) are oxidized by permanganate to carboxyl substituents. Oxidation of methylimidazoles with selenium dioxide is only useful in the case of benzimidazoles for the synthesis of imidazole aldehydes.426 The chemiluminescence of aryl-substituted imidazoles has been studied.427... 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

The reaction between o-phenylenediamine and an equimolar amount of an aromatic or heterocyclic aldehyde has been shown to proceed by initial formation of a monoanil (74). In the presence of oxidizing agents (e.g. nitrobenzene, which also acts as the solvent) this can form the 2-substituted benzimidazole. With two moles of aldehyde the bis-anil (75) forms, giving rise to a 1,2-disubstituted benzimidazole (Scheme 42). This aldehyde route to benzimidazoles is particularly suited to the synthesis of compounds with a heterocyclic group (e.g. 2-thienyl-, 2-pyridyl-) at C-2. Reaction of 2,2,4,4-tetrakis(trifluoromethyl)-l,3-dithietane with o-phenylenediamine gives 2,2-bis(trifluoromethyl)benzimidazoline (7430785). 

Under this heading fall some approaches to the synthesis of benzimidazole A-oxides which are formed when -nitro- or -nitrosoanilines react with aldehydes. Undoubtedly these reactions involve cyclization of an initially formed... 

SC2395>. Reaction of o-phenylenediamine and an aryl aldehyde in the presence of a catalytic amount of scandium triflate Sc(OTf)3 gives 2-(aryl)benzimidazoles in moderate to good yields. In this transformation, oxygen serves as the oxidant (Scheme 302) <2004H(63)2769>. 

Reaction of a-aminooximes or a-dioximes with aldehydes leading to imidazole Al-oxides will be discussed in Section II,F since all of these reactions have a common basis. The widely employed reaction of an a-diamine with an alcohol, aldehyde, or carboxylic acid has been restricted mainly to the synthesis of benzimidazoles. " ... 

Glyoxal reacts with primary amines to give diazadienes which cyclize in the presence of dry HCl to form imidazolium salts <86CB1868>. Similar methods have b n applied to the synthesis of imidazoline and benzimidazole 1-oxides (or their tautomers). Thus, 1-hydroxylamino oximes react at room temperature with formaldehyde (or on heating with other aldehydes) to give 1-hydroxy-3-... 

Important variants for the synthesis of benzimidazoles allow the use of aldehydes, rather than acids ytterbium triflate (best for aliphatic aldehydes) or scandium triflate catalyse the condensation and the subsequent air oxidation of the dihydrobenzimidazole immediate product. Incorporating nitrobenzene in the reaction mixture as the oxidant can also be used. orf/to-Nitroanilines can be used by incorporating a reducing agent in the reaction mixture - e.g. hydrogen over palladium or sodium dithionite - for in situ generation of the orffto-phenylenediamine. 2-Aryl-benzothiazoles can be made from 2-aminobenzenethiol, aromatic aldehydes and air, in the presence of activated carbon. ... 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

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