Imidazole 3-oxide ring benzimidazole 3-oxides

Electrophilic reagents preferentially attack benzimidazoles in the fused benzene ring, while nucleophiles react at C-2 which has enhanced nucleophilic activity because of the electron-withdrawal effect of the benzene moiety. The fused aryl ring appears to exhibit less aromatic stability than the heteroring as evidenced by the ready oxidation of benzimidazole to imidazole-4,5-dicarboxylic acid, and by its catalytic reduction over platinum... 

Anodic oxidation of substituted hydrazones may induce ring closure. Oxidation of /7flrfl-substituted phenylhydrazones of 2-oxophenylacetonitrile yields derivatives of 1-phenyl-3-cyano-l/7-indazoles [73] p-nitrobenzylidene-o-phenylenediamine is oxidized in MeCN-LiC104 to 2-(pnitrophenyl)benzimidazole [74], chalchone phenylhydrazone in MeCN-C5H5N-LiC104 to 1,3,5-triphenylpyrazol [74], and benzylidene 2-pyridylhydra-zone (XXIV) to 3-phenyl-j -triazolo[4,3-a]pyridine (XXV) oxazoles and imidazoles may be prepared similarly [74] ... 

Starting from acylated 2-azidomethylbenzimidazoles (145), an additional imidazole ring can be condensed by transformation of the azido group with tri-n-butylphosphane into the appropriate iminophosphorane intermediate 146. After extrusion of phosphane oxide, cyclization occurs to the 1-substituted 4//-imidazo[l,5-a]benzimidazole 147 (Scheme 58) (89T1823 94S1197). 

Imidazole was converted by hydrogenation over platinum oxide in acetic anhydride to 1,3-diacetylimidazolidine in 80% yield, and benzimidazole similarly to 1,3-diacetylbenzimidazoline in 86% yield [480. While benzimidazole is very resistant to hydrogenation over platinum at 100° and over nickel at 200° and under high pressure, 2-alkyl- or 2-aryl-substituted imidazoles are reduced in the benzene ring rather easily. 2-Methylbenzimidazole was hydrogenated over platinum oxide in acetic acid at 80-90° to 2-methyl-... 

Omeprazole 5 -Methoxy-2- [(4 -methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinylj -17/-benzimidazol O-methylation, imidazole ring formation using thiourea, A-oxidation, nucleophilic displacement, A-methylation, S -oxidation... 

Vigorous oxidation (e.g., with KMn04) usually degrades fused benzene rings in preference to many azole rings, especially under acidic conditions. Thus, benzimidazoles are oxidized by chromic acid or 30% hydrogen peroxide to imidazole-4,5-dicarboxylic acid, and 2,1,3-benzothiadiazole is oxidized by ozone or potassium permanganate to the dicarboxylic acid 553. 

That imidazoles and benzimidazoles have high stability has been known for many years. Resistance to acids, bases, heat and oxidation or reduction are common traits of these compounds, which display considerable aromatic character. Thus treatment of benzimidazole with permanganate leads to imidazole-4,5-dicarboxylic acid imidazoles, in general, are not easily oxidized or reduced (Sections 4.07.1.4.11, 4.07.1.5.6, 4.07.1.7.4). Thermal stability too is evidenced by the resistance of the imidazole nucleus to ring fission... 

There are no known examples of direct Af-oxidation of imidazoles or benzimidazoles by peracids. With hydrogen peroxide imidazole is cleaved to give oxamide, while perbenzoic acid destroys the ring giving ammonia and urea. 

Benzimidazole (but not 1-methylbenzimidazole) is oxidized by permanganate, dichromate or hydrogen peroxide to imidazole-4,5-dicarboxylic acid, while napth-[l,2-d]- and -[2,3-d]-imidazoles also form products in which the heterocyclic ring remains intact, hence demonstrating its stability to these conditions. With lead peroxide benzimidazole is subject to an unusual oxidation as it forms (101), also the reaction product of lead dioxide and 2,2 -bibenzimidazolyl. In dioxane, selenium dioxide oxidizes 2-methylbenzimidazole to o-hydroxyacetanilide (66RCR122). 

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). 

Examples exist of ring fission of purines to give 4,5-disubstituted imidazoles (Scheme 104) (78TL5007). The conversion of benzimidazoles into imidazoles has been discussed as an example of oxidation (Section 4.07.3.1). 

Such synthetic approaches can only be valid if the other heterocycles are readily available, or if their transformations lead to imidazoles difficult to make by other means. It is certainly important to be able to aromatize imidazolines since a number of ring-synthetic procedures lead to reduced imidazoles. 4-Aminoisoxazoles are sources of a-acylaminoenaminones which cyciize with bases to give 4-acylimidazoles. Oxazole-imidazole conversion has largely historical importance, but it is also implicated in some ring-synthetic procedures (e.g. the Bredereck method, see Chapter 5). Transformations of benzofuroxans into 2-substituted benzimidazole iV-oxides have some synthetic importance. Few, if any, ring contractions appear to have major application. 

Although it is frequently more convenient to make imidazole and benzimidazole sulfones (and sometimes sulfoxides) by direct oxidation of the thioethers, 4-tosyl groups can also be introduced quite conveniently by a ring synthesis based on the reagent TOSMIC (see Section 4.2 and Scheme 4.2.1). 

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