2- benzimidazoles preparation

Examples of syntheses in which the heterocyclic ring is generated by cyclization of an exocyclic amine to an electrophilic carbon atom include the preparation of triazolo[4,3-6]triazoles (137) by elimination of alkanethiol from guanidine derivatives 136137 (cf. 132 - 133), and many examples (mostly in patents) of pyrazolo[l,5-a]benzimidazoles prepared according to Eq. (18).138-142... 

Some examples of benzimidazoles prepared from o-(iV-acylamino) and o-(iV-aroylainino)aiylaniines are listed in Table 2.1.7. Yields can vary considerably. 

A second synthetic route to poly(aryl ethers) containing heterocyclic units involved the reaction of an aromatic dihydroxy heterocycle with conventional activated difluoro compounds. Bisphenols containing quinoxaline, phenylimidazole, oxadizaole, pyrazole, triazole, phenolphthalein, phenolphthalimidine, and phenolphthalein anilide heterocycles were prepared and polymerized to high molecular weight (84-95), However, the most noteworthy examples are the poly(aryl ether benzimidazoles), prepared from bis(4-hydroxyphenyl) bibenzimidazole, due to their unique combination of adhesive, thermal and mechanical properties (Scheme VIII) (93-95),... 

Several biologically and pharmacologically active compounds have been prepared from the condensation of the acid chloride of 1-naphthoxyacetic acid with carbazole, iadole, or pyrrole ia 2A[ NaOH solution ia ethanol (63). Also, naphthyloxy derivatives of imidazole, benzimidazole, and benzotriazoles have been synthesized and screened for their antimicrobial, analgesic, and antiinflammatory activities. 2-Naphthyloxy derivatives are comparatively more active than 1-naphthyloxy derivatives (64). 

The dianhydride of 1,4,5,8-naphthalene tetracarboxyhc acid [81-30-1] has been of research interest for the preparation of high temperature polymers, ie, polyimides. The condensation of the dianhydride with o-phenylenediamines gives vat dyes and pigments of the benzimidazole type. 

A large number of a-hydroxybenzylbenzimidazole [50-97-5] (HBB, 39), C24H22N2O, derivatives has been prepared and extensively studied as selective inhibitors of the RNA containing enterovimses (91). Although none of these derivatives have shown any antiviral activity in animals, l,2-bis(5-methoxy-2-benzimidazol-2-yl)-l,2-ethanediol [16656-27-2] (40), C2gH2gN404, was found to be active against an experimentally induced rhino vims infection in chimpanzees (92). However, the in vivo antiviral efficacy was accompanied by significant toxicity. 

Chemical Reactions of Dyes. Decolorization is important for cyanines used ia imaging materials. Understanding decolorization provides clues to dye reactions that may cause degradation of imaging materials duting preparation and storage. For many dyes, protonation of the methine chain occurs readily and reversibly (64). Highly basic carbocyanine dyes like those from benzimidazole (eg, 36) protonate so readily that this provides a practical decolorization method. 

However, there are differences between o-phenylenediamine and 4,5-diaminopyrazoles in the synthesis of [5.5] systems. For example, the formation of pyrazolo[3,4-d]-[l,2,3]triazole (550) is similar to that of benzotriazole, but all attempts to extend the synthesis of benzimidazoles to the preparation of the imidazo[4,5-c]pyrazole system (551) have failed (78TH40400). 

Benzimidazoles are generally synthesized from ortho-diamino-benzenes and carboxylic acid derivatives. The antihistaminic agent, clemizole (60), for example, can be prepared by first reacting ortho-diaminobenzene (57) with chloroacetic acid to form 2-chloro-methylbenzimidazole (58). Displacement of the halogen with pyro-... 

A still different scheme is used for the preparation of the benzimidazole buterizine (74). Alk lation of... 

Amides and carbamates of 2-ami nobenzimidazole have proved of considerable value as anthelminic agents, particularly in veterinary practice. A very considerable number of these agents have been taken to the clinic in the search for commercially exploitable agents. (See the section on Benzimidazoles in Chapter 11 of Volume 2 of this series.) A small number of additional compounds have been prepared in attempts to uncover superior agents. 

Overberger and associate110) also prepared copolymers of 6(6)-vinylbenzimid azole with acrylic add 62 (PBzJm - AA). In 40%-propanol water, the activities of the copolymers indicated a strong dependence on the carboxylate-benzimidazole-carboxylate triad. These effects were ascribed to strong electrostatic interactions between these sequences and substrates. 

The ring expansion of benzimidazoles to afford qunoxalines has been done in several ways, mostly of little preparative value. They are illustrated in the following examples. 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Dihydropyrazoles were prepared by reaction of a monosubstituted hydrazine with benzimidazole amino acrylates 120. The reaction was carried... 

Benzimidazoles have been prepared by direct condensation of o-phenylene-diamine 190 with a carboxyhc acid at 110 °C in water and under microwave irradiation (Scheme 69) [124]. Differently functionahzed benzimidazoles 192 were obtained with this method especially regarding the nature of the substituent on the imidazole ring. 

The photoaddition reaction of 2-phenylbenzimidazole with Michael acceptors was investigated <96JHC1031> as was the preparation and cycloaddition-reactivity of benzimidazole-2-carbonitrile oxide <96AJC199>. The nitration of 1-methylbenzimidazole was found to give only the 5- and 6-nitrated products as a mixture of isomers in 87% yield... 

---