Benzimidazole rule

Benzimidazole derivatives, III, 161 Benzimidazole rule of rotation, I, 21 1,3-Benzodioxan, 8,8 -methyIenebis(6- nitro-), III, xvii Benzoic acid, cellulose esters, I, 320 labelled with isotopic C, III, 231 starch esters, I, 302, 303 —, 2,4-dihydroxy-, effect on conductivity of boric acid, IV, 195 —, 2,4,5-trihydroxy-, effect on conductivity of boric acid, IV, 195 —, 3,4,5-trihydroxy-. See Gallic acid. 

This is the second book in the sub-series of Best Synthetic Methods — Key Systems and Functional Groups and is particularly close to my heart. As a young research chemist I recall we formulated the Benzimidazole Rule . This stated that given the right number of carbons and nitrogens, any starting material would ultimately end up as a benzimidazole A good example is shown below ... 

The photolysis of 1,2-benzisoxazole in the absence of air in acetonitrile gave salicylonitrile and benzoxazole (67AHC(8)277). When air-saturated acetonitrile was employed, 2,2 -dimeriz-ation to (38) occurred, accompanied by benzoxazole. Photolysis of the 2,2 -dimer (38) and benzoxazole did not alter the ratio, thus indicating that neither one arose from the other. Selective excitation also ruled out dimer formation from benzoxazole under the reaction conditions (Scheme 9). This dimerization is similar to that observed for benzimidazole, except that in that series no 2,2 -dimerization was observed (74TL375). 

There are some known unsuccessful attempts to carry out alkylation (Mel, Me2S04), halogenation (tert-butyl hypochloride) and nitration of aromatic dihydrobenzodiazepines [7, 105]. Such attempts only resulted in the destruction of the seven-membered heterocycle. As a rule, these destructive processes are typical of dihydrodiazepine systems and often manifest themselves during the synthesis and study of these compounds. Therefore, the results of the destruction of a seven-membered heterocycle are most widespread and include its decomposition into ortho-diamine and carbonyl compounds (Scheme 4.43, reactions A and B) [105, 106] and benzimidazole rearrangement accompanied by splitting out of a methyl aryl ketone molecule (Scheme 4.43, reaction C) [117]. 

The nitration of benzazoles is usually effected using concentrated (65%) to fuming (100%) nitric acid generally at temperature between 0 and 5°C. Indazoles are usually nitrated into 5 position, benzimidazoles - as a rule - into 5- or 6-position of the phenylene fragment whereas benzotriazole into position 4 or 7. For the preparation of other nitrobenzazoles the reaction of heterocyclization is used. 

It is a general rule that imidazoles and benzimidazoles are resistant to Friedel-Crafts reactions. This is not surprising since such basic compounds must be markedly deactivated in the presence of Lewis acids. Imidazolin-2-ones appear to be an exception and apparently possess sufficient activation to react. Reactions between imidazoles and Af-methylfor-manilide and phosphoryl chloride are also unproductive. With 4,5-diphenylimidazole, phenyl isocyanate at 80 °C gives products of both N- and C-substitution, but in boiling nitrobenzene only the latter (86) is formed. 2-Methyl-4-phenylimidazole gives (87) under the same conditions, and 1,3-diphenylimidazolium perchlorate is transformed by potassium t-butoxide into a ylide which reacts at C-2 with phenyl isothiocyanate. Sufficient activation is present in l-methyl-2-phenyl-4-phenylaminoimidazole for it to react by substitution at C-5 with acetic anhydride (71JOC3368). 

Reaction of benzofuro[2,3-y]benzimidazole-2-thione (423) with chloro-acetic acid gives acid 424 which, on cyclization with acetic anhydride, yields a cyclized product for which structure thiazolo[2, 3 -(>]benzofuro [2,3-/]benzimidazol-3(2/y)-one (425) was assigned (77M12) however, alternate structure 426 cannot be ruled out in the absence of adequate data (Scheme 97). 

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