Benzimidazoles, 1-acylamino

Acyl-2-amino-benzimidazole werden durch Pyridin (100° 1 h) zu 2-Acylamino-benzimid-azolen umacyliert (s.a. S. 351, 3S6)447. 

Mit den aus Carbonsaure-aziden erzeugten Nitrenen reagieren Benzimidazole nicht unter der iiblichen Ringerweiterung, sondern unter Insertion zu Acylamino-benzimidazolen540,... 

A particular case of a photochemical strategy towards functionalized benzimidazoles regards the synthesis of 2-acylamino derivatives 70, which can be obtained from irradiations in methanol of 3-(o-amino)phenyl-l,2,4-oxadiazoles 68. In this reaction, a photolytic cleavage of the ring O—N bond, followed by migration of the aryl substituent, leads to the carbodiimide intermediate 69, a precursor of the benzimidazole nucleus (Scheme 12.20) [47]. 

In a Study of the formation of benzimidazoles by the peroxy acid-catalyzed cyclization of o-acylamino-iV,lV-dialkylaniIines, it has been demonstrated that the reaction proceeds via an iV-oxide intermediate, since it has proved possible to synthesize this N-oxide and cyclize it under the reaction conditions (B-73MI40800). Both ortho-N-acylated and -N-... 

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. 

In the uncondensed imidazoles the standard method reacts an a-aminocarbonyl compound with a thiocyanate (see Section 4.1 and Table 4.1.1). If a 2-alkylthioimidazole is required directly, one can combine an N-alkyT or A -arylcarbonimidodithioate in refluxing acetic acid with the aminocarbonyl substrate (see Section 4.1 and Scheme 4.1.3). Alternatively, reaction between thiourea and a two-carbon synthon (ot-hydroxy-, a-halogeno-, a-dicarbonyl) leads to imidazoline-2-thiones (see Section 4.3). In sulfuric acid, 3-butynylthiourea cyclizes to 4,5-dimethylimidazolin-2-thione (see Section 2.2.1). 1-Substituted 2-methylthioimidazoles can be made, albeit in rather poor yields, from appropriately substituted 2-azabutadienes (see Section 3.2 and Scheme 3.2.3), and 2-arylthioimidazoles are available in moderate yields from benzyl isocyanides and arylsulfenyl chlorides (see Section 4.2 and Scheme 4.2.12). Ring transformations of 5-amino-2-alkylaminothiazoles and 2-acylamino-5-aminothiazoles may have occasional applications (see Section 6.1.2.7). The ease with which a thiol group or imidazole or benzimidazole can be alkylated, in comparison with the annular nitrogens, usually makes it more convenient to prepare alkylthioimidazoles from the thiols (or thiones). 

At the same time, it was not possible to cyclize 7-acylamino-8-amino-theophilline, even on long-term heating with anhydrides acid or in PPA (87KGS1398). The cyclization of l-acylamino-2-aminobenzimidazoles (403) proceeds not by a simple course. Ho and Day described products, formed on refluxing 403 in acetic or benzoic anhydride, as l-acyl-2-R-triazolo[l,5-a]benzimidazoles (404) (73JOC3084). However, reinvestigation showed that, in fact, the compounds are 4-acyl derivatives (407) (89KGS209). Probably, cyclization proceeds via salt 405 and then via imine 406. 

These studies indicated that replacement of the methoxycarbonylamino group at 2-position of benzimidazoles by acylamino or urea pharmacophores may help to retain the biological activity, although they are weaker than the benzimidazole-2-car-bamates. Thus, it may be concluded that the presence of a methoxycarbonylamino function at 2-position of a 5(6)-substituted benzimidazole is usually essential for optimal anthelmintic activity. 

Disubstituted benzimidazoles 10 are also obtained by Cu-mediated amination of (2-acylamino)aryl iodides with arylamines in the presence of L-proline and K2CO3 followed by add-catalyzed cydization [417]. 

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