Ring Synthesis of Benzo-1,2-Azoles

The most important strategy for the synthesis of benzothiazoles, benzimidazoles and benzoxazoles is the insertion of C-2 into a precnrsor with ortfto-heteroatoms on a benzene ring. The component that is reqnired for this pnrpose usually has the future C-2 at the oxidation level of an acid, but many variants on this have been described. 

In the standard form of this route, a carboxylic acid is heated with the orffto-disubstituted benzene orf/to-amino-phenol, -thiophenol or -aniline. An iminoether will react at a much lower temperature and iminochlorides, generated in situ using the acid, triphenylphosphine and hot carbon tetrachloride, can be used for benzimidazole or benzoxazole synthesis. Orthoesters with a KSF clay is a highly recommended variant and can be used for the synthesis of all three unsubstituted benzo-l,3-azoles.  

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 efficient ways in which to use starting materials that have the carboxylic acid component already installed on both heteroatoms conversion to bis(silyloxy) derivatives, or simply heating with p-toluenesulfonic acid. An excellent route to mono-acylated precursors utilises mixed anhydrides. A very mild method for the dehydrative ring closure of ortfto-hydroxyarylamino-amides utilises typical Mitsunobu conditions - triphenylphosphine and diethyl azodicarboxylate.  

A device that has been frequently used to produce an ortto-acylamino-phenol synthon is to carry out a Beckmann rearrangement on an ort/to-hydroxyaryl ketone, the Beckmann intermediate cyclising in situ, as illustrated below.  

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