Synthesis and toxicity of new ring-fused imidazo[5,4-f]benzimidazolequinones and mechanism using amine N-oxide cyclizations

A new synthetic route to ring-fused imidazo[5,4-f]benzimidazoles is reported that can be used to access symmetrical and unsymmetrical quinone anticancer agents. Oxone in formic acid allows cyclisation of o-tert-aminoacetanilides to give ring-fused benzimidazoles and imidazobenzimidazoles in superior yields. A mechanism for these oxidative cyclisations is proposed that proceeds through a hydrogen-bonded amine N-oxide intermediate. The amine N-oxide is shown to act as an oxidant in the aromatisation to the imidazole ring. X-ray crystal structures of the dimorpholine N-oxide intermediate and bis[1,4]oxazinoimidazo[5,4-f] benzimidazolequinone bis(trifluoroacetate) adduct are included. Two unsymmetrical quinones are shown to have greater cytotoxicity than the previously reported imidazobenzimidazolequinones. Double oxidative cyclisations of o-tert-aminoacetanilides give [1,4-oxazino]- and alicyclic ring-fused imidazo[5,4-f]benzimidazoles. The hydrogen-bonded orientation of the amine N-oxide intermediate is used to propose a mechanism. Unsymmetrical quinone derivatives are more potent than previously reported imidazobenzimidazolequinones.