Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations

The reactivity of hydrogen peroxide
and catalytic hydroiodic acid
toward 3,6-dimethoxy-2-(cycloamino)­anilines is tunable to give ring-fused
benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms
via a detected nitroso-intermediate are proposed for oxidative cyclization
and the unexpected intermolecular displacement of the oxazine. An
aqueous solution of molecular iodine is capable of the same transformations.
Oxidative demethylation gave targeted benzimidazolequinones, including
without cleavage of the incorporated oxetane.

过氧化氢（hydrogen peroxide）与催化氢碘酸（catalytic hydroiodic acid）对3,6-二甲氧基-2-(环氨基)苯胺类化合物（3,6-dimethoxy-2-(cycloamino)anilines）的反应活性可调控，能够以高收率得到环融合苯并咪唑类化合物（ring-fused benzimidazoles）或1,4,6,9-四甲氧基吩嗪（1,4,6,9-tetramethoxyphenazine）。针对氧化环化（oxidative cyclization）与恶嗪的意外分子间置换反应，本研究提出了基于检测到的亚硝基中间体（nitroso-intermediate）的反应机理。单质碘水溶液（aqueous solution of molecular iodine）同样可实现上述转化过程。通过氧化脱甲基反应（oxidative demethylation）可获得目标苯并咪唑醌类化合物（benzimidazolequinones），其中包括未发生所引入氧杂环丁烷（oxetane）断裂的产物。