A Mild and Versatile Friedel-Crafts Methodology for the Diversity-Oriented Synthesis of Redox-Active 3-Benzoylmenadiones with Tunable Redox Potentials.

Abstract

A series of highly diversified 3-aroylmenadiones was prepared by a new Friedel-Crafts acylation variant/oxidative demethylation strategy. A mild and versatile acylation was performed between 1,4-dimethoxy-2-methylnaphthalene and various activated/deactivated benzoic and heteroaromatic carboxylic acids, in the presence of mixed trifluoroacetic anhydride and triflic acid, at room temperature and in air. The 1,4-dimethoxy-2-methylnaphthalene-derived benzophenones were isolated in high yield, and submitted to oxidative demethylation with cerium ammonium nitrate to produce 3-benzoylmenadiones. All 1,4-naphthoquinone derivatives were investigated as redox-active electrophores by cyclic voltammetry. The electrochemical data recorded for 3-acylated menadiones are characterized by a second redox process, the potentials of which cover a wide range of values (500 mV). These data emphasize the ability of the generated structural diversity at the 3-aroyl chain of these electrophores to fine-tune their corresponding redox potentials. These properties are of significance in the context of antimalarial drug development and understanding of the mechanism of bioactivation/action.