Overcoming quinone deactivation: rhodium catalysed C-H activation as a new gateway for potent trypanocidal prototypes

Abstract

The following manuscript encompasses all efforts in the development of a methodology that aims for the direct functionalization of the benzenoid and dicarbonyl ring of 1,4-naphthoquinones, referred to as A-ring and B-ring, respectively, via rhodium catalysed C-H activation-functionalization, and all other reactions that have been discovered during the research process. In a first approach, optimization studies were carried out to define the best reactional conditions for C5 and C2-halogenation, followed by the appliance of the optimized methodology in different naphthoquinoidal substrates. In a second part, the recently discovered C-2 halogenation/phenyl selenylation protocol was explored and the new methodology applied to a wild range of 1,4-benzoquinones. The C5-halogenation process opened way for new modifications in the A-ring, such as palladium cross-coupling and copper-catalysed organoyl-thiolation reactions. Finally, all new compounds were evaluated against Trypanosoma cruzi trypomastigote forms, with the majority of them presenting remarkable bioactivity.