Ruthenium(II)- and Palladium(II)-Catalyzed Position-Divergent C–H Oxygenations of Arylated Quinones: Identification of Hydroxylated Quinonoid Compounds with Potent Trypanocidal Activity

Abstract A diversity-oriented synthesis of hydroxylated aryl-quinones via C–H oxygenation reactions and their evaluation against Trypanosoma cruzi, the etiological agent of Chagas disease, was accomplished. With the use of ruthenium(II)- or palladium(II)-based catalysts, complementary regioselectivities were observed in the hydroxylation reactions and we have identified 9 compounds more potent than benznidazole (Bz), among these novel arylated and hydroxylated quinones. For instance, 5-hydroxy-2-[4-(trifluoromethyl)phenyl]-1,4-naphthoquinone (4h) with an IC50/24 h value of 22.8 µM is 4.5-fold more active than the state-of-the-art drug Bz. This article provides the first example of the application of C–H activation for the position-selective hydroxylation of arylated quinones and the identification of these compounds as trypanocidal drug candidates.