Synthesis of fused polycyclic heterocycles of biological interest via palladium and copper catalysis

Heterocyclic scaffolds are central to medicinal chemistry, owing to their widespread occurrence in bioactive natural products and pharmaceuticals. Their structural and electronic properties enable selective interactions with biological targets, rationalizing the continuous effort devoted to developing efficient methods for their construction and post-functionalization. In this context, palladium catalysis provides powerful tools for C–C and C–heteroatom bond formation, particularly through Tsuji–Trost allylations and C–H activation processes, while copper catalysis—including the Cu-catalyzed azide–alkyne cycloaddition (CuAAC)—offers complementary strategies for rapid heterocycle diversification under mild conditions. Building on this foundation, the present doctoral work investigates the reactivity of (1H-indol-2-yl)methyl and (1H-indol-3-yl)methyl acetates toward an expanded set of soft nucleophiles—including phenols, arylsulfinates, α-amino acids, and β-dicarbonyl compounds. These transformations proceed either through palladium-mediated pathways, involving η³-π-indolyl–palladium intermediates, or via the in situ generation of highly electrophilic 2-alkylideneindolenines. In parallel, a modular copper-assisted strategy was developed, comprising propargylation, CuAAC, and intramolecular C–H activation, to construct polycyclic 1,2,3-triazole-fused heterocycles. This platform provided access to structurally diverse scaffolds—including triazoloquinolines and triazoloazepines—that are otherwise challenging to obtain through classical synthetic routes. Furthermore, a copper-mediated domino cyclization/oxidation protocol was established, enabling one-pot access to furanyl-substituted 1,2-diketones from diynyl diols, thereby expanding the synthetic utility of copper catalysis toward biologically relevant 1,2-dione frameworks. Finally, a six-month research stay at KU Leuven focused on the synthesis of novel SF₅-containing analogues, leveraging the unique steric and electronic properties of the pentafluorosulfanyl group for potential biological applications. Overall, this research demonstrates how the synergistic application of palladium- and copper-based catalysis enable the efficient synthesis of architecturally complex and pharmacologically relevant molecular frameworks.