Ligand-Driven Development of Pd-Catalyzed Nondirected C–H Activation of Arenes

With the common goal of exploring the potential of dual-ligand enabled palladium-catalyzed aromatic C–H activation, this dissertation presents and discusses three research projects.
The first project describes the development of a nondirected C–H olefination method for the late-stage installation of clickable alkyne motifs into (hetero)arenes. Using a dual-ligand palladium catalyst system based on an N-acylsulfonamide (NASA) ligand and a pyrazine-derived ligand, the methodology enables broad substrate scope and direct access to alkyne-tagged scaffolds suitable for copper-catalyzed azide-alkyne cycloaddition (CuAAC) derivatization and activity-based protein profiling (ABPP) studies.
Building on the discoveries of the first study, the second project investigates more sustainable reaction conditions for dual-ligand enabled C–H olefination by reducing reliance on silver salts and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Although photoredox-based reoxidation strategies for silver replacement were unsuccessful, optimized catalyst systems employing NASA ligands enabled efficient reactions in non-halogenated and environmental benign solvents. Mechanistic studies highlighted the importance of the electronic properties of NASA ligands for improved solvent  compatibility.
The final project explores a Catellani-type reaction via initial nondirected C–H activation for the para selective arylation of electron-poor arenes. Structurally modified norbornenes and careful optimization of the reaction conditions were essential for unlocking the correct reactivity and selectivity, while mechanistic investigations identified key competing pathways and the critical role of silver salts in promoting the reaction. Yields of up to 30% were obtained, with the desired selectivity (meta:para = 30:70). The study demonstrates that the functionalization is fundamentally achievable while highlighting the mechanistic challenges associated with controlling competing pathways.