Sustainable methodology development for cross-coupling reactions

The development of sustainable methodologies for carbon–carbon bond formation remains a central challenge in modern organic synthesis. This thesis addresses key limitations of classical cross-coupling reactions—namely, reliance on pre-functionalized substrates, hazardous solvents, and high process mass intensity—by advancing greener catalytic strategies grounded in C–H activation and aqueous micellar catalysis.
A primary focus is placed on palladium-catalyzed C–H arylation, enabling direct functionalization of (hetero)arenes without the need for pre-activation. Mechanistic insights, particularly involving concerted metalation–deprotonation (CMD) pathways, guided the design of efficient and selective catalytic systems. The scope of these transformations was expanded to include fluoroarenes, azaindoles, and nitrogen-containing heterocycles, demonstrating broad applicability and functional group tolerance.
To further enhance sustainability, micellar catalysis in aqueous media was integrated with C–H activation protocols. This approach exploits surfactant-based nanoreactors to solubilize hydrophobic substrates, enabling reactions under mild conditions while significantly reducing organic solvent use. Silver-free and water-compatible methodologies were developed, highlighting the potential of combining green chemistry principles with transition-metal catalysis.
Additionally, light-driven decarboxylative trifluoroethylation strategies were explored, providing access to valuable fluorinated motifs under mild photochemical conditions.
Overall, this work demonstrates that the convergence of C–H activation, micellar catalysis, and enabling technologies such as photochemistry offers a viable pathway toward more sustainable and scalable cross-coupling methodologies. These advances contribute to the ongoing transition from traditional synthetic approaches to environmentally responsible practices in both academic and industrial settings.