Controlling Reactivity and Regioselectivity in Nondirected Palladium-Catalyzed C(sp²)–H Activation
This doctoral work deals with nondirected activation and functionalization of unreactive aromatic C–H bonds using dual ligand-based palladium catalysts. In the first part, an efficient yet underexplored multi-substrate screening strategy is described for the first time in C–H activation and hydrogen isotope exchange (HIE) catalysis. This approach rapidly identified efficient catalyst systems and optimal conditions for diverse heteroarenes with minimal experimental work. Using D2O as a cost-effective deuterium source, the method showed broad functional group tolerance and enabled labeling of bioactive molecules. The second part focuses on the nondirected C–H alkylation of arenes to access β-aryl carbonyl compounds via a Pd(II)/Pd(0) cycle. Two complementary semi-optimized conditions were identified, one providing the highest activity and the other improved steric control of regioselectivity. Although chemoselectivity was improved, mechanistic studies revealed that a major side product inhibited catalytic turnover, preventing further enhancement in efficiency. The third part presents a strategy for the regioselective installation of carboxyl and formyl groups that complements classical SEAr-based methods. A novel dual ligand-based palladium catalyst enabled sterically controlled nondirected arene C–H olefination, followed by oxidative cleavage to furnish carboxylic acids and aldehydes. This approach provided access to sterically favored regioisomers otherwise difficult to obtain, in good yields with broad functional group tolerance and applicability to bioactive molecules.
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