Site Selectivity in Palladium-Catalyzed Oxidative Functionalization Reactions.

Abstract

The development of transformations for selective and functional group tolerant methods for the direct functionalization of C–H bonds is an important challenge in organic chemistry. Recent work in our group has shown that Pd(OAc)2 in conjunction with PhI(OAc)2 serves as an efficient catalyst for ligand-directed palladium-catalyzed C–H activation/acetoxylation reactions. These reactions are believed to proceed via a PdII/IV catalytic cycle. In order to expand the scope of these oxygenation reactions we sought to explore whether high and predictable levels of site selectivity could be achieved for the functionalization of meta-substituted arenes. In general, our results show that the palladium-catalyzed C–H activation/acetoxylation of meta-substituted arenes occurs preferentially at the less congested position. Additionally, we desired to install other functionalities such as halogen and aryl groups in the final products using electrophilic halogenating and arylating reagents as terminal oxidants. A detailed exploration of palladium-catalyzed chelate-directed halogenation of arenes using N-halosuccinimides as terminal oxidants has been conducted. Additionally, we have shown that diaryl iodonium salts can be used as oxidants for site selective C–H activation/arylation reactions in the presence of Pd(OAc)2 as the catalyst. Preliminary results suggest that the mechanism of this reaction involves a PdII/PdIV catalytic cycle, which is of interest because nearly all palladium mediated C–C bond forming reactions proceed via a Pd0/PdII cycle. Finally, we have applied the insights gained from the aforementioned oxidation reactions toward the oxidative halogenation of PdII-alkyl complexes generated via olefin insertion into Pd-aryl bonds to form 1,2-arylhalogenated products. Interestingly, the isomeric 1,1-arylhalogenated products could also be obtained in high selectivity just by tuning the reaction conditions. In all, this thesis describes a variety of site selective palladium-catalyzed oxidative functionalization reactions. These include palladium-catalyzed chelate-directed C–H activation/C–X (X = C, O, Cl, Br, I) bond formation and the palladium-catalyzed difunctionalization of olefins. The PdII/IV catalytic cycle proposed for many of these transformations has allowed for bond formations (e.g., carbon-halogen) that previously proved challenging via traditional Pd0/II catalytic cycles. The generality, high selectivity, and functional group tolerance of these reactions make them attractive for the functionalization, late stage derivatization, and the synthesis of complex biologically active molecules.