Site Selectivity in Palladium-Catalyzed Oxidative Functionalization Reactions.

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.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61588/1/dkalyani_1.pd

Palladium-Catalyzed Intramolecular C–H Arylation of Arenes Using Tosylates and Mesylates as Electrophiles

This paper describes a method for the palladium catalyzed intramolecular C–H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented

Nickel-Catalyzed Electrochemical Reductive Cross-Electrophile Coupling of Alkylpyridinium Salts and Aryl Halides

An electrochemically driven, nickel-catalyzed cross-electrophile coupling reaction of alkylpyridinium salts and aryl halides is reported. High-throughput experimentation (HTE) was employed for rapid reaction optimization and evaluation of a broad scope of pharmaceu-tically relevant structurally diverse aryl halides, including complex drug-like substrates. In addition, the transformation is compatible with both primary and secondary alkylpyridinium salts. Systematic comparisons of the electrochemical and non-electrochemical methods revealed the complementary scope and efficiency of the two approaches

Palladium-Catalyzed Intramolecular C–H Arylation of Arenes Using Tosylates and Mesylates as Electrophiles

This paper describes a method for the palladium catalyzed intramolecular C–H arylation using tosylates and mesylates as electrophiles. The transformation is efficient for the synthesis of various heterocyclic motifs including furans, carbazoles, indoles, and lactams. Additionally, a protocol for the one-pot sequential tosylation/arylation of phenol derivatives is presented

Palladium-Catalyzed Intra- and Intermolecular C–H Arylation Using Mesylates: Synthetic Scope and Mechanistic Studies

This paper describes the development of Pd-catalyzed inter- and intramolecular direct arylation using mesylates. Furthermore, a sequential mesylation/arylation protocol using phenols as substrates is described. These transformations are general with respect to the electronics of the C–H substrates and allow for the synthesis of diverse heterocyclic motifs in good yields. Both arenes and heteroarenes efficiently participate in these reactions. Preliminary mechanistic studies are presented for both inter- and intramolecular arylations

Palladium-Catalyzed Intra- and Intermolecular C–H Arylation Using Mesylates: Synthetic Scope and Mechanistic Studies

This paper describes the development of Pd-catalyzed inter- and intramolecular direct arylation using mesylates. Furthermore, a sequential mesylation/arylation protocol using phenols as substrates is described. These transformations are general with respect to the electronics of the C–H substrates and allow for the synthesis of diverse heterocyclic motifs in good yields. Both arenes and heteroarenes efficiently participate in these reactions. Preliminary mechanistic studies are presented for both inter- and intramolecular arylations

Persistent Organonickel Complexes as General Platforms for Csp2-Csp3 Coupling Reactions

Coupling reactions between aryl electrophiles and alkyl/perfluoroalkyl precursors have inspired elegant methodologies that leverage electrochemical, photochemical, or thermal activation modalities. This work consolidates these myriad strategies to a single set of conditions and enables previously unknown alkyl-aryl couplings. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)-C(sp3) coupling. Aryl, heteroaryl, or vinyl complexes of Ni can be inexpensively prepared on multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to µL scales by integrating soluble battery chemistries as redox initiators, which enabled a high-throughput exploration of substrate diversity

Nickel or Phenanthroline Mediated Intramolecular Arylation of sp³ C–H Bonds Using Aryl Halides

The development of the intramolecular arylation of sp³ C–H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)₂ or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates

Nickel or Phenanthroline Mediated Intramolecular Arylation of sp³ C–H Bonds Using Aryl Halides

The development of the intramolecular arylation of sp³ C–H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)₂ or 1,10-phenanthroline in substoichiometric amounts, and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates

Nickel-Catalyzed Decarboxylative Cross-Coupling of Perfluorobenzoates with Aryl Halides and Sulfonates

A Ni-catalyzed method for the coupling of perfluorobenzoates with aryl halides and pseudohalides is described. Aryl iodides, bromides, chlorides, triflates, and tosylates participate in these transformations to afford the products in good yields. Penta-, tetra-, and trifluorinated biaryl compounds are obtained using these newly developed Ni-catalyzed decarboxylative cross-coupling reactions