Developing Mechanistic Insights into Copper Mediated Ligand Directed C-H Functionalization
Blythe, Isaac
2023
Abstract
The installation of functional groups onto arenes is an important transformation in the diversification of small molecules relevant to pharmaceutical, agrochemical, and materials industries. One common approach to functionalized arene products involves Cu-catalyzed C(sp2)–H functionalization. While a significant number of these reactions have been reported, they often require high catalyst loadings (≥50 mol%) and/or forcing conditions (≥100 ºC). Mechanistic insight into the structure and oxidation states of reaction intermediates and their reactivity towards C-C and C-heteroatom bond formations could enable development of more effective catalyst systems. This thesis focuses on studying the organometallic CuI, CuII, and CuIII intermediates in these transformations. Chapter 1 provides a detailed overview on the area of directed C–H functionalization using Cu salts as catalysts. Many challenges in reaction development stem from poorly understood reaction mechanisms, and the approaches others have developed to study these mechanisms from discrete CuII complexes are discussed as the framework for Chapters 2, 3, and 4. Chapter 2 details successful efforts towards the isolation of CuII intermediates in 8-aminoquinoline directed C(sp2)–H bond functionalization. The synthesis and characterization of these complexes is reported in detail. Incorporation of a polyfluoroaromatic moiety proved critical for the characterization and isolation of stable -aryl CuII species. Reactivity studies showing the relationship between various complexes are discussed, particularly the intermediacy of cyclometalated CuII complexes in oxidative dimerization of 8-aminoquinoline derived benzamides using AgI and ferrocenium salts as oxidants. Preliminary investigations into the synthesis of similar complexes with less fluorinated and non-fluorinated ligand scaffolds are also disclosed. Chapter 3 establishes mechanistic insight into C(sp2)–H bond metalation and the intermediates involved at CuII and CuIII. Initial computational investigations in conjunction with observation and isolation of novel complexes provide support for the intermediacy of bischelate coordination complexes in 8-aminoquinoline directed C–H activation at CuII. These studies implicate a concerted metalation-deprotonation pathway with acetate as the base. The mechanism of oxidatively induced dimerization at Cu centers is also investigated using both UV-vis and NMR spectroscopy as well as cross-over studies. A diamagnetic high-valent CuIII intermediate is observed through various spectroscopic techniques and is shown to participate in C(sp2)–H activation. These studies implicate the formation of high-valent CuIII preceding a C–H activation of an appended arene, likely through an electrophilic aromatic substitution type mechanism. Chapter 4 establishes foundational reactivity studies of cyclometalated CuII intermediates with various heteroatom oxidants and nucleophiles. For instance, reactivity with AgNO2 affords C(sp2)–NO2 bond formation at room temperature. Use of ferrocenium tetrafluoroborate at low temperatures to form a discrete CuIII complex and subsequent addition of NBu4NO2 is shown to afford the same product, implicating CuIII in the bond forming reaction. In contrast, reactions of the cyclometalated CuII complex with several other AgX salts (X = F, trifluoroacetate, acetate) afford very little C(sp2)–X coupling and instead generate products of aminoquinoline ligand dimerization and/or transmetalation to Ag. Finally, a preliminary study of the reaction between CuII intermediates and N–F oxidants (N-fluoro-2,4,6-trimethylpyridium triflate, N-fluorobenzenesulfonimide, and Selectfluor) demonstrates diverse reactivity, including C(sp2)–C(sp3) and C(sp2)–N bond formation and future directions in reaction development are discussed.Deep Blue DOI
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organometallics C-H activation mechanism copper
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