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New base-catalyzed processes enable new approaches to C–H functionalization reactions




Puleo, Thomas R., author
Bandar, Jeffrey, advisor
McNally, Andy, committee member
Zadrozny, Joseph, committee member
Chatterjee, Delphi, committee member

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Brønsted bases are ubiquitous, inexpensive, and widely available reagents used in synthetic chemistry due to their well-studied and predictable activation mode. This thesis details the discovery and incorporation of new Brønsted base-catalyzed processes into fundamental proton transfer equilibria to enable new approaches to C–H functionalization reactions. The direct functionalization of C–H bonds represents a streamlined and attractive approach to access valuable synthetic targets, and this utility will be highlighted throughout the discussion of each method.Chapter one describes the discovery and development of a base-catalyzed α-selective styrene deuteration reaction. The mechanistic studies that led to the conceptualization and optimization of this reaction will be highlighted. α-Deuterated styrenes are compounds frequently utilized in the mechanistic studies of alkene functionalization reactions and this work represents the first method to achieve α-selective hydrogen isotope exchange on styrene derivatives. Chapter two provides an overview of existing approaches to catalytic aryl halide isomerization reactions. A particular focus on base-catalyzed aryl halide isomerization reactions will be provided, as these reports serve as the mechanistic foundation for the reactions developed throughout the remainder of the thesis. Chapter three describes our discovery and application of a general approach to base-catalyzed aryl halide isomerization. Aryl halides are valuable compounds in synthetic chemistry, and this new catalytic isomerization process unlocks a new mode of reactivity for these compounds. The scope of this process is demonstrated on several simple aryl bromides and iodides. The second part of this chapter will highlight an application of this process to enable the 4-selective nucleophilic substitution of 3-bromopyridines. Chapter four describes our approach to achieve nucleophilic C–H etherification of electron-deficient N-heteroarenes via a base-catalyzed halogen transfer mechanism. 2-Halogenated thiophenes efficiently transfer halogens to N-heteroaryl anions to generate N-heteroaryl halide intermediates that undergo nucleophilic aromatic substitution with alkoxide nucleophiles. Additionally, C–H etherification can be sequenced with a cascade base-promoted elimination to enable N-heteroarene C–H hydroxylation. The scope of process is highly general, and regioselective C–H etherification and hydroxylation is demonstrated on thiazoles, oxazoles, imidazoles, pyridines, pyrimidines, pyridazines, and polyazines. Chapter five briefly highlights two new C–H functionalization reactions currently being developed that are enabled by base-catalyzed halogen transfer. First, use of this approach to enable the C–H hydroxylation of benzenes will be described. Second, the monoselective and site-selective benzylic C–H etherification of toluenes and polyalkyl benzenes will be detailed. In the final part of the chapter, I will summarize my contributions and discuss the future outlooks on this chemistry.


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base-catalyzed halogen transfer
hydrogen isotope exchange
C–H functionalization


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