| dc.description.abstract | Fluorination is an important strategy for perturbing the biophysical properties of compounds in medicinal chemistry. Specifically, fluorination modulates both the pharmacodynamic and pharmacokinetic properties of bioactive molecules in generally beneficial ways. However, fluorination similarly manipulates the reactivity of compounds in synthetic chemistry, leaving many traditional synthetic methods unable to perform as expected in organofluorine chemistry. Chapter 1 provides background on the effects of fluorine on medicinal and synthetic chemistry, and specifically discusses the effects of fluorine upon alkenes. Gem-difluoroalkenes are an appealing substructure for nucleophilic addition reactions, as they readily react with nucleophiles. However, upon nucleophilic addition defluorination reactions occur, providing fluoroalkene products. Reactions of difluoroalkenes which retain both fluorine atoms would provide access to underexplored difluorinated substructures. To this end, Chapter 2 describes the development of organocatalyzed addition of thiols to gem-difluoroalkenes to provide a,a-difluorophenethyl thioethers. Alcohol nucleophiles possess similar reactivity to thiols, including with gem-difluoroalkenes. Moreover, in medicinal chemistry ethers are a more common substructure than thioethers. Thus, Chapter 3 describes the addition of phenolic nucleophiles across gem-difluoroalkenes in a hydrophenolation reaction to provide a,a-difluorophenethyl arylethers. Gem-difluoroalkenes also possess unusual reactivity with transition metal catalysts. Typically, transition metals perform oxidative addition to C–halogen bonds to initiate cross coupling chemistry. However, the high C–F bond strength generally precludes oxidative addition, enabling alternate mechanistic pathways. Chapter 4 discusses the development of a Co-catalyzed deoxygenation reaction of gem-difluoroalkenes with phenol nucleophiles and O2 to provide b-phenoxy-b,b-difluorobenzyl alcohols. This reaction proceeds by an unusual radical reaction pathway in which superoxide oxidizes phenol to phenoxyl radical, which adds to gem-difluoroalkenes to provide a benzyl radical that quenches with peroxide anion. Finally, Chapter 5 discusses the ongoing work on metal-catalyzed dioxygenation reactions of gem-difluoroalkenes. This work covers the further development of b-phenoxy-b,b-difluorobenzyl alcohols under Pt catalysis, specifically to expand the reaction scope to heteroaryl alcohols, aliphatic alcohols, and aliphatic gem-difluoroalkenes. Further, Cu-catalysis enables the production of b-phenoxy-b,b-difluorobenzyl ketones. | |
