UC Berkeley

The following dissertation discusses the development and study of reactions that introduce fluorine-containing substituents to functionalized aromatic compounds. In particular, the focus of this work will be directed towards transition metal-catalyzed or -mediated reactions that couple abundant aryl halide or aryl pseudohalide electrophiles with trifluoromethyl, pentafluoroethyl, difluorobenzoyl, difluoromethyl, or aryldifluoromethyl groups.

Chapter 1 provides a review of the properties and applications of fluorinated organic compounds, as well as synthetic methods to prepare such compounds. The challenges associated with preparing organic compounds that possess fluorinated-substituents are also discussed along with the progress that has been made towards addressing these challenges. In addition, this chapter highlights unsolved challenges in the fluoroalkylation reactions of functionalized aromatic compounds and provides the author’s opinion on future directions for research in this area.

Chapter 2 discusses the perfluoroalkylation of abundant heteroaryl bromide electrophiles with stoichiometric perfluoroalkylcopper complexes, (phen)CuRF. These reactions occurred with excellent scope and functional group compatibility for the preparation of medicinally-relevant trifluoromethyl-substituted heterocycles.

Chapter 3 discusses a new procedure for the copper-catalyzed trifluoromethylation and pentafluoroethylation of aryl iodides and heteroaryl bromides. These reactions occurred under mild conditions and could be conducted with as little as 5% of a Cu-catalyst. In addition, the preparation and reactivity of new (L)CuCF2CF3 complexes were studied to gain insight on how the electron-donating properties of the ligand on copper affect the perfluoroalkylation reaction.

Chapter 4 discusses a route for the α-arylation of α,α-difluoroacetophenone with phenol derivatives that is catalyzed by palladium complexes. Different catalyst systems were developed to allow for the coupling of assorted aryl sulfonate electrophiles. The products of this reaction have been previously reported to undergo base-induced cleavage to difluoromethylarenes. The overall transformation provides a route from phenols to difluoromethylarenes, a phenol bioisostere.

Chapter 5 discusses the synthesis of diaryldifluoromethane compounds by a palladium-catalyzed cross-coupling of aryl bromides with aryldifluoromethyl trimethylsilanes. This work is the first example of the coupling of an aryldifluoromethyl group with an aryl electrophile.