Transition-Metal Mediated Fluorination and Fluoroalkylation Reactions
- Author(s): Fier, Patrick Scott
- Advisor(s): Hartwig, John F
- et al.
The following dissertation discusses the development, study, and applications of
methods to prepare perfluoroalkyl arenes, difluoromethyl arenes, aryl difluoromethyl
ethers, and aryl fluorides. The final section discusses the use of a C-H fluorination
reaction for the synthesis and late-stage functionalization of complex molecules. In
addition to developing reactions to prepare fluorinated compounds, the mechanisms were
investigated through experimental and computational methods.
Chapter 1 provides a review of the importance of fluorinated compounds and how
such compounds are typically prepared. The challenges involved with developing new
reactions to form Ar-F or Ar-CF2R bonds are discussed, along with the approaches that
have been taken to address these challenges. A detailed discussion of state of the art
methods follows, particularly focused on reactions with transition metal reagents or
catalysts. Comments on how these new reactions have expanded the field of fluorination
and fluoroalkylation are provided. Each section closes with a forward looking statement
on what major challenges remain, and how such issues may be overcome.
Chapter 2 describes a method for the synthesis of perfluoroalkyl arenes from aryl
boronate esters. This method was extended to the perfluoroalkylation of Ar-H and Ar-Br
bonds through initial formation of ArBPin reagents in-situ.
Chapter 3 discusses a reaction to extend the scope of perfluoroalkylation
chemistry to include a variety of heteroarylbromide substrates as reacting partners. These
reactions occur with remarkable scope and functional group tolerance for the preparation
of trifluoromethyl heteroarenes.
Chapter 4 discusses the development of the first difluoromethylation crosscoupling
reaction. These reactions occur with simple reagents and occur in good yields
for the difluoromethylation of electron-neutral and electron-rich aryl iodides.
Chapter 5 describes the development of a broadly applicable method for preparing
aryl difluoromethyl ethers. These reactions occur under mild conditions within seconds at
Chapter 6 describes the design of a new copper reagent for the fluorination of aryl
iodides with AgF. This work was the first example of copper in the synthesis of
functionalized aryl fluorides, and the first example for the fluorination of unactivated aryl
Chapter 7 discusses the extension of the work in Chapter 6 for the fluorination of
aryl boron reagents with our newly designed copper reagent. The mechanism of this
transformation was investigated, and our data is consistent with the formation of the aryl
fluoride from an Ar-Cu(III)-F species.
Chapter 8 describes a simple and general method for prepare fluorinated
heteroarenes directly through C-H fluorination. The design of such a fluorination reaction
was inspired by a classic C-H amination reaction.
Chapter 9 extends from the work discussed in Chapter 8 and demonstrates how
the C-H fluorination reaction can be used as a versatile reaction for accessing a variety of
2-heteroaryl compounds. The utility of this was demonstrated in several syntheses and
late-stage functionalization reactions of important medicinal compounds.