UC Berkeley

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

room temperature.

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

halides.

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.