Transition-Metal Mediated Fluorination and Fluoroalkylation Reactions

The following dissertation discusses the development, study, and applications ofmethods to prepare perfluoroalkyl arenes, difluoromethyl arenes, aryl difluoromethylethers, and aryl fluorides. The final section discusses the use of a C-H fluorinationreaction for the synthesis and late-stage functionalization of complex molecules. Inaddition to developing reactions to prepare fluorinated compounds, the mechanisms wereinvestigated through experimental and computational methods.Chapter 1 provides a review of the importance of fluorinated compounds and howsuch compounds are typically prepared. The challenges involved with developing newreactions to form Ar-F or Ar-CF2R bonds are discussed, along with the approaches thathave been taken to address these challenges. A detailed discussion of state of the artmethods follows, particularly focused on reactions with transition metal reagents orcatalysts. Comments on how these new reactions have expanded the field of fluorinationand fluoroalkylation are provided. Each section closes with a forward looking statementon what major challenges remain, and how such issues may be overcome.Chapter 2 describes a method for the synthesis of perfluoroalkyl arenes from arylboronate esters. This method was extended to the perfluoroalkylation of Ar-H and Ar-Brbonds through initial formation of ArBPin reagents in-situ.Chapter 3 discusses a reaction to extend the scope of perfluoroalkylationchemistry to include a variety of heteroarylbromide substrates as reacting partners. Thesereactions occur with remarkable scope and functional group tolerance for the preparationof trifluoromethyl heteroarenes.Chapter 4 discusses the development of the first difluoromethylation crosscouplingreaction. These reactions occur with simple reagents and occur in good yieldsfor the difluoromethylation of electron-neutral and electron-rich aryl iodides.Chapter 5 describes the development of a broadly applicable method for preparingaryl difluoromethyl ethers. These reactions occur under mild conditions within seconds atroom temperature.Chapter 6 describes the design of a new copper reagent for the fluorination of aryliodides with AgF. This work was the first example of copper in the synthesis offunctionalized aryl fluorides, and the first example for the fluorination of unactivated arylhalides.Chapter 7 discusses the extension of the work in Chapter 6 for the fluorination ofaryl boron reagents with our newly designed copper reagent. The mechanism of thistransformation was investigated, and our data is consistent with the formation of the arylfluoride from an Ar-Cu(III)-F species.Chapter 8 describes a simple and general method for prepare fluorinatedheteroarenes directly through C-H fluorination. The design of such a fluorination reactionwas inspired by a classic C-H amination reaction.Chapter 9 extends from the work discussed in Chapter 8 and demonstrates howthe C-H fluorination reaction can be used as a versatile reaction for accessing a variety of2-heteroaryl compounds. The utility of this was demonstrated in several syntheses andlate-stage functionalization reactions of important medicinal compounds