Transition-Metal Mediated Fluorination and Fluoroalkylation Reactions

The following dissertation discusses the development, study, and applications of/nmethods to prepare perfluoroalkyl arenes, difluoromethyl arenes, aryl difluoromethyl/nethers, and aryl fluorides. The final section discusses the use of a C-H fluorination/nreaction for the synthesis and late-stage functionalization of complex molecules. In/naddition to developing reactions to prepare fluorinated compounds, the mechanisms were/ninvestigated through experimental and computational methods./nChapter 1 provides a review of the importance of fluorinated compounds and how/nsuch compounds are typically prepared. The challenges involved with developing new/nreactions to form Ar-F or Ar-CF2R bonds are discussed, along with the approaches that/nhave been taken to address these challenges. A detailed discussion of state of the art/nmethods follows, particularly focused on reactions with transition metal reagents or/ncatalysts. Comments on how these new reactions have expanded the field of fluorination/nand fluoroalkylation are provided. Each section closes with a forward looking statement/non what major challenges remain, and how such issues may be overcome./nChapter 2 describes a method for the synthesis of perfluoroalkyl arenes from aryl/nboronate esters. This method was extended to the perfluoroalkylation of Ar-H and Ar-Br/nbonds through initial formation of ArBPin reagents in-situ./nChapter 3 discusses a reaction to extend the scope of perfluoroalkylation/nchemistry to include a variety of heteroarylbromide substrates as reacting partners. These/nreactions occur with remarkable scope and functional group tolerance for the preparation/nof trifluoromethyl heteroarenes./nChapter 4 discusses the development of the first difluoromethylation crosscoupling/nreaction. These reactions occur with simple reagents and occur in good yields/nfor the difluoromethylation of electron-neutral and electron-rich aryl iodides./nChapter 5 describes the development of a broadly applicable method for preparing/naryl difluoromethyl ethers. These reactions occur under mild conditions within seconds at/nroom temperature./nChapter 6 describes the design of a new copper reagent for the fluorination of aryl/niodides with AgF. This work was the first example of copper in the synthesis of/nfunctionalized aryl fluorides, and the first example for the fluorination of unactivated aryl/nhalides./nChapter 7 discusses the extension of the work in Chapter 6 for the fluorination of/naryl boron reagents with our newly designed copper reagent. The mechanism of this/ntransformation was investigated, and our data is consistent with the formation of the aryl/nfluoride from an Ar-Cu(III)-F species./nChapter 8 describes a simple and general method for prepare fluorinated/nheteroarenes directly through C-H fluorination. The design of such a fluorination reaction/nwas inspired by a classic C-H amination reaction./nChapter 9 extends from the work discussed in Chapter 8 and demonstrates how/nthe C-H fluorination reaction can be used as a versatile reaction for accessing a variety of/n2-heteroaryl compounds. The utility of this was demonstrated in several syntheses and/nlate-stage functionalization reactions of important medicinal compounds.

Advisor: Hartwig, John F