Year: 2025
Type: dissertation
Abstract: Organofluorine molecules are central to pharmaceutical, agrochemical, and materials science applications. The introduction of fluorine or fluorine-containing building blocks, however, remains challenging. This Thesis describes several projects related to the synthesis of organofluorine molecules, specifically reactions that leverage non-traditional starting materials. Chapter 2 describes a directing-group enabled, Cu-catalyzed fluoroalkylation method for aryl halides. This work demonstrates that ortho-chelating groups promote the oxidative addition of aryl bromides and chlorides to Cu(I)-fluoroalkyl complexes containing N-heterocyclic carbene (NHC) ligands, a mechanistic step previously limited to aryl iodides. This novel reactivity was leveraged for the first Cu-catalyzed difluoromethylation reaction of aryl bromides. In Chapter 3, a conceptually-novel approach for aromatic C-F bond formation is reported. Traditionally, fluorination reactions require the use of anhydrous metal fluoride salts, which pose significant operational challenges. To address this issue, I developed a reaction that converts (hetero)aryl sulfonyl fluorides to (hetero)aryl fluorides without the need for exogenous fluoride via the Pd-catalyzed extrusion of SO2. To quantify the substrate limitations of this method and guide ligand selection, I initiated a collaboration with data scientists in the Sigman Group at the University of Utah. Preliminary results are also shown for the analogous decarbonylative fluorination of acid fluorides, a long-time target reaction of the Sanford Lab. In Chapter 4, three complementary protocols are described for synthesizing sulfonyl fluorides from primary sulfonamides, a common but synthetically-underutilized functional group. In the first method, sulfonamides are converted to sulfinate salts via a photochemical reduction and then treated with electrophilic fluorination reagents. In the second, sulfonyl imines are homolyzed photochemically and the resulting sulfonyl radicals undergo copper-mediated fluorination. In the final method, an NHC-catalyzed deamination method converts sulfonamides to sulfinate salts, which are treated with electrophilic fluorination reagents. This chapter represents not only significant progress in the ease of access to sulfonyl fluorides, but also in the emerging field of sulfonamide-functionalization chemistry. Finally, in Chapter 5, summaries of how these projects contribute to the field of organofluorine chemistry, and brief discussions of future and on-going related work from the Sanford lab, are provided.
DOI: 10.7302/25539
Author: Hall, Jonathan
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4414684500
Cites:
Cited by:
Related to: