Fluorination of alkyl radicals using electrophilic N-F reagents and investigation on the intramolecular chemoselectivity of alkoxy radicals

The selective fluorination of organic molecules has become increasingly important for the pharmaceutical and agrochemical industries, given that the presence of this atom enhances the lipophilicity and bioavailability of molecules. Despite the extensive research in fluorine chemistry, there is a paucity of selective and safe sources of fluorine for radical reactions. I hereby present the investigation of N−F reagents as efficient fluorine atom transfer agents to alkyl radicals. Although most of the research presented in this work focuses on fluorination methodologies, a study on the intramolecular chemoselectivity of alkoxy radicals is also discussed. Chapter 2 describes the exploratory work into the feasibility of transferring a fluorine atom to alkyl radicals from electrophilic sources of fluorine. Diacyl peroxides and t-butylperesters were homolyzed to generate alkyl radicals in the presence of different N−F fluorine sources. Primary, secondary, and tertiary fluoroalkanes were successfully synthesized under the reaction conditions. This methodology was successfully applied to the fluorination of a cholic acid derivative. In Chapter 3, photoredox catalysis was explored as an alternative method to generate alkyl radicals in the context of radical fluorination. Trisbipyridylruthenium (II) and visible light were utilized to promote the decarboxylative fluorination of phenoxyacetic acid derivatives. Electronwithdrawing groups on the aryl ring favoured the transformation, while electron-donating groups provided undesired products. An estrone derivative was successfully fluorinated with our visible-light mediated methodology. Additionally, transient absorption spectroscopy studies in collaboration with the Wolf group at the University of British Columbia, along with cyclic voltammetry experiments performed in collaboration with the Bizzotto group at the same institution, provided evidence to support an oxidative mechanism of the photocatalytic cycle. Chapter 4 describes a study to assess the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers, when other radical pathways can occur. Cyclization of intramolecular competition substrates showed that 5-exo cyclization of alkoxy radicals onto silyl enol ethers were preferred over 5-exo cyclizations onto terminal, disubstituted and trisubstituted alkenes, as well as 1,5-hydrogen atom transfer reactions and β-fragmentations. Silyl enol ethers as alkoxy radical acceptors strongly favour 6-exo cyclization over 1,5-hydrogen atom transfer from an allylic position.

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