UBC Theses and Dissertations

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UBC Theses and Dissertations

Radical methods for the synthesis of fluoroalkanes and fluoromethyl aryl ethers and copper-catalyzed three-component carboetherification of alkenes Chatalova Sazepin, Claire


Fluorinated molecules have become popular compounds among pharmaceuticals. The introduction of fluorine atoms on bioactive compounds has indeed the potential to improve their biophysical properties. Given the utility of fluorinated substituents on pharmaceuticals, fluorine chemistry has become an area of intensive research. Despite the progress made in selective fluorination, however, radical fluorination has been limited notably due to the paucity of atomic fluorine sources. In this thesis, the uncovering of new atomic fluorine sources and the development of new radical fluorination methods will be described. Chapter 1 presents the importance of fluorinated molecules and the currently available fluorinating agents. A discussion on radical fluorination is presented that includes the most recent advances in the field. In Chapter 2, the exploratory work on the ability of electrophilic N—F fluorinating agents to transfer fluorine to alkyl radicals is detailed. Peresters were chosen as radical precursors and reacted with traditionally electrophilic fluorine sources, NFSI and Selectfluor®. Under those conditions, various fluoroalkanes could be synthesized in good yields. A radical fluorination method subsequently developed using Selectfluor® is described in Chapter 3. The ability of phenoxyacetic acid derivatives to undergo fluorodecarboxylation under UV-light excitation using Selectfluor® was demonstrated. The methodology was successfully applied to the synthesis of mono- and difluoromethyl aryl ethers in 40 to 86% yields. Chapter 4 details the application of the photofluorodecarboxylation to the synthesis of trifluoromethyl aryl ethers. It was found that the wavelength required for the substrate’s excitation led to the decomposition of the desired products. A method using benzophenone as a photosentizer was developed allowing the use of another wavelength to promote the reaction, which proved to be substrate dependent. The use of a faster fluorine transfer agent, XeF2, allowed the synthesis of trifluoromethoxy arenes in good yields. A copper catalyzed difunctionalization of alkenes, developed in collaboration with Prof. Jieping Zhu, is presented in Chapter 5. This reaction allows the direct introduction of alkyl nitriles via C—H activation. A C—O bond and a C—C bond were created in a single step. A wide range of α substituted styrenes were difunctionalized in yields up to 82%.

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