New late-stage strategies towards difluoromethylarenes

Thesis

This thesis consists of the development of novel methodology to access difluoromethylated compounds both in the context of photoredox catalysis and fluorine-18 radiochemistry for Positron Emission Tomography (PET). First a general introduction to late-stage difluoromethylation will be showcased in Chapter I. In Chapter II, a metal-free visible light catalysed synthesis of difluoromethylarenes via a controlled hydrodefluorination of electron-poor trifluoromethylarenes is described. The reaction works both in batch and in flow and proves to be useful in the context of late-stage functionalisation. In Chapter III, a general introduction to PET is provided. General radiochemistry concepts are also introduced. In Chapter IV, a facile and robust radiochemical methodology for PET describing the synthesis of 18F-difluoromethylarenes from aryl boronic acids, ethyl bromofluoroacetate and cyclotron produced [18F]fluoride is presented. The two key steps involve a copper catalysed cross-coupling reaction using bench-stable aryl boronic acids to yield 2-fluoro-2-arylacetic acids in a two-step one-pot reaction followed by a manganese mediated 18F-fluorodecarboxylation to afford 18F-difluoromethylarenes in a streamlined fashion. Chapter V discusses the synthesis of the first 18F-difluorocarbene reagent and its application to react as a difluoromethylating reagent with phenols, thiophenols, N-heterocycles, and boronic acids. Chapter VI provides experimental data for compounds described within this thesis.

Authors: Sap, JBI

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: photoredox catalysis; radiofluorination; difluorocarbene; difluoromethylation; hydrodefluorination
• Subjects: Photoredox Catalysis; Organic Chemistry; Radio chemistry