Development of Selective Processes for C(sp3)-H Chlorination and Alkyl Halide Elimination

Abstract

Alkyl halides are prevalent in organic chemistry, often finding their way into chemical syntheses due to their broad reactivity. Methods of selective C(sp3)-H halogenation are therefore of considerable interest as they allow the introduction of these valuable reactivity handles in otherwise inaccessible positions. Late-stage modification in this manner opens up new routes for synthesis and allows for complex molecule derivatisation without the need for de novo route design. In this thesis the development of a methodology capable of C(sp3)-H chlorination will be described. The method makes use of the properties of aminium radicals to achieve high selectivity both in terms of steric and electronic effects enabling the selective chlorination of a variety of molecules. By varying the structure of the aminium radical used it was also found to be possible to switch the position of functionalisation on sclareolide, allowing for the formation of a chlorinated analogue in one step that has previously required either a de novo synthesis or bacterial fermentation to make. One of the most classical reactivities of alkyl halides is their elimination to form olefins. Elimination reactions often suffer from a lack of selectivity and (when they are selective) tend to favour the formation of the more thermodynamically favoured product. Herein the development of a process for the selective formation of the contra-thermodynamic product is described. The reaction makes use of halogen atom transfer for the mild activation of alkyl halides and cobaloxime catalysis for the generation of the corresponding olefin. Through tuning of the steric properties of the cobaloxime it was found to be possible to significantly improve the selectivity of the olefination for the less hindered site, often giving the thermodynamically disfavoured product.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Procter (Supervisor) & Daniele Leonori (Supervisor)