meta-Functionalisation of Fluoroarenes via a Traceless Directing Group Strategy and Cross-Dehydrogenative Arylation of Benzylic C–H Bonds

Abstract

Fluoroarenes are some of the most important structural motifs in the chemical industry. This has led to direct C-H functionalisation methodologies to form C-C bonds on fluoroarenes becoming an incredibly valuable tool to synthetic chemists. Early seminal work from Fagnou and Daugulis on direct arylation of perfluoroarenes has laid the foundation for a plethora of methodologies for C-C bond formation. In chapters 1, 2 and 3 of this thesis, a thorough account of the development of regioselective C-H functionalisation reactions targeting the meta position of fluoroarenes is given. To give a context, in chapter 1, methodologies for the direct C-H functionalisation of fluoroarenes to form C-C bonds are discussed. Early methodologies that focussed on functionalisation of perfluoroarenes are discussed, then moving towards more modern reports that aim to overcome the low reactivity of monofluoroarenes. In chapter 2 and chapter 3, an account is given of developing both a meta-selective arylation and olefination of monofluoroarenes (Scheme 0.1). Details of initial optimisation, reaction scope and synthetic utility in the synthesis of a bioactive molecule are disclosed for both methods. Cross-dehydrogenative coupling (CDC) via the sequential activation of two inert C-H bonds offers an efficient and environmentally benign route to complex molecules. CDC at benzylic positions would provide rapid and facile access to 1,1-diarylmethanes, which are highly valuable to the chemical industry. In chapters 4 and 5 of this thesis, a thorough account is given of the development of a cross-dehydrogenative arylation of benzylic C-H bonds. In chapter 4, context is given by a complete review of methods for benzylic C-H arylation, starting with methods using one pre-activated coupling partner and moving to crossdehydrogenative methods. In chapter 5, an account is given for initial optimisation, the scope of the reaction in alkyl benzene and nucleophilic arene and the application of the method to the late stage elaboration of bioactive molecules (Scheme 0.2).

Date of Award	13 Jan 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Igor Larrosa (Main Supervisor) & Daniele Leonori (Co Supervisor)