A Study of the Fluorine Effect in C-H Borylation

Abstract

Iridium-catalysed C-H borylation of fluoroarenes represents a very powerful method for the synthesis of fluorinated aryl boronic esters, which are a range of versatile synthetic building blocks. Following a brief review of the developments of Ir-catalysed C-H borylation reactions and synthesis of fluoroaromatics, this thesis describes the investigation of the influence of fluorine substituents on selectivity and effectiveness of iridium-catalysed C-H borylation of polyfluorinated arenes. As observed through the reactions of 1-fluoro-4-methylbenzene, 1-bromo-4-fluorobenzene, and other related substrates, simple fluoroarenes react considerably faster than their non-fluorinated counterparts. Polyfluoroarenes and fluorinated pyridines are even more reactive substrates. The fluorine atom is of low steric bulk and this coupled with a strong inductive electron-withdrawing effect leads to the activation of the C-H bonds ortho to a fluorine atom. However, with 1,3-difluoro-2-substituted arenes, as the electron-withdrawing nature of the 2-substituent increases there is a corresponding increase in the formation of the 1,3-difluoro-5-Bpin product. The parent arene, 1,3-difluorobenzene, shows variable selectivity depending on the nature of the boron source (B2pin2 and HBpin) and this observation challenges the accepted catalytic cycle for these reagents for which the key C-H activation step is supposed to be common. The resulting fluorinated aryl boronic esters can be used in the synthesis of fluorinated biaryls through Suzuki-Miyaura cross-coupling reactions using CsF as an anhydrous base to circumvent protodeboronation observed with more classical aqueous base conditions.