New Fluorination Methodology using a Hypervalent Fluoroiodane Reagent

In medicinal chemistry the incorporation of fluorine into the organic framework continues to be an important strategy for the development of new pharmaceutical products because of the beneficial properties imparted by fluorine such as increased metabolic stability, increased lipophilicity and/or to tune the pharmacokinetic properties.1 The cyclic hypervalent fluoroiodane reagent 7 was introduced as a new, air and moisture stable, fluorinating reagent in 2013 and it can be prepared from cheap sources of nucleophilic fluoride. The fluoroiodane reagent 7 was used for an efficient transition metal catalysed fluorocyclisation of unsaturated carboxylic acids to prepare γ-lactones, containing tertiary alkyl fluorides. The reaction integrated a cyclisation, an aryl migration and a fluorination all in one step.

In contrast to the previous work reported in the literature, the metal catalysts (Ag(I), Cu(I) and Zn(II)) were used in catalytic rather than stoichiometric amounts in chapter 2 and the reactions were performed at room temperature for 4 hours generating the desired fluorinated γ-lactones in good yields. The scope of the unsaturated carboxylic acids was expanded from geminal-disubstituted alkenes to monosubstituted, trans-disubstituted and trisubstituted alkenes. Furthermore, it was discovered that the fluoroiodane reagent 7 can be activated by hydrogen bonding to hexafluoroisopropanol and so, metal-free fluorocyclisations of unsaturated carboxylic acids were developed. The efficiency of these new reaction conditions was demonstrated by the synthesis of eight fluorinated lactones in moderate to high yields.

In chapter 3, a new fluoroiodane reagent 91 containing an additional phenyl sidearm was synthesised and used to prepare a series of unsymmetrical diaryliodonium salts from Grignard reagents and arylboronic acids. The unsymmetrical diaryliodonium salts were fluorinated in the presence and absence of Cu(II) catalyst, generating fluorinated aromatics.

Finally, the novel fluoroiodane reagent 91 was reacted with terminal and internal alkyne substrates to form four β-fluorovinyliodonium salts in good yields. Since the overall aim of chapter 4 was to develop new methodology for the synthesis of fluoroalkenes, a preliminary fluorination of (E)-(2-fluorooct-1-en-1-yl)(2-(1-phenylvinyl)phenyl)iodonium tetrafluoroborate was attempted in the presence of a Cu(II) catalyst.