Novel Synthetic Routes to Fluorinated Heterocycles using the Fluoroiodane Reagent

Over 85 % of small molecule pharmaceuticals approved by the FDA in 2019 contained a nitrogen-based heterocycle and over a quarter of all FDA approved drugs on the market contain at least one fluorine atom. The activity of heterocycles in vivo justifies their prominence, and the modest C-F bond has an instrumental influence on the pharmacokinetic properties of therapeutics. In chapter 2, the fluorocyclisation of unsaturated oximes to form novel fluorinated dihydro-oxazines was achieved using the hypervalent iodine(III) reagent, fluoroiodane, and stoichiometric AgBF4. Moderate yields (42-53 %) were delivered under rapid and mild reaction conditions. This unique reaction showed novel chemoselectivity over existing methodology using electrophilic fluoraza reagents which normally produce fluorinated dihydroisoxazoles.

In chapter 3, an aminofluorination reaction was developed using β,γ-unsaturated hydrazones to prepare novel fluorinated tetrahydropyridazines (70-99 %) in just 15 minutes at room temperature. The reaction conditions were refined from stoichiometric AgBF4 to metal-free reaction conditions in the solvent, hexafluoroisopropanol (HFIP). NMR studies showed that the fluoroiodane reagent was activated by hydrogen bonding to HFIP. The methodology was also extended to the chlorocyclisations of β,γ-unsaturated hydrazones using chloroiodane to generate chlorinated tetrahydropyridazines in excellent yields (70-93 %). To our knowledge, this is the first time that chloroiodane has shown divergent selectivity, since traditional electrophilic fluorinating and chlorinating reagents normally form halogenated dihydropyrazoles.

Further exploration of hydrogen bond catalysis in the aminofluorination reaction was performed in chapter 4. When the amount of HFIP was reduced from neat solvent to catalytic quantities, excellent yields (93 %) were still obtained. A range of urea catalysts were screened and shown to perform the same transformation in good yields (up to 75 %). The pursuit of enantioselective fluorination was then investigated and a series of chiral bis-urea catalysts bearing a (S)-binaphthalene backbone were synthesised. Unfortunately, the enantioselective fluorination was unsuccessful (up to 12 % ee) with the system suffering from a background fluorination, low reaction conversions and incompatibility with conventional methods for determining the enantiomeric excess.