The synthesis of novel fluorinated heterocycles and their antitrypanosomal activity

A range of fluorinated heterocyclic scaffolds: quinazolines, benzofurans, benzothiophenes, benzothiazoles, indoles, and phenoxazines have been synthesised in this project using a tandem S_NArring closing strategy employing perfluoroarenes as starting materials. A range of novel compounds including quinazolines, benzofurans and many more have been characterised by IR spectroscopy, ¹H/¹⁹F/¹³C NMR spectroscopy, elemental analysis, HRMS, and eight X-ray crystal structures have been determined. The novel fluorinated compounds accessed in this work were screened against T b rhod, T cruzi and L. don. Ax am the causative agents of three neglected tropical diseases: sleeping sickness, Chagas disease and leishmaniasis respectively.

Of the compounds screened quinazoline 129 presented itself as a lead compound with IC₅₀ values of 0.84 μM and 0.22 μM against T b rhod and T cruzi respectively. Subsequently synthetic reactions involving further SNAr reaction, or functional group modification have been carried out to explore the chemical space of the lead compound to build up SAR data. An improved synthesis of fluorinated quinazolines involving condensation of fluoroaryl nitriles or ketones with amidines has been developed. Microwave irradiation has been shown to be a viable method to obtain this scaffold in a more efficient and greener synthesis.

Mechanistic studies have been undertaken to ascertain the mechanism of the deacylation of polyfluoroaryl aldehydes, ketones and esters identified as a competing side reaction during attempts to access benzofurans, indoles and quinazolines under basic reaction conditions. NMR spectroscopic experiments involving deuterium labelling established that in the presence of base deacylation occurs with generation of an aryl anion, a short-lived intermediate which subsequently reacts with moisture forming protonated fluoroarene products. The findings are in agreement with earlier studies on related perfluoroaryl systems.

Additionally, a mechanistic study has been carried out on the ring closing reaction of 2-benzamidophenylsulfanyl fluoroarenes which forms fluorinated phenothiazine scaffold to ascertain whether a Smiles rearrangement occurs before ring closure. Experiments to follow the course of the reaction by ¹⁹F NMR spectroscopy were undertaken, and the determination of the X-ray crystal structure of 367 confirmed that Smiles rearrangement had occurred before ring closure.