Nucleophilic aromatic substitution of fluoroarenes to synthesise drug compounds for combatting neglected tropical diseases
Creators: name: Buchanan, Adam
Publisher: name: Loughborough University
Year: 2023
Subjects: Other chemical sciences not elsewhere classified

description: Using organofluorine molecules in medicinal chemistry has become commonplace in recent times, not just because of the effect of fluorine on pharmacokinetic and physiological properties of drug molecules, but also due to the wide range of chemical reactions they can undertake as building blocks during synthetic processes. Nucleophilic aromatic substitution (S<sub>N</sub>Ar) is often employed in synthetic processes involving fluorinated aromatics (fluoroarenes) due to the excellence of fluorine as a leaving group. However, the reactions involved often require harsh conditions along with expensive reactants such as transition metal catalysts making scientists reluctant to employ them in drug synthesis programs due to cost and environmental impact. Improving the reaction process via exploration of the discipline known as mechanochemistry, as well as further investigating how S<sub>N</sub>Ar of fluoroarenes can be affected by reaction conditions could provide valuable knowledge to spur the use of this well-known mechanism, further into the spotlight. Presented here is an in depth look into organofluorine compounds, and how S<sub>N</sub>Ar and other fluorine-based chemistry can be used to synthesise promising drug candidates. Chapter 2 reports an exploration into how mechanochemistry can be used to conduct S<sub>N</sub>Ar of per-fluorinated arenes. Reactions were conducted using a planetary ball mill, with limited solvent and common bases. Whilst limited reactions of this nature have been previously conducted, this is the first report of a synthesis of a set of compounds with a large substrate scope, outlining the versatility of the discipline as well as the environmental and monetary benefits. Of the compounds that had been previously synthesised in batch, the yields were comparable other than a few anomalies. Also featured in this chapter, is an investigation into how fluorine effects the success of S<sub>N</sub>Ar reactions via its electron withdrawing properties. Mono-fluorinated and di-fluorinated benzyl esters were reacted with various nucleophiles to show how the additional fluorine atom increases the yield of reactions because of its high electronegativity. Chapter 3 delves deeper into the realm of S<sub>N</sub>Ar by exploring an intramolecular variation of the mechanism known as the Truce-Smiles rearrangement. Work on this mechanism with regards to fluoroarenes has been previously conducted with a small substrate scope, so the aim was to expand upon this work by attempting to conduct reactions with various linker atoms and electron withdrawing groups, to see how if they affected the nature of the products produced. Reactions were also conducted using a sterically hindered base synthesised in situ, proving that the rearrangement can be conducted without for a strong base. A mixture of novel and previously synthesised compounds were synthesised using batch S<sub>N</sub>Ar and the rearrangement was attempted with varying degrees of success, but it was shown that the Truce-Smiles rearrangement can be conducted without a strong base through the use of a sterically hindered base. Chapter 4 explores the real-world applications of organofluorines in the pharmaceutical industry. Neglected tropical diseases are becoming more and more of an issue due to their spread into ‘first world’ countries and the limited treatment options available. The lack of treatment options is due to the fact that limited research is conducted on the subject, mainly due to the diseases not causing widespread fatalities and the majority of cases being reported in the ‘third world’. Drugs containing fluorine are becoming more and more prevalent, and they could be employed to combat some of these neglected diseases that affect so many people around the world. In this chapter a set of 1,2,4-triazole based inhibitors, some of which contained fluorine, were synthesised, with the hope that a hit compound could be achieved for further research.