Investigation of the Truce-Smiles rearrangement of perfluoroarenes and its application to the synthesis of polycyclic heterocycles

<p dir="ltr">Fluorine plays a critical role in agricultural, pharmaceutical, and materials chemistry due to the unique physical and chemical properties of the fluorine atom. Chapter 1 illustrates the development of fluorinated compounds focuses on late-stage fluorination and the use of fluorinated building blocks. Perfluorinated aromatic compounds offer multiple reaction sites for functionalisation and the construction of new ring systems, leveraging the high regioselectivity of SNAr reactions based on the special reactivity of perfluoroarenes. The fluorine atom serves as an excellent leaving group in SNAr reactions and activates the aromatic ring due to its strong electron-withdrawing properties.</p><p dir="ltr">The Truce-Smiles rearrangement, an intramolecular SNAr reaction, has been explored to achieve aryl-aryl bond formation using perfluoroarenes as starting materials via a lithium-halogen exchange method, without employing transition metals. This rearrangement involves a 4-membered transition state, which is unusual, with limited examples reported in the literature. Studying the Truce-Smiles rearrangement could elucidate why a strained 4-membered ring transition state is preferred over the geometrically more favourable 5-membered ring transition state for the direct cyclisation pathway. The Truce-Smiles rearrangement of perfluoroarenes, followed by cyclisation, provides a synthetic route to fluorinated dibenzofuran or benzofuropyridine derivatives.</p><p dir="ltr">Chapter 2 reports the SNAr reaction of pentafluoropyridine with phenol and thiophenol as nucleophiles, yielding mono-, di-, and tri-substituted derivatives. An optimised procedure for the Truce-Smiles rearrangement using the lithium-halogen exchange method was developed, achieving increased yield and higher purity of the rearrangement product compared to literature reports. DFT calculations suggested that the rearrangement mechanism might involve an ¿ate¿ complex as an intermediate rather than a lithiated species, with the ¿ate¿ complex potentially inducing the Thorpe-Ingold effect, leading to the 4-membered transition state as the preferred reaction pathway. Additionally, a pentacyclic heteroaromatic ring was synthesised and characterised by SC-XRD analysis. However, attempts to synthesise heptacyclic compounds using decafluorobiphenyl as the core were unsuccessful due to solubility issues and insufficiently activated aromatic rings.</p><p dir="ltr">Chapter 3 investigates the Truce-Smiles rearrangement of diarylamines, focusing on the influence of aniline protecting groups on the reaction outcome. The N-methyl-protected aniline yielded a mixture of rearrangement and cyclisation products, with the rearrangement product as the major component. However, only cyclisation products were isolated via recrystallisation for both perfluoropyridine and perbenzotrifluoride cores. Additionally, N-acetyl- and N-pivaloyl-protected derivatives exhibited potential atropisomerism, as indicated by 19F NMR spectra; a computational study revealed a 9.3 kcal/mol energy barrier for rotation between the amide and tetrafluoropyridine ring. In contrast, N-tosyl-protected derivatives exclusively afforded the rearrangement product using the lithium-halogen exchange method. Alternatively, lithiation with LiTMP as the base proceeded via a 5-membered transition state, yielding a product where the tosyl-substituted aromatic ring migrated instead of the aniline bearing the DoM group. The subsequent cyclisation step generated novel heterocyclic compounds containing a [1,2]thiazine dioxide ring.</p><p dir="ltr">Chapter 4 demonstrates a fluoride-induced desilylative Truce-Smiles rearrangement, overcoming the limitations of using n-BuLi to initiate the rearrangement. A cascade reaction was observed where rearrangement and cyclisation occurred simultaneously, yielding trifluorodibenzofuran derivatives. The fluoride-induced desilylation method enhanced the functional group tolerance of tetrafluoroarenes. Unlike the lithium-halogen exchange method, which was incompatible with carbonyl functional groups, ketone and ester groups tolerated fluoride as a nucleophile. A bis-dibenzofuran was synthesised when decafluorobiphenyl was used as the perfluoroarene core, although low yields were observed due to the lack of a strong activating group. Additionally, debenzoylation with TBAF was investigated, revealing that trifluorodibenzofuran could be deprotonated by LiTMP, enabling potential functionalisation with various electrophiles and the heptacyclic compounds could be synthesised using trifluorodibenzofuran as the starting material.</p>