Fluorinated Azaheterocycles

Fluorinated heterocyclic motifs have found wide application across the life science industries. Therefore, there is profound interest in the development of new and efficient methodology for the incorporation of fluorine into heterocyclic structures. This thesis is concerned with the development of processes for the incorporation of fluorine into the biologically important azaheterocycles, pyrroles and pyrido[1,2-a]pyrimidines, for which current methods are limited. Firstly, the fluorination of pyrroles with SelectfluorTM was studied systematically. Pyrrole substrates bearing electron-withdrawing substituents were found to give fluorinated products but, in all cases, competing oxidation and subsequent polymerisation limited the attainable yields. From this, a tetrabromopyrrole was instead employed which, by lithiation and subsequent reaction with NFSI, gave access to polybrominated 2- and 3-fluoropyrroles. The bromine atoms could be used for subsequent derivatisation by debromolithiation and reaction with a range of electrophiles as well as palladium catalysed Suzuki cross-couplings to give access to a diverse library of highly functionalised fluoropyrrole products. The synthesis of a fluorinated pyrido[1,2-a]pyrimidin-4-one scaffold was also investigated using a fluorinated building block approach. The cyclisation of 2-fluoromalonic acid with 2-aminopyridine in POCl3 gave a fluorinated pyrido[1,2-a]pyrimidin-4-one substrate which was further derivatised by Suzuki cross-coupling reactions

Multifunctional 2- and 3-fluoropyrroles

Sequential reaction cascades for the synthesis of polysubstituted 2‐ and 3‐fluoropyrrole derivatives from common polybromopyrrole precursors have been developed. A strategic variation of a combination of regioselective debromolithiation followed by trapping of the corresponding carbanions by electrophilic fluorination and Pd catalysed cross coupling reactions allows access to polyfunctional fluoropyrrole products by methodology applicable to drug discovery programs, extending the range of five‐membered fluoroazaheteroaromatic derivatives potentially available for incorporation into screening libraries

Synthesis of fluoro- and cyano-aryl containing pyrene derivatives and their optical and electrochemical properties

Mono‐ and 1,6‐disubstituted pyrene derivatives bearing perfluorotoluene or perfluorobenzonitrile moieties were synthesized by nucleophilic substitution processes. The compounds were characterized by NMR, UV‐vis, photoluminescence (PL), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), cyclic voltametry (CV) and density functional theory (DFT) calculations. We found that derivatives substituted with perfluorobenzonitrile showed better thermal stability, stronger electron with‐drawing ability and better fluorescence properties than the corresponding perfluorotoluyl‐pyrene system