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Aim: This thesis is focused on the synthesis of new pyridine-based 1,2,3-triazoles to be employed as potential scaffolds for drug discovery and for diverse applications in organic chemistry such as C-H activation and organocatalysis. In particular, this thesis will focus on the biological importance of the synthesised pyridine-based triazoles as potential inhibitors of the KAT2A protein and on their transformations through copper- and palladium- catalysed C-H activations into potentially active compounds. Moreover, it is also described the attempted synthesis of proline-based organocatalysts, enclosing a triazole moiety in their backbone, that will be further evaluated for future applications in organocatalytic reactions such as aldol condensations, Mannich and Michael reactions.

The aim of this project is based on the optimization of new route of synthesis of phenyl alkyl halides, in particular benzylic bromides that are considered versatile intermediates in organic synthesis and often employed in the preparation of bioactive materials. Though this project, we have provided an innovative method that is alternative to methodologies based on phosphorous (III) and (V) for the preparation of bromides having EWG group in β position. This procedure allowed to by-pass the methodologies based on the oxygen-based leaving group and their significant drawnbacks, such as bromide product racemisation and undesired alkene side product arising from elimination of sensitive bromides. Moreover, we have showed that the oxidative activation of sulphide via SN2 could be useful for the development of C-X bond forming reactions. We showed how alkyl bromides and chlorides could be employed for the preparation of Carbon-Oxygen bond in bioactive molecules such as API with an aryl propanamine core. For example, a full synthesis of five steps is showed for the synthesis of Atomoxetine, anti-depressant known as Strattera.

This PhD thesis describes the use of hypervalent sulfur(IV) for the development of new synthetic methodologies to prepare much sought alkyl bromides and fluorides.In order to frame the context of the work and rationalise the results obtained we present, in the first chapter of this thesis, a literature review of sulfur(IV) and (VI) hypervalent compounds detailing their preparation and application in organic synthesis.In the second chapter of this thesis, we describe a novel procedure to prepare alkyl fluorides in up to 77% isolated yields and 35% enantiomeric excess. The reaction made use of electrophilic fluorinating reagent N-fluorobenzenesulfonimide (NFSI) to achieve desulfurative fluorination of alkyl sulfides under mild conditions and in short (10-120 minutes) reaction times. Moreover, the presence of hypervalent sulfur(IV) intermediates was observed via NMR analysis.In the third chapter of this thesis, we report other means to achieve enantioselective desulfurative fluorination of chiral thia-Michael derived alkyl sulfides. Though no conditions suitable for the production of highly enantioenriched alkyl fluorides have been found, three different sets of fluorinating conditions have been identified for the efficient production of thia-Michael derived alkyl fluorides in excellent isolated yields (up to 92% yield) and short reaction times. Moreover, an unexpected and unprecedented methodology to form carbon–carbon bonds has been discovered.In the fourth and final chapter of the thesis, we present the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the conversion of secondary activated alkyl sulfides to benzylic alkyl bromides, in 80-99% isolated yields and excellent enantioselectivity (up to 92% ee; 94% es). The conditions identified required no temperature control, made use of no solvent and did not employ liquid-liquid organic extraction on a multigram-scale.

The use of silicon-based reagents in organic synthesis has received significant attention and has been an ever-growing area of focus in recent years. Since Hosami and Sakurai first described the fluoride-initiated reaction of allytrimethylsilane to aldehydes, there have been several advancements in the field. Alternative sources of silicon activation have been developed such as tBu-P4 and proazaphosphotrane bases as well as work completed by my research group into the tetrabutylammonium controlled addition to aldehydes under mild conditions for a wide variety of substituted trimethylsilanes. It was recognized that these reaction conditions could be further developed through the tailoring of tetrabutylammonium activators for use with specific trimethylsilane substrates, to provide mild and efficient routes to β-hydroxy esters and α,β-unsaturated esters. Conditions for tetrabutylammonium controlled addition and olefination reactions of ethyl 2-(trimethylsilyl)acetate were developed under both batch and continuous flow conditions, employing catalytic amounts of activator at ambient temperature. The synthesis of a diverse range of β-hydroxy esters was achieved through the addition reactions of various aromatic, heteroaromatic, aliphatic aldehydes and ketones to ethyl 2-(trimethylsilyl)acetate using of catalytic amounts of Bu4NOAc. In parallel, conditions for the batch synthesis of the corresponding α,β-unsaturated esters using catalytic amounts of Bu4NOTMS were developed by another member of my research group. A stepwise reaction pathway to the α,β-unsaturated ester was demonstrated via formation of the silylated β-hydroxy ester and subsequent elimination reaction. The use of a specific tetrabutyl ammonium activator was key to the desired product formation. The weaker acetate activator was unable to effect the elimination, whereas it’s trimethylsilyloxide counterpart effectively completed the elimination reaction to provide α,β-unsaturated esters. In both cases, the tetrabutylammonium counterion was shown to play a vital role in the effectiveness of the reaction. The synthesis of these β-hydroxy esters and α,β-unsaturated esters were achieved using mild conditions without the specialized precautions associated with other organometallic synthesis. To further develop these conditions, the reactions were transferred from traditional batch style synthesis methods to continuous flow. The time required to achieve full conversion was significantly reduced for both addition and olefination reactions, from the one hour required for batch to one minute for continuous flow, while maintaining the employment of catalytic amounts of activator and the use of ambient temperature. Teaming this reduction in reaction time with the improved process safety that flow chemistry offers, highlights the significant benefits of adapting pharmaceutical synthesis from batch to continuous flow.