Fluorine incorporation has become increasingly important in pharmaceutical applications. Upon fluorination and incorporation of fluorinated moieties such as trifluoromethoxy groups, many small molecules become more bioavailable and metabolically stable and additionally can better cross the blood-brain-barrier. This thesis describes the development of a method mediated by silver salts for the synthesis of pharmaceutical-like trifluoromethoxylated compounds via \(C-OCF_3\) bond formation. Additionally the synthesis of 3-deoxy-3-fluoromorphine via late-stage fluorination of morphine is described as well as in vitro and in vivo evaluation of 3-deoxy-3-fluoromorphine as a potential analgesic. / Chemistry and Chemical Biology

Visible light photoredox catalysis has proven to be a powerful tool for promoting transformations in organic synthesis. Hence this project was carried out to develop tools for predicting reactivity patterns of visible light- promoted redox reactions. Fluorination is of immense importance in organic chemistry, and so is trifluoromethoxylation. The fluorination reaction has been studied for a long time and has been accomplished in milder ways, while the generation of a trifluoromethoxy-radical at room temperature and atmospheric pressure remains a challenge. The design of the reaction in this project is to overcome the instability and take control of the catalytic event under visible- light photocatalytic conditions. The trifluoromethoxylation reaction proceeded at room temperature with the reaction time of 60 min using acetonitrile as the solvent and blue LED (10 W) as the external light source. No yield of the desired product was obtained for any of the substrates. More surprisingly, in all entries, 3,3-diphenylprop-2-en-1-ol was attained as a side product. The same side product was also detected in the entry with ambient light, concluding that the reaction was completed without any external light source. Thus, no photoredox catalysis took place. / Fotoredoxkatalys via ljus inom det synliga spektrat har visat sig vara ett kraftfullt verktyg för att gynna reaktioner inom organisk syntes. Detta projekt genomfördes med syfte att utveckla verktyg avsedda för att förutspå reaktivitetsmönster vid fotoredoxkatalys med synligt ljus. Fluorinering och trifluorometoxylering är viktiga verktyg inom organisk syntes. Fluorineringsreaktionen har studerats länge och har kunnat genomföras under milda reaktionsbetingelser, medan generering av trifluorometoxyradikal vid rumstemperatur och atomsfärstryck fortfarande är en utmaning. Reaktionen i det här projektet är designad för att kringgå instabilitetsproblemet och ta kontroll över katalysmomentet, under fotokatalysförhållanden i synligt ljus. Reaktionen utfördes i rumstemperatur med en reaktionstid på 60 minuter, med acetonitril som lösningsmedel och blå LED (10 W) som extern ljuskälla. Inget av substraten reagerade till den önskade produkten. Mer överraskande var att 3,3-difenylprop-2-en-1-ol erhölls som sidoprodukt vid alla reaktionsstillfällen. Samma sidoprodukt upptäcktes även vid reaktion genomförd i dagsljus, vilket indikerar att reaktionen skedde utan någon extern ljuskälla. Således skedde ingen fotoredoxkatalys.

Dans une première partie, une méthode efficace et générale de préparation de pyrroles E-fluoroalkylés a été développée. Ces derniers ont été facilement obtenus en deux étapes à partir d'énones E-fluoroalkylées avec de bons rendements. L'oxydation sélective du squelette furanique des pyrroles E-fluoroalkylés, comportant un groupement 2-furyl en position 5 du cycle pyrrolique, puis leur décarboxylation, ont alors donné accès à deux nouvelles familles de synthons pyrroliques fluoroalkylés, très intéressantes pour la conception de molécules bioactives. Dans une seconde partie, deux méthodes originales de trifluorométhoxylation nucléophile, utilisant le triflate de rifluorométhyle (TFMT) ou le 2,4-dinitro(trifluorométhoxy) benzène (DNOB) en tant que générateurs de l'anion trifluorométhanolate, ont été développées. Certains trifluorométhyl éthers ainsi synthétisés ont alors été employés pour la préparation d'énaminones trifluorométhoxylées, précurseurs d’hétérocycles aromatiques trifluorométhoxylés inédits tels que des nicotinates, des pyrimidines, des pyrazoles et des isoxazoles / In a first part, an efficient and versatile method of preparation of E-fluoroalkylated pyrroles has been developed. These compounds have been readily obtained in two steps starting from E-fluoroalkylated enones with good yields. Then, the selective oxidation of the furyl moiety of E-fluoroalkylated pyrroles, bearing a 2-furyl group in the 5-position of the pyrrole ring, followed by their decarboxylation, provided two new classes of pyrrolic building-blocks. In a second part, two original methods of nucleophilic trifluoromethoxylation, using trifluoromethyl triflate (TFMT) or 2,4-dinitro(trifluoromethoxy)benzene (DNOB) as generators of the trifluoromethoxide anion, have been developed. Among the trifluoromethyl ethers so-prepared, some of them have been used to synthesise trifluoromethoxylated enaminones, precursors of novel trifluoromethoxylated aromatic heterocycles such as nicotinates, pyrimidines, pyrazoles and isoxazoles, which are very interesting for the design of bioactive molecules