This thesis is based on research in Cu-catalyzed electrophilic trifluoromethylation and exploiting Cu/Cu2O nanowires with novel catalytic reactivity for developing of catalytic and greener synthetic methods. A large number of biological active pharmaceuticals and agrochemicals contain fluorine substituents (-F) or trifluoromethyl groups (-CF3) because these moieties often result in profound changes of their physical, chemical, and biological properties, such as metabolic stability and lipophilicity. For this reason, the introduction of fluorine or trifluoromethyl groups into organic molecules has attracted intensive attention. Among them, transition metal-catalyzed trifluoromethylation reactions has proved to be an efficient and reliable strategy to construct carbon-fluorine (C-F) and carbontrifluoromethyl (C-CF3) bond. We have developed a catalytic process for the first time for trifluoromethylation of terminal alkynes with Togni’s reagent, affording trifluoromethylated acetylenes in good to excellent yields. The reaction is conducted at room temperature and exhibits tolerance to a range of functional groups. Derived from this discovery, the extension of work of copper catalyzed electrophilic trifluoromethylation were investigated which include the electrophilic trifluoromethylation of arylsulfinate salts and electrophilic trifluoromethylation of organotrifluoroborates. Because of growing environmental concern, the development of greener synthetic methods has drawn much attention. Nano-sized catalysts are environment-friendly and an attractive green alternative to the conventional homogeneous catalysts. The nano-sized catalysts can be easily separated from the reaction mixture due to their insolubility and thus they can be used recycled. Notably, because of the high reactivities of nano-sized metal catalysts, the use of ligands can be avoided and the catalysts loadings can be reduced greatly. Moreover, the nano-sized catalysts can increase the exposed surface area of the active component, thereby enhancing the contact between reactants and catalyst dramatically. Based on the above-mentioned concepts and with the aim of achieving one “green and sustainable” approach, C-S bond formation and click reactions catalyzed by Cu/Cu2O nanowires were investigated. It was found that the recyclable core-shell structured Cu/Cu2O nanowires could be applied as a highly reactive catalysts for the cross-coupling reaction between aryl iodides and the cycloaddition of terminal alkynes and azides under ligand-free conditions. Furthermore, these results were the first report for the crosscoupling reaction and click reaction catalyzed by one-dimensional (1D) copper nanowires.

This thesis concerns method development of new synthetic routes by applying electrophilic hypervalent iodine reagents, such as trifluoromethyl-benziodoxole (Togni reagent) and fluoro-benziodoxole. The first project involved the addition of an oxygen moiety and trifluoromethyl group across double and triple bonds (both groups derived from the hypervalent iodine reagent). We observed that electron donating substituents on the aromatic ring of the substrate accelerated the oxytrifluoromethylation reaction. This transformation was further expanded to halo-trifluoromethylation reaction of a vinyl silane substrate. We also developed a copper mediated cyanotrifluoromethylation reaction, which was accelerated by PCy3 additive. This transformation allowed for the creation of two new C-C bonds in a single addition reaction. The direct C-H trifluoromethylation reaction of quinones was achived using the Togni-reagent in the presence of B2pin2 additive. The intriguing additive effects of both B2pin2 and PCy3 inspired us to examine the mechanism of these transformations. Fluoro-benziodoxole is the fluoroiodane analogue of the trifluoromethylating Togni reagent. We developed a AgBF4 mediated geminal difluorination of styrenes using this fluoroiodine reagent. In this process one fluorine atom came from the fluoroiodane, while the other fluorine was derived from the tetrafluoroborate ion. A similar approach was applied for the 1,3-oxyfluorination and difluorination of cyclopropanes. Similarly, this fluorinative ring opening of unactivated cyclopropanes involved the introduction of an electrophilic fluorine atom from the fluoroiodane reagent and a nucleophilic one from the tetrafluoroborate ion. This reaction was extended to synthesis of 1,3-oxyfluorinated products. When alkenes reacted with the fluoro-benziodoxole reagent in the presence of palladium catalyst the iodofluorination reaction occurred.  Both the iodine and fluorine atoms were derived from the fluoroiodane reagent. The iodofluorination reaction with disubstituted and cyclic alkenes proceeded with high regio- and stereoselectivity.

The first part of this thesis presents a novel approach for synthesising enantioenriched cyclic allylsilanes via asymmetric ring-closing metathesis (ARCM). The second part of this thesis focuses on the reactivity of allylsilanes in electrophilic trifluoromethylation under transition metal and photoredox catalysis. <strong>Chapter 1</strong> provides a general introduction to existing methods for preparing compounds containing Si-stereogenic centres. The motivation for using ARCM to form Si-stereogenic centres is discussed. To set the stage for this work, the development of olefin metathesis as a tool in organic synthesis is briefly summarised. <strong>Chapter 2</strong> describes the synthesis of various prochiral silicon-containing trienes and their reactivity in Ru-, Mo- and W-catalysed ring-closing metathesis. . Following extensive screening of chiral catalysts, few catalysts were identified that enabled selective ARCM to access Si-stereogenic products in up to 98% ee. A systematic investigation of the relationship between the structure of the starting material (i.e., hydrocarbon chain length, steric and electronic properties of the silicon substituents) and the resulting efficacy in ARCM was undertaken, the results from these experiments are discussed. Importantly, this study represents the first example in which ARCM has been successfully used to desymmetrise prochiral substrates to form a new chiral Si centre (Scheme 1). <strong>Chapter 3</strong> provides a general introduction to the field of trifluoromethylation, with a special focus on recent applications of transition metal catalysts in Csp²–CF₃ and Csp³–CF₃ bond formation. A myriad of effective nucleophilic, electrophilic and radical trifluromethylating reagents have been developed during the past several years; the properties of these reagents and their compatibility with various modes of catalysis are summarised to provide a context for the second part of this thesis research. <strong>Chapter 4</strong> presents two novel methods for effecting trifluoromethylation of allylsilanes . First, it was discovered that the combination of an electrophilic trifluoromethlyating reagent and a copper catalyst effectively mediated trifluoromethylation of allylsilanes. The silicon substituent was crucial for improving the nucleophilicity of the substrate and dictating the regioselectivity of the Csp³–CF₃ bond-forming step. With this method, alkyl or aryl substitution at the &beta;-position of the allylsilane was critical for reactivity. Second, in a complementary study, it was found that copper could be replaced by a ruthenium photocatalyst and visible light. This latter method allowed for trifluoromethylation of substrates that were ineffective with copper catalysis. Mechanistic studies of both reaction systems were undertaken, and plausible reaction pathways for both reactions are proposed. <strong>Chapter 5</strong> gives full experimental procedures and characterisation data for all compounds.

There are immense efforts to install the trifluoromethyl group (CF3) into organic molecules since it significantly affects reactivity, as well as the biological and pharmaceutical properties of the molecule. The α-trifluoromethylacrylates are useful synthetic intermediates for the synthesis of trifluoromethyl-bearing nucleosides or peptides. However, methods to prepare such derivatives are scarce and suffer narrow substrate scope, lack of diastereoselectivity, use of costly reagents, and lack of user‐friendliness. Chapter 2 discusses the synthesis of α‐trifluoromethylacrylates from converting shelf-stable α‐trifluoroborylacrylates via a stereoretentive radical trifluoromethylation with inexpensive reagents NaSO2CF3 and TBHP with copper catalysis at room temperature. Under these conditions, a wide substrate scope afforded the (E)‐diastereomer exclusively in moderate to good yield. The reaction products' utility is demonstrated in synthesizing phenyl‐4H‐pyran, a potent and selective class of IKCa channel blockers. Branching out from metal-catalyzed reactions, Chapter 3 and 4 discusses metal-free organo-catalytic reactions which are more economical and greener. Boron-containing compounds are important in organic chemistry due to the different transformations that can be performed to afford useful synthetic intermediates and pharmaceuticals. Chapter 3 elaborates on the Borylation of 1,3-butadiynes, which are molecules that are widely used to synthesize biologically active molecules, polymers, and supramolecular tools under phosphine-catalyzed conditions. The reaction proceeds with both regio- and stereo-selectivity, and the boryl group is installed on the beta carbon to the alkyne in a trans fashion as established from 2D NMR and X-ray crystallography. The reaction products are converted into useful intermediates under Suzuki Miyuara, protodeborylation, etc. 31P NMR tudies were conducted to understand the mechanism of the reaction, which is supported by the DFT calculations revealing that phosphine attack is the most crucial step. A similar strategy was utilized with pinacol borane and tri-n-butyl phosphine catalyst to achieve borylation on ynamides (Chapter 4). A wide variety of ynamides underwent hydroboration to install the boron group in a regio- and stereoselective fashion. Under radical trifluoromethylating conditions, the boryl moeity was converted into the trifluoromethyl group to afford β-CF3 enamides. 31P NMR studies were conducted to elucidate the mechanism. Finally, chapter 5 provides insight into the synthesis of 1,2,4-Oxadiazoles which are privileged scaffolds in medicinal chemistry. The developed reaction occurs under metal-free conditions using sodium carbonate to couple N-hydroxylbenzenecarbonimodyl chlorides with nitriles. / Doctor of Philosophy / Installing fluorine in organic molecules significantly improves their pharmaceutical properties and the trifluoromethyl (CF3) group is one such group. Chapter 2 describes a simple, cost-effective method to synthesize trifluoromethylated compounds with readily available reagents under copper-catalyzed conditions, whereas in Chapters 3 and 4, a metal-free method is discussed. In comparison with metal catalysts, organo catalysts are less toxic, readily available, avoid contamination, and are more economic. Boron is used for different transformations in organic chemistry and for making medicinally relevant molecules. An organo-catalytic method to install boron on various substrates and potential applications of such molecules as synthetic intermediates are discussed. 1,2,4-Oxadizoles are molecules that are considered privileged scaffolds imparting pharmaceutical properties. Finally, in Chapter 5, a procedure to synthesize 1,2,4-Oxadiazoles under mild reaction conditions and readily available reagents are discussed.

This thesis concerns the use of various potent oxidants in organic synthesis. The main focus is directed at selectively introducing trifluoromethyl groups into compounds containing double or triple bonds. All reactions proceed under mild conditions and can in most cases be performed on the bench-top. We have developed three different procedures for transformations of activated alkenes and alkynes as well as quinones. In paper I the selective introduction of a trifluoromethyl group together with an oxygen functionality to double and triple bonds is demonstrated. Paper II is focused on the related chemoselective cyanotrifluoromethylation in which a cyano group is added instead of the oxygen functionality. Paper III describes a new procedure for C–H trifluoromethylation of quinones. Our studies on the mechanistic aspects of the above reactions are described in Paper IV. In these studies we investigated the ligand and substituent effects in Cu-catalyzed reactions. Paper V is focused on a conceptually new palladium-catalyzed allylic C–H acyloxylation of olefins under oxidative conditions. The procedure uses an inexpensive, safe and environmentally benign oxidant, sodium perborate, which is activated with acetic anhydride. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.</p>

This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthesized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. It was also shown that a transfer of chirality occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium-catalyzed functionalization of allylic C-H bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium intermediates. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 1: Accepted.</p>

In this thesis new synthetic routes towards perfluorinated compounds are described, as well as their radiolabelling with fluorine-18, with the aim of application in pharmaceutically interesting targets. Part A investigates late-stage fluorination, i.e. retrosynthetic C–F bond disconnections. A silver catalysed electrophilic fluorodecarboxylation of fluorinated carboxylic acids for the formation of difluoromethyl-, trifluoromethyl-, and pentafluoroethylarenes is developed and transferred to a radiochemistry setting using [¹⁸F]Selectfluor bis(triflate). Part B explores late-stage perfluoroalkylation via cross-coupling strategies. The use of visible light-mediated ruthenium catalysis is investigated for the radical trifluoromethylation and pentafluoroethylation of vinyl- and alkynylsilanes and alkynes. Finally, the first generally applicable copper-mediated cross-coupling of Ruppert-Prakash-like aryl(tetrafluoroethyl)trimethylsilanes (ArCF2CF2SiMe3) is presented.

La métathèse d'oléfines est une des réactions les plus efficaces pour former des liaisons carbone-carbone et elle est maintenant utilisée pour synthétiser une large gamme de composés tels que des polymères, des produits issus de la pétrochimie, des produits pharmaceutiques ou des molécules naturelles. Une large gamme de groupes fonctionnels est tolérée comme des alcools, des amides, des carbamates et des sulfonamides. Cependant, des limites restent à surmonter comme la présence de N-hétéroaryles enrichis qui désactivent le catalyseur par coordination au centre métallique et/ou réagissent avec les intermédiaires. Nous décrivons dans ce manuscrit que le choix du substituant approprié d'une pyridine contenant une oléfine permet à la métathèse croisée d'avoir lieu et cette méthode a été appliquée à d'autres N-hétéroaryles.Outre les N-hétéroaryles, les composés fluorés sont largement utilisés en chimie médicinale, en agrochimie et dans le domaine des matériaux. Parmi ces composés fluorés, le groupement trifluorométhyle est le motif le plus utilisé. En effet, comparés à leurs analogues non fluorés, les composés possédant un groupement trifluorométhyle ont souvent de meilleures propriétés biologiques. C'est pourquoi il est intéressant de développer de nouvelles méthodes d'introduire ce groupement sur des molécules organiques, plus particulièrement des hétérocycles azotés. Dans ce but, nous avons développé une nouvelle méthode de trifluorométhylation d'ènes-carbamates cycliques pour accéder à des pipéridines, tétrhydropyridines et dihydropyridines trifluorométhylées. / Has now been applied to the synthesis of a wide range of compounds such as polymers, petrochemicals, pharmaceuticals and naturals compounds. A large range of functional groups are well tolerated including alcohols, amides, carbamates and sulfonamides. However, some limitations still have to be overcome Olefin metathesis has emerged has one of the most efficient carbon-carbon bond forming reaction and such as rich N-heteroaryles which are probably causing desactivation of the ruthenium catalyst by coordination of the metal center and/or reacting with the intermediates. We describe in this manuscript that a suitable choice of the 2-substituent olefinic substituted pyridine allows the cross-metathesis to occur and the method has been applied to others N-heteroaryles. Apart from N-heteroaryles, fluorinated compounds are widely used in pharmaceuticals, agrochemicals and materials. Among the organofluorides, the trifluoromethyl group is the most important motif used. In fact, compared to their non-fluorinated counterpart, trifluoromethylated compounds often show enhanced biological properties. Thus, new ways to introduce trifluoromethyl group into organic molecules, especially nitrogen heterocycles, are of keen interest. In this aim, we have developed a new method to introduce the trifluoromethyl moiety onto various cyclic ene-carbamates to access trifluoromethylated piperidines, tetrahydropyridines and dihydropyridines.

Aromatic rings are privileged structures found in a diverse range of natural and synthetic compounds, thus synthetic methods for their functionalisations are important in organic synthesis. Despite significant advancements made, especially in the field of transition metal catalysis, work still continues for the development of milder, more efficient, and more atom economical reactions. We describe here our efforts towards the development of decarboxylative/direct C(aryl)–N and C(aryl)–C bond forming reactions using aromatic carboxylic acids and unfunctionalised arenes as cheap and widely available aromatic sources. The investigations into copper-catalysed and copper/palladium-catalysed intermolecular and copper/silver/palladium-catalysed intramolecular decarboxylative amination of aromatic carboxylic acids are reported. A new approach to decarboxylation of benzoic acids is also described. The reaction uses silver (I) catalyst and peroxydisulfate salt to generate aryl radicals via oxidative decarboxylation. The applications of this approach in intra- and intermolecular decarboxylative C–H arylation, and protodecarboxylation are described. Also described is the development of silver-catalysed trifluoromethylation of simple arenes and heteroarenes. The reaction proceeds via radical trifluoromethylation using trimethyl(trifluoromethyl)silane as the trifluoromethyl radical source. This method has been applied to the trifluoromethylation of complex agrochemical molecules, proving its synthetic utility in late-stage functionalisation. Furthermore, we describe the exploitation of trifluoroacetate derivatives as cheap trifluoromethylating reagents in copper-mediated decarboxylative C–H trifluoromethylation of 2-phenylpyridine.

No description available.