Small interfering RNAs (siRNAs) and antisense oligonucleotides (AONs) use natural cellular machinery to enact sequence-specific mRNA inhibition. The development of synthetic oligonucleotides (ONs) as potent and specific agents for silencing the expression of target genes has provided incredibly useful tools for molecular biology, functional genomics, and biochemistry research. Gene silencing nucleic acids are under active investigation in the clinic for the treatment of a wide variety of diseases. While promising, ON therapeutics face several challenges. siRNAs and AONs are rapidly degraded in the body, may cause undesired side effects, and the delivery of active ONs to target cells remains a significant challenge. Chemical modification of the natural nucleic acid structure can address several of these shortcomings. This thesis describes a series of studies directed towards the development of fluorinated nucleic acid analogues as gene silencing agents with improved biological and chemical properties. A screen of chemically modified siRNA constructs revealed that 2′F-ANA, a fluorinated DNA analogue, can be combined with 2′F-RNA or LNA, rigid RNA analogues, to produce potent gene silencing agents devoid of natural RNA. Several rules were developed to optimize the potency of these chemically modified siRNAs, including a method for creating duplex binding asymmetry within 21mer duplexes through alternating 2′F-ANA and 2′F-RNA inserts along the siRNA passenger strand. These active siRNAs have enhanced nuclease stability, and reduced immunostimulatory properties.Thermal stability studies revealed that 1-1 alternations of 2′F-ANA and 2′F-RNA are destabilizing in siRNA duplexes, whereas 3-3 alternations are neutral. siRNAs incorporating 3-3 and 1-1 2′F-ANA/2′F-RNA motifs produce potent gene silencing. Experiments suggest that the gene silencing cellular machinery, the RISC complex, readily binds the 5′ terminus of siRNA guide strands modified with 2′F-ANA and 2′F-RNA. Gene silencing siRNAs chemically modified with 2′F-ANA, 2′F-RNA, and LNA were applied towards silencing the expression of several endogenous and therapeutically relevant genes, demonstrating the versatility and therapeutic potential of these constructs. Genes linked to antiviral (4E-BP1 and 4E-BP2) and anticancer (Bcl-2 and DRR) applications were readily silenced with chemically modified siRNAs and AONs in a variety of disease models.Phosphorothioated (PS) 2′F-ANA oligonucleotides were investigated as AONs targeting the cancer-linked Bcl-2 and AR genes. Results demonstrate that PS-2′F-ANA oligonucleotides are fully compatible with gymnotic cellular delivery, a carrier-free method for achieving cellular uptake in tissue culture. In a second delivery approach, chemically modified siRNAs and AONs were conjugated with maleimide, alkyne, and cyclooctyne functionalities to allow straightforward and robust coupling to the exterior of an antibody-targeted nanoparticle delivery system (Her-NP). This novel delivery system features an enzyme-mediated ON release approach, and an antibody-targeted cellular uptake mechanism allowing specific cell targeting. Results demonstrate that siRNAs and AONs delivered on Her-NPs enact gene silencing as efficiently as siRNAs delivered with Lipofectamine, but without the associated cellular toxicity. The first synthesis of novel difluorinated nucleoside analogues 2′,4′-difluorouridine (DiF-U) and 2′,4′-difluorocytidine (DiF-C) is described. In-depth NMR-based structural characterization reveals that these nucleoside analogues adopt rigid North sugar conformations. DiF-U was incorporated in a variety of oligonucleotide duplexes, demonstrating several interesting effects on duplex stability. DiF-U is highly destabilizing in the DNA strand of DNA:RNA and DNA:DNA duplexes, mildly destabilizing in the RNA strand of a DNA:RNA duplex, and neutral in the RNA strand of an RNA:RNA duplex. / Les petits ARN interférents (siARN) et les oligonucléotides antisens (OA) se servent de mécanismes cellulaires naturels pour inhiber l'expression de l'ARN messager (ARNm) de manière spécifique à la séquence. Le développement des oligonucléotides synthétiques (ON) comme agents efficaces et spécifiques de l'inhibition de l'expression de gènes cibles a permis de fournir des outils d'importance majeure dans les domaines de la biologie moléculaire, de la génomique fonctionnelle et pour la recherche en biochimie. Les acides nucléiques inhibiteurs de l'expression de gènes font l'objet de nombreux tests cliniques en vue d'être utilisés pour le traitement d'un grand nombre de maladies. Cependant, ces résultats encourageants doivent être contrebalancés par plusieurs difficultés auxquelles les thérapies à ON doivent faire face. siARN et OA sont rapidement métabolisés dans le corps, ils peuvent déclencher des effets secondaires indésirables et le transport d'ON actifs dans les cellules cibles demeure un important problème. Modifier chimiquement la structure naturelle d'un acide nucléique peut permettre de résoudre certaines de ces difficultés. Cette thèse décrit la réalisation d'un ensemble d'études visant à développer des analogues fluorés d'acides nucléiques aux propriétés chimiques et biologiques améliorées et à les employer comme agents inhibiteurs de l'expression de gènes.

Over the recent years, dendrimers have found applications in an extended range of fields due to their unique features and properties, such as their core, backbone, internal cavities and surface groups. Synthetic elaboration of dendrimers to enhance their efficacy in carrying out different functions continues to be a topical area of research. In this thesis, a new methodology to synthesize dendrimers was developed using a combination of two important reactions: copper catalyzed alkyne-azide and A3-coupling reactions. The so called 'click' CuAAC reaction has been widely used in the synthesis of dendrimers, while A3-coupling had never been employed for such a purpose. Through a combination of these reactions, we aimed to streamline their synthesis, and make it more versatile. The divergent synthesis of dendrimers, employing almost exclusively A3-coupling, proved to be troublesome due to the rapid increase in polarity of the generated macromolecules. The convergent methodology, on the other hand, where the dendrimers synthesis was achieved through a combination of 'click' CuAAC and A3-coupling reactions, was found to be more promising for their synthesis. Using these coupling methodologies, various dendrimers with differing cores and backbones have been prepared and characterized. Dendrimers (1), (2), (4) and (5) were synthesized through the divergent approach, while the protected generation 1 dendrimer (10), its unprotected counterpart (19) and the protected generation 2 dendrimer (18) were afforded from the convergent methodology. / Au cours des dernières années, les dendrimères ont trouvé des applications dans une gamme étendue de domaines. Ces macromolécules ont des caractéristiques et propriétés uniques, telles qu'un noyau central, l'embranchement, les cavités internes et les groupements fonctionnelles le long de leur surface. L'élaboration synthétique de dendrimères pour améliorer leur efficacité afin d'obtenir des fonctionnalités variés continue d'être un domaine d'actualité de la recherche. Dans cette thèse, une nouvelle méthodologie pour synthétiser des dendrimères a été développée en utilisant une combinaison de deux réactions importantes: l'addition cyclique alcyne-azide catalysée par le cuivre (I) et l'accouplement A3 (aldéhyde-alcyne-amine). La réaction couramment appelée CuAAC a été régulièrement utilisé dans la synthèse de dendrimères, tandis que l'accouplement A3 n'avait jamais été utilisé auparavant à de telles fins. Grâce à une combinaison de ces réactions, nous avons cherché à expédier leur synthèse et à la rendre plus polyvalente. La synthèse divergente des dendrimères, employant presque exclusivement l'accouplement A3, s'est avérée difficile en raison de l'augmentation rapide de la polarité de la macromolécule générée. Quant à la méthodologie convergente, la synthèse des dendrimères a été atteinte grâce à une combinaison des réactions de type «clic» CuAAC et de couplage A3; celle-ci a été jugée plus prometteuse pour la synthèse puisque différentes générations de dendrimère ont été synthétisées. Grâce à l'utilisation de ces méthodes d'accouplement, plusieurs dendrimères avec de différents cœurs centraux et embranchements ont été préparés et caractérisés. Les dendrimères (1), (2), (4) et (5) ont été synthétisés par l'approche divergente, tandis que la version protégée de première génération de dendrimère (10), son homologue non protégé (19) et la version protégée de la deuxième génération de dendrimère (18) ont été préparé à partir de la méthode convergente.

Due to the heavy reliance of modern medicine on antimicrobials our world faces a serious threat in the form of antimicrobial resistance. Since many current antimicrobials are no longer clinically effective, and the development of new ones suffered from an innovation gap of nearly four decades, our ability to effectively treat infections is diminishing. Efforts to counteract this growing concern have taken a variety of paths from a renewed push for novel antimicrobial agents, to attempting to understand and inhibit the mechanisms of resistance. The work presented in this thesis focuses on the synthesis of novel derivatives of N-alkylpantothenamides. Many of these compounds have previously demonstrated antimicrobial activity, and further derivatization for antibacterial and antiplasmodial testing was desired. Here two strategies were applied for the development of new derivatives. First, stereoselective modifications of the geminal dimethyl group of pantothenamide, and second, cross-metathesis addition of ligands to existing pantothenamide scaffolds. In Chapter 2 the synthesis of a compound of interest in antiplasmodial studies is described. While improvements to the synthetic route were made by the author, the amount obtained was insufficient and the compound was ultimately synthesized by Dr. Emelia Awuah. Efforts were refocused towards the synthesis of novel pantothenamide derivatives via cross-metathesis as discussed in Chapter 3. This new synthetic route exploited the existing allyl group of one of the most activite pantothenamide derivatives synthesized by the Auclair group, allowing for the installation of ligands through cross-metathesis. / La forte dépendance de la médecine moderne aux antimicrobiens confronte notre monde à une grave menace de résistance à ceux-ci. Avec de nombreux antimicrobiens actuels qui ne sont plus cliniquement efficaces et ayant soufferts d'un déficit d'innovation de près de quatre décennies, notre capacité à traiter efficacement les infections diminue. Les efforts pour contrer cette préoccupation croissante ont pris plusieurs directions allant de la découverte de nouveaux agents antimicrobiens, jusqu'a tenter de comprendre et inhiber les mécanismes de résistance. Le travail présenté dans cette thèse porte sur la synthèse de nouveaux pantothenamides pour les tests antibactériens et antiplasmodiaux, et comprend deux stratégies: premierement des modification stéréosélective du groupe diméthyle géminal d'une pantothenamide, et deuxièment l'ajout de ligands aux échafaudages existants par métathèse croisée. Dans le chapitre 2, la synthèse d'un composé d'intérêt dans les études antiplasmodiales est décrite. Bien que des améliorations à la voie de synthèse ont été faites par l'auteur, la quantité obtenue était insuffisante et le composé a finalement été synthétisé par le Dr Emelia Awuah. Les efforts ont dès lors été réorientés vers la synthèse de nouveaux dérivés de pantothenamide par métathèse croisée comme décrite dans le chapitre 3. Cette nouvelle voie de synthèse exploite la presence du groupe allyle existant sur le derive de la pantothenamide présentant la meilleure activitée et ayant été précédement synthétisé par le groupe Auclair, ce qui permet l'installation de ligands par métathèse croisée.

<p> Thiophene-containing liquid crystals (LCs) often exhibit attractive physical characteristics for use as ferroelectric materials, which offer several advantages for display applications. In addition, fluorine substituents on the aryl core of LCs are known to confer favorable LC properties; they often suppress or eliminate higher ordered smectic mesophases and improve dielectric anisotropy, viscosity and melting points. However, the development of smectic ferroelectric LC devices has proven challenging due to chevron defects. Our goal is to further understand structure-mesophase property relationships in LCs that bear <i>S</i>-heterocycle cores and to begin to understand those structural features that favor chevron defect-free ferroelectric LCs. In this dissertation, we present an exploration into the effect of the fluorothiophene core unit on the mesogenic properties of LCs. We thus synthesized three fluorothiophene-2-carboxylate-based targets (<b>2.2</b>, <b>2.3</b> and <b>2.4</b>), a novel series of 2-alkoxy-3-fluorothiophene-based (<b>4.2a-4.2e</b> and <b> 4.3</b>) and 5-alkoxy-3-fluorothiophene-based (<b>5.1a</b>, <b> 5.1b</b> and <b>5.2</b>) LCs. We also present the synthesis of thienyl-<i> O</i>-carbamate and phosphoramide precursors with a view to investigating the directing ability of the carbamate and phosphoramide groups in electrophilic fluorination reactions. In the synthesis of the three 3-fluorothiophene-2-carboxylate-based targets (compounds <b>2.2-2.4</b>), all of which did not display the desired SmC* phases, sequential Balz-Schiemann (thermal-/microwave-assisted), fluorination, bromination, and regioselective Suzuki coupling reactions were utilized. Fluoro-alkoxy thiophene-based compounds are largely unknown in the literature. We investigated several strategies as potential pathways for generating fluoro-alkoxythiophenes. Using a halogen/lithium exchange-fluorination approach, the synthesis of the first series of 3-fluoro-2-alkoxythiophene-based LCs (compounds <b>4.2a-4.2e</b> and <b>4.3</b>) was accomplished in good yields. Notably, these reactions gave high fluorination to protodemetalation ratios. A practical solution to remove the protodemetalated byproduct by mercuration was found, thus making the purification/isolation of the fluoro-product easy. No synthetic approaches to 5-alkoxy-substituted 3-fluorothiophenes have previously been reported. 5-Alkoxy-3-fluorothiophene-based LCs (compounds <b>5.1a </b>, <b>5.1b</b> and <b>5.2</b>) were synthesized using a bromine/lithium exchange-fluorination protocol. In a final study, we have developed an efficient approach to 2-thienyl-<i>O</i>-carbamate, and 2-thienyl-<i>O</i>- phosphorodiamidate derivatives. In this dissertation we present in detail a review of the relevant literature, the synthesis of the above materials, and the results of mesophase evaluation of these novel materials.</p>

<p> The fundamental objective of this project is to design, synthesize, and characterize fluorescent dyes, which may be utilized in super resolution imaging techniques. In Chapters 1, 2 and 3, we concentrated on photoswitchable rhodamine dyes. We synthesized several rhodamine dyes and increased their water solubility, installed a bioconjugation unit and, more importantly, we optimized the absorption properties (close to 400 nm) of the rhodamine spirolactams in their closed state and studied their basic photophysical properties as well. In Chapter 4, we synthesized azido-DCDHF fluorogens that can be converted to the bright state after a 1,3-dipolar cycloaddition reaction between an azide-Ph-DCDHF and a strained alkene. We synthesized some strained alkenes, which may speed up the kinetics in 1,3-dipolar cycloaddition. This chemical method of turning the dyes from dark to bright state is a new dimension in the bioconjugation arena. In Chapter 5, we synthesized Nile red derivatives which can switch to a bright state from a dark state by collision on the cell surface utilizing PAINT methodology. We expected that the design of new Nile red derivatives may have better properties than the parent Nile red. Besides the PAINT technique, we worked on some active control of emission by enzymatic cleavage of fluorescent dyes in a dark state to the bright state, which can be utilized in super resolution imaging. Related to the 1,3-dipolar cycloaddition reaction between azido-DCDHF and norbornene, we have examined recently popularized tetrazine chemistry. We linked pyridyl tetrazines to DCDHF with short spacer. In Chapter 6, we describe the preparation of co-crystals between perfluorophenazine and several polynuclear aromatic compounds/polynuclear heteroaromatic compounds. In Chapter 7 we describe the preparation of some partially fluorinated heteropolynuclear aromatic compounds such phenzaine and acridine class of compounds for possible use in organic semiconductors.</p>

<p> Heterocycles are an abundant class of compounds found throughout nature as well as the chemical industry. Due to their common occurrence in biologically active compounds as well as their use as ligands for asymmetric catalysis, nitrogen and oxygen heterocycles and the means for their synthesis are of particular interest. The research that follows has helped to further expand the utility of the copper(II)-catalyzed, enantioselective difunctionalizations of alkenes for the formation of saturated chiral nitrogen and oxygen heterocycles. In chapter one, a brief review of current aminohalogenation technology is given before a new copper(II)-catalyzed, enantioselective alkene aminohalogenation reaction is discussed. Both aryl and aliphatic gamma-alkenyl sulfonamides are reactive substrates, providing chiral vicinal haloamine products with good to excellent yields and enantiomeric excesses. This reaction represents a significant advancement in the area of aminohalogenation reactions as it occurs through a unique reaction mechanism that allows previously unexplored terminal alkenes to participate in an enantioselective process. In this reaction, a sulfonyl protected nitrogen and an iodide, bromide or chloride are added across an unactivated alkene with concomitant creation of an amine-bearing stereocenter. These chiral haloamines can be useful chiral synthetic building blocks for the construction of more complex synthetic targets. Chapter two will detail my contribution of a concise and scalable ligand synthesis for application to a multi-gram scale enantioselective copper-catalyzed aminooxygenation reaction. This reaction provides a scalable synthetic route to chiral 2-alkoxymethyl indolines. Lastly, in chapter three, the copper(II)-catalyzed, doubly intramolecular carboetherification reaction is first rendered enantioselective and then expanded to include an intra/intermolecular version. In this reaction, an alcohol and a carbon are added across an unactivated alkene with creation of an oxygen-bearing stereocenter. Several reactive alcohol substrates as well as alkene acceptors have been identified with yields and enantiomeric excesses ranging from good to excellent. The chiral tetrahydrofuran products formed can be useful synthetic building blocks for more complex targets.</p>

<p> A new reaction of <i>para</i>-benzyne diradicals with anionic nucleophiles is different from their usual homolytic atom abstraction. Our studies show cyclodeca-1,5-diyn-3-ene undergoing rate-limiting cycloaromatization to a <i>para</i>-benzyne, which rapidly adds nucleophiles to produce an aryl anion, which is then quenched by solvent or water to form 1-(Nu)tetrahydronaphthalenes. Our results represent the first example of anionic nucleophiles, other than halides, reacting towards a <i>para</i>-aryne. Our reactivity scale reflects the ease of Nu^&minus; desolvation, with the smaller, more highly solvated ions being slower in their reaction towards the para-benzyne diradical. Experimental results are in good agreement with computational data, and these suggest Nu^&minus; additions to <i>para</i>-benzyne to be governed by solvation other than basic strength or nucleophilic character. Deuterium can be incorporated from aryl anion reacting with such weak acids as water, DMSO or CH₃CN. The question addressed here is the relative reactivity of these two solvents and water, which can be measured by competition experiments with a mixture of labeled and non-labeled solvent. The relative reactivities <i>k</i>H₂O/<i>k</i>Solvent-<i> d, k</i>D₂O/<i>k</i>Solvent, and <i>k</i>Solvent/<i> k</i>Solvent<i>-d</i> were measured, and these values were combined to evaluate other relative reactivities including some which could not be measured directly, because there is no way to determine the source of the H or D in product. The low selectivity for CH₃CN over DMSO, despite a difference in acidities of nearly 10⁴-fold, is evidence for high basicity of the aryl anion. Moreover, the observation that the same relative reactivities are obtained with Bu₄NI as with LiI is evidence that the aryl anion reacts more rapidly than the Li⁺ can reach the <i>para</i> carbon to form an aryllithium. To our knowledge, this is the first example of a metal-free aryl carbanion in solution. Finally, this new <i>para</i>-benzyne reactivity could represent an alternative mechanism, besides homolytic atom abstraction, for detoxifying enediyne antibiotics.</p>

<p> Developing new synthetic methods and strategies is an important area of research in organic chemistry. Especially useful are transformations that rapidly and rationally generate complex molecular architectures, with multiple new bonds and new stereocenters, from simple, achiral and modular precursors. This dissertation discusses the synthetic investigation and exploitation of two such reactions.</p><p> In PART I, the intramolecular Diels&ndash;Alder (IMDA) reaction of aromatic dienes and allene dienophiles, utilized in conjunction with ring-rearrangement metathesis (RRM) to prepare angularly-fused polycyclic lactams, is discussed. The mechanism of the IMDA reaction was investigated with the aid of computational molecular modeling. The reaction was determined to proceed through a concerted mechanism; however, competing radical pathways accounted for stereochemical infidelity and fragmentation observed for some substrates.</p><p> An improved, modular synthesis of the precursors was developed to directly couple aromatic amines with the allene fragment precursor, which allowed for the preparation of a small library of heterocyclic compounds. This two-step protocol generates topologically interesting structures, containing two or more new rings, and two new <i>sp</i>³ stereocenters. Computational modeling also guided the development of the unknown analogous reaction for allenyl ketone substrates, which yield carbocyclic products. </p><p> Unexpected stereoselectivity and reactivity observations were made in the alkene metathesis reaction, which could not be readily explained. Computational studies were able to elucidate a subtle yet fundamental relationship between reaction mechanism and length of alkene tether in these types of substrates. </p><p> In PART II, efforts toward the synthesis of the alkaloid natural product gelsemine are discussed. The synthetic strategy employs a Zincke aldehyde rearrangement/IMDA cascade previously developed by the Vanderwal lab. Using 4-phenylpyridine as a model system, the expected transformation successfully gives an advanced synthetic intermediate lacking only the oxindole substructure, and the key C3&ndash;O4 and C5&ndash;C16 bonds present in the target. Elaboration of this intermediate toward the target is detailed.</p><p> A number of protected 4-(2-aminophenyl)pyridine analogues were prepared to facilitate oxindole formation and circumvent later stage complications that arose in the model system. These compounds all either failed to undergo Zincke salt formation, pyridinium ring-opening, or subsequent rearrangement/IMDA, thus delineating the synthetic boundaries of this type of chemistry.</p>

In-silico methods used to aid the development of therapeutic drugs have gained utility in the recent past and continue to grow in importance. Small molecule drugs for the use in the treatment of type 2 diabetes were designed using computational methods to probe the active site of Dipeptidyl Peptidase IV (DPP-IV) and were subsequently synthesized and tested in-vitro. A number of pseudodipeptides formed from derivatives of tryptophan and proline were synthesized. The effects of a tetrazole group on the pyrrolidine of proline were studied, as well as the effect of protecting groups on the activity on DPP-IV. Exploring the effects of rigidifying the active dipeptides was next explored by attempting to synthesize the analogous bicyclic structures. / In order to add to the knowledge in the realm of computation tools used for drug discovery, eight docking programs were used to screen a subset of a small molecule database, the Database of Useful Decoys (DUD). This study focused on the effects of protein flexibility, crystallographic waters and program/protein dependence on active compound identification accuracy. This knowledge gained on the efficacy of current docking programs in VS campaign on real world therapeutic targets will allow for more efficient drug design in the search for new therapeutic agents. / Les méthodes in-silico, utilisées pour faciliter le développement de composés thérapeutiques, ont dernièrement vu leur utilité croître en considérablement. Au cours de ce travail, une série de petites molécules visant le traitement du diabète de type 2 a été conçue en se servant de méthodes informatiques pour sonder le site actif de Dipeptidyl Peptidase IV (DPP-IV) et a, par la suite, été synthétisée et testée in-vitro. / Tout d'abord, de nombreux pseudo-dipeptides construits à partir de dérivés de tryptophane et proline ont été préparés. Les effets sur l'activité biologique d'un groupe tétrazole sur le groupe pyrrolidine de la proline ont été étudiés, ainsi que l'effet de la protection des groupes fonctionnels. L'étude de l'impact de la rigidification de ces dipeptides actives a ensuite été envisagée et une synthèse de structures bi-cycliques debutée. / Dans le but d'accroitre les connaissances sur les outils informatiques servant pour la découverte de médicaments, huit programmes d'amarrage ont été évalués sur une banque de données d'une petites molécules, "Database of Useful Decoys" (DUD). Nous nous sommes plus particulièrement intéressés à l'impact de la flexibilité des protéines, de l'eau cristallographique et du type de programme utilisé sur la fiabilité des résultats. Les données collectées au cours de cette étude va nous permettre de développer des programmes plus efficaces et par la suite permettre une meilleure fiabilité de ces programmes dans les campagnes de criblage virtuel futures qui auront pour but de trouver de nouveaux agents thérapeutiques.

This thesis is an investigation on the generation and reactivity of carbocations adjacent to a trisubstituted nitrogen atom (iminium). / In the first part of this thesis, a copper-catalyzed oxidative alkylation of sp3 C-H bond adjacent to a nitrogen atom is described. This environmentally respectful process used molecular oxygen as oxidant and water as solvent. / In the second part of the thesis, an aerobic sp3 C-H bond phosphonation reaction is presented. This process catalyzed by copper(I) bromide using dialkylphosphites as nucleophiles offered direct C-P bond formation via direct oxidative coupling of C-H and P-H bonds. / In the third part of the thesis, a copper-catalyzed sp3 C-H bond arylation with boronic acids in absence of directing group is described. The oxidative arylation reaction provided easy access to biologically active tetrahydroisoquinoline derivatives and can either use peroxide or molecular oxygen as oxidant. / In the last part of the thesis, the aerobic and electrochemical Cross-Dehydrogenative-Coupling in ionic liquids is presented. Ionic liquids have demonstrated high efficiency when applied as solvent and electrolyte solvent for the oxidative nitro-Mannich carbon-carbon bond formation. / Cette thèse est une investigation sur la génération et la réactivité de carbocations adjacents à un atome d'azote trisubstitué (iminium). / Dans la première partie de cette thèse, une alkylation d'une liaison sp3 C-H adjacente à un atome d'azote catalysée au cuivre est décrite. Ce procédé respectueux de l'environnement utilisa l'oxygène comme oxydant et l'eau comme solvant. / Dans la deuxième partie de cette thèse, une réaction aérobique de phosphonation de liaison sp3 C-H est présentée. Ce procédé catalysé par un sel de bromure de cuivre(I) et utilisant des bis-alkylphosphites comme nucléophiles permit la synthèse directe de liaisons C-P via le couplage oxydant de liaisons carbone-hydrogène et phosphore-hydrogène. / Dans la troisième partie de cette thèse, une réaction d'arylation de liaison sp3 C-H, catalysée par le cuivre, avec des acides boroniques en absence de groupement directeur est décrite. Cette réaction d'arylation, utilisant soit un peroxyde soit l'oxygène comme oxydant, donna des dérivés de la tétrahydroisoquinoline biologiquement actifs. / Dans la dernière partie de cette thèse, le couplage croisé déshydrogénant aérobique et électrochimique en liquides ioniques est présenté. Les liquides ioniques ont démontré une grande efficacité pour la formation de liaisons C-C (nitro-Mannich oxydante) lors de leurs utilisations comme solvant et solvant électrolyte.