Hydroamination stands as a desirable approach to nitrogen-containing molecules, which have important applications ranging from pharmaceuticals (fine chemicals) to paints, coatings, insecticides and agrochemicals (bulk chemicals). It features the use of alkene and alkyne starting materials, which are abundant and rarely used in the formation of C-N bonds. This work aims at building on the improved Cope-type reactivity developed in the Beauchemin group by expanding the reach of the reaction and understanding its mechanistic complexities. The first part of this thesis describes the development of cascade reactions to provide a thermodynamic driving force for the intermolecular Cope-type hydroamination of alkenes. The methodology serves as a proof of concept that the dipolar reaction intermediates can be engineered to further react irreversibly to more stable products, and has shown potential in improving the syntheses of natural alkaloids. The second part of the thesis describes the expansion of Cope-type hydrazide hydroaminations through a systematic investigation of hydrazine analogs as reactants. Optimized reagents are featured in the first reported intermolecular Cope-type hydrohydrazidation of alkenes. Mechanistic investigations and isolation of ammonium ylide intermediates support a 5-membered concerted and planar mechanistic pathway for hydrazide hydroaminations, similar to that observed with hydroxylamines. The final section presents mechanistic data disproving a previously assumed difficult proton transfer step in the hydroamination using hydroxylamines. From such findings, early results are presented towards a hydrogen-bond catalyzed hydroamination, which has potential applicability across the field of Cope-type hydroaminations and beyond.

In recent years, N-hetereocyclic carbenes (NHCs) have received considerable attention as organocatalysts due to their unusual ability to induce a reversal of reactivity (Umpolung) in aldehydes. Indeed, NHCs unique properties have been applied to the efficient and metal-free synthesis of organic compounds that have proven elusive using traditional approaches.<p> My Masters research program has been focused on the use of NHCs as organocatalysts in ring expansion reactions and their applications to cascade reactions.<p> During my Masters studies, an NHC-catalyzed efficient ring expansion of 4-, 5-, and 6-membered oxacycloalkane-2-carboxaldehydes to generate the corresponding lactone derivatives was developed. This reaction provides access to a variety of lactones using readily available NHCs under mild conditions.<p> Then, the ring-expansion lactonization has been successfully extended to an efficient lactamization using azacycloalkane-carboxaldehydes, which could provide functionalized lactams in moderate yields under mild conditions.<p> In addition, intrigued by the possibility of effecting the Umpolung of electron-poor dienes using NHC catalysts, the ring-expansion lactonization was applied to an attempted Diels-Alder-ring expansion cascade reaction. Though no cascade reactions were observed, some very interesting results were obtained, and those results will guide future investigations in this area.

In recent years, N-hetereocyclic carbenes (NHCs) have received considerable attention as organocatalysts due to their unusual ability to induce a reversal of reactivity (Umpolung) in aldehydes. Indeed, NHCs unique properties have been applied to the efficient and metal-free synthesis of organic compounds that have proven elusive using traditional approaches.<p> My Masters research program has been focused on the use of NHCs as organocatalysts in ring expansion reactions and their applications to cascade reactions.<p> During my Masters studies, an NHC-catalyzed efficient ring expansion of 4-, 5-, and 6-membered oxacycloalkane-2-carboxaldehydes to generate the corresponding lactone derivatives was developed. This reaction provides access to a variety of lactones using readily available NHCs under mild conditions.<p> Then, the ring-expansion lactonization has been successfully extended to an efficient lactamization using azacycloalkane-carboxaldehydes, which could provide functionalized lactams in moderate yields under mild conditions.<p> In addition, intrigued by the possibility of effecting the Umpolung of electron-poor dienes using NHC catalysts, the ring-expansion lactonization was applied to an attempted Diels-Alder-ring expansion cascade reaction. Though no cascade reactions were observed, some very interesting results were obtained, and those results will guide future investigations in this area.

In the interests of synthetic efficiency several cascade reactions involving iminium ion intermediates have developed to allow for the rapid assembly of complex molecules from relatively simple starting materials. A cascade methodology for the rapid, diastereoselective synthesis of quinolizidine ring systems has been expanded to encompass a greater range of substrates. The utility of this extension was demonstrated in the efficient syntheses of the tricyclic core structures found in halichlorine and the cylindricine family of alkaloids. Additionally a second cascade sequence has been developed that progresses through an S[subscript N]1 followed by nucleophilic attack on an N-acyl iminium ion to deliver the products of a formal [4+3] cycloaddition. This methodology has been successfully employed to synthesize a [3.3.2] bridgehead system that serves as a key intermediate in a proposed synthesis of (±)-actinophyllic acid. Synthesis of this compound represent progress in the ongoing effort to synthesize this natural product.

Hydroamination stands as a desirable approach to nitrogen-containing molecules, which have important applications ranging from pharmaceuticals (fine chemicals) to paints, coatings, insecticides and agrochemicals (bulk chemicals). It features the use of alkene and alkyne starting materials, which are abundant and rarely used in the formation of C-N bonds. This work aims at building on the improved Cope-type reactivity developed in the Beauchemin group by expanding the reach of the reaction and understanding its mechanistic complexities. The first part of this thesis describes the development of cascade reactions to provide a thermodynamic driving force for the intermolecular Cope-type hydroamination of alkenes. The methodology serves as a proof of concept that the dipolar reaction intermediates can be engineered to further react irreversibly to more stable products, and has shown potential in improving the syntheses of natural alkaloids. The second part of the thesis describes the expansion of Cope-type hydrazide hydroaminations through a systematic investigation of hydrazine analogs as reactants. Optimized reagents are featured in the first reported intermolecular Cope-type hydrohydrazidation of alkenes. Mechanistic investigations and isolation of ammonium ylide intermediates support a 5-membered concerted and planar mechanistic pathway for hydrazide hydroaminations, similar to that observed with hydroxylamines. The final section presents mechanistic data disproving a previously assumed difficult proton transfer step in the hydroamination using hydroxylamines. From such findings, early results are presented towards a hydrogen-bond catalyzed hydroamination, which has potential applicability across the field of Cope-type hydroaminations and beyond.

Hydroamination stands as a desirable approach to nitrogen-containing molecules, which have important applications ranging from pharmaceuticals (fine chemicals) to paints, coatings, insecticides and agrochemicals (bulk chemicals). It features the use of alkene and alkyne starting materials, which are abundant and rarely used in the formation of C-N bonds. This work aims at building on the improved Cope-type reactivity developed in the Beauchemin group by expanding the reach of the reaction and understanding its mechanistic complexities. The first part of this thesis describes the development of cascade reactions to provide a thermodynamic driving force for the intermolecular Cope-type hydroamination of alkenes. The methodology serves as a proof of concept that the dipolar reaction intermediates can be engineered to further react irreversibly to more stable products, and has shown potential in improving the syntheses of natural alkaloids. The second part of the thesis describes the expansion of Cope-type hydrazide hydroaminations through a systematic investigation of hydrazine analogs as reactants. Optimized reagents are featured in the first reported intermolecular Cope-type hydrohydrazidation of alkenes. Mechanistic investigations and isolation of ammonium ylide intermediates support a 5-membered concerted and planar mechanistic pathway for hydrazide hydroaminations, similar to that observed with hydroxylamines. The final section presents mechanistic data disproving a previously assumed difficult proton transfer step in the hydroamination using hydroxylamines. From such findings, early results are presented towards a hydrogen-bond catalyzed hydroamination, which has potential applicability across the field of Cope-type hydroaminations and beyond.

Ces travaux de thèse nous ont permis de mettre en évidence un accès à un large nombre de composés polycycliques. Les étendues des méthodes employant des cascades réactionnelles palladocatalysées et leurs limites ont été étudiées. L’initialisation de ces cascades se fait par une cyclocarbopalladation de type de 4-exo-dig, suivie par un couplage de Sonogashira. Avec des substrats et des conditions adéquats, la cascade réactionnelle continue avec une alcynilation, une électrocyclisation à huit électrons p et une électrocyclisation à six électrons p. En un nombre limité d’étapes sont ainsi obtenus des châssis moléculaires complexes : les fenestradiènes et les cyclooctatriènes. Des dérivés portant des substituants variés dans différentes positions ont été synthétisés, notamment possédant des hétéroatomes. Leurs accès a été assuré par des synthèses linéaires ou encore par une approche plateforme. Ceci a été complété par une étude in silico en vue du potentiel thérapeutique de ces châssis moléculaires. / This PhD thesis was focused on the study of cascade reactions and allowed the access to a large variety of polycyclic compounds. The extension of several methods employing palladocatalyzed cascade reactions and their limits have been studied. Those cascades are initiated by a 4-exo-dig cyclocarbopalladation, followed by a Sonogashira coupling. With an adequate substrate and the appropriate conditions, the cascade reaction can even be extended by an alcynilation, followed by an eight p electron electrocyclization and a six p electron electrocyclization. Complex scaffolds are thus obtained in only a few steps: fenestradienes and cyclooctatrienes. Derivatives with various substituents in different positions have been synthesized, particularly with heteroatoms. Their access has been ensured by either linear synthesis or a platform approach. This project was completed by an in silico study of the scaffolds regarding their drug-like potential.

In dieser Arbeit wird ein neuer Ansatz beschrieben, elektroaktive Verbindungen auf mesoporösen Elektroden zu fixieren. Dies wurde durch die Bildung eines sich selbst organisierenden Monolayers auf der Innenseite eines mesoporösen Trägers (ITO, FTO, ATO, TiO2) erreicht. Dieser Layer wurde dann vernetzt und in Richtung des Porenzentrums weiter aufgebaut durch Substitutions- Kondensations- oder Elektropolymerisations- Reaktionen. Es wurde ein Vernetzungsverfahren entwickelt, welches die Herstellung stabiler elektrochromer Bilder mit verbessertem Kontrast und einer Haltbarkeit von mehr als 18 Monaten erlaubt. Es beinhaltet die Synthesen von molekularen Einheiten mit latent vorhandenen oder voll entwickelten elektrochromen Eigenschaften. Diese Einheiten waren 4,4´- Bipyridine, die entweder mit optionalen N-Alkyl, N-Benzyl oder N-Phenyl Gruppen mit nukleophilem oder elektrophilen Eigenschaften oder mit TiO2 Ankergruppen versehen waren. Die Kaskadenreaktion ergab Elektroden mit unterschiedlichen Oberflächenkonzentrationen und unterschiedlichen Pimerisationsgraden. Darüber hinaus gelang es, die Haltbarkeit und den Kontrast so weit zu steigern, dass sie kommerziellen Ansprüchen genügen. Die Optimierung der Gegenelektroden wurde durch ein ähnliches Verfahren unter Verwendung von Ferrocen- Derivaten erreicht. Die Ladungskapazitäten, die durch Multilayer Vernetzung auf ATO-Ferrocen Elektroden erhalten wurden, waren hervorragend mit Ausnahme der Tatsache dass ein schwach grüner Farbton, verursacht durch oxidiertes Ferrocen, vorhanden war. Schließlich wurde die Kaskadenreaktion auf B12 Derivate zur Herstellung von katalytisch aktiven TiO2 Elektroden angewandt. Die mit B12 modifizierten Elektroden zeigten verbesserte Stabilität, höhere turn over - Zahlen und größere turn over -Raten im Vergleich zu unvernetzten B12 modifizierten Elektroden.

Ces travaux de thèse ont permis, au cours de deux projets, de s’attacher à la synthèse de structures complexes au moyen de réaction en cascade et de catalyse au rhodium.Dans une première partie, une méthodologie robuste pour la synthèse de 2,4,6-cycloheptatriénones entièrement substituées et non-symétriques par réaction de cycloaddition carbonylative [2+2+2+1] catalysée par des complexes de rhodium a été développée. Des mécanismes expliquant la formation des différents composés ont été proposés. Dans une seconde partie, l’application de l’hydroformylation désymétrisante catalysée au rhodium à la synthèse totale d’alcaloïdes indoliques de la famille Aspidosperma a été étudiée. Un intermédiaire clé de la synthèse de composés de type eburnane a ainsi été obtenu et sa transformation par différente stratégies été explorée. La synthèse totale de composés de type aspidosperma a été étudié, et les voies de synthèse explorées pourront être appliquées à des aldéhydes issus d’hydroformylation désymétrisante. / Through the course of two projects, this thesis work was concerned with the synthesis of complex scaffolds by means of cascade reactions and rhodium catalysis.In a first part, a new methodology was developed for the synthesis of non-symmetrical and fully substituted 2,4,6-cycloheptatrienones by rhodium-catalysed [2+2+2+1] carbonylative cycloaddition. Mechanisms for the formations of the observed compounds were proposed.In a second part, the application of rhodium-catalysed desymmetrising hydroformylation to the total synthesis of Aspidosperma indole alkaloids was studied. A key intermediate in the synthesis of eburnan-type alkaloids was thus obtained, and its transformation into th desired compounds using various strategies was explored. The total synthesis of aspidosperma-type alkaloids was studied, and the explored syntheses will be applied to aldehydes obtained by desymmetrising hydroformylation.

Ces travaux de thèse ont permis dans un premier temps, d'aborder différentes voies de synthèse d'un nouvel antipsychotique potentiel (F17464) proposé par les laboratoires Pierre Fabre. Trois stratégies basées sur des synthèses convergentes ont été initiées. La première stratégie repose sur une étape clé de métathèse croisée, la seconde sur une réaction de Sonogashira et la troisième aborde une nouvelle méthodologie d'alkylation des chromones en position 3. Ces méthodes nous ont permis d'accéder à des intermédiaires de synthèse originaux, utiles pour préparer la molécule F17464 en respectant les contraintes industrielles.Dans un deuxième temps, différents types de molécules polycycliques complexes ont été synthétisés par cascades réactionnelles palladocatalysées. Une série de naphtalènes condensés a été préparée par réaction domino palladocatalysée issue de cyclocarbopalladations successives suivies d'une activation C(sp2)-H. Plusieurs types de cycles à sept atomes de carbone condensés ont été synthétisés en une seule étape, à partir de substrats faciles d'accès, via des cascades réactionnelles cyclocarbopalladations/activation C(sp2) ou C(sp3)-H.Finalement, des cyclooctatriènes et des fenestradiènes ont été obtenus à partir du même substrat,en une seule étape, via des réactions en cascade débutant par une cyclocarbopalladation 4-exodigsuivie d'un couplage de Stille puis d'une addition d'alcynes sur une triple liaison s'achevant par des réactions d'électrocyclisations. La température est le seul paramètre réactionnel qui diffère dans la synthèse de ces deux polycycles complexes, à partir du même substrat. / This PhD thesis allowed us in the first part to develop different synthesic pathways to a new potential antipsychotic (F17464) invented by Pierre Fabre laboratories. Three strategies based on convergent syntheses are initiated. The key step of the first strategy is olefin cross metathesis. The second strategy rests on Sonogashira coupling and the third one involves a new methodology ofchromones alkylation in position 3. These methods allowed us access to novel synthetic intermediates, useful in the preparation of the F17464 molecule by following industrial confines.ln the second part, different types of polycyclic molecules were synthesized by palladium-catalyzed cascade reactions. A set of fused naphthalenes was prepared by palladium-catalyzed dominoreaction including cyclocarbopalladations followed by C(sp2)-H bond activation. Several types of fused seven-membered carbocycles were synthesized in a one-pot reaction from convenient substrates, via cascade reactions including cyclocarbopalladations followed by C(sp2 or sp3)-Hbond activation. Finally, cyclooctatrienes and fenestradienes were obtained also in a one-pot reaction from the same substrate via cascade reactions involving 4-exo-dig cyclocarbopalladation, followed by Stille coupling, alkyne addition onto a triple bond, finishing by electrocyclization reactions. Temperature is the only parameter that differs in the synthesis ôf the two complex polycycles starting from the same substrate.