Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

Intermolecular reactions are inherently more difficult than intramolecular reactions, and several transformations can only occur as cyclizations, often to form 5-membered rings. The use of directing or tethering groups allowing preassociation with a reagent or catalyst is a common strategy to overcome such low reactivity, which can lead to increases in the rate, regioselectivity and stereoselectivity of intermolecular reactions. Typically, such preassociation involves hydrogen bonds, coordination to a metal ion/catalyst or stepwise installation of a temporary tether. As part of ongoing investigations on metal-free hydroaminations, it was speculated that a simple organic molecule could allow the formation of a temporary tether and enable directed intermolecular Cope-type hydroaminations to proceed at room temperature. Recently, it was found that alkylhydroxylamines add to allylic amines regioselectively in the presence of an aldehyde catalyst. This thesis presents the background material, design elements, optimization and scope of this reactivity.

La catalyse de la réaction d'hydroamination intramoléculaire asymétrique d'aminoalcènes a été étudiée en utilisant différents complexes d'Au(I) et (III) activés par un sel d'argent. Parmi les ligands phosphorés et diaminocarbènes testés, les complexes mononucléaires d'Au(I) composés de ligands phosphoramidites dérivés du BINOL ont d'abord présenté les meilleurs résultats. Ces ligands ont été améliorés par l'addition de substituants stériquement encombrants sur le fragment BINOL. L'utilisation de ces ligands pour la catalyse à l'Au(I) de l'hydroamination asymétrique des aminoalcènes a donné de bonnes conversions et des excès énantiomériques notables à température ambiante. Par la suite, des complexes binucléaires d'Au(I) ont aussi été étudiés comme catalyseurs pour la réaction d'hydroamination intramoléculaire asymétrique d'aminoalcènes. Un complexe binucléaire d'Au(I) basé sur une diphosphine sélectionnée et combiné à un sel d'argent a permis d'obtenir de bonnes conversions et énantiosélectivités à température ambiante et en présence d'eau. Les deux énantiomères du produit de réaction ont pu être obtenus en contrôlant les paires d'ions du catalyseur via la polarité du solvant de réaction employé. Le complexe actif a été caractérisé à l'état solide par diffraction des rayons X et en solution par RMN DOSY 1H. Aucun atome d'argent ne prend part au mode de coordination de ce complexe. / The intramolecular gold catalyzed asymmetric hydroamination of alkenes was studied screening a series of mononuclear gold(I) and (III) complexes in combination with silver salts. Among the various chiral phosphine and diaminocarbene ligands tried, the best catalysts arose from mononuclear gold(I) complexes synthesized from BINOL based phosphoramidite ligands. The latest were improved by addition of bulky substituents at specific positions of the BINOL scaffold. The resulting gold(I) complexes were combined with selected silver salts to afford efficient catalysts for intramolecular hydroamination of alkenes at mild temperatures, with good conversions and average enantioselectivities. Afterwards binuclear gold(I) complexes were investigated as catalysts for the intramolecular asymmetric hydroamination of alkenes. When combined to a silver salt, selected diphosphine binuclear gold(I) chloride complex afforded chiral amines for the first time in high conversions and enantioselectivities, within mild conditions and the presence of water. Both enantiomers of the products could be obtained by controlling the molecular ion-pairs through the solvent polarity. The gold(I) cationic active species was characterized for the first time unambiguously at the solid state by X-ray analysis and in solution by DOSY 1H NMR experiments. No contribution of silver chloride was observed on the bonding mode of the catalyst.

Advances in synthesis of boron-containing molecules significantly enlarged the usage of boron-containing subunits in medicinal chemistry. Interestingly, few recently approved drugs are boron analogues of natural amino acid derivatives. They contain an aminoboronic subunit. This subunit is also known to serve as a useful synthetic intermediate. However, despite its unique properties, limited examples of its synthesis are reported. In this work, a new method of obtaining aminoboronic acids derivatives is discussed. In Chapter 2 conditions towards obtaining β-aminoboronic acid derivatives via anti-Markovnikov Cope-type hydroamination are presented. Cope-type hydroamination with boron containing species have shown to proceed at lower temperatures compared to unsubstituted alkene derivatives. The products of Cope-type hydroamination reaction are new: to our knowledge similar oxazaborolidine heterocycles have not been reported. Despite reduced stability of the synthesised products and their proneness to conduct bora-Cope type elimination reaction, it was possible to demonstrate oxazaborolidine synthetic utility by various derivatization reactions. A scope with primary and secondary hydroxylamines is presented for a vinylboronate substrate. This work required access to a range of hydroxylamines. Recently our group discovered simple conditions to oxidize amines to hydroxylamines. In Chapter 3 an investigation of isolation conditions for a variant of this newly developed hydroxylamine synthesis is presented. While the oxidation is generally efficient in the presence of excess amine, the main challenge proved to be the propensity of the unreacted amine and hydroxylamine product to interact together. The efficiency and main limitations of different isolation strategies are presented. In general, the best results of removal of the excess amine via filtration were obtained using oxalic acid to form the corresponding amine salt. This filtration was followed by a short silica plug to further remove the amine salt causing contamination.

Stereoselective hydroaminations of unactivated alkenes are rare as this represents a very challenging synthetic transformation. The most efficient examples occur in biased intramolecular systems and highly enantioselective intermolecular examples are rare, which is consistent with the forcing conditions required to catalyze the reactions. This limited reactivity also accounts for the lack of highly diastereoselective hydroamination variants. Recently our group has shown that intermolecular Cope-Type hydroamination of unactivated alkenes can be achieved using simple aldehydes as catalysts. The aldehyde promotes pre-association of the two reaction partners, inducing temporary intramolecularity resulting in a remarkably facile hydroamination event. This thesis will present the development of two reactions: intermolecular enantioselective Cope-type hydroamination and intermolecular diastereoselective Cope-type hydroamination of allylic amines.

Stereoselective hydroaminations of unactivated alkenes are rare as this represents a very challenging synthetic transformation. The most efficient examples occur in biased intramolecular systems and highly enantioselective intermolecular examples are rare, which is consistent with the forcing conditions required to catalyze the reactions. This limited reactivity also accounts for the lack of highly diastereoselective hydroamination variants. Recently our group has shown that intermolecular Cope-Type hydroamination of unactivated alkenes can be achieved using simple aldehydes as catalysts. The aldehyde promotes pre-association of the two reaction partners, inducing temporary intramolecularity resulting in a remarkably facile hydroamination event. This thesis will present the development of two reactions: intermolecular enantioselective Cope-type hydroamination and intermolecular diastereoselective Cope-type hydroamination of allylic amines.

Les motifs azotés sont présents dans de nombreuses molécules d’intérêts pharmaceutiques. Les méthodes de synthèses traditionnelles de ces motifs vont, par exemple, de la substitution nucléophile d’amines sur des halogénures d’alkyles à de l’amination réductrice des composés carbonylés. Ces méthodes, bien qu’efficaces, nécessitent néanmoins des quantités stœchiométriques de réactifs pour être appliquées et génèrent souvent des quantités importantes de déchets. Un des challenges de la chimie organique moderne consiste à développer de nouvelles méthodes de synthèses de ces motifs plus économiques et plus respectueuses de l’environnement en produisant un taux de déchets le plus faible possible. L’addition directe d’une amine sur une double liaison carbone-carbone non-activée que l’on appelle la réaction d’hydroamination des alcènes est une approche très prometteuse pour le développement d’une méthodologie de synthèse alternative de ces composés. En effet, dans cette réaction, tous les atomes du substrat de départ sont transférés au produit réduisant ainsi considérablement les déchets produits. De plus, les amines et les oléfines employées sont des réactifs relativement bon marché, abondants et variés. Néanmoins, cette transformation a priori simple nécessite généralement l’emploi d’un catalyseur. Dans la littérature, la réaction d’hydroamination des alcènes a été étudiée en utilisant comme catalyseur des complexes de métaux alcalins, alcalino-terreux, de terre-rares et de métaux de transition. Au commencement de ce projet, il n’existait pas d’exemples de réaction d’hydroamination des alcènes mettant en jeu des amines primaires non protégées catalysée par des complexes de fer ou de de cobalt. Dans ce contexte, notre équipe s’est intéressée à la réactivité de complexes de fer(II) et de cobalt(II) de basse valence stabilisés par des ligands de type β-dicétiminate. Ces complexes se sont révélés être d’excellents catalyseurs pour promouvoir la réaction d’hydroamination des amines primaires non protégées liées à des alcènes non activés.Dans un premier temps, les synthèses des complexes de fer(II) et de cobalt(II) alkyles stabilisés par des ligands β-dicétiminates ainsi que leurs applications en réaction de cyclohydroamination des amines primaires non protégées seront présentées. De plus, des études mécanistiques poussées permettront d’éclaircir le mécanisme de la réaction, qui est proposé de passer par une étape élémentaire clé d’insertion 1,2 migratoire aboutissant à la formation d’une liaison carbone-azote.Dans un second temps, les influences des propriétés électroniques et stériques des ligands sur la réactivité en réaction d’hydroamination des alcènes des complexes de fer(II) alkyles seront étudiées. Nous nous attarderons particulièrement sur des complexes stabilisés par des ligands β-dicétiminates dissymétriques ou iminoanilidures. Les données cristallographiques des complexes à l’état solide permettront alors de rationaliser les variations de réactivités de ces différents complexes.Enfin, les complexes de fer(II) et de cobalt(II) synthétisés précédemment seront exploités pour développer de nouvelles réactivités en réactions d’oxydation, d’amination oxydante ou de création de liaison azote-silicium par un couplage déshydrogénant. / The nitrogenous units are present in many molecules of pharmaceutical interest. The traditional synthesis methods of these units range, for example, from the nucleophilic substitution of amines on alkyl halides to reductive amination of the carbonyl compounds. These methods, although effective, nevertheless require stoichiometric amounts of reagents to be applied and often generate large amounts of waste. One of the challenges of modern organic chemistry is to develop new methods of synthesizing these more economical and environmentally friendly patterns by producing the lowest waste rate possible. The direct addition of an amine to an unactivated carbon-carbon double bond known as the alkene hydroamination reaction is a very promising approach for the development of an alternative synthesis methodology for these compounds. Indeed, in this reaction, all the atoms of the starting substrate are transferred to the product thus considerably reducing the waste produced. In addition, the amines and olefins employed are relatively inexpensive, abundant and varied reagents. Nevertheless, this simple transformation generally requires the use of a catalyst. In the literature, the hydroamination reaction of alkenes has been studied using alkali metal, alkaline earth, rare earth and transition metal complexes as catalysts. At the beginning of this project there were no examples of the hydroamination reaction of alkenes involving unprotected primary amines catalysed by iron or cobalt complexes. In this context, our team was interested in the reactivity of iron (II) and cobalt (II) complexes of low valence stabilized by β-diketiminate ligands. These complexes have proved to be excellent catalysts for promoting the hydroamination reaction of unprotected primary amines bound to non-activated alkenes.In a first step, the syntheses of the iron (II) and cobalt (II) complexes stabilized by β-diketiminate ligands as well as their applications in cyclohydroamination reaction of the unprotected primary amines will be presented. In addition, advanced mechanistic studies will clarify the mechanism of the reaction, which is proposed to go through a key elementary 1..2 migratory insertion leading to the formation of a carbon-nitrogen bond.In a second step, the influence of the electron and steric properties of the ligands on the reactivity in the hydroamination reaction of the alkenes of the iron (II) alkyl complexes will be studied. We will focus particularly on complexes stabilized by asymmetric β-diketiminate ligands or iminoanilides. The crystallographic data of the solid state complexes will then make it possible to rationalize the variations of reactivities of these various complexes.Finally, the iron (II) and cobalt (II) complexes synthesized above will be exploited to develop new reactivities in oxidation reactions, oxidative amination or the creation of a nitrogen-silicon bond by a dehydrogenating coupling.

The study of organometallic chemistry in the context of catalysis can be approached from a stoichiometric perspective, in which PGM complexes are examined in the context of understanding fundamental reactions to provide insight into established catalytic transformations. Alternatively, a catalytic perspective can be adopted, in which an unknown or underdeveloped transformation is identified and PGM catalysis is employed to assist in the further development of this area. In this regard, two general goals of this thesis are: 1) to explore alternative ligation strategies based on P,S-functionalized indene ligands, with a particular focus of studying divergent stoichiometric reactivity between related cationic and zwitterionic PGM complexes; and 2) to identify general PGM catalysts for the cyclohydroamination of alkylaminoalkenes and the hydroamination of internal alkynes with secondary alkylamines. The preparation and divergent reactivity of a previously unreported class of coordinatively unsaturated cationic and zwitterionic Cp*Ir(P,S) complexes that feature structurally analogous P,S-indene and mono-deprotonated P,S-indenide ancillary ligands, respectively, are discussed. The cationic complex was observed to activate organosilanes via the first well-documented H-Si addition across an M-SR linkage. In contrast, the unusual stoichiometric reactivity of the putative zwitterion with CH3CN or Ph2SiH2 can be viewed as resulting from the dual action of the Lewis acidic Cp*Ir fragment and the Lewis basic 10?-electron indenide unit within this formally charge-separated zwitterion. Building on these initial studies, the synthesis of structurally related (benzyl)Pt(P,S) borato- and carbanion-based zwitterions and cationic complexes featuring the P,S-indene and indenide ligand framework are also presented. In the context of hydroamination studies, [Ir(COD)Cl]2 was identified as an effective pre-catalyst for the efficient synthesis of pyrrolidine and piperidine heterocycles via the cyclohydroamination of tethered aminoalkenes. Following optimization studies of this catalyst system, a broad substrate scope that included the cyclization of primary and secondary alkyl- or arylamines was established. A kinetic and mechanistic evaluation of this reaction suggested the operative pathway as involving olefin activation in a manner that had not previously been documented for Ir-catalyzed alkene hydroamination. In the pursuit of a general catalyst for the alkyne hydroamination reaction, an effective gold pre-catalyst featuring a P,N-ligand was identified and was used in the addition of a variety of functionalized dialkylamines to internal alkynes. In particular, the first examples of the regioselective addition of dialkylamines to unsymmetrically substituted alkynes are discussed. A preliminary mechanistic survey, consisting of kinetic and stoichiometric experiments, has provided empirical evidence to support a mechanism comprised of turnover-limiting alkyne insertion into a Au?N bond followed by proto-deauration.