Previous work was successful at delineating reaction pathways for the photoactivated synthesis of an amine, [CztBu(PyriPr)(NH2−PyriPr)], by double intramolecular C−H activation and functionalization via irradiating a metal(II) azido complex, [CztBu(PyriPr)2NiN3. The present work seeks to expand upon earlier research, and to substitute the metal with iron or cobalt, and to expand the study to photocatalyzed intermolecular C−H activation and functionalization of organic substrates. Density functional theory (DFT) – B3LYP/6-31+G(d') and APFD/Def2TZVP – and time-dependent density functional theory (TDDFT) were used to propose a detailed pathway comprised of intermediates of low, intermediate, or high spin multiplicity and photo-generated excited states for the reaction of the azido complex, [CztBu(PyriPr)2MN3] to form the amine complex [CztBu(PyriPr)M(NH2−PyriPr)], M = Co, Ni or Fe, and the intermediates along the reaction pathway. For applications on quantum computing, the photophysical properties of photoactive d8 nickel(II) complexes are modeled. Such systems take advantage of a two-level system pathway between ground to excited state electronic transitions and could be useful for the discovery of successful candidates for a room temperature qubit, the analogue of a classical computational bit. A modified organometallic model, inspired by a nitrogen vacancy selective intersystem crossing model in diamond, was developed to take advantage of the formation of excited states. Tanabe-Sugano diagrams predict areas where these excited states may relax via phosphorescent emission. Under Zeeman splitting, these transitions create the conditions required for a two-level system needed to design a functional organometallic qubit.

The base-catalysed reaction of 4H-pyran-4-one with a range of nucleophiles, namely diethyl malonate, ethyl acetoacetate, nitromethane, acetylacetone and ethyl cyanoacetate, was developed as a reliable, high yielding method for the preparation of para-substituted phenols. The methodology was extended to include the use of the substituted pyranones, maltol, 2,6-dimethyl-4H-pyran-4-one and diethyl chelidonate. Reactions were studied using conventional heating methods and microwave irradiation. Microwave irradiation had definite beneficial effects, with improved yields, reduced reaction times and cleaner reaction profiles. The potential of this methodology was examined for the regioselective placement of ¹³C-atoms into benzene rings using ¹³C-labelled nucleophiles or ¹³C-labelled 4H-pyran-4-ones. [3,5-13C₂]4H-Pyran-4-one and [2,6-13C₂]4H-pyran-4-one were prepared from various ¹³C-labelled versions of triethyl orthoformate and acetone. This methodology was applied to the synthesis of [1,3,5-¹³C₃]gallic acid, via the base-catalysed reaction of [3,5-¹³C₂]4H-pyran-4-one with diethyl [2-¹³C]malonate, followed by subsequent transformations to yield [1,3,5-¹³C₃]gallic acid. The preparation of [2-¹³C]phloroglucinol was carried out via [2-¹³C]resorcinol, with regioselective placement of a single ¹³C-atom into the aromatic ring. This was accomplished from non-aromatic precursors, with the source of the ¹³C-atom being [¹³C]methyl iodide. The key step in this synthesis was the introduction of the third hydroxyl group, which was achieved using a modified iridium-catalysed C-H activation/borylation/oxidation procedure. The scope of an existing C-H activation/borylation reaction was modified and expanded to include a range of protected resorcinol derivatives. A catalyst system was developed which allowed high conversion to the intermediate arylboronic acids, followed by oxidation using aqueous Oxone® to yield the corresponding phenols. Finally, to demonstrate the potential of these new methods for application in the synthesis of isotopically labelled natural products and polyphenols, the syntheses of ¹³C-labelled anthocyanins were studied. A route was developed that could be applied to the synthesis of either cyanidin-3-glucoside or delphinidin-3-glucoside. Only the final coupling/cyclisation step to yield the desired anthocyanin targets remains to be carried out.

L’attrait des compagnies pharmaceutiques pour des structures cycliques possédant des propriétés biologiques intéressantes par les compagnies pharmaceutiques a orienté les projets décrits dans ce mémoire. La synthèse rapide, efficace, verte et économique de ces structures suscite de plus en plus d’attention dans la littérature en raison des cibles biologiques visées qui deviennent de plus en plus complexes. Ce mémoire se divise en deux projets ciblant la synthèse de deux structures aromatiques importantes dans le monde de la chimie médicinale. Dans un premier temps, l’amélioration de la synthèse de dérivés phénoliques a été réalisée. L’apport de la chimie en flux continu dans le développement de voies synthétiques plus vertes et efficaces sera tout d’abord discuté. Ensuite, une revue des antécédents concernant l’hydroxylation d’halogénure d’aryle sera effectuée. Finalement, le développement d’une nouvelle approche rapide de synthèse des phénols utilisant la chimie en flux continu sera présenté, suivi d’un survol de ses avantages et ses limitations. Dans un deuxième temps, le développement d’une nouvelle méthodologie pour la formation de 3-aminoindazoles a été réalisé. Tout d’abord, un résumé de la littérature sur la synthèse de différents indazoles sera présenté. Ensuite, une présentation de deux méthodes efficaces d’activation de liens sera effectuée, soit l’activation d’amides par l’anhydride triflique et l’activation de liens C–H catalysée par des métaux de transition. Finalement, le développement d’une nouvelle méthodologie pour la synthèse de 3-aminoindazole utilisant ces deux approches sera discuté. / The continuous attraction towards accessing cyclic structures that possess interesting biological properties by pharmaceutical companies has guided the projects described in this M.Sc. thesis. Due to the increasing complexity of drug targets, methodologies encompassing efficient, rapid, economical and environmentally friendly syntheses are highly sought in the organic chemistry literature. The present work consists of two projects targeting the synthesis of two important aromatic structures in the field of medicinal chemistry. The first part of the thesis will present an improved synthesis of phenol derivatives. The recent chemical contributions in the continuous development of greener and efficient synthetic routes will be discussed, followed by a quick review of the literature on the hydroxylation of aryl halides. Then, the development of a new approach for rapid synthesis of phenol derivatives using continuous flow chemistry will be presented, including an overview of its benefits and limitations. The second part of the thesis will put forward the development of a novel methodology for the formation of 3-aminoindazoles. A summary of the literature on the synthesis of various indazoles will be presented, followed by an overview of two effective bond activation methods: the amide activation using triflic anhydride and transition metal catalyzed C–H activation. Finally, the evolution of a new method for the synthesis of 3-aminoindazole using the previously mentioned two approaches will be discussed.

Ce travail est centré sur la synthèse de complexes du rhodium contenant un ligand azoté et leur mise en œuvre dans la réaction catalytique de carbonylation du méthanol en acide acétique. Dans une première partie, nous nous intéressons à la préparation de complexes neutres de formule générale [RhI2(CO)(L)] (L = amines, imidazoles et pyrazoles) et à quelques homologues chlorés. Ces complexes plans carrés manifestent une réactivité directement liée à l’encombrement stérique du ligand azoté L dans la réaction d’addition oxydante de l’iodomethane suivie de la cis-migration du groupement méthyle pour former l’espèce acétyle. Dans une deuxième partie, les complexes précédents ont été engagés dans des essais catalytiques de carbonylation du méthanol dans les conditions du procédé industriel. Comme il s’est avéré que les complexes neutres se transforment en espèce [RhI2(CO)2]- pour laquelle les contre-cations associés sont constitués du ligand azoté protoné ou methylé, nous avons effectué la préparation et la caractérisation des complexes [HNR3][RhI2(CO)2] ou [MeNR3][RhI2(CO)2]. Par IR, RMN et électrochimie, nous nous sommes intéressés aux phénomènes d’appariement d’ions et nous montrons qu’il s’agit dans le meilleur des cas d’interactions hydrogènes. Celles-ci influent la vitesse de la réaction oxydante de CH3I. Dans la dernière partie, nous avons complété une étude, précédemment initiée au laboratoire, sur le mécanisme, qui dans la dernière étape du cycle catalytique permet de passer de l’espèce acétyle [RhI3(COCH3)(CO)2]- à l’espèce active [RhI2(CO)2]- avec production de l’iodure d’acyle. A l’inverse du concept admis d’élimination réductrice de CH3COI suivie de son hydrolyse immédiate en CH3COOH et HI, nous montrons, avec l’appui de calculs théoriques (DFT) qu’en fait un ligand I- est substitué par un ligand acetate pour conduire à l’espèce [RhI2(OAc)(COCH3)(CO)2]-. L’élimination réductrice produit alors l’anhydride acétique qui est hydrolysé en CH3COOH régénérant [RhI2(CO)2]-. Un tel mécanisme opère en présence d’ions acetate dans les milieux faiblement hydratés visés par l’industriel. / This study focuses on the synthesis and reactivity of rhodium complexes bearing N- containing ligands or counter-cations for the [Rh]-catalyzed methanol carbonylation reaction to produce acetic acid under the industrial Celanese Acid Optimization (AO) process conditions. In a first part, full synthesis and characterization of neutral Rh(I) square planar cis- [RhX(CO)2(L)] (X = Cl or I) complexes have been described, for which L is an N-ligand belonging to the amine, imidazole or pyrazole family. For the [RhI(CO)2(L)] complexes, variable-temperature 13C{1H} NMR spectroscopy has put in evidence a fluxional behavior for the different sized L ligands involved. The rate of this fluxional process reveals to be related to both electronic and steric contributions brought by L to the Rh center. These parameters (mainly steric), supported by single-crystal X-ray analyses in the solid state, also influence significantly the kinetics of the methyl iodide oxidative addition reaction followed by rapid CO migratory insertion, the overall being the rate determining step of the [Rh]-catalyzed methanol carbonylation cycle. In absence of CO, this reaction gives rise to the corresponding neutral Rh(III) acetyl complex, which immediately dimerizes to afford [Rh(μ- I)I(COMe)(CO)(L)]2 complex, for which several X-ray crystal structures have been obtained and studied. In addition, the surprising C-H activation in the case of a tBu-pyrazole ligand giving rise to a cyclometalated Rh dimer is reported. In a second part, the reactivity of the latter neutral Rh(I) [RhI(CO)2(L)] complexes as potential precursors has been investigated by batch experiments for the methanol carbonylation reaction. Mechanistic understanding via VT-HP-NMR experiments enabled to detect mainly anionic Rh(I) [RL][RhI2(CO)2] (R = H or CH3 according to the working conditions) complexes formed by decoordination followed by quaternization of the L ligand. Despite this result, the pyrazole family ligands showed better stability under the harsh process conditions. Thus, it cannot be ruled out that equilibrium between neutral and anionic species co-exist in the reaction medium at high temperatures and that [RL]I salt dissociation occurs, restoring the L ligand into the Rh coordination sphere. At this stage we focused on the anionic Rh(I) complex and prepared a series of [XNR3][RhI2(CO)2] (X = H or CH3) species, which have been fully characterized. Infrared, NMR, conductivity experiments and DFT model calculations together put in evidence ion interactions according to the nature of the ammonium counter-cation. Protonated cations significantly impact on the kinetics of the methyl iodide oxidative addition presumably due to H-interactions with the Rh square plane. The final part deals with the mechanism of the reductive elimination reaction, the last step of the [Rh]-catalyzed methanol carbonylation cycle, which from complex [RhI3(COCH3)(CO)2]-, regenerates [RhI2(CO)2]-. In contrast to the classically admitted mechanism of reductive elimination of CH3COI followed by subsequent hydrolysis to form AcOH and HI, we demonstrate from experimental DFT calculation that substitution of an iodo ligand by an acetate ion occurs to give rise to the [RhI2(OAc)(COCH3)(CO)2]- species. Thus, reductive elimination regenerates [RhI2(CO)2]- and produces acetic anhydride, which after hydrolysis affords two molecules of acetic acid. Such a mechanism operates under process conditions at low water content with a significant amount of acetate ions.

Au cours de cette thèse, nous nous sommes intéressés à l'activation de liaisons sp² et sp³ C-H catalysée par le palladium pour la préparation d'(hétéro)aryl-aryles et de biaryles. Cette méthode est considérée comme attractive pour l'environnement par rapport aux méthodes classiques, tels que Suzuki, Heck, ou Negishi. Tout d'abord, nous avons décrit que la C2-arylation directe de benzothiophènes peut être effectuée par un catalyseur du palladium en l'absence de ligand phosphine avec une grande sélectivité. Nous avons également démontré qu'il est possible d'activer les positions C2 et C5 de pyrroles pour accéder en une seule étape a des 2,5-diarylpyrroles. Des 2,5-diarylpyrroles non-symétriques ont été formés par arylation séquentielle en C2 suivie par une arylation en C5. Nous avons également étudié la réactivité de polychlorobenzenes pour l'activation de liaisons C-H catalysé au palladium. Nous avons finalement étudié l'activation sp² et sp³ sélective catalysé au palladium de liaisons C-H du guaiazulene. La sélectivité de la réaction dépend du solvant et de la base : C2-arylation (KOAc en éthylbenzène), C3-arylation (KOAc dans le DMAc) et C4-Me arylation (CsOAc/K₂CO₃ dans le DMAc). Grâce à cette méthode, une liaison sp³ C-H peu réactive a été activée. / During this thesis, we were interested in the sp² and sp³ C-H bond activation catalyzed by palladium catalysts for the preparation of (hetero)aryl-aryls and biaryls. This method is considered as cost effective and environmentally attractive compared to the classical couplings such as Suzuki, Heck, or Negishi. First we described the palladium-catalyzed direct C2-arylation of benzothiophene in the absence of phosphine ligand with high selectivity. We also demonstrated that it is possible to active both C2 and C5 C-H bonds for access to 2,5-diarylated compounds in one step, and also to non-symmetrically substituted 2,5-diarylpyrroles via sequential C2 arylation followed by C5 arylation. We also studied the reactivity of polychlorobenzenes via palladium-catalyzed C-H activation. We finally examined the palladium-catalysed selective sp² and sp³ C-H bond activation of guaiazulene. The selectivity depends on the solvent and base: sp² C2-arylation (KOAc in ethylbenzene), sp² C3-arylation (KOAc in DMAc) and sp³ C4-Me arylation (CsOAc/K₂CO₃ in DMAc). Through this method, a challenging sp³ C-H bond was activated.

The two stage Lucite Alpha Process for the industrial manufacturing of methyl methacrylate (MMA) represents one of the most efficient technologies currently available for the large scale production of this important chemical commodity. The second stage of this process, which involves the condensation of methyl propanoate (MeP) with formaldehyde over a heterogeneous fixed bed catalyst, however, still shows great scope for improvement. Herein the development of a novel homogeneous catalytic system that would promote the condensation of either propanoic acid or MeP with formaldehyde is explored. Since C–C bond forming reactions which proceed via C–H activation pathways typically display high atom efficiency, our efforts were particularly focussed on employing a functionalisation strategy that is mediated by C–H activation. In the case of propanoic acid, the possibility of achieving regioselective α-methylenation by linking the substrate to phosphorus was evaluated. Thus, a series of acyloxyphosphines and acylphosphites derived from either propionic acid or phenylacetic acid was prepared and, where stability allowed, fully characterised. Some of the resultant simple mixed anhydrides posed problems relating to their stability, and the stabilisation of such ligand systems by using electronic and / or steric effects was therefore explored. In addition, the coordination chemistry and in solution behaviour of Rh(I) and Ru(II) complexes containing these ligands was examined. Similar to the free ligands, complexes derived from these mixed anhydrides rearranged in solution via a number of decomposition pathways, with the specific pathway dependent on the nature of the auxiliary ligands. For most of these complexes, however, ligand decarbonylation was the route of preference for decomposition. Despite the instability of these complexes, a selection of Rh(I) mixed anhydride complexes were assessed for their potential as C-H activation catalysts in reactions aimed at the α-methylenation of saturated carboxylic acids. Furthermore, the stabilisation of Rh(I) mixed anhydride complexes with chelating auxilary ligands, such as bisphosphines or N-substituted diphosphinoamines, was explored. In particular, a series of new Rh(I) mixed anhydride complexes containing dppe, dppb and dppbz as secondary ligands were prepared and the effects of these secondary ligands on the in solution stability of these complexes assessed. As MeP represents the final product in the first stage of the Alpha process and not propanoic acid, the utilisation of PNP iridium pincer complexes in the regioselective sp³ C–H activation of MeP and related esters was also examined. The factors that govern the regioselectivity of such reactions were of great interest to us and, in particular, the effects of water on the reactivity and regioselectivity of these reactions were explored. For MeP, preferential C–H activation of the methoxy group was found to proceed under anhydrous conditions and the catalytic functionalisation of this site with ethene using this activation approach was considered. Formaldehyde, employed in the second stage of the Alpha process, is a difficult substance to manufacture and handle, especially on a large scale. A preliminary study on the in situ production of anhydrous formaldehyde via the catalytic dehydrogenation of methanol was therefore performed. During this study, catalytic systems based on carbonate salts and / or transition metal complexes were considered. In the hope of reducing the number of steps required in the production of MMA, a new one-pot cascade reaction for the indirect α-methylenation of MeP with methanol was developed. Although the production of MMA using this system only proceeded with low efficiency, the obtained results serve as an important proof of concept for future developments in this area. Finally, the capacity of a series of simple bases to catalyse the condensation of MeP with formaldehyde was assessed as part of a fundamental study directed towards determining the factors that govern the efficiency of this reaction. In addition, the extent to which each base effects the deprotonation in the α-position of MeP was determined with the aid of deuterium labelling experiments. Similarly, using sodium propanoate as model base a rough estimate of the kinetics of deprotonation could be made based on the degree of deuterium incorporation over time. These studies suggested that the low efficiency of this condensation reaction is not caused by ineffective deprotonation but rather by the weak nucleophilicity of the generated carbanion. For this reason, attempts to increase the electrophilicity of formaldehyde through Mannich-type condensations reactions involving secondary amine and carboxylic acid additives were made.

La fonctionnalisation de liaisons C-H réputées peu réactives ouvre de nouvelles perspectives en synthèse organique. La catalyse par un métal de transition comme le palladium représente une solution particulièrement efficace à ce problème. Les travaux de thèse présentés dans ce mémoire s’inscrivent dans ce contexte. Dans un premier temps, la réaction étudiée, catalysée par le palladium, a visé à étendre une méthodologie mise au point au laboratoire pour la synthèse de carbocycles et d’hétérocycles à cinq chaînons par activation intramoléculaire de liaisons C(sp3)-H à partir de chlorures d’aryles. Ces derniers sont en effet plus disponibles et moins onéreux que les bromures d’aryle correspondants. Des études d’optimisation ont été effectuées pour la mise au point d'une réaction diastéréosélective et régiosélective. Plusieurs substrats ont été synthétisés pour être ensuite placés dans les conditions optimales de la réaction d’activation C(sp3)-H, et ont conduit à une grande diversité de cycles à cinq chaînons fusionnés. Dans un deuxième temps, nos travaux ont consisté à étendre l’activation C(sp3)-H pallado-catalysée à des précurseurs non aromatiques cycliques ou acycliques. Pour des raisons d'accessibilité, nos études se sont alors portées sur la préparation de bromures vinyliques azotés pouvant conduire après activation C-H à des motifs hexahydroindoles ou pyrrolidines. De nouvelles conditions d’activation CH ont alors été trouvées pour cette famille de substrats, et ont conduit aux hétérocycles cibles de manière diastéréosélective et régiosélective. Après extension de la réaction à divers précurseurs, nous nous sommes intéressés à la synthèse d’un intermédiaire poly-fonctionnalisé permettant d'accéder aux aéruginosines, famille de produits naturels bioactifs. / The direct functionalization of unactivated C-H bonds represents an atom- and step-economical alternative to more traditional synthetic methods based on functional group transformation, which often require multi-step sequences. In particular, transition-metal catalysis has recently emerged as a owerful tool to functionalize otherwise unreactive C-H bonds. In this context, we first investigated the extension of a methodology that has been developed in our laboratory for the synthesis of fused five-membered rings via palladium-catalyzed C(sp3)-H activation from aryl chlorides. Optimization studies were conducted and reaction conditions leading to a regioand diastereoselective process were found. These optimal conditions were applied to various ubstrates, giving rise to a variety of fused five-membered carbocycles and heterocycles. Next, our work was devoted to the extension of the palladium-catalyzed C(sp3)-H activation to cyclic and acyclic non aromatic precursors. Our studies focused on the preparation of the more accessible nitrogen-containing bromoalkene substrates, leading to interesting hexahydroindole or pyrrolidine motifs by C-H activation. New C-H activation conditions were adapted to this family of substrates and led to the synthesis of the target heterocycles in a regio- and diastereoselective manner. As a more complex application of this method, we investigated the synthesis of a polyfunctionalized intermediate allowing the access to the aeruginosin family of bioactive natural products.