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The homoaldol reaction is one of the most powerful methods for the construction of C–C bonds as well as 1,4-oxygenated compounds yet this reaction remains in challenging tasks due to the instability of homoenolates which spontaneously cyclize to the cyclopropanolate. A regioselective catalytic homoaldol equivalent reaction of 3-bromo vinyl acetate with aldehydes under Cr(III)-Mn(0) redox condition was developed. This homoaldol equivalent reaction allows access to the 1,4-oxygenated compounds that are not possible by a conventional aldol process. Mild hydrolysis of the vinyl acetate and reduction of the homoaldol adducts generated diols and lactols in high yield (99%). Further manipulation including stereoselective epoxidation and cyclopropanation was achieved in an efficient manner. Furans, found in many natural products and utilized in drug discovery, have been well studied but current synthetic methods toward furans have some limitations in functional group tolerance, substrate scope, and low product yield in many cases. A highly efficient and catalytic cycloisomerization reaction that transforms acetylenic α,β-epoxides to 2,3,5-tri-substituted furans under InCl3 catalysis was developed. This reaction sequence allows access to rapid construction of highly valuable, tri-substituted furan derivatives. Cross-coupling reactions utilizing transition metals and Lewis acids are important synthetic tools for the formation of C–C and C–N bonds and a number of cross-coupling reactions between α-bromo carbonyl compounds and metal reagents such as aryl metals, alkenyl metals, and alkyl metals have been reported. Transition metal-catalyzed cross-coupling reaction for the construction of α-alkynyl carbonyl compounds has reported in a limited case. The first approach to secondary α-alkynyl carbonyl compounds from secondary α-bromo esters and amides with tributyl(phenylethynyl)stannane under palladium-catalyzed cross-coupling reaction conditions was developed. This synthetic method allows access to secondary α-alkynyl carbonyl compounds which are valuable precursors in pharmaceuticals and agricultural applications.

Ce mémoire porte sur l’étude théorique d’une réaction permettant la formation de macrocycles via une alkynylation de thiol catalysée au cuivre(I) (macro-CGS). Ce type de réaction implique le couplage entre un thiol et un carbone C(sp). Bien que le volet synthétique associé à cette réaction soit complété, jusqu’à ce jour aucune information n’existe concernant le mécanisme réactionnel. Des outils théoriques tels que la théorie de la fonctionnelle de la densité (DFT), la théorie de l’état de transition (TST) et les orbitales des liens naturels (NBO) ont été utilisés afin de mener cette étude à terme. Le mémoire comporte aussi un volet expérimental associé à la synthèse totale du macrocycle utilisé dans la réaction modèle. Le mémoire débutera avec une introduction portant sur la liaison de type S-C(sp) et sur les macrocycles. Nous introduirons ensuite en quoi consiste une étude théorique de mécanisme réactionnel. L’objectif du projet et la stratégie de recherche seront ensuite établis. L’introduction sera suivie d’un chapitre sur la méthodologie, dans lequel nous ferons un survol des concepts théoriques importants concernant le calcul de la structure électronique et la détermination des propriétés thermodynamiques d’un système chimique. Nous verrons ensuite les concepts théoriques importants qui ont été utilisés concertant la cinétique chimique et la modélisation de l’environnement chimique. Ce chapitre sera suivi de la justification du choix de la méthode computationnelle. Pour ce faire, différentes propriétés chimiques ont été prédites et comparées avec les résultats expérimentaux en utilisant différentes méthodes de calculs de structure électronique. Finalement, nous passerons aux résultats de la recherche, ce qui impliquera une courte section concernant la synthèse totale du macrocycle, une section concernant le profil énergétique des mécanismes examinés et une dernière section où nous proposerons une description des mécanismes les plus probables en se basant sur une analyse des orbitales de liaison naturelles (NBO). Les résultats de l’étude favorisent un mécanisme d’α-addition, mais un mécanisme d’α-cuprathiolation et d’addition oxydante - élimination réductrice seraient aussi à prendre en considération. Une étude expérimentale approfondie serait nécessaire afin de pouvoir obtenir plus d’informations concernant le mécanisme le plus probable. / This thesis is about the theoretical study of a reaction allowing the formation of macrocycles via Cu(I) -catalyzed S-C(sp) coupling to form a macrocyclic alkynyl sulfide. This type of reaction involves the coupling between a thiol and a C(sp) carbon. Although the synthetic part of that reaction is complete, to date, no information exists regarding the reaction mechanism. Theoretical tools such as density functional theory (DFT), transition state theory (TST) and natural bond orbitals (NBO) were used in order to undertake this study. The thesis also includes an experimental part associated with the total synthesis of the macrocycle used in the model reaction. The thesis will begin with an introduction on the S-C(sp) bond and on macrocycles in general. Afterwards, we will introduce the concept of theoretical study applied to a reaction mechanism. The goal and strategy of the study will then be established. The introduction will be followed by a chapter on the methodology, in which we make an overview of important theoretical concepts concerning electronic structure calculations and thermodynamic properties of a chemical system. We will then discuss theoretical concepts that have been used in concert with chemical kinetics and chemical environment. This chapter will be followed by a discussion on the choice of the computational method. For that purpose, different chemical properties were predicted and compared with experimental results using different electronic structure calculation methods. Finally, we will discuss the results of the study on the reaction investigated, which include a short section concerning the total synthesis of the macrocycle, a section concerning the energy profile of the studied mechanisms and a section where we provide a description of the most probable mechanisms based on a natural bond orbital (NBO) analysis. The results of the study are in favor of the α-addition mechanism, but the α-cuprathiolation and oxidative addition - reductive elimination mechanism should also be considered. Nevertheless, a thorough experimental study would be necessary in order to be able to obtain more information about the mechanism.

Les travaux décrits dans ce mémoire de thèse ont pour objet d'une part l'étude de la réactivité de céto-3-alcynoates et de céto-sulfonylynamides. Les céto-3-alcynoates conduisent à la formation d'allénoates bi- ou tricycliques par catalyse au carbonate de césium. La sélectivité est totale au niveau de l'allénoate bicyclique obtenu. Il est également possible d'effectuer cette réaction de cyclisation de façon monotope au départ de l'alcynyl-cétone correspondante, dans ce cas les allénoates tricycliques sont obtenus avec de très bons rendements. Les 3-alcynoates peuvent également être utilisés pour la synthèse de dérivés oxydés de l'acide jasmonique. Ainsi deux composés énantiomériquement enrichis, le (-)-12-COOH-JA et le (-)-12-COOH-JA-Ile, observés dans les plantes blessées on été synthétisés. Ces composés ont permis d'élucider deux voies cataboliques : une voie oxydative et une voie hydrolytique. L'étude de la réactivité de céto-sulfonylynamides en présence de triflimide d'argent a conduit à l'obtention d'aza-bicyclo[n.m.1]alcanones. Cette réaction de Conia-ène formelle s'applique à différentes cycloalcanones, ainsi qu’à une grande variété d’ynamides fonctionnalisés / The work described in this manuscript involved the reactivity of keto-3-keto-alkynoates and and keto-sulfonamides. Keto-3-alkynoates led to bi- or tricyclic allenoates in the presence of a catalytic amount of cesium carbonate. Cyclization proceeds in a totally stereoselective manner in the case of the two-carbon linker chain. A one-pot reaction starting from alkynyl ketones afforded tricyclic fused ring systems with good yields. Enantiomerically enriched, oxidized, conjugated or non-conjugated jasmonate derivatives were obtained through 3-alkynoates, in particular (-)-12-COOH-JA and (-)-12-COOH-JA-Ile found in wounded leaves. The availability of those synthetic compounds allowed deeper exploration of the complex regulation of JA-Ile hormone homeostasis and unraveled an oxidative and a hydrolytic pathway. Aza-bicyclo[n.m.1]alkanone frameworks could be obtained when keto-sulfonylynamides were treated under silver catalysis. This formal Conia-ene reaction was compatible with various cycloalkanones, as well as a wide range of functionalized ynamides.

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)