La synthèse d’oléfines et plus précisément de vinylchalcogénures di- ou trisubstitués sous contrôle régio- et stéréosélectif constitue l’objectif de ce travail. La stratégie adoptée consiste à utiliser des dérivés acétyléniques comme précurseurs, et des alcénylboranes comme intermédiaires réactionnels. Deux voies synthétiques distinctes ont été sélectionnées : l’hydroboration de 1-chalcogéno-1-alcynes (préparation d’alcénylboranes α-chalcogénés) et le réarrangement de sels d’alcynyltriorganylborates induit par des électrophiles chalcogénés (préparation d’alcénylboranes β-chalcogénés). La cis hydroboration du 1-phénylthio-1-hexyne par le dicyclohexylborane est régiosélective et fixe majoritairement l’entité dicyclohexylboryle en &alpha du soufre, conséquence d’une interaction de type acide-base de Lewis entre les deux hétéroatomes. Les tentatives d’optimisation de la régiosélectivité ([α :β] = [97 :3]) montrent que la modification de la densité électronique autour du soufre (par introduction de substituants électroattracteurs ou -donneurs en para sur le cycle aromatique) ou la présence de substituants (alkyl/aryl)thio à demande stérique plus importante impactent à plusieurs niveaux, mais ne permettent pas d’augmenter le degré de régiosélectivité de l’hydroboration. La fonctionnalisation des vinylboranes α-chalcogénés par transmétalation stœchiométrique (bore-cuivre) suivie de l’alkylation ou par couplage de Suzuki-Miyaura donne accès à des vinylsulfures disubstitués. L’utilisation de fluorure de tétrabutylammonium en solution dans le tétrahydrofurane, à la place d’une solution aqueuse d’hydroxyde de sodium comme base pour le couplage Suzuki, permet l’évitement de la réaction parasite principale, la protodéborylation du vinylborane. Le réarrangement des 1-acynyltriarylborates de lithium induit par les halogénures d’(alkyl/aryl)chalcogényle est totalement stéréosélectif et dispose le groupement migrateur du bore en trans par rapport à l’électrophile entrant. La migration de substituants aromatiques (phényle, thiényle et anisyle) est tout à fait inédite dans le domaine de la préparation d’alcénylboranes chalcogénosubstitués. La conversion de ceux-ci ouvre des perspectives très intéressantes pour la préparation d’arylcétones α-chalcogénées par oxydation, de vinylsulfures disubstitués par traitement à l’acide acétique, ainsi que de vinylsulfures trisubstitués par couplage ou transmétalation stœchiométrique (bore-cuivre ou bore-zinc). Toutes ces transformations sont totalement stéréosélectives. L’utilisation de l’une de ces deux voies synthétiques assure une formidable flexibilité pour l’introduction des divers substituants sur les futurs carbones oléfiniques.

The 2-aryl-2,3-dihydroquinolin-4(1H)-ones were prepared via acid-catalyzed cyclization of the corresponding 2-aminochalcones, which were in turn, prepared by base-promoted Claisen-Schmidt aldol condensation of 2-aminoacetophenone and benzaldehyde derivatives. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were prepared by reacting 2-aryl-2,3-dihydroquinolin-4(1H)-ones with N-bromosuccinimide (NBS) in carbon tetrachloride-chloroform mixture at room temperature. The 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones were subjected to palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acid using dichlorobis(triphenylphosphine)palladium(II)-tricycohexylphosphine as catalyst mixture and potassium carbonate as a base in dioxane-water under reflux to afford the corresponding novel 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones in a single-pot operation. The latter were subjected to thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to yield the 2,6,8-triarylquinolin-4(1H)-ones. The 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones were treated with molecular iodine in refluxing methanol to afford the corresponding 2,6,8-triaryl-4-methoxyquinolines. All the new compounds were characterized using a combination of 1H NMR & 13C NMR spectroscopy, IR and mass spectroscopic techniques. / Chemistry / M.Sc. (Chemistry)

Redox-active ligands deliver redox equivalents to impart multi-electron functionality at 3d metals that typically undergo to one electron redox events. It was proposed that 3d metals with redox-active ligands could form unusually well-defined catalysts for C-C bond forming reactions to mimic palladium-type reactivity. Therefore, several new complexes containing an iron or cobalt with redox-active ligands were synthesized and tested for their ability to form new C-C bonds. A bis(iminosemiquinone) iron (III) complex was able to homocouple aryl Grignards using dioxygen as the terminal oxidant. However, ligand redistribution prevented detailed mechanistic study of the C-C bond forming reaction and led to catalyst degradation. To address the challenges seen in the iron catalyst a new cobalt electron transfer (ET) series containing a pincer-type bis(phenolate) N-heterocyclic carbene ligand (CoNHC) was synthesized. Studies indicate the CoNHC ET series spans multiple-electrons by corporative metal and ligand redox. These complexes were evaluated for cross-coupling of alkyl halides and aryl Grignards. Mechanistic studies imply that the low cross-coupling yields were due to ligand degradation. However, CoNHC catalytically activate cross-couples ether nitriles and aryl Grignards via a novel C-O bond activation leading to a new C-C bond. Findings concerning redox-active ligands on iron and cobalt for C-C bond forming reactions and implications for future research are discussed.

This thesis investigates a total synthesis of the incednine aglycon by utilising alkenylsilane reagents to assemble the pentaenyl and tetraenyl systems through cross-coupling reactions. The early chapters develop methodology to access both cyclic alkenylsiloxanes and functionalised (E)-alkenylsilanes by the controlled hydrogenation of alkynylsiloxanes and silylolefination of aldehydes, respectively, and culminate in the synthesis of a C6-C13 bis(alkenylsilane)incednine fragment (Scheme 1). The C1-C5 and C14-C23 coupling partners are synthesised in three and ten steps from propargyl alcohol and L-alanine methyl ester through phosphorous-based olefination strategies. In the final chapter we describe our first generation approach to incednine which entails orthogonal cross-couplings to construct the C5-C6 and C13-C14 bonds (Scheme 2).

<p>This thesis deals with the copper-catalyzed substitution of allylic substrates.</p><p>In the first part of this thesis, the synthesis of a series of metallocenethiolates is described. The thiolates were examined as ligands in the enantioselective copper(I)-catalyzed γ-substitution of allylic acetates.</p><p>The second part describes a study on copper-catalyzed α-substitution of enantiomerically pure secondary allylic esters. It was observed that the degree of chirality transfer is strongly dependent on the reaction temperature. The loss of chiral information is consistent with an equilibration of the allylCu(III) intermediates prior to product formation, which is essential in order to realize a copper-catalyzed dynamic kinetic asymmetric transformation process.</p><p>The third part describes a study on copper-catalyzed stereoselective α-substitution of enantiopure acyclic allylic esters. This method, when combined, with ruthenium and enzyme catalyzed dynamic kinetic resolution of allylic alcohols, provides a straightforward route to pharmaceutically important α-methyl carboxylic acids.</p><p>The fourth part is a mechanistic study on the reaction of perfluoroallyl iodide with organocuprates. Experimental studies as well as theoretical calculations were used to explain the contrasting reactivity of perfluoroallyl iodide vs. allyl iodide in cuprate allylation reactions.</p><p>In the fifth part, the development of a practical and useful method for the preparation of pentasubstituted acylferrocenes is presented.</p>

Les hétérocycles aromatiques sont des motifs structuraux rencontrés dans un grand nombre de substances d'intérêts biologiques ou pharmacologiques. Plus particulièrement, les pyridazines substituées font l'objet d'un intérêt grandissant pour leurs propriétés pharmaceutiques (antibactériens, anti-inflammatoires, médicaments cardiovasculaires…). De plus, les structures comportant des pyridazines peuvent également être utilisées en tant qu'agents chélatants de cations métalliques et s'ordonner en édifices utilisés en chimie supramoléculaire.Nous nous sommes donc intéressés à l'élaboration d'éléments de base comportant des cycles pyridaziniques de type aryl ou hétéroarylpyridazines. La mise au point de méthodes impliquant des espèces organométalliques a été l'un de nos objectifs primordial. L'élaboration de ces composés a été réalisée par formation de liaisons C-C. Une approche électrochimique d'hétérocouplage associé à une catalyse au nickel a été utilisée. Quelques limites à cette méthode ont cependant été observées dans le cas des couplages mettant en jeu des 3,6-dihalogénopyridazines. Une étude par électrochimie analytique a permis d'en comprendre les raisons. La seconde partie de notre travail a consisté en l'étude de la réactivité d'arylzinciques ou de triarylbismuths vis-à-vis de 3,6-dihalogénopyridazines / Heteroaromatic rings are present in various biological and pharmacological active molecules. Substituted aryl-pyridazines have given rise to considerable interest because of their diverse pharmacological properties (antibacterial, anti-inflammatory, cardiovascular drugs…). Moreover, structures which contain pyridazines are used in supramolecular chemistry for their applications through self-assembly processes in the presence of metal ions.In order to elaborate building blocks containing pyridazine rings such as aryl or heteroaryl-pyridazines, we turned our intention on the development of complementary methods involving organometallic reagents. Transition metal-catalyzed cross-coupling reaction of organometallic compounds with organic halides is one of the most powerful methods for the generation of C-C bonds.We chose to develop the most straightforward method involves heterocoupling reaction of aryl/heteroaryl compounds under electrochemical conditions (sacrificial anode process) associated to a nickel catalysis. However some limitations have been pointed out when 3,6-dihalogenopyridazines are involved in the cross-coupling reaction. An electrochemical study was investigated in order to propose some mechanistic considerations. A second part of this work consisted in the study of arylzinc and triarylbismuths reagents toward 3,6-dihalogenopyridazines

In the following thesis, new methodologies towards the synthesis of a range of sulfonyl (-SO₂-) containing functional groups are documented. These methods utilise easy-to-handle sulfur dioxide surrogates, such as DABSO (vide infra), and exploit palladium catalysis as a new mechanistic protocol for the incorporation of the -SO2- unit. <b>Chapter 1</b> is a literature review surveying sulfur dioxide in organic synthesis, the established uses of SO₂ surrogates and the importance of the sulfonyl moiety in chemistry. Palladium-catalysed (carbonylative) cross-couplings are also broadly discussed as they provide inspiration for, and mechanistic similarities with, the proposed chemistry. <b>Chapter 2</b> describes a de novo synthesis of the sulfonamide functional group; a three-component and convergent methodology coupling (hetero)aryl and alkenyl halides with sulfur dioxide (provided by easy-to-handle surrogates such as DABSO) and hydrazine nucleophiles, is documented. This is achieved through the action of a readily available palladium catalytic system and is the first example of a metal-catalysed sulfonylative cross-coupling of halide based electrophiles. <b>Chapter 3</b> presents a new method of generating (hetero)aryl and alkenyl sulfones. The ability of organometallic reagents to add to sulfur dioxide (supplied via DABSO) is applied to deliver the corresponding metal sulfinate salt. This in situ derived sulfinate is coupled with an (hetero)aryl or alkenyl (pseudo)halide using palladium catalysis to form the desired sulfone. An electronically modified XantPhos-type ligand was designed for the reaction in order to suppress unwanted aryl-aryl exchange. <b>Chapter 4</b> documents the generation of (hetero)aryl and alkenyl sulfinates from the corresponding halide and DABSO through a palladium-catalysed sulfination protocol, obviating the need for organometallic reagents. A mild set of conditions using IPA as both a solvent and reductant together with a low loading of palladium catalyst offers an attractive route to sulfonyl compounds thanks to the in situ derived sulfinates being converted into a broad variety of functional groups via established onwards reactivity. <b>Chapter 5</b> discusses the conclusion of the research and the potential for future work. <b>Chapter 6</b> presents the experimental data.

The 2,2'-disubstituated 1,1'-binaphthyls (BINOLs) are important ligands in enantioselective synthesis . The major approach for their preparation is based on transition-metal-mediated oxidative C-C coupling of 2-substituted naphtalenes. This diploma thesis examined the mechanism of the coupling reaction in the gas phase using mass spectrometry with electrospray ionization. The aim of this thesis was to compare the selectivity of the copper(II)- catalyzed coupling reaction of 2-naphthol and its derivative with an electron-withdrawing group, to detect possible reaction intermediates, and to determine the origin of the preference of the cross-coupling. The electron-withdrawing group of naphthol slows down the coupling reaction which enabled us to detect the reaction intermediates. The intermediates in the reaction of 2-naphthol were not observed, because the coupling reaction proceeds too quickly. Hence, we have observed only complexes of the coupling products. The preferential cross coupling was explaned on the basis of an interplay between the probability of the formation of binuclear copper complexes and the reactivity of such complexes.

The prevalence of fluorine in natural products is scarce. There are but a handful of compounds that have been discovered to date. This could be largely attributable to the occurrence of fluorine in nature as fluoride (F-). — One might recognize such nomenclature from the ingredients list on a toothpaste tube — In fact, naturally occurring fluoride is most commonly found as fluorite (CaF2) or cryolite (Na3AlF6). As such, the introduction of fluorine via biological pathways has been limited to use of aqueous F- (a very poor nucleophile). This fact — coupled with its naturally low concentration in water — has created the ripe conditions for this shortage. In a way this has proven fertile for synthetic chemists because nature has not yet evolved a method for the deconstruction of partially or fully fluorinated compounds. Considering the above, as synthetic methodologies for the construction of carbon-fluorine bonds became available, so too did the discovery of their valuable properties. So beneficial are these properties that C-F bond-containing compounds have become commonplace in many households throughout the world. For example, practically every home relies on these compounds for use in their refrigerators. Other examples of useful fluorinated materials include blowing agents, non-stick coatings, pharmaceuticals, agrochemicals, liquid crystals, and lubricants. With all these applications and seemingly easy availability of these compounds, it is interesting to learn that original synthetic methods are still being employed today. As such, the objective of this Thesis is to develop ‘greener’ routes for the synthesis of fluorocarbons. We hypothesized that by studying transition metal-fluoroalkyl complex-mediated reactions, a more efficient catalytic system could be developed. A foreseen complication arises from the thermodynamic stability of C-F, transition metal-F and transition metal-CRF bonds. Improvements to overcome these caveats include the use of first-row late transition metal complexes. Presented herein are additions to this body of knowledge by expanding on the reactivity of nickel, copper and silver fluoroalkyl complexes. The approach applied in this work, in line with ‘green’ chemistry principles, was to source readily available fluorinated reagents, i.e. fluoroalkenes and fluoroarenes, to reduce the number of steps for the synthesis of new fluorinated compounds. Chapter 2 builds on the well-established oxidative cyclization of C2 fluoroalkenes to nickel (0), which yields new C4 units. The use of a bulky N-heterocyclic carbene ligand was found to enhance reactivity by reducing the coordination number at nickel. Examples of room temperature Cα-F and Ni-CF bond activation and functionalization reactions are presented. Chapters 3, 4 and 5 re-examine the insertion of fluoroalkenes into silver and copper fluorides and hydrides. Building on precedent of addition reactions to hexafluoropropene, this fluoroalkene was examined first. In so doing, a versatile and inexpensive copper heptafluoroisopropyl reagent was developed (Cu-F addition to (CF3)CF=CF2. With easy access to new heptafluoroisopropyl complexes, they were systemically studied for their applications in catalysis. This revealed key features, particularly the lability of the M-hfip bond, which could be detrimental to catalytic reactions. As such, a nickel complex-mediated carbonylative heptafluoroisopropylation reaction and copper complex-mediated nucleophilic addition to electrophiles were developed. When a copper hydride was used instead, the in situ generated fluoroalkyl [Cu-H addition to (CF3)CF=CF2] was susceptible to β-fluoride elimination. Chapter 4 expands this methodology to achieve the catalytic consecutive hydrodefluorination of fluoroalkenes, demonstrating the scope and limitations of this system. Furthermore, the critical role of the phosphine ligand in accessing an L3Cu-H addition and unusual β-fluoride elimination mechanism is highlighted. However, tetrafluoroethylene proved resistant to this reaction because the fluoroalkyl resting state of this alkene, Cu-CF2CF2H, is unusually robust. Chapter 5 investigates the utility of this fragment and others in C(sp2)-RF cross-coupling and nucleophilic substitutions. With focus on new routes for late stage fluorination and examples of nickel (0) complex-catalyzed selective C-F bond functionalization reactions, Chapter 5, continues studies for low-temperature and DMAP-assisted conditions for aryl-F cross-coupling reactions with boronic acid esters. Lastly, Chapter 6 reviews the advances presented in this Thesis, provides a link to the expected lasting impacts and attempts to provide guidance to future research on transition-metal complexes in the synthesis of C-F or C-RF containing compounds. Moreover, with the introduction of a new hydrodefluorination technology, previously scarce fluoroalkenes (e.g. 1,2-difluoroethylene) can now be used more freely, potentially leading to the development of new refrigerants or materials applications.

Cross-coupling reactions, where a transition metal catalyst facilitates the formation of a new carbon-carbon or carbon-heteroatom bond between two coupling partners, has become one of the most widely used, reliable, and robust family of transformations for the construction of molecules. The Nobel Prize was awarded to pioneers in this field who primarily used aryl iodides, bromides, and triflates as electrophilic coupling partners. The expansion of the reaction scope to non-traditional electrophiles is an ongoing challenge to enable an even greater number of useful products to be made from simple starting materials. The major goal of this thesis research is to improve and expand upon this field by using esters as electrophiles via the activation of the strong C(acyl)−O bond. Esters are particularly robust in comparison to other carboxylic acid derivatives used in cross-coupling reactions. Success on the activation of such inert functional group using catalysis has both fundamental and practical value. By discovering new reaction modes of this abundant functional group, synthetic routes to access novel or industrially important molecules can be improved. Chapter 1 of this thesis describes a literature overview of what has been accomplished in the field of cross coupling reactions using carboxylic acid derivatives as electrophilic coupling partners. Chapter 2 discloses the first palladium Suzuki-Miyaura couplings of phenyl esters to produce ketones. The method is efficient and robust, giving good yields of useful products. The reaction is proposed to proceed via an oxidative addition to the strong C(acyl)−O bond of the ester. In contrast to previous efforts in this field that use traditional catalysts such as Pd(PPh3)4, the developed reaction requires use of an electron-rich, bulky N-heterocyclic carbene ligand, which facilitates the strong bond activation. Furthermore, a palladium-catalyzed cross-coupling between aryl esters and anilines is reported, enabling access to diverse amides. The reaction takes place via a similar activation of the C−O bond by oxidative addition with a Pd−NHC complex, which enables the use of relatively non-nucleophilic anilines that otherwise require stoichiometric activation with strong bases to react. Chapter 3 discloses a nickel-catalyzed amide bond formation using unactivated and abundant esters. In this transformation, an accessible nickel catalyst can facilitate the activation of diverse aliphatic and aromatic esters to enable direct amide bond formation with amines as nucleophiles. No stoichiometric base, acid, or other activating agent is needed, providing exceptional functional group tolerance and producing only methanol as a by-product. This reaction is of both fundamental and practical importance because it is the first to demonstrate that simple conditions can enable Ni to cleave the C–O bond of an ester to make an oxidative addition product, which can be subsequently coupled with amines. This discovery contrasts industrially-common and wasteful methods that still require stoichiometric activating agents or multistep synthesis. Chapter 4 describes the evaluation of different types of cross-coupling reactions using methyl esters as electrophilic coupling partner. A high-throughput screening technique has been applied to this project. A combination between specific ligands, known by their efficiency to activate strong C−O bonds, and literature-based conditions has been designed for the chosen transformations. Using this strategy, two promising hits have been obtained using the same NHC ligand: a decarbonylative Suzuki-Miyaura and a decarbonylative borylation reaction.