Im ersten Teil der Arbeit wird die Synthese neopentyl- und neosilylsubstituierter Phosphane zur Verwendung als Liganden in katalytisch aktiven Palladiumkomplexen beschrieben. Die Aktivität wurde in der Suzuki-Miyaura Kreuzkupplungsreaktion getestet. Während die neosilylsubstituierten Phosphane 2:1 Addukte (5b und 5d) mit geeigneten Palladiumsalzen bilden, welche moderate Katalyseaktivität zeigen, untergehen die neopentylsubstituierten Komplexe schnelle Cyclometalierungsreaktionen in Gegenwart von Basen und bilden die katalytisch wenig aktiven Palladacyclen (6a, 6e, and 6g). Die deaktivierende Cylometallierung konnte durch Darstellung der Palladiumcomplexe ausgehend von Pd(cod)Cl2 in Abwesenheit von Basen vermieden werden. Die erhaltenen 2:1 Phosphaneaddukte zeigten deutlich verbesserte Aktivität. Daraus wurde geschlossen, dass die Cyclomettalierung als Nebenreaktion eine wichtige Deaktiverungsmöglichkeit darstellt, diese Überlegung veranlasste uns Trialkylphosphane mittlerer Größe, mit Substituenten die nur schwer eine Cyclometallierungen eingehen können zu testen. Die Verwendung der Phosphoniumsalze 4h (R = Cy, R‘ = neopentyl) und 4m (R = iPr, R‘ = CH2Cy) führt zu höheren Aktivitäten in der Suzuki-Miyaura Kreuzkupplung, als bestes Katalysatorsystem hat sich die Kombination aus Pd2(dba)3 oder Pd(OAc)2 und entsprechendem Phosphoniumsalz ergeben. Im zweiten Teil dieser Arbeit werden Synthesen zu neuen biphenylbasierten Diphosphanen (70, 71, 76, and 77) vorgestellt. Die Palladiumkomplexe wurden ebenfalls auf ihre Eignung als Katalysatoren in palladiumkatalysierten Suzuki-Miyaura Kreuzkupplungen getestet und zeigen für diese Klasse von Komplexen gute Aktivität. Das Tetraphosphan 82 wurde für die Synthese des zweikernigen Palladium(II)-komplex 83 eingesetzt. Durch die Koordination des D2h-symmetrischen Tetraphosphanes an die Palladiumatome wird die Symmetrie des Moleküls erniedrigt und folglich erhält man den formal D2-symmetrischen Komplex 83. / In the first part of this thesis, the synthesis and catalytic activity of neopentyl and neosilyl substituted phosphine palladium complexes is described. The complexes have been tested in the Suzuki-Miyaura cross-coupling reaction. Whereas the neosilyl substituted phosphines form 2:1 adducts (5b and 5d) with Palladium salts which showed moderate activity, the neopentyl complexes quickly undergo cyclometallation in presence of bases to form Palladacycles (6a, 6e, and 6g) which showed only moderate catalytic activity. Cyclometallation could be avoided by the preparation starting from Pd(cod)Cl2 in the absence of bases. The obtained 2:1 phosphine adducts showed superior activity. We concluded that cyclometallation process is an important deactivation pathway, this prompted us to test trialkyl phosphine ligands with medium size but substituents not reliable to cyclometallation. We have been pleased to find that 4h (R = Cy, R‘ = neopentyl) and 4m (R = iPr, R‘ = CH2Cy) showed good activity in the Suzuki-Miyaura cross-coupling reaction. The best results have been obtained by in situ preparation of active catalyst from Pd2(dba)3 or Pd(OAc)2 and the appropriate phosphonium salt. In the second part of this thesis, the first synthesis of a new family of biphenyl based bisphosphine ligands (70, 71, 76, and 77) has been reported. Their palladium complexes were successfully tested as catalyst in the Suzuki cross-coupling reaction. Within the class of bisphosphine based palladium complexes they show good activity in Suzuki-Miyaura cross-coupling reaction. Systematically, was expanded our synthesis strategy and we were able to introduce the first synthesis of a highly symmetric 2,2',6,6'-tetraphosphinobiphenyl. Tetraphosphine 82 was used as ligand in a dinuclear palladium(II) complex 83. Upon complexation the D2h symmetric 2,2’,6,6’-tetraphosphine lead to a chiral D2 symmetric complex 83.

Die vorliegende Dissertation beschäftigt sich mit der Synthese und Charakterisierung drei verschiedener Typen chiraler Phosphinoferrocene sowie deren Anwendung in der Palladiumkatalysierten Suzuki-Miyaura-Reaktion. Der Schwerpunkt liegt dabei auf Untersuchungen zur Synthese räumlich gehinderter Biaryle sowie auf atropselektiven Biarylkupplungen. Über eine Ullmann-artige Kupplung von Iodferrocen mit sekundären Alkoholen wurden zunächst chirale Ferrocenylalkylether synthetisiert, die mit Hilfe dirigierter Lithiierungen in 1,1'-disubstituierte Phosphinoferrocene der Art Fe( 5-C5H4OR)( 5-C5H4-C6H4-2-PR'2) sowie planar-chirale 1,2,1'-trisubstituierte Ferrocene des Typs Fe( 5-C5H3-1-PPh2-2-OR)( 5-C5H4SiMe3) überführt werden konnten. Erstere eignen sich für die Umsetzung räumlich gehinderter Arylhalogenide in der Suzuki-Miyaura-Reaktion, wobei die katalytische Produktivität mit sinkendem Tolman Kegelwinkel der Phosphine steigt. Darüber hinaus ist es möglich, Kupplungsreaktionen zwischen nicht aktivierten Bromaromaten und Phenylboronaäure bei ultraniedriger Katalysatorbeladung (1 ppm) durchzuführen. Die 1,2-P,O-substituierten Ferrocene erlauben die Synthese tri-ortho-substituierter Biaryle. Dabei zeigte sich, dass die Enantioselektivität der Umsetzung hauptsächlich durch die planare Chiralität des Ferrocens und nicht durch den chiralen Alkoxysubstituenten bestimmt wird. Darauf aufbauend wurde eine Serie verschieden substituierter planar-chiraler Phosphinoalkenylferrocene der Art Fe( 5-C5H3-2-PR'2-(E)-CH=CHR)( 5-C5H5) synthetisiert. Die elektrochemische Untersuchung dieser Verbindungen zeigte, dass die -Donoreigenschaften des Phosphins durch die elektronischen Eigenschaften des alkenylgebundenen Substituenten R nicht verändert werden. Dies erlaubt die unabhängige Variation der -Donor-/ -Akzeptoreigenschaften des Phosphins und des Alkens. Abschließend wurde ein Vertreter der Phosphinoalkenylferrocene in der Synthese tri- und tetra-ortho-substituierter Biaryle sowie in atropselektiven Biarylkupplungen eingesetzt. Die Leistungsfähigkeit des Katalysators in der Suzuki-Miyaura-Reaktion wurde durch die Variation der Substratpalette untersucht.

Metallfluoride sind dank ihrer hohen chemischen und thermischen Stabilität, insbesondere bei Reaktionen unter Beteiligung von hoch korrosiven Gasen (HF, HCl, Cl2, F2) den entsprechenden Oxiden überlegen. Über den Sol-Gel Prozess synthetisierte Produkte weisen oft spezifische, zum Teil sehr unterschiedliche Eigenschaften im Vergleich zu klassisch hergestellten Verbindungen auf. In dieser Arbeit wurde der Sol-Gel Prozess zur Herstellung von binären Fluoriden (AlF3, MgF2, CaF2, CuF2 und FeF3) genutzt und zum Teil weiter entwickelt sowie das Synthesepotential dieser Methode als Zugang für komplexe Fluoride (KMgF3, K3AlF6), für Metallfluorid-geträgerte „nano Edelmetall-Systeme (Pd/AlF3, Pt/AlF3, Pd/CaF2, Pd/MgF2) und für Gast–Wirt–Metallfluorid-Systeme (CuF2/AlF3, FeF3/AlF3) untersucht. Die Eigenschaften der als kompakte Materialien hergestellten Metallfluorid Systeme wurden mit Hilfe spektroskopischer Methoden untersucht und dabei insbesondere deren Oberflächeneigenschaften bestimmt. Die neuen Materialien wurden für die Nutzung akademisch und industriell bedeutsamer Katalysereaktionen evaluiert und mit klassischen Katalysatoren verglichen. Es konnte gezeigt werden, dass der Sol-Gel Prozess für Fluoride zu neuartigen Materialien mit außergewöhnlichen Eigenschaften führt. Insbesondere infolge der Synthese-bedingten Vergrößerung der spezifischen Oberflächen um einen bis zu 20-fachen Faktor im Vergleich zu klassisch hergestellten Fluoriden konnten auch eine Reihe von katalytisch interessanten Metallen (Pd, Pt) in die nanoskopischen Festkörperfluoride eingebracht werden. Die TEM Aufnahmen zeigen, dass z. B. 2-5 nm große Palladiumpartikel sehr homogen in ca. 80 nm große CaF2- bzw. 20 nm große AlF3-Matrices in nur einem einzigen Reaktionsschritt eingeführt werden können. Die neuen Materialien wurden in verschiedenen katalytischen Reaktionen getestet und zeigten sich in mehreren Fällen den „Standard Katalysatoren“ überlegen. / Because of their high chemical and thermal stabilities, metal fluorides have found to be advantageous over metal oxides in such cases where reactions involving generation of corrosive acids like HCl and HF are concerned. The Sol-gel method is known for the synthesis of materials with considerably different properties to those prepared by classical routes. In this work, sol-gel route has been employed for the synthesis of binary fluorides (AlF3, MgF2, CaF2, CuF2 and FeF3), hydroxyfluorides [AlF3-x(OH)x, MgF2-x(OH)x] complex fluorides (KMgF3, K3AlF6), metal fluoride supported nanoscopic noble metals (Pd, Pt) and host-guest fluoride systems (CuF2/AlF3, FeF3/AlF3). Besides the successful synthesis of metal fluorides described above, the present thesis deals with investigation of their bulk and surface properties using various analytical and spectroscopic methods (XRD, BET, NH3-TPD FTIR-pyridine adsorption, XPS, microscopic studies) as well as with their catalytic properties for the reactions of academic and industrial interest. Metal fluorides prepared via sol-gel method have shown to possess extraordinary surface properties in terms of surface area, particle size, porosity, Lewis acidity and distortion in their structures as compared to those of classical methods like aqueous synthesis or impregnations. A homogeneous dispersion of Pd nanoparticles supported on high surface area metal fluoride prepared by this method was confirmed by XRD, XPS and TEM imaging. Catalytic properties of these materials have been investigated for dehydrofluorination of hydrofluorocarbons, isomerization of citronellal, hydrodehalogenation of chlorodifluoromethane, Suzuki cross coupling and oxidative fluorination of benzene.

Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

Dans ce mémoire, deux principaux sujets seront présentés. Nos efforts se sont d’abord tournés vers la synthèse du cylindrocyclophane F, un [7,7]-paracyclophane naturel, puis vers l’élaboration d’une nouvelle classe d’hétérocycles fluorescents. Premièrement, la cyclopropanation, une des étapes clés de la synthèse du cylindrocyclophane F, ainsi qu’une nouvelle voie de synthèse passant par une réaction de cyclopropénation ont été revisitées. La possibilité d’employer une méthode de macrocyclisation, incluant une réaction de couplage de Suzuki sur deux centres sp3, a ensuite été étudiée sur un substrat modèle. Deuxièmement, la synthèse de benzo[a]imidazo[2,1,5-c,d]indolizines à partir de N-[(6-bromo-2-pyridinyl)méthyl]benzamides a été développée. Dans un premier temps, le tandem cyclodéshydratation/aromatisation effectué en présence de 2-méthoxypyridine a été optimisé afin d’obtenir la 5-bromo-3-phénylimidazo[1,5-a]pyridine. Puis, une arylation intramoléculaire en présence d’une quantité catalytique d’un complexe de palladium a permis d’obtenir l’hétérocycle fusionné désiré. Les propriétés photochimiques de cette nouvelle classe d’hétérocycles seront aussi présentées. / In this thesis, two main points will be introduced. First, we focused our efforts on a synthetic approach towards cylindrocyclophane F, a natural [7,7]-paracyclophane. Then, the synthesis of a new fluorescent class of molecule will be disclosed. First, an asymmetric cyclopropanation, one of the key steps of the synthesis of cylindrocyclophane F, will be revisited. Furthermore, a new route, including a cyclopropenation reaction, was explored. Then, the possibility of using a Suzuki coupling reaction on two sp3 centres for macrocyclisation has been studied on a model substrate. In a separate study, the synthesis of benzo[a]imidazo[2,1,5-c,d]indolizines from N-[(6-bromo-2-pyridinyl)methyl]benzamides will be disclosed. A mild cyclodehydratation-aromatisation was performed in the presence of 2-methoxypyridne in order to obtain 5-bromo-3-phenylimidazo[1,5-a]pyridine. This sequence was followed by an intramolecular direct arylation to form the desired compound. The photophysical properties of this new heterocycle class were measured.

The diploma thesis presents the preparation of ,-bisterpyridinylfluorenes (unimers) containing fluorene unit in the central block either directly attached to terpyridine (tpy) end groups or via 1,4-phenylene or thiophene-2,5-diyl linker. Synthesized unimers were subsequently used for the preparation of metallo-supramolecular polymers with Zn2+ and Fe2+ ions. The prepared unimers were characterized by NMR, IR and HR-MS, their optical properties were investigated using absorption and emission spectroscopy and cyclic voltammetry. Molecular weight distribution for the prepared Fe-polymers was determined by GPC. The number-average degree of polymerization equal to 7 for an equimolar ratio between unimer and Fe2+ in a diluted solution was determined for polymers composed of unimer with thiophene-2,5- diyl linker. By using the viscometric measurements the ongoing constitutional dynamics in solutions of metallo-supramolecular polymers was proven. The overstoichiometric amount of metal ions in solution resulted in equilibrium shortening of the polymer chains together with end-capping of terminal tpy ligands by Mt2+ ions. Unimer with thiophene-2,5-diyl linker exhibited unique properties involving significantly red-shifted absorption and emission maxima, as well as the different behavior during assembling...

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Les cancers représentent un problème majeur de santé public d'où la nécessité de rechercher de nouvelles classes de médicaments. Parmi les pistes pour développer de nouveaux traitements, deux ont retenu notre attention et celle de nos collaborateurs : la modulation de l’épissage par des composés comme le NVS-SM2, et l’inhibition de l’oncogène KRAS par des dérivés de produits naturels, les flavaglines. Dans ce contexte, nous avons développé la première synthèse robuste du NVS-SM2, qui peut satisfaire la demande globale de cet agent pour examiner en détail son potentiel thérapeutique dans différents types d’affection. En outre, la stratégie de synthèse rapportée ici pourrait être étendue à de nouveaux analogues de ce composé. D’autre part, nous avons synthétisé de nouvelles flavaglines qui sont en cours d'étude pour leurs effets sur l’inhibition de KRAS. Au cours de cette étude, nous avons découvert de nouvelles réactions, notamment une inversion de configuration d’amines induite par du chlorure de diméthylcarbamoyle. / Cancers represent a major public health problem hence the need to use new classes of medicines. Among the opportunities for developing new treatments, two have caught our attention and that of our collaborators: the modulation of splicing by compounds such as NVS-SM2, and the inhibition of the oncogene KRAS by derivatives of natural products, the flavaglines.In this context, we have developed the first robust synthesis of NVS-SM2, which can satisfy the global demand of this agent to examine in detail its therapeutic potential in different types of disorders. In addition, the synthetic strategy reported here could be extended to new analogues of this compound. Furthermore, we have synthesized new flavaglines that have been examined for their effects on KRAS inhibition. During this study, we discovered new reactions, including a dimethylcarbamoyl chloride-induced amine inversion of configuration.

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules. This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon. In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant. The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction. Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted. In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors. Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme. / The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.

It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors. The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus. As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water. Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated. Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.