No description available.

Ruthenium-based homogenous catalysis is a broad and extremely useful branch of transition metal catalysis. Surely, the most famous example is olefin metathesis, for which Yves Chauvin, Robert Grubbs and Richard Schrock were awarded the 2005 Chemistry Nobel Prize. Although some of the most well-known catalysts are widely used and considered benchmark catalysts, the research around this topic has not stopped. The modification of known systems to achieve better performance and better understanding of the catalytic mechanism is very important and an example of such modification is reported in this thesis. The newly synthesised catalysts were compared to the parent commercially available catalyst showing better reactivity. Ruthenium catalysis, though, is not limited to olefin metathesis and C-H activation, for example, it has become a useful approach to the functionalisation of organic molecules. In this field, the deuteration of C-H bonds is an interesting transformation, which has many applications. The synthesis of new hydridosilylruthenium complexes and their application in the deuteration of a variety of substrates is reported in this manuscript. The unprecedented synthesis of tetradeuterated Ketoprofene is also reported. Recently, ruthenium-based catalysts have found application in the dehydrogenation of suitable compounds, such as formic acid, ammonia-borane and other hydrogen-rich substances. The driving force behind these discoveries is the use of H2 as an energy vector in place of fossil fuels. A hydrido-ruthenium catalyst was shown to catalyse the decomposition of formic acid in CO2 and H2 and to catalyse the reduction of olefinic substrates. The released CO2 from the reaction did not interfere with the fuel cell due to its inertness. This property makes its employment as C1 source very challenging, although its use would also be extremely attractive because of the abundance of this gas. In these regards, both frustrated Lewis pairs (FLPs) and gold catalysts have shown interesting reactivity in the activation of CO2. A new FLP and a silica supported gold catalyst were synthesised to test them in CO2 activation and the results are reported in this manuscript.

L'activation de la liaison Csp3-H peu réactive et sa fonctionnalisation en liaison carbone-hétéroatome constituent un défi pour les chimistes de synthèse. Un exemple d'intérêt industriel est la réaction d'oxydation du cyclohexane, dont les produits finaux (cétone et alcool) sont des intermédiaire clés pour la production de polyamides tels que les Nylon-6 et 6,6. Parmi les possibilités d'activation, la catalyse représente une méthode de choix. Dans le cadre de cette thèse des suspensions aqueuses à base de nanoparticules ont été évaluées en termes de stabilité et de performances catalytiques. Dans un premier temps, des colloïdes de ruthénium ont été synthétisés à partir de RuCl3,3H2O et caractérisés par des analyses physico-chimiques (MET, SPX, SAXS, UV-visible, etc.). Des espèces actives de Ru+3 dont la structure est de type Ru(OH)3-xClx ont été obtenues. Après optimisation des conditions de réaction, des conversions élevées, associées à des sélectivités pertinentes vis-à-vis de la cétone (jusqu'à 98%), ont été obtenues. Des études cinétiques et mécanistiques ont montré que la voie radicalaire est prépondérante. De plus, ces colloïdes de Ru aisément recyclables ont également été testés avec succès en oxydation d'autres hydrocarbures saturés et insaturés. Dans un second temps, un catalyseur à base de dioxyde de manganèse, métal moins coûteux et abondant, a été synthétisé par un procédé redox original, à partir de KMnO4 et en présence d'un ammonium quaternaire à tête polaire hydroxylée (HEA16Cl), qui joue simultanément le rôle de réducteur et d'agent stabilisant. Ce système s'est révélé être une alternative pertinente aux procédés à base de métaux nobles. Les nanobâtonnets de MnO2 se sont ainsi montrés actifs en oxydation du cyclooctane avec une sélectivité totale en cétone. / The activation of the Csp3-H bond and its transformation into a carbon-heteroatom bond remains a great challenge for the organic chemistry. An example of industrial application is the oxidation reaction of cyclohexane, leading to the production of the corresponding ketone and alcohol, key intermediates of Nylon-6 and Nylon-6,6 polyamides. Among the strategies to activate this unreactive bond, catalysis affords a relevant and sustainable tool. In this work, aqueous suspensions of metal nanoparticles were evaluated in terms of their stability and catalytic performances. Firstly, ruthenium colloids were synthesized from RuCl3.3H2O and fully characterized by various physico-chemical analyses (TEM, XPS, SAXS, UV-visible, etc.). Ru+3 active species were obtained, with a Ru(OH)3-xClx structure. After optimization of the reaction conditions, high conversions, combined with pertinent selectivities towards the ketone (up to 98%), were achieved. The presence of radical species was proved through kinetic and mechanistic studies. Furthermore, these easily recyclable Ru colloids were also evaluated in the oxidation of several saturated and unsaturated hydrocarbons. Secondly, a catalyst based on manganese dioxide, a cheap and abundant metal, was synthesized by an original redox process, starting from KMnO4 and in the presence of a hydroxylated quaternary ammonium (HEA16Cl), which plays the role of a reducing and stabilizing agent. This system proved to be a relevant alternative to methodologies based on noble metals. The MnO2 nanorods showed a good activity in the cyclooctane oxidation with a 100% selectivity towards the ketone.

No description available.

As fossil fuel resources become more and more scarce, attention has been turned to alternative sources of fuels and energy. One promising prospect is the conversion of methane (natural gas) to methanol, which requires an initial activation of a C-H bond and subsequent formation of a C-O bond. The most well studied methodologies for both C-H activation and C-O bond formation involve oxidation of the metal center. Metal complexes with facile access to oxidation states separated by four charge units, required for two subsequent oxidations, are rare. Non-oxidative methods to perform C-H bond activation or C-O bond formation must be pursued in order for methane to methanol to become a viable strategy. In this dissertation studies on redox and non-redox methods for both C-H activation and C-O bond formation are discussed. In the early chapters C-O bond formation in the form of reductive functionalization is modeled. Polypyridine ligated rhodium complexes were studied computationally to determine the properties that would promote reductive functionalization. These principles were then tested by designing an experimental complex that could form C-O bonds. This complex was then shown to also work in acidic media, a critical aspect for product stabilization. In the later chapters, non-oxidative C-H activation is discussed with Ir complexes. Both sigma bond metathesis and concerted metalation deprotonation were investigated. For the former, the mechanism for an experimentally known complex was elucidated and for the latter the controlling factors for a proposed catalyst were explored.

La maladie d’Alzheimer est une maladie neurodégénérative touchant près d’un million de personnes en France et dont les perspectives actuelles laissent suggérer une forte augmentation dans les années à venir. Si les mécanismes biochimiques responsables des symptômes sont connus, aucun traitement curatif n’est aujourd’hui disponible. Parmi les cibles incrimées, le récepteur sérotoninergique 5-HT4 a fait l’objet de nombreuses études et de nombreux ligands ont été synthétisés dans l’optique de trouver un traitement efficace. Cependant, en raison de sa complexité et de sa sensibilité, une étude approfondie du cerveau en conditions fonctionnelles s’avère délicate. C’est pourquoi, l’utilisation des techniques d’imagerie médicale constitue une méthode non invasive et prometteuse pour améliorer les recherches sur ce récepteur en conditions physiologiques et physiopathologiques. Dans la continuité des travaux réalisés au laboratoire depuis plus d’une vingtaine d’années, une nouvelle génération de ligands iodés, a lipophilie réduite, basés sur un système diazaphénanthridine, a été synthétisée. Différentes fonctions hydrophiles ont été introduites et 25 nouveaux composés ont été obtenus et évalués biologiquement. Les meilleurs candidats ont été envoyés en radiomarquage et les images ont montré la capacité de ces ligands à déplacer le radiotraceur de référence in vitro sur coupe de cerveau humain.En parallèle de cette étude, suite aux difficultés rencontrées pour préparer les précurseurs de radiomarquage, une nouvelle technique de radioiodation par activation C-H a été investiguée. Après une mise au point sur les N-tosylbenzamides comme groupement directeur, cette réaction a été exemplifiée sur une quinzaine de groupements directeurs et appliquée à des molécules biologiquement actives plus complexes. / Alzheimer’s disease is a neurodegenerative disorder affecting almost 50 millions people in the world. Even if the biological mechanisms implied on this pathology are known, no treatments stop or reverse its progression. Serotoninergic receptor 5-HT4R is one of the incriminated target and many ligands have been synthesized in order to develop an efficient treatment but a functionnal study of the brain is impossible. That’s why, development of efficient radiotracers is essential for the in vivo evaluation of new drugs targeting 5-HT4R and also for investigation of the receptor involvement in a variety of neurodegenerative and neuropsychiatric disorders. Starting from previsous studies made in the laboratory, a new generation of ligands, focused on diazaphenanthridine scaffold and with reduced lipophilicity, have been designed. Various hydrophilic functions have been introduced and 25 new ligands have been synthesized and biological assays have been realised. Five of this compounds have been radiolabeled and the in vitro imaging experiments on human slice brain showed the ability of the new « hit » compound to move the radioligand of reference and to label the 5-HT4R.Due to the difficulties encountered to the synthesis of tin precursors for the radiolabeling, a new strategy of radioiodation has been developed based on palladium mediated C-H activation. Using first N-tosylbenzamide as directing group for the proof of concept, the scope of this methodology have been enhanced to about fifteen directing groups. Finally, the C-H radioiodation have been applied to more complex biological molecules.

Etant au quatrième rang des cancers les plus fréquents chez l'homme, le cancer de la vessie représente un enjeu médical important. Pourtant, à ce jour, seuls des traitements chirurgicaux handicapants et/ou chimiothérapiques non spécifiques peuvent être envisagés. Le projet de thèse s'inscrit dans le cadre de la recherche de thérapies ciblées du cancer de la vessie en ayant pour objectif le blocage, au niveau moléculaire et de manière sélective, des voies de signalisation mises en œuvre par la tyrosine kinase Tyro3 au sein des cellules cancéreuses. La mise en évidence de la surexpression de ce récepteur membranaire dans la majorité des tumeurs de vessie et son rôle dans la survie des cellules cancéreuses ont en effet permis de valider Tyro3 comme cible thérapeutique pour ce type de cancers. Le projet peut se diviser en trois parties : le développement de nouvelles méthodologies de synthèse autour du motif imidazo[4,5-b]pyridine, la synthèse d'une librairie de candidats inhibiteurs en utilisant les méthodes mises au point et enfin l'étude des relations structure-activité vis-à-vis de la protéine kinase Tyro3. / Bladder cancer is a major medical issue, being the fourth most frequent cancer in men and treatable only with heavy surgery and/or broad-spectrum chemotherapy. This thesis project deals with the discovery of new targeted therapies of bladder cancer by blocking specifically, at a molecular scale in cancer cells, the signaling pathways in which protein kinase Tyro3 is involved. Indeed, its overexpression in most bladder cancers and the major part it plays in cancer cells survival have led to the validation of protein kinase Tyro3 as a therapeutic target for the treatment of bladder cancer. This thesis project can be divided into three main parts: the development of new synthetic methods around the imidazo[4,5-b]pyridine scaffold, the synthesis of a library of compounds using these methods and eventually the study of structure-activity relationships of these compounds versus Tyro3.

This PhD thesis reports the development of novel C-H activation strategies and aqueous-phase Suzuki-Miyaura cross-coupling reactions for the synthesis of modified deazapurine nucleobases. The methodologies of chemo- and regioselective synthesis of highly functionalized deazapurines have been developed by using modern C-H activation chemistry. Various functional groups such as amino-, imido-, silyl- and phosphonyl- were introduced by C-H activation reactions. Amino deazapurine derivatives were synthesized by developed Pd/Cu-catalyzed direct C-H amination and C-H chloroamination of 6-substituted 7-deazapurines with N-chloro-N- alkyl-arylsulfonamides. C-H imidation reactions of pyrrolopirimidines were performed under ferrocene catalysis with N-succinimido- or N-phtalimidoperesters. In order to obtain silylated derivatives, Ir-catalyzed C-H silylations of phenyldeazapurines with alkyl silanes were designed. Highly interesting deazapurine phosphonates were prepared by using Mn-promoted C-H phosphonation method and were further transformed into the corresponding phosphonic acids. All of the developed direct C-H functionalization reactions proceeded regioselectively at position 8 in deazapurine core, except for C-H silylation where reaction undergoes mainly as directed ortho C-H silylation on phenyl ring,...

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18808号 / 理博第4066号 / 新制||理||1585(附属図書館) / 31759 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 時任 宣博, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

The first project in this dissertation presents a simplified and efficient protocol for synthesizing pyrrolines through 5-exo iminyl radical cyclizations. The microwave irradiation of O-Phenyloximes tethered to alkenes causes N-O homolysis resulting in iminyl radical generation, which subsequently undergoes 5-exo-trig cyclizations furnishing pyrrolines. This eliminates the need for toxic radical initiators (AIBN, benzoyl peroxide), propagating agents (Bu3SnH, (Me3Si)3SiH), and expensive catalysts or single-electron transfer (SET) cycles. We explored the scope of diverse traps and substrates for iminyl radical cyclizations. The iminyl radical cyclizations formed versatile pyrrolines with moderate to excellent yields. The diastereoselectivity also ranged from low to high. Moreover, these versatile pyrrolines were further transformed via various reactions, such as hydrogenation, allylation, dihydroxylation, and cross-metathesis. The second part of this project extends the scope of the non-redox iminyl-radical based approach to γ-C(sp3)−H ketone activation. The sequence of N-O homolysis triggered by microwave irradiation of O-phenyloximes, 1,5-hydrogen atom transfer (HAT), trapping of the radical intermediate, and in situ imine hydrolysis, ultimately leads to the formal γ-C–H functionalization of ketones. We achieved both C-O and C-C bond formation by using diverse O-phenyloxime substrates. This work's notable achievement was accomplishing γ-C–H activation of 1o carbon atoms, a feat that has not been attained using SET-based iminyl radical chemistry. The third part of this dissertation focuses on the influence that dehydroamino acids have on secondary structures. This project describes the synthesis of incipient 310 helical tetrapeptides containing dehydroamino acids. A bulky dehydroethylnorvaline-containing tetrapeptide was synthesized. Based on our published data, we speculated that dehydroethylnorvaline might increase peptide proteolytic stability.