京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21784号 / 工博第4601号 / 新制||工||1717(附属図書館) / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 中村 正治, 教授 近藤 輝幸, 教授 村田 靖次郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

This thesis concerns the use of various potent oxidants in organic synthesis. The main focus is directed at selectively introducing trifluoromethyl groups into compounds containing double or triple bonds. All reactions proceed under mild conditions and can in most cases be performed on the bench-top. We have developed three different procedures for transformations of activated alkenes and alkynes as well as quinones. In paper I the selective introduction of a trifluoromethyl group together with an oxygen functionality to double and triple bonds is demonstrated. Paper II is focused on the related chemoselective cyanotrifluoromethylation in which a cyano group is added instead of the oxygen functionality. Paper III describes a new procedure for C–H trifluoromethylation of quinones. Our studies on the mechanistic aspects of the above reactions are described in Paper IV. In these studies we investigated the ligand and substituent effects in Cu-catalyzed reactions. Paper V is focused on a conceptually new palladium-catalyzed allylic C–H acyloxylation of olefins under oxidative conditions. The procedure uses an inexpensive, safe and environmentally benign oxidant, sodium perborate, which is activated with acetic anhydride. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.</p>

Cette thèse porte sur l’étude mécanistique de réactions mettant en jeu des complexes de palladium. Deux systèmes différents sont étudiés, mettant ainsi en évidence des approches mécanistiques à différents niveaux. La première étude réalisée concerne l’addition oxydante de complexes [palladium - ligands azotés] sur des iodoarènes. Une cinétique d’ordre 2 en palladium(0) a été mise en évidence expérimentalement, pour une grande variété de conditions (ligands, solvants, iodoarènes). Un mécanisme coopératif faisant intervenir l’activation de la liaison CI par un complexe de palladium, suivi par l’insertion oxydante d’un deuxième complexe de palladium a été proposé et étudié par DFT. La deuxième étude porte sur formation d’oxazolidine-2,4-diones à partir d’adduits de Passerini, catalysée au palladium. L’objectif est ici de déterminer les intermédiaires mis en jeu dans cette réaction impliquant la formation de 3 nouvelles liaisons sur le squelette carboné. Une double réaction de Tsuji-Trost a été mise en évidence et le rôle particulier de l’allylméthylcarbonate utilisé a été étudié. A la lumière de ces résultats, un cycle catalytique a été proposé. Cette étude montre le potentiel de la compréhension détaillée des phénomènes à l’échelle moléculaire pour imaginer de futurs développements. / In this thesis, the mechanistic study of reactions involving palladium complexes is presented. Two systems have been studied, with different levels of mechanistic investigation. The first study aims at explaining the peculiar behavior of palladium ligated to nitrogen-containing ligands in the oxidative addition on iodoarenes. A second order in palladium(0) reaction rate has been experimentally demonstrated for various conditions (ligand, solvent, iodoarene). A cooperative mechanism involving the pre-activation of the C-I bond by a palladium complex prior to the oxidative insertion itself has been proposed and studied by DFT. In the second study, the palladium-catalyzed formation of oxazolidine-2,4-diones from Passerini adducts is investigated. The goal is to determine the relevant intermediates of the reaction and to explain the formation of the three new bonds. Two Tsuji-Trost reactions occur and the special role of allylmethylcarbonate has been studied. This mechanistic study highlights the potential of thorough understanding of mechanisms at the molecular level to envision further synthetic developments.

Orientadores: Fernando Antônio Santos Coelho, Marcos Nogueira Eberlin / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-18T09:36:09Z (GMT). No. of bitstreams: 1 Regiani_Thais_M.pdf: 3410899 bytes, checksum: 644a869c89a9637d8fd2d96a7f65ce6f (MD5) Previous issue date: 2011 / Resumo: Essa dissertação visa explorar o mecanismo da reação de aza-Morita-Baylis-Hillman (aza-MBH) por espectrometria de massas (ESI-MS). Essa técnica está bem consolidada para o estudo do mecanismo de reações orgânicas. Os dados disponíveis na literatura assumem que o mecanismo dessa reação é similar ao da reação de Morita-Baylis-Hillman (MBH) convencional. Entretanto, existem várias versões assimétricas para a reação de aza-MBH que podem ser consideradas como gerais, o que não ocorre com a reação de MBH. Sendo assim o objetivo desse trabalho foi conhecer as etapas envolvidas no mecanismo da reação de aza-MBH e fornecer subsídios para explicar os pontos em que esses mecanismos diferem. Avaliamos a influência do uso de diferentes bases terciária e de olefinas na reação de aza-MBH. Interceptamos e caracterizamos dois novos intermediários de m/z 665 e m/z 777 que aparentemente desempenham um importante papel no ciclo catalítico da reação de aza-MBH. A formação desses intermediários foi corroborada em um estudo envolvendo o propiolato de metila como componente nucleofílico da reação de aza-MBH. Em outra parte de trabalho monitoramos por ESI-MS uma reação de MBH para demonstrar a habilidade de um aduto de MBH como uma fonte de próton para a etapa lenta da reação. Assim, um aduto contendo um átomo de bromo foi utilizado como fonte de próton. Fomos capazes de interceptar e caracterizar intermediários nos quais essa fonte de próton (aduto MBH bromado) estava ligada. Esses resultados são uma evidência experimental do processo de autocatálise que pode ocorrer durante o desenvolvimento dessa reação. Finalmente, um monitoramento on-line por espectrometria de massas de uma reação de MBH convencional nos permitiu realizar um estudo cinético dessa reação. Esse monitoramento foi realizado utilizando uma nova fonte de ionização ambiente, baseada na ionização por Sonic Spray (V-EASI). A curva cinética nos permitiu acompanhar a reação em tempo real e observar a formação de todos os intermediários transientes do seu ciclo catalítico / Abstract: This dissertation aimed at exploring the monitoring of the mechanism of the aza-Morita-Baylis-Hillman reaction (aza-MBH) by mass spectrometry (ESI-MS). This technique is well established for studying the mechanism of organic reactions. Normally, it is assumed that the mechanism of the aza-MBH reaction is quite similar to the conventional Morita-Baylis-Hillman reaction. However, there are several general asymmetric versions for the aza-MBH reaction, which does not occur with the MBH reaction. The aim of this study was to understand the steps involved in the mechanism of aza-MBH reaction and provide evidences to explain the points at which these mechanisms would differ. We have evaluated the behavior of bases and acrylates often used in the reaction of aza-MBH. We were able to intercept and characterize by tandem MS/MS two new intermediate of m/z 665 and m/z 777 which apparently play an important role in the catalytic cycle of the aza-MBH reaction. The formation of these intermediates was corroborated in a study involving methyl propiolate as nucleophilic for a aza-MBH reaction. The two intermediates have never been cited or featured in this reaction. In another part of this work we monitored a MBH reaction by ESI-MS in order to evaluate the ability of a MBH adduct act as a proton source in the rate-determining step (RDS) of this reaction. Thus, a brominated adduct was used as a source of proton in an anhydrous medium. We were able to isolate and characterize intermediates in which the proton source (brominated adduct MBH) was on. These results provide experimental evidence that the process of autocatalysis may occur during the development of this reaction. Finally, an on-line monitoring of a conventional Morita-Baylis-Hillman by mass spectrometry enabled us to perform a kinetic study of this reaction. This monitoring was carried out using a new ionization source environment based on Sonic Spray ionization (V-EASI). The kinetic curve allowed us to monitor the reaction in real time and observe the formation of all transient intermediates which participate in its catalytic cycle / Mestrado / Quimica Organica / Mestre em Química

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20391号 / 工博第4328号 / 新制||工||1671(附属図書館) / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 中村 正治, 教授 辻 康之, 教授 小澤 文幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Les réactions de couplage croisé ont révolutionné la chimie organique. Par exemple, dans le domaine de la chimie médicinale, les réactions de couplage sont de puissants outils pour générer rapidement et facilement une librairie de composés. Depuis la découverte des premières réactions de couplage croisé catalysé par des complexes de palladium, ce métal reste le plus utilisé. Cependant, d’autres métaux tels que le cuivre, le nickel, le cobalt ou le fer sont apparus comme de bonnes alternatives aux complexes de palladium, chers et toxiques.D’autre part, en chimie médicinale, les hétérocycles sont des motifs essentiels puisqu’ils sont présents dans un grand nombre de médicaments. Le développement de nouvelles méthodes permettant de former des molécules incorporant des motifs hétérocycliques tels que des azétidines, des pyrrolidines ou des oxétanes, est un réel défi pour un chimiste organicien. Les halogénures d’alkyle sont généralement des substrats difficiles à utiliser en couplage croisé car l’addition oxydante du métal y est difficile. Des réactions parasites peuvent également avoir lieu telles que des réactions de -H élimination ou de déshalogénation. Cependant, les sels de cobalt et de fer se sont révélés être des catalyseurs efficaces pour réaliser des réactions de couplage sur des halogénures d’alkyle. Au cours de cette thèse, deux systèmes catalytiques à base de sels de cobalt ou de fer ont été développés pour réaliser des réactions de couplage croisé entre des halogénures d’alkyle hétérocycliques et des réactifs de Grignard. Une étude mécanistique des réactions de couplage croisé catalysé par des sels de cobalt a également été réalisée. / Cross-coupling reactions, as Prof. K. C. Nicolaou said “have changed the way we think about synthesis”. Indeed, cross-coupling reactions are powerful tools to access easily and rapidly to a library of compounds in the context of medicinal chemistry. Palladium-catalysed cross-coupling rules the field and was recognized by the Nobel Prize in 2010 but, since its discovery, others metals have appeared as good alternatives to the expensive and toxic palladium salts such as copper, nickel, cobalt and iron salts. In medicinal chemistry, heterocycles are essential moieties since they are found in a great number of drugs on the market. It is always a challenge for organic chemists to develop new methods to produce motifs with interesting pharmacological properties such as substituted azetidines, pyrrolidines and oxetanes. sp3 Halides are challenging substrates for cross-coupling because the oxidative addition of the metal in the C-X bond is difficult and because side reactions can take place like -hydride elimination or dehydrohalogenation. Nevertheless, cobalt and iron are suitable catalysts to perform cross-coupling reactions on sp3 halides. Herein, we would like to report two catalytic systems allowing the cross-coupling between heterocyclic alkyl halides and Grignard reagents using cobalt and iron salts. A mechanistic study on cobalt-catalysed cross-coupling reaction between halides and Grignard reagents will be also presented.

Every year millions of tons of lignin, a complex biopolymer present in plants that naturally contains aromatic subunits, are produced as a by-product of industries like the food sector and paper sector. Until now it has been considered as a waste but proper valorisation through optimized depolymerization techniques would allow to recover of high-added value fine chemicals and bulk commodities. Vanadium(V) triphenolamine complexes (VO-TPA), developed and studied in the group of Giulia Licini (University of Padova, IT), are of interest in this context as they are efficient catalysts for the oxidative cleavage of carbon-carbon bonds typical of those present in lignin. However, the mechanism of this reaction had not yet been elucidated and the catalysts have exclusively been used in organic solvents. This Thesis is a contribution to the further development of these catalysts and takes different Green Chemistry principles into account such as waste prevention, atom economy, renewable feedstocks, catalysis, energetic efficiency and the use of benign solvents. A first part of this thesis is a contribution to the elucidation of the reaction mechanism. The work was undertaken with vicinal diols, which are the simplest model compounds of lignin. Based on a review of the literature, radical trapping experiments, kinetics, 13C KIE experiments, Hammett plots and multi-parametric correlations, the C-C cleavage of a non-oxo or oxo chelate has been identified as the rate determining step. Attempts were made to synthesise the chelate and identify it via MS. Moreover, three hypothetic pathways were posited to reach this intermediate. Isotopic labelling experiments, determination of reaction activation parameters via an Eyring plot and computations of the different pathways along EPR elucidation of reduced species, have been used to discriminate the operative mechanism. The second part of this thesis is devoted to the transfer of the reaction into water, which can be considered a benign solvent. The VO-TPA complexes were successfully transferred to water using both non-ionic TPGS-750-M and zwitterionic DPC micelles. The latter maintained the catalyst stability over a broad pH range and temperature range which was not the case with the non-ionic micelles. The substrate scope was evaluated with the DPC micelles and a strong selectivity was observed for hydrophobic substrates. After scaling up the process to reach standards used in the literature, mixed DPC/TPGS micelles were characterized and used as a simple solution to combine the pH stability of the former and extractive properties of the latter. This allowed to completely recycle the micellar phase while maintaining good yields. / Doctorat en Sciences de l'ingénieur et technologie / info:eu-repo/semantics/nonPublished

Ce mémoire est consacré à la réactivité rédox de la porphine de magnésium, à l’étude de son électropolymérisation et des matériaux résultants, à sa fonctionnalisation par des nucléophiles ainsi qu’à l’étude mécanistique du couplage oxydant C-C sur une porphyrine modèle tri-méso-substituée.L’oxydation électrochimique de la porphine de magnésium au stade du radical cation, génère des oligomères en solution et des polymères à la surface de l’électrode dont la structure moléculaire dépend du potentiel imposé. La réactivité du radical cation a également été exploitée en additionnant un nucléophile (pyridine et triphénylphosphine) dans le milieu réactionnel en quantité suffisante, afin d’inhiber le processus d’oligomérisation/polymérisation et conduire exclusivement aux produits de mono-substitution. En dépit des deux types de positions libres sur l’anneau porphyrinique (positions méso et ?-pyrrolique), la réaction est idéalement régio-sélective sur la position méso.L’analyse d’un dérivé modèle, une porphyrine tri-substituée en position méso, ne possédant donc qu’un seul site méso réactif, a permis de simplifier l’étude mécanistique du couplage oxydant C-C puisque celui-ci ne peut conduire qu’à la formation du dimère simplement lié. Par ailleurs, ce dernier a été électrosynthétisé avec des rendements inégalés et compétitifs avec ceux de la voie chimique. Enfin, la substitution nucléophile anodique (phosphination, nitration et pyridination) en position méso a été élargie à des porphyrines tri-substituées de nickel, magnésium et zinc. Le complexe de magnésium nitré a été quantitativement converti en amine par hydrogénation électrocatalytique / This work deals with the redox reactivity of magnesium porphine, the study of its electropolymerization and resulting materials, of its functionalization by nucleophiles as well as the mechanistic investigation of the C-C oxidative coupling on a tris-meso-substituted porphyrin model.The electrochemical oxidation of magnesium porphine to its cation radical leads to oligomers in solution and polymers on the electrode, which molecular structure depends on the imposed potential. The reactivity of the cation radical has also been exploited by adding sufficient amount of nucleophiles (pyridine and triphenylphosphine) in the reactional in order to inhibit the oligomerization/polymerization process and to lead exclusively to the mono-substitution product. In spite of the two types of free positions on the porphyrin ring (meso and ? positions), the reaction is ideally regio-selective on the meso position. The analysis of a model derivative, a tris-meso-substituted porphyrin, thus having only one reactive site méso, rendered the mechanistic study of the C-C oxidative coupling easier since this one can only lead to the formation of the meso-meso dimer. In addition, the latter was electrosynthesized with high and competitive yields compared with those reported for the chemical way. Lastly, the anodic nucleophilic substitution (phosphination, nitration and pyridination) in meso position was extended to tris-meso-substituted porphyrins of nickel, magnesium and zinc. The nitro-porphyrin magnesium complex was converted quantitatively into amine by electrocatalytic hydrogenation

Les « -Izidines » sont des motifs présents dans de nombreuses alcaloïdes. Pour accéder à ces structures, la formation de la liaison C=C exendo est une méthode de choix. L’application de la réaction de Julia-Kocienski intramoléculaire sur des imides permettrait d’obtenir des enamides portant la liaison C=C exendo. Notre équipe s’est intéressée depuis 2005 à l’application de la réaction de Julia-Kocienski les lactones. Dans la continuité de travaux précédents, cette thèse décrit l’application de la réaction de Julia-Kocienski intramoléculaire pour former des enamides. Cette réaction permet d’obtenir tous les motifs « -Izidine » tels que le pyrrolidizine, l’indolizidine ou le quinolizidine. Selon les conditions réactionnelles, il est possible d’obtenir les enamides ou les vinylsulfones. Pour ces deux types de réactions, les résultats obtenus peuvent être classés en fonction des groupements présents sur les imidesL’étude mécanistique par les calculs de DFT, en collaboration avec Dr. Lionel Perrin, montre que l’effet stérique ou électronique des groupements sur les imides peut influencer les résultats de la formation des enamides ou des vinylsulfones. Afin d’illustrer la méthodologie de la réaction de Julia-Kocienski intramoléculaire sur les imides, un analogue oxo du FR901483 a été choisi comme une cible de la synthèse totale. Les réactivités différentes de celles observées dans la littérature des groupements présents sur les intermédiaires nous avons conduits à appliquer d’autres alternatives à littérature. Ce phénomène pourrait bien être lié à l’interaction entre les groupements sur une espace atomique restreint / “-Izidines” units are often found as structural subunits of many alkaloids. One of the powerful methods to access this structure is the formation of the C=C bond exendo. The application of the intramolecular Julia-Kocienski reaction on imides should allow this formation.Our group has a long-standing interest in the application of the Julia-Kocienski reaction on lactones. In line with previous efforts, the herein presented work details the syntheses of enamides via application of the intramolecular Julia-Kocienski reaction on imides. This new method enables us to obtain different “-Izidine” units such as pyrrolizidine, indolizidine, and quinolizidine. Depending on the reaction conditions, it is possible to obtain the enamide or vinylsulfones. In both reactions, the present moiety on imides can affect the outcome.Computational mechanistic study, by collaboration with Dr. Lionel Perrin, shows the steric or electronic effect of the present functional groups on imides influence the results of the formation of the enamides or vinylsulfones.Having a goal of applying this new methodology towards total synthesis of natural products, we started the synthesis of oxo-analog of FR901483. During our synthesis, a number of uncommon reactivities of the presented functional groups were observed. This phenomenon led us to applying different methods than those of the literature

The use of small molecule building blocks in, for example, pharmaceutical research and new material development, creates a need for new and improved organic synthesis methods. The use of transition metals as mediators and catalysts opens up new reaction pathways that have made the synthesis of completely new compounds possible as well as greatly improved the synthetic routes to known compounds. Herein, the development of new metal-mediated and catalyzed reactions for construction of vinylic and allylic carbon-carbon and carbon-heteroatom bonds is described.  The use of iodonium salts as coupling partners in Pd-catalyzed Heck type reactions with alkenes is shown to improve the current substrate scope. Results from a mechanistic study indicate that the reaction proceeds via high oxidation state palladium intermediates. The use of IIII reagents is also believed to facilitate a PdII/PdIV catalytic cycle in allylic silylation of alkenes using (SiMe3)2, which, to the best of our knowledge, is the first method developed for metal-catalyzed allylic C-H silylation. The same silyl-source, (SiMe3)2, has previously been used in a Pd-catalyzed allylic substitution reaction in which allylic silanes are formed from allylic alcohols. A detailed mechanistic investigation of this reaction is described in which by-products as well as intermediates, including the resting state of the catalyst, are identified using 1H, 11B, 19F and 29Si NMR spectroscopy. Kinetic experiments are performed that give information about the turn-over limiting step and the mechanism of the analogous borylation using B2pin2 is also investigated. Insights from this study further made it possible to improve the stereoselectivity of this reaction. Additionally, a new method for Cu-mediated trifluoromethylation of allylic halides is presented in which linear products are formed exclusively from both linear and branched allylic substrates at room temperature.  Identification of allylic fluorides as by-products during the reaction also led to the development of a similar Cu-mediated reaction for the fluorination of allylic halides. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>