La chimie du fluor suscite un intérêt croissant de la part des chimistes organiciens de par son exploitation industrielle dans les domaines pharmaceutique et agrochimique. Ainsi, depuis plusieurs années, de nouvelles méthodes permettant d'introduire de manière efficace et sélective des groupements fluorés - et plus particulièrement des fluoroalkyles - sur des molécules cibles sont activement recherchées. Les hydrazones sont des molécules largement utilisées en synthèse organique, notamment comme précurseurs de nombreux composés très recherchés par les industries pharmaceutiques ou agrochimiques, incluant les amines primaires et les hétérocycles azotés tels que les pyrazoles et les indoles. Dans le cadre de cette thèse, nous nous sommes intéressés à la fluoroalkylation des hydrazones. Les premières études ont visé la trifluorométhylation cupro-catalysée d'hydrazones d'aldéhydes et de cétones, lesquelles ont conduit respectivement à la formation d'hydrazones trifluorométhylées et de diimides alpha-trifluorométhylés. Par la suite, cette transformation a été entendue à la béta-trifluorométhylation régiosélective d'hydrazones alpha,béta-insaturées. Enfin, nous nous sommes intéressés au développement de réactions de difluoroalkylation d'hydrazones d'aldéhydes catalysées par le palladium ou le cuivre. Les divers composés obtenus lors de ces études se sont avérés être d'excellents précurseurs de cétones et d'indoles trifluorométhylés, d'alpha,alpha-difluoro-béta-cétoesters, ou encore d'alpha,alpha-difluorocétones / Fluorine chemistry is attracting the growing interest of organic chemists due to its industrial exploitation in the pharmaceutical and agrochemical fields. Thus, new methods for the effective and selective introduction of fluorinated groups – and particularly fluoroalkyls - on target molecules have been sought in recent years. Hydrazones are widely used reagents in organic synthesis, notably as precursors of many compounds pursued by the pharmaceutical or agrochemical industries, including primary amines and nitrogen heterocycles such as pyrazoles and indoles. This thesis work focused on the fluoroalkylation of hydrazones. The first studies have been directed toward the copper-catalyzed trifluoromethylation of aldehyde- and ketone-derived hydrazones, which led to the formation of trifluoromethylated hydrazones and alpha-trifluoromethylated azenes, respectively. Subsequently, this transformation was extended to the regioselective beta-trifluoromethylation of alpha,beta-unsaturated hydrazones. Finally, our interest focused on the development of difluoroalkylation reactions of aldehyde-derived hydrazones under palladium or copper catalysis. The various compounds obtained in these investigations have proven to be valuable precursors of trifluoromethylated ketones and indoles, alpha, alpha-difluoro-beta-ketoesters, as well as alpha,alpha-difluoroketones

The more we learn about fluorine, the more we understand why this fascinating element has been extensively explored for use in polymers, surfactants, refrigerants, agrochemicals, pharmaceuticals, and PET imaging. Switching chlorine to fluorine and adding a double bond drastically decreases fluorocarbons’ atmospheric half-lives and pushes the development of new routes to hydrofluoroolefins (HFOs) as 4th generation refrigerants. In another application, the inclusion of fluorine into drugs improves their pharmacokinetic and pharmacodynamic properties. Since the first fluorinated drugs were introduced in the 1960s, the use of organoflruoine compounds has greatly expanded in both the pharmaceutical and agrochemical markets. However, there is still a need for improved synthetic methodologies for late-stage fluoroalkylation of bioactive compounds. Moreover, moving beyond -CF3 and -CF2H, the use of additional RF groups like -CF2CF2H that increase lipophilicity while also allowing for H-bonding may also lead to the identification of improved bioactivity over a broad spectrum. Previous work in the Baker group demonstrated that regioselective insertion of hexafluoropropene, CF2=CF(CF3) into a Cu-F bond generated the hexafluoroisopropyl group that could be efficiently transferred to aroyl chlorides. Moreover, the insertion of tetrafluoroethylene (TFE) into Cu-H gave a stable Cu-CF2CF2H complex that could also transfer its RF group to aryl iodides in the presence of catalytic CuCl(NHC) (NHC = N-heterocyclic carbene). In this thesis we expand the regioselective Cu-H insertion strategy to include chlorotrifluoroethylene, CTFE, CF2=CFCl, and perfluoro(methyl vinyl ether), PMVE, CF2=CF(OCF3). With the former, we showed the importance of ancillary ligands in stabilizing the Cu complex and enabling the successful transfer of the -CFClCF2H group to aroyl chlorides (aryl iodides gave only biaryls). In contrast, we found that stable Cu[CF(OCF3)(CF2H)] complexes could be prepared using a variety of ligands spanning 2- to 4-coord Cu, and we showed that DMSO serves as a ‘privileged’ ligand for transfer of this RF group to organic electrophiles. With the help of a computational chemistry collaborator, we identified the importance of pre-equilibria that hampered the aryl iodide addition step, leading us to develop a ‘ligandless’ polar solvent-stabilized Cu-RF strategy, using added CuBr to trap the phosphine ligands for efficient transfer of the novel -CF(OCF3)(CF2H) group. Further calculations showed that rate-limiting product elimination for RF transfer to aroyl chloride involves an asynchronous transition state occurring at a single Cu coordination site. Finally, adding the ‘ligandless’ Cu-RF strategy with our previously reported Cu-CF2CF2H complexes, derived from the stable 1:1 TFE: CO2 mixture, allowed for the successful tetrafluoroethylation of alkenyl iodide nucleobases, nucleosides and glycals with potential biological activity. In another collaboration, we report the results of preliminary molecular docking studies of fluorinated-carboxamides as potential fungicide targets. In an effort to expand the range of readily available fluoroalkenes using the Baker group’s Ni-catalyzed homologation approach, we first collaborated with another computational chemistry to investigate the mechanism of fluoronickelacyclopentane formation. This work showed that the NiL2 fragment often led to reduced activation barriers (vs. NiL) and that the transition state involves a wide L-Ni-L angle of ca. 150°. Using the wide bite-angle bis(phosphine) DPEPhos, we were able to characterize a model for the initially formed pseudotetrahedral metallacycle. We then expanded the range of isolated fluoronickelacycles to include those derived from PMVE and CTFE. While the former gave regio- and stereoselective formation of stable metallacycles with trans -OCF3 groups on C, the stability and regioselectivity of the latter depended on the ancillary ligands. Preliminary reactivity of these metallacycles with Lewis and Brønsted acids is also reported. In summary, using two functionalized fluoroalkenes, we have advanced our understanding of the stabilization of Cu-RF complexes and their ability to transfer their RF group to organic electrophiles. In addition, we assessed the synthesis, stability, and reactivity of new fluoronickelacycles to provide additional insight into the Baker group’s Ni-catalyzed fluoroalkene homologation strategy.

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In the Introduction part of this thesis, the chemistry of organofluorine compounds is discussed, particularly the methods for the preparation of organofluorine compounds mainly by fluoroalkylation methods. Furthermore, the chemistry of fluorinated phosphonates, methods of their preparation, reactivity and biological activity is discussed. Additionally, the reactivity of fluoromethane derivatives is briefly mentioned and especially, the reactivity of diethyl fluoromalonate and fluorobisfenylsulfonylmethane is described. The Results and discussion part is devoted to the reactivity of three fluorinated phosphonates: tetraethyl fluoromethylenbisphosphonate, diethyl fluorophenylsulfonylphosphonate and previously not described diethyl fluoronitromethylphosphonate. These fluorinated phosphonates belong to the family of nucleophilic monofluoroalkylation reagents, meaning that these compounds are convenient starting materials for the synthesis of complex organic molecules containing the fluorine atom. The results deal with the reactivity of above mentioned fluorinated phosphonates, mainly with alkylation reactions, Horner-Wadsworth-Emmons reactions and conjugated additions. Also, other synthetic methods such as the Mitsunobu reaction or the palladium catalyzed allylation reaction were investigated; however,...

Les sulfoximines sont une famille de composés dont les domaines d’applications sont très variés. Elles sont utilisées comme auxiliaires, ou ligands pour la synthèse asymétrique et répertoriées comme groupements à forts potentiels dans des composés biologiquement actifs. Les sulfoximines fluorées sont bien plus rares et difficiles d’accès, mais de par les propriétés spéciales induites par le fluor, ont récemment attirées l’attention. Elles ont notamment été utilisées avec succès en tant que réactifs de (per)-fluoroalkylation ou comme groupements super-électroattracteurs. Cependant, il n’y a que de rares exemples de sulfoximines fluorées dans des composés bioactifs. De plus, à notre connaissance, les S-perfluoroalkyl sulfoximines n’ont encore jamais été utilisées comme ligands de métaux ou organocatalyseurs.La thèse porte sur le développement de la synthèse et la fonctionnalisation des sulfoximines fluorées pour la préparation de ligands et d’organocatalyseurs, notamment en version énantiopures. Elle est divisée en 3 chapitres.Le premier chapitre porte sur la synthèse des sulfoximines et des sulfilimines fluorées énantiopures. Sur différentes étapes de la synthèse de ces composés, plusieurs méthodes ont été utilisées, par exemple, la séparation de diastéréoisomères par l’acide de camphorsulphonique, l’oxydation asymétrique de Kagan, Modena, Uemura et aussi l’imination oxydante asymétrique. La CFS (Chromatographie par Fluide Supercritique) semi-préparative a permis de séparer les différents énantiomères des sulfilimines fluorées. L’oxydation des sulfilimines a permis d’obtenir les sulfoximines énantiopures avec de bons rendements. Ces sulfilimines et sulfoximines ont des configurations absolues stables, leurs caractéristiques optiques ont été mesurées ainsi que leurs structures ont été déterminées par diffraction des rayons-X. Le deuxième chapitre est principalement axé sur la N-fonctionnalisation des sulfoximines et leurs développements comme ligands et organocatalyseurs pour la catalyse. Nous avons pu montrer que l’utilisation des micro-ondes pour activer le couplage entre les sulfoximines libres et les aromatiques halogénés permettait d’obtenir de bons résultats et même de diminuer le temps de réaction par rapport à la méthode de chauffage conventionnel. Ce développement a également été utilisé pour préparer des ligands/organocatalyseurs chiraux. Ces nouveaux ligands, sulfoximines fluorées chirales, ont été appliqués dans des procédés de catalyse pour la réaction de Friedel-Crafts, de Biginelli et même comme réactif de Shibata asymétrique pour la trifluoromethylation. Nous avons montré également que ces composés peuvent être utilisés comme ligands ou organocatalyseurs chiraux dans la réaction de Mukaiyama ou de cycloaddition de Diels-Alder conduisant aux produits avec de bons rendements.Le dernier chapitre est basé sur la fonctionnalisation des sulfoximines fluorées par une réaction inédite d’ortholithiation. Dans cette partie, nous démontrons que la fonction sulfoximine fluorée joue le rôle de groupe ortho-directeur. Cela nous a permis d’accéder à une grande variété de sulfoximines orthosubstituées aux structures totalement nouvelles. Les produits dérivés ortho ont été utilisés comme réactifs dans de nombreuses réactions: dans la réaction de Sonogashira, dans la préparation de nouveaux réactif de trifluorométhylation et dans la synthèse d’analogues de composés biologiquement actifs. / Sulfoximines belong to a family of compounds with various application areas. They are used as auxiliaries or ligands for asymmetric synthesis and classified as high potential groups in biologically active compounds. Fluorinated sulfoximines are even more scarce and difficult to access, but special properties induced by fluorine, have attracted particular attention. They have been successfully used as (per)-fluoroalkylating reagent or as super-electron-withdrawing groups. However, there are only a few examples of fluorinated sulfoximines in bioactive compounds. To our knowledge, S-perfluoroalkylated sulfoximines have never been used as ligands of metals or organocatalysts so far.The Thesis focuses on the synthesis and functionalization of fluorinated sulfoximines for the preparation of chiral ligands and/or organocatalysts. It is divided into three chapters.The first chapter deals with the synthesis of enantiopure fluorinated sulfoximines and sulfilimines. During our synthesis, several methods were used, for example, separation of diastereoisomers by using camphorsulphonic acid, and the asymmetric oxidation of Kagan, Modena, Uemura as well as the asymmetric oxidizing imination. The SFC (Supercritical Fluid Chromatography) semi-preparative permits to separate the different enantiomers of fluorinated sulfilimines. Oxidation of sulfilimines led to the formation of enantiopure sulfoximines in good yields. These sulfilimines and sulfoximines are stable retaining their absolute configuration. Optical characteristics were measured and their structures were determined by X-ray diffractions. The second chapter focuses mainly on the N-functionalization of sulfoximines and their developments as organocatalysts and/or ligands for catalysis. Coupling reaction of free sulfoximines with halogenated aromatic under microwave activation led to the formation of products in good yields within short reaction time. This development has also been used to prepare chiral ligands/ organocatalysts. These new chiral fluorinated sulfoximines have been applied in catalytic processes for Friedel-Crafts reaction, Biginelli transformation and as Shibata’s asymmetric trifluoromethylation reagent. We also showed that these compounds may be used as chiral ligands or organocatalysts in Mukaiyama reaction or in Diels-Alder cycloaddition affording products in good yields.The last chapter is based on the functionalization of fluorinated sulfoximines by an ortholithiation reaction. In this part, we have demonstrated that the fluorinated sulfoximine function acts as ortho-directing group. This allowed us to access a wide variety of new ortho-substituted sulfoximine structures. Ortho-derivatives were used as reagents in Sonogashira reaction, in the preparation of novel trifluoromethylation reagents and in the synthesis of some biologically active compound analogues.

Charles University in Prague, Faculty of Science Department of Organic Chemistry Ing. Yana Chernykh Sulfur-Based Reagents for Nucleophilic and Radical Introduction of Tetrafluoroethyl and Tetrafluoroethylene Groups Ph.D. Thesis Prague 2014 ABSTRACT This project was aimed at developing new methodologies for selective introduction of tetrafluoroethyl and tetrafluoroethylene groups into organic molecules. The study was focused on reactivities of fluorinated sulfones and sulfides as tetrafluoroalkylation reagents. In the Introduction part of the thesis, main aspects of organofluorine chemistry are outlined, illustrating beneficial effects of fluorine atoms on physical, chemical and biological properties of organic compounds. General synthetic methods for the selective introduction of fluorine atoms and fluoroalkyl groups to organic molecules are described. Particular attention is given to reactivity and applications of CF2CF2-containing compounds, indicating challenges in synthetic approaches toward tetrafluoroalkylation. The Results and discussion part describes reactivities of four new fluorinated organosulfur reagents as tetrafluoroethyl and tetrafluoroethylene building blocks. The application of these reagents as various carbanionic or radical synthons proved to be effective for the incorporation of CF2CF2...