Les nanorubans de carbone présentent aujourd’hui un grand intérêt en tant que segments de graphène aux propriétés électroniques modulables. Alors que des techniques de synthèse destructives top down donnent des rubans de très grande taille, d’autres techniques constructives bottom up, par synthèse organique, pourraient former des nanorubans bien définis de géométries contrôlées. Dans cette optique, la réaction de Scholl est un outil chimique précieux car elle permet la graphénisation de longs précurseurs flexibles de type polyphénylène.Etonnamment, des structures distordues peuvent être obtenues majoritairement même si des isomères plans moins encombrés sont a priori favorisés. Nous avons ainsi montré que contre toute attente même un encombrement stérique important n’a aucun effet notoire sur la régiosélectivité et que des composés aromatiques polycycliques courbés sont préférentiellement formés. Ainsi, des structures particulièrement tordues, tel que l’hexabenzotriphénylène (HBTP) peuvent être facilement obtenues à partir de précurseurs de type polyphénylène.Après avoir découvert cette régiosélectivité inattendue, nous en avons tiré parti pour former des composés de type polyhélicène. Plusieurs tentatives de formation de l’hexaphénanthrotriphénylène (HPTP) furent infructueuses à cause de problèmes de réactivité lors des synthèses des précurseurs flexibles correspondants. En mettant au point une stratégie de synthèse versatile fondée sur un précurseur commun, plusieurs substrats flexibles de symétrie C3 ont été synthétisés puis soumis à la réaction de Scholl. Des produits de réarrangement ont cependant été obtenus au détriment des [6]hélicènes attendus. Toutefois, un HBTP fonctionnalisé par des groupements TMS a pu être efficacement préparé, ainsi qu’un hexabenzocoronène (HBC) dont l’exceptionnelle solubilité est due à la distorsion du coeur aromatique sous l’effet des groupements encombrants situés dans les régions baie.Ce fragment [5]hélicène favorisé a enfin été incorporé dans la formulation de nanorubans de carbone tordus, alors composés d’une succession de ce motif. En tant que réactions test, les synthèses du monomère et du dimère correspondants ont été effectuées avec d’excellents rendements et les deux composés entièrement caractérisés. Leurs structures ont été déterminée par diffraction de rayons X sur monocristaux et ont fourni d’intéressantes informations complémentaires quant à leurs configurations. Une stratégie plus générale a enfin été développée et optimisée pour la synthèse systématique d’oligomères plus longs de nanorubans de carbone tordus. En utilisant cette technique les trimère et tétramère correspondants ont été synthétisés et caractérisés par spectrométrie de masse. / Carbon nanoribbons are today of great interest as graphene segments with modulable electronic properties. Whilst top down techniques give giant ribbons, bottom-up organic synthesis may lead to exactly designed nanoribbons of controlled geometries. The Scholl reaction is a precious chemical tool for that purpose since it yields efficiently to the graphitization of long and flexible polyphenylene precursors.Surprisingly, twisted structures may be obtained preferentially even if less crowded isomers are also feasible. It has been shown that, against all expectation, even a strong steric hindrance has no marked effect on regioselectivity and highly twisted polycyclic aromatic hydrocarbons are sometimes preferentially formed, whereas their flat and more symmetrical isomers are only obtained in minority. Highly twisted structures such as hexabenzotriphenylene (HBTP) may then be obtained very easily from flexible polyphenylene precursors.After discovering this unexpected regioselectivity, we used it on purpose to form polyhelicenic species. Attempts to prepared hexaphenanthrotriphenylene (HPTP) were unsuccessful due to reactivity issues when synthesizing the corresponding flexible precursors. By using a new versatile strategy leading to an advanced common precursor, several C3-symmetrical flexible substrates have been synthesized and submitted to Scholl reaction. The expected [6]helicenes were not obtained and rearranged products were formed instead, but TMS-bearing HBTP could be prepared, as well as a hexabenzocoronene (HBC) which exceptionnal solubility is due to the distortion of the aromatic core under the effect of bulky tert-butyl substituents in bay regions.The easily formed [5]helicene fragment has been incorporated in the design of twisted carbon nanoribbons that would be composed of a succession of such motifs. As a test reaction, the corresponding monomer and dimer have been synthesized with an excellent yield and fully characterized. Their X-ray structures have even been determined, giving interesting information about their configuration. A more general strategy has then been developed and optimized for the systematic synthesis of longer oligomers of twisted nanoribbons. Using this technique, the trimer and tetramer have been synthesized and characterized by mass spectrometry.

Synthesis and Studies of Dendritic Poly(Ether Imine) Boronates and Cholesteryl-Functionalized Mesogens SYNOPSIS Dendrimers are hyperbranched synthetic macromolecules having branches-upon-branches structures, high molecular weights, globular shapes and monodispersities. Dendrimers possess a large number of modifiable functional groups at their peripheries. Initial efforts were largely concerned with the synthesis, design and development of new dendrimers. Exploring the chemical, biological and material applicability of these macromolecules are relevant to current interests, as a result of the unique structural features of dendrimers. Incorporation of transition metals and organic moieties at the peripheries of the dendrimers was studied to determine their efficacies in catalysis. Evolution of dendritic effects was observed in few instances, that were non-linear in nature. On the other hand, dendritic peripheries were also utilized to study mesogenic properties in liquid crystals. Chapter 1 of the Thesis gives an overview of the types of dendrimers, its structural features and their application in catalysis and as liquid crystalline materials. Chapter 2 describes the synthesis of a new type of poly(ethyl ether imine) dendrimer, having nitrogen as a branching unit, ethylene moiety as the spacer and an oxygen as the connecting linker. Synthesis, characterization, and studies of the photophysical properties of these dendrimers are described in this chapter. The molecular structure of second generation dendrimer is shown in Figure 1. Synthesis of this dendrimer was initiated using 2,2'-oxy-bis(ethan-1¬amine) as the core. The reaction sequence of two alternate nucleophilic substitutions and two alternate reductions, involving ethyl bromoacetate and bromoacetonitrile as monomers was employed in the synthesis of the dendrimer. The formation of dendrimers having ether linkage and tertiary amines as branching unit was established by spectroscopies and mass spectrometry. A number of functional groups, such as, acid, alcohol, amine, ester and nitrile are present at the peripheries of each generation the dendrimers that open up the possibilities for further studies. Carboxylic acid terminated poly(ethyl ether imine) dendrimers are substituted iminodiacetic acids, belonging to the class of polyaminocarboxylic acid. Methyl iminodiacetic acid boronates with NB coordination have emerged as an excellent substitute for unstable boronic acids. Upon increasing the steric bulk on the nitrogen moiety, the hydrolytic stability of the boronates to a base-catalyzed hydrolysis is increased. Combining the structure of carboxylic acid terminated dendrimer and the stability of the dendritic boronates, such dendritic iminodiacetic acids were reacted with arylboronic acids to prepare bis-and tetrakis-boronates (Figure 2). Kinetic hydrolytic studies of boronates were conducted to assess the stabilities of the newly synthesized dendritic boronates. From the studies it was observed that the tetrakis-boronate was ~20 times more stable in comparison with dimeric and monomeric boronates (Figure 3). Subsequent to synthesis and hydrolytic stability studies, C-C bond-forming Suzuki-Miyaura cross-coupling reactions were conducted. A comparison of the reactivities among monomeric, dimeric and tetrameric arylboronates in C-C bond-forming reactions showed a higher reactivity of monomeric and dimeric boronates, than the tetrameric aryl boronate to construct ter-and tetra-aryl in one-pot iterative manner (Figure 4). Chapter 3 of this Thesis describes the synthesis and characterization of dendritic boronates and studies of their hydrolytic stability in Suzuki-Miyaura cross¬coupling reactions to construct ter-and tetraaryls. Figure 4. Synthesis of (a) ter-(6) and (b) tetra-aryls (7) by following one-pot iterative cross-coupling reactions. Step-wise iterative synthesis of dendrimer allows a uniform branching throughout the structure. The first and second generation poly(ether imine) dendrimer series, having hydroxyl groups at their peripheries were chosen for further modification. A versatile mesogenic group, namely, cholesterol was covalently attached at the peripheries of the dendrimers with succinic moiety as linker, so as to install 4 and 8 cholesteryl moieties at the peripheries of the dendrimers (Figure 5), that were characterized by H, C NMR spectroscopies and elemental analysis, so as to confirm their structural homogeneities. Figure 5. Molecular structures of the first and second generation dendritic mesogens. Subsequent to synthesis and characterization, liquid crystalline properties of all the dendritic mesogens was assessed through differential scanning calorimetry (DSC), polarizing optical microscopy (POM) and X-ray diffraction (XRD) studies. In POM study, broken fan or leaf like texture revealed the lamellar arrangement, whereas homeotropic appearance of texture on surfactant (cetyltrimethylammonium bromide) coated substrate indicated the lamellar nature of G1-Et-(OCS)4, G1-Pr-(OCS)4 and G2-Pr-(OCS)8 (Figure 6). From DSC studies, the change in enthalpy was found to increase with increase in generation and change in enthalpy per mesogenic unit was found to be ~ -1 1-2 kJ mol, which indicated the mesophase arrangement to be lamellar. Decrease in the length of spacer dendritic backbone and increase in the generation increased the isotropization temperature of the dendritic liquid crystals. Variable temperature XRD studies were undertaken to characterize the mesophase property. Two sharp peaks in small angle region and a diffused halo in wide angle region in XRD pattern of the material suggested the smectic A (SmA) liquid crystalline arrangement of G1-Et-(OCS)4, G1-Pr-(OCS)4 and G2-Pr-(OCS)8 (Figure 7). Figure 6. POM textures of (a) G1-Et-(OCS)4 at 136 oC; (b) G2-Et-(OCS)8 at 129 oC; (c) G1-Pr-(OCS)4 at 92 oC; (d) G2-Pr-(OCS)8 at 118 oC and (e) transition temperatures for dendromesogens (DSC second heating cycle, heating-cooling rate = 10 oC min-1). Figure 7. Small angle XRD profiles of: (a) G1-Pr-(OCS)4 and (b) G2-Et-(OCS)8 at 60 o C (black), 150 oC (red) and 180 oC (green), (Insets: Lorentzean fit of wide angle peak). The second generation ethyl-linker dendrimer G2-Et-(OCS)8 exhibited a layered structure with a superimposed in-plane modulation (SmÃ), the length of which corresponded to a rectangular column width. Chapter 4 describes the synthesis, characterization and studies of mesophase property and fluorescence property of cholesterol functionalized homologous pairs of the PETIM dendritic liquid crystals. Peripheral functionalization of the dendrimers provides an easy access to dendritic liquid crystalline materials. The covalent functionalization was extended further with the dendrimers for both the series, so as to have 2, 4, 8 and 16 cholesteryl groups at the peripheries of 0, 1, 2 and 3 generation dendrimers, respectively, having succinic amide and phthalic ester functionalities for 1, 2 and 3 generation dendrimers with 4, 8 and 16 cholesteryl groups. Molecular structures of third generation dendrimers are shown in Figure 8. Figure 8. Molecular structures of third generation G3-Pr-(NHCS)16 and G3-Pr-(OCP)16. Subsequent to synthesis and characterization, mesophase property was studied through POM, DSC and XRD techniques. In POM study, a birefringent texture was observed in heating and cooling cycles. Leaflet, broken fan or bâtonnet like texture suggested the layered arrangement of the molecules (Figure 9). In DSC studiues, it was observed that the amide-linked dendrimers showed higher glass transition and isotropization temperatures than that of ester-linked dendrimers within the same generation irrespective of the back-bone of the dendrimer. Succinic moiety linked dendrimers showed lower glass transition temperature than that of phthalic moiety linked dendrimers and consequently, larger mesophase range. The change in enthalpy for isotropization was found to increase with increase in generation, whereas change in -1 enthalpy per mesogenic unit was 1-2 kJ mol, indicative of a layered arrangement in the mesophase. Figure 9. POM textures (20x) of (a) G3-Pr-(NHCS)16 at 90 oC; (b) G3-Pr-(OCS)16 at 90 ooo C; (c) PG1-(NHCS)4 at 134 C; (d) G3-Pr-(OCP)16 at 98 C and (e) transition temperatures for dendromesogens (second cycle, heating-cooling rate = 10 oC min-1). Appearance of two sharp peaks in small angle region and a wide halo in wide angle region in XRD pattern supported lamellar mesophase property of the material (Figure 10). On decreasing the temperature, increase in the layer thickness also suggested the smectic A arrangement of the molecules except third generation phthalate derivative G3-Pr-(OCP)16, which showed rectangular columnar mesophase. For all the dendromesogens, the layer thickness increased with the increase in generation. Upon protonation, the first generation dendrimer showed a change in mesophase from simple smectic A to modulated smectic A with decrease in layer thickness. The change in liquid crystal property of the dendromesogens from lamellar to columnar mesophase by changing the linker of the mesogen is unknown so far in the dendrimer liquid crystals. Chapter 5 gives details of synthesis, characterization and mesophase property study of ester-and amide-linked dendritic liquid crystals. Overall, the Thesis establishes a synthetic methodology for the synthesis of a new homologous series of poly(ether imine) dendrimers with ethyl spacer; synthesis of dendritic boronates and their studies in cross-coupling reactions through in-situ slow release of boronic acid; hydrolytic stability study showed higher stability of dendritic boronates which was used in one-pot iterative cross-coupling reactions to construct ter-and tetra-aryls. decrease in linker length in dendrimer backbone modified the thermal, as well as, mesophase behavior of the dendritic liquid crystals; change in the linker functionality from ester to amide changed the thermal behavior of dendritic liquid crystals; a switching of mesophase property from lamellar to columnar was observed by changing the rigidity of the linker from succinate to phthalate without changing the linker length. The results of the above chapters are in different stages of publications: 1 Dendritic iminodiacetic acids and their boronates in Suzuki-Miyaura cross¬coupling reactions. Sharma, A.; Kumar, P.; Pal, R.; Jayaraman, N. Revised Manuscript submitted. 2 In-plane modulated smectic à vs smectic A lamellar structures in homologous pairs of dendritic liquid crystals. Kumar, P.; Rao, D. S. S.; Prasad, S. K.; Jayaraman, N. Revised Manuscript submitted. 3 Effect of protonation on dendritic liquid crystals of poly(ether imine) dendrimers: structure property relationship studies. Kumar, P.; Rao, D. S. S.; Prasad, S. K.; Jayaraman, N. Manuscript submitted. 4 Smectic to rectangular columnar switch from succinic to phthalic linker alteration in poly(ether imine) dendritic liquid crystals. Kumar, P.; Rao, D. S. S.; Prasad, S. K.; Jayaraman, N. Manuscript in preparation.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-09-12T12:14:46Z No. of bitstreams: 1 arquivototal.pdf: 6051062 bytes, checksum: 9d8a71da8da5797495aee64e3b141b54 (MD5) / Made available in DSpace on 2017-09-12T12:14:46Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 6051062 bytes, checksum: 9d8a71da8da5797495aee64e3b141b54 (MD5) Previous issue date: 2016-10-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Natural compounds, as coumarins and others oxygenated heterocycles, has been shown with a rich source of bioactive substances, however, due to difficulty of getting into large amounts of these substances isolated, many total synthesis or semi-synthesis methods has been developed. Among these many synthetic derivation strategies currently, the metal-catalyzed cross-coupling reactions have been highlighted in the literature, such as: Suzuki-Miyaura, Sonogashira, Heck, Negishi and Buchwald-Hartwig. In the present work, it is aimed the obtaining and preparation of natural heterocycles skeleton, and your derivations via cross-coupling palladium-catalyzed reactions; of which were obtained excellent results for the first three mentioned above, which was not repeated for the last two protocols, from the reactional conditions used. In all synthetics strategies realized, reactional conditions were diversify, such as temperature, reactional time, energy source, base, catalysts, among others; with the in order to observe the effects these changes and obtain the best sets of conditions. Besides the palladium-catalyzed reactions, some of cumarinic alkynes obtained by Sonogashira were submitted to the catalytic hydrogenation, to provide new alkanes with different spacers between the coumarinic ring and their phenyl groups. In general, the final compounds obtained showed from good to great yield values, reflecting on success in mostprotocols tested, where a total of 48 final molecules were obtained, of which 26 are novel compounds, all being characterized and proven according to their chemical structures. / Compostos naturais, como cumarinas e outros heterociclos oxigenados, tem se mostrado como uma rica fonte de substâncias bioativas, porém, devido à dificuldade da obtenção em grandes quantidades dessas substâncias isoladas, vários métodos de síntese total, ou semi-síntese têm sido desenvolvidos. Dentre as muitas estratégias de derivação sintética utilizadas atualmente, as reações de acoplamento cruzado catalisadas por metais têm tido destaque na literatura, como: Suzuki-Miyaura, Sonogashira, Heck, Negishi e Buchwald- Hartwig. No presente trabalho, objetivou-se a obtenção e preparação de esqueletos de heterociclos naturais, e suas derivações via reações de acoplamento cruzado catalisadas por paládio; das quais foram obtidos excelentes resultados para as três primeiras citadas anteriormente, o que não se repetiu para os dois últimos protocolos, a partir das condições reacionais utilizadas. Em todas as estratégias sintéticas realizadas, condições reacionais foram variadas, como temperatura, tempo recional, fonte de energia, base, catalisadores, entre outros; com o intuito de se observar os efeitos dessas mudanças e obter os melhores conjuntos de condições. Além das reações catalisadas por paládio, alguns dos alcinos cumarínicos obtidos por Sonogashira foram submetidos à hidrogenação catalítica, para fornecer novos alcanos com diferentes espaçadores entre o anel cumarínico e seus grupos fenílicos. De maneira geral, os compostos finais obtidos demonstraram de bons a ótimos valores de rendimento, refletindo no sucesso em boa parte dos protocolos testados, onde um total de 48 moléculas finais foram obtidas, das quais 26 são compostos inéditos, sendo todas caracterizadas e comprovadas de acordo com suas estruturas químicas.

Les triarylbismuths sont des réactifs organométalliques d’un intérêt croissant en synthèse organique, pour leur aptitude à transférer leurs trois groupements aryles dans les réactions de couplage croisé C-C pallado-catalysées. Ces réactifs essentiellement non toxiques et « économiques en atomes » sont attrayants dans le cadre d’une chimie plus respectueuse de l’environnement, et présentent des applications en chimie pharmaceutique et en science des matériaux. Cependant, leur développement est ralenti par le manque de connaissances théoriques à leur sujet. Cette thèse vise alors à comprendre la réactivité de ces espèces en confrontant les données expérimentales avec celles obtenues à travers une étude théorique fondamentale (propriétés structurelles, spectroscopiques, thermodynamiques et cinétiques) résultant de calculs DFT. Le but ultime est de prévoir de nouvelles réactivités et sélectivités. Un premier volet se rapporte à une étude comparative de relation structure-propriétés sur des composés incluant un pnictogène comme atome central, tel que le bismuth, et sur différents organobismuths. Les données expérimentales existantes (cristallographiques, RMN, IR) ont été comparées aux résultats théoriques (structures, énergies, modes de vibration, indices de réactivité, etc.). Une fois les propriétés intrinsèques de ces composés mises en évidence et la méthode DFT validée, une nouvelle étude de relation structure-réactivité a été entreprise. Dans ce deuxième volet, nous avons validé le mécanisme des réactions de couplage croisé impliquant des triarylbismuths catalysées par le palladium. Les trois étapes principales du cycle catalytique ont été examinées, à savoir l'addition oxydante, la transmetallation et l'élimination réductrice, et validées en caractérisant les différents intermédiaires et états de transition. La deuxième étape de transmetallation impliquant les triarylbismuths a également fait l'objet d'une étude approfondie. En particulier, la transférabilité des trois groupements aryles et l'influence des substituants (effets électroniques et stériques) sur les barrières de transfert ont été évaluées. Enfin, la réactivité des triarylbismuths a été comparée avec celle d’autres organométalliques afin de développer de nouvelles voies de synthèse / Triarylbismuths are organometallic reagents of growing interest for organic synthesis, for their ability to transfer the three aryl moieties in C-C Pd-catalysed cross-coupling reactions. These essentially non-toxic, atom efficient reactants are attractive in the context of environment-friendly chemistry and have applications in pharmaceutical chemistry and in material science. However, their development is hampered by lack of theoretical understanding. This thesis aims to explore the reactivity of these species by comparing the experimental data to fundamental theoretical studies (structural, spectroscopic, thermodynamic and kinetic properties) resulting from DFT calculations. The ultimate goal is to predict new reactivities and selectivities. A first approach consists in a comparative study on the relation between structure and properties in compounds having a pnictogen central atom like bismuth, and in different organobismuths. The existing experimental data (crystallographic, NMR, IR) were compared to the results of theoretical calculations (structures, energies, vibrational modes, reactivity parameters, etc.). After highlighting the intrinsic properties of these compounds and validating the DFT method, a new study was undertaken to elucidate the relations between structure and reactivity. This second investigation enabled us to validate the mechanism of the cross-coupling reaction involving triarylbismuths under palladium catalysis. The three major steps of the catalytic cycle have been examined, i.e. the oxidative addition, transmetallation and reductive elimination, and validated by characterizing the different intermediates and transition states. The second transmetalation step involving the triarylbismuths has also been deeply investigated. The transferability of the three aryl groups and the influence of the electronic and steric effects of the substituents on the energy barrier have been evaluated. Finally, the reactivity of triarylbismuths has been compared with that of other organometallics, to develop new synthetic approaches

This thesis is engaged in the synthesis of polysubstituted pyrimidines with anti- inflammatory properties. Such molecules can inhibit production of prostaglandin E2 (PGE2). The aim of this study was to enhance water-solubility and anti-inflammatory efficacy of such derivatives via structural modifications of the lead scaffold. Among applied synthetic tools, the Suzuki-Miyaura cross-coupling was the prevalent reaction, however, many other synthetic procedures (Heck reaction, condensation, borylation, ozonolysis, nucleophilic substitution, etc.) were utilized as well. Overall, 43 final products were prepared. The anti-inflammatory efficacy (inhibition of PGE2 production) was successfully increased as the most potent compound achieved three orders of magnitude higher activity compared to the current lead structure WQE-134. Furthermore, no general influence of the length of the substituent in the C5 position of pyrimidine (C5pyr) on the anti-inflammatory efficacy of synthesized compounds was observed. Significant bioavailability obstacle in future development of the current lead WQE-134 is its poor solubility which was successfully enhanced by introduction of heteroatom bearing moieties to C5pyr. The most water-soluble compound achieved two orders of magnitude higher solubility than WQE-134 while...

Un grand nombre de 3,4-bisindolylmaléimides possède une activité inhibitrice des protéine-kinases. Les 3-isothiazolone-1,(1)-(di)oxydes pouvant être considérées comme des analogues de la maléimide, la fonctionalisation des 5-chloro- et 4,5-dichloro-3-isothiazolone 1,(1)-(di)oxydes par des réactions de couplage palladocatalysé de Suzuki-Miyaura, permet d'accéder aux analogues “thia” des 3,4-bisindolylmaléimides. La synthèse de sulfonamides primaires tels que les dérivés 4-(hétéro)aryl substitués du benzènesulfonamide comme inhibiteurs potentiels de l'anhydrase carbonique, a également été envisagée dans ce travail.Une collection de matériaux hybrides constitués de nanoparticules de palladium adsorbées sur des nanostructures de carbone a été préparée et testée dans des réactions de couplages palladocatalysés, comme catalyseurs en milieu hétérogène. Le plus efficace d'entre eux, associant des nanoparticules de palladium stabilisées par le dodécanethiol et adsorbées sur des nanotubes de carbones “multi-walled”, a été employé afin de préparer vingt-quatre nouveaux dérivés 4-(hétéro)aryl substitués du benzènesulfonamide. L'échec de l'utilisation de ce catalyseur dans les reactions de fonctionalisation des isothiazolone-1,(1)-(di)oxydes nous a contraints à employer un catalyseur plus conventionnel, le PdCl2(dppf)•CH2Cl2.Le dernier volet de ce projet visait à concevoir des catalyseurs à base de nanoparticules de palladium encapsulées dans des nanofibres de carbone “grafitisées” (nanoréacteurs). Une série de nanoréacteurs a pu être préparée et nous avons étudié l'effet du confinement généré à l'intérieur de la nanofibre, sur la réaction palladocatalysée de Suzuki-Miyaura. / 3,4-bisindolylmaleimides possess an inhibitory activity against protein kinase. Because 3-isothiazolone-1,(1)-(di)oxide can be considered as maleimide analog, 5-chloro and 4,5-dichloro-3-isothiazolone-1,(1)-(di)oxide were functionalised using a palladium-catalysed Suzuki-Miyaura cross-coupling reaction achieving the “thia” analogs of 3,4-bisindolylmaleimides. We were also interested in the preparation primary sulfonamides such as 4-(hetero)aryl substituted benzenesulfonamides as carbonic anhydrases inhibitors.A series of hybrid materials comprising palladium nanoparticles adsorbed on carbon nanostructures has been prepared and tested as heterogeneous catalysts of palladium-mediated cross-coupling reactions. The best catalyst, resulting in palladium nanoparticles stabilised by dodecanethiol adsorbed on multi-walled carbon nanotubes, was employed in Suzuki-Miyaura reactions for the preparation of twenty-four new 4-(hetero)aryl substituted benzenesulfonamides. As this catalyst failed in the functionalisation of isothiazolone-1,(1)-(di)oxides, this latter was realised using a more conventional catalyst, PdCl2(dppf)•CH2Cl2.A last part of the project aimed to the conception of catalysts made of palladium nanoparticles encapsulated in graphitised carbon nanofibres (nanoreactors). We prepared a series of nanoreactors and we studied the effect of the confinement inside the nanofibre channel on the Suzuki-Miyaura cross-coupling reaction.

Les couplages croisés sont des réactions très étudiées et ont même fait l’objet d’un prix Nobel. Ces réactions consistent à coupler une espèce organométallique nucléophile avec une espèce électrophile et sont la meilleure façon de former une nouvelle liaison peu ou pas polarisée telle qu’une liaison C–C ou C–S. Cependant, leur mise en place emploie souvent des nucléophiles forts limitant ainsi leur sélectivité et leur tolérance. D’abord, les organosilanes sont des nucléophiles attrayants grâce à leur abondance, leur sélectivité, leur stabilité, leur tolérance aux groupements fonctionnels, leur faible toxicité, leur manipulation facile et leur faible coût. Toutefois, leur faible nucléophilie peut représenter un défi à surmonter lors de leur utilisation. Ensuite, pour une économie d’atome maximale, le dioxyde de carbone (CO₂) représente la meilleure source de carbone et de fonction ester ; et le dioxyde de soufre (SO₂), la meilleure source de soufre et de fonction sulfone. Dans ce manuscrit sont relatées plusieurs nouvelles réactions de couplage des organosilanes pour la synthèse directe d’esters à partir du CO₂ et de sulfones à partir du SO₂. Une étude théorique et expérimentale a été réalisée pour permettre la mise en place de la réaction de couplage du CO₂ avec un arylsilane et un halogénure d’alcane, catalysée par un complexe de cuivre(I). Les caractères plus nucléophile et plus électrophile du SO₂ ont été exploités pour son couplage, sans catalyseur, avec des arylsilanes et des halogénures d’alcanes et pour son couplage, pallado-catalysé, avec des allylsilanes et des halogénures d’aryles, communément appelé le couplage de Hiyama sulfonylant. / Cross coupling reactions are well studied reactions and their development was awarded a Nobel price. These reactions aim at coupling organometallic nucleophiles and electrophiles compounds and are the best way to form a little to none polarized bond such as C–C and C–S bond. They however make use of strong nucleophiles, decreasing their selectivity and tolerance. On one hand, among all available nucleophiles, organosilanes are very attractive because of their abundance, selectivity, stability and tolerance towards functional groups, they are also less toxic, easy to handle, and cheap. Their use though is a challenge because of their lower reactivity. On the other hand, for the sake of increasing the atom economy of a reaction, carbon dioxide (CO₂) is the best source of carbon and ester functional group; and sulfur dioxide (SO₂) is the best source of sulfur and sulfone functional group. In this manuscript, we herein report several coupling reactions between organosilanes giving a direct access to esters from CO₂ and to sulfones from SO₂. Experimental and theoretical studies have been carried out to develop a coupling reaction between arylsilanes, CO₂ and alkyl halides catalyzed by a copper(I) complex. SO₂ being more electrophilic and more nucleophilic, is used in a catalyzed less coupling reaction with arylsilanes and alkyl halides and in a coupling reaction with allylsilanes and aryl halides catalyzed by a palladium(II) complex, known as sulfonylating Hiyama coupling.

A bifunctional imidazolium linker was used for the production of highly crosslinked element organic frameworks by Suzuki-coupling with tetrafunctional boronic acids. The resulting porous materials are good heterogeneous organocatalysts in the N-heterocyclic carbene-catalyzed conjugated umpolung of α,β-unsaturated cinnamaldehyde. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The homoaldol reaction is one of the most powerful methods for the construction of C–C bonds as well as 1,4-oxygenated compounds yet this reaction remains in challenging tasks due to the instability of homoenolates which spontaneously cyclize to the cyclopropanolate. A regioselective catalytic homoaldol equivalent reaction of 3-bromo vinyl acetate with aldehydes under Cr(III)-Mn(0) redox condition was developed. This homoaldol equivalent reaction allows access to the 1,4-oxygenated compounds that are not possible by a conventional aldol process. Mild hydrolysis of the vinyl acetate and reduction of the homoaldol adducts generated diols and lactols in high yield (99%). Further manipulation including stereoselective epoxidation and cyclopropanation was achieved in an efficient manner. Furans, found in many natural products and utilized in drug discovery, have been well studied but current synthetic methods toward furans have some limitations in functional group tolerance, substrate scope, and low product yield in many cases. A highly efficient and catalytic cycloisomerization reaction that transforms acetylenic α,β-epoxides to 2,3,5-tri-substituted furans under InCl3 catalysis was developed. This reaction sequence allows access to rapid construction of highly valuable, tri-substituted furan derivatives. Cross-coupling reactions utilizing transition metals and Lewis acids are important synthetic tools for the formation of C–C and C–N bonds and a number of cross-coupling reactions between α-bromo carbonyl compounds and metal reagents such as aryl metals, alkenyl metals, and alkyl metals have been reported. Transition metal-catalyzed cross-coupling reaction for the construction of α-alkynyl carbonyl compounds has reported in a limited case. The first approach to secondary α-alkynyl carbonyl compounds from secondary α-bromo esters and amides with tributyl(phenylethynyl)stannane under palladium-catalyzed cross-coupling reaction conditions was developed. This synthetic method allows access to secondary α-alkynyl carbonyl compounds which are valuable precursors in pharmaceuticals and agricultural applications.

Le rhinovirus (RV) est connu pour être l'étiologie de plus de la moitié des rhumes bénins. Ces virus ont également été associés à des pathologies respiratoires beaucoup plus graves (asthme, bronchopneumopathie chronique obstructive (BPCO) et mucoviscidose). Le développement d'inhibiteurs de décapsidation du virus, appelés agents « capsid-binders », est ainsi devenu une priorité pour de nombreux laboratoires de recherche. Dans ce contexte, une classe d’inhibiteurs se liant au sein de la poche hydrophobe de la protéine capsidaire VP1 a été développée par notre équipe au travers d’une stratégie radicalaire médiée par le TDAE (Tétrakis(DiméthylAmino)Ethylène). Dans le but de poursuivre les investigations sur le hit LPCRW_0005, un travail de pharmacochimie a été entrepris selon deux approches. Dans un premier temps, une optimisation de la taille du LPCRW_0005 a été envisagée par un allongement du squelette chimique. La conception de ces molécules a été guidée par l’utilisation de modélisation moléculaire via la réalisation de docking rigide ligand/protéine. La synthèse de nombreux composés et leur évaluation in vitro, ont permis de mieux apprécier le potentiel biologique de ce type de dérivés. L’identification de la configuration active du centre stéréogène porté par le linker alcool a été rendue possible par la séparation énantiosélective de certains inhibiteurs suivie d’une caractérisation basée sur un protocole de Mosher. Dans un second temps, une étude comparative des séquences primaires protéiques, nous ont conduits à concevoir de nouveaux composés afin de développer des « capsid-binders » à plus large spectre d'action. / Rhinovirus (RV), virus of Picornaviridae family, is known to be the aetiology of more than half of the common cold. Through advances in molecular biology, the rhinoviruses have been associated with much more serious respiratory pathologies (asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). So, the development of viral attachment and/or uncoating inhibitors named « capsid-binders » molecules has become a priority for many research laboratories. In this context, a class of inhibitors binding into a hydrophobic pocket of the VP1 capsid protein has been identified by our team through a TDAE strategy. In order to follow the investigations on the LPCRW_0005 hit, a pharmacochemistry work was begun according to two approaches. Initially, an optimisation of the LPCRW_0005 size was envisaged by an extension of the scaffold via various pallado-catalyzed cross-coupling reactions. The design of these molecules was guided by the use of molecular modeling via a rigid ligand/protein docking. The synthesis of many compounds and their in vitro biological evaluation on HeLa cells infected with the rhinovirus 14 (RV-B14), refined our knowledge about the biological potential of such a scaffold. The enantioselective separation of some inhibitors followed by a Mosher’s protocol allowed us to identify the active configuration of the alcohol linker. Finally, a comparative study of protein primary sequences as well as drug design, led us to design and develop more potent broad-spectrum capsid-binders.