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Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metallation-deprotonation (CMD) pathway. Competition experiments were conducted using N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)2 plays a pivotal role in the reaction mechanism as more than merely a pre-catalyst, but as a source of acetate base required for the C-H bond cleavage step.

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metallation-deprotonation (CMD) pathway. Competition experiments were conducted using N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)2 plays a pivotal role in the reaction mechanism as more than merely a pre-catalyst, but as a source of acetate base required for the C-H bond cleavage step.

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metallation-deprotonation (CMD) pathway. Competition experiments were conducted using N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)2 plays a pivotal role in the reaction mechanism as more than merely a pre-catalyst, but as a source of acetate base required for the C-H bond cleavage step.

Detailed mechanistic studies on the palladium-catalyzed direct arylation of pyridine N-oxides are presented. The order of each reaction component is determined to provide a general mechanistic picture. The C-H bond cleaving step is examined in further detail through computational studies, and the calculated results are in support of an inner-sphere concerted metallation-deprotonation (CMD) pathway. Competition experiments were conducted using N-oxides of varying electronic characters, and results revealed an enhancement of rate when using a more electron-deficient species which is in support of a CMD transition state. The effect of base on reaction rate was also examined and it was found that a carboxylate base was required for the reaction to proceed. This led to the conclusion that Pd(OAc)2 plays a pivotal role in the reaction mechanism as more than merely a pre-catalyst, but as a source of acetate base required for the C-H bond cleavage step.

As a first step to producing a shape selective catalysts or enzyme mimic, two preorganized host molecules were synthesized. Binding studies of the two hosts with a variety of guests in three solvents demonstrated that an important driving force in the association was the formation of C-H???X-R hydrogen bonds (X = halogen). A deuterated host was utilized to further examine the formation of the C-H???X-R hydrogen bonds. In an effort to place functionality in the hydrophobic pocket of these hosts, two methods were developed. The first utilized directed ortho metallation to place electrophiles above and/or directed into the cavity. Perlithiation of the host could lead to sixty-nine products but reaction conditions and host rigidity limited product formation. This reaction technique led to the placement of carboxylic acid groups onto the host and the isolation of twelve products. Two different positions of the carboxylic acids (endoand exo-) direct the orientation of the guest. 1D- and 2D-NMR were utilized to examine how the was orientated inside the host. The second method employed to place functionality on the host, sited a tripodal zinc binding ligand on the side of the hydrophobic pocket of the host. The synthesized host was able to bind zinc strongly and in a 1:1 manner.

Desde sua descoberta, os reagentes organometálicos tem sido amplamente utilizados em estudos metodológicos para preparação de novas substâncias orgânicas e na síntese de moléculas bioativas. De maneira geral, a escolha pelo uso de determinado reagente organometálico envolve o conhecimento de sua natureza química bem como de sua reatividade. Assim, o objetivo deste trabalho foi investigar a reatividade de novos reagentes mistos de magnésio e de lítio na funcionalização de 2-oxazolinas e dioxinonas, que são importantes intermediários na síntese de substâncias bioativas. No caso das 2-oxazolinas, embora as reações de troca iodo-magnésio nos substratos iodados não tenham levado aos resultados esperados, um estudo complementar, envolvendo a base TMPMgCl.LiCl, levou ao desenvolvimento de uma nova metodologia de funcionalização de halofenil-2-oxazolinas. Neste estudo, após a etapa de metalação, os reagentes organometálicos puderam ser reagidos com diferentes eletrófilos, levando aos produtos em bons rendimentos. Além disso, após uma etapa de transmetalação com cloreto de zinco, os intermediários puderam ser arilados através de reações de acoplamento cruzado. De forma similar, na sequência do trabalho, a funcionalização de uma série de piridino-oxazolinas com TMPMgCl.LiCl foi também avaliada, levando aos produtos desejados com um interessante controle da quimio- e da regiosseletividade. Na etapa final do projeto, foi realizado um estudo sobre a funcionalização de dioxinonas, que são importantes precursores da síntese de produtos naturais. Nestes estudos, a dibase mista de lítio-magnésio TMP2Mg.2LiCl levaram aos produtos ortofuncionalizados com grande seletividade. O sucesso desta metodologia nos motivou a realizar também investigações preliminares sobre a síntese de um análogo da caramboxina, um produto natural de grande interesse farmacológico / Since their discovery, organometallic reagents have been widely used in methodological studies aiming the preparation of new organic compounds and in the synthesis of bioactive molecules. In general, the choice by the use of certain organometallic reagent involves the knowledge of their chemical nature as well as their reactivity. Thus, the objective of this study was to investigate the reactivity of new mixed magnesium-lithium reagents in the functionalization of 2-oxazolines and dioxinones, which are important intermediates in the synthesis of bioactive substances. In the case of the 2-oxazolines, though the iodinemagnesium exchange reactions in iodinated substrates have not led to the expected results, an additional study involving the base TMPMgCl.LiCl led to the development of a new methodology for functionalization halophenyl-2- oxazolines. In this study, after the metalation step, the organometallic reagents could be reacted with various electrophiles, leading to the desired products in good yields. Furthermore, after a transmetalation step with zinc chloride, intermediates could be arylated via cross-coupling reactions. Similarly, the functionalization of a series of pyridine-oxazolines with TMPMgCl.LiCl was evaluated and led to the desired products in an interesting control chemo- and regioselectivity. In the final stage of the project, studies on the functionalization of dioxinones, that are important precursors in the synthesis of natural products, were conducted. In these studies, the mixed lithium-magnesium dibase TMP2MgCl.LiCl was used leading to the orhto-functionalized products with high selectivity. The success of this approach led us to perform preliminary investigations on the synthesis of an analogue of caramboxin, a natural product of great pharmacological interest

A funcionalização regiosseletiva e quimiosseletiva de arenos e heterociclos utilizando reagentes organometálicos têm sido uma ferramenta importante na síntese de novas moléculas bioativas, assim como na química de materiais. Neste contexto, o objetivo deste trabalho foi investigar a reatividade de novos reagentes mistos de magnésio e de lítio na funcionalização de nitrilas aromáticas (dicianobenzeno) e heteroaromáticas (furano, tiofeno, piridina e pirazina), uma vez que o grupo ciano é um importante intermediário sintético e pode ser transformado em diversos grupos funcionais. Para todos os substratos, foram realizados testes metodológicos, a fim de obter a melhor condição reacional de metalação utilizando a base organometálica TMPMgCloLiCl na presença ou ausência de aditivos, como ZnCl2. Após a formação do intermediário magnesiado, diferentes eletrófilos foram testados, levando aos produtos desejados em bons rendimentos. Por outro lado, após reações de transmetalação com cloreto de zinco, os intermediários puderam ser arilados através de reações de acoplamento cruzado de Negishi. Além disso, o estudo de metalação dirigida de nitrilas contendo furano e tiofeno em sua estrutura resultou na síntese de nitrilas heterocíclicas funcionalizadas em bons rendimentos. De forma similar, na sequência do trabalho, as funcionalizações de uma série de piridinas e pirazinas foram avaliadas utilizando a base TMPMgCloLiCl , tanto em condições convencionais, quanto pelo uso de irradiação de micro-ondas na etapa de metalação. Após as reações dos reagentes organomagnésio correspondentes com diversos eletrófilos, foram obtidos pirazinas e piridinas funcionalizadas com interessantes quimio- e regiosseletividades, e em rendimentos moderados. Finalmente, a reatividade de cianobenzenos e dicianobenzenos frente à base TMPMgCloLiCl foi também avaliada, e neste caso os reagentes de lítio se mostraram mais eficientes para funcionalização destes compostos. / The regio- and chemoselective functionalization of arenes and heterocycles using organometallic reagents has been an important synthetic tool in the synthesis of new bioactive molecules, as well as in materials chemistry. In this context, the objective of this study was to investigate the reactivity of new mixed magnesium-lithium reagents in the functionalization of aromatic nitriles (dicyanobenzene) and heteroaromatic (furan, thiophene, pyridine and pyrazine), whereas the cyano group is an important synthetic intermediate and can be transformed into various functional groups. For all substrates, methodological trials were performed in order to stablish the best reaction conditions of metalation using organometallic base TMPMgCloLiCl in the presence or absence of additives such as ZnCl2. After formation of the magnesiated intermediated, reactions were quenched with several electrophiles, leading to the desired products in good yields. Following a transmetalation step with ZnCl2, intermediates could be arylated using Negishi cross-coupling reactions. Moreover, the metalation study using nitrile-substituted furan and thiophene substrates resulted in functionalized heterocyclic nitriles in good yields. Similarly, the functionalization of pyridines and pyrazines with TMPMgCloLiCl were also evaluated using both conventional conditions and under microwave irradiation in the metalation step. After that, the treatment of the corresponding organomagnesium intermediates with various electrophiles provided functionalized pyrazines and pyridines with interesting chemo- and regioselectivity and in moderated yields. Finally, the reactivity of cyano- and dicyanobenzenes against the base TMPMgCloLiCl was also evaluated, however in this case the organolithium reagents appeared to be more efficient for the functionalization of this class of compounds

La détection et l'identification des protéines sur gel d'électrophorèse dépend aussi bien du marqueur des protéines utilisés (généralement un marqueur fluorescent) que de ses propriétés physicochimiques propres (rendement quantique, Stokes' shift et recouvrement des bandes d'absorption et d'émission, photoblanchiment), de sa stabilité (chimique et photochimique), et de son accessibilité. Créer une gamme de nouveaux fluorophores dont les propriétés physicochimiques peuvent être modulées en partant d'une structure bien connue et très avantageux dans l'optique d'anticiper les caractéristiques supposées des composées envisagés. Cependant, même si de nombreux fluorophores sont disponibles commercialement, ils souffrent généralement de différentes contraintes telles que leurs prix prohibitifs, leur manque de sensibilité, leur stockes' shift trop faible ou bien encore leur stabilité. L'accès à une famille de fluorophores résolvant l'ensemble de ces contraintes pour la détection de protéines sur gel d'électrophorèse représenterait donc un réel défi. L'épicocconone, isolée du champignon Epicoccocum Nigrum, se lie de façon covalente aux amines (et donc également aux protéines) en conduisant à un adduit énaminique qui est très fluorescent. Cet adduit émet dans le rouge (610 nm) lorsqu'irradié dans l'UV (395 nm) ou le visible (520 nm). Ces propriétés ont donc conduit à l'utilisation de ce produit naturel comme marqueur fluorescent de protéines sur gel d'électrophorèse menant à une sensibilité de détection rarement atteinte et à une gamme de linéarité très importante (104). La première synthèse de l'épicocconone a alors été engagée au sein de notre laboratoire. Elle a finalement conduit à une chimiothèque d'analogues encore plus efficace ayant permis d'établir une véritable relation structure-fluorescence.

La détection et l’identification des protéines sur gel d’électrophorèse dépend aussi bien du marqueur des protéines utilisés (généralement un marqueur fluorescent) que de ses propriétés physicochimiques propres (rendement quantique, Stokes’ shift et recouvrement des bandes d’absorption et d’émission, photoblanchiment), de sa stabilité (chimique et photochimique), et de son accessibilité. Créer une gamme de nouveaux fluorophores dont les propriétés physicochimiques peuvent être modulées en partant d’une structure bien connue et très avantageux dans l’optique d’anticiper les caractéristiques supposées des composées envisagés. Cependant, même si de nombreux fluorophores sont disponibles commercialement, ils souffrent généralement de différentes contraintes telles que leurs prix prohibitifs, leur manque de sensibilité, leur stockes’ shift trop faible ou bien encore leur stabilité. L’accès à une famille de fluorophores résolvant l’ensemble de ces contraintes pour la détection de protéines sur gel d’électrophorèse représenterait donc un réel défi. L’épicocconone, isolée du champignon Epicoccocum Nigrum, se lie de façon covalente aux amines (et donc également aux protéines) en conduisant à un adduit énaminique qui est très fluorescent. Cet adduit émet dans le rouge (610 nm) lorsqu’irradié dans l’UV (395 nm) ou le visible (520 nm). Ces propriétés ont donc conduit à l’utilisation de ce produit naturel comme marqueur fluorescent de protéines sur gel d’électrophorèse menant à une sensibilité de détection rarement atteinte et à une gamme de linéarité très importante (104). La première synthèse de l’épicocconone a alors été engagée au sein de notre laboratoire. Elle a finalement conduit à une chimiothèque d’analogues encore plus efficace ayant permis d’établir une véritable relation structure-fluorescence. / Detection and identification of proteins either in 2D electrophoresis gels or in biological media depends largely on the quality of protein sensitive dye used (generally a fluorescent dye) as well on the efficiency of their fluorescent properties (quantum yield, Stokes’ shift and overlap of excitation frequency with common laser sources), their stability (chemical and photophysical) and their accessibility. To be able to create a range of new fluorescent dyes whose profiles can be modulated starting from a proven scaffold is advantageous in terms of predicting the properties of the final products. Even if many fluorescent dyes are available on the market, they suffer from a prohibitive price, a lack of sensitivity or a restricted wavelength range (absorption/emission) or limited stability. Access to a family of fluorophores displaying similar physicochemical properties, but shifted excitation and emission wavelengths constitutes an invaluable tool Epicocconone, isolated from the fungus Epicoccum nigrum, covalently binds to primary amines (e.g. lysine of proteins), leading to a protein linked conjugate which is strongly fluorescent, emitting light in the red (610 nm) when submitted to UV-visible light (395 or 520 nm). This is a novel pro-fluorophore that allows protein quantification with unprecedented sensitivity and with an excellent linearity on a broad range of concentrations. A program of synthesis of epicocconone and analogues in order to provide a library of complementary fluorophores has been undertaken. The results concerning either the better efficiency of the analogs and the structure-fluorescence relation are presented in this dissertation.