Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules. This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon. In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant. The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction. Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted. In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors. Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme. / The time 12:05 for the public defense mentioned in the thesis is incorrect. It will take place at 09:15, 2012-06-08.

Nous avions pour objectif de mettre au point une voie permettant la synthèse de diaryléthers par catalyse au cuivre en utilisant des ligands immobilisés sur des matériaux silylés organiques-inorganiques élaborés par voie sol-gel. L'intérêt de ces systèmes hétérogènes réside dans le fait qu'ils sont recyclables et réutilisables, moins polluants et moins toxiques grâce à leur grande capacité de piégeage du catalyseur métallique. Ce point est particulièrement important pour une utilisation des diaryléthers obtenus en industrie pharmaceutique. Nous sommes parvenus à synthétiser par voie sol-gel des matériaux incorporant des ligands de type bipyridine ou β-dicarbonyle. Ces matériaux ont été ensuite appliqués en arylation des phénols par des iodures et bromures d'aryles catalysée au cuivre. Les nouveaux catalyseurs hétérogènes ont permis d'obtenir de bonnes performances en arylation de nucléophiles oxygénés et aussi en termes de récupération et de réutilisation. Par ailleurs, les produits diaryléthers obtenus ne sont pas pollués par des traces de cuivre. La méthode que nous avons mise au point s'avère donc particulièrement compétitive en termes de coût, de pollution et de toxicité résiduelle. Elle constitue à notre connaissance le premier exemple de ligand supporté sur silice par voie sol-gel appliqué en arylation de phénols catalysée au cuivre.

Orientador: Eduardo René Pérez Gonzáles / Banca: Alvicler Magalhães / Banca: Wanda Pereira Almeida / O Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, PosMat, tem caráter institucional e integra as atividades de pesquisa em materiais de diversos campi da Unesp / Resumo: Amino ésteres lactâmicos derivados do PABA e que podem ser potencialmente bioativos, por exemplo, como anestésicos locais, foram sintetizados com bons rendimentos por uma reação seletiva de SnAr de ácidos benzóicos com n-(3-aminopropil)-lactamas seguida por esterificação com aminoálcoois terciários. Produtos da N-arilação do N, N-dimetilformamida foram também obtidos através da esterificação direta do ácido 4-cloro-3-nitrobenzóico / Abstract: Lactamic amino esters PABA-related, and can potentially bioactive, for exemple, as local anesthetics were synthesized in good yields by a selective 'S IND. n'Ar reactions of benzoic acids with N-(3-aminopropyl)lactams followed by esteterification with tertiary aminoalcohols. Products of the N-arylation with N,N-dimethylformamide are also obtained through of direct esterification of 4-chloro3-nitrobenzoic acid / Mestre

Abstract Carbon nanotubes are a promising material for various applications due to their unique collection of properties. However, carbon nanotube material as such is inert and insoluble, which hampers the true realization of its potential. In order to enhance the applicability of carbon nanotubes, their surface must be modified. This work concerned the chemical modification of single-walled carbon nanotubes (SWNT) by the Birch reduction, which is based on the reduction of the SWNT surface with the valence electron of alkali metal solvated in liquid ammonia. The reduction generates a SWNT anion, which reacts with electrophiles resulting in the covalent attachment of functional groups to the tube surface. In this work, aryl halides or alcohols were used as electrophiles to yield arylated or hydrogenated SWNTs, respectively. At first, the goal was to modify SWNTs as a filler material for polystyrene. The use of five halogenated ethenylphenyl derivatives as electrophiles revealed that the structure of electrophile affected the success of functionalization and the solubility of SWNTs in polystyrene-toluene solution. The most successful functionalization and solubilization of SWNTs were achieved with 1-chloro-4-ethenylbenzene. In the second part, liquid ammonia was replaced with a new solvent, 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme) in order to avoid the restrictions, hazards and inconvenience of its handling. The work concentrated on the study of alkali metal reduction of SWNTs in diglyme by the use of arylation with 4-iodobenzoic acid or 4-chlorobenzoic acid and hydrogenation as model reactions. Li, Na or K was used as an alkali metal while naphthalene or 1-tert-butyl-4-(4-tert-butylphenyl)benzene was used in order to enhance the solvation of electrons. As a result, functionalization was simplified and enhanced. Electrophile affected the functionalization in such a way that arylation was significantly more successful than hydrogenation. The effect of alkali metal and electron carrier varied with electrophile. The most successful hydrogenation was achieved with the complex of Li and 1-tert-butyl-4-(4-tert-butylphenyl)benzene while arylation was the most successful with the complex of K and naphthalene. The solubility of SWNTs in water, ethanol, methanol and dimethylformamide was clearly improved by arylation whereas hydrogenation led to moderate improvement. / Tiivistelmä Hiilinanoputket ovat ainutlaatuisten ominaisuuksiensa vuoksi lupaava materiaali moniin sovelluksiin, mutta liukenemattomuus ja epäreaktiivisuus haittaavat niiden tehokasta hyödyntämistä. Käytettävyyttä voidaan parantaa kemiallisella modifioinnilla. Tässä työssä yksiseinäisiä hiilinanoputkia modifioitiin Birch-pelkistyksellä, joka perustuu putken pinnan pelkistykseen nestemäiseen ammoniakkiin solvatoituneella alkalimetallin valenssielektronilla. Pelkistyksessä hiilinanoputkesta muodostuu anioni, joka reagoi elektrofiilin kanssa johtaen funktionaalisten ryhmien kovalenttiseen sitoutumiseen putken pintaan. Tässä työssä hiilinanoputkia aryloitiin käyttämällä aryylihalideja elektrofiilinä tai vedytettiin käyttämällä alkoholia. Aluksi tavoitteena oli hiilinanoputkien modifiointi sellaiseen muotoon, että niitä voitaisiin käyttää polystyreenin täyteaineena. Viittä aryylihalidia käyttämällä havaittiin, että elektrofiilin rakenne vaikutti funktionalisoinnin määrään ja putkien liukoisuuteen polystyreeni-tolueeni-liuokseen. 1-Kloori-4-etenyylibentseenillä saavutettiin onnistunein arylointi ja paras liukoisuus. Työn toisessa osassa luovuttiin ammoniakin käytöstä siihen liittyvien rajoitteiden ja haittojen vuoksi. Keskityttiin hiilinanoputkien alkalimetallipelkistyksen tutkimiseen uudessa liuottimessa, 1-metoksi-2-(2-metoksietoksi)etaanissa (diglyymi). Mallireaktioina käytettiin arylointia 4-jodibentsoehapolla tai 4-klooribentsoehapolla ja vedytystä alkoholilla. Ammoniakin korvaaminen diglyymillä yksinkertaisti ja tehosti funktionalisointia. Reaktiot suoritettiin eri alkalimetalleilla (Li, Na tai K). Naftaleenia tai 1-tert-butyyli-4-(4-tert-butyylifenyyli)bentseeniä käytettiin elektronien solvatoinnin parantamiseksi. Elektrofiilin rakenne vaikutti funktionalisointiin siten, että aryylihalidi johti huomattavasti onnistuneempaan funktionalisointiin kuin alkoholi. Alkalimetallin ja elektroninkantajamolekyylin vaikutus vaihteli elektrofiilin mukaan. Litiumin käyttö 1-tert-butyyli-4-(4-tert-butyylifenyyli)bentseenin kanssa johti onnistuneimpaan vedytykseen. Kaliumin käyttö naftaleenin kanssa johti onnistuneimpaan arylointiin. Hiilinanoputkien liukoisuus vaihteli elektrofiilin mukaan. Arylointi paransi selkeästi hiilinanoputkien liukoisuutta veteen, etanoliin, metanoliin ja dimetyyliformamidiin. Vedytyksen vaikutus liukoisuuteen oli vähäisempi.

Les recherches sur le photovoltaïque organique depuis une dizaine d’année ont permis une constante progression de l’efficacité des cellules solaires. Plusieurs groupes de recherche ont amorcé une réflexion sur les procédés de synthèse qui permettraient de limiter les déchets. Ainsi le couplage par arylation directe qui évite l’utilisation de dérivés organométalliques a émergé comme alternative au couplage organométallique classique. Une première partie est consacrée à l’étude méthodologique du couplage par arylation directe de la triphénylamine avec des dérivés du thiophène-2- carboxaldéhyde substitués en C3 et C4 par des groupements électro-accepteurs et électro-donneurs. Ce motif de base permet l’accès à trois séries de petites molécules par simple condensation. Des cellules photovoltaïques atteignant des rendements de photo-conversion de 3% en cellules bicouches, ont été obtenues. Dans une deuxième partie, la polymérisation par arylation directe sur des monomères du thiophène substitué par des groupements nitriles comme accepteur et des groupements alcoxy ou thioalkyl comme donneur conduit en une seule étape à une nouvelle famille de polymères conjugués. Ces polymères ont été utilisés comme matériaux donneurs et accepteur dans des cellules. Enfin en dernière partie, un travail exploratoire sur les propriétés d’émission de dérivés du benzofurane a été entrepris. Des réactions de condensation de Knoevenagel ont été développées pour obtenir toute une série de dérivés contenant l’unité cyano-vinylbenzofurane. La plupart des composés présente une forte émission à l’état solide. / Research on organic photovoltaics over a decade allowed a steadily increasing in the efficiency of solar cells. Several research groups have begun a reflection on the synthesis processes to limit wastes. Thus the direct arylation coupling which avoids the use of organometallic compounds, has emerged as an example of green reaction. The first part is devoted to the methodological study of direct arylation of bromotriphenylamine with thiophene-2-carboxaldehyde derivatives substituted in C3 and C4 by electron-withdrawing groups and electron-donor groups. This basic pattern allows access to three small molecules by condensation. Photovoltaic cells reaching photoconversion efficiencies of 3% were obtained. In the second part, the polymerization by direct arylation of sustituted thiophene monomers by nitrile groups as the acceptor and by alkoxy or thioalkyl as the donor led in one step to a novel family of conjugated polymers having donor and acceptor groups alternately. Solar cells were made with the polymers as donors or as acceptors materials. Finally, in the last part, exploratory work on the emission properties of benzofuran derivatives have been made. Knoevenagel condensations have been developed for a range of compounds containing the cyano-vinylbenzofuran unit. Most compounds have high emission in the solid state.

No description available.

Les ions phosphiraniums sont connus depuis plus d’une cinquantaine d’année mais leur ouverture C-centrée n’a jamais été décrite. Une telle réactivité permettrait d’obtenir des phosphines β fonctionnalisées de façon innovante ouvrant ainsi la voie à de nouvelles perspectives synthétiques. De nouveaux phosphiranes ainsi que les ions phosphiraniums correspondant ont été synthétisés au travers de réactions innovantes d’alkylations et d’arylations. Ces composés ont par la suite pus être ouverts sélectivement sur le carbone du cycle pour la première fois, ce par l’intermédiaires de différents nucléophiles azotés. La méthodologie proposée au cours de ce projet de thèse a permis l’obtention de composés de type β-aminophosphines innovants tant par la structure que par la voie d’accès. De nombreux paramètres ont pu être étudiés pendant cette étude afin de mieux appréhender les différentes interactions et facteurs régissant cette réactivité singulière. / Phosphiraniums ions are known for more than fifty years. However, heir C-centered ring opening has never been reported. This novel reactivity would grant access to β-functionalized phosphines in an innovative manner, opening the way to new synthetic perspectives. Novel phosphiranes as well as their corresponding phosphiraniums have been synthesized through alkylation and arylation reactions. Then, these compounds were reacted with different nitrogen compounds allowing their ring opening in a C-centered fashion for the very first time. New β-aminophosphines could be accessed this way in regards for their innovative structure and synthetic pathway. Various parameters have been studied to increase our understanding on these specific yet promising reactions.In this line, along this PhD project, interactions and factors which might rule this particular reactivity were screemed.

[pt] O advento da catálise fotorredox permitiu o desenvolvimento de uma série de novas reações de formação de ligação C-C utilizando luz visível e catalisadores para gerar radicais orgânicos. Isso permite que metodologias sejam desenvolvidas à temperatura ambiente e com curtos períodos de tempo. Reações de arilação, que envolvem a inserção de grupos aril, podem ser realizadas utilizando sais de diazônio como fontes de radicais arila. O objetivo dessa tese foi estudar reações de alfa-arilação de compostos carbonílicos usando catálise fotorredox. A tese é dividida em quatro capítulos, sendo o primeiro, a Introdução Geral. No segundo, foi desenvolvida uma metodologia de arilação de cumarinas, baseada na Arilação de König, para obtenção de compostos do tipo 4-(N-fenil)amino-3-fenilcumarina. Esses compostos foram obtidos em rendimentos de até 95 por cento. O mecanismo da reação foi estudado a partir de experimentos de trapeamento com TEMPO e correlação de Stern-Volmer. As cumarinas obtidas tiveram suas atividades biológicas avaliadas, e três delas mostraram-se promissoras como fármacos contra leishmaniose. Por fim, uma das cumarinas foi utilizada para a síntese do azacumestano, análogo nitrogenado do produto natural cumestano. No terceiro capítulo da tese, um estudo teórico via Teoria do Funcional da Densidade (DFT) foi realizado para estudar a alfa-arilação de enóis acetatos para obtenção de aril-cetonas. Estudos previamente realizados mostraram que essas reações têm melhor performance quando grupos retiradores de elétrons estão presentes nos sais de diazônio. O uso do modelo de Fischer-Radom permitiu verificar que efeitos polares são mais proeminentes do que efeitos entálpicos. A origem desses efeitos foi verificada como partindo de efeitos de campo e não de efeito de ressonância, uma vez que o orbital SOMO em radicais fenila é ortogonal ao sistema Pi. Finalmente, o efeito de substituintes nos enóis acetatos foi estudado a partir das correlações de Taft e Charton. Finalmente, no quarto capítulo foram abordadas as tentativas de alfa-arilação de cetonas cíclicas combinando-se catálise fotoredox com organocatálise, trabalho esse desenvolvido durante período sanduíche na Universidade de Michigan. Diversas metodologias foram testadas, entretanto nenhuma permitiu a formação do produto desejado. Estudos via DFT mostraram que a combinação da nucleofilicidade das cetonas e efeitos estéricos impediram que essa reação pudesse ser realizada. Sendo assim, uma nova metodologia foi testada a partir do uso de isonitrilas de haletos de alquila. Após extensa otimização, foi possível obter uma metodologia de tosilação catalisada por níquel. / [en] The advent of photoredox catalysis allowed the development of a series of new C-C bond formation reactions using visible light and photocatalysts to generate organic radicals. It allows methodologies to be developed at room temperature and within short periods of time. Arylation reactions, which involve the insertion of aryl groups, can be performed using diazonium salts as source of aryl radicals. The aim of this dissertation was to study alfa-arylation reactions of carbonyl compounds using photoredox catalysis. This dissertation is divided into four chapters, being the General Introduction the first one. In the second chapter, a coumarin arylation methodology was developed, based on Konig s Arylation, to obtain 4-(N-phenyl)amino-3-phenylcoumarins. These compounds were obtained in up to 95 percent yield. The reaction mechanism was studied from trapping experiments with TEMPO and Stern-Volmer correlation. The obtained coumarins had their biological activities evaluated, and three of them showed promising results as antileishmaniasis candidates. Finally, one of the coumarins was used for the synthesis of azacoumestan, a nitrogenous analog of the natural product coumestan. In the third chapter of the thesis, a theoretical study via Density Functional Theory (DFT) was carried out to study the alfa-arylation of enols acetates to obtain aryl ketones. Previous studies have shown that these reactions perform better when electron withdrawing groups are present in diazonium salts. The use of the Fischer-Radom model allowed us to verify that polar effects are more prominent than enthalpic effects. The origin of these effects was verified as field effects and not resonance effect, since the SOMO orbital in phenyl radicals is orthogonal to the Pi system. Finally, the effect of substituents on enol acetates was studied by Taft and Charton correlations. In the fourth and last chapter, attempts were made to alfa-arylate cyclic ketones combining photoredox catalysis with organocatalysis, work developed during the internship period at the University of Michigan. Several methodologies were tried, however none allowed the formation of the desired product. Studies via DFT showed that the combination of ketone nucleophilicity and steric effects prevented this reaction from being carried out. Therefore, a new methodology was tested using isonitriles of alkyl halides. After extensive optimization, it was possible to obtain a nickel-catalyzed tosylation methodology.

A brief summary of the use of palladium as a catalyst, the characteristic reactivity of palladium complexes and the commonly used palladium-catalysed cross coupling reactions is given, with a special focus on the palladium-catalysed α-arylation of enolates and its application to the synthesis of aromatic heterocycles. The synthesis of aromatic heterocycles via both traditional methods and more recent metal-catalysed approaches is discussed in the context of isoquinolines. The palladium-catalysed oxidation of dihydrofurans bearing an ortho-bromophenyl group at the 2-position to the corresponding 2-phenyl furans is disclosed along with some preliminary mechanistic investigations. A novel synthetic route to isoquinolines is detailed involving the palladium-catalysed α-arylation of ketone enolates with an appropriate ortho-substituted aryl halide to furnish a protected 1,5-dicarbonyl intermediate. The versatility of these intermediates is demonstrated with their conversion into isoquinolines, isoquinoline N-oxides and naphthols. The scope of the synthetic procedure is fully exemplified across more than 30 different scaffolds covering the full spectrum of electron-rich to electron-deficient moieties. The intermediates were shown to be amenable to functionalisation with electrophiles, leading to isoquinolines bearing additional substitution at the C4 position. Sequential one-pot procedures were developed allowing three and four component couplings to directly deliver highly-substituted isoquinolines from commercially available starting materials. This methodology was utilised in the total synthesis of the natural product berberine in 26% overall yield and a longest linear sequence of six steps.

<strong>Chapter 1. Introduction</strong> Scientific background on the development of homogeneous palladium-catalysed cross coupling reactions, focusing on the &alpha;-arylation reaction of enolates and its application to the synthesis of heteroaromatic compounds. The classical syntheses of isoquinolines are discussed, followed by an account of modern methods for their synthesis, including the recent &alpha;-arylation-based methodology developed by the Donohoe group. <strong>Chapter 2. Results and Discussion</strong> 2.1 Studies towards the development of a palladium-catalysed, C–H activation-based &alpha; arylation reaction of ketones, resulting in a C–H bromination/&alpha;-arylation sequence for the synthesis of isoquinolines and isoquinoline N-oxides. 2.2 The one-pot, four component coupling of a ketone, an acetal protected ortho-bromobenzaldehyde or ketone, an electrophile, and an ammonia source is described. This protocol, which ultimately provides C4 functionalised isoquinolines, is later extended to a novel &alpha;,&alpha; heterodiarylation protocol to furnish C4-aryl isoquinolines. 2.3 It is shown that the synthesis of 3 aminoisoquinolines can be achieved via the &alpha; arylation of nitriles. tert-Butyl cyanoacetate can act as a substitute for primary alkyl nitriles, with sequential &alpha;-arylation, in situ functionalisation, decarboxylation and cyclisation reactions provide C4 functionalised 3 aminoisoquinolines. 2.4 The synthetic utility of the &alpha; arylation based methodology for isoquinoline synthesis is exemplified by the total synthesis of the alkaloid berberine in 68% yield over five steps. This is followed by syntheses of pseudocoptisine, palmatine, dehydrocorydaline, and an unnatural fluorine containing analogue, in yields of 46%, 73%, 60% and 37%, respectively. 2.5 Finally, preliminary investigations demonstrate the utility of palladium-catalysed enolate arylation in the synthesis of &beta;-carbolines.