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No. of bitstreams: 1 TeseKSF.pdf: 23261470 bytes, checksum: 5b1d96df4f120f2aa4446a1eda8ba6c0 (MD5) Previous issue date: 2016-04-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / This thesis consists in a collection of projects wherein the focus is the application of organocatalysts to accelerate the reactions, its primary function, as to induce asymmetry to the synthetic targets, within a perspective of sustainable chemistry. Thus, this thesis was arranged in four sections, the first two being about conjugate additions reactions; the third one related to 1,6-Friedel-Crafts/ 1,4-oxa-Michael cascade, and finally the fourth related to a formal [3 + 3] cycloaddition reaction. The first chapter describes the application of ionic liquids as basic catalysts in the conjugate addition of diketones to nitroolefins irradiated by ultrasound. Thus, the Michael adducts, which are important synthetic building blocks were synthesized efficiently under solvent free conditions. In the second chapter is presented the formal synthesis of Pregabalin Phenibut and Bacoflen. The synthetic intermediate of theses are obtained via a conjugate addition of aldehydes to nitroolefins, using an organocatalyst developed by our group in PEG-400, as recyclable solvent. In this regard, a collection of Michael adducts was synthesized within the principles of green chemistry in good yields and selectivities. The third section describes the first organocatalytic asymmetric cascate 1,6- Friedel-Crafts / 1,4- Oxa-Michael of hydroxyarenes to 2,4-dienal for the construction of chiral chromans, which are important bioactive compounds. A collection of chiral chromans was synthesized with high yields and selectivities (94-99% ee). Furthermore, several manipulations were made including the formation of a macrocyclic lactam. Finally, the fourth section dedicated to the formal [3 + 3] cycloaddition of azomethine imine with methyl isocyanoacetates leading to 1,2,4 triazines derivatives, which are relevant biological activity heterocyclic. We used either organocatalytic approach as cooperative catalysis (organocatalysis and metal catalysis). This work is still in the primary stages, however the product has been obtained with up to (42% ee, 69% yield), as just one diastereomer. / Essa tese consiste em uma coleção de projetos cujo foco central foi a aplicação de organocatalisadores tanto para acelerar as reações, sua função primária, quanto para induzir assimetria aos alvos sintéticos, dentro de uma ótica da química sustentável. Assim, a presente tese foi organizada em quatro capítulos, sendo os dois primeiros envolvendo reações de adições conjugadas, o terceiro referente a uma reação cascata tipo Friedel-Crafts seguida de oxa-Michael e por fim o quarto referente a uma reação de cicloadição formal [3+3]. O primeiro capítulo refere-se a aplicação de uma classe de líquidos iônicos de tarefa específica, como catalisadores básicos em reações de adição conjugada de dicetonas à nitroolefinas irradiadas por ultrassom. Desta forma, em uma condição livre de solventes, foram sintetizados de forma eficiente, uma coleção de adutos de Michael, os quais são importantes blocos de construção sintéticos. No segundo capítulo apresenta-se a síntese formal dos fármacos Pregabalina, Phenibut e Bacofleno. O intermediário sintético dos medicamentos citados são produtos de adição conjugada de aldeídos à nitroolefinas, os quais foram facilmente sintetizados utilizando um organocatalisador desenvolvido pelo próprio grupo em PEG-400, como solvente reciclável. Assim foi sintetizado uma coleção de adutos de Michael em bons rendimentos e seletividades, dentro dos príncipios da química verde. O terceiro capítulo descreve o primeiro exemplo de adição-1,6 tipo Friedel-Crafts seguida de adição- 1,4 Oxa-Michael organocatalítica assimétrica de hidroxiarenos a 2,4-dienais para a construção de cromanos enantioenriquecidos. Foram sintetizados uma coleção de cromanos quirais com altos rendimentos e seletividades (94-99% ee), os quais, posteriormente sofreram uma série de manipulações, incluindo uma macrolactamização.Por fim, o quarto capítulo dedica-se a cicloadição formal [3+3] de azometina imina com isocianoacetato de metila, levando a produtos derivados do 1,2,4 triazenos, heterocíclicos de relevante atividade biológica. Utilizou-se tanto a organocatálise, quanto a catálise cooperativa (organocatálise e catálise metálica) como ferramentas sintéticas. Este trabalho está ainda nas etapas iniciais, sendo os resultados preliminares, entretanto o produto já foi obtido com até (42% de ee e 69%) de rendimento, sendo a síntese diastereoseletiva.

Submitted by Livia Mello (liviacmello@yahoo.com.br) on 2016-10-05T19:33:10Z No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:34Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:39Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Made available in DSpace on 2016-10-20T18:49:47Z (GMT). No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) Previous issue date: 2014-11-28 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / The derivatization of organocatalysts with functional appendages suitable to anchor onto solid supports is usually achieved by stepwise syntheses. As an alternative to such a strategy, this work describes a one-pot approach to silylated prolyl-peptide catalysts by a multicomponent reaction that enables the simultaneous incorporation of the catalytic and the heterogenizable (triethoxysilane) moieties. A microreactor with high catalytic efficacy and reproducibly in the conjugate addition of aldehydes to nitroolefins was obtained by grafting onto HPLC-grade silica (10 μm) and packing into a column with a selected catalyst. A 3 D continuous-flow system that includes the on-line monitoring of the reaction outcome was set up. For that, the microreactor was coupled to a chromatographic column for the separation of the remaining substrates from the Michael adduct in the second dimension, followed by a chiral polysaccharide column for the analysis of conversion and stereoselectivity. This approach represents a new instrumental setup that combines the advantages of multidimensional chromatography and flow catalysis. / A derivação de Organocatalisadores com apêndices funcionais adequados para ancorar em suportes sólidos é geralmente obtida por síntese “passo a passo”. Como uma alternativa para tal estratégia, este trabalho descreve uma abordagem de síntese one-pot de catalisadores prolil-peptio sililados através de uma reação multicomponentes, que permite a incorporação simultânea do sítio catalítico e o grupo funcional de ancoragem (trietoxisilano). Um micro-reactor foi obtido, tendo elevada eficácia catalítica e reprodutibilidade, na adição conjugada de aldeídos a nitro-olefinas, enxertando sobre sílica de grau HPLC (10 um) e preenchendo uma coluna com um catalisador escolhido. Um sistema de fluxo contínuo 3D que inclui a monitoração em linha do resultado da reação foi ajustado para cima. Para isso, o micro-reator foi acoplado a uma coluna cromatográfica para a separação dos substratos restantes do aduto de Michael na segunda dimensão, seguido por uma coluna de polissacarídeo quiral para a análise de conversão e estereosselectividade. Essa abordagem representa uma nova configuração do instrumento que combina as vantagens de cromatografia multidimensional e reações catálisadas em fluxo.

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T16:31:07Z (GMT). No. of bitstreams: 1 Godoi_MarlaNarciso_D.pdf: 10035986 bytes, checksum: 6deb65c44c4239f0ee6985fb972c18b1 (MD5) Previous issue date: 2010 / Resumo: Este trabalho de tese visou desenvolver rotas sintéticas eficientes para síntese de prolinas ariladas utilizando como etapa-chave a reação de arilação de Heck-Matsuda. Além disso, os aminoácidos arilados tiveram seu potencial organocatalítico avaliado frente a reações aldólicas e Mannich multicomponente. No primeiro capítulo serão apresentados resultados referentes à síntese de 5-arilprolinas. A preparação estereosseletiva destes compostos teve como etapa-chave uma das reações de arilação de Heck-Matsuda e envolveu um enecarbamato derivado do ácido piroglutâmico. Após foi realizada a avaliação organocatalítica destes aminoácidos, e constatamos que seu desempenho não superou a L-prolina. Diante disso, partimos para síntese e investigação do desempenho organocatalítico de derivados da prolina arilados em C-4. Iniciamos o segundo capítulo com resultados sobre o desempenho organocatalítico do arilcainóide 61, arilado em C-4. Este aminoácido foi inicialmente testado em uma reação aldólica e apresentou um desempenho catalítico um pouco superior ao da L-prolina. Desta forma, partimos para síntese de 4-arilprolinas, explorando uma segunda reação de arilação de Heck- Matsuda que utiliza L-desidroprolinas como olefinas. Nesta etapa do trabalho, realizamos um estudo metodológico para obtenção de enecarbamatos monoarilados. O uso de microondas na reação de arilação proporcionou uma redução bastante significativa nos tempos reacionais. A partir da eliminação estereosseletiva com hidreto de silano e BF3.Et2O dos intermediários 2- metoxiprolinas 4-arilados foi possível a obtenção de cis-4-arilprolinas em apenas 3 etapas. / Abstract: This work aimed at the development of efficient routes for the synthesis of aryl prolines with the Heck-Matsuda reaction as key step. The potential of these arylated amino acids as organocatalysts was evaluated through aldol and multicomponent Mannich reactions. In the first chapter results will be presented concerning the synthesis of 5-aryl prolines. The stereoselective preparation of these compounds employed the Heck-Matsuda reaction as key step and involved an enecarbamate derived from piroglutamic acid. The organocatalytic behavior of these amino acids was evaluated and one noted that its performance was inferior to that of L-proline. Due to this observation, derivatives of prolines arylated in C-4 were synthesized and tested as organocatalysts. The second chapter begins with studies on the performance of the C-4- arylated aryl kainoid xx as organocatalyst. This amino acid was initially tested in aldol reactions and presented an organocatalytic performance slightly superior to that of L-proline itself. Hence, 4-arylprolines were synthesized, exploring the Heck-Matsuda reaction with L-dehydroprolines as olefins, and their potential as organocatalysts was also investigated. In this moment of the work, a methodologic study concerning the preparation of monoarylated enecarbamates was performed. Employ of microwaves-based heating on the arylation reactions allowed significant reduction of reaction times. From a stereoselective methanol elimination from 4-arylated 2-methoxy-prolines, employing silane hydrides and BF3.Et2O, one could obtain cis-4-aryl-prolines in only three steps. / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Fernando Antonio Santos Coelho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T03:26:42Z (GMT). No. of bitstreams: 1 Gomes_JulianaCristina_D.pdf: 10331708 bytes, checksum: ab47fef95625c8a9b0232f0e3db6d428 (MD5) Previous issue date: 2014 / Resumo: A reação de Morita-Baylis-Hillman (MBH) é um método atrativo para a formação de ligação carbono-carbono. Esta transformação tem atraído a atenção devido ao fato dela ser seletiva (quimio-, régio-, diastereo-, e enantio-) e ser também um método com alta economia de átomos, convertendo substratos simples em produtos poli-funcionalizados de grande versatilidade sintética. Entretanto, apesar de suas inúmeras vantagens, essa reação possui vários inconvenientes tais como baixas velocidades, rendimentos moderados, alta concentração de catalisador nucleofílico e o uso de solventes orgânicos, o que dificulta a sua utilização industrial. Dessa maneira, fica claro a necessidade da busca de novos catalisadores e metodologias eficientes, tanto em termos de rendimentos, velocidades reacionais, quanto em termos de versatilidade, para que se possa ser aplicada a uma ampla variedade de substratos. Neste trabalho foi demonstrado o uso de um novo catalisador, um álcool derivado imidazólico bicíclico, para reações de MBH com enonas cíclicas. Esse novo catalisador funcionou eficientemente em um protocolo ecologicamente amigável, no qual as reações de MBH procederam em meio aquoso e com uma quantidade catalítica de dodecil sulfato de sódio (SDS), sem a necessidade de co-solventes orgânicos. Além disso, foi demonstrado que esse álcool imidazólico bicíclico é o único catalisador para reações de MBH aquosas entre isatinas não protegidas e enonas cíclicas, fornecendo núcleos 3-hidroxi-2-oxoindóis substituídos. Esse catalisador também pôde ser resolvido e aplicado na versão assimétrica dessa reação. E outros derivados imidazólicos foram sintetizados e também testados em MBH / Abstract: The Morita-Baylis-Hillman reaction is an attractive method for the construction of carbon_carbon bonds. This transformation has attracted attention due to the fact that it is selective (chemo, regio-, diastereomeric and enantiomeric) and also a method with high atom economy, converting simple substrates in poly-functionalized products of great synthetic versatility. Despite its interesting benefits, the MBH reaction suffers from several drawbacks, such as low reaction rates, moderate yields, high concentration of the nucleophilic catalyst, poor reactivities of ?-substituted activated olefins and of cyclic enones, and use of hazardous organic solvents, that have hampered its industrial utilization. Thus, it is clear the need to search for new catalysts and efficient methodologies, both in terms of yields, reaction speeds, and in terms of versatility, so that it can be applied to a wide variety of substrates. This work demonstrated the use of a new catalyst, an alcohol bicyclic imidazole derivative, for reactions with cyclic enones MBH. Thus, it is clear the necessity of finding new catalysts and efficient methodologies, both in terms of yields, reaction speeds, and in terms of versatility, so that it can be applied to a wide variety of substrates. This work demonstrated the use of a new catalyst, an alcohol bicyclic imidazole derivative, for reactions with cyclic enones MBH. This new catalyst worked effectively in ecofriendly conditions, where the MBH reactions proceeded in an aqueous medium with a catalytic amount of sodium dodecyl sulfate (SDS), without organic co-solvents. Furthermore, it was shown the imidazole bicyclic alcohol is the only catalyst for MBH aqueous reactions between isatins unprotected and cyclic enones, providing cores 3-hydroxy-2-substituted oxoindóis. This catalyst could also be resolved and applied to the asymmetric version of this reaction. And other imidazole derivatives were synthesized and also tested in MBH / Doutorado / Quimica Organica / Doutora em Ciências

Orientador: : Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-24T05:38:03Z (GMT). No. of bitstreams: 1 Martinez_PabloDavidGrigol_D.pdf: 10635816 bytes, checksum: b6d50b746463694bb1ef50352d36d1e3 (MD5) Previous issue date: 2013 / Resumo: O emprego de enecarbamatos endocíclicos como substratos na organocatálise foi avaliado na primeira parte deste trabalho. Explorou-se a ação catalítica de ácidos fosfóricos na reação de Friedel-Crafts envolvendo enecarbamatos di e trissubstiuídos como eletrófilos. Foram empregados indóis, furanos, naftol e sesamol como nucleófílos neste tipo de reação. Foi possível desenvolver um protocolo operacional simples e em condições brandas capaz de fornecer bons rendimentos. A diastereosseletividade observada com enecarbamatos trissubstituídos favoreceu o produto trans numa faixa de 2,7:1 até 95:5. Usando ácidos fosfóricos quirais, a enantiosseletividade também foi verificada, atingindo-se excesso enantiomérico de 20% até o momento, fato que demonstra a potencialidade da metodologia. Posteriormente, realizou-se um estudo sobre a preparação de aminoálcoois a pela hidrogenólise de 2-aril-3-epoxipirrolidinas. Esses substratos foram obtidos pela arilação de Heck-Matsuda em enecarbamatos derivados do ácido L-piroglutâmico como etapa chave. Observou-se que a estereoquímica dos substituintes da pirrolidina apresentou decisiva influência para as condições reacionais e rendimento da hidrogenólise, permitindo em alguns casos a clivagem de até duas ligações numa única reação. Os aminoálcoois obtidos a partir desta metodologia foram utilizados na síntese concisa da 2-epi-bulgecinina bem como de bases esfingóides exemplificada na síntese de análogo da esfingosina / Abstract: In the first part of this work, the use of endocyclic enecarbamates as substrates in organocatalysis was evaluated. The effect of phosphoric acids as catalysts in promoting Friedel-Crafts reactions involving di and trisubstituted enecarbamates as electrophiles was explored. Different arenes were employed as nucleophiles like indols, furans, naftol and sesamol. It was possible to develop a simple protocol with mild conditions and good yields. The diastereoselectivity observed with trisubstituted enecarbamates favored the trans product in a range of 2.7:1 to 95:5. By using chiral phosphoric acids, the enantioselectivity achieved, so far, was 20% ee, evidencing the potentiality of this methodology. Later, hydrogenolysis reactions over 2-aryl-3-epoxypyrrolidines were performed to prepare aminoalcohols. The key step to synthesize the former pyrrolidines was the Heck-Matsuda reaction of enecarbamates obtained from L-pyroglutamic acid. The stereochemistry of the substituents in the hydrogenolytic step did influence the experimental conditions and yields, allowing in some cases two bonds cleavage in one pot. The aminoalcohols prepared in this methodology were used in a short synthesis of 2-epibulgecinine and in preparation of sphingoid bases exemplified in the synthesis of sphingosine analogue / Doutorado / Quimica Organica / Doutor em Ciências

Abstract The synthesis of α-hydroxy aldehydes and hydroxymethyl ketones as well as their interconversion to each other are discussed in this thesis. The literature survey of the monograph reviews the synthetic methods for the preparation of 1,2-bifunctionalized hydroxy aldehydes and ketones. The keto-aldehyde isomerisation reaction catalyzed by Triosephosphate isomerase enzyme (TIM) and organic compounds that interact with the TIM are also introduced. In addition, the microwave heating techniques in organic syntheses are reviewed. The practical work consists of two entities: The synthesis of new substrate candidates and transition state analogues for a mutated monomeric TIM. These compounds are model compounds for the catalytic activity and the structural studies of the mutated monomeric TIM. The synthesis of the sulphonyl α-hydroxy ketone-based substrate candidates consists of four successive syntheses. The microwave-activation was utilized in the preparation of a carbon-sulphur bond and the synthesis of hydroxymethyl ketones. The improved synthesis of the terminal α-hydroxy ketone functionality with microwave activation is presented. The formation of charged compounds was utilized to improve the absorption of microwave energy of reaction mixtures. The design and the synthetic work were carried out in accordance to principles of green chemistry. The second part of the practical work is the development of an organocatalytic α-oxybenzoylation reaction of aldehydes with high enantiomeric selectivity. This novel method generated enantiomerically pure α-hydroxy aldehydes in the stable benzoate-protected form from achiral starting materials under mild conditions at the presence of air and moisture.

Presented diploma thesis follows the long-term study running at the Department of Organic Chemistry at the University of Chemistry and Technology Prague in the field of using flavinium salts as catalysts of oxidation reactions. The aim was to verify the reactivity of flavinium salt 13 with different types of O- and N-nucleophiles by monitoring of the corresponding C4a-adducts formation. In the thesis a simple alloxazinium salt 13 and one of the nucleophiles (hydroxylamine 25) were prepared. According to the results obtained from the UV-VIS measurements nucleophile 25 is the only one of the newly tested wchich formed desired C4a-adduct 13d with alloxazinium salt 13. KEYWORDS flavinium salt, nucleophile, C4a-adduct, organocatalysis, IBSE

This diploma thesis deals with the stereoselective addition reaction of benzothiophenone derivatives to ketimines derived from isatin using bifunctional organocatalysis. The stereoselective addition reaction was optimized to provide the appropriate reaction conditions which were subsequently used to study the scope of the reaction. Keywords Organocatalysis, stereoselective synthesis, bifunctional organocatalysts, ketimines, sulphur heterocykles.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.