Les hétérocycles constituent une des classes les plus importantes de composés chimiques. Ces motifs structuraux sont les éléments clés d’une large gamme de produits naturels possédant des activités biologiques ou thérapeutiques. Toutes ces raisons expliquent le vif intérêt suscité par le développement de nouvelles méthodes de synthèse d'hétérocycles au sein de la communauté scientifique. Avec une volonté de réduire toujours plus l'empreinte environnementale de nos recherches, notre laboratoire vise à développer de nouvelles méthodologies de synthèse efficaces plus vertes et respectueuses de l'environnement. Ainsi, mes travaux de thèse ont fait appel à deux thématiques largement étudiées au sein de notre laboratoire que sont la catalyse photorédox et l'organocatalyse. Dans une première partie, l'utilisation de la catalyse photorédox comme outils pour la synthèse et la fonctionnalisation d'hétérocycles sera détaillée. Des motifs hétérocycliques originaux ont ainsi été préparés avec de bons rendements et dans des conditions réactionnelles très douces. La deuxième partie est quant à elle consacrée à la synthèse d'hétérocycles azotés énantioenrichis grâce à des réactions énantiosélectives organocatalysées d'aza-Diels-Alder à demande inverse d'électrons. En effet, la demande toujours plus accrue en composés optiquement actifs par l'industrie chimique et pharmaceutique explique le fort engouement pour le développement de méthodes de synthèse asymétriques. Ainsi, les procédés développés fournissent de nouvelles voies d'accès à des structures hétérocycliques chirales complexes avec d'excellents résultats en termes d'efficacité mais aussi de stéréosélectivité. / Heterocycles are one of the most important classes of chemical compounds. These structural scaffolds are the key elements of a wide range of natural products with biological or therapeutic activities. As a result, a great deal of research carried out in chemistry is devoted to development of new heterocycle synthesis methods. With a desire to further reduce the environmental footprint of our research, our laboratory aims to develop new methodologies for effective synthesis, more green and environmentally friendly. Thus, my thesis works lie on two themes widely studied in our laboratory that are photoredox catalysis and organocatalysis. In the first part, the use of photoredox catalysis as an efficient tool for the synthesis and functionalization of heterocycles is detailed. Original heterocyclic units have thus been prepared in good yields and under mild reaction conditions. The second part is devoted to the synthesis of enantioenriched nitrogen-containing heterocycles through organocatalyzed enantioselective inverse electron-demand aza-Diels-Alder reactions. Indeed, the increasing demand of optically pure compounds by the chemical and pharmaceutical industry explains the strong craze for the development of asymmetric synthesis methods. Thus, the developed processes provide new access routes to complex chiral heterocyclic structures with excellent results in terms of efficiency as well as stereoselectivity.

Visible light photoredox catalysis has proven to be a powerful tool for promoting transformations in organic synthesis. Hence this project was carried out to develop tools for predicting reactivity patterns of visible light- promoted redox reactions. Fluorination is of immense importance in organic chemistry, and so is trifluoromethoxylation. The fluorination reaction has been studied for a long time and has been accomplished in milder ways, while the generation of a trifluoromethoxy-radical at room temperature and atmospheric pressure remains a challenge. The design of the reaction in this project is to overcome the instability and take control of the catalytic event under visible- light photocatalytic conditions. The trifluoromethoxylation reaction proceeded at room temperature with the reaction time of 60 min using acetonitrile as the solvent and blue LED (10 W) as the external light source. No yield of the desired product was obtained for any of the substrates. More surprisingly, in all entries, 3,3-diphenylprop-2-en-1-ol was attained as a side product. The same side product was also detected in the entry with ambient light, concluding that the reaction was completed without any external light source. Thus, no photoredox catalysis took place. / Fotoredoxkatalys via ljus inom det synliga spektrat har visat sig vara ett kraftfullt verktyg för att gynna reaktioner inom organisk syntes. Detta projekt genomfördes med syfte att utveckla verktyg avsedda för att förutspå reaktivitetsmönster vid fotoredoxkatalys med synligt ljus. Fluorinering och trifluorometoxylering är viktiga verktyg inom organisk syntes. Fluorineringsreaktionen har studerats länge och har kunnat genomföras under milda reaktionsbetingelser, medan generering av trifluorometoxyradikal vid rumstemperatur och atomsfärstryck fortfarande är en utmaning. Reaktionen i det här projektet är designad för att kringgå instabilitetsproblemet och ta kontroll över katalysmomentet, under fotokatalysförhållanden i synligt ljus. Reaktionen utfördes i rumstemperatur med en reaktionstid på 60 minuter, med acetonitril som lösningsmedel och blå LED (10 W) som extern ljuskälla. Inget av substraten reagerade till den önskade produkten. Mer överraskande var att 3,3-difenylprop-2-en-1-ol erhölls som sidoprodukt vid alla reaktionsstillfällen. Samma sidoprodukt upptäcktes även vid reaktion genomförd i dagsljus, vilket indikerar att reaktionen skedde utan någon extern ljuskälla. Således skedde ingen fotoredoxkatalys.

No description available.

[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.

Die stöchiometrische Aktivierung von Trifluormethylschwefelpentafluorid mit dem Carben SIMes (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) wird thermisch und photochemisch beschrieben. Beide Formen der Aktivierung führen zur Detektion von 1,3-dimesityl-2,2-difluoroimidazolidin (SIMesF2), 1,3-dimesitylimidazolidin-2-sulfid (SIMes=S) und 1,3-dimesityl-2-fluoro-2-trifluoromethylimidazolidin (SIMes(CF3)F). Die Aktivierung von SF5CF3 wurde mit Radikalabfang-Experimenten untersucht, wobei die Ergebnisse auf die Bildung von CF3-Radikalen in der photochemischen Reaktion, nicht aber in der thermischen Reaktion hindeuten. Mechanistisch wird ein Einelektronentransfer von SIMes auf SF5CF3 postuliert. Weiterhin wurde die Reaktivität von SIMesF2 als Deoxyfluorierungsreagenz für verschiedene organische Substrate beobachtet. Zur mechanistischen Aufklärung der Acylfluorid-Synthese wurde das Imidazolidiniumsalz [SIMes-F]+F(HF)2- synthetisiert. Letzteres reagiert mit Benzoesäure zu Benzoylfluorid. Quantenmechanische Rechnungen bestätigen die These, dass ein externes Polyhydrogenfluorid für die Fluorierung der Benzoesäure verantwortlich ist. Anschließend wurde eine photoredoxkatalytische Trifluormethylierungen von Aromaten entwickelt. Ebenso wie bei der stöchiometrischen SF5CF3 Aktivierung wurde auch im Falle der photoredoxkatalytischen Aktivierung ein Einelektronentransfer auf SF5CF3 durch Oxidation des angeregten Katalysators oder Reduktion des zuvor oxidierten Katalysators vorgeschlagen. Experimentelle Untersuchungen des Mechanismus deuten auf die Entstehung von CF3-Radikalen, SF4 und Schwefel hin. Durch die Zugabe von Octanol zur Reaktionsmischung konnte die Bildung von Fluoroctan neben der Bildung von trifluormethylierten Aromaten erzielt werden. Dies deutet auf die Entstehung von Schwefeltetrafluorid hin und zeigt, dass SF5CF3 gleichzeitig als CF3-Quelle und als Quelle für SF4 dienen kann. / The stoichiometric activation of trifluoromethyl sulfur pentafluoride with the carbene SIMes (1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) is described thermally and photochemically. Both forms of activation lead to the detection of 1,3-dimesityl-2,2-difluoroimidazolidine (SIMesF2), 1,3-dimesitylimidazolidine-2-sulfide (SIMes=S) and 1,3-dimesityl-2-fluoro-2-trifluoromethylimidazolidine (SIMes(CF3)F). The activation of SF5CF3 was investigated by radical scavenging experiments, and the results indicate the formation of CF3 radicals in the photochemical reaction but not in the thermal reaction. Mechanistically, a one-electron transfer from SIMes to SF5CF3 is postulated. Furthermore, the reactivity of SIMesF2 as a deoxyfluorination reagent for several organic substrates was observed. The imidazolidinium salt [SIMes-F]+F(HF)2- was synthesized for the mechanistic investigation of the acyl fluoride synthesis. The latter reacts with benzoic acid to form benzoyl fluoride. Quantum mechanical calculations confirm that an external polyhydrogen fluoride is responsible for the fluorination of benzoic acid. Subsequently, a photoredox catalytic trifluoromethylation of aromatic compounds was developed. As in the case of stoichiometric SF5CF3 activation, a one-electron transfer to SF5CF3 by oxidation of the excited catalyst or reduction of the previously oxidized catalyst was also proposed in the case of photoredox catalytic activation. Experimental studies indicate the formation of CF3 radicals, SF4 and sulfur. The addition of octanol to the reaction mixture results in the formation of fluorooctane in addition to the formation of trifluoromethylated aromatics. This indicates the formation of sulfur tetrafluoride and shows that SF5CF3 can simultaneously serve as a CF3 source and as a source of SF4.

No description available.

Le développement de nouvelles méthodologies de synthèse douces et soucieuses de l'environnement apparait de nos jours comme un véritable besoin. Dans ce contexte, la chimie radicalaire permet de réaliser une grande variété de réactions grâce à des initiations douces (électrochimique ou photochimique). Les indoles tétracycliques et les molécules gem-difluoroacylées étant présent dans de nombreux composé d'intérêt thérapeutique, sont des cibles pertinentes pour le développement de méthodes de synthèse radicalaire. Des indoles tétracycliques 3,4-fusionnés ont été synthétisés par Substitution Radicalaire Nucléophile Unimoléculaire (SRN1). Connue depuis les années 1960, la réaction SRN1 permet de réaliser des réactions de couplages entre un nucléophile et un accepteur d'électrons par un processus radicalaire. D'autre part, des indoles tétracycliques gem-difluoroacylés ont été synthétisés par cyclisation radicalaire tandem, initiée par catalyse électrochimique et photoredox. La catalyse photoredox, similaire à la catalyse électrochimique a connu un essor depuis sa redécouverte à la fin des années 2000. Elle est basée sur l'emploi d'un photocatalyseur qui peut être excité sous irradiation visible pour devenir oxydant ou réducteur / The development of new, soft and ecofriendly synthetic methodologies is today a real need. In this context, radical Chemistry allows to make a wide diversity of reactions thanks to soft initation steps (electrochemical or photochemical). Tetracyclic indoles and gem-difluoroacyles molecules, present in a lot of therapeutic compounds, appeared as relevant targets. 3,4-fused tetracyclic indoles, had been synthesized by Unimolecular Nucleophilic Radical Substitution (SRN1). Since the 1960s, SRN1 reaction allows coupling reactions between a nucleophilic species and a radical acceptor to be performed. On the other hand, gem-difluoroacyles tetracyclic indoles had been synthesized by tandem radical cyclisation initiated by electrochemical and photoredox catalysis. Since its rediscovery by the end of the 2000s, photoredox catalysis, similar to electrocatalysis, had seen an increasing interest. Photoredox catalysis is based on the use of a photocatalyst that become an oxidant or a reductant under visible irradiation

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-04-27T10:56:43Z No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-04-27T11:18:27Z (GMT) No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Made available in DSpace on 2018-04-27T11:18:27Z (GMT). No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) Previous issue date: 2018-02-20 / A obtenção de aminoácidos halogenados é de grande importância para síntese orgânica e para a área biológica, uma vez que estes são valiosos intermediários sintéticos e se apresentam como produtos biologicamente funcionais. Neste contexto, as azalactonas são precursores interessantes, uma vez que podem atuar como aminoácidos protegidos e serem utilizadas na síntese de derivados de aminoácidos e heterociclos complexos. Neste trabalho são descritas a abertura e halogenação das azalactonas de Erlenmeyer-Plöchl sob uma abordagem organocatalítica, utilizando ácido canforsulfônico (ACS) e N-bromosuccinimida (NBS) como agente halogenante. A condição otimizada para obtenção do produto halogenado consistiu na utilização de 30 mol% de ACS, 1.2 equivalente de NBS e 4 mL de metanol, a 65°C por 7 horas, obtendo-se uma imina halogenada com 83% de rendimento. Devido as dificuldades encontradas durante a avaliação do escopo de substratos, investigou-se a redução one-pot da imina halogenada, entretanto não foi possível obter um aumento da razão diastereoisomérica no produto desejado. Diante dos contratempos encontrados na metodologia proposta, investigou-se o uso da catálise foto redox irradiada por luz visível na tentativa de halogenação do heterociclo azalactônico. Entretanto, ao utilizar esta abordagem, observou-se a homodimerização das azalactonas de Erlenmeyer-Plöchl ao invés da halogenação da mesma, levando a um produto de cicloadição [2+2]. Em diclorometano, a utilização do fotocatalisador de rutênio favoreceu a formação de um sistema tricíclico do tipo espiro. Já em meio metanólico, o fotocatalisador metálico favoreceu a formação do produto de abertura dos dois anéis azalactônicos com 59% de rendimento, enquanto que o uso do corante orgânico Eosina Y levou à formação de um cicloaduto assimétrico, com a abertura de apenas um dos anéis azalactônicos (40% de rendimento). Avaliou-se o escopo de substratos utilizando Eosina Y como fotocatalisador e os rendimentos obtidos foram de moderados a bons (12 a 78%). Todos os produtos foram caracterizados por RMN de 1H, 13C, e IV. / Halogenated amino acids are of great importance for both organic synthesis and biological areas, once these are valuable synthetic intermediates and presented as biologically functional products. In this context, azlactones are interesting precursors that can act as protected amino acids and have been used in the synthesis of amino acid derivatives and complex heterocycles as well. This work describes Erlenmeyer-Plöchl’s azlactone ring opening following by halogenation under an organocatalytic approach, using camphorsulfonic acid (CSA) and N-bromosuccinimide (NBS) as halogenating agent. The optimized reaction conditions for the halogenated product consisted on the use of 30 mol% CSA, 1.2 equivalent of NBS and 4 mL of methanol, at 65°C for 7 hours, to afford a halogenated imine with 83% of yield. Due to the difficulties in the substrate scope (purification process), a one-pot reduction of the halogenated imine was investigated, however, it was not possible to obtain a good diastereoisomeric ratio of the desired product. In view of setbacks encountered in the proposed methodology, the use of visible light photoredox catalysis in attempt to halogenate the azlactone heterocycle was investigated. However, using this approach, homodimerization of Erlenmeyer-Plöchl’s azlactones was observed instead of halogenation, leading to a cycloaddition [2+2] derived product. In dichloromethane, the use of ruthenium photocatalyst favored the formation of a tricyclic spiro type system. Switching to methanol as solvent, the metallic photocatalyst led the formation of the opening product with two azlactone rings, in 59% yield, whereas the organic dye Eosin Y conducted the formation of an asymmetric cycloadduct, with the ring opening of only one of the azlactone (40% yield). The substrate scope was evaluated using Eosin Y as photocatalyst and the products were isolated in yields ranging from 12 to 78%. All products were characterized by 1H NMR, 13C and IR.

Fotoredoxkatalys tillhandahåller möjligheter att utveckla nya hållbara kemiska reaktionsvägar. När fotokatalysatorn bestrålas med synligt ljus möjliggörs elektronöverföring till eller från substratet som i sin tur medför alstring av reaktiva fria radikaler. Kolradikaler, genererade med fotoredox-katalys från alkyloxalataktiverade alkoholer, har framgångsrikt kopplats till sulfinyliminer och möjliggör därigenom syntes av onaturliga α-aminosyror. Reaktionen utförs vid rumstemperatur och kräver endast extern energi i form av synligt ljus för att aktivera den iridium-baserade fotokatalysatorn. Den höga tillgängligheten av alkoholer utgör ett rimligt skäl för att använda dem som startmaterial. I detta projekt har tertiära alkoholer resulterat i framgångsrika reaktioner. / Photoredox catalysis provides opportunities to develop new sustainable chemical reaction pathways through single-electron transfer events and generation of reactive free-radical species. In this thesis carbon radicals, generated with photoredox catalysis from alkyl oxalate-activated alcohols, have successfully been coupled to sulfinyl imines and thereby enabling synthesis of unnatural α-amino acids. The reaction is performed at room temperature and only requires external energy in the form of visible light to activate the iridium-based photocatalyst. The abundance and availability of alcohols presents good reasons to use them as radical precursors. Under the developed reaction conditions, tertiary alcohols proved to be successful radical precursors, giving the desired product in good yield.

Fotoredoxkatalys har nyligen genomgått en renässans inom organisk kemi då metoden har möjliggjort framtagandet utav nya reaktionsvägar med milda reaktionsbetingelser genom att använda sig av synligt ljus. I det här arbetet undersöktes metodens bredd genom att kombinera metoden med väteatomöverföringskatalys för att funktionalisera C–H bindningar i α-position till heteroatomer och på så sätt skapa icke-naturliga α-aminosyror. Resultaten från detta arbete gav upp till 60% utbyte genom att kombinera dessa två katalysmetoder för substrat med Boc som skyddsgrupp, medan tertiära aminer inte krävde en väteatomöverföringskatalysator för kunna funktionaliseras. Den syntetiska metoden utan väteatomöverföringskatalys verkar dock inte vara applicerbara för sekundära aminer, men ser ut att fungera för C–H aktivering i α-position till svavelatomer vilket tyder på denna simplare metod utan väteatomsöverföring bör vara applicerbar för flera typer av substrat än för bara aminer / Photoredox catalysis has recently undergone a renaissance in the field of organic chemistry due the enabling of new reaction pathways under mild reaction conditions using visible light. In this work, the scope of this technology was explored by combining it with hydrogen atom transfer (HAT) to perform C–H functionalization in α-position to heteroatoms for synthesis of unnatural α-amino acids. The results showed that this is a viable method, gaining up to 60% yield using a dual catalytic system for Boc protected amines, while the functionalization of tertiary amines does not require HAT in order to work. Secondary amines proved to be non-applicable using the developed synthetic route without HAT catalyst while C–H activation in α-position to sulfur atoms gave similar response as tertiary amines – indicating that C–H activation without HAT should be applicable to a wider substrate scope than only using amines.