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L'une des préoccupations de la chimie moderne est de développer des procédés éco-compatibles : une tendance consiste à remplacer les solvants organiques par les Liquides Ioniques (LI). Ainsi ces travaux décrivent l'utilisation des LI dans deux réactions à économie d'atomes : l'addition de Michael et la réaction de cycloaddition 1,3-dipolaire catalysée (ou non) par un sel de cuivre (CuAAC). La première partie des travaux relate l'emploi de Liquides Ioniques Super-Acides (LISA), connus pour générer une activation électrophile. Une optimisation du LISA a été effectuée sur une réaction-modèle, puis l'application à d'autres électrophiles et nucléophiles a été étudiée. La pureté du LISA influe sur la chimiosélectivité : s’il est partiellement hydrolysé, la réaction d'annélation de Robinson devient prépondérante. La version asymétrique du processus a été abordée, montrant qu'il est possible d'obtenir un excès énantiomérique à partir de dérivés d'acides aminés. La seconde partie de l'étude a permis de mettre au point une synthèse de (triazolylméthyl)vinylphosphonates à partir d'un acétoxyméthylvinylphosphonate selon une procédure monotope reposant sur la cycloaddition 1,3-dipolaire dans différents LI. Nous avons ensuite montré que le LI joue aussi le rôle d'activateur pour cette réaction. / In the context of sustainable chemistry, an alternative to conventional organic solvents is the use of ionic liquids. These works reported here aims to describe the use of ionic liquids (IL) in two atoms economy reactions, namely the Michael addition reaction and 1,3-dipolar cycloaddition catalyzed (or not) by a copper salt (CuAAC). In the first part of the work reports the use of Super-Acid Ionic Liquids (SAIL), which initiate an electrophilic activation. After optimization of SAIL on a reaction model, application to other electrophiles and nucleophiles is discussed. The purity of SAIL affects the chemioselectivity: if the SAIL is partially hydrolyzed, a Robinson annulation predominates. The asymmetric version of the process is investigated, showing that it is possible to carry out an enantioselective reaction with amino acid derived SAIL. The second part of the study deals with setting up an original synthesis of (triazolylmethyl)vinylphosphonate from acetoxymethylvinylphosphonate using a one-pot procedure involving a 1,3-dipolar cycloaddition in different LI. We further showed that the ionic liquid can also act as an activator for this reaction.

L'imagerie de biomolécules, et plus particulièrement des glycanes, au sein d'organismes vivants, représente un incroyable challenge. Cependant, des progrès significatifs ont été réalisés ces dix dernières années grâce au développement de la stratégie du rapporteur chimique bioorthogonal. Cette technique implique, dans un premier temps, l'incorporation d'une fonctionnalité chimique non native (rapporteur) au sein de biomolécules complexes. Ce rapporteur peut ensuite réagir sélectivement avec une sonde moléculaire spécifique permettant ainsi la détection de la biomolécule ciblée. Afin d'imager ces biomolécules en temps réel, les sondes fluorogènes, des réactifs non fluorescents qui deviennent fluorescents après réaction avec le rapporteur chimique, ont été récemment développées. Ces dernières années, la cycloaddition 1,3-dipolaire sans métaux, entre les cylooctynes et les azotures, a été élégamment employée comme réaction bioorthogonale pour l'imagerie de biomolécules au sein d'organismes vivants. Cependant, l'azoture présente certaines limitations, notamment il peut être réduit par les thiols cellulaires. En conséquence, nous avons étudié l'utilisation de 1,3-dipôles plus stables, en tant que nouveaux rapporteurs chimiques bioorthogonaux pour l'imagerie de biomolécules par fluorescence. De plus, nous avons aussi développé de nouvelles sondes fluorogènes bioorthogonales ayant de bonnes propriétés de fluorescence, telles que de hautes valeurs de rendement quantique et des longueurs d'ondes d'émission déplacées dans le rouge, pour une potentielle application chez l'animal. / Imaging biomolecules, such as glycans, in living systems remains a formidable chemical challenge. However, significant progress has been made over the past ten years, with the ground-breaking development of the bioorthogonal chemical reporter strategy. In this context, complex biomolecules are fitted with a non-native chemical functionality (reporter) that can react selectively with a complementary bioorthogonal probe for detection. In order to image these biomolecules in real time, fluorogenic probes, non fluorescent reagents that produce highly fluorescent products, have recently been developed. This last decade, the metal-free 1,3-dipolar cycloaddition between cyclooctynes and azides have been elegantly employed for biomolecules imaging in living systems. However, azides suffer from limitations such as their reduction by endogenous cellular thiols. Consequently, we have investigated the use of more stable 1,3-dipoles as new chemical reporters for fluorescent biomolecule imaging. In addition, we also developed novel bioorthogonal fluorogenic probes with improved fluorescence properties such as high quantum yields and red-shifted fluorescence emission for potential applications in living animals.

In the first part of this study, four new chiral ligands (FAM) were synthesized and used in catalytic amounts in asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides. This method leads to the synthesis of chiral pyrrolidines, which are found in the structure of many biologically active natural compounds and drugs. It was found that using 10 mol% of one of these chiral ligands with different dipolarophiles (dimethyl maleate, dimethyl fumarate, methyl acrylate, tert-butyl acrylate, and Nmethylmaleimide), pyrrolidine derivatives could be synthesized in up to 94% yield and 95% ee. In the second part of the study, the catalytic activity of these chiral ligands were tested with titanium in asymmetric alkynylzinc addition reactions to aldehydes. By this method, chiral propargylic alcohols, which are important precursors for the natural products and pharmaceuticals can be synthesized. Using our catalyst, chiral propargylic alcohols were obtained in up to 96% yield and 98% ee. Although, most of the catalyst systems in the literature worked only with aromatic or aliphatic aldehydes and phenylacetylene, the catalyst system developed in this study worked with four different types of aldehydes (aromatic, aliphatic, heteroaromatic and a,b-unsaturated) and two different aliphatic acetylenes very successfully. Additionally, chiral ligand can be recovered in more than 90% yield and reused without losing its activity.

In this study new twelve phosphorus based chiral ligands were synthesized and characterized. Then the catalytic activity of these chiral ligands was tested with Cu(II) and Ag(I) salts in asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides. This method provides the synthesis of different pyrrolidine derivatives with up to four stereogenic centers. Pyrrolidine derivatives are found in the structure of many biologically active natural compounds and drugs. Therefore the asymmetric synthesis of these compounds is highly important and many groups are involved in this area. As the precursor of the azomethine ylides, N-benzyliden-glycinmethylester, N-(4-methoxy benzyliden)-glycinmethylester, N-(naphthalene-1-ylmethylene)-amino-acetic acid methyl ester, and N-(naphthalen-2-ylmethylene)-amino-acetic acid methyl ester were synthesized and used. As the dipolarophiles, methyl acrylate, dimethyl maleate and N-methyl maleimide were used. Using these imines and dipolarophiles with 6 mol % of one of the P-FAM chiral ligands in the presence of Ag(I) salt, pyrrolidine derivatives were synthesized in up to 95% yield and 89% enantioselectivity. Additionally, chiral ligand was recovered in more than 80% yield and reused without losing its activity.

As reações de cicloadição 1,3-dipolar são uma poderosa ferramenta para a síntese de uma variedade de anéis heterocíclicos de cinco membros. A cicloadição de óxidos de nitrila à olefinas, em particular, é de considerável interesse para a obtenção de isoxazolinas, que são intermediários versáteis na síntese de produtos naturais e de materiais com potencial aplicação como cristais líquidos. A Teoria do Funcional da Densidade foi utilizada para estudar o mecanismo da reação cicloadição [3+2] 1,3-dipolar que ocorre, inicialmente, entre o óxido de benzonitrila e o ácido vinilacético. Para tal, foram empregados os funcionais PBE1PBE, B3LYP e CAM-B3LYP, no nível 6-311+G(2d,p). O efeito do solvente foi avaliado através dos modelos PCM e CPCM, com os solventes THF, acetonitrila e formamida. A análise dos Orbitais Moleculares de Fronteira e do recente modelo da distorção e interação do estado de transição (TS), foram utilizadas para explicar a regioquímica dos produtos obtidos e a formação do bisaduto 2:1, originário de duas sucessivas cicloadições envolvendo o óxido de benzonitrila. Na primeira etapa da reação, os cálculos evidenciaram a formação do produto 3,5-dissubstiuído. Embora existam diferenças quantitativas nas barreiras de ativação e reação calculadas com os três diferentes funcionais, a previsão dos produtos majoritários e estados de transição mais favoráveis é a mesma, independentemente do funcional utilizado. Contudo, a conformação dos estados de transição e dos produtos intermediário e final da reação sofre uma pequena alteração com a inclusão do efeito do solvente. A energia de ativação nas duas cicloadições aumenta com o incremento da polaridade do solvente, porém, a possibilidade de formação de uma ligação de hidrogênio no estado de transição é responsável por uma diminuição na energia total de ativação. Esse resultado está diretamente vinculado à polaridade do TS. Quando comparados os resultados obtidos com os dois modelos de solvente, observou-se que ΔE≠ e ΔEreação são essencialmente as mesmas, embora as energias eletrônicas calculadas com CPCM sejam levemente inferiores às calculadas com PCM. / The 1,3-dipolar cycloaddition reactions are a powerful tool for synthesizing a wide range of 5-membered heterocyclic rings. Particularly, the cycloaddition of nitrile oxides to olefins is considerably interesting to obtain isoxazolines, which are versatile intermediaries in the synthesis of natural products and materials with potential application such as liquid crystals. The Density Functional Theory has been used to study the [3+2] 1,3-dipolar cycloaddition reaction mechanism that initially occurs between benzonitrile oxide and vinylacetic acid. To do that, PBE1PBE, B3LYP and CAM-B3LYP functionals have been used at level 6- 311+G(2d,p). The solvent effect was evaluated through the PCM and CPCM models, with the THF, acetonitrile and formamide solvents. The analysis of the Frontier Molecular Orbitals and of the recent distortion and interaction model of transition state (TS) have been used to explain the regiochemistry of the products obtained and the formation of the bisadduct 2:1, which is originated from two successive cycloadditions involving benzonitrile oxide. In the first reaction step, the calculations showed the formation of the 3,5-dissubstituted product. Although there are quantitative differences in the activation and reaction barriers calculated with the three different functionals, the forecasting of more favorable majoritary products and transition states is the same, no matter the functional used. However, the conformation of the transition states and of the final and intermediary products of the reaction is slightly changed by the inclusion of the solvent effect. The activation energy of both cycloadditions increases with the polarity increment of the solvent, but the possibility of formation of a hydrogen bond in the transition state is responsible for a reduction of the total activation energy. That result is directly linked to the TS polarity. When we compare the results obtained with the two solvent models, we observe that ΔE≠ and ΔEreaction are essentially the same, although the electronic energies calculated with CPCM are slightly smaller than the ones calculated with PCM.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The present dissertation describes a chemical methodology for the synthesis of three series containing fourteen new molecules of trifluoro(chloro)methyl substituted 1H-1,2,3-triazoles, which are structural analogues to the antiepileptic drug Rufinamide. The protocol used consisted in reactions of 1,3-dipolar cycloaddition of 2,6-difluorobenzyl azide and 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoro(chloro)-3-alken-2-ones, where the 4-substituents are H, Me, Ph, 4-OMeC6H4, 4-NO2C6H4,4-FC6H4,2-Thienyle 4,4 -Biphenyl. The optimized reactios were carried-out in absense of solvente, in reaction times of 48 to 96 hours at 100-150°C and in yields of 30-75%. The reactions employing the 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoro-3-alken-2-ones 1and 2,6-difluorobenzyl azidedemonstrated a 4-substituent dependency of the enones precursors (above mentioned) and conducted to the formation of isomeric mixtures of 4-trifluoroacetyl substituted and/or 5-trifluoromethyl substituted triazoles in varying proportions, which were separated and purified by chromatographic columns. On the other hand, the reactions employing the 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trichloro-3-alken-2-ones and the same 2,6-difluorobenzyl azide produced exclusively a series of 4- trichloroacetyl substituted triazoles without the detection of the respective 5-trichloromethyl substituted regioisomer. The synthesized triazoles were characterized by 1H, 13C, uni- and two-dimensional NMR Spectroscopy techniques as HMQC, gas chromatography coupled to mass spectrometry (GC-MS), mono-crystal X-ray diffraction, high resolution mass spectrometry (HRMS) and their purity determined by CHN Elemental Analysis. / A presente dissertação descreve uma metodologia química para a síntese de três séries de 1H-1,2,3-triazóis trifluor(cloro)metil substituídos, totalizando quatorze moléculas inéditas, as quais são análogas estruturais do fármaco antiepiléptico Rufinamida. O protocolo consistiu na realização de reações de cicloadição 1,3-dipolares envolvendo 2,6-difluorbenzil azida e 4-alcóxi-4-alquil(aril/heteroaril)-1,1,1-trifluor(cloro)-3-alquen-2-onas, sendo os substituintes 4-alquila(arila/heteroarila) iguais a H, Me, Ph, 4-OMeC6H4, 4-NO2C6H4,4-FC6H4,2-Tienila e 4,4 -Bifenila. As reações otimizadas se processaram na ausência de solvente, em tempos reacionais de 48 a 96 horas a 100-150°C e levaram a rendimentos na faixa de 30-75%. As reações que utilizaram 4-alcóxi-4-aril(heteroaril)-1,1,1-triflúor-3-alquen-2-onase 2,6-difluorbenzil azida apresentaram uma dependência quanto a substituição da posição 4 das enonas precursoras (acima descritos) e conduziram à formação de misturas isoméricas de triazóis 4-trifluoracetil substituídos e/ou 5-trifluormetil substituídos em proporções variadas, as quais foram passíveis de separação e purificação por cromatografia em coluna. Por outro lado, as reações empregando 4-alcóxi-4-alquil(aril/heteroaril)-1,1,1-tricloro-3-alquen-2-onas e a mesma 2,6-difluorbenzil azida produziram, exclusivamente, uma série de triazóis 4-tricloroacetil substituídos sem a detecção dos respectivos regioisômeros 5-triclorometil substituídos. Os triazóis sintetizados foram caracterizados por espectroscopia de RMN de 1H, 13C por técnicas uni- e bidimensionais (HMQC), cromatografia a gás acoplada à espectrometria de massas (GC-MS), difração de raios-X em mono-cristal, espectrometria de massas de alta resolução (HRMS) e a sua pureza determinada através de análise elementar CHN.

As reações de cicloadição 1,3-dipolar são uma poderosa ferramenta para a síntese de uma variedade de anéis heterocíclicos de cinco membros. A cicloadição de óxidos de nitrila à olefinas, em particular, é de considerável interesse para a obtenção de isoxazolinas, que são intermediários versáteis na síntese de produtos naturais e de materiais com potencial aplicação como cristais líquidos. A Teoria do Funcional da Densidade foi utilizada para estudar o mecanismo da reação cicloadição [3+2] 1,3-dipolar que ocorre, inicialmente, entre o óxido de benzonitrila e o ácido vinilacético. Para tal, foram empregados os funcionais PBE1PBE, B3LYP e CAM-B3LYP, no nível 6-311+G(2d,p). O efeito do solvente foi avaliado através dos modelos PCM e CPCM, com os solventes THF, acetonitrila e formamida. A análise dos Orbitais Moleculares de Fronteira e do recente modelo da distorção e interação do estado de transição (TS), foram utilizadas para explicar a regioquímica dos produtos obtidos e a formação do bisaduto 2:1, originário de duas sucessivas cicloadições envolvendo o óxido de benzonitrila. Na primeira etapa da reação, os cálculos evidenciaram a formação do produto 3,5-dissubstiuído. Embora existam diferenças quantitativas nas barreiras de ativação e reação calculadas com os três diferentes funcionais, a previsão dos produtos majoritários e estados de transição mais favoráveis é a mesma, independentemente do funcional utilizado. Contudo, a conformação dos estados de transição e dos produtos intermediário e final da reação sofre uma pequena alteração com a inclusão do efeito do solvente. A energia de ativação nas duas cicloadições aumenta com o incremento da polaridade do solvente, porém, a possibilidade de formação de uma ligação de hidrogênio no estado de transição é responsável por uma diminuição na energia total de ativação. Esse resultado está diretamente vinculado à polaridade do TS. Quando comparados os resultados obtidos com os dois modelos de solvente, observou-se que ΔE≠ e ΔEreação são essencialmente as mesmas, embora as energias eletrônicas calculadas com CPCM sejam levemente inferiores às calculadas com PCM. / The 1,3-dipolar cycloaddition reactions are a powerful tool for synthesizing a wide range of 5-membered heterocyclic rings. Particularly, the cycloaddition of nitrile oxides to olefins is considerably interesting to obtain isoxazolines, which are versatile intermediaries in the synthesis of natural products and materials with potential application such as liquid crystals. The Density Functional Theory has been used to study the [3+2] 1,3-dipolar cycloaddition reaction mechanism that initially occurs between benzonitrile oxide and vinylacetic acid. To do that, PBE1PBE, B3LYP and CAM-B3LYP functionals have been used at level 6- 311+G(2d,p). The solvent effect was evaluated through the PCM and CPCM models, with the THF, acetonitrile and formamide solvents. The analysis of the Frontier Molecular Orbitals and of the recent distortion and interaction model of transition state (TS) have been used to explain the regiochemistry of the products obtained and the formation of the bisadduct 2:1, which is originated from two successive cycloadditions involving benzonitrile oxide. In the first reaction step, the calculations showed the formation of the 3,5-dissubstituted product. Although there are quantitative differences in the activation and reaction barriers calculated with the three different functionals, the forecasting of more favorable majoritary products and transition states is the same, no matter the functional used. However, the conformation of the transition states and of the final and intermediary products of the reaction is slightly changed by the inclusion of the solvent effect. The activation energy of both cycloadditions increases with the polarity increment of the solvent, but the possibility of formation of a hydrogen bond in the transition state is responsible for a reduction of the total activation energy. That result is directly linked to the TS polarity. When we compare the results obtained with the two solvent models, we observe that ΔE≠ and ΔEreaction are essentially the same, although the electronic energies calculated with CPCM are slightly smaller than the ones calculated with PCM.

As reações de cicloadição 1,3-dipolar são uma poderosa ferramenta para a síntese de uma variedade de anéis heterocíclicos de cinco membros. A cicloadição de óxidos de nitrila à olefinas, em particular, é de considerável interesse para a obtenção de isoxazolinas, que são intermediários versáteis na síntese de produtos naturais e de materiais com potencial aplicação como cristais líquidos. A Teoria do Funcional da Densidade foi utilizada para estudar o mecanismo da reação cicloadição [3+2] 1,3-dipolar que ocorre, inicialmente, entre o óxido de benzonitrila e o ácido vinilacético. Para tal, foram empregados os funcionais PBE1PBE, B3LYP e CAM-B3LYP, no nível 6-311+G(2d,p). O efeito do solvente foi avaliado através dos modelos PCM e CPCM, com os solventes THF, acetonitrila e formamida. A análise dos Orbitais Moleculares de Fronteira e do recente modelo da distorção e interação do estado de transição (TS), foram utilizadas para explicar a regioquímica dos produtos obtidos e a formação do bisaduto 2:1, originário de duas sucessivas cicloadições envolvendo o óxido de benzonitrila. Na primeira etapa da reação, os cálculos evidenciaram a formação do produto 3,5-dissubstiuído. Embora existam diferenças quantitativas nas barreiras de ativação e reação calculadas com os três diferentes funcionais, a previsão dos produtos majoritários e estados de transição mais favoráveis é a mesma, independentemente do funcional utilizado. Contudo, a conformação dos estados de transição e dos produtos intermediário e final da reação sofre uma pequena alteração com a inclusão do efeito do solvente. A energia de ativação nas duas cicloadições aumenta com o incremento da polaridade do solvente, porém, a possibilidade de formação de uma ligação de hidrogênio no estado de transição é responsável por uma diminuição na energia total de ativação. Esse resultado está diretamente vinculado à polaridade do TS. Quando comparados os resultados obtidos com os dois modelos de solvente, observou-se que ΔE≠ e ΔEreação são essencialmente as mesmas, embora as energias eletrônicas calculadas com CPCM sejam levemente inferiores às calculadas com PCM. / The 1,3-dipolar cycloaddition reactions are a powerful tool for synthesizing a wide range of 5-membered heterocyclic rings. Particularly, the cycloaddition of nitrile oxides to olefins is considerably interesting to obtain isoxazolines, which are versatile intermediaries in the synthesis of natural products and materials with potential application such as liquid crystals. The Density Functional Theory has been used to study the [3+2] 1,3-dipolar cycloaddition reaction mechanism that initially occurs between benzonitrile oxide and vinylacetic acid. To do that, PBE1PBE, B3LYP and CAM-B3LYP functionals have been used at level 6- 311+G(2d,p). The solvent effect was evaluated through the PCM and CPCM models, with the THF, acetonitrile and formamide solvents. The analysis of the Frontier Molecular Orbitals and of the recent distortion and interaction model of transition state (TS) have been used to explain the regiochemistry of the products obtained and the formation of the bisadduct 2:1, which is originated from two successive cycloadditions involving benzonitrile oxide. In the first reaction step, the calculations showed the formation of the 3,5-dissubstituted product. Although there are quantitative differences in the activation and reaction barriers calculated with the three different functionals, the forecasting of more favorable majoritary products and transition states is the same, no matter the functional used. However, the conformation of the transition states and of the final and intermediary products of the reaction is slightly changed by the inclusion of the solvent effect. The activation energy of both cycloadditions increases with the polarity increment of the solvent, but the possibility of formation of a hydrogen bond in the transition state is responsible for a reduction of the total activation energy. That result is directly linked to the TS polarity. When we compare the results obtained with the two solvent models, we observe that ΔE≠ and ΔEreaction are essentially the same, although the electronic energies calculated with CPCM are slightly smaller than the ones calculated with PCM.