A series of 3-alkyl and 3-aryl-5-hydroxy-5-trichloromethyl-4,5-dihydro-1Hpirazoles-1-carboxiamide that possess biological activity they were synthesized, in good yeld, through the cyclocondensation, in microwaves, of 4-alcoxi-1,1,1-trihalometyl-3alquen-2-onas with semicarbazyde chloride using MeOH/H2O as solvent. The advantage obtained with the use of irradiation of microwaves in relation to the classic methodology it is the decrease of the time reacional and revenue increase as it will be demonstrated. / Uma série de 3-alquil(aril) 5-hidroxi 5-triclorometil-4,5-diidropirazol-1-carboxiamida, que possuem atividade biológica foram sintetizadas, em bons rendimentos, através da ciclocondensação, em microondas, de 4-alcoxi-1,1,1-trialometil-3-alquen-2-onas com cloreto de semicarbazida e MeOH/H2O como solvente. A vantagem obtida com o uso de irradiação de microondas em relação à metodologia clássica é a diminuição do tempo reacional e aumento de rendimento como será demonstrado.

L’aromaticité et l’antiaromaticité demeurent un sujet d’actualité au niveau fondamental puisque ces concepts permettent d’expliquer la réactivité de diverses classes de molécules. Certains composés polycycliques ayant une conjugaison π étendue, comme par exemple les tétraoxa[8]circulènes, ont des cycles aromatiques et antiaromatiques qui affectent leurs propriétés physicochimiques. Les oxacirculènes sont formés d’un anneau de quatre furanes et de quatre benzènes positionnés en alternance et créant un cœur formellement antiaromatique de cyclooctatétraène (COT). Malgré cela, ces composés démontrent une grande stabilité et peuvent servir en tant que composantes de dispositifs optoélectroniques comme des diodes électroluminescentes. Les propriétés optoélectroniques de ces composés et leur organisation moléculaire à l’état solide sont à l’origine d’un comportement unique. Le présent mémoire décrit la synthèse de tétraoxa[8]circulènes par une réaction très spéciale de cyclocondensation de 1,4-quinones catalysée par des acides, permettant d’accéder à des grandes molécules conjuguées en une étape. Les composés synthétisés ont une géométrie qui empêche leur empilement efficace et crée des vides dans la structure cristalline pouvant servir à l’inclusion de molécules invitées. En particulier, l’inclusion de C60 effectuée par cocristallisation cause l’uniformisation des longueurs des liens du cœur COT des oxacirculènes, suggérant des interactions de transfert de charge. Enfin, les propriétés optiques étudiées par spectroscopie UV-vis et par fluorescence indiquent que les oxacirculènes sont sensibles à leur environnement moléculaire et pourraient donc être utilisés comme des senseurs chimiques. / Aromaticity and antiaromaticity remain important topics of chemical research because these concepts explain the reactivity of various classes of molecules. For instance, certain polycyclic compounds with π-extended conjugation, such as tetraoxa[8]circulenes, contain both aromatic and antiaromatic rings, which affect their physicochemical properties. Oxacirculenes consist of a circular arrangement of four furan and four benzene rings positioned in an alternating fashion, thus creating a formally antiaromatic cyclooctatetraene (COT) core. Despite this, oxacirculenes exhibit great stability. They can serve as components in optoelectronic devices such as electroluminescent diodes, and their molecular organisation in the solid state can be controlled in ways that influence their properties. The present memoir describes the synthesis of tetraoxa[8]circulenes by a very special acid-catalysed cyclocondensation reaction starting from suitable 1,4-quinones, thereby allowing the preparation of large conjugated molecules in a single step. The compounds prepared have an awkward molecular structure that inhibits efficient packing and creates voids in the crystal structure, allowing the inclusion of guests. In particular, the inclusion of C60, achieved by cocrystallization, appears to create charge-transfer interactions as indicated by uniformization of bond lengths in the COT core. Optical properties studied by UV-vis spectroscopy and fluorescence show that oxacirculenes are sensitive to their local chemical environment, suggesting that they can be used as chemical sensors for the rapid detection of guests.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of a series of 3-haloacetyl-4-methyl-quinolines from the cyclocondensation reaction of 4-alkoxyvinyl ketones [R1C(O)CH=C(R2)(OCH3), where R1 = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 and R2 = Me, Et, Pr, Bu, i-Bu, i- Pent] with 2-aminoacetophenone is reported. The reaction was performed in the presence of p-toluene sulphonic acid (p-TsOH), ionic liquid ([HMIM][TsO]) and under microwave irradiation. The molar ratio of the reactants 4-alkoxyvinyl ketone and 2-aminoacetophenone was of 1:1, respectively, for the quinoline with R1 = CHCl2, while for the other reactions was necessary a molar ratio of 1.2:1, respectively. The results showed that the combination of ionic liquid and microwave irradiation was effective for this synthesis, since the products were obtained with short rteaction times (10-20 min) and high yields (70-91%). In addition, the advantages of using the microwave irradiation method in comparison to the conventional thermal heating were also demonstrated. / Neste trabalho é descrita a síntese de uma série de 3-haloacetil-4-metilquinolinas a partir da reação de ciclocondensação de 4-alcoxivinil cetonas [R1C(O)CH=C(R2)(OCH3), onde R1 = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 e R2 = Me, Et, Pr, Bu, i-Bu, i-Pent] com 2-aminoacetofenona. As condições reacionais utilizadas para a obtenção dos compostos heterocíclicos foram realizadas na presença d6 ácido p-tolueno sulfônico (ac. p-TsOH) e líquido iônico ([HMIM][TsO]) sob irradiação de micro-ondas. A relação molar empregada da 4-alcoxivinil cetona e da 2-aminoacetofenona foi de 1:1, respectivamente, para a quinolina R1 = CHCl2, enquanto que para as outras reações foi necessário uma relação molar de 1,2:1. Os resultados obtidos demonstraram que a combinação de líquido iônico e irradiação de micro-ondas foram eficazes para essa síntese, já que os produtos foram obtidos em tempo reacionais curtos (10- 20 min) e altos rendimentos (70-91%). Além disso, também foram mostradas as vantagens do método de irradiação de micro-ondas sobre o método convencional de aquecimento.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / In this study the reactivity of β-enamino diketones [RC(O)C(=CHNMe2)C(O)CO2Et, R = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Br-C6H4, 4-NO2-C6H4, tien-2-il] with NCN bisnucleophiles as amidine and guanidine was investigated. The tiopirimidines ethyl 2-benzylthio-pyrimidine-4-carboxylates, (65-91 %) and Ethyl 2-metiltiopirimidine-4-carboxylates (69-91 %) were obtained in a highly regioselective manner by cyclocondensation reaction of β-enamino diketones with benzylisothiourea hydrochloride and methylisothiourea sulfate, respectively. Following the studies, was also investigated the reactivity of β-enamino diketones with guanidine hydrochloride and was possible to synthesize 2-aminopyrimidines that were obtained in a regioisomeric mixture of compounds with yields of 64-89 % and the reaction of β-enamino diketones with 2-acethylguanidine led to a highly regioselective synthesis of 2-acethylaminopyrimidines-4-carboxylates in yields (74-88 %). Ethyl 2-benzylthio-pyrimidine-4-carboxylates obtained were cyclized with hydrazine monohydrate and pyrimidopyridazinones were obtained in 52-95 % yields. Finally, were β-enamino diketones were cyclocondensed with 3(5)-amino-5(3)methylpyrazole leading to pyrazolo[1,5-a]pyrimidines of highly regioselective manner. These, in turn, are cyclized with an equivalent amount of hydrazine monohydrate to form a series of pyrazolo-pyrimido-pyridazinone (43-68%) and when using excess hydrazine monohydrate pyrazole-pyridazinone were formed by ANRORC (Addition of Nucleophile followed by Ring-Opening and Ring-Closure)mechanism yields 62-84%. The reactions for the synthesis of these heterocyclic systems involving simple steps, mild conditions and short reaction times. / Nesta tese foi investigada a reatividade de β-enaminodicetonas [RC(O)C(=CHNMe2)C(O)CO2Et, em que R = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Br-C6H4, 4-NO2-C6H4, tien-2-il] frente NCN dinucleófilos como amidinas e guanidina. As tiopirimidinas 2-benziltio-pirimidinas-4-carboxilato de etila (65-91 %) e 2-metiltiopirimidinas-4-carboxilatos de etila (69-91 %) foram obtidas de maneira altamente regiosseletiva através da reação de ciclocondensação das β-enaminodicetonas com cloreto de benzilisotioureia e sulfato de 2-metilisotioureia, respectivamente. Já nas reações com cloridrato de guanidina foram obtidas 2-aminopirimidinas numa mistura regioisomérica de compostos com rendimentos de 64-89 % e a reação de β-enaminodicetonas com 2-acetilguanidina conduziu a uma síntese altamente regiosseletiva das 2-acetoamidopirimidinas-4-carboxilatos de etila em rendimentos de (74-87%). As 2- benziltio-pirimidinas-4-carboxilato de etila foram escolhidas para verificar o potencial sintético das pirimidinas sintetizadas, e, através da reação de ciclização destas com monoidrato de hidrazina foram obtidas as pirimido-piridazinonas, (52-95 %). Por fim, as β-enaminodicetonas foram ciclocondensadas com 3-(5)-amino-5(3)metilpirazol formando pirazolo[1,5-a]pirimidinas de maneira altamente regiosseletiva. Essas, por sua vez, foram ciclizadas com quantidade equivalente de monoidrato de hidrazina formando uma série de pirazolo-pirimido-piridazinona (43-68 %) e quando cilcizadas utilizando excesso de monoidrato de hidrazina formaram pirazolo-piridazinona através do mecanismo ANRORC (Addition of Nucleophile followed by Ring-Opening and Ring-Closure) com rendimentos de 62-84 %. As reações para a síntese desses sistemas heterocíclicos envolveram etapas simples, condições brandas e curtos tempos de reação.

Ce travail s'inscrit dans le cadre d'un programme de collaboration entre l'Université Libanaise et l'université de Rennes 1. La thèse est divisée en deux parties :Chimie du fluor : synthèse de nouveaux hétérocycles portant des chaînes latérales fluorées ; chimie médicinale : recherche de nouvelles molécules à visées anticancéreuses. La première partie se compose de trois chapitres : dans le premier chapitre, des intermédiaires de synthèse de type énones fluorées ont été synthétisés par une voie originale, et leur réactivité en cyclocondensation a été étudiée pour obtenir de pyrazolines et de pyrrolines avec des chaînes latérales fluorés. Dans le deuxième chapitre, nous nous sommes intéressés à la préparation d'hétérocycles de type chroman-4-one, en utilisant les intermédiaires difluorés précédents. Dans le dernier chapitre, la réaction de Kinugasa a été appliquée pour la première fois sur des dérivés propargyliques gem-difluorés. Cette réaction nous a permis de découvrir une voie de synthèse originale à une famille de composés nouveaux, à savoir des exoalkylidène b-lactames portant un fluor en position vinylique. Dans la seconde partie, notre objectif était de restaurer les propriétés apoptotiques au sein des cellules cancéreuses afin d'obtenir de nouveaux composés à activité antitumorale. A partir de données obtenues par modélisation moléculaire, nous avons fait le design de plusieurs séries d'analogues d'un inhibiteur connu (MIM-1) de la protéine anti-apoptotique Mcl-1. Plus de 40 analogues ont été préparés et testés sur trois variétés de cellules cancéreuses (sein, ovaire et mélanome). Un certain nombre de ces composés ont présenté des activités prometteuses dans ces différents domaines. / This work is a part of a collaboration program between Lebanese University and University of Rennes 1. The thesis is divided into two parts: fluorine chemistryv : synthesis of new heterocycles bearing fluorine-containing side chains ; medicinal chemistry : research towards new anticancer molecules. The first part consists of three chapters: in the first chapter, gem-difluoro enone-type intermediates were synthesized through a new route and their cyclocondensation reactions were studied to get pyrazolines and pyrrolines with fluorinated side chains. In the second chapter, type-chroman-4-one heterocycles were prepared using the previous difluorinated intermediates. In the third chapter, the Kinugasa reaction was applied for the first time on gem-difluoro propargylic derivatives. This reaction has allowed us to discover a pathway to a new family of molecules, the fluorine-containing exoalkylidene β-lactames. In the second part, our goal was to reinduce the proapoptotic properties in cancer cells in order to obtain new antitumor compounds. Starting from data obtained through molecular modeling studies, we designed and prepared several series of analogs for a known inhibitor (MIM-1) of the anti-apoptotic protein Mcl-1. Over 40 analogs have been synthetized and screened towards three types of cancer cells (breast, ovarian and melanoma). Some of these derivatives have demonstrated promising data in these areas.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The synthesis of two series of N-substituted pyrazoles from the cyclocondensation reaction of β-enaminones ([R1C(O)C(R2)=CHN(Me2)], where R1 = Me, C6H5, 3-MeOC6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, fur-2-il, thien-2-il; R2 = H, 2-MeO-C6H4) and 2-hydroxyethylhydrazine or 1-pentafluorophenylhydrazine was demonstrated. The reactions were performed in five ionic liquids ([BMIM][BF4], [BMIM][Br], [BMIM][OH], [HMIM][HSO4] e [BPy][BF4]) with different physical and chemical properties to establish the best reaction conditions. In addition, a Brönsted (HCl) and a Lewis catalyst (BF3●OEt2) and two molecular solvents (ethanol and water) were evaluated. The best ionic liquid found for all reactions was [BMIM][BF4]; molecular solvent ethanol for reaction with 2- hydroxyethylhydrazine; and water for reaction with 1-pentafluorophenylhydrazine. On the other hand, in the case of the reaction with 2-hydroxyethylhydrazine, BF3●OEt2 was found to be the best catalyst, while with 1- pentafluorophenylhydrazine, HCl, was found to be the best one, when comparing both reactions in [BMIM][BF4]. In general, the results showed it is advantage in yields and reaction time the use of ionic liquids in relation to molecular solvents. This work also shows the synthesis and characterization of a series of ionic liquids containing a pharmacological cation and/or anion. The new ionic liquids were synthesized from the metathesis reaction between the lidochaine, benzalkonium or didecyldimethylamonium salts, to furnish the cation part; and sodium diclofenac, sodium flurbiprofenate, sodium flufenamicate, sodium salicylate, sodium saccharinate and potassium acesulfamate, to furnish the anion part. The new ionic liquids were obtained in moderate to good yields (56-89%) and were identified and characterized through the NMR, DSC and TGA data. / Este trabalho descreve a síntese de duas séries de pirazóis N-substituídos, a partir da reação de ciclocondensação entre β-enaminonas ([R1C(O)C(R2)=CHN(Me2)], onde R1 = Me, C6H5, 3-MeO-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4- Br-C6H4, 4-O2N-C6H4, fur-2-il, tien-2-il; R2 = H, 2-MeO-C6H4) e 2-hidroxietilidrazina ou 1-pentafluorfenilidrazina. As reações foram realizadas em diferentes líquidos iônicos ([BMIM][BF4], [BMIM][Br], [BMIM][OH], [HMIM][HSO4] e [BPy][BF4]) com propriedades físicas e químicas diferentes a fim de estabelecer as melhores condições para a obtenção dos 1-hidroxietilpirazóis e dos 1-pentafluorfenilpirazóis. Além disso, também foram avaliados diferentes catalisadores (HCl e BF3●OEt2) e dois solventes moleculares (etanol e água). Em ambos os casos, o líquido iônico [BMIM][BF4] apresentou os melhores resultados. No entanto, quanto ao catalisador avaliado, foi verificado um comportamento distinto. A reação entre hidroxietilidrazina e enaminonas [BMIM][BF4] foi melhor quando BF3●OEt2 foi utilizado como catalisador, enquanto que para a reação da pentafluorfenilidrazina, HCl se mostrou mais adequado. Além disso, o melhor solvente molecular encontrado para a reação com a 2-hidroxietilidrazina foi o etanol enquanto que no caso da 1- pentafluorfenilidrazina, a água apresentou resultados superiores em termos de tempo reacional e rendimento. Através dos resultados obtidos foi possível observar que a utilização de líquidos iônicos apresenta vantagens em relação a utilização de solventes moleculares. Nesta tese, também foram sintetizadas series de líquidos iônicos contendo componentes farmacologicamente ativos, tanto no cátion quanto no ânion do referido composto. Os novos líquidos iônicos duais foram sintetizados através de uma reação de metátese entre sais de lidocaína, benzalcônio ou didecildimetilamônio, os quais forneceram a parte catiônica, com diferentes sais como, diclofenaco de sódio, flurbiprofenato de sódio, flufenamicato de sódio, salicilato de sódio, sacarinato de sódio e acesulfamato de potássio. Esses compostos foram obtidos em rendimentos moderados a bons (56-89%), e foram identificados e caraterizados através de dados de RMN, DSC e TGA.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of a series of 1-aryl-4-[(dimethylamino)methylene] pyrrolidine- 2,3,5-trione from the cyclocondensation reaction between b-enaminodiketone [Cl3C(O)C(=CHNMe2)C(O)CO2Et] and aniline derivatives [R = Ph, 3-Me-C6H4, 3- MeO-C6H4, 3-HO-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 4- MeCO-C6H4] was performed. The reaction conditions used to synthesize the pyrrolidine-2,3,5-triones involved environmentally benign techniques, as the use of microwave irradiation, employing the reactants b-enaminodiketone and amine in a molar ratio of 1:1.1, respectively, and a non-halogenated solvent. The reaction was carried out with short time (12-16 min) and the products were obtained in moderate to good yields (50- 76%). In addition, the advantages of using the microwave irradiation method in comparison to the conventional thermal heating were demonstrated. / A síntese de uma série de 4-(dimetilamino)metileno-1-aril-pirrolidino-2,3,5-triona foi realizada a partir da reação de ciclocondensação da b-enaminodicetona [Cl3C(O)C(=CHNMe2)C(O)CO2Et] com derivados da anilina [R = Ph, 3-Me-C6H4, 3- MeO-C6H4, 3-HO-C6H4, 4-Me-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-O2N-C6H4, 4- MeCO-C6H4]. As condições reacionais utilizadas para a síntese das pirrolidino-2,3,5- trionas envolveram técnicas ambientalmente corretas, como o uso de irradiação de micro-ondas, empregando uma relação molar da b-enaminodicetona e da amina de 1:1.1, respectivamente e solvente não halogenado. A reação foi realizada em curtos períodos de reação (12-16 min) e os produtos foram obtidos com rendimentos de moderados a bons (50-76%). Além disso, foram demonstradas as vantagens da utilização do método de irradiação de micro-ondas sobre o método convencional de aquecimento térmico.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of new compounds alkyl 3-azolyl propanoate e alkyl 3-azolyl propanoic acid structurally analogues to gamma-aminobutiric acid (GABA) is reported. One more time using the acetal acylation method, now the acetal derivative of 4-oxopentanoic acid (levulinic acid), the methyl 4,4- dimethoxypentanoate, were obtained the precursors methyl 7,7,7-trifluoro[chloro]-4- methoxy-6-oxo-heptenoates, 1,3-dieletrophilic precursor with alcanoate substituent. Are presented efficient and regioespecific synthetic routes from reactions of cyclocondensation [3+2] among 1,3-dieletrofilic precursors with hydroxylamine and different hydrazines, until training isoxazoles and pyrazoles, functionalized with the side chain alkyl propanoate or propanoic acid. Simultaneously to the formation of heterocycles, were studied the hydrolysis reaction of trichloromethyl group and transesterification reaction of methyl propanoate, in the same reactional medium. All products are novel, presenting a good to excellent yields, high purity and the structures were assigned by 1H NMR, 13C NMR and mass spectrometry. / A síntese de novos compostos 3-azolil-propanoatos de alquila e 3-azolilácidos propanóicos, análogos estruturalmente ao ácido gama-aminobutírico (GABA) é relatada. Novamente aplicando o método de acilação de acetais, agora ao acetal derivado do ácido 4-oxopentanóico (ácido levulínico), o 4,4-dimetoxipentanoato de metila, foram obtidos os precursores 7,7,7-triflúor[cloro]-4-metoxi-6-oxo-heptenoatos de metila, precursores 1,3-dieletrofílicos com o substituinte alcanoato. São apresentadas rotas sintéticas eficientes e regioespecíficas a partir de reações de ciclocondensação [3+2] entre os precursores 1,3-dieletrofílicos, com hidroxilamina e hidrazinas diferentes, até a formação de isoxazóis e pirazóis, funcionalizados com a cadeia lateral propanoato de alquila ou ácido propanóico. Simultaneamente à formação dos heterociclos, foram estudadas as reações de hidrólise do grupamento triclorometila e hidrólise ou transesterificação do propanoato de metila, no mesmo meio de reação. Todos os produtos obtidos são inéditos, apresentando rendimentos de bons a excelentes e pureza alta e suas estruturas foram atribuídas por RMN1H e 13C e por espectrometria de massas.