Tetrahydrobenzofurans and tetrahydroindoles are two very valuable classes of substances which have wide usage area / either as starting materials for drug substances or many other compounds which have fused heterocyclic rings in their structures and pharmacophore for many complex natural products / syntheses of derivatives of these compounds with different substitution patterns, is an exciting challenge for many scientists. Benzofuran and tetrahydroindole derivatives, which are potent bioactive substances, are synthesized from various cyclohexanone derivatives that are allylated by Stork-enamine or Mn(OAc)3 mediated allylation methods. Allylated ketones are later transformed to benzofuran derivatives upon treatment with base or tetrahydroindole derivatives upon treatment with primary amines.

Neste trabalho, as fragmentações de 2-aroilbenzofuranos e de neolignanas diidrobenzofurânicas (NDB) foram investigadas empregando espectrometria de massas sequencial com ionização por eletrospray (ESI-MS/MS). Os compostos estudados foram sintetizados e, em seguida, suas vias de fragmentação em condições de dissociação induzida por colisão (CID) foram associadas às suas respectivas estruturas. Além das relações estrutura-fragmentação, espectrometria de massas de múltiplos estágios (MSn) e dados termoquímicos, obtidos por Química Quântica Computacional, foram também utilizados para a elucidação das vias de fragmentação. Para os 2-aroilbenzofuranos protonados, os resultados demonstraram que dois íons acílios, provenientes de rearranjos de hidrogênio competitivos, são os mais intensos nos espectros de íons produtos. O íon acílio [M+HC6H6]+ foi o mais intenso para todos os 2-aroilbenzofuranos investigados devido ao fato de que sua decomposição requerer energia crítica maior que a de outras vias de fragmentação competitivas. No caso das NDBs, os resultados indicaram que perdas de CH3OH e CO são comuns aos compostos analisados, tanto na forma protonada como na forma desprotonada. Entretanto, as perdas de CH3OH a partir de NDB protonadas envolvem migração de carga, enquanto que para moléculas desprotonadas, a perda de metanol é um processo remoto à carga. A perda de ceteno (C2H2O) diretamente da molécula protonada é uma via diagnóstica das NDB acetiladas, enquanto que os íons produtos [M+HC3H6O2]+ ou [M+HC6H6O]+ são diagnósticos das NDB que apresentam saturação entre C7 e C8. Para NDBs desprotonadas, íons produtos formados por perdas de CH3 são diagnósticos de grupos metoxila ligados ao anel aromático. A presença do grupo acetil também levou à formação de alguns íons diagnósticos devido à mudança no sítio de desprotonação. Por sua vez, clivagens da cadeia lateral remotas à carga são fragmentações diagnósticas de NDBs que apresentam saturação entre C-7 e C-8. As estruturas dos íons propostos foram suportadas por dados termoquímicos (entalpia e energia de Gibbs). Os resultados deste trabalho contribuem para o conhecimento da química em fase gasosa desses compostos e auxiliarão na identificação dos mesmos diretamente de misturas. / In this work, the fragmentation of 2-aroylbenzofuran and dihydrobenzofuran neolignans (DBN) was investigated using electrospray ionization tandem mass spectrometry (ESI-MS/MS). The studies compounds were synthesized and their fragmentation pathways under collision-induced dissociation (CID) were associated with their respective structures. Besides the structure-fragmentation correlations, multiple-stage mass spectrometry (MSn) and thermochemical data, which were estimated by Quantum Computational Chemistry, were also employed in the elucidation of the fragmentation pathways. For protonated 2-aroylbenzofuran, the results demonstrated that two acylium ions, which arises from two competitive hydrogen rearrangements, are the most intense in the product ion spectra. The acylium ion [M+HC6H6]+ was the most intense for all the investigated 2-aroylbenzofuran, since its decomposition requires a higher critical energy as compared to other competitive fragmentation processes. In the case of DBNs, our results indicated that eliminations of CH3OH e CO are common to the analyzed compounds in their protonated and deprotonated forms. However, eliminations of CH3OH from protonated DBNs involve charge migration, whereas elimination of CH3OH from deprotonated DBNs is a fragmentation remote to the charge site. Elimination of ketene (C2H2O) directly from the protonated molecule is diagnostic for acetylated DBNs, whereas the product ions [M+HC3H6O2]+ or [M+HC6H6O]+ are diagnostic for DBNs displaying a saturated bond between C7 and C8. For deprotonated DBNs, product ions resulting of CH3 losses are diagnostic for methoxyl groups attached to the aromatic ring. The presence of the acetyl group also led to the formation of some diagnostic ions due to the change of the deprotonation site. For compounds that display a saturated bond between C-7 and C-8, cleavages of the side chain of DBNs are also diagnostic. The structures of the proposed ions were supported by thermochemical data (enthalpy and Gibbs energy). The results of this work will contribute to the knowledge of the gas-phase ion chemistry of these compounds and will aid in their identification directly from mixtures.

L'ouverture de cycle aromatique catalysée par le palladium a été récemment observée par une équipe de l'ENSTA. Ce type de réactivité du palladium n’a jamais été observé auparavant et entre en compétition avec l’activation C-H classique. Ce travail de thèse a consisté à étudier ces réactions d'un point de vue théorique pour mieux en comprendre les mécanismes.Nous avons tout d'abord cherché la fonctionnelle permettant la meilleure description de la compétition entre la complexation azote/alcène en comparant plus de soixante fonctionnelles à des calculs CCSD(T)/CBS. Nous avons retenu la fonctionnelle GGA BP86.Nous avons ensuite étudié la réaction de Heck intramoléculaire à partir de la N-allyl-2-iodo-aniline. Nous avons justifié que l'indole soit le produit majoritairement obtenu, et montré que l'azote ne joue pas de rôle sur la régiosélectivité. Cependant, dans certains cas, l'azote inhibe la réaction en piégeant le complexe de palladium. Une étude théorique a montré que le facteur prépondérant de cette inhibition est la population électronique de l'azote et non l'hybridation du carbone benzylique.L'ouverture du furane a été ensuite considérée. Parmi tous les mécanismes proposés, notre étude théorique a montré que la voie principale est celle de la β-alkoxyelimination, potentiellement assistée par la trialkylamine présente dans le milieu.Enfin, nous avons étudié l'ouverture du benzylfurfurylaniline. Le mécanisme est similaire à celui observé pour l'ouverture du furane jusqu'à la régénération du complexe de palladium catalytique. En effet, dans le ce cas, la base azotée joue le rôle d'un donneur de proton. / Aromatic cyclic compound opening catalyzed by palladium has been recently observed by ENSTA team. That kind of reactivité for palladium has not been shown before and is in competition with the C-H activation. This work studies theses reactions from a theoretical point of view to better understand the mechanisms. We first look for the functional who gives the best description of the competition between the nitrogen/alkene complexation comparing more than sixty functionals with CCSD(T)/CBS calculation. We choose at last the GGA functional BP86.We then study the intramolecular Heck reaction starting from the N-allyl-2-iodo-aniline. We justified that the indole moiety was the major product and showed that the nitrogen plays no rôle in the regioselectivity.However, in some cases, the nitrogen inhibits the reaction by trapping the palladium complex. A theoretical study showed that the main factor for this inhibition was the population of nitrogen lone pair and not the hybridation of the benzylic carbon.Furan opening was then considered. Between all the mechanisms proposed, our theoretical study showed that the main way is the β-alkoxyelimination, potentially assisted by the trialkylamine present in the environment.Finally, we have studied the benzylfurfurylaniline opening. The mechanism is similar to the one observed for the furan opening until the regeneration of the palladium complex. Indeed, in that case, the base plays the rôle of a proton donor.

Inositols belong to an important class of biologically active compounds, named as cyclitols (cyclic polyols), which have attributed high interest in the past decade due to the glycosidase inhbition property that affects many biological processes. Initially, 1,3,3a,7a-tetrahydro-2-benzofuran (69) was synthesized as a key compound to synthesize bishomo-inositol derivatives. Then photooxygenation and manganese(III) acetate oxidation reactions of this key compound were studied in order to obtain isomeric inositol derivatives. Moreover, dihydroxylation and acid catalyzed ring opening reactions were investigated. Finally, new synthetic approaches for the synthesis of bishomo-inositol derivatives have been developed. In addition to that whole products were conscientiously purified and characterized and mechanism for the formation of the products has been discussed.

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

Les maladies tropicales provoquées par des parasites protozoaires tels que Trypanosoma brucei, Plasmodium falciparum et Leishmania donovani, infectent des milliards d'individus dans le monde et en tuent des millions chaque année. Actuellement, les phénomènes de résistance face aux thérapies actuelles utilisées pour traiter ces maladies dites " négligées " deviennent inquiétants et problématiques. Par conséquent, la découverte de nouvelles classes de molécules bioactives antiparasitaires est primordiale.C'est dans ce contexte que s'inscrit ce travail de thèse. La cissampeloflavone est un dimère chalcone-flavone isolé en 2003 d’une plante vénézuélienne, Cissampelos pareira. Cette molécule a démontré une bonne activité contre T. brucei (CI50 = 1 µM). Par ailleurs, des études de modélisation moléculaire ont prédit que son dérivé 4-désoxycissampeloflavone possèderait une bonne affinité pour une enzyme essentielle à la survie du parasite. Pour ces raisons, nous avons entrepris la synthèse totale de ces deux molécules originales jamais réalisée à ce jour.Des analogues simplifiés ont d’abord été synthétisés afin de mettre au point le schéma réactionnel pour former la cissampeloflavone et la 4-désoxycissampeloflavone. Ces composés ont pour base commune le noyau benzofurane qui porte soit la " partie chalcone " soit la " partie flavone " de ces dimères. Les deux synthèses totales ont ensuite été entreprises.Ce travail de thèse a notamment permis la création d'une librairie d'analogues benzofuranes polysubstitués, la découverte d'une réaction de méthylénation originale et la formation de nouveaux dérivés furanoflavones. La plupart ont été évalués sur T. brucei, P. falciparum et L. donovani. Plusieurs d'entre eux ont présenté une activité trypanocide intéressante et prometteuse. / Tropical diseases caused by protozoan parasites such as Trypanosoma brucei, Plasmodium falciparum and Leishmania donovani, infect billions of people worldwide and kill millions of them every year. Nowadays, resistance phenomena against actual therapies used to treat these " neglected " diseases are becoming worring and problematic. Therefore, discovery of new classes of antiparasitic bioactive molecules is primordial.This is the aim of this PhD work. Cissampeloflavone is a chalcone-flavone dimer isolated in 2003 from a Venezuelan plant, Cissampelos pareira. This molecule has showed a good activity against Trypanosoma brucei (IC50 = 1 µM). Besides, molecular docking studies have predicted that its derivative 4-desoxycissampeloflavone would possess a good affinity for an essential enzyme for parasite survival. For these reasons, we undertook the total synthesis of these two original molecules never carried out to date.Simplified analogues have been prepared in order to elaborate a synthetic pathway to form cissampeloflavone and 4-desoxycissampeloflavone. These compounds possess the benzofuran ring as common core which bears either the "chalcone part" or the "flavone part" of these dimers. The total syntheses were then undertaken.This PhD work has particularly enabled the creation of a polysubstituted benzofuran library, the discovery of an original methylenation reaction and the formation of new furanoflavone derivatives. Most of them were evaluated on T. brucei, P. falciparum and L. donovani. Several compounds have showed an interesting and promising trypanocidal activity.

Text in English / Specially prepared 2-amino-5-bromo-3-iodoacetophenone and 5-bromo-2-hydroxy-3 iodoacetophenone were subjected to Claisen-Schmidt aldol condensation with benzaldehyde derivatives followed by sequential and/or one-pot palladium catalyzed Sonogashira cross coupling and heteroannulation of the 3-alkynylated intermediates to afford indole-chalcones and benzofuran-chalcones, respectively. The indole-chalcones derivatives were, in turn, subjected to trifluoroacetic anhydride in tetrahydrofuran under reflux to afford the corresponding 3-trifluoroacetyl substituted indole-chalcone derivatives. The coupling constant values (Jtrans) of about 16.0 Hz for the chalcone derivatives corresponding to the vinylic protons confirmed the trans geometry of the α,β-unsaturated carbonyl framework in all the cases. Their trans geometry of the chalcone derivatives was further confirmed by single crystal X-ray diffraction (XRD) analyses. Further structural elaboration of the ambident electrophilic α,β unsaturated carbonyl (chalcone) moiety of the indole-chalcones and the analogous benzofuran chalcones with 2-aminothiophenol afforded novel benzothiezapine-appended indole and benzofuran hybrids, respectively. Sonogashira cross-coupling of 5-bromo-2-hydroxy-3 iodoacetophenone with terminal acetylenes followed by heteroannulation of the intermediate 3-alkynylated 5-bromo-2-hydroxyacetophenones afforded the corresponding 7-acetyl-2-aryl-5-bromobenzofurans in a single-pot operation. The oximes derived from the 7-acetyl–substituted 2-aryl-5-bromobenzofurans were subjected to Beckmann rearrangement with triflic acid in acetonitrile under reflux. We isolated the corresponding 7-amino-2-aryl-5 bromobenzofuran derivatives formed from hydrolysis in situ of the intermediate 7-acetamide 2-aryl-5-bromobenzofurans. Amino-dechlorination of the 4-chloroquinazoline derivatives with the 7-aminobenzofurans afforded novel benzofuran 4-aminoquinazoline hybrids. The prepared compounds were characterized using a combination of nuclear magnetic resonance (1H-NMR & 13C-NMR including 19F-NMR), infrared (IR) and mass spectroscopic techniques complemented with single crystal X-ray diffraction (XRD) analyses and/or density functional (DFT) method. The benzofuran-chalcone 203a–y derivatives were evaluated for anti-growth effect against the breast cancer (MCF-7) cell line by the MTT cell viability assay. Their mode of cancer cell death (apoptosis versus necrosis) was detected by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The most cytotoxic compounds 203i and 203o were also evaluated for potential to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. The experimental results were complemented with theoretical data from molecular docking into ATP binding site of the EGFR and colchicine binding site of tubulin, respectively. The benzofuran–4-aminoquinazoline hybrids 215a–j, on the other hand, were evaluated for antiproliferative propeties in vitro against the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (C3A) cell lines. The benzofuran-aminoquinazoline hybrids were also evaluated for potential to induce apoptosis and for their capability to inhibit EGFR-TK phosphorylation complemented with molecular docking (in silico) into the ATP binding site of EGFR. Mechanistic studies demonstrated that the benzofuran-appended aminoquinazoline hybrids 215d and 215j induced apoptosis via activation of caspase-3 pathway. Moreover, compounds 215d and 215j exhibited significant and moderate inhibitory effects against EGFR (IC50 = 29.3 nM and 61.5 nM, respectively) when compared to Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 215 into EGFR-TK active site suggested that they bind to the region of EGFR like Gefitinib does. / Chemistry / D. Phil. (Chemistry)

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