Dissertations / Theses on the topic 'Quinoxalinona'

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This work describes the synthesis of a number of polyaza heterocycles and the mechanistic study to obtain these products. Furthermore, the characterization was performed by spectroscopic method and the structural study by X-ray diffraction and theoretical calculations of molecular orbitals. The synthesis of polyaza heterocyclic compounds began from the cyclocondensation reaction between a β- enaminodiketone and 2-aminopyridine, 2-aminothiazole or 2-aminobenzoimidazole in order to achieve pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one or 2- oxo-pyrimido[1,2-a]benzimidazole, respectively, with a α-keto ester substituent, in high regioselectivity. The mechanistic proposal developed in this step is based on the semi-empirical theoretical calculations by the PM3 method. From these data it was possible to say that the reaction was controlled by frontier molecular orbital, according to values of HOMO/LUMO coefficient obtained for the reactants. In the next step, the α-keto esters previously obtained, were reacted with ethylenediamine and derivatives ledding to the pyrazinones formation and the reaction with 1,2- phenylenediamine and derivatives led to the formation quinoxalinones. The same reaction of α-keto esters with amidines did not lead to the formation of imidazolonas as expected, since only the formation of the substitution product in the ester group occurred. The reaction mechanisms proposed in these steps are also based in theoretical calculations, where it was possible to infer that the reaction was thermodynamically controlled, since the reactivity sites were less important than the stability of the intermediates. The compounds were characterized by 1D nuclear magnetic resonance experiments of such as 1H and 13C and 2D such as COSY, HETCOR and HMBC, besides of mass spectrometry. The molecular structural studies by X-ray diffraction (for the compounds that could be measured) revealed that polyaza heterocycles pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one and 2-oxo-pyrimido[1,2-a]benzimidazole are essentially plane. All these compounds showed as pattern at least one intramolecular interaction between a carbonyl oxygen atom and a carbonyl carbon via π-hole, forming a five membered pseudo-ring, which stabilizes the position of a carbonyl group. The study revealed that all structural supramolecular compounds exhibit a large number of weak hydrogen bonds of the type CH···X (where X = O, N) and the compounds which exhibited a NH group in its structure or water in the asymmetric unit formed additionally strong hydrogen bonds of the type X-H···X (where X = O, N). Since the structures studied are aromatic heterocycles, all compounds showed interactions involving π systems in their interactions like π···π and/or lone-pair···π in their crystal packing. Only one intermolecular interaction via σ-hole (C=O···S) and another via π-hole (C=O···C=O) were found.
Neste trabalho é descrita a síntese de uma série de poliaza heterociclos e o estudo mecanístico para a obtenção destes produtos. Além disso, é realizada sua caracterização utilizando métodos espectroscópicos e o estudo estrutural por difração de Raios-X e cálculos teóricos de orbitais moleculares. A síntese dos compostos poliaza heterocíclicos teve inicio a partir de reações de ciclocondensação entre uma β-enaminodicetona e 2-aminopiridina, 2-aminotiazol ou 2-aminobenzoimidazol para obter pirido[1,2-a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5- ona e 2-oxo-pirimido[1,2-a]benzoimidazol, respectivamente, com um substituinte α- ceto éster, de maneira altamente regiosseletiva. A proposta mecanística elaborada nesta etapa está embasada em cálculos teóricos semi-empíricos pelo método PM3. A partir destes dados é possível afirmar que a reação é controlada por orbital molecular de fronteira, conforme os valores de coeficiente de HOMO/LUMO obtidos para os reagentes. Na etapa seguinte, os α-ceto ésteres, previamente obtidos, ao reagirem com etilenodiamino e derivados levaram a formação de pirazinonas, bem como, a reação com 1,2-fenilenodiamino e derivados levou a formação de quinoxalinonas como produto. A reação dos mesmos α-ceto ésteres com amidinas não levou a formação de imidazolonas como desejado, pois ocorreu apenas a formação do produto de substituição no grupo éster. Os mecanismos de reação propostos nestas etapas também estão embasados em cálculos teóricos, onde foi possível inferir que a reação foi termodinamicamente controlada, já que, a reatividade dos sítios foi menos importante que a estabilidade dos intermediários. Os compostos foram caracterizados utilizando ressonância magnética nuclear em experimentos de 1D como 1H e 13C, e 2D como COSY, HETCOR e HMBC, além de espectrometria de massas. O estudo estrutural molecular por difração de Raios-x (referente aos compostos que puderam ser medidos) revelou que os poliaza heterociclos pirido[1,2- a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5-ona e 2-oxo-pirimido[1,2-a]benzoimidazol são essencialmente planos. Um padrão observado nestes compostos é que todos apresentam, pelo menos, uma interação intramolecular entre um átomo de oxigênio carbonílico e um carbono carbonílico via π-hole, formando um pseudo-anel de cinco membros, que estabiliza a posição de uma carbonila. O estudo estrutural supramolecular revelou que todos os compostos apresentam um amplo número de ligações de hidrogênio fracas do tipo C-H· · ·X (quando, X = O, N) e os compostos que apresentaram um grupo N-H em sua estrutura ou água na unidade assimétrica formam, adicionalmente, ligações de hidrogênio fortes do tipo X-H···X (quando, X = O, N). Como as estruturas estudadas apresentam heterociclos aromáticos, todos os compostos mostraram interações envolvendo seus sistemas π em interações do tipo π· · ·π e/ou lone-pair· · ·π em seus empacotamentos cristalinos. Apenas uma interação intermolecular via σ-hole (C=O· · ·S) e uma via π-hole (C=O· · ·C=O) foram encontradas.

This work describes the synthesis and functionalization of azoles employing different methodologies, based on organometallic catalysis or not. Firstly, we disclose the synthesis tetra-substituted 5-trifluoromethyl pyrazoles via sequential halogenation of 5-trifluoromethyl pyrazoles and palladium-catalyzed carbon–carbon and carbon–nitrogen cross-coupling reactions employing organozinc reagents and amines as coupling partners, respectively. This work allowed to achieve new pyrazolic systems in moderated to good yields. Posteriorly, we show the synthesis of 1,3-di(hetero)aryl indazoles exploring the complementary catalytic activity of nickel and copper complexes. We commenced this study evaluating different nickel pre-catalysts to perform the intramolecular amination of unprotected 2-chlorophenyl hydrazones. In a second moment, we described the N-(hetero)arylation of the in situ generated NH indazoles, using a simple catalytic system based on copper/DMEDA. This sequential one-pot fashion procedure allowed the achievement of several 1,3-di(hetero)aryl indazoles in moderate to good yields. Lastly, we disclose the formation of pyrazolo[1,5-a]quinoxalin-4(5H)-ones by the reaction between ethyl 1-(2-chlorophenyl)-1H-pyrazole-5-carboxylate and primary amines. The one-pot methodology undergoes by two sequential reactional pathways: i) amidation of the ester moiety attached to the pyrazole ring, and ii) intramolecular cyclization via nucleophilic aromatic substitution. This synthetic approach proved to be efficient only for primary aliphatic amines, allowing to achieve molecules with different substitution patterns in moderate to good yields. Key-words: Azoles, quinoxalinones, Negishi cross-coupling, Buchwald-Hartwig cross-coupling.
Este trabalho descreve a síntese e a funcionalização de azóis através de diferentes metodologias, ancoradas ou não na catálise organometálica. Primeiramente, descrevemos a síntese de 5-trifluormetil pirazóis tetrassubtituídos através de reações de acoplamento cruzado catalisadas por complexos de paládio entre 5-trifluormetil-4-halo pirazóis, reagentes organozinco e aminas. Este trabalho permitiu a obtenção de novos sistemas pirazólicos com rendimentos moderados a bons. Posteriormente realizamos a síntese de 1,3-di(hetero)aril indazóis explorando as atividades catalíticas complementares de complexos de níquel e cobre. Primeiramente avaliamos diferentes pré-catalisadores de níquel para realizar a aminação intramolecular de diferentes 2-clorofenil hidrazonas não protegidas. Em um segundo momento, realizamos a N-(hetero)arilação dos NH indazóis gerados in situ, através do emprego de um sistema catalítico baseado em cobre/DMEDA. A metodologia permitiu a obtenção de diferentes indazóis 1,3-di(hetero)aril substituídos, com rendimentos moderados a bons. Por fim, demonstramos a síntese de pirazolo[1,5-a]quinoxalin-4(5H)-onas a partir da reação entre 1-(2-clorofenil)-1H-pirazolo-5-carboxilatos de etila e aminas primárias. A metodologia one-pot envolve duas etapas sequenciais; i) amidação da função éster do pirazol e ii) ciclização intramolecular via substituição nucleofílica aromática. Esta abordagem sintética provou ser eficiente ao se empregar aminas alquílicas primárias, permitindo a obtenção de diferentes padrões de substituição com rendimentos moderados a bons.

Depuis quelques décennies, l’étude de systèmes biologiques complexes est un domaine en plein essor. Ainsi, des outils de ligation des biomolécules avec des reporters chimiques ont été mis en place afin d’avoir une compréhension toujours fine du vivant. Les ligations sont des réactions chimiques biocompatibles permettant de lier deux entités synthétiques ou biologiques entre elles. On regroupe généralement ces ligations en deux catégories, les réactions de bioconjuguaison, qui font intervenir des fonctions chimiques naturellement présentes dans les biomolécules, et les réactions bio-orthogonales qui n’interfèrent pas avec les fonctions chimiques présentes dans ces milieux, mais nécessitent en amont une modification des partenaires de réaction. Cependant, il convient de faire la distinction avec une troisième catégorie, les réactions de conjugaison chimiosélectives, qui mettent en oeuvre des fonctions non naturellement présentes sur les biomolécules. En ce sens, elles se rapprochent donc des réactions bio-orthogonales, mais les fonctions ou conditions mises en jeu ne sont pas suffisamment bio-orthogonales ou les réactions ne sont pas suffisamment rapides pour pouvoir être réalisées dans les systèmes biologiques. Ces ligations sont toutefois très utilisées pour de la construction biomoléculaire allant de la petite molécule (par exemple oligopeptide modifié) à la biomacromolécule (type protéine modifiée) et se distinguent par une facilité de mise en oeuvre et purification des conjugués, ce qui n’est pas toujours réa lisable avec l’arsenal des réactions bio-orthogonales qui conduisent à la formation de multiple isomères. Ainsi, mes travaux de thèse se sont orientés vers la découverte et/ou l’étude de ligations chimiosélectives ainsi qu’à leur utilisation dans la préparation de sondes fluorescentes voire fluorogéniques. L’étude de la ligation Kondrat’eva préalablement développée au sein du laboratoire, a permis de mettre en évidence son caractère fluorogénique, et a été exploitée pour le marquage fluorescent de molécules via une étape unique de ligation fluorogénique. Puis, le développement d’une ligation utilisant le système tétrazine/pyrazolone a été développée afin de pallier le manque de sélectivité des réactions basées sur le motif tétrazine proposées jusqu’alors, qui conduisent aux bioconjugués sous la forme d’un mélange de produits. Cette approche a été illustrée par le marquage fluorescent d’une protéine humaine. Enfin, le développement d’une nouvelle voie d’accès aux quinoxalinones a permis leur étude photophysique et la mise en évidence de propriétés fluorogéniques utilisées notamment pour la synthèse d’une biosonde
In recent decades, the study of complex biological systems has been a growing field. Thus, biomolecules ligation tools with chemical reporters were set up in order to have a better and fine understanding of the living. Ligations are biocompatible chemical reactions that link two synthetic or biological entities one antother. These ligations are generally gathered into two categories, bioconjugation reactions, using chemical functions naturally present in the biomolecules, and bio-orthogonal reactions which does not interfere with these function, but require a prior engineering of the biological partner. However, it is necessary to distinguish a third category, the chemoselective conjugation reactions, which implement functions not naturally present on biomolecules. In this sense, they are therefore closer to bio-orthogonal reactions, but the functions or conditions involved are not sufficiently bioorthogonal or the reactions are not fast enough to be carried out in any biological systems. These ligations are, however, widely used for biomolecular constructions ranging from the small molecule (for example modified oligopeptides) to the biomacromolecule (protein modification) and are distinguished by their ease of implementation and purification of the conjugates, which is not always feasible with the arsenal of bio-orthogonal reactions that leads to the formation of multiple isomers. Thus, my PhD work focused on the discovery and / or the study of chemoselective ligations as well as their use in the preparation of fluorescent or fluorogenic probes. The study of the Kondrat'eva ligation previously developed within the laboratory, highlighted its fluorogenic behaviour, and was exploited for the fluorescent labelling of molecules through a single fluorescence-ligation step. Then, the development of a ligation using the tetrazine / pyrazolone system was developed in order to overcome the lack of selectivity of the reactions based on the tetrazine scaffold which often lead to the formation of bioconjugates as a mixture of isomers. This approach has been illustrated by the fluorescent labelling of a human protein. Finally, the development of a new access route to quinoxalinones allowed to study their photophysical properties and to highlight their fluorogenic properties which were leveraged in particular for the synthesi s of a bioprobe

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Gliomas are the most common and devastating tumors of the central nervous system (CNS). Among the gliomas group, the GBM is the most prevalent, aggressive and deadly malignant. Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. Chalcones are group of natural precursors of flavonoid and display a wide variety of biological and pharmacological proprieties that include anti-proliferative and anti-cancer activities. This study aimed at evaluating the in vitro anti-proliferative activity and cell viability inhibition of nine quinoxaline derived chalcones, structurally based on the selective PI3Ky inhibitor AS605240. These synthetic compounds were tested at different time-periods of incubation (24, 48 e 72 h) and concentrations (0,1; 0,1; 1; 5 e 10 μg/mL) in glioma cell lines from human and rat origin (U-138 MG and C6, respectively).The results showed by MTT assay and cell couting revealed that four chalcones (compounds N2, N9, N10 and N12), displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration dependent manner. These four compounds which present methoxy groups at A-ring and their efficacy was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with chalcone N9 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, chalcone N9 was able to visibly inhibit AKT activation, allied to the stimulation of ERK 1/2 MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent at A-ring, might well represent promising molecules for the treatment of gliomas.
Os gliomas são os tumores do SNC mais comuns e devastadores. Dentre os gliomas, o GBM é o mais prevalente, agressivo, maligno e apresenta um mau prognóstico. A relevância dos compostos naturais, incluindo as chalconas, no tratamento e na prevenção do câncer está sendo muito evidenciada. As chalconas formam um grupo de compostos naturais derivados dos flavonóides que apresentam diferentes propriedades biológicas e farmacológicas, incluindo as atividades anti-proliferativas e anti-tumorais. O objetivo deste estudo foi avaliar a ação anti-proliferativa e a capacidade de inibição da viabilidade celular in vitro de nove chalconas derivadas da quinoxalina, baseadas estruturalmente no inibidor seletivo de PI3Ky, o AS605240. Estes compostos sintéticos foram testados em diferentes tempos de incubação (24, 48 e 72 h) e concentrações (0,1; 0,1; 1; 5 e 10 μg/mL) em linhagens de glioma humano e de rato (U-138 MG e C6, respectivamente). Os resultados observados nos experimentos de MTT e na contagem celular revelaram que quatros chalconas (compostos N2, N9, N10 e N12), apresentaram grande eficácia e potência, sendo capazes de inibir a proliferação e a viabilidade celular, de maneira tempo e concentração dependente. Estes quatro compostos que possuem radicais metóxi no anel A de sua estrutura demonstraram uma eficácia superior àquela do composto AS605240, usado como controle positivo. Os resultados da citometria de fluxo demonstraram que a incubação das células C6 com a chalcona N9 levaram a um bloqueio celular na fase G1, possivelmente indicando interferência com a apoptose. Além disto, a chalcona N9 foi capaz de inibir visivelmente a ativação da AKT, aliada à estimulação de ERK 1/2 MAP-quinase. As chalconas estudadas neste projeto, especialmente as que apresentam o radical metoxi no anel A, representam promissoras moléculas para o tratamento dos gliomas.

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Gliomas are the most common and devastating tumors of the central nervous system (CNS). Among the gliomas group, the GBM is the most prevalent, aggressive and deadly malignant. Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. Chalcones are group of natural precursors of flavonoid and display a wide variety of biological and pharmacological proprieties that include anti-proliferative and anti-cancer activities. This study aimed at evaluating the in vitro anti-proliferative activity and cell viability inhibition of nine quinoxaline derived chalcones, structurally based on the selective PI3Ky inhibitor AS605240. These synthetic compounds were tested at different time-periods of incubation (24, 48 e 72 h) and concentrations (0,1; 0,1; 1; 5 e 10 μg/mL) in glioma cell lines from human and rat origin (U-138 MG and C6, respectively). The results showed by MTT assay and cell couting revealed that four chalcones (compounds N2, N9, N10 and N12), displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration dependent manner. These four compounds which present methoxy groups at A-ring and their efficacy was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with chalcone N9 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, chalcone N9 was able to visibly inhibit AKT activation, allied to the stimulation of ERK 1/2 MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent at A-ring, might well represent promising molecules for the treatment of gliomas.
Os gliomas s?o os tumores do SNC mais comuns e devastadores. Dentre os gliomas, o GBM ? o mais prevalente, agressivo, maligno e apresenta um mau progn?stico. A relev?ncia dos compostos naturais, incluindo as chalconas, no tratamento e na preven??o do c?ncer est? sendo muito evidenciada. As chalconas formam um grupo de compostos naturais derivados dos flavon?ides que apresentam diferentes propriedades biol?gicas e farmacol?gicas, incluindo as atividades anti-proliferativas e anti-tumorais. O objetivo deste estudo foi avaliar a a??o anti-proliferativa e a capacidade de inibi??o da viabilidade celular in vitro de nove chalconas derivadas da quinoxalina, baseadas estruturalmente no inibidor seletivo de PI3Ky, o AS605240. Estes compostos sint?ticos foram testados em diferentes tempos de incuba??o (24, 48 e 72 h) e concentra??es (0,1; 0,1; 1; 5 e 10 μg/mL) em linhagens de glioma humano e de rato (U-138 MG e C6, respectivamente). Os resultados observados nos experimentos de MTT e na contagem celular revelaram que quatros chalconas (compostos N2, N9, N10 e N12), apresentaram grande efic?cia e pot?ncia, sendo capazes de inibir a prolifera??o e a viabilidade celular, de maneira tempo e concentra??o dependente. Estes quatro compostos que possuem radicais met?xi no anel A de sua estrutura demonstraram uma efic?cia superior ?quela do composto AS605240, usado como controle positivo. Os resultados da citometria de fluxo demonstraram que a incuba??o das c?lulas C6 com a chalcona N9 levaram a um bloqueio celular na fase G1, possivelmente indicando interfer?ncia com a apoptose. Al?m disto, a chalcona N9 foi capaz de inibir visivelmente a ativa??o da AKT, aliada ? estimula??o de ERK 1/2 MAP-quinase. As chalconas estudadas neste projeto, especialmente as que apresentam o radical metoxi no anel A, representam promissoras mol?culas para o tratamento dos gliomas.

La détection et l'imagerie par fluorescence de systèmes biologiques nécessite la mise en place d'outils efficaces, robustes et simples d'utilisation. Les sondes fluorogéniques conventionnelles, actuellement utilisées en microbiologie manquent de précision puisqu'elles résultent de la simple modification chimique de la structure d'un fluorophore déjà formé, conduisant souvent à une extinction incomplète de sa fluorescence intrinsèque. Mes travaux de thèse ont pour but de développer de nouveaux substrats fluorogéniques d'enzymes basés sur le principe du "covalent assembly". Cette approche de synthèse chimique in situ d'un cœur fluorescent à partir d'un précurseur dit "cagé" non-fluorescent, met en jeu des réactions domino caractérisées par la formation et la rupture de liaisons covalentes, déclenchées par une réaction enzymatique déclenchée par les bactéries à identifier. Les avantages d'une telle approche sont nombreux (meilleur rapport signal sur bruit, exemplification aisée à un large éventail d'analytes, …). Dans ce contexte, le premier objectif de ma thèse a été de synthétiser des fluorophores de type hétéro-xanthène originaux afin de valider leur stabilité dans des conditions physiologiques. De nouvelles sulfone- et Si-pyronines ont été obtenus. La synthèse des précurseurs "cagés" correspondant aux composés les plus stables en milieux aqueux, a été entreprise pour pouvoir les utiliser comme sondes à peptidases. L'ensemble de ces travaux sont décrits dans le chapitre I et II de ce manuscrit. Les difficultés rencontrées lors de la mise en œuvre de l'approche "covalent assembly" avec ces hétéro-xanthènes, nous ont conduit à explorer une nouvelle famille de fluorophores, les quinoxalinones. La formation in-situ de ces hétérocycles fluorescents, faisant suite à un stimuli enzymatique d'un précurseur "cagé" est présenté dans le chapitre III. Enfin le dernier chapitre traite de la synthèse d'une sonde conventionnelle dérivée d'une bis-sulfonyle-bis-aniline récemment publiée dans la littérature
Detection and fluorescence imaging of biologic systems requires the implementation of efficient, robust and easy-to-use tools. Conventional fluorogenic probes currently used in microbiology lack efficiency since they are based on the single chemical modification of a fluorophore bearing an optically tunable reactive group, which often leads to incomplete fluorescence quenching. The main goal of my Ph.D thesis was to develop novel fluorogenic enzymatic substrates based on the "covalent assembly" principle. This approach also named "in situ synthesis" is based on the use of domino reactions to form a fluorescent moiety starting from a "caged" non-fluorescent molecule. In our case, the bioanalyte that triggers the reaction is present in bacteria, that we want to detect. This strategy provides many advantages (improved signal-to-noise ratio, easy exemplification to a wide range of analytes, …). In this context, the first goal of my thesis was to synthesize original fluorescent hetero-xanthene dyes to assess their stability under physiological conditions. Novel sulfone- and Si-pyronin derivatives were obtained. Synthesis of the corresponding "caged" precursors to the most stable compounds was then undertaken for their use as a peptidase-responsive probes. This work is described in the first and second chapter of this manuscript. Faced with difficulties to implement "covalent assembly" probe design principle to Si-pyronins, another class of fluorophores, namely quinoxalinone was explored. In situ formation of these fluorescent heterocycles triggered by an enzyme is presented in the third chapter. Finally, the last chapter was devoted to the synthesis of a conventional probe derived from a bis-sulfonyl-bis-aniline recently reported in the literature

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The synthesis of some sampangine analogs was accomplished by using suitable natural and synthetic quinones, namely lapachol and nor-lapachol. These readily available compunds were functionalized by a sequence of O-methylation using dimethylsulfate in basic media, and chemoselective nucleophylic displacement with 2-aminoethanol and 3-aminopropanol. Further transformation of hydroxyl group in azide by a sequence involving tosylation results in the key intermediates. These 2-amino-ω-azido compunds were submitted to catalytic hydrogenation over palladium on charcoal yielding the corresponding quinoxaline and 1,4-diazepine nucleus. Some of these compounds were sequentially cyclized with the aid of DDQ to yield the corresponding tetracyclic analogs of sampagine alkaloids. All compounds were characterized by usual methods including proton and carbon-13 NMR, infrared.
Partindo-se de quinonas naturais e sintéticas facilmente disponíveis em nosso laboratório foi sintetizada uma série de 2-amino-quinonas intermediárias e derivados cíclicos nitrogenados, sendo alguns inéditos na literatura. Assim, a partir das 2-hidroxi-quinonas, lapachol e nor-lapachol obteve-se os correspondentes derivados 2-metoxilados via alquilação com sulfato de dimetila em meio básico. A seguir reagiram quimiosseletivamente com 2-etanolamina e 3-propanolamina, formando os amino-álcoois correspondentes. Através da sequência de tosilação seguida de substituição nucleofílica com azida de sódio, obteveram-se os azido compostos correspondentes, os quais são os intermediários-chave na síntese de análogos cíclicos do alcalóide natural quinonóide sampangina. Os azidos compostos, deram origem a novas quinoxalinas e diazepinas, quando submetidos a hidrogenação catalítica usando-se paládio sobre carvão que oxidadas com DDQ permitiram a ciclização da cadeia lateral prenílica originando um novo composto tetracíclico análogo da sampangina. Os rendimentos globais obtidos variaram de 58 a 91%. Os compostos foram caracterizados por espectroscopia de RMN 1H, RMN 13C, IV.

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A s?ntese de compostos heteroc?clicos, tais como derivados de quinoxalina, tem se mostrado bastante relevante e promissora devido ?s diversas aplica??es verificadas nas ?reas biol?gicas e tecnol?gicas. Este trabalho dedicou-se a s?ntese, caracteriza??o e reatividade de derivados quinoxal?nicos a partir de dois precursores sint?ticos: o ?cido-L-asc?rbico (1) e do bloco de constru??o 2,3-dicloro-6,7-dinitroquinoxalina (2). A partir da s?ntese e caracteriza??o dos compostos derivados do ?cido-L-asc?rbico (1) foram realizados estudos visando sua aplica??o como quimiossensores, no qual o composto 36 demonstrou-se seletivo para o ?on Cu2+, em metanol, mediante an?lises colorim?trica e por espectroscopia UV-vis?vel. Al?m disto, an?lises iniciais sugerem que o composto 39 derivado de 36, uma base de Schiff, tamb?m apresenta caracter?sticas de quimiossensor para o mesmo metal. A partir do composto 2, foram sintetizados cinco compostos atrav?s de rea??es de substitui??o nucleof?lica arom?tica com aminas alif?ticas. O controle das condi??es experimentais permitiu a obten??o tanto de produtos mono- quanto dissubstitu?dos. Estudos de reatividade foram realizados com dois prop?sitos: i) investigar a possibilidade de atua??o do composto 47 como quimiossensor para ?nions, a partir da rea??o com hidr?xido de s?dio em DMSO, atrav?s dos resultados obtidos pela an?lise de imagem e espectroscopia UV-vis?vel; ii) caracterizar cineticamente a convers?o do composto 44 em 46 atrav?s da an?lise de imagens pelos m?todos RGB e multivariada a partir de dados de CCD, mostrando-se uma ferramenta simples e de baixo custo para an?lises qualitativas e quantitativas.
Synthesis of heterocyclic compounds, as quinoxaline derivatives, has being shown to be relevant and promissor due to expressive applications in biological and technological areas. This work was dedicated to the synthesis, characterization and reactivity of quinoxaline derivatives in order to obtain new chemosensors. (L)-Ascorbic acid (1) and 2,3-dichloro-6,7- dinitroquinoxalina (2) were explored as synthetic precursors. Starting from synthesis of 1 and characterization of compounds derived from (L)-ascorbic acid, studies were performed investigating the application of products as chemosensors, in which compound 36 demonstrated selective affinity for Cu2+ ?ons in methanolic solution, by naked-eye (colorimetric) and UVvisible analyses. Further, initial analysis suggests that 39 a Schiff?s base derived from 36 also presents this feature. Five quinoxaline derivatives were synthesized from building block 2 through nucleophilic aromatic substitution by aliphatic amines, in which controlling the experimental conditions allows to obtain both mono- and di-substituted derivatives. Reactivity studies were carried out with two purposes: i) investigate the possibility of 47 compound being a chemosensor for anion, based on its interaction with sodium hydroxide in DMSO, using image analysis and UV-visible spectroscopy; ii) characterize kinetically the conversion of compound 44 into 46 based on RGB and multivariate image analysis from TLC data, as a simple and inexpensive qualitative and quantitative tool.

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O estudo dos compostos heteroc?clicos nitrogenados compreende um dos ramos mais interessantes da qu?mica org?nica. Dentre as diversas classes de heterociclos nitrogenados relatados, as quinoxalinas possuem papel de destaque por suas relevantes aplica??es, notavelmente em ?reas biol?gicas e tecnol?gicas. Existem diversos protocolos de s?ntese de derivados quinoxal?nicos relatados na literatura, dentre os quais se destacam as rea??es a partir do precursor sint?tico 2,3-dicloroquinoxalina (1). O presente trabalho tem como enfoque a atua??o do composto 1 como precursor sint?tico para mol?culas relevantes, estando os resultados dividido em duas partes principais. Primeiramente, ? apresentado um estudo preparativo focado nas rea??es da quinoxalina 1 com aminoalco?is, al?m de outras transforma??es sint?ticas. Foram obtidos produtos tais como 2,3-dietanolaminoquinoxalina (2), 2-(2,3-diidro-]1,4]oxazino[3,2-b]quinoxal-4-il)etanol (3) a partir de dupla substitui??o do cloro, al?m do produto 3-[bis-(2-hidroxi-etil)-amino]-1H-quinoxalin-2-ona (4) como fruto da hidr?lise do composto (3), dentre outros. Um fator de destaque ? que enquanto etanolamina reage via duplo N-ataque nucleof?lico, dietanolamina reage via processo de cicliza??o intramolecular atrav?s de N- e O-ataques. Todos os produtos foram devidamente caracterizados por resson?ncia magn?tica nuclear de 1H e 13C. Os produtos 2 e 3 apresentaram atividade antic?ncer atrav?s de estudos citot?xicos em c?lulas HT29 (c?ncer colorretal), a qual pode estar relacionada com a inibi??o da enzima PI3K?. Ambas as quinoxalinas impactaram significativamente a viabilidade celular, na menor concentra??o (3,125?g/mL) j? ? poss?vel vermos que o crescimento foi retardado. O que p?de tamb?m ser constatado por meio de um estudo de docking dos compostos no s?tio ativo da enzima PI3K?, o qual mostrou que a intera??o acontece fundamentalmente atrav?s de liga??es de hidrog?nio entre as hidroxilas dos ligantes e os amino?cidos valina (Val851) e serina (Ser854), conhecidos por serem cruciais nesse processo inibit?rio provocado por f?rmacos. Na ?ltima parte do trabalho, foi avaliada a capacidade do composto 2 como agente redutor e estabilizante de nanopart?culas de prata (NanoAg), utilizando um planejamento fatorial 22, e tamb?m sua atua??o apenas como estabilizante em sua concentra??o m?nima conseguida (0,2mmol-1) utilizando o sistema glicerol/NaOH, na qual o derivado 2 foi capaz de estabilizar (NanoAg) em meio b?sico e neutro (fisiol?gico). Os resultados apontaram que a referida quinoxalina apresenta capacidade de redu??o de prata (I) em meio b?sico, por?m em cin?tica mais lenta, comparado ao seu uso apenas como agente estabilizante. E as an?lises por espectroscopia na regi?o do ultravioleta/vis?vel (UV-Vis) indicaram forma??o de NanoAg esf?ricas, assim como o c?lculo da largura ? meia altura da banda (LMAB) indicaram a forma??o de nanopart?culas mais uniformes para estes ensaios. Portanto, em ambos os testes a atua??o do composto 2 frente ? forma??o de NanoAg deixa a possibilidade de aplica??es futuras dos sistemas nanoestruturados para terapia do c?ncer.
The study of nitrogen heterocyclic compounds comprises one of the most interesting branch of the organic chemistry. Among several nitrogen heterocycles reported in literature, quinoxaline derivatives have been attracted great attention due their relevant applications, notably in biological and technological fields. There are several synthetic protocols reported in literature for the synthesis of quinoxaline derivatives, in which calls attention the use of compound 2,3-dichloroquinoxaline (1) as synthetic precursor. The present work focus on the synthesis of relevant quinoxaline from compound 1, with the results being divided in two main parts. Many of the presented reactions lead to quinoxaline derivatives with relevance in several areas, especially due their relevant activities against several pathologies. The second part of the work is focused in the obtainment of quinoxaline derivatives from reactions of building block 1 with aminoalcohol, besides other synthetic transformations. They were obtained interesting quinoxaline derivatives, such as compounds 2,3-diethanolaminoquinoxaline (2), 2-(2,3-dihydro-1-oxa-4,9,10-triaza-anthracen-4-yl)-ethanol (3), from the double substitution by the nucleophilic species, compound 3-[bis-(2-hydroxy-ethyl)-amino]-1H-quinoxalin-2-one (4) originated from the hydrolysis of compound 3, among others. An important factor is that while ethanolamine reacts via double nucleophilic N-attack, diethanolamine reacts via intramolecular cyclization process through N- and O-attacks. All products were adequately characterized by 1H and 13C nuclear magnetic resonance spectroscopies. Compounds 2 and 3 had presented interesting activity against colon rectal HT29 cancer cells, in which the activity may be associated to the inhibition of enzyme PI3K?. Both quinoxalines significantly affected cell viability depending on the lower concentration (3.125 ?g / mL), it is possible to see that the growth was delayed. This could also be verified by means of a docking study of the compounds in the active site of the enzyme PI3K?, which showed that the interaction occurs mainly through hydrogen bonds between the hydroxyls of the ligands and the amino acids valine (Val851) and serine ( Ser854), known to be crucial in this drug-induced inhibitory process. Lastly, the ability of compound 2 as a silver nanoparticle reducing agent (NanoAg), using a factorial design 22, and its performance as a stabilizer in its minimum achieved concentration (0.2 mmol / l) using the glycerol / NaOH, in which derivative 2 was able to stabilize (NanoAg) in basic and neutral (physiological) medium. The results showed that quinoxaline has silver (I) reduction capacity in basic medium, but in slower kinetics. And spectroscopy analyzes in the ultraviolet / visible (UV-Vis) region indicated a formation of spherical NanoAg, and the bandwidth width calculation indicated the formation of more uniform nanoparticles for these assays. Therefore, in both tests the performance of compound 2 against the formation of NanoAg leaves the possibility of future applications of nanostructured systems for cancer therapy.

Triostins are members of the quinoxaline antibiotic family, together with the "prototypical bisintercalator" echinomycin. These molecules display interesting antitumour activities as they inhibit transcription through insertion of their two planar quinoxaline rings into the DNA double helix, spanning two base pairs, while the peptide backbone is placed in the minor groove. The main objective of this Doctoral Thesis has been the design, synthesis and characterization of novel compounds with antitumoral activity, taking as basis the chemical structure of the natural bisintercalator triostin A. Synthetically challenging peptides bearing consecutive N-methyl and beta-branched amino acids were obtained after careful selection of a suitable coupling system for the solid-phase synthesis of the peptidic scaffolds. The introduction of the heterocycles and side-chains deprotection were carried out in solution as final stages. At the end, a small library of twelve peptides, fifteen quinoxaline-containing peptides and three fluorescent versions were obtained in excellent purities and employed in further biological evaluations. The synthesized compounds were evaluated for their antitumoral activity using the MTT assay, performing preliminar determinations of the detection limits of the assay, the lenght of the exponential phase of the cell lines tested and their doubling times. The most active compound was RZ2, with low micromolar cytotoxic activities, being in all cases more active than the natural parent compound triostin A, and with better cytotoxic activity than the commercial drug doxorubicin against cervical and breast adenocarcinoma cells. Unfortunatelly, compound RZ2 was also cytotoxic against non-tumor endotelial cells. However, this same compound resulted also active against the parasite Plasmodium falciparum. The stability of RZ2 in human serum and in presence of two overexpressed tumor proteases, MMP2 and cathepsin B, was studied. A little percentage of degradation was observed from 24 hours, with a maximum degradation of 30% in presence of serum at 48 hours. These data indicate that the peptide is advantageous in terms of proteolytic stability in vivo. Moreover, RZ2 is not hemolytic ex vivo, pointing out the great potential of this compound in antiplasmodial treatment without nocive effects on human erythrocytes. Furthermore, a liposomal formulation of compound RZ2 was prepared using egg phosphatidylcholine and cholesterol so as to obtain small unilamellar vesicles and improve the solubility of the quinoxaline-containing peptide. In regard of the mode of action of the synthesized compounds, it was demonstrated through circular dichroism, band-shift and DNase I footprinting experiments that there is no interaction with the genetic material. Molecular dynamics simulations showed that the analogues do adopt the predicted antiparallel beta-sheet conformation, but the separation between the quinoxaline moieties is too little to allow the sandwitching of two DNA base pairs. Non-synchronized HeLa cells cultures treated with compound RZ2 resulted in S phase-arrest. PI permeability assays coupled to annexin V labeling in HeLa cells showed increased PI/annexin V labeling in response to RZ2 in a time-dependant manner. Induction of apoptosis was confirmed by an increase in the sub-G1 DNA fragmentation in response to the compound over time. Furthermore, cells treated with RZ2 for 48 hours showed increase in active caspase 3 and poly(ADP-ribose) polymerase levels, confirming that HeLa cells die as a result of apoptosis when exposed to RZ2. Internalization into the cytosol was studied using a fluorescent version of RZ2 that displayed similar cytotoxicity. It was observed that the compound accumulates in acidic compartments and may inhibit the autophagic responsed triggering apoptosis. Changes in gene expression before the apoptotic pathway activation were studied using a gene expression microarray. Results suggest that RZ2 induces metabolic stress in HeLa cells.

Nesta tese são apresentados, em dois capítulos, os resultados da reatividade química de quinoxalinas e os estudos visando à síntese de quinona natural, a vegfrecina. Modificações específicas em estruturas privilegiadas, padrões estruturais relevantes para bioatividade, representam uma alternativa viável na busca de novos ligantes para alvos macromoleculares. Neste cenário, as quinoxalinas apresentam destacada importância no âmbito da química medicinal, sendo assim é de grande importância o desenvolvimento de metodologias de funcionalização que conduzam a diversidade molecular deste núcleo. Neste contexto, foram realizadas reações de ativação C - H, como uma estratégia para a síntese de derivados vinil quinoxalinicos, com base na abordagem de Fujiwara-Moritani. Os resultados obtidos com este estudo indicaram que a densidade eletrônica das olefinas utilizadas neste estudo foi determinante para o rendimento reacional. Assim, as reações envolvendo olefinas ricas em elétrons, resultaram em maior rendimento do produto alquenilado, alcançando 89%. A deoxidação ocorreu em rendimentos de 43 - 54%, levando a ampliação da coleção de compostos desenvolvidos neste projeto. Os compostos aqui desenvolvidos foram testados quanto à atividade antimicobacteriana, entretanto, nenhum deles apresentou resultados promissores. O segundo capítulo desta tese abordou a síntese da Vegfrecina, que possui seletividade de inibição dos receptores do fator de crescimento endotelial vascular (VEGFR), bloqueando a ativação de VEGFR-1 e VEGFR-2 e, consequentemente, interferindo na vascularização, proliferação e metástase tumoral. Nossa estratégia utilizou o intermediário chave 6-Bromo-5,8-dimetoxi-2,2-dimetil-2,3-dihidroquinazolin-4(1H)-ona em reações de aminação de Buchwald Hartwig com três anilinas diferentes. Embora tenhamos obtido três intermediários sintéticos inéditos, em bons rendimentos, a etapa de oxidação não foi promissora, impossibilitando a obtenção da Vegfrecina e de seus análogos.
The study of chemistry reactivity of quinoxalines and the study aiming total syntheses of natural quinone, vegfrecine, are shown in this thesis in two chapters. The specific modifications privileged scaffold represents a promising way following for new macromolecular ligands targets. Considering the great importance of quinoxaline core in medicinal chemistry, the development of efficient methodologies in orther to obtain molecular diversity have attracted large attention. In this context, using Fujiwara-Moritani approach the C-H activation reactions were performed as good strategy in synthesis of vinyl- quinoxaline derivatives. Our results indicated the importance of olefin electron density in the reaction yields. In this way, reactions involving high electron density olefines, results in the high alkenilated products, achieving 89% of yield. The deoxygenation process occurred in yields of 43 until 54. The compounds obtained were tested against Mycobacterium tuberculosis, however no primissing results were observed. The second chapter in this thesis show our attempt to total synthesis of Vegfrecine, that have inhibitory activity of vascular endothelial growth factor receptor (VEGFR), Our strategy used the 6-bromo-5,8-dimethoxy-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one in Buchwald Hartwig reaction with three different olefins. Although these new synthetic intermediates were obtained with good yield, the last step of oxidation didn\'t work. Therefore, it was not possible to obtain the Vegfrecine and its analogous.

碩士
國立中央大學
化學學系
101
Abstract This thesis aims to systematically design and synthesizie a number of model molecules with tetraethynylethene and quinoxalinoid structural units. We tentatively construct several model compounds with various structure. By changing their connecting electron-withdrawing group or electron-donating group , π-bridge and their number of branches, we can investigate how these changes in structure influence the two-photon absorptivities and other optical properties. After a series of linear and nonlinear optical measurements, our findings can be summarized as the following: The experimental results show that adding electron donor to the structure or extending the π-conjugation length will enhance the molecular two-photon absorptivities. We also found that inserting quinoxalinoid hetercyclic structures to our model chromophores especially indenoquinoxaline structure may exhibit strong two-photon activities and also cause outstanding solvent effects in solution phase.

碩士
國立交通大學
應用化學系
87
Abstract The goal of our research is to synthesize the precursors for quinoxalino-o-quinodimethanes, and to explore their potential application in Diels-Alder reaction. The advantage of using sultines is their ease of SO2 extrusion at lower temperature than the corresponding sulfolenes. After successfully synthesizing 2,3-diphenylquinoxalino-6,7-sultine (55c), we have studied their thermochemistry and photochemistry. These heterocyclic sultines extrude SO2 and form the corresponding o-quinodimethanes at high temperature (200 oC), which in turn react with dienophiles to give excellent yield of cycloadducts. The products from photochemical reactions (irradiated with 254 nm UV-light) are similar to those from thermochemical reactions besides that corresponding sulfolene and some quantity of insoluble ploymers are formed photochemically. When quinoxalino-fused sultine (47d)、(55b-c), 2,3-bis (bromomethyl) -5,10-benzo[g]quinoxalinedione (94) and naphtho-sultine (113) are heated with C60, the mono-Diels-Alder-adducts of the C60 are obtained successfully. Variable temperature 1H-NMR experiments show that the sxistence of nitrogen atoms and the distance between the nitrogen atoms and C60 core may have a great influence on the rate of boat-to-boat conformations exchange of C60 mono-adducts. Laser flash photolysis (248 nm) on these quinoxalino-sultine leads to the detection of a new transient spices, which is very likely to be the corresponding o-quinodimethane or biradical intermediates. Further work and theoretical calculation is needed to confirm these observations.

碩士
國立中央大學
化學研究所
100
Several series of multi-branched chromophores containing tetra-substituted ethylene and quinoxalinoid hetercyclic structures have been synthesized and characterized for their linear and nonlinear optical properties. The experimental results show that adding electron donor to the structure or extending the??-conjugation length will make a red-shift in the best absorption wavelength and also enhance the molecular two-photon absorptivities. We also found that inserting quinoxalinoid hetercyclic structures to our model chromophores especially indenoquinoxaline structure may exhibit strong two-photon activities and also cause conspicuous solvent effects in solution phase. It will have higher fluorescence quantum yield in nonpolar solvent like toluene, but longer fluorescence life time in polar solvent like THF. Because these model chromophores possessed excellent effective optical power limiting behaviors with strong two-photon absorption, so they could be efficacious optical limiters especially when against longer laser pulses.

碩士
國立中央大學
化學學系
101
The purpose of this thesis is to systematically design and synthisize a number of model molecules containing quinoxaline units. These model compounds can be catergorized into two types: symmetrically branched and unsymmetrically branched structures. We tentatively construct several model compounds with various structural parameters in order to investigate the influene that may be caused by electronic properties of the central π-bridge and the number of branches on the molecular two-photon absorptivities. After a series of linear and nonlinear optical measurements, our findings can be summarized as the following: Either the electronic nature or the length of the conjugated bridge or the number of peripheral branches in a dye molecule is closely related to the molecular two-photon absorptivities. On the other hand, it has been demonstrated that the incorperation of quinoxaline units may lead to longer excited-state lifetime, which is beneficial to the optical-control related applications.

碩士
國立中正大學
化學所
95
Carbonic anhydrase (CA) is a zinc-containing metalloenzyme that is widespread in nature and catalyzes the reversible hydration of CO2 to HCO3- and H+. CA is expressed in a number of isoforms (CA I-XIV) with varying degrees of enzymatic activity and participates in various physiological/pathological processes in human body. Inhibition of the zinc metalloenzyme human CAII by sulfonamides has the potential to treat clinically important diseases such as glaucoma, osteoporosis and most recently cancers. In this study, a new class of human CAII inhibitors with conformationally constrained core structure was designed to increase its binding affinity. Totally, Sixteen quinoxalinone-based sulfonamide inhibitors were synthesized in 2~3 steps with the total isolated yields of 5-89%. The activity (Ki) of these inhibitors toward human CAII were screened spectrometrically and determined by the Lineweaver-Burk plots. The inhibition constants obtained were in the range of 370-8200 nM. In this study, the conformationally constrained inhibitors were demonstrated to be more potent in the inhibition of human CAII, as compared to the conformationally relaxed inhibitors. In addition, the rigidity of the fused aromatic ring appears to play important role in enzymatic inhibition. Ionic liquids are solvents systems that consist of cation and anions at ambient temperature. We previously reported the new ionic liquid, [b-3-C-im][NTf2], which is not only chemically stable, but also has a low melting point, low water content and dynamic viscosity. In this work, this new ionic liquid was applied to the Claisen rearrangement reaction，in conjunction with focused microwaves. Under the optimized conditions, the Claisen rearrangement reaction was achieved in 3 minutes. Moreover, the Lewis acid (MgCl2) was introduced to decrease the reaction temperature (250℃→200℃) successfully, and with good overall isolated yield.