Carbon-Carbon bond forming reactions are very important in organic synthesis. Preparation of most of the leading drugs on the market involves at least one carbon-carbon bond forming transformation. However, use of preformed oganometallics for this purpose is neither atom economical nor cost effective. Thus, development of atom economical and environmentally benign carbon-carbon bond forming methods is highly desirable. Catalytic hydrogenation is one of the most widely used transformations in the pharmaceutical and chemical industry. However, for several years the catalytic hydrogenation was limited to the carbon-carbon bond forming processes such as alkene hydroformylation and the Fischer-Tropsch reactions. In 2004 Krische group demonstrated a novel reductive aldol cyclization under rhodium catalyzed hydrogenation conditions. Following this, a variety of reductive carbon-carbon bond forming reactions were developed under hydrogenation conditions. The first chapter of this dissertation summarizes the reductive couplings of π-unsaturates to imines. N-heterocyclic compounds are very valuble in pharmaceutical and agrochemical industries. In the second chapter a variety of hydrogen mediated reductive couplings to aromatic N-heterocycles have been described. Transfer hydrogenation represents another important class of reactions in organic chemistry. This process employs hydrogen sources other than gaseous dihydrogen, such as isopropanol. Very recently, the Krische group reported a number of novel C-C coupling reactions using the concept of transfer hydrogenation. Thus, in chapter 3 a very elegant ruthenium catalyzed allylation reaction has been described. Finally, chapter 4 focuses on the reactivity of zinc enolates toward less reactive electrophiles such as allylic carbonates in the absence of any transition metal catalyst. During this process a direct allylic substitution of allylic carbonates with diorganozinc reagents has been discovered. These two transformations are conceptually very interesting. / text

Chiral cyclic alkenols with hydroxymethyl functionality are important structural units in many biologically active natural compouds such as prostaglandins, sesquiterpene antiviral agents, pentenomycins, xanthocidin, sarkomycin, etc. 1,3-cycloalkanediones are converted into bicyclic polyoxo derivatives with formaldehyde and trioxane in the presence of Lewis acid. Selective oxidation of the bicyclic compounds by using manganese(III)acetate followed by enzyme-catalyzed kinetic resolution afforded chiral bicyclic hydroxy ketones. Reduction of carbonyl group and cleavage of the ether functionality furnished the desired chiral cycloalkanols with hydroxymethyl group. This study is a model for the synthesis of these type of compounds.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of two 1-methyl-3-alkylimidazolium tetrafluoroborate (where alkyl = butyl, octyl; [BMIM]BF4 and [OMIM]BF4) based on room temperature ionic liquids (RTIL) is reported. The usefulness of these ionic liquids in organic synyhesis was evaluated through three reactions such as: (i) preparation of the N,N-dimethylenaminones (RCOCH=CHNMe2, where R = Ph, 4-Me-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph, 4-O2N-Ph, fur-2-yl, tien-2-yl, pyrrol-2-yl, pyrid-2-yl, CH(OMe)2, octyl) from the condensation reaction of N,Ndimethylformamide dimethyl acetal with methylketones; (ii) preparation of the 6-dimethylamino-1,1,1-trifluoro-4-methoxy-3,5-dien-2-one [CF3COCH=CH(OMe)CH=CHNMe2, from the condensation reaction of N,Ndimethylformamide dimethyl acetal with appropriated 1,1,1-trifluoro-4-methoxy-3-penten-2- one and (iii) N-alkylation reaction of 3,5-dimethyl- and 5-trifluoromethyl-3-methyl-1Hpyrazoles, from the reaction of the N-H pyrazoles with alkyl halides (R1 X, where R1 = Bu, octyl, allyl, benzyl, CH₂CH₂CONEt₂). The reaction time, and the yields were investigated and this method showed advantages over the methods described in the literature. / Neste trabalho é relatado a síntese de dois líquidos iônicos, tetrafluorborato de 1-alquil-3-metil imidazolíneo, com alquil = butil, octil ([BMIM]BF4 and [OMIM]BF4) e sua utilização como meios reacionais. A adequabilidade dos líquidos iônicos foi avaliada em três reações: (i) síntese de N,N-dimetilenaminonas (RCOCH=CHNMe2, com R = Ph, 4-Me-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph, 4-O2N-Ph, fur-2-il, tien-2-il, pirrol-2-il, pirid-2-il, CH(OMe)2, octil) a partir da reação de condensação N,N-dimetilformamida dimetilacetal com metilcetonas; (ii) síntese de 6-dimetilamino-1,1,1-trifluor-4-metoxi-3,5-dien-2-ona [CF3COCH=CH(OMe)CH=CHNMe2, a partir da reação de condensação de N,Ndimetilformamida dimetilacetal com 1,1,1-trifluor-4-metoxi-3-penten-2-ona e (iii) reação de N-alquilação de 3,5-dimetil- and 5-trifluorometil-3-metil-1H-pirazol, a partir da reação de NH pirazóis com haletos de alquila (R¹ X, com R¹ = Bu, octil, alil, benzil, CH₂CH₂CONEt₂). O tempo reacional e os rendimentos foram avaliados e o método mostrou vantagens em relação aos outros métodos descritos na literatura.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The regiochemistry study of the formation of a series of aryl-, heteraryl- and haloalkyl-substituted isoxazoles from the reaction of β-dimethylaminovinyl ketones and hydroxylamine is reported. The precursors β-imethylaminovinyl ketones were obtained from the condensation reaction of N,N-dimethylformamide dimethyl acetal and the substituted ketones [R-C(O)-CH3, where R = Ph, MeO-4-C6H4, Me-4-C6H4, F-4-C6H4, Cl- 4-C6H4, Br-4-C6H4, O2N-4-C6H4, Fur-2-yl, Tien-2-yl, Pyrrol-2-yl, Pyrid-2-yl, and CCl3]. The study shown that for R = trichloromethyl substituent was obtained regiospecifically 5-halomethyl-4,5-dihydroisoxazoles. For precursors with R = O2N-4-C6H4, Fur-2-yl were obtained 3-aryl-4,5-dihydroisoxazole, for R = MeO-4-C6H4, F-4-C6H4, Br-4-C6H4, Pyrrol-2-yl were obtained 5-aryl[heteroaryl]isoxazoles, and for remainder substituents (R = Ph, Me-4-C6H4, Cl-4-C6H4, Tien-2-yl, Pyrid-2-yl) were obtained a mixture of the 4,5-dihydroisoxazoles-1,3 and isoxazoles-1,5. The effect of the substituent on the regiochemistry of isoxazoles obtained was discussed with bases on a MO calculations data. / Este trabalho descreve o estudo da regioquímica de formação de uma série de isoxazóis aril-, heteroaril- e haloalquil substituídos, a partir da reação de β- dimetilaminovinil cetonas e hidroxilamina. O precursor β-dimetilaminovinil cetona foi obtido a partir da reação de condensação de N,N-dimetilformamida dimetil acetal e a cetona substituída [R-C(O)-CH3, onde R = Ph, MeO-4-C6H4, Me-4-C6H4, F-4-C6H4, Cl-4-C6H4, Br-4-C6H4, O2N-4-C6H4, Fur-2-il, Tien-2-il, Pirrol-2-il, Pirid-2-il, e CCl3]. O estudo mostrou que para R = triclorometil substituinte foi obtido regioespecificamente 5-halometil-4,5-diidroisoxazóis. Para precursores com R = O2N-4-C6H4, Fur-2-il foram obtidos 3-aril-4,5-diidroisoxazóis, para R = MeO-4-C6H4, F-4-C6H4, Br-4-C6H4, Pirrol-2-il foram obtidos 5-aril[heteroaril]isoxazóis, e para os demais substituintes (R = Ph, MeO-4- C6H4, Cl-4-C6H4, Tien-2-il, Pirid-2-il) foram obtidos uma mistura de 4,5-diidroisoxazóis-1,3 e isoxazóis-1,5. O efeito do substituinte na regioquímica dos isoxazóis obtidos foi discutido com base nos dados de cálculos de orbitais moleculares (AM1).

Orientador: Fernando Antonio Santos Coelho / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T03:26:42Z (GMT). No. of bitstreams: 1 Gomes_JulianaCristina_D.pdf: 10331708 bytes, checksum: ab47fef95625c8a9b0232f0e3db6d428 (MD5) Previous issue date: 2014 / Resumo: A reação de Morita-Baylis-Hillman (MBH) é um método atrativo para a formação de ligação carbono-carbono. Esta transformação tem atraído a atenção devido ao fato dela ser seletiva (quimio-, régio-, diastereo-, e enantio-) e ser também um método com alta economia de átomos, convertendo substratos simples em produtos poli-funcionalizados de grande versatilidade sintética. Entretanto, apesar de suas inúmeras vantagens, essa reação possui vários inconvenientes tais como baixas velocidades, rendimentos moderados, alta concentração de catalisador nucleofílico e o uso de solventes orgânicos, o que dificulta a sua utilização industrial. Dessa maneira, fica claro a necessidade da busca de novos catalisadores e metodologias eficientes, tanto em termos de rendimentos, velocidades reacionais, quanto em termos de versatilidade, para que se possa ser aplicada a uma ampla variedade de substratos. Neste trabalho foi demonstrado o uso de um novo catalisador, um álcool derivado imidazólico bicíclico, para reações de MBH com enonas cíclicas. Esse novo catalisador funcionou eficientemente em um protocolo ecologicamente amigável, no qual as reações de MBH procederam em meio aquoso e com uma quantidade catalítica de dodecil sulfato de sódio (SDS), sem a necessidade de co-solventes orgânicos. Além disso, foi demonstrado que esse álcool imidazólico bicíclico é o único catalisador para reações de MBH aquosas entre isatinas não protegidas e enonas cíclicas, fornecendo núcleos 3-hidroxi-2-oxoindóis substituídos. Esse catalisador também pôde ser resolvido e aplicado na versão assimétrica dessa reação. E outros derivados imidazólicos foram sintetizados e também testados em MBH / Abstract: The Morita-Baylis-Hillman reaction is an attractive method for the construction of carbon_carbon bonds. This transformation has attracted attention due to the fact that it is selective (chemo, regio-, diastereomeric and enantiomeric) and also a method with high atom economy, converting simple substrates in poly-functionalized products of great synthetic versatility. Despite its interesting benefits, the MBH reaction suffers from several drawbacks, such as low reaction rates, moderate yields, high concentration of the nucleophilic catalyst, poor reactivities of ?-substituted activated olefins and of cyclic enones, and use of hazardous organic solvents, that have hampered its industrial utilization. Thus, it is clear the need to search for new catalysts and efficient methodologies, both in terms of yields, reaction speeds, and in terms of versatility, so that it can be applied to a wide variety of substrates. This work demonstrated the use of a new catalyst, an alcohol bicyclic imidazole derivative, for reactions with cyclic enones MBH. Thus, it is clear the necessity of finding new catalysts and efficient methodologies, both in terms of yields, reaction speeds, and in terms of versatility, so that it can be applied to a wide variety of substrates. This work demonstrated the use of a new catalyst, an alcohol bicyclic imidazole derivative, for reactions with cyclic enones MBH. This new catalyst worked effectively in ecofriendly conditions, where the MBH reactions proceeded in an aqueous medium with a catalytic amount of sodium dodecyl sulfate (SDS), without organic co-solvents. Furthermore, it was shown the imidazole bicyclic alcohol is the only catalyst for MBH aqueous reactions between isatins unprotected and cyclic enones, providing cores 3-hydroxy-2-substituted oxoindóis. This catalyst could also be resolved and applied to the asymmetric version of this reaction. And other imidazole derivatives were synthesized and also tested in MBH / Doutorado / Quimica Organica / Doutora em Ciências

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Several methods for the regioselective synthesis of trifluoromethylated heterocycles from 4-alcoxy-1,1,1-trifluoro-3-alken-2-ones and hydrazones are described. In the first part of this work, a series of (E)-2-[N -benzyl(1-phenylethyl)idenehydrazino]-4-trifluoromethyl-pyrimidines were obtained in a convergent manner from the cyclocondensation reaction between Nguanidinobenzylimines and 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in excellent yields (68-99%). Most reactions were highly diastereoselective and the benzyliminic bound presented preferably the E configuration which was determined by single-crystal X-ray analysis of two diastereoisomeric pure benzylidenepyrimidines derivatives. Afterwards, the synthetic versatility of these pyrimidines was demonstrated through the synthesis of 2-(N -enzylhydrazino)-4-trifluoromethyl-pyrimidines and 3-aryl-7-trifluoromethyl[1,2,4]triazolo[4,3- a]pyrimidines. The synthesis of benzylhydrazinopyrimidines were achieved from the selective reduction of the benzyliminic moiety of the benzylidenepyrimidines employing NaBH3CN as reduction agent in an acidic media (pH 3-5). Yields were in the 33-74% range. The 1,2,4-triazolo[4,3-a]pyrimidines were isolated after oxidative heterocyclisation promoted by a copper II catalyst. Those reactions proceeded under mild conditions (DMF, 1.5h, 50-90 °C), were highly chemoselective and yields from 33 and 70%. In the second part of this work, the synthesis of 1-phenyl-3-trifluoromethyl-1H-pyrazoles from 4-alkoxyvinyl trifluoromethyl ketones and phenylhydrazine hydrazones are reported. Those heterocyclisations were highly selective, presented good yields (40-93%) and furnished a series of new enaminones as reaction intermediates. Those reactions that furnished a mixture isomeric pyrazoles, the major isomer was easily isolated through column chromatography. / Esta tese descreve diversas metodologias para a síntese regiosseletiva de heterociclos trifluormetilados a partir de 4-alcóxi-1,1,1-triflúor-3-alquen-2-onas e hidrazonas. Na primeira parte do trabalho, uma série de (E)-2-[N -benzil(1-feniletil) idenohidrazino]-4-trifluormetilpirimidinas inéditas foi obtida de maneira convergente a partir da ciclocondensação entre N-guanidinobenziliminas e 4-alcóxi-1,1,1-triflúor-3-alquen-2-onas em ótimos rendimentos (68-99%). A maior parte das reações foram altamente diastereosseletivas e a configuração E da ligação benzilimínica foi considerada preferencial após análise por difração de raios X dos monocristais de duas benzilidenopirimidinas diastereoisomericamente puras. Posteriormente, a versatilidade sintética desses heterociclos foi demonstrada através da obtenção das 2-(N - benzilhidrazino)-4-trifluormetilpirimidinas e das 3-aril-7- trifluormetil[1,2,4]triazolo[4,3-a]pirimidinas. As benzilhidrazinopirimidinas foram obtidas a partir da redução seletiva do grupo benzilimínico das benzilidenopirimidinas empregando NaBH3CN como agente redutor em meio ácido (pH 3-5) com rendimentos que variaram entre 33-74%. As 1,2,4-triazolo[4,3-a]pirimidinas, por sua vez, foram sintetizadas a partir do mesmo precursor através de heterociclização oxidativa mediada por cloreto de cobre II. Essas reações empregaram condições reacionais relativamente brandas (DMF, 1,5h, 50-90 °C), foram altamente quimiosseletivas e apresentaram rendimentos entre 33-70%. Na segunda parte deste estudo, a síntese de 1-fenil-3-trifluormetil-1Hpirazóis a partir das 4-alcoxivinil-trifluormetil cetonas e das hidrazonas derivadas da fenilhidrazina foi descrita. Essas heterociclizações foram altamente seletivas, apresentaram bons rendimentos (40-93%) e ainda possibilitaram a obtenção de uma série de enaminonas inéditas como intermediários reacionais. Nas reações em que foram obtidas misturas de pirazóis isoméricos, os isômeros majoritários desejados foram isolados por cromatografia em coluna.

Rhodium-catalysed hydroacylation provides a highly atom economic synthesis of ketone products from the combination of aldehydes and multiple bond systems by C-H bond activation. This work evaluates the combination of intermolecular hydroacylation for the synthesis of classical heterocycle precursors and their dehydrative cyclisation to give rise to a range of substituted heterocyclic compounds. Chapter 1 outlines recent developments in the chemistry of hydroacylation. Particular attention is paid to the various chelation strategies employed in intermolecular hydroacylation. Chapter 2 discusses some relevant and recent developments in the field of pyridine and pyrrole synthesis. Having established that β-sulphur chelation controlled hydroacylation can be used to synthesise pyridines in Chapter 3; attention was turned to hydroacylation of propargyl amines in Chapter 4. The methodology was expanded to provide a synthesis of γ-amino enones. The hydroacylation reaction and cyclisation is combined in a procedure that utilises thermal Boc-deprotection and cyclisation to give a range of highly-substituted pyrroles. The regioselectivity of the hydroacylation of propargyl amines is investigated in Chapter 5 by application of statistical Design of Experiments methodology. Optimised conditions were identified with minor improvements in the selectivity of the reaction.

Ce travail traite de l’exploration de la biodiversité des Baeyer-Villiger MonoOxygénases (BVMOs) : des enzymes utilisées en biocatalyse pour la production de lactones optiquement pures à partir de cétones. Pour mettre à bien cet objectif nous avons réalisé, en association avec le Génoscope d’Evry, une sélection de plusieurs centaines d’enzymes couvrant une forte diversité génétique. Après clonage et criblage à haut débit sur plus de vingt substrats différents nous avons obtenus plus de 90 nouvelles BVMOs. Avec ce résultat nous avons triplé le nombre de BVMOs connues dans la littérature. Dans un second temps nous avons étudié l’activité de certaines de ces nouvelles enzymes sur les cétones α,β-insaturées (ou enone), Ces substrats sont peu étudiés en biocatalyse et, lors de la réaction chimique, aboutissent à la formation de nombreux sous-produits. Deux enzymes d’O.batsensis et de P. lavamentivorans se sont révélées être actives aboutissant à la production d’ene-lactone et d’enol-lactone respectivement. La conversion de certaines enones chirales a abouti à des lactones présentant un fort excès énantiomérique.Nous avons ensuite étudié la régio-sélectivité de 35 enzymes issues du criblage sur une série de cétones aliphatiques acycliques. Alors que la formation de l’ester méthylique est très rare, nous avons obtenu des résultats très variés pour la formation de l’ester éthylique allant jusqu’à 80%. Le travail de thèse s’est terminé par le développement d’une cascade enzymatique sur la production d’ester à partir d’alcool secondaire. La cascade implique deux enzymes : une Alcool Déshydrogénase et une BVMO. La cascade est à la fois fonctionnelle et est très efficace. / -

Au cours de nos différents travaux sur les réactions de cyclisations électrophiles diastéréosélectives 5-endo d’hydroxamates insaturés par l’hexafluorophosphate de bromo biscollidine (HBB). Nous avons constaté la formation d’imidates cycliques et nous avons mis en évidence un réarrangement lactames-imidates. Une fragmentation de type Beckman aboutissant à la formation d’une famille de cyano énones, anisi qu’une nouvelle formation d’imidates a été étudiée.Dans l’introduction générale, nous avons rapporté différents exemples d’halolactonisations électrophiles 5-endo et 5-exo, énantio et diastériosélectives rapportés dans la littérature, ainsi que les facteurs influençant la régio et la diastereoselectivité de ces cyclisations.Dans le premier chapitre, après un rappel bibliographique sur les différentes synthèses de lactames à partir de différents substrats par cyclisation électrophile, nous avons présenté nos propres travaux.Le traitement d’hydroxamates β, γ−éthyléniques γ-disubstitués avec de l’hexafluorophosphate de bromo bis(sym-collidine) dans du dichlorométhane aboutit à la formation de lactames et d’imidates cycliques. On a pu confirmer par des études RMN, l’existence d’un réarrangement lactame-imidate cyclique.Dans une deuxième partie, nous avons étudié la diastereosélectivité de la cyclisation. A cet effet, des hydroxamates optiquement actifs ont été synthétisés via la méthodologie développée par Evans. Dans tous les cas, un seul produit, un bromo-imidate cyclique optiquement actif est obtenu.Dans le deuxième chapitre, l’étude de la réaction de cyclisation des hydroxamates β, γ−éthyléniques γ-monosubstitués avec HBB, nous a permis de mettre en évidence une fragmentation de type Beckmann. Cette dernière est améliorée par réaction des produits de cyclisation avec de la triethylamine. On a généralisé cette fragmentation en l’appliquant à différents substrats.Enfin, dans le troisième chapitre, après une étude bibliographique sur la synthèse d’imidates et leurs utilités en synthèse organique, on a synthétisé des imidates β, γéthyléniques, afin de les utiliser comme substrats dans la réaction de cyclisation éléctrophile utilisant HBB. Dans ce cas aussi, la formation d’imines cycliques est constatée. / This work deals with the 5-endo halogeno electrophilic cyclization reactions of β,γ-ethylenic hydroxamates to give halolactames and halo cyclic iminolactones.In the first chapter, the reaction of γ-disubstituted β,γ-unsaturated hydroxamates with bis(collidine)bromine(I) hexafluorophosphate is studied. This type of reaction led mainly to the formation of bromo cyclic imidates, which were the thermodynamic products. Unsaturated cyclic imidates were then obtained by reaction with triethylamine. A lactame-iminolactone rearrangement was obtained during those reactions. In a next step we decided to study the diastereoselectivity of the reaction, using optically actif hydroxamates. In the second chapter, we decided to study the reaction of bis(collidine)bromine(I) hexafluorophosphate with γ-aryl β,γ-unsaturated hydroxamates, the corresponding bromo cyclic imidates were also obtained. However, by reaction with triethylamine, these compounds led with good yields, to the formation of 3-cyano-2-propen-1-ones by a Beckmann type fragmentation reaction. In the third chapter, the reaction of γ-mono and disubstituted β,γ-unsaturated imidates with bis(collidine)bromine(I) hexafluorophosphate is studied. The results that we obtained were not sufficient enough to understand the electrophilic cyclization mechanism of these types of substrates.

The first part of the thesis presents the reinvestigation of the synthetic and mechanistic aspects of manganese (III) acetate mediated reactions. The main concern about this subject was to perform a &cent / - acetoxylation reactions of enones and saturated systems in shorter reactions times and higher yields than the ones known in literature reproducibly. Although successful a &cent / -acetoxylation of a great variety of substrates have been reported so far, there are some problems associated with the use of Mn(OAc)3. Considering that there are not many simple methods for the direct acetoxylation of enones, optimization of Mn(OAc)3 mediated a &cent / -acetoxylation of enones and reaching its maximum potential has a great importance from a synthetic and economical point of view. In the second part of the thesis, 1,2,4-trisubstituted pyrrole derivatives were the target molecules to be synthesized. Although there are quite a number of methods available for the synthesis of pyrroles, most of them involve multistep synthetic operations which lower the overall yield. There are limited reports on the preparation of the enantiomers of pyrrole derivatives having 1-N directly linked to the stereogenic center. Thus, developing a new synthetic method for the efficient preparation of polysubstituted pyrroles without racemization still remains an attractive goal.