Palladium catalyzed Heck coupling with aryl and alkenyl halides has become a powerful means of carbon-carbon bond formation. This standard synthetic method has been developed to a high level of utility using various catalysts, conditions and substrates. Yet significant drawbacks remain, including poor reactivity, the need for high temperatures and base, limited substrate generality, and selectivity. Mixed products often suffer from olefin migration following insertion. N-Heterocyclic carbenes (NHC) have proven to be electron-rich donors which provide higher stability and reactivity than phosphines. In a previous paper reported by our research group the imidazolium-palladium carbene has proven to be highly efficient for the Suzuki-Miyaura cross couplings. The most active bis-2,6- diisopropylphenyl dihydroimidazolium chloride ligand 1 in that series together with palladium acetate were employed as the catalyst, to efficiently catalyze the Heck coupling of aryl diazonium ions with olefins with useful yields at room temperature. Added base is not needed either to form the carbene catalyst or for alkene product formation. Phase-Transfer Catalysis (PTC) is a very useful approach and has been widely used in synthetic organic chemistry. A novel class of fluoroanthracenylmethyl PTC catalysts were synthesized and explored for asymmetric glycolate and glycine alkylation. Phosphorous pentoxide was used for the challenging electron-deficient electrophilic aromatic substitution step. These new catalysts proved to have high selectivities for glycine alkylation under mild conditions.

No description available.

No description available.

O emprego da catálise de transferência de fase substituindo uma ou mais etapas da síntese de um fármaco, pode ser um recurso vantajoso sob o ponto de vista tecnológico. Empregado na síntese de importantes fármacos que são a dicicloverina, caramifeno eamiodarona, a catálise de transferência de fase revelou-se muito vantajosa na síntese dos dois primeiros. A dicicloverina e o caramifeno tiveram as suas rotas de obtenção verticalizadas, com bons resultados e custos bem mais baixos quando comparados com os atualmente adquiridos no exterior. Ficou evidente que a catálise de transferência de fase pode ser aplicada com sucesso na produção destes e outros fármacos em associação com técnicas já conhecidas com ótimos resultados. / The phase transfer catalysis application replacing one or more steps in the drug synthesis, can be of advantage in the technologycal approach. Applied to the synthesis of important drugs such as diciclomine, caramiphen,and amiodarone, the phase transfer catalysis resulted in a very advantageous method in the first two drugs. The diciclomine and the caramiphen, gets their obtention routes from raw materiaIs wi th good resul ts and low coasts, when compared wi th the drugs presently purchassed in foreign countries. It is clear that the phase transfer catalysis, can be applied succesfully in the manufacturing of these and other drugs, in conjuction with known techniques with good results.

O presente trabalho teve como objetivo central estudar, sob condições de Catálise de Transferência de Fase, as reações de C-alquilação de diversos compostos contendo em sua estrutura molecular os grupos α-fenil ou α-naftilacetila: (Ver arquivo PDF). Nas várias reações efetuadas, foram empregados o hidrogenossulfato de tetrabutilamônio (TBAH) e catalisadores quirais derivados de alcalóides da cinchona. Foram investigadas, para cada substrato, várias condições experimentais, tanto em sistema sólido-líquido como líquido-líquido. Nas reações dos ésteres (24), (25) e (26) foram observados produtos derivados da hidrólise do grupo éster. No entanto, para os ésteres (27), (28) e (29) a reação de C-alquilação era preponderante, o que permitiu a extrapolação ao uso de catalisadores quirais. Para estes substratos, apenas o produto de C-alquilação do éster (28) apresentou excesso enantiomérico (8-12%). Os resultados insatisfatórios obtidos para os 6 ésteres estudados foram atribuídos à baixa acidez dos prótons metilênicos, à enolização do produto ou a fatores estruturais. O produto da C-benzilação da amida (31) foi isolado em baixo rendimento e 30% de excesso enantiomérico. Uma comparação com os resultados obtidos para amida (30) permitiu inferir que a substituição de um grupo fenila por um grupo naftila produz um aumento de reatividade e uma melhor interação com o catalisador quiral. No caso da acil-imina (32) e das acil-hidrazonas (33) e (34) os produtos foram obtidos em rendimentos de médios a bons e apresentavam atividade óptica. No entanto, a dificuldade técnica de determinar seu excesso enantiomérico impossibilitou a avaliação da enantiosseletividade das reações de C-alquilação efetuadas com estes substratos. O conjunto dos resultados obtido foi analisado à luz dos modelos atualmente propostos para reações de CTF assimétrica. / The present work focussed on the alkylation reactions, via Phase Transfer Catalysis, of several acyl derivatives: (See files PDF). In order to evaluate the extension of the backgroud reaction, several blank experiments were performed, in the absence of catalyst. The efficiency of the catalitic process was determined using as catalyst an achiral ammonium salt (TBAH). Experimental conditions were optimized using liquid-liquid or solid-liquid systems. In reactions performed with the ester derivatives (24), (25) and (26), hydrolytic acyl cleavage could be observed. However, for compounds (27), (28) and (29), C-alkylated products could be isolated in reasonable yields. Reactions conducted under asymmetric PTC conditions led, in most cases, to racemic products. Esters were considered inadequate substrates for C-alkylation as a consequence of three main factors: (i) low reactivity under PTC conditions, (ii) product racemization or (iii) formation of loose ion-pairs, or diastereomeric intermediates of equal thermodynamic stability. Asymmetric PTC alkylation of amide (31) afforded a C-benzylated optically active product in low yield (ee= 30%). Improved reactivity could be observed for this substrate as compared to amide (30), as a result of increasing acidity and a more favorable interaction between the catalyst and the corresponding enolate. For compounds (32), (33) and (34), the enantiomeric excess of the corresponding C-benzylated products could not be determined, precluding a comparison of the efficiency of the stereoselective catalytic process. For each case, results were discussed in terms of currently accepted models for the enolate/catalyst interaction.

In this dissertation, we discuss the development of new phase transfer agents, which are capable of rapid fluorination of silicon. These are 18-C-6 derivatives containing a hydroxyl group in the side arm (podand), also known as C-pivot lariats. The syntheses of these lariats including several that have not been previously reported and their efficient purification are described. The synthesis route leads to a robust and generalized approach to obtain these lariats on the gram scale. These agents were initially designed for applications in positron emission tomography (PET). In this medical imaging modality, tracer agents containing silicon have found promising utility as fluoride receptors for more rapid radiolabeling. Phase transfer agents are generally required for 18F-labeling due to the low solubility in organic reaction media and reactivity of cyclotron-generated [18F]potassium fluoride. We envisioned that 18-C-6 derivatives may serve as both phase transfer agents as well as nucleophilic catalysts (CENCs). In this conception, CENCs were rapidly pre-complexed with KF followed by silicon fluorination, which takes advantage of a previously established silicon dianion mechanism. In collaboration with researchers at the NIH, we studied the effect of various linkers connecting the metal chelating unit to the nucleophilic hydroxyl group on the radiofluorination of silicon under mild condition. A hydrolysis resistant aryl silicon fragment has also been developed that contains various functional groups for convenient attachment to the potential PET radiotracer agents. In a second project, we demonstrate the unique reactivity of γ-silyl allenyl esters. Taking advantage of the silyl group as a fluoride acceptor, these allenoates readily underwent addition to a variety of carbon electrophiles, including aryl fluorides, to afford all-carbon quaternary centers bearing an ethynyl group. Surprisingly, in the presence of aldehydes, exclusive bis-substitution occurs at the γ-position to afford the dicarbinol. Details relating to reaction optimization and substrate scope for both the reactions are presented. Dicarbinol allenes were subsequently converted to highly substituted δ-lactones, a novel 6-hydro-2-pyrone as single diastereomers. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

O emprego da catálise de transferência de fase substituindo uma ou mais etapas da síntese de um fármaco, pode ser um recurso vantajoso sob o ponto de vista tecnológico. Empregado na síntese de importantes fármacos que são a dicicloverina, caramifeno eamiodarona, a catálise de transferência de fase revelou-se muito vantajosa na síntese dos dois primeiros. A dicicloverina e o caramifeno tiveram as suas rotas de obtenção verticalizadas, com bons resultados e custos bem mais baixos quando comparados com os atualmente adquiridos no exterior. Ficou evidente que a catálise de transferência de fase pode ser aplicada com sucesso na produção destes e outros fármacos em associação com técnicas já conhecidas com ótimos resultados. / The phase transfer catalysis application replacing one or more steps in the drug synthesis, can be of advantage in the technologycal approach. Applied to the synthesis of important drugs such as diciclomine, caramiphen,and amiodarone, the phase transfer catalysis resulted in a very advantageous method in the first two drugs. The diciclomine and the caramiphen, gets their obtention routes from raw materiaIs wi th good resul ts and low coasts, when compared wi th the drugs presently purchassed in foreign countries. It is clear that the phase transfer catalysis, can be applied succesfully in the manufacturing of these and other drugs, in conjuction with known techniques with good results.

No description available.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Neste trabalho foram realizadas reaÃÃes de C-alquilaÃÃo via CatÃlise de TransferÃncia de Fase (CTF) com a finalidade de obter os precursores de aminoÃcidos para uma posterior resoluÃÃo cinÃtica enzimÃtica. As reaÃÃes de C-alquilaÃÃo ocorreram a 70 ÂC, vÃrios agentes transferidores de fase foram testados, e o mais promissor foi o cloreto de benziltributilamÃnio (CBTBA). As reaÃÃes se processaram com o uso de 3 mmol do cianoacetoamido acetato de etila, 3 mmol de carbonato de potÃssio, 6 mmol do agente alquilante, cloreto de benzila. ApÃs purificaÃÃo do produto, realizou-se uma reaÃÃo de hidrÃlise total com posterior proteÃÃo dos grupos amino e carboxila resultando em trÃs diferentes compostos rac-33, rac-34 e rac-35. A resoluÃÃo cinÃtica enzimÃtica do rac-33 por reaÃÃo de interesterificaÃÃo usando o butirato de butila (PrCO2Bu) foi inicialmente testada com diversas lipases (Candida antarctica Lipase B e sua isoenzima Candida antarctica Lipase A, ACYLASE I obtida de Aspergillus melleus, PSL-C I, Lipase a partir da Candida rugosa e a LIPOZYME RM IM) variando tempo, temperatura e solvente. A LIPOZYME RM IM foi a Ãnica enzima capaz de promover a reaÃÃo de interesterificaÃÃo e com altos valores de enantiosseletividade (E). As melhores reaÃÃes ocorreram à temperatura de 55 ÂC. A resoluÃÃo do rac-33 a 55 ÂC ocorreu em oito horas e quinze minutos, em sistema sem solvente, com uma conversÃo de 50%, ees >99%, eeP>99% com um alto valor de enantiosseletividade, E>200 (10633), Esquema 3. A resoluÃÃo cinÃtica do 2-acetilamino-3-fenil-propanoato de alila (rac-35) ocorreu em quatro horas e trinta minutos, sem solvente à temperatura de 55 ÂC, resultando em 49% de conversÃo, eeS98%, eeP>99% e E>200 (9278). / In this work reactions of C-alkylation were carried out via Phase Transfer Catalysis (PTC) in order to obtain precursors of amino acids and them to perform enzymatic kinetic resolution. The reactions of C-alkylation occurred at 70 ÂC, several phase transfer agents were tested, and the most promising was the benzyltributylammonium chloride (CBTBA). The reaction were performed using 3 mmol of ethyl cianoacetoamidoacetate, 3 mmol of potassium carbonate, 6 mmol of alkylating agent, benzylchloride. After purification of the product, a reaction of total hydrolysis was carried out with subsequent protection of amino and carboxyl groups resulting in three different compounds rac-33 rac-34 and rac-35. The enzymatic kinetic resolution of rac-33 via interesterification with butyl butyrate (PrCO2Bu) was initially tested with different lipases (Candida antarctica Lipase B and itâs isoenzyme, Lipase Candida antarctica Lipase A, ACYLASE I obtained from Aspergillus melleus, PSL-C I, Lipase from Candida rugosa and Lipozyme RM IM) varying time, temperature and solvent. The Lipozyme RM IM was the only enzyme capable of promoting the reaction of interesterification and with high values of enantioselectivity (E). The best reactions occurred at 55 ÂC. The resolution of rac-33 at 55  C occurred in eight hours and fifteen minutes in system solvent free, with conversion of 50%, eeS>99%, eeP>99% with a high value of enantioselectivity, E > 200 (10633), Scheme 3. The kinetic resolution of allyl 2-acetylamino-3-phenyl-propanoate (rac-35) occurred in four hours and thirty minutes, without any solvent at 55  C, resulting in 49% of conversion, eeS>98%, eeP>99% and E > 200 (9278).

The main topic of the Diploma Thesis is the conversion of the batch N-alkylation reaction into a continuous regime. It is the reaction of 10α-methoxydihydrolysergic acid methyl ester to 1-methyl-10α-methoxydihydrolysergic acid methyl ester. It represents one step in the industrial synthesis of Nicergoline, a pharmaceutical used for senile dementia treatment. This methylation reaction is performed in two immiscible liquid phases. Phase-transfer catalysis is used to increase the efficiency of the reaction, which allows the reaction to proceed in the entire volume of the organic solvent, not only at the phase interface. The reaction is rapid, with an exothermic character. The advantages of continuous arrangement are better control of the reaction, increased operational safety due to handling smaller volumes of reaction components, and more intensive removal of heat of the reaction. The Thesis deals with the influence of reaction conditions on the course of the reaction in a microfluidic reactor. The glass microchip reactor was chosen to perform the reaction in a flow arrangement. This reactor could produce up to grams of the product per hour. Several series of experiments were performed on this apparatus. The conversion of the starting material, and selectivities to the product and the side products...