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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2020.tde-19122019-090933
Document
Author
Full name
Leandro Alves Bozzini
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Clososki, Giuliano Cesar (President)
Silva, Gil Valdo Jose da
Donate, Paulo Marcos
Emery, Flavio da Silva
Júnior, Emilio Carlos de Lucca
Milagre, Humberto Marcio Santos
Title in Portuguese
Aplicação de amidetos metálicos na funcionalização de aril-2-oxazolinas de interesse sintético
Keywords in Portuguese
Metalação
Organometálicos
Oxazolinas
Abstract in Portuguese
As bases organometálicas mistas de zinco, magnésio e lítio já foram aplicadas com sucesso na funcionalização de vários anéis aromáticos e heteroaromáticos. No entanto, sua reatividade frente substratos importantes ainda não foi ompletamente estudada. Este é o caso das aril-2-oxazolinas, compostos importantes em química orgânica, encontrando aplicações como blocos de construção, catalisadores e ligantes na síntese assimétrica. Assim, o objetivo principal deste trabalho foi o desenvolvimento de uma metodologia que permitisse a metalação direta de aril-2-oxazolinas funcionalizadas com amidetos de magnésio, zinco e lítio, que podem tolerar a presença de diferentes grupos funcionais nos substratos. Fenil-2-oxazolinas que carregam grupos ciano, éster, amidas, pivalatos e carboxilatos podem ser funcionalizadas seletivamente na posição orto a oxazolina através da reação de TMPMgCl.LiCl ou TMP2Mg.2LiCl com o substrato apropriado. No caso de éster fenil-2-oxazolinas a base TMP2Mg.2LiCl foi seletiva na metalação na posição orto ao grupo éster. A reação subsequente com diferentes eletrófilos forneceu os derivados funcionalizados com bons rendimentos. Os cálculos da teoria funcional da densidade (DFT) foram realizados para avaliar a influência dos substituintes do anel sobre a acidez dos hidrogênios aromáticos. Além disso, com o objetivo de demonstrar a importância sintética das metodologias desenvolvidas, estas foram aplicadas com sucesso na síntese de substâncias bioativas, como ftalidas e um análago de tamibaroteno.
Title in English
Application of metal amide in functionalization of aryl-2-oxazolines of synthetic interest
Keywords in English
Metallation
Organometallic
Oxazolines
Abstract in English
Mixed organometallic bases of zinc, magnesium and lithium have already been successfully applied in the functionalization of various aromatic and heterocyclic rings. However, its reactivity against important substrates has not yet been fully studied. This is the case of aryl-2-oxazolines, compounds important in organic chemistry, finding applications as building blocks, catalysts and binders in asymmetric synthesis. Thus, the main objective of this work was the development of a methodology that allowed the direct metallation of functionalized aryl-2-oxazolines using magnesium, zinc and lithium amides, which can tolerate the presence of different functional groups in the substrates. Phenyl-2-oxazolines with cyano, ester, amide, pivalate and carboxylate groups may be selectively functionalized at the ortho oxazoline position by the reaction of TMPMgCl.LiCl or TMP2Mg.2LiCl with the appropriate substrate. In the case of the ester phenyl-2-oxazolines the base TMP2Mg.2LiCl was selective in the orto metallation in the ester group. Subsequent reaction with different electrophiles furnished the functionalized derivatives in good yields. Density functional theory (DFT) calculations were performed to evaluate the influence of the ring substituents on the acidity of the aromatic hydrogens. In addition, in order to demonstrate the synthetic importance of the methodologies developed, they were successfully applied in the synthesis of bioactive substances, such as phthalides and an analysis of tamibarotene.
 
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Release Date
2021-12-18
Publishing Date
2020-01-07
 
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