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Doctoral Thesis
DOI
https://doi.org/10.11606/T.59.2020.tde-12092019-081819
Document
Author
Full name
Rodolfo Hideki Vicente Nishimura
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Clososki, Giuliano Cesar (President)
Donate, Paulo Marcos
Moraes, Luiz Alberto Beraldo de
Oliveira, Dioneia Camilo Rodrigues de
Pilli, Ronaldo Aloise
Schwab, Ricardo Samuel
Title in Portuguese
Funcionalização de compostos N-heterocí­clicos visando a sí­ntese de substâncias bioativas
Keywords in Portuguese
Compostos N-heterocíclicos
Fluxo-contínuo
Metalação
N-arilação
Quinazolinas
Quinazolinonas
Troca halogênio-metal
Abstract in Portuguese
Compostos N-heterocíclicos tais como quinolinas, isoquinolinas, quinoxalinas, quinazolinas e quinazolinonas estão presentes em muitos fármacos, produtos naturais, polímeros e corantes. Nesse contexto, o presente trabalho teve como principal objetivo o desenvolvimento de metodologias de metalação, troca halogênio-metal e reações de N-arilação que pudessem ser aplicados na funcionalização de compostos N-heterocíclicos visando a preparação de substâncias bioativas. Inicialmente, investigamos a metalação de algumas quinazolinonas N-protegidas e de duas quinazolinas halogenadas, bem como reações de troca halogênio-metal dos substratos halogenados. Apesar das 4-cloro-2-fenil-6-haloquinazolinas terem possibilitado a eficiente formação dos respectivos derivados organometálicos usando ambas as estratégias, a baixa reatividade demonstrada pelos intermediários frente diversos eletrófilos inviabilizou o uso destas estratégias em outras etapas do trabalho. Como opção, investigamos a aplicação de TMPLi na presença de ZnCl2, uma metodologia recentemente desenvolvida, na funcionalização de quinolinas, isoquinolinas, quinoxalinas e quinazolinas. Esta metodologia foi eficiente na metalação de todos os substratos investigados e proporcionou a formação de 15 produtos isolados em rendimentos de 45-90%. Posteriormente, por meio da N-arilação de 4-cloroquinazolinas, sintetizamos 20 compostos do tipo 4-anilinoquinazolina em rendimentos isolados de 56-90%, as quais foram planejadas por docagem molecular visando a atividade antiproliferativa relacionada à possível interação com a tubulina (sítio da colchicina). Por fim, estudamos a troca halogênio-metal de brometos ou iodetos de heteroarila usando n-BuLi na presença de MgCl2?LiCl em um microrreator de fluxo contínuo. Tais reações demonstraram-se mais rápidas (0,1 - 2,5 s), puderam ser realizadas na maioria das vezes com temperaturas mais amenas (-20 ou 0 °C) e foram mais seletivas quando comparadas as reações em batelada, resultando na formação de 20 produtos em rendimentos variando de 56-95%
Title in English
Functionalization of N-heterocyclic compounds aiming the synthesis of bioactive substances
Keywords in English
Continuous flow
Halogen-metal exchange
Metalation
N-arylation
N-heterocyclic compounds
Quinazolines
Quinazolinones
Abstract in English
N-heterocyclic compounds such as quinolines, isoquinolines, quinoxalines, quinazolines and quinazolinones are present in many drugs, natural products, polymers and dyes. In this context, the main objective of this work was the development of methodologies of metalation, halogen-metal exchange and N-arylation reactions that could be used to the functionalization of N-heterocyclic compounds aiming the preparation of bioactive substances. Initially, we investigated the metalation of some N-protected quinazolinones and two halogenated quinazolines as well as the halogen-metal exchange of the halogenated substrates. Albeit the 4-chloro-6-halo-2-phenylquinazolines provided the efficient formation of the corresponding organometallic species through the use of both methodologies, the low reactivity of these intermediates against several electrophiles has precluded further applications of these strategies in our work. Consequently, we investigated the application of TMPLi in the presence of ZnCl2, a recently developed methodology, in the functionalization of quinolines, isoquinolines, quinoxalines and quinazolines. This strategy was efficient in the metalation of all investigated substrates and allowed the isolation of 15 functionalized products in 45-90% yields. Posteriorly, by means of N-arylation of 4-chloroquinazolines, we synthesized 20 compounds of 4-anilinoquinazoline type in yields ranging from 56-90%, which were planned by molecular docking aiming the antiproliferative activity related to the possible interaction with tubulin colchicine site. Finally, we studied the halogen-metal exchange of heteroaryl bromides or iodides using n-BuLi in the presence of MgCl2?LiCl in a flow continuous micro-reactor. These reactions were shown to be faster (0.1 - 2.5 s), most of them could be performed with milder temperatures (-20 or 0°C) and were more selective when compared to batch reactions, resulting in formation of 20 products in yields ranging from 56-95%
 
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Release Date
2021-09-11
Publishing Date
2020-01-14
 
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