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Functionalization of N-heterocyclic compounds aiming the synthesis of bioactive substances

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Author(s):
Rodolfo Hideki Vicente Nishimura
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Giuliano Cesar Clososki; Paulo Marcos Donate; Luiz Alberto Beraldo de Moraes; Dioneia Camilo Rodrigues de Oliveira; Ronaldo Aloise Pilli; Ricardo Samuel Schwab
Advisor: Giuliano Cesar Clososki
Abstract

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% (AU)

FAPESP's process: 15/01466-9 - Directed functionalization of quinazolines and quinazolinones aiming the synthesis of bioactive substances
Grantee:Rodolfo Hideki Vicente Nishimura
Support Opportunities: Scholarships in Brazil - Doctorate