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Directed functionalization of quinoxalines aiming the synthesis of bioactive compounds

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Samuel Remotto Alves Ferreira
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Giuliano Cesar Clososki; Ricardo Vessecchi Lourenço; Luiz Alberto Beraldo de Moraes; Dioneia Camilo Rodrigues de Oliveira; Leandro Piovan
Advisor: Giuliano Cesar Clososki

Since its discovery in the mid-nineteenth century, organometallic reagents have been widely used in organic synthesis, being very effective in the formation of new carbon-carbon bonds. The choice of the ideal organometallic reagent for certain reaction involves knowledge related to their chemical nature and reactivity of the substrate itself. The quinoxaline core has great potential for medicinal chemistry and is present in many natural and synthetic products presenting biological activity. Nevertheless, there are few studies on the application of organometallic reagents in the functionalization of quinoxalines. The directed metalation reaction using metal bases is powerful synthetic tool for functionalization of aromatic substrates. However, examples on the application of such strategy to the functionalization of of quinoxalines are very rare. This work mainly aimed to investigate the reactivity of organometallic reagents of zinc, magnesium and lithium in the metalation of quinoxalines substituted with functional groups at the C-2 and C-6 positions. Although C-2 substituted quinoxalines with ester and amide groups have not shown the expected reactivity with mixed amides of zinc, magnesium and lithium (TMPZnCl?MgCl2?LiCl, TMP2Zn?2MgCl2?2LiCl, TMPMgCl?LiCl and TMP2Mg?2LiCl), a new methodology was developed using TMPLi as a base in the presence of ZnCl2, allowing the preparation of various difuncionalized derivatives in good yields, many of them new compounds. Quinoxalines unsubstituted at the C-2 and C-3 positions have recognized intolerance to the presence of organometallic reagents, preferably yielding dimerization products. Thus, an important contribution of this work was the development of a functionalization methodology of the simplest quinoxaline in microwave mediated by the TMPMgCl?LiCl/ZnCl2, allowing the preparation of various arylated derivatives in yields ranging from reasonable to good (25 to 94%). Furthermore, the methodology could be applied to the synthesis of bidentate ligands of interest for catalysis (AU)

FAPESP's process: 12/08589-0 - Directed functionalization of quinoxalines aiming the synthesis of bioactive compounds
Grantee:Samuel Remotto Alves Ferreira
Support Opportunities: Scholarships in Brazil - Doctorate