Application of organometallic reagents in the functionalization of indolizines of synthetic interest

Author(s)

Mônica Franco Zannini Junqueira Toledo

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2015-01-30

Examining board members

Giuliano Cesar Clososki; Flavio da Silva Emery; Dioneia Camilo Rodrigues de Oliveira; Cristiano Raminelli; Alcindo Aparecido dos Santos

• Advisor: Giuliano Cesar Clososki

Abstract

In recent years, there has been a considerable increase in studies involving the indolizinic core, one of thousands of existing heterocycles, with 2012 being the most outstanding year, with 102 publications. This growing interest is mainly attributed to the search for new functionalized substrates that have medicinal and biological characteristics. However, indolizines are unexplored when compared to other heterocycles, particularly regarding their functionalization with the use of organometallic reagents. Thus, the object of this work was the reactivity study of several indolizines with different organometallics by means of directed metalation reactions, iodine-magnesium exchange and Negishi cross-coupling, in order to build functionalized poly-indolizines. Therefore, initially, it was investigated the reactivity of organometallic bases upon some indolizines and the reactions of their organometallic intermediates with a variety of electrophiles. To achieve this, indolizines were divided according to their function position, i.e. indolizines functionalized at position 1 of the ring (-CO2Et, CN and -CO2tBu), indolizines functionalized at position 2 of the ring (-CO2Et, CN) and functionalized at positions 1 and 3 of the ring. Furthermore, the iodine-magnesium exchange reactions of indolizines functionalized at positions 1 and 3 were studied and, finally, directed metalation reactions with 2-aryl indolizinic substrates followed by Negishi cross-coupling reactions were performed. The ultimate products of such reactions showed strong fluorescent properties and, for this reason, were subject of detailed studies on these characteristics. The synthetic strategies developed in this research were highly efficient, enabling the preparation of a large number of compounds with structural diversity, having been synthesized 64 novel poly-functionalized indolizines and 11 known poly-functionalized indolizines, with yields ranging from 15% to 87%. (AU)

• FAPESP's process: 11/20742-6 - Application of organometallic reagents in the functionalization of indolizines of synthetic interest
• Grantee: Mônica Franco Zannini Junqueira Toledo
• Support Opportunities: Scholarships in Brazil - Doctorate