Infoscience

Thesis

The regiochemically flexible functionalization of fluoro-and trifluoromethyl-substituted indoles

The use of organometallic reagents for functionalization of arenes and heterocycles has recently been renewed by our group. The use of bulky trialkylsilyl groups allows one to shield an acidic position by steric hindrance and the introduction of a chlorine atom permits the activation of the nearby site. The organometallic methods were applied to fluorinated indoles, taking into account the growing attention toward halogen as a key factor for improving drug activity. Only few commercial fluoroindoles are inexpensive. Therefore it was necessary to find a method allowing an efficient preparation of the staring material. Many methods have been developed to synthesize halogenated indoles. The more common ways implies electrophilic cyclization. Once obtained the starting material, all four fluoroindoles were subjected to exhaustive functionalization by organometallic reagents, using either bromine/metal permutation or direct metalation in conjunction with chlorine or triisopropylsilyl residues as protecting groups. Once protected position 2 by steric shielding, the metalation occurs at the position next to the fluorine. In the case of 4 and 7-fluoroindoles there is no ambiguity, but for the 4 and 6 isomers we were obliged to play with bases in order to achieve a good regioselectivity. The use of chlorine was necessary to reach the meta position to the fluorine. Only a few derivatives of fluoroindoles are known in literature. However one could expect such compounds to be versatile building blocks for the synthesis of biologically active compound, due to the presence of fluorine or trifluoromethyl group, helping to fine-tune the lipophilicity of a molecule or to protect against metabolic oxidation. This thesis work aimed to fill the gaps in this field by elaborating methods to efficiently and easily prepare functionalized derivatives of fluoroindoles and in particular all twelve possible regioisomeric fluoroindole carboxylic acids.

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 3071 (2005)
    Section de chimie et génie chimique
    Faculté des sciences de base
    Institut des sciences et ingénierie chimiques
    Jury: Kai Johnsson, Christian Margot, Bruno Schaub, Pierre Vogel

    Public defense: 2005-2-18

    Reference

    Record created on 2005-04-06, modified on 2016-08-08

Fulltext

Related material

Contacts

EPFL authors