14 - Introduction of Substituents on the Carbocyclic Ring

Abstract

Introduction of substituents on the carbocyclic ring relies primarily on electrophilic substitution and on organometallic reactions. The former reactions are not under strong regiochemical control. The nitrogen atom can stabilize any of the C-ring or-complexes and both pyrrole and benzo ring substituents can influence the substitution pattern, so that the position of substitution tends to be dependent on the specific substitution pattern. Electrophilic substitution on the carbocyclic ring requires deactivation of the heterocyclic ring and this is usually achieved by the presence of an EW substituent at N1, C2 or C3 or a combination thereof. For example, ethyl indole-2-carboxylate can give either C3 or C5, 7 acylation, depending upon reaction conditions. Use of excess AlCl3 favors carbocylic subsitution. Carbocyclic substitution can also be achieved by first introducing a reactive organometallic substituent. Preparation of organolithium reagents can be done by one of the conventional methods, especially halogen-metal exchange or directed lithiation. Indoles with carbocyclic halogen or triflate substituents are potential starting materials for vinylation, arylation and acylation via palladium-catalyzed processes. Indolylstannanes, indolylzinc halides and indolylboronic acids are also potential reactants.