Synthesis of 3-Substituted 2-Indolinones by a Multicomponent Coupling Isocyanide-Dependent Microwave-Assisted Intramolecular Transamidation Process

A small-molecule library synthesis of 3-substituted 2-indolinones using methyl isocyanide and a microwave-assisted intramolecular transamidation process with 10% TFA in dichloroethane has been achieved in 3 steps. A modified Fe-0 Bechamp-type reduction of a substituted bifunctional substrate, o-nitrobenzaldehyde, renders 3-substituted 2-indolinones in yields ranging from 76-91% (21 examples). Furthermore, it has been determined that symmetrical 2(o)N-alkyl or aryl substituents, as a component of the amine starting material, suppresses 3-substituted 2-indolinone rotameric mixtures and allows for facile compound H-1 NMR characterization. In the absence of methyl isocyanide, 3,4-dihydroquinazolines or transamidation products predominate under both BrOnsted or Lewis acid conditions in reasonable yields.