Synthesis of CF₃-Substituted <i>N</i>-Heterocyclic Compounds Based on C–H Activation-Initiated Formal [2 + 3] Annulation Featuring with a Latent Nucleophilic Site

Abstract

Presented herein is a novel synthesis of CF₃-substituted pyrrolo[1,2-<i>a</i>]indole derivatives based on the cascade reactions of <i>N</i>-alkoxycarbamoyl indoles with CF₃-ynones. Mechanistically, the formation of a product involves a tandem process initiated by Rh(III)-catalyzed and <i>N</i>-alkoxycarbamoyl group-directed regioselective C2-H alkenylation of the indole scaffold followed by in situ removal of the directing group and intramolecular <i>N</i>-nucleophilic addition/annulation under one set of reaction conditions. To our knowledge, this is the first example in which a <i>N</i>-alkoxycarbamoyl unit initially acts as a directing group for C2-H functionalization of the indole scaffold and is then removed to provide the required reactive <i>NH</i>-moiety for subsequent intramolecular condensation. Moreover, the products thus obtained could be conveniently transformed into structurally and biologically attractive cycloheptenone fused indole derivatives through an acid-promoted cascade transformation. In addition, studies on the activity of selected products against human cancer cell lines demonstrated their potential as lead compounds for the development of novel anticancer drugs.