The fact that the average number of nitrogen atoms in drugs is about 3 highlights the great significance of incorporating nitrogen-containing functional groups into organic molecules. 7-Aminoindoles are important structural motifs in numerous pharmaceuticals and other bioactive molecules. Thus, substantial efforts have been made to develop efficient methods for their synthesis. Direct C–H amination of indoles represents an attractive route for 7-aminoindole synthesis given the readily accessibility of indole substrates, and the step-economy and sustainability of C–H functionalization. However, these reactions typically provided the 7-aminoindole products as protected forms, such as sulfonamide, amide and, in very few cases, diaryl anilines, necessitating additional deprotection step(s) to release free 7-aminoindole for subsequent elaborations. On the other hand, noble metal catalysts, such as iridium and ruthenium, are employed in these reactions, while highly C-7 selective amination of indole mediated by sustainable and earth-abundant transition metals remain elusive.

Recently, Fei Wang’s group have developed the first iron-catalyzed C-7 selective NH₂ amination of indole via a directed homolytic aromatic substitution (HAS), using N–P(O)^tBu₂ (TBPO) as directing group. Important features of this reaction include the broad substrate scope, mild reaction conditions, good functional groups tolerance, use of earth-abundant iron catalyst and low catalyst loading, and the ease to scale up. Systematic mechanistic studies on directed HAS for NH₂ amination, especially the structure of the reactive iron-supported NCR intermediate, and the use of this concept for introducing other functionalities are ongoing in Wang’s laboratory. Relevant achievements were published in Angew. Chem. Int. Ed., 2024, DOI: 10.1002/anie.202412103.