This Perspective article traces the evolution of modern approaches to functionalise the indole C4–H bond.

The mechanochemical, solvent‐free, highly regioselective, rhodium‐catalyzed C−H methylation of (hetero)arenes is reported. The reaction shows excellent functional‐group compatibility and is demonstrated to work for the late‐stage C−H methylation of biologically active compounds. The method requires no external heating and benefits from considerably shorter reaction times than previous solution‐based C−H methylation protocols. Additionally, the mechanochemical approach is shown to enable the efficient synthesis of organometallic complexes that are difficult to generate conventionally.

The Ru‐catalysed C2H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole‐based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on‐cycle intermediates do not possess a para‐cymene ligand and that the on‐cycle metalation occurs through an electrophilic attack by the Ru centre.

Weinreb amides are a privileged, multi-functional group with well-established utility in classical synthesis. Recently, several studies have demonstrated the use of Weinreb amides as interesting substrates in transition metal-catalyzed C-H functionalization reactions. Herein, we review this part of the literature, including the metal catalysts, transformations explored so far and specific insights from mechanistic studies.

(Pinacolato)boryl ortho‐silyl(hetero)aryl triflates are presented as a new class of building blocks for arylation. They demonstrate unique versatility by delivering boronate or (hetero)aryne reactivity chemoselectively in a broad range of transformations. This approach enables the unprecedented postfunctionalization of fluoride‐activated (hetero)aryne precursors, for example, as substrates in transition‐metal catalysis, and offers valuable new possibilities for aryl boronate postfunctionalization without the use of specialized protecting groups.

Directed and undirected Ru-catalysed C–H silylation of unprotected heteroarenes is presented which requires no protecting groups.