Ruthenium(II)-Catalyzed Macrocyclization via Site-Selective Hydroarylation of Alkynes: Access to Indoline-Braced Metacyclophanes

Macrocycles are emerging as new therapeutic modalities in drug discovery. However, their efficient and diversity-oriented synthesis has significant challenges, as the conventional approaches often require conformationally flexible tethers and suitably functionalized termini for end-to-end coupling. In this regard, transition-metal-catalyzed C-H activation offers a potential solution. Here we report a Ru-catalyzed regioselective macrocyclization of Ar C(sp²)-H with an internal alkyne to afford macrocycles via the formation of a trisubstituted alkene. The method furnished indoline and other heteroarene-embedded cyclophanes of various ring sizes ranging from 13 to 23. The method is also applicable to various substrates that are tethered with quinols, carbohydrates, amino acids, and drug candidates.