Harnessing C−H Activation of Benzhydroxamates as a Macrocyclization Strategy: Synthesis of Structurally Diverse Macrocyclic Isoquinolones

Macrocycles are arising considerable interest in medicinal chemistry. With the goal of harnessing C−H activation reactions for the development of efficient macrocyclization processes, the ruthenium(II)‐catalyzed cyclization of O ‐methyl benzhydroxamates possessing an ω‐acetylenic chain was investigated to access new structurally diverse macrocyclic isoquinolones. A slow addition of the substrate and the presence of Cu(OAc) 2 ⋅ H 2 O as an additive were crucial for the success of the macrocyclization that features an excellent functional‐group compatibility, as illustrated by the successful synthesis of a library of 21 macrocyclic isoquinolones of different ring sizes and substitution patterns. These results contribute to significantly highlight the synthetic interest of C−H activation‐mediated processes for the synthesis of new macrocyles incorporating heterocyclic scaffolds of potential interest in medicinal chemistry.