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 -acetylenic chain was investigated to access new structurally diverse macrocyclic isoquinolones. A slow addition of the substrate and the presence of Cu(OAc)(2)H2O 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 21macrocyclic 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.