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

• Published in: Chemistry : a European journal 2016-09, Vol.22 (38), p.13469-13473
• Main Authors: Krieger, Jean-Philippe, Ricci, Gino, Lesuisse, Dominique, Meyer, Christophe, Cossy, Janine
• Format: Article
• Language: English
• Subjects: Activation; Activation analysis; Chemical reactions; Chemical Sciences; Chemistry; Compatibility; C−H activation; isoquinolones; macrocycles; Macrocyclic compounds; macrocyclization; Organic chemistry; Pharmaceutical sciences; ruthenium; Strategy; Substrates; Synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201602332

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⋅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 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. Ruthenium(II)‐catalyzed annulation of ω‐alkynyl benzhydroxamates has been developed as an efficient strategy toward new structurally diverse macrocyclic isoquinolones (see scheme). The devised experimental conditions are suitable for a wide range of substrates, as illustrated by the successful preparation of 21 macrocyclic isoquinolones possessing 12‐ to 20‐membered rings in good to excellent yields.