Ruthenium(II)-Catalyzed Synthesis of Pyrrole- and Indole-Fused Isocoumarins by C−H Bond Activation in DMF and Water

• Published in: ChemCatChem 2016-03, Vol.8 (6), p.1046-1050
• Main Authors: Singh, Keisham S., Sawant, Sneha G., Dixneuf, Pierre H.
• Format: Article
• Language: English
• Subjects: annulation; Chemical Sciences; C−H activation; natural products; nitrogen heterocycles; ruthenium
• ISSN: 1867-3880; 1867-3899; 1867-3899
• DOI: 10.1002/cctc.201501261

Pyrrole‐ and indole‐fused isocoumarins constitute important structural units in natural products and pharmacophores, although the direct and selective bifunctionalization of pyrrole and indole remain a challenge. Herein, we report a one‐pot synthesis of pyrrole‐ and indole‐fused isocoumarins from simple 1‐methylpyrrole‐2‐carboxylic acid and 1‐methylindole‐3‐carboxylic acid by annulation with alkynes in the presence of a ruthenium(II) catalyst based on [RuCl2(p‐cymene)]2 with Cu(OAc)2⋅H2O as the oxidant in DMF. This ruthenium(II)‐catalyzed transformation was shown to be profitably performed in water as the solvent. The reaction, which involves carboxylate coordination, activation of the heterocyclic sp2 C−H bond, and insertion of the alkyne, is regioselective, which leads to good yields of the isocoumarins. Ring, ring! 1‐Methylpyrrole‐2‐carboxylic acid and 1‐methylindole‐3‐carboxylic acid are efficiently annulated with alkynes by using the inexpensive and stable‐to‐water [RuCl2(p‐cymene)]2 catalyst with Cu(OAc)2⋅H2O as the oxidant and as acetate provider by C−H and O−H bond activation to give their respective pyrrole‐ and indole‐fused isocoumarin derivatives. These catalytic reactions can be performed in DMF and competitively in water.