Ru-catalyzed CH functionalization of phenylglycine derivatives: Synthesis of isoquinoline-1-carboxylates and isoindoline-1-carboxylates

• N-unprotected phenylglycine derivatives have been functionalized selectively.
• Functionalization is catalyzed by Ru(II) complexes through oxidative coupling.
• Isoquinoline-1-carboxylates are obtained by coupling with internal alkynes.
• Isoindoline-1-carboxylates are obtained by coupling with methylacrylates.

The reaction of N-unprotected methylesters of phenylglycine derivatives (1a–1f) with electron-rich internal alkynes (2a–2e), catalyzed by [Ru(cymene)Cl2]2 (10%), gives the corresponding 3,4-disubstituted isoquinoline-1-carboxylates 3 through CH/NH oxidative coupling. The CH bond activation step is assisted by carboxylates, and N-fluoro-2,4,6-trimethylpyridinium triflate works as the terminal oxidant. The process shows a remarkable tolerance to the presence of diverse electron-releasing and electron-attracting functional groups at the phenyl ring of the amino acid. In addition, the reaction of phenylglycine derivatives (1a–1f) with methyl acrylate (4a) catalyzed by [Ru(cymene)Cl2]2 (10%) under the same experimental conditions, gives the corresponding 3,N-disubstituted isoindoline-1-carboxylates 5 through CH/NH coupling. Isoindolines 5 are obtained as a mixture of diastereoisomers, with moderate to high values of diastereomeric excess (up to 80%).

Figure optionsDownload high-quality image (79 K)Download as PowerPoint slide