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Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules.

ABSTRACT: A simple cobalt(ii)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90-100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.

SUBMITTER: Hruszkewycz DP

PROVIDER: S-EPMC5359875 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Co/NHPI-mediated aerobic oxygenation of benzylic C-H bonds in pharmaceutically relevant molecules.

Hruszkewycz Damian P DP Miles Kelsey C KC Thiel Oliver R OR Stahl Shannon S SS

Chemical science 20161007 2

A simple cobalt(ii)/<i>N</i>-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C-H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C-H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc s ...[more]

PMID: 28451270

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