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Issue 2, 2017
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Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules

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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.

Graphical abstract: Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules

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Supplementary files

Article information


Submitted
26 Aug 2016
Accepted
06 Oct 2016
First published
07 Oct 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 1282-1287
Article type
Edge Article

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

D. P. Hruszkewycz, K. C. Miles, O. R. Thiel and S. S. Stahl, Chem. Sci., 2017, 8, 1282
DOI: 10.1039/C6SC03831J

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