Issue 2, 2017

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
26 Сер 2016
Accepted
06 Жов 2016
First published
07 Жов 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 1282-1287

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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