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

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.
Authors:
 [1] ;  [1] ;  [2] ;  [1]
  1. Univ. of Wisconsin, Madison, WI (United States). Department of Chemistry
  2. Process Development, Drug Substance Technologies, Amgen Inc., Thousand Oaks, CA (United States)
Publication Date:
Grant/Contract Number:
FG02-05ER15690
Type:
Accepted Manuscript
Journal Name:
Chemical Science
Additional Journal Information:
Journal Volume: 8; Journal Issue: 2; Journal ID: ISSN 2041-6520
Publisher:
Royal Society of Chemistry
Research Org:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
OSTI Identifier:
1429913

Hruszkewycz, Damian P., Miles, Kelsey C., Thiel, Oliver R., and Stahl, Shannon S.. Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules. United States: N. p., Web. doi:10.1039/c6sc03831j.
Hruszkewycz, Damian P., Miles, Kelsey C., Thiel, Oliver R., & Stahl, Shannon S.. Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules. United States. doi:10.1039/c6sc03831j.
Hruszkewycz, Damian P., Miles, Kelsey C., Thiel, Oliver R., and Stahl, Shannon S.. 2016. "Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules". United States. doi:10.1039/c6sc03831j. https://www.osti.gov/servlets/purl/1429913.
@article{osti_1429913,
title = {Co/NHPI-mediated aerobic oxygenation of benzylic C–H bonds in pharmaceutically relevant molecules},
author = {Hruszkewycz, Damian P. and Miles, Kelsey C. and Thiel, Oliver R. and Stahl, Shannon S.},
abstractNote = {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.},
doi = {10.1039/c6sc03831j},
journal = {Chemical Science},
number = 2,
volume = 8,
place = {United States},
year = {2016},
month = {10}
}