ORGANIC
LETTERS
2011
Vol. 13, No. 7
1622–1625
Copper-Catalyzed Benzylic C-H
Oxygenation under an Oxygen
Atmosphere via N-H Imines as an
Intramolecular Directing Group
Line Zhang, Gim Yean Ang, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
Received January 5, 2011
ABSTRACT
Copper-catalyzed benzylic C-H oxygenation under an oxygen atmosphere was developed starting from carbonitriles and Grignard reagents via
N-H imine intermediates. The present process is characterized by the following two-step sequence in a one-pot manner: (1) addition of Grignard
reagents to carbonitriles to form N-H imines and (2) benzylic C-H oxygenation (CdO bond formation) triggered by 1,5-hydrogen atom transfer
with transient iminyl copper species.
The incorporation of an oxygen atom into the organic
frameworks from atmospheric molecular oxygen (O2)
offers one of the most ideal processes in organic synthesis.
Activation of O2 by copper enzymes has been observed in
some biological oxygenase systems such as monooxygen-
ase tyrosinase and dopamine β-monooxygenase that effect
hydroxylation of C-H bonds.1 Biomimetic studies of such
enzymatic reactions using rather simple models have been
intensively studied.2,3 Although there have been various
reported nonbiomimetic approaches for copper-mediated
oxygenation of organic molecules4 as well as with other
metals,5 it is still challenging todevelopcatalytic oxygenase
processes that possess distinct reaction mechanisms and
are highly efficient.
Our group has explored the intriguing chemical reactiv-
ity of the iminyl copper species for aerobic oxidation
reactions.6 Recently we have disclosed a copper-catalyzed
synthesis of azaspirocyclohexadienones from R-azido-N-
arylamides under an O2 atmosphere via a sequence of
denitrogenative formation of the iminyl copper species
from R-azido-N-arylamides and their imino-cupration
with an intramolecular benzene ring on the amido nitrogen
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€
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Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12,
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10.1021/ol200425c
Published on Web 03/07/2011
2011 American Chemical Society