.
Angewandte
Communications
DOI: 10.1002/anie.201304359
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Radical C H Oxidation
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Site-Selective Oxidation of Unactivated Csp3 H Bonds with
Hypervalent Iodine(III) Reagents
Shin A. Moteki, Asuka Usui, Tiexin Zhang, Cꢀsar R. Solorio Alvarado, and Keiji Maruoka*
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Functionalization of unactivated Csp3 H bonds is one of the
most sought-after chemical transformations and has high
potential to simplify synthetic sequences as well as to expedite
the functionalization of various organic molecules.[1] Unfortu-
nately, such a transformation remains challenging owing to
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the high bond energy of C H, thereby making it inert toward
various reagents and catalysts. Initial attempts to transform
these bonds through either metal-mediated or metal-free
reactions has often resulted in poor yields and/or low
selectivity, thus making those methods less practical for
synthesis.[2] In recent years, several methods have emerged
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that efficiently transform saturated C H bonds in a site-
specific manner.[3] Du Bois and co-workers reported a metal-
free approach, in which they used a catalytic amount of
pentafluorophenyl-substituted benzoxathiazine for the hy-
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droxylation of aliphatic tertiary C H bonds in the presence of
H2O2 in acetic acid.[3j] Curci and co-workers used a stoichio-
metric amount of methyl(trifluoromethyl)dioxirane (TFDO)
Scheme 1. Methods for the generation of radicals from hypervalent
iodine(III) reagents. EWG=electron-withdrawing group, LG=leaving
group.
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to oxidize tertiary C H bonds, although the instability of the
reagent makes it difficult to handle.[2c,3b] White and co-
workers have shown that a bulky Fe-based catalyst can
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efficiently oxidize unactivated secondary C H bonds in
radical. When 1 was used in the oxidation tert-butyl-substi-
tuted cyclohexane, very small amounts of products were
obtained after 24 h (Table 1, entry 1). Yeung and co-workers
generated tert-butylperoxy radicals under mild reaction con-
ditions from diacetoxyiodobenzene (DIB; 2).[3m] Both acetyl
groups on the iodine are replaced by tert-butylperoxy groups,
thus resulting in the formation of highly the unstable bis(tert-
butylperoxy) iodane intermediate B. As a result, intermediate
B quickly decomposes to generate tert-butylperoxy radicals,
which oxidized tert-butylcyclohexane in a nonselective fash-
ion (Table 1, entry 2). We are interested in generating an
iodanyl radical with enhanced reactivity/selectivity under
mild reaction conditions. To this end, we decided to employ
acyclic iodane reagent 3 with two different ligands, where one
ligand acts as a steric/electronic modifier on the iodine center
and the other as a leaving group, which is replaced by a peroxy
substituent. With this approach, unstable iodane intermediate
C would be generated, thus leading to the formation of both
an iodanyl radical and a tert-butylperoxy radical. We intend to
accelerate the formation of C by choosing an appropriate
leaving group (LG), and create a more-reactive iodanyl
radical by tuning the electron-withdrawing group (EWG) on
the iodine center. Competition between the tert-butylperoxy
radical and iodanyl radical for the deprotonation step is
inevitable, and thus increasing the reactivity of the more-site-
selective iodanyl radical should improve the selectivity. An
investigation of different ligands revealed that a more elec-
tron-withdrawing group provides the better selectivity
(Table 1, entries 3 and 4). For the leaving group (LG), both
a highly predictable fashion.[2c,3e,h,i] In marked contrast,
however, there is no report of the use of a metal-free
system for the site-selective oxidation of unactivated secon-
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dary C H bonds in the absence of directing groups. Herein,
we report our initial results on the oxidation of unactivated
secondary C H bonds in the absence of directing groups with
a hypervalent iodine(III) reagent with predictable site-
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selectivity.[4]
Our proposed method to generate radical reagents from
hypervalent iodine(III) compounds for the site-selective
oxidation of unactivated C H bond is depicted in Scheme 1.
Ochiai et al. prepared stable tert-butylperoxy iodane A from
hypervalent iodane 1 through a ligand exchange reaction in
the presence of a Lewis acid.[5] The stability of the reagent
stems from fixation of an axial peroxy ligand and an
equatorial aromatic ligand on the iodine(III) center. In
solution, slow homolytic cleavage of the peroxy–iodine
bond results in formation of a peroxy radical and an iodane
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[*] Dr. S. A. Moteki, A. Usui, T. Zhang, C. R. Solorio Alvarado,
Prof. Dr. K. Maruoka
Laboratory of Synthetic Organic Chemistry and Special Laboratory of
Organocatalytic Chemistry, Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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