COMMUNICATION
DOI: 10.1002/asia.200900420
Manganese-Catalyzed Direct Oxidation of Methyl Ethers to Ketones
[
a]
Shin Kamijo, Yuuki Amaoka, and Masayuki Inoue*
Dedicated to the 150th anniversary of Japan–UK diplomatic relations
Alkyl ether linkages generally exhibit high chemical sta-
bility under a wide array of synthetic procedures and reac-
tion conditions. Therefore, such ethers are often employed
The reaction conditions for the CÀH oxidation were
screened and optimized using methyl cyclododecyl ether 1a
(Table 1). Treatment of methyl ether 1a with four equiva-
lents of reagent-grade mCPBA in the presence of 0.1 mol%
of MnCl ·4H O in CH CN produced the corresponding cy-
[1]
as protective groups for hydroxyl functionalities, which are
present in a number of naturally occurring substances of
biological and synthetic interest. During syntheses of multi-
hydroxylated molecules, judicious choice of protective
groups, and their selective introduction and removal, are ex-
tremely important issues. Accordingly, a number of ethereal
protective groups have been designed and developed, and
various substituted benzyl ethers are among the most fre-
quently employed in organic synthesis. On the other hand,
the simplest, most robust methyl ethers have received less
attention mainly owing to the harsh acidic conditions re-
2
2
3
clododecanone 2a in 32% yield (Table 1, entry 1), although
the reaction was not complete even after 12 h at room tem-
[11]
perature. Use of 0.1 mol% of 2,2’:6’,2”-terpyridine (terpy,
Table 1, entry 2) as a tridentate nitrogen ligand increased
the reaction rate, and 50% of 2a was isolated after 2 h at
[9b,c]
room temperature.
To improve the oxidation ability of
the catalyst even further, addition of a variety of ligands was
examined (Table 1, entries 3–5). Complexation with ligands
bearing electron-donating groups, such as 4,4’,4’’-tri(tert-
[2]
quired for deprotection.
butyl)-2,2’:6’,2’’-terpyridine (tBu-terpy, entry 3) and 4,4’,4’’-
3
[3]
[12]
We envisioned that direct sp CÀH oxidation under mild
tri
A
H
U
G
R
N
U
G
(MeO-terpy, entry 4)
conditions should be useful for oxidative removal of methyl
accelerated the ether oxidation, whereas addition of the
ethers, because CÀH bonds in the position a to the oxygen
ligand bearing an electron-withdrawing group, 4,4’,4’’-tri-
ACHTUNGENTRNUNG( nitro)-2,2’:6’,2’’-terpyridine (NO -terpy, entry 5), showed no
2
[4]
atom are generally susceptible to oxidation. A number of
oxidizing agents have been reported to perform one-step ox-
idation of dialkyl ethers to the corresponding carbonyl prod-
beneficial effect for the conversion. Consequently, tBu-terpy
was selected as the ligand for further investigation, because
of its high performance and commercial availability. As a
primary oxidant, mCPBA was found to be far more reactive
than magnesium monoperoxyphthalate (MMPP) and tetra-
[5]
[6]
ucts. Among them, dioxirane and oxaziridine are repre-
sentative non-metallic stoichiometric reagents for oxidation
of dialkyl ethers. Several metal catalysts, such as Ru, Cr,
Mn, and Fe, are also reported to oxidize ethers when uti-
[9b,c,13]
n-butylammonium oxone (TBA-oxone)
(Table 1, en-
[4,7]
lized with a stoichiometric amount of primary oxidant.
tries 6 and 7). Overall, the optimized conditions (entry 3),
However, the starting ethers are restricted mainly to cyclic
ethers, and systematic studies on metal-catalyzed oxidation
which employed MnCl ·4H O (0.1 mol%), tBu-terpy (0.1
2
2
mol%) and mCPBA (4 equiv; 70 wt%) in CH CN (0.1m),
3
[8]
of acyclic alkyl ethers are scarce. We herein report a direct
oxidation method of methyl ethers to ketones using a newly
developed reagent system that involves a catalytic amount
resulted in formation of 2a in 50% yield within 2 h at
[14]
08C. The reaction most likely occurs through insertion of
oxygen into the tertiary CÀH bond, which is generally more
prone to oxidation than the methyl CÀH bond
[9,10]
of Mn reagent and m-chloroperbenzoic acid (mCPBA).
[15]
(
Scheme 1).
Ejection of methanol from the generated
[
a] Dr. S. Kamijo, Y. Amaoka, Prof. Dr. M. Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5841-0568
hemiacetal 3 would then lead to ketone 2a. It is also impor-
tant to note that mCPBA did not promote the Baeyer–Vil-
liger type of oxidation of ketone 2a under these mild condi-
tions.
The procedure developed here is operationally simple.
For instance, the reaction of 1a to 2a took place even in the
presence of a small amount of water under aerobic atmos-
E-mail: inoue@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900420.
486
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 486 – 489