Vanadium-catalyzed oxidative aromatization of 2-cyclohexenones under molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2009.10.070

An efficient catalytic oxidative aromatization of 2-cyclohexenones was achieved by a combination of a commercially available inexpensive ligand-free vanadium catalyst, a bromide source, and an acid under atmospheric oxygen to afford the corresponding phenol derivatives. This catalytic oxidative aromatization proceeded even under air. Furthermore, a gram-scale reaction was performed successfully.

Full text of DOI:10.1016/j.tetlet.2009.10.070

Tetrahedron Letters 50 (2009) 7385–7387
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Vanadium-catalyzed oxidative aromatization of 2-cyclohexenones under
molecular oxygen
*
*
Toshiyuki Moriuchi , Kotaro Kikushima, Tomomi Kajikawa, Toshikazu Hirao
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient catalytic oxidative aromatization of 2-cyclohexenones was achieved by a combination of a
commercially available inexpensive ligand-free vanadium catalyst, a bromide source, and an acid under
atmospheric oxygen to afford the corresponding phenol derivatives. This catalytic oxidative aromatiza-
tion proceeded even under air. Furthermore, a gram-scale reaction was performed successfully.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 September 2009
Revised 14 October 2009
Accepted 16 October 2009
Available online 21 October 2009
Oxidative transformation of organic molecules constitutes a
fundamental and important reaction.1 Dehydrogenative aromati-
zation is one of the most important oxidative transformations in
organic synthesis.1,2 Some methods for catalytic dehydrogenative
operate as a catalyst under argon atmosphere (entry 5), indicating
that molecular oxygen is essential for an efficient catalytic oxida-
tive-aromatization reaction. NaVO3 was found to be less effective
than NH4VO3 (entry 6). V2O5 was not effective in the oxidative aro-
matization (entry 7). High catalytic activity was observed with
VOSO4 to give the further monobrominated product 2ab (entry 8)
although the oxidative aromatization was not effectively per-
formed under argon atmosphere (entry 9). With VOSO4, the reac-
tion proceeded smoothly in 4 h (entry 10). The catalytic oxidative
aromatization was effectively performed even under air to afford
75% of 2aa although a longer reaction time was required (entries
11 and 12). VO(acac)2 exhibited a similar catalytic activity (entry
13). The oxo metal complexes, (NH4)2MoO4 and NH4ReO4 displayed
no promising results (entries 14 and 15). The catalytic oxidative
aromatization of 3,5-dimethyl-2-cyclohexen-1-one (1b) with
5 mol % of NH4VO3, 1000 mol % of Bu4NBr, and 1000 mol % of TFA
led to the formation of 2,4,6-tribromo-3,5-dimethylphenol (2bb)
in 73% isolated yield (Scheme 1).
The catalytic oxidative aromatization of 1a also proceeded mod-
erately by a combination of 5 mol % of VOSO4 and 300 mol % of HBr
aq (48%), indicating that HBr serves as both a bromide source and
Brønsted acid (Table 2, entry 1). Furthermore, the amount of HBr
aq (48%) could be reduced to 50 mol % to give phenol (2aa) in
77% yield although a longer reaction time, 9 h, was required (entry
2). The oxidatively aromatized product 2aa could also be obtained
even under air with a long reaction time (entries 3 and 4). Catalytic
activity of other catalysts was surveyed using these conditions.
VO(acac)2 and NH4VO3 could be also effective as a vanadium cata-
lyst (entries 5 and 6). NaVO3, V2O5, and VO(OiPr)3 exhibited less
effective catalytic activities than VOSO4 (entries 7, 8, and 9).
(NH4)2MoO4 showed no promising result (entry 10) although a
moderate catalytic activity was observed with NH4ReO4 (entry 11).
The reaction of 4-carbethoxy-3-methyl-2-cyclohexen-1-one
(1c) with 5 mol % of VOSO4, 300 mol % of Bu4NBr, and 300 mol %
of TFA resulted in the efficient catalytic oxidative aromatization
aromatization of a,b-unsaturated cyclohexenones to phenols have
been reported.3 These catalytic systems, however, require severe
conditions or a long reaction time. In a previous letter, Lewis acid,
VO(OR)Cl2, with oxidation capability has been reported to induce
the oxidative aromatization of
a,b-unsaturated cyclohexenones
to aryl ethers.4 This system, however, requires a stoichiometric
amount of the oxidant. Catalytic processes using molecular oxygen
as a terminal oxidant are desirable from the viewpoint of environ-
mentally benign synthesis. We have already demonstrated that the
aerobic vanadium-catalyzed oxidative bromination reaction of are-
nes, alkenes, and alkynes is achieved by using a commercially
available inexpensive ligand-free vanadium catalyst, a bromide
ion source, and an acid under atmospheric oxygen or air, wherein
a brominium cation-like species is proposed to be a key intermedi-
ate.5 These results prompted us to investigate a catalytic scope of
the vanadium-catalyzed oxidation system. We herein report the
vanadium-catalyzed oxidative aromatization of 2-cyclohexenones
to phenols under molecular oxygen.
The oxidative aromatization reaction of 2-cyclohexen-1-one
(1a) with 5 mol % of NH4VO3, 300 mol % of Bu4NBr, and 300 mol %
of trifluoroacetic acid (TFA) was performed at 80 °C in 1,4-dioxane
under atmospheric oxygen for 6 h (Table 1). The oxidative aromati-
zation proceeded smoothly to afford phenol (2aa) in 80% yield with
the concomitant formation of p-benzoquinone in 7% yield (Table 1,
entry 1). The reaction without NH4VO3 catalyst gave only a trace
amount of 2aa (entry 2). No aromatization product was obtained
in the absence of Bu4NBr or TFA (entries 3 and 4). NH4VO3 did not
* Corresponding authors. Tel.: +81 6 6879 7413; fax: +81 6 6879 7415 (T.M.).
E-mail addresses: moriuchi@chem.eng.osaka-u.ac.jp (T. Moriuchi), hirao@chem.
eng.osaka-u.ac.jp (T. Hirao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.070

7386
T. Moriuchi et al. / Tetrahedron Letters 50 (2009) 7385–7387
Table 1
Table 2
Catalytic oxidative aromatization of 1a
Catalytic oxidative aromatization of 1a by using HBr aq (48%) as proton and bromide
sources
Cat.
Br− source 300 mol%
Acid 300 mol%
5 mol%
O
OH
OH
O
O
OH
OH
O
Cat.
5 mol%
HBr aq (48%)
50 mol%
+
+
+
+
1,4-Dioxane, O2, 80 °C, 6 h
1,4-Dioxane, O2, 80 °C, 9 h
Br
2ab
O
3
Br
2ab
O
3
1a
2aa
1a
2aa
Entry
Cat.
BrÀ source
Acida
NMR yield (%)
Entry
Cat.
NMR yield (%)
2aa
2ab
3
2aa
2ab
3
1
NH4VO3
—
Bu4NBr
Bu4NBr
—
TFA
TFA
TFA
—
80
3
0
0
6
67
25
64
4
75
45
75
86
16
0
0
0
0
0
0
0
0
24
0
4
7
1
0
0
1
6
1a
2
VOSO4
VOSO4
VOSO4
VOSO4
VO(acac)2
NH4VO3
NaVO3
54
77
32
73
72
71
46
64
57
30
59
0
0
0
0
0
0
0
0
0
0
0
15
10
4
10
8
5
4
7
8
2
3b
4
NH4VO3
NH4VO3
NH4VO3
NaVO3
V2O5
VOSO4
VOSO4
VOSO4
VOSO4
3b
4c
5
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
5c
6
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
6
7
8
9
10
11
7
8
Trace
4
1
6
9
14
6
V2O5
9c
10d
11e
12f
13
14g
15g
VO(OiPr)3
(NH4)2MoO4
NH4ReO4
2
31
0
0
0
0
VOSO4
a
With 300 mol % of HBr aq (48%) for 6 h.
Under air.
Under air for 47 h.
VO(acac)2
(NH4)2MoO4
NH4ReO4
b
c
3
0
0
a
b
c
d
e
f
TFA = trifluoroacetic acid.
Ethylene glycol diformate was obtained as a by-product.
Under argon atmosphere.
4 h.
Under air.
Under air for 21 h.
24 h.
Table 3
Oxidative aromatization of 1c catalyzed by VOSO4
O
OH
VOSO4
5 mol%
x mol%
Br−/Acid source
g
1,4-Dioxane, Atmosphere,
80 °C, Time
O
O
O
O
1c
2c
NH4VO3
Bu4NBr
TFA
5 mol%
1000 mol%
1000 mol%
Entry BrÀ/acida
source
x mol % Atom
Time
(h)
NMR yield
(%)
2c
O
OH
Br
Br
sphere
1,4-Dioxane, O2, 80 °C, 72 h
1
2
Bu4NBr/TFA
300/
300
300/
300
50
O2
9
91b
Br
2bb
Bu4NBr/TFA
Air
14
92
1b
73% isolated yield
3
4
HBr aq (48%)
HBr aq (48%)
O2
Air
15
18
86
82
50
Scheme 1. Oxidative aromatization of 1b catalyzed by NH4VO3.
a
TFA = trifluoroacetic acid.
Isolated yield is 89%.
b
to give the phenol derivative 2c in 91% yield (Table 3, entry 1). Fur-
thermore, the catalytic oxidative aromatization was also effectively
performed even under air to afford 92% of 2c although a longer
reaction time was required (entry 2). The oxidatively aromatized
product 2c could be produced by the combination of 5 mol % of
VOSO4 and 50 mol % of HBr aq (48%) under both oxygen atmo-
sphere and air (entries 3 and 4).
It should be noted that the catalyst loading could be success-
fully reduced to 1 mol % in a gram-scale reaction for the catalytic
oxidative aromatization of 1c to afford 2c in 81% isolated yield,
as shown in Scheme 2.6 With the combination of 5 mol % of VOSO4
and 50 mol % of HBr aq (48%), 1.27 g (71% yield) of the aromatized
product 2c was isolated.
VOSO4
Bu4NBr
TFA
1 mol%
200 mol%
200 mol%
O
OH
1,4-Dioxane, O2, 80 °C, 21 h
O
O
O
O
1c
2c
1.82 g
1.46 g
81%
Scheme 2. Gram-scale catalytic oxidative aromatization of 1c catalyzed by VOSO4.
In conclusion, the combination of a commercially available inex-
pensive ligand-free vanadium catalyst, a bromide source, and an
acid under atmospheric oxygen was demonstrated to provide a ver-
satile synthetic method for the catalytic oxidative aromatization of
2-cyclohexenones, affording the corresponding phenol derivatives.
This catalytic oxidative aromatization could be performed even un-
der air. Furthermore, a gram-scale reaction successfully proceeded
to give the desired product. Further investigations on the applica-
tion of the catalytic oxidation system to other reactions and the
reaction mechanism are now in progress.
Acknowledgments
One of the authors K.K. acknowledges a JSPS fellowship for
young scientists, and expresses special thanks for the Global COE
(center of excellence) Program ‘Global Education and Research

T. Moriuchi et al. / Tetrahedron Letters 50 (2009) 7385–7387
7387
2. For a review Hayashi, M. Chem. Rec. 2008, 8, 252–267.
Center for Bio-Environmental Chemistry’ of Osaka University.
Thanks are due to the Analytical Center, Graduate School of Engi-
neering, Osaka University, for the use of the NMR instrument.
3. (a) Hayashi, M.; Yamada, K.; Nakayama, S. J. Chem. Soc., Perkin Trans. 1 2000,
1501–1503; (b) Kamiguchi, S.; Nishida, S.; Kodomari, M.; Chihara, T. J. Clust. Sci.
2005, 16, 77–91; (c) Yi, C. S.; Lee, D. W. Organometallics 2009, 28, 947–949.
4. (a) Hirao, T.; Mori, M.; Ohshiro, Y. J. Org. Chem. 1990, 55, 358–360; (b) Hirao, T.;
Mori, M.; Ohshiro, Y. Chem. Lett. 1991, 20, 783–784.
Supplementary data
5. Kikushima, K.; Moriuchi, T.; Hirao, T. Chem. Asian J. 2009, 4, 1213–1216.
6. Gram-scale catalytic oxidative aromatization of 4-carbethoxy-3-methyl-2-
cyclohexen-1-one (1c) catalyzed by VOSO4: In
a 50 mL two-necked flask
Supplementary data (general information, procedure, and NMR
spectral data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.10.070.
equipped with reflux condenser, vanadium(IV) oxide sulfate hydrate
a
(22.6 mg, 0.10 mmol) and tetrabutylammonium bromide (6.45 g, 20 mmol)
were placed. The flask was evacuated and backfilled with atmospheric oxygen.
To the mixture, 1,4-dioxane (20 mL), 4-carbethoxy-3-methyl-2-cyclohexen-1-
one (1.82 g, 10 mmol), and trifluoroacetic acid (1.5 mL, 10 mmol) were added.
The mixture was stirred at 80 °C for 21 h. The mixture was diluted with ether,
then treated with deionized water, and was extracted three times with ether.
The organic layer was dried over MgSO4, filtered, and evaporated. The product
was isolated by column chromatography (SiO2, hexane/AcOEt = 1:1 v/v) to give
1.46 g of ethyl-4-hydroxy-2-methylbenzoate (2c, 81%).
References and notes
1. (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1984; (b) Hudlicky, M.. Oxidations in
Organic Chemistry. In ACS Monograph Series; American Chemical Society:
Washington, DC, 1990.