An alternative synthesis of 2,6-dimethoxyl-1,4-benzoquinone

Article abstract of DOI:10.3184/174751917X14894997017379

An economic four-step synthesis of 2,6-dimethoxy-1,4-benzoquinone was achieved in 68 % overall yield starting from aniline. The reaction sequence involved conversion to1,3,5-tribromoaniline, deamination, methoxylation, and oxidation. The procedure is operationally simple and amenable to scale-up production.

Full text of DOI:10.3184/174751917X14894997017379

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 APRIL, 193–194
RESEARCH PAPER 193
An alternative synthesis of 2,6-dimethoxyl-1,4-benzoquinone
Qian Wang, Jian Yang*, Yang Zheng and Xiali Liao
Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 South Jingming Road, Chenggong District, Kunming, Yunnan
Province 650500, P.R. China
An economic four-step synthesis of 2,6-dimethoxy-1,4-benzoquinone was achieved in 68 % overall yield starting from aniline. The reaction
sequence involved conversion to1,3,5-tribromoaniline, deamination, methoxylation, and oxidation. The procedure is operationally simple
and amenable to scale-up production.
Keywords: 2,6-dimethoxy-1,4-benzoquinone, aniline
2
,6-Dimethoxy-1,4-benzoquinone is a naturally occurring
Thirdly, 4 was treated with CH ONa and CH OH and DMF
3 3
metabolite found in many plants worldwide, including many
in the presence of a catalytic amount of CuCl at 100–110 °C
to produce 1,3,5-trimethoxybenzene 5. In the final step, 5 was
oxidised with H O in acidic methanol at room temperature to
1,2
Chinese traditional medicinal herbs. In recent years, it has
attracted considerable attention due to its potent deodorant,
antimicrobial, anticancer, and anti-neuroinflammatory
properties and other possible applications, although the exact
2
2
afford 2,6-dimethoxybenzoquinone 1 in high yield.
In conclusion, a practical and novel method which uses
a commercially available starting material and accessible
reagents for the synthesis of 2,6-dimethoxyl-1,4-benzoquinone
has been achieved in overall good yield. All steps of the
sequence take place under mild reaction conditions, are easy
to operate and involve simple workups, which makes the
synthesis a useful addition to the reported methods for the
preparation of the benzoquinone.
3
–8
mechanisms of action are far from understood. Also, the
compound is believed to be the key active component in the
“starters” of Korean wheat germ fermentation, Avemar®
and Nuruk®, which have also been used for the treatment of
9,10
many types of cancer. In addition, the compound could be
an intermediate for the synthesis of other natural biological
11,12
compounds and their analogues.
,6-Dimethoxy-1,4-benzoquinone can be obtained by
2
13,14
Experimental
purification of solvent extracts of certain plants.
However,
its total synthesis is an alternative source. Up to now, there
have been only two reports of its synthesis. However, these
methods have some drawbacks such as the use of expensive
starting materials, or a greater consumption of reagents, which
lead to higher costs of production. Therefore, an alternative
and efficient procedure for its synthesis is still in demand.
All reactions were monitored and the purity of the products was checked
by TLC performed on GF-254 silica gel plates with visualisation by UV
light and iodine colouring. Melting points were measured on a YRT-
1
3
temperature apparatus. H NMR spectral data were recorded on a
1
5,16
Bruker DRX 500 NMR spectrometer in DMSO-d , and the chemical
6
shifts are reported in parts per million (ppm) against internal standard
tetramethylsilane. Mass spectra were determined on a VG Auto Spec-
3
000 spectrometer and reported as m/z. All reagents were purchased
from Tansoole-reagent, China, and used without further purification.
,4,6-Tribromoaniline (3): To a stirred mixture of aniline (9.30 g,
.10 mol) in a mixture of aqueous HBr (47%; 70 mL, 0.40 mol) and
Results and discussion
Our synthetic route to 2,6-dimethoxy-1,4-benzoquinone 1
starts from inexpensive aniline 2 and is shown in Scheme 1.
Initially, aniline was brominated with bromine produced in
situ at room temperature from the reaction of HBr and H O
in methanol, a process which occurred rapidly and almost
quantitatively to yield 2,4,6-tribromoaniline 3. Secondly,
2
0
methanol (200 mL) was added dropwise a solution of aqueous H O2
2
2
2
(30%; 34 mL, 0.30 mol) over a period of 1 h at room temperature.
Then the reaction mixture was continuously stirred for 1 h. The
mixture was filtered and the resulting precipitate was collected and
recrystallised from ethanol to give 3: White needles; yield 31.40 g,
95%; m.p. 124–125 °C (lit. 124–126 °C); H NMR (500 MHz,
DMSO-d ) δ 7.64 (s, 2H), 5.53 (s, 2H); MS (m/z): 331 [M + H] .
3
was diazotised with a little excess of 1 equiv. of NaNO2
17
1
and H SO in ethanol, the solvent effecting in situ reduction
2
4
+
efficiently to give 1,3,5-tribromobenzene 4 in high yield.
6
Br
Br
a
b
c
Br
Br
Br
Br
NH2
NH2
4
2
3
O
O
OCH3
d
H CO
OCH3
H
3
CO
OCH
3
3
5
1
Scheme 1. Reagents and conditions: a)HBr, H O , 95%; b)NaNO , H SO , CH CH OH, 90%; c)CH ONa, CH OH, DMF, CuCl, 90%; d)H O , H SO , 89%.
2
2
2
2
4
3
2
3
3
2
2
2
4
*
Correspondent. E-mail: pharmacistkg101@126.com

194 JOURNAL OF CHEMICAL RESEARCH 2017
1
,3,5-Tribromobenzene (4): To a stirred solution of compound 3
Received 20 January 2017; accepted 15 February 2017
Paper 1704552
https://doi.org/10.3184/174751917X14894997017379
Published online: 28 March 2017
(
9.90 g, 0.03 mol) in ethanol containing H SO (3.0 g, 0.03 mol) at room
temperature, NaNO (2.10 g, 0.03 mol) was added in 10 portions over a
period of 1 h at room temperature. Then the reaction mixture was heated
to reflux for several hours. The mixture was cooled to room temperature
and the resulting precipitate was filtered and recrystallised from ethanol to
2
4
2
Reference
18
give 4: Light brownish needles; yield 8.50 g, 90%; m.p. 119–121 °C (lit.
1
2
3
4
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+
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3
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+
6
,6-Dimethoxy-1,4-benzoquinone (1): To a solution of compound
5
(1.68 g, 0.01 mol) in CH OH, 30% H O (3.00 mL, 0.03 mol) and a
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completely. The resulting precipitate was filtered off and recrystallised
from CH OH–CHCl (1:1) to give 1: Yellowish crystals; yield 1.50 g, 89%;
5
1
1
2
3
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3
16
1
m.p. 241–244 °C (lit. 242–245 °C); H NMR (500 MHz, DMSO-d ) δ
.98 (s, 2H), 3.76 (s, 6H); MS (m/z): 169 [M + H] .
6
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Support by the National Natural Science Foundation of
China (NSFC) (no. 81460631) and the Analysis and Testing
Foundation of Kunming University of Science and Technology
1
7
1
1
8
9
(no. 20150728) is gratefully acknowledged.