Synthesis of anthraquinone derivatives: Tandem Diels-Alder-decarboxylation- oxidation reaction of 3-hydroxy-2-pyrone with 1,4-naphthoquinone

Article abstract of DOI:10.1055/s-2005-922769

In the presence of triethylamine, the Diels-Alder reaction of 3-hydroxy-2-pyrones with 1,4-naphthoquinones by a decarboxylation-oxidation process gave anthraquinone derivatives in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922769

124
LETTER
Synthesis of Anthraquinone Derivatives: Tandem Diels–Alder-Decarboxyl-
ation–Oxidation Reaction of 3-Hydroxy-2-pyrone with 1,4-Naphthoquinone
Synthesis of
A
n
a
thraquinon
k
e
D
erivative
s
uzo Komiyama, Yutaka Takaguchi, Sadao Tsuboi*
Department of Material and Energy Science, The Graduate School of Environmental Science, Okayama University, Okayama 700-8530,
Japan
Fax +81(86)2518898; E-mail: stsuboi6@cc.okayama-u.ac.jp
Received 3 October 2005
cyclobutenedione chemistry,6 direct ortho-metalation,7
Abstract: In the presence of triethylamine, the Diels–Alder reac-
Hauser annulation,8 direct arene oxidation,9 and Friedel–
tion of 3-hydroxy-2-pyrones with 1,4-naphthoquinones by a decar-
boxylation–oxidation process gave anthraquinone derivatives in
Crafts reaction10 have been reported.
good to excellent yields.
In connection with our synthesis of 3-hydroxy-2-py-
Key words: 3-hydroxy-2-pyrone, tandem reactions, Diels–Alder rone,11 we found that the treatment of 3-hydroxy-2-pyrone
reactions, anthraquinone, oxidations
(1a) and 1,4-naphthoquinone (2a) with triethylamine gave
1-hydroxyanthraquinone (4a) smoothly.12 A plausible
mechanism for the synthesis of 4a is shown in Scheme 1.
Firstly, base-catalyzed Diels–Alder reaction of 1a13 and
The anthraquinone moiety is an important component of a
2a involving decarboxylation gave dihydroanthraquinone
3, then oxidation of 3 by 2a gave 4a. This one-pot reaction
proceeds very smoothly under mild conditions and is
operationally very easy. Furthermore, various substituted
anthraquinone derivatives can be prepared from various
3-hydroxy-2-pyrones by this reaction. Herein, we de-
scribe the novel one-pot synthesis of anthraquinone deriv-
atives by the base catalyzed Diels–Alder reaction of 3-
hydroxy-2-pyrones with 1,4-naphthoquinones by a decar-
boxylation–oxidation process.
large number of natural products, which exhibit a wide
range of biological activities. For example, emodine
(1,3,8-trihydroxy-6-methylanthraquinone) is a tumor cell-
growth inhibitor and possesses other various biological
activities.1 Fridamycin2 and vineomycin3 are well known
potent antibiotic compounds, which have the anthrarufin
(1,5-dihydroxy-9,10-anthraquinone) unit present. Even
recently, unknown anthraquinone derivatives have been
isolated4 and newly designed anthraquinone derivatives
have also been synthesized as biologically active agents.5
In the presence of triethylamine, 3-hydroxy-2-pyrones
1a–e were converted to their corresponding anthraqui-
nones in excellent to good yields14 (Scheme 2, Table 1).
As mentioned above, anthraquinone derivatives are very
attractive compounds and have drawn much attention due
to interest in the synthesis of their analogues; for example,
O
O
OH
O
O
O
O
O
OH
Diels–Alder
HO
O
– CO2
O
2a
O
1a
3
OH
O
OH
O
OH
O
O
2a
oxidation
4a
Scheme 1
SYNLETT 2006, No. 1, pp 0124–0126
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922769; Art ID: U28605ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Anthraquinone Derivatives
125
Treatment of 3-hydroxy-2-pyrone (1a) and 1,4-naphtho- Then we applied this reaction to substituted 1,4-naphtho-
quinone (2a) with 0.1 equivalents of triethylamine in quinones to investigate the regioselectivity of this reac-
toluene under reflux for two hours provided 1-hydroxy- tion. 3-Hydroxy-2-pyrones 1a–d were converted to the
anthraquinone (4a) in 80% yield after purification by corresponding anthraquinones 4f–j in excellent to reason-
silica gel flash column chromatography (Table 1, entry 1). able yields (Scheme 3, Table 2). The regioselectivity was
Other 3-hydroxy-2-pyrones 1b–e were also smoothly shown to be consistent and the products which have the
converted to their corresponding anthraquinones 4b–e substituted group on the opposite side (Scheme 3, com-
(Table 1, entries 2–5).
pound A) were obtained selectively.
In conclusion, we have developed an efficient and novel
one-pot method for the synthesis of anthraquinone deriv-
atives by the triethylamine-catalyzed Diels–Alder reac-
tion of 3-hydroxy-2-pyrones and 1,4-naphthoquinones.
This one-pot reaction proceeds very smoothly under mild
conditions. Various substituted anthraquinone derivatives
can be prepared from various 3-hydroxy-2-pyrones and
1,4-naphthoquinones by this reaction. Further exploita-
tion of this strategy towards the synthesis of biologically
active compounds is in progress and will be reported in
the future.
O
OH
O
O
X
HO
Et3N
O
+
toluene, reflux
X
Y
O
Y
O
1a–e
2a
4a–e
Scheme 2
Table 1 Synthesis of Various Anthraquinone Derivativesa
Entry Substrate
X
Y
Time (h) Product Yield (%)
1
2
3
4
5
1a
1b
1c
1d
1e
H
H
2
3
2
3
3
4a
4b
4c
4d
4e
80
94
93
76
95
References and Notes
Cl
H
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SPh
Br
SPh
H
H
Me
a Reagents: 1,4-Naphthoquinone (2 equiv) and Et3N (0.1 equiv).
(2) (a) Krhon, K.; Baltus, W. Tetrahedron 1988, 44, 49.
(b) Matsumoto, T.; Jona, H.; Katsuki, M.; Suzuki, K.
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OAc
O
OAc
O
O
OAc
O
OH
O
Y
Y
Y
X
HO
X
Et3N
O
+
toluene, reflux
X
O
OH
O
1a–d
A
2b,c
B
4f–j
Scheme 3
Table 2 Investigation of the Regioselectivity in the Synthesis of Various Anthraquinone Derivativesa
Entry
Substrate
2-Pyrone
Time (h)
Product
Yield (%)
Isomer ratio (A/B)
X
1,4-Naphthoquinone
Y
1
2
3
4
5
1a
1b
1c
1c
1d
H
2b
2b
2b
2c
2c
H
1
4f
4g
4h
4i
74
81
94
96
71
5.0:1
4.8:1
12.8:1
8.0:1
3.5:1
Cl
H
1
SPh
SPh
Br
H
0.5
0.5
0.5
Cl
Cl
4j
a Reagents: 1,4-Naphthoquinone (2 equiv) and Et3N (0.1 equiv).
Synlett 2006, No. 1, 124–126 © Thieme Stuttgart · New York

126
T. Komiyama et al.
LETTER
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traces of desired compound 4a.
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(14) Anthraquinone 4c; Typical Procedure. To a stirred
solution of 1,4-naphthoquinone 2a (72 mg, 0.46 mmol) and
2-pyrone 1c (50 mg, 0.23 mmol) in toluene (5 mL) was
added Et3N (2 mg, 0.02 mmol) and the reaction mixture was
heated to reflux for 2 h. Then the reaction mixture was
allowed to cool to r.t. After evaporation of the solvent, the
crude product was purified by column chromatography
(hexane–EtOAc, 50:1) to give anthraquinone 4c (70 mg,
93%) as an orange solid; mp 210–212 °C. IR (neat): 1662,
1630, 1591, 1424, 1349, 1285, 1217, 1126, 1017, 747, 708
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.07 (d, J = 8.1 Hz,
1 H), 7.47–7.49 (m, 3 H), 7.57–7.61 (m, 2 H), 7.67 (d,
J = 8.1 Hz, 1 H), 7.80–7.85 (m, 2 H), 8.27–8.34 (m, 2 H),
13.3 (br, 1 H). Anal. Calcd for C20H12O3S: C, 72.27; H, 3.64.
Found: C, 72.48; H, 3.66.
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Synlett 2006, No. 1, 124–126 © Thieme Stuttgart · New York