Efficient one-pot synthesis of hydroxyflavanones by cyclization and O-demethylation of methoxychalcones

Article abstract of DOI:10.1080/00397910801991465

An efficient one-pot method for the synthesis of hydroxyflavanones is described. Methoxychalcones are treated with 36% HBr to afford cyclization and regioselective O-demethylation products (2a-i) while cyclization and complete O-demethylation products (3a

Full text of DOI:10.1080/00397910801991465

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Efficient One‐Pot Synthesis of
Hydroxyflavanones by Cyclization and
O‐Demethylation of Methoxychalcones
Tao Liu a , Huazhou Ying a , Guan Lin a & Yongzhou Hu a
a Zhejiang University-Ecole Normale Supérieure (ZJU‐ENS) Joint Laboratory
of Medicinal Chemistry, School of Pharmaceutical Sciences , Zhejiang
University , Hangzhou, China
Published online: 09 May 2008.
To cite this article: Tao Liu , Huazhou Ying , Guan Lin & Yongzhou Hu (2008) Efficient One‐Pot Synthesis of
Hydroxyflavanones by Cyclization and O‐Demethylation of Methoxychalcones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:11, 1815-1821, DOI:
10.1080/00397910801991465
To link to this article: http://dx.doi.org/10.1080/00397910801991465
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Synthetic Communicationsw, 38: 1815–1821, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801991465
Efficient One-Pot Synthesis of
Hydroxyflavanones by Cyclization and
O-Demethylation of Methoxychalcones
Tao Liu, Huazhou Ying, Guan Lin, and Yongzhou Hu
´
Zhejiang University-Ecole Normale Superieure (ZJU-ENS) Joint Lab-
oratory of Medicinal Chemistry, School of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, China
Abstract: An efficient one-pot method for the synthesis of hydroxyflavanones is
described. Methoxychalcones are treated with 36% HBr to afford cyclization and regio-
selective O-demethylation products (2a–i) while cyclization and complete O-demethy-
lation products (3a–e) are obtained in the presence of 45% HI.
Keywords: Cyclization, O-demethylation, hydrobromic acid, hydroiodic acid,
hydroxyflavanones, methoxychalcones
INTRODUCTION
Flavanones attract the attention of researchers as physiologically active
substances with a wide range of biological activities. They have been found
use as radical scavenging agents,[1] inhibitors of nitric oxide production,[2]
antiproliferative agents,[3] apoptosis-inducing agents,[4] inhibitors of
aromatase,[5] and inhibitors of trypsin.[6] It is also known that flavanones
have been used to construct flavonoid-related molecules such as flavones[7]
and other heterocyclic compounds.[8] Flavanone is usually obtained by cycli-
zation of 20-hydroxychalcones in acidic or alkaline media such as acetic
acid,[9] sulfuric acid,[3] phosphoric acid,[10] or triethylamine.[11] Sodium
Received September 10, 2007
Address correspondence to Yongzhou Hu, Zhejiang University-Ecole Normale
´
Superieure (ZJU-ENS) Joint Laboratory of Medicinal Chemistry, School of
Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou
310058, China. E-mail: huyz@zju.edu.cn
1815

1816
T. Liu et al.
acetate is also used for this purpose.[12] However, these procedures led to low
conversions and yields, even prolonging the reaction time. On the other hand,
biologically active flavanones always bear free hydroxy groups on the
backbone. For synthesis of hydroxyflavanone, it is need to protect free
hydroxy groups, followed by deprotection. The regular approaches to
synthesis of hydroxyflavanones when using methoxychalcones as starting
material use these two steps, cyclization and O-demethylation.
In the course of our continuing studies on the antitumor activities of fla-
vonoids,[13] we occasionally found when treating 2-chloro-20-hydroxy-40,60-
dimethoxychalcone 1a with 36% hydrobromic acid, no intented product
(20,40,60-trihydroxychalcone) was obtained. Further research revealed that
20-chloro-5-hydroxy-7-methoxy-flavanone 2a was the main product
(Scheme 1). On the basis of this unexpected result, here we are gratified to
report an efficient and convenient method for the cyclization and O-demethy-
lation of polymethoxychalcones into corresponding hydroxyflavanones in
glacial acetic acid in the presence of hydrogen halide in one pot.
RESULTS AND DISCUSSION
With the discovery of this new route, the cyclization and O-demethylation of
1a were explored. Initial efforts focused on optimizing the proportion of
substrate 1a to 36% hydrobromic acid. The proportions of substrate 1a to
36% hydrobromic acid were from 1 mmol:0.3 mL to 1 mmol:1.5 mL under
refluxing for 1 h. The above reaction was successfully carried out, and
better results were obtained when the proportion was 1 mmol:1.2–1.5 mL
(Table 1, entries 3 and 4). Also we investigated the duration for the
reaction. As can be seen from Table 1, the best yield was achieved when
Scheme 1. Hydrogen halide–mediated direct conversion of methoxychalcones to
hydroxyflavanones.

Hydroxyflavanones
Table 1. Selection of the reaction conditions for preparation of 2a
1817
Sub./36% HBr
(mmol/mL)
Entry
Time (hr)
Yield (%)a
1
2
3
4
5
6
7
1:0.3
1:0.6
1:1.2
1:1.5
1:1.2
1:1.2
1:1.2
1
1
59
67
75
76
69
78
74
1
1
0.25
0.5
1.25
aIsolated yield.
the proportion of 1a to 36% hydrobromic acid was 1:1.2 (mmol/mL) with
heating for 0.5 h (Table 1, entry 6).
In the presence of 36% hydrobromic acid, the O-demethylation sequence
was regioselective, yielding 20-chloro-5-hydroxy-7-methoxyflavanone 2a
only. Otherwise, when 36% hydrobromic acid was replaced by 45% hydroio-
dic acid, the result of cyclization and O-demethylation was slightly different
from this, yielding 20-chloro-5,7-dihydroxyflavanones 3a as the main
product. The optimization of reaction conditions by using 45% hydroiodic
acid solution was further investigated (Table 2). When the proportion of 1a
to 45% hydroiodic acid was increasd up to 1:20, the reaction became compli-
cated and the amount of the desired product was reduced. For comparison, the
yield was higher when the proportion of 1a to 45% hydroiodic acid was 1:16
(mmol/mL) with refluxing for 2 h (Table 2, entry 3).
To establish the scope of these two reactions, a number of methoxychal-
cones were subjected to cyclization and O-demethylation in glacial acetic acid
in the presence of hydrogen halide, and the results are given in Table 3. As can
be seen from Table 3, all methoxychalcones with electron-donating as well as
Table 2. Selection of the reaction conditions for preparation of 3a
Sub./45% HI
Entry
(mmol/mL)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
1:8
1:12
1:16
1:20
1:24
1:16
1:16
1:16
2
2
64
64
68
54
44
61
63
67
2
2
2
1
1.5
2.5
aIsolated yield.

1818
T. Liu et al.
Table 3. Cyclization and O-demethylation of methoxychalcones into corresponding
hydroxyflavanones
R
Product
Yield (%)a
Product
Yield (%)a
2-Cl
H
2a
2b
2c
2d
2e
2f
78
65
63
64
75
43
40
51
63
3a
3b
3c
3d
3e
68
60
71
63
73
4-CH3
4-Cl
4-N(CH3)2
2-OCH3
4-OCH3
3,4-OCH2O
3-NO2
2g
2h
2i
aIsolated yield.
electron-withdrawing substituents except other methoxyl groups on the B ring
underwent cyclization and O-demethylation smoothly to give their corre-
sponding hydroxyflavanones in 60–78% yields. We also observed that
applying 36% hydrobromic acid protocol to substrates with a methoxyl
group on the B ring resulted in poor conversions (40–51%). The desired
products (3f–h) could not be obtained in the presence of 45% hydroiodic
acid. We speculated that the main product was a dehydrated product of two
molecules of hydroxyflavanone (see attachment 1) after further research. As
for compound 3i, which has nitro group on B ring, we also could not get it,
because the reaction mixture was easy to turn brown and black and might
form polymers.
CONCLUSIONS
In conclusion, we have elaborated an efficient and convenient method for the
one-pot synthesis of hydroxyflavanones. It is noteworthy that when using
methoxychalcones as starting materials, cyclization and regioselective
O-demethylation products are yielded using 36% hydrobromic acid,
whereas cyclization and complete O-demethylation products are obtained in
the presence of 45% hydroiodic acid. Compared with other synthetic
methods, this protocol has the advantage of an easy workup, more efficient
cyclization and O-demethylation procedures, and moderate to high yields in
a one-pot synthesis of hydroxyflavanones.
EXPERIMENTAL
Reagents and solvents were commercially available and were used without
1
further purification. H and 13C NMR spectra were recorded on a Brucker

Hydroxyflavanones
1819
Advance DMX 400-MHz spectrometer with SiMe4 as the internal standard in
DMSO-d6. Melting points were determined on a B-540 Buchi melting-point
apparatus and are uncorrected. Infrared spectra were recorded on a Bruck
Vector 200 spectrophotometer (Brucker Optic GmbH, Germany). Electro-
spray ionization mass spectrometry (ESI) were measured on a Esquire-LC-
00075 spectrometer (Germany). Column chromatography was performed on
silica gel (200–300 mesh).
Representative Procedure for Preparation of 2a
To a solution of chalcones 1a (1 mmol) in glacial acetic acid (20 mL), 36%
HBr solution (1.2 mL) was added. The mixture was refluxed under N2 for
30 min. After the reaction mixture was cooled to room temperature, solvent
was evaporated in vacuo. Water (30 mL) was added to the residue, and the
mixture was neutralized to pH 7 with saturated sodium bicarbonate
solution. The solution was extracted with dichloromethane (20 mL ꢀ 3) and
washed with brine. The organic layer was dried over anhydrous sodium
sulfate and concentrated. The crude product was further purified by column
chromatography on silica gel with petroleum ether and acetone (30:1) as
eluent to give hydroxyflavanones 2a.
Data for 2a
White crystalline solid, mp 120–123 8C. IR (KBr): 3053, 2924, 2852, 1664,
1
1575, 1442, 1304, 1191, 1157, 1092, 745 cm21; ESI-MS: 305 (M þ 1); H
NMR (400 MHz, DMSO-d6): d 12.11 (s, 1H, 5-OH), 7.78 (d, 1H,
J ¼ 7.6 Hz, Ar-30-H), 7.49–7.41 (m, 3H, Ar-40-H, 50-H and 60-H), 6.18
(s, 1H, 8-H), 6.16 (s, 1H, 6-H), 5.90 (dd, 1H, J ¼ 13.2 Hz, 2.8 Hz, 2-H),
3.90 (s, 3H, OCH3), 3.02–2.98 (m, 2H, 3-Ha and 3-Hb); 13C NMR
(100 MHz, DMSO-d6): d 195.8 (C55O), 168.3 (C-7), 164.2 (C-8a), 160.4
(C-5), 136.1 (C-10), 131.5 (C-20), 129.7 (C-30), 129.6 (C-40), 127.4 (C-60),
127.0 (C-50), 103.9 (C-4a), 102.5 (C-6), 92.8 (C-8), 66.4 (C-2), 56.0
(O-CH3), 45.7 (C-3).
Representative Procedure for Preparation of 3a
To a solution of chalcones 1a (1 mmol) in glacial acetic acid (20 mL), 45% HI
solution (16 mL) was added. The reaction mixture was refluxed under N2 for
2 h. After the reaction mixture was cooled to room temperature, solvent was
evaporated in vacuo. Water (25 mL) was added to the residue and neutralized
to pH 7 with saturated sodium bicarbonate solution. The solution was
extracted with dichloromethane (20 mL ꢀ 3) and washed with brine. The
organic layer was dried over anhydrous sodium sulfate and concentrated.

1820
T. Liu et al.
The crude product was further purified by column chromatography on silica
gel with petroleum ether and acetone (10:1) as eluent to give hydroxyflava-
nones 3a.
Data for 3a
White crystalline solid, mp 270–272 8C. IR (KBr): 3117, 3017, 2924, 2850,
1637, 1601, 1577, 1481, 1303, 1168, 1089, 761 cm21; ESI-MS: 291
1
(M þ 1); H NMR (400 MHz, CDCl3): d 12.12 (s, 1H, 5-OH), 10.80 (s, 1H,
7-OH), 7.75 (d, 1H, J ¼ 7.6 Hz, Ar-30-H), 7.45-7.41 (m, 3H, Ar-40-H, 50-H
and 60-H), 6.01 (s, 1H, 8-H), 5.99 (s, 1H, 6-H), 5.67 (dd, 1H, J ¼ 13.2 Hz,
2.8 Hz, 2-H), 3.12–3.08 (m, 2H, 3-Ha and 3-Hb); 13C NMR (100 MHz,
CDCl3) : d 196.4 (C55O), 162.5 (C-7), 161.0 (C-8a), 159.4 (C-5), 137.1
(C-10), 130.5 (C-20), 129.1 (C-30), 128.9 (C-40), 128.0 (C-60), 126.6 (C-50),
102.7 (C-4a), 94.5 (C-6), 93.8 (C-8), 66.7 (C-2), 47.5 (C-3).
ACKNOWLEDGMENTS
This work was supported by the Natural Science Foundation of Zhejiang
Province of China (Project No. Y206340). We also gratefully thank the Exper-
imental Center of School of Pharmaceutical Sciences in Zhejiang University,
China.
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