Selective monomethylation of quercetin

Article abstract of DOI:10.1055/s-0030-1258310

Quercetin was monomethylated under mild conditions in moderate yields through selective deprotection. The combined effects of the protecting group and the heating mode on the reactivity were investigated. The presence of borax and the use of microwave irradiation significantly improved the yield and selectivity of alkylation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258310

3980
PAPER
Selective Monomethylation of Quercetin
S
elective Mono
h
m
ethylation
o
of
Q
uercetinng-hua Zhou,a Zhuan Fang,a Hui Jin,a Yue Chen,b Ling He*a
a
Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, P. R. of China
Department of Nuclear Medicine Affiliated Hospital, Luzhou Medical College, No. 25 Taiping Street, Luzhou, Sichuan, 646000,
b
P. R. of China
Fax +86(28)85503365.; E-mail: lhe2001@sina.com
Received 24 June 2010; revised 24 August 2010
are rarely found as natural products. However, quercetin
is the main flavonoid found in foods and in plants such as
Sophora japonica. Therefore, the partial synthesis of fla-
vonoids from quercetin is would be an attractive option
Abstract: Quercetin was monomethylated under mild conditions in
moderate yields through selective deprotection. The combined ef-
fects of the protecting group and the heating mode on the reactivity
were investigated. The presence of borax and the use of microwave
irradiation significantly improved the yield and selectivity of alky- for the construction of monomethylated derivatives of
lation.
quercetin. Although several monomethylquercetins have
been prepared,5–8 a number of challenges in their synthesis
Key words: alkylations, regioselectivity, methylation, heterocy-
cles, quercetin
remain. These include achieving selectivity, purification
from byproducts, achieving a high yield, and devising a
convenient method that promotes rapid reactions, requires
much less energy than existing methods, and uses less-
toxic reagents and solvents under milder conditions.
Moreover, flavone derivatives are widespread and attrac-
tive components of many natural and therapeutic products
of biological significance. It is therefore a desirable goal
to develop an efficient, novel, simple, and convenient
method for the preparation of monomethylquercetins,
preferably by means of a selective one-pot reaction that
will save materials and time, while giving high yields.
Quercetins [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-
4H-chromen-4-one] (Figure 1) and its derivatives are
widely distributed in the plant kingdom; for example,
quercetin is found in the flowers of the pagoda tree, in
onion, in tea, and in gingko nuts.
OH
2' 3'
1
O
8
4'
1'
OH
HO
B
7
2
A
C
5'
6'
3
Here, we report an efficient method for monomethylation
of quercetin to give 5-O-methylquercetin, 3¢-O-methyl-
quercetin, 7-O-methylquercetin, or 4¢-O-methylquercetin
by using a boron complex as a protective group in a one-
pot reaction with microwave assistance (Scheme 1).
6
4
OH
5
OH
O
Figure 1 Quercetin
Quercetin plays a key role in the preparation of many
pharmacologically active compounds.1–4 It is of particular
interest that monomethylated derivatives of quercetin ex-
hibit anticancer, anticarcinogenic, antibacterial, anti-
inflammation, antiallergic, antiviral, antioxidant, anti-
thrombogenic, and antiatherogenic properties. 3-O-Meth-
ylquercetin evidently possesses antiviral, anti-
inflammation, and antioxidant properties, and regulates
immune functions. 5-O-Methylquercetin (azaleatin) is
used to relieve cough sputum and to treat cardiovascular
disease. 7-O-Methylquercetin (rhamnetin) has anti-in-
flammatory and antitumor properties, and resists human
immunodeficiency virus. 3¢-O-Methylquercetin (isotham-
netin) fights cardiovascular effects of ischemia, relieves
heartstroke, regulates arrhythmia, and depresses choles-
terol levels. 4¢-O-Methylquercetin (tamarixetin) has anti-
oxidation, anticancer, and heart-stimulation effects and
eliminates free radicals. These five derivatives of flavones
We also report an intermolecular amidation of saturated
C–H bonds of benzyl ethers catalyzed by copper(II) tri-
flate and using 4-methyl-N-(phenyl-l3-iodanylidene)ben-
zenesulfonamide (PhI=NTs) or tosyl azide as a nitrene
source; we also report a debenzylation reaction catalyzed
by a Lewis acid.
Inspired by our work on copper(II) triflate catalyzed ami-
dation of ethers,9 and as part of our continuing study on
nitrene insertions into C–H bonds, we explored the amida-
tion of dibenzyl ethers with bis(acetyloxy)(phenyl)-l3-io-
dane [PhI(OAc)2] and tosylamide (TsNH2) catalyzed by a
metal complex in dichloromethane to form C–N bonds
(for example, in benzylideneaniline) and benzyl alcohol.10
Because this procedure is of no great practical use, we
wondered if the catalytic amidation could be applied in
debenzylation as a method for selective deprotection. We
therefore examined the intermolecular amidation of satu-
rated C–H bonds of pentabenzylquercetin in the presence
of copper(II) triflate as a catalyst and PhI=NTs or
PhI(OAc)2 and TsNH2 as a nitrene source. This reaction
gave 3,3¢,4¢,5-tetrabenzylquercetin in ~40% yield. Subse-
quently, we demonstrated that intermolecular amidation
SYNTHESIS 2010, No. 23, pp 3980–3986
x
x.
x
x
.
2
0
1
0
Advanced online publication: 21.10.2010
DOI: 10.1055/s-0030-1258310; Art ID: F10710SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Monomethylation of Quercetin
3981
OMe
OH
OH
HO
O
O
OH
OBn
OBn
MeO
O
O
OH
OH
HO
O
O
OH
OH
OAc
10 35%
OH
OBn
OBn
4 ~40%
6
BnO
BnO
O
O
OAc
53%
PhI=NTs, Cu(OTf)2
OAc
OBn
OH
8
OBn
HO
O
O
OBn
BnO
O
OH
OH
OBn
OBn
BnO
O
OH
BnO
O
1
OH
OH
2
OMe
OH
O
TsN3, CuCl2
73%
HO
O
O
OH
OBn
7
OH
OH
BnO
O
HO
O
OH
OBn
9 30%
OH
OH
O
O
MeO
3 81%
5
Scheme 1 Synthesis pathways of monomethylation products of quercetin
by using tosyl azide as the nitrogen source in the presence amide, sodium salt) was used as the nitrogen source in the
of copper(II) chloride under microwave irradiation for ten presence of copper(II) chloride under identical conditions.
minutes is an effective method for the selective prepara-
tion of 3,3¢,4¢,7-tetrabenzylquercetin in 81% yield
(Scheme 2). When this reaction was carried out in the ab-
Under appropriate conditions, 3,3¢,4¢,7- tetrabenzylquer-
cetin underwent methylation and hydrogenolysis to give
5-O-methylquercetin (Scheme 3). We therefore achieved
sence of TsN3 as a nitrogen source under identical condi-
a selective deprotection of pentabenzylquercetin through
tions, the same product was obtained in an identical yield.
nitrene insertion into the benzyl ether by using PhI=NTs
Strangely, the debenzylation reaction hardly proceeded
in presence of copper(II) chloride as a Lewis acid.
when chloramine-T (N-chloro-4-methylbenzenesulfon-
OBn
OBn
OBn
OBn
HO
O
O
BnO
O
O
PhI=NTs, Cu(OTf)2
CH2Cl2
+
OBn
OBn
BnO
NTs
BnO
4 (~40%)
2
OBn
MeCN
OBn
CuCl2
BnO
O
O
OBn
OH
3 (81%)
Scheme 2 Debenzylation of pentabenzylquercetin under various reaction conditions
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York

3982
Z.-h. Zhou et al.
PAPER
OH
OBn
OH
OBn
HO
O
BnO
O
O
+
BnCl, K2CO3, BnNEt3Cl–
TsN3, CuCl2
MeCN, MW
OH
HMPA, N2
OBn
OH
O
OBn
1
2
OBn
OH
OBn
OBn
OH
BnO
O
O
OBn
HO
O
O
BnO
O
Me2SO4
H2, Pd/C
EtOH
OBn
OH
K2CO3, MW
OBn
OH
OMe
OMe
O
3
5
11
Scheme 3 Synthesis of 5-O-methylquercetin
The intermolecular C–N bond-formation reaction mediat- from the proton in the 6-position (d = 6.44) and the proton
ed by 20% copper(II) salt provides a convenient access to in the 8-position (d = 6.46) to the methylene proton in the
deprotection products. When pentabenzylquercetin was 7-position (d = 5.13); and from the methylene proton in
used as the substrate together with PhI(OAc)2 and TsNH2 the 7-position (d = 5.13) to the protons in the 6-position
in a 1:3:1.5 molecular ratio, a tetrabenzylquercetin was (d = 6.44) and the 8-position (d = 6.46). NOE difference
obtained. The reaction may proceed by intermolecular spectroscopy of 3,5,3¢,4¢-tetra-O-benzylquercetin (4)
transfer of a nitrogen atom from the copper imido com- gave the following NOE correlations: from the proton in
plexes to the benzyl position of pentabenzylquercetin. The the 5-position (d = 6.98) to the methylene proton in the 4¢-
C–H insertion intermediate is converted into a tetraben- position (d =5.25); and from the proton in the 2¢-position
zyl(a-tosylaminobenzyl)quercetin, which undergoes (d = 7.89) to the methylene proton in the 3¢-position (d =
elimination of PhCH=NTs to give a tetrabenzylquercetin 4.98). NOE difference spectroscopy showed no NOE cor-
(Scheme 4).
relation from the proton in the 8-position proton (d = 5.58)
to the methylene protons in any position.
PhI(OAc)2 + TsNH2
CuY2
NHTs
OR
ROH
OCH2Ph
2' 3'
PhI
1
O
4'
8
1'
OCH2Ph
PhCH2O
B
7
6
2
NTs
A
C
6'
5'
TsN=CuY2
3
4
OCH2Ph
5
OH
O
Ts
N
3
OR
CuY2
OCH2Ph
4'
RO
2' 3'
B
H
1
O
8
1'
OCH2Ph
HO
7
2
A
C
5'
6'
3
R = 5-quercetin, 7-quercetin
Y = Cl, Tf
6
OCH2Ph
5
4
PhCH2O
O
Scheme 4 Mechanism for the amidation of pentabenzylquercetin
4
The structure of the debenzylated products were con-
Figure 2 Nuclear Overhauser effect spectroscopy of variously de-
protected derivatives
1
firmed by H NMR, 13C NMR, and mass spectroscopy.
The positions of the benzyl groups in the mondebenzylat-
ed products 3 and 4 were determined by means of nuclear
Overhauser effect spectroscopy. NOE difference spec-
troscopy of 3,3',4',7-tetra-O-benzylquercetin (3) gave the
following NOE correlations (Figure 2): from the proton in
the 5¢-position (d = 6.96) to the methylene proton in the 4¢-
position (d = 5.25); from the proton in the 2'-position (d =
7.71) to the methylene proton in the 3¢-position (d = 4.99);
Jain and coworkers found that o-dihydroxy groups can be
protected by chelation with a boron complex prepared by
treatment with borax.11–15 We investigated the effects of
this complexation on the selective alkylation of quercetin
and its derivatives, and we found that borax-type protec-
tion of adjacent hydroxy groups could be effective in
inducing selective alkylation (Figure 3).
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York

PAPER
Selective Monomethylation of Quercetin
Table 1 Optimization of the Solvent
3983
OH
B–
H
O
Entrya Solvent
Temp
Time
(h)
Product
Yieldb
(%)
OH
OH
HO
O
O
1
2
3
4
5
6
7
MeCN
r.t.
24
24
24
24
24
24
35
–
–
OH
–B
OH
MeOAc
DMF
r.t.
mixturec
mixtured
7
–
HO
O
OH
– B
OH
60 °C
r.t.
–
DMF
52
–
Figure 3 The boron complex of quercetin
DMF–H2O (2:1)
r.t.
mixturee
mixturef
7g
When the methylation of quercetin was carried in the
presence of borax as a complexant by using sodium bicar-
bonate as the base and dimethyl sulfate as the methylating
agent at 60 °C, 7-O-methylquercetin was obtained in 53%
yield (Scheme 5). We also examined the effect of the sol-
vent on the methylation of quercetin. N,N-Dimethyl-
formamide was found to be the most effective solvent for
this reaction (Table 1).
DMA–H2O (2:1) r.t.
HMPA r.t.
–
53
a All reactions were carried out a quercetin/borax/BnCl/K2CO3/
BnN(Et3)Cl molar ratio of 1:3:4:3:0.1.
b Yield of isolated product.
c Mixture of di-, tri-, tetra-, and pentabenzylquercetins (3:3:2:2).
d Mixture of di-, tri-, tetra-, and pentabenzylquercetins (1:3:3:3).
e Mixture of di-, tri-, tetra-, and pentabenzylquercetins (5:2:2:1).
f Mixture of di-, tri-, tetra-, and pentabenzylquercetins (2:3:3:3).
g Mixture of di-, tri-, tetra-, and pentabenzylquercetins (8:1:1:0).
Thus, 4¢-O-Methylquercetin (9) was synthesized three
steps and 30% overall yield, starting from quercetin, by
selective benzylation, partial methylation in the presence
of borax, and final deprotection of the benzyl groups
(Scheme 6).
yl)ammonium chloride system under microwave irradia-
tion at 545 W for 10 min. This reaction gave 7,4¢-
dibenzylquercetin triacetate (8) in 55% yield, as a result of
the lower degree of steric hindrance at the 7- and 4¢-posi-
tions. When quercetin pentaacetate was treated with a the
same reagents under identical condition for 40 minutes,
the stable tetrabenzyl derivative 3, in which the hydroxy
group at the 5-position forms a hydrogen bond with the
carbonyl group, was obtained in 55% yield (Table 2).
Once we had developed the protection system using bo-
rax, we examined the selective benzylation of quercetin
derivatives by using microwave irradiation and conven-
tional heating (Scheme 7). Only the 7- and 4¢-positions of
quercetin pentaacetate underwent rapid benzylation with
the benzyl chloride/sodium bicarbonate/benzyl(trieth-
OH
OH
OH
OH
MeO
O
HO
O
O
Na2B4O7⋅10H2O, NaHCO3
Me2SO4, NaHCO3
OH
OH
OH
O
OH
6
1
Scheme 5 Synthesis of 7-O-methylquercetin
OH
OBn
OH
OH
HO
O
O
BnO
O
O
+
1. Na2B4O7⋅10H2O, BnNEt3Cl–
2. K2CO3, BnCl
OH
OH
OH
OH
1
7
OBn
OMe
OH
OMe
BnO
O
O
HO
O
O
Pd/C, H2
1. Na2B4O7⋅10H2O
2. Me2SO4, NaHCO3
OH
OH
OH
OH
9
12
Scheme 6 Synthesis of 4¢-O-methylquercetin
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York

3984
Z.-h. Zhou et al.
PAPER
Benzylation of quercetin pentaacetate by conventional re- methylated to give the desired derivatives. The use of bo-
fluxing gave mixtures in low yields. Microwave irradia- rax and heating by microwave irradiation have the advan-
tion evidently has the advantages of producing good tages of greater selectivity and shorter reaction times than
yields, high selectivities, and shorter reaction times com- earlier procedures.
pared with conventional heating.
The reactions were carried out in an MCL-II microwave reactor.
Table 2 Comparison of Reactivity for Microwave and Convention-
Silica gel F254 plates were used for TLC, and spots were examined
al Heating
under UV light at 254 nm and developed with I2 vapor. Flash chro-
matography was performed on silica gel H. NMR spectra were re-
corded on Bruker AC-E 200 MHz, Varian Mercury 400 MHz, and
Entrya Time (min) Conventional Microwaveb Product yieldc
Bruker Avance 600 MHz spectrometers. Mass spectra were record-
ed on a Bruker Daltonics Data Analysis 3.2 mass spectrometer.
1
2
3
4
5
6
3
10
15
18
25
40
–
~100:0
~99:0
~30%
55%
50%
–
trace
trace
trace
trace
~20%
Pentabenzylquercetin (2)
~98:0
A mixture of quercetin (1; 2.00 g, 6.617 mmol), BnCl (8.38 g,
0.0662 mol), HMPA (11.86 g, 0.0662 mol), K2CO3 (5.49 g, 0.0397
mol), and BnN(Et3)Cl (0.20 g) was stirred at r.t. under N2 for 35 h.
H2O (30 mL) was added, and the resulting mixture was filtered. The
residue was washed with H2O (3 × 30 mL) to give a yellow solid
that was crystallized (EtOAc) to give a white solid; yield: 4.73 g
(95%); mp 156–158 °C (lit.16 156–159 °C).
1H NMR (400 MHz, CDCl3): d = 4.98 (s, 2 H), 5.11 (s, 2 H), 5.12
(s, 2 H), 5.26 (s, 2 H), 5.30 (s, 2 H), 6.48 (d, J = 2.4 Hz, 1 H), 6.55
(d, J = 2.4 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 7.24–7.64 (m, 25 H),
7.56 (dd, J = 2.0, 8.4 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H).
~50:50
~90:10
~100:0
55%
55%
a All reactions were carried out with a quercetin pentaacetate/BnCl/
NaHCO3/BnN(Et3)Cl molar ratio of 1:7:12:0.1.
b Ratio of 8 and 3.
c Yield of isolated product.
13C NMR (100 MHz, CDC13): d = 70.4, 70.8, 70.9, 71.0, 74.1, 93.7,
98.1, 110.0, 113.7, 115.2, 122.1, 123.9, 126.6, 127.2, 127.3, 127.6,
127.8, 127.9, 128.1, 128.4, 128.5, 128.6, 128.7, 128.8, 135.7, 136.4,
136.8, 137.0, 139.8, 148.2, 150.5, 153.1, 158.6, 159.7, 162.7, 173.6.
Finally, we synthesized of 3¢-O-methylquercetin (10)
from quercetin in four steps and 35% overall yield
(Scheme 7). Benzylation of quercetin pentaacetate at 4¢,7-
position with the benzyl chloride/sodium bicarbonate/
benzyl(triethyl)ammonium chloride system under micro-
wave irradiation (545 W, 160 °C) for 10 minutes gave
compound 8. This underwent methylation at the 3¢-posi-
tion with an excess of dimethyl sulfate and sodium bicar-
bonate in the presence of borax to give the dibenzyl
monomethyl ether 14. Hydrogenolysis of the benzyl
groups on palladium-on-carbon in ethanol at room tem-
perature gave the desired 3'-O-methylquercetin.
3,3¢,4¢,7-Tetra-O-benzylquercetin (3)
CuCl2 (89 mg, 0.664 mmol) and TsN3 (0.20 g, 1.01 mmol) were
added to a soln of pentabenzylquercetin (2; 0.50 g, 0.664 mmol) in
MeCN (5 mL). The mixture was irradiated with microwaves (545
W) at 160 °C for 10 min. On completion of the reaction (TLC), the
crude product was purified by flash column chromatography [silica
gel, PE–EtOAc (4:1, 3:1, 2:1)] to give a light-yellow solid; yield:
0.36 g (81%). mp 139–142 °C.
1H NMR (400 MHz, CDCl3): d = 4.99 (s, 2 H), 5.04 (s, 2 H), 5.13
(s, 2 H), 5.25 (s, 2 H), 6.44 (d, J = 2.0 Hz, 1 H), 6.46 (d, J = 2.4 Hz,
1 H), 6.96 (d, J = 8.8 Hz, 1 H), 7.22–7.47 (m, 20 H), 7.55 (dd,
J = 2.0, 8.8 Hz, 1 H), 7.71 (d, J = 2.0 Hz, 1 H).
13C NMR (100 MHz, CDC13): d = 70.4, 70.9, 71.2, 74.3, 93.0, 98.5,
113.8, 115.4, 122.6, 123.5, 125.6, 127.2, 127.3, 127.4, 127.9, 128.0,
In summary, we have demonstrated an efficient procedure
for the synthesis of monomethylated quercetins by using
amidation in the presence of a Lewis acid to achieve se-
lective debenzylation; the resulting products are then
OAc
OAc
OH
OH
OAc
OBn
AcO
O
BnO
O
HO
O
O
+
BnCl, NaHCO3, BnNEt3Cl–
Ac2O, NaAc
MW
OAc
MW
OAc
OH
OAc
O
OAc
O
OH
1
13
8
OMe
OMe
OBn
OH
+
1. NaHCO3, BnNEt3Cl–
BnO
O
HO
O
H2, Pd/C
2. Na2B4O7⋅10H2O
3. Me2SO4, NaHCO3
OH
OH
OH
O
OH
O
10
14
Scheme 7 Synthesis of 3¢-O-methylquercetin
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York

PAPER
Selective Monomethylation of Quercetin
3985
128.2, 128.3, 128.5, 128.6, 128.8, 129.8, 135.8, 136.5, 136.7, 136.9,
137.5, 148.3, 151.1, 156.3, 156.7, 162.1, 164.5, 178.8.
to give a light-yellow solid; yield: 0.13 g (55%); mp 152–154 °C
(lit.18 154–156 °C).
MS (ESI): m/z [M + Na]+ calcd for C43H34NaO7: 685.2; found:
685.3.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 2.33 (s, 3 H), 2.43
(s, 3 H), 5.14 (s, 2 H), 5.17 (s, 2 H), 6.70 (d, J = 2.0 Hz, 1 H), 6.90
(d, J = 2.4 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 7.32–7.43 (m, 10 H),
7.56 (d, J = 2.0 Hz, 1 H), 7.67 (dd, J = 2.0, 8.8 Hz, 1 H).
3,3¢,4¢,7-Tetra-O-benzyl-5-O-methylquercetin (11)
Me2SO4 (2 mL) was added to a mixture of 3,3¢,4¢,7-tetra-O-ben-
zylquercetin (3; 0.50 g, 0.664 mmol) and K2CO3 (0.021 g, 0.152
mmol), and the mixture was irradiated with microwaves (545 W) at
160 °C for 5 min. On completion of the reaction (TLC), the mixture
was extracted with CH2C12 (3 × 10 mL). The extracts were purified
by flash column chromatography [silica gel, PE–EtOAc (1:1, 2:1,
3:1)] to give a white solid; yield: 0.025 g (99%); mp 157–159 °C
(lit.17 160 °C). Starting material 3 (0.025 g) was also recovered.
1H NMR (400 MHz, CDCl3): d = 3.95 (s, 3 H), 4.96 (s, 2 H), 5.07
(s, 2 H), 5.13 (s, 2 H), 5.23 (s, 2 H), 6.42 (d, J = 2.4 Hz, 1 H), 6.53
(d, J = 2.4 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 7.22–7.47 (m, 20 H),
7.56 (dd, J = 2.0, 8.8 Hz, 1 H), 7.76 (d, J = 2.0 Hz, 1 H).
4¢,7-Di-O-benzyl-3¢-O-methylquercetin (14)
A mixture of triacetate 8 (0.30 g, 0.493 mmol), NaHCO3 (0.17 g,
1.97 mmol), BnN(Et3)Cl (0.030 g), anhyd MeOH (0.096 g, 3.00
mmol), and acetone (7 mL) was stirred at 50 °C for 5 h. Na2B4O7·10
H2O (0.061 g, 0.170 mmol), H2O (8 mL), Me2SO4 (0.25 g, 1.98
mmol), NaHCO3 (0.084 g, 1.00 mmol), and acetone (12 mL) added,
and the mixture was stirred at 50–55 °C for 6.5 h. The mixture then
was concentrated in vacuo to give a residue that was acidified to pH
3–4 with 10% HCl. The mixture was extracted with CH2Cl2 (3 × 30
mL), and the extracts were concentrated in vacuo. The residue was
purified by chromatography [silica gel, PE–EtOAc–CHCl3
(7:1.5:0.5, 7:2:0, 6:2:0, 5:2:0)] to give a yellow solid; yield: 0.18 g
(75%); mp 170–174 °C (lit.6 172–174 °C).
5-O-Methylquercetin (5; Azaleatin)
A mixture of 3,3¢,4¢,7-tetra-O-benzyl-5-O-methylquercetin (11;
0.41 g, 0.606 mmol), 10% Pd/C (0.041 g), and anhyd EtOH (20 mL)
was stirred under H2 at ordinary pressure at r.t. for 6 h. The mixture
was then filtered and the filtrate was concentrated in vacuo. The
crude product was purified by flash column chromatography [silica
gel, PE–EtOAC (1:3, 1:4, 1:6)] to give an off-white solid; yield:
0.18 g (95%); mp 260–263 °C (lit.8 259–261 °C).
1H NMR (400 MHz, DMSO-d6): d = 3.83 (s, 3 H), 6.35 (d, J = 2.0
Hz, 1 H), 6.45 (d, J = 1.6 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 7.48
(dd, J = 1.6, 8.8 Hz, 1 H), 7.62 (d, J = 1.6 Hz, 1 H), 8.63 (s, 1 H),
9.25 (s, 1 H), 9.46 (s, 1 H), 10.71 (s, 1 H).
1H NMR (400 MHz, CDCl3): d = 3.87(s, 3 H), 5.14 (s, 2 H), 5.21 (s,
2 H), 5.77 (s, 1 H), 6.43 (d, J = 2.4 Hz, 1 H), 6.51 (d, J = 2.0 Hz, 1
H), 7.03 (d, J = 8.4 Hz, 1 H), 7.34–7.45 (m, 10 H), 7.69 (dd, J = 2.0,
10.8 Hz, 1 H), 7.80 (d, J = 2.0 Hz, 1 H), 12.64 (s, 1 H).
3¢-O-Methylquercetin (10; Isothamnetin)
A mixture of 3¢-O-methyl-4¢,7-di-O-benzylquercetin (14; 0.10 g,
0.201 mmol), 10% Pd/C (0.010 g), and anhyd EtOH (10 mL) was
stirred under H2 at ordinary pressure at r.t. for 5 h. The mixture was
filtered, and the filtrate was concentrated in vacuo to give a residue
that was purified by column chromatograph [silica gel, PE–EtOAc
(4:1, 3:1, 2:1)] to afford a white solid; yield: 0.057 g (90%), mp
302–304 °C (lit.5 305–306 °C).
3,5,3¢,4¢-Tetra-O-benzylquercetin (4)
CuTf2 (0.019 g, 0.053 mmol), TsNH2 (0.068 g, 0.398 mmol),
PhI(OAc)2 (0.385 g, 1.20 mmol), and Al2O3 (0.163 g, 1.59 mmol)
were added to a soln of 3,3¢,4¢,5,7-pentabenzylquercetin (2; 0.20 g,
0.266 mmol) in CH2Cl2 (10 mL) under N2. The mixture was stirred
at r.t. under N2. On completion of the reaction (TLC), the crude
product was purified by flash column chromatography [silica gel,
PE–EtOAc (4:1, 3:1)] to give a light-yellow solid; yield: 50 mg
(40%).
1H NMR (600 MHz, acetone-d6): d = 3.95 (s, 3 H), 6.28 (d, J = 6.2
Hz, 1 H), 6.57 (d, J = 6.1 Hz, 1 H), 7.02 (d, J = 25.3 Hz, 1 H), 7.84
(dd, J = 6.1, 25.3 Hz, 1 H), 7.90 (d, J = 6.0 Hz, 1 H), 8.15 (s, 1 H),
8.38 (s, 1 H), 9.70 (s, 1 H), 12.20 (s, 1 H).
7-O-Methylquercetin (Rhamnetin) (6)
A mixture of quercetin (1; 0.050 g, 0.165 mmol), acetone (3 mL),
NaHCO3 (5.0 mg, 0.0595 mmol), Na2B4O7·10 H2O (0.015 g, 0.0419
mmol), and H2O (6 mL) was stirred at 70 °C for 30 min. Me2SO4
(0.038 g, 0.297 mmol), NaHCO3 (0.056 g, 0.667 mmol), and ace-
tone (8 mL) were added, and the resulting mixture was stirred at 50
°C for 6 h. The mixture was then concentrated in vacuo, and the res-
idue was acidified to pH 3–4 with 10% HCl and extracted with
EtOAc (3 × 20 mL). The extracts were concentrated in vacuo to give
a residue that was purified by column chromatograph [silica gel,
PE–EtOAc (2:1, 1:1, 1:2)] to give a white solid; yield: 0.025 g
(53%); mp 282–286 °C (lit.19 280–285 °C).
1H NMR (400 MHz, CDCl3): 4.98 (s, 2 H), 5.10 (s, 2 H), 5.15 (s, 2
H), 5.25 (s, 2 H), 6.50 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H),
6.98 (d, J = 8.8 Hz, 1 H), 7.21–7.54 (m, 20 H), 7.78 (dd, J = 2.0, 8.4
Hz, 1 H), 7.89 (d, J = 2.0 Hz, 1 H).
HRMS (ESI): m/z [M + H] calcd for C43H35O7: 663.2383; found:
663.2387.
Quercetin Pentaacetate (13)
A mixture of quercetin (1; 2.00 g, 6.62 mmol), NaOAc (1.60 g, 24.3
mmol), and Ac2O (20 mL, 0.21 mol) was subjected to microwave
irradiation (545 W) at 160 °C for 10 min. On completion of the re-
action (TLC), the mixture was poured into ice-water (250 mL) and
filtered. The crude product was crystallized (95% EtOH) to give a
white solid; yield: 3.15 g (93%); mp 190–193 °C (lit.18 192–194
°C).
1H NMR (400 MHz, DMSO-d6): d = 3.87 (s, 3 H), 6.37 (d, J = 2.4
Hz, 1 H), 6.71 (d, J = 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 7.58
(dd, J = 2.4, 8.4 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1 H), 9.33 (s, 1 H),
9.52 (s, 1 H), 9.66 (s, 1 H), 12.46 (s, 1 H).
3¢,7-Di-O-benzylquercetin (7)
A mixture of quercetin (1; 1.002 g, 3.315 mmol), Na2B4O7·10 H2O
(3.801 g (9.966 mmol), BnN(Et3)Cl (0.11 g), anhyd DMF (30 mL),
BnCl (1.683 g, 13.29 mmol), and K2CO3 (1.376 g, 9.957 mmol) was
stirred at r.t. for 24 h. The mixture was then poured into H2O (90
mL), and the mixture was extracted with EtOAc (4 × 30 mL). The
extracts were washed with H2O (3 × 30 mL), dried (MgSO4), and
concentrated in vacuo. The residue was purified by chromatography
[silica gel, PE–EtOAc (6:1,4:1, 3:1, 2:1)] to give a light-yellow sol-
id; yield: 0.827 g (52%); mp 201–204 °C
4¢,7-Di-O-benzylquercetin 3,3¢,5-Triacetate (8)
A mixture of quercetin pentaacetate (13; 0.20 g, 0.390 mmol), BnCl
(0.35 g, 2.73 mmol), NaHCO3 (0.40 g, 4.76 mmol), and BnN(Et3)Cl
(0.020 g) was irradiated with microwaves (545 W) at 160 °C for 10
min. On completion of the reaction (TLC), the mixture was washed
with PE (3 × 10 mL) and the residue was purified by flash column
chromatography [silica gel, PE–EtOAc–CHCl3 (8:4:1, 7:4:1,6:4:1)]
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York

3986
Z.-h. Zhou et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 5.02 (s, 2 H), 5.24 (s, 2 H), 6.47
(d, J = 2.0 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1
H), 7.30–7.49 (m, 11 H), 7.55 (d, J = 2.0 Hz, 1 H), 9.34 (s, 1 H),
9.82 (s, 1 H), 12.73 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 70.2, 73.5, 93.3, 98.7, 105.5,
115.8, 116.0, 121.0, 121.2, 128.1, 128.3, 128.4, 128.5, 128.7, 128.8,
136.4, 136.7, 136.9, 145.2, 149.1, 156.5, 157.0, 161.3, 164.3, 178.3.
J = 2.4 Hz, 1 H), 9.33 (s, 1 H), 9.45 (s, 1 H), 9.80 (s, 1 H), 12.44 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 55.8, 93.6, 98.4, 103.3, 112.0,
114.8, 120.0, 123.6, 136.4, 146.4, 146.6, 150.4, 156.4, 161.8, 164.2,
176.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H12O7Na: 339.0475;
found: 339.0471.
HRMS (ESI): m/z [M + Na]+ calcd for C29H22NaO7: 505.1258;
found: 505.1262.
References
3¢,7-Di-O-benzyl-4¢-O-methylquercetin (12)
(1) Manthey, J. A.; Grohmann, K.; Montanari, A.; Ash, K.;
Manthey, C. L. J. Nat. Prod. 1999, 62, 441.
(2) Marrero, P. Y. J. Chem. Inf. Comput. Sci. 2004, 44, 2010.
(3) Peng, W.-J.; Li, Y.-W.; Zhu, C.-S.; Han, X.-W.; Yua, B.
Carbohydrate Res. 2005, 340, 1682.
(4) Hosny, M.; Dhar, K.; Rosazza, J. P. N. J. Nat. Prod. 2001,
64, 462.
(5) Jurd, L. J. Org. Chem. 1962, 27, 1294.
(6) Needs, P. W.; Kroon, P. A. Tetrahedron 2006, 62, 6862.
(7) Li, H.-J.; Luan, X.-H.; Zhao, Y.-M. Youji Huaxue 2004, 24,
1619.
(8) Bouktaib, M.; Lebrun, S.; Atmani, A.; Rolando, C.
Tetrahedron 2002, 58, 10001.
(9) He, L.; Yu, J.; Zhang, J.; Yu, X.-Q. Org. Lett. 2007, 9, 2277.
(10) He, L.; Wang, Q.; Zhou, G.-C.; Guo, L.; Yu, X.-Q.
ARKIVOC 2008, (xii), 103.
A mixture of 3¢,7-di-O-benzylquercetin (7; 0.20 g, 0.414 mmol),
acetone (25 mL), Na2B4O7·10 H2O (0.481 g, 1.26 mmol), and H2O
(1 mL) was stirred and heated to 50 °C. Me2SO4 (0.225 g, 1.79
mmol) and NaHCO3 (0.141 g, 1.67 mmol) were added, and the mix-
ture was stirred at 50 °C for 4 h. The mixture was then cooled to r.t.,
and H2O (20 mL) was added. The resulting mixture was extracted
with EtOAc (3 × 20 mL), and the extracts were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chro-
matograph [silica gel, PE–EtOAc (6:1, 5:1, 4:1)] to give a light-gray
solid; yield: 0.105 g, (72%); mp 157–161 °C.
1H NMR (400 MHz, CDCl3): d = 3.98 (s, 3 H), 5.08 (s, 2 H), 5.16
(s, 2 H), 5.66 (s, 1 H), 6.44 (d, J = 1.6 Hz, 1 H), 6.51 (d, J = 2.0 Hz,
1 H), 6.90 (d, J = 8.8 Hz, 1 H), 7.27–7.45 (m, 10 H), 7.61 (d, J = 2.0
Hz, 1 H), 7.65 (dd, J = 2.0, 8.4 Hz, 1 H), 12.71 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 55.9, 70.2, 73.5, 93.3, 98.7,
105.5, 111.8, 115.5, 120.9, 122.4, 128.1, 128.3, 128.4, 128.6, 128.8,
136.3, 136.8, 137.0, 146.5, 150.5, 156.5, 156.6, 161.2, 164.3, 178.3.
(11) Jain, A. C.; Pankajamani, K. S.; Seshadri, T. R. J. Sci. Ind.
Res. 1953, 127.
(12) Emri, J.; Gyori, B. In Comprehensive Coordination
Chemistry, Vol. 3; Wilkinson, G.; Gillard, R. D.;
McCleverty, J. A., Eds.; Pergamon: Oxford, 1987, Chap. 24,
81; and references cited therein.
(13) Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769.
(14) Yoshino, K.; Kotaka, M.; Okamoto, M.; Kakihana, H. Bull.
Chem. Soc. Jpn. 1979, 52, 3005.
(15) Hu, G.; Huang, L.; Huang, R.-H.; Wulff, W. D. J. Am. Chem.
Soc. 2009, 131, 15615.
(16) Caldwell, S. T.; Crozier, A.; Hartley, R. C. Tetrahedron.
2000, 56, 4101.
(17) Pacheco, H.; Grouiller, A. Bull. Soc. Chim. Fr. 1965, 3, 779.
(18) Jin, C.-R.; Ma, D.-Z.; Wang, Y.-H.; Feng, H.-X. Huaxi
Yaoxue Zazhi 1986, 1, 152.
(19) Itokawa, H.; Suto, K.; Takeya, K. Chem. Pharm. Bull. 1981,
29, 254.
HRMS (ESI): m/z [M + Na]+ calcd for C30H24NaO7: 519.1414;
found: 519.1410.
4¢-O-Methylquercetin (9; Tamarixetin)
A mixture of 3¢,7-di-O-benzyl-4¢-O-methylquercetin (12; 0.071 g,
0.143 mmol), 10% Pd/C (0.007 g), and anhyd EtOH (8 mL) was
stirred under H2 at ordinary pressure at r.t. for 5.5 h. The mixture
was then filtered and the filtrate was concentrated in vacuo. The res-
idue was purified by column chromatography [silica gel, PE–
EtOAc (3:1, 2:1)] to give a yellow solid; yield: 0.036 g (81%), mp
246–248 °C (lit.8 252–254 °C).
1H NMR (400 MHz, DMSO-d6): d = 3.83 (s, 3 H), 6.18 (s, 1 H), 6.41
(s, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 2.4 Hz, 1 H), 7.66 (d,
Synthesis 2010, No. 23, 3980–3986 © Thieme Stuttgart · New York