158 JOURNAL OF CHEMICAL RESEARCH 2017
O
OH
OH
O
OH
OH
O
a
b
c
H CO
OCH3
H CO
OCH3
H CO
OCH3
3
3
3
H CO
OCH3
OCH3
3
O
3
OH
4
OH
5
6
OCH3
OH
H
3
CO
O
O
HO
HO
O
d
e
HO
H CO
OH
O
3
7
Scutellarein, 1
Scheme 2 Reagents and conditions: (a) Na S O , H O, r.t., 98%; (b) Ac O, BF Et O, ClCH CH Cl, 90%; (c) p-methoxybenzaldehyde, KOH, r.t., 80 h,
•
2
•
2
4
2
2
3 2 2 2
9
0%; (d) DMSO, l , 100 °C, 2 h, 85%; (e) Py HCl, 190 °C, 6 h, 89%.
2
In the first step, 3 was rapidly reduced with Na S O in
1-(3,6-Dihydroxy-2,4-dimethoxyphenyl)-ethanone (5): To a solution
of compound 4 (17.0 g, 0.10 mol) in 1,2-dichloroethane (30 mL) in
2
2
4
neutral aqueous solution to afford compound 4 in good yield.
Then compound 4 was treated with a slight excess of two equiv.
acetic anhydride and boron trifluoride in chloroform solution
at 80 °C for several hours to yield the acetylated compound 5
in high yield. Thirdly, Claisen-Schmidt condensation of 5 with
p-methoxybenzaldehyde at room temperature for 3 days gave
the corresponding chalcone 6 smoothly in about 90% yield,
which was then heated in dimethyl sulfoxide in the presence of
a catalytic amount of iodine at 120 °C for 3 h to produce 7 in
the presence of a catalytic amount of BF (0.5 mL BF ·Et O solution),
3
3
2
Ac O (20 mL) was added dropwise under stirring over a period of 30
2
min at room temperature. Then the mixture was stirred continuously
for about an hour before the temperature was raised to 80 °C. BF ·Et O
3
2
(
20 mL) was added and the reaction mixture was stirred for several
hours until the reaction was complete. Then water (200 mL) was added
and the mixture was heated to reflux to evaporate the organic solvent.
After cooling to ambient temperature, the mixture was filtered and the
filter cake was recrystallised from methanol to afford compound 5 as
8
5% yield. In the final step, compound 7 was demethylated with
17
1
yellow crystals (19.8 g, 90%); m.p. 159–161 °C (lit. 162 °C); H NMR
pyridine hydrochloride under a N atmosphere at 180 °C for 6 h
2
(
(
500 MHz, DMSO-d ) δ 12.87 (s, 1H), 8.39 (s, 1H), 6.32 (s, 1H), 3.83
6
to afford scutellarein 1 in good yield.
+
s, 6H), 2.59 (s, 3H); MS (m/z): 213 [M + H] .
In conclusion, a practical and novel method of synthesis of
scutellarein has been achieved which used the cheap starting
material, 2,6-dimethoxy-1,4-benzoquinone. All steps took
place under mild reaction conditions and featured simple
workups. Compared to the previous reported methods, the cost
was decreased and a good overall yield was obtained. Taken
together, these advances significantly enhance opportunities
for industrial scale-up production of this pharmacological
compound and could be a useful addition to the reported
methods for the preparation of scutellarein.
1
-(3,6-Dihydroxy-2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-
propenone (6): Potassium hydroxide (14.0 g, 0.25 mol) was dissolved
in methanol (80 mL). After cooling to room temperature, compound 5
10.6 g, 0.05 mol) and p-methoxybenzaldehyde (8.16 g, 0.06 mol) were
added to the solution. The reaction mixture was stirred for about 72
h at room temperature under a N atmosphere. Then the mixture was
neutralised with conc. HCl. After the mixture cooled, the precipitate
was filtered off and recrystallised from methanol to afford compound
6 as orange crystals (14.9 g, 90%). m.p. 130–132 °C (lit. 128–130 °C);
(
2
17
1
H NMR (500 MHz, DMSO-d ) δ 12.45 (s, 1H), 8.41 (s, 1H), 7.68 (d,
6
J = 8.5 Hz, 2H), 7.66 (s, J = 16.0 Hz, 1H), 7.58 (s, J = 16.0 Hz, 1H), 7.03
Experimental
(
d, J = 8.5 Hz, 2H), 6.36 (s, 1H), 3.85 (s, 3H), 3.82 (s, 6H), 3.76 (s, 3H);
+
All reactions were monitored and the purity of the products was
checked by TLC which was performed on GF-254 silica gel plates with
visualisation by UV light or staining with iodine. Melting points were
measured on a YRT-3 temperature apparatus and were uncorrected.
MS (m/z): 331 [M + H] .
6-Hydroxy-5,7-dimethoxy-2-(4-methoxyphenyl)-chromen-4-one
(7): Compound 6 (3.30 g, 0.01 mol) and iodine (0.1 g) in DMSO (20
mL) were stirred at 120 °C for 3 h. After cooling to room temperature,
the mixture was poured into ice water and stirred vigorously for a
while. The precipitate was filtered off, washed and recrystallised from
methanol to give compound 7 as yellowish needles (2.8 g, 85%), m.p.
1
H NMR spectra were obtained on a Bruker DRX 500 NMR
spectrometer in DMSO-d using TMS as internal standard. Chemical
6
shifts (δ) are given in ppm and coupling constants (J) are given in Hz.
Mass spectra were determined on a VG Auto Spec-3000 spectrometer
and reported as m/z. All reagents were purchased from Tansoole-
reagent, China, and used without further purification.
18
1
222–224 °C (lit. 222–223 °C); H NMR (500 MHz, DMSO-d ) δ 9.01
6
(s, 1H, OH), 8.02 (d, J = 9.0 Hz, 2H), 7.16 (s, 1H), 7.11 (d, J = 9.0 Hz,
2H), 6.69 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H); MS (m/z): 329
+
2
,6-Dimethoxyhydroquinone (4): 2,6-Dimethoxybenzoquinone 3
[M + H] .
(
16.8 g, 0.10 mol) and Na S O (17.4 g, 0.10 mol) were added to distilled
5,6,7-Trihydroxy-2-(4-hydroxyphenyl)-chromen-4-one (1): A mixture
of compound 7 (3.28 g, 0.01 mol) and excess pyridine hydrochloride
2
2
4
water (250 mL), and the mixture was stirred at room temperature
until the colour disappeared completely. Ethyl acetate (3 × 200 mL)
was added and the mixture stirred vigorously for 5 minutes. The
combined organic extracts were washed with brine once and dried over
anhydrous sodium sulfate. After filtering, the solvent was removed
under vacuum and the residue was recrystallised from H O to give
compound 4 as white crystals (15.3 g, 90%); m.p. 150–152 °C (lit.
1
6
(17.4 g, 0.15 mol) was heated at 180 °C for 6 h under a N atmosphere. The
2
mixture was then cooled to room temperature and pre-cooled dilute acid
(50 mL) was added. The precipitate was filtered off and recrystallised
from n-butyl alcohol to give compound 1 as yellow crystals (2.6 g, 91%);
12
1
m.p. 161–162 °C (lit. 160–162 °C); H NMR (500 MHz, DMSO-d )
2
6
16
δ 13.43 (s, 1H), 11.44 (s, 1H), 10.45 (s, 1H), 10.37 (s, 1H), 7.94 (d,
J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.76 (s, 1H), 6.63 (s, 1H); MS
1
49 °C); H NMR (500 MHz, DMSO-d ) δ 8.78 (s, 1H), 7.47 (s, 1H),
6
+
+
.03 (s, 2H), 3.67 (s, 6H); MS (m/z): 171 [M + H] .
(m/z): 287 [M + H] .