An efficient synthesis of chrysin

Article abstract of DOI:10.3184/174751914X13899617275193

Two routes for the synthesis of the flavones chrysin are described. In the first 1,3,5-trimethoxybenzene was converted to 2-hydroxy-4,6- dimethoxyacetophenone and then by condensation with benzaldehyde to 2′-hydroxy-4′,6′-dimethoxychalcone. The latter was cyclised with iodine and demethylated with pyridine hydrochloride to form chrysin in 53% overall yield. In the second route, 1,3,5-trimethoxybenzene was acylated with cinnamic acid to form the chalcone which was then converted to chrysin in 30.7% overall yield.

Full text of DOI:10.3184/174751914X13899617275193

134 RESEARCH PAPER
VOL. 38 MARCH, 134–136
JOURNAL OF CHEMICAL RESEARCH 2014
An efficient synthesis of chrysin
Man Liu, Ji Zhang, Jian Yang*, Bo Yang and Wei Cui
Faculty of Life Science and Technology, Kunming University of Science and Technology (ChengGong Campus), Kunming 650500, Yunnan
Province, P.R. China
Two routes for the synthesis of the flavones chrysin are described. In the first 1,3,5-trimethoxybenzene was converted to
2
-hydroxy-4,6-dimethoxyacetophenone and then by condensation with benzaldehyde to 2′-hydroxy-4′,6′-dimethoxychalcone.
The latter was cyclised with iodine and demethylated with pyridine hydrochloride to form chrysin in 53% overall yield. In the
second route, 1,3,5-trimethoxybenzene was acylated with cinnamic acid to form the chalcone which was then converted to
chrysin in 30.7% overall yield.
Keywords: chrysin, 1,3,5-trimethoxybenzene, benzaldehyde, cinnamic acid
Chrysin (5,7-dihydroxy-2-phenyl-4H-chromen-4-one) (Fig. 1),
a naturally occurring flavone, is widely distributed and has
previously been isolated from Populus, Pinus and Prunus
Results and discussion
As shown in Schemes 1 and 2, the last two steps of the routes
involved cyclisation of the key precursor 5 and demethylation
of the precursor 6. The first approach gave 1 in five steps. The
second shorter pathway can be carried out in just three steps.
As shown in Scheme 1, the first step started with the
acylation of 2 under mild conditions (BF –Et O, r.t., 2 h) to
1
species. It has been reported to have extensive pharmacological
2
,3
4
activities, such as anti-tumour, antiallergic, and aromatase
5
6
7
inhibitory activity, as well as anti-inflammatory, antiviral,
anti-microbial, and hypoglycaemic activity.
8
9
3
2
give acetophenone 3 in great yield (93%). 2-Hydroxy-4,6-
dimethoxyacetophenone (4) was obtained by the selective
Owing to its wide pharmacological activity, a number
of syntheses of 1 have been reported. Recently, chrysin
10
demethylation with BCl (0 °C, 2 h) in a yield of 89%. Aldol
has been synthesised by Kun Hu et al. in five steps using
,4,6-trihydroxyacetophenone as the starting material in a
low overall yield (26.3%). It has also been prepared by other
3
condensation of 4 with benzaldehyde (KOH, r.t., 80 h) gave
the chalcone 5 in good yield (88%). Conversion of 5 to 6 was
2
catalysed by I in dimethyl sulfoxide (120°C, 4 h), and the
11
2
authors, but most of these methods have low yields or use
special reagents. Two approaches to the synthesis of 1 have
been developed.
resulting product 6 (85%) was demethylated with pyridine
hydrochloride under N atmosphere (180 °C, 6 h) to give the
2
desired natural product 1 in good yield (86%).
Although compound 1 was prepared in a fairly good overall
yield (53.1%) from 1,3,5-trimethoxybenzene, we decided to
improve the strategy by shortening the conversion of 2 to 1 in a
three-step procedure. The second route (Scheme 2) began with
the treatment of the readily available cinnamic acid 7 and 2 in
BF –Et O (100 °C) to give chalcone 5 in moderate yield (42%).
Then, the following two steps were performed under identical
conditions as shown in Scheme 2. Although this synthetic
pathway gave a lower yield of 1 (30.7%), the method was shorter
and the workup was simplified.
HO
O
O
3
2
OH
Fig. 1 Structure of chrysin.
O
O
O
O
OH
O
O
c
a
b
O
O
O
O
2
3
4
OH
O
O
O
O
O
HO
O
e
d
O
O
OH
O
5
6
1
Scheme 1 The first approach to chrysin: (a) BF –Et O, EtOAc, r.t., 2 h, 93%; (b) BCl , CH Cl , 0 °C,2 h, 89%;
3
2
3
2
2
(
c) benzaldehyde, KOH, r.t., 80 h, 88%; (d) DMSO, I , 120 °C, 4 h, 85%; (e) Py·HCl, 180 °C, 6 h, 86%.
2
*
Correspondent. E-mail: pharmacistkg101@gmail.com
JCR1302308_FINAL.indd 134
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JOURNAL OF CHEMICAL RESEARCH 2014 135
O
OH
O
O
O
O
O
COOH
d
f
+
O
O
O
O
7
2
5
6
HO
O
O
e
OH
1
Scheme 2 The second approach to chrysin: (f) BF –Et O, 100 °C, 4 h, 42%; (d) DMSO, I , 120 °C, 4 h, 85%; (e) Py·HCl, 180 °C, 6 h, 86%.
3
2
2
In conclusion, two novel routes which used commercially
available starting materials and reagents for the synthesis of
chrysin were described. The first improved procedures had
better yields and the second one shortened the reaction time.
Moreover, each step gave the product easily. Hence, we believe
that this improved procedure could be an efficient approach for
a scaled-up synthesis of chrysin.
CDCl ), δ 2.61 (s, 3H, COCH ), 3.82 (s, 3H, OCH -6), 3.85 (s, 3H,
3
3
3
OCH -4), 5.93 (s, 1H, H-3), 6.06 (s, 1H, H-5), 14.03 (s, 1H, OH-2). MS
3
+
(m/z): 197 [M+1] .
2
′-Hydroxy-4′, 6′-dimethoxychalcone (5); Step c (Scheme 1):
Potassium hydroxide (11.2 g, 0.200 mol) was added to methanol
80 mL). After it had cooled to ambient, compound 4 (2.0 g, 0.010 mol)
(
and benzaldehyde (1.2 g, 0.011 mol) were added to the solution. It was
stirred for 80 h at room temperature. Then the mixture was neutralised
to pH 5–6 with 5% aqueous HCl. The precipitate was filtered off,
washed with water and recrystallised from ethanol to give yellow
crystals of compound 5 (2.5 g, yield 88%).
Experimental
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. IR spectra were recorded on Impact
Step f (Scheme 2): A mixture of 1,3,5-trimethoxybenzene (2) (0.84 g,
0
.005 mol) and cinnamic acid (7) (1.1 g, 0.008 mol) in BF ·Et O
3 2
4
00 FT-IR instrument. Melting points were measured on a YRT-3
(15 mL) was stirred at 100 °C for 4 h. The red solid was filtered and
1
temperature apparatus, H NMR spectral data were recorded on a
Bruker Avance 400 NMR spectrometer and chemical shifts were
reported in ppm(δ) relative to TMS as internal standard. Mass spectra
were determined on VG Auto Spec-3000 spectrometer and reported as
m/z. All reagents were purchased from Aladdin-reagent, China, and
used without further purification.
dried to give red needles. A suspension of the needles in EtOH/H O
2
(10:1) was refluxed for 2 h to give a clear orange solution. After being
decolourised with active charcoal and cooled to 0°C, the yellow
crystals of compound 5 were filtered and dried to give 0.6 g (42%);
14
–1
m.p. 80–82°C (lit. 78–80°C); IR, ṽ/cm : 1630 (C=O), 1589 (C=C);
1
H NMR (400 MHz, DMSO-d ), δ 3.83 (s, 3H, OCH -4′), 3.91 (s, 3H,
6
3
2
,4,6-Trimethoxyacetophenone (3): BF –Et O 2.0 mL (2.3 g,
3 2
OCH -6′), 6.14 (d, J=1.6 Hz, 1H, H-3′), 6.17 (d, J=1.6 Hz, 1H, H-5′),
3
0.013 mol) was added to a solution of 1,3,5-trimethoxybenzene (2):
7.45–7.49 (m, 3H, H-3,4,5), 7.65 (d, 1H, J=16 Hz, H-α), 7.72–7.74 (m,
(
4.2 g, 0.025 mol) and Ac O 3.6 mL (3.8 g, 0.038 mol) in EtOAc (20 mL)
2
2
2
H, H-2,6), 7.78 (d, J=16 Hz, 1H, H-β), 13.41 (s,1H, OH-2′). MS (m/z):
85 [M+1] .
over 30 minutes. The mixture was stirred at room temperature for
+
2
h. Then water (50 mL) was added and the mixture was extracted
5,7-Dimethoxyflavone (6): Compound 5 (2.8 g, 0.010 mmol) and
with ethyl acetate twice (50×2 mL). The combined organic layers
iodine (0.2 g) in DMSO (25 mL) were stirred at 120 °C for 4 h and then
were washed with H O (50 mL), Saturated Na CO solution (50 mL),
2
2
3
it was added to 2.0% NaHSO (100 mL). The precipitate was filtered
3
brine (50 mL), dried with anhydrous sodium sulfate overnight. Then
the solution was concentrated under reduced pressure to give a solid
off, washed with water and recrystallised from methanol to give
15
almost white crystals of 6 (2.4 g, yield 85%); m.p. 143–146 °C (lit. 148–
residue, which was recrystallised from methanol/H O to afford the
2
–1
1
12
149 °C); IR, ṽ/cm : 1651(C=O); H NMR (400 MHz, DMSO-d ), δ 3.83
compound 3 as white powders (4.8 g, 93%); m.p. 100–102°C (lit.
01–103°C); IR, ṽ/cm : 1704 (C=O); H NMR (400 MHz, CDCl ), δ
6
–1
1
(s, 3H, OCH -7), 3.90 (s, 3H, OCH -5), 6.50 (d, 1H, J=2.4 Hz, H-8),
1
3
3
3
6
.76 (s, 1H, H-3), 6.85 (d, 1H, J=2.4 Hz, H-6), 7.56 (m, 3H, H-4′,5′,6′),
2
.46 (s, 3H, COCH ), 3.79 (s, 6H, OCH -2,6), 3.83 (s, 3H, OCH -4), 6.10
3
3
3
+
+
8.03 (m, 2H, H-2′,3′). MS (m/z): 283 [M+1] .
(s, 2H, H-3,5). MS (m/z): 211 [M+1] .
Chrysin (1): The mixture of the compound 6 (1.4 g, 0.005 mol) and
excess pyridine hydrochloride (5.0 g) was heated at 180 °C for 6 h under
2
-Hydroxy-4,6-dimethoxyacetophenone (4): A solution of compound
3
1
(3.2 g, 0.015 mol) in dichloromethane (15 mL), was treated with
mol L BCl3 in dichloromethane (18 mL, 0.018 mol) for 1 h at
–1
an N atmosphere. Then the mixture was cooled to room temperature
2
and H O (100 mL) was added. The mixture was stirred for another
approximately 0 °C. After the reaction mixture had been stirred at 0 °C
2
30 min and cooled to approximately 5 °C for several hours. The
for another 2 h, H O (50 mL) was added and the mixture stirred for
2
precipitate was filtered off, washed with cold ethanol and recrystallised
from absolute ethanol to give a light yellow powdery (1.1 g, yield 86%);
another 1 hour and extracted with dichloromethane twice (50 mL×2).
The combined organic layers were washed with H O (50 mL), saturated
2
16
–1
NaHCO3 solution (50 mL), brine (50 mL), dried with anhydrous
magnesium sulfate overnight. The solvent was removed under reduced
pressure and the residue was recrystallised from ethanol to give
m.p. 280–284°C (lit. 282–285°C); IR, ṽ/cm : 3410 (OH) 1654 (C=O);
1
H NMR (400 MHz, DMSO-d ), δ 6.23 (d, 1H, J=2.0 Hz, H-6), 6.53
6
(d, 1H, J=2.0 Hz, H-8), 6.97 (s, 1H, H-3), 7.55–7.62 (m, 3H, H-4′,5′,6′),
8.06 (m, 2H, H-2′,3′), 10.94 (s, 1H, OH-7),12.83 (s, 1H, OH-5). MS (m/z):
1
3
compound 4 as white crystal (2.6 g, yield 89%); m.p. 79–80°C (lit.
8
–1
1
+
2–83°C); IR, ṽ/cm : 2952 (OH), 1619 (C=O); H NMR (400 MHz,
255 [M+1] .
JCR1302308_FINAL.indd 135
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136 JOURNAL OF CHEMICAL RESEARCH 2014
This work was supported by National Natural Science
Foundation of China (NSFC) (No. 21062009) and the Natural
Science Foundation of Yunnan Province (No. 2011FZ059),
which are gratefully acknowledged.
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Received 26 November 2013; accepted 7 January 2014
Paper 1302308 doi: 10.3184/174751914X13899617275193
Published online: 7 March 2014
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