Development of a concise synthesis of the flavonoid chrysin

Article abstract of DOI:10.3184/174751915X14307337733513

Two novel routes for the synthesis of the flavonoid chrysin are described. In the first, 3,5-dimethoxyphenol (taxicatigenin) 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 50% overall yield. In the second route, taxicatigenin was acylated with cinnamoyl chloride to form a chalcone under special conditions. This was then converted to chrysin in 42% and 56% overall yield, respectively. Several disadvantages of previous syntheses like long reaction time, tedious work-up and low overall yield have been overcome.

Full text of DOI:10.3184/174751915X14307337733513

300 RESEARCH PAPER
VOL. 39 MAY, 300–302
JOURNAL OF CHEMICAL RESEARCH 2015
Development of a concise synthesis of the flavonoid chrysin
Qian Wang, Wei Cui, Jian Yang* and Bo Yang
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan Province, P.R. China
Two novel routes for the synthesis of the flavonoid chrysin are described. In the first, 3,5-dimethoxyphenol (taxicatigenin) 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 50% overall yield. In the second route,
taxicatigenin was acylated with cinnamoyl chloride to form a chalcone under special conditions. This was then converted to chrysin in
42% and 56% overall yield, respectively. Several disadvantages of previous syntheses like long reaction time, tedious work-up and low
overall yield have been overcome.
Keywords: chrysin, taxicatigenin, benzaldehyde, cinnamoyl chloride, chalcone
Chrysin (5,7-dihydroxyflavone, see Fig. 1) is a naturally
occurring dietary monoflavonoid,1,2 which is widely
distributed in the plant kingdom3 and possesses a variety of
HO
O
O
biological activities including antibacterial,4 antioxidant,5 anti-
inflammatory,6 antiallergic,7 anticancer,8 antiestrogenic,9 and
anxiolytic activities.10 Chrysin is also found to have tyrosinase
inhibitory activity11, moderate aromatase inhibitory activity12
and to improve cognitive deficiency and brain damage.13
Consequently, a number of syntheses of 1 have been reported.
In 2005, Seijas et al.14 described a synthesis of chrysin via
microwave irradiation of a β-keto-ester as starting material
to give a excellent yield of 96%. However, the key starting
β-keto-ester could not be prepared easily and the microwave
irradiation was a harsh and inconsistent laboratory procedure.
Hu et al.15 reported another route to chrysin in five steps
using 2,4,6-trihydroxyacetophenone as the starting material.
However, the route did not have the potential for industrial
production on account of the low overall yield (26.3%). Chrysin
has also been prepared by others,16 but most of these methods
consist of a multistep process, involving low yields and the use
of poorly accessible starting materials. As a result, there is a
need for a more straightforward and cost-effective procedure
for the synthesis of chrysin.
OH
Fig. 1 Structure of chrysin.
Results and discussion
As shown in Schemes 1 and 2, the last two steps of the routes
involved cyclisation of the key intermediate 4 and demethylation
of the precursor 5. The first approach gave 1 in four steps. The
second shorter pathway involves just three steps.
As shown in Scheme 1, the first step started with the acylation
of 3,5-dimethoxyphenol (taxicatigenin) 2 by acetic acid with
ZnCl2 as a catalyst (145 °C, 2 h) to give the acetophenone 3 in
good yield (79%). Aldol condensation of 3 with benzaldehyde
(KOH, room temperature, 84 h) gave the chalcone 4 in better
yield (89%). The conversion of 4 to 5 was catalysed by I2 in
dimethyl sulfoxide (110 °C, 5 h), and the resulting product 5
(83%) was demethylated with pyridine hydrochloride under an
N2 atmosphere (180 °C, 5 h) to give the target natural product 1
in good yield (85%).
We have already reported the synthesis of chrysin17 by two
routes in 53% and 31% yield, respectively. As part of our
investigations on the synthesis of the bioactive natural flavones
and their biological activity,17,18-23 we have carried out further
studies and we now report a shorter, improved synthesis of
chrysin 1 in satisfactory yield using commercially available
starting materials.
Although chrysin 1 had been prepared in four steps in fairly
good overall yield (50%) from taxicatigenin 2 (Scheme 1), we
decided to simplify the process by shortening the synthesis
of 1 to a three-step procedure. This was accomplished by the
OH
OH
O
O
OH
O
a
b
O
O
O
O
O
2
4
3
c
d
O
O
HO
O
O
O
OH
O
5
1
Scheme 1 Reagents and conditions: (a) ZnCl2, CH3COOH, 145 °C, 2 h, 79%; (b) benzaldehyde, KOH, room temperature, 84 h, 89%;
(c) I2, DMSO, 110 °C, 5 h, 83%; (d) Py·HCl, 180 °C, 5 h, 85%.
* Correspondent. E-mail: trueyangjian@163.com

JOURNAL OF CHEMICAL RESEARCH 2015 301
O
OH
OH O
e
f
+
Cl
O
O
O
O
2
6
4
g
O
O
O
O
7(not isolated)
Scheme 2 Reagents and conditions: (e) BF3•Et2O, reflux, 0.5 h, 59%; (f) cinnamoyl chloride, toluene, reflux, 1h, and then
(g) 10% BF3 Et2O in toluene, reflux, 2 h, 78% two-step yield.
•
were determined on VG Auto Spec-3000 spectrometer and reported as
m/z. All reagents were purchased from Aladdin-reagent and Tansoole-
reagent, China, and used without further purification.
single-step preparation of chalcone 4 in moderate yield (59%) by
treatment of the readily available taxicatigenin 2 with cinnamoyl
chloride 6 in BF3•Et2O (reflux, 0.5 h) (step e). The chalcone was
formed in only one step, however, we try to improve the method
in consideration of the mild yield. According to the literature,24
the harsh condition of refluxing neat boron trifluoride etherate
resulted in relative low yield. For improving the yield and reducing
impurities, a milder reaction condition with low concentration of
BF3•Et2O was selected. The alternative plan to 4 was two step-
like procedure without purification of aryl ester 7. Initially, the
coupling of dimethoxyphenol 2 and slightly excess of cinnamoyl
chloride in refluxing toluene for 1 h cleanly gave compound 7
(step f). Then without any purification, 10% BF3•Et2O in toluene
was addition to the above reaction mixture under refluxing
for 2 h, treated with sodium hydroxide and then neutralised to
afford the desired chalcone 4 in good yield (78%). Obviously,
the improved condition raised the yield of chalcone 4. Then, the
subsequent two steps were performed under identical conditions
to give chrysin as shown in Scheme 1. These synthetic pathways
from the same starting materials featured shorter reaction time,
simplified workup and higher yield than the previous method.
In conclusion, two different routes which used commercially
available starting materials and reagents for the synthesis of
chrysin were described. The methods had improved procedures,
better yield and shortened reaction times. Futhermore, each
step gave the product easily. Compared to our previous work,
we decreased the reaction procedures by selecting taxicatigenin
as starting material and rasied the yield via replacing cinnamic
acid with cinnamoyl chloride. Consequently, we believe that this
improved procedure could be an efficient approach for a scaled-
up synthesis of chrysin.
2-Hydroxy-4,6-dimethoxyacetophenone (3): A mixture of fused ZnCl2
(13.6 g, 0.1 mol) and acetic acid (6 mL, 0.1 mol) was heated slowly with
stirring until the solution became homogeneous. Compound 2 (15.4 g,
0.1 mol) was added and the reaction mixture was kept for about 2 h at
145 °C. The reaction mixture was cooled and poured over crushed ice
containing hydrochloric acid (1:1). The solid that separated was filtered
and washed separately with water and sodium bicarbonate solution.
The crude product was purified by column chromatography over silica
gel. Elution was with a gradient solvent system of petroleum ether/ethyl
acetate gave compound 3 as a white powder (15.5 g, yield 79%); m.p.
80–82 °C (lit.25 82–83 °C); IR νmax (KBr/cm−1): 3448 (OH), 1613 (C=O);
1H NMR (400 MHz, CDCl3): δ 2.60 (s, 3H, COCH3), 3.76 (s, 3H, OCH3-
6), 3.82 (s, 3H, OCH3-4), 5.97 (s, 1H, H-3), 6.12 (s, 1H, H-5), 13.88(s, 1H,
OH-2); MS (m/z): 197 [M+H]+.
2′-Hydroxy-4′, 6′-dimethoxychalcone (4); Scheme
1 (Step b):
Potassium hydroxide (11.2 g, 0.2 mol) was added to methanol (80 mL).
After cooling to room temperature, compound 3 (2.0 g, 10 mmol) and
benzaldehyde (1.2 g, 11 mmol) were added to the solution. It was stirred
for 84 h at room temperature. Then the mixture was acidified to pH 5
with 10% aqueous HCl. The precipitate was filtered off, washed with
water and recrystallised from hexane/ethyl acetate to give yellow
crystals of compound 4 (2.5 g, yield 89%).
Scheme 2 (Step e): A mixture of 3,5-dimethoxyphenol (2) (3 g,
20 mmol) and cinnamoyl chloride (3.7 g, 22 mmol) was dissolved
in BF3•Et2O complex (20 mL) and heated to reflux for 0.5 h, and then
quenched with water (100 mL). Filtration and recrystallisation from
hexane/ethyl acetate gave yellow crystals of compound 4 (3.4 g, 59%).
Scheme 2 (Steps f,g): A mixture of 3,5-dimethoxyphenol (2) (3 g, 20
mmol) and cinnamoyl chloride (6) (4 g, 24 mmol) in toluene (30 mL) was
refluxed for 1 h. The cooled resulting mixture was treated with BF3•Et2O
(3 mL) and then the reaction mixture was stirred for another 2 h under
reflux. After cooling to room temperature, the resulting mixture was
diluted with ethyl acetate (25 mL) and treated with 2N NaOH (25 mL)
in an ice-bath and stirred for 10 mins at room temperature and acidified
with conc. HCl to pH 2. The organic phase was separated and washed
with brine. The resulting organic phase was dried over anhydrous
sodium sulfate and filtered. The solvent was removed under reduced
pressure and the product was recrystallised with hexane/ethyl acetate to
give the compound 4 as a yellow crystal(4.4 g, 78%); m.p. 79–81 °C (lit.26
Experimental
All glassware was thoroughly washed and dried in an oven at 120 °C.
Teflon-coated magnetic stirring bars were washed with acetone and
dried. 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 400 FTIR
instrument. Melting points were measured on a YRT-3 temperature
1
apparatus, H NMR spectral data were recorded on a Bruker Avance
1
400 or a Bruker DRX 500 NMR spectrometer and chemical shifts were
78–80 °C); IR νmax (KBr/cm−1): 1642 (C=O), 1596 (C=C); H NMR
reported in ppm(δ) relative to TMS as internal standard. Mass spectra
(500 MHz, DMSO-d6), δ 3.83 (s, 3H, OCH3-4′), 3.90 (s, 3H, OCH3-

302 JOURNAL OF CHEMICAL RESEARCH 2015
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This work was supported by the National Natural Science
Foundation of China (NSFC) (Nos 21361014, 21302074 and
21062009), and the Analysis and Testing Foundation of Kunming
University of Science and Technology (No. 20150728), which is
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Received 17 April 2015; accepted 29 April 2015
Paper 1503321 doi: 10.3184/174751915X14307337733513
Published online: 08 May 2015
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