An improved synthesis of apigenin

Article abstract of DOI:10.3184/174751915X14204548288464

Two routes for the synthesis of the flavone apigenin are described. In the first, taxicatigenin was converted to 2-hydroxy-4,6- dimethoxyacetophenone and then by condensation with anisaldehyde to 2′-hydroxy-4,4′,6′-trimethoxychalcone. The latter was cyclised with iodine and demethylated with pyridine hydrochloride to form apigenin in 53% overall yield. In the second route, a single step for the preparation of the chalcone was used in which 1,3,5-trimethoxybenzene was acylated with p-methoxycinnamic acid. Although the synthesis of apigenin was achieved in a lower overall yield of 34%, the process was simpler.

Full text of DOI:10.3184/174751915X14204548288464

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 FEBRUARY, 67–69
RESEARCH PAPER 67
An improved synthesis of apigenin
Qian Wang, Wei Cui, Man Liu, Ji Zhang, Rong-qiang Liao, Xia-li Liao and Jian Yang*
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 flavone apigenin are described. In the first, taxicatigenin was converted to 2‑hydroxy‑4,6‑
dimethoxyacetophenone and then by condensation with anisaldehyde to 2′‑hydroxy‑4,4′,6′‑trimethoxychalcone. The latter was
cyclised with iodine and demethylated with pyridine hydrochloride to form apigenin in 53% overall yield. In the second route, a
single step for the preparation of the chalcone was used in which 1,3,5‑trimethoxybenzene was acylated with p‑methoxycinnamic
acid. Although the synthesis of apigenin was achieved in a lower overall yield of 34%, the process was simpler.
Keywords: apigenin, taxicatigenin, anisaldehyde, 1,3,5-trimethoxybenzene, p-methoxycinnamic acid
Flavonoids are a group of common phenolic plant pigments
composed of a C6–C3–C6 backbone which occur widely in
higher plants and exhibit a broad spectrum of interesting
biological activities including anticancer, antioxidant,
neuroprotective and antihypertensive activities.1 Apigenin
(4′,5,7-trihydroxyflavone) is a flavone which is abundantly
present in common fruits, vegetables and plant-derived
beverages (e.g. tea and wine),2 which has anti-inflammatory,
free radical scavenging and anticancer effects.3
H
O
H
O
O
O
H
O
1
Fig. 1 Structure of apigenin.
Owing to its attractive biological characteristics and
commercial utility, apigenin has attracted much attention and
sparked tremendous efforts on its total synthesis. Yeole et al.4
reported a route to apigenin in three steps. However, the second
step was difficult to achieve and the route did not have the
potential of industrial production on account of the low overall
yield. Seijas and co-workers5 described another synthetic
route to apigenin via microwave irradiation of a β-ketoester
as starting material to give a good yield of 81%. However, the
key starting β-ketoester could not be prepared easily and the
microwave irradiation signified harsh terms to a number of
researchers because of the inconsistent laboratory conditions
in China. Apigenin has also been prepared,6–8 but almost all of
the published methods have in common, problems of low yields
and poorly accessible starting materials.
We have already reported two methods for the synthesis
of apigenin. In the first, apigenin was synthesised in five
steps9 with an overall yield of 40%. In the second, the yield
was increased to 55%, also in five steps.10 Building on these
two approaches, we have carried out further studies and we
report here a shorter, improved synthesis of apigenin 1 (Fig. 1)
in satisfactory yield using commercially available starting
materials.
Results and discussion
The first route (Scheme 1) gave 1 in four steps. The second
route involved, instead of two steps for the preparation of the
chalcone 4, just a single step (Scheme 2).
OH
O
H
O
O
O
OH
a
b
d
O
O
O
O
O
O
O
4
3
2
O
H
O
O
HO
O
c
O
O
OH
O
5
1
Scheme 1 Reagents and conditions: (a) ZnCl2, CH3COOH, 145 °C, 2 h, 79%; (b) anisaldehyde, KOH, room temperature, 80 h, 86%; (c) DMSO, I2, 120 °C, 4 h,
86%; (d) Py·HCl, 180 °C, 6 h, 90%.
* Correspondent. E-mail: trueyangjian@163.com

68 JOURNAL OF CHEMICAL RESEARCH 2015
6
7
4
Scheme 2
(400 MHz, CDCl3): δ 13.88 (s, 1H, OH), 6.12 (s, 1H), 5.97 (s, 1H), 3.82
(s, 3H, OCH3), 3.76 (s, 3H, OCH3), 2.60 (s, 3H, COCH3); MS (m/z): 197
[M+H]+.
As shown in Scheme 1, the initial step of the first route
was the acylation of 3,5-dimethoxyphenol 2 by acetic acid
using ZnCl2 as catalyst (145 °C, 2 h) to give acetophenone 3 in
good yield (79%). Aldol condensation of 3 with anisaldehyde
(KOH, r.t., 80 h) gave the chalcone 4 in a very good yield
(86%). Conversion of 4 to 5 was catalysed by I2 in dimethyl
sulfoxide (120 °C, 4 h), and the resulting product 5 (86%)
was demethylated with pyridine hydrochloride under a N2
atmosphere (180 °C, 6 h) to give the target natural product 1 in
commendable yield (90%).
2′-Hydroxy-4,4′,6′-trimethoxychalcone (4): Step b (Scheme 1):
Potassium hydroxide (11.2 g, 0.2 mol) was added to methanol (80 mL).
After it had cooled to ambient, compound 3 (2.0 g, 0.01 mol) and
anisaldehyde (1.5 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 by adding 5% aqueous HCl. The precipitate was filtered off,
washed with water and recrystallised from ethanol to give compound 4
as yellow crystals. (2.7 g, yield 86%).
Although apigenin 1 had been prepared in four steps in fairly
good overall yield (53%) 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
single-step preparation of chalcone 4 in moderate yield (44%)
by treatment of the readily available p-methoxycinnamic acid
7 with 1,3,5-trimethoxybenzene 6 in BF3–Et2O (100 °C, 5 h)
(Scheme 2). Although this synthetic pathway gave a lower yield
of 1 (34%), the method was shorter and the workup was simpler.
In conclusion, two novel routes using commercially available
starting materials and reagents for the synthesis of apigenin
are described. The former improved procedure had a better
yield and the latter shortened the reaction time; moreover,
each step gave the product easily. Compared to our previous
work, we decreased the reaction procedures and kept the
satisfactory yield at the same time. Consequently, we believe
that this improved procedure could be an efficient approach
for a scaled-up synthesis of apigenin. Further study towards a
synthesis of apigenin-7-O-β-D-glucuronide (a known flavonoid
glycoside with excellent pharmacological activities) is ongoing,
and will be reported in due course.
2′-Hydroxy-4,4′,6′-trimethoxychalcone (4): (Scheme 2): A mixture of
1,3,5-trimethoxybenzene (6) (1.7 g, 0.01 mol) and p-methoxycinnamic
acid (7) (2.7 g, 0.015 mol) in BF3–Et2O (30 mL) was stirred at
100 °C for 5 h. After overnight standing, the resulting mixture was
filtered and dried to give red needles. A suspension of the needles
in alcohol was refluxed for 2 h to give a clear orange solution. After
decolourising with active charcoal and cooling to 0 °C, the yellow
crystals of compound 4 were filtered off and dried to give 1.4 g (44%);
m.p. 114–115 °C (lit.12 113–114 °C); IR νmax (KBr/cm−1): 3622 (OH),
1635 (C=O), 1564 (C=C); 1H NMR (400 MHz, CDCl3) (δ, ppm): 13.98
(s, 1H, OH), 7.96–7.89 (m, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.88–6.86 (d,
J=8.5 Hz, 2H), 6.02 (s, 1H), 5.94 (s, 1H), 3.82 (s, 3H, OCH3), 3.77 (s,
3H, OCH3), 3.73 (s, 3H, OCH3); MS (m/z): 315 [M+H]+.
4′,5,7-Trimethoxyflavone (5): Compound 4 (3.1 g, 0.01 mol) and
iodine (0.2 g, 0.008 mol) in DMSO (25 mL) were stirred at 120 °C for
4 h and then the reaction mixture was added to 1.0% NaHSO3 solution
(100 mL). The precipitate was filtered off, washed with water and
recrystallised from ethanol/H2O (1:1) to give off-white crystals of 5
(2.7 g, yield 86%); m.p. 154–155 °C (lit.13 157 °C); IR νmax (KBr/cm−1):
1662 (C=O), 1619 (C=C); 1H NMR (400 MHz, DMSO-d6), δ 7.90–7.86
(d, J=8.8 Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 6.76 (s, 1H), 6.63(d,
J=2.0 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 3.92 (s, 3H, OCH3), 3.89 (s,
3H, OCH3), 3.85 (s, 3H, OCH3); MS (m/z): 313 [M+H]+.
Experimental
All reagents were purchased from Aladdin-reagent, China, and used
without further purification. 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 an Impact 400 FTIR instrument. Melting points were
Apigenin (1): Compound 5 (1.4 g, 0.005 mol) and excess pyridine
hydrochloride (5.0 g, 0.04 mol) were heated at 180 °C for 6 h under a
N2 atmosphere. The mixture was cooled to room temperature and H2O
(100 mL) was added. The mixture was stirred for another 30 min and
cooled to below 5 °C for several hours. The precipitate was filtered
off, washed with cold ethanol and recrystallised from absolute
ethanol to give compound 1 as yellow crystals (1.2 g, yield 90%); m.p.
347–348 °C (lit.8 348–350 °C); IR νmax (KBr/cm−1): 3508 (OH), 1629
1
measured on a YRT-3 temperature apparatus. H NMR spectra were
recorded on a Bruker Avance 400 spectrometer and chemical shifts are
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.
1
(C=O), 1432 (C=C); H NMR (400 MHz, DMSO-d6), δ 12.92 (s, 1H,
OH), 10.62 (s, 1H, OH), 10.54 (s, 1H, OH), 7.85 (d, J=8.4 Hz, 2H),
6.97(d, J=8.4 Hz, 2H), 6.64(s, 1H), 6.36 (s, 1H), 6.20 (s, 1H); MS
(m/z): 271 [M+H]+.
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 out was filtered and washed separately with water
and sodium bicarbonate solution. The crude product was purified by
column chromatography over silica gel; elution was effected with
a gradient solvent system of petroleum ether/ethyl acetate to give
compound 4 as white powder (15.5 g, yield 79%); m.p. 80–82 °C (lit.11
82–83 °C); IR νmax (KBr/cm−1): 3448 (OH), 1613 (C=O); 1H NMR
This work was supported by the National Natural Science
Foundation of China (NSFC) (No. 21062009) and the Natural
Science Foundation of Yunnan Province (No. 2011FZ059),
which are gratefully acknowledged.
Received 6 December 2014; accepted 1 January 2015
Paper 1403065 doi: 10.3184/174751915X14204548288464
Published online: 13 February 2015

JOURNAL OF CHEMICAL RESEARCH 2015 69
7
H. Matsuda, T. Morikawa, I. Toguchida and M. Yoshikawa, Chem. Pharm.
Bull., 2002, 50, 788.
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