Total synthesis of baicalein

Article abstract of DOI:10.1080/10286020903508416

In this paper, a simple and novel synthesis of baicalein is described. This transformation features the novel synthesis of helilandin B and a different way to demethylate. The overall yield of 59% is acceptable.

Full text of DOI:10.1080/10286020903508416

Journal of Asian Natural Products Research
Vol. 12, No. 2, February 2010, 124–128
ORIGINAL ARTICLE
Total synthesis of baicalein
Duo-Zhi Chen, Jian Yang*, Bo Yang, Yuan-Shuang Wu and Ting Wu
Faculty of Life Science and Technology, Kunming University of Science and Technology,
Kunming 650224, China
(Received 26 September 2009; final version received 23 November 2009)
In this paper, a simple and novel synthesis of baicalein is described. This
transformation features the novel synthesis of helilandin B and a different way to
demethylate. The overall yield of 59% is acceptable.
Keywords: baicalein; helilandin B; demethylate; synthesis
1. Introduction
Herein, we report a novel and effective
procedure to synthesize baicalein with
a new preparation of 4 and a different way
to demethylate.
Baicalein (5,6,7-trihydroxyflavone, 1;
Scheme 1) is a flavone with certain
pharmacological and biological activities
such as antihypertensive effect [1], decreas-
ing LDH release of the cultured neuron [2],
activation of gene estrogenicity [3], and so
on. Until now, several synthetic routes have
been reported. In 1973, Agasimundin and
Siddappa [4] first reported a route to
synthesize baicalein starting from 1-(2,4,6-
trihydroxyphenyl)ethanone and 1-ethyl-3-
phenyl-1,3-propanedione to get 6-acetyl-
5,7-dihydroxyflavone, which was treated
with H2O2 to give baicalein. In 2004, Shaw
et al. [5] utilized the reaction of 3,4,5-
trimethoxyphenol and cinnamoyl chloride
to get helilandin B (4), and then treated with
HBr–HOAc to obtain compound 1.
Furthermore, Zhang et al. [6] also reported
a procedure to synthesize 1 from nitrogen-
containing flavonoid by the Mannich
reaction.
2. Results and discussion
As shown in Scheme 2, the title compound
(1) has been synthesized from 3,4,5-
trimethoxyphenol (2) in four steps. First,
compound 2 was acetylated to get 2-acetyl-
3,4,5-trimethoxyphenol (3) by Fries
rearrangement. Second, 3 is condensed with
benzaldehyde to afford 20-hydroxy-40,50,60-
tetramethoxychalcone (4). Third, 5,6,7-tri-
methoxyflavone (5) was acquired through
cyclization. In the last step, 5 was treated
with pyridine hydrochloride for demethyla-
tion to obtain baicalein (1) in good yield.
The efficiency of conversion from 2 to
3 was found to depend mainly on the
amount of BF3–Et2O. When an excess
amount of BF3–Et2O was used, an ideal
transformation could be obtained even in a
short reaction time.
*Corresponding author. Email: huaxi2003yxybs@126.com
ISSN 1028-6020 print/ISSN 1477-2213 online
q 2010 Taylor & Francis
DOI: 10.1080/10286020903508416
http://www.informaworld.com

Journal of Asian Natural Products Research
125
amount of 0.22 eq. of iodine was optimal
for the preparation of 5. The optimization
results are summarized in Table 2.
Demethylation in the last step mainly
depended on the quantity of pyridine
hydrochloride. In this study, the
ideal equivalence of pyridine hydrochloride
is found to be 9 (as shown in Table 3).
Finally, the total yield of compound 1,
i.e. 59% baicalein, has been obtained.
Moreover, the synthesis of compound 4
was demonstrated as a convenient and
efficient approach.
Scheme 1. Structure of baicalein (1).
Optimization studies in the second step
revealed that 3.0–3.8 eq. of KOH was not
enough to achieve an ideal conversion.
Especially, less than 3.5 eq. of KOH was
observed to result in the worst yield and
purity. As shown in Table 1, 4.0 eq. was
eventually found to be the optimal value
for this transformation.
3. Experimental
3.1 General experimental procedure
Melting points were measured on a YRT-3
temp apparatus and are uncorrected. NMR
spectra and MS data were recorded on a
Bruker DRX 500 NMR spectrometer and a
ZAB-2F mass spectrometer, respectively.
Inthecyclization,theyieldandpurityof
compound 5 were determined depending
on the number of equivalence of I2. An
Scheme 2. The synthesis route of baicalein. Reagents and conditions: (a) acetic anhydride and
BF3–Et2O, 608C, 3 h, 86%; (b) KOH, 70 h, 88%; (c) I2, DMSO, 1008C, 2.5 h, 93%; (d) pyridine
hydrochloride, 1908C, 6.5 h, 85%.

126
D.-Z. Chen et al.
solution of H2O (400 ml) and ethanolamine
(40 ml). The mixture was kept under
stirring for 1 h and then extracted with
ethyl acetate (300 ml). The extract was
dried with anhydrous magnesium sulfate
overnight and the solvent was evaporated to
Table 1. Quantification of KOH in the
conversion of 3 to 4.
Input 3
(mol)
KOH
(eq.)
Time
(h)
Yield
(%)
Entry
1
2
3
4
5
6
0.2
0.2
0.2
0.2
0.2
0.5
3.0
3.3
3.5
3.8
4.0
4.0
70
70
70
70
70
70
76.5
78.2
79.9
85.3
91.2
91.4
1
obtain compound 3 (97 g, 86%). H NMR
(CDCl3): d 13.43 (s, 1H), 6.22 (s, 1H),
3.97 (s, 3H), 3.87 (s, 3H), 3.76 (s, 3H),
2.63 (s, 3H).
3.2.2 20-Hydroxy-40,50,60-
tetramethoxychalcone (4)
Table 2. Quantification of I2 in the conversion
of 4 to 5.
A mixture of compound 3 (45.2 g,
0.2 mol), benzaldehyde (26.5 g, 0.25 mol),
and methanol (300 ml) was charged into a
dry round-bottomed flask. Potassium
hydroxide (45 g, 0.8 mol) was slowly
added and the solution was stirred for
70 h at room temperature. Then, diluted
hydrochloric acid was added to make the
pH to 6–7 to precipitate much yellow
crystal. The reaction mixture was filtered
and the cake was washed by water
(200 ml). The solid was recrystallized
from ethanol to give compound 4 (55 g,
88%); mp 103–1058C; 1H NMR (CDCl3):
d 13.80 (s, 1H), 8.00 (d, 1H, J ¼ 15.6 Hz),
7.86 (d, 1H, J ¼ 15.6 Hz), 7.67 (d, 2H,
J ¼ 7.5 Hz), 7.49–7.54 (m, 3H), 6.38
(s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.86
(s, 3H); MS (FABþ) m/z: 315 [Mþ1]þ.
Entry Input 4 (mol) I2 (eq.) Yield (%)
1
2
3
4
5
0.1
0.1
0.1
0.1
0.1
0.15
0.17
0.20
0.22
0.30
85.3
86.4
84.6
93.2
90.1
Table 3. Quantification of pyridine hydro-
chloride in the conversion of 5 to 1.
Input 5
(mol)
Pyridine
hydrochloride (eq.)
Yield
(%)
Entry
1
2
3
0.1
0.1
0.1
14
11
9
80.3
82.4
85.3
TLC was carried out on silica gel layers
(Qingdao Haiyang Chemical Co., Ltd,
Qingdao, China).
3.2.3 5,6,7-Trimethoxyflavone (5)
A dry round-bottomed flask equipped with
a reflux condenser was charged with
compound 4 (31.4 g, 0.1 mol), DMSO
(200 ml), and iodine (2.8 g, 0.22 mol),
and heated at 1008C for 2.5 h. The mixture
was then poured into sodium hydrogen
sulfite solution (300 ml, 10%) and left to
stand overnight. Then, the mixture was
filtered and the cake was recrystallized
from ethanol to give compound 5 as
light yellow crystals (29 g, 93%); mp
164–1658C ([6] 165–1678C); 1H NMR
(CDCl3): d 7.91 (d, 2H, J ¼ 5.0 Hz),
3.2 Synthesis procedure
3.2.1 2-Acetyl-3,4,5-trimethoxyphenol
(3)
A dry round-bottomed flask charged with
compound 2 (92 g, 0.5 mol), acetic anhy-
dride (150 ml), and BF3–Et2O (5 ml) was
heated at 608C for 2 h, and then cooled to
the ambient temperature. Subsequently,
ethyl acetate(300 ml) was added and stirred
for a minute. The mixture was kept in the
refrigerator for 2 h. Then, it was filtered to
get the cake which was poured into the

Journal of Asian Natural Products Research
7.49–7.54 (m, 3H), 6.84 (s, 1H), 6.70 4. Conclusion
127
(s, 1H), 3.86–3.97 (m, 9H).
In conclusion, this is an efficient, simple,
and novel synthesis of baicalein. Relatively
simple reaction procedure, utilization
of cheap and readily available reagents,
and ideal yields of products are some main
advantages of the present approach.
3.2.4 5,6,7-Trihydroxyflavone
(baicalein, 1)
A three-necked round-bottomed flask
equipped with a reflux condenser was
charged with excess pyridine hydrochloride
(102.6g, 0.9 mol) and compound 5 (31.2 g,
0.1 mol) under N2 atmosphere. The mixture
was then heated at 1908C and refluxed for
6.5 h. The resultant hot, dark mixture was
diluted with ethanol and poured into water
(300ml), and the reaction mixture was
stirred for 1 h and then filtered. The solid
so obtained was washed with water to give
a yellow solid (1) (23 g, 85%); mp
263–2668C ([5] 264–2658C); 1H NMR
(CDCl3): d 12.63 (s, 1H), 11.84 (br, 1H),
10.39 (br, 1H), 8.04, 8.05 (d, 2H,
J ¼ 7.5 Hz), 7.55–7.59 (m, 3H), 6.92 (s,
1H), 6.61 (s, 1H); HR-ESI-TOF-MS m/z:
269.0456 [M2H]2 (calcd for C15H9O5,
269.0449).
References
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W. Gary, and S. Naftali, Am. J. Hypertens.
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[2] H.H. Lee, L.L. Yang, C.C. Wang, S.Y. Hu,
S.F. Chang, and Y.H. Lee, Brain Res. 986,
103 (2003).
[3] T.W. Schultz, D.G. Sinks, and
M.T.D. Cronin, Environ. Toxicol. 17, 14
(2002).
[4] Y.S. Agasimundin and S. Siddappa,
J. Chem. Soc. Perkin Trans. 1: Org.
Bioorg. Chem. (1972–1999) 5, 503 (1973).
[5] J.J. Shaw, A.R. Lee, and W.H. Huang, US
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D.-Z. Chen et al.
Preparation of baicalein through a modified process is described.
Duo-Zhi Chen, Jian Yang, BoYang, Yuan-Shuang Wu and Ting Wu
Total synthesis of baicalein
124–128

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