Total synthesis of luteolin

Article abstract of DOI:10.3184/174751914X13867643876192

Luteolin is a naturally-occurring polyphenolic flavonoid compound which has received considerable attention because of its wide range of biological and pharmacological properties. Efficient methods are reported for preparing luteolin, based on the acylation of 1,3,5-trimethoxybenzene and condensation with 3,4-dimethoxybenzaldehyde or the reaction of 3,4-dimethoxycinnamic acid with 1,3,5-trimethoxybenzene. The first of these is the better method.

Full text of DOI:10.3184/174751914X13867643876192

60 RESEARCH PAPER
JANUARY, 60–61
JOURNAL OF CHEMICAL RESEARCH 2014
Total synthesis of luteolin
Ji Zhang, Man Liu, Wei Cui, Jian Yang* and Bo Yang
Faculty of Life Science and Technology, Kunming University of Science and Technology (ChengGong Campus), Kunming 650500, Yunnan
Province, P.R. China
Luteolin is a naturally-occurring polyphenolic flavonoid compound which has received considerable attention because of its wide
range of biological and pharmacological properties. Efficient methods are reported for preparing luteolin, based on the acylation
of 1,3,5-trimethoxybenzene and condensation with 3,4-dimethoxybenzaldehyde or the reaction of 3,4-dimethoxycinnamic acid
with 1,3,5-trimethoxybenzene. The first of these is the better method.
Keywords: flavonoid, luteolin, Claisen–Schmidt condensation, one-pot reaction
The flavonoids are polyphenolic compounds possessing a
C6–C3–C6 skeleton (Fig. 1)1, which occur widely in fruits
and vegetables, and exhibit a broad spectrum of interesting
biological activities against cancer, cardiovascular, and
neurodegenerative diseases.2 They are divided into several sub-
groups based on structural differences in their ring C involving
its oxidation state.3 The A and B-rings of naturally occurring
flavonoids are usually functionalised by OH, OMe, isoprenyl,
and glycosyl groups. The OH and glycosyl residues can be
further functionalised by acyl, glycosyl or other flavonoid
moieties.3 They exert antioxidant and biological activities due
to their aromatic moieties and the presence of oxygen functions.
Luteolin (Fig. 2) is a polyphenolic flavonoid compound which
has attracted considerable attention owing to its biological and
pharmacological activities.4–6 However, only a small amount of
luteolin is available for biological studies because it is difficult
to obtain. Among the published syntheses of luteolin,7–9 none is
attractive for large-scale synthesis due to drawbacks such as the
use of expensive starting materials that are not easily accessible.
Therefore, a simple and efficient synthetic method of luteolin is
very desirable. We now report an efficient synthetic route for
the preparation of luteolin (Scheme 1) based on our previous
work.10–15
R2
B
O
C
R1
A
Fig. 1 Flavonoid skeleton.
OH
OH
HO
O
OH
O
luteolin
Fig. 2 Structure of luteolin.
Experimental
All reactions were monitored by TLC on silica gel GF254. Melting
points were measured on a YRT-3 temperature apparatus and are
uncorrected. H NMR spectral data were recorded on a Bruker DRX
1
500 NMR spectrometer and chemical shifts are reported in ppm (δ)
relative to TMS as internal standard. IR spectra were recorded on
Impact 400 FT-IR instrument. All reagents were purchased from
Aladdin-reagent, China, and used without further purification.
2,4,6-Trimethoxyacetophenone (2): 1,3,5-Trimethoxybenzene 2 (8.4 g,
0.05 mol) and acetic anhydride 7 mL (7.6 g, 0.075 mol) were dissolved
in ethyl acetate (30 mL) and BF3–Et2O 3.8 mL (4.3 g, 0.025 mol) was
added dropwise. The reaction mixture was stirred at room temperature
for 2 h. Then, H2O (50 mL) was added and the reaction mixture was
extracted with ethyl acetate (2×50 mL) The organic layers were
combined and washed sequentially with H2O (100 mL×2), saturated
sodium bicarbonate (100 mL×2) and H2O (100 mL×1) and then dried
with anhydrous sodium sulfate overnight. Removal of the solvent under
reduced pressure gave a solid residue, which was recrystallised from
ethanol to afford the compound 3 as white crystals (9.8 g); yield 93%,
m.p. 101–102 °C (lit.16 101–103 °C) 1H NMR (400 MHz, CDCl3) (δ, ppm):
2.46 (s, 3H, COCH3), 3.79 (s, 6H, OCH3), 3.83 (s, 3H, OCH3), 6.10 (s, 2H,
ArH). IR νmax (KBr/cm−1): 1704 (C=O).
Results and discussion
As shown in Scheme 1, compound 6 is the key intermediate
for the synthesis of luteolin and quercetin, which prepared
by a reaction sequence starting from the commercially
available
1,3,5-trimethoxybenzene
via
Friedel–Crafts
acylation, demethylation selectively, Claisen–Schmidt
condensation with compound 4. It was also afforded by using
1,3,5-trimethoxybenzene and 3,4-dimethoxycinnamic 5 as
starting materials in the presence of excess of BF3–Et2O through
one-pot reaction, but its yield is lower than the previous one
within three steps.
Compound 6 was heated with iodine in DMSO at 130 °C,
which gave the compound 7. Compound 7 was then completely
demethylated in the presence of pyridine hydrochloride for
6.5 h to afford 8.
2-Hydroxy-4,6-dimethoxyacetophenone (3):
A solution of the
compound (4.2 g, 0.02 mol) in dichloromethane (20 mL) at
2
In conclusion, a short route for the synthesis of the compound
8 has been achieved in an overall yield 47.2%. This synthesis
of 8 is a green and convenient approach. Moreover, this
method not only has the advantages of mild conditions, easily
accessible starting materials and facile separation, and it is also
less expensive, more practical, and environmentally friendly.
Hence, we believe that this procedure could be an efficient
synthetic approach for a scaled-up synthesis of luteolin.
approximately 0 °C was treated with 1 mol L–1 BCl3 in dichloromethane
(24 mL, 0.024 mol) dropwise for about 1 h, and then the reaction
mixture was stirred at room temperature for another 1 h. H2O (100 mL)
was added, the mixture was stirred for another hour and extracted
with dichloromethane twice (50 mL×2). The organic layers were
combined and washed sequentially with H2O (100 mL×2), saturated
sodium bicarbonate (100 mL×2) and H2O (100 mL×1) and then dried
with anhydrous sodium sulfate overnight. The solvent was removed
under reduced pressure, and the residue was recrystallised from
ethanol to give compound 3 (3.24 g); yield 87%, white crystals, m.p.
1
* Correspondent. E-mail: zhangji614@gmail.com
79–80 °C (lit.17 80–81 °C) H NMR (400 MHz, CDCl3) (δ, ppm): 2.61
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JOURNAL OF CHEMICAL RESEARCH 2014 61
O
O
OHC
O
O
O
OH
O
O
O
OH
3
O
O
a
b
4
O
O
c
1
O
O
O
O
O
c
2
6
2
1
O
O
COOH
+
O
O
O
O
OH
5
1
O
OH
OH
O
O
O
O
O
O
HO
O
d
e
O
O
O
OH
O
8
6
7
Scheme 1 Reagents and conditions: (a) BF3–Et2O, EtOAc, r.t., 2 h, 93%; (b) BCl3, CH2Cl2, 0 °C, r.t., 2 h, 87%; (c1) KOH, r.t., 72 h, 83% (c2) BF3–Et2O, 100 °C,
6 h, 45%; (d) DMSO, I2, 130 °C, 4 h, 80%; (e) pyridine HCl, 180 °C, 6.5 h, 88%.
(s, 3H, COCH3), 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.93 (s, 1H,
ArH), 6.06 (s, 1H, ArH), 14.03 (s, 1H, OH). IR νmax (KBr/cm−1): 3461
(OH), 1619(C=O).
was stirred for another 1 h. The precipitate was filtered off, washed
with water and recrystallised from ethyl acetate to give compound 8 as
1
yellow crystals (1.46 g); yield 88%, m.p. 326 °C (lit18. 328–330 °C) H
NMR (500 MHz, DMSO-d6) (δ, ppm): 12.97 (s, 1H, OH), 10.83 (s, 1H,
OH), 9.91 (s, 1H, OH), 9.40 (s, 1H, OH), 7.40 (d, J = 8.4 Hz, 1H), 7.38 (s,
1H), 6.88 (d, J = 8.3 Hz, 1H), 6.66 (s, 1H), 6.43 (s, 1H), 6.18 (s, 1H). IR νmax
(KBr/cm−1): 1655 (C=O), 1437 (C=C).
2′-Hydroxy-3,4,4′,6′-trimethoxychalcone (6): Method (c1): A mixture
of compound 3 (3.0 g, 0.015 mol), anisaldehyde 4 (2.98 g, 0.018 mol) and
methanol (100 mL) was placed in a dry round-bottomed flask. Potassium
hydroxide (15.0 g, 0.27 mol) was slowly added and the solution was
stirred for 72 h at room temperature. Then the reaction mixture was
neutralised to pH 7 with 37% aqueous HCl. The precipitate was filtered
off, washed with water and recrystallised from EtOH to give compound
6 (4.28 g); yield 83%; yellow crystals, 149–151 °C (lit17. 154–156 °C) 1H
NMR (400 MHz, CDCl3) (δ, ppm): 14.29 (s, 1H, OH), 8.07 (d, J = 15.2 Hz,
1H), 7.75 (d, J = 15.6 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.12
(d, J = 2.4 Hz, 1H), 5.96 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 3.90 (s, 3H, OCH3), 3.84 (s, 3H, OCH3). IR νmax (KBr/cm−1):
3420 (OH), 1625 (C=O).
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.
Received 9 November 2013; accepted 23 November 2013
Paper 1302277 doi: 10.3184/174751914X13867643876192
Published online: 8 January 2014
Method (c2): A mixture of 1,3,5-trimethoxybenzene (1) (0.8 g, 5 mmol)
and 3,4-dimethoxycinnamic 5 (1.56 g, 7.5 mmol) in BF3–Et2O (15 mL)
was heated at 100 °C for 4 h. After one night at room temperature, the
red solid was filtered and dried to give red needles. A suspension of
the needles in EtOH was heated at reflux for 2 h to give a clear orange
solution. After the solution was decolourised with active charcoal and
cooled to 0°C, the precipitate was filtered and dried to give compound
6 (0.77 g); yield 45%, yellow crystals, 149–151 °C (lit17. 154–156 °C) 1H
NMR (400 MHz, CDCl3) (δ, ppm): 14.29 (s, 1H, OH), 8.07 (d, J = 15.2 Hz,
1H), 7.75 (d, J = 15.6 Hz, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.12
(d, J = 2.4 Hz, 1H), 5.96 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 3.90 (s, 3H, OCH3), 3.84 (s, 3H, OCH3). IR νmax (KBr/cm−1):
3420 (OH), 1625 (C=O).
References
1
A. Crozier, I.B. Jaganath and M.N. Clifford, Nat. Prod. Rep., 2009, 26,
1001.
2
3
4
5
6
7
J. Chen, W. Huang, G. Lian and F. Lin, Carbohyd. Res., 2009, 344, 2245.
K.-i. Oyama, K. Yoshida and T. Kondo, Curr. Org. Chem., 2011, 15, 2567.
D. Jiang, D. Li and W. Wu, Nutrients, 2013, 5, 1648.
J.V. Formica and W. Regelson, Food Chem. Toxicol., 1995, 33, 1061.
J.B. Harborne and C.A. Williams, Phytochemistry, 2000, 55, 481.
M. Barontini, R. Bernini, F. Crisante and G. Fabrizi, Tetrahedron, 2010,
66, 6047.
8
9
R. Kobayashi, T. Itou, K. Hanaya, M. Shoji, N. Hada and T. Sugai, J. Mol.
Catal. B-Enzym., 2013, 92, 14.
D. Nagarathnam and M. Cushman, J. Org. Chem., 1991, 56, 4884.
3′,4′,5,7 -Tetramethoxyflavone (7): Compound 6 (2.7 g, 8.0 mmol) and
iodine (0.2 g, 0.8 mmol) in DMSO (25 mL) were heated at 130 °C for
4.5 h. Then 0.5% NaHSO3 (50 mL) was added to remove the iodine. The
precipitate was filtered off, washed with water and recrystallised from
ethanol to give compound 7 (2.2 g); yield 80%, white crystals, m.p. 192–
194 °C (lit7. 190–194 °C) 1H NMR (500 MHz, CDCl3) (δ, ppm): 7.51 (dd,
J = 2.1 Hz/8.5 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H),
6.61 (s, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 3.97 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.92 (s, 3H, OCH3). IR
10 Q.-X. Qin, J. Yang. B. Yang, M. Liu, D. Xiao and X.-M. Yang, J. Chem.
Res., 2013, 37, 38.
11 J. Wang, R.-G. Zhou, T. Wu, T. Yang, Q.X. Qin, L. Li, B. Yang and J. Yang,
J. Chem., Res., 2012, 36, 121.
12 J. Wang, J. Yang, B. Yang, X. Hu, J.-Q. Sun and T. Yang, J. Chem. Res.,
2010, 34, 717.
13 J. Wang, J. Yang, B. Yang, J.-Q. Sun and T. Yang, J. Chem. Res., 2010, 34,
724.
14 J. Wang, J. Yang, R.-G. Zhou, B. Yang and Y.-S. Wu, J. Chem. Res., 2011,
35, 428.
15 J. Wang, J. Yang, R.-G. Zhou, B. Yang and Y.-S. Wu, J. Chem. Res., 2011,
35, 431.
16 M. Tsukayama, E. Kusunoki, M.M. Hossain, Y. Kawamura and S. Hayashi,
Heterocycles, 2007, 71, 1589.
17 H.W. Chu, H.T. Wu and Y.J. Lee, Tetrahedron, 2004, 60, 2647.
18 M.P. Yuldashev, Chem. Nat. Compd, 2002, 38, 291.
ν
max (KBr/cm−1): 1637 (C=O), 1595 (C=C).
3′,4′,5,7-Tetrahydroxyflavone (8): A mixture of compound 7 (2.0 g,
5.8 mmol) and excess pyridine hydrochloride (6.9 g, 0.06 mol) was
heated at 180 °C for 6.5 h under a N2 atmosphere. The mixture was then
cooled to room temperature and H2O (100 mL) was added. The mixture
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