Synthesis and structure characterization of novel luteolin derivatives

Article abstract of DOI:10.1007/s10600-010-9723-1

A series of novel luteolin derivatives was synthesized employing the Vilsmeier-Haak-Arnold reaction from the intermediate compound 3',4',7-trichloro-5-hydroxyflavone, which was obtained from luteolin. These derivatives may be used to improve the pharmacol

Full text of DOI:10.1007/s10600-010-9723-1

Chemistry of Natural Compounds, Vol. 46, No. 5, 2010
SYNTHESIS AND STRUCTURE CHARACTERIZATION
OF NOVEL LUTEOLIN DERIVATIVES
1
2*
2
Jing Fen Li, Li Sheng Wang, Hai Qiang Bai,
UDC 547.972
2
2
Bin Yang, and Zhi Gang Chen
A series of novel luteolin derivatives was synthesized employing the Vilsmeier-Haak-Arnold reaction from
the intermediate compound 3ꢀ,4ꢀ,7-trichloro-5-hydroxyflavone, which was obtained from luteolin. These
derivatives may be used to improve the pharmacological activities of luteolin.
Keywords: luteolin, derivatives, 3ꢀ,4ꢀ,7-trichloro-5-hydroxyflavone, synthesis.
Luteolin, one of the flavones, exists mainly in herbs of Lonicera japonica, Chrysanthemum morifolium, Nepeta
cateria L., and Ajuga decumbens Thunb. Luteolin has been studied extensively as it possesses important pharmacological
activities, such as antiviral, antimicrobial, anticholesterol, etc. [1–3]. However, there are few reports about the derivatives of
luteolin. Based on the fact that Schiff bases have been reported as anticancer [4ꢁ, antibacterial and anti-inflammatory agents
[5, 6], we used the Vilsmeier-Haak-Arnold reaction to obtain new luteolin derivatives, in which we expected to find some
compounds with better pharmacological activities.
A series of luteolin (1) derivatives was obrained by the reaction of 3ꢀ,4ꢀ,7-trichloro-5-hydroxyflavone and R-NH ꢂ7ꢁ
2
based on the Vilsmeier-Haak-Arnold reaction. Synthesis of the title compounds is outlined in Scheme 1. 3ꢀ,4ꢀ,7-Trichloro-5-
hydroxyflavone (2) was obtained in good yield by adding luteolin to POCl in DMF with heating [8–10], then recrystallized in
3
1
13
ethanol to give compound 3a. We found from its H NMR and C NMR data that there was one molecular ethanol in 3a
structure. The synthesis routes are as shown in Scheme 1.
13
The C NMR spectroscopy of compound 3a indicated that there were 15 peaks of carbon between ꢃ 102 and ꢃ 182.
13
Comparison of the C NMR data of compound 3a and luteolin suggested that the hydroxyl groups connected to C-3ꢀ, C-4ꢀ,
and C-7 were replaced by chlorine.
In the IR spectra of compounds 3c, 3d, and 3e, the absorption peaks at 1460 cm and 1380 cm indicated that there
were methyl and methylene in the compounds. The IR absorption peaks (1385, 1460, and 1370 cm ) showed that compound
–1
–1
–1
1
3d included the (CH ) CH-group. In the H NMR of compound 3f, the proton peaks at ꢃ 7.24, 7.29, 7.31, 7.34, and 7.52 ppm
3 2
were observed to agree with -CH -C H . MS and NMR data further confirmed their structures.
2
6 5
EXPERIMENTAL
Materials and Methods. Chemicals were purchased from Baoji Aimu Food Co. and used as such without further
purification; TLC was performed on silica gel plates with visualization by UV light; melting points were taken in an X-4
digital melting point apparatus; all compounds were characterized by a combination of GC-MS, IR, NMR, and elemental
1
13
analyses. IR spectra in KBr pellets were recorded on FT-IR. H NMR (400 MHz) and C NMR (400 MHz) spectra were
13
recorded on a Bruker 5000 spectrometer in DMSO-d (with TMS for C NMR as an internal reference). GC-MS analyses
6
were performed with QP5050A. Elemental analyses of all compounds were performed on a Perkin–Elmer 2400 analyzer.
1) Department of Life Science, Huzhou Normal College, Huzhou, 537000, China; 2) College of Chemistry and
Chemical Engineering, Guangxi University, Nanning, 530004, China, e-mail: lswang@gxu.edu.cn. Published in Khimiya
Prirodnykh Soedinenii, No. 5, pp. 606–607, September–October, 2010. Original article submitted May 15, 2009.
716
0009-3130/10/4605-0716 02010 Springer Science+Business Media, Inc.

Cl
Cl
.
HOC H
2
5
Cl
O
O
5'
Cl
Cl
OH
OH
CH CH OH
3
2
1
O
OH
3a
3'
Cl
HO
O
O
1'
Cl
Cl
7
POCl
DMF
3
3
RNH
Cl
O
2
5
OH
O
OH
1
2
OH
N
R
3b-f
7''
5''
2''
2''
4''
1''
R =
1''
3b
3''
3''
1''
3''
3''
1''
1''
3e
79.4
3c
62.8
3d
71.8
3f
yield, %
38.9
47.8
Scheme 1. Synthesis of luteolin derivatives.
3ꢀ,4ꢀ,7-Trichloro-5-hydroxyflavone (3 mmol) in anhydrous DMF (2 mL) and methylamine (1 mL) were added to
ethyl acetate. The reaction solution was stirred for 5 min and gave a yellow precipitate, which was filtered and recrystallized
to give product 3b in a yield of 38.9%. 3ꢀ,4ꢀ,7-Trichloro-5-hydroxyflavone reacted with different amines under the same
condition to give compounds 3c–3f as shown in Scheme 1.
1
All the products were characterized by IR, GC-MS, H NMR, and elemental analyses. The analytical data of compounds
3a–3f are as follows:
–1
1
Compound 3a: mp 244–245ꢄC; IR (KBr, ꢅ, cm ): 3445, 2923, 1562, 1480, 1432; H NMR (DMSO-d , ꢃ, ppm, J/Hz):
6
1.05 (3H, t, J = 6.6, H-3ꢀꢀ), 3.43 (2H, m, J = 6.6, H-2ꢀꢀ), 4.35 (1H, s, H-1ꢀꢀ), 6.93 (1H, s, H-6), 6.99 (1H, s, H-8), 7.28 (1H, s, H-3),
+
7.32 (1H, d, J = 8.4, H-5ꢀ), 7.47(1H, s, H-2ꢀ), 7.51 (1H, d, J = 8.4, H-6ꢀ), 12.83 (1H, s, 5-OH); ESI-MS (m/z): 342.9 ꢂM + 1ꢁ .
–1
1
Compound 3b: mp 240–242ꢄC; IR (KBr, ꢅ, cm ): 3415, 2923, 1651, 1480, 1430; H NMR (DMSO-d , ꢃ, ppm, J/Hz):
6
2.35 (3H, s, H-1ꢀꢀ), 6.86 (1H, s, H-6), 6.91 (1H, s, H-8), 7.15 (1H, s, H-3), 7.33 (1H, d, J = 8.4, H-5ꢀ), 7.43 (1H, s, H-2ꢀ), 7.47
+
(1H, d, J = 8.4, H-6ꢀ); ESI-MS (m/z): 353.8 ꢂM + 1ꢁ .
–1
1
Compound 3c: mp 246–247ꢄC; IR (KBr, ꢅ, cm ): 3415, 1653, 1460, 1380; H NMR (DMSO-d , ꢃ, ppm, J/Hz):
6
0.86 (3H, t, J = 7.4, H-3ꢀꢀ), 1.45 (2H, m, J = 7.4, 7.3, H-2ꢀꢀ), 2.62–2.65 (2H, t, J = 7.3, H-1ꢀꢀ), 6.80 (1H, s, H-6), 6.84 (1H, s,
+
H-8), 7.05 (1H, s, H-3), 7.22 (1H, d, J = 8.5, H-5ꢀ), 7.39 (1H, s, H-2ꢀ), 7.41 (1H, d, J = 8.5, H-6ꢀ); ESI-MS (m/z): 381.8 ꢂM + 1ꢁ .
–1
1
Compound 3d: mp 243–245ꢄC; IR (KBr, ꢅ, cm ): 3426, 1651, 1385, 1370, 1460; H NMR (DMSO-d , ꢃ, ppm,
6
J/Hz): 1.13 (6H, d, J = 6.4, H-2ꢀꢀ, H-3ꢀꢀ), 3.18–3.24 (1H, m, J = 6.4, H-1ꢀꢀ), 6.85 (1H, d, J = 1.7, H-6), 6.89 (1H, s, H-8), 7.12
(1H, d, J = 1.7, H-3), 7.32 (1H, dd, J = 8.4, 1.9, H-5ꢀ), 7.44 (1H, s, H-2ꢀ), 7.47 (1H, dd, J = 8.4, 1.9, H-6ꢀ); ESI-MS (m/z): 381.9
+
ꢂM + 1ꢁ .
–1
1
Compound 3e: mp 241–243ꢄC; IR (KBr, ꢅ, cm ): 3415, 3072, 1650, 1380, 1460; H NMR (DMSO-d , ꢃ, ppm,
6
J/Hz): 0.83–0.87 (3H, t, J = 7.2, H-4ꢀꢀ), 1.24–1.34 (2H, m, J = 7.2, 7.6, H-3ꢀꢀ), 1.38–1.45 (2H, m, J = 7.6, 7.3, H-2ꢀꢀ), 2.62–2.66
(2H, t, J = 7.3, H-1ꢀꢀ), 6.80 (1H, s, H-6), 6.84 (1H, s, H-8), 7.05 (1H, s, H-3), 7.21 (1H, d, J = 8.0, H-5ꢀ), 7.38 (1H, s, H-2ꢀ), 7.40
+
(1H, d, J = 8.0, H-6ꢀ); ESI-MS (m/z): 395.9 ꢂM + 1ꢁ .
–1
1
Compound 3f: mp 238–240ꢄC; IR (KBr, ꢅ, cm ): 3438, 1646, 1609, 1552, 1474; H NMR (DMSO-d , ꢃ, ppm):
6
3.77 (2H, s, H-1ꢀꢀ), 6.91 (1H, d, J = 1.5, H-6), 6.96 (1H, s, H-8), 7.22 (1H, s, H-3), 7.24 (1H, m, H-5ꢀꢀ), 7.29 (1H, d, J = 6.5,
H-7ꢀꢀ), 7.31 (1H, d, J = 6.5, H-3ꢀꢀ), 7.34 (1H, d, J = 8.5, H-5ꢀ), 7.39 (1H, s, H-2ꢀ), 7.42 (1H, d, J = 8.5, H-6ꢀ), 7.49 (1H, m,
+
H-6ꢀꢀ), 7.52 (1H, m, H-4ꢀꢀ); ESI-MS (m/z): 429.9 ꢂM + 1ꢁ .
ACKNOWLEDGMENT
This work was supported by the Natural Science Foundation of Zhejiang Province (Y205706).
717

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