A novel and efficient synthesis of norathyriol using Pd(II) as a catalyst

Article abstract of DOI:10.1007/s11164-013-1068-5

A facile and simple procedure for the synthesis of norathyriol using Pd(II) as a catalyst via two steps under mild conditions is described. The major advantages of this method are the use of a commercially available catalyst, short reaction times, and the simplicity of the reaction and work-up. The overall yield of 36.6 % is acceptable.

Full text of DOI:10.1007/s11164-013-1068-5

Res Chem Intermed
DOI 10.1007/s11164-013-1068-5
A novel and efficient synthesis of norathyriol using
Pd(II) as a catalyst
•
Qi-xue Qin Jian Yang Bo Yang
•
Received: 27 October 2012 / Accepted: 21 January 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract A facile and simple procedure for the synthesis of norathyriol using Pd(II) as
a catalyst via two steps under mild conditions is described. The major advantages of this
method are the use of a commercially available catalyst, short reaction times, and the
simplicity of the reaction and work-up. The overall yield of 36.6 % is acceptable.
Keywords Synthesis Á Norathyriol Á Catalyst Á Transition metal
Introduction
Norathyriol (Fig. 1) is a naturally-occurring polyphenolic xanthone which has
received considerable attention because of its wide range of biological and
pharmacological properties [1–3]. Human exposure to norathyriol occurs primarily
through the consumption of chamomile and through its presence as a glycoside in
many folk medicinal plants [4–7]. Norathyriol, like most xanthones, has antioxidant
[8], anti-inflamrnatory [9], and anticholinesterase activities [10]. Recently,
norathyriol has been synthesized by Hu et al. [11] in four steps with an overall
yield of 45.5 %. In addition, norathyriol has also been prepared by other authors [6,
12, 13], but most of the published synthesis methods report low yields and use
starting materials that are not easily accessible.
Here, we report a novel and efficient procedure to synthesis 1 with the
commercially available 4,6-dimethoxy-2-hydroxybenzaldehyde and 4,5-dibromo-
1,2-dimethoxybenzene as the starting material. (Scheme 1).
Q. Qin Á J. Yang (&) Á B. Yang
Faculty of Life Science and Technology, Kunming University of Science and Technology
(ChengGong Campus), Kunming 650500, Yunnan, People’s Republic of China
e-mail: pharmacistkg101@gmail.com
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Q. Qin et al.
H
O
O
O
Fig. 1 Structure of norathyriol
(1)
H
H
O
O
H
O
H
O
H
OC
3
O
O
r
r
B
B
H
H
OC
H
3
C
O
H
OC
3
a
OC
H
3CO
H
3
OC
H
3CO
H
OC
3
3
4
2
3
H
O
O
H
H
O
O
b
H
O
O
1
Scheme 1 Reagents and conditions: a 5 mol% PdCl2(PPh3)2, DMF, K2CO3, 130 °C, 12 h, 43 %,
b pyridine HCl, 180 °C, 5 h, 85 %
Results and discussion
As shown in Scheme 1, norathyriol has been synthetized with good total yields from
4,6-dimethoxy-2-hydroxybenzaldehyde 2 in two steps. Firstly, 4,6-dimethoxy-2-
hydroxybenzaldehyde 2 was reacted with 4,5-dibromo-1,2-dimethoxybenzene 3 in
DMF at 130 °C in the presence of 5 mol% of PdCl2(PPh3)2 and K2CO3 (2 equiv.) to
obtain the compound 4 in mild yield. Secondly, the compound 4 was demethylated
completely in excess pyridine hydrochloride at 180 °C for 5 h to afford the title
compound 1 in high yield.
In conclusion, a convenient and efficient synthesis of 1 has been achieved via
only two steps in a very high overall yield (36 %). The starting material is
commercially available and the intermediate is sufficiently stable to permit
isolation. We believe that this new procedure could be an efficient synthetic
approach for scaling-up of 1 and be a useful addition to the reported methods for the
preparation of the xanthone.
Experimental
All reactions were monitored by TLC and TLC was performed on silica gel GF254
Melting points were measured on a YRT-3 temperature apparatus and are
.
1
uncorrected. H NMR spectral data were recorded on a Bruker DRX 500 NMR
spectrometer and chemical shifts are reported in ppm(d) relative to TMS as internal
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A novel and efficient synthesis of norathyriol
standard. Mass spectra were determined on VG Auto Spec-3000 spectrometer and
reported as m/z. All reagents were purchased from Aladdin-reagent, China, and used
without further purification.
1,3,6,7-tetramethoxyxanthone(4)
To a mixture of compound 2 (364 mg, 2 mmol) and compound 3 (1.17 g 2 mmol),
K2CO3 (560 mg, 4 mmol), (PPh3)2PdCl2 (75 mg, 0.11 mmol) and 10 mL DMF
were added. The mixture was heated to 130 °C under N2 atmosphere for 12 h. Then
the mixture was cooled to room temperature and diluted with diethyl ether (50 mL)
and washed with water and brine. The aqueous layer was extracted with diethyl
ether (2 9 80 mL). The organic layers were combined and dried with NaSO4,
filtered, and the solvent was removed under reduced pressure. The residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 50/1)
to afford the desired product 4 as white crystals (271 mg), yield: 43 %, m.p.
202–203 °C ([14], 206–207 °C); 1H NMR (500 MHz, CDCl3) (d, ppm): 7.65
(s, 1H), 6.82 (s, 1H), 6.47 (s, 1H), 6.34 (s, 1H),3.99 (s, 3H), 3.97 (s, 6H),3.91
(s, 3H); MS (m/z): 316 (M?).
1,3,6,7-tetrahydroxyxanthone(1)
The mixture of the compound 4 (1.6 g, 5 mmol) and excess pyridine hydrochloride
(6.4 g, 50 mmol) were heated at 180 °C for 4.5 h under an N2 atmosphere. Then the
mixture was cooled to room temperature and dilute hydrochloride
(1.0 M 9 100 mL) was added. The mixture was stirred for another 40 min and
cooled at approximately 0 °C for several hours. The precipitate was filtered off,
washed with water, and recrystallized from 75 % ethanol to give the compound 1 as
1
yellow crystals (1.10 g), yield: 85 %, m.p.[320 °C (decomp.) (lit.6 [ 320 °C); H
NMR (500 MHz DMSO) (d, ppm): 13.15 (s, 1H), 9.60–10.79 (br, 3H), 7.35 (s, 1H),
6.84 (s, 1H), 6.31 (s, 1H), 6.13 (s, 1H); MS (m/z): 260 (M?).
Acknowledgments 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.
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