A facile synthesis of norathyriol

Article abstract of DOI:10.3184/174751912X13547158602399

In this paper, norathyriol has been synthesised from 2-bromo-4,5- dimethoxybenzoic acid and 1,3,5-trimethoxybenzene by a three-step sequence of transformations involving a Friedel-Crafts acylation with cyclisation and demethylation. The procedure was faci

Full text of DOI:10.3184/174751912X13547158602399

38 RESEARCH PAPER
JANUARY, 38–39
JOURNAL OF CHEMICAL RESEARCH 2013
A facile synthesis of norathyriol
Qi-xue Qin, Jian Yang*, Bo Yang, Man Liu, Dan Xiao, Xuemin Yang
Faculty of Life Science andTechnology, Kunming University of Science andTechnology (ChengGong Campus), Kunming 650500, Yunnan
Province, P. R. China
In this paper, norathyriol has been synthesised from 2-bromo-4,5-dimethoxybenzoic acid and 1,3,5-trimethoxyben-
zene by a three-step sequence of transformations involving a Friedel–Crafts acylation with cyclisation and demethyl-
ation. The procedure was facile and should be easily scaled-up. The overall yields reached approximately 70%.
Keywords: norathyriol, synthesis, Friedel–Crafts acylation, cyclisation, demethylation, xanthone
Norathyriol (1, see Fig. 1), also known as 1,3,6,7-tetrahy-
droxyxanthone, is a naturally-occurring polyphenolic xan-
thone which was found present in various herbal plants.1–4 It is
attracting more and more the attention of organic and medici-
nal chemists for its wide range of biological and pharmaco-
logical properties and it is believed to be the important active
component in some traditional medicinal plants.3–6 Related
studies on the chemical modifications and structure–activity
relationships of 1 are on-going.7–8 Although Ueno3 first reported
the synthesis of 1 from a mixture of 2,4,5-trihydrobenzoic
acid, phloroglucinol, fused ZnCl2 and an excess of POCl3
by one-pot reaction in 1962, the yield was very poor and the
product was difficult to isolate and purify. In 1992, Lin et al.9
reported a synthesis from the corresponding benzophenone as
precursor by Friedel–Crafts acylation and base-catalysed
cyclisation to give 1. However, the key benzophenone interme-
diate was not easily available and the yield was poor. The
absence of efficient preparation of 1 has encouraged further
studies on synthetic procedures. In 2011, Li et al.10 have
reported the synthesis of 1 with 2-bromo-4,5-dimethoxyben-
zoic acid and 3,5-dimethoxyphenol as the key precursors by
Ullmann condensation followed by Friedel–Crafts acylation
cyclisation and complete demethylation. The yield was still
very poor and the precursors were difficult to prepare and the
Ullmann reaction conditions were very harsh. In 2011, Hu
et al.8 reported a synthetic route in four steps to give 1 with
2,4,5-trimethoxybenzoic acid and 1,3,5-trimethoxy-benzene
as the starting materials. The yield was still unsatisfactory and
open to improvement.
compound 4 in the presence of a Lewis acid such as PPA,
POCl3, BF3, etc. Then, compound 4 was demethylated selec-
tively with BCl3 at approximately 0 °C to produce the com-
pound 5, which was smoothly cyclised to provide 6 in hot,
strong alkali solution with good yield. Lastly, compound 6 was
demethylated completely in excess pyridine hydrochloride at
180 °C for 5h to afford the title compound 1 in high yield.
However, further investigations suggested that compound 4
could also be demethylated selectively with BF3 at 80–90 °C to
produce compound 5 in good yield. Thus, compound 2 could
be condensed with 1,3,5-trimethoxybenzene by Friedel–Crafts
acylation followed by demethylation selectively at 80–90 °C in
the presence of a little excess of a Lewis acid such as BF3 in a
one pot reaction to produce the key intermediate 5. Hence, our
patented procedure was improved by removing one reaction
step.
In conclusion, a convenient and efficient synthesis of 1 has
been achieved using only three reaction steps. The overall
yield is approximately 70% and satisfactorily high. All the
starting materials and reagents are commercially available and
inexpensive. Each step of reaction was carried out to give the
product easily. Hence, we believe that this improved procedure
could be an efficient synthetic approach for scaled-up synthe-
sis 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 tempera-
ture apparatus and are uncorrected. 1H NMR spectroscopic data were
recorded on a Bruker DRX 500 NMR spectrometer and chemical shift
are reported in ppm (δ) relative to TMS as internal standard. Mass
spectra were determined on a VG Auto Spec-3000 spectrometer and
reported as m/z.
2-Bromo-4, 5, 2′, 4′, 6′-pentamethoxyl benzophenone (4): To the
mixture of the compound 2 (5.7 g, 22 mmol) and the compound 3
(3.3 g 20 mmol) in chlorobenzene (15 mL), POCl3 (4.8 mL, 50 mmol)
was added dropwise. After the reaction mixture was stirred at 80 °C
for 4 h, H2O (100 mL) was added and the mixture was kept heating
and stirring for another 1h. Then, the mixture was cooled to room
temperature and extracted with 1,2-dichloroethane twice (2×100 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 4
as white crystals (7.00 g), yield: 85.0%, m.p. 129–130 °C (lit.14 129–
130 °C), 1HNMR (500 MHz CDCl3) δ: 7.26 (s, 1H), 7.01 (s, 1H), 6.13
(s, 2H), 3.91 (s, 3H), 3.85 (s, 6H), 3.70 (s, 6H). MS (m/z): 412, 410
(M+).
In our studies of the structure–activity relationships of active
compounds from natural sources,11–13 we had also established
the efficient preparation of 1 by an alternative procedure,
which has been patented in China.14 Our team has continued
further investigations of the procedure, which has resulted in
improvements in the preparation of 1. Here, we report our
preparation of 1 using the commercially available starting
materials, which features an improved procedure and better
yields, and should be better for the scaled-up preparation of 1
(see Scheme 1).
Results and discussion
As shown in Scheme 1, the title compound 1 has been synthe-
sised with good overall yield from 2-bromo-4,5-dimethoxy-
benzoic acid 2 and 1,3,5-trimethoxybenzene 3. In our patent,
the compound 2 was condensed with compound 3 to give the
2-Bromo-2′-hydroxy-4, 5, 4′, 6′-tetramethoxyl benzophenone (5):
Method A: To the solution of the compound 4 (4.1 g, 10 mmol) in
dichloromethane (30 mL) at approximately 0 °C, 1 mol L−1 BCl3 in
dichloromethane (12 mL, 12 mmol) was added dropwise for about
1 h, and then the reaction mixture were stirred at room temperature for
another 3 h. H2O (100 mL) was added, the mixture was stirred for
another hour and extracted with dichloromethane twice (100 mL×2).
The organic layers were combined and washed sequentially with
Fig. 1 Structure of norathyriol (1).
* Correspondent. E-mail: pharmacistkg101@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2013 39
Scheme 1 Reagents and conditions:(a) BF3–Et2O, ClCH2CH2Cl, 90 °C, 6h, 85% (a1) POCl3, ClCH2CH2Cl, 70–80 °C, 4h, 85% (a2) BCl3,
CH2Cl2, 0 °C r.t., 4h, 90% (b) KOH, H2O, reflux, 15h, 95% (c) pyridine HCl, 180 °C, 5h, 85%.
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 5 as
white crystals (3.56 g), yield: 90.0%, m.p. 153–154 °C (lit.14153–
154 °C), 1H NMR (500 MHz CDCl3) δ: 7.00 (s, 1H), 6.77 (s, 1H), 6.14
(s, 1H), 5.85 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.46 (s,
3H). MS (m/z): 398, 396 (M+).
2-Bromo-2′-hydroxy-4, 5, 4′, 6′-tetramethoxyl benzophenone (5):
Method B: To the mixture of the compound 2 (5.7 g, 22 mmol) and the
compound 3 (3.3 g 20 mmol) in chlorobenzene (10 mL), BF3–Et2O
solution (7.0 mL, 47%, 50 mmol) was added dropwise. The reaction
mixture was heated at 90 °C for 6 h. H2O–methanol (100 mL, V/V =
1/1) was added and the mixture was stirred for another 1 h. Then, the
mixture was extracted with 1,2-dichloroethane twice (2×100 mL).
The organic layers were combined and washed sequentially with satu-
rated sodium bicarbonate (100 mL×2), H2O (100 mL) and 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 5 as white crystals (6.73 g), yield:
85.0%, m.p. 153–154 °C (lit.14153–154 °C), 1HNMR (500 MHz
CDCl3) δ: 7.00 (s, 1H), 6.77 (s, 1H), 6.14 (s, 1H), 5.85 (s, 1H), 3.92 (s,
3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.46 (s, 3H). MS (m/z): 398, 396
(M+).
1,3,6,7-Tetramethoxyxanthone (6): The mixture of the compound 5
(4.0 g, 10 mmol) and potassium hydroxide (1.12 g, 20 m mol) in H2O
(60 mL) was heated under reflux for 15 h. The mixture was cooled to
room temperature and neutralised with dilute hydrochloric acid (1M).
The precipitate was filtered off, washed with water, and the aqueous
phase was extracted with 1,2-dichloroethane twice (2×100 mL). The
organic layers were combined and washed with H2O (100 mL) once
and dried with anhydrous sodium sulfate overnight. Removal of the
solvent under reduced pressure gave a solid residue. The solid was
combined with the above precipitate and recrystallised from ethanol
to give the compound 6 as white crystals (2.60 g), yield: 95%, m.p.
202–203 °C (lit.15 206–207 °C), 1H NMR (500 MHz CDCl3) δ: 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+).
another 40 min and cooled at approximately 0 °C for several hours.
The precipitate was filtered off, washed with water and recrystallised
from 75% ethanol to give the compound 1 as yellow crystals (1.10 g),
yield: 85%, m.p. >320 °C (decomp.) (lit.3 >320 °C), 1H NMR
(500 MHz DMSO) δ: 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+).
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (NSFC) (No.21062009)
and the Natural Science Foundation of Yunnan Province (No.
2011FZ059).
Received 14 September 2012; accepted 6 November 2012
Paper 1201519 doi: 10.3184/174751912X13547158602399
Published online: 15 January 2013
References
1
P.T. Nedialkov, G.M. Kitanov, D.Z. Zheleva-Dimitrova and U. Girreser,
Biochem. Syst. Ecol., 2007, 35, 118.
2
V. Rukachaisirikul, W. Naklue, S. Phongpaichit, N.H. Towatana and
K. Maneenoon, Tetrahedron., 2006, 62, 8578.
3
4
5
6
A. Ueno, Yakugaku Zasshi., 1962, 82, 1482.
C. Bock, K.H. Waldmann and W. Ternes, Nutr. Res., 2008, 28, 879.
T.B. Ng, Recent Prog. Med. Plant., 2006, 12, 129.
A.S. Wilkinson, G.R. Monteith, P.N. Shaw, C.N. Lin, M.J. Gidley and
S.J. Roberts-Thomson, J. Agric. Food Chem., 2008, 56, 3037.
H. Hu, H. Liao, J. Zhang, W. Wu, J. Yan, Y. Yan, Q. Zhao, Y. Zou, X. Chai,
S. Yu and Q.Y. Wu, Bioorg. Med. Chem. Lett., 2010, 20, 3094.
L. Hu, H. Hu, W. Wu, X. Chai, J. Luo and Q. Wu, Bioorg. Med. Chem. Lett.,
2011, 21, 4013.
7
8
9
C.N. Lin, S.S. Liou, F.N. Ko and C.M. Teng, J. Pharm. Sci., 1992, 81,
1109.
10 L. Li, L. Song, X. Liu and S. Gao. CN, 2011, 102002031A[P], Kunmming
Medical College, China.
11 J. Wang, J. Yang, B. Yang, J.Q. Sun and T. Yang, J. Chem. Res., 2010, 34,
724
12 J. Wang, J.Yang, R.G. Zhou, B.Yang andY.S. Wu, J. Chem. Res., 2011, 35,
428.
13 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.
1,3,6,7-Tetrahydroxyxanthone (1): The mixture of the compound 5
(1.6 g, 5 mmol) and an excess of pyridine hydrochloride (6.4 g,
50 mmol) was heated at 180 °C for 4.5h under an N2 atmosphere.
Then the mixture was cooled to room temperature and dilute hydro-
chloric acid (1.0 M×100 mL) was added. The mixture was stirred for
14 J.Yang, R. Zhou, Z.Yang, B.Yang andW. Zhang. CN, 2011, 10004591.6[P],
Kunmming Pharmaceutical Co., Ltd., China.
15 A. Jefferson and F. Scheinmamm, J. Chem. Soc.(S), 1966, 175.

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