Microwave-assisted efficient and green synthesis of hydroxyxanthone in water

Article abstract of DOI:10.1080/00397911.2011.573170

An efficient and green procedure has been developed for the synthesis of hydroxyxanthones from substituted 2,2-dihydroxybenzophenone precursors via microwave-assisted base-catalyzed cyclization in water. This method provides excellent yields of products in a short time, making it a useful strategy for the synthesis of structurally diverse hydroxyxanthones.

Full text of DOI:10.1080/00397911.2011.573170

This article was downloaded by: [Selcuk Universitesi]
On: 04 February 2015, At: 17:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Microwave-Assisted Efficient and Green
Synthesis of Hydroxyxanthone in Water
Xiao-Jin Zhang a b , Suo-Fu Ye b , Yu Zhang b , Hu-Yan Meng b , Ming-
Qian Zhang b , Wen-Lei Gao b & Qi-Dong You a b
a State Key Laboratory of Natural Medicines, China Pharmaceutical
University , Nanjing , China
b Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University , Nanjing , China
Accepted author version posted online: 03 Jan 2012.Published
online: 21 Jun 2012.
To cite this article: Xiao-Jin Zhang , Suo-Fu Ye , Yu Zhang , Hu-Yan Meng , Ming-Qian Zhang , Wen-
Lei Gao & Qi-Dong You (2012) Microwave-Assisted Efficient and Green Synthesis of Hydroxyxanthone
in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:20, 2952-2958, DOI: 10.1080/00397911.2011.573170
To link to this article: http://dx.doi.org/10.1080/00397911.2011.573170
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 42: 2952–2958, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.573170
MICROWAVE-ASSISTED EFFICIENT AND GREEN
SYNTHESIS OF HYDROXYXANTHONE IN WATER
Xiao-Jin Zhang,1,2 Suo-Fu Ye,2 Yu Zhang,2 Hu-Yan Meng,2
Ming-Qian Zhang,2 Wen-Lei Gao,2 and Qi-Dong You1,2
1State Key Laboratory of Natural Medicines, China Pharmaceutical
University, Nanjing, China
2Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing, China
GRAPHICAL ABSTRACT
Abstract An efficient and green procedure has been developed for the synthesis of hydroxyx-
anthones from substituted 2,20-dihydroxybenzophenone precursors via microwave-assisted
base-catalyzed cyclization in water. This method provides excellent yields of products in
a short time, making it a useful strategy for the synthesis of structurally diverse hydroxyx-
anthones.
Keywords Green synthesis; hydroxyxanthones; microwave; water
INTRODUCTION
Xanthones are oxygenated heterocyclic compounds with a dibenzo-c-pyrone
framework that are widely distributed in nature. The xanthone scaffold has been
described as a ‘‘privileged structure’’ for biological profiles that vary depending on
the nature and position of the substituents.[1] A large number of naturally occurring
or synthetic xanthones that consist of the hydroxyxanthone scaffold have been reported,
and these show a multitude of interesting biological activities, such as anti-Alzheimer,
anticancer, and antimalarial activities and inhibition of Na=K-ATPase (Fig. 1).[2–5]
Generally, hydroxyxanthones can be achieved through condensation of the
corresponding hydroxybenzoic acids with polyphenols by the Grover, Shah, and
Shah (GSS) reaction.[6] However, this method is restricted to xanthones possessing
Received January 19, 2011.
Address correspondence to Qi-Dong You, Department of Medicinal Chemistry, China
Pharmaceutical University, P. O. Box 51, 24 Tongjiaxiang, Nanjing 210009, China. E-mail:
youqidong@gmail.com
2952

SYNTHESIS OF HYDROXYXANTHONE
2953
Figure 1. Some biological compounds with hydroxyxanthone scaffold. (Figure is provided in color online.)
a hydroxyl group at the 1-position. Thermal condensation of different methyl
hydroxybenzoates with polyphenols has also been reported to directly give
hydroxyxanthones in refluxing diphenyl ether, but the reactions are carried out in
extremely harsh conditions and afford very poor yields.[7] Another method involving
Friedel–Crafts acylation, cyclization, and demethylation has been described to
provide diverse hydroxyxanthones, but it is stepwise and not environmentally
friendly.[8,9] For these reasons, a facile, efficient, and environmentally benign pro-
cedure for the synthesis of this class of heterocyclic compounds is urgently needed.
Nowadays, microwave-assisted organic synthesis (MAOS) has become a useful
and important tool for rapid organic synthesis.[10] Some of the major advantages
include spectacularly, reduced reaction time, improved conversions, and clean product
formation.[11] Because water is very efficient at absorbing microwaves, and is obviously
the cleanest and safest available solvent, numerous reports have recently focused on the
combination of water as an environmentally friendly solvent for chemical transforma-
tions with the use of microwave irradiation (MWI) as an efficient heating method.[12]
Herein, we present a facile, efficient, and green method to synthesize hydroxyx-
anthones in a short time under MWI in water. To the best of our knowledge, this is
the first time that synthesis of hydroxyxanthones in water by use of MWI has been
reported.
RESULTS AND DISCUSSION
First, to investigate the effect of MWI on the cyclization reaction, hydroxyben-
zophenone 1a was used as a test substrate. As shown in Table 1, the cyclization of
hydroxybenzophenone 1a to hydroxyxanthone 2a under MWI at 100 ꢀC in water
as solvent was accomplished in 60 min with quantitative yield. On the other hand,
when the reaction was carried out under conventional heating using the same sealed
microwave tube at 100 ꢀC for 24 h, only a trace amount of cyclization product 2a
was observed (entry 1, Table 1). Furthermore, a weak base, sodium acetate
(NaOAc), was employed in trying to facilitate the deprotonation of the phenolic
hydroxyl group and promote intramolecular nucleophilic cyclization. Fortunately,

2954
X.-J. ZHANG ET AL.
Table 1. Microwave effect observed in the intramolecular cyclization of 1a to 2a
Microwave irradiation
Conventional heating
Entry
Base (10 mol%)
Temp. (ꢀC)
Time (min)
Yield (%)
Time (h)
Yield (%)
1
2
—
NaOAc
100
100
60
12
99
99
24
24
Tracea
8b
aThe progress of the reaction was monitored by TLC.
bIsolated yield.
quantitative conversion of 1a to 2a was achieved in 12 min under MWI in the
presence of NaOAc as a base catalyst, whereas only 8% conversion was detected
in 24 h under conventional heating (entry 2, Table 1). All the evidence suggested that
the cyclization reaction could be accelerated by MWI in water.
Subsequently, temperatures and basicity of catalysts were examined for their
effects on the microwave-assisted cyclization of 1a to 2a (Table 2). The reaction time
was significantly reduced from 15 min to 8 min when the temperature was raised
from 90 ꢀC to 120 ꢀC. Further increase in temperature did not shorten the reaction
time (entry 5, Table 2). Besides the relatively weak base NaOAc, moderate to strong
bases such as Na2CO3 and NaOH were also applied as base catalysts. The results in
Table 2 (entries 4, 6, and 7) showed that the reaction could complete rapidly in 8 min
with excellent yields using different bases as catalysts, and the strength of basicity
had no correlation with the reaction rate.
With the optimal reaction conditions (entry 4, Table 2) in hand, the scope of the
cyclization reaction was extended to various hydroxybenzophenone substrates
(Table 3). The hydroxybenzophenone precursors 1a–f were conveniently prepared
by Friedel–Crafts acylation of substituted benzoic acids with reactive polyphenols
in the presence of phosphorus oxychloride and zinc(II) chloride according to
Table 2. The effects of the temperature and basicity of the cyclization of 1a to 2a under MWI
Entry
Base (10 mol%)
Temp. (ꢀC)
Timea (min)
Yieldb (%)
1
2
3
4
5
6
7
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
NaOH
90
15
12
10
8
99
99
99
99
99
98
98
100
110
120
130
120
120
8
8
8
aThe progress of the reaction was monitored by TLC.
bIsolated yields.

SYNTHESIS OF HYDROXYXANTHONE
2955
Table 3. Microwave-assisted synthesis of hydroxyxanthones from benzophenones in water
Entrya
Benzophenone
Hydroxyxanthone
Time (min) Yieldb,c (%)
1
8
8
99
98
2
3
4
5
8
8
99
99
96
12
6
15
94
aRun using P ¼ 150 W.
bIsolated yields.
cAll the hydroxyxanthones were characterized by 1H NMR, 13C NMR, IR, EI-MS, and HRESIMS (see
Experimental section).

2956
X.-J. ZHANG ET AL.
GSS[6] and Davies and coworkers.[13] The data in Table 3 demonstrated that
hydroxybenzophenones 1a–f could successfully convert into structurally diverse
hydroxyxanthones 2a–f under MWI in a short time (8–15 min) with good to quanti-
tative yields (94–99%). Meanwhile, it was observed that the introduction of additional
hydroxyl groups to any benzene ring of the hydroxybenzophenones could result in
more reaction times for the completely conversions (compare entry 1 to entry 5,
and entry 3 to entry 6, Table 3). Presumably, the p-p conjugation effect of phenolic
hydroxyl group led to an increase in the electron densities at the ortho- and para- posi-
tions, which hampered the process of the intramolecular nucleophilic substitution.
In conclusion, in this work we have demonstrated a facile, efficient, and
green procedure for the synthesis of hydroxyxanthones from substituted 2,20-
dihydroxybenzophenone precursors under MWI in water with base catalysts. This
method provides excellent yields and purities of products in a short time, making
it a useful strategy for the synthesis of structurally diverse hydroxyxanthones.
EXPERIMENTAL
Microwave irradiation was carried out in Discover microwave synthesizer of
CEM Corporation. Melting points (mp) were determined with a Melt-Temp II
apparatus and are reported without any correction. Infrared (IR) spectra were
obtained with Nicolet iS10 Fourier transform (FT) spectrophotometer using KBr
film. The 1H NMR and 13C NMR spectra were collected on either a Brucker
AMX300 or a Brucker AMX500 spectrometer (300 MHz for 1H; 75 MHz or
125 MHz for 13C) using dimethyl sulfoxide (DMSO-d6) as solvent with tetramethyl-
silane (TMS) as the internal standard. Mass spectra were recorded on a Shimadzu
GC-MS 2010 (EI-MS) or a LC=MSD TOF mass spectrometer (HRESIMS).
General Procedure for the Synthesis of Hydroxyxanthones 2a–f
A sealed 10-mL glass tube containing a suspension of the benzophenones
(1 mmol) and base (10% mol) in water (4 ml) was introduced in the cavity of the
CEM microwave reactor and irradiated for the appropriate time and temperature
under magnetic stirring. The process of reaction was monitored by thin-layer chroma-
tography (TLC). After cooling to room temperature by air flow, the tube was removed
from the rotor, and the reaction mixture was diluted with water and filtered. The pre-
cipitate was washed with water and dried to give hydroxyxanthones (‘‘one-spot’’ on
TLC), which were further purified by silica-gel column chromatography.
3-Hydroxy-9H-xanthen-9-one 2a
1
White solid. Mp: 254–255 ꢀC (lit.[14] mp: 254–255 ꢀC). H NMR (DMSO-d6,
300 MHz): d 6.91 (m, 2 H), 7.44 (t, J ¼ 7.5 Hz, 1 H), 7.60 (d, J ¼ 8.4 Hz, 1 H), 7.82 (t,
J ¼ 7.8 Hz, 1 H), 8.05 (d, J ¼ 8.6 Hz, 1 H), 8.15 (d, J ¼ 7.9 Hz, 1 H), 11.02 (br, 1 H).[15]
13C NMR (DMSO-d6, 125 MHz): d 102.12, 113.99, 114.11, 117.83, 121.20, 124.07,
125.82, 127.97, 134.74, 155.54, 157.54, 164.00, 174.73.[15] IR (cmꢁ1, KBr): 3137,
1614, 1561, 1455, 1310, 844, 751. EI-MS (m=z): 212 (Mþ). HRESIMS calcd. for
C13H8O3 [M ꢁ H]ꢁ 211.0395; found 211.0400.

SYNTHESIS OF HYDROXYXANTHONE
2957
2,6-Dihydroxy-9H-xanthen-9-one 2b
1
Pale yellow solid. Mp: >300 ꢀC (lit.[7] mp: >310 ꢀC). H NMR (DMSO-d6,
300 MHz): d 6.84(s, 1 H), 7.60 (d, J ¼ 8.8 Hz, 1 H), 7.25 (m, 1 H), 7.47 (m, 2 H),
8.02 (d, J ¼ 8.6 Hz, 1 H), 9.19 (br, 1 H), 10.84 (br, 1 H). 13C NMR (DMSO-d6,
75 MHz): d 101.84, 118.67, 113.50, 113.84, 119.02, 121.78, 123.47, 127.84, 149.13,
153.63, 157.54, 163.60, 174.71. IR (cmꢁ1, KBr): 3280, 3185, 2932, 1632, 1460,
1293, 1151,795. EI-MS (m=z): 228 (Mþ). HRESIMS calcd. for C13H8O4 [M ꢁ H]ꢁ
227.0344; found 227.0348.
3,6-Dihydroxy-9H-xanthen-9-one 2c
White solid. Mp: >300 ꢀC (lit.[6] mp:>330 ꢀC). 1H NMR (DMSO-d6,
300 MHz): d 6.85 (m, 2 H), 6.89 (m, 2 H), 8.00 (d, J ¼ 8.6 Hz, 2 H), 10.82 (br,
2 H). 13C NMR (DMSO-d6, 75 MHz): d 112.02, 113.60, 113.98, 127.74, 147.44,
163.24, 173.93.[16] IR (cmꢁ1, KBr): 3385, 3138, 1614, 1457, 1276, 1174, 848. EI-MS
(m=z): 228 (Mþ). HRESIMS calcd. for C13H8O4 [M ꢁ H]ꢁ 227.0344; found 227.0347.
3,5-Dihydroxy-9H-xanthen-9-one 2d
1
Pale yellow solid. Mp: >300 ꢀC. H NMR (DMSO-d6, 300 MHz): d 6.91 (m,
2 H), 7.24 (m, 2 H), 7.57 (d, J ¼ 7.5 Hz, 1 H), 8.03 (d, J ¼ 6.3 Hz, 1 H), 10.57 (br,
2 H). 13C NMR (DMSO-d6, 75 MHz): d 102.10, 113.83, 114.08, 115.17, 119.66
122.29, 123.67, 127.90, 145.02, 146.22, 15.27, 163.77, 174.97. IR (cmꢁ1, KBr):
3375, 3086, 1611, 1448, 1342, 1236, 745. EI-MS (m=z): 228 (Mþ). HRESIMS calcd.
for C13H8O4 [M ꢁ H]ꢁ 227.0344; found 227.0347.
3,4-Dihydroxy-9H-xanthen-9-one 2e
1
White solid. Mp: 241–242 ꢀC (lit.[8] mp: 237–239 ꢀC). H NMR (DMSO-d6,
300 MHz): d 6.95 (d, J ¼ 8.7 Hz, 1 H), 7.46 (t, J ¼ 7.5 Hz, 1 H), 7.56 (d, J ¼ 8.7 Hz,
1 H), 7.60 (d, J ¼ 9.0 Hz, 1 H), 7.83 (t, J ¼ 7.8 Hz, 1 H), 8.15 (d, J ¼ 8.2 Hz, 1 H),
9.91 (br, 2 H).[8] 13C NMR (DMSO-d6, 75 MHz): d 103.03, 114.66, 116.52, 117.88,
120.77, 123.85, 125.81, 132.45, 134.69, 146.30, 151.37, 155.45, 175.22.[16] IR (cmꢁ1
,
KBr): 3550, 3121, 1613, 1460, 1349, 1062, 754. EI-MS (m=z): 228 (Mþ). HRESIMS
calcd. for C13H8O4 [M ꢁ H]ꢁ 227.0344; found 227.0349.
3,4,5,6-Tetrahydroxy-9H-xanthen-9-one 2f
Yellow solid. Mp: >300 ꢀC (lit.[8] mp: >300 ꢀC). 1H NMR (DMSO-d6,
300 MHz): d 6.92 (d, J ¼ 8.4 Hz, 2 H), 7.53 (d, J ¼ 8.5 Hz, 2 H), 9.42 (br, 4 H).[8] 13
C
NMR (DMSO-d6, 75 MHz): d 112.99, 114.00, 116.15, 132.51, 145.23, 150.24,
174.70. IR (cmꢁ1, KBr): 3515, 3105, 1614, 1570, 1471, 1392, 1342, 1292, 1078, 1040,
770. EI-MS (m=z): 260 (Mþ). HRESIMS calcd. for C13H8O4 [M ꢁ H]ꢁ 259.0243;
found 259.0248.

2958
X.-J. ZHANG ET AL.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (NSFC
Grant No. 21072231), National Foundation for Fostering Talents of Basic Science
(NFFTBS Grant no. J0630858), and the Innovation Program for College Students
in Jiangsu Province for financial support.
REFERENCES
1. El-Seedi, H. R.; Barbary, M. A.; El-Ghorab, D. M.; Bohlin, L.; Borg-Karlson, A.;
Go¨ransson, U.; Verpoorte, R. Recent insights into the biosynthesis and biological activi-
ties of natural xanthones. Curr. Med. Chem. 2010, 17, 854–901.
2. Piazzi, L.; Belluti, F.; Bisi, A.; Gobbi, S.; Rizzo, S.; Bartolini, M.; Andrisano, V.; Recanatini,
M.; Rampa, A. Cholinesterase inhibitors: SAR and enzyme inhibitory activity of
3-[x-(benzylmethylamino)alkoxy]xanthen-9-ones. Bioorg. Med. Chem. 2007, 15, 575–585.
3. Na, Y. Recent cancer drug development with xanthone structures. J. Pharm. Pharmacol.
2009, 61, 707–712.
4. Riscoe, M.; Kelly, J. X.; Winter, R. Xanthones as antimalarial agents: Discovery, mode of
action, and optimization. Curr. Med. Chem. 2005, 12, 2539–2549.
5. Zhang, Z. B.; Li, Z. C.; Tian, J.; Jiang, W.; Wang, Y.; Zhang, X. J.; Li, Z. R.; You, Q. D.;
Sharpiro, J. I.; Si, S. Y.; Xie, Z. J. Identification of hydroxyxanthones as Na=K-ATPase
ligands. Mol. Pharmacol. 2010, 77, 961–967.
6. Grover, P. K.; Shah, G. D.; Shah, R. C. Xanthones, part IV: A new synthesis of hydro-
xylxanthones and hydroxybenzophenones. J. Chem. Soc. 1955, 3982–3985.
7. Fatel, G. F.; Trivedi, K. N. A convenient synthesis of naturally occurring xanthones.
Synth. Commun. 1989, 19, 1641–1647.
8. Xiang, H. L.; Hu, G. Y.; Liu, P.; Chen, J.; Jia, S. J.; Chen, Z. Synthesis and antioxidant
activity of polyhydroxyxanthones and their derivatives. Chin. J. Med. Chem. 2005, 15,
207–211.
9. Evangelista, E. A.; Couri, M. R.; Alves, R. B.; Raslan, D. S.; Gil, R. P. Microwave-
assisted xanthone synthesis. Synth. Commun. 2006, 36, 2275–2280.
10. Santagada, V.; Frecentese, F.; Perissutti, E.; Fiorino, F.; Severino, B.; Caliendo, G.
Microwave-assisted synthesis: A new technology in drug discovery. Mini. Rev. Med.
Chem. 2009, 9, 340–358.
11. Cao, X.; You, Q. D.; Li, Z. Y.; Yang, Y.; Wang, X. J. Microwave-assisted simple syn-
thesis of substituted 4-quinolone derivatives. Synth. Commun. 2009, 39, 4375–4383.
12. Dallinger, D.; Kappe, C. O. Microwave-assisted synthesis in water as solvent. Chem. Rev.
2007, 107, 2563–2591.
13. Davies, J. S.; Scheinmann, F.; Suschitzky, H. 2,20,4-and 2,20,6-trihydrobenzophenone.
J. Org. Chem. 1958, 23, 307–308.
14. Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Koga, H. Studies on uricosuric diuretics, I:
Synthesis and activities of (xanthonyloxy)acetic acids and dihydrofuroxanthone-2-
carboxylic acids. Chem. Pharm. Bull. 1990, 38, 1266–1277.
15. Fernandes, E. G.; Silva, A. M.; Cavaleiro, J. A.; Silva, F. M.; Borges, M. F.; Pinto, M. M.
1H and 13C NMR spectroscopy of mono-, di-, tri-, and tetrasubstituted xanthones. Magn.
Reson. Chem. 1998, 36, 305–309.
16. Westerman, P. W.; Gunasekera, S. P.; Uvais, M.; Sultanbawa, S.; Kazlauskas, R.
Carbon-13 NMR study of naturally occurring xanthones. Org. Magn. Reson. 1977, 9,
631–636.