A green and efficient synthesis of 9-aryl-3,4,5,6,7,9-hexahydroxanthene-1, 8-dione using a task-specific ionic liquid as dual catalyst and solvent

Article abstract of DOI:10.1071/CH06225

A green and efficient method for the preparation of 9-aryl-3,4,5,6,7,9- hexahydro-1H-xanthene-1,8(2H)-dione has been developed using functionalized ionic liquids as a catalyst and a reaction medium. The nature of both the counter anion and cation influenc

Full text of DOI:10.1071/CH06225

Communication
CSIRO PUBLISHING
Aust. J. Chem. 2007, 60, 146–148
www.publish.csiro.au/journals/ajc
A Green and Efficient Synthesis of 9-Aryl-3,4,5,6,7,9-
hexahydroxanthene-1,8-dione using a Task-Specific
Ionic Liquid as Dual Catalyst and Solvent
Jingjun Ma,A Xin Zhou,A Xiaohuan Zang,A Chun Wang,A,B Zhi Wang,A
Jingci Li,A and Qing LiA
ACollege of Sciences, Agricultural University of Hebei, Baoding 071001, China.
BCorresponding author. Email: wangc69@yahoo.com.cn
A green and efficient method for the preparation of 9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione has been
developed using functionalized ionic liquids as a catalyst and a reaction medium. The nature of both the counter anion
and cation influence the catalytic performance of the ionic liquids. The ionic liquid can be recycled and reused without
apparently loss of activity.
Manuscript received: 29 June 2006.
Final version: 21 December 2006.
Table 1. The condensation reaction of 4-cholorobenzaldehyde and
cyclohexane-1,3-dione in different ionic liquids
Reaction conditions: 1 mmol 4-chlorobenzaldehyde, 2 mmol cyclohexane-
1,3-dione, 1 mL ionic liquid
Due to environmental concerns, the development of environ-
mentally friendly catalysts and solvents for organic reactions
has received considerable attention in recent years. Recently,
room-temperature ionic liquids (RTILs) have been recognized
as a possible environmentally benign alternative to conven-
tional volatile organic solvents, and they have been investigated
extensively as solvents or catalysts for many important organic
reactions because of their special properties such as their negli-
gible vapour pressure, tunable polarity, high thermal stability,
good solvating ability, ease of recyclability, and their poten-
tial to enhance reaction rates and selectivity.[1,2] They have also
been referred as ‘designer solvents’, as their properties can be
altered by the fine tuning of parameters such as the choice of
organic cation, inorganic anion, and alkyl chain attached to the
organic cation. These structural variations offer flexibility to the
chemist to devise the most idealized solvent and catalyst for a
specific chemistry task. Task-specific ionic liquids, which have
a functional group in their framework, have been successfully
employed as efficient catalysts or dual catalyst–solvent for a
variety of reactions.[3–5]
Xanthene derivatives have attracted considerable attention
owing to their biological activity, being potent non-petidic
inhibitors of recombinant human calpain I.[6] In particular, xan-
thenedione derivatives constitute a structural unit in several
natural products[7] and they are valuable synthons because of the
inherent reactivity of the inbuilt pyran ring.[8] The conventional
synthetic methods of xanthenedione derivatives were carried out
in organic solvent. An improved reaction is the condensation
of aromatic aldehydes with 5,5-dimethylcyclohexane-1,3-dione
in water for 6 h using NH2SO3H and sodium dodecyl sulfate
(SDS) as catalyst.[9] It has also been reported that xanthene-
diones were prepared in glycol under microwave irradiation.[10]
Very recently, Fan et al. reported that the above condensation
process could proceed in ionic liquid [bmim]BF4 catalyzed by
Lewis acids InCl3[11] and FeCl3·6H2O,[12] respectively, in which
the reaction times were between 4 and 10 h. However, some of
Entry
RTIL
Temperature
[◦C]
Time
[min]
Isolated yield
[%]
1
2
3
4
5
6
7
8
9
[hmim]HSO4
[emim]HSO4
[bmim]HSO4
[bmim]H2PO4
[bmim]Br
[bmim]BF4
[bmim]PF6
[bmim]HSO4
[bmim]HSO4
80
80
80
80
80
80
80
30
30
30
30
60
60
60
30
30
83
81
84
37
Trace
Trace
Trace
21
Room temp.
100
93
these methods have not been entirely satisfactory, with disad-
vantages such as relatively long reaction times, using a catalyst
that cannot be recycled, and so on. Therefore, the development
of simple, efficient, and environmentally benign methods for the
synthesis of xanthenediones remains desirable.
As a continuation of our endeavor in green synthesis and
using ionic liquids as a recyclable, eco-friendly reaction medium
and catalyst,[13–15] herein we reported a simple and green
procedure for the preparation of 9-aryl-3,4,5,6,7,9-hexahydro-
1H-xanthene-1,8(2H)-dione 3 using task-specific acidic ionic
liquid as catalyst and reaction media.
In our initial research, 4-chlorobenzaldehyde was selected
as a representative reactant in order to optimize the reaction
conditions. As shown in Table 1, the reaction proceeded effi-
ciently in acidic ionic liquids [hmim]HSO4, [emim]HSO4, and
[bmim]HSO4 (entries 1–3). However, only moderate yields of
3e could be obtained when [bmim]H2PO4 was employed (entry
4). Attempts to perform the reaction in [bmim]Br, [bmim]BF4,
© CSIRO 2007
10.1071/CH06225
0004-9425/07/020146

Synthesis of 9-Aryl-3,4,5,6,7,9-hexahydroxanthene-1,8-dione Using Task-Specific Ionic Liquid
147
Table 2. Studies on the reuse of [bmim]HSO4 for the preparation of 3e
Table3. Synthesisof 9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione in acidic ionic liquid [bmim]HSO4
O
Ar
O
Round
Yield [%]
1
93
2
91
3
92
4
90
5
88
O
O
RTILs
ArCHO ϩ 2
O
1
2
3
and [bmim]PF6 (entries 5–7) led only to recovery of unreacted
starting material even at prolonged reaction time. These results
suggested that the Brønsted acidic ionic liquids play the dual
role of acidic catalyst and solvent. The catalytic activity of the
ionic liquids to the condensation reaction was dependent very
much upon the Brønsted acidity of the counter anion. The cat-
alytic performance of the ionic liquids with hydrogen sulfate
counter anion was much better than that of the other employed
ionic liquids under the same reaction conditions. Probably, this
is due to the high Brønsted acidity of the hydrogen sulfate
counter anion. According to the literature, the Hammett func-
tion (H0) of [bmim]HSO4 and [bmim]H2PO4 is 0.73 and 2.55,
respectively.[16] The catalytic performance of [emim]HSO4,
[bmim]HSO4, and [hmim]HSO4 were similar, indicating that the
low impact of the cation on the catalytic activity. [bmim]HSO4
was chosen for further study in this work. The Lewis acidic ionic
liquids, especially those based upon chloroaluminate anions, are
sensitive to moisture and unstable in water. However, the Brøn-
sted acidic ionic liquids with hydrogen sulfate as counter anion
are insensitive to moisture and stable in water, so they were easily
prepared and application without special operation conditions.
Effects of reaction temperature on the yields of the prod-
ucts were also studied by processing the condensation reac-
tion at room temperature, 80◦C, and 100◦C (entries 3, 8, 9,
respectively). The results shown that the higher the reaction
temperature, the more efficiently the reaction could proceed.
Since the recovery and reuse of catalyst and solvent are highly
preferable for a green process, we next investigated the reusabil-
ity and recycling of the ionic liquid. After completion of the
reaction, water was added into the reaction mixture, and the
solid was collected by filtration to give the product. The filtrate
containing [bmim]HSO4 was concentrated under reduced pres-
sure to recover the ionic liquid. The recycled [bmim]HSO4 was
reused in the model reaction of 1c and 2. The catalytic activ-
ity of [bmim]HSO4 did not show any significant decrease even
after five runs. The results were shown in Table 2. The results
also indicated that the acidic liquid employed was stable at the
reaction temperature.
Entry Ar
Time
[min]
mp [◦C] (lit.)
Yield
[%]
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
35
25
25
40
30
30
25
25
25
40
274–275 (270–271)[17]
204–206 (201–202)[17]
248–249 (250–251)[17]
286–287 (286–288)[17]
283–284 (289–291)[17]
284–285 (285–286)[17]
242–243 (245–246)[17]
258–260
85.3
92.3
93.6
90.1
93.3
93.3
92.2
91.1
88.2
84.6
4-CH3OC6H4
2-ClC6H4
3-NO2C6H4
4-ClC6H4
4-BrC6H4
4-HO-3-CH3OC6H3
4-HOC6H4
4-CH3C6H4
250–252
238–239
3j
3,4-(OCH2O)C6H3
Experimental
Materials and Instruments
Melting points were recorded on an electrothermal apparatus
and are uncorrected. H (400 MHz) and 13C NMR (100 MHz)
1
spectra were determined with a Bruker AVANCE 400 spec-
trometer (CDCl3) using TMS as internal standard. IR spectra
were measured with a BIO-RAD FTS3000 spectrometer. Mass
spectra were measured with a VG7070E spectrograph. Ele-
ment analyses were preformed on Perkin–Elmer 2400CHN
instrument. 1-n-Butyl-3-methylimidazolium tetrafluoroborate
([bmim]BF4), 1-hexyl-3-methylimidazolium hydrogen sulfate
([hmim]HSO4), 1-ethyl-3-methylimidazolium hydrogen sulfate
([emim]HSO4), 1-n-butyl-3-methylimidazolium hydrogen sul-
fate ([bmim]HSO4), 1-n-butyl-3-methylimidazolium dihydro-
genphosphate([bmim]H2PO4), 1-n-butyl-3-methylimidazolium
bromide ([bmim]Br), and 1-n-butyl-3-methylimidazolium hex-
afluorophosphate ([bmim]PF6) were prepared according to the
literature.[18,19]
General Procedure for the Preparation of Xanthenediones
A mixture of 1.0 mmol aromatic aldehydes 1, 2.0 mmol
cyclohexane-1,3-dione 2, and 1 mL [bmim]HSO4 were stirred
at 100◦C for a specified time (shown in Table 3) to complete
the reaction (monitored by TLC). After completion, water was
added into the reaction mixture and the resulting solid prod-
ucts were filtered off to afford the primary product. The pure
desired product, 9-aryl-3,4,5,6,7,9-hexahydro-1H-xanthene-
1,8(2H)-dione 3a–3j, was obtained by further recrystallization
with 80% ethanol. The results are summarized inTable 3. All the
A variety of substituted aromatic aldehydes were subjected to
the condensation reaction to study the substituted effects on the
reactivity of them. The results are summarized in Table 3. For
most of the substrates, the reaction was complete at 25–40 min
with high yields, whether the substrates bore electron-donating
or -withdrawing groups. However, when the aromatic aldehydes
with a bigger ortho-substituent, such as 2-nitrobenzaldehyde and
2,4-dinitrobenzaldehyde, were used the reaction could not take
place owing to the stereo effect.
1
known products 3a–3g were fully characterized by IR and H
In conclusion, the present synthetic method offers a
simple, efficient, and green synthesis of 9-aryl-3,4,5,6,7,9-
hexahydro-1H-xanthene-1,8(2H)-dione. The method offers
marked improvements with regard to operational simplicity,
reaction time, general applicability, high yields of products, and
greenness of the procedure, avoiding hazardous organic solvents
and toxic catalysts, so it provides a practical alternative to the
existing procedures. The application studies of the task-specific
ionic liquids for other reactions are in progress.
NMR spectroscopy, and melting points, which were consistent
with the literature data. The new compounds 3h–3j were iden-
tified by IR and 1H NMR spectroscopy, mass spectrometry, and
elemental analysis.
3h: δH (CDCl3, 400 MHz) 1.995–2.063 (m, 4H, CH2), 2.342–
2.398 (m, 4H, CH2), 2.592–2.704 (m, 4H, CH2), 4.844 (s, 1H,
CH), 7.124–7.160 (m, 1H, OH), 7.246 (d, J 7.6,ArH), 7.324 (d, J
7.6, 2H, ArH). νmax (KBr)/cm−1 3360, 2950, 1671, 1654, 1620,
1520, 1361, 1205, 1176, 1135, 956. m/z [%] 293 (M+ − 17, 100),

148
J. Ma et al.
276 (14), 216 (99), 77 (38), 55 (26). (Calc. for C19H18O4: C 73.5,
H 5.8. Found C 73.4, H 5.8.)
[5] A. L. Zhu, T. Jiang, D. Wang, B. X. Han, L. Liu, J. Huang, J. C. Zhang,
D. H. Sun, Green Chem. 2005, 7, 514. doi:10.1039/B501925G
[6] S. Chatterjee, M. Iqbal, J. C. Kauer, J. P. Mallamo, S. Senadhi,
S. Mallya, Bioorg. Med. Chem. Lett. 1996, 6, 1619. doi:10.1016/S0960-
894X(96)00286-7
[7] S. Hatakeyama, N. Ochi, H. Numata, S. Takano, Chem. Commun.
1988, 17, 1202, and references therein. doi:10.1039/C39880001202
[8] C. N. O’Callaghan, T. B. H. McMurry, J. Chem. Res. S 1995, 214.
[9] T. S. Jin, J. S. Zhang, A. Q. Wang, F. S. Zhang, Chin. J. Org. Chem.
2005, 25, 335.
3i: δH (CDCl3, 400 MHz) 1.995–2.056 (m, 4H, CH2), 2.28
(s, 3H, CH3), 2.335–2.391 (m, 4H, CH2), 2.583–2.660 (m, 4H,
CH2), 4.803 (s, 1H, CH), 7.054 (d, J 8.0, 2H, ArH), 7.214 (d, J
8.0, 2H, ArH). νmax (KBr)/cm−1 2954, 1658, 1619, 1510, 1423,
1361, 1200, 1176, 1124, 956. m/z [%] 308 (M+, 12), 307(48),
292 (68), 216 (100), 55 (20). (Calc. for C20H20O3: C 77.9, H
6.5. Found C 77.9, H 6.5.)
3j: δH (CDCl3, 400 MHz) 1.961–2.064 (m, 4H, CH2), 2.343–
2.411 (m, 4H, CH2), 2.581–2.689 (m, 4H, CH2), 4.757 (s, 1H,
CH), 5.896 (s, 1H, OCH2O), 6.676–6.820 (m, 3H, ArH). νmax
(KBr)/cm−1 2956, 1672, 1655, 1620, 1504, 1486, 1440, 1384,
1361, 1246, 1200, 1178, 1136, 1037, 956, 927. m/z [%] 338 (M+,
93), 321 (18), 308 (13), 282 (30), 252 (10), 217 (100), 55 (29).
(Calc. for C20H18O5: C 71.0, H 5.3. Found C 71.0, H 5.3.)
[10] S. J. Tu, Y. Gao, X. H. Liu, S. F. Tang, X. J. Qiu, Chin. J. Org. Chem.
2001, 21, 1164.
[11] X. S. Fan, X. Y. Hu, X. Y. Zhang, J. J. Wang, Can. J. Chem. 2005, 83,
16. doi:10.1139/V04-155
[12] X. S. Fan, Y. Z. Li, X. Y. Zhang, X. Y. Hu, J. J. Wang, Chin. J. Org.
Chem. 2005, 25, 1482.
[13] C. Wang, J. J. Ma, X. Zhou, X. H. Zang, Z. Wang,Y. J. Gao, P. L. Cui,
Synth. Commun. 2005, 35, 2759. doi:10.1080/00397910500288254
[14] G. S. Li, C. Wang, J. C. Li,Y. Q. Zhang, X. L. Li, Chin. J. Org. Chem.
2003, 23, 858.
[15] C. Wang,Y. Q. Zhang, G. S. Li, J. C. Li, X. L. Li, Chin. J. Org. Chem.
2003, 23, 1416.
[16] Y. L. Gu, J. Zhang, Z. Y. Duan, Y. Q. Deng, Adv. Synth. Catal. 2005,
347, 512. doi:10.1002/ADSC.200404316
[17] G. P. Hua, T. J. Li, S. L. Zhu, X. J. Zhang, Chin. J. Org. Chem. 2005,
25, 716.
[18] G. S. Owens, M. M. Abu Omer, J. Mol. Catal. Chem. 2002, 187, 215.
doi:10.1016/S1381-1169(02)00236-4
Acknowledgments
This work was financially supported by the Research Development Founda-
tion of Agricultural University of Hebei (no. 2004-20; no. 2005-18).
References
[1] T. Welton, Chem. Rev. 1999, 99, 2071. doi:10.1021/CR980032T
[2] J. Dupont, R. F. de Souza, P.A. Z. Suarez, Chem. Rev. 2002, 102, 3667.
doi:10.1021/CR010338R
[19] J. Fraga-Dubreuil, K. Bourahla, M. Rahmouni, J. P. Bazureau,
J. Hamelin, Catal. Commun. 2002, 3, 185. doi:10.1016/S1566-
7367(02)00087-0
[3] S. G. Lee, Chem. Commun. 2006, 10, 1049. doi:10.1039/B514140K
[4] B. C. Ranu, S. Banerjee, Org. Lett. 2005, 7, 3049. doi:10.1021/
OL051004H