Eco-friendly synthesis of 1,8-dioxo-octahydroxanthenes catalyzed by ionic liquid in aqueous media

Article abstract of DOI:10.1002/jhet.543

A biodegradable functionalized ionic liquid 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulfate ([DDPA][HSO₄]) was prepared and used as a Bronsted acid-surfactant-combined catalyst for the eco-friendly one-pot synthesis of 1,8-dioxo-octahydroxanthenes at 100°C in water. Under these conditions, the reaction of various aromatic aldehydes with dimedone generated 1,8-dioxo-octahydroxanthenes in good yields with a simple postreaction procedure. The products could simply be separated from the catalyst/water system, and the catalyst could be reused at least six times without noticeably decreasing the catalytic activity.

Full text of DOI:10.1002/jhet.543

468
Eco-Friendly Synthesis of 1,8-Dioxo-octahydroxanthenes
Catalyzed by Ionic Liquid in Aqueous Media
Vol 48
Dong Fang,a,b* Jin-Ming Yang,a and Zu-Liang Liub
aJiangsu Provincial Key Laboratory of Coast Wetland Bioresources & Environment Protection,
Yancheng 224002, People’s Republic of China
bSchool of Chemistry and Chemical Engineering, Yancheng Normal University, Yancheng 224002,
People’s Republic of China
*E-mail: fang-njust@hotmail.com
Received February 22, 2010
DOI 10.1002/jhet.543
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
A biodegradable functionalized ionic liquid 3-(N,N-dimethyldodecylammonium)propanesulfonic acid
hydrogen sulfate ([DDPA][HSO4]) was prepared and used as a Brønsted acid–surfactant-combined cata-
lyst for the eco-friendly one-pot synthesis of 1,8-dioxo-octahydroxanthenes at 100ꢀC in water. Under
these conditions, the reaction of various aromatic aldehydes with dimedone generated 1,8-dioxo-octahy-
droxanthenes in good yields with a simple postreaction procedure. The products could simply be sepa-
rated from the catalyst/water system, and the catalyst could be reused at least six times without
noticeably decreasing the catalytic activity.
J. Heterocyclic Chem., 48, 468 (2011).
INTRODUCTION
times, harsh reaction conditions, toxicity, and difficulty
in postprocedure of product separation. Because of these
drawbacks, the synthetic approaches have been
improved by the condensation of aromatic aldehydes
and active methylene carbonyl compounds in the pres-
ence of the catalysts, such as p-dodecylbenzenesul-
phonic acid [3], p-toluenesolfonic acid [4], Fe3þ-mont-
morilonite [5], NaHSO4-SiO2 or silica chloride [6],
Amberlyst-15 [7], silica sulfuric acid [8], trichloroiso-
cyanuric acid [9], (NH4)2HPO4 [10], Dowex-50W [11],
SbCl3/SiO2, cyanuric chloride and BiCl3 [12],
ZrOCl2ꢁ8H2O [13], and HPWA/MCM-41[14]. Addition-
ally, these compounds could also be obtained with the
assistance of microwave [15] or ultrasound irradiation
[16]. However, the search for the new readily available
and green catalysts is still being actively pursued.
1,8-Dioxo-octahydroxanthenes are an important class
of heterocyclic compounds which have been found as a
substructure in a large number of naturally occurring
molecules. Because of their biological activity, 1,8-
dioxo-octahydroxanthenes and their derivatives occupy a
prominent position in medicinal chemistry [1]. These
heterocyclic compounds have also been investigated for
agricultural bactericide activity, anti-inflammatory
effect, and antiviral activity. Additionally, 1,8-dioxo-
octahydroxanthenes have been used as versatile synthons
because of their inherent reactivity of the inbuilt pyran
ring [2]. Various methods have been reported for the
synthesis of these compounds catalyzed mainly by or-
ganic and mineral acids; however, these methods often
suffer from the disadvantages such as long reaction
C
V
2010 HeteroCorporation

March 2011
Eco-Friendly Synthesis of 1,8-Dioxo-octahydroxanthenes Catalyzed
by Ionic Liquid in Aqueous Media
469
Scheme 1
RESULTS AND DISCUSSION
The biodegradable surfactant zwitterionic-type precur-
sor (N,N-dimethyl-N-dodecylammonium propane sulfo-
nate) was prepared through a one-step direct sulfonation
reaction of N,N-dimethyl-N-dodecyl amine and 1,3-pro-
panesulfone. The zwitterions acidification was accom-
plished by mixing of zwitterions with sulfuric acid
(98%, aq.) to convert the pendant sulfonate group into
[DDPA][HSO4] (Scheme 1). The chemical yields for
both the biodegradable zwitterions formation and acidifi-
cation steps were essentially quantitative as neither reac-
tion produced byproducts, the [DDPA][HSO4] synthesis
ꢂ
was 100% atom efficient. The fresh new IL with HSO4
anion is somewhat viscous colorless liquid at room tem-
perature and entirely miscible with water and soluble or
partly soluble in organic solvents.
Nowadays ionic liquids (ILs) have attracted much in-
terest as excellent alternatives to organic solvents due to
their favorable properties. Functionalized ionic liquids
(FILs), which possess the advantageous characteristics
of solid acids and mineral acids, are designed to be used
as novel catalysts in organic synthesis. The use of ILs
as reaction medium/catalysts may offer a convenient so-
lution to both the solvent emission and catalytic recy-
cling problem. Some researchers have already used ILs
as solvents/catalyst for condensation reactions [17]. Fan
et al. [17a] used InCl3ꢁ4H2O and Wang and coworkers
[17b] used NaHSO4 in IL 1-butyl-3-methylimidazolium
tetrafluoroborate ([bmim]BF4) for the synthesis of 1,8-
dioxo-octahydroxanthenes via condensation of aromatic
aldehydes with 1,3-cyclohexanedione. Dabiri et al. [17c]
used acidic IL 1-methlyimidazolium triflouroacetate
([Hmim]TFA) as an efficient reusable catalyst for the
synthesis of these compounds. Srinivasan and coworkers
[16b] reported an efficient method promoted by acidic
IL [Hbim]BF4 under ultrasound irradiation. In fact, the
use of task specific ionic liquids (TSILs) as catalysts is
an area of ongoing activity; however, the development
and exploration of Brønsted-acidic TSILs are currently
in the preliminary stage. To date, research of some
‘‘greener’’ halogen-free ILs with phosphate or octyl sul-
fate anions and the effects of the anion and toxicology
have appeared in literature [18]. Thus, it is necessary to
synthesize less expensive and halogen-free TSILs, which
can also be used straightforwardly with the simple
procedure.
In the initial catalytic activity experiments (Scheme
2), 4-hydroxybenzaldehyde and dimedone were used as
the model reactants at reflux in different solvents as
reaction media (Table 1). As shown that the reaction
could proceed effectively in water and organic solvents,
including C2H5OH, CH3CN, CHCl3, CH2Cl2, C6H12,
C6H6 (entries 3–9), and [DDPA][HSO4]/H2O, was found
to be the most effective catalyst system and gave the
highest yield of 94% (entry 2) among the solvents
selected. However, in case of [DDPA][HSO4]/solvent-
free catalyst system, only the noncyclodehydrated
intermediate 9-(4-hydroxyphenyl)-3,3,6,6-tetramethy-3,4,
5,6,7,9-hexahydro-H-xanthene-1,8(2H)-dione 3a was ob-
tained with a high yield of 95% (entry 1), furthermore,
4a could be obtained when water or organic solvents
were added to 3a and stirred for 1 h at reflux conditions.
It indicated that the solubility of reactants and catalyst
in the solvent could effect the cyclodehydration step of
the intermediate 3a to afford 1,8-dioxo-octahydroxan-
thenes. The [DDPA][HSO4] could not disperse and con-
tact efficiently with the reactant under solvent-free con-
dition, which hinders the conversion of 3a to 4a in the
cyclodehydration reaction.
Scheme 2
In our previous work, some novel and efficient func-
tionalized halogen-free acidic ILs have been designed
and synthesized for eco-friendly synthesis in aqueous
media [19]. In continuation of our work in studying
acid-catalyzed reactions in IL-water system, we report
here the synthesis of 1,8-dioxo-octahydroxanthenes via
one-pot condensation of aldehydes and dimedone in the
halogen-free acidic IL 3-(N,N-dimethyldodecylammo-
nium)propanesulfonic acid hydrogen sulfate ([DDPA]
[HSO4]).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

470
D. Fang, J.-M. Yang, and Z.-L. Liu
Vol 48
Table 1
Table 3
Reusing of the ionic liquid [DDPA][HSO4].a
Influence of the catalytic system of [DDPA][HSO4]/solvent
on 1,8-dioxo-octahydroxanthenes.a
Entry
Run
Isolated yield of 4a (%)
Isolated
yield (%)
1
2
3
4
5
6
7
Fresh
94
93
93
92
91
91
90
1
2
3
4
5
6
Entry
Catalyst/Solvent
4
3
1
2
3
4
5
6
7
8
9
[DDPA][HSO4]/solvent free
[DDPA][HSO4]/H2O
/
95b
94
76
85
87
83
80
78
82
/
/
/
/
/
/
/
/
[DDPA][HSO4]/C2H5OH
[DDPA][HSO4]/CH3CN
[DDPA][HSO4]/CHCl3
[DDPA][HSO4]/CH2Cl2
[DDPA][HSO4]/C6H12
[DDPA][HSO4]/C6H6
a 5 mmol 4-hydroxybenzaldehyde, 10 mmol dimedone, 0.5 mmol
[DDPA][HSO4], 100ꢀC, 1.0 h.
[DDPA][HSO4]/C6H5CH3
indicated that the catalysts should be absolutely neces-
sary for this condensation. Varying the percentage of
the catalyst showed that 10 mol % of [DDPA][HSO4]
was optimum (entry 5), the use of larger amounts of
catalyst did not improve yields, whereas decreasing the
amounts of [DDPA][HSO4] decreased yields. Furthermore,
the effect of reaction temperature on the condensation
was also investigated and the optimum temperature was
100ꢀC. It is noteworthy that the reaction did not go to
completion and only noncyclodehydrated 3a was
obtained at room temperature for 6 h (entry 8).
a 5 mmol 4-hydroxybenzaldehyde, 10 mmol dimedone, 0.5 mmol
[DDPA][HSO4], reflux, 1 h.
b The reaction was carried out at 100ꢀC.
The chemical industry is under extensive pressure to
replace many of the volatile organic compounds that are
currently used as solvents in organic synthesis. For over-
coming these problems, one approach is to use the water
as the green medium, another approach is to develop
new processes involving the solvent-free conditions. For
the environmental and economic reasons, the
[DDPA][HSO4]/H2O was then used as catalytic system
with the above same model reaction to optimize the
reaction condition. As shown in Table 2, no desirable
product could be detected when a mixture of 4-hydroxy-
benzaldehyde and dimedone was heated at 100ꢀC for 6
h in the absence of [DDPA][HSO4] (entry 1), which
When optimizing the reaction condition, the recycling
performance of [DDPA][HSO4] was investigated using
the above same model reaction. After the separation of
the produced 4a, the catalyst-containing filtrate was
reused in the next run without further purification. The
data listed in Table 3 showed that the [DDPA][HSO4]
could be reused at least six times without obviously
decreasing the catalytic activity. Compared with the tra-
ditional solvents and catalysts, the easy recycling per-
formance is also an attractive property of this IL for the
environmental protection and economic reasons.
Table 2
Then, the condensation reaction of structurally varied
aldehydes with dimedone in the presence of [DDPA]
[HSO4] as an environment catalyst was explored under
the optimized reaction conditions described above and
the results are presented in Table 4.
Synthesis of 1,8-dioxo-octahydroxanthenes
under different conditions.a
TSILs
T
Time Yields
(%)c
Entry
Catalyst
(mol %)b (ꢀC)
(h)
It can easily be seen that in all cases, the reactions
gave the products not only in good yields ranged from
87 to 95%m but also in excellent selectivity of 4a–l. Ar-
omatic aldehydes carrying either electron-donation or
electron-withdrawing substituents afforded good yields
of 1,8-dioxo-octahydroxanthenes in high purity, addi-
tionally, and ortho-, meta- and para-substituted sub-
strates reacted almost equally well, although orthogroup
(entry 3) has steric hindrance.
1
2
3
4
5
6
7
8
9
10
–
–
100
100
100
100
100
100
100
r.t.
6.0
6.0
4.5
1.5
1.0
1.0
1.0
6.0
4.0
1.0
–
90
92
92
94
94
94
72d
79
84
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
[DDPA][HSO4]
4
6
8
10
12
15
10
10
10
50
80
a 5 mmol 4-hydroxybenzaldehyde, 10 mmol dimedone, water is used
as a solvent.
The results obtained with benzaldehyde and dimedone
under the optimized conditions were compared with the
results of other catalysts reported in the literatures, the
data listed in Table 5 showed that the [DDPA][HSO4]
b Molar ration of [DDPA][HSO4] to benzaldehyde.
c Isolated yields of 4a.
d Isolated yields of 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Eco-Friendly Synthesis of 1,8-Dioxo-octahydroxanthenes Catalyzed
by Ionic Liquid in Aqueous Media
471
Table 4
Synthesis of 1,8-dioxo-octahydroxanthenes catalyzed by [DDPA][HSO4].a
Entry
Ar
Product
Time (h)
mp (ꢀC) [Lit]
Yields (%)b
1
2
p-HOC6H4
p-FC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.0
1.0
1.0
1.0
1.5
1.0
1.0
1.5
2.0
1.0
1.0
1.0
245–247 [5]
223–225 [15]
226–228 [5]
230–232 [5]
231–233 [15]
146–117 [15]
221–223 [5]
212–214 [5]
235–237 [5]
198–200 [5]
159–161 [12b]
200–202 [12b]
94
95
94
96
87
97
95
94
95
93
88
87
3
4
o-ClC6H4
p-ClC6H4
p-BrC6H4
5
6
7
m-NO2C6H4
p-NO2C6H4
8
9
p-CH3C6H4
p-CH3OC6H4
10
11
12
C6H5
Thiophene-2-carbaldehyde
Pyridine-2-carbaldehyde
4j
4k
4l
a 5 mmol benzaldehyde, 10 mmol dimedone, 0.5 mmol [DDPA][HSO4], 100ꢀC.
structure of [DDPA][HSO4] was analyzed by 1H-NMR, ele-
mental analyses, and MS spectral data (Scheme 1).
was relatively a good catalyst for this reaction, addition-
ally, this catalyst was biodegradable.
To a solution of 13.3 g N, N-dimethyl-N-dodecyl amine
(0.10 mol) in 30 mL 1,2-dichloroethane was added 12.2 g
1,3-propanesultone (0.10 mol) in portion within 15 min, and
then the mixture was stirred under nitrogen for 2 h at 55–
60ꢀC. When cooled to room temperature, a white precipitate
thus formed was then filtered and washed with petroleum
ether. The product was refined from a mixture of water, etha-
nol, and ether, 98% yield of white solid product was
obtained, mp 320–322ꢀC (decomposing) with darkening at
300ꢀC.
In conclusion, a Brønsted acid–surfactant-combined
IL DDPA][HSO4] was synthesized in an atom-economic
procedure. The [DDPA][HSO4] was found to be an effi-
cient catalyst for one-pot synthesis of 1,8-dioxo-octahy-
droxanthenes in aqueous media, offering the practical
convenience in the product separation from the catalytic
system. The merit of this methodology is that it is sim-
ple, mild, and efficient and has potential application in
green chemistry.
The mixture of 13.3 g N, N-dimethyl-N-dodecylammonium
propane sulfonate (0.10 mol) and 10.0 g sulfuric acid solutions
(98%; 0.10 mol) was stirred for 2 h at 80ꢀC. Then, the com-
bined solution was dried in a vacuum at 100ꢀC. The produced
[DDPA][HSO4] was washed repeatedly with diethyl ether to
remove unreacted material and dried in a vacuum again, and
then the [DDPA][HSO4] was obtained quantitatively and in
high purity as colorless oil.
The selected spectral data for SO3H-functionalized halogen-
free [DDPA][HSO4]: [DDPA][HSO4] 1H-NMR (300 MHz,
D2O): d 0.53 (t, 3H, J ¼ 6.62 Hz, ACH3), 0.95–1.02 (m, 18H,
A(CH2)9A), 1.42 (m, 2H, ACACH2ACAN), 1.83–1.87 (m,
EXPERIMENTAL
Melting points were determined on an X-6 microscope melt-
ing apparatus and reported uncorrected. The IR spectra were
run on a Nicolete spectrometer and expressed in cmꢂ1 (KBr).
1H-NMR spectra were recorded on a Bruker DRX300 (300
MHz) and 13C-NMR spectra on a Bruker DRX300 (75.5 MHz)
spectrometer. Elemental analyses were recorded on Perkin-
Elmer C apparatus. Mass spectra were obtained with an auto-
mated Finnigan Trace Ultra-Trace DSQ LC-MS spectrometer.
2H, ACACH2ACASO3), 2.60 (t, 2H,
J
¼
6.91 Hz,
All chemicals (AR grade) were commercially available and
used without further purification.
Synthesis of acidic halogen-free acidic ionic liquid
([DDPA][HSO4]). The FIL [DDPA][HSO4] was prepared
according to our previous work with some changes [16]. The
ACH2ASO3), 2.77 (s, 6H, NACH3), 2.98 (t, J ¼ 7.95 Hz, 2H,
ACACH2AN), 3.14 (t, J ¼ 8.25 Hz, 2H, ACH2ACACASO3).
Anal. Calcd. For CHNOS: C, 47.09; H, 9.07; N, 3.23; Found:
C, 46.82; H, 9.08; N, 3.09. MS (m/z): 432.18 (Mþ ꢂ 1).
Table 5
Condensation reaction with different catalystic system.
Entry
Catalyst/Solvent
T (ꢀC)
Time (h)
Yields (%)
Ref.
1
2
3
4
5
6
[DDPA][HSO4]/H2O
Fe3þ-montmorillonite
Cyanuric chloride
BiCl3
100
100
120
80
80
80
1.0
6.0
50 min
3.0
4.0
93
94
92
90
87
85
This worka
[5]
[12b]
[12c]
[17a]
InCl3ꢁ4H2O/[bmim]BF4
[Hmim]TFA
3.0
[17c]
a 5 mmol benzaldehyde, 10 mmol dimedone, 0.5 mmol [DDPA][HSO4], 100ꢀC, 1.0 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

472
D. Fang, J.-M. Yang, and Z.-L. Liu
Vol 48
[7] Das, B.; Thirupathi, P.; Mahender, I.; Reddy, V. S.; Rao, Y.
K. J Mol Catal A: Chem 2006, 247, 233.
General procedure for 1,8-dioxo-octahydroxanthenes cat-
alyzed by [DDPA][HSO4]. To round-bottomed flask
charged with aldehyde (5 mmol) 1, 5,5-dimethyl-1,3-cyclohex-
anedione (dimedone) in mL of water was added
[DDPA][HSO4] (0.5 mmol) under stirring. The mixture was
then stirred for a certain time at 100ꢀC. On completion (moni-
tored by thin layer chromatography), the precipitated crude
product was collected by filtration and recrystallized form
ethanol (95%) to afford pure 1,8-dioxo-octahydroxanthenes 4.
The filtrate containing the catalyst could be reused directly in
the next run without further purification. The products were
identified by IR, 1H-NMR, and physical data (mp) with those
reported in the literatures (Table 4).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet