An unexpected tetracyclic product isolated during the synthesis of biscoumarins catalyzed by [MIM(CH2)4SO3H] [HSO4]: Characterization and X-ray crystal structure of 7-(2-hydroxy-4-oxo-4H-chromen-3-yl)-6H,7H-chro

Article abstract of DOI:10.1016/j.molliq.2011.08.007

Under solvent-free conditions and in the presence of 3-methyl-1-(4-sulfonic acid)butylimidazolium hydrogen sulfate [MIM(CH₂)₄SO ₃H][HSO₄], a Br?nsted acidic ionic liquid, the reaction of aromatic aldehydes with

Full text of DOI:10.1016/j.molliq.2011.08.007

Journal of Molecular Liquids 163 (2011) 122–127
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
An unexpected tetracyclic product isolated during the synthesis of biscoumarins
catalyzed by [MIM(CH ) SO H][HSO ]: Characterization and X-ray crystal structure
2
4
3
4
of 7-(2-hydroxy-4-oxo-4H-chromen-3-yl)-6H,7H-chromeno[4,3-b]chromen-6-one
a,
b
a
Niloofar Tavakoli-Hoseini ⁎, Majid M. Heravi , Fatemeh F. Bamoharram ,
a
c
Abolghasem Davoodnia , Mitra Ghassemzadeh
Department of Chemistry, Mashhad Branch, Islamic Azad University, Mashhad, Iran
Department of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2011
Received in revised form 1 August 2011
Accepted 16 August 2011
Available online 9 September 2011
Under solvent-free conditions and in the presence of 3-methyl-1-(4-sulfonic acid)butylimidazolium hydro-
gen sulfate [MIM(CH ) SO H][HSO ], a Brønsted acidic ionic liquid, the reaction of aromatic aldehydes
2 4 3 4
with 4-hydroxycoumarin has been investigated. A wide range of aromatic aldehydes easily undergoes con-
densation with 4-hydroxycoumarin to afford biscoumarins with good purity in excellent yields. However, re-
action of 2-hydroxybenzaldehyde with 4-hydroxycoumarin gave, not the corresponding biscoumarin, but a
tetracyclic compound, 7-(2-hydroxy-4-oxo-4H-chromen-3-yl)-6H,7H-chromeno[4,3-b]chromen-6-one, in
high yield.
Keywords:
Biscoumarins
4-Hydroxycoumarin
© 2011 Elsevier B.V. All rights reserved.
Ionic liquid
Unexpected product
Coumarins are a large group of heterocycles with diverse and in-
teresting biological activities. These compounds are reported to pos-
sess significant anticoagulant, insecticidal, antihelminthic, hypnotic,
antifungal, and HIV protease inhibition activities [1–3]. Biscoumarins,
the bridge substituted dimers of 4-hydroxycoumarin, have enormous
potential as anticoagulants [4,5]. A number of biscoumarins have also
been found to be urease inhibitors [6]. Recently, a number of methods
have been reported for the synthesis of biscoumarins by reaction of 4-
hydroxycoumarin and various aldehydes [7–12]. Although these
methods may be effective, some of them have relatively long reaction
times and unsatisfactory yields. This finding prompted us towards
further investigation in search for a new catalyst, which will carry
out the synthesis of biscoumarins under simpler experimental set
up and eco-friendly conditions.
functional groups into cations or anions of the ILs, especially the
SO H-functional groups, obviously enhanced their acidities and
water solubilities [17–19]. Therefore, Brønsted-acidic ILs can be
used as highly efficient acid catalysts and have been receiving exten-
3
2 4 3
sive interest as green substitute for H SO , HF and AlCl catalysts in
chemical processes [20]. In fact, the use of Brønsted-acidic ILs as cat-
alysts is an area of ongoing activity; however, development and ex-
ploration of Brønsted-acidic ILs are currently in the preliminary
stage. To the best of our knowledge, there are no examples of the
use of Brønsted-acidic ILs as catalyst for the synthesis of biscoumarin
derivatives.
Thus, in continuation of our previous works on the applications of
reusable acid catalysts in organic synthesis [21–29] we decided to in-
vestigate the synthesis of biscoumarins using 3-methyl-1-(4-sulfonic
Ionic liquids (ILs) are salt-type compounds, which are liquid at
room temperature and possessing low vapor pressure. Due to the
lack of evaporation, they are considered as promising “green sol-
vents” for replacing the volatile – therefore flammable and harmful
acid)butylimidazolium hydrogen sulfate [MIM(CH
Brønsted-acidic IL, as catalyst.
2 4 3 4
) SO H][HSO ], a
1. Experimental
–
conventional solvents. ILs are also known as environmentally be-
nign catalysts and much attention has currently been focused on
the organic reactions in the presence of these compounds as cata-
lysts or solvents [13–16]. The introduction of Brønsted-acidic
1.1. Chemicals and apparatus
All chemicals were available commercially and used without
additional purification. The Brønsted-acidic ionic liquid [MIM
(
2 4 3 4
CH ) SO H][HSO ] was synthesized according to the literature [30].
Melting points were recorded on a Stuart SMP3 melting point appara-
tus. The IR spectra were obtained using a Tensor 27 Bruker
⁎
Corresponding author. Tel.: +98 511 8435000; fax: +98 511 8424020.
E-mail address: niloofartavakoli@mshdiau.ac.ir (N. Tavakoli-Hoseini).
0167-7322/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molliq.2011.08.007

N. Tavakoli-Hoseini et al. / Journal of Molecular Liquids 163 (2011) 122–127
123
2 4 3 4
Scheme 1. Synthesis of biscoumarins catalyzed by [MIM(CH ) SO H][HSO ].
1
Table 1
spectrophotometer as KBr disks. The H NMR (500 MHz) spectra were
13
Synthesis of compound 3a in the presence of various amount of [MIM(CH
2
)
4
SO
3
H]
recorded with
a
Bruker DRX500 spectrometer. The
C NMR
a
[
HSO
4
] at different temperatures under solvent-free conditions .
(
125 MHz) spectrum was recorded with a Bruker DRX500 spectrom-
Entry
Catalyst (mol%)
T (°C)
Time/min
Yield/%b
eter. Mass spectrum was recorded with a FINNIGAN-MAT 8430 mass
spectrometer operating at an ionization potential of 70 eV. Elemental
1
2
3
4
5
6
7
8
9
None
5
10
15
5
10
15
20
5
10
15
120
60
60
60
80
80
80
80
120
30
20
15
15
10
8
10
15
10
10
Trace
51
67
74
67
84
92
93
71
analysis was performed with
microanalyzer.
a Thermo Finnigan Flash EA
1.2. General procedure for the synthesis of biscoumarins 3a-i and
compound 4
120
120
120
A mixture of an aromatic aldehyde (5 mmol), 4-hydroxycoumarin
10 mmol) and [MIM(CH SO H][HSO ] (15 mol%) without solvent
1
1
0
1
85
92
(
2
)
4
3
4
was heated on the oil bath at 80 °C for 18–30 min. The reaction was
monitored by TLC. After completion of the reaction, the reaction mix-
ture was cooled to room temperature and water was added. The pre-
cipitate was filtered off and recrystallized from ethanol to give
compounds 3a–i and 4 in high yields. The catalyst was recovered
from the filtrate by evaporation of the water and reused for the sim-
ilar reaction. The catalyst could be used at least three times with only
slight reduction in catalytic activity.
a
5
mmol benzaldehyde, 10 mmol 4-hydroxycoumarin.
b
Isolated yields.
Table 2
Synthesis of compound 3a in the presence of [MIM(CH
different solvents .
2
)
SO
4 3
H][HSO
4
] (15 mol%) in
a
Entry
Solvent
T (°C)
Time (min)
Yield (%)b
1
2
3
4
5
EtOH
MeOH
Reflux
Reflux
Reflux
Reflux
80
30
40
40
60
8
63
56
51
26
92
1
.3. Spectral and microanalytical data for compound 4
CH
CH
3
CN
Cl
1
2
2
H NMR (500 MHz, CDCl
H, arom-H), 7.23 (d, 1H, J=8.0 Hz, arom-H), 7.30–7.38 (m, 3H,
3
, δppm): 5.41 (s, 1H, CH), 7.10–7.20 (m,
Solvent-free
2
a
5
mmol benzaldehyde, 10 mmol 4-hydroxycoumarin.
Isolated yields.
arom-H), 7.40–7.50 (m, 2H, arom-H), 7.53 (td, J=7.5, 1.5 Hz, 1H,
arom-H), 7.67 (td, J=7.8, 1.5 Hz, 1H, arom-H), 8.07 (dd, J=7.9,
b
Table 3
[MIM(CH
2
)
SO
4 3
H][HSO
Ar
4
] catalyzed synthesis of biscoumarinsa.
Productb
Entry
Time
min)
Yield
(%)
mp °C
Found
Ref.
c
(
Reported
OH
O
OH
1
2
3
30
30
25
92
88
89
229–231
201–203
221–223
228–230
8
O
O
O
3
a
Cl
OH
OH
Cl
198–199
10
O
O
O
O
3
b
Cl
OH
O
OH
O
Cl
O
O
222–224
10
3
c
(continued on next page)

124
N. Tavakoli-Hoseini et al. / Journal of Molecular Liquids 163 (2011) 122–127
Table 3 (continued)
Entry
Ar
Productb
Time
min)
Yield
(%)
mp °C
Found
Ref.
c
(
Reported
Cl
OH
O
OH
O
4
Cl
25
93
261–263
258–259
11
O
O
3
d
N
O2
NO2
OH
O
OH
5
30
86
198–200
200–202
10
O
3
O
O
e
NO2
OH
O
OH
O
O N
2
6
20
89
214–215
212–215
10
O
O
3
f
NO2
OH
O
OH
O
7
O N
20
96
233–235
232–234
8
2
O
O
3
g
Me
OH
O
OH
O
8
Me
25
90
266–269
269–270
11
O
O
3
h
OMe
OH
O
OH
O
9
MeO
30
89
250–252
249–250
11
O
O
3
i
O
O
O
O
10
18
94
254–256
–
–
OH
O
O
H
4

N. Tavakoli-Hoseini et al. / Journal of Molecular Liquids 163 (2011) 122–127
125
Scheme 2. Reaction of 2-hydroxybenzaldehyde with 4-hydroxycoumarin.
1
1
1
1
1
3
2
.5 Hz, 1H, arom-H), 8.19 (dd, J=8.0, 1.5 Hz, 1H, arom-H), 10.43 (s,
H, OH); C NMR (125 MHz, CDCl , δppm): 30.41, 100.64, 109.09,
3
Furthermore, the same model reaction in presence of 15 mol% of
the catalyst was carried out at different solvents to assess the effect
of solvent on the reaction. As shown in Table 2, the yield of the reac-
tion under solvent-free conditions was greater and the reaction time
was generally shorter than the conventional methods.
In order to evaluate the generality of this model reaction, we pre-
pared a range of biscoumarin derivatives under optimized reaction con-
ditions. In all cases (except for 2-hydroxybenzaldehyde), aromatic
aldehydes with substituents carrying either electron-donating or
electron-withdrawing groups reacted successfully and gave the
expected products in excellent yields and short reaction times. The
type of aromatic aldehyde had no significant effect on the reaction.
The results are shown in Table 3. The structure of the products (3a–i)
was established from their IR spectral data and comparison of their
1
3
15.04, 116.68, 116.76, 117.27, 117.40, 121.82, 123.84, 124.29,
24.78, 125.44, 125.98, 128.96, 129.16, 132.37, 133.19, 151.40,
52.52, 153.50, 159.22, 161.59, 161.84, 166.58; IR (KBr disk): υ
419 (OH), 1717 (CO), 1689 (CO) cm−1; MS, m/z: 410 (M ), 289,
+
14 6
62, 249, 221, 165, 121, 92; Anal. calcd. for C25H O (410.37) (%):
C, 73.17; H, 3.44. Found (%): C, 74.01; H, 3.51.
. Results and discussion
The efficient synthesis of biscoumarins was achieved by con-
2
densation of aromatic aldehydes and 4-hydroxycoumarin in the pres-
ence of 3-methyl-1-(4-sulfonic acid)butylimidazolium hydrogen
sulfate [MIM(CH
Scheme 1).
MIM(CH
2
)
4
SO
3
H][HSO
4
], a Brønsted-acidic IL, as catalyst
melting points with those of authentic samples. Also, the structure of
some products was confirmed by H NMR spectral data.
1
(
[
2
)
4
SO
3
H][HSO
4
] was prepared according to the literature
When 2-hydroxybenzaldehyde was allowed to react with 4-
procedure [30]. Initially, the synthesis of compound 3a was selected
as a model reaction to optimize the reaction conditions. The reaction
was carried out by heating a mixture of benzaldehyde (5 mmol) and
hydroxycoumarin under optimized reaction conditions, surprisingly,
the product was isolated that its H NMR data did not show the for-
1
mation of biscoumarin 3j (Scheme 2). While three hydroxyl groups
1
1
4
-hydroxycoumarin (10 mmol) in the presence of various amount of
are expected in H NMR spectrum of compound 3j, the H NMR spec-
trum of the isolated product showed only one hydroxyl group at
10.43 ppm which was removed on deuteration. We thus turned our
attempt for the characterization of this compound by means of
other spectroscopic methods. The MASS spectrum of this compound
[MIM(CH SO H][HSO ] at different temperatures under solvent-
)
2 4
3
4
free conditions. As can be seen from Table 1, the shortest time and
best yield were achieved in the presence of 15 mol% of catalyst at
8
0 °C (Entry 7).
Notes to Table 3
a
5
mmol aromatic aldehyde, 10 mmol 4-hydroxycoumarin, 0.75 mmol (15 mol%) [MIM(CH
2 4 3 4
) SO H][HSO ] at 80 °C in solvent-free conditions.
b
The products 3a–i were characterized by IR spectral data and comparison of their melting points with those of authentic samples. Also, the structures of some of them were confirmed by
1
1
13
H NMR spectral data. The product 4 was characterized by IR, H NMR, C NMR and MASS spectral and microanalytical data and also by single crystal X-ray crystallography.
c
Isolated yields.

126
N. Tavakoli-Hoseini et al. / Journal of Molecular Liquids 163 (2011) 122–127
between two coumarin rings. However, for biscoumarin 3j, there are
three alternatives for cyclization process. Distinguishing between the
structures 4, 5 and 6 is not possible by MASS spectrum and microan-
alytical data.
13
The structure of the studied compound was finally proven by
C
1
3
NMR spectrum and X-ray analysis. 25 Signals in C NMR spectrum
show that all carbon atoms are nonequivalent that is in accordance
with structure 4. Also, an ORTEP representation of the structure has
been shown in Fig. 1. As depicted in this figure, this compound has
a tetracyclic structure containing two fused chromene rings along
with an chromene substituent at 7 position that clearly shows the
structure to be that of 4. Crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication CCDC 819933. Copies of
the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: 44 (0)1223 336033 or e-
mail: deposit@ccdc.cam.ac.uk).
Fig. 1. X-ray crystal structure of compound 4.
A plausible mechanism for the synthesis of biscoumarins and com-
pound 4 in the presence of [MIM(CH
ceed as depicted in Scheme 3.
2 4 3 4
) SO H][HSO ]≡HA may pro-
showed a molecular ion peak at m/z 410 which is in accordance with
a cyclization reaction by the removal of one water molecule from cor-
responding biscoumarin 3j. Indeed, this compound gave satisfactory
elemental analysis data corresponding to the molecular formula
Reusability of the catalyst was also investigated. For this purpose,
the same model reaction was again studied in the optimized condi-
tions. After the completion of the reaction, the reaction mixture was
cooled to room temperature and then water was added. The precipi-
tated solid was filtered off and the catalyst was recovered from the fil-
trate by evaporation of the water and reused for the similar reaction.
As it shown in Fig. 2, the catalyst could be used at least three times
with only slight reduction in catalytic activity.
25 14 6
C H O .
Synthesis and cyclization reaction of some biscoumarins have
been reported by Hamdi and co-workers [12]. Though, they did not
investigate the synthesis and cyclization reaction of biscoumarin 3j,
but in other cases, cyclization reactions have occurred by dehydration
2 4 3 4
Scheme 3. Plausible mechanism for the formation of biscoumarins and compound 4 in the presence of [MIM(CH ) SO H][HSO ]≡HA as catalyst.

N. Tavakoli-Hoseini et al. / Journal of Molecular Liquids 163 (2011) 122–127
127
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hydes with 4-hydroxycoumarin has been developed, which involves
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of the products, the short reaction times and ease of work up
make the method advantageous. However, reaction of 2-hydroxyben-
zaldehyde with 4-hydroxycoumarin gave, not the corresponding
biscoumarin, but a tetracyclic compound, 7-(2-hydroxy-4-oxo-4H-
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The authors are thankful to Islamic Azad University, Mashhad
3
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