A novel sulfonic acid functionalized ionic liquid catalyzed multicomponent synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives in water

Article abstract of DOI:10.1016/j.tetlet.2011.03.059

Three-component reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl compounds were prompted by novel sulfonic acid functionalized ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl)imidazolidine-1,3-diium hydrogen sulfate ([DMDBSI]·2HS

Full text of DOI:10.1016/j.tetlet.2011.03.059

Tetrahedron Letters 52 (2011) 2601–2604
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Tetrahedron Letters
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A novel sulfonic acid functionalized ionic liquid catalyzed multicomponent
synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
derivatives in water
⇑
Zhiwei Chen, Qiang Zhu, Weike Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three-component reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl compounds
were prompted by novel sulfonic acid functionalized ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobu-
tyl)imidazolidine-1,3-diium hydrogen sulfate ([DMDBSI]Á2HSO4) in water at reflux temperature to pro-
vide a novel series of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives for the
first time in high yields.
Received 14 February 2011
Revised 3 March 2011
Accepted 14 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Sulfonic acid functionalized ionic liquids
1,3-Dimethyl-2-oxo-1,3-bis(4-
sulfobutyl)imidazolidine-1,3-diium
hydrogen sulfate ([DMDBSI]Á2HSO4)
10,11-Dihydrochromeno[4,3-b]chromene-
6,8(7H,9H)-dione derivatives
Multicomponent reactions (MCRs) are important in organic and
medicinal chemistry.1 Also in combinatorial chemistry, they are
predicted to exhibit negative activation volumes owing to the con-
densation of several molecules into a single reactive intermediate
and product, thus avoiding complicated purification operations
and allowing savings of both solvents and reagents.2
and cyclic 1,3-dicarbonyl compounds to provide a novel series of
coumarin derivatives12 (Scheme 1).
Recently, sulfonic acid functionalized ionic liquids received
great attention due to their unique properties like environmental
compatibility, reusability, greater selectivity, and ease of isolation.
They are used as dual solvent-catalyst13 for several organic reac-
tions, such as esterification,14 alkylation,15 nitration of aromatic
compounds,16 hydrolysis,17 and heterocyclic synthesis, such as
Fisher indole synthesis,18 and Friedlander quinoline synthesis.19
As part of our ongoing interest in green chemistry and task specific
ionic liquids (TSILs) catalyzed organic reactions, we synthesized a
novel SO3H-functional Brønsted-acidic halogen-free TSILs that bear
two butane sulfonic acid groups in 1,3-dimethyl-2-oxoimidazoli-
dine-1,3-diium cation21 (Scheme 2). As a mild, highly efficient,
and environmentally benign catalyst, [DMDBSI]Á2HSO4 has been
successfully applied to perform the three-component reaction of
4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl com-
pounds (Scheme 3).
The coumarin derivatives have received considerable attention
because they possess several types of pharmacological properties,
such as antibacterial, anticancer, anti-HIV, anticoagulant, antioxi-
dant, and spasmolytic activities.3 Recently, several methods have
been reported for synthesis of coumarin derivatives because of
its enormous biological and industrial importance. They have been
synthesized by one-pot three-component condensation of
4-hydroxycoumarin, aldehydes, and meldrum’s acids or malono-
nitrile or
a
-cyanocinnamonitriles in the presence of [bmim]OH,4
HPAs,5 TMGT,6 MgO,7 DAHP,8 TBAB,9 DBU,10 KAl(SO4)2Á12H2O.11
Most of the methods have their own merits. However, these proce-
dures described the synthesis of only a narrow range of coumarin
derivatives and also suffered from using of expensive catalyst, long
reaction times, low yield, and poor selectivity or commercial
unavailability. To the best of our knowledge, there are few reports
on three-component coupling of 4-hydroxycoumarin, aldehydes
At the onset of our work, 4-hydroxycoumarin (1a), benzalde-
hyde (2a), and 5,5-dimethylcyclohexane-1,3-dione (3a) were em-
ployed as the model reactions in the presence of different
catalysts to compare the catalytic performance in EtOH. It should
be mentioned that besides (4a), a noticeable amount of (5a) was
also obtained (Scheme 3).
As shown in Table 1, the yield of the desirable product 4a was
low and 5a was also obtained in 42% yield when these three
⇑
Corresponding author. Tel./fax: +86 571 88320752.
E-mail address: pharmlab@zjut.edu.cn (W. Su).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.059

2602
Z. Chen et al. / Tetrahedron Letters 52 (2011) 2601–2604
R2 R2
used, and proved to be very active, leading to 84–87% yield of 4a
in the presence of 10% TSILs (Table 1, entries 6–9). In addition,
the TSILs that bore two butane sulfonic acid groups in 1,3-di-
methyl-2-oxoimidazolidine-1,3-diium cation with two HSOÀ4 anion
were used in this three-component reaction, it gave a yield of 91%
(Table 1, entry 10). Hence, [DMDBSI]Á2HSO4 should be the best
catalyst for this multicomponent reaction.
O
O
O
R1
O
Next, we investigated the appropriate loading amount of cata-
lyst. It was found that 10 mol % of [DMDBSI]Á2HSO4 was enough
to promote the reaction efficiently (Table 1, entry 12). Different or-
ganic solvents, such as DMF, CH2Cl2, CH3CN were used, which
afforded 4a in moderate yields (Table 1, entries 16–19). We extre-
mely expected the reaction to perform in aqueous media, the result
was satisfactory (Table 1, entry 20). H2O was a better solvent than
the others tested. Moreover, solvent-free condition was also exam-
ined, and viscous reaction system and the yield was low (Table 1,
entries 21 and 22).
In order to investigate the possibility of recycling this TSILs
[DMDBSI]Á2HSO4, a recycling experiment was conducted using
the above mentioned model reaction. After the separation of the
products, the ILs-containing filtrate was reused in the next run
without further purification. The TSILs as catalysts for multi-
component reaction could be reused at least five times without
the apparent loss of catalytic activity (yield: 93%, 93%, 92%, 90%,
90%). The subsequent study was performed under the optimized
conditions: with 10 mol % [DMDBSI]Á2HSO4 in H2O at reflux, as de-
scribed in Scheme 4.22 Most of the corresponding products, 10,11-
dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives 4,
Scheme 1. 10,11-Dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-diones.
O
O
CH3CN,reflux
N
N
O
O
S
N
N
SO3
O3S
N
O
O
2HSO4
H2SO4
C2H5OH
N
SO3H
HO3S
Scheme 2. Synthesis of ionic liquid [DMDBSI]Á2HSO4.
components were heated at reflux for 6 h in the absence of catalyst
(Table 1, entry 1). To minimize the formation of 5a and improve
the yield of 4a, PTSA, trifluoro methanesulfonate and DBU were
undertaken (Table 1, entries 2–5). The yields were improved but
the selectivity was also poor. Some other TSILs that bore butane
sulfonic acid groups in different cations with HSOÀ4 anion20 were
OH
O
OH
O
O
O
O
OH
O
CHO
cat.
solvent,reflux
O
O
O
O
O
1a
2a
5a
3a
4a
Scheme 3. Reaction of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl compounds under different conditions.
Table 1
Synthesis of 10,10-dimethyl-7-phenyl-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione 4a under different conditionsa
Entry
Catalysts
Loading (mol %)
Solvents
Time (h)
Yieldb (%)
4a
5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
—
PTSA
Y(OTf)3
Zn(OTf)2
—
10
10
10
10
10
10
10
10
10
5
10
15
20
50
10
10
10
10
10
10
—
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
6
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
40
56
72
75
69
85
84
84
87
91
86
91
90
91
90
81
43
55
60
93
31
59
42
35
20
19
DBU
25
[TMBSA]ÁHSO4
[PyBSA]ÁHSO4
[MIMBSA]ÁHSO4
[NMPBSA]ÁHSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]ÁHSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
[DMDBSI]Á2HSO4
—
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
20
18
15
Trace
6
10
CH2Cl2
CH3CN
THF
H2O
—
[DMDBSI]Á2HSO4
a
2 mmol 4-hydroxycoumarin, 2 mmol benzaldehyde, 2 mmol 5,5-dimethylcyclohexane-1,3-dione was carried out at reflux.
Isolated yields based on 1a.
b

Z. Chen et al. / Tetrahedron Letters 52 (2011) 2601–2604
2603
R2 R2
R2 R2
OH
O
O
O
[DMDBSI] 2HSO4
R1
R1 CHO
H2O, reflux
O
O
O
O
O
1
2
3
4
Scheme 4. [DMDBSI]Á2HSO4 catalyzed condensation of 4-hydroxycoumarin, aldehydes and cyclic 1,3-dicarbonyl compounds.
Table 2
the first report on the synthesis of 10,11-dihydrochromeno[4,3-
b]chromene-6,8(7H,9H)-dione derivatives.
[DMDBSI]Á2HSO4 promoted synthesis of 10,11-dihydrochromeno[4,3-b]chromene-
6,8(7H,9H)-dione derivatives in H2O at refluxa
Entry
R1
R2
Time (h)
Product
Yieldb (%)
Acknowledgments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Ph
2-ClC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
93
88
87
90
91
90
89
92
90
90
91
92
89
88
90
78
79
92
89
92
91
93
90
89
90
79
4.5
4.5
3.5
3.5
3
3
3
3
4
We are grateful to the National Natural Science Foundation of
2-MeOC6H4
3-MeOC6H4
3-OHC6H4
3-NO2C6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
3,4-(Me)2C6H3
2-F-6-ClC6H3
2,4-(Cl)2C6H3
3-MeO-4-OHC6H3
Furan-2-yl
Thiophene-2-yl
CH3CH2
CH3CH2CH2
Ph
2-ClC6H4
3-MeOC6H4
3-NO2C6H4
4-ClC6H4
3-MeO-4-OHC6H3
2,4-(Cl)2C6H3
Thiophene-2-yl
CH3CH2
China
(20876147), Zhejiang Natural Science Foundation
(Y4090346) for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.059.
4
4
3.5
3.5
3.5
4.5
4.5
3.5
4
3
3
3
4
References and notes
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4s
4t
4u
4v
4w
4x
4y
4z
4
3.5
4.5
a
All reactions were carried out on a 2 mmol 4-hydroxycoumarin with 2 mmol
aldehydes, and 2 mmol cyclic 1,3-dicarbonyl compounds in the presence of
0.2 mmol [DMDBSI]Á2HSO4 in H2O (3 mL) at reflux.
b
Isolated yields based on 1a.
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were obtained in good yields, as shown in Table 2. It was observed
that the protocol tolerated both electron donating and electron
withdrawing groups on phenyl. When phenyl was replaced with
furan-2-yl, or thiophene-2-yl the corresponding product was ob-
tained in high yields. But when aliphatic aldehydes, such as propi-
onaldehyde and butyraldehyde were used in this protocol under
the same conditions, it led to a slight decrease in the yields due
to the incomplete reaction of raw materials. Cyclic 1,3-dicarbonyl
compounds with a substituent R2 being substituted of methyl
and hydrogen similarly obtained the corresponding products in
satisfying yields.
In conclusion, a convenient and environmentally green method-
ology for the synthesis of 10,11-dihydro-chromeno[4,3-b]chro-
mene-6,8(7H,9H)-dione derivatives via the three-component
reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicar-
bonyl compounds has been developed. The attractive features of
this protocol are simple reaction procedure, short reaction time,
easy product separation, and purification, reusability of acidic ionic
liquid [DMDBSI]Á2HSO4, and its adaptability synthesis of a broad
range of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-
dione derivatives in moderate to high yields. To the best of our
knowledge, the catalyst [DMDBSI]Á2HSO4 was synthesized and
used in multi-component reactions for the first time, and this is
19. Akbari, J.; Heydari, A.; Kalhor, H. R.; Kohan, S. A. J. Comb. Chem. 2010, 12, 137.
20. Fang, D.; Gong, K.; Liu, Z. L. Catal. Lett. 2009, 127, 291.
21. Synthesis of 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl) imidazolidine-1,3-diium
hydrogen sulfate ([DMDBSI]Á2HSO4): To
a solution of 1,3-dimethyl-2-
imidazolidinone (10 mmol) in CH3CN (3 mL) was added 1,4-butanesultone
(20 mmol) in portion within 30 min, and then the mixture was stirred at reflux
for 12 h and evaporated under reduced pressure. Then H2SO4 (20 mmol) was
added dropwise in ethanol (3 mL) in 30 min. The final solution was stirred at

2604
Z. Chen et al. / Tetrahedron Letters 52 (2011) 2601–2604
50 °C for another 8 h and evaporated under reduced pressured to give
reaction mixture was cooled to room temperature, filtered, and washed with
water, and recrystallized from ethanol/methylene chloride (12 mL, 4:1) to give
the corresponding compound 4a. Other products (4b–4z) were prepared
according to the same method of 4a. For the representative compound 4a:
[DMDBSI]Á2HSO4 as a viscous light brown liquid. [DMDBSI]Á2HSO4: viscous
light brown liquid; 1H NMR (400 MHz, D2O): d = 4.24 (t, J = 5.6 Hz, 4H), 3.01–
2.95 (m, 8H), 2.37 (s, 6H), 1.90–1.82 (m, 4H), 1.51–1.46 (m, 4H). 13C NMR
(100 MHz, D2O): d = 195.8, 55.2, 51.6, 36.9, 32.5, 27.2, 20.3. MS (ESI): m/z 583
[M+1]+.
white solid; mp 226–227 °C. IR (KBr):
mmax = 2953, 1718, 1666, 1605, 1364,
1187, 1051 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.86 (dd, J1 = 8.0, J2 = 1.6 Hz,
.
22. Typical Procedure for the synthesis of 10,10-dimethyl-7-phenyl-10,11-
1H), 7.56 (t, J = 7.2 Hz, 1H), 7.41–7.29 (m, 4H), 7.28–7.20 (m, 2H), 7.15 (t,
J = 7.2 Hz, 1H), 4.97 (s, 1H), 2.89–2.61 (m, 2H), 2.36–2.25 (m, 2H), 1.18 (s, 3H),
1.11 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 195.6, 161.7, 160.3, 153.6, 152.3,
142.3, 132.0, 128.4 (CH Â 2), 128.1 (CH Â 2), 126.9, 124.1, 122.2, 116.7, 115.0,
113.5, 106.7, 50.7, 40.9, 33.4, 32.4, 29.2, 27.6. MS (ESI): m/z = 373 [M+1]+.
HRESI MS: calcd for C24H20O4+Na: 395.1259; found: 395.1244.
dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione 4a: To
a mixture of 4-
hydroxycoumarin 1a (2 mmol), benzaldehyde 2a (2 mmol) and 5,5-
dimethylcyclohexane-1,3-dione 3a (2 mmol) was added [DMDBSI]Á2HSO4
(0.2 mmol) in water (4 mL). The reaction mixture was stirred at reflux
temperature and monitored by TLC. After completion of the reaction, the