Choline Hydroxide: An Efficient and Biocompatible Basic Catalyst for the Synthesis of Biscoumarins Under Mild Conditions

Article abstract of DOI:10.1007/s10562-015-1487-6

In this work, choline hydroxide is found to be an efficient and green catalyst for the synthesis of biscoumarins through the Domino Knoevenagel-Michael reaction of a series of aldehydes with 4-hydroxylcoumarin under mild conditions. A series of aldehydes with different substituted functional groups, especially those which are sensitive to acid, have been converted to biscoumarins with good to excellent isolated yields, and the reactions can be easily scaled up to multigrams. The target products can be simply separated by filtration, and the aqueous solution of choline hydroxide (as filtrate) can then be reused for the next run reaction.

Full text of DOI:10.1007/s10562-015-1487-6

Catal Lett
DOI 10.1007/s10562-015-1487-6
Choline Hydroxide: An Efficient and Biocompatible Basic
Catalyst for the Synthesis of Biscoumarins Under Mild Conditions
•
Anlian Zhu Shukun Bai Lingjun Li
•
•
•
Mingyue Wang Jianji Wang
Received: 16 December 2014 / Accepted: 17 January 2015
Ó Springer Science+Business Media New York 2015
Abstract In this work, choline hydroxide is found to be an
efficient and green catalyst for the synthesis of biscoumarins
through the Domino Knoevenagel–Michael reaction of a series
of aldehydes with 4-hydroxylcoumarin under mild conditions.
A series of aldehydes with different substituted functional
groups, especially those which are sensitive to acid, have been
converted to biscoumarins with good to excellent isolated
yields, and the reactions can be easily scaled up to multigrams.
The target products can be simply separated by filtration, and
the aqueous solution of choline hydroxide (as filtrate) can then
be reused for the next run reaction.
1 Introduction
Biscoumarin and its derivatives have received increasing
attention due to their wide range of biological activity such
as anti-HIV, anti-bacterial, anti-oxidant, anti-cancer, and
anti-coagulant activities [1–4]. Biscoumarins are usually
synthesized through the Domino Knoevenagel–Michael
reactions of aldehydes with two equivalents of 4-hy-
droxycoumarin in the presence of catalyst. The present
catalyst systems such as molecular iodine [5], SO3H-
functionalized ionic liquids [6], ionic liquids with both
Lewis acid and bronsted acid sites [7], Zn(Proline)2 [8],
sodium dodecyl sulfate [9], p-dodecylbenzenesulfonic
acid/piperidine [10], sulfated titania [11], heteorpoly acid
[12], nano silica chloride [13], propane-1,2,3-triyltris
(hydrogen sulfate) [14] and Ce2(SO4)Á4H2O [15], are
almost acidic and often suffered from drawbacks like low
yield, long reaction time, high reaction temperature,
necessity of refluxing in organic solvent and use of
expensive, toxic and unreusable catalyst. In the aspect of
green chemistry and industrial application, a non-toxic,
reusable and efficient catalytic system at reduced temper-
ature for the synthesis of biscoumarins is in great
necessary.
Graphical Abstract Choline hydroxide was found to be a
green and efficient catalyst for the synthesis of biscouma-
rins through the Domino Knoevenagel–Michael reactions
under mild conditions.
Keywords Basic ionic liquid Á Biscoumarins Á One-pot
reaction Á Aldehyde
As a non-toxic and naturally abundant derivative of
choline and a water soluble essential nutrient, choline
hydroxide has shown excellent catalysis performance for
aldol reaction [16, 17] and transesterification reaction for
biodiesel production [18]. This suggests that choline
hydroxide is a suitable basic catalyst in organic transfor-
mations. However, its utilization in the basic catalyzed
Domino reactions has not been reported to our knowledge.
As a continuation of our longstanding interest in the
development of choline-based ionic liquids in sustainable
catalysis [19–23], we describe here a simple and efficient
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1487-6) contains supplementary
material, which is available to authorized users.
A. Zhu Á S. Bai Á L. Li Á M. Wang Á J. Wang (&)
Collaborative Innovation Center of Henan Province for
Green Manufacturing of Fine Chemicals, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education,
School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang 453007, Henan, People’s Republic of
China
e-mail: jwang@htu.cn
123

A. Zhu et al.
procedure for the synthesis of biscoumarins under mild
conditions through the Domino Knoevenagel–Michael
reactions by using aqueous solution of choline hydroxide as
a cheap and reusable basic catalyst. This catalyst system
benefits from feasible catalyst preparation, simple work-up
and separation procedures, high tolerance to various
functional groups, and no use of volatile organic solvents.
In addition, the catalyst itself is non-toxic and biocom-
patible, and this catalysis system can be scaled up for
multi-gram synthesis with high isolated yield for the target
biscoumarin. This suggests that the approach reported here
is green and has great promising in industrial application.
performed at the temperature above 90 °C, this result
suggested that basic catalysts would have better catalysis
performance compared with acidic catalysts under reduced
temperature.
Then, the effect of the amount of ionic liquid on catal-
ysis performance was investigated using the model reaction
at 50 °C, and the results were included in Table 2. It can be
seen that the isolated yield of the target compound reached
to a maximum within 1 h when the amount of the catalyst
was 1.5 equivalent of aldehyde. Further increase of the
amount of choline hydroxide resulted in a slight decrease
of biscoumarin yield. These results demonstrated that low
catalyst amount led to a relatively low reaction rate, while
excess catalyst gave rise to side reactions. Therefore, 1.5
equivalent amount of choline hydroxide based on aldehyde
was selected as the optimal catalyst amount. Under this
optimized condition, the effect of reaction temperature was
investigated and the results were given in Table 3. It was
shown that 50 °C is the most favorable reaction tempera-
ture because of the high reactivity and selectivity for the
formation of the target compound.
2 Results and Discussion
First, the reaction between benzaldehyde and 4-hydroxyl-
coumarin was used as a model reaction to investigate the
catalytic activities of the choline-based ionic liquids for the
synthesis of biscoumarin, and the results were collected in
Table 1. It was found that aqueous solution of choline
hydroxide could promote this reaction at 50 °C to give a
82 % isolated yield for the target product after 3 h, while
the other choline-based ionic liquids which have a little
weaker basicity such as choline acetate ([choline][Ac]),
N,N-dimethylethanolamine acetate ([DMEA][Ac]) and
N,N-dimethylethanolamine lactate ([DMEA][Lac]), had
lower catalytic activity. Comparatively, catalytic activity
of the choline-based ionic liquids with acidic anions was
even much weaker. Considering the fact that almost all of
the acidic catalyzed biscoumarins synthesis were
Next, a series of biscoumarins were synthesized using
different aldehydes and 4-hydroxycoumarin under opti-
mized reaction conditions. It can be seen from Table 4 that
in almost of the cases, whether the nature of the substitu-
tion was electron withdrawing or electron donating, the
aromatic aldehydes could be reacted to arrive at excellent
isolated yields within 2 h (entries 1–14, Table 4). Similar
results were obtained with the heteroaromatic aldehydes
(entries 15, 16, Table 4). Interestingly, when piperonyl
aldehyde was used as a substrate, the acetal group could be
Table 1 Catalytic performance of different choline-based ionic liquids on the synthesis of biscoumarin
Entrya
Catalyst
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
7
8
a
ChOH (40 %)
[choline][Ac]
2
2
2
2
4
4
4
4
82
74
69
60
47
55
40
54
[DMEA][Ac]
[DMEA][Lac]
[choline][HSO4]
[choline][H2PO4]
[DMEA][HSO4]
[DMEA][H2PO4]
The mole ratio of benzaldehyde: 4-hydroxylcoumarin: ionic liquid = 1:2:0.2
b
Isolated yield
123

Choline Hydroxide
Table 2 Optimization of catalyst amount using the model reaction
Entry
Catalyst
Ratioa
Time (h)
Yield (%)b
1
2
3
4
5
6
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
1:2:0.1
1:2:0.2
1:2:0.5
1:2:1
2
2
2
2
1
1
81
82
90
96
99
97
1:2:1.5
1:2:2
The reaction was performed at 50 °C
a
Isolated yield
b
The molar ratio of benzaldehyde: 4-hydroxylcoumarin: ionic liquid
Table 3 Optimization of reaction temperature using the model reaction
Entry
Catalyst
Temperature (°C)
Time (h)
Yield (%)a
1
2
3
4
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
ChOH (40 %)
r.t.
35
50
70
2
2
1
1
80
85
99
98
The molar ratio of benzaldehyde: 4-hydroxylcoumarin: ionic liquid = 1: 2: 1.5
a
Isolated yield
Table 4 Reaction of aromatic/heteroaromatic aldehydes with 4-hydroxycoumarin catalyzed by choline hydroxide
Entrya
R
Product
Time (h)
Yield (%)
1
R = H
3a
3b
3c
3d
3e
3f
1
1
2
2
1
1
2
2
2
2
2
1
2
2
99
99
99
94
94
99
89
93
75
94
96
95
93
81
2
R = 4-F
3
R = 4-Cl
4
R = 4-Br
5
R = 4-OH
R = 2-OH
R = 4-NO2
R = 3-NO2
R = 2-NO2
R = 4-CH3
R = 4-CF3
R = 4-OCH3
R = 4-(OH)-3-(OCH3)
6
7
3g
3h
3i
8
9
10
11
12
13
14
3j
3k
3l
3m
3n
123

A. Zhu et al.
Table 4 continued
Entrya
R
Product
Time (h)
1
Yield (%)
98
15
16
3o
3p
3
95
17b
R = H
3a
1
Quanti
a
Reaction conditions: the molar ratio of benzyaldehyde: 4-hydroxylcoumarin: choline hydroxide was 1:2:1.5, and the reaction temperature was
50 °C
b
The reaction scale was 10 mmol benzaldehyde, 20 mmol 4-hydroxylcoumarin and 15 mmol choline hydroxide
well kept and excellent isolated yield could be obtained for
the target compound within 3 h, suggesting that the acidic
sensitive groups were well tolerant in this catalytic system.
In these reactions, the solid target compounds could be
filtered off from the reaction mixture after the completion
of the reaction. Simple recrystallization using aqueous
ethanol would give pure biscoumarins and no column
purification for the products was needed. The filtrate of the
aqueous solution of ionic liquid could be directly reused for
the next run of catalysis. In addition, the scaled up reaction
between benzaldehyde and 4-hydroxylcoumarin was con-
ducted under the optimized reaction condition, the target
compound could be obtained with quantitative isolated
yields within 1 h (entry 17, Table 4).
3 Conclusions
In this work, an efficient basic catalyst was developed for
the one-pot synthesis of biscoumarins under mild condi-
tions. A series of biscoumarins with different substitute
groups could be synthesized with good to excellent isolated
yields, and acidic sensitive groups could be well kept in
this catalytic system. These reactions could be efficiently
scaled up to multigrams, and the target products could be
simply separated by filtration. The ionic liquid catalyst,
choline hydroxide, is cheap, easy to prepare, highly bio-
compatible and biodegradable. These benefits plus its
excellent catalytic efficiency and reusability make it an
ideal green catalyst for the one-pot preparation of
biscoumarins.
The recovered aqueous solution of choline hydroxide
was used directly for the next run reaction under the same
conditions, and the reutilization results were collected in
Fig. 1. It was found that the catalytic activity could be well
maintained for at least five cycles without significant
decrease.
4 Experimental
4.1 Preparation of Ionic Liquids
Choline hydroxide was prepared as follows: analytical
grade choline chloride was recrystallized using aqueous
solution of ethanol and then ion exchanged to hydroxide
anion using strong basic anion exchange resin until no
chloride anion could be detected using aqueous solution of
AgNO3. The concentration of choline hydroxide was
determined by acid–base titration. The other ionic liquids
were prepared according to the literatures [20, 21].
100
90
80
70
60
50
40
30
20
10
0
4.2 Typical Procedure for the Preparation
of Biscoumarins
Aldehyde (1 mmol), 4-hydroxylcoumarin (2 mmol) and
aqueous solution of 40 wt% choline hydroxide (1.5 mmol)
were added to a 10 ml round bottom flask and then the
mixture was stirred at 50 °C at desired time, and the
reaction was monitored by TLC. When the reaction was
completed, the mixture was cooled to room temperature
0
1
2
3
4
5
Run times
Fig. 1 The reusability of choline hydroxide
123

Choline Hydroxide
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Acknowledgments This work was financially supported by
National Natural Science Foundation of China (No. 21373079) and
Program for Science & Technology Innovation Talents in Universities
of Henan Province (No. 14HASTIT015).
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