Tetramethylguanidium-based ionic liquids as efficient and reusable catalysts for the synthesis of biscoumarin at room temperature

Article abstract of DOI:10.1039/c5ra14247d

In this work, a basic ionic liquid, tetramethylguanidium acetate ([TMG][Ac]), was found to be an efficient catalyst for the one-pot preparation of biscoumarins through a domino Knoevenagel-Michael reaction at room temperature. This novel catalytic system

Full text of DOI:10.1039/c5ra14247d

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DOI: 10.1039/C5RA14247D
Tetramethylguanidium-based ionic liquids as efficient and reusable
catalyst for the synthesis of biscoumarin at room temperature
Anlian Zhu, Mingyue Wang, Lingjun Li, Jianji 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, Henan 453007, P. R. China
Telephone: +86-0373-3325805; Fax: +86-0373-3329030
jwang@htu.cn
Abstract: In this work, a basic ionic liquid tetramethylgunidium acetate ([TMG][Ac])
was found to be an efficient catalyst for the one-pot preparation of biscoumarins
through the Domino Knoevenagel-Michael reaction at room temperature. This novel
catalytic system avoids the utilization of volatile organic solvents and has excellent
tolerance to various functional groups on substrates. The convenient preparation,
excellent catalytic efficiency, good reusability and the perspective in scale up
reactions make this catalyst intriguing in the industrial applications.
Keywords: tetramethylguanidium acetate; ionic liquid; biscoumarin; Domino
Knoevenagel- Michael reaction.
Introduction
In the past decades, ionic liquids (ILs) have been widely utilized in catalysis and
organic synthesis as substitution of volatile organic solvents mainly due to their
excellent solubility and low vapor pressure.1-3 However, with the development of task
specific ionic liquids, the functions of ionic liquids have been extended to catalyst,
extractant, absorbent, structure orientation regents, etc.4-8 Although the research and
development of basic ionic liquids are relative unparallel compared with acidic ionic
liquids, promising perspectives have been shown for such a class of ionic liquids.9 For
example, amine-functionalized imidazolium ionic liquids were found to be efficient
catalysts
for
the
hydrogenation
of
carbon
dioxide.10,11

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1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU)
or
1,4-Diazabicyclo[2.2.2]octane
(DABCO)-based basic ionic liquids also showed excellent catalytic activity for the
fixation of CO212-14 and various multi-component reactions.15, 16 In our previous work,
a series of basic ionic liquids based on cholinium or guanidium were synthesized and
utilized in aldol and Knoevenagel Henry reactions, and the difference in chemo- or
regio-selectivity was found between these basic catalytic systems and traditional
acidic catalysis systems.17-20
Biscoumarins is an important kind of vitamin K antagonists which has wide
biological activities such as anti-HIV, anti-bacterial, anti-oxidant, anti-cancer, and
anti-coagulant activities,21-24 Recently, it is found that the inhibition of
NAD(P)H:quinone oxidoreductase (NQO1) with biscoumarins can induce cell killing
and oxidative stress in pancreatic cancer cells.25 Several methods have been adopted
for the synthesis of biscoumarins through the catalyzed Domino
Knoevenagel-Michael reactions of aldehydes with two equivalents of
4-hydroxycoumarin. Actually, this Domino reaction can also be catalyzed by acidic
catalysts such as molecular iodine,26 Zn(Proline)2,27 sodium dodecyl sulfate,28
heteorpoly acid,29 nano silica chloride,30 propane-1,2,3-triyltris (hydrogen sulfate),31
and SO3H-functionalized ionic liquids.32,33 However, these catalytic systems often
suffer from high reaction temperature, low yield, long reaction time and necessary
refluxing in volatile organic solvents. Recently, basic ionic liquids based on
N-hydroxyethylammonium type cations were found to catalyze this reaction at
relative mild conditions but still suffered from low or moderate isolated yields for the
target compounds at room temperature.34, 35 Therefore, it is still interesting to develop
a reusable catalytic system which can efficiently catalyze this type of reactions at
room temperature from the viewpoint of atom economy and energy efficiency.
Herein, the catalytic performances of a series of basic tetramethylguanidium (TMG)
-based ionic liquids on the Domino Knoevenagel-Michael reactions have been
investigated for the one-pot synthesis of biscoumarins. It is shown that
tetramethylguanidium acetate has the highest catalytic activity for the Domino
Knoevenagel-Michael reactions, and the target biscoumarins with various functional

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groups can be synthesized with excellent isolated yields at room temperature. In
addition, the catalyst is easy to regenerate and reuse, and the catalytic activity has no
significant decrease after six runs.
Results and discussion
The catalytic performances of tetramethylguanidium-based ionic liquids with
different anions on the one-pot Knoevenagel-Michael reactions were investigated by
using the reaction between benzaldehyde and 4-hydroxycoumarin as a model. The
influence of the reaction temperature and the amounts of the ILs on the catalytic
performance were also studied. It is clear from Table 1 that the ionic liquids with
acetate (Ac), propionate (Pr) and lactate (Lac) as anions could catalyze this reaction.
Nevertheless, the ionic liquid with TMG cation and Ac anion has the highest catalytic
activity, and the target compound can arrive at 96% isolated yield at room temperature
within 3.5 hours when the molar ratio of ionic liquid to aldehyde was increased to
1.5:1.
Table 1. Catalytic performance of the TMG-based ionic liquids on the one-pot
Knoevenagel-Michael reactions between aldehyde and 4-hydroxylcoumarin under
different conditions
aldehyde:coumarin:IL Temperature
Time
(h)
Yielda
(%)
Entry
IL
Molar ratio
(oC)
1
2
3
4
5
6
7
[TMG][Ac]
[TMG][Pr]
[TMG][Lac]
[TMG][Ac]
[TMG][Ac]
[TMG][Pr]
[TMG][Lac]
1:2:0.1
50
2
4
4
2
3
3
4
64
49
51
53
64
61
60
1:2:0.1
1:2:0.1
1:2:0.1
1:2:0.5
1:2:0.5
1:2:0.5
50
50
25
25
25
25

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8
9
[TMG][Lac]
[TMG][Ac]
[TMG][Ac]
1:2:1.0
25
25
25
2
4
73
90
96
1:2:1.0
1:2:1.5
10
3.5
a Isolated yields.
In order to evaluate the generality of this catalyst, a range of biscoumarin
derivatives were prepared under the optimized reaction conditions using the reactions
of 4-hydroxycoumarin with various aldehydes. The results were collected in Table 2.
It can be seen that in all cases, aromatic aldehydes with substituents bearing either
electron-donating or withdrawing groups reacted smoothly and gave the target
biscoumarin products with excellent isolated yields (entries 1-13). Heteroaromatic
aldehydes such as 4-pyridinecarboxaldehyde and 2-furaldehyde could also react with
4-hydroxycoumarin efficiently to give excellent yields for the target compounds
(entries 14, 15). Piperonyl aldehyde with acidic sensitive groups on the aromatic ring
also showed excellent reactivity under the catalysis of [TMG][Ac], leaving the acetal
1
group intact (entry 16). The structures of all these products were confirmed by H
NMR spectral data, which are found to be in accordance with those reported in
literatures.26-34
Table 2. Reaction of 4-hydroxycoumarin with aromatic/heteroaromatic aldehydes
catalyzed by [TMG][Ac]
Entry
1
aldehyde
Product
Time(h)
3.5
Yielda,b(%)
96
3a

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2
3.5
92
3b
3c
3
4
0.5
0.5
90
93
3d
3e
3f
5
6
7
8
1.5
88
96
91
90
4
O
4
H
F3C
3g
3h
2.5

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9
4.5
86
3i
3j
10
2
99
11
12
13
14
2
3
2
4
87
92
84
87
3k
3l
O
H
NO2
OH
OCH3
OH
O
OH
O
O
O
3m
3n
3o
15
16
0.5
2.5
95
98
3p
aReaction condition: aldehyde (0.5mmol), 4-hydroxycoumarin (1mmol), tetramethyl
guanidine acetate (0.75mmol), room temperature; b Isolated yields.

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100
80
60
40
20
0
1
2
3
4
5
6
Run times
Fig.1. The reusability of [TMG][Ac] under optimized reaction conditions
From the industrial point of view, the scale-up reaction and reusability of the
catalyst are two important aspects for the application of a given catalytic system. The
scale up reaction between benzaldehyde (10 mmol) and 4-hydroxylcoumarin (20
mmol) was conducted under the optimized conditions. The result showed that almost
quantitative yield of the target compound was given, suggesting that this catalytic
system is easy to scale-up. The reusability of the ionic liquid was also examined by
using the reaction between 4-hydroxylcoumarin and 4-nitroaldehyde. The ionic liquid
can be recovered from the reaction system using water as extracting agent, and then
reused directly after drying under vacuum. The isolated yields for the target
compound in different cycles were illustrated in Fig.1. It is clear that after six cycles,
the catalytic activity of the catalyst has no significant decrease. Therefore, it can be
conclude that this catalytic system has great potential in industrial applications.
In addition, a plausible mechanism for [TMG][Ac] catalyzed one-pot
Knoevenagel- Michael reaction was outlined in Scheme 1. As a hydrogen bond donor,
NH2 groups on the cation of the IL activated C=O of aldehyde, and the Ac anion of
the IL activated the O-H of 4-hydroxylcoumarin as a hydrogen bond acceptor. This
dual activation effect from ionic liquid led to the addition of one molecular
4-hydroxylcoumarin to aldehyde. Then, under the catalysis of basic Ac anion,
intermediate 4 was dehydrated to produce intermediate 5, which was also activated by
cation of the ionic liquid and then reacted with another molecular

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4-hydroxylcoumarin activated by the anion of the ionic liquid, leading to the target
compound with high efficiency. In this catalytic procedure, the cation and the anion
have synergetic effect on the substrates. This is possible reason why this catalytic
system could reduce the reaction temperature significantly.
N
H
N
H
CH3COO
N
O
H
O
O
-H2O
OH
H
O
CH3COO
H
O
O
O
O
intermediate 4
substrate 1
substrate 2
O
N
N
H
N
OH
OH
H
O
OH
O
O
O
O
O
O
product 3
intermediate 5
Scheme 1. Plausible reaction mechanism
Conclusion
A sustainable catalytic system for the one-pot preparation of biscoumarins was
developed through the Domino Knoevenagel-Michael reactions at room temperature.
The [TMG][Ac] catalyst is very cheap, easy to prepare, easy to handle and has high
catalytic activity and selectivity for a wide range of substrates. The weak basic
property of this catalyst leads to its excellent performance in the conversion of
reactants involving acidic sensitive groups. In addition, this catalyst is feasible to
scale-up, which makes it promising in the industrial production of biscoumarins.
Experiments
All starting materials (A. R. grade) were purchased from Beijing chemical
reagents
company
and
used
without
further
purification.
1,1,3,3-
tetramethylguanidium based ionic liquids were prepared by neutralizing equivalent
molar TMG with corresponding carboxyl acids according to the procedure described

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in literatures.17-19
Typical experimental procedures for the preparation of biscoumarins using ionic
liquid catalyst:
1.5mmol of tetramethylguanidium acetate was added to the mixtures containing
1mmol of aldehyde and 2mmol of 4-hydroxylcoumarin under stirring at room
temperature. The extent of the reaction was monitored by TLC analysis. After the
reaction was completed, the reaction mixture was washed with water three times and
the ionic liquid catalyst was recovered and reutilized directly from the combined
water phase after the water evaporation. The pure biscoumarin product can be
obtained through recrystalization from aqueous ethanol solution.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of
China (No.21373079) and the Program for Science & Technology Innovation Talents
in Universities of Henan Province (No.14HASTIT015).
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Graphic Abstracts
Ionic liquid tetramethylgunidium acetate is very efficient for the one-pot catalysis
preparation of biscoumarins through the Domino Knoevenagel-Michael reaction
under room temperature. The convenient preparation and reutilization of the catalyst,
and its excellent catalytic efficiency and the perspective in scale up reactions make
this catalyst intriguing in the industrial applications.