Ionic liquid [Dabco-H][AcO] as a highly efficient and recyclable catalyst for the synthesis of various bisenol derivatives: Via domino Knoevenagel-Michael reaction in aqueous media

Article abstract of DOI:10.1039/c6ra23018k

A simple and highly efficient domino Knoevenagel-Michael reaction procedure for the synthesis of a series of bisenols has been successfully developed. In the presence of 1,4-diazabicyclo[2.2.2]octane (Dabco)-based ionic liquid catalysts, which are environ

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Ionic liquid [Dabco-H][AcO] as a highly efficient and
recyclable catalyst for the synthesis of various bisenol
derivatives via domino Knoevenagel–Michael reaction in
aqueous media
Cheng Yang, Wan-Qi Su, Da-Zhen Xu*
An efficient, green and reusable catalystic system for synthesis of various bisenol derivatives is
presented.
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Ionic liquid [Dabco-H][AcO] as a highly efficient and recyclable catalyst for the synthesis of various bisenol
derivatives via domino Knoevenagel–Michael reaction in aqueous media
Cheng Yang, WanꢀQi Su, DaꢀZhen Xu*
National Pesticide Engineering Research Center (Tianjin), State Key Laboratory and Institute of
ElementoꢀOrganic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of
China
Fax: +86 22 2350 5948; Eꢀmail: xudazhen@nankai.edu.cn
Keywords
aldehydes, aqueous medium, ionic liquid, recyclability, domino Knoevenagel−Michael reaction
Abstract
A simple and highly efficient domino Knoevenagel–Michael reaction procedure for the synthesis of a series of
bisenols has been successfully developed. In the presence of 1,4ꢀdiazabicyclo[2.2.2]octane (Dabco)ꢀbased ionic
liquid catalysts, which are environmental friendly, inexpensive, and recyclable, the reaction afforded the
corresponding bisenols compounds in excellent yields within short times in aqueous media. This green synthetic
protocol is applicable to a wide range of aldehydes with enol compounds, including 4ꢀhydroxycoumarin,
2
,4ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone, cyclohexaneꢀ1,3ꢀdione, Meldrum's acid, 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone (Lawsone)
and their derivatives. This method is readily amenable to largeꢀscale synthesis. The use of water as the reaction
medium makes the process environmentally benign. Moreover, water is the only byproduct. The catalysts can be
recycled five times without activity loss.
Introduction
Nowadays, the increasing environmental pollution and its intensive impact on living systems have attracted
significant attention. It is very urgent to develop chemical processes using environmentally acceptable chemicals,
solvents, catalysts, employing atom efficient procedures and reducing waste. The concept of green chemistry has
been more and more deeply rooted in the people’s hearts. Based on the principles of green chemistry, firstly,
hazardous organic solvents should be avoid and replaced with nonpolluting alternative reaction media, particularly
[1]
aqueous media. Water is cheap, safe, nonꢀtoxic and readily available. To perform the organic reactions in water is
[2]
one of the fundamental challenges. Secondly, using low toxic and recyclable catalysts instead of transition metals,
which are often toxic and difficult to dispose of properly in large quantities, is a significant part of this innovation.
So, the catalysts should be with characteristics, such as high activity, selectivity and easy separation, recovery,
recycling. Ionic liquids (ILs) as homogeneous catalysts, which could be easily separated from reaction mixtures for
[3]
reuse, have consequently attracted significant attention as environmentally benign media for chemical processes.
Among the various ionic liquids, functional ionic liquids (ILs) catalysts are particularly attractive and important.
They have been applied as soluble and recyclable organocatalysts in many reactions with good to excellent
[4ꢀ8]
performance.
Thirdly, efficient procedures with high atom economy are essentials for green chemistry. The
oneꢀpot multiꢀcomponent reactions (MCRs), which have emerged as a highly valuable synthetic tool in the context
of modern drug discovery, could rapidly create several new bonds in a single step to give highly functionalized
[9]
organic molecules. Development and utilization of multiꢀcomponent reactions (MCRs) are of prime important
for both drug discovery and green chemistry. Therefore, people have paid increasingly attention on the
development of MCRs in order to find new, efficient synthetic methodologies to afford a broad range of
[10]
complexity and diversity of the molecules. Finally, the purification procedure must be simply. After completion
of the reaction, the desired products could be easily separated and purified without any requirement of column
2

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chromatographic purification. So the reaction is readily amenable to largeꢀscale synthesis and the waste can be
reduced effectively in both academic and industrial research.
Enol is an important structural component and widespread in natural compounds. In particular, the compounds of
bisenols, such as biscoumarins, bis(1Hꢀpyrazolꢀ5ꢀols), bis(cyclic 1,3ꢀdiketones), bis(Meldrum's acids),
bis(2ꢀhydroxynaphthaleneꢀ1,4ꢀdiones) etc. and their derivatives, are often appeared a wide variety of
pharmacologically and biologically activities. For example, biscoumarins and its derivatives showed diverse range
of biological properties such as antiꢀHIV, antibiotic, antifungal, antibacterial, antioxidant, anticancer, and
[
11]
anticoagulant.
Bis(1Hꢀpyrazolꢀ5ꢀols), as an important class of pyrazoles which are an important class of
[
12]
bioactive drug target in the pharmaceutical industry, have been used as antiꢀinflammatory, antipyretic, gastric
[13]
secretion stimulatory, antidepressant, antibacterial, and antifilarial agents.
Bis(cyclic 1,3ꢀdiketones) and
bis(Meldrum's acids), as important class of tetraketones, are key intermediates for the preparation of heterocyclic
[
14]
threeꢀring systems xanthendione and acridindione. 2ꢀHydroxyꢀ1,4ꢀnaphthoquinone (Lawsone), isolated from a
medicinal plant Lawsonia inermis, has been used for more than 4000 years as hair dye, body paint and tattoo dye.
Recently, chemists have found that lawsone and its derivatives also have a wide range of biological and
[
15]
pharmacological activities, including antibacterial, antioxidant, trypsin inhibitor, and anticoagulant activity.
These bisenols usually synthesized through the domino Knoevenagel–Michael reactions of aldehydes with two
equivalents of enol compounds in the presence of catalyst. Various procedures involving different catalysts and
[16]
solvents have been reported for the synthesis of biscoumarins, tetraketones (including bis(cyclic 1,3ꢀdiketones)
[17]
[18]
[19]
and bis(Meldrum's acids)), bis(1Hꢀpyrazolꢀ5ꢀols) and bis(2ꢀhydroxynaphthaleneꢀ1,4ꢀdiones). But there is
no universal procedure that could promote the domino Knoevenagel–Michael reaction to afford more than two
kinds of bisenols under the same conditions. Even though, the reported catalyst systems often suffered from
drawbacks like low yield, long reaction time, expensive reagents, harsh conditions, and use of expensive, toxic and
unreusable catalyst. Therefore, the development of green, efficient and universal procedures for the synthesis of
bisenols is crucial in terms of both synthetic technology and environmental concerns. In continuation of our
[20]
interest in green chemistry and ILs catalyzed organic reactions , here, following the principles of green
chemistry (pure water as solvent, reusable catalysts, high atom economy and easy purification), we wish to
disclose a domino Knoevenagel–Michael reaction for the synthesis of various bisenols catalyzed by Dabcoꢀbase
ionic liquid in nearly quantitative yields.
Results and discussion
The ionic liquid catalysts 1,4ꢀdiazabicyclo[2.2.2]octane hydroacetate ([DabcoꢀH][AcO]), hydrochloride
(
4
[DabcoꢀH]Cl), and hydrotetrafluoroborate ([DabcoꢀH][BF ]), and 1ꢀbutylꢀ1,4ꢀdiazabicyclo[2.2.2]octanylium
bromide ([DabcoꢀC ]Br), chloride ([DabcoꢀC ]Cl), 1ꢀ(3ꢀhydroxypropyl)ꢀ1,4ꢀdiazabicyclo[2.2.2]octanylium
4
4
chloride
([DabcoꢀC
3
OH]Cl)
and
1ꢀ(2,3ꢀdihydroxypropyl)ꢀ1,4ꢀdiazabicyclo[2.2.2]octanylium
chloride
[20(c)]
(
[DabcoꢀDHP]Cl) were synthesized by the literature we have reported and shown in Figure 1.
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Figure 1. Structures of the Dabcoꢀbase ionic liquid catalysts.
Initially, the reaction between 4ꢀmethylbenzaldehyde (1a) and 4ꢀhydroxycoumarin (2a) was employed as the
model reaction to screen the Dabcoꢀbase ILs catalysts in ethanol as well as other common solvents in order to
develop appropriate reaction conditions. As can be seen from the results summarized in Table 1, all the tested
Dabcoꢀbase ILs catalysts could drive well the reaction, and afford the product 3a with moderate to excellent yield
(
71ꢀ95%)(Table 1, entries 1ꢀ7). Among them, the catalyst [DabcoꢀH][AcO] gave 3a with a very high yield of 95%
in 3 hours at 30 ºC (Table 1, entry 1). The initial trials were very encouraging as the biscoumarin 3a could be
achieved via domino Knoevenagel–Michael reaction catalyzed by Dabcoꢀbase ionic liquids. Next, [DabcoꢀH][AcO]
was used as the catalyst of choice and evaluated in different solvents. We found that when the reaction performed
in the solvent containing OH group, such as ethanol, methanol and water, the target products were often formed in
very high yields (95%, 92%, 96%)(Table 1, entries 1, 8 and 9). Other solvents also provided 3a with moderate to
good yields (Table 1, entries 10ꢀ12). It was very fortunate that the best results were obtained for water, which is a
desirable solvent from the green chemistry viewpoint. Then we tried to raise the reaction temperature up to 50 and
8
0 ºC in water in the presence of 10 mol% [DabcoꢀH][AcO] catalyst (Table 1, entries 13ꢀ14). Finally, we found
that under conditions of 80 ºC in water product 3a could be obtained in an excellent yield of 96% within only 0.25
hour (Table 1, entry 14). It was particularly gratifying that when we decreased the catalyst loading to 5 mol% or 3
mol%, the reaction still smoothly proceeded in water to provide 3a in good yield, just only more reaction time was
needed (Table 1, entries 15 and 16). Importantly, without any catalyst only a trace of the product was observed
even after 24 hours which further necessitates the use of [DabcoꢀH][AcO] catalyst in this transformation (Table 1,
entry 17). Moreover, this simple procedure allowed easy scaleꢀup of the reaction, and as shown in Table 1, 92%
yield was obtained in the 50 mmol scale reaction (Table 1, entry 18), indicating the practicability of our protocol.
Under the optimal conditions, after completion of the reaction, the crude products were easily separated from the
mixture just by filtering and no chromatographic technique was used for product purification. The ionic liquid
catalysts dissolved in water which could be easily recover and directly reused in the next recycling run under the
same conditions. This is an atom economic procedure, and it just produces water as waste. In addition, using water
as the solvent is cheap, safe, nonꢀtoxic, readily available, and allowed the domino Knoevenagel–Michael reaction
for the synthesis of bisenol derivatives to be performed in a very simple, cheap and green manner.
a
Table 1. Optimization of reaction conditions
b
Entry Cat (10 mol%)
Solvent
T (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
[DabcoꢀH][AcO]
[DabcoꢀH]Cl
C H OH 30
3
4
4
3
4
4
4
95
90
85
94
88
83
71
2
2
2
2
5
5
5
5
C
C
C
H
H
H
OH 30
OH 30
OH 30
[DabcoꢀH][BF
[DabcoꢀC ]Br
[DabcoꢀC ]Cl
4
]
4
C H OH 30
4
2
5
[DabcoꢀC OH]Cl C H OH 30
3
2
5
[DabcoꢀDHP]Cl
C
2
H
5
OH 30
4

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8
9
1
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
[DabcoꢀH][AcO]
ꢀꢀꢀ
CH OH
30
30
30
30
30
50
80
80
80
80
80
4
92
3
H
2
O
3
96
0
DCE
CH CN
4
63
11
3
4
82
1
1
1
1
1
1
1
2
3
4
5
6
7
8
THF
4
69
H O
2
1.5
0.25
0.25
0.3
24
1
96
H
H
H
H
2
2
2
2
O
O
O
O
96
c
93
d
90
Trace
92
c,e
[DabcoꢀH][AcO]
H O
2
a
Conditions: 4ꢀmethylbenzaldehyde (1a, 1 mmol), 4ꢀhydroxycoumarin (2a, 2 mmol), Dabcoꢀbase IL catalyst (0.1
mmol) and solvent (2 mL).
b
Isolated yield.
c
5
3
mol% catalyst.
mol% catalyst.
d
e
50 mmol scale.
With the optimal conditions in hand, we then examined the scope of various aldehydes (1aꢀm) with
ꢀhydroxycoumarin (2a) to synthesis of biscoumarins (3aꢀm) via domino Knoevenagel–Michael reaction catalyzed
4
by [DabcoꢀH][AcO] in water under 80°C. As shown in Table 2, a large number of aromatic aldehydes with
electron withdrawing groups or donating groups were all converted to the corresponding products in near
quantitative yields within 15 minutes (Table 2, entries 1ꢀ10). Different subsituted aryl group has not shown much
effect on the formation of final product. Similar results were obtained with the heteroaromatic aldehydes (Table 2,
entries 11ꢀ12). nꢀButyraldehyde as an aliphatic aldehyde was also tested in this procedure, the corresponding
product was obtained in a quantitative yield (Table 2, entry 13).
Table 2. Domino Knoevenagel–Michael reaction of aromatic/heteroaromatic/aliphatic aldehydes with
a
4ꢀhydroxycoumarin catalyzed by [DabcoꢀH][AcO]
b
Entry
R
Product Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
4ꢀMeC
6
H
4
3a
3b
3c
3d
3e
3f
15
3
96
98
98
99
99
98
98
99
96
Ph
4ꢀMeOC
4ꢀClC
4ꢀBrC H
6
H
4
3
6
H
4
2
2
6
4
4
4
3ꢀBrC
6
6
H
H
3
2ꢀBrC
3g
3h
3i
3
pꢀNO
2
C
6
H
4
5
2,4ꢀCl
2
C
6
H
3
15
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1
0
Naphthalenꢀ2ꢀyl 3j
6
99
98
98
99
11
Thiophenꢀ2ꢀyl
Furanꢀ2ꢀyl
nꢀPropyl
3k
3l
8
1
1
2
3
10
6
3m
a
Conditions: aldehyde (1, 1 mmol), 4ꢀhydroxycoumarin (2, 2 mmol), IL catalyst [DabcoꢀH][AcO] (0.1 mmol) in
water (2 mL), 80°C.
b
Isolated yield.
It is of interest to further extend the application of this procedure to structurally complex skeleton synthesis. Thus,
we
Bis[bis(4ꢀhydroxycoumarinyl)methanes] 3n with an excellent yield of 99% in the presence of 10 mol%
DabcoꢀH][AcO] in aqueous medium within 5 minutes at 80 °C (Scheme 1).
selected
the
reaction
of
terephthaldehyde
with
4ꢀhydroxycoumarin
to
give
the
[
Scheme 1. Synthesis of Bis[bis(4ꢀhydroxycoumarinyl)methanes] 3n.
After the above success, to confirm the generality of the present approach, we then extended the method to
synthesis more kinds of bisenol derivatives in aqueous media. The results are summarized in Table 3. Under the
optimal reaction conditions, the substrates, such as 5ꢀmethylꢀ2ꢀphenylꢀ2,4ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone,
3ꢀmethylꢀ1Hꢀpyrazolꢀ5(4H)ꢀone, dimedone and cyclohexaneꢀ1,3ꢀdione, gave the corresponding products 4-7 in
quantitative yields within 1ꢀ10 minutes (Table 3, entries 2ꢀ5). Furthermore, product benzylideneꢀbisꢀ(Meldrum's
acid) (8) could be formed with an excellent yield of 93% in only 30 minutes even at room temperature (Table 3,
entry 6). When 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone was used as substrate in the reaction, a good yield of 81% (9) was
also obtained (Table 3, entry 7).
a
Table 3. The reaction of aromatic aldehydes with different enols compounds
b
Entry Enols
1
Product
Time
min)
15
Yield (%)
96
(
6

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2
3
4
5
<1
98
5
98
96
98
Me
Me
Me
N
HN
N
NH
OH HO
(5)
10
10
c
6
7
30
93
81
d
O
O
120
OH
(2g)
a
Conditions: aromatic aldehyde (1, 1 mmol), enols (2, 2 mmol), IL catalyst [DabcoꢀH][AcO] (0.1 mmol) in water
(
2 mL), 80°C.
b
Isolated yield.
c
Room temperature.
d
2
EthanolꢀH O (1:1).
The reusability of the catalyst was examined for the synthesis of 3c. After completion of the reaction, the catalyst
could be easily recycled by filtering the products from the mixture. The filtrate containing the water and the IL
catalyst [DabcoꢀH][AcO] could be directly reused for the next cycle. The crude product was purified by the
crystallization technique and no column purification was followed. It was observed that this Dabcoꢀbase catalyst
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could be recovered and reused in the domino Knoevenagel–Michael reaction for five times at least. The results are
presented in Figure 2.
Figure 2. Recycling of the catalyst [DabcoꢀH][AcO] for the synthesis of 3c.
A plausible mechanism for the formation of bisenols in the presence of [DabcoꢀH][AcO] is shown in Scheme 2.
The process represents a typical domino reaction by doubleꢀactivation. In the initiation step of the catalytic cycle,
doubleꢀactivation of the carbonylgroup of aldehydes and enols (4ꢀhydroxycoumarin as example) by the catalyst
(
[DabcoꢀH][AcO]) occurred to formation of Knoevenagel intermediate. Then the catalyst may activate both the
+
Knoevenagel intermediate and another molecule of enol to occur the Michael reaction, and take the H from enol
+
by the right N and give the H attaching to left N to –C=O. Finally, a tautomerzation via H [1, 3] shift takes place
to produce target product.
Scheme 2. Proposed mechanism for the synthesis of bisenols.
Conclusion
In conclusion, we have described a green and simple protocol for highly efficient synthesis of a series of bisenols
using catalytic amount of efficiently reusable Dabcoꢀbase ionic liquid catalysts. Performing in aqueous media
allowed these domino Knoevenagel–Michael reactions to be driven in a very simple, clean and green manner.
After completion of the reaction, the desired products could be easily separated and purified without any
requirement of column chromatographic purification. This procedure also offers other significant advantages
including simple operation, excellent yield, short reaction time, atom economy, scaling up to multigram quantities,
ease of separation and recyclability of the catalyst. To the best of our knowledge, such an efficient domino
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Knoevenagel–Michael reaction performed in water for the synthesis of a wide variety of bisenols is reported for
the first time. A plausible reaction mechanism was proposed. We believe that this method will be found useful
applications in the synthesis of bisenols.
Experimental
General experimental information. All chemicals were purchased from commercial suppliers and were used
without further purification. Flash column chromatography was performed on silica gel (200–300 mesh). Melting
1
13
points were determined with an Xꢀ4 apparatus and are uncorrected. H NMR and C NMR spectra were recorded
6 3
on a Bruker AVꢀ400 spectrometer with DMSOꢀd and CDCl as the solvent. Chemical shifts are reported relative to
1
TMS as internal standard. The H NMR data are reported as the chemical shift in parts per million, multiplicity (s,
singlet; d, doublet; t, triplet; m, multiplet), coupling constant in hertz, and number of protons.
General procedure for the synthesis of bisenols.
A 5ꢀmL round bottomed flask was charged with the aldehydes (1, 1 mmol), enols (2, 2 mmol), [DabcoꢀH][AcO]
catalyst (0.1 mmol), and water 2.0 mL. Then the mixture was vigorously stirred at 80 °C. The formation of the
products was monitored by TLC. After completion of the reaction, the mixture was cooled to room temperature,
filtered and washed with cold water. The crude products were purified by recrystallization from ethanol and no
column purification was followed. After removing more water under vacuum, the catalyst [DabcoꢀH][AcO] left in
water could be directly reused in the next recycling run under the same conditions.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (NSFC) (No.
2
1302101), NFFTBS (No. J1103306), and National Training Programs of Innovation and Entrepreneurship for
Undergraduates (No. 201610055092, 201610055085). We also thank the Nankai University State Key Laboratory
of ElementoꢀOrganic Chemistry for support.
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