Green Synthesis of 2-Substituted Imidazolines using Hydrogen Peroxide Catalyzed by Tungstophosphoric Acid and Tetrabutylammonium Bromide in Water

Article abstract of DOI:10.1002/jhet.3482

Various 2-substituted imidazolines were constructed from aromatic aldehydes with ethylenediamine using hydrogen peroxide as an oxidant in water. Tungstophosphoric acid (HPW) was found to be active for this transformation due to its ubiquitous catalytic and oxidative nature, and further combination of tetrabutylammonium bromide (TBAB) made this transformation more efficient and attractive. It was found that the yields of the corresponding 2-substituted imidazolines were markedly influenced by the position and nature of the substituents on the phenyl ring. A plausible mechanism was also proposed to clarify this catalytic oxidative system.

Full text of DOI:10.1002/jhet.3482

Month 2019
Green Synthesis of 2-Substituted Imidazolines using Hydrogen Peroxide
Catalyzed by Tungstophosphoric Acid and Tetrabutylammonium Bromide
in Water
a
b
b
b
b
b
Shuai Liu, Wang Li, Yiying Pang, Hesheng Xiao, Yi Zhou, and Xiaoji Wang *
a
Dongguan University of Technology, Dongguan, Guangdong 523000, China
b
School of Life Science, Jiangxi Science and Technology Normal University, Nanchang 330013, China
*
E-mail: 2012207455@tju.edu.cn
Received September 26, 2018
DOI 10.1002/jhet.3482
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Various 2-substituted imidazolines were constructed from aromatic aldehydes with ethylenediamine using
hydrogen peroxide as an oxidant in water. Tungstophosphoric acid (HPW) was found to be active for this
transformation due to its ubiquitous catalytic and oxidative nature, and further combination of
tetrabutylammonium bromide (TBAB) made this transformation more efficient and attractive. It was found
that the yields of the corresponding 2-substituted imidazolines were markedly influenced by the position and
nature of the substituents on the phenyl ring. A plausible mechanism was also proposed to clarify this cata-
lytic oxidative system.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
developed for the synthesis of 2-substituted imidazolines
starting from nitriles [4], esters [5], carboxylic acids [6],
and amides [7]. However, some of these methods involve
disadvantages such as harsh reaction conditions and the
use of highly toxic cyanide. More recently, aromatic
aldehydes and ethylenediamine have been selected as
starting materials for the synthesis of 2-substituted
imidazolines using NXS (X = Cl, Br, and I) [8] or DIB
The synthesis of 2-substituted imidazolines has become
of great importance and interest, not only because they
are important intermediates but also because they have
been found promising applications in many
pharmaceutical and synthetic areas [1–3]. Due to its
increasing importance, a series of methods have been
©
2019 Wiley Periodicals, Inc.

S. Liu, W. Li, Y. Pang, H. Xiao, Y. Zhou and X. Wang
Vol 000
13
[9] as oxidants. Although these methods have solved some
and
C NMR spectra were recorded at 600 and
of the previous problems, some procedures still have
shortcomings such as the use of toxic organic solvents
and environmentally unfriendly and expensive halide
reagents as oxidants. Therefore, there is still considerable
interest in developing a new convenient and green
synthetic method of 2-substituted imidazolines using
environmentally friendly and efficient oxidants or solvents.
On the other hand, the use of polyoxometalates as
catalysts has attracted much attention in organic synthesis
due to their excellent catalytic activity, good solubility,
and non-toxicity [10,11]. The most important class of
polyoxometalates are heteropoly acids with Keggin
structures, such as tungstophosphoric acid (HPW),
tungstosilicic acid (HSiW), and phosphomolybdic acid
150 MHz, respectively, on a Bruker spectrometer in
CDCl3 using TMS as the internal standard at room
temperature.
General procedure for synthesis of 2-substituted
imidazoline.
A
mixture of aromatic aldehyde
(1.0 mmol) and ethylenediamine (1.1 mmol) was first
stirred in tert-butyl alcohol or water (8.0 mL) at room
temperature for 30 min. HPW (0.125 g) and TBAB
(0.125 g) were then added into the aforementioned
reaction mixture, respectively. The reaction mixture was
gradually heated up to 80°C and kept at this temperature
with stirring. Then, aq 30.0% H O (0.5 mL) was added
2
2
dropwise to this reaction mixture and reacted for a
requisite period of time while monitoring the reaction
progress by thin layer chromatography. After completion
of the reaction, the mixture was extracted with
ethyl acetate (3 × 10 mL). The organic layer was
concentrated, and the products were isolated by column
(HPMo), owing to their unique physical properties. For
instance, Mohammadpoor-Baltork and co-workers [12]
have reported the synthesis of various imidazolines and
oxazolines over HPW and obtained excellent yields in a
short time. However, the use of toxic cyanide has limited
the practical application of this approach.
chromatography
using
petroleum
ether:
ethyl
acetate = 6:1~1:1 as eluent.
Recently, hydrogen peroxide has attracted considerable
attention as a mild and green oxidant in the organic
synthesis [13,14]. For example, Bai et al. [13] have
applied hydrogen peroxide in the synthesis of
Product characterization data. 2-Phenylimidazoline.
1
mp 99–101°C. H NMR (600 MHz, CDCl ) δ = 7.83
3
(d, J = 7.1 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.43
(
t, J = 7.4 Hz, 2H), 5.11 (s, 1H), 3.80 (s, 4H).
1
2-substituted imidazolines from aromatic aldehydes and
2-(4-Chlorophenyl)imidazoline.
mp 188°C. H NMR
ethylenediamine catalyzed by NaI. Considering that NaI
is not a green catalyst, we have continued to develop
some new catalytic system for the green synthesis of
(600 MHz, CDCl ) δ = 7.74 (d, J = 8.5 Hz, 2H), 7.41
3
(d, J = 8.5 Hz, 2H), 4.73 (s, 1H), 3.78 (s, 4H).
1
2
-(2, 4-Dichlorophenyl)imidazoline.
mp 98–100°C. H
2-substituted imidazolines. Herein, we report our recent
NMR (600 MHz, CDCl
) δ = 7.72 (d, J = 8.4 Hz, 1H),
3
research on the green synthesis of 2-substituted
imidazolines via a novel hydrogen peroxide oxidative
system catalyzed by HPW and tetrabutylammonium
bromide (TBAB) in water with the synthesis of
7.41 (d, J = 2.0 Hz, 1H), 7.27 (dd, J = 8.4, 2.0 Hz, 1H),
.10 (s, 1H), 3.71 (s, 4H).
5
1
2
-(4-Methylphenyl)imidazoline.
mp 178–180°C.
H
NMR (600 MHz, CDCl ) δ = 7.61 (d, J = 8.1 Hz, 2H),
3
7
.19 (d, J = 7.9 Hz, 2H), 3.74 (s, 4H), 2.38 (s, 3H).
mp 136–138°C.
NMR (600 MHz, CDCl ) δ = 7.71 (d, J = 8.9 Hz, 2H),
2-phenylbenzimidazoline
from
benzaldehyde
and
1
2
-(4-Methoxyphenyl)imidazoline.
H
ethylenediamine (Scheme 1) being chosen as a model system.
3
6
.94 (d, J = 8.9 Hz, 2H), 4.72 (s, 1H), 3.84 (s, 4H), 3.71
(s, 3H).
EXPERIMENTAL
Apparatus, materials, and measurements.
Unless
RESULTS AND DISCUSSION
otherwise stated, all chemicals were purchased from
Baoding Huaxin Reagent and Apparatus Co., Ltd. and
were used as received without further purification. The
reaction mixture was analyzed by gas chromatography
using a 30 m SE-30 capillary column. Flash column
chromatography was carried out on silica 200–300 mesh.
Selection of catalytic system.
According to the good
results of our previous work [13], the synthesis of
-phenylimidazoline was initially performed using HPW
2
instead of NaI in tert-butyl alcohol under similar reaction
conditions, and the results are listed in Table 1. As can
be seen, poor yield of 2-phenylimidazoline was obtained
while solely using HPW or H O , especially for the
Melting points of all products were measured with an X-
melting point apparatus and are uncorrected. H NMR
1
4
2
2
former. In contrast, the yield of 2-phenylimidazoline
markedly increased to 83.6% in the presence of both
HPW and H O , indicating certain synergistic effect
Scheme 1
2
2
between them. Considering the benefit of phase transfer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Green Synthesis of 2-Substituted Imidazolines
Table 1
a
Effect of different oxidants and catalysts for the synthesis of 2-phenylimidazoline .
Catalyst
b
Entry
Time (h)
Temperature (°C)
HPW
TBAB
Oxidant
Yield (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
4
80
80
80
80
80
80
100
80
0.125
—
—
—
—
0.05
0.125
0.25
0.125
0.125
—
7.8
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
2
2
2
2
2
2
2
47.9
83.6
89.1
93.7
75.4
93.1
91.5
0.125
0.125
0.125
0.125
0.125
0.125
a
2 2
Reaction condition: benzaldehyde (1.0 mmol), ethylenediamine (1.1 mmol), t-BuOH (8.0 mL), H O (0.5 mL).
Determined by gas chromatography.
b
catalysts on the oxidations using H O as oxidant [15],
similar while solely using HPW or H O . Fortunately,
2 2
2
2
TBAB was then investigated in attempts to further
improve the reaction efficiency. As envisaged, the
addition of only 0.05 g TBAB increased the yield of
further addition of TBAB markedly increased the yield of
2-phenylimidazoline in water to 89.2%, similar to that in
tert-butyl alcohol, suggesting the good phase transfer
effect of TBAB in this catalytic system. Moreover, we
also investigated the catalytic performance of HSiW and
HPMo under the same reaction conditions for comparison
and found both of them showed lower activity than HPW
in this reaction. Thus, HPW was finally chosen as the
proper catalyst of choice for further study in water.
2-phenylimidazoline to 89.1%. The yield of 2-
phenylimidazoline further increased to 93.7% while the
amount of TBAB was increased from 0.05 to 0.125 g but
sharply decreased to 75.4% with further increasing the
amount of TBAB to 0.25 g. Thus, 0.125 g was selected
as the appropriate amount of TBAB for this catalytic
system. Furthermore, the effect of reaction time and
temperature was also preliminarily examined and found
they conferred no advantage to the yield in certain range.
Although 93.7% is a good result for the synthesis of
Speculation of reaction mechanism.
A plausible
mechanism is then proposed based on the experimental
results and some previous literatures [13,18–20], as
shown in Scheme 2. In organic phase, intermediate 2 is
first formed via cyclization of Schiff base intermediate
2-phenylimidazoline, tert-butyl alcohol was used as
solvent in the aforementioned catalytic system. Due
to the increasing demand on the environmentally
friendly and economical syntheses, the application of
green solvents, such as water, instead of the harmful
organic solvents is a fundamental strategy [16,17]. Thus,
we attempted to carry out this reaction in water
instead of tert-butyl alcohol, and the results are
summarized in Table 2. It was found that the yield of
Scheme 2
2-phenylimidazoline was only 59.3% in water, much
lower than that in tert-butyl alcohol, although they are
Table 2
a
Synthesis of 2-phenylimidazoline in water .
b
Entry
Catalyst
Oxidant
Yield (%)
1
2
3
4
5
6
—
HPW
HPW
H
—
2
O
2
46.1
15.7
59.3
89.2
43.3
72.0
H
2
2
2
2
O
2
2
2
2
HPW/TBAB
HSiW/TBAB
HPMo/TBAB
H
H
H
O
O
O
a
Reaction condition: benzaldehyde (1.0 mmol), ethylenediamine
1.1 mmol), H O (8.0 mL), H (0.5 mL), catalyst (HPW/HSiW/HPMo
.125 g, TBAB 0.125 g) for 2 h at 80°C.
(
2
2 2
O
0
b
Determined by gas chromatography.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Liu, W. Li, Y. Pang, H. Xiao, Y. Zhou and X. Wang
Vol 000
Table 3
a
Synthesis of 2-substituted imidazoline from aldehydes and ethylenediamine .
b
Entry
1
Aldehyde
Product
Time (h)
2
Yield (%)
89.2
2
3
4
2
2
2
87.9
76.8
56.8
5
6
Trace
a
Reaction condition: aldehyde (1.0 mmol), ethylenediamine (1.1 mmol), water (8.0 mL), H
Yields of isolated products.
2
O
2
(0.5 mL), HPW (0.125 g), and TBAB (0.125), 80°C.
b
1, which is formed by the rapid condensation of
CONCLUSIONS
benzaldehyde and ethylenediamine in the absence of
any catalyst. In aqueous phase, a novel peroxo complex
In summary, we have developed an environmentally
benign and economical one-pot synthetic method to
construct 2-substituted imidazolines from aromatic
aldehydes and ethylenediamine using hydrogen peroxide
as oxidant catalyzed by tungstophosphoric acid and
tetrabutylammonium bromide in water. The noteworthy
advantages of this method are its green solvent, high
efficiency, and inexpensive and easily available reagents,
making it an attractive and valuable contribution to
present methodologies.
3
is in situ generated from the combination of H O /
2 2
HPW/TBAB. It can then be rapidly transferred into the
organic phase and accelerate the formation of the
desired 2-phenylimidazoline 5 from intermediate 2.
After that, peroxo complex 3 is changed back to its
precursor 4 and then regenerated via the further
oxidation by H O , confirming the effective recycling of
2
2
this transformation.
Synthesis of derivatives. To evaluate the versatility of
the catalytic system, a series of aromatic aldehydes was
investigated with ethylenediamine under the same
reaction conditions, as shown in Table 3. Both electron-
donating (entry 2) and electron-withdrawing groups
Acknowledgment. We thank the National Natural Science
Foundation of China (no. 21562020) and Institute of Science
and Technology Innovation, DGUT (No. KCYCXPT2017007).
(entry 3) underwent smoothly to give the desired
products in good isolated yields. However, 2,4-
dichlorobenzaldehyde (entry 4) was converted to the
corresponding product in a moderate yield under the
same conditions, and there are conclusions [13,21,22]
from other researchers showing that the o-substituted
aldehydes gave rather lower yields than the m-substituted
and p-substituted aldehydes, suggesting that the main
effect is steric factor rather than electronic. Notably, no
product was detected in 6 h when phenylacetaldehyde
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet