A facile and economical procedure for the synthesis of maleimide derivatives using an acidic ionic liquid as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.06.025

Seven maleimide derivatives were synthesized in good yields and high purity from the corresponding maleamic acids using a Bronsted acidic room temperature ionic liquid (RTIL) as a catalyst. The products were obtained through merely a decanting and removal of the solvent, suggesting that this procedure is superior to the conventional routes, in which the strong organic/inorganic acids were used as the catalysts, as well as a complicated post-processing procedure for the separation and purification of the products was employed.

Full text of DOI:10.1016/j.tetlet.2012.06.025

Tetrahedron Letters 53 (2012) 4245–4247
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Tetrahedron Letters
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A facile and economical procedure for the synthesis of maleimide
derivatives using an acidic ionic liquid as a catalyst
Kai Li a,b, Chao Yuan a, Shijun Zheng b, Qiang Fang a,c,
⇑
a Key Laboratory of Organofluorine Chemistry and Laboratory for Polymer Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, PR China
b School of Materials Science and Engineering, Zhengzhou University, Zhengzhou 450052, PR China
c Shanghai Advanced Research Institute, Chinese Academy of Sciences, 99 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Seven maleimide derivatives were synthesized in good yields and high purity from the corresponding
maleamic acids using a Brønsted acidic room temperature ionic liquid (RTIL) as a catalyst. The products
were obtained through merely a decanting and removal of the solvent, suggesting that this procedure is
superior to the conventional routes, in which the strong organic/inorganic acids were used as the cata-
lysts, as well as a complicated post-processing procedure for the separation and purification of the prod-
ucts was employed.
Received 8 March 2012
Revised 30 May 2012
Accepted 5 June 2012
Available online 12 June 2012
Keywords:
Ionic liquids
Catalysts
Ó 2012 Elsevier Ltd. All rights reserved.
Maleimides
Heat resistant polymers
Maleimide derivatives have been widely used in industry as anti-
bacterial agents,1–4 pharmaceutical intermediates,3,5 crosslinking
reagents for natural rubbers,6,7 encapsulation resins of integrated
circuit (IC) dies,8 and structural adhesives for fiber-reinforced
composites in the aerospace industry.9 Among these compounds,
N-arylmaleimides have recently aroused special interest because
they can be used as the modifiers for the engineering plastics,10
and the modified plastics show excellent heat resistance.11,12 There-
fore, their consumption in industry has increased year after year.
However, high cost derived from the use of expensive agents
and complicated procedure for the separation of the products,
has hindered the applications of these compounds. Accordingly,
developing a convenient route for the preparation of maleimide
derivatives is very desirable.
Usually, the synthesis of maleimide derivatives was carried out
via a two step route.13,14 For example, mixing maleic anhydride
and an amine produced a maleamic acid, which was then dehy-
drated through a ring-closing process to form a maleimide. Herein,
the dehydration was a crucial step that greatly influenced the cost of
maleimides. In many cases,14,15 acetic anhydride was used as
a dehydrating agent, in which maleamic acids can be almost quan-
titatively converted into maleimides. Nevertheless, large amounts
of water were required to decompose the excess acetic anhydride
and remove acetic acid formed during the dehydration and
post-processing, which may bring about an additional cost for treat-
ment of waste water. In particular, acetic anhydride has been added
to a list of safety monitoring chemicals in many countries because it
is an important reactant to prepare a notorious drug heroin. To
change such a situation, researchers developed a new route, in
which azeotropic dehydrating agents and some Brønsted or Lewis
acidic catalysts were used.16 Among these new procedures, general
azeotropic dehydrating agents were aromatic/or alicyclic hydrocar-
bons such as toluene17,18 and cyclohexane,17,18 and typical Brønsted
acidic catalysts including phosphoric acid, concentrated sulfuric
acid, and p-toluenesulfonic acid. Lewis acidic catalysts19,20 were
also used sometimes, and organotin compounds were usual.
Although the routes mentioned above can avoid the use of acetic
anhydride, they generated lower yields of the maleimides during
a longer reaction time. Moreover, large amount of waste water
was produced from the removal of acidic catalysts, which still
caused environmental problems.
Room temperature ionic liquids (RTILs) have received much
attention in the past decades because of their liquidity in room
temperature, nonvolatile and tunable physical properties,21,22
which provide great convenience for the organic reactions. Of var-
ious RTILs, strong Brønsted acidic RTILs are more attractive due to
their stability to moisture,22 unlike some Lewis acidic RTILs that
are easily hydrolyzed even in the presence of trace amounts of
water.21,23 Therefore, their application fields have been greatly
extended in the recent years, involving esterification,22,24 rear-
rangement,24 and Friedel–Crafts reaction.25 However, they were
⇑
Corresponding author.
E-mail address: qiangfang@mail.sioc.ac.cn (Q. Fang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.025

4246
K. Li et al. / Tetrahedron Letters 53 (2012) 4245–4247
Table 1
HSO4
Optimization of reaction conditions
N
N
SO3H
O
O
OH
I
I, propyl acetate
N
reflux
-H2O
NH
Figure 1. Chemical structure of the ionic liquid used in this work.
O
O
a
Entry
a/I (molar ratio)
Time (h)
Yieldsa (%)
Purityb (%)
O
O
O
O
O
N
O
1
2
3
4
5
6
1.0/1.0
1.0/1.0
1.0/1.0
2.0/1.0
3.0/1.0
5.0/1.0
2
4
7
3
3
4
72
76
78
80
83
80
98.20
98.30
97.90
98.00
98.00
98.20
solvents
r.t
-H2O
OH
NHR1
+
R1NH2
R1
O
R1 = aryl, alkyl; solvents = touluene, acetone, CHCl3
Scheme 1. General procedure for the synthesis of maleimides.28
a
Isolated yields.
b
Measured by HPLC. All characterization data are listed in Supplementary data.
not applied in the synthesis of maleimide derivatives. Although
there was a report regarding the preparation of some phenylimide
derivatives employing a non strong Brønsted acidic RTIL,26 its
application was much limited due to the use of a complicated
post-processing procedure, including the use of high volatile sol-
vent (ether) for extracting the products from RTIL, purification of
the products by recrystallizations, and removal of water in RTIL
for a long period. Accordingly, we have made an effort to synthe-
size maleimides using the acidic room temperature ionic liquids.
On the basis of low cost and easy synthesis of the imidazole based
RTIL, the following RTIL27 was used in our investigation, and its
chemical structure is shown in Figure 1.
Most of maleimides were synthesized via a two step route, as
shown in Scheme 1. Because maleamic acids were usually obtained
in almost quantitative yields, our interest was focused on the ring-
closing step. To examine whether the Brønsted acidic room tem-
perature ionic liquid can realize the ring- closing of maleamic
acids, our initial approach was performed with N-phenylmaleic
acid as a substrate in the presence of I (Fig. 1). When equal moles
of N-phenylmaleamic acid and I were mixed in acetone and the
mixture was heated at 50 °C for 7 h, N-phenylmaleimide was ob-
tained in a yield of 30%, suggesting Brønsted acidic room temper-
ature ionic liquid can catalyze ring-closing of maleamic acids.
Considering that removal of the water formed during the reaction
may improve the yield of the maleimide, we employed propyl ace-
tate as an azeotropic dehydrating agent, and the yield of N-phenyl-
maleimide increased to 72% after the reaction had run for 2 h.
Further optimization of the reaction conditions was carried out,
and the results indicated that the highest yield was obtained when
the molar ratio of N-phenylmaleamic acid to I was 3:1 and the
reaction time was 3 h, as shown in Table 1.
To compare the synthetic procedure in this work with the con-
ventional routes, p-toluenesulfonic acid was used for replacement
of I as the catalyst. N-Phenylmaleimide was obtained in a yield of
near 60% with a purity of 89% after refluxing for 18 h in ethanol,
suggesting that ionic liquid procedure is superior to the conven-
tional route.
Table 2
An application of the catalytic reaction in the preparation of maleimide derivatives30
O
O
OH
N
O
R2
NH
R2
O
1a-4a
5a
1-4
O
O
N
O
O
O
O
I, propyl acetate
OH
NH
HO
N
CH2
H
N
CH2
O
reflux
-H2O
O
O
O
5
OH
N
NH
O
O
6
6a
Entry
R2
Products
Yieldsa (%)
Purityb (%)
1
2
3
4
5
6
–COOH (1)
–OH (2)
–CF3 (3)
–C6F13 (4)
—
1a
2a
3a
4a
5a
6a
51
50
77
67
50
52
98.20
98.80
98.50
99.80
98.00
98.90
–C4H9 (6)
a
Isolated yields, 1a and 2a were purified by recrystallization from isopropanol. Compound 5a was recrystallized from toluene.
Measured by HPLC. All characterization data are listed in Supplementary data.
b

K. Li et al. / Tetrahedron Letters 53 (2012) 4245–4247
4247
Table 3
References and notes
Recycling of I in the synthesis of N-phenylmaleimide
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2005, 40, 732–735.
Cyclea
Yieldsb (%)
Purityc (%)
1
2
3
4
5
6
83
83
80
81
80
81
98.30
97.90
98.50
98.00
98.30
98.20
a
b
c
The molar ratio of N-phenylmaleamic acid to I = 3:1; reaction time was 3 h.
Isolated yields.
Measured by HPLC.
7. Patel, R.; Sabet, S. A. US Patent 5621045, 1997.
8. Switky, A. US Patent 2413489, 1995.
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Stiteler, C. H. J. Org. Chem. 1960, 25, 56–60.
16. Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997, 62, 2652–2654.
17. Vegh, Z.; Balko, J. US Patent 2008125597, 2008.
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19. Masasuke, O.; Hyogo, A. S.; Toshimitsu, N.; Osaka, T. S.; European Patent,
0812824A1, 1997.
20. Takamichi, A. European Patent 0393713A1, 1990.
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22. Dubreuil, J. F.; Bourahla, K.; Rahmouni, M.; Bazureau, J. P.; Hamelin, J. Catal.
Commun. 2002, 3, 185–190.
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2698–2700.
24. Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes, D. C.; Davis, J.
H., Jr. J. Am. Chem. Soc. 2002, 124, 5962–5963.
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2097–2098.
26. Le, Z. G.; Chen, Z. C.; Hu, Y.; Zheng, Q. G. Synthesis 2004, 7, 995–998.
27. Gui, J.; Cong, X.; Liu, D.; Zhang, X.; Hu, Z.; Sun, Z. Catal. Commun. 2004, 5, 473–
477. Characterization data of RTIL used in our investigation, 1H NMR (300 MHz,
D2O) d 8.52 (s, 1H), 7.25 (d, J = 17.4 Hz, 2H), 4.03 (t, J = 7.0 Hz, 2H), 3.67 (s, 3H),
2.81–2.64 (m, 2H), 1.79 (d, J = 15.0, 7.4 Hz, 2H), 1.53 (d, J = 15.5, 8.0 Hz, 2H).
28. (a) Hao, J.; Jiang, L.; Cai, X. Polymer 1996, 37, 3721–3727; (b) Peng, J.; Zhang, L.;
Zhou, W.; Zuo, G. Henan Huagong (in Chinese) 2003, 7, 13–16.
29. (a) Chandra, R.; Rajabi, L. J. Macromol. Sci., Rev. Macromol. Chem. Phys. 1997, C37,
61–96; (b) Fang, Q.; Jiang, L. J. Appl. Polym. Sci. 2001, 81, 1248–1257; (c) Fang,
Q.; Ding, X.; Wu, X.; Jiang, L. Polymer 2001, 42, 7595–7602.
By using the above optimized synthetic route, we further inves-
tigated the generality of the substrates (Table 2, entries 1–6). The
bismaleimide (5a) and the substituted monomaleimides (1a–4a,
6a) were obtained with high purity and isolated yields of higher
than 50%, exhibiting that the Brønsted acidic ionic liquid is suitable
for a wide range of substrates. It is noted that 2a was usually pre-
pared by dehydration of 2 in acetic anhydride at first and then by
alcoholysis in methanol or ethanol.28 In many cases, incomplete
alcoholysis during the reaction often caused that the product was
difficult to be purified.28a In contrast, in our case, crude 2a (con-
taining a trace of impurity according to a TLC result) was obtained
through merely a decanting and removal of the solvent (propyl
acetate), and pure 2a can be collected by washing the crude prod-
uct with isopropanol or recrystallization from isopropanol. Because
functional maleimides, such as 1a and 2a, can be easily derivated
to a series of important polymers,29 as well as the bismaleimides
such as 5a has a broad application in industry,29 the results in this
work indicate that the synthetic route based on ionic liquid would
be a good choice for the preparation of maleimides.
In order to evaluate the reusability of I, a series of recycle exper-
iments were carried out with taking N-phenylmaleimide as an
example, and the results are summarized in Table 3. As can be seen
in Table 3, I still showed high catalysis activity after being reused
for six times, suggesting that the RTIL procedure is much superior
to the conventional routes.
In conclusion, we have successfully synthesized seven typical
maleimides via a direct imidation of the corresponding maleamic
acids using a Brønsted acidic room temperature ionic liquid as a
catalyst and propyl acetate as an azeotropic dehydrating agent,
respectively. In comparison with the conventional routes using
the strong organic/inorganic acids as the catalysts or using acetic
anhydride as a dehydrating agent, RTIL procedure is very conve-
nient and economical. Because maleimides have been widely used
in industry, RTIL route would be a good method for the preparation
of maleimide derivatives.
30. General synthetic procedure: To
a stirring solution of maleic anhydride
(29.42 g, 30 mmol) in dry toluene (300 mL) was added dropwise a solution
of aniline (27.4 mL, 30 mmol) in dry toluene (10 mL) at room temperature. The
mixture was vigorously stirred for 3 h, and the formed precipitate was
separated by filtration. The cake was washed with toluene and dried under
reduced pressure to give N-phenylmaleamic acid, as a yellow solid, 95% yield.
N-phenylmaleamic acid (4.176 g, 21.8 mmol) thus obtained was added to a
flask charged with ionic liquid I (2.302 g, 7.28 mmol) and propyl acetate
(66 mL), and the mixture was heated to reflux, and the formed water during
the reaction was removed by using a Dean–Stark trap. After maintaining the
refluxing for 3 h under intensive stirring, the mixture was cooled to room
temperature. The upper layer containing propyl acetate and product were
separated by decanting, and the lower layer was extracted by propyl acetate
(50 mL Â 3). The organic layers were combined, followed by evaporation under
vacuum to give N-phenylmaleimide as a pale-yellow crystal solid. Yield, 83%.
1H NMR (300 MHz, CDCl3) d 7.47 (t,2H), 7.33–7.39 (t, 3H), 6.85 (s, 2H).
Analogously, 1a–6a was prepared. Characterization: Compound 1a, 1H NMR
Acknowledgments
(300 MHz, DMSO-d6) d 8.05 (d, 2H), 7.50 (d, 2H), 7.23 (s, 2H). Compound 2a, 1
H
Financial supports from the Ministry of Science and Technology
of China (2010BAK67B12 and 2011ZX02703) are gratefully
acknowledged.
NMR (300 MHz, DMSO-d6) d 9.69 (s, 1H), 7.27–7.01 (m, 4H), 6.80 (d, 2H).
Compound 3a, 19F NMR (282 MHz, CDCl3) d À63; 1H NMR (300 MHz, CDCl3) d
6.56 (2H), 7.1 (2H), 7.5 (2H). Compound 4a, 1H NMR (300 MHz, CDCl3) d 7.74
(d, 2H), 7.55 (d, 2H), 6.90 (s, 2H); 19F NMR (282 MHz, CDCl3) d À81.48 (t, 3F),
À110.04 (t, 2F), À122.08 (s, 2F), -122.59 (s, 2F), À123.43 (s, 2F), À126.78 (s, 2F).
Compound 5a, 1H NMR (300 MHz, DMSO-d6) d 7.35 (d, J = 8.3 Hz, 4H), 7.30–
7.20 (d, 4H), 7.20–7.12 (s, 4H), 4.02 (s, 2H). Compound 6a, 1H NMR (300 MHz,
CDCl3) d 6.62 (s, 2H), 3.43 (t, J = 7.2 Hz, 2H), 1.48 (m, J = 14.5, 7.4 Hz, 2H), 1.23
(m, J = 14.7, 7.3 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H). The detailed characterization
data are summarized in Supplementary data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
025.