An efficient protocol for the synthesis of N-Alkyl- and N-Arylimides using the lewis acidic ionic liquid choline chloride-2ZnCl2

Article abstract of DOI:10.1002/jccs.200900124

Lewis acidic ionic liquid choline chloride-2ZnCl₂ is shown to be for the first time an excellentmedium and efficient catalyst for the synthesis of N-alkyl- and N-arylimides in good yields under mild conditions.

Full text of DOI:10.1002/jccs.200900124

Journal of the Chinese Chemical Society, 2009, 56, 839-842
839
An Efficient Protocol for the Synthesis of N-Alkyl- and N-Arylimides Using
the Lewis Acidic Ionic Liquid Choline Chloride·2ZnCl2
You-Teng Xiea (
), Rei-Sheu Houb* (
), Huey-Min Wangb (
),
Iou-Jiun Kangc (
) and Ling-Ching Chena* (
)
aGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
bChung Hwa University of Medical Technology, Tainan 717, Taiwan, R.O.C.
cDivision of Biotechn ology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 350, Taiwan, R.O.C.
Lewis acidic ionic liquid choline chloride·2ZnCl2 is shown to be for the first time an excellent medium
and efficient catalyst for the synthesis of N-alkyl- and N-arylimides in good yields under mild condi-
tions.
Keywords: Choline chloride·2ZnCl2; Succinic anhydride; Phthalic anhydride; Ionic liquid.
INTRODUCTION
Imide derivatives are an important class of substrates
have been studied extensively for use in acid-catalysed re-
actions, particularly in Friedel-Crafts reactions.6 However,
for practical utilization, these imidazolium-based ionic liq-
uids still suffer from the relatively expensive cost. In the
case of chloroaluminate ionic liquid, its poor stability to-
ward moisture can lead to undesired side reactions. More
recently, a series of inexpensive and moisture-stable Lewis
acidic ionic liquids have been prepared from choline chlo-
ride and ZnCl2,7 and been used in Diels–Alder reactions8
and Fischer indole synthesis.9 We have reported an effi-
cient protocol for the Friedländer quinoline synthesis using
Lewis acidic ionic liquid choline chloride·2ZnCl2.10 In this
paper, we report the use of choline chloride·2ZnCl2 as a sol-
vent and catalyst for the synthesis of N-alkyl- and N-aryl-
imides (Scheme I).
for biological and chemical applications.1 Accordingly, ex-
tensive progress toward the synthesis of these derivatives
has been made in recent years. Well known methods in-
clude (1) dehydrative condensation of anhydride and amine
catalyzed by conc. H2SO4 in acetic anhydride under reflux
conditions,2 (2) Direct N-alkylation of phthaloyl dichloride
with azide in the presence of PPh3 in CH2Cl2,3 (3) N-alkyla-
tion of imides using of alcohol promoted by PPh3 and DIAP
in THF,4 etc. These methods have not been entirely satis-
factory owing to the drawbacks such as using of organic
solvents. It is necessary to develop an alterative solvent for
the synthesis of imides under mild and environmentally
benign conditions.
Ionic liquids have been the subject of consideeable
interest in the context of green synthesis because of their
wide acceptability as alternative green reaction media.5 Re-
cently, the alkylimidazolium-aluminium chloride mixtures
First, we found that the reaction of succinic anhydride
with aniline in ionic liquid choline chloride·2ZnCl2 at 60
°C for 1 h to gave N-phenylsuccinimide (3a) in 90% yield.
In a similar fashion, the reaction of phthalic anhydride with
Scheme I

840 J. Chin. Chem. Soc., Vol. 56, No. 4, 2009
Xie et al.
a variety of amines also underwent smooth dehydrative
condensation to afford the respective imides in good yields.
As can be seen from Table 1, the reaction is general and ap-
plicable to aliphatic and aromatic amines bearing different
functionalities such as methyl, methoxy, chloro, nitro and
cyano groups. When the reaction was conducted in ionic
liquid 1-butyl-3-methylimidazolium hexafluorophosphate
([bmim][PF6]), however, the preparation of N-phenylphthal-
imide (3f) required 8 h at 80 °C to go to completion.11
The ionic liquid choline chloride·2ZnCl2 can typi-
cally be recovered by extracting it from the reaction mix-
tures and next by vacuum drying. The recovered solvent
can be reused with no appreciable decrease in yields. The
representative results are summarized in Table 2. The pres-
ent method has many advantages including high efficiency,
operational simplicity, environmentally benign character
and ability to be recycled.
Table 1. The synthesis of N-alkyl- and N-arylimides using ionic
liquid choline chloride·2ZnCl2
Entry Anhydride
O
Amine
Product Yield (%)
O
NH2
1
3a
90
O
2a
1a
CH2NH2
2
3
1a
1a
3b
3c
86
84
2b
n-C4H9NH2
2c
O
O
4
5
2a
2b
3d
3e
88
92
O
1b
1b
In conclusion, we describe a mild and efficient route
for the synthesis of N-alkyl- and N-arylimides utilizing
choline chloride·2ZnCl2 as a solvent and catalyst in good
yields under mild conditions. Compared to imidazolium-
based ionic liquids, choline chloride·2ZnCl2 is easier to the
prepared, less moisture-sensitive and cheaper.
O
O
6
2a
3f
87
O
1c
1c
Me
MeO
Cl
NH2
NH2
EXPERIMENTAL SECTION
7
3g
3h
3i
89
82
84
87
90
All melting points are uncorrected. The IR spectra
were recorded on a Shimadzu IR-27 G spectrophotometer.
1H NMR and 13C NMR spectra were recorded on a Varian
Unity Plus 400 MHz. Chemical shifts (d) were measured in
ppm with respect to TMS. MS were obtained on a JEOL
JMS D-300 instrument. Elemental analyses were per-
formed on an EA-1110 instrument.
2d
2e
8
1c
1c
1c
1c
NH2
NH2
NH2
NH2
9
2f
2g
2h
N-Phenylsuccinimide (3a); Typical procedure
Br
10
11
3j
A mixture of succinic anhydride (100 mg, 1.0 mmol)
and aniline (93 mg, 1.0 mmol) in ionic liquid choline chlo-
ride·2ZnCl2 (0.5 mL) was stirred for 1 h at 60 °C. The reac-
tion mixture was extracted with ethyl acetate. The remain-
ing ionic liquid was reused after drying in vacuum. The ex-
tract was dried (MgSO4) and concentrated under reduced
pressure and the residue was purified by chromatography
on a silica gel column eluting with n-hexane-ethyl acetate
(1:1) to give 3a, mp 152-154 °C (lit.12 mp 156-167 °C),
yield 90%. IR (KBr) n: 3054, 2935, 1708, 1500, 1390,
1187, 764, 699 cm-1; 1H NMR (CDCl3) d: 2.90 (s, 4H), 7.28
(d, J = 7.2 Hz, 2H), 7.39-7.40 (m, 1H), 7.49-7.50 (m, 2H);
13C NMR (CDCl3, 100 MHz) d: 28.4, 126.4, 128.6, 129.2,
131.8, 176.2; EI-MS m/z (relative intensity) 175 (M+), 147,
O2N
3k
N
C
12
13
1c
1c
3l
85
83
2i
2b
3m
O
O
14
2b
3n
87
O
1d

Synthesis of N-Alkyl- and N-Arylimides
J. Chin. Chem. Soc., Vol. 56, No. 4, 2009 841
1
3033, 1771, 1713, 1513, 1382, 1116, 792, 720 cm-1; H
Table 2. Results obtained using recycled ionic liquid choline
chloride·2ZnCl2
NMR (CDCl3) d: 2.41 (s, 3H), 7.31 (s, 4H), 7.80 (dd, J =
5.2, 3.2 Hz, 2H), 7.95 (dd, J = 5.4, 2.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) d: 21.1, 123.7, 126.4, 128.9, 129.7,
131.7, 134.3, 138.2, 167.4; EI-MS m/z (relative intensity)
237 (M+), 194, 193, 192, 165, 76.
Entry
Product
Cycle
Yield (%)
1
2
3
3a
3a
3a
1
2
3
90
91
89
N-(4-Methoxyphenyl)phthalimide (3h)
mp 164-166 °C. IR (KBr) n: 3064, 1715, 1516, 1387,
1102, 784, 713 cm-1; 1H NMR (CDCl3) d: 3.83 (s, 3H), 7.01
(dt, J = 9.6, 2.4 Hz, 2H), 7.33 (dt, J = 9.6, 2.4 Hz, 2H), 7.76
120, 119, 118, 93.
N-Benzylsuccinimide (3b)
mp 99-100 °C (lit.12 mp 98-99 °C). IR (KBr) n: 3307,
3036, 1695, 1431, 1307, 713, 698 cm-1; 1H NMR (CDCl3)
d: 2.67 (s, 4H), 4.64 (s, 2H), 7.26-7.32 (m, 3H), 7.38 (d, J =
6.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d: 28.1, 42.3,
127.9, 128.5, 128.8, 135.7, 176.8; EI-MS m/z (relative in-
tensity) 189 (M+), 161, 160, 132, 119, 104.
(dd, J = 5.4, 2.8 Hz, 2H), 7.92 (dd, J = 5.6, 2.8 Hz, 2H); 13
C
NMR (CDCl3, 100 MHz) d: 55.4, 114.4, 123.5, 124.1,
127.8, 131.6, 134.2, 159.1, 167.5; EI-MS m/z (relative in-
tensity) 253 (M+), 238, 210, 130. Anal. Calcd for
C15H11NO3: C, 71.14; H, 4.38; N, 5.53. Found: C, 71.32; H,
4.15; N, 5.78.
N-Butylsuccinimide (3c)
N-(4-Chlorophenyl)phthalimide (3i)
mp 202-204 °C (lit.11 mp 192-194 °C). IR (KBr) n:
Oily compound (lit.13 oily compound). IR (neat) n:
2957, 1767, 1697, 1403, 875, 731 cm-1; 1H NMR (CDCl3)
d: 0.85 (t, J = 7.6 Hz, 3H), 1.47 (m, 2H), 1.25 (m, 2H), 2.64
(s, 4H), 3.43 (t, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100
MHz) d: 13.4, 19.9, 28.0, 29.6, 38.4, 177.2; EI-MS m/z
(relative intensity) 156 (M+), 113, 100, 84.
1
3060, 1789, 1711, 1494, 1389, 1118, 789, 715 cm-1; H
NMR (CDCl3) d: 7.39-7.49 (m, 4H), 7.80 (dd, J = 5.4, 2.8
Hz, 2H), 7.95 (dd, J = 5.4, 2.8 Hz, 2H); 13C NMR (CDCl3,
100 MHz) d: 123.8, 127.6, 129.3, 130.1, 131.5, 133.8,
134.5, 167.0; EI-MS m/z (relative intensity) 259 (M++2)
257 (M+), 178, 76.
N-Phenylmaleimide (3d)
mp 86-87 °C (lit.12 mp 89-90 °C). IR (KBr) n: 3158,
3092, 1709, 1594, 1503, 1391, 1144, 831, 694 cm-1; H
N-(4-Bromophenyl)phthalimide (3j)
mp 205-206 °C (lit.11 mp 202-204 °C). IR (KBr) n:
1
1
3060, 1787, 1710, 1491, 1386, 1118, 789, 715 cm-1; H
NMR (CDCl3) d: 6.86 (s, 2H), 7.33-7.39 (m, 3H), 7.47 (t, J
= 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d: 126.1,
128.0, 129.2, 131.1, 134.2, 169.5; EI-MS m/z (relative in-
tensity) 173 (M+), 129.
NMR (CDCl3) d: 7.36 (dt, J = 9.2, 2.2 Hz, 2H), 7.61-7.64
(m, 2H), 7.80 (dd, J = 5.6, 3.2 Hz, 2H), 7.95 (dd, J = 5.6, 2.8
Hz, 2H); 13C NMR (CDCl3, 100 MHz) d: 121.8, 123.8,
127.9, 130.7, 131.6, 132.3, 134.5, 166.9; EI-MS m/z (rela-
tive intensity) 303 (M++2), 301 (M+), 259, 257, 178.
N-(4-Nitrophenyl)phthalimide (3k)
N-Benzylmaleimide (3e)
mp 83-84 °C (lit.12 mp 69-70 °C). IR (KBr) n: 3092,
3062, 3033, 1700, 1576, 1497, 1342, 1308, 1136, 841, 781,
724, 693 cm-1; 1H NMR (CDCl3) d: 4.67 (s, 2H), 6.70 (s,
2H), 7.25-7.35 (m, 5H); 13C NMR (CDCl3, 100 MHz) d:
41.3, 127.8, 128.3, 128.6, 134.1, 136.1, 170.4; EI-MS m/z
(relative intensity) 187 (M+), 169, 130, 106.
mp 266-267 °C (lit.11 mp 264-266 °C). IR (KBr) n:
1
3061, 1782, 1732, 1520, 1343, 1077, 747, 709 cm-1; H
NMR (CDCl3) d: 7.75-7.79 (m, 2H), 7.84-7.86 (m, 2H),
8.01 (dd, J = 5.6, 3.2 Hz, 2H), 8.38 (dt, J = 9.6, 2.0 Hz, 2H);
13C NMR (CDCl3, 100 MHz) d: 24.1, 124.4, 126.3, 131.3,
135.0, 137.5, 146.4, 166.4; EI-MS m/z (relative intensity)
268 (M+), 238, 178, 166, 76.
N-Phenylphthalimide (3f)
mp 206-208 °C (lit.12 mp 208-209 °C). IR (KBr) n:
1
3047, 1771, 1699, 1495, 1380, 1109, 755, 703 cm-1; H
NMR (CDCl3) d: 7.39-7.53 (m, 5H), 7.80 (dd, J = 5.4, 2.8
Hz, 2H), 7.96 (dd, J = 5.6, 3.2 Hz, 2H); 13C NMR (CDCl3,
100 MHz) d: 123.7, 126.5, 128.1, 129.1, 131.7, 134.4,
167.3; EI-MS m/z (relative intensity) 223 (M+), 179, 178,
76.
N-(4-Cyanophenyl)phthalimide (3l)
mp 184-186 °C. IR (KBr) n: 3063, 1781, 1720, 1508,
1377, 1079, 785, 710 cm-1; 1H NMR (CDCl3) d: 7.67-7.70
(m, 2H), 7.78-7.81 (m, 2H), 7.82-7.84 (m, 2H), 7.98 (dd, J
= 5.6, 2.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d: 111.3,
118.2, 124.1, 126.4, 131.3, 132.9, 134.9, 135.9, 166.4;
EI-MS m/z (relative intensity) 248 (M+), 205, 204, 177.
N-(4-Methylphenyl)phthalimide (3g)
mp 200-202 °C (lit.11 mp 203-204 °C). IR (KBr) n:

842 J. Chin. Chem. Soc., Vol. 56, No. 4, 2009
Xie et al.
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N-Benzylphthalimide (3m)
mp 118-119 °C (lit.12 mp 118-119 °C). IR (KBr) n:
1
3055, 1767, 1701, 1392, 1106, 951, 787, 722 cm-1; H
NMR (CDCl3) d: 4.83 (s, 2H), 7.24-7.31 (m, 3H), 7.41 (d, J
= 6.8 Hz, 2H), 7.65-7.67 (m, 2H), 7.80-7.82 (m, 2H); 13
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128.6, 132.0, 134.0, 136.2, 167.9; EI-MS m/z (relative in-
tensity) 237 (M+), 219, 208, 130, 105, 104, 78, 77.
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1
3025, 2924, 1723, 1457, 1355, 755, 702 cm-1; H NMR
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4H), 4.95 (s, 2H), 7.23-7.37 (m, 5H); 13C NMR (CDCl3,
100 MHz) d: 17.0, 32.8, 42.6, 127.4, 128.3, 128.8, 137.2,
172.4; EI-MS m/z (relative intensity) 203 (M+), 175, 146,
118, 104, 92, 84.
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ACKNOWLEDGEMENT
We gratefully acknowledge the National Science
Council of the Republic of China for financial support of
this work.
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Received September 3, 2008.
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