Polyethylene glycol as a nonionic liquid solvent for the synthesis of N-alkyl and N-arylimides

Article abstract of DOI:10.1080/00397910802474966

Polyethylene glycol (PEG) an inexpensive, nontoxic, environmentally friendly reaction medium for the synthesis of N-alkyl and N-arylphthalimides to afford the corresponding adducts in excellent yields under mild reaction conditions. The use of PEG avoids the use of acidic or basic catalysts, and moreover PEG could be recovered and reused.

Full text of DOI:10.1080/00397910802474966

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Polyethylene Glycol as a
Nonionic Liquid Solvent for
the Synthesis of N-Alkyl and N-
Arylimides
Jun Liang a , Jing Lv a , Ji-cai Fan a & Zhi-cai Shang a
a Department of Chemistry, Zhejiang University,
Hangzhou, China
Published online: 14 Jul 2009.
To cite this article: Jun Liang , Jing Lv , Ji-cai Fan & Zhi-cai Shang (2009)
Polyethylene Glycol as a Nonionic Liquid Solvent for the Synthesis of N-Alkyl
and N-Arylimides, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:16, 2822-2828, DOI:
10.1080/00397910802474966
To link to this article: http://dx.doi.org/10.1080/00397910802474966
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Synthetic Communications1, 39: 2822–2828, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802474966
Polyethylene Glycol as a Nonionic Liquid Solvent
for the Synthesis of N-Alkyl and N-Arylimides
Jun Liang, Jing Lv, Ji-cai Fan, and Zhi-cai Shang
Department of Chemistry, Zhejiang University, Hangzhou, China
Abstract: Polyethylene glycol (PEG) an inexpensive, nontoxic, environmentally
friendly reaction medium for the synthesis of N-alkyl and N-arylphthalimides
to afford the corresponding adducts in excellent yields under mild reaction
conditions. The use of PEG avoids the use of acidic or basic catalysts, and
moreover PEG could be recovered and reused.
Keywords: N-Arylimides, nonionic liquid, nontoxic, phase-transfer catalysts,
polyethylene glycol (PEG)
INTRODUCTION
Imide derivatives are among organic compounds that have numerous
applications in biological properties,[1] synthetic chemistry,[2] and poly-
mer chemistry. To date, most commonly N-substituted phthalimides
are formed by direct dehydrative condensation of an amine with phthalic
anhydride,[3] but those methods need high temperatures and long reac-
tion times and sometimes give poor yields. Recently, our interest has been
in the development of synthetic methods using polyethylene glycol (PEG)
as a novel environmentally and industrially benign medium and promo-
ter. In this article, we describe the use of a simple and widely available
polymer, PEG, as a nontoxic, inexpensive, nonionic liquid solvent of
low volatility. PEG and its monomethyl ethers are inexpensive, thermally
Received June 5, 2008.
Address correspondence to Zhi-cai Shang, Department of Chemistry, Zhejiang
University, Zheda Road, No. 38, Hangzhou 310027, China. E-mail: shangzc@
zju.edu.cn
2822

PEG as Solvent for Imide Synthesis
2823
Scheme 1.
stable, recoverable, and nontoxic media for phase-transfer catalysts.[4]
PEG, a biologically acceptable polymer used extensively in drug delivery
and in bioconjugates as tool for diagnostics, has hitherto not been widely
used as a solvent medium but has been used as a support for various
transformations.[5]
Herein, we report PEG 400 as a recyclable reaction medium for the
synthesis of N-alkyl and N-arylphthalimides without any use of acidic
and basic catalysts (Scheme 1). Such reactions do not generate any toxic
waste by-products.
RESULTS AND DISCUSSION
Our efforts began with succinic anhydride and benzylamine (Table 1,
entry 3c) in PEG (400 MW) at 120 ꢀC for 3 h, and the corresponding pro-
duct N-benzylsuccinimide was obtained in 97% yields after a standar-
dized workup protocol. Other amines were treated with two kinds of
anhydride using PEG 400 as reaction media. As can be seen from
Table 1, the reaction is general and applicable to aliphatic and aromatic
amines bearing various groups such as chloro, methyl, and nitro groups.
The reactions proceeded efficiently at 120 ꢀC without the need for any
further acidic or basic catalyst and went to completion in a short time
(3–6 h). Nevertheless, the yields of entries 7 and 14 were lower than other
amines relatively, perhaps caused by the steric hindrance effect. PEG as a
recyclable reaction medium used in these reactions eliminates the use of
volatile organic solvents. In addition to the often-referred advantages
of using PEG 400 as solvent, this procedure has the following remarkable
features as compared to the conventional method: (1) short reaction
times, (2) clean reaction protocol, and (3) high yields.

2824
J. Liang et al.
Table 1. Reaction of anhydride with amines in PEGa
Entry
Substrate
Product
Time (h)
Yield (%)b
1
2
3
a
b
c
3
3
3
95
98
97
4
5
d
e
6
6
96
95
6
7
f
6
6
97
89
g
8
a
3
95
(Continued )

PEG as Solvent for Imide Synthesis
2825
Table 1. Continued
Entry
9
Substrate
b
Product
Time (h)
3
Yield (%)b
97
10
11
12
c
d
e
3
6
6
96
95
94
13
14
f
6
6
98
92
g
aReaction conditions: anhydride 2 mmol, amine 2 mmol, PEG-400 4.0 g, 120 ꢀC.
bIsolated yield.
To prove that the use of PEG as solvent is also practical, it must be
conveniently recycled with minimal loss and decomposition. Because
PEG is immiscible with aliphatic hydrocarbons, the desired product
may be extracted with compounds such as cyclohexane, and the retained
PEG phase may be reused.[6] The solvent phase was recycled with no loss
of reactivity for three cycles, although a weight loss of about 5% of PEG
was observed from cycle to cycle. The recovered solvent can be reused
with no appreciable decrease in yield. The representative results are
summarized in Table 2.
To investigate the effect of PEG, we studied the reaction of succinic
anhydride (2 mmol) and benzylamine (2 mmol) in protic solvents (4 g)
(water, methanol, and ethanol) at refluxing condition. These results are
presented in Table 3. However, in the presence of these solvents, the
yields of the product were found to be comparatively lower than in
PEG and also needed long reaction times. Therefore, in our procedure,
PEG is employed as a promoter, a cheap, cost-effective, ecofriendly
solvent for the reaction.

2826
J. Liang et al.
Table 2. Recycling of PEGa
Entry
Cycle
Yield (%)
1
2
3
1
2
3
97
95
96
aAll reactions were run with succinic anhydride
(2 mmol) and benzylamine (2 mmol) in PEG400 (4 g) at
120 ꢀC for 3 h.
In conclusion, PEG offers a convenient, inexpensive, nonionic liquid,
non-toxic, and recyclable reaction medium for direct dehydrative conden-
sation of an amine with phthalic anhydride, thus substituting for volatile
and other expensive organic solvents. This protocol offers a rapid and
clean alternative and reduces reaction times. The recyclability of the
catalyst makes the reaction economically and potentially viable for com-
mercial applications.
EXPERIMENTAL
All chemicals and solvents were obtained through commercial sources
and used as supplied. Melting points were determined on a digital melting-
point apparatus and were not corrected. 1H NMR spectra were recorded
on an Advance DMX 500 (Bruker) spectrometer. Gas chromatographic–
mass spectroscopic (GC-MS) spectra were recorded on an HP5989B
instrument.
General Procedure
Typically, reactions were carried out as follows: a mixture of amine
(2 mmol), anhydride (2 mmol), and PEG 400 (4 g) was placed in a
25-mL, round-bottomed flask. The reaction mixture was stirred at
Table 3. Effect of different solvents
Entry
Solvents
Time (h)
Yield (%)
1
2
3
4
Water
6
6
6
3
47
76
72
97
Methanol
Ethanol
PEG

PEG as Solvent for Imide Synthesis
2827
120 ꢀC for 3–6 h (for reaction times, see Table 1). The reaction mixture
was extracted with dry ether until the reaction was complete; the extract
was dried and concentrated under reduced pressure. The resulting crude
product was purified by silica column chromatography using ethyl acet-
ate and hexane as an eluent to obtain the corresponding imines in excel-
lent yield. The recovered PEG can be reused for a number of cycles
without significant loss of activity. All organic compounds were reported
in literature[3h,4] and fully characterized by spectral analysis.
Selected Data
N-Phenylsuccinimide (1a)
The general procedure gave an colorless solid. Mp 156–157 ꢀC; 1H NMR
(500 MHz, CDCl3, Me3SiCl): dH ¼ 7.49 (2H, m, Ph), 7.42 (1H, m, Ph),
7.30 (2H, d J ¼ 7.8 Hz, Ph), 2.80 (4H, s, CH2CH2); GC-MS: m=z 175
(Mþ), 147 (M-CO), 119 (M-CO), 93 (PhNH2þ, M-COCHCHCO), 77
(C6H5þ), 55.
N-p-Methylphenylsuccinimide (2b)
The general procedure gave an colorless solid. Mp 155–156 ꢀC; 1H NMR
(500 MHz, CDCl3, Me3SiCl): dH ¼ 7.38 (2H, d J ¼ 8.5 Hz, Ph), 7.13 (2H,
d J ¼ 8.0 Hz, Ph), 2.82 (4H, s, CH2CH2), 2.37 (3H, s, CH3); GC-MS: m=z
189 (Mþ), 161 (M-CO), 133 (M-CO), 107 (M-COCHCHCO), 77
(PhCH2þ), 55.
N-p-Methylphenylphthalimide (9b)
The general procedure gave an colorless solid. Mp 190–192 ꢀC; 1H NMR
(500 MHz, CDCl3, Me3SiCl): dH ¼ 7.96 (2H, dd J ¼ 5.5, 3.0 Hz, Ph), 7.80
(2H, dd J ¼ 5.5, 3.0 Hz, Ph), 7.26 (4H, m, p-MePh), 2.42 (3H, s, CH3);
GC-MS: m=z 237 (Mþ), 193 (M-CO2), 104 (p-MePhNH2þ), 76 (C6H4þ).
REFERENCES
1. (a) Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. Cyclic carboxylic mono-
imides. Chem. Rev. 1970, 70, 439–469; (b) Blicq, S.; Danze, P. M.; Dumur, V.;
Formstecher, P.; Dautrevaux, M. Inhibition of glucocorticoid receptor trans-
formation, subunit dissociation, and temperature-dependent inactivation by
various N-substituted maleimides. Biochem. 1988, 27, 8436–8442; (c) Miyachi,

2828
J. Liang et al.
H.; Azuma, A.; Ogasawara, A.; Uchimura, E.; Watanabe, N.; Kobayashi, Y.;
Kato, F.; Kato, M.; Hashimoto, Y. Novel biological response modifiers:
Phthalimides with tumor necrosis factor-a production-regulating activity.
J. Med. Chem. 1997, 40, 2858–2865.
2. (a) Mhaske, S. B.; Argade, N. P. Base-induced alcoholysis of N-arylmalei-
mides: Facile in situ oxa-michael addition to alkyl maleanilates: Two-step
one-pot rapid access to alkoxysuccinic acids. Synthesis 2003, 863–870; (b)
Chandrasekhar, S.; Padmaja, M. B.; Raza, A. Solid phase-solid state synthesis
of N-alkyl imides from anhydrides. Synlett 1999, 1597–1599.
3. (a) Garne, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.; Kennedy, V. O.
Development of an asymmetric approach to the 3,8-diazabicyclo[3.2.1]octane
moiety of quinocarcin via intramolecular 1,3-dipolar cycloadditions of photo-
chemically generated azomethine ylides. J. Org. Chem. 1991, 56, 5893–5903;
(b) Nielsen, O.; Buchardt, O. Facile synthesis of reagents containing a terminal
maleimido ligand linked to an active ester. Synthesis 1991, 819–821; (c) Reddy,
P. Y.; Kondo, S.; Toru, T.; Ueno, Y. Lewis acid and hexamethyldisilazane-
promoted efficient synthesis of N-alkyl- and N-arylimide derivatives. J. Org.
Chem. 1997, 62, 2652–2654; (d) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.;
Westrum, L. J. A facile synthesis of chiral bicyclic lactams utilized in the for-
mation of chiral quaternary carbon compounds. J. Org. Chem. 1989, 54, 4243–
4246; (e) Braish, T. F.; Fox, D. E. A practical synthesis of N-substituted
maleimides. Synlett. 1992, 979–980; (f) Barchin, B. M.; Cuadro, A. M.; Julio,
A. B. Microwave-assisted parallel synthesis of a 2-aryl-1H-isoindole-1,3-dione
library. Synlett 2002, 343–345; (g) Vidal, T.; Petit, A.; Loupy, A.; Gedye, R. N.
Re-examination of microwave-induced synthesis of phthalimides. Tetrahedron
2000, 56, 5473–5478; (h) Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Organic
reactions in ionic liquids: Ionic liquid–promoted efficient synthesis of N-alkyl
and N-arylimides. Sythesis 2004, 995–998.
4. (a) Harris, J. M.; Zalipsky, S. Polyethylene Glycol: Chemistry and Biological
Application; ACS Books: Washington, D. C., 1997, 489; (b) Kamal, A.; Reddy,
D. R.; Rajendar. Polyethylene glycol (PEG) as an efficient recyclable medium
for the synthesis of b-amino sulfides. Tetrahedron Lett. 2006, 47, 2261–2264;
(c) Jain, S. L.; Singhal, S.; Sain, B. PEG-assisted solvent and catalyst free
synthesis of 3,4-dihydropyrimidinones under mild reaction conditions. Green
Chem. 2007, 9, 740–741.
5. Dickerson, T. J.; Reed, N. N.; Janda, K. D. Soluble polymers as scaffolds for
recoverable catalysts and reagents. Chem. Rev. 2002, 102, 3325–3344.