Polyethylene glycol (PEG-400) as an efficient and recyclable reaction medium for the one-pot synthesis of n-substituted azepines under catalyst-free conditions

Article abstract of DOI:10.1055/s-0031-1289542

Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the one-pot synthesis of N-substituted azepines under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of the PEG are the important features of this protocol. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289542

2730
LETTER
Polyethylene Glycol (PEG-400) as an Efficient and Recyclable Reaction
Medium for the One-Pot Synthesis of N-Substituted Azepines under
Catalyst-Free Conditions
P
olyethylene Gly
a
col as
R
eac
g
tionMedium
h
for the
O
ne
u
-Pot Synthesis of
N
M
-Substituted
A
zepinesallepalli,a Lingappa Yeramanchi,*a Rajashaker Bantu, b Lingaiah Nagarapu*b
a
Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27193382; E-mail: lnagarapuiict@yahoo.com
b
Received 10 June 2011
field of the PEG-catalyzed synthesis of heterocyclic com-
pounds under catalyst-free conditions,9 we report herein
the first synthesis of N-substituted azepine derivatives via
tandem Michael addition–cyclization using PEG-400 as a
recyclable medium without additional organic solvent and
catalyst (Scheme 1).
Abstract: Polyethylene glycol (PEG) was found to be an inexpen-
sive nontoxic and effective medium for the one-pot synthesis of N-
substituted azepines under catalyst-free conditions in excellent
yields. Environmental acceptability, low cost, high yields, and recy-
clability of the PEG are the important features of this protocol.
Key words: anilines, dialkylacetylene dicarboxylates, 2,5-
dimethoxytetrahydrofuran, N-substituted azepines, polyethylene
glycol, catalyst-free conditions
To the best of our knowledge there are no previous reports
for the synthesis of azepine derivatives by using PEG-400
as a reaction medium under catalyst-free conditions.
The generality of this reaction was investigated for the
synthesis of various N-substituted azepine derivatives by
using a variety of anilines and dialkylacetylene dicarboxy-
lates with 2,5-dimethoxytetrahydrofuran (Table 1).10
N-Substituted azepines and their derivatives are an impor-
tant class of organic compounds found in many biologi-
cally active molecules. These compounds exhibit
properties such as antihistaminic, spasmolytic, serotonin
antagonistic, anticonvulsive, antiemetic, anti-inflammato-
ry, and fungicidal activity.1 They have also been widely
used in antimalarial2a–2c and anti-HIV drug therapy,2d and
in treatments for stomach disorders,3 arrhythmia,4 and hy-
pertension (glaucoma).5,6
In general, all the reactions were very clean, and the N-
substituted azepine derivatives were obtained in high
yields. Anilines bearing electron-donating groups (Me,
OMe) reacted efficiently; whereas in the presence of elec-
tron-withdrawing groups (NO2) a slight decrease in the
yield of the N-substituted azepines was observed (Table 1
entries 6, 7, 15, and 16). Aliphatic amines gave the desired
products in low yields (Table 1, entries 9 and 18). The
structures of all the products were determined from their
analytical and spectroscopic (IR, 1H NMR, and 13C NMR)
data and by direct comparison with authentic samples.
Although several protocols have been developed for the
synthesis of azepine derivatives,7 many of the methods
possess drawbacks such as harsh reaction conditions, te-
dious experimental procedures, unsatisfactory yields,
long reaction times or use of expensive and moisture-
sensitive catalysts. Hence, there is a need for a rapid and
efficient method for the synthesis of N-substituted
azepine derivatives under catalyst-free conditions.
In conclusion, we have developed an efficient and facile
method for the synthesis of N-substituted azepine deriva-
tives by treatment of aniline, dialkylacetylene dicarboxy-
late, and 2,5-dimethoxytetrahydrofuran using PEG as a
recyclable medium without the addition of any additive or
organic co-solvent. Mild reaction conditions, inexpensive
reaction medium, operational simplicity, and high yields
are the advantages of the protocol.
In recent years, polyethylene glycol (PEG) has emerged
as a powerful phase-transfer catalyst and performs many
useful organic transformations under mild reaction condi-
tions. Moreover, PEG is inexpensive, easy to handle, ther-
mally stable, nontoxic, and recyclable in various organic
transformations.8 In continuation of our interest in the
NH2
CO2R
PEG-400
N
+
+
MeO
OMe
O
RO2C
60 °C, 7 h
CO2R
CO2R
Scheme 1
SYNLETT 2011, No. 18, pp 2730–2732
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289542; Art ID: D17711ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polyethylene Glycol as Reaction Medium for the One-Pot Synthesis of N-Substituted Azepines
2731
Table 1 Synthesis of N-Substituted Azepine Derivatives in PEGa
CO2R
PEG-400
60 °C, 7 h
N
Ar–NH2
+
+
Ar
MeO
OMe
O
RO2C
CO2R
CO2R
Entry
1
Ar
Ph
R
Yield (%)
94
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-O2NC6H4
4-HOC6H4
Bn
89
3
91
4
88
5
89
6
81
7
76
8
85
9
35
10
11
12
13
14
15
16
17
18
Ph
92
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-O2NC6H4
4-HOC6H4
Bn
Et
88
Et
90
Et
86
Et
87
Et
79
Et
74
Et
81
Et
31
a Reaction conditions: amine (1.0 mmol), diethyl acetylenedicarboxylate (DEAD, 1.0 mmol) or dimethyl acetylenedicarboxylate (DMAD,
1.0 mmol), 2,5-dimethoxytetrahydrofuran (1.0 mmol), PEG (5 mL), 60 °C.
Andries, K.; Moens, L. J.; Janssen, M. A. C.; Janssen, P. A.
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(4) Cross, P. E.; Arrowsmith, J. E. EP 2853231988, 1988;
Acknowledgment
Chem. Abstr. 1989, 110, 173115.
(5) (a) Kimball, S. D.; Floyd, D. M.; Das, J.; Hunt, J. T.;
The authors are thankful to J. S. Yadav, Director, IICT, for his kind
permission and support and thanks UGC-BSR New Delhi for finan-
cial assistance.
Krapcho, J.; Rovnyak, G.; Duff, K. J.; Lee, V. G.; Moquin,
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Synlett 2011, No. 18, 2730–2732 © Thieme Stuttgart · New York

2732
R. Mallepalli et al.
LETTER
(10) General Procedure for the Synthesis of N-Substituted
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Azapins by Using PEG as a Reaction Medium
A mixture of the requisite aniline (1.0 mmol), dialkyl-
acetylene dicarboxylate (1.0 mmol), and 2,5-dimethoxy-
tetrahydrofuran (1.0 mmol) was taken in PEG (5 mL) and
stirred at 60 °C for the appropriate time. After completion of
the reaction, as monitored by TLC, the reaction mixture was
poured into H2O and extracted with EtOAc. The organic
layer was removed under reduced pressure, and the crude
product was purified by column chromatography. The
recovered PEG could be reused for a number of cycles
without significant loss of activity.
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Synlett 2011, No. 18, 2730–2732 © Thieme Stuttgart · New York

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