Rapid and efficient synthesis of 2-imidazolines and bis-imidazolines under ultrasonic irradiation

Article abstract of DOI:10.1016/j.tetlet.2006.01.127

Rapid and efficient preparation of 2-imidazolines and bis-imidazolines by reaction of ethylenediamine with nitriles in the presence of catalytic amounts of sulfur under ultrasonic irradiation is reported. The advantages of this system are short reaction times, high yields and the ability to carry out large scale reactions.

Full text of DOI:10.1016/j.tetlet.2006.01.127

Tetrahedron Letters 47 (2006) 2129–2132
Rapid and efficient synthesis of 2-imidazolines and
bis-imidazolines under ultrasonic irradiation
Valiollah Mirkhani,a,* Majid Moghadam,b,* Shahram Tangestaninejada and Hadi Kargara
aDepartment of Chemistry, Isfahan University, Isfahan 81746-73441, Iran
bDepartment of Chemistry, Yasouj University, Yasouj 75914-353, Iran
Received 30 November 2005; revised 16 January 2006; accepted 25 January 2006
Available online 13 February 2006
Abstract—Rapid and efficient preparation of 2-imidazolines and bis-imidazolines by reaction of ethylenediamine with nitriles in the
presence of catalytic amounts of sulfur under ultrasonic irradiation is reported. The advantages of this system are short reaction
times, high yields and the ability to carry out large scale reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
Table 1. Methods for synthesis of 2-imidazolines by the reaction of
ethylenediamine (EDA) to nitriles and their disadvantages
Imidazoline derivatives are of great importance because
they exhibit significant biological and pharmacological
activities including antihypertensive,1,2 antihyperglyce-
N
Catalyst
mic,3–7 antidepressive,8 antihypercholesterolemic9 and
+
R
RCN
H2NCH2CH2NH2
antiinflammatory.10 These compounds are also used as
catalysts11 and synthetic intermediates.12
N
H
There are several methods for the synthesis of 2-imidazo-
lines from carboxylic acids,13 esters,14 nitriles,15 ortho-
esters,16 hydroximoylchlorides,17 hydroxy amides18 and
mono- or disubstituted (chlorodicyanovinyl)benzene.19
However, some of these methods suffer from disadvan-
tages such as long reaction times, low yields, difficulty
in preparation of starting materials and tedious work-
up. Due to these problems, there is still scope to find
new methods for the synthesis of imidazolines and bis-
imidazolines. The synthesis of 2-imidazolines by the
reaction of ethylenediamine (EDA) with nitriles using
different reaction conditions has been reported previ-
ously. These methods have some disadvantages which
are summarized in Table 1.
Entry
Catalyst
Disadvantage
1
2
3
No catalyst15c
H2S15b
HCl/EtOH15d
High temperature
Long reaction times (4 days)
Low product yield
Long reaction times (12–24 h)
Needs multi-step synthesis
Low product yield
Long reaction times
Needs high quantity of catalyst
High temperature
Long reaction times (24 h)
Low product yield
High temperature
4
CuCl/MeOH15e
15f
5
6
La(OTf)3
15g
CS2
yields, short reaction times and mild reaction condi-
tions, are well documented.20–22 Ultrasonic irradiation
can also be used to influence selectivity and yields of
reactions. In this letter, we describe an efficient method
for the synthesis of 2-imidazolines and bis-imidazolines
by the reaction of ethylenediamine (EDA) with nitriles
in the presence of catalytic amounts of sulfur under
ultrasonic irradiation (Scheme 1).
The application of ultrasonic irradiation in reactions
using heterogeneous catalyst is a promising technique.
The advantages of ultrasound procedures, such as good
Keywords: Nitrile; Imidazoline; Ultrasonic irradiation; Ethylene-
diamine.
*
Corresponding authors. Tel.: +98 311 7932713; fax: +98 311 6689732
(V.M.); tel.: +98 913 3108960; fax: +98 741 2223048 (M.M.);
e-mail addresses: mirkhani@sci.ui.ac.ir; moghadamm@mail.yu.ac.ir;
majidmoghadamz@yahoo.com
Typically, benzonitrile 1a, ethylenediamine and sulfur
were mixed and exposed to ultrasonic irradiation for
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.127

2130
V. Mirkhani et al. / Tetrahedron Letters 47 (2006) 2129–2132
NH), 7.30–7.40 (m, 2H, ArH), 7.70–7.81 (m, 3H,
ArH); IR (KBr): 3190 (NH), 1598 (C@N) cmÀ1
N
.
R
N
H2NCH2CH2NH2
H2NCH2CH2NH2
RCN
+
+
N
S
1
Compound 2b: Mp 177–179 °C (lit.15 175–176 °C). H
NMR (CDCl3):15b d = 2.38 (s, 3H, CH3), 3.75 (s, 4H,
2CH2), 4.45 (s, 1H, NH), 7.15 (d, 2H, J = ArH), 7.63
(d, 2H, J = ArH). IR (KBr): 3130 (NH), 1598 (C@N)
H
.
N
)
)
)
NCR'CN
)
R'
N
H
cmÀ1
.
N
H
1
Compound 2c: Mp 186–188 °C (lit.16 185–187 °C). H
NMR (CDCl3):25 d = 3.75 (s, 4H, 2CH2), 4.22 (s, 1H,
NH), 7.30 (d, 2H, J = ArH), 7.93 (d, 2H, J = ArH).
Scheme 1.
IR (KBr) 3140 (NH), 1590 (C@N) cmÀ1
.
5 min. Cold water was added and the mixture was
extracted with chloroform. Removal of the solvent and
recrystallization of the crude product from cyclohexane
gave the corresponding 2-imidazoline 2a in 90% yield.
The effect of ultrasonic irradiation intensity on this reac-
tion was also investigated. The results show that the
highest yield of compound 2a was obtained at 100%
intensity. Under the same reaction conditions, a variety
of nitriles were cleanly and rapidly converted to their
corresponding 2-imidazolines and bis-imidazolines in
84–95% yields within 5–30 min.23 When N-methylethy-
lenediamine was used instead of ethylenediamine, in
the reaction with 4-chlorobenzonitrile under the same
reaction conditions, the corresponding N-substituted
2-imidazoline 2l was obtained in high yield (Table 2).
The presence of sulfur was shown to be necessary by
blank experiments in the absence of sulfur, but with
ultrasonic irradiation, which showed that the reaction
did not proceed at all. The exact mechanism of the
reaction is not clear at this time. However, a plausible
explanation is that sulfur reacts with the nitrile grove
to produce a thioamide. The thioamide reacts with
ethylenediamine, which upon elimination of hydrogen
sulfide and ammonia, produces the 2-imidazoline.15b
Evolution of hydrogen sulfide evidence for the above
statement. Reaction of benzonitrile with a monoamine
such as n-butylamine gave corresponding thiobenz-
amide, which provided further evidence for the sug-
gested mechanism. On the other hand, 2-imidazoline
can be synthesized by reaction of thioamides and
ethylenediamine.24
1
Compound 2d: Mp 133–135 °C. H NMR (CDCl3):26
d = 3.76 (s, 4H, 2CH2), 4.25 (s, 1H, NH), 7.22–7.75
(m, 4H, ArH). IR (KBr): 3140 (NH), 1595 (C@N) cmÀ1
.
1
Compound 2e: Mp 134–135 °C (lit.14 136–137 °C). H
NMR (CDCl3):27 d = 3.79 (s, 4H, 2CH2), 4.30 (s, 1H,
NH), 7.61 (d, 2H, J = ArH), 8.65 (d, 2H, J = ArH).
IR (KBr): 3180 (NH), 1594 (C@N) cmÀ1
.
1
Compound 2f: Mp 111–113 °C (lit.14 106–107 °C). H
NMR (CDCl3):27 d = 3.78 (s, 4H, 2CH2), 4.54 (s, 1H,
NH), 7.20–7.38 (m, 1H, ArH), 8.02–8.15 (m, 1H,
ArH), 8.60–8.67 (m, 1H, ArH), 8.92 (s, 1H, ArH). IR
(KBr): 3150 (NH), 1586 (C@N) cmÀ1
.
1
Compound 2g: Mp 101–102 °C. H NMR (CDCl3):28
d = 3.81(s, 4H, 2CH2), 5.38 (s, 1H, NH), 7.22–7.38 (m,
1H, ArH), 7.62–7.85 (m, 1H, ArH), 8.12 (d, 1H,
J = ArH), 8.55 (d, 1H, J = ArH). IR (KBr): 3240
(NH), 1594 (C@N) cmÀ1
.
1
Compound 2h: Mp 139–140 °C (lit.16 138–140 °C). H
NMR (CDCl3):4 d = 3.74 (s, 4H, 2CH2), 3.81 (s, 3H,
CH3), 4.42 (s, 1H, NH), 6.87 (d, 2H, J = ArH), 8.70 (d,
2H, J = ArH). IR (KBr): 3170 (NH), 1605 (C@N) cmÀ1
.
Compound 2i: Mp 156–157 °C. 1H NMR (CDCl3):
d = 3.00 (s, 1H, NH), 3.59 (s, 4H, 2CH2), 5.05 (s, 1H,
CH), 7.25–7.30 (m, 10H, ArH). IR (KBr): 3180 (NH),
1594 (C@N) cmÀ1. Elemental analysis calculated for
C16H16N2: C, 81.32; H, 6.82; N, 11.85%. Found: C,
81.21; H, 6.91; N, 11.71%.
When sulfur was replaced with selenium, no product
was detected in the reaction of nitriles and ethylenedi-
amine under ultrasonic irradiation.
Compound 2j: Mp 312 °C (lit.15 318 °C). 1H NMR
(DMSO-d6):15b d = 3.60 (s, 8H, 2CH2), 6.94 (s, 2H,
NH), 7.83 (s, 4H, ArH). IR (KBr): 3180 (NH), 1576
One advantage of this method is its large scale applica-
bility: imidazolines and bis-imidazolines were prepared
on a 100 mmol scale, and the results were comparable
to the small scale experiments.
(C@N) cmÀ1
.
Compound 2k: Mp 242 °C (lit.15 244 °C). 1H NMR
(DMSO-d6):15b d = 3.60 (s, 8H, 2CH2), 6.88 (s, 2H,
NH), 7.45 (m, 1H, ArH), 7.86 (d, 2H, J = ArH), 8.29
In conclusion, a simple and efficient procedure for the
synthesis of 2-imidazolines and bis-imidazolines has
been developed. Mild reaction conditions, absence of
solvent, short reaction times, easy and quick isolation
of the products, excellent yields and large scale applica-
bility are the main advantages.
(s, 1H, ArH). IR (KBr): 3150 (NH), 1565 (C@N) cmÀ1
.
Compound 2l: Oily yellow compound. 1H NMR
(CDCl3): d = 2.66 (s, 3H, CH3), 3.36 (t, 2H, J = CH2),
3.71 (t, 2H, J = CH2), 7.25 (d, 2H, J = ArH), 7.43 (d,
2H, J = ArH). IR: 1318 (N–CH3), 1603 (C@N) cmÀ1
.
1
Compound 2a: Mp 100–101 °C (lit.16 101–102 °C). H
Elemental analysis calculated for C10H11ClN2: C, 61.70;
H, 5.70; N, 14.39%. Found: C, 61.65; H, 5.78; N, 14.21%.
NMR (CDCl3):15b d = 3.75 (s, 4H, 2CH2), 4.8 (s, 1H,

V. Mirkhani et al. / Tetrahedron Letters 47 (2006) 2129–2132
Table 2. Synthesis of imidazolines and bis-imidazolines under ultrasonic irradiationa
2131
Entry
Substrate
Product
Time (min)
5
Yieldb (%)
N
CN
1a
2a
2b
90
N
H
N
H3C
Cl
1b
15
89
H3C
Cl
CN
N
H
N
1c
1d
2c
2d
7
7
88
89
CN
N
H
N
CN
N
H
Cl
N
Cl
N
N
1e
1f
2e
2f
5
5
7
95
93
90
CN
N
H
N
CN
N
N
N
H
N
CN
1g
2g
N
N
N
H
N
MeO
1h
2h
20
15
89
92
MeO
CN
N
H
N
1i
2i
CN
N
H
N
N
1j
2j
5
5
85
84
NC
CN
N
N
H
H
N
CN
N
1k
2k
H
N
NC
Cl
NH
N
Cl
1l
2l
30
90c
CN
N
Me
a Reaction conditions: nitrile (10 mmol), EDA (40 mmol) and sulfur (2.5 mmol).
b Isolated yields.
c N-Methylethylenediamine was used instead of ethylenediamine.

2132
V. Mirkhani et al. / Tetrahedron Letters 47 (2006) 2129–2132
Chem. Abstr. 1978, 30, 478, 4313; (e) Rousselet, G.;
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