Efficient and one-pot catalytic synthesis of 2-imidazolines and bis-imidazolines with p-toluenesulfonic acid under solvent free conditions

Article abstract of DOI:10.1002/jhet.516

A practical, efficient, and inexpensive method for the synthesis of 2-imidazoline from the reaction of nitriles with ethylenediamine or 1,2-propanediamine using p-toluenesulfonic acid or pyridinium p-toluenesulfonate under reflux conditions is reported. This catalyst can be successfully applied for the chemoselective conversion of dicyanobenzenes to corresponding mono- and bis-imidazolines. The applications of these catalysts are feasible because of easy preparation, easy handling, stability, inexpensive, good activity, and eco-friendly.

Full text of DOI:10.1002/jhet.516

March 2011
Efficient and One-Pot Catalytic Synthesis of 2-Imidazolines and
Bis-Imidazolines with p-Toluenesulfonic Acid under Solvent Free
Conditions
249
Masoud Nasr-Esfahani,* Morteza Montazerozohori, and Safie Mehrizi
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
*E-mail: manas@mail.yu.ac.ir
Received January 31, 2010
DOI 10.1002/jhet.516
Published online 18 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
A practical, efficient, and inexpensive method for the synthesis of 2-imidazoline from the reaction of
nitriles with ethylenediamine or 1,2-propanediamine using p-toluenesulfonic acid or pyridinium p-tolue-
nesulfonate under reflux conditions is reported. This catalyst can be successfully applied for the chemo-
selective conversion of dicyanobenzenes to corresponding mono- and bis-imidazolines. The applications
of these catalysts are feasible because of easy preparation, easy handling, stability, inexpensive, good
activity, and eco-friendly.
J. Heterocyclic Chem., 48, 249 (2011).
INTRODUCTION
enantiopure 1,2-diamines [22]. A good source of C-1 for
preparation of imidazolines is nitriles. Some novel condi-
tions have been developed for this reaction, using Lewis
2-Imidazolines are very important moieties because of
their extensive utilities in chemistry, biochemistry, and
pharmacology [1]. These heterocycles exhibit several
pharmaceutical activities such as antidiabetic [2], antihy-
pertensive [3], antidepressive [4], anticancer [5], anti
HIV-1 [6], antitumor [7], and anti-Alzheimer [8] activ-
ities. These compounds are also used as catalysts [9] and
synthetic intermediates [10]. Various reaction conditions
including homogeneous and/or heterogeneous catalysts
have been used for this purpose. Several publications
have been described for the preparation of 2-substituted
imidazolines from different precursors such as carboxylic
acids [11], esters [12], nitriles [13], amides [14], aziri-
dines [15], aldehydes [16], orthoesters [17], hydroxi-
moylchlorides [18], hydroxy amides [19], mono- or dis-
ubstituted (chlorodicyanovinyl)benzene [20], and N-tert-
butoxycarbonyl-protected a-amino acids [21]. However,
many of the synthetic protocols reported have certain
limitations, such as needing anhydrous conditions, the
applications of stoichiometric amounts of catalysts, or-
ganic solvents and metals and expensive reagents, harsh
reaction conditions and prolonged reaction times. There-
fore, the development of an efficient, simple and environ-
mentally benign catalytic procedure for the synthesis of
these heterocycles is still in high demand.
¨
acids, Bronsted acids, or other small molecules as cata-
lysts, such as HCl [13d], CuCl [13e], thioacetamide [23],
sulfur [13i], ZrOCl2 [13j], silica sulfuric acid [24], 12-
tungstophosphoric acid [25], and carbon disulfide [13k].
We have found that p-toluenesulfonic acid (p-TSA)
and pyridinium p-toluenesulfonate (PPTS) as inexpensive
and common organic chemicals are efficient catalysts for
the synthesis of 2-imidazolines and bis-imidazolines.
Crystalline pyridinium p-toluenesulfonate can easily be
prepared from pyridine and p-toluenesulfonic acid monohy-
drate [26]. It is soluble in methylene chloride, chloroform,
ethanol, and acetone, and slightly soluble in benzene but in-
soluble in ether. It is noteworthy that pyridinium p-toluene-
sulfonate is a weaker acid (pH 3.0 in 1.0M aqueous solution)
than acetic acid (pH 2.4 in 1.0M aqueous solution). Conse-
quently, this catalyst is mild enough to be used on complex
systems containing sensitive polyfunctional groups.
In this work, we wish to report an efficient synthesis
of imidazolines and bisimidazolines using catalytic
amounts of a Brønsted acid, such as p-toluenesulfonic
acid or pyridinium p-toluenesulfonate.
RESULTS AND DISCUSSION
The application of 1,2-diamines is the first class synthe-
sis methods of imidazolines. The highlighted advantage of
this method is the easy introduction of chirality by using
In this article, we describe an efficient method for the
synthesis of 2-imidazolines and bis-imidazolines by the
C
V
2010 HeteroCorporation

250
M. Nasr-Esfahani, M. Montazerozohori, and S. Mehrizi
Vol 48
Scheme 1
of 2-imidazoline was performed in longer time with
slightly reduced yields in comparison with p-TSA. For
example, in the presence of p-TSA, the reaction of ben-
zonitrile was completed in 35 min, whereas PPTS cata-
lyst carried out the reaction in 85 min with 85% yield.
These results show that PPTS probably can be used in
the synthesis of imidazolines containing sensitive
groups.
reaction of ethylenediamine or 1,2-propanediamine with
nitriles in the presence of catalytic amounts of p-tolue-
nesulfonic acid (p-TSA) or pyridinium p-toluenesulfo-
nate (PPTS) under reflux condition (Scheme 1).
CONCLUSIONS
Synthesis of 2-imidazolines catalyzed by p-toluene-
sulfonic acid. The results from the reaction of ethylene-
diamine or 1,2-propanediamine and various nitriles in
the presence of optimized amount of p-toluenesulfonic
acid are shown in Table 1. As shown in entries 1–17,
the reactions using various aromatic nitriles proceeded
well to give the corresponding 2-imidazolines and bis-
imidazolines in good to excellent yields.
A simple and efficient procedure for the synthesis of
2-imidazolines and bis-imidazolines has been developed.
Mild reaction conditions, absence of solvent, moderate
reaction times, easy and quick isolation of the products,
good to excellent yields (75–92%), inexpensive and eas-
ily preparation of the catalyst, and large scale applicabil-
ity are the main advantages.
Typically, benzonitrile (4), ethylenediamine, and p-
TSA were mixed and exposed to heating for 35 min.
Cold water was added and the mixture was extracted by
CHCl3. Removal of the solvent and recrystallization of
the crude product from cyclohexane gave the corre-
sponding 2-imidazoline in 92% yield.
EXPERIMENTAL
Chemicals were purchased from Merck, Fluka, and Aldrich
chemical companies. All of the products were identified by
comparison of their physical and spectral data with those of
authentic samples. IR spectra were recorded on a Jasco IR-680
spectrophotometer. 1H NMR spectra were obtained with a
Bruker-Arance AQS 300 MHz or a Bruker 400 Ultrasheilld
(400 MHz) spectrometers.
General procedure for the preparation of 2-imidazolines
and bis-imidazolines. A mixture of nitrile (10 mmol), ethyl-
enediamine or 1,2-propanediamine (40 mmol), and p-toluene-
sulfonic acid (3 mmol) or pyridinium p-toluenesulfonate (4
mmol) was heated under reflux for 45–220 min. After comple-
tion of the reaction as indicated by TLC (eluent:EtOAc/
MeOH, 4:1), cold water was then added after the reaction mix-
ture cooled down to room temperature. After stirred, the mix-
ture was extracted by 15 mL (3 ꢀ 5) CHCl3 and solvent
evaporated. The crude products were recrystallized from suita-
ble solvents (4 was recrystalised from cyclohexane; 12 and 14
were recrystallized from methanol and others were recrystal-
lized from n-hexane) gave the pure products in 75–95% yields
based on the starting nitrile (Table 1). Spectroscopic data of
new compounds:
Surprisingly, it was observed that both mono- and
bis-imidazolines can be obtained by this catalytic sys-
tem. As shown in Table 1, mono-imidazolines were pro-
duced from dinitriles in 90–92% yields with shorter
reaction times (50–60 min). Increasing of the reaction
times to 100–110 min, produced bis-imidazolines in 85–
87% yields. The preparation of mono-imidazolines from
dinitrile compounds is of great interest because the
remaining nitrile group can be converted to other func-
tional groups [28].
As it has been reported, catalytic synthesis of bis-imi-
dazolines from the reaction of dinitriles with ethylenedi-
amine in the presence of supported tungstophosphoric
was not successful [25], whereas in the presence of p-
TSA, the corresponding bis-imidazolines were synthe-
sized from dinitriles in the good yields (entries 11, 13;
Table 1).
2-(4-Chlorophenyl)-4,5-dihydro-4-methyl-1H-imidazole (Table
3, entry 1). Mp:150–152ꢁC; Rf ¼ 0.464 (ethyl acetate:methanol
¼ 9:1); IR (KBr) m(cmꢂ1): 3100 (NH), 2953, 1600, 1583,
One advantage of this method is large scale applic-
ability so that imidazolines and bis-imidazolines were
prepared on a 100 mmol scale, and the results were
comparable with the small scale experiments.
1
1479, 1368, 1331, 831; H NMR (400 MHz, DMSO) d(ppm) :
1.27 (d, 3H, CH3), 3.33 (m, 2H, CH2), 3.92 (m, 1H, CH), 4.25
(s, 1H, NH), 7.55–7.85 (dd, 4H, ArH). 13C NMR (400 MHz,
DMSO) d(ppm): 22.23, 56.47, 57.34, 126.92, 128.77, 129.6,
138.55, 162.06. Anal. Calcd. for C10H11ClN2: C 61.70, H
5.70, N 14.39; found: C 61.6, H 5.8, N 14.3.
2-(3-Chlorophenyl)-4,5-dihydro-4-methyl-1H-imidazole (Table
3, entry 2). Mp:147–149ꢁC; Rf ¼ 0.500 (ethyl acetate:methanol
¼ 9:1); IR (KBr) m(cmꢂ1): 3120 (NH), 2962, 1592, 1542,
1490; 1H NMR (400 MHz, DMSO) d(ppm): 1.14 (d, 3H,
CH3), 3.18 (t, 1H, CH2), 3.37 (s, 1H, NH), 3.75 (t, 1H, CH2),
3.97 (m, 1H, CH), 7.43–7.91 (m, 4H, ArH). 13C NMR (400
A plausible mechanism is shown in Scheme 2. The
nitrile is first activated by the catalyst to give 1 then
ethylenediamine attacks 1 to produce 2 and in final cy-
clization of 2 gives product and releases of the catalyst
for the next catalytic cycle.
Synthesis of 2-imidazolines catalyzed by pyridin-
ium p-toluenesulfonate. As shown in Table 2, in the
presence of pyridinium p-toluenesulfonate, the synthesis
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Efficient and One-Pot Catalytic Synthesis of 2-Imidazolines and Bis-imidazolines
with p-Toluenesulfonic Acid under Solvent Free Conditions
251
Table 1
Synthesis of imidazolines and bis-imidazolines in the presence of p-TSA.
Entry
Substrate
R00
Producta
Time (min) Yieldb (%) Mp (ꢁC) found Mp (ꢁC) reported
1
CH3
90
30
75
90
150–152
–
2
3
CH3
147–149
–
CH3
75
80
148–150
–
4
5
6
7
8
9
H
H
H
H
H
H
35
60
92
92
92
85
85
90
100–101
300–302
177–179
134–135
101–102
175–178
101–102
–
75
175–176
136–137
94
100
140
105
178
(Continued)
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252
M. Nasr-Esfahani, M. Montazerozohori, and S. Mehrizi
Vol 48
Table 1
(Continued)
Entry
Substrate
R00
Producta
Time (min) Yieldb (%) Mp (ꢁC) found Mp (ꢁC) reported
10
11
12
H
H
H
50
100
60
92
85
90
204–205
312–314
132–134
202
318
133–134
13
H
110
87
242–243
244
14
15
16
17
H
H
H
H
180
72
80
87
92
230–232
139–140
186–188
136–137
231
138–140
185–187
134–136
80
50
25
a Characterized by spectral analysis and comparison with these reported in the literature [13, 16, 25, 27].
b Yields refer to isolated and purified products.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Efficient and One-Pot Catalytic Synthesis of 2-Imidazolines and Bis-imidazolines
with p-Toluenesulfonic Acid under Solvent Free Conditions
253
Scheme 2
d(ppm): 1.19 (d, 3H, CH3), 3.23 (dd, 1H,CH2), 3.80 (t, 1H,
CH2), 4.23(m, 1H, CH), 4.42 (s, 1H, NH), 4.72 (s, 1H, OH),
6.70 (d, 2H, ArH), 7.64 (d, 2H, ArH). 13C NMR (400 MHz,
DMSO) d(ppm): 21.81, 53.42, 54.67, 114.25, 116.72, 130.20,
163.20, 165.57. Anal. Calcd. for C10H12N2O: C 68.16, H 6.86,
N 15.90; found: C 68.2, H 6.8, N 15.8.
2-(4-Hydroxyphenyl)-4,5-dihydro-1H-imidazole (Table 1,
entry 5). Mp:300–302ꢁC; Rf ¼ 0.536 (ethyl acetate:methanol
¼ 9:1); IR (KBr) m(cmꢂ1): 3323 (b, OH), 3201 (NH), 1613,
1
1592, 1503, 1186, 853; H NMR (400 MHz, DMSO) d(ppm) :
3.55 (s, 4H, 2CH2), 3.40 (s, 1H, NH), 6.70 (d, 2H, ArH), 7.61
(d, 2H, ArH), 8.31 (s, 1H, OH). Anal. Calcd. for C9H10N2O: C
66.65, H 6.21, N 17.27; found: C 66.5, H 6.3, N 17.2.
Acknowledgment. The partial support of this work by Yasouj
University is acknowledged.
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