Rapid and efficient synthesis of imidazolines and bisimidazolines under microwave and ultrasonic irradiation

Article abstract of DOI:10.1007/s00706-007-0645-y

Small assemblies of 2-imidazolines and bisimidazolines from appropriate nitriles and ethylenediamine with catalytic amounts of P₂S ₅ employing a microwave assisted protocol were prepared. Sonication of this system also led to successful synthesis of 2-imidazolines and bisimidazolines. Another advantage of these systems is the ability to carry out large scale reactions. Springer-Verlag 2007.

Full text of DOI:10.1007/s00706-007-0645-y

Monatshefte fu¨r Chemie 138, 579–583 (2007)
DOI 10.1007/s00706-007-0645-y
Printed in The Netherlands
Rapid and Efficient Synthesis of Imidazolines and Bisimidazolines
Under Microwave and Ultrasonic Irradiation
Majid Moghadam1;ꢀ, Iraj Mohammadpoor-Baltork2, Valiollah Mirkhani2, Shahram Tangestaninejad2,
Mohammad Abdollahi-Alibeik3, Behrooz H. Yousefi4, and Hadi Kargar2
1
Department of Chemistry, Yasouj University, Yasouj, Iran
2
Catalysis Division, Department of Chemistry, Isfahan University, Isfahan, Iran
3
Department of Chemistry, Yazd University, Yazd, Iran
4
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria
Received December 4, 2006; accepted (revised) December 12, 2006; published online April 23, 2007
# Springer-Verlag 2007
Summary. Small assemblies of 2-imidazolines and bisimid-
azolines from appropriate nitriles and ethylenediamine with
catalytic amounts of P2S5 employing a microwave assisted
However, preparation of bisimidazolines from the re-
protocol were prepared. Sonication of this system also led
to successful synthesis of 2-imidazolines and bisimidazolines.
Another advantage of these systems is the ability to carry out
large scale reactions.
low yields of the products, difficulty in preparation
of starting materials, and tedious workup procedures.
action of dinitriles with ethylenediamine (EDA) is of
practical importance [13, 20, 21].
The rapid development of combinatorial and
parallel synthesis has led to a growing demand for
fast reactions and efficient purification procedures.
Moreover, high speed parallel synthesis is proving
to be a powerful tool and valuable strategy for drug
discovery. Since the first reports using domestic
multimode cavities [22], microwave-assisted organic
synthesis (MAOS) has created new possibilities in
performing chemical transformations. Microwaves
heat reactants much more quickly than conventional
means. Therefore, it has been frequently observed
that instead of a long time, synthesis usually occurs
just in a few minutes. The salient reported features of
the MAOS approach are the enhanced selectivity, im-
proved reaction rates, milder and solvent-free reac-
tion conditions, formation of cleaner products, and
associated ease of manipulation [23]. Another im-
portant issue for a chemist is the scalability of micro-
wave reactions and the possibility of direct translation
from small to large scale reactions [24].
Keywords. Imidazolines; Nitriles; P2S5; Microwave-assisted
organic synthesis; Ultrasonic irradiation.
Introduction
Many naturally occurring and synthetic compounds
containing an imidazoline scaffold possess interesting
biological activities as e.g. antihypercholesterolemic
[1], anti-inflammatory [2], antihyperglycemic [3–7],
and antihypertensive [8, 9]. Moreover, these com-
pounds are used as intermediates [10], auxiliaries
[11], and catalysts [12] for different organic syntheses.
Several preparation approaches to 2-imidazolines
from carboxylic acids [13], esters [14], nitriles [15],
orthoesters [16], hydroximoyl chlorides [17], hydrox-
yl amides [18], iminoester hydrochlorides [16–19],
and mono- or di-substituted chlorodicyanovinylben-
zene [20] have been reported. Some of these methods
suffer from limitations, such as long reaction times,
In continuation of our interest in the synthesis
of imidazolines [25] we aimed to develop a MAOS
procedure for preparation of assemblies of 2-imid-
ꢀ
Corresponding author. E-mail: moghadamm@mail.yu.ac.ir

580
M. Moghadam et al.
Scheme 1
azolines and bisimidazolines, from appropriate ni-
triles and EDA in the presence of catalytic amounts
of P2S5, which could be applied to a high-throughput
format. We also report the rapid and efficient syn-
thesis of 2-imidazolines and bisimidazolines by the
reaction of nitriles and EDA under ultrasonic irradia-
tion (Scheme 1).
irradiation. After completion of the reaction, the mix-
ture was cooled to room temperature. Next, cold
water was added and the mixture was extracted with
chloroform. Removal of the solvent and recrystalli-
zation of the crude product from cyclohexane gave
the corresponding 2-imidazoline (2a) in 93% yield.
Similarly, the substituted benzonitriles 1b–1e were
reacted with EDA, which afforded the corresponding
2-imidazolines 2b–2e in 91–98% yields with ex-
cellent purities. The heterocyclic nitrile compounds
1f–1i were converted to the corresponding 2-imida-
zolines 2f–2i in 86–95% yields with an HPLC purity
>98%. Surprisingly, dinitriles 1j and 1k also reacted
with EDA and thus furnished the corresponding bis-
imidazolines 2j and 2k in excellent yields (90–98%)
and the same purities (Table 1).
Results and Discussion
Synthesis of 2-Imidazolines and Bisimidazolines
under Microwave Irradiation
Initially, benzonitrile (1a) was chosen as a model sub-
strate for the synthesis of 2-imidazoline. A mixture
of 1a, EDA, and P2S5 was subjected to microwave
Table 1. Preparation of 2-imidazolines and bisimidazolines 2 from nitriles and dinitriles 1 under microwave and ultrasonic
irradiationa
Entry
Nitrile 1
Imidazoline 2b
MW Irradiation
Yield=%c
US irradiation
Refs. for known
compounds
Time=min
Time=min
Yield=%c
a
b
c
d
e
f
g
h
i
Ph-CN
4-Me-Ph-CN
4-Cl-Ph-CN
3-Cl-Ph-CN
4-MeO-Ph-CN
4-Py-CN
3-Py-CN
2-Py-CN
Thien-2-yl-CN
3-CN-Ph-CN
4-CN-Ph-CN
4-Cl-Ph-CN
Ph-Im
4-Me-Ph-Im
4-Cl-Ph-Im
3-Cl-Ph-Im
4-MeO-Ph-Im
4-Py-Im
5.50
6.50
3.75
2.50
8.00
1.75
1.65
1.25
2.50
1.5
93
96
94
98
91
95
86
92
94
95
98
93d
10
20
10
10
25
10
10
10
15
10
10
10
90
85
90
91
85
95
90
95
90
85
86
91d
[14, 15]
[14]
[15, 16]
[32a]
[4, 15]
[13, 32b]
[13, 32b]
[32c]
3-Py-Im
2-Py-Im
Thien-2-yl-Im
3-Im-Ph-Im
4-Im-Ph-Im
4-Cl-Ph-(N-Me-Im)
[13]
j
k
l
[14, 15]
[14, 15]
[27]
2
5
a
Reaction conditions: nitrile 1 (4 mmol), EDA (16 mmol), P2S5 (0.14 mmol) under MW irradiation, and nitrile 1 (10 mmol), EDA
(40 mmol), P2S5 (0.35 mmol) under ultrasonic irradiation
b
c
d
1
The identities of products were confirmed by m.p., IR, and H NMR spectroscopic data
Isolated yields
N-Methylethylenediamine was used instead of EDA

Synthesis of Imidazolines and Bisimidazolines
581
In order to confirm the scalability of our fast
MAOS protocol, the reaction of benzonitrile was
directly translated to a 100 mmole scale and per-
formed under the same irradiation condition. The
result (90% yield) was comparable to that obtained
by the small scale experiment. In addition, using a
combinatorial parallel approach one ensemble was
performed with 5 min irradiation time in the same
cavity and the results were comparable to the se-
quential reaction conditions (yields 81–98% and
excellent purities).
irradiation can also be used to influence selectivity
and yields of reactions.
Typically, 1a, EDA, and P2S5 were mixed and
exposed to ultrasonic irradiation for 10 min. Cold
water was added and the mixture was extracted with
chloroform. Removal of the solvent and recrystalli-
zation of the crude product from cyclohexane gave
the corresponding 2-imidazoline 2a in 90% yield.
The effect of ultrasonic irradiation intensity on this
reaction was also investigated. The results show
that the highest yield of 2a was obtained at 100%
intensity. Under the same reaction conditions, a
variety of nitriles and dinitriles were cleanly and
rapidly converted to their corresponding 2-imida-
zolines and bisimidazolines in 85–95% yields with-
in 10–25 min. When N-methylethylenediamine was
used instead of EDA in the reaction with 4-chlo-
robenzonitrile under the same reaction conditions,
both under microwave irradiation and under ultra-
sonic irradiation, the corresponding N-substituted
2-imidazoline 2l was obtained in high yield (Table 1,
entry l).
Blank experiments in the absence of P2S5 showed
that the reactions did not proceed at all, and the
starting materials remained unchanged in the reac-
tion mixture.
For this purpose, the model reaction with benzo-
nitrile was performed using the sealed vessel capa-
bilities of a dedicated single-mode microwave reactor,
CEM ExplorerTM [26]. Therefore, the synthesis re-
ported in our study was successful under a mono-
mode environment with careful optimization. It has
been frequently observed that a large variety of the
chemistry accelerated under microwave heating do
not at all times claim a specific microwave effect
(non-thermal). However, this is still not a generally
accepted idea for microwave heating and the actual
nature of the effect of microwaves is still discussed
to augment the understanding in other cases. In our
approach to synthesize assemblies of imidazolines,
we do not wish to express our interest in the ongoing
argument for the existence of a microwave effect
(non-thermal). However, we observed that the syn-
theses became significantly accelerated using micro-
wave irradiation.
The presence of P2S5 was shown to be necessary
by blank experiments in the absence of P2S5, but with
ultrasonic irradiation, which showed that the reaction
did not proceed at all.
To the best of our knowledge, the mechanism of
this reaction is not completely clear. However, a
plausible explanation is that P2S5 reacts with the ni-
trile 1 to produce the thioamide. The latter reacts with
EDA, which upon elimination of hydrogen sulfide
and ammonia produces 2-imidazoline 2. Evolution
of H2S is a good indication of the above statement
(Scheme 2). The produced H2S, which is dissolved
in the reaction mixture, can then catalyze the con-
version of nitriles to imidazolines [14]. Thus, a cat-
alytic amount of P2S5 is able to catalyze the reaction.
Reaction of 1a with e.g. n-butylamine gave the cor-
responding thiobenzamide. On the other hand, it has
been reported that thioamides could be converted to
the corresponding nitriles in the presence of EDA
[31]. All these observations provide good evidence
for the suggested mechanism.
Synthesis of 2-Imidazolines and Bisimidazolines
Under Ultrasonic Irradiation
The application of ultrasonic irradiation in reactions
using heterogeneous catalysts is a promising techni-
que. The advantages of ultrasound procedures, such
as good yields, short reaction times, and mild reaction
conditions, are well documented [27–30]. Ultrasonic
Scheme 2

582
M. Moghadam et al.
H2O was added, and then extracted with CHCl3. The organic
layer was dried (Na2SO4). Evaporation of the solvent gave an
almost pure product. Further purification was achieved by
recrystallization of the product (2a was recrystallized from
cyclohexane, 2b–2i were recrystallized from n-hexane, and
2j and 2k were recrystallized from methanol) and gave the
pure 2-imidzolines and bisimidazolines 2 in 84–98% yields
(Table 1). The identities of products were confirmed by mp,
In conclusion, we have demonstrated that assem-
blies of different 2-imidazolines and bisimidazolines
can be rapidly prepared by microwave-assisted pro-
tocols. The isolated yields in the both parallel and
sequential synthesis were comparable (81–98%) and
provided the desired compounds in high purity after a
simple workup. We have demonstrated that the syn-
theses reported herein could equally be successfully
executed under a monomode environment with care-
ful optimizations. Also, feasibility of a direct scale-up
has been confirmed. In comparison with the reported
procedure for the synthesis of 2-imidazolines cata-
lyzed by P2S5, the workup of this method is easier
and extraction of the reaction mixture gives almost
pure products. The application of ultrasonic irradia-
tion also led to the synthesis of 2-imidazolines and
bisimidazolines in high yield in short reaction times.
1
IR, and H NMR spectroscopic data.
General Procedure for the Synthesis of 2-Imidazolines
and Bisimidazolines Under Ultrasonic Irradiation
A mixture of 10mmol nitrile 1, 40 mmol EDA, and 0.35 mmol
P2S5 was irradiated with ultrasonic waves for appropriate time
(Table 1). After completion of the reaction as indicated by
TLC (eluent: EtOAc=MeOH ¼ 4=1), cold H2O was added
and the product was extracted with 2ꢁ10 cm3 CHCl3.
Evaporation of the solvent under reduced pressure and purifi-
cation by a silica gel column (eluent: EtOAc=MeOH¼ 4=1)
gave the imidazoline 2. Recrystallization of product (2a was
recrystallized from cyclohexane, 2b–2i were recrystallized
from n-hexane, and 2j and 2k were recrystallized from metha-
nol) gave the pure product in good to excellent yields based on
the starting nitrile (Table 1). The identities of products were
Experimental
All chemicals were commercial products. EDA was distilled
over KOH before use. All melting points were obtained using
a Stuart Scientific apparatus. TLC monitoring for all reactions,
and all yields refer to isolated products. For reaction monitor-
ing and quality (purity) control of the product a Waters 996
HPLC system, that included Waters 600-MS pumps, an auto-
sampler (Waters 712 WISP), and Waters 996 photodiode array
UV detector was used. The separations were carried out using
a Chromolith Performance reversed phase analytical column
(E. Merck, 100ꢁ4.6 mm) at 25ꢂC and a mobile phase from
(A) 0.1% TFA in 97=3 H2O=MeCN and (B) 0.1% TFA in
MeCN (all solvents were HPLC grade, Fisher and Merck;
TFA was analytical reagent grade, Roth). The following gra-
dients were applied at a flow rate of 3 cm3=min: linear in-
crease from 3 to 60% solution B in 8 min, hold at 60%
solution B for 2 min. 1H NMR spectra were recorded in CDCl3
on a Brucker AC 80 spectrometer. Infrared spectra were re-
corded on a Shimadzu IR-435 spectrophotometer in KBr with
1
confirmed by mp, IR, and H NMR spectral data.
Acknowledgements
We are grateful to the Graduate Studies and Center of Excel-
lence of Chemistry of Isfahan University (CECIU) for finan-
cial support of this work. B.H.Y. acknowledges Prof. U. Jordis
scientific supervision and help during his postdoctoral re-
search at IAS 2004–2005.
References
[1] Li HY, Drummond S, De Lucca I, Boswell GA (1996)
Tetrahedron 52: 11153
[2] Ueno M, Imaizumi K, Sugita T, Takata I, Takeshita M
(1995) Int J Immunopharmacol 17: 597
[3] Wang X, Rondu F, Lamouri A, Dokhan R, Marc S,
Touboul E, Pfeiffer B, Manechez D, Renard P,
Guardiola-Lemaitre B, Godfroid JJ, Ktorza A, Penicaud
L (1996) J Pharmacol Exp Ther 278: 82
[4] Rondu F, Le Bihan G, Wang X, Lamouri A, Touboul E,
Dive G, Bellahsene T, Pfeiffer B, Renard P, Guardiola-
Lemaitre B, Manechez D, Penicaud L, Ktorza A,
Godfroid JJ (1997) J Med Chem 40: 3793
[5] Le Bihan G, Rondu F, Pele-Tounian A, Wang X, Lidy S,
Touboul E, Lamouri A, Dive G, Huet J, Pfeiffer B,
Renard P, Guardiola-Lemaitre B, Manechez D, Penicaud
L, Ktorza A, Godfroid JJ (1999) J Med Chem 42: 1587
[6] Chan S (1993) Clin Sci 85: 671
[7] a) Tsujii S, Rinehart KL, Gunasekera SP, Kashman Y,
Cross SS, Lui MS, Pomponi SA, Diaz MC (1998) J Org
Chem 53: 5446; b) Ohtani I, Moore RE, Runnegar MTC
(1992) J Am Chem Soc 114: 7941
absorption in cmꢃ1
.
The reactions, under MW irradiation, were performed using
the sealed vessel capabilities of a dedicated single-mode mi-
crowave reactor, CEM ExplorerTM (a single mode automated
microwave instrument). The reactions, under ultrasonic irra-
diation, were carried out at room temperature in a 40 cm3 glass
reactor. A UP 400S ultrasonic processor equipped with a 3 mm
wide and 140 mm long probe, which was immersed directly
into the reaction mixture, was used for sonication.
General Procedure for the Synthesis of 2-Imidazolines
and Bisimidazolines Under MW Irradiation
A mixture of 4 mmol nitrile 1, 16mmol EDA, and 0.14 mmol
P2S5 was irradiated with microwave (720W) for 1.25–20min
by pulsed irradiation (30 s with 20s interval). The progress of
the reaction was monitored by TLC. After completion of the
reaction the mixture was cooled to room temperature, cold

Synthesis of Imidazolines and Bisimidazolines
583
[8] a) Schorderet M (1992) In Pharmacologie: Des Concepts
Fondamentaux aux Applications Therapeutiques, Frison-
Roche: Paris, pp 130–153; b) Blancafort P (1978) Drugs
of the Future 3: 592; c) Serradell MN, Castaner J (1986)
Drugs of the Future 6: 470
[9] a) Jones RCF, Nichols JR (1990) Tetrahedron Lett 31:
1771; b) Hayashi T, Kishi E, Soloshonok VA, Uozumi Y
(1996) Tetrahedron Lett 37: 4969; c) Jung ME, Huang A
(2000) Org Lett 2: 2659
[10] a) Jones RCF, Turner I, Howard KJ (1993) Tetrahedron
Lett 34: 6329; b) Jones RCF, Howard KJ, Snaith JS
(1996) Tetrahedron Lett 37: 1707; c) Langlois Y, Dalko
PI (1998) J Org Chem 63: 8107
[21] a) Gedye R, Smith F, Westaway K, Ali H, Baldisera L,
Laberge L, Rousell J (1986) Tetrahedron Lett 27: 279; b)
Giguere RJ, Bray TL, Duncan SM, Majetich G (1986)
Tetrahedron Lett 27: 4945
[22] a) Hayes BL (2002) Microwave Synthesis: Chemistry at
the Speed of Light, CEM Publishing: Matthews NC; b)
Loupy A (ed) (2002) Microwaves in Organic Synthesis,
Wiley-VCH: New York
[23] Stadler A, Yousefi BH, Dallinger D, Walla P, Van der
Eycken E, Kaval N, Kappe CO (2003) Org Proc Res Dev
7: 707
[24] Mohammadpoor-Baltork I, Abdollahi-Alibeik M (2003)
Bull Korean Chem Soc 24: 1354
[11] a) Corey EJ, Grogan MJ (1999) Org Lett 1: 157; b) Isobe
T, Fukuda K, Araki Y, Ishikawa T (2001) Chem Com-
mun 243
[12] Vorbriiggen H, Krolikiewicz K (1981) Tetrahedron Lett
22: 4471
[13] Neef G, Eder U, Sauer G (1981) J Org Chem 46:
2824
[14] Levesque G, Gressier JC, Proust M (1981) Synthesis 963
[15] Hill AJ, Johnston JV (1954) J Am Chem Soc 76: 922
[16] Salgado-Zamora H, Campos E, Jimenez R, Cervantes H
(1998) Heterocycles 47: 1043
[17] Boland NA, Casey M, Hynes SJ, Matthews JW, Smyth
MP (2002) J Org Chem 67: 3919
[18] Biedermann J, Leon-Lomeli A, Borbe HO, Prop G
(1986) J Med Chem 29: 1183
[19] Shin GI, Lee JI, Kim JH (1996) Bull Korean Chem Soc
17: 29
[20] Sawa N, Masahiro YJP (1964) Chem Abstr 66: 95042
[25] CEM-Explorer is an automated reaction handling module
for maximum throughput and flexibility in a microwave-
enhanced synthesis workstation. For more information
see: http:==www.cemsynthesis.com
[26] Mirkhani V, Moghadam M, Tangestaninejad S, Kargar H
(2006) Tetrahedron Lett 47: 2129
[27] Mason TJ, Luche JL (1997) Chemistry under Extreme or
Non-Classical Conditions. In: Eldick RV, Hubbard CD
(eds) Wiley: New York, p 317
[28] Bonrath W (2003) Ultrason Sonochem 10: 55
[29] Suslick KS (1998) Ultrasound, its Chemical, Physical
and Biological Effect, VCH: Weinheim, p 165
[30] Crane LJ, Anastassiadou M, Stigliani J, Baziard-
Mouysset G, Payard M (2004) Tetrahedron 60: 5325
[31] a) Houlihan WJ, Boja JW, Parrino VA, Kopajtic TA,
Kuhar MJ (1996) J Med Chem 39: 4935; b) Upshall DG
(1972) Teratology 5: 287; c) Sawa N (1968) Nippon
Kagaku Zasshi 89: 780