One-pot synthesis of iminoimidazolines under microwave irradiation in solvent-free conditions

Article abstract of DOI:10.1080/00397910701545320

Substituted iminoimidazolines were synthesized from a one-pot reaction of aromatic or hetero-aromatic amines with imidazolidine-2-thione under solvent-free conditions using microwave irradiation with good to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701545320

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One‐Pot Synthesis of Iminoimidazolines
under Microwave Irradiation in Solvent‐Free
Conditions
a
a
Süleyman Servi & Murat Genc
a
Department of Chemistry, Firat University, Elazig, Turkey
Published online: 10 Sep 2007.
To cite this article: Sleyman Servi & Murat Genc (2007) One‐Pot Synthesis of Iminoimidazolines under
Microwave Irradiation in Solvent‐Free Conditions, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:18, 3173-3179, DOI: 10.1080/00397910701545320
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Synthetic Communications , 37: 3173–3179, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701545320
One-Pot Synthesis of Iminoimidazolines
under Microwave Irradiation in
Solvent-Free Conditions
S u¨ leyman Servi and Murat Genc
Department of Chemistry, Firat University, Elazig, Turkey
Abstract: Substituted iminoimidazolines were synthesized from a one-pot reaction of
aromatic or hetero-aromatic amines with imidazolidine-2-thione under solvent-free
conditions using microwave irradiation with good to excellent yields.
Keywords: imidazolidine-2-thione, iminoimidazoline, microwave irradiation, one-pot
synthesis
The imidazole ring system is an important nucleus for drug discovery and as
such represents the core structure of a number of biologically significant
molecules. Iminoimidazolines (2-arylimino-2-imidazolines) are effective
[1,2]
pharmacophores in medicinal chemistry.
The most recognized of these
compounds are clonidine, moxonidine, and phentolamine. These compounds
have shown a - and a -adrenoceptor activities, and phentolamine, which
contains an imidazoline ring, is a known a -adrenergic antagonist. Imidazo-
1
2
1
line I receptors are widely distributed in the body and brain of different
2
species including humans. Functionally these receptors have been implicated
in a variety of disease states such as psychiatric disorders, opiate withdrawal,
[3]
Parkinson’s and Alzheimer’s disease, and Huntington’s chorea.
Received in the U.K. November 7, 2006
Address correspondence to S u¨ leyman Servi, Faculty of Science and Arts,
Department of Chemistry, Firat University, Elazig 23169, Turkey. E-mail: sservi@
firat.edu.tr
3
173

3
174
S. Servi and M. Genc
Knowing the importance of the iminoimidazolines as a pharmacophoric
scaffold, our attention has turned to improving the synthesis of this
important nucleus, bearing in mind new synthetic methodologies. Because
synthetic methods for the iminoimidazolines involved is generally a long
process, we decided to develop original and one-pot synthetic methods
especially under microwave irradiation in solvent-free conditions using
imidazolidine-2-thione. The application of microwave energy to organic
compounds for conducting synthetic reactions at highly accelerated rates is
an emerging technique. In fact in recent years, microwaves have become
popular among synthetic organic chemists both to improve classical organic
reactions, shortening reaction times and/or improving yields, as well as to
promote new reactions. The combination of solvent-free conditions and
microwave irradiation leads to large reductions in reaction times with
[4–6]
several advantages of this eco-friendly approach.
In our previous study, we reported both microwave-assisted synthesis in
solvent-free conditions and conventional two-step synthesis of several new
iminoimidazolines from dimethyl N-aryldithioimidocarbonates and ethylene-
[7]
diamine on silica gel as solid support (Scheme 1). The aim of this study is to
synthesize substituted iminoimidazolines in one pot, using different precursors
than those previously reported, under microwave irradiation in solvent-free
conditions. Furthermore, this article reports the first synthesis of compounds
6
–10.
A few conventional methods to synthesize iminoimidazolines from the
corresponding aromatic amines have been reported in the literature. In these
methods, two different strategies have been used to synthesize iminoimidazo-
lines. In the firstmethod, before the imidazoline ring has been formed, iminoi-
midazolines have been synthesised by reaction of aromatic or aliphatic amines
Scheme 1.

Synthesis of Iminoimidazolines
3175
[
8–12]
and the imidazoline ring.
been synthesized from the reaction of the suitable derivatives of amines and
In the second strategy, iminoimidazo lines have
[
13–18]
1
very high, and the reactions are generally long.
,2-diaminoethane.
In all these methods, yields of reaction are not
There is not a method for one-pot synthesis of substituted iminoimidazo-
lines, and these compounds have not been synthesized using imidazolidine-2-
thione so far. A method for microwave-assisted solvent-free synthesis of
[7]
substituted iminoimidazolines is available in literature, and this method
was developed in our previous study.
Imidazolidine-2-thione (1) is very inexpensive and can be easily obtained.
The compound was successfully used as the starting material in this work.
This compound has allowed the one-pot synthesis of substituted iminoimida-
zolines. Nucleophilic addition–elimination reaction of imidazolidine-2-
thione (1) with aromatic amines was performed completely within a few
minutes under microwave irradiation in solvent-free synthesis (method A).
These reactions have not previously been carried out using conventional heating,
because hydrogensulfide is a difficult leaving group to eliminate. The syntheses
of compounds 2–10 are depicted presented in Schemes 1 and 2.
To compare microwave irradiation with conventional heating
conditions, substituted iminoimidazolines was synthesized by both conven-
tional heat method and microwave irradiation. In the conventional method
(
method B), the compounds 3–8 were synthesized from the reaction of
-methylthio-2-imidazoline and aromatic amines in the presence of dimethyl-
2
formamide (DMF). 2-Methylthio-2-imidazoline was synthesized by imidazo-
lidine-2-thione according to Ref 9.
(3-Aminobenzofuran-2-yl)[3-methyl-3-(2,4,6-trimethylphenyl)cyclobutyl]-
methanone (9) was synthesized in our laboratory. Synthesis of compound 10 was
carried out with this novel method in a short time, very easily, and with high yield
(Scheme 2 and Table 1).
EXPERIMENTAL
Imidazolidine-2-thione, aromatic amines, 1,2-diaminoethane, and other
chemicals such as CS and CH I were obtained from commercial sources.
Melting points were determined with a Gallenkamp melting-point
2
3
Scheme 2.

3
176
S. Servi and M. Genc
Table 1. Comparison between microwave-assisted and conventional method of
synthesis of iminoimidazolines in terms of yield and time
Method A
Time (min)
Method B
Time (min)
Starting materials
Products
Yield
75
Yield
57
3
10.0
9.5
480
450
4
74
52
5
6
7
79
67
78
9.5
12.0
14.0
65
41
52
480
540
480
8
73
73
14.0
10.0
55
—
540
—
1
0
apparatus without any correction. IR spectra were measured on a Mattson
1
model FT-IR spectrometer, and H NMR spectra were measured on
FX-90Q Jeol, 200-MHz Bruker AC, and 400-MHz Bruker XWIN-NMR
instruments. Chemical shift values (d) are reported in parts per million
(ppm) relative to TMS. The elemental analysis results are within 0.3% of
the calculated value.
Microwave Instrumentation
All microwave-assisted reactions were performed in a conventional
microwave oven (900 W with a frequency of 2450 MHz). Silica gel as solid
support was used in all microwave-assisted reactions in solvent-free
conditions. During experiments, the final temperature was measured by
using a thermometer at the end of MW irradiation. The final temperatures
were measured around 140–1498C for all of the compounds. All reactions
w
were performed in standard Pyrex glassware. Conventional heating and
microwave irradiation of the reactions were compared (Table 1).

Synthesis of Iminoimidazolines
3177
General Procedure for the Preparation of Substituted
Iminoimidazolines
Method A; Synthesis of Iminoimidazolines under Microwave
Irradiation in Solvent-Free Conditions
A mixture of imidazolidine-2-thione (10 mmol) and aromatic amine
10 mmol) was stirred for a few minutes with 6 g of silica gel. The mixture
(
was placed into a microwave oven (900 W) and irradiated for the length of
time indicated in Table 1 by the pulsed irradiation tecnique (1 min with
2
0-s intervals). After completion of the reaction, which was monitored by
thin-layer chromatography TLC using hexane/ethyl acetate (4:1), the
reaction mixture was allowed to cool, and then the product was extracted
with ethanol/dichloromethane (2/1, 4 ꢀ 25 ml). The crude products were
purified by crystallization from appropriate solvents.
Method B: Synthesis of Iminoimidazolines with Conventional
Conditions
A solution of 2-methylthio-2-imidazoline (0.01 mol) in DMF (15 ml) was
added to a solution of aromatic amine (0.02 mol) in DMF (15 ml) with
stirring at room temperature. The reaction mixture was maintained at 1458C
for the length of time indicated in Table 1. After completion of the reaction,
the mixture was cooled and then added to ice-cold water. The resulting
solid was washed with water, dried, and recrystallized from appropriate
solvents.
Data
1
3
: White solid, mp 1158C; H NMR (DMSO-d , 200 MHz) d 3.48 (s, 1H), 3.73
6
(
s, 4H), 6.30 (broad peak, 1H), 7.12–8.20 (m, 5H) ppm; IR (KBr): y 3277,
2
1
3
N, 26.07. Found: C, 67.51; H, 6.24; N, 26.36%.
257, 1660, 1537 cm , Anal. calcd. for C H N (161): C, 67.06; H, 6.88;
9 11 3
1
4
: Light solid, mp 1888C; H NMR (DMSO-d , 90 MHz): d 2.01 (s, 1H), 2.24
6
(s, 3H), 3.74 (s, 4H), 6.44 (broad peak, 1H), 7.71 (m, 4H) ppm; IR (KBr):
y 3382, 3252, 1660, 1523, 1498 cm , Anal. Calcd. for C H N (175):
C, 68.54; H, 7.48; N, 23.98. Found: C, 68.93; H, 7.96; N, 23.41%.
2
1
1
0 13 3
1
5
: Light grey solid, mp 1908C; H NMR (DMSO-d , 90 MHz): d 3.63 (s, 1H),
6
2
y 3364, 3249, 1486 cm . Anal. calcd. for C H N (175): C, 68.54; H, 7.48;
.38 (s, 3H), 3.77 (s, 4H), 6.31 (broad peak, 1H), 7.71 (m, 4H) ppm; IR (KBr):
2
1
1
0 13 3
N, 23.98. Found: C, 67.74; H, 7.36; N, 23.74%.

3
178
S. Servi and M. Genc
1
6
: Black solid, mp 1408C; H NMR (DMSO-d , 90 MHz): d 1.20 (s, 2H), 2.50
6
(
s, 2H), 3.66 (s, 4H), 6.50– 6.67 (m, 4H) ppm; IR (KBr): y 3372, 1625, 1520,
2
458 cm . Anal. calcd. for C H N (176.22): C, 61.34; H, 6.86; N, 31.79.
1
1
Found: C, 61.69; H, 6.36; N, 31.11%.
9 12 4
1
7
: Yellow solid, mp 1658C; H NMR (DMSO-d , 90 MHz): d 3.30 (s, 4H),
6
3.47 (s, 4H), 4.65 (s, 2H), 7.25–7.51 (m, 4H), 7.98 (s, 2H) ppm; IR (KBr):
y 3342, 3252, 1626, 1588, 1575 cm . Anal. calcd. for C H N (204.17):
C, 64.68; H, 7.89; N, 27.43. Found: C, 64.93; H, 7.96; N, 27.11%.
2
1
1
1 16 4
1
8
: Red solid, mp 1758C; H NMR (DMSO-d , 90 MHz) d 2.80 (s, 1H), 3.52
6
(
y 3372, 1626, 1537 cm , Anal. calcd. for C H N (226.28): C, 69.00;
s, 4H), 4.90 (s, 1H), 6.68–7.17 (m, 6H), 7.65 (s, 2H) ppm; IR (KBr):
2
1
1
3 14 4
H, 6.24; N, 24.76. Found: C, 68.81; H, 6.22; N, 24.83%.
1
1
2
6
0: Grey solid, mp 1538C; H NMR (DMSO-d , 400 MHz) d 1.57 (s, 3H),
6
.15 (s, 9H), 2.44–2.60 (m, 4H), 3.49 (s, 4H), 3.89 (p, 1H), 6.69 (s, 2H),
.91 (s, 2H), 7.24–7.26 (m, 2H), 7.51–7.52 (d, J ¼ 3.71 Hz, 2H) ppm; IR
21
KBr): y 3337, 3252, 1722, 1639, 1616, 1527, 1459 cm , Anal. calcd.
(
for C H N O (415.53): C, 75.18; H, 6.98; N, 10.12. Found: C, 76.51;
H, 7.22; N, 10.83%.
2
6 29 3 2
CONCLUSION
In conclusion, we have described a novel one-pot method for the synthesis of
substituted iminoimidazolines starting from imidazolidine-2-thione with
solid-support, microwave-irradiation reaction conditions. To establish the
general validity of our newly developed method, several selected one-pot,
microwave-assisted syntheses were carried out. This method appeared to be
rapid and economical, with a wide range of applications. The reaction was
found to proceed smoothly under microwave irradiation within 3–5 min,
whereas under reflux conditions, 7–9 h were required.
ACKNOWLEDGMENTS
¨
We are indebted to Firat University Research Foundation (FUBAP 1055) for
financial support of this work and to Murat Koca for synthesizing compound 9.
REFERENCES
1
. Gust, R.; Busch, S.; Keilitz, R.; Schmidt, K; von Rauch, M. Investigations on the
influence of halide substituents on the estrogen receptor interaction of 2,4,5-tris(4-
hydroxy phenyl)imidazoles. Arch. Pharm. 2003, 336, 456–465.

Synthesis of Iminoimidazolines
3179
2. Li, H. Y.; DeLucca, I.; Boswell, G. A.; Billheimer, J. T.; Drummond, S.;
Gillies, P. J.; Robinson, C. Design, synthesis and structure–activity relationship
studies of novel 4,4-bis(trifluoromethyl)imidazolines as acyl-CoA: Cholesterol
acyltransferase (ACAT) inhibitors and antihypercholesterolmic agents. Bioorg.
Med. Chem. 1997, 5, 1345–1361.
3
. Dardonville, C.; Goya, P.; Rozas, I.; Alsasua, A.; Martin, M. I.; Borrego, M. J.
New aromatic iminoimidazolidine derivatives as alpha (1)-adrenoceptor
antagonists: A novel synthetic approach and pharmacological activity. Bioorg.
Med. Chem. 2000, 8, 1567–1577.
4
5
. Loupy, A. Solvent-free microwave organic synthesis as an efficient procedure for
green chemistry. C. R. Chimie 2004, 7, 103–112.
. Perreux, L.; Loupy, A. A tentative rationalization of microwave effects in organic
synthesis according to the reaction medium and mechanistic considerations-
Tetrahedron 2001, 57, 9199–9223.
6
7
8
. Caddick, S. Microwave-assisted organic reactions. Tetrahedron 1995, 51,
10403–10432.
. Genc, M.; Servi, S. Microwave-assisted from synthesis of 2-arylamino-2-imidazo-
lines on a solid support. Heteroatom Chem. 2005, 16, 142–147.
. Chapleo, C. B.; Butler, R. C. M.; England, D. C.; Myers, P. L.; Roach, A. G.;
Smith, C. F. C.; Stillings, M. R.; Tulloch, I. F. Heteroaromatic analogs of the
alpha-2-adre noreceptor partial agonist Clonidine. J. Med. Chem. 1989, 32,
1627–1630.
9. Kiec-Kononowicz, K.; Szymanska, E. Antimycobacterial activity of 5-arylidene
derivatives of hydantoin. Il Farmaco 2002, 57, 355–362.
1
0. Munk, S. A.; Harcourt, D.; Ambrus, G.; Denys, L.; Gluchowski, C.; Burke, J. A.;
Kharlamb, A. B.; Manlapaz, C. A.; Padillo, E. U.; Runde, E.; Williams, L.;
Wheeler, L. A.; Garst, M. E. Synthesis and evaluation of 2-[(5-methylbenz-1-
ox-4-azin-6-yl)imino] imidazoline, a potent, peripherally acting alpha(2) adreno-
ceptor agonist. E. J. Med. Chem. 1996, 39, 3533–3538.
1
1. Trani, A.; Bellasio, E. Synthesis of 2-chloro-2-imidazoline and its reactivity with
aromatic amines, phenols and thiophenols. J. Heterocyclic Chem. 1974, 257–262.
2. Saczewski, F.; Saczewski, J.; Gdaniec, M. Synthesis, molecular structure, and
applications of 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate to the
synthesis of novel heterocyclic ring systems. J. Org. Chem. 68, 4791–4796.
3. Cupps, T. L.; Bogdan, S. E.; Nikolaides, N.; Gilbert, S.; Gazda, M.; Dobson, R. L.;
Cruze, C. A. US Patent 6486190.
1
1
1
1
4. Cupps, T. L.; Bogdan, S. E. US patent 5478858.
5. Garin, J.; Melendez, E.; Merchan, F. L.; Merino, P.; Orduna, J.; Tejero, T.
Diheterocyclic compounds from dithiocarbamates and derivatives thereof, 3:
0
3,3 - Arylenebis(2,4-dioxo-1,2,3,4-tetrahydroquinazolines). J. Heterocycl. Chem.
1990, 27, 1341–1344.
1
1
1
6. Melendez, E.; Merchan, F. L.; Merino, P.; Orduna, J.; Urchegui, R. Diheterocyclic
compounds from dithiocarbamates and derivatives thereof, 6: Unsymmetrical N1,
N4 bis(2-benzazolyl) sulphanilamides. J. Heterocycl. Chem. 1991, 28, 653–656.
7. Servi, S. The efficient synthesis of 2-arylamino-2-imidazolines, 2-heteroarylsubsti-
tuted benzimidazoles, and their morpholin-4-ylmethyl derivatives. S. Afr. J. Chem.
2002, 55, 119–123.
8. Servi, S.; Genc, M.; G u¨ r, S.; Koca, M. The synthesis and antimicrobial activity of
some new methyl N-arylthiocarbamates, dimethyl N-aryldithiocarbonimidates and
2-arylamino-2-imidazolines. Eur. J. Med. Chem. 2005, 40, 687–693.