A rapid, catalyst-free, three-component synthesis of rhodanines in water using ultrasound

Article abstract of DOI:10.1055/s-0030-1260158

A green, efficient, rapid, high-yielding, catalyst-free method for the synthesis of rhodanines in water using ultrasonic irradiation is described. The procedure is straightforward and the rhodanine products are isolated by simple filtration. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260158

3080
SHORT PAPER
A Rapid, Catalyst-Free, Three-Component Synthesis of Rhodanines in Water
Using Ultrasound
U
ltrasound-
M
a
ediated Syn
d
thesis of Rh
e
s
in
g
W
ater h Rostamnia,* Kamran Lamei
Organic & Nano Lab, Department of Chemistry, Faculty of Science, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran
Fax +98(421)2276066; E-mail: rostamnia@maragheh.ac.ir; E-mail: srostamnia@gmail.com
Received 27 May 2011; revised 26 June 2011
Table 1 Investigation of the Reaction Conditions for the Synthesis
of Rhodanine 3aa
Abstract: A green, efficient, rapid, high-yielding, catalyst-free
method for the synthesis of rhodanines in water using ultrasonic ir-
radiation is described. The procedure is straightforward and the
rhodanine products are isolated by simple filtration.
MeO2C
MeO2C
conditions
S
N
CS2
+
NH2
Ph
Key words: ultrasound, rhodanines, sonochemistry, carbon disul-
fide, catalyst-free
O
S
MeO2C
CH2Ph
1a
2a
3a
The use of water as a solvent has many advantages in or-
ganic processes and reactions, both in industry and in
green chemistry applications. It is economical, non-toxic
and environmentally friendly. The hydrophobic products
produced when using water as the solvent are separable by
extraction with an organic solvent.1 Increasingly, ultra-
sound has been used in organic synthesis.2 Compared with
traditional methods, the use of ultrasound is more conve-
nient and easily controlled. A large number of organic re-
actions can be carried out in higher yields and shorter
times under mild ultrasonic irradiation conditions.2–5
Solvent
H2O
Methodb
Yield (%)c
94
US
H2Od
H2O
US
92
HSS
HSS
US
<10
<10
90
H2Od
EtOH
EtOH–H2O (1:1)
EtOH
US
93
HSS
HSS
US
<10
<10
91
One of the main objectives of organic and medicinal
chemistry is the design and synthesis of molecules having
value as human therapeutic agents.6 Rhodanines, in par-
ticular, are known to possess a wide spectrum of biologi-
cal activity including the inhibition of targets such as
HCV NS3 protease6 and b-lactamase.7 As a part of our on-
going research on the synthesis of heterocyclic com-
pounds with medicinal applications,8 and based on our
previous study on the synthesis of rhodanine,9 we became
interested in the development of a green and practical
method to synthesize rhodanines of potential pharmaco-
logical and biological interest via sonochemistry.
EtOH–H2O (1:1)
THF
THF
HSS
US
<10
92
MeCN
MeCN
HSS
<10
a Reaction conditions: DMAD (8 mmol), CS2 (40 mmol), BnNH2 (8
mmol), solvent (40 mL), 3 min.
b All reactions were run at 34–36 °C based on the internal temperature
of the ultrasound-assisted reaction system. US = ultrasound; HSS =
high-speed stirring.
Herein, we report a simple, efficient, one-pot method for
the synthesis of rhodanine derivatives in high yields (86–
94%) and in short times (3–5 minutes) using ultrasonic ir-
radiation and water as the reaction medium.
c Yield of isolated product based on the starting alkyne.
d H2O (10 mL) was used.
In order to evaluate the efficiency of this method the syn-
thesis of rhodanine 3a, via reaction of dimethyl acetylene-
dicarboxylate (DMAD, 2a), carbon disulfide (CS2) and
benzylamine (1a) as a model system, was carried out in
water using ultrasonic irradiation (US) or high-speed stir-
ring (HSS) (Table 1).
To our surprise, the one-pot, three-component synthesis
of rhodanine 3a in water as the solvent using ultrasonic ir-
radiation was complete in three minutes, but the high-
speed stirring method required a reaction time of one hour
to go to completion (Figure 1).
We next investigated the effect of various solvents on the
synthesis of rhodanine 3a (model system) using ultrasonic
irradiation and high-speed stirring. In each case reactions
using the ultrasound method were complete within three
minutes with the highest yield of 94% being obtained in
SYNTHESIS 2011, No. 19, pp 3080–3082
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.08.2011
DOI: 10.1055/s-0030-1260158; Art ID: Z54711SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Ultrasound-Mediated Synthesis of Rhodanines in Water
3081
Table 2 Synthesis of Rhodanines in Water Using Ultrasounda
R2
R2
S
, H2O
R1NH2
+
CS2
+
S
O
3–5 min
N
R2
R1
1
3
2
Product R1
R2
Time (min) Yield (%)b
3a
3b
3c
3d
3e
3f
PhCH2
CO2Me
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
3
4
4
4
3
5
5
5
94
93
91
92
92
88
90
86
4-ClC6H4CH2
2-ClC6H4CH2
2-ClC6H4CH2
PhCH(Me)
i-Bu
3g
3h
allyl
i-Pr
Figure 1 Comparison of the reaction time for the synthesis of rho-
danine 3a in water using ultrasound and high-speed stirring
a Reaction conditions: amine (1 mmol), alkyne (1 mmol), CS2 (5
mmol), H2O (5 mL).
b Yield of isolated product based on the starting alkyne.
water. However, the yields of rhodanine 3a using the
high-speed stirrer method were less than 10% after three
minutes reaction time regardless of the solvent employed.
Decreasing the volume of water (10 mL) had a negligible
effect on the reaction yield under ultrasonic conditions
(Table 1). As the reaction was complete within three min-
utes using the ultrasound method, and based on green
chemistry criteria and the straightforward workup, we se-
lected water as the solvent for further studies.
In conclusion, we have described a simple, green, rapid,
ultrasound-mediated and catalyst-free procedure for the
synthesis of rhodanine derivatives in high yields. The re-
action is performed under neutral conditions by simple
mixing of the starting materials and the products were iso-
lated by straightforward filtration. The product rhoda-
nines are of potential pharmacological and biological
interest.
The scope of this sonochemical method for the synthesis
of other rhodanine derivatives using the optimized condi-
tions was studied (Table 2). In each case good to excellent
yields of products were obtained which lend support to the
specific effects of ultrasound. It should be noted that this
procedure showed some limitations with aromatic or hin-
dered amines, with enaminones being obtained as the
main products.10
All reagents were obtained from Merck (Germany) and Fluka
(Switzerland) and were used without further purification. A multi-
wave ultrasonic generator (Sonicator 3000; Misonix Inc., Farm-
ingdale, NY, USA), equipped with a converter/transducer and
titanium oscillator (horn), 12.5 mm in diameter, operating at 20 kHz
with a maximum power output of 600 W, was used for ultrasonic ir-
radiation. The ultrasonic generator automatically adjusted the pow-
er level. The reactions were performed in open vessels.
The proposed mechanism for the sonochemical synthesis
of rhodanines 3 is shown in Scheme 1. It is conceivable
that reaction between the amine and carbon disulfide ini-
tially forms dithiocarbamate 4.9,11–13 This species under-
goes addition of the negatively charged sulfur to the
alkyne 2 to afford intermediate vinyl dithiocarbamate 5.
Finally, intramolecular cyclization of 5 yields the rhoda-
nine 3.
Rhodanines 3a–h; General Procedure
To a mixture of a primary amine (1 mmol) and CS2 (5 mmol) in H2O
(5 mL) was added the appropriate alkyne (1 mmol). The resulting
mixture was subjected to ultrasonic irradiation for 3–5 min using a
high-density ultrasonic probe. After completion of the reaction as
indicated by TLC, the mixture was filtered, the orange residue
washed with H2O and then dried to afford the rhodanine. All the
products are known9 and were characterized by comparison of their
IR spectra and physical data with those of authentic samples.
S
S
R1NH2
+
E
S
R1
2,
NHR1
3
N
S
Acknowledgment
E = ester
– R2OH
5 R2 = Me, Et
H2
S
•
S
O
R2O
We are grateful for the funding support from the University of
Maragheh. The authors also thank the referees for their valuable
comments.
4
Scheme 1 Proposed mechanism for synthesis of rhodanines 3
Synthesis 2011, No. 19, 3080–3082 © Thieme Stuttgart · New York

3082
S. Rostamnia, K. Lamei
SHORT PAPER
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(e) Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006,
1592. (f) Alizadeh, A.; Oskueyan, Q.; Rostamnia, S.
Synthesis 2007, 2637.
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Synthesis 2011, No. 19, 3080–3082 © Thieme Stuttgart · New York