Synthesis of thioureas in ionic liquid medium

Article abstract of DOI:10.1080/17415993.2012.739623

A highly efficient procedure for the synthesis of symmetrical thioureas by means of simple condensation of primary amines and carbon disulfide in 1-butyl-3-methylimidazolium chloride [BMIM][Cl] as a cheap and commercially available ionic liquid is presented. This procedure works for aromatic and aliphatic primary amines and give high to excellent yields of symmetrical thioureas without need for any catalyst or tedious work-up.

Full text of DOI:10.1080/17415993.2012.739623

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Synthesis of thioureas in ionic liquid
medium
Azim Ziyaei Halimehjani a & Fataneh Farahbakhsh a
a Faculty of Chemistry, Kharazmi University (Tarbiat Moallem
University), 49 Mofateh Street, Tehran, Iran
Published online: 03 Dec 2012.
To cite this article: Azim Ziyaei Halimehjani & Fataneh Farahbakhsh (2013) Synthesis
of thioureas in ionic liquid medium, Journal of Sulfur Chemistry, 34:3, 284-288, DOI:
10.1080/17415993.2012.739623
To link to this article: http://dx.doi.org/10.1080/17415993.2012.739623
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Journal of Sulfur Chemistry, 2013
Vol. 34, No. 3, 284–288, http://dx.doi.org/10.1080/17415993.2012.739623
Synthesis of thioureas in ionic liquid medium
Azim Ziyaei Halimehjani* and Fataneh Farahbakhsh
Faculty of Chemistry, Kharazmi University (Tarbiat Moallem University), 49 Mofateh Street, Tehran, Iran
(Received 11 August 2012; final version received 10 October 2012)
A highly efficient procedure for the synthesis of symmetrical thioureas by means of simple condensation of
primary amines and carbon disulfide in 1-butyl-3-methylimidazolium chloride [BMIM][Cl] as a cheap and
commercially available ionic liquid is presented. This procedure works for aromatic and aliphatic primary
amines and give high to excellent yields of symmetrical thioureas without need for any catalyst or tedious
work-up.
S
[BMIM]Cl
(R)Ar
Ar(R)
2Ar(R)NH2
CS2
N
H
N
H
100ºC
Keywords: ionic liquid; thiourea; carbon disulfide; amine; symmetrical
1. Introduction
The development of simple and eco-friendly synthetic procedures constitutes an important goal in
organic synthesis. One accepted green chemistry area is the use of ionic liquids. Ionic liquids have
been recognized as green, alternatives for volatile organic solvents in industrial and laboratory
processes for their unique physical and chemical properties (1) They can act both as reaction
medium and promoter in many organic transformations (2)
Thioureas have attracted much attention by virtue of their bioactivities as pharmaceuticals and
pesticides. Also, thioureas are important as building blocks in the synthesis of heterocycles (3).
Moreover, the use of thiourea as an organocatalyst has been described (4). A great variety of
procedures have been reported for the preparation of substituted thioureas. The numerous proce-
dures can be divided into three groups: (i) reaction of primary amines mainly with thiophosgene
or its less toxic and less hazardous substitutes (5); (ii) reaction of primary or secondary amines
with isothiocyanates that are usually prepared primarily from thiophosgene (6); (iii) reaction of
primary amines with carbon disulfide in the presence of mercury acetate and reaction of unsub-
stituted thioureas with primary alkyl amines at high temperature (7). Recently, several other new
methods for the preparation of substituted thioureas have been reported. For example, Prabhu
and coworkers (8) reported an efficient method for the synthesis of substituted thioureas via the
condensation of aliphatic amines and carbon disulfide in basic aqueous medium. Also, MCM-
41-TBD and ZnO/Al2O3composite as new and efficient supported heterogeneous catalysts for
*Corresponding author. Email: ziyaei@tmu.ac.ir
© 2013 Taylor & Francis

Journal of Sulfur Chemistry 285
the synthesis of thioureas were reported by Ballini and coworkers (9). Recently, Azizi et al. (10)
have reported an interesting procedure for the synthesis of symmetrical thioureas in water with-
out using any catalyst. However, many reported methods suffer from drawbacks and limitations
related to harsh reaction conditions such as high reaction temperature, long reaction times, the
use of a strong acid or base, and toxic reagents such as thiophosgene and hydrogen sul?de. Also
most of the reported methods are not applicable for aromatic amines. Therefore, development of
a mild, efficient, and environmentally benign procedure for the synthesis of thioureas is of great
importance in the search for bioactive molecules as well as in synthetic chemistry.
2. Results and discussion
In continuation of our interest in environmentally benign procedures (11) and encouraged by the
work of Shi et al. (12) on the synthesis of symmetrical ureas with carbon dioxide in an ionic
liquid, we wish to report here a novel, mild, catalyst-free, and green procedure for the synthesis
of symmetrical thioureas using commercially available amines and carbon disulfide in an ionic
liquid medium under neutral conditions (Scheme 1).
S
[BMIM]Cl
Ar(R)
2Ar(R)NH2
CS2
(R)Ar
N
H
N
H
100ºC
Scheme 1. Synthesis of thiourea in ionic liquid.
Reaction of aniline with carbon disulfide was studied in the presence of 1-butyl-3-
methylimidazolium chloride [BMIM]Cl as a cheap and commercially available ionic liquid as
model reaction to optimize the reaction conditions. These conditions included the equivalents of
the amine, carbon disulfide and ionic liquid, the temperature and the reaction time. As shown
in Scheme 1, the reaction gave high yield of the symmetrical thiourea as the only product after
10 h at 100◦C. Figure 1 shows the results in terms of the yield of 1,3-diphenylthiourea as a func-
tion of time for both ionic liquid and catalystfree mediums. The ionic liquid medium enhances
the reactivity of the system with respect to the uncatalyzed process. In particular, after 2 h, the
thiourea production ceased in the uncatalyzed system, while the reaction continued in the ionic
liquid medium finally producing an excellent yield of thiourea after 12 h
Ionic liquid
No catalyst
100
80
60
40
20
0
0
2
4
6
8
10
12
14
Time (h)
Figure 1. Camparison of the yields of the thiourea synthesis in ionic liquid and ionic-liquid-free condition.

286 A.Z. Halimehjani and F. Farahbakhsh
Table 1. Synthesis of symmetrical di-substituted thiourea derivatives.
Entry
Product
Yield (%)a,b Entry
Product
Yield (%)a,b
H H
N N
=
=
=
1
2
3
X
X
X
H
Cl
Br
95 (10)c
81 (10)
64 (10)
18
64 (20)
H
N
H
N
S
X
X
S
=
X
=
X
=
X
=
X
4
5
6
7
CH3
98 (10)
19
93 (10)
89 (8)
H
N
H
N
OCH2CH3 90 (13)
OH
OCH3
85 (14)
96 (10)
S
S
O
H
N
H
N
20
O
=
=
=
8
9
10
Y
Y
Y
Cl
OCH3
CH3
78 (10)
98 (15)
96 (16)
H H
N N
S
H
N
H
N
21
22
quant. (10)
75 (20)
Y
Z
Y
Z
S
=
OCH3
=
Cl
11
12
13
14
Z
Z
X
X
95 (17)
73 (10)
H
N
H
N
H
N
H
N
=
=
OCH2CH3 80 (18)
CH3
S
S
73 (10)
CH
CH
3H
H
N
CH3
3H
H
CH3
N
N
N
15
16
75 (10)
23
24
40 (10)
62 (9)
S
S
H C
CH3
CH3
CHH33C
H3C
3
H
H
H H
N N
quant. (10)
45 (19)
N
N
N
N
S
S
S
H
N
H
N
H
N
17
25
40
S
Cl
Cl
Cl
Cl
O
Notes: aIsolated yields.
bReaction conditions: amine (3 mmol), CS2 (5 mmol), ionic liquid (0.5 g), 12 h, 100◦C.
cReferences for the known compounds.
After optimization of the reaction conditions, the generality of this procedure was examined by
using different aliphatic and aromatic amines. As shown in Table 1 aromatic amines with electron
donating groups such as 2-methyl aniline, 3-methyl aniline, o- and p-methoxy aniline and o- and
p-ethoxyaniline gave excellent yields of products. Also, aromatic amines with moderate electron
withdrawing groups such as 4-chloroaniline, 4-bromoaniline, 2-chloroaniline, 3,4-dichloroaniline
and 3-chloroaniline gave high yields. 2,4,6-Trimethylaniline and 2,6-dimethylaniline as hindered
aromatic amines gave high yields of the corresponding thiourea. In addition, aliphatic amines
such as benzyl amine, furfuryl amine, butyl amine, sec-butyl amine, cyclohexyl amine and
1-phenylethyl amine give high yields of symmetrical thioureas. This procedure is not applicable
for secondary amines. This may be of the fact that the secondary amines cannot produce the active
isothiocyanate as an intermediate. Also, anilines with potent electronwithdrawing groups such as

Journal of Sulfur Chemistry 287
4-nitroaniline do not give any products. 2-hydroxy aniline gave benzo[d]oxazole-2(3H)-thione
in 40% yield. 2-Amino pyridine gave a good yield of the corresponding thiourea under the same
conditions.
Cross-condensation reactions of amines with carbon disulfide have been carried out for the
synthesis of unsymmetrical thioureas by using benzyl amine and an aromatic amine in an ionic
liquid medium. As shown in Scheme 2, unsymmetrical thioureas were obtained as major products
and symmetrical NNꢀ-diaryl thioureas were obtained as minor products.
S
S
S
[BMIM]Cl
100ºC
Ar
N
H
N
H
NH2
Ar
Ar
N
H
N
H
N
H
N
H
CS2
ArNH2
Ar =aniline
16%
13%
77%(16)
75%(16)
7%
12%
Ar= o-toluidine
Scheme 2. Unsymmetrical thiourea synthesis by cross-condensation reaction of amines with
carbon disulfide.
Reusability of the ionic liquid was investigated by recovering it from the reaction mixture and
by showing that it can promote the thiourea synthesis three times without loss of activity.
In conclusion, we have developed an efficient method for the synthesis of symmetrical thioureas
from commercially available building blocks such as amines and carbon disulfide in ionic liquid
medium. This method represents a simple procedure involving mild reaction conditions and has
general applicability. It avoids toxic catalysts and typically provides high to excellent yields of
products. Another advantage of this procedure is its successful application for the synthesis of
both aromatic and aliphatic amines.
3. Experimental
All reactions were carried out in an atmosphere of air. All chemicals and solvents were purchased
1
from Merck or Fluka and used as received. The H and 13C NMR spectra were recorded on
Brucker Avance 300 MHz NMR spectrometers. Melting points were recorded on a Branstead
Electrothermal 9200 instrument.
3.1. General procedure for the synthesis of thiourea
In a test tube equipped with magnet stirrer, an aromatic or aliphatic amine (3 mmol), carbon
disulfide (5 mmol), and ionic liquid (0.5 g) were added and the reaction mixture was stirred for
12 h at 100◦C. After completion, the product was extracted with diethyl ether or ethyl acetate
(3 × 15 ml) and the organic phase was washed with water and aqueous hydrochloric acid solution
(2 M) to remove unreacted amines. Then, the organic phase was dried with anhydrous sodium
sulfate and evaporated under reduced pressure to give pure thioureas in most of the cases. Further
purifications have been done by recrystallization in ethanol. Cross-condensation of amines with
carbon disulfide had been done by using 1.5 mmol of each amine. All the products are known and
were characterized by their 1H and 13C NMR and melting points compared with those reported
in the literature.

288 A.Z. Halimehjani and F. Farahbakhsh
Acknowledgement
We are grateful to the Research Council of Faculty of Chemistry of Tarbiat Moallem University for supporting this work.
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