Efficient and green protocol for the synthesis of thioamides in C 6 (mim)2Cl2 as a dicationic ionic liquid

Article abstract of DOI:10.1007/BF03246065

A simple, efficient, facile and eco-friendly process for the synthesis of thioamides from nitriles using 1,6-bis(3methylimidazolium-1-yl)hexane chloride [C₆(mim)₂Cl₂] as a dicationic ionic liquid (DIL) was developed. The ionic liquid was easily separated from the reaction mixture and was recycled at least four times without any loss of its activity.

Full text of DOI:10.1007/BF03246065

J. Iran. Chem. Soc., Vol. 7, No. 3, September 2010, pp. 752-758.
JOUIRrNaAnLiaOnF THE
Chemical Society
Efficient and Green Protocol for the Synthesis of Thioamides in C6(mim)2Cl2 as a
Dicationic Ionic Liquid
A.R. Khosropour*, J. Noei and A. Mirjafari
Catalyst Division, Department of Chemistry, Faculty of Science, University of Isfahan, Isfahan 81746-73441, Iran
(Received 22 May 2009, Accepted 9 November 2009)
A simple, efficient, facile and eco-friendly process for the synthesis of thioamides from nitriles using 1,6-bis(3-
methylimidazolium-1-yl)hexane chloride [C6(mim)2Cl2] as a dicationic ionic liquid (DIL) was developed. The ionic liquid was
easily separated from the reaction mixture and was recycled at least four times without any loss of its activity.
Keywords: Thioamides, Nitriles, Dicationic ionic liquid, Ammonium sulfide, Green chemistry, C6(mim)2Cl2
INTRODUCTION
mesoionic rhodanine [10], betaines [11] and other heterocyclic
compounds [12,13]. Owing to their versatile properties,
thioamides are used in rubber vulcanization as boosters or as
inhibitors of metal corrosion [14]. In addition, thioamides such
as 6-mercapto-purine show antitumor activity of their own
[15]. More recently, a platinum-pyridine thione complex has
been patented for clinical use in cancer treatment [16].
Fungicidal activity has also been reported for these
compounds [17]. Thus, the direct synthesis of thioamides is of
prime importance. Consequently, various methods have been
developed for the thioamide synthesis using a variety of
reagents under diverse reaction conditions [18,19]. However,
these classical methods often involve harsh reaction conditions
and the yields are typically low. Some modifications have
been made in two general ways: (i) the thionation of amides
with electrophilic reagents [20-22] and (ii) the reaction of
nucleophilic thionating reagent with amides or nitriles [23,24]
However, most of these procedures suffer from drawbacks
such as long reaction times, low yields, harsh reaction
conditions, tedious work-up and the use of environmentally
toxic reagent or media.
The increasing demand for clean and efficient chemical
synthesis is especially important from both economical and
environmental points of view [1]. Recently, ionic liquids (ILs)
have attracted considerable interest as environmentally benign
reaction media in synthetic chemistry [2]. Numerous chemical
reactions can take place in ILs [3]. Although ionic liquids
were initially introduced as an alternative green reaction
medium, today they have gone far beyond it, exhibiting
significant role in controlling reactions as catalysts [4-6]. So,
the development and application of so-called ‘‘task-specific’’
ionic liquids are highly desirable. Polyvalent ionic liquids are
a new class of ionic liquids which have not yet been studied
extensively [7]. In this paper, we describe the use of 1,6-bis(3-
methylimidazolium-1-yl)hexane chloride [C6(mim)2Cl2] as a
dicationic ionic liquid for the synthesis of thioamides.
Thioamides and their derivatives have received
considerable attention due to their prsence as useful synthon in
organic chemistry, for instance, synthesis of a variety of
hetrocycles such as thiazoline or thiazole derivatives [8,9],
Recently, Kaboudin et al., demonstrated a process for the
synthesis of thioamides which was limited in that only
*Corresponding author. E-mail: khosropour@chem.ui.ac.ir

Khosropour et al.
carbocyclics tolerated [25]. More recently, Williams et al.
cold water to afford a precipitate of the thioamide. This was
collected by suction filtration and recrystallised from ethanol
where appropriate.
reported another procedure for the synthesis of these
compounds through the two-step reaction with azides in the
presence of dithiobenzoic acid/Et3N [26]. The latter strategy
seems to be more flexible but harsh reaction conditions to
completion and narrow scope/purification of the desired
products are limitations of this protocol. On the other hand,
high toxicity of the reagent, and non-recyclability of the
catalyst or solvent make the method objectionable, especially
from the standpoint of green chemistry. Very recently,
Lukyanov et al. used O,O-diethyl dithiophosphate, in
concentrated HCl for direct conversion of nitriles to their
primary thioamides. However, the corresponding products
were obtained in moderate yields (39-85%) after long reaction
times (8-100 h) [27].
Typical Procedure for the One-Pot Synthesis of
Secondary and Tertiary Thioamides in C6(mim)2Cl2
To a mixture of nitrile (1 mmol) in C6(mim)2Cl2 (1.1
mmol), ammonium sulfide (1.2 mmol) was added. The
resulting mixture was stirred at 70 ºC for the appropriate time
shown in Table 2. After the completion of the reaction, as
indicated by TLC, amine (5 mmol) was added to the reaction
and stirred at 70 ºC for 10 min to 5 h (Table 3). Then the
reaction took place, was quenched with ice-water (10 ml) and
stirred at room temperature for 10 min. The above mixture
was extracted with ethyl acetate (3 ꢀ 5 ml) and the organic
layers were combined. When the residue was dried and
concentrated in vacuo, it was chromatographied on silica gel
(n-heptane/ethyl acetate as eluent) to afford the pure products
in 70-95% yields.
Consequently, due to the beneficial biological and
synthetic properties of certain molecules containing the
thioamide moiety, a short selective and low-cost protocol for
their synthesis is clearly in order.
EXPERIMENTAL
Recycling of Ionic Liquid C6(mim)2Cl2
The residual ionic liquid was washed with Et2O (3 ꢀ 10
ml) to remove any organic impurity and dried at 80 °C. Under
this procedure, C6(mim)2Cl2 could be reused for four runs
without any loss of its activity.
All compounds were identified by comparison of their
spectral data and physical properties with those of the
authentic samples. 1N NMR and 13C NMR spectra were
recorded on a Bruker DRX-500 Avance spectrometer at 500.1
and 125.7 MHz, respectively using CDCl3 as the solvent.
Chemical shifts (1) are given in ppm relative to TMS.
Coupling constants are given in Hz. IR spectra were recorded
on Mattson 1000 IR spectrometer using KBr pellets. Nitriles
and ammonium sulfide were purchased from Merck chemical
company. C6(mim)2Cl2 was prepared according to the
procedures reported in the literature [7]. TLC was performed
on silica gel on precoated silica gel plates (Merck 60 F254,
0.25 mm).
Spectroscopic Data
Compound 2a. pale yellow solid, m.p.: 113-114 °C. ꢀH
7.40 (t, J = 7.1, 2H), 7.51 (t, J = 8.13, 1H), 7.87 (d, J = 8.16,
2H), 9.50 (s, 1H), 9.88 (s, 1H).
Compound 2b. yellow solid, m.p.: 207-210 °C. ꢀH 7.44 (t,
J = 7.5, 1H), 7.94 (d, J = 8.6, 2H), 8.29 (s, 1H), 9.57 (s, 2H),
9.99 (s, 2H). 2max (cm-1) 3286, 3178, 3114, 1627.
Compound 2c. pale yellow solid, m.p.: 107-108 °C. ꢀH
7.36-7.46 (m, 4H), 9.69 (s, 1H), 10.17 (s, 1H).
Compound 2d. pale yellow solid, m.p.: 112-115 °C. ꢀH
7.45 (t, J = 8.3, 1H), 7.57 (d, J = 7.4, 1H), 7.82 (d, J = 8.3,
1H), 7.89 (s, 1H), 9.63 (s, 1H), 10.04 (s, 1H).
Typical Procedure for the Synthesis of Primary
Thioamides in C6(mim)2Cl2
To a mixture of nitrile (1 mmol) in C6(mim)2Cl2 (1.1
mmol), ammonium sulfide (1.2 mmol) was added. The
resulting mixture was stirred at 70 ºC for the appropriate time
as shown in Table 2. After the completion of the reaction, as
indicated by TLC, the mixture quenched immediately with
Compound 2e. pale yellow solid, m.p.: 126-129 °C. ꢀH
7.49 (d, J = 8.9, 2H), 7.9 (d, J = 7.9, 2H), 9.57 (s, 1H), 9.97 (s,
1H).
Compound 2f. pale yellow solid, m.p.: 83-85 °C. ꢀH 7.46-
7.53 (m, 2H), 7.72 (s, 1H), 9.81 (s, 1H), 10.32 (s, 1H).
753

Efficient and Green Protocol for the Synthesis of Thioamides
Compound 2g. yellow solid, m.p.: 120-123 °C. ꢀH 7.39 (t,
RESULTS AND DISCUSSION
J = 8, 1H), 7.70 (d, J = 8.5, 1H), 7.86 (d, J = 6.4, 1H), 8.03 (s,
1H), 9.62 (s, 1H), 10.03 (s, 1H). ꢀC 121.5, 126.6, 130.2, 130.4,
134.0, 141.8, 198.6.
Compound 2h. pale yellow solid, m.p.: 139-142 °C. ꢀH
7.63 (d, J = 9.3, 2H), 7.83 (d, J = 9.3, 2H), 9.58 (s, 1H), 9.96
(s, 1H).
Compound 2i. pale yellow solid, m.p.: 144-146 °C. ꢀH
7.04 (m, 2H), 7.57 (m, 2H), 9.31 (s, 1H), 9.70 (s, 1H). ꢀC
115.1, 130.3, 136.2, 163.1, 198.9.
Compound 2j. yellow solid, m.p.: 114-115 °C. ꢀH 7.55 (t,
J = 7.5, 1H), 8.05 (d, J = 7.5, 1H), 8.15 (d, J = 7.5, 1H), 8.45
(s, 1H), 9.66 (s, 1H), 10.05 (s, 1H). ꢀC 122.6, 125.9, 130.1,
133.5, 141.1, 143.7, 197.4.
Compound 2k. pale yellow solid, m.p.: 146-148 °C. ꢀH
3.8 (s, 3H), 6.95 (d, J = 9.7, 2H), 7.95 (d, J = 8.9, 2H), 9.33 (s,
1H), 9.66 (s, 1H). ꢀC 55.8, 113.3, 129.8, 131.6, 162.2, 198.9.
Compound 2l. yellow solid, m.p.: 170-172 °C. ꢀH 5.18 (s,
2H), 7.03 (d, J = 9.7, 2H), 7.33-7.47 (m, 5H), 7.94 (d, J = 8.1,
2H), 9.34 (s, 1H), 9.67 (s, 1H).
Compound 2m. pale yellow solid, m.p.: 205-207 °C. ꢀH
7.49 (s, 2H), 8.44 (s, 2H), 9.59 (s, 1H), 10.01 (s, 1H). ꢀC
125.8, 131.2, 132.7, 135.4, 201.1. 2max (cm-1) 3339, 3243,
3039, 1678. (Found: C, 51.89; H, 4.51; N, 20.43; S, 23.67%.
C6H6N2S requires: C, 52.15; H, 4.38; N, 20.27; S, 23.20%).
Compound 2o. pale yellow solid, m.p.: 134-137 °C. ꢀH
7.59 (m, 1H), 7.97 (m, 1H), 8.55 (m, 2H), 9.95 (s, 1H), 10.18
(s, 1H). ꢀC 124.9, 126.6, 137.7, 147.9, 152.1, 195.0.
Compound 2p. yellow solid, m.p.: 103-105 °C. ꢀH 6.93 (t,
J = 4.4, 1H), 7.48 (d, J = 3.2, 1H), 7.56 (d, J = 4.8, 1H), 9.25
(s, 1H), 9.48 (s, 1H). ꢀC 134.6, 141.9, 152.7, 165.2, 189. 2max
(cm-1) 3329, 3275, 3157, 1624. (Found: C, 46.96; H, 4.10; N,
11.17; S, 25.67%. C5H5NOS requires: C, 42.22; H, 3.96; N,
11.01; S, 25.22%).
To expand our work to design new synthetic
methodologies [28,29], specially in ionic liquids [30,31], we
developed a simple, green and efficient procedure for direct
synthesis of primary thiamides from various nitriles using
C6(mim)2Cl2 [7] as a dicationic ionic liquid (Scheme 1).
In an initial study, to examine the activity of different ionic
liquids, 4-chlorobenzonitrile was caused to react with
ammonium sulfide in the presence of each ionic liquid
separately. As shown in Table 1, C6(mim)2Cl2 is the most
effective in terms of yield of the corresponding thioamide
(97%) while in the presence of other ionic liquids the product
was obtained in 15-85% yields.
Interestingly, no reaction was observed in the absence of
ionic liquids. Consequently, we focused our attention only on
the reaction in C6(mim)2Cl2 as a dicationic ionic liquid. Using
S
(NH4)2S
RCN
NH2
R
+
N
N
N
+
N
1
2
2Cl-
Scheme 1. Synthesis of primary thioamides from nitriles in the
dicationic ionic liquid
Table 1. Ionic Liquid Effect on the Thionation of 4-Chloro-
benonitrile with Ammonium Sulfidea
Entry
Ionic liquid
Yield (%)b
1
2
3
4
5
6
7
8
[bmim]cOTf
[bmim]BF4
[bmim]PF6
[bmim]Cl
32
25
41
89
85
15
51
97
Compound 2q. pale yellow solid, m.p.: 232-235 °C. ꢀH
6.8 (s, 2H), 7.53 (s, 1H), 8.26 (s, 1H), 8.32 (s, 1H), 11.64 (s,
2H). ꢀC 141.9, 152.7.18, 175.1, 189.0. 2max (cm-1) 3436, 3329,
3232, 2931, 1640. (Found: C, 33.61; H, 4.04; N, 39.56; S,
22.79%. C4H6N4S requires: C, 33.79; H, 4.25; N, 39.40; S,
22.55%).
[bmim]Br
d
[Hmim]HSO4
PYR1n4TFSIe
C6(mim)2Cl2
aAfter 5 min. bIsolated yields. c1-Buthyl-3-methylimidazolium.
d1-Methylimidazolium hydrogen sulfate. N-butyl-N-methyl-
e
Compound 2r. pale yellow solid, m.p.: 154-156 °C. ꢀH
5.14 (s, 1H), 7.24-7.41 (m, 10H), 8.27 (s, 1H), 9.07 (s, 1H).
pyrrolidinium bis(trifluoromethanesulfonyl)imide.
754

Khosropour et al.
these optimal conditions, we evaluated the scope of this
Table 2. Continued
method for transformation of various nitriles to their
thoamides. The experimental results are summarized in Table
2.
The experimental procedure for this reaction is very simple
and requires no organic solvent or inert atmosphere. The
reaction took place by stirring an aromatic or aliphatic nitrile
with ammonium sulfide in the presence of C6(mim)2Cl2 at 70
ºC. All the products were characterized by IR and NMR
spectroscopic data.
S
Cl
CNH2
f
95
96
5
5
Cl
S
CNH2
g
Br
S
Br
A broad range of aromatic or heterocyclic nitriles bearing
electron donating or electron withdrawing substitutents
underwent this reaction to produce thioamides in high to
excellent yields. Interestingly, we found that in the case of 1,3-
dicyanobenzene, dithioamidation occurred under the same
reaction conditions (Table 2, compound 2b). Moreover,
CNH2
h
i
93
92
4
6
S
F
CNH2
S
CNH2
j
94
89
6
O2N
S
CNH2
MeO
BnO
N
k
l
50
Table 2. Thionation of Nitriles with Ammonium Sulfide in
C6(mim)2Cl2
S
CNH2
95
98
50
4
S
(NH4)2S
RCN
NH2
R
S
C6(mim)2Cl2
m
n
CNH2
Product
Yield (%)a Time (min)
CNH2
S
S
95
90
10
10
N
a
95
89
7
CNH2
CNH2
S
o
N
b
20
C
S
S
C
p
q
97
86
5
CNH2
S
O
NH2
NH2
S
H2N
H
N
c
d
e
93
94
97
6
3
5
CNH2
45
H2N
N
Cl
S
S
S
Ph
Ph
CNH2
r
s
90
94
35
15
CNH2
Cl
S
S
CNH2
Cl
CNH2
aIsolated yield.
755

Efficient and Green Protocol for the Synthesis of Thioamides
various functionalities such as ether, halide or nitro, survived
C6(mim)2Cl2 which gave the desired thioamides in high to
excellent yields (Table 3, 3a-j). This method can also be
considered as an efficient and novel protocol for the synthesis
of secondary and tertiary thioamides from nitriles through a
one-pot procedure with clearly short reaction times (Table 3).
To the best of our knowledge, this is the first attempt for
the synthesis of thioamides in ionic liquids. In general, the
reactions were clean and no side products were detected. The
use of C6(mim)2Cl2 as a new catalytic media in this
transformation exhibited rate enhancements, high yields and
under the said reaction conditions. On the other hand,
heterocyclic (Table 2, compounds 1m-1q) or aliphatic nitriles
(Table 2, compounds 1r and 1s), which normally would
produce poor yields in the reported methods [16,17], gave the
corresponding thioamides in excellent yields at short reaction
times (4-45 min).
Furthermore, in order to demonstrate the efficiency and the
applicability of the suggested method, we started the reaction
of nitriles and ammonium sulfide with different amines in
Table 3. Synthesis of Secondary and Tertiary Thioamides with Nitriles in C6(mim)2Cl2
S
S
(NH4)2S
RCN
or
N
R
NHR'
R
+
N
N
O
N
+
N
1
3
2Cl-
R'NH2 or morpholine
R
Amine
Yield (%)a
Time (min)
95
92
15
10
a
CH3NH2
CH3NH2
b
Cl
95
10
c
CH3NH2
Cl
Br
d
e
CH3NH2
CH3NH2
91
90
10
10
N
CH3O
89
94
15
10
f
CH3NH2
CH3NH2
g
h
l
O
CH2CH3NH2
CH2CH3NH2
93
80
90
CH3O
120
j
CH2CH3NH2
Morpholine
90
70
60
O
k
300
756

Khosropour et al.
In conclusion, we have described an efficient and eco-
short reactions times.
friendly method for the transformation of nitriles to their
thioamides in C6(mim)2Cl2 as a dicationic ionic liquid in high
to excellent yields. This ionic liquid is a low-cost and
recyclable medium. Reduced reaction time, no need for toxic
solvents and simple experimental work-up make this a green,
facile and superior method for the synthesis of thioamides.
We also examined the reusability of the IL with 3-
cyanopyridine as a substrate. We found that when the reaction
occurred, after washing the reaction mixture with ethyl acetate
and drying it at 80 °C, C6(mim)2Cl2 could be reused for at least
four runs without any loss of its activity (Table 4).
Although the mechanistic details of the reaction are not yet
known exactly, a plausible rationalization may be advanced to
explain the product formation (Fig. 1). Presumably, the
interaction between the IL and nitrile group (Fig. 1, A) and
then its conversion to the intermediate B and finally proton
transfer can form the product.
ACKNOWLEDGEMENTS
We are thankful to both the ‘Center of Excellence of
Chemistry (Catalysis and Fuel Cell)’ and the Research Council
of University of Isfahan for the partial support of this work.
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757

Efficient and Green Protocol for the Synthesis of Thioamides
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