Rapid and highly efficient synthesis of thioureas in biocompatible basic choline hydroxide

Article abstract of DOI:10.1080/17415993.2017.1327591

A straightforward and convenient synthesis of symmetrical thiourea derivatives by the reaction of primary amines and carbon disulfide in biocompatible basic choline hydroxide is presented. A variety of biologically important thiourea derivatives can be obtained in good to excellent yields without a tedious work-up under mild reaction conditions. A series of primary aliphatic and aromatic amines with different substituted functional groups have been converted to thiourea derivatives under milder reaction conditions and short reaction times.

Full text of DOI:10.1080/17415993.2017.1327591

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Rapid and highly efficient synthesis of thioureas in
biocompatible basic choline hydroxide
Najmedin Azizi & Elham Farhadi
To cite this article: Najmedin Azizi & Elham Farhadi (2017): Rapid and highly efficient synthesis
of thioureas in biocompatible basic choline hydroxide, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2017.1327591
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Date: 25 May 2017, At: 02:13

JOURNAL OF SULFUR CHEMISTRY, 2017
https://doi.org/10.1080/17415993.2017.1327591
Rapid and highly efficient synthesis of thioureas in
biocompatible basic choline hydroxide
Najmedin Azizi and Elham Farhadi
Department of Green Chemistry, Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 18 January 2017
Accepted 2 May 2017
A straightforward and convenient synthesis of symmetrical thiourea
derivatives by the reaction of primary amines and carbon disulfide
in biocompatible basic choline hydroxide is presented. A variety
of biologically important thiourea derivatives can be obtained in
good to excellent yields without a tedious work-up under mild reac-
tion conditions. A series of primary aliphatic and aromatic amines
with different substituted functional groups have been converted
to thiourea derivatives under milder reaction conditions and short
reaction times.
KEYWORDS
Choline hydroxide; thiourea;
amines; sulfur chemistry;
basic ionic liquid
1. Introduction
Ionic liquids are considered to be ideal solvents with diverse application due to their unique
properties, namely, solvation power and catalytic activity and extensively used as solvents
and co-solvents in organic synthesis [1–3]. Choline hydroxide (ChOH) as a biocompat-
ible and naturally abundant basic ionic liquid with unique physico-chemical properties
has received more attention over the last few years [4–6]. The basic functional groups in
the ionic liquid (Figure 1) provides extra capacity to behave not only as a green reaction
medium, but also as a recyclable basic promoter in different organic transformation [7–10].
Substituted thioureas are important functional groups due to their usefulness as build-
ing blocks in heterocyclic chemistry, as synthetic intermediates and as a result of their
broad-spectrum of biological activities [11,12]. Furthermore, thioureas are used as vulcan-
ization accelerators in the rubber industry and useful thiourea organocatalysis in organic
synthesis [13–17]. In view of diverse applications, many powerful methods have been
CONTACT Najmedin Azizi
azizi@ccerci.ac.ir
Department of green chemistry, Chemistry and Chemical
Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2017.1327591
© 2017 Informa UK Limited, trading as Taylor & Francis Group

2
N. AZIZI AND E. FARHADI
OH
N
OH
Figure 1. Structure of ChOH.
appearing for their synthesis in the literature [12,18]. Conventionally, thiourea and its
derivatives are prepared from ammonium thiocyanate or by the reaction of hydrogen sul-
fide with calcium cyanamide [19–21]. Therefore, there have been considerable efforts in
the development of green methods in the synthesis of thiourea derivatives by condensa-
tion reactions of amines and carbon disulfide in various reaction media in the literature
[22–32].
2. Results and discussion
In the past few years, our research group has explored the applicability of alternative green
solvents for highly efficient synthesis of dithiocarbamate derivatives whilst adopting a more
eco-sustainable approach [33–36]. For the first time, we report here a convenient pro-
tocol for the preparation of thiourea derivatives in ChOH-based ionic liquid. From our
previous experience with the thiourea chemistry and as a continuation of our research
interest in the use of alternative reaction media for organic synthesis, herein we wish to
report the rapid synthesis of substituted thioureas. For this purpose, the model reaction
between benzyl amine and carbon disulfide was investigated in ChOH as a novel basic
reaction media. When the reaction was carried out at room temperature in the presence
of ChOH for approximately 10 min, most of the starting material, 1a, was converted to the
corresponding thiourea 2a.
After this unexpected result, further investigations were carried out by using ben-
zyl amine (1a) and carbon disulfide with various solvents and promoters, and the
results are presented in Table 1. Screening of diverse additives (TMG, DABCO, DBU,
Table 1. Optimization of model reaction.
Entry
Base
Solvent
Yields(%)a,b
1
2
3
4
5
6
7
8
9
10
ChOH
DABCO
DBU
Et3N
TMG
NaOH
Et3N
Et3N
Et3N
Et3N
ChOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
Toluene
DMF
97
60
68
72
40
58
40
25
68
72
H2O
aIsolated yields.
bReaction conditions: benzyl amine 1a (2.0 mmol), CS2 (1.2 mmol) solvent (0.5 mL)) and
bases (1 mmol). DABCO:1,4-diazabicyclo[2.2.2]octane, DBU: 1,8-diazabicycloundec-7-ene,
TMG: tetramethylguanidine.

JOURNAL OF SULFUR CHEMISTRY
3
Table 2. Synthesis of symmetrical thiourea in ChOH-based ionic liquid.
m.p (°C)
Entry
1
Product
Yield (%)a
97
Found
Reported [ref.]
146–148 [23]
2a
2b
2c
2d
2e
2f
145–147
2
3
4
5
6
74
72
68
76
97
149–151
178–180
36–38
150–152 [23]
176–177 [22]
34–36 [24]
150–152
128–130
150–152 [24]
129–130 [27]
7
8
9
2g
2h
2i
93
90
80
149–150
74–77
145–146 [22]
75–79 [25]
182–184
184–185 [8]
10
2j
2k
2l
72
76
72
74
149–150
66–68
149 [24]
69–71 [24]
54–56 [24]
130 [24]
11
12
56–58
13
2m
130–131
aIsolated yields.

4
N. AZIZI AND E. FARHADI
Figure 2. Recyclability study of the reaction medium.
Et3N, K2CO3 and NaOH) in diverse solvents such as H2O, EtOH, toluene, CH3CN
and DMF in the model reaction revealed that ChOH was the most effective in terms
of yield and time. All solvents and bases which we screened did not give any satisfac-
tory results (Table 1, Entries 1–10). After a variety of reaction condition’s screening, it
was surprising to find that the best reaction condition was ChOH at room temperature
(Table 1).
Under the above optimized reaction conditions, the scope and generality of this new
procedure are summarized in Table 2. Different primary aliphatic amines such as ben-
zylamine, butyl amine, 1-phenylethylamine, 2-phenylethylamine, 3-phenylpropylamine
and cyclopropylamine reacted smoothly under optimized condition to give the corre-
sponding symmetrical thiourea derivatives in good to excellent yield. Primary aryl amines
such as aniline, 4-methoxyaniline, 4-n butylaniline were also found to be good substrates
and afford the desired products in good yield (Table 2). However, when conducting the
model reaction with secondary amines, such as pyrrolidine, only starting materials were
obtained.
The recyclability of basic ionic liquid was important which helps address both economi-
cal and environmental viewpoints in industrial scale. To demonstrate this issue, the recycle
efficiency of the ChOH-based ionic liquid was investigated for compound 2a in the reaction
between benzyl amine (5.0 mmol), CS2 (5.0 mmol) and ChOH (3 mL) under the optimized
conditions (Table 2, Entry 1). After completion, the reaction mass was filtered to obtain
crude solid product, which was washed with water. ChOH was recovered by evaporation
of water under vacuum from the filtrate and used for recyclability study. The results shown
in Figure 2 reveal that ChOH can be recycled for at least four cycles with a little loss of its
reactivity.
3. Conclusion
In summary, the practical preparation of symmetrical thiourea derivatives can be per-
formed through the fast and high yield reaction of primary amines and carbon disulfide
under the mild reaction conditions. The isolation of the pure products was achieved by sim-
ple filtration washing with water, and purified via recrystallization from ethanol without
harmful organic solvent.

JOURNAL OF SULFUR CHEMISTRY
5
4. Experimental section
4.1. Materials and methods
Melting points are measured on a Buchi Melting Point B-545 apparatus and are uncor-
rected. NMR spectra were recorded on a Bruker ACF 500 using CDCl3/CCl4 or
CDCl3/DMSO-d6 as solvent. Low-resolution mass spectra or high-resolution mass spectra
were obtained on a Finnigan GC-MS 4021 or a Finnigan MAT-8430 instrument using the
electron impact ionization technique (70 eV1), respectively. All chemicals were obtained
from commercial suppliers and used without further purification. Water and other solvent
were distilled before use.
4.2. Preparation of ChOH
The ChOH-based ionic liquid was prepared according to the literature [10]; choline chlo-
ride (20 mmol) and KOH (20 mmol) in methanol (25 mL) were heated at reflux for 8 h
under N2. After cooling to room temperature, the reaction mixture was filtered to remove
solid KCl and the solution was concentrated under vacuum to remove methanol. The
residue was dissolved in water to prepare 50 wt.% in H2O and used without any further
purification.
4.2.1. Typical procedure for the preparation of thiourea derivatives (2a–2m)
A mixture of aliphatic or aromatic amines (2 mmol), carbon disulfide (1.2 mmol) and
ChOH (0.5 mL) was added into a test tube with a magnetic stirring bar under an ice-
cold condition. The test tube was stirred at room temperature (aliphatic amines) or 80°C
(aromatic amines) until TLC showed completion. After the completion of the reaction,
the reaction mixture was cooled to room temperature and water was added that in most
cases resulted in formation of solid products. The crude product was washed with water
(10 mL) and purified by recrystallization from hot ethanol or washing with a mixture of
EtOAc/hexane to obtain the pure product.
4.2.1.1. Recyclability of ChOH. A 10 mL round-bottom flask was cooled at 0°C and slowly
charged with ChOH (2 mL), benzyl amine (6.0 mmol) and CS2 (4.0 mmol) respectively and
the solution was stirred at room temperature for 20 min. After completion of the reaction,
the solid was obtained by addition of water and recrystallized with ethanol to give pure
N,N’-dibenzyl thiourea. ChOH was recovered by evaporation of water under vacuum from
the filtrate and used for recyclability study.
Disclosure statement
No potential conflict of interest was reported by the authors.
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