Green process development for the synthesis of aliphatic symmetrical N,N'-disubstituted thiourea derivatives in aqueous medium

Article abstract of DOI:10.1080/00397911.2014.960939

A highly efficient green process for the synthesis of N,N'-disubstituted aliphatic thiourea derivatives using primary aliphatic amines and carbon disulfide in aqueous medium at room temperature via a nonisothiocyanate route is described. This protocol illustrates the rapid preparation of N,N'-disubstituted aliphatic thiourea derivatives in excellent yields with some advantages such as no catalyst and simple workup without any side product formation. Moreover the new route is concise, chromatography-free, and adaptable to pilot-scale preparation.

Full text of DOI:10.1080/00397911.2014.960939

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A Green Process Development for the Synthesis of
Aliphatic Symmetrical N, N′- Disubstituted Thiourea
Derivatives in Aqueous Medium
Asha D. Jangalea, Priyanka P. Kumavata, Yogesh B. Wagha, Yogesh A. Tayadea, Pramod P.
Mahulikara & Dipak S. Dalala
a School of Chemical Sciences, North Maharashtra University, Jalgaon, India
Accepted author version posted online: 25 Sep 2014.
To cite this article: Asha D. Jangale, Priyanka P. Kumavat, Yogesh B. Wagh, Yogesh A. Tayade, Pramod P. Mahulikar & Dipak
S. Dalal (2014): A Green Process Development for the Synthesis of Aliphatic Symmetrical N, N′- Disubstituted Thiourea
Derivatives in Aqueous Medium, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI: 10.1080/00397911.2014.960939
To link to this article: http://dx.doi.org/10.1080/00397911.2014.960939
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A Green Process Development for the Synthesis of Aliphatic Symmetrical N, N´-
Disubstituted Thiourea Derivatives in Aqueous Medium
Asha D. Jangale1, Priyanka P. Kumavat1, Yogesh B. Wagh1, Yogesh A. Tayade1, Pramod
P. Mahulikar1, Dipak S. Dalal1
1School of Chemical Sciences, North Maharashtra University, Jalgaon, India
School of Chemical Sciences, North Maharashtra University, Jalgaon - 425 001(M. S.),
India, Email: dsdalal2007@gmail.com
Abstract
A highly efficient green process for the synthesis of N, N´-disubstituted aliphatic thiourea
derivatives using primary aliphatic amines and carbon disulphide in aqueous medium at
room temperature via non-isothiocyanate route is described. This protocol illustrates the
rapid preparation of N, N´-disubstituted aliphatic thiourea derivatives in excellent yields
with some advantages such as catalyst free, simple workup without any side product
formation. Moreover the new route is concise, chromatography-free, and adaptable to
pilot-scale preparation.
1

KEYWORDS: Amine, Carbon disulphide, Water, Green synthesis, Catalyst free, 1, 3-
disubstituted Thioureas.
INTRODUCTION
In recent years, chemical industry is paying more attention towards developing green
chemical processes as it involves more environmentally acceptable chemicals, reagents,
solvents, and catalyst.1–3 Therefore, in the consent of green chemistry, it is important to
develop large scale preparation of the target compounds involving water-based reaction
media. Thiourea has received considerable attention due their applications. The
significance of thioureas lies in their pharmaceutically relevant physiological activity
encompassing antibacterial,4 antimalarial,5 antiviral,6 antitumor,7 antitubercular,8
anticancer,9 insecticide, herbicide,10 antithyroid,11 antiarrhythmic,12 RT-inhibitor,13
antihypertensive14 and on connection with biomimetic models.15 Thiourea derivatives are
valuable building blocks for the synthesis of amides, guanidine’s and variety of
heterocycles.16 Several studies have revealed that thiourea derivatives have not only been
used in medical and agriculture applications, but also, they play major contribution in the
environmental and industrial applications17 such as gold leaching,18 redox
polymerization.19 Thiourea derivatives have been used as important organo-catalyst in
organic reaction.20
Thioureas have been synthesized by using various reagents, such as thiophosgene21 and
isothiocyanates,22 Phase Transfer Catalyst,23 thiazolidine-2-thione.24 Some methods have
been reported for the synthesis of thiourea derivatives consists of reacting a primary
2

amine with carbon disulphide by using MCM-41-TBD,25 Zn/Al2O3,26 1-
(methyldithiocarbonyl)imidazole,27 Zn-Al hydrotalcite (500),28 Lac Sulfur,29
Polyethylene glycol-40030 under microwave irradiation. Recently, thiourea derivatives
have been prepared by condensing primary or secondary amines with carbon disulphide
in aqueous Prabhu and coworkers31, Azizi et. al.32 and Halimehjani, A. Z. et. al.33
reported the synthesis of thioureas in aqueous medium under heating. Besides contrary
fact is that carbon disulphide is a volatile liquid having low (46oC) and had used in excess
amount. Thus, it is important to develop an effective and convergent process for a scale-
up preparation of thiourea derivatives at room temperature particularly in green solvent
such as water which constitutes an important goal in organic synthesis.34
In persistence of our work in organic synthetic methods,35 we account here study on
developing a strategy to synthesize N, N´-disubstituted aliphatic thiourea derivatives
using primary aliphatic amines and carbon disulphide via non-isothiocyanate route by
simple stirring in aqueous medium without using any catalyst. This procedure is reliable
since catalyst free, aqueous conditions are significant in small scale (academia) and large
scale (industry) preparations.
RESULTS AND DISCUSSION
With the escalating interest in developing environmentally benign, catalyst free reactions
in aqueous media we have synthesized symmetrical N, N´-disubstituted thiourea
derivatives using aliphatic primary amines, carbon disulphide in water with stirring at
room temperature (Scheme 1). There is no such appropriate method reported in the
3

literature for the direct synthesis of symmetrical N, N´-disubstituted series of aliphatic
thiourea derivatives.
The reaction proceeds with different aliphatic amine, carbon disulphide in water via
simple stirring is summarized (Table 2). In a first attempt, we tried for neat reaction with
same components but amine remains unreacted. It was observed that the solvent required
for the completion of reaction. Screening of various solvents with n-butyl amine and
benzyl amine revealed that water was most efficient for the transformation of n-butyl
amine and benzyl amine into N, N’-dibutyl thiourea and N, N’-dibenzyl thiourea
respectively (Table 1, entry 1). For n-butyl amine, it was found that in aq. EtOH (1:1),
MeOH, EtOH, DCM and EtOAc, the moderate yields (Table 1, entries 2–6) while in
toluene and hexane, poor yields were obtained with prolonged reaction time (Table 1,
entries 7, 8). However, the yield in given solvents were not too much decreased in case of
benzyl amine since it is immiscible with water. Therefore, solvent study was carried out
for both water miscible as well as immiscible substrate.
Initially, benzyl amine was selected as the model reagent with carbon disulphide. In
round bottom flask, benzyl amine (2 mmol) was added to carbon disulfide (2 mmol) in
water and stirred at room temperature. It was found that dithiocarbamic acid 3 was
obtained by nucleophic attack of benzyl amine on carbon disulphide. To this reaction
mixture, again benzyl amine (2 mmol) was added which on heating in situ generated
isothiocyanate to afford N, N’-dibenzyl thiourea. When the same reaction was carried out
without heating, isothiocyanate formation was not observed (confirmed by TLC) to
4

afford N, N’-dibenzyl thiourea and required prolonged reaction time with lower yields.
Subsequently, benzyl amine (6 mmol) added to carbon disulfide (3 mmol) in water with
stirring at room temperature. During addition the flask became hot because this is
exothermic reaction. This heat is sufficient to liberation of H2S, and confirmed by smell
and lead acetate paper which turns black. Significantly, no isothiocyanate formation28
was observed and furnishes product N, N’-dibenzyl thiourea within short time. In
literature, amines react with carbon disulphide to form dithiocarbamate amine salt 5.
Generally these salts are formed in presence of stronger bases and are quite stable on
heating forms isothiocyanate 6.
Plausible mechanism of the reaction:
When the reaction is carried out in water, the rate of reaction is considerably enhanced
and significant improvement in the yield was observed by stirring at room temperature.
The time required for completion of reaction was shorter in the case of aliphatic amines
compared to aromatic amines. It has been found that the reaction proceeds smoothly with
diverse aliphatic primary amines and carbon disulphide in aqueous medium to give
symmetrical thiourea derivatives, in excellent yields. Accordingly, we decided to focus
our attention on the development of a simple procedure in water for the synthesis of
symmetrical disubstituted thioureas. Since, water shows unique properties such as, the
network of hydrogen bonds; the large surface tension, the high specific heat capacity, the
high cohesive energy and the high polarity that can significantly influence the
transformations.36 Thus reactions of structurally diverse amines were carried out with
5

carbon disulphide in aqueous medium to synthesize symmetrical dialkylsubstituted
thioureas (Scheme 1).
To explore the scope of the reactions, we extended the procedure to several types of alkyl
amines (entries 1-7). Later different cyclo-amines (entries 8, 9), aryl, substituted
heterocyclic amines (entries 10-13), in addition hydrazines, (entries 14, 15), were chosen
to react with carbon disulphide under optimized conditions (entries 1-15). The product
was obtained in dissolve state in aqueous medium and isolated by evaporation of solvent
under reduced pressure (entries 1-6, 8, 12 and 13) while in some cases the reaction
mixture solidified when the reaction was completed (entries 7, 9-11, 14 and 15). Certain
of the circumstances have been applied for some of the reactions when demanded. For
entry 14, 2-3 mL of water is used since the product remains solid on addition of 2-3 mL
water and the product is easily obtained by filtration (entry 14). The time required for
completion of reaction was shorter in the case of aliphatic amines (10-60 minutes) while
in case of aryl hydrazine it was slightly extended (entry 15). We examined a number of
primary amines and found that the reaction affords the expected products in excellent
yields (Table. 2).
The synthetic procedure were optimized on a small scale and subsequently transferred to
large scale to excellent yield. In a controlled experiment in our laboratory, when
isopropyl amine (100 mmol) was mixed with carbon disulphide (50 mmol) and water (15
mL) in ice cold condition, the mixture began to start to convert into solid within addition
of 25-30 minutes with 97% yield. This is exothermic reaction, cooling is sagacious for
6

large scale reaction. Then water (35 mL) is added to the reaction mixture for further
completion of reaction. By using these optimized conditions and designed reactors,
process will be useful to industries for larger scale production of symmetrical thioureas.
No operational problems are foreseen for a large scale version of this green process. This
provided an additional advantage of capacity enhancement on commercial Scale.
CONCLUSION
In conclusion, we have been simple, green scale up process under mild reaction
conditions for the synthesis of symmetrical thioureas by facile reaction between alkyl
amines and carbon disulphide in water at room temperature, proceeded well without any
catalyst, and generated virtually no byproducts. To the best of our knowledge, this is the
first report wherein symmetrical N, N’-disubstituted thioureas derivatives are synthesized
via non-isothiocyanate route at room temperature. It avoids hazardous organic solvents,
toxic catalysts and typically provides nearly quantitative yields of product. However, the
synthetic procedure was not only amplified on a small scale but also to large scale to
allow production of symmetrical thiourea, certainly without operational problems.
EXPERIMENTAL SECTION
Typical Experimental Procedure For Symmetrical Thioureas Derivatives
To a 50 mL round bottom flask equipped with a magnetic stirrer, add carbon disulphide
(5 mmol) and amine (10 mmol) in ice cold condition followed by addition of water (5
mL). Cork the flask. The reaction mixture was stirred vigorously at room temperature.
The progress of the reaction was checked by TLC (10% MeOH/chloroform or
7

EtOAc/hexane). After completion of reaction, solid was obtained by removal of water
under reduced pressure on rotary evaporator while in some cases (Entry 7, 9, 10, 11 and
14, 15) the reaction mixture solidified when the reaction on completion. The obtained
solid product was recrystallized with ethanol or washing with mixture EtOAc: hexane.
The products were characterized by their physical constants, IR, NMR, mass
spectroscopy, and comparative TLC data, which were in good agreement with the
authentic samples.
ACKNOWLEDGEMENT
The authors are thankful to University of Pune and SAIF, Punjab University, Chandigarh
for providing the spectral analysis. One of the author ADJ is thankful to University Grant
Commission, New Delhi for SAP fellowship under the scheme ‘Research Fellowship in
Sciences for Meritorious Students’.
SUPPORTING INFORMATION
Supplementary material, which includes some of the scan copies of IR, 1H-NMR, 13H-
NMR and Mass analysis, for this article can be accessed on the publisher’s website.
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Table 1. Optimization of reaction solventsa
Entry
Solvent
Reaction Time
n-Butyl amine Benzyl
amine
Yield (%)
n-Butyl amine Benzyl
amine
1
2
3
4
5
6
7
8
Water
50 min
80 min
110 min
140 min
80 min
3 h
96
77
73
70
68
63
45
34
97
92
90
89
85
84
80
74
1:1 aq. EtOH
MeOH
4.5 h
5 h
EtOH
Dichloromethane 3 h
6 h
Ethyl Acetate
Toluene
3.5 h
6.5 h
8 h
5 h
Hexane
5 h 40 min
10.5 h
aReaction conditions: (06 mmol) amine, (03 mmol) CS2, and (03 mL) solvent
13

Table 2. Synthesis of symmetrical thiourea derivatives in aqueous mediumb
Entry
Amine
Product
Time
Yield
(min) (%)c
10
50
10
50
60
10
10
30
50
60
50
10
10
20
120
99
95
97
96
93
98
95
96
95
97
97
90
98
98
90
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
15
bReaction conditions: (10 mmol) amine, (05 mmol) CS2 & (05 mL) H2O.
cIsolated yields. d(2-3 mL) H2O.
14

Scheme 1. The synthesis of N, N´-disubstituted thioureas with primary amine, carbon
disulphide in water.
15

Scheme 2. Proposed reaction mechanism of formation of N, N´-disubstituted thiourea
16