Highly efficient and catalyst-free synthesis of unsymmetrical thioureas under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2008.10.063

A highly efficient and simple synthesis of unsymmetrical thioureas is reported based on the reaction of readily synthesized dithiocarbamates with amines, without using any catalyst under solvent-free conditions. The short reaction time, high yields, and s

Full text of DOI:10.1016/j.tetlet.2008.10.063

Tetrahedron Letters 50 (2009) 32–34
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient and catalyst-free synthesis of unsymmetrical
thioureas under solvent-free conditions
Azim Ziyaei Halimehjani a, Yaghoub Pourshojaei b, Mohammad R. Saidi b,
*
a Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh Street, Tehran, Iran
b Department of Chemistry, Sharif University of Technology, PO Box 11465-9516, Tehran 11365, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2008
Revised 5 October 2008
Accepted 14 October 2008
Available online 18 October 2008
A highly efficient and simple synthesis of unsymmetrical thioureas is reported based on the reaction of
readily synthesized dithiocarbamates with amines, without using any catalyst under solvent-free condi-
tions. The short reaction time, high yields, and solvent-free conditions are advantages of this method. We
did not observe the formation of any symmetric disubstituted thiourea, under these reaction conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
With increasing global environmental concerns, the design of
‘solvent-free’ green processes has gained significant attention from
synthetic organic chemists.1 As a result, many reactions are
designed to proceed cleanly and efficiently in the solid state or
under solvent-free conditions.2 Less chemical pollution, lower cost,
and an easier workup procedure are the main reasons for the
recent increase in the popularity of solvent-free reactions.
example, Yin et al. reported an efficient method for the synthesis
of disubstituted thioureas via the reaction of N,N0-di-Boc-substi-
tuted thiourea with alkyl or aryl amines in the presence of NaH
as base.20 However, many reported methods suffer from draw-
backs 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 hydro-
gen sulfide. Therefore, the development of mild, efficient, and envi-
ronmentally benign methods for the synthesis of novel thioureas is
of great importance in the search for bioactive molecules as well as
in synthetic chemistry. Thus, we report here a novel, mild, catalyst-
free, and green procedure for the synthesis of unsymmetrical thio-
ureas using dithiocarbamates and various amines under solvent-
free conditions.
In previous work, we reported a one-pot and simple method for
the synthesis of dithiocarbamates from an amine, CS2, and different
nucleophile acceptors, such as alkyl halides, activated olefins, and
epoxides, under solvent-free or aqueous conditions (Scheme 1).21
Encouraged by the work of Artuso and co-workers which utilized
dimethyl dithiocarbonate for the synthesis of substituted ureas in
water,22 we focused our attention on the synthesis of unsymmetri-
cal thioureas from easily prepared dithiocarbamates and different
amines under solvent-free conditions. After synthesizing the start-
ing dithio-carbamates,21a–c we optimized the reaction conditions
by changing the temperature, solvent, and equivalents of amine
for the reaction of 1 with aniline and morpholine as model reac-
tions. We screened the reaction in solvents including H2O, ethanol,
CH2Cl2, THF, ClCH2CH2Cl, and CH3CN. As shown in Scheme 1, the
reaction of morpholine with 1 gave moderate to excellent yields
in various organic solvents, but aniline gave only poor to moderate
yields in these organic solvents. However, under solvent-free con-
ditions, the reaction of the dithiocarbamate with various aromatic
and aliphatic amines proceeded to completion, affording unsym-
metrical thioureas in excellent yields without the use of any
Thioureas have attracted much attention by virtue of their bio-
activities as pharmaceuticals and pesticides. Various thiourea
derivatives and their metal complexes exhibit analgesic,3 anti-
inflammatory,4 antimicrobial,5 anticancer,6 and antifungal activi-
ties.7 Moreover, thioureas are important as building blocks in the
synthesis of heterocycles. For example, thiourea condenses with
2-halocarbonyl compounds to afford 2-aminothiazoles.8 Benzo-
thiazoles can be prepared from arylthioureas in the presence of
bromine.9 The use of thioureas to make iminothiazolines,10 thi-
ohydantoins,11 1,3,5-triazines,12 and 2-amino-oxazolidines13 has
been described. Also, the use of thiourea as an organocatalyst has
been described.14 A great variety of procedures have been reported
for the preparation of substituted thioureas. The procedures having
widest use, which are also of practical interest for industrial syn-
thesis, can be collected into three groups: (i) reaction of primary
amines mainly with thiophosgene or its less toxic and less hazard-
ous substitutes;15 (ii) reaction of primary or secondary amines
with isothiocyanates16 (isothiocyanates are prepared mainly from
thiophosgene in an organic solvent); and (iii) reaction of primary
amines with carbon disulfide in the presence of mercury acetate
and reaction of unsubstituted thioureas with primary alkylamines
at high temperature in aqueous ammonia,17 which gave the sym-
metrical thioureas.18 Recently, several other new methods for the
preparation of substituted thioureas have been reported.19 For
* Corresponding author. Tel.: +98 21 6600 5718; fax: +98 21 6601 2983.
E-mail address: saidi@sharif.edu (M. R. Saidi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.063

A. Z. Halimehjani et al. / Tetrahedron Letters 50 (2009) 32–34
33
Table 1
MeO
S
NH2
50-60 o
Synthesis of unsymmetrical thioureas from dithiocarbamates and amines under
OMe
solvent-free conditionsa
N
N
H
H
C
Or
S
S
+ Or
O
neat
S
R1
HN
S
+ R1R2NH
O
N
NH
RHN
N
RHN
NH
S
60 º C
MeO
1
S
N
H
R2
NH2
NH2
NH2
Solvent: THF CH2Cl2 H2O ClCH2CH2Cl EtOH CH3CN neat
NH2
NH2
NH
NH
b
Yielda
(Morpholine)
46
33
quant. 46
quant. quant.
quant.
95
NH
NH3
O
NH2
MeO
a
b
c
d
e
f
g
h
i
j
k
Yielda
NR
NR
60
NR
30
10
(Aniline)
Entry
Dithiocarbamate
Amine
Yieldc (%)
a Isolated yield. NR = No reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
b
c
d
e
f
g
h
j
k
a
b
d
f
h
a
b
c
d
e
f
95
Quant.
Quant.
Quant.
89
95
92
Quant.
Quant.
Quant.
90
76
85
90
64
Quant.
60
50
90
Quant.
95
80
Quant.
Quant.
S
S
Scheme 1. Screening of solvents.
NH
MeO
catalyst. Our studies showed that the reactions were complete at
50–60 °C in most cases. The reaction of 1 was also carried out with
different equivalents of aniline and morpholine. We found that
about 1.1 equiv of amine was sufficient to achieve complete con-
version of the dithiocarbamate to a thiourea.
1
S
Next, the scope and limitations of this process were explored by
using a wide range of amines. Structurally diverse amines includ-
ing primary and secondary aliphatic amines, primary aromatic
amines, and ammonia underwent the reaction without using any
catalyst or solvent to afford the corresponding unsymmetrical
thiourea. Also, the reaction was carried out with four different
S-alkyl dithiocarbamates. The results are summarized in Table 1.
As shown in Table 1, the reaction of dithiocarbamates derived
from primary aliphatic and aromatic amines gave substituted thio-
ureas with excellent yields. However, reaction with dithiocarba-
mates based on a secondary amine was not possible. Thioureas
containing adamantyl groups were synthesized in excellent yields.
Also, optically active thioureas were synthesized by the reaction of
a chiral amine with dithiocarbamates or of amines with a chiral
dithiocarbamate.
The reaction of 1,3-propanediamine with dithio-carbamates 1
and 3 gave the corresponding bis-thioureas 5 and 6 in quantitative
yields as shown in Scheme 2.
We also compared the reactivities of primary and secondary ali-
phatic amines with a dithiocarbamate as outlined in Scheme 3. We
found that pyrrolidine reacted with dithiocarbamate 1 in the pres-
ence of butylamine to give an unsymmetrical thiourea in more
than 95% yield, but butylamine gave less than 5% of the corre-
sponding unsymmetrical thiourea.
Generally, the solvent-free reaction is experimentally simple
and proceeded well without any catalyst, and generated virtually
no byproducts. All the reactions performed here involved stirring
homogenous liquids, due to the low melting point of the S-alkyl
dithiocarbamates. As the reaction proceeded, the mixture solidified
as the product formed. As the reactions are run under neat and cat-
alyst-free conditions, no side products form in the reaction mixture
(apart from entries 28 and 29, Table 1), and in some cases, the pure
thioureas were isolated by simple extraction. Usually, washing the
solidified mixture with 2 M HCl and filtration of the solids gave the
pure unsymmetrical thiourea. All compounds gave satisfactory
NMR spectra (see Supplementary data).
N
S
H
2
H
N
S
S
3
h
id
j
25
26
27
28
29
a
c
d
ge
ie
Quant.
Quant.
Quant.
85
Me
H
N
S
S
4
70
b
1.0 mL of a 25% aqueous solution of ammonia was used in the reaction.
a
Reaction conditions: dithiocarbamate (5 mmol), amine (7 mmol), 60° C, 4 h.
Isolated yields.
c
d
e
Reaction performed at 90° C.
10% of isothiocyanate was also obtained.
OMe
NH
OMe
OMe
neat
H N
NH2
+
2
60 oC, 100%
H
H
HN
N
N
HN
S
5
S
S
1
S
H
N
H
N
H
N
neat
60 oC, 100%
S
H N
NH2
+
2
S
S
N
H
S
N
H
3
6
Scheme 2. Reaction of a diamine with dithiocarbamates.
In conclusion, we have developed an efficient method for the
synthesis of unsymmetrical thioureas from readily synthesized S-
alkyl dithiocarbamates and amines. Importantly, no symmetrical
disubstituted thioureas were formed under these reaction condi-
tions. This method represents a simple procedure involving mild
reaction conditions, and has general applicability. It avoids hazard-
ous organic solvents and toxic catalysts and typically provides
nearly quantitative yields of products.
General procedure for the synthesis of unsymmetrical thioureas: To
a test tube equipped with a magnetic stirrer bar, dithiocarbamate
(5 mmol) and amine (7 mmol) were added. The reaction mixture
was warmed to 60 °C with vigorous stirring. The progress of the
reaction was checked by TLC (silica gel; ethyl acetate/petroleum
ether 1:5). In most cases, the reaction mixture solidified when

34
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OMe
NH
N
H
and
MeO
+
more than 95%
NH2
HN
S
S
S
1
N
H
N
H
less than 5%
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unsymmetrical thiourea. In most cases, pure unsymmetrical thio-
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