A simple and straightforward synthesis of phenyl isothiocyanates, symmetrical and unsymmetrical thioureas under ball milling

Article abstract of DOI:10.1039/c3ra43252a

Promoted by KOH under ball milling, anilines were efficiently transformed into isothiocyanates (in presence of 5.0 equiv. CS₂) or symmetrical thioureas (in presence of 1.0 equiv. CS₂), without using any other harsh or toxic decomposition reagent. Some in situ generated isothiocyanates can directly "click" with other amines to afford unsymmetrical thioureas.

Full text of DOI:10.1039/c3ra43252a

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A simple and straightforward synthesis of phenyl
isothiocyanates, symmetrical and unsymmetrical
thioureas under ball milling3
Cite this: DOI: 10.1039/c3ra43252a
Received 27th June 2013,
Accepted 23rd July 2013
Ze Zhang,* Hao-Hao Wu and Ya-Jun Tan
DOI: 10.1039/c3ra43252a
www.rsc.org/advances
Promoted by KOH under ball milling, anilines were efficiently
transformed into isothiocyanates (in presence of 5.0 equiv. CS2) or
symmetrical thioureas (in presence of 1.0 equiv. CS2), without
using any other harsh or toxic decomposition reagent. Some in
situ generated isothiocyanates can directly ‘‘click’’ with other
amines to afford unsymmetrical thioureas.
cyanuric acid as the desulfurylation reagent, and long reaction
times with tedious work up were desired.10
To circumvent these problems, one of the best alternatives is to
carry out these kind of reactions under solvent-free conditions,
which can also overcome the instability of isothiocyanates in
solution. Among current solvent-free techniques, mechanical ball-
milling has recently been contributing more and more to the
efficient promotion of various organic reactions in a greener
way.11,12 We have also successfully applied this technique in
several transformations in recent years, including Diels–Alder
reactions, reductive benzylization, Michael addition and free
radical addition reactions.13 Herein we are keen to report a
mechanochemical ball-milling-promoted method for the facile
synthesis of various phenyl isothiocyanates, in which just cheap
KOH is employed both as base and decomposition reagent,
avoiding the use of any other harsh or toxic chemical. And further
investigation on the synthesis of symmetrical and unsymmetrical
thioureas was also explored.
Firstly, we chose the synthesis of 4-methyl-phenyl isothiocya-
nate (3g) as the model reaction to optimize the reaction
conditions. A series of experiments were carried out in solution
and under ball milling by varying the base, the solvent and the
usage amount of CS2, and the results are summarized in Table 1.
At first, the reaction was carried out using the reactant CS2 as
solvent, and several common bases were explored. In most cases,
the conversion is rather low even after 24 h, giving only trace to
The isothiocyanate moiety is ubiquitous structural unit in a
number of biologically active compounds, and is widely used in
the synthesis of various sulfur-nitrogen-containing heterocycles or
applied as chemoselective electrophiles in bioconjugate chemis-
try.1 Numerous methods have been developed for the conversion
of amines into isothiocyanates, in which thiophosgene was mostly
employed.2 In view of its high toxicity and incompatibility with
many functional groups, various ‘thiocarbonyl transfer’ reagents
were developed as thiophosgene equivalents (Scheme 1), including
thiocarbonyl-ditriazole3 or diimidazole,4 dipyridylthionocarbo-
nate,5 etc. Most of these reagents are not readily available, and
often do not work as desired due to the formation of thiourea as a
side product.
On the other hand, it is a fact that the treatment of an amine
with carbon disulfide in the presence of a suitable base can easily
afford the corresponding dithiocarbamic acid salt, which may be
desulfurylated into isothiocyanate when a certain decomposition
reagent is employed. Therefore, various decomposition reagents
for the desulfurylation of in situ generated dithiocarbamates have
been developed as alternative approaches, including uronium-
and phosphonium-based peptide coupling reagents,6 triphenyl-
phosphine dibromide,7 tosyl chloride,8 dialkyl dicarbonates,9 and
other harsh reagents. Frankly, these methods are efficient enough,
but most of them possess drawbacks such as rigorous or
hazardous conditions and intractable side reactions. Recently, a
relatively green method was reported for the synthesis of various
isothiocyanates in aqueous media, but it still involves the use of
School of Biological and Chemical Engineering, Anhui Polytechnic University, Wuhu,
241000, China. E-mail: zhangze@ustc.edu.cn; Tel: (+86) 553 2871254
Electronic supplementary information (ESI) available: Experimental section,
3
characterization details and NMR spectra for all products. See DOI: 10.1039/
c3ra43252a
Scheme 1
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Table 1 Optimization of the reaction conditions for synthesis of 4-methyl-phenyl isothiocyanate (3g)a
Entry
CS2 (equiv.)
Base
Solvent
Time
Product (yield)b
1
2
3
4
5
6
7
8
Solvent
Solvent
Solvent
Solvent
Solvent
Solvent
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
Na2CO3
K2CO3
NaOH
KOH
CS2
CS2
CS2
CS2
CS2
CS2
CH2Cl2
THF
CH3COCH3
CH3OH
DMF
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
40 min
40 min
40 min
40 min
40 min
40 min
40 min
40 min
3g (trace)
3g (trace)
3g (36%) + 4g (trace)
3g (41%) + 4g (trace)
3g (45%) + 4g (trace)
2 (major) + 3g (28%) + 4g (22%)
3g (10%) + 4g (trace)
3g (22%) + 4g (16%)
3g (16%) + 4g (25%)
3g (11%) + 4g (36%)
3g (trace) + 4g (45%)
3g (trace) + 4g (49%)
2 (major) + 3g (26%)
3g (57%) + 4g (trace)
3g (61%) + 4g (trace)
3g (92%)
tBuOK
Et3N
KOH
KOH
KOH
KOH
KOH
KOH
Et3N
Na2CO3
K2CO3
NaOH
tBuOK
KOH
KOH
KOH
9
10
11
12
13
14
15
16
17
18
19
20
DMSO
ball milling
ball milling
ball milling
ball milling
ball milling
ball milling
ball milling
ball milling
3g (86%)
3g (98%)
3g (58%) + 4g (27%)
3g (trace) + 4g (93%)
1.0
a
Reactions were carried out with 4-methylaniline 1g (10.0 mmol), CS2 (designated usage) and base (10.0 mmol) at room temperature; 1800
b
rpm (30 Hz) vibration frequency for ball-milling and 15 mL solvent for stirring in solution. Determined by HPLC analysis based on
4-methylaniline.
very poor yields for 3g (entries 1–5, Table 1). This inefficacy may be
due to the insolubility of the base in non-polar CS2. Although the
case of Et3N afforded almost complete conversion, the reactant 1g
was mainly converted into dithiocarbamate 2 (entry 6, Table 1).
Herein the chemoselectivity is somewhat different from the
similar reaction of fullerene in solution.14
an obvious effect on the chemoselectivity. For examples, organic
base Et3N still favored the formation of dithiocarbamate 2 (entry
13, Table 1), similar to the result from solution case (entry 6,
Table 1). The strong inorganic base KOH gave almost quantitative
yield (entry 18, Table 1). On the other hand, the usage amount of
CS2 is crucial for the reaction selectivity (entries 18–20, Table 1).
Excessive (5.0 equiv) CS2 is both necessary and also enough for
highly selective generation of the desired product 3g. Further
reducing the usage of CS2 led to the formation of byproduct
thiourea 4g.
Inspired by the above-described results as summarized in
Table 1, we then employed KOH and 5.0 equivalents of CS2 under
ball milling conditions to access a wide variety of phenyl
isothiocyanates from anilines bearing different substituents.
Under this mechanically-promoted condition, the reactions
proceeded cleanly without intermediate work-up and left no, or
only traces of, byproducts. The detailed results are outlined in
Table 2.
The results from entries 1–6 prompted us to use KOH as the
best base to promote this transformation in polar solvents or
under ball milling condition. The results from entries 7–12 in
Table 1 demonstrated that the more polar the solvent, the higher
the conversion of the aniline, and stronger polarity favored the
formation of thiourea 4g. In general, all solution cases furnished
poor conversion and chemoselectivity. In contrast, ball milling
conditions accelerated the conversion significantly. That is, the
aniline 1g was almost completely consumed in very short time (40
min), whatever base was employed (entries 13–18, Table 1). The
rapid conversion of the current solid-state procedure may be
ascribed to an enhanced reaction rate resulting from ultimately
high concentrations of reactants with no use of solvent, and the
high mechanical energy that can greatly enforce the reaction.
Furthermore, it should be noted that the basicity of the bases has
As can be seen from Table 2, anilines containing ortho, meta
and para substituents are all smoothly converted into the
corresponding isothiocyanates in good yields in a relatively short
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time (within 1.5 h), except that 1,2-diaminobenzene exclusively
afforded the corresponding thiourea 4l (entry 13). Specifically for
anilines bearing electron-donating substituents, just 40–45 min
were needed for complete conversion and almost quantitative
formation of the desired products 3. For anilines bearing electron-
withdrawing substituents, the corresponding isothiocyanates
could still be obtained in moderate to good yields, although
relatively long reaction times were needed. Under traditional
solution conditions, anilines bearing strong electron-withdrawing
substituents are very difficult to be transformed into in the
corresponding isothiocyanates unless harsh conditions or decom-
position reagent is employed. For example, a mixture containing
4-nitrophenyl amine 1k (10.0 mmol), KOH (10.0 mmol) and CS2
(20 mL) was stirred at room temperature for 48 h, and only a trace
of product 3k was detected. But in this protocol, ball milling for 90
min could afford 61% isolated yield in the presence of just 5.0
equivalents of CS2. In all cases, the desired products 3 were
isolated directly from the resulting reaction mixtures just through
short column chromatography eluted with hexane/ethyl acetate (v/
v = 20 : 1), thus the work up procedure is very simple.
Table 2 Mechanochemical synthesis of phenyl isothiocyanates 3 from anilines 1
and CS2 promoted by KOHa
Entry
R
Product 3
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
40
40
40
70
45
90
40
40
60
90
90
90
40
85
92
91
71
93
72
96
95
83
75
61
52
97
2-Me
2-OMe
2-Cl
3-Me
3-Cl
4-Me
4-OMe
4-Br
9
10
11
12
13
4-Cl
3j
3k
3l
4-NO2
3,4-Cl
2-NH2
4l
Considering the fact that isothiocyanates are easy to react with
amino groups, we were inspired to directly add some other
anilines (equal equiv.) into those almost quantitatively in situ
generated isothiocyanates (3e, 3g, 3h) for a one-pot synthesis of
unsymmetrical thioureas. Gratifyingly, all the afterward added
anilines 19 proceeded through a ‘‘click’’15 reaction sequence within
one hour, affording the unsymmetrical thiourea 5 in almost
quantitative yield (Table 3). The products were obtained just
through immersing the resulting reaction mixtures in diluted HCl
with the aid of ultrasonic irradiation and Bu¨chner filtration. In
contrast, the traditional synthesis of unsymmetrical thioureas
a
Reactions were carried out with aniline 1 (10.0 mmol), CS2 (50.0
mmol) and KOH (10.0 mmol) at room temperature at a vibration
frequency of 30 Hz. Isolated yield combined from two parallel runs
via Retsch MM400 ball miller, by direct separation of the reaction
mixtures through short column chromatography.
b
Table 3 Mechanochemical one-pot synthesis of unsymmetrical phenylthioureas 5 by addition of phenyl amines 19 on in situ generated isothiocyanatesa
Entry
R
R9
Product 5
Time 1 (min)
Time 2 (min)
Yield (%)b
1
2
3
4
5
6
7
8
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-OMe
3-Me
2-Me
3-Me
4-OCH3
4-Br
4-Cl
H
4-Cl
3-Cl
2-Cl
4-Br
4-OMe
4-Br
5a
5b
5c
5d
5e
5f
5g
5h
5i
40
40
40
40
40
40
40
40
40
40
45
45
35
35
30
45
60
40
60
60
75
60
40
60
89
92
95
92
87
94
90
89
85
94
96
91
9
10
11
12
5j
5k
5l
3-Me
a
Reactions were carried out with aniline 1 (10.0 mmol), CS2 (50.0 mmol), KOH (10.0 mmol) and afterward added aniline 19 (10.0 mmol) at
b
room temperature at a vibration frequency of 30 Hz. Isolated yield combined from two parallel runs.
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often involves preliminary preparation and handing of isothiocya-
nates, which is somewhat tedious and hazardous.
unsymmetrical thioureas in a straightforward way. This protocol
is fast, clean and of low cost, and the work-up procedure is very
simple and safe. These advantages make it a very efficient and
green alternative to traditional methods for the synthesis of
aromatic isothiocyanates and thioureas. Under this mechano-
chemical condition, it can be reasonably anticipated that various
thiocarbonyl compounds or sulfur-nitrogen-containing hetero-
cycles would be obtained if a suitable nucleophile was employed
in addition with such in situ generated isothiocyanates in a one-
pot way. Work in this direction is under investigation.
On the other hand, the result from entry 20 in Table 1
demonstrated that the symmetrical thiourea was almost exclu-
sively generated when the usage amount of CS2 was reduced to 1.0
equivalent. This result prompted us to attempt other anilines for
the synthesis of various symmetrical phenyl thioureas, and
satisfactory results were also achieved as shown in Table 4.
As expected, the yields of the products are significantly affected
by the nature of the amines, similarly to those in the transforma-
tion to isothiocyanates. That is, anilines bearing electron-rich
substituents are good substrates for this process and show higher
reactivity than those bearing electron-deficient groups. To
demonstrate the utility and substrate scope of this methodology,
1,4-phenylenediamine was also attempted to synthesize the
corresponding bis-isothiocyanate and further conversion into
symmetrical and unsymmetrical thioureas. Unfortunately, the
results were rather complicated with very poor chemoselectivity.
In conclusion, an environmentally friendly method has been
developed for facile transformation of phenyl amines into
isothiocyanates and thioureas by using a mechanochemical ball-
milling technique. Cheap KOH is employed both as base and
decomposition reagent, avoiding the use of any other harsh or
toxic chemical. Phenyl amines bearing both electron-rich and
electron-deficient substituents could give desired products in good
to excellent yields. Furthermore, some in situ generated isothio-
cyanates can directly ‘‘click’’ with other amines to afford
We are grateful to financial support from National Natural
Science Foundation of China (21242013, 20902002).
Notes and references
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Product 3
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H
4a
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4c
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4e
4f
4g
4h
4i
45
45
50
90
50
75
40
40
60
80
90
40
86
84
87
74
88
75
93
95
82
77
43c
97
2-CH3
2-OCH3
2-Cl
3-CH3
3-Cl
4-CH3
4-OCH3
4-Br
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