Silica gel promoted synthesis of N-sulfonylcyclothioureas in water

Article abstract of DOI:10.1016/j.tetlet.2011.09.075

N-Sulfonylcyclothioureas were synthesized from N-sulfonyldiamines and CS₂ with moderate to good yields in silica gel-water system. Moreover, the silica gel can be recycled for at least three times.

Full text of DOI:10.1016/j.tetlet.2011.09.075

Tetrahedron Letters 52 (2011) 6250–6254
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silica gel promoted synthesis of N-sulfonylcyclothioureas in water
⇑
Guo-Xiang Wan, Liang Xu, Xiao-Si Ma, Ning Ma
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2011
Revised 5 September 2011
Accepted 16 September 2011
Available online 21 September 2011
N-Sulfonylcyclothioureas were synthesized from N-sulfonyldiamines and CS2 with moderate to good
yields in silica gel-water system. Moreover, the silica gel can be recycled for at least three times.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Silica gel
Water
Synthesis
N-Sulfonylcyclothioureas
Because water is natural, nontoxic, cheap, and readily available,
it is thought to be an ideal solvent for both laboratory and indus-
trial chemical processes.1 Although water is a clean solvent,
aqueous organic reactions frequently suffer from poor solubility
of the substrates.2 In order to solve this problem, co-solvents or
phase-transfer catalysts (PTC) were introduced to organic transfor-
mations in water.3 An alternative approach is to use silica gel (SG)-
water system, which was originally established by Minakata et al.
in the research of formation and ring opening of aziridines.4 Sub-
strates contact each other more efficiently in this system than only
in water because they can be adsorbed to the surface of SG by the
hydrophobic interactions between the surface of SG and the organ-
ic molecule. In this context, SG promotes the aqueous organic reac-
tions like PTC. Furthermore, SG was reported to promote various
organic transformations in organic media. SG facilitated these reac-
tions due to its adsorptive nature and moderate surface acidity.5
Thioureas represent a versatile and useful class of application in
medicinal chemistry, asymmetric catalysis and building blocks in
the synthesis of heterocycles.6,7 As a kind of derivatives of thio-
ureas, N-sulfonylcyclothioureas are synthetic intermediates for a
variety of compounds and they are present as important substruc-
tures of bioactive compounds.8 Direct sulfonamidation of
cyclothioureas by sulfonyl chlorides in the presence of organic or
inorganic bases is the general procedure for the synthesis of N-
sulfonylcyclothioureas. Another synthetic route is the conversion
of N-sulfonyldiamine to the target structures by thiophosgene.
The alternative synthesis of N-sulfonylcyclothioureas is achieved
via sulfonyl thioisocyanate, which is prepared from sulfonamide
and CS2 in the presence of SOCl2 or COCl2. Since the aforemen-
tioned methods are frequently limited by harsh reaction condi-
tions, low yields, long reaction times, and use of toxic solvents or
catalysts,9–12 they are rarely described as ‘‘green’’ reactions.
Although the synthesis of thiourea derivatives in water under
sodium hydroxide and reflux condition has been investigated
just recently,13 the synthesis of N-sulfonylcyclothioureas from
N-sulfonyldiamines and CS2 in SG-water system has not been
exploited. As a part of our continuing effort to develop green
synthetic protocol for sulfonylthioureas,14 we herein report an effi-
cient and practical approach to N-sulfonylcyclothioureas via the
reaction of N-sulfonyldiamines and CS2 in water promoted by silica
gel (Fig. 1).
Initially, N-(2-aminoethyl)-4-methylbenzenesulfonamide (1c)
was used as a typical substrate to investigate the reaction condi-
tions. When 1c (1.5 mmol) was treated with CS2 (2.0 mmol) in
H2O at room temperature for 12 h, 1-(4-methylphenylsulfo-
nyl)imidazolidine-2-thione (2c) was obtained only in 8% yield
(Table 1, entry 1). The use of equivalent NaOH improved the yield
to 18% (Table 1, entry 2). When SG (0.50 g) was added instead of
sodium hydroxide, the yield of 2c achieved 60% (Table 1, entry
3). While ethanol was used as the reaction media the yield de-
creased to 36% (Table 1, entry 4). The addition of NaOH into the
SG-H2O system did not affect on the yields remarkably, either at
room temperature or at 45 °C (Table 1, entries 5 and 6). However,
the synthetic condition for 1-(4-methylphenylsulfonyl)-1,3-dihy-
dro-2H-benzimidazole-2-thione (2o) was a little different. The
reaction of 1o with CS2 in H2O at room temperature did not pro-
ceed (Table 1, entries 1 and 2). In SG-H2O system, the product 2o
was not observed no matter even if the ethanol existed (Table 1,
entries 3 and 4). The addition of NaOH at room temperature led
to the desired product 2o in a poor yield of 27% (Table 1, entry
⇑
Corresponding author.
E-mail address: mntju@tju.edu.cn (N. Ma).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.075

G.-X. Wan et al. / Tetrahedron Letters 52 (2011) 6250–6254
6251
S
A
S
C
S
A
H2O
O
S
H2O
H2O
H2O
NH2
RSO2NH
H2O
H2O
1a-q
NH2
S
R
N
NH
A
C
H2O
H2O
H2O
RSO2NH
S
O
H2O
H2O
2a-q
surface of silica gel
R = C6H5, 2-MeC6H4, 3-NO2C6H4, 2-NO2C6H4, 4-MeC6H4, 4-ClC6H4, 4-FC6H4, 4-MeCONHC6H4, Me;
A = (CH2)2, (CH2)3, (CH2)4, (CH2)6, 1,2-C6H4, 1,2-C6H10
Figure 1. Cyclization of N-sulfonyldiamines and CS2 in SG-H2O.
and 2e in moderate to good yields (64% and 72%, Table 2, entries
4 and 5). The halogen substituted N-sulfonyldiamines 1f and 1g
also gave the corresponding products in reasonable yields (69%
and 68%, Table 2, entries 6 and 7). N-sulfonylcyclothioureas 2a–g
were synthesized in SG-H2O system without inorganic base at
room temperature for 12 h (condition A).
Table 1
Optimization of the reaction conditionsa
S
CS2
H2O
Ts NH
1c
NH2
NH2
Ts
Ts
N
N
NH
NH
2c
However, the other N-sulfonylcyclothioureas 2h–q were
synthesized in the presence of sodium hydroxide at 45 °C in SG-
H2O (condition B, Table 2, entries 8–17). For example, the chiral
N-[(1R,2R)-2-aminocyclohexyl]-4-methylbenzenesulfonamide (1h)
was converted to 2h in good yield (75%, Table 2, entry 8). N-(3-Ami-
nopropyl)benzenesulfonamide (1i) and N-(3-Aminopropyl)-4-
methyl-benzenesulfonamide (1j) also led to good yields of 2i and
2j, respectively (both 75%, Table 2, entries 9 and 10). Moreover,
N-sulfonyl butanediamine and N-sulfonyl hexanediamines reacted
with CS2 to produce the corresponding seven- and nine-membered
N-sulfonylcyclothioureas in good yields (Table 2, entries 11–13). N-
(2-Aminophenyl)benzenesulfonamide (1n) and its acetamido
derivative 1p afforded the corresponding products 2n (87%) and
2p (65%) in moderate to good yields, respectively (Table 2, entries
14, 16). N-Mesyl-1,2-benzenediamine (1q) underwent similar reac-
tion to produce the corresponding product 2q in good yield (85%,
Table 2, entry 17). The above results indicated that the nucleophilic
ability of the amino group decreased when it bonded directly to
benzene or cyclohexane ring, because of the delocalization of the
nitrogen lone-pair electrons into the aromatic system and/or steric
hindrance. To enhance the nucleophilic ability, bases such as NaOH
should be introduced into the SG-H2O system. NaOH might not only
diminish both the amine-SG and amine-H2O interactions, but also
abstract a proton from the sulfonamido group to form an anion
and facilitate the nucleophilic cyclization. Furthermore, N-Cbz dia-
mines (1r–1s) were not converted to the corresponding cyclothiou-
rea derivatives under both condition A and condition B (Table 2,
entries 18–20).
It is commonly thought that the reaction of primary amine with
CS2 produces the corresponding isocyanate via thiocarbamic acid.
Recently Prabhu and co-workers proposed a new pathway through
amino dithiol derivative as an intermediate for the reaction of a
primary amine, a secondary amine, and CS2.13 Since both sulfonyl
dithiocarbamic acid 4 and symmetric disulfonyl thiourea 6 were
not isolated in the synthesis of 2, the cyclization of N-sulfo-
nyldiamine with CS2 in SG-H2O system was also likely to have been
achieved via the sulfonamido dithiol derivative 3 or its sodium salt
as the intermediate. N-Sulfonyldiamines and CS2 was adsorbed on
the surface of SG simultaneously, which facilitated the synergic
nucleophilic addition of amino and sulfonamido group to the two
C@S bonds of CS2. To determine if SG promotes the reaction by acid
catalysis, additional experiments were conducted. The SG was pre-
S
Ts NH
CS2
H2O
2o
1o
Entry
Base
Media
Temp
Yieldb (%)
2c
2o
1
2
3
4
5
6
—
H2O
rt
rt
rt
rt
rt
45 °C
8
18
60
36
58
61
0
0
0
0
27
75
NaOH
—
H2O
SG-H2O
—
NaOH
NaOH
SG-EtOH
SG-H2O
SG-H2O
a
1c or 1o (1.5 mmol), CS2 (2.0 mmol), H2O or EtOH (5 ml), silica gel (0 or 0.5 g),
NaOH (0 or 1 equiv), 12 h.
b
Isolated yield.
5). Satisfactorily, the reaction furnished 2o in good yield (75%) at
45 °C (Table 1, entry 6). Therefore, the synthesis of N-
sulfonylcyclothioureas from N-sulfonyldiamines and CS2 is
thought to be fulfilled under two different conditions: condition
A, SG-H2O system at room temperature for N-sulfonylethylenedi-
amines as substrates; condition B, SG-NaOH-H2O system at 45 °C
for N-sulfonyl-1,2-benzenediamines as substrates. Additional
experiments showed that 200–300 mesh of SG performed better
than 100–200 and 60–100 mesh. Furthermore, the SG could be
recycled at least three times without the loss of catalytic activity.
With these optimized conditions in hand, we explored the
scope of the reaction. As seen in Table 2, N-(2-aminoethyl)ben-
zenesulfonamide (1a) reacted with CS2 under condition A to
produce 2a in moderate yield (63%, entry 1). Similarly, N-(2-
aminoethyl)-2-methylbenzenesulfonamide
(1b)
underwent
cyclization reaction to produce the corresponding N-sul-
fonylcyclothiourea 2b in 60% yield (Table 2, entry 2). Encouraged
by these results, we turned our attention to N-sulfonyldiamines
with strong electron-withdrawing group. To our delight, N-(2-ami-
noethyl)-3-nitrobenzenesulfonamide (1d) and N-(2-aminoethyl)
-2-nitrobenzenesulfonamide (1e) furnished the corresponding 2d

6252
G.-X. Wan et al. / Tetrahedron Letters 52 (2011) 6250–6254
Table 2
The scope of the cyclization of N-monosulfonyldiamine and CS2
S
A
O
O
S
CS2
R
S
NH
NH2
R
N
NH
silica gel, water
A
O
O
Entry
1
Substrate
Product
Conditiona
Yieldb (%)
O
S
O
S
O
NH NH2
NH NH2
S N NH
A
63
O
2a
1a
S
O
S
O
O
S
O
2b
N
NH
2
3
4
A
A
A
60
60
64
1b
O
S
S
O
S N
O
S NH NH2
O
NH
NH
1c
2c
O2N
O2N
O
O
S
NH NH2
S
N
O
O
2d
1d
NO2
O
S
NO2
O
S
S
NH NH2
N
NH
S
5
A
72
O
1e
O
2e
O
O
F
S NH NH2
O
F
S N NH
O
6
7
A
A
69
68
1f
2f
O
S
O
S
O
S
O
Cl
NH NH2
Cl
N
NH
1g
2g
O
S
O
S
O
S NH NH2
O
N
S
NH
8
B
75
1h
2h
O
S
O
O
S
O
2i
NH NH2
N
NH
S
9
B
B
75
75
1i
O
S
O
O
S N
O
NH NH2
NH
10
1j
2j

G.-X. Wan et al. / Tetrahedron Letters 52 (2011) 6250–6254
6253
Table 2 (continued)
Entry
Substrate
Product
Conditiona
Yieldb (%)
O
S
S
O
S
O
2k
NH NH2
N
NH
11
12
B
72
81
O
1k
O
S NH NH2
O
S
O
S N NH
O
B
1l
2l
NO2
NO2
S
O
O
S
N
NH
S
NH NH2
13
14
O
B
B
81
87
O
2m
1m
O
S
S
O
S
O
NH NH2
N
NH
O
1n
2n
O
S
O
S N
O
S NH NH2
O
NH
N
15
16
B
B
75
65
1o
2o
O
O
S
O
S
O
S
HN
NH NH2
HN
NH
O
O
1p
2p
O
S
O
S
O
S
O
NH NH2
N
NH
17
B
85
1q
2q
CbzHN NH2
S
18
19
A, B
A, B
—
—
CbzN NH
1r
2r
S
CbzHN
CbzHN
NH2
CbzN
CbzN
NH
1s
2s
S
NH2
NH
20
A, B
—
1t
2t
a
Condition A: 1 (1.5 mmol), CS2 (2.0 mmol), silica gel (0.5 g), H2O (5 ml), rt, 12 h; Condition B: 1 (1.5 mmol), CS2 (2.0 mmol), NaOH (1.5 mmol), silica gel (0.5 g), H2O (5 ml),
45 °C, 12 h.
b
Isolated yield.

6254
G.-X. Wan et al. / Tetrahedron Letters 52 (2011) 6250–6254
S
A
H
SH
S C S
O
S
O
O
S
CS2
R
NH
NH2
R
S
NH
NH2
R
N
NH
A
A
O
O
O
1
3
O
S
R
NH
N
C
S
A
5
O
O
S
S
R
NH
HN
C
SH
R
S
S
O
O
S
O
O
A
H2S
S
NH HN C NH HN
S
R
R
N
NH
4
A
A
A
O
O
O
6
2
Scheme 1. Possible route for the cyclization reaction (SG was omitted for clarity).
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treated in an oven to transform silanol („SiOH) groups partially to
siloxane bridges („SiOSi„).5d It might result in poorer acidity of
SG because the silanol group is commonly thought to be responsi-
ble for the Lewis or Brønsted acidity of SG. As the result, pre-heated
SG did not show lower promoting activity than normal SG. There-
fore, SG probably mainly plays a role via the adsorptive nature of
its surface, which is similar to that described by Minakata et al.4
The surface area of silica gel available for a reaction in SG-H2O sys-
tem would be quite large compared with that of the interface in a
conventional liquid-liquid biphasic system. Thus, based on the
aforementioned literatures and our observation, the plausible
mechanism is proposed as depicted in Scheme 1.
In conclusion, we have developed a mild and efficient method
for the synthesis of N-sulfonylcyclothioureas via the reaction of
N-sulfonyldiamines with CS2 in silica gel-water system. This proto-
col is appropriate for the cyclization of a variety of N-sulfonyl dia-
mines on a cheap, neutral, environmentally benign, and recyclable
surface of silica gel.
Acknowledgment
We thank the National Natural Science Foundation of China
(Grant no. 20802049) for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.075.
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