A facile synthesis of substituted N-benzoylthiourea

Article abstract of DOI:10.1081/SCC-120021977

One pot reaction of benzoyl isothiocyanate and Tris(hydroxymethyl)aminomethane (Tris) at room temperature with polyethylene glycol-400 (PEG-400) as solid-liquid phase-transfer catalyst produced substituted N-benzoylthioureas with high yield. A reasonable pathway for their formation has been suggested.

Full text of DOI:10.1081/SCC-120021977

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A Facile Synthesis of Substituted N-Benzoylthiourea
a b
a b
a
a b
c
Xiaoyong Xu
, Zhongli
, Zhengyu Yang , Gang Chen
& Xuhong Qian
a
Institute of Pesticides and Pharmaceuticals, East China University of Science and
Technology, Shanghai, China
b
Shanghai Key Lab of Chemical Biology, ECUST, China
c
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China
Published online: 17 Aug 2006.
To cite this article: Xiaoyong Xu , Zhongli , Zhengyu Yang , Gang Chen & Xuhong Qian (2003) A Facile Synthesis of Substituted
N-Benzoylthiourea, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:15, 2585-2592, DOI: 10.1081/SCC-120021977
To link to this article: http://dx.doi.org/10.1081/SCC-120021977
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 15, pp. 2585–2592, 2003
A Facile Synthesis of Substituted
N-Benzoylthiourea
1
,2
1,2
Xiaoyong Xu, Zhongli, Zhengyu Yang,
1
1
,2
3,
Gang Chen, and Xuhong Qian *
1
Institute of Pesticides and Pharmaceuticals, East China
University of Science and Technology, Shanghai, China
2
Shanghai Key Lab of Chemical Biology,
ECUST, China
3
State Key Laboratory of Fine Chemicals, Dalian
University of Technology, Dalian, China
ABSTRACT
One pot reaction of benzoyl isothiocyanate and Tris(hydroxy-
methyl)aminomethane (Tris) at room temperature with polyethylene
glycol-400 (PEG-400) as solid–liquid phase-transfer catalyst pro-
duced substituted N-benzoylthioureas with high yield. A reasonable
pathway for their formation has been suggested.
Key Words: Synthesis; N-Benzoylthiourea; One-pot reaction.
*
Correspondence: Xuhong Qian, State Key Laboratory of Fine Chemicals,
Dalian University of Technology, P.O. Box 40, 158 Zhongshan Road, Dalian
16012, China; Fax: 86-021-64252603; E-mail: xhqian@ecust.edu.cn or xhqian@
dlut.edu.cn.
1
2
585
DOI: 10.1081/SCC-120021977
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2
586
Xu et al.
N-Benzoylthioureas are usually used as starting material for reaction
[
or intermediate in organic synthesis. The property of substituted
1]
[
2,3]
N-benzoylthioureas has been investigated widely.
In the course of our recent study, we tried to synthesize substituted
0
N-benzoyl-N -tris(hyroxymethyl)methyl-thiourea using benzoyl isothio-
cyanate and Tris, but we found that we only obtained substituted
N-benzoylthiourea.
During the experiment, we synthesized benzoyl isothiocyanate
[4]
according to Lit. Without further separate procedure, we directly
added Tris(hydroxymethyl)aminomethane to benzoyl isothiocyanate in
methylene dichloride solvent at room temperature (Sch. 1). Through
simple work-up process the products were obtained. The reaction was
1
followed by TLC analysis. By IR, Mass spectra, and H NMR analysis,
we confirmed the products were benzoylthiourea. Yields, melting points,
1
IR, Mass Spectra, H NMR, and High Resolution Mass Spectra data of
the compounds are given in Tables 2–5.
R1
R1
CH OH
2
NH SCN, PEG-400
4
R2
COCl
R2
CON=C=S
+
H
2
N
CH OH
2
CH Cl , R.T.
2
2
CH OH
2
R3
R4
R3
R4
R.T.
CH Cl2
2
R1
R3
R
1
O
S
O
S
CH OH
2
R2
N
H
NH2
R2
N
H
N
H
CH OH
2
CH OH
2
R3
R4
R4
Scheme 1.
Compound
R1
R2
R3
R4
1
1
1
1
1
1
1
1
a
b
c
H
F
H
F
H
OCH3
H
H
F
H
Cl
H
H
H
F
d
e
F
NO2
H
Cl
H
H
H
H
H
f
CH
H
3
H
g
h
CH3
H
H
OCH3
H

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N-Benzoylthiourea
2587
According to our knowledge, the known preparation methods of
substituted N-benzoylthiourea includes the reactions with the following
raw materials: (1) sodium thiocyanate, benzoyl chloride, and aqueous
[
1,5]
[6]
ammonia,
isothiourea and hydrochloride acid, (4) S-cyano-thiohydroxylamine
(2) benzoyl chloride and thiourea,
[
(3) S-benzoyl
7]
[
8]
and benzoyl chloride,
(5) As byproduct was obtained in many
About the preparation of N-benzoylthiourea, new method
[9–15]
reactions.
has seldom been reported since 1980s.
According to the reported method, the reaction condition is not mild
and the procedure is not convenient, such as the smell ammonia or higher
reaction temperature. In addition, the yield is rather low. But the method
we mentioned above avoided irritant smell of ammonia, the reaction
temperature at room temperature is mild. Except -OCH group, the
3
[
15]
yield is higher than that reported in previous Lit.
Work-up process
is also simple, by simple filtration and recrystallization, the target com-
pound can be obtained.
In order to confirm the mechanism of this reaction, we tried a series
of reactions shown in Table 1.
Based on all of the experiment phenomena, we give a explanation to
this reaction (Sch. 2) as follows: Firstly, the system is almost a heteroge-
neous and difficult to proceed normal reaction to product D, as Tris only
have limited solubility in CH Cl . Secondly, because of the steric hindrance
2
2
and weak nucleophilicity of Tris, it is very difficult to produce product D at
room temperature. But, Tris is a real base in solution system (pK ¼ 8.08,
a
ꢀ
25 C), which can slowly discompose NH Cl (formed during reaction) to
generate NH (confirmed by pH reagent paper), then NH reacted with
4
3
3
benzoyl isothiocyanate to yield product C. In the presence of trace
water, Tris’s basicity was enhanced, and prompted the decomposition of
NH Cl, and gave higher yield of N-benzoylthiourea (Sch. 3). However, in
4
O
O
PEG-400
Cl + A
NCS + B NH2
CH Cl r.t.
2
2
O
S
N
H
NH2
product C
O
S
N
N B
H
H
product D
Scheme 2.

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Xu et al.
Table 1. The reaction reagents, condition, and experimental phenomena.
Reaction
no.
Product Product
C
Reaction
time
e
f
A
B-NH
2
D
NH
3
Yield
p
p
a
b
a
a
d
1
2
NH
NH
4
NCS
NCS
Tris
Tris
Tris
Â
66
53
/
16 h
38 h
p
p
4
Â
c
3
NH NCS
Â
p
Â
p
Â
p
10 h
30 min
4
4
5
NH NCS NH C(CH )
34
4
2
3 3
(
NCS NH (CH OH
dropwise)
)
p
p
a
NH
4
2
2
2
Â
Â
/
/
15 min
30 h
(
dropwise)
Tris
6
NaNCS
Â
Â
a
Powered NH NCS without further treatment.
Water was removed from powered NH NCS by benzene azeotropic distallition
4
b
4
and under N
2
protection condition.
Cl was filtered, benzoyl isothiocyanate was extracted from water and then
reacted with Tris.
c
NH
4
d
ꢀ
: Means not detected.
Released from reaction.
e
f
The yield of benzoylthiourea.
CH OH
CH OH
2
2
trace H O
2
NH Cl
H N
CH OH
NH3
+
HCl.
H N
CH OH
2
4
+
2
2
2
CH OH
CH OH
2
2
O
S
R
R
CON=C= S
+
NH
3
N
H
NH2
Scheme 3.
case of tert-butylamine, both of products D and C were obtained. The
formation of D is due to that tert-butylamine has good solubility in
CH Cl , weaker steric hindrance (compared with Tris) and strong nucleo-
2
2
philicity. The formation of product C is due to that it is a strong base
ꢀ
(
pK ¼ 10.69, 25 C), which also discomposed NH Cl to proceed the com-
a
4
petitive reaction. In the case of ethanolamine, it is easily understood to
afford only product D. All of the result suggested that water is catalytic
and important factor but not the only factor in this reaction. The further
study in details is now in progress.
In conclusion, we developed a facile and efficient method for synthesis
of N-benzoylthiourea. The present procedure has some advantages such as

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N-Benzoylthiourea
Table 2. Physical and IR spectral data of compounds prepared.
2589
Yield
Compound (%)
M.P.
ꢀ
Molecular
formula
À1
)
( C)
IR (KBr) (cm
1
1
1
1
a
b
c
66.4
49.2
69.5
62.7
186–187
[
C
8
H
8
N
2
OS 3,300, 3,220, 3,150, 1,680, 1,600,
1,530,1,410, 1,240,1,110,780,
16]
1
68–170
7
10, 660, 620
C H F N O S 3,300,3,150,1,700,1,620,1,540,
190–191
9
7
3
2
2
1
1
,500, 1,460, 1,370, 1,210,
,100, 1,010, 740, 710, 660
205–206
C H FN OS 3,300, 3,180, 1,690, 1,600, 1,540,
8 7 2
1
1
,500, 1,230, 1,170, 1,100,
,000, 850, 760, 670, 600
d
170–171 C H Cl FN OS 3,300, 3,250, 3,200, 3,000, 1,700,
2
8
5
2
1
1
7
,600, 1,540, 1,460, 1,410,
,390, 1,240, 1,210, 1,020,
20, 650, 620
1
1
1
1
e
42.1
46.3
81.3
15.8
239–240
[
C
8
H
7
N
3
O
3
S
3,370, 3,250, 3,140, 1,690, 1,600,
1,530, 1,360, 1,230, 1,120,
15]
15]
2
01–203
1
C H N OS 3,300, 3,225, 3,150, 1,680, 1,600,
,010, 700
f
223–224
[
9
10
2
1
91–192
1,530, 1,500, 1,230, 1,180,
,100, 1,010, 1,005, 750, 730
C H N OS 3,370, 3,230, 3,150, 1,680, 1,600,
1
g
h
174–175
1
9
10
2
[
15]
67–169
1,520, 1,400, 1,250, 1,180,
,100, 1,010, 750, 660
C H N O S 3,350, 3,230, 3,170, 1,680, 1,600,
1
224–225
[
9
10
2
2
15]
2
09–210
1,510, 1,230, 1,170, 1,100,
,030, 760, 610
1
simple work-up process, mild condition, high yield, and easily available
reagent over the reported method.
EXPERIMENTAL
Melting points were obtained with an electrothermal digital apparatus
made in Beijing and are uncorrected. The infrared (IR) spectra were
recorded on a Nicolet 470 infrared fourier transform spectrometer using
a potassium bromide pellets. The proton nuclear magnetic resonance
1
(
H NMR, 500 MHz) spectra were recorded on a Bruker WP-500SY
spectrometer with CD Cl as the solvent and TMS as internal standard.
3
High Resolution Mass Spectra were obtained on MicroMass GCT CA 055

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Xu et al.
1
Table 3. H NMR data of compounds prepared.
R1
2
O
S
3
1
6
1
2
R2
N
NH2
4
H
5
R3
R4
Compound
Solvent: CDCl , 500 Hz/TMS, ꢀ, J (Hz)
3
1
a
7.52 (t, 2H,
J
23 ¼ J56 ¼ 7.8 Hz, H-3, H-5), 7.63 (t, 1H,
J34 ¼ J ¼ 7.4 Hz, H-4), 7.85 (dd, 2H, J23 ¼ J ¼ 8.2 Hz,
54
56
J
24 ¼ J46 ¼ 0.91 Hz, H-2 and H-6), 9.10 (brs, 0.8H, N
2
H),
1
0.05 (brs, 0.8H, N H)
1
1
1
c
7.24 (t, 2H, J23 ¼ J56 ¼ 8.7 Hz, J34 ¼ J45 ¼ 8.4 Hz, H-3 and H-5),
7
.91 (dd, 2H, J2 ¼ J ¼ 8.7 Hz, J ¼ J ¼ 5.1 Hz, H-2, H-6),
3
56
24
46
9
.10 (brs, 0.99H, N
2
H), 10.06 (brs, 0.97H, N
1
H)
H), 9.81 (brs,
d
7.51 (m, 2H, H-2, H-5), 9.61 (brs, 0.70H, N
.89H, N H)
2
0
1
Table 4. Mass spectra data of compounds prepared.
MS (70 eV) m/z (%)
Compound
þ
þ
1
a
181 (M þ 1) (10.38), 180 (M ) (100), 105 (C H C¼O) (99.52),
6 5
6
5
7
7 (C H ) (44.44)
þ
þ
1
b
264 (M ) (81.70), 233 (M À OCH
3
8 5 3 2
) (59.40), 190 (C H F O )
(
12.02), 189 (C H F O ) (100.00), 161 (C H F O) (31.16),
8 4 3 2 7 4 3
1
198 (M ) (25.23), 139 (FC
6 3
46 (C HF O) (17.47)
þ
1
c
6
4
H CONH
2
)
(78.57), 123
(
266 (M ) (21.43), 207 (FCl
FC H CO)(100.00), 95 (FC H ) (71.40), 75 (24.95)
4
6
4
þ
6
1
d
2
C
6
H
2
CONH
2
)
(53.33), 191
) (33.33), 128
(
FCl
2
C
6
H
2
C¼O) (100.00), 163 (FCl
2
C
6
H
2
(
225 (M ) (29.75), 166 (NO
FClC H ) (16.67), 93 (FC H) (13.21)
6
2
6
þ
1
e
2
C
H
6 4
CONH (15.76), 150
2
)
(
(
NO
2
C
6
H
4
C¼O) (100.00), 120 (C
6
H
4
CONH ) (20.97), 104
2
C H O) (44.00), 76 (N H CS) (15.19), 75 (N H CS) (6.56)
7
4
2
4
2
3
þ
1
1
1
f
194 (M ) (25.13), 135 (CH C H CONH ) (50.90), 119
3
6
4
2
(
194 (M ) (27.23), 119 (CH
CH
3
C
6
þ
H
4
C¼O) (100.00), 91 (CH
3
C
6
H
4
) (63.64), 65 (18.18)
g
h
3
C
6
H
4
C¼O) (100.00), 91
(
210 (M ) (31.3), 135 (CH
CH C H ) (61.84), 65 (14.72)
3
6
þ
4
3
OC
6
H
4
C¼O) (100), 107
(
3 6 4
CH OC H ) (11.2), 92 (15.7)

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N-Benzoylthiourea
2591
Table 5. High resolution mass and elemental analytical data of compounds
prepared.
Compound
Calculated
180.0357
Found
1
a
180.0363
C 53.33%, H 4.44%, N 15.56%, C 53.24%, H 4.46%, N 15.47%,
264.0180 264.0175
1
b
C 40.91%, H 2.65%, N 10.61% C 41.13%, H 2.72%, N 10.56%
C 48.48%, H 3.54%, N 14.14% C 48.42%, H 3.52%, N 14.05%
C 36.09%, H 1.88%, N 10.53% C 36.11%, H 1.93%, N 10.60%
1
1
c
d
spectrometer. Analytical thin-layer chromatography (TLC) was carried
out on precoated plated (silica gel 60 F254), and spots were visualized
with ultraviolet light. All chemicals or reagents were purchased from
standard commercial suppliers.
General Procedure
Powered ammonium thiocyanate (15 mmol), appropriate benzoyl
chloride (10 mmol), PEG-400 (0.18 g, 3% with respect to ammonium
thiocyanate) and methylene dichloride (25 mL) were placed in a dried
round-bottomed flask containing a magnetic stirrer bar and stirred
at room temperature for 1 h, then Tris(hydroxymethyl)aminomethane
(
10–12 mmol) was added, and the mixture was stirred for 8–12 h. The
mixture was filtered off to remove inorganic salts and the solvent was
concentrated under reduced pressure. The resulting solid was recrystal-
lized from anhydrous ethanol to give corresponding N-benzoylthiourea.
ACKNOWLEDGMENT
This work was partly supported by National 863 High-tech Research
Award, National Natural Science Foundation of China, The Ministry of
Education and Science and Technology foundation of Shanghai.
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Received in Japan October 15, 2002