One-pot synthesis of N-allylthioureas using supported reagents

Article abstract of DOI:10.1016/j.tetlet.2005.05.063

A simple and efficient method has been developed for the synthesis of N-allylthioureas from allylic bromides in one-pot by using a supported reagents system, KSCN/SiO₂-RNH₃OAc/Al₂O₃, in which allyl bromide reacts first with KSCN/SiO₂ and the product, allyl isothiocyanate, reacts with RNH₃OAc/Al₂O₃ to give the final product, N-allylthiourea, in good yield.

Full text of DOI:10.1016/j.tetlet.2005.05.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4875–4878
One-pot synthesis of N-allylthioureas using supported reagents
a
a,
Tadashi Aoyama, Sumiko Murata, Yasutaka Nagata,
a
*
a
Toshio Takido and Mitsuo Kodomari
b
a
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai,
Chiyoda-ku, Tokyo 101-8308, Japan
b
Department of Applied Chemistry, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan
Received 18 April 2005; revised 11 May 2005; accepted 16 May 2005
Available online 4 June 2005
Abstract—A simple and efficient method has been developed for the synthesis of N-allylthioureas from allylic bromides in one-pot
by using a supported reagents system, KSCN/SiO –RNH OAc/Al , in which allyl bromide reacts first with KSCN/SiO and the
OAc/Al to give the final product, N-allylthiourea, in good yield.
2
3
2
O
3
2
product, allyl isothiocyanate, reacts with RNH
3
2 3
O
Ó 2005 Elsevier Ltd. All rights reserved.
Polymer or inorganic solid-supported reagents have
been widely used in organic synthesis. However, there
are few examples using a mixture of supported reagents
aminating reagent respectively in the same vessel. For
instance 2-aminothiazoles were synthesized by using a
supported reagents system, KSCN/SiO –RNH OAc/
2
3
1
for synthetic purposes. Cohen et al. described two-stage
Al O , in which a-bromo ketones react first with
2 3
reactions in which a starting material was modified suc-
cessively by two polymeric-transfer reagents (wolf and
lamb reaction). The analogous soluble reagents would
react with each other rapidly in solution, whereas they
could be rendered mutually inactive on their attachment
to the respective polymeric phase and therefore coexist
in the same reaction vessel. While basically using the
KSCN/SiO and the products react with RNH OAc/
2 3
Al O to give the 2-aminothiazoles in high yields. The
3
2
halides react with potassium thiocyanate to afford thio-
cyanates or isothiocyanates depending on the reactivity
of the halides and reaction conditions. Alkyl halides
yield preferentially thiocyanates which, depending on
the structure of organic residue, rearrange themselves
more or less into the corresponding isothiocyanates.
Allylic thiocyanates isomerize thermally with much
greater ease than benzylic thiocyanates. Isothiocyanates
readily react with amines to give the corresponding
thioureas. Therefore, we tried to synthesize thiourea
derivatives from the reaction of allylic bromide using
supported reagents system ÔKSCN/SiO –RNH OAc/
2
same principle, Kim and Regen have realized a Ôvacil-
lating reactionÕ, using a couple of redox reagents sepa-
rately adsorbed onto inorganic solid supports.
However, this concept has not been extended to reagents
adsorbed on inorganic supports. Recently, we have re-
ported novel synthetic procedures by using a couple of
3
supported reagents. For example, we have developed
direct allylation of aromatic compounds using a couple
2
3
Al O Õ. Symmetrical and unsymmetrical thioureas are
2 3
3a
of acid and base supported reagents in one-pot. The
one-pot multi-step synthesis using inorganic solid-sup-
useful compounds in agricultural and medicinal chemis-
4
try. They are also used as building blocks for the syn-
5
3
b–d
ported reagents system has also been reported.
We realized that KSCN and NH OAc could not coexist
thesis of both five- and six-membered heterocycles.
The common methods for the synthesis of symmetrical
and unsymmetrical thioureas are the condensation of
4
in the same vessel due to interaction with each other but
these reagents which were supported on separate in-
organic supports, silica gel and alumina, were able to co-
exist and to work as a thiocyanating reagent and
6
primary or secondary amines with thiophosgene and
4
,7
isothiocyanates. However, these methods are hazard-
ous due to the toxic properties of both thiophosgene
and isothiocyanates. On the other hand, our method
does not need to handle directly isothiocyanates.
Recently, several methods have been developed for the
synthesis of both symmetrical and unsymmetrical
thioureas involving: (a) reaction of reductive alkylation
Keywords: Thiourea; Supported reagents; One-pot synthesis.
*
Corresponding author. Tel./fax: +81 3 3259 0818; e-mail: aoyama@
chem.cst.nihon-u.ac.jp
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.063

4876
T. Aoyama et al. / Tetrahedron Letters 46 (2005) 4875–4878
R2
R1
isomerize thermally with much greater ease than other
2
S
R
4
thiocyanates, for example, benzyl thiocyanate. Benzyl
bromide did not give the corresponding thiourea under
similar reaction conditions.
R
R1
Br
N
H
N
H
R3
R3
4
1
Several solvents were tested for the reaction with cinn-
amyl bromide by using the combination of KSCN/
SiO and RNH OAc/Al O . Among the solvents tested,
benzene and toluene were suitable solvents for the reac-
tion. The reaction in polar solvents such as THF gave
the product in moderate yield (44%) (Table 1).
4
R NH OAc/Al O
KSCN/SiO2
3
2
3
R1
R2
2
3
2
3
R2
R1
SCN
NCS
R3
R3
3
2
As shown in Table 2, various allylic bromides reacted
with KSCN/SiO and BnNH OAc/Al O in one-pot to
Scheme 1. One-pot synthesis of using supported reagents system.
2
3
2
3
afford the corresponding thioureas. The reaction of cro-
tyl bromide and of 1-bromo-3-methyl-2-butene gave the
8
of thioureas; (b) reaction of carbon disulfide and amine
9
1
5
desired products, 4c and 4d, in excellent yields. Cinn-
amyl bromide and 1-bromo-2-methyl-2-butene were also
converted into the products in good yields under the
same conditions. When cinnamyl chloride was used in-
stead of cinnamyl bromide for the reaction, the yield
of 4b was lower than that of cinnamyl bromide.
in the presence of MCM-41-TBD; (c) reaction of amine
1
0
and benzotriazole-1-carbothioic acid derivatives; (d)
reaction of 1-(methyldithiocarbonyl)imidazole and
1
1
amine; (e) solid phase reaction using peptide coupling
1
2
reagents. Herein, we report a simple, efficient and
safety method for the one-pot synthesis of N-allylthio-
ureas using a combination of supported reagents
0
Table 1. Synthesis of N-a-phenylallyl-N -benzylthiourea in various
solvent
(
Scheme 1).
For example, a mixture of cinnamyl bromide (1 mmol),
1
Ph
S
3
3c
KSCN/SiO2
(5 mmol) and BnNH OAc/Al O
3 2 3
Bn
Ph
Solvent
Br
N
N
(
6
3 mmol) was stirred in benzene (10 mL) at 80 °C for
h, and then the used supported reagents were removed
H
H
Yield (%)
by filtration. The filtrate was evaporated to leave crude
product, which was purified by column chromatography
Benzene
Toluene
Xylene
78
75
0
14
to give N-a-phenylallyl-N -benzylthiourea
in 78%
57
Trace
44
yield. Allylic halides react readily with KSCN to pro-
duce allylic thiocyanates, which isomerizes with allyl
rearrangement into isothiocyanate. Allylic thiocyanates
Cyclohexane
THF
0
a
Table 2. One-pot synthesis of N-allyl-N -benzyl thioureas
R2
R1
S
R2
KSCN/SiO -BnNH OAc/Al O
2 3
2
3
R1
Br
N
N
Ph
Benzene, 80˚C, 6 h
H
H
R3
R3
Entry
1
Allylic bromide
Product
Yield (%)
59
S
Br
N
N
H
Ph
4a
H
Ph
S
S
2
3
4
5
78
92
94
75
Ph
Br
4
b
c
N
H
N
H
Ph
Ph
Br
4
N
H
N
H
S
S
Br
4d
N
H
N
H
Ph
Ph
Br
4e
N
H
N
H
a
2 3 2 3
Allylic bromide: 1 mmol, KSCN/SiO : 5 mmol, BnNH OAc/Al O : 3 mmol.

T. Aoyama et al. / Tetrahedron Letters 46 (2005) 4875–4878
4877
Table 3. One-pot synthesis of N-allylthioureas from crotyl bromide and various alkylammonium acetates
S
KSCN/SiO -RNH OAc/Al O
2 3
2
3
R
Br
N
H
N
Benzene, 80˚C, 6 h
H
Entry
1
Amine
Product
Yield (%)
S
S
S
S
S
S
S
S
Ph
Ph
89
88
89
82
88
—
—
92
90
47
H N
2
N
H
N
H
2
3
4
5
6
7
8
9
H N
2
N
H
N
H
H N
2
N
H
N
H
H N
2
N
H
N
H
H N
2
N
H
N
H
H N
2
N
H
N
H
NH
3
N
H
NH2
H N
2
N
H
N
H
S
S
H N
2
N
H
N
H
10
HN
N
H
N
The results of the reaction of crotyl bromide with alu-
mina-supported alkylammonium acetates were shown
in Table 3. The reactions of crotyl bromide with a series
of butylammonium acetate gave the corresponding thio-
ureas except for the reaction with tert-butylammonium
acetate (entries 3–6). When using not only normal- and
iso-butylammonium acetates but also sec-butylammo-
nium acetate, the N-allylthioureas were obtained in high
yields. However, tert-butylammonium acetate did not
give the desired thiourea. Ammonium acetate also gave
no expected compound (entry 7). The reactions of cyclo-
alkyl- and allyl-ammonium acetates gave the expected
thioureas in good yields (entries 2, 8 and 9). The reaction
with the acetate of piperidine was also proceeded to
afford expected compound in 47% yield (entry 10).
method may be applicable for laboratory scale and
combinatorial synthesis of N-allylthioureas. Further
applications of this reagents system are now under
investigation.
References and notes
1. Choen, B. J.; Krans, M. A.; Patchorink, A. J. Am. Chem.
Soc. 1981, 103, 7620.
2. Kim, B.; Regen, S. L. Tetrahedron Lett. 1983, 24, 689.
3
. (a) Kodomari, M.; Nawa, S.; Miyoshi, T. Chem. Commun.
1
1
995, 1895; (b) Suzuki, Y.; Kodomari, M. Chem. Lett.
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Tetrahedron Lett. 2002, 43, 1717; (d) Aoyama, T.; Takido,
T.; Kodomari, M. Tetrahedron Lett. 2004, 45, 1873.
. (a) Bloom, J. D.; Dushin, R. G.; Curran, K. J.; Donahue,
C. F.; Norton, E. B.; Terefenko, E.; Jones, T. R.; Ross, A.
A.; Feld, B.; Lang, S. A.; DiGrandi, M. J. Bioorg. Med.
Chem. Lett. 2004, 14, 3401; (b) Lee, J.; Kim, S. Y.; Lee, J.;
Kang, M.; Kil, M.-J.; Choi, H.-K.; Jin, M.-K.; Wang, Y.;
4
In conclusion, we have developed a simple and efficient
method for the synthesis of N-allylthioureas in one-pot
from commercially available starting materials. This

4878
T. Aoyama et al. / Tetrahedron Letters 46 (2005) 4875–4878
0
1
Toth, A.; Pearce, L. V.; Lundberg, D. J.; Tran, R.;
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14. N-a-phenylallyl-N -benzylthiourea (4b), mp 80–81 °C. H
NMR (300 MHz, CDCl
3 2
): d 4.55 (2H, s, CH ), 5.06–5.18
5
. St. Laurent, D. R.; Gao, Q.; Wu, D.; Serrano-Wu, M. H.
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(2H, m, CH @CH), 5.54 (1H, br s, CH), 5.83–5.93 (1H, m,
2
CH
7.26 (10H, m, arom). C NMR (75 MHz, CDCl
(CH ), 60.3 (CH), 117.0 (CH @CH), 127.0, 127.3, 127.6,
2
@CH), 6.30 (1H, br s, NH), 6.40 (1H, br s, NH), 7.08–
13
6
3
): d 48.7
7
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2
2
128.0, 128.7, 128.9, 136.5 (CH @CH), 136.8, 139.0, 181.2
2
+
S (MH ):
(C@S). HR-MS (TOF-CI) calcd for C17
283.1268. Found: 283.1273.
H
19
N
2
8
9
0
1
15. N-a-methylallyl-N -benzylthiourea (4c), mp 68–69 °C. H
. Ballini, R.; Bosica, G.; Fiorini, D.; Maggi, R.; Righi, P.;
Sartori, G.; Sartorio, R. Tetrahedron Lett. 2002, 43, 8445.
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NMR (300 MHz, CDCl
4.42 (1H, br s, CH), 4.62 (2H, s, CH), 5.02–5.10 (2H, m,
CH @CH), 5.67–5.78 (1H, m, CH @CH), 6.08 (1H, br s,
NH), 6.29 (1H, br s, NH), 7.23–7.30 (5H, m, arom).
NMR (75 MHz, CDCl ): d 20.5 (CH ), 48.6 (CH ), 52.0
(CH), 115.2 (CH @CH), 127.5, 127.7, 128.7, 137.0, 138.9
(CH @CH), 181.1 (C@S). HR-MS (TOF-CI) calcd for
C H N S (MH ): 221.1112. Found: 221.1108. The
3 3
): d 1.20 (3H, d, J = 6.8 Hz, CH ),
1
1
1
1
2
2
1
3
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C
3
3
2
2
2
+
1
2
17
2
1
3
1
1
NMR assignments were aided by C DEPT, H– H and
C– H COSY spectroscopy.
1
3
1
1983, 141.