Novel synthesis of 1-aroyl-3-aryl-4-substituted imidazole-2-thiones.

Article abstract of DOI:10.1021/ol030024l

[reaction: see text] An efficient route to 1-aroyl-3-aryl-4-substituted imidazole-2-thiones (2, 4-6) has been developed. The methodology involves the cyclization of 1-aroyl-3-arylthioureas with a variety of carbonyl compounds bearing alpha-H in the presen

Full text of DOI:10.1021/ol030024l

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1657-1659
Novel Synthesis of
1-Aroyl-3-aryl-4-substituted
Imidazole-2-thiones
,†
Run-Sheng Zeng,† Jian-Ping Zou,* San-Jun Zhi,‡ Jun Chen,† and Qi Shen†
Department of Chemistry, Suzhou UniVersity, Suzhou 215006,
Jiangsu ProVince, China, and Department of Chemistry, Huaiyin Teacher’s College,
Huaiyin, 223000, Jiangsu ProVince, China
jpzou@suda.edu.cn
Received February 18, 2003
ABSTRACT
An efficient route to 1-aroyl-3-aryl-4-substituted imidazole-2-thiones (2, 4−6) has been developed. The methodology involves the cyclization of
1-aroyl-3-arylthioureas with a variety of carbonyl compounds bearing r-H in the presence of bromine and triethylamine.
Imidazole-2-thione and its derivatives have received attention
because of their bioactivities and application for pharma-
ceutical synthesis.1,2 Marckwald established the first synthetic
route to 1-substituted imidazole-2-thione by reaction of
isothiocyanate with aminoacetal in 1889.3 Lawson prepared
imidazole-2-thione and its derivatives from KNCS and the
corresponding amino acid ester hydrochloride.4 Matsuda
modified Marckwald’s method into a one-pot fashion in
1997.1 In recent years, imidazole-2-thione nucleosides have
received much attention. Palacios reported the synthesis of
optically pure 1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)-
imidazolidine-2-thione, which may be used as chiral auxil-
iaries and ligands for asymmetric catalysis.5 Fuentes de-
scribed the reaction of D-fructosamines with different sugar
isothiocyanates to obtain chiral imidazolidine-2-thione N-
nucleosides.6 Furthermore, the same author used imidazoli-
dine-2-thione C-nucleoside as a precursor for the synthesis
of azidonucleosides and fluoronucleosides; these compounds
are of pharmaceutical interest due to their anti-AIDS activity.7
A few years ago, we developed a new method for the
preparation of 1,5-disubstituted-2,4-imidazolidinedione and
1,5-disubstituted 2-thioxo-4-imidazolidinones by the reaction
of R-ketohemithioacetal with ureas and thioureas.8 In this
communication, we wish to describe a novel synthesis of
1-aroyl-3-aryl-4-substituted imidazole-2-thiones (2, 4-6).
* Corresponding author.
† Suzhou University.
‡ Huaiyin Teacher’s College.
(5) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C.;
Silvero, G.; Valencia, C. Tetrahedron 1999, 55, 4377.
(6) Gasch, C.; Pradera, M. A.; Salameh, B. A. B.; Molina, J. L.; Fuentes,
J. Tetrahedron: Asymmetry 2000, 11, 435.
(7) Fuentes, J.; Angulo, M. and Pradera, M. A. J. Org. Chem. 2002, 67,
2577.
(8) (a) Zou, J.-P.; Lu, Z.-E.; Qiu, L.-H.; Chen, K.-Q. Heterocycles 1996,
43, 49. (b) Zou, J.-P.; Liu, X.-J.; Lu, Z.-E.; Chen, K.-Q. Sulfur Lett. 1997,
20, 225.
(1) Matsuda, K.; Yanagisawa, I.; Isomura, Y.; Mase, T.; Shibanuma, T.
Synth. Commun. 1997, 27, 3565 and references therein.
(2) du Mont, W.-W.; Mugesh, G.; Wismach, C.; Jones, P. G. Angew.
Chem., Int. Ed. 2001, 40, 2486.
(3) (a) Wohl, A. and Marckwald, W. Chem. Ber. 1889, 22, 568. (b)
Marckwald, W. Chem. Ber. 1892, 25, 2354.
(4) (a) Heath, H.; Lawson, A.; Rimington, C. J. Chem. Soc. 1951, 2217.
(b) Bullerwell, R. A. F.; Lawson, A. J. Chem. Soc. 1951, 3030.
10.1021/ol030024l CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/18/2003

In the course of our search for compounds bearing
bioactivities, we required some thiazole derivatives such as
2-benzoylamino benzothiazole. Therefore, the reaction of
1-benzoyl-3-phenylthiourea (1a) and K3Fe(CN)3 in basic
medium was explored, but the expected products were not
formed. Furthermore, the reactions of 1a and bromine in
chloroform or other organic solvents were also explored, but
the expected products were not found. However, when the
same reaction was performed in acetone, one main spot was
detected by TLC, and after normal isolation, a small amount
of a pure compound was obtained, whose structure was
confirmed to be 1-benzoyl-3-phenyl-4-methylimidazole-2-
thione (2a) by 1H NMR, 13C NMR, DEPT, IR, HRMS, and
elemental analysis.
reaction was found to be complete in 30 min. Later, this
reaction was extended to the other 1-benzoyl-3-arylthioureas,
and the corresponding 1-benzoyl-3-aryl-4-methylimidazole-
2-thiones (2b-f) were obtained (Table 1).
To further demonstrate the scope of the reaction, the
cyclization of 1-(o-chlorobenzoyl)-3-arylthioureas (3) and
Br2/acetone in the presence of triethylamine were carried out,
and similar results were obtained (Table 2).
On the basis of the above results, we tried to use
acetophenone instead of acetone. The expected products,
1-benzoyl-3-aryl-4-phenylimidazole-2-thiones (5), were ob-
tained (Table 3).
Table 3. Reaction of 1-Benzoylthioureas with Br2/
Acetophenone
Table 1. Reaction of 1-Benzoylthioureas with Br2/Acetone
product 5
1, 5
R
yield (%)
mp (°C)
a
b
c
d
e
f
Ph
4-ClC6H4
4-BrC6H4
4-IC6H4
2-Cl-4-F-C6H3
4-CH3C6H4
85
83
87
88
86
76
208∼210
215∼217
233∼235
249∼251
242∼244
268∼270
product 2
1, 2
R
yield (%)
mp (°C)
a
b
c
d
e
f
Ph
75
82
84
70
70
78
157∼159
209∼211
192∼194
205∼207
196∼198
215∼217
4-ClC6H4
4-BrC6H4
4-IC6H4
2-Cl-4-F-C6H3
4-CH3C6H4
The success of synthesis of compounds 5 prompted us to
further explore the reaction of 1 with acetaldehyde. Similar
products, 1-benzoyl-3-arylimidazole-2-thiones (6), were pre-
pared (Table 4).
According to the structure of 2a, it is obvious that the
solvent acetone was involved in the reaction in the presence
of bromine. We think that base may facilitate the reaction.
Therefore, triethylamine was added into the system, and the
Table 4. Reaction of 1-Benzoylthioureas with Br2/
Acetaldehyde
Table 2. Reaction of 1-(o-Chlorobenzoyl)thioureas with
Br2/Acetone
product 6
1, 6
R
yield (%)
mp (°C)
a
b
c
d
e
f
Ph
4-ClC6H4
4-BrC6H4
4-IC6H4
2-Cl-4-F-C6H3
4-CH3C6H4
93
85
81
92
93
89
105∼106
205∼207
221∼223
216∼218
208∼210
166∼168
product 4
3, 4
R
yield (%)
mp (°C)
a
b
c
d
e
f
C6H5
80
87
89
70
75
82
176∼177
135∼136
180∼181
170∼171
156∼157
106∼107
C6H5CH2
4-BrC6H4
4-CH3OC6H4
2-CH3C6H4
3-CH3C6H4
According to the structures of 2, we can propose a
mechanism for the reaction of 1-benzoyl-3-arylthioureas (1)
with Br2/acetone in the presence of triethylamine (Scheme
1658
Org. Lett., Vol. 5, No. 10, 2003

of 7 to form intermediate 9. The 3-H of 9 is attacked by
triethylamine, followed by intramolecular attack of the
carbonyl by the 3-nitrogen and hydrogen transfer to give 10
and loss of H2O from 10 to afford compounds 2. The
formation of compounds 4-6 can be explained by a similar
mechanism.
Scheme 1
In conclusion, we have developed a good method for the
preparation of 1-aroyl-3-aryl-4-substituted imidazole-2-
thiones (2, 4-6) from the cyclization of 1-aroyl-3-arylthio-
ureas with a variety of carbonyl compounds bearing R-H
such as acetone, acetophenone, and acetaldehyde in the
presence of bromine and triethylamine.
Acknowledgment. We thank the Key Laboratory of
Organic Synthesis of Jiangsu Province for financial support.
Supporting Information Available: General procedure
1
for preparation of 2; IR, HNMR, 13CNMR, HRMS, and
elemental analysis for 2a-f; HRMS for 4a-f; IR, 1HNMR,
and HRMS for 5a-f; HNMR, 13CNMR, and HRMS for
6a-c,f; and HRMS for 6d-e. This material is available free
1
1). Triethylamine attacks the 1-H of 1-benzoyl-3-arylthio-
ureas (1) in the first step. Bromoacetone (8) is produced in
situ by bromination of acetone, and the carbon of the
bromomethyl group of 8 is attacked by the 1-nitrogen atom
of charge via the Internet at http://pubs.acs.org.
OL030024L
Org. Lett., Vol. 5, No. 10, 2003
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