A simple iodine-promoted synthesis of 2-substituted benzothiazoles by condensation of aldehydes with 2-aminothiophenol

Article abstract of DOI:10.1246/cl.2006.460

Iodine is used to promote the condensation of 2-aminothiophenol with aldehydes in DMF, which affords corresponding 2-substituted benzothiazoles efficiently. Mild and manipulable procedure, use of available and less toxic oxidant, and shorter reaction times are the advantageous features of this method. Copyright

Full text of DOI:10.1246/cl.2006.460

460
Chemistry Letters Vol.35, No.4 (2006)
A Simple Iodine-promoted Synthesis of 2-Substituted Benzothiazoles
by Condensation of Aldehydes with 2-Aminothiophenol
Yan Li,1 Yu-Lu Wang,Ã1 and Jin-Ye WangÃ2;3
1College of Chemical and Environmental Science, Henan Normal University, Xinxiang, 453007, Henan, P. R. China
2Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, P. R. China
3Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, 200032, P. R. China
(Received January 10, 2006; CL-060032; E-mail: wyl@henannu.edu.cn)
Iodine is used to promote the condensation of 2-aminothio-
Table 1. Variation of ratio of iodine in condensation of 2-ami-
nothiophenol with 4-chlorobenzaldehyde
phenol with aldehydes in DMF, which affords corresponding 2-
substituted benzothiazoles efficiently. Mild and manipulable
procedure, use of available and less toxic oxidant, and shorter
reaction times are the advantageous features of this method.
Entry
I2/mol %
Time/min
Yielda/%
1
2
3
4
5
6
7
0
10
25
50
75
100
100
60
60
30
30
30
15
30
Little
33
71
78
73
2-Substituted benzothiazoles are an important class of com-
pounds in medicinal and industrial chemistry.1 The benzothia-
zole nucleus constitutes the core unit of many antitumor drugs2
and other pharmaceutic utilities,3 some fluorescent4 and photo-
chromic5 compounds, and some benzothiazoles have been found
in some organism.1 Thus, the synthesis of them is of considera-
ble interests. The reported methods of benzothiazole synthesis
involve two major routes: the condensation of 2-aminothiophe-
nol with aldehydes,6 carboxylic acids,7 acid chlorides,8 or esters9
and by the cyclization of thiobenzanilides.10 Other general meth-
ods include microwave-mediated reaction of 2-aminothiophenol
with ꢀ-chlorocinnamaldehydes,11 palladium-catalyzed Suzuki
biaryl coupling of 2-bromobenzothiazole with arylboronic
acids12 and coupling of benzothiazoles with aryl bromides,13
and the reaction between thiophenols and aromatic nitriles.14
However, most of these methods suffer from one or more disad-
vantages such as high reaction temperature,3d harsh reaction
condition,10a multistep process,7a,7e prolonged reaction time,10c
requirement of excess of reagents,6c,6d,11 and the use of costly,6c
air sensitive10b,12,13 catalysts, etc. Consequently, there is a need
to develop a simple and mild protocol for synthesis of 2-substi-
tuted benzothiazoles without toxic oxidant.
Iodine is an inexpensive and readily available reagent and
usually used as effective oxidant15 and catalyst16 in organic syn-
thesis. We try to use it to promote the condensation of 2-amino-
thiophenol with aldehyde. When the mixture of 2-aminothiophe-
nol and aldehyde was treated with iodine in a suitable solvent,
the corresponding benzothiazole was afforded efficiently. To
the best of our knowledge the employment of iodine in this area
has not been reported previously.
In order to establish the optimum condition for this reaction,
various ratio of iodine and various solvents were examined.
Using 2-aminothiophenol and 4-chlorobenzaldehyde as a model,
iodine was added in various ratio in DMF at 100 ꢀC. As shown in
Table 1, different results would be afforded in the presence of
different ratio of iodine. Few desired products would be obtained
in the absence of iodine. Substrates and intermediate could not
be converted efficiently with too less iodine and more by-prod-
ucts would be obtained with too much iodine, higher yield was
given in the presence of 50 mol % iodine. Four polar solvents
were also investigated and the results summarized in Table 2
69
67
aAll yields refer to isolated product.
Table 2. Variation of solvent in condensation of 2-aminothio-
phenol with 4-chlorobenzaldehyde
Yielda
/%
Entry
Solvent
1
2
3
4
CH3CH2OH (reflux)
CH3OH (reflux)
CH3CN (reflux)
DMF (100 ꢀC)
33
71
73
78
aAll yields refer to isolated product.
Table 3. Condensation of 2-aminothiophenol with aldehydes
promoted by iodine in DMF
Time/
min
Yielda
/%
Entry
R
mp/ꢀCLit
1
2
3
4
5
6
7
8
9
C6H5
4-FC6H4
4-ClC6H4
2-BrC6H4
3-O2NC6H4
2-HOC6H4
4-H3CC6H4
4-CH3OC6H4
Furyl
25
25
30
40
35
30
30
30
30
60
60
88
82
78
66
78
81
80
71
79
41
31
112–1136d
101–1032a
112–1146e
66–682a
183–1856e
129–1312a
83–852a
120–1222a
102–1046d
110–11217
Liquid18
10
11
C6H5CH=CH
CH3CH2CH2
aAll yields refer to isolated product, characterized by melting
points, GC-MS, IR, and H NMR spectroscopy.
1
showed that DMF gave higher yield than others.
Consequently the reaction was carried in DMF with
50 mol % iodine (Eq 1).
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.4 (2006)
461
NH2
N
S
d) M. Kodomari, Y. Tamaru, T. Aoyama, Synth. Commun.
2004, 34, 3029. e) K. Bougrin, A. Loupy, M. Soufiaoui,
Tetrahedron 1998, 54, 8055.
I2 ( 50 mol % )
(1)
R
RCHO
+
DMF, 100 °C
SH
Various aldehydes were treated with 2-aminothiophenol
in DMF in the presence of iodine (50 mmol %) at 100 ꢀC to
examine the generality of this procedure. Excellent results were
obtained in most of the cases. The results were summarized
in Table 3. Among them, benzaldehyde and substituted benzal-
dehydes gave higher yields than aliphatic aldehyde and ꢁ,ꢀ-
unsaturated aldehyde.
7
a) S. Mourtas, D. Gatos, K. Barlos, Tetrahedron Lett. 2001,
42, 2201. b) Y. Njoya, A. Gellis, M. Crozet, P. Vanelle,
Sulfur Lett. 2003, 26, 67. c) A. K. Chakraborti, C. Selvam,
G. Kaur, S. Bhagat, Synlett 2004, 851. d) I. Yildiz-Oren, I.
Yalcin, E. Aki-Sener, N. Ucarturk, Eur. J. Med. Chem.
2004, 39, 291. e) C. Chen, Y. J. Chen, Tetrahedron Lett.
2004, 45, 113.
In conclusion, a methodology has been developed for the
synthesis of 2-substituted benzothiazoles via the condensation
of 2-aminothiolphenol with aldehyde promoted by iodine.19
Mild and manipulable procedure, use of available and less toxic
oxidant, and shorter reaction times are the advantageous features
of this method.
8
9
a) I. R. Laskar, T. M. Chen, Chem. Mater. 2004, 16, 117.
b) R. N. Nadaf, S. A. Siddiqui, T. Daniel, R. J. Lahoti,
K. V. Srinivasan, J. Mol. Catal. A: Chem. 2004, 214, 155.
a) H. Matsushita, S. H. Lee, M. Joung, B. Clapham, K. D.
Janda, Tetrahedron Lett. 2004, 45, 313. b) A. K. Chakraborti,
C. Selvam, G. Kaur, S. Bhagat, Synlett 2004, 851.
10 a) I. Hutchinson, M. F. G. Stevens, A. D. Westwell, Tetra-
hedron Lett. 2000, 41, 425. b) C. Benedi, F. Bravo, P. Uriz,
E. Fernandez, C. Claver, S. Castillon, Tetrahedron Lett.
2003, 44, 6073. c) L. L. Joyce, G. Evindar, R. A. Batey,
Chem. Commun. 2004, 446. d) X. J. Mu, J. P. Zou, R. S.
Zeng, J. C. Wu, Tetrahedron Lett. 2005, 46, 4345. e) F. M.
Moghaddam, H. Z. Boeini, Synlett 2005, 1612.
11 S. Paul, M. Gupta, R. Gupta, Synth. Commun. 2002, 32,
3541.
12 V. J. Majo, J. Prabhakaran, J. J. Mann, J. S. D. Kumar,
Tetrahedron Lett. 2003, 44, 8535.
13 D. Alagille, R. M. Baldwin, G. D. Tamagnan, Tetrahedron
Lett. 2005, 46, 1349.
14 R. H. Tale, Org. Lett. 2002, 4, 1641.
15 J. S. Yadav, B. V. Subba Reddy, G. Sabitha, G. S. K. K.
Reddy, Synthesis 2000, 1532.
This work was supported by the National Program on
Key Basic Research Projects of China (973 Program, 2005
CB724306).
References and Notes
1
2
H. Ulrich, Science of Synthesis, 2002, Vol. 11, p. 835.
a) L. W. Wattenberg, M. A. Page, J. L. Leong, Cancer Res.
1968, 28, 2539. b) I. Hutchinson, M. S. Chua, H. L. Browne,
V. Trapani, J. Med. Chem. 2001, 44, 1446. c) T. D.
Bradshaw, A. D. Westwell, Curr. Med. Chem. 2004, 11,
1009.
3
a) T. Mouri, J. Tokumura, S. Kochi, H. Fukui, J. Nakano,
T. Ando, Nippon Noyaku Gakkaishi 2002, 27, 353. b) J.
Koci, V. Klimesova, K. Waisser, J. Kaustova, H. M. Dahse,
U. Mollmann, Bioorg. Med. Chem. Lett. 2002, 12, 3275.
c) K. Oketani, T. Inoue, M. Murakami, Eur. J. Pharmacol.
2001, 427, 159. d) C. W. Phoon, P. Y. Ng, A. E. Ting,
S. L. Yeo, M. M. Sim, Bioorg. Med. Chem. Lett. 2001, 11,
1647. e) C. Chen, Y. J. Chen, Tetrahedron Lett. 2004, 45,
113. f) C. A. Mathis, Y. M. Wang, D. P. Holt, G. F. Huang,
M. L. Debnath, W. E. Klunk, J. Med. Chem. 2003, 46,
2740. g) Y. A. Jackson, M. A. Lyon, N. Townsend, K.
Bellabe, F. Soltanik, J. Chem. Soc., Perkin Trans. 1 2000,
205.
16 H. S. Wang, J. Y. Miao, L. F. Zhao, Chin. J. Org. Chem.
2005, 25, 615.
17 V. Dryanska, C. Ivanov, Tetrahedron Lett. 1975, 16, 3519.
18 G. Vernin, J. Metzger, Bull. Soc. Chim. Fr. 1967, 846.
19 General procedure for the synthesis of benzothiazole: 2-
Aminothiophenol (25.0 mg, 0.2 mmol) and 4-chlorobenzal-
dehyde (28.0 mg, 0.2 mmol) were mixed in DMF (0.5 mL)
thoroughly, then the solution of iodine (25.4 mg, 0.1 mmol)
in DMF (0.5 mL) was added, heated and stirred at 100 ꢀC
for appropriate time (monitored by TLC). When the reaction
was finished, the mixture was cooled to room temperature.
Then, the solution of sodium thiosulfate (10%) was dropped
into the mixture until the color of iodine was disappeared.
The precipitate was filtrated and washed with water. After
vacuum drying, the crude products was purified by column
chromatography over silica gel (petroleum ether/ethyl ace-
tate, 8:1) to afford the corresponding benzothiazole.
4
5
6
S. P. G. Costa, J. A. Ferreira, G. Kirsch, M. F. J.
Oliveira-Campos, Chem. Res. 1997, 314.
A. Heynderickx, R. Guglielmetti, R. Dubest, J. Aubard,
A. Samat, Synthesis 2003, 1112.
a) R. M. F. Batista, S. P. G. Costa, M. M. M. Raposo,
Tetrahedron Lett. 2004, 45, 2825. b) B. C. Ranu, R. Jana,
S. Dey, Chem. Lett. 2004, 33, 274. c) T. Itoh, K. Nagata,
H. Ishikawa, A. Ohsawa, Heterocycles 2004, 62, 197.
Published on the web (Advance View) March 25, 2006; DOI 10.1246/cl.2006.460