Water-promoted dowex 50W catalyzed highly efficient green protocol for 2-arylbenzothiazole formation

Article abstract of DOI:10.1002/jhet.9

2-Aminothiophenol and a variety of aryl aldehydes were allowed to react in one-pot operation to give 2-aryl-benzothiazoles in excellent yields in the presence of Dowex 50W in water. Very high yields coupled with the ease of work-up procedure, formation of no side products, employment of "reusable" catalyst, and "green" synthesis in aqueous medium without maintaining anhydrous reaction conditions are the most important aspects of this methodology.

Full text of DOI:10.1002/jhet.9

January 2009
Water-Promoted Dowex 50W Catalyzed Highly Efficient Green
Protocol for 2-Arylbenzothiazole Formation
91
Chhanda Mukhopadhyay* and Arup Datta
Department of Chemistry, University of Calcutta, Kolkata 700009, India
*E-mail: csm@vsnl.net or cmukhop@yahoo.co.in
Received December 18, 2007
DOI 10.1002/jhet.9
Published online 5 February 2009 in Wiley InterScience (www.interscience.wiley.com).
2-Aminothiophenol and a variety of aryl aldehydes were allowed to react in one-pot operation to give
2-aryl-benzothiazoles in excellent yields in the presence of Dowex 50W in water. Very high yields
coupled with the ease of work-up procedure, formation of no side products, employment of ‘‘reusable’’
catalyst, and ‘‘green’’ synthesis in aqueous medium without maintaining anhydrous reaction conditions
are the most important aspects of this methodology.
J. Heterocyclic Chem., 46, 91 (2009).
INTRODUCTION
such an important organic moiety in aqueous medium
still needs to be explored.
The 2-substituted benzothiazole moiety is particularly
very interesting in the area of medicinal and organic
chemistry. The benzothiazolyl system possesses highly
selective and potent antitumor activity. An example is
that of substituted 2-(4-aminophenyl)-benzothiazoles,
which show nanomolar inhibitory in vitro activity
against a wide range of human breast, ovarian, colon,
and renal cell lines [1]. Another such compound that
shows potent and selective inhibitory activity against
lung, colon, and breast cancer cell lines is 2-(3,4-dime-
thoxyphenyl)-5-fluorobenzothiazole [2]. Also, the 2-(4-
dimethylaminophenyl)-benzothiazole is an integral com-
ponent used for the treatment of Alzheimer’s disease
[3]. The presence of the benzothiazole nucleus is essen-
tial in the thermally stable rigid-rod polymers with high
tensile strength and modulus [4]. Thus, the synthesis of
this benzothiazole moiety is always a great challenge.
A number of synthetic routes are available for the
construction of the benzothiazole nucleus. Among
them, the most common ones being the condensation of
2-aminothiophenols with substituted carboxylic acids,
acyl chlorides, aldehydes, and nitriles [5]. An alternate
method includes potassium ferricyanide cyclization of
thiobenzanilides (Jacobson’s method [6]). Solvent-free
synthesis of benzothiazoles under microwave irradiation
in the presence of silica gel is also known [7a]. Very
recently, the synthesis of this moiety under microwaves
in absence of any catalyst has been reported by us [7b].
Most of these methods employ costly reagents and per-
fectly dry reaction conditions or the use of microwaves.
Thus, a truly efficient diverse green synthetic scheme of
RESULTS AND DISCUSSION
It has been recently reported from our laboratory [8]
that Dowex 50W has proved to be a very effective and
efficient catalyst for the construction of the 4-aryl-dihy-
dropyrimidone nucleus. On the basis of such observa-
tion, we chose the sulfonic acid resin Dowex 50W in
aqueous medium for the construction of the benzothia-
zole ring. Thus, a variety of aromatic aldehydes (1)
were coupled with 2-aminothiophenol (2) in the pres-
ence of 10 mol % of Dowex 50W in water in a one-pot
operation for the first time to synthesize the 2-substi-
tuted benzothiazoles (3) (Scheme 1, Table 1) in excel-
lent yields. Water proved to be the best medium for this
reaction. The yields of the products decreased on per-
forming the reaction in water-methanol, water-ethanol,
or water-tetrahydrofuran mixed solvents (all 50:50 by
volume).
The advantages of using Dowex 50W are as follows:
(a) it can be reused at least three times without
Scheme 1
C
V
2009 HeteroCorporation

92
C. Mukhopadhyay and A. Datta
Vol 46
Table 1
Synthesis of 2-arylbenzothiazoles by Dowex 50W in water under aerial oxygen.
Entry
R (1)
Time (h)
Yield (%) (3)
Observed mp (ꢀC)
Reported mp (ꢀC)
References
1
2
a: H
12
10
08
08
12
06
10
12
10
08
10
09
05
10
07
08
07
07
a: 85
b: 89
c: 83
d: 88
e: 90
f: 87
g: 92
h: 86
i: 90
j: 92
k: 88
l: 85
m: 83
n: 85
o: 82
p: 84
q: 87
r: 85
112–114
120–121
101–103
181–182
115–117
228–230
225–226
161–163
162–164
84–86
114–115
121–122
101–102
183–185
117–118
229–230
227–228
160–162
161–163
83–84
[5a,10]
[5a,10]
[7]
b: 4-OMe
c: 2-OMe
d: 3-NO2
3
4
[5b]
5
e: 4-Cl
f: 4-NO2
g: 4-OH
h: 3-OH
i: 3-OMe- 4-OH
j: 3-Br
k: 4-N(CH3)2
l: 2-furanyl
m: 2-NO2
n: 2-Cl
[5a,11]
[5a,7]
[7]
6
7
8
9
[12]
[12]
10
11
12
13
14
15
16
17
18
[13]
[3]
160–162
103–104
135–136
84–85
160–161
103–104
138–140
82
[5a,7,11]
[7]
[7]
o: 2-cinnamyl
p: 4- Br
110–111
132
112
130
[5b]
[14]
q: 3,4- (OMe)2
r: 2.5-(OMe)2
141–143
147–149
142–144
Not reported
[15]
[16]
substantial loss of activity (b) dry conditions are not
required (c) the reaction takes place very smoothly (d)
no side products are obtained (e) the purification of the
final product is very simple (f) no hazardous wastes
from solvents or chemicals take place (g) the reaction
conditions are very mild employing temperature of only
70ꢀC, thus being able to sustain quite a large number of
functional groups. Therefore, Dowex 50W is a ‘‘green
catalyst’’ for the 2-aryl-benzothiazole formation in aque-
ous medium.
dehyde (1s) is converted to 2-hydroxyphenyl benzothia-
zole (3s) in good yield but under very drastic conditions
(Scheme 3, Table 3, entry 1). The isolation of 2-hydrox-
yphenyl benzothiazoline [4(i)(s)] surely proves that the
reaction passes through this intermediate. Following the
same mechanistic pathway cited in our earlier reference
[7b], benzothiazoles (3) are the final products for all the
cases cited in Table 1.
The reaction therefore proceeds via the intermediate
formation of benzothiazoline [7b]. This is further proved
by the actual isolation of such intermediates from 2-
chloro and 4-nitrobenzaldehydes by carrying out the
reaction for a shorter time (entries 2 and 3, Table 2),
which then proceed to completion (entries 2 and 3, Ta-
ble 3). When the same reaction with Dowex 50W was
carried out under argon atmosphere (in absence of oxy-
gen) (carried out with 2-chloro, 4-nitro- and 2-hydroxy
benzaldehydes), the reactions stopped at the benzothia-
zoline stage, which never proceeded to benzothiazoles.
This surely proves that aerial oxygen is not essential for
benzothiazoline formation, though it is absolutely essen-
tial for the oxidation step leading to the formation of
benzothiazoles. The overall yield of the stepwise reac-
tion was more or less the same as that of the one-step
reaction, although the total time required for the step-
wise reaction was slightly greater. It was not possible to
isolate the intermediate benzothiazoline for all the other
substrates as the next steps of oxidation and dehydration
were very fast leading to the formation of benzothia-
zoles (the ultimate products in all cases). Stopping
the reaction at various stages resulted in the formation
of a mixture of benzothiazoline and benzothiazole of
varied percentage compositions (done for 4-methoxy
With salicaldehyde (1s), the reaction stopped at the
benzothiazoline [4(i)(s)] stage (Scheme 2, Table 2, entry
1), and the stability of this intermediate by six-mem-
bered hydrogen bond (intramolecular) (Fig. 1) prevents
it to react further to produce the benzothiazole. The iso-
lation of this intermediate [4(i)(s)] confirms our earlier
proposed mechanism [7b].
The fact that the reaction of salicaldehyde (1s) and 2-
aminothiophenol (2) stops at the benzothiazoline stage
is further proved by the work of Charles and Freiser [9].
The intermediate benzothiazoline [4(i)(s)] from salical-
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Water-Promoted Dowex 50W Catalyzed Highly Efficient Green Protocol for
2-Arylbenzothiazole Formation
93
Table 2
Synthesis of 2-aryl and 2-alkyl-benzothiazolines by Dowex 50W in water both under aerobic and anaerobic conditions.
Entry
Z (Scheme 2)
Time (h)
Yield (%)(4)
Observed mp (ꢀC)
Literature mp (ꢀC)
References
1
2
3
4
5
1s: (2-OH)C6H4
1n: (2-Cl)C6H4
1f: (4-NO2)C6H4
t: A(CH2)2CH3
u: ACH2CH3
06
02
01
06
07
(i) s: 90
(i) n: 85
(i) f: 87
(ii) t: 50
(ii) u: 55
141–142
76
115–117
141–144
Not reported
117–118
[9,17]
[18]
[19]
[20]
[20]
benzaldehyde) [benzothiazoline: benzothiazole ¼ 43:57
(obtained by the 1H NMR integration of the methoxy
peaks after 2 h and benzothiazoline: benzothiazole ¼
26:74 after 6 h].
operation is a green, highly efficient, and cost effective
method than the existing procedures. We hope that our
method will be highly beneficial to both academic and
industrial processes, being a highly general one with
varied substituents in the aromatic aldehydes.
Thus, Dowex 50W catalyses both the steps; the for-
mation of the benzothiazoline ring and the formation of
benzothiazole from benzothiazoline. Carrying out the
reaction in argon (truly oxygen free) atmosphere, results
in the isolation of benzothiazolines (for 2-chloro and 4-
nitro benzaldehydes). Thus, the presence of the aerial
oxygen is essential for the benzylic oxidation (CAH to
CAOH) step, which is the penultimate one for benzo-
thiazole formation. Without Dowex 50W, the reaction
just initializes to 20% formation of the benzothiazoline
along with unreacted aldehyde, which then never pro-
ceeds further. Thus, Dowex 50W has a definitive cata-
lytic role toward benzothiazole formation. The reaction
is widely applicable to a variety of substrates; nitro,
methoxy, chloro, bromo, and hydroxy groups on the aryl
nucleus perform smooth reactions (Table 1). With ali-
phatic aldehydes, the reaction stops at the benzothiazo-
line stage (done with n-propanal and n-butanal, Table
2), probably because of lower stability of the resultant
benzothiazole (absence of conjugation with the aromatic
ring).
EXPERIMENTAL
A typical experimental procedure is as follows: A mixture
of 2-aminothiophenol (5 mmol), aromatic aldehyde (5 mmol),
and Dowex 50W (10 mol %) were stirred in water (4 mL) at
70ꢀC for the specified time period (Table 1), till the TLC
showed the absence of the starting aldehyde. The reaction mix-
ture was cooled, diluted with ethyl acetate (20 mL), filtered to
remove Dowex 50W and extracted the aqueous part with ethyl
acetate (2 ꢁ 20 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The crude products were purified by crystallization
from ethyl acetate and petroleum ether (60–80ꢀC) to afford the
2-aryl-benzothiazoles (or 2-aryl-benzothiazolines) in excellent
yields. All the products were characterized by their melting
points, IR, H NMR, and 13C NMR spectral analyses. The data
1
for a few selected compounds are given below:
2-(20-Methoxyphenyl)-benzothiazole. (Table 1, entry 3): IR
(KBr): 3435, 2932, 2372, 1586, 1458, 1427, 1286, 1246, 1013,
and 754 cmꢂ1; H NMR (CDCl3, 300 MHz) d: 8.51 (dd, J ¼
1
7.9 Hz and 1.7 Hz, 1H, C4-H), 8.07 (dt, J ¼ 7.8 Hz and 1.0
0
Hz, 1H, C7-H), 7.89 (dt, J ¼ 7.4 Hz and 0.6 Hz, 1H, C6 -H),
7.48–7.38 (m, 2H, C5-H and C6-H), 7.33 (dt, J ¼ 7.5 Hz and
0
0
1.1 Hz, 1H, C4 -H), 7.10 (dt, J ¼ 7.8 Hz and 1.1 Hz, 1H, C5 -
CONCLUSIONS
0
H), 7.02 (dd, J ¼ 8.0 Hz and 0.7 Hz, 1H, C3 -H), 4.00 (s, 3H,
OMe); 13C NMR (CDCl3, 75 MHz), d: 163.1, 157.2, 152.2,
136.1, 131.7, 129.5, 125.8, 124.5, 122.8, 122.3, 121.1, 121.1,
111.7, 55.7.
This procedure of the synthesis of 2-aryl-benzothia-
zoles by Dowex 50W in aqueous medium in one-pot
2-(40-Hydroxyphenyl)-benzothiazole. (Table 1, entry 7): IR
(KBr): 3436, 2366, 1601, 1479, 1308, 1256, 1171, 1025, 832,
and 760 cmꢂ1; H NMR (DMSO-d6, 300 MHz) d: 10.23 (brs,
1
1H, OH), 8.07 (brd, J ¼ 7.9 Hz, 1H, C4-H), 7.98 (brd, J ¼ 8.1
Scheme 3
Figure 1. Intramolecular six-membered H-bond formation in 2-
phenylbenzothiazoline.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

94
C. Mukhopadhyay and A. Datta
Vol 46
Table 3
Conversion of 2-arylbenzothiazolines to 2-arylbenzothiazoles under aerobic conditions (does not take place without oxygen).
R [4(i)]
(Scheme 3)
Time
(h)
Yield (%) (overall)
(w.r.t. starting aldehyde) (3)
Observed
mp (ꢀC)
Literature
[7b] mp (ꢀC)
Entry
1
2
3
s: 2-OH
n: 2-Cl
f: 4-NO2
25
10
05
s: 70
n: 85
f: 88
124–126
84–85
228–230
127–128
82
229–230
0
0
Hz, 1H. C7-H), 7.94 (d, J ¼ 8.6 Hz, 2H, C2 -H and C6 -H),
H), 7.00 (dt, J ¼ 6.4 Hz, and 1.3 Hz, 1H, C5-H), 6.81(dt, J ¼
6.4 Hz and 1.1 Hz, 1H, C6-H), 6.75 (dd, J ¼ 6.7 Hz and 0.8
Hz, 1H, C7-H), 6.43 (d, J ¼ 3.7 Hz, 1H, C2-H), 4.52 (s, 1H,
NH) ; 13C NMR (CDCl3, 75 MHz), d: 149.3, 147.9, 145.8,
127.2, 126.0, 125.9, 124.1, 121.8, 121.5, 110.5, 68.3.
7.50 (brt, J ¼ 7.1 Hz, 1H, C5-H), 7.40 (brt, J ¼ 7.6 Hz, 1H,
C6-H), 6.94 (d, J ¼ 8.6 Hz, 2H, C3 -H and C5 -H); 13C NMR
(DMSO-d6, 75 MHz), d: 167.9, 161.0, 154.2, 134.6, 129.5,
126.9, 125.4, 124.5, 122.8, 122.6, 116.6.
0
0
2-(20-Hydroxyphenyl)-benzothiazoline. (Table 2, entry 1):
2-(40-Nitrophenyl)-benzothiazole. (Table 3, entry 3): IR
IR(KBr): 3256, 1585, 1484, 1460, 1232, 755 cmꢂ1
;
1H NMR
(KBr): 3436, 2372, 1520, 1343, 852 and 764 cmꢂ1; H NMR,
1
0
0
0
(DMSO-d6, 300 MHz) d: 9.87 (s, 1H. OH), 7.39 (dd, J ¼ 7.6
CDCl3, 300 MHz) d: 8.43–8.35 (m, 4H, C3 -H, C5 -H, C2 -H
0
0
Hz and 1.5 Hz, 1H, C6 -H), 7.11 (dt, J ¼ 7.6 Hz and 1.2 Hz,
and C6 -H), 8.24 (dd, J ¼ 7.7 Hz and 1.0 Hz, 1H, C4-H), 8.16
0
1H, C4 -H), 6.94 (brd, J ¼ 7.3 Hz,1H, C7-H), 6.89–6.76 (m,
(dd, J ¼ 7.7 Hz and 0.9 Hz, 1H, C7-H), 7.63 (dt, J ¼ 6.0 Hz
and 1.3 Hz, 1H, C5-H), 7.55 (dt, J ¼ 6.9 Hz and 1.4 Hz, 1H,
C6-H ) ; 13C NMR (CDCl3, 75 MHz), d: 165.4, 154.0, 149.3,
138.8, 135.6 128.9, 127.6, 126.9, 125.1, 124.0, 123.1.
3H, C4-H, C5-H and C6-H), 6.67 (dd, J ¼ 7.8 Hz and 0.7 Hz,
0
0
1H, C3 -H), 6.57 (dt, J ¼ 7.5 Hz and 1.1 Hz, 1H, C5 -H), 6.48
(d, J ¼ 1.4 Hz, 1H, C2-H), [the absence of the NH proton
around d (4–4.5) indicates that it is H-bonded to the more
electronegative O-atom]; 13C NMR (DMSO-d6, 75 MHz), d:
154.0, 148.3, 130.1, 129.1, 126.4, 125.7, 125.6, 121.7, 119.3,
119.0, 115.4, 109.1, 63.5.
2-(n-Propyl)-benzothiazoline. (Table 2, entry 4): IR (KBr):
3355, 2958, 2930, 2872, 2360, 1583, 1468, 1402, 1119 and
741 cmꢂ1; H NMR (CDCl3, 300 MHz) d: 7.04 (dd, J ¼ 7.5
1
Hz and 1.2 Hz, 1H, C4-H), 6.88 (dt, J ¼ 6.0 Hz and 1.3 Hz,
1H, C5-H), 6.71 (dt, J ¼ 6.0 Hz and 1.2 Hz, 1H, C6-H), 6.61
(dd, J ¼ 6.0 Hz and 1.1 Hz, 1H, C7-H), 5.24 (t, J ¼ 6.6 Hz,
1H, C2-H), 1.87–1.77 (m, 2H, -CH2-CH2-CH3), 1.49–1.36 (m,
2H, -CH2-CH2-CH3), 0.94 (t, J ¼ 7.3 Hz, 3H, -CH3); 13C
NMR (CDCl3, 75 MHz), d: 146.6, 127.5, 125.0, 121.9, 120.7,
110.7, 68.5, 40.6, 19.3, 13.7.
2-(20-Hydroxyphenyl)-benzothiazole. (Table 3, entry 1): IR
(KBr): 3437, 2923, 2372, 1580, 1477, 1210, 742 cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) d: 12.52 (brs, 1H, OH), 8.00 (brd, J
¼ 8.1 Hz, 1H, C4-H), 7.91 (brd, J ¼ 7.7 Hz, 1H, C7-H), 7.71
0
(dd, J ¼ 7.9 Hz and 1.5 Hz, 1H, C6 -H), 7.51 (dt, J ¼ 7.2 Hz
and 1.2 Hz, 1H, C5-H), 7.40 (dt, J ¼ 7.4 Hz and 1.1 Hz, 2H,
0
0
C6-H and C4 -H), 7.11 (dd, J ¼ 8.4 Hz and 1.1 Hz, 1H, C3 -
H), 6.97 (dt, J ¼ 7.5 Hz and 1.0 Hz, 1H, C5 -H); 13C NMR
0
Acknowledgments. One of the authors (A.D.) thanks the Coun-
cil of Scientific and Industrial Research (New Delhi) for his fel-
lowship (J.R.F.). The authors also thank CAS Instrumentation
facility, University of Calcutta, for providing spectral data.
(CDCl3, 75 MHz), d: 169.4, 158.0, 151.9, 132.8, 132.6, 128.4,
126.7, 125.6, 122.2, 121.5, 119.5, 117.9, 116.8.
2-(20-Chlorophenyl)-benzothiazoline. (Table 2, entry 2):
IR(KBr): 3344, 3063, 2371, 1573, 1462, 1240, 1033 and 734
cmꢂ1
;
H NMR (CDCl3, 300 MHz) d: 7.77–7.71(m, 1H, C3 -
1
0
REFERENCES AND NOTES
0
0
H), 7.40–7.31(m, 1H, C4-H), 7.28–7.18 (m, 2H, C4 -H and C6 -
H), 7.04 (dd, J ¼ 7.5 Hz and 0.9 Hz, 1H, C7-H), 6.95 (dt, J ¼
9.0 Hz and 1.3 Hz, 1H, C5-H), 6.79–6.71 (m, 2H, C6-H and
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C5 -H), 6.66 (s, 1H, C2-H), 4.43 (brs, 1H, NH) ; 13C NMR
0
(CDCl3, 75 MHz), d: 146.1, 140.0, 131.6. 129.6, 129.3, 127.4,
127.3, 126.3, 125.5, 122.0, 121.1, 110.4, 65.6.
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1
(KBr): 3435, 2363, 1423, 1266, 1053 and 755 cmꢂ1; H NMR
0
(CDCl3, 300 MHz) d: 8.21–8.18 (m, 1H, C3 -H), 8.12 (dd, J ¼
9.0 Hz and 0.6 Hz, 1H, C4-H), 7.94 (dd, J ¼ 7.8 Hz and 0.6
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0
Hz, 1H, C7-H), 7.54–7.49 (m, 2H, C4 -H and C6 -H), 7.44–7.38
0
(m, 3H, C5-H, C6-H and C5 -H); 13C NMR (CDCl3, 75 MHz),
d: 164.2, 152.5, 136.1, 132.7, 132.3, 131.7, 131.1, 130.8,
127.1, 126.3, 125.4, 123.5 and 121.4.
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2-(40-Nitrophenyl)-benzothiazoline. (Table 2, entry 3): IR
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;
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NMR (CDCl3, 300 MHz) d: 8.22 (dt, J ¼ 8.8 Hz and 1.9 Hz,
0
0
2H, C3 -H and C5 -H), 7.68 (dt, J ¼ 8.5 Hz and 2.3 Hz, 2H,
0
0
C2 -H and C6 -H), 7.06 (dd, J ¼ 6.5 Hz and 1.0 Hz, 1H, C4-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Water-Promoted Dowex 50W Catalyzed Highly Efficient Green Protocol for
2-Arylbenzothiazole Formation
95
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