Improved synthesis of 2-(3H)benzothiazolethiones under microwave irradiation

Article abstract of DOI:10.1080/00397910601038665

2-(3H)Benzothiazolethiones (2-mercaptobenzothiazole) are prepared by an improved method, which utilizes microwave-assisted cyclization of the corresponding ortho-haloanlines with potassium O-ethyl dithiocarbonate. By using microwave irradiation, the relative reactivity of 2-chloroanilines was greatly improved to the same level as that of 2-fluoroanilines and 2-bromoanilines. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038665

This article was downloaded by: [University of Waikato]
On: 13 July 2014, At: 05:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Improved Synthesis of
2‐(3H)Benzothiazolethiones under Microwave
Irradiation
a
a
a
a
Wei Huang , Ying Tan , Ming‐Wu Ding & Guang‐Fu Yang
a
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education ,
College of Chemistry, Central China Normal University , Wuhan, China
Published online: 06 Feb 2007.
To cite this article: Wei Huang , Ying Tan , Ming‐Wu Ding & Guang‐Fu Yang (2007) Improved Synthesis of
2‐(3H)Benzothiazolethiones under Microwave Irradiation, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:3, 369-376, DOI: 10.1080/00397910601038665
To link to this article: http://dx.doi.org/10.1080/00397910601038665
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
Synthetic Communications , 37: 369–376, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038665
Improved Synthesis of
-(3H)Benzothiazolethiones under
Microwave Irradiation
2
Wei Huang, Ying Tan, Ming-Wu Ding, and Guang-Fu Yang
Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, College of Chemistry, Central China Normal University,
Wuhan, China
Abstract: 2-(3H)Benzothiazolethiones (2-mercaptobenzothiazole) are prepared by an
improved method, which utilizes microwave-assisted cyclization of the corresponding
ortho-haloanlines with potassium O-ethyl dithiocarbonate. By using microwave
irradiation, the relative reactivity of 2-chloroanilines was greatly improved to the
same level as that of 2-fluoroanilines and 2-bromoanilines.
Keywords: 2-mercaptobenzothiazole, microwave irradiation, ortho-haloanline,
potassium O-ethyl dithiocarbonate
2-Substituted benzothiazoles are an important class of compounds in
medicinal and organic chemistry. The benzothiazoyl moiety is a structural
[1]
element of compounds with a wide range of biological activities. For
example, 2-(4-aminophenyl)benzothiazoles exhibit nanomolar inhibitory
activity against a range of human breast, ovarian, colon, and renal cell lines
[
2]
in vitro. In addition, the benzothiazole nucleus is a key element in some
thermally stable rigid-rod polymers, possessing high tensile strength and
[
3]
modulus.
Although numerous synthetic methods are available for construction of
the benzothiazole ring, facile and scalable routes to highly versatile benzothia-
[4]
zole building blocks, such as 2-mercaptobenzothiazole, are still lacking.
Received April 20, 2006
Address correspondence to Guang-Fu Yang, Key Laboratory of Pesticide and
Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, China. E-mail: gfyang@mail.ccnu.edu.cn
3
69

3
70
W. Huang et al.
[
4a]
Recently, Zhu
2
and his coworkers reported a new method for synthesis of
-mercaptobenzothiazole via nucleophilic aromatic substitution reaction of
ortho-haloanilines with potassium/sodium O-ethyl dithiocarbonate with
good yields. However, the yields of 2-mercaptobenzothiazole were not
satisfied when ortho-chloroanlines rather than ortho-fluoroanlines (ortho-
fluoroanlines are much expensive than ortho-chloroanlines) were used as
substrate. In addition, the reaction time is very long (always from 1 to
2
0 h), and it is difficult to isolate and purify the products.
In recent decades, microwave irradiation has emerged as a powerful
[5]
technique for promoting a variety of chemical reactions.
The main
benefits of performing reactions under microwave-irradiation conditions are
significant rate enhancements and higher product yields. The methods for
the synthesis of benzothiazoles under microwave irradiation conditions have
[
6]
also been reported as follows: a condensation of orthoesters with ortho-
[
6a]
aminothiophenol using montmorillonite (KSF) clay,
aromatic aldehydes with ortho-aminothiophenol using Ca(OCl) /Al O or
benzaldoximes or
2
2 3
[
6b]
MnO /SiO ,
using p-toluenesulfonic acid,
nothiophenol in an ionic liquid.
b-chlorocinnamaldehydes with ortho-aminothiophenol
[
2
2
6c]
and aromatic aldehydes with ortho-ami-
6d]
However, so far no report is available
[
about the synthesis of 2-mercaptobenzothiazole under microwave-irradiation
conditions. As part of an ongoing program in our laboratory to rapidly syn-
thesize a variety of heterocylic coMpounds under mild conditions, we herein
report the first exaMple of synthesizing 2-mercaptobenzothiazole via
microwave-assisted cyclization of the corresponding ortho-haloanlines and
potassium O-ethyl dithiocarbonate.
We initially examined the model reaction of 2,6-dichloro-4-trifluoromethyl-
aniline with potassium O-ethyl dithiocarbonate in N,N-dimethylformamide
(
(
DMF) under various conditions to optimize the reaction condition
Scheme 1). Microwave reactions were performed in sealed heavy-walled
w
Pyrex tubes under controlled conditions in a safe and reproducible manner.
Single-mode microwave irradiation was used at a fixed temperature, pressure,
and irradiation power during the reaction time by automatic power control.
The optimization results are summarized in Table 1. As shown in Table 1,
raising the reaction temperature from 90 to 1208C for the same irradiation
time of 20 min improved the yield of 2-mercapto- benzothiazole remarkably,
Scheme 1.

2-(3H)Benzothiazolethiones
371
Table 1. Optimization for the reaction of 2,6-dichloro-4-trifluoromethyl-aniline with
potassium O-ethyl dithiocarbonate
No.
1a/2
Temp. (8C)
Time (min)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1/2.2
1/2.2
1/2.2
1/2.2
1/2.2
1/2.2
1/2.2
1/2.2
1/2.2
1/2.0
1/2.4
90
100
110
120
130
140
120
120
120
120
120
20
20
20
20
20
20
25
15
12
15
15
45
52
68
87
84
82
84
87
73
77
84
1
1
0
1
from 45% to 87%. On further increase of the temperature above 1208C, the yield
was reduced. For the reaction at 1208C, varying the reaction time from 15 to
2
0 min did not affect the yield, but further reducing the reaction time to
2 min led to a considerable decrease in yields. Moreover, further optimization
1
of the stoichiometric ratio of the reactant indicated that 2.2 equiv of potassium
O-ethyl dithiocarbonate gave the best results. Thus, the optimal conditions in
DMF solution for the synthesis of 2-mercaptobenzothiazole are 1208C,
1
5 min, and 2.2 equiv of potassium O-ethyl dithiocarbonate.
These conditions were extended to the synthesis of other 2-mercaptoben-
zothiazole bearing various substituents (Scheme 2). The microwave-assisted
results are shown in Table 2, which also shows the results of control exper-
iments in which the reactions were carried out under conventional heating.
It has been reported that the relative reactivity of 2-chloroanilines was
[4b]
much lower than that of 2-fluoroanilines and 2-bromoanilines. Under tra-
ditional conditions, we got similar results, and the reaction of 2-chloroanilines
always gave no or very low yields (,50%) of product within 2–4 h, whereas
2-fluoroanilines and 2-bromoanilines afforded high yields (.85%) of
products within the same reaction time. It should take a much longer time
(12–24 h) to complete the reaction for 2-chloroanilines and 2-bromoanilines
Scheme 2.

3
72
W. Huang et al.
Table 2. Results of synthesis of 2-mercaptobenzothizaoles
Microwave
irradiation
Traditional heating
Time
(min)
Isolated
yield (%)
Time
a
(h)
Isolated
yield (%)
a
No.
R
X
1
2
3
4
5
6
7
8
9
4-CF , 6-Cl
3
Cl
Cl
Cl
Cl
Br
Br
F
15
15
12
10
10
12
8
87(3a)
90(3b)
93(3c)
85(3d)
92(3e)
92(3f)
98(3g)
95(3h)
99(3i)
99(3j)
81(3k)
18
24
12
18
12
14
2
64(3a)
80(3b)
78(3c)
72(3d)
82(3e)
85(3f)
96(3g)
95(3h)
98(3i)
93(3j)
58(3k)
4-Cl
5-Cl
6-Cl
4-NO
4-F
2
6-F
5-F
F
8
4
3,4-F
4-Br
2
F
8
3
1
1
0
1
F
Cl
10
15
4
24
5-OMe
a
Monitored by TLC.
under conventional conditions than for 2-fluoroanilines (2–4 h). However,
compared to the reaction time of 2–24 h for the conventional heating
technique, it took only 8–15 min to complete the reaction under microwave
irradiation. Furthermore, as shown in Table 2, the same level of yields
under microwave irradiation was obtained for 2-chloroanilines, 2-fluoroani-
lines, and 2-bromoanilines. Remarkably, in the case where ortho-haloaniline
was deactivated by the strong donating group OMe, the reaction occurred
smoothly to afford the product in 81% under microwave-irradiation conditions
corresponding to 58% under conventional heating. Thus, by using microwave
irradiation, various 2-haloanilines reacted with 2.2 equiv of potassium O-ethyl
dithiocarbonate at 1208C for 8–15 min to afford the 2-mercaptobenzothia-
zoles in excellent to quantitative yields, which provided an efficient
synthesis of 2-mercaptobenzothiazoles under mild conditions.
In conclusion, we have presented the first report of a rapid and efficient
synthesis 2-(3H)benzothiazolethiones (2-mercaptobenzothiazole) via micro-
wave-assisted cyclization of the corresponding ortho-haloanlines and
potassium O-ethyl dithiocarbonate. By using microwave irradiation, the
relative reactivity of 2-chloroanilines was greatly improved to the same
level as that of 2-fluoroanilines and 2-bromoanilines. The combination of
good to excellent yields, shorter reaction time (8–15 min), readily available
starting material, and simple purification procedure makes this a highly
efficient protocol for the preparation of 2-mercaptobenzothiazole derivatives.
Moreover, this protocol outperforms other currently available methods for the
synthesis of 2-mercaptobenzothiazole.

2-(3H)Benzothiazolethiones
373
EXPERIMENTAL
Melting points are uncorrected. Mass spectroscopy was measured on a
Finnigan Trace MS spectrometer. NMR was recorded in d-DMSO or CDCl3
on a Varian Mercury 400 spectrometer and resonance are given in parts
pere million (d) relative to TMS. Elementary analyses were performed on a
Vario EL III elementary analysis instrument. Microwave-irradiation
reactions were carried out on a Smith synthesizerTM instrument.
General Procedures for Microwave-Assisted Preparation
of 2-Mercaptobenzothiazole
4
-Chloro-6-trifluoromethyl-2-mercaptobenzothiazole is an example) In a
microwave tube, potassium O-ethyl dithiocarbonate (0.35 g, 2.2 mmol) was
added to a solution of 2,6-dichloro-4-trifluoromethyl-anline 1a (0.23 g,
1
microwave tube was placed in a Smithsynthesizer
mmol) in 3 mL of N,N-dimethylformamide (DMF). Then, the sealed
TM
and irradiated at
1208C for 15 min. The reaction mixture was cooled, diluted with 10 mL
of ice water, and acidified with 3 mL of HCl solution (1 mol/L).
Solid products were filtrated and recrystallized from CHCl /petroleum ether
3
(30–608C) to afford 4-chloro-6-trifluoromethyl-2-benzothiazolethione 3a.
General Procedures for Preparation of 2-Mercaptobenzothiazole
under Conventional Heating
4
-Chloro-6-trifluoromethyl-2-mercaptobenzothiazole is an example. Potassium
O-ethyl dithiocarbonate (0.35 g, 2.2 mmol) was added to a solution of
,6-dichloro-4-trifluoromethylanline 1a (0.23 g, 1 mmol) in 3 mL of DMF.
2
The resulting solution was heated at 1208C in an oil bath for 18 h. The
reaction mixture was cooled, diluted with 10 mL of ice water, and acidified
with 3 mL of HCl solution (1 mol/L). Solid products were isolated by
filtration and recrystallized from CHCl /petroleum ether (30–608C) to afford
3
4
-chloro-6-trifluoromethyl-2-benzothiazolethione 3a.
4
-Chloro-6-trifluoromethyl-2-mercaptobenzothiazole (3a)
1
Mp 216–2188C. H NMR (DMSO-d ): d ¼ 14.22 (s, 1H), 8.16 (s, 1H), 7.88
6
þ
(
s, 1H). ESI-MS: m/z (M þ H ) ¼ 269. Anal. calcd. for C H ClF NS : C,
8
3
3
2
3
5.63; H, 1.12; N, 5.19. Found: C, 35.42; H, 1.05; N, 5.06.

3
74
W. Huang et al.
[4a,4b]
6-Chloro-2-mercaptobenzothiazole (3b)
1
Mp 245–2478C. H NMR (DMSO-d ): d ¼ 13.90 (s, 1H), 7.87 (s, 1H), 7.43
6
þ
(d, J ¼ 8.8, 1H), 7.28 (d, J ¼ 8.8, 1H). ESI-MS: m/z (M þ H ) ¼ 201. Anal.
calcd. for C H ClNS : C, 41.68; H, 2.00; N, 6.94. Found: C, 41.52; H, 2.05; N,
7
4
2
6
.86.
5
-Chloro-2-mercaptobenzothiazole (3c)
1
Mp 195–1978C.
H
NMR (DMSO-d6): d ¼ 13.85 (s, 1H), 7.72
(
d, J ¼ 8.8 Hz, 1H), 7.34 (d, J ¼ 8.8, 1H), 7.29 (s, 1H). ESI-MS: m/z
þ
(
Found: C, 41.45; H, 1.92; N, 6.79.
MH ) ¼ 201. Anal. calcd. for C H ClNS : C, 41.68; H, 2.00; N, 6.94.
7
4
2
4-Chloro-2-mercaptobenzothiazole (3d)
1
Mp 209–2108C. H NMR (CDCl ): d ¼ 10.14 (s, 1H), 7.36 (d, J ¼ 2.8 Hz,
3
1
H), 7.34 (d, J ¼ 2.8, 1H), 7.23 (t, J ¼ 8.0 Hz, 1H). ESI-MS: m/z
þ
(
Found: C, 41.55; H, 1.94; N, 6.89.
MH ) ¼ 201. Anal. calcd. for C H ClNS : C, 41.68; H, 2.00; N, 6.94.
7
4
2
6-Nitro-2-mercaptobenzothiazole (3e)
1
Mp 249–2518C. H NMR (DMSO-d ): d ¼ 14.26 (s, 1H), 8.73 (s, 1H), 8.27
6
þ
(
calcd. for C H N O S : C, 39.61; H, 1.90; N, 13.20. Found: C, 39.45; H,
d, J ¼ 8.8, 1H), 7.43 (d, J ¼ 8.8, 1H). ESI-MS: m/z (MH ) ¼ 212. Anal.
7
4 2 2 2
2
.01; N, 13.06.
[4a]
6
-Fluoro-2-mercaptobenzothiazole (3f)
1
Mp 225–2278C. H NMR (CDCl ): d ¼ 10.99 (s, 1H), 7.19–7.24
3
þ
(
calcd. for C H FNS : C, 45.39; H, 2.18; N, 7.56. Found: C, 45.22; H, 2.05;
m, 2H), 7.10 (d, J ¼ 8.8 Hz, 1H). ESI-MS: m/z (MH ) ¼ 186. Anal.
7
4
2
N, 7.36.
4
-Fluoro-2-mercaptobenzothiazole (3g)
1
Mp 187–1888C.
H
NMR (CDCl ):d ¼ 10.75 (s, 1H), 7.20–7.25
3
þ
(m, 2H), 7.10 (t, J ¼ 7.2, 1H). ESI-MS: m/z (MH ) ¼ 186. Anal. calcd. for
C H FNS : C, 45.39; H, 2.18; N, 7.56. Found: C, 45.26; H, 2.09; N, 7.35.
7
4
2

2-(3H)Benzothiazolethiones
375
[4b]
5
-Fluoro-2-mercaptobenzothiazole (3h)
1
Mp 189–1918C. H NMR (DMSO d ): d ¼ 13.86 (s, 1H), 7.74 (d, J ¼ 8.0,
6
1
H), 7.20 (t, J ¼ 9.2, 1H), 7.09 (d, J ¼ 8.8, 1H). ESI-MS m/z
þ
(
MH ) ¼ 186. Anal. calcd. for C H FNS : C, 45.39; H, 2.18; N, 7.56.
7
4
2
Found: C, 45.34; H, 2.01; N, 7.39.
[4b]
6
,7-Difluoro-2-mercaptobenzothiazole (3i)
1
Mp 192–1938C. H NMR (DMSO-d6): d ¼ 14.09 (s, 1H), 7.44 (m, 1H), 7.04
þ
(
m, 1H). ESI-MS: m/z (MH ) ¼ 204. Anal. calcd. For C H F NS : C, 41.37;
7
3
2
2
H, 1.49; N, 6.89. Found: C, 41.19; H, 1.40; N, 6.73.
[4a]
6
-Bromo-2-mercaptobenzothiazole (3j)
1
Mp 260–2638C. H NMR (DMSO-d ): d ¼13.86 (s, 1H), 7.98 (s, 1H), 7.56
6
þ
(
d, J ¼ 8.8 Hz, 1H), 7.23 (d, J ¼ 8.0 Hz, 1H). ESI-MS: m/z (MH ) ¼ 245.
Anal. calcd. for C H BrNS : C, 34.16; H, 1.64; N, 5.69. Found: C, 34.00;
7
4
2
H, 1.51; N, 5.48.
5
-Methoxy-2-mercaptobenzothiazole (3k)
1
Mp 190–1928C. H NMR (DMSO-d ): d ¼ 13.64 (s, 1H), 7.57 (d, J ¼ 8.8 Hz,
6
þ
1H), 6.93 (d, J ¼ 8.8, 1H), 6.82 (s, 1H). ESI-MS: m/z (MH ) ¼ 197. Anal.
calcd. for C H NOS : C, 48.71; H, 3.58; N, 7.10. Found: C, 48.51; H, 3.48;
8
7
2
N, 7.02.
ACKNOWLEDGMENTS
The present work was supported by National Natural Science Foundation of
China (No. 20572030, 20432010, and 20476036), Key Project of Chinese
Ministry Education (Nos. 104205 and 103116), Program for Excellent
Research Group of Hubei Province (No. 2004ABC002), and Program for
New Century Excellent Talents in the University of China.
REFERENCES
1. (a) Chua, M.; Shi, D.; Wrigley, S.; Bradshaw, T. D.; Hutchinson, I.; Shaw, P. N.;
Barrett, D. A.; Stanley, L. A.; Stevens, M. F. G. J. Med. Chem. 1999, 42, 381;
(
b) Hutchinson, I. N.; Chua, M. E.; Browne, H. L.; Trapani, V.;

3
76
W. Huang et al.
Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2001, 44,
1
446; (c) Hutchinson, I.; Jennings, S. A.; Vishnuvajjala, B. R.; Westwell, A. D.;
Stevens, M. F. G. J. Med. Chem. 2002, 45, 744; (d) Mortimer, C. G.; Wells, G.;
Crochard, J.; Stone, E. L.; Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D.
J. Med. Chem. 2006, 49, 179.
2
. Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schultz, R. J.; Paull, K. D.;
Stevens, M. F.G. Br. J. Cancer 1998, 77, 745.
3
4
. Wang, S.; Bao, G.; Lu, Z.; Wu, P.; Han, Z. J. Mater. Sci. 2000, 35, 5873.
. (a) Zhu, L.; Zhang, M. B.; Dai, M. J. Heterocycl. Chem. 2005, 42, 727; (b) Zhu, L.;
Zhang, M. B. J. Org. Chem. 2004, 69, 7371; (c) Chaudhuri, N. C. Synth. Commun.
1996, 26, 3783; (d) Singh, B.; Pennock, P. O.; Lesher, G. Y.; Bacon, E. R.;
Page, D. F. Heterocycles 1993, 36, 133.
5
. (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250–6284; (b) Lead
Beater, N. E.; Torenius, H. M.; Tye, H. Comb. Chem. High Through. Screen.
2
004, 7, 511–528; (c) Wu, C. Y.; Sun, C. M. Synlett 2002, 17, 1709–1711;
(
(
(
d) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org. Lett. 2003, 5, 1205–1208;
e) Chang, W. J.; Yeh, W. B.; Sun, C. M. Synlett 2003, 18, 1688–1692;
f) Lin, M. J.; Sun, C. M. Synlett 2004, 18, 663–666; (g) Lee, M. J.; Sun, C. M.
Tetrahedron Lett. 2004, 45, 437–440; (h) Tung, C. L.; Sun, C. M. Tetrahedron
Lett. 2004, 45, 1159–1162; (i) Nuchter, M.; Ondruschka, B.; Bonrath, W.;
Gum, A. Green Chem. 2004, 6, 128–141.
6
. (a) Villemin, D.; Hammadi, M.; Martin, B. Synth. Commun. 1996, 26, 2895;
(b) Bougrin, K.; Loupy, A.; Soufiaoui, M. Tetrahedron 1998, 54, 8055;
(c) Poul, S.; Gupta, M.; Gupta, R. Synth. Commun. 2002, 32, 3541;
(d) Rann, B. C.; Jana, R.; Dey, S. S. Chem. Lett. 2004, 33, 274.