A robust one-pot synthesis of benzothiazoles from carboxylic acids including examples with hydroxyl and amino substituents

Article abstract of DOI:10.1016/j.tetlet.2012.10.035

The cyclocondensation of 2-aminothiophenol and carboxylic acids to give benzothiazoles has been carried out under mild conditions using tetrabutylammonium bromide (TBAB) as the reaction medium and triphenyl phosphite as the catalyst. Shorter reaction times, rapid isolation of the products, and excellent yields are advantages of this method. The reaction is found to be general and quite tolerant to the nature of the substituted carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2012.10.035

Tetrahedron Letters 53 (2012) 6950–6953
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Tetrahedron Letters
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A robust one-pot synthesis of benzothiazoles from carboxylic acids
including examples with hydroxyl and amino substituents
Soraia Meghdadi a, , Mehdi Amirnasr b, , Peter C. Ford b
⇑
⇑
,
a Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111, Iran
b Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2012
Revised 16 September 2012
Accepted 9 October 2012
Available online 16 October 2012
The cyclocondensation of 2-aminothiophenol and carboxylic acids to give benzothiazoles has been
carried out under mild conditions using tetrabutylammonium bromide (TBAB) as the reaction medium
and triphenyl phosphite as the catalyst. Shorter reaction times, rapid isolation of the products, and excel-
lent yields are advantages of this method. The reaction is found to be general and quite tolerant to the
nature of the substituted carboxylic acids.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzothiazole
Substituted carboxylic acid
2-Aminothiophenol
Ionic liquid
Triphenyl phosphite
Step economy is an important goal of simple, efficient, and pro-
tecting group free syntheses of organic compounds using readily
available reagents. Unnecessary steps can be avoided if a reaction
sequence is designed that does not need sequential separation
and purification processes. Functionality tolerance, mild reaction
conditions, short reaction times, economy, and simple work-up
leading to the isolation of pure products are other key factors that
must be taken into account. In line with these considerations we
have focused on the development of a new method for the synthe-
sis of 2-substituted benzothiazoles from substituted aromatic
carboxylic acids under convenient reaction conditions.
2-Substituted benzothiazoles have attracted considerable inter-
est due to their diverse biological and pharmaceutical properties
such as antitumor,1 antifungal,2 anti-inflammatory,3 antimicro-
bial,4 antiviral,5 and enzyme inhibitory activity.6 Recently,
radiolabeling of some derivatives of benzothiazoles has been
developed for PET imaging in the diagnosis of Alzheimer’s disease.7
The increasing application of metal complexes of 2-(2-hydroxy-
phenyl)benzothiazolate (BTZ), which is an N,O-donor chelating
ligand capable of forming multifunctional complexes in optoelec-
tronics, and utilized for the synthesis of fluorogenic enzyme sub-
strates, and fluorescent materials is well recognized.8–10
A range of methods is currently available for the synthesis of 2-
substituted benzothiazoles including condensation-dehydration of
2-aminothiophenol with carboxylic acids,11 aldehydes, alcohols,12
and by cyclization of thiobenzamides.13 While the reported
methodologies are generally efficient, most require long reaction
times, harsh reaction conditions including the use of corrosive
acids (e.g., polyphosphoric acid, PPA) and heating in high boiling
point solvents, and are associated with the generation of hazardous
wastes, low functional group tolerance, and tedious work-up
procedures.
We became aware of an earlier study11c that used ionic liquids
for the synthesis of substituted benzothiazoles from carboxylic
acids. However, the present studies use a simpler and less
expensive ionic liquid and describe the preparation of hydroxyl
and amino substituted benzothiazoles under mild and protecting
group free conditions. Even in recent applications of these com-
pounds harsh reaction conditions (PPA) were used for their
synthesis.14–16 Hence, there is a significant interest in developing
more efficient, convenient, and environmentally benign methods
that support different substitution patterns in the desired
products.
In continuation of our studies on the development of synthetic
methodologies,17 we report an efficient and straightforward proce-
dure for the synthesis of 2-arylbenzothiazoles from 2-aminothio-
phenol and a variety of substituted carboxylic acids under benign
and metal-free conditions using triphenyl phosphite in the simple
ionic liquid, tetrabutylammonium bromide (TBAB) (Scheme 1).
The key step in the synthesis involved the reaction of substi-
tuted aromatic carboxylic acids with 2-aminothiophenol. Acids
⇑
Corresponding authors. Tel.: +98 311 391 3282; fax: +98 311 391 2350 (S.M.);
tel.: +98 311 391 3264; fax: +98 311 391 2350 (M.A.).
E-mail addresses: smeghdad@cc.iut.ac.ir (S. Meghdadi), amirnasr@cc.iut.ac.ir
(M. Amirnasr).
On sabbatical leave from Isfahan University of Technology, Isfahan 84156-83111,
Iran.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.035

S. Meghdadi et al. / Tetrahedron Letters 53 (2012) 6950–6953
6951
Table 1
Synthesis of various 2-substituted benzothiazoles
R = heteroaryl, substituted aryl (-OH, -NH2, -halide, -CN,-NO2).
Entry Product
Time (min) Yield (%)
Scheme 1. Formation of 2-substituted benzothiazoles from carboxylic acids.
containing both electron-donating [e.g., OH, NH2, N(CH3)2] and
electron-withdrawing groups (e.g., CN, NO2) were successfully
employed to prepare the corresponding benzothiazoles. These sub-
stituents had little effect on the product yields, the highest being
obtained for quinaldic acid.
1
1
2
3
15
60
60
87
70
82
2
3
The synthesis was accomplished using a mixture of substituted
aryl carboxylic acid and 2-aminothiophenol with triphenyl phos-
phite in the presence of the inexpensive ionic liquid, tetrabutylam-
monium bromide (TBAB) at 120 °C. The resulting viscous slurry
was treated with methanol and the remaining solid filtered and
washed with cold methanol and dried in vacuo.18 This simple
work-up procedure gave pure benzothiazole products without
the need for further purification by column chromatography, apart
from one case in which the product 12 was recrystallized.19 The
reaction time was in the range of 15–60 min, and the isolated prod-
uct yields in the majority of cases were >65% (Table 1). Detailed
synthetic procedures, spectroscopic (1H NMR, MS, and FTIR)
characterization data, and elemental analysis (CHN) data are pro-
vided in Supplementary data (SI). Similar results were obtained
using bis-(2-aminophenyl) disulfide instead of 2-aminothiophenol,
however, the latter is much less expensive and its use is more
economical.
In comparison, the synthesis of a benzothiazole from pyridine
carboxylic acid using more stringent reaction conditions, (i.e., heat-
ing in the presence of PPA at 160 °C for 4 h), has been reported, giv-
ing the product benzothiazole in only 31% yield. 20 In contrast, this
product was obtained in 1 h, at 120 °C and in 70% yield using the
method reported here (Table 1, entry 2). A further notable feature
of this method is the ability to synthesize phenolic and 2-amino-
phenyl benzothiazoles without the need for protecting groups.
Furthermore, aromatic carboxylic acids bearing various functional-
ities such as chloro, iodo, amino, and nitro tolerated the reaction
and provided moderate to high yields of the corresponding
benzothiazoles.
4
4
15
65
5
6
7
5
6
7
15
15
60
86
85
66
8
8
9
15
60
86
72
61
9
To the best of our knowledge, no synthetic procedure has been
reported for 2-(2-aminonaphthyl)benzothiazole (Table 1, entry 11,
67%). The synthesis of 2-(2-amino-5-chlorophenyl)benzo-thiazole,
(Table 1, entry 10, 61%), has also been reported previously in 13%
yield, via two successive steps from 2-nitro-5-chlorobenzalde
hyde.21
10
10 30
The application of 2-(2-aminophenyl)benzothiazole derivatives
as fluorogenic substrates for the detection of enzyme activity in
clinically important bacteria has been reported.22 The present
synthetic method opens a new avenue to the convenient synthesis
of these compounds and the two 2-amino derivatives (Table 1, en-
tries 10 and 11) merit consideration for similar applications.
This new methodology was also successfully utilized for the
one-step synthesis of 2-(2-hydroxy-5-chlorophenyl)benzo-thia-
zole from 5-chlorosalicylic acid in high yield (Table 1, entry 5,
86%), the synthesis of which has been reported previously by a
lengthy and complicated procedure in 46% yield.23 Similarly, the
synthesis of 2-(2-hydroxy-5-iodophenyl)benzothiazole (6) via
iodination of 2-(2-hydroxyphenyl)benzothiazole in 61% yield has
been reported.24 There is no report on the synthesis of 6 from 2-
aminothiophenol and iodine-substituted aldehydes or acids.
11
11 30
67
12
13
14
12 60
13 15
14 60
60
60
70

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S. Meghdadi et al. / Tetrahedron Letters 53 (2012) 6950–6953
Scheme 2. Proposed reaction mechanism.
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However, this compound was prepared in high yield (Table 1, entry
6, 85%) using the method described here. It is worth noting that
iodinated derivatives of aromatic compounds are used extensively
as imaging agents in non-invasive medical diagnostic techniques.24
It is well known that amines can react with carboxylic acids to
give amides. The formation of amides has also been documented in
our previous work on the synthesis of related compounds.17 The
thiol group could attack the CO of intermediate 15 to give, after
intramolecular cyclization, the title products. The mechanism as
shown in Scheme 2 is assumed to be operative.
In summary, we have developed a novel and simple protocol for
the synthesis of substituted benzothiazoles from o-aminothiophe-
nol and substituted carboxylic acids. This method features mild
reaction conditions, short reaction times (<60 min), high efficiency,
good functional group tolerance, and a simple work-up without the
need for column chromatographic purification. By using carboxylic
acids as the starting materials, we have eliminated the need for the
toxic oxidants which are necessary for the reaction to proceed
when alcohols or aldehydes are used. Moreover, the reaction uses
readily available starting materials and is applicable for the syn-
thesis of a wide range of substituted 2-phenylbenzothiazoles.
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Acknowledgments
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Partial support of this work by the Isfahan University of Tech-
nology Research Council is gratefully acknowledged. Also acknowl-
edged is partial support from the U.S. National Science Foundation,
Grant NSF-CHE-0749524 to P. C. F.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
035. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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18. Typical procedure for the synthesis of 2-arylbenzothiazoles: A mixture of 1.55 g
(5 mmol) of triphenyl phosphite (TPP), 1.66–2.25 g (5–7 mmol) of
tetrabutylammonium
bromide
(TBAB),
0.625 g
(5 mmol)
of
2-
aminothiophenol, and the corresponding substituted benzoic acid (5 mmol)
in a 25 mL round bottomed flask was placed in an oil bath. The solution was
stirred (15–60 min depending on the acid used) at 120 °C. The product
precipitated from the viscous solution by adding MeOH, and the resulting solid
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S. Meghdadi et al. / Tetrahedron Letters 53 (2012) 6950–6953
6953
was filtered off and washed with cold MeOH to give the desired benzothiazole.
This procedure was followed for the synthesis of all the products listed in Table
solid product was filtered off and then dispersed in 500 ml of water. After
stirring for 15 min, pure 11 was filtered off and dried under vacuum. In the case
of compound 12, the resulting white solid was filtered off and then
recrystallized from ethanol to give pure 12.
1
with minor modification for compounds 10, 11, and 12 (see Ref. 19)
(Supplementary data). Details of the analytical data for compound 6 (Table 1,
entry 6): mp 168–170 °C; 1H NMR (400 MHz, CDCl3) d: 12.61 (s, 1H, OH), 8.02
(dd, J = 7.6, 1.2 Hz, 1H), 7.9 (d, J = 2 Hz, 1H), 7.95 (dd, J = 8, 1.2 Hz, 1H), 7.64 (dd,
J = 8.8, 2 Hz, 1H), 7.55 (td, J = 8, 1.2 Hz, 1H), 7.47 (td, J = 7.6, 1.2 Hz, 1H), 6.92 (d,
20. Gao, L.-H.; Guan, M.; Wang, K.-Z.; Jin, L.-P.; Huang, C.-H. Eur. J. Inorg. Chem.
2006, 3731–3737.
21. Fabrega, O.; James, A.; Salwatura, V. L.; Orenga, S.; Stanforth, S.P. PCT Int. WO
152306 A2, 2008; Chem. Abstr. 2008, 150, 50003.
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D.; Salwatura, V. L.; Stanforth, S. P. Bioorg. Med. Chem. 2011, 19, 2903–
2910.
J = 8.8 Hz, 1H); IR: 2769, 1615, 1571, 1478, 1437, 1373, 1301, 1268, 1207 cmÀ1
.
EI-MS: m/z calcd for C13H8INOS (M+) 353.18, found 353.0. Elemental analysis:
calcd for C13H8INOS (353.18) C, 44.21; H, 2.28, N, 3.97; found: C, 44.24; H, 2.10;
N, 3.89.
19. The following three compounds were synthesized by the typical procedure
described in Ref. 18. The pure product 10 was precipitated by addition of a
mixture of acetone–water to the final viscous solution. Precipitation of product
11 was carried out by adding a mixture of methanol–water (1:1). The yellow
23. Pla-Dalmau, A. J. Org. Chem. 1995, 60, 5468–5473.
24. Rodriguez-Rodriguez, C.; Sánchez de Groot, N.; Rimola, A.; Álvarez-Larena, Á.;
Lloveras, V.; Vidal-Gancedo, J.; Ventura, S.; Vendrell, J.; Sodupe, M.; González-
Duarte, P. J. Am. Chem. Soc. 2009, 131, 1436–1451.