One-pot approach for the synthesis of 2-aryl benzothiazoles via a two-component coupling of gem-dibromomethylarenes and o-aminothiophenols

Article abstract of DOI:10.1016/j.tetlet.2011.08.055

One-pot synthesis of 2-aryl benzothiazoles from gem-dibromomethylarenes using 2-aminoarylthiols is described. Benzothiazoles were obtained in high chemical yields under mild conditions. This transformation would facilitate synthesis by short reaction times, large-scale synthesis, easy and quick isolation of the products, which are the main advantages of this procedure.

Full text of DOI:10.1016/j.tetlet.2011.08.055

Tetrahedron Letters 52 (2011) 5474–5477
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Tetrahedron Letters
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One-pot approach for the synthesis of 2-aryl benzothiazoles
via a two-component coupling of gem-dibromomethylarenes
and o-aminothiophenols
⇑
Chandrappa Siddappa, Vinaya Kambappa, Muddegowda Umashankara, Kanchugarakoppal S. Rangappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot synthesis of 2-aryl benzothiazoles from gem-dibromomethylarenes using 2-aminoarylthiols is
described. Benzothiazoles were obtained in high chemical yields under mild conditions. This transforma-
tion would facilitate synthesis by short reaction times, large-scale synthesis, easy and quick isolation of
the products, which are the main advantages of this procedure.
Received 22 July 2011
Revised 7 August 2011
Accepted 8 August 2011
Available online 16 August 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Benzothiazole
gem-Dibromomethylarenes
o-Aminothiophenols
Potassium tertiary butoxide
The exploration of privileged structures in drug discovery is a
rapidly emerging area in medicinal chemistry. These structures
represent a class of molecules capable of binding to multiple recep-
tors with high affinity. By probing into these molecules, it enables
the medicinal chemist to rapidly discover biologically active
compounds across a wide range of therapeutic areas within a rea-
sonable time scale. The substituted 2-arylbenzothiazoles have
emerged in recent years as an important pharmacophore in a num-
ber of diagnostic and therapeutic settings and attractive features of
drug candidates based on this benzothiazole scaffold include their
synthetic accessibility as imaging agents for b-amyloid, antitumor
agents, calcium channel antagonists, antituberculotics, antiparasi-
tics, chemiluminescent agents and also as photosensitizers.1–7
A number of recent variants on the traditional solvent-based
thermal synthetic conditions have been reported. For example,
the classic methods for the synthesis of 2-aryl benzothiazoles are
the condensation of o-aminothiophenol with aromatic carboxylic
acids,8 or aromatic aldehydes, followed by the oxidation with
strong oxidants, such as molecular O2,9 H2O2,10 MnO2,11 and co-oxi-
dant DMSO12 as described. We herein describe a new, efficient and
straightforward approach starting from gem-dibromomethylarenes
using o-aminobenzenethiols in the absence of strong oxidants, and
this tandem process involving cyclization and aromatization, fur-
nished 2-aryl benzothiazoles in high yields.
The substitution of carboxylic acid or aldehyde component with
an alternative functional group has not been explored so far. There-
fore, the development of a simple and stable substitute for these
aromatic acids or aldehydes by using gem-dihalomethylarenes
would extend the scope of the reaction in organic synthesis. Re-
cently, gem-dihalomethylarenes have received considerable atten-
tion due to their application in the preparation of aldehydes,13 the
use of gem-dihalomethylarenes is limited to the synthesis of alde-
hydes and a
,b-unsaturated carboxylic acids and esters.14,15
In continuation of our work16 on the development of useful syn-
thetic methodologies from gem-dibromomethylarenes, in this
study we wish to report the one-step conversion of gem-dibro-
momethylarenes into the corresponding benzothiazoles by using
aminobenzenethiols, potassium tertiary butoxide (t-BuOK) and
catalytic amount of iodine in pyridine at reflux conditions with
excellent yields (Scheme 1).17,18
In the preliminary stage of investigation we focused on the sys-
tematic evaluation of different base catalysts for the model reaction
of gem-dibromomethylarenes and o-aminobenzenethiols at reflux
conditions in pyridine. A wide variety of base catalysts including
DBU, triethylamine, DABCO, K2CO3, Cs2CO3, and piperidine were
Br
Br
R
N
S
R
H2N
HS
Pyridine / t-BuOK
Ar
Ar
I2 , Reflux / 2 h
3(a-r)
1
2
⇑
Corresponding author.
E-mail address: rangappaks@gmail.com (K.S. Rangappa).
Scheme 1. General approach to synthesis of 2-arylbenzothiazoles.
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.08.055

C. Siddappa et al. / Tetrahedron Letters 52 (2011) 5474–5477
5475
Table 1
Synthesis of benzothiazoles from gem-dibromomethlarenes using 2-amino benzenethiols
Entry
Substratea
2-Aminobenzene thiols (R)
Product
Time (h)
1.5
Yieldb (%)
Br
Br
N
S
R = ÀH
1
92
86
2a
1a
3a
N
CF3
Cl
R = ÀCF3
2
3
1a
2
2
S
2b
3b
N
R = ÀCl
1a
83
87
S
2c
3c
Br
Br
N
N
N
S
4
5
2a
2b
2
2
Br
Br
1b
3d
CF3
N
S
N
1b
1b
90
85
Br
3e
N
Cl
N
S
6
2c
2
Br
3f
Br
Br
Br
Br
Br
N
7
8
9
2a
2b
2c
2
2
2
82
85
77
S
Br
1c
3g
CF3
Cl
N
1c
1c
S
3h
N
S
3i
Br
Br
Br
Br
N
10
2a
2
82
83
S
O2N
O2N
O2N
O2N
1d
3j
Br
CF3
N
S
11
12
1d
2b
2c
2
2
3k
Br
Cl
N
S
1d
86
3l
(continued on next page)

5476
C. Siddappa et al. / Tetrahedron Letters 52 (2011) 5474–5477
Table 1 (continued)
Entry
Substratea
2-Aminobenzene thiols (R)
Product
Time (h)
Yieldb (%)
Br
Br
N
S
Br
Br
13
14
2a
2
81
Cl
Cl
1e
3m
CF3
Cl
N
S
Br
Br
1e
2b
2c
2
2
85
81
Cl
Cl
3n
N
S
15
1e
3o
Br
Br
N
S
S
S
S
16
17
2a
2b
2c
2
2
2
77
80
75
S
Br
Br
Br
Br
3p
1f
CF3
N
S
1f
3q
N
Cl
S
18
1f
3r
a
Substrates are prepared from the commercial methyl analogs by radical bromination.
Isolated yields.
b
treating gem-dibromomethylarenes 1 with o-aminophenol 4 using
the same procedure as described in Scheme 1 to obtain 2-phenyl-
benzoxazole (Scheme 2) in a very low yield (25%). Hence, o-amino-
phenol was not a good substrate for this protocol.
In summary, this one-step reaction presents an efficient method
to convert gem-dibromomethylarenes to 2-aryl benzothiazoles.
The mild reaction conditions offer the potential for the use of this
method in the synthesis of complex molecules. It is anticipated
that this methodology will have versatile applications in the prac-
tical syntheses of biologically important pharmaceutical molecules
with benzothiazole moiety.
Br
Br
H2N
HO
N
Pyridine / t-BuOK
Ar
Ar
O
5
I2 , Reflux / 2 h
4
1
Yield, 25 %
Scheme 2. Synthesis of 2-phenylbenzoxazole.
employed to improve the yield for the specific synthesis of 2-aryl
benzothiazoles. While piperidine catalysed the reaction to give
quantitative yield in 4–5 h, the other bases did not promote this
reaction. Interestingly, when the reaction was carried out in the
presence of t-BuOK, it led to the desired product in high yields in
1.5–2.0 h; the results were tabulated in Table 1.
Acknowledgement
The authors are grateful to UGC, Govt. of India for financial sup-
port to K.S.R. under the Project vide No. F. 31-143/2005(SR).
The synthetic approach starting from the corresponding com-
mercially available methyl analogs using radical bromination is
well documented.13 Our approach was initiated using a mixture
of gem-dibromomethylarenes (1.0 equiv) 1 and aminobenzenethi-
ols (1.1 equiv) 2 with anhydrous pyridine in the presence of a t-
BuOK (0.5 equiv) followed by the addition of iodine (0.2 equiv)
and refluxing at 90 °C for 2 h. The starting material was consumed
in 2 h as indicated by TLC analysis and the results are presented in
Table 1. This transformation would extend the scope in organic
synthesis, in addition, it is interesting to note that both aromatic
and heteroaromatic gem-dibromomethylarenes bearing various
functionalities such as chloro, bromo, nitro, and trifluoro methyl
groups survived the reaction and provided high yields of corre-
sponding benzothiazoles. The reaction was further probed by
Supplementary data
Supplementary data (compounds characterization data and
copies of 1H NMR, 13C NMR of all the synthesized compounds de-
scribed in scheme (1) are available as supplementary data) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.08.055.
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18. To a mixture of benzal bromide 1a (25 g, 100 mmol) and 2-aminobenzenethiol
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7.76–7.74 (1H, d, J = 8.0 Hz, Ar–H), 7.4–7.36 (2H, m, Ar–H), 7.34–7.31 (2H, m,
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5 (Scheme 2).
C
m
(KBr) 2996, 2932, 2789, 1643, 1532, 1276, 810 cmÀ1; dH (CDCl3, 400 MHz):
7.94–7.91 (1H, m, Ar–H), 7.54–7.49 (3H, m, Ar–H), 7.37–7.30 (2H, m, Ar–H),
7.22–7.18 (2H, m, Ar–H), 7.03–7.01 (1H, d, J = 8.0 Hz, Ar–H); dC (CDCl3,
100.6 MHz), 157.1, 131.7, 129.7, 129.0, 128.9, 128.4, 128.0, 127.6, 127.6, 120.1,
116.0; MS (Maldi) calcd for C13H9NO (M+H+) 196.0710; found, 196.0703.
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