Phenyliodonium diacetate mediated arylation of benzothiazoles with substituted styrenes

Article abstract of DOI:10.1016/j.tetlet.2014.05.019

A metal-free synthesis of 2-arylbenzothiazoles was achieved using phenyliodonium diacetate (PIDA) from benzothiazoles and styrenes or β-nitrostyrenes. This transformation tolerates various functional groups such as methoxy, hydroxy, fluoro, chloro, and nitro groups.

Full text of DOI:10.1016/j.tetlet.2014.05.019

Accepted Manuscript
Phenyliodonium diacetate mediated arylation of benzothiazoles with substituted
styrenes
Ahmed Kamal, N.V. Subba Reddy, B. Prasad
PII:
S0040-4039(14)00797-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.019
TETL 44610
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2014
5 May 2014
7 May 2014
Please cite this article as: Kamal, A., Subba Reddy, N.V., Prasad, B., Phenyliodonium diacetate mediated arylation
of benzothiazoles with substituted styrenes, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.05.019
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Graphical Abstract
Phenyliodonium diacetate mediated arylation
of benzothiazoles with substituted styrenes
Ahmed Kamal, N.V. Subba Reddy, B. Prasad
Leave this area blank for abstract info.

1
Tetrahedron Letters
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Phenyliodonium diacetate mediated arylation of benzothiazoles with substituted
styrenes
Ahmed Kamal,∗ N.V. Subba Reddy, B. Prasad
Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India
E-mail: ahmedkamal@iict.res.in, Fax: +91-40-27193189
ARTICLE INFO
ABSTRACT
Article history:
Received
A metal-free synthesis of 2-arylbenzothiazoles was achieved using phenyliodonium diacetate
(PIDA) from benzothiazoles and styrenes or β-nitrostyrenes. This transformation tolerates
various functional groups such as methoxy, hydroxy, fluoro, chloro and nitro groups.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Arylation
Benzothiazoles
PIDA
Styrenes
Oxidative cyclization
2-Aryl benzothiazoles have received considerable interest due
to their significant biological activities such as antitumor,
antiviral and antimicrobial activities. Benzothiazoles 1 and 2 are
potent ligands for the aryl hydrocarbon receptor (AhR),1 whereas
3 and 4 have exhibited excellent antitumor activity.2 The
biologically active arylamine is generated from the prodrug (5),3
which exhibits potent activity against human mammary tumor
xenografts and is presently in clinical trials (Figure 1). Moreover,
benzothiazoles are found in other molecules such as industrial
dyes, functional materials, natural products, and agrochemical
compounds.4 Therefore, development of new methods for the
synthesis of benzothizoles and its analogues has drawn much
attention.
Scheme 1 a, b). However these methods have some limitations
like high temperatures or strong acidic conditions. Other methods
are based on transition metal (Pd or Cu) catalyzed
decarboxylation of benzothiazole with benzoic acid, and phenyl
acetic acid9 and cyclization of thiobenzanilides using Jacobson
method,10 which actually requires several steps for starting
material preparation. The direct arylation of benzothiazoles is an
alternative and versatile method for the synthesis of 2-aryl
benzothiazoles. These methods include transition metal catalyzed
cross coupling reactions of benzothiazoles with arylsilanes,11 aryl
halides,12 aryl boronic acids,13 aryl triflates14 and sodium
sulfinates (Scheme 1, c).15 These catalytic methods have drawn
considerable interest, however, they suffer from the use of
expensive transition metal catalysts. Recently, an iron catalyzed
arylation of benzothiazoles (Scheme 1, d, condition 1) from
aldehydes has been reported by Deng and co-workers.16 The
major limitation of the direct arylation of benzothiazoles using
metal catalysts is the contamination of metal in the synthesized
biologically active molecules or synthesized drug intermediates
that is important in pharmaceutical industry. To avoid this, Yang
and co-workers have developed a method to synthesize 2-
substituted benzothiazoles from benzothiazole and aryl aldehydes
using K2S2O8 and this method is applicable for only electron rich
aryl aldehydes (Scheme 1, d).17 To overcome these problems,
development of transition metal-free, direct and an efficient
method for the synthesis of benzothiazoles from cost-effective
staring materials needs to be explored. To the best of our
knowledge, the preparation of aryl substituted benzothiazoles
from benzothiazoles and styrenes is not known (Scheme 2).
Figure 1. Chemical structures of benzothiazoles having antitumor
activity.
Several methods have been reported for the formation of
benzothiazoles including condensation of aminothiophenol with
benzaldehydes,5 nitriles,6 carboxylic acids7 and acyl chlorides8
———
∗ Ahmed Kamal. Tel.: +91-40-27193157; fax: +91-40-27193189 ; e-mail: ahmedkamal@iict.res.in

2
Tetrahedron Letters
using PIDA, the reaction did not progress (Table 1 entry 10)
indicating the necessity of phenyliodonium diacetate (PIDA).
Similar yields were obtained when 0.5 mL or 1 mL of H2O was
added to DMSO (Table 1, entry 8, 9). On the basis of these
results, the optimal reaction conditions emerged as benzothiazole
(1 equiv), styrene (1.2 equiv), PIDA (3 equiv), DMSO (2 mL),
H2O (0.5 mL) at 110 °C for 14 h.
To evaluate the scope and limitations of this reaction with
respect to styrenes, we performed the reactions of benzothiazoles
with styrenes bearing electron withdrawing substituents (nitro,
nitrile and halides) as well as electron donating substituents
(methoxy and hydroxyl) under optimal conditions19 and results
are summarized in Table 2. These results showed that styrenes
with wide variety of substituents afford 2-aryl substituted
benzothiazoles in 42-72% yields. It should be pointed out that
halides (Table 2, 3a, 3g and 3j) are well tolerated on the benzene
ring that could be utilized for further transformations through
metal catalyzed coupling reactions. However, the reaction of
benzothiazoles with nitrostyrenes afforded the desired products
3f and 3h in 45 and 42% yields respectively. The formation of
aryl substituted benzothiazole with 4-hydroxystyrene indicated
that free hydroxyl group tolerated well under these conditions.
Furthermore, arylation of benzothiazoles with some
heteroaromatic styrenes such as 2-vinylfuran, 2-vinylpyrrole and
4-vinylpyridine also provided the desired products in 50-62%
yields (Table 2, 3m-3o).
Scheme 1. Strategies for 2-arylbenzothiazole synthesis.
N
S
N
S
PIDA
Ar
Ar
metal-free
Scheme 2. Arylation of benzothiazoles using PIDA.
According to previous reports, phenyliodonium diacetate
(PIDA) can oxidize alkenes into corresponding aldehydes18 and
aryl substituted benzothiazoles could be prepared through the
condensation of benzothiazoles with aromatic aldehydes.
Therefore, we conceived that 2-arylsubstituted benzothiazoles
could be achieved directly from styrenes and benzothiazoles
using PIDA. Initially, we tested this hypothesis by treating the
benzothiazole with 4-chlorostyrene in the presence of PIDA as
the model reaction to screen the various parameters. Reaction of
4-chlorostyrene with benzothiazole did not give the desired
product in CH3CN/H2O and CH3OH/H2O at 70 °C for 14 h
(Table 1, entries 1, 2). Later, the reaction was performed in
DMSO and H2O at 70 °C for 14 h, the desired
Table 2. Reaction of benzothiazoles with various substituted
styrenes.a,b
Table 1.Optimization of the reaction parameters for the synthesis
of 2-(4-Chlorophenyl)benzothiazole.a
N
S
3h
NO2
OMe
42%
MeO
OMe
OMe
OMe
Entry
PIDA
(equiv)
solvent
T (°C)
Yield (%)
N
S
N
S
MeO
3k 65%
1
2
1.2
1.2
1.2
1.2
1.2
1.2
2.4
3.0
3.0
CH3OH/H2O
CH3CN/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
70
70
0
3l
72%
0
3
70
10
30
40
40
60
65
64
0
4
90
aconditions: benzothiazole (0.75 mmol), styrene (0.9 mmol),
b
PIDA (2.25 mmol), DMSO/H2O = 2:0.5 mL, 110 °C, 14 h. All
yields are isolated yields.
5
110
130
110
110
110
110
6
7
8
Next, we performed this reaction with β-nitrostyrenes and
benzothiazole that also afford 2-aryl benzothiazoles20 under
optimal conditions and the results are shown in Table 3. The
amount of β-nitrostyrenes used in this transformation is lesser
compare with styrenes (Table 2). Initially we found that the
9b
10
abenzothiazole (0.75 mmol), styrene (0.9 mmol), PIDA (2.25 mmol),
DMSO/H2O = 2:0.5 mL, 110 °C, 14 h. bDMSO/H2O = 2:1 mL.
treatment
of
(E)-1-chloro-4-(2-nitrovinyl)benzene
with
benzothiazole provided 2-(4-chlorophenyl)benzothiazole in 63%
yield (Table 3, entry 1). Interestingly, functional groups such as
chloro and methoxy tolerated well under these conditions.
Heteroaromatic such as furanyl, and pyrrolyl substituted
benzothiazoles were obtained in good yields with benzothiazole
and corresponding nitrostyrenes. (Table 3, entries 4 and 5).
product was formed in low yield. Further, we proceeded to screen
the temperature and found that optimal temperature was 110 °C
for arylation of benzothiazoles (Table 1 entries 3-6). The
maximum yield was obtained when the amount of PIDA was
increased from 1.2 equiv to 3.0 equiv (Table 1 entry 8). Without

3
initially converted to the corresponding aldehyde, while
benzothiazole gave ring opening product in the presence of
PIDA. Next, the reaction of aminothiophenol with aldehyde
produced imine which was further cyclized followed by
oxidation to give the desired product.
Table 3. Reaction of benzothiazoles with β-nitrostyrenes.a,b
In conclusion, we have developed a novel way for the
synthesis of 2-substituted benzothiazoles using phnyliodonium
diacetate (PIDA) employing benzothiazole and various styrenes
Entry
1
Substrate
Product
Yield (%)
63
o
at 110 C in DMSO and H2O. PIDA can oxidize benzothiazole
and styrenes into 2-aminothiophenol and corresponding
benzaldehydes in situ thus providing a variety of benzothiazoles.
Particularly, this method was carried out without using any
additive or base. This method is significant because it does not
require any transitional metal catalysts, it is reasonably broad in
scope and it is operationally simple. Finally, this method can be
used in the synthesis of biologically active molecules having
benzothiazloe scaffold.
2
3
62
59
Acknowledgments
4
59
62
N.V.S.R and B.P acknowledge CSIR-UGC, New Delhi for the
award of senior research fellowship. We also acknowledge CSIR
for financial support under the 12th Five Year plan project
“Affordable Cancer Therapeutics (ACT)” (CSC0301).
5
a
Conditions: benzothiazole (0.75 mmol), nitrostyrene (0.62 mmol),
PIDA (2.25 mmol), DMSO/H2O = 2:0.5 mL, 110 °C, 14 h. bAll
yields are isolated yields.
References and notes
To elucidate the reaction mechanism, we have conducted
some experiments as shown in Scheme 3. Treatment of
chlorostyrene with PIDA under our standard conditions afforded
the chlorobenzaldehyde in 75% yield. This was further supported
by the reaction of benzothiazole with chlorobenzaldehyde to
yield desired product in 65% yield. The reaction of benzaldehyde
with both benzothiazole and aminothiophenol provided the
desired product in good yield which indicated that this
transformation might proceed via opening of benzothiazole ring.
On this basis and the results of previous literature, a plausible
mechanism was proposed as shown Scheme 4. Styrene was
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Scheme 4. Possible reaction mechanism.

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Tetrahedron Letters
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20. General procedure for the synthesis 2-aryl benzothiazoles
from nitrostyrenes: To a solution of benzothiazole (0.75 mmol)
and β-nitrostyrenes (0.62 mmol) in DMSO/H2O (2:0.5 mL), PIDA
(2.25 mmol) was added. The reaction mixture was heated at 110
oC for 14 h. After completion of the reaction indicated by TLC,
the reaction mixture was diluted with water and extracted with
ethyl acetate. The combined organic extracts were dried with
anhydrous Na2SO4 and concentrated under vacuum to afford crude
product which was purified by column chromatography (silica gel,
hexane/ethyl acetate, 10:1)to give 2-aryl substituted benzothiazole.
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Supplementary Material
18. Xu, J. H.; Jiang, Q.; Guo, C. C. J. Org. Chem. 2013, 78, 11881.
19. General procedure for the synthesis 2-aryl benzothiazoles
from styrenes: To a solution of benzothiazole (0.75 mmol) and
styrenes (0.9 mmol) in DMSO/H2O (2:0.5 mL), PIDA (2.25
mmol) was added. The reaction mixture was heated at 110 oC for
14 h. After completion of the reaction indicated by TLC, the
reaction mixture was diluted with water and extracted with ethyl
acetate. The combined organic extracts were dried with anhydrous
Na2SO4 and concentrated under vacuum to afford crude product
which was purified by column chromatography (silica gel,
hexane/ethyl acetate, 10:1) to give 2-aryl substituted
benzothiazole.
Supplementary material that may be helpful in the review
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5
Graphical Abstract
A
metal free PIDA mediated arylation of
benzothiazoles from styrenes or β–nitrostyrenes
was developed. The reaction proceeded well for
wide variety of substituted styrenes to give 2-aryl
substituted benzothiazoles.