Synthesis of N-substituted-2-aminobenzothiazoles using nano copper oxide as a recyclable catalyst under ligand-free conditions, in reusable PEG-400 medium

Article abstract of DOI:10.1016/j.cclet.2014.02.003

A simple and practical method for the synthesis of N-substituted-2- aminobenzothiazoles via a cross-coupling reaction of 2-iodo anilines with isothiocyanates is envisaged using nano copper oxide as a recyclable catalyst and Cs₂CO₃ as a base in PEG-400, as a bio-degradable, reusable, inexpensive and non-toxic reaction medium, under ligand-free conditions. The present tandem process underlines environmental acceptability to access a wide range of N-substituted-2-aminobenzothiazoles in good to excellent yields.

Full text of DOI:10.1016/j.cclet.2014.02.003

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Contents lists available at ScienceDirect
Chinese Chemical Letters
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Original article
Synthesis of N-substituted-2-aminobenzothiazoles using nano copper
oxide as a recyclable catalyst under ligand-free conditions, in reusable
PEG-400 medium
Satish Gaddam, Harshavardhan Reddy Kasireddy, Karnakar Konkala, Ramesh Katla,
*
Nageswar Yadavalli Venkata Durga
CSIR-Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple and practical method for the synthesis of N-substituted-2-aminobenzothiazoles via a cross-
coupling reaction of 2-iodo anilines with isothiocyanates is envisaged using nano copper oxide as a
recyclable catalyst and Cs2CO3 as a base in PEG-400, as a bio-degradable, reusable, inexpensive and non-
toxic reaction medium, under ligand-free conditions. The present tandem process underlines
environmental acceptability to access a wide range of N-substituted-2-aminobenzothiazoles in good
to excellent yields.
Received 11 July 2013
Received in revised form 17 January 2014
Accepted 21 February 2014
Available online xxx
Keywords:
ß 2014 Nageswar Yadavalli Venkata Durga. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
2-Aminobenzothiazoles
2-Iodo anilines
Isothiocyanates
CuO nanoparticles
Recyclability
PEG-400
1. Introduction
isothiocyanates [16]. Recently, direct oxidative coupling between
benzothiazoles and amines, Domino three-component reactions of
In modern organic synthesis, biologically active benzothiazoles
are considered privileged building blocks. In particular 2-
aminobenzothiazoles like 2-(N-alkyl amino)benzothiazoles, 2-
(N-acyl amino)benzothiazoles are involved in several applications
in medicinal chemistry [1–3]. 2-Aminobenzothiazoles are unique
scaffolds that are widely used in medicinal and biological
chemistry [4]. A large number of 2-anilinobenzothiazole deriva-
tives are found to be anticancer agents and represent an important
pharmacophore as well as a reactive intermediate [5]. These
compounds have remarkable biological activity and are widely
employed for the treatment of various diseases such as tuberculo-
sis [6], epilepsy [7], diabetes [8] and cancer [9] (Fig. 1).
Due to the pharmaceutical significance of the benzothiazole
core structure, several synthetic approaches have been reported.
These include coupling of 2-aminobenzothiazoles with aryl halides
[10,11], coupling of aryl amine with 2-halobenzothiazoles [12–14],
arylthioureas with liquid bromine [15], and oxidative cyclization
of the intermediates generated by 2-amino thiophenol with
carbon disulfides, amines, 2-halo anlines and intermolecular C–S
bond formation in the synthesis of 2-aminobenzothiazoles
catalyzed by Cu/Pd/Fe have been reported [17–22]. However,
the reported catalytic systems or solvent media are not recyclable.
In continuation of our work in cross-coupling reactions and
heterogeneous catalysis [23–34], herein we describe an inexpen-
sive, air-stable and recyclable nano copper oxide as a catalyst for
the synthesis of 2-aminobenzothiazoles under ligand-free condi-
tions (Scheme 1). In the present protocol, PEG-400 (polyethylene
glycol) is employed as a low cost and reusable solvent. PEG has
received attention of many research groups because it is a
hydrophilic polymer. PEG-400 is inexpensive, recyclable, biode-
gradable, relatively nonflammable andnontoxic, miscible with a
wide variety of organic solvents and can be used as an ecofriendly
solvent for various organic transformations such as coupling [35],
substitution [36], oxidation [37], addition [38] and reduction
reactions [29–40].
The deployment of PEG in the organic synthesis could reduce
the use of volatile organic solvents and environmental burden. PEG
can be used as an alternate medium for different reactions with
easy recyclability of solvent and catalysts, unlike several of the
‘‘neoteric solvents’’ such as the expensive ionic liquids (ILs).
*
Corresponding author.
E-mail address: dryvdnageswar@gmail.com (N.Y.V. Durga).
http://dx.doi.org/10.1016/j.cclet.2014.02.003
1001-8417/ß 2014 Nageswar Yadavalli Venkata Durga. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: S. Gaddam, et al., Synthesis of N-substituted-2-aminobenzothiazoles using nano copper oxide as a
recyclable catalyst under ligand-free conditions, in reusable PEG-400 medium, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.02.003

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Fig. 1. Biologically active N-substituted-2-aminobenzothiazole derivatives.
Scheme 2. Plausible mechanism for the formation of N-substituted-2-
aminobenzothiazoles.
Scheme 1. Recyclable nano CuO catalyzed synthesis of N-substituted-2-
CDCl3): d201.4, 139.9, 129.4, 128.8, 128.2, 123.6, 119.2, 117.9, 22.6,
aminobenzothiazoles.
21.2; ESI-MS m/z 255 (M+H)+.
A model reaction was attempted under the optimized reaction
conditions with 2-iodoaniline and isothiocyanates as a coupling
partner. In general, the reaction proceeded well with these
substrates to produce the 2-aminobenzothiazoles in good to
excellent yields. It was found that both electron rich and electron
poor aryl isothiocyanates underwent the tandem coupling reaction
efficiently. The generality of the method was further explored by
reacting a wide range of substituted 2-iodoanilines and substituted
isothicyanates, resulting in the formation of the corresponding 2-
N-substituted benzothiazole derivatives, as shown in (Table 1). All
the products were confirmed by 1H NMR, 13C NMR spectroscopy,
and compared spectroscopically with the authentic samples
reported in the literature [41].
Recently, heterogeneous catalysts have become attractive both
from economic and industrial points of view. The high surface area
and reactive morphology of the nanomaterials allow them to be
effective catalysts for organic synthesis. Nano copper oxides (CuO
nps) have the advantages of improved recyclability, easier workup,
and cleaner reaction profiles in addition to the lack of necessity of
external ligands, which minimizes the organic waste generation, as
compared to the conventional catalytic systems.
2. Experimental
Recyclability of the nano copper oxide catalyst was examined
under optimized reaction conditions and the results are described in
(Table 2). After the reaction, the reaction mixture was centrifuged
and catalyst was separated from the reaction mixture and then
followed by washing with ethyl acetate and acetone, dried in vacuo
and used directlyfor further catalyticreactions. Nosignificant loss of
catalyst activity was observed up to four cycles. The native and used
nano copper oxide was analyzed by powder XRD. The powder XRD
spectra confirmed that, the peaks of the both fresh and recovered
nano copper oxide are identical. It is observed that the morphology
of the catalyst remains the same even after four recycls.
Allmaterials were purchased from Sigma Aldrich. Dry solvents and
CuO nanopowders (<50 nm) were used for the reactions. Analytical
thin layer chromatography (TLC) was carried out using silica gel 60
F254 pre-coated plates. Column chromatography was carried out
using silica gel (60–120 mesh size). Visualization was accomplished
with UV lamp, I2 stain, and Phosphomolybdic acid charring. 1H NMR
and 13C NMR were recorded at 300 MHz and 75 MHz, respectively, in
CDCl3 using TMS as an internal standard. Chemical shifts were
reported in parts per million (ppm) downfield from TMS.
General procedure: A mixture of 2-iodoaniline (0.5 mmol),
isothiocyanate (0.6 mmol), CuO nanoparticles (0.05 mmol), and
Cs2CO3 (1.5 mmol) in PEG-400 (3 mL) was stirred at 80 8C for 8 h
(Scheme 1). After the reaction, the reaction mixture was
centrifuged and catalyst was separated from the reaction mixture
and then followed by washing with ethyl acetate and acetone,
dried in vacuo and used directly for further catalytic reactions. The
cooled solution was partitioned between ethyl acetate and water,
and the organic layer was washed with water and brine, and then
dried over Na2SO4. After the removal of the solvent in vacuo, the
residue was purified by silica-gel chromatography to give the
desired N-substituted-2-aminobenzothiazoles. All the compounds
were characterized by comparison with authentic samples [41].
N-Phenylbenzo[d]thiazol-2-amine (Table 1, entry 1) [40]:
White solid, mp 158–160 8C; yield 180 mg (80%); 1H NMR
3. Results and discussion
Initially, 2-iodo aniline and phenylisothiocyanates were used to
optimize the reaction conditions such as base and solvent used and
reaction temperature (Table 3), Among several bases screened,
Cs2CO3 was found to be an excellent base (Table 3, entry 1). In
presence of bases such as K2CO3, Na2CO3, and K3PO4, lesser amount
of the desired product was obtained (Table 3, entries 2–4). The
effect of solvent was also investigated and the highest yield was
observed in PEG-400, while reaction in solvents such as THF,
CH3CN, and Toluene resulted in moderate yields (Table 3, entries
6–8). The experiment confirmed that the reaction did not occur in
the absence of the base (Table 3, entry 9). When the reaction was
conducted at room temperature a lower yield was obtained
(Table 3, entry 5). The reaction did not occur in absence of the
catalyst (Table 3, entry 10). Ideal temperature for the reaction was
found to be 80 8C. The influence of the amount of catalyst on the
yield of the product was also evaluated. It was observed that
0.05 mmol of CuO nano was ideal for the synthesis of N-
substituted-2-aminobenzothiazoles in good to excellent yields.
(300 MHz, CDCl3):
d
8.18–8.04 (m, 3H), 7.58–7.47 (m, 1H), 7.46–
162.4,
7.35 (m, 4H), 7.37–7.25 (m, 1H); 13C NMR (75 MHz, CDCl3):
d
157.7,129.3, 126.6, 124.5, 122.0, 121.3, 120.0, 112.6; ESI-MS m/z
227 (M+H)+.
4,6-Dimethyl-N-phenylbenzo[d]thiazol-2-amine (Table 1, en-
try 2) [40]: Yield 190 mg (85%); 1H NMR (300 MHz, CDCl3):
d 7.52–
7.45 (m, 2H), 7.41–7.33 (m, 2H), 7.29–7.25 (m, 1H), 7.19–7.05 (m,
2H), 6.199 (s, 1H), 2.58 (s, 3H) 2.38 (s, 3H); 13C NMR (75 MHz,
Please cite this article in press as: S. Gaddam, et al., Synthesis of N-substituted-2-aminobenzothiazoles using nano copper oxide as a
recyclable catalyst under ligand-free conditions, in reusable PEG-400 medium, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.02.003

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3
Table 1
Synthesis of N-substituted-2-aminobenzothiazoles.a
Entry
1
1
Substrates
NCS
Product
Yield (%)b
80
NH2
I
N
S
H
N
2
85
NCS
NH2
N
S
H
N
I
3
4
5
6
90
91
60
78
NH2
I
NCS
NCS
N
H
N
S
F3C
F
F3C
F
NH2
N
H
N
S
I
NH2
NCS
N
S
H
N
NO2
O
I
O2N
O
NH2
O
O
NCS
N
S
H
N
O
I
O
7
8
75
80
NH2
NCS
N
S
H
N
CF3
F
F
I
F3C
O
NH2
I
O
O
NCS
N
S
H
N
O
O
F3C
F3C
O
9
79
90
NH2
NCS
N
H
N
NO2
Br
S
F3C
F3C
F3C
F3C
F
I
O2N
Br
10
11
12
13
NH2
NCS
N
H
N
S
I
88
91
88
80
NH2
NCS
N
S
H
N
Br
F
I
Br
NH2
N
NCS
H
N
S
I
NH2
NCS
NCS
N
H
N
O
S
I
O
14
NH2
N
H
N
Cl
S
I
Cl
a
Reaction conditions: 2-iodoaniline (0.5 mmol), isocyanate (0.6 mmol), nano copper oxide (0.05 mmol), and base (1.5 mmol) in solvent (3 mL) at 80 8C for 8 h.
Isolated yield.
b
Table 2
A plausible mechanism, which demonstrates the formation of
N-substituted-2-aminobenzothiazoles from the 2-iodoanilines
and isothiocyanates, is given in Scheme 2. [D] is formed by the
reaction of 2-iodo aniline and isothiocyanate via the de
protonation reaction. Then coordination of copper with [D]
provides intermediate [E], which upon oxidative addition would
form [F], which undergoes a reductive elimination to produce
required final compound [G] with concomitant regeneration of
the catalyst.
Recyclability of CuO nanoparticles.a
Recycles
Yield (%)b
Catalyst recovery (%)
Native
91
89
87
85
97
95
92
90
1
2
3
a
The conditions are same as that in Table 1.
Isolated yield.
b
Please cite this article in press as: S. Gaddam, et al., Synthesis of N-substituted-2-aminobenzothiazoles using nano copper oxide as a
recyclable catalyst under ligand-free conditions, in reusable PEG-400 medium, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.02.003

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Entry
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1
2
Cs2CO3
K2CO3
Na2CO3
K3PO4
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In conclusion, we have developed a novel protocol for the
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We thank CSIR, New Delhi, India, for fellowship to GS, KH, KK,
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recyclable catalyst under ligand-free conditions, in reusable PEG-400 medium, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
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