A Synthesis of Benzothiazoles and Indoles by Direct C(sp2)-I Activation Catalyzed by Copper(II) on Silica-Coated Magnetite Nanoparticles

Article abstract of DOI:10.1055/s-0035-1561406

N-Substituted 2-amino-1,3-benzothiazoles and 2,3-disubstituted indoles were prepared by C-S and C-C cross-coupling reactions of 2-iodoanilines with isothiocyanates or 1,3-dicarbonyl compounds, respectively, in the presence of magnetic nanoparticles functionalized with a copper(II)-Schiff base complex as an efficient and reusable catalyst.

Full text of DOI:10.1055/s-0035-1561406

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©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
A
letter
Synlett
F. K. Moghadam et al.
Letter
2
A Synthesis of Benzothiazoles and Indoles by Direct C(sp )–I
Activation Catalyzed by Copper(II) on Silica-Coated Magnetite
Nanoparticles
Faeze Kiani Moghadama
I
I
O
O
+
S
C
N
Ar
+
R1
OR2
Najmeh Jarrahb
NH2
NH2
Ali Mashayekh-Salehic
Rashid Ghanbaripour*d
Fe3O4
SiO2
CTAB (10 mol%),
DABCO (2 equiv),
CTAB (10 mol%),
K2CO3 (1 equiv),
50 °C, 2 h
50 °C, 3 h
CO2R2
a
S
Department of Chemistry, Faculty of Science, Ferdowsi
NH
Ar
University of Mashhad, Mashhad 91779-48974, Iran
Department of Chemistry, Catalysis Division, University of
R1
b
N
N
Si
Isfahan, Isfahan 81746-73441, Iran
Department of Environmental Health Engineering, Faculty
H
c
6 examples
8–96% yield
–
6 examples
65–85% yield
N
N
O
5
of Medical Sciences, Tarbiat Modares University, Tehran
Cu
=
14117-13116, Iran
O
Si
d
Young Researchers and Elite Club, Central Tehran Branch,
Islamic Azad University, Tehran 19379-58814, Iran
r.ghanbaripour@gmail.com
Received: 07.12.2015
Accepted after revision: 05.02.2016
Published online: 07.03.2016
yltrimethylammonium bromide (CTAB, 10 mol%) at 50 °C
for two hours (Table 1, entry 1). Performing the reaction in
3
DOI: 10.1055/s-0035-1561406; Art ID: st-2016-d0026-l
the presence of various other additives (entries 8–10) and
bases (entries 11–15) failed to improve the yield. Increasing
the amount of catalyst (entry 5), CTAB (entry 6), or DABCO
Abstract N-Substituted 2-amino-1,3-benzothiazoles and 2,3-disubsti-
tuted indoles were prepared by C–S and C–C cross-coupling reactions
of 2-iodoanilines with isothiocyanates or 1,3-dicarbonyl compounds,
respectively, in the presence of magnetic nanoparticles functionalized
with a copper(II)–Schiff base complex as an efficient and reusable cata-
lyst.
(entry 3), or raising the temperature (entry 16) similarly
failed to improve the yield, as did decreasing the amount of
DABCO or CTAB or lowering the temperature (entries 2, 17,
and 4, respectively). None of the desired product was ob-
tained in the absence of the magnetic catalyst, DABCO, or
CTAB (entries 18–20).
Key words cross-coupling, benzothiazoles, indoles, copper, catalysis,
Schiff bases
With the optimized reaction conditions in hand, we ex-
tended our study to various other isothiocyanate deriva-
tives 1. We found that the reaction tolerates a variety of iso-
thiocyanates containing either electron-withdrawing or
electron-donating substituents. The reactions were gener-
ally clean and gave the desired products 3a–f in moderate
to excellent yields (Table 2).
A plausible mechanism for the reaction of 2-iodoaniline
with isothiocyanate compounds has been proposed in the
literature.1j
Following our successful synthesis of N-substituted 2-
amino-1,3-benzothiazoles derivatives, we decided to evalu-
ate the effect of this catalyst system in the cross-coupling
reaction of 2-iodoaniline with 1,3-dicarbonyl compounds.
For this purpose, we chose the reaction of 2-iodoaniline
with methyl acetoacetate as a model reaction to determine
the optimal conditions. Various additives, bases, and
amounts of catalyst were studied, and the best results were
obtained by performing the reaction in the presence of 20
mg of magnetic catalyst (containing 0.021 mmol copper),
In recent years, several syntheses of various heterocyclic
compounds such as pyrrole, indole, furan, or benzothio-
phene derivatives through cross-coupling reactions cata-
lyzed by copper derivatives have been reported in the liter-
1
ature. In a continuation of our work on heterogeneous cat-
2
alysts and cross-coupling reactions, we recently reported
the synthesis of benzoate and carbamate derivatives
through oxidative C–O coupling reactions in the presence of
new magnetic nanoparticles functionalized with a copper–
2d
Schiff base complex. We therefore decided to examine
this catalyst in carbon–halogen bond-activation reactions
for the synthesis of 2,3-disubstituted indoles and N-substi-
tuted 2-amino-1,3-benzothiazole derivatives.
In an initial attempt, the cross-coupling reaction of 2-io-
doaniline with phenyl isothiocyanate was probed in the
presence of subequivalent amounts of the catalyst in water
as a green solvent. To optimize the reaction conditions, var-
ious bases, additives, and amounts of catalyst were investi-
gated. The best results were obtained by performing the re-
action in the presence of 15 mg of the magnetic catalyst
K CO3 (1 equiv), and CTAB (10 mol%) at 50 °C for three
2
4
hours to give an 85% yield of product 4a (Table 3, entry 1).
(containing 0.016 mmol copper), DABCO (2 equiv), and cet-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Synlett
F. K. Moghadam et al.
Letter
Table 1 Optimization of Reaction Conditions for the Synthesis of Benzothiazole 2a
I
NH2
S
N
catalyst, additive, base
NHPh
+
temperature
S
C
N
Ph
2a
1a
a
Entry
Catalyst (mg)
Additive (mol%)
Base (equiv)
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
15
15
15
10
20
15
15
15
15
15
15
15
15
15
15
15
15
–
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (15)
CTAB (5)
DABCO (2 equiv)
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
60
40
50
50
50
93
70
90
68
85
95
80
60
87
83
40
trace
30
45
trace
90
69
–
DABCO (1.5 equiv)
DABCO (2.5 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
TBAF (10)
TBAB (10)
b
1
1
1
1
1
1
1
1
1
1
2
0
SDS (10)
1
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
–
K
K
2
CO
3
(2 equiv)
(2 equiv)
2
3
PO
4
3
Na
2
3
CO (2 equiv)
4
py (2 equiv)
5
NaOH (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
–
6
7
8
9
15
15
–
0
DABCO (2 equiv)
trace
a
Isolated yield,
SDS = sodium dodecyl sulfate
b
Increasing the amount of CTAB (Table 3, entry 6) and/or
night. The recovered catalyst could be used at least five
consecutive times without significant loss in product yield
(Figure 1).
using another additive (entries 8–10) failed to improve the
yield. Increasing the amount of K CO (entry 3) or the cata-
2
3
lyst (entry 5), or changing the base (entries 11–15) also
failed to improve the yield, whereas decreasing the amount
of base or catalyst (entries 2 and 4) led to reduced yields. In
the absence of the catalyst, base, or additive, the model re-
action failed to give the desired product (entries 18–20).
With the optimized reaction conditions in hand, we ex-
tended our study to a range of 1,3-dicarbonyl compounds
3b–f (Table 4).
Catalyst recovery and reuse was evaluated for both reac-
tions. After completion of the first reaction in both proto-
cols, the catalyst was recovered by using an external mag-
net, washed with methanol, and oven dried at 100 °C over-
Figure 1 Reusability of the catalyst
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Synlett
F. K. Moghadam et al.
Letter
Table 2 Synthesis of 2-Amino-1,3-benzothiazole Derivatives
Table 4 Synthesis of Indole Derivatives 4a–f
I
I
CO2R2
R1
N
H
magnetic catalyst (15 mg),
magnetic catalyst (20 mg),
CTAB (10 mol%), K2CO3 (1 equiv)
NH2 CTAB (10 mol%), DABCO (2 equiv)
S
NH2
+
NHR
+
H2O, 50 °C, 2 h
R
H2O, 50 °C, 3 h
S
C
N
N
O
O
1
2
R1
OR2
4
a
Entry
R
Products 2
Yield (%)
Ref.
1b,k
3
1
2
3
4
5
Ph
2a
2b
2c
2d
2e
2f
93
71
89
96
85
58
R1
Me
R2
Me
Products 4 Yield (%)
a
Ref.
Entry
4-ClC
4-Tol
6
H
4
1k
1
2
3
4
5
4a
4b
4c
4d
4e
4f
85
80
75
69
70
65
1a
1a
1a
1a
1a
1a
1b,k
1k
Et
Me
Me
Me
Et
2 6 4
4-O NC H
i-Pr
4-FC
6
H
4
1k
t-Bu
Ph
6
Cy
1b
a
Isolated yield.
6
Naphth
Et
Table 3 Optimization of the Reaction Conditions for the Synthesis of
Indole 4a
a
Isolated yield
I
CO2Me
catalyst, additive, base
NH2
After investigating the catalyst recovery, we examined
the leaching of copper. For this purpose, we removed the
catalyst with an external magnet ten minutes after the be-
ginning of the reaction. We observed that the reaction did
not subsequently reach completion, even after 24 hours.
This clearly confirmed that no significant leaching of cop-
per into the solvent had occurred after ten minutes. An ad-
ditional study by inductively coupled plasma analysis con-
firmed that no leaching of the copper complex had oc-
curred.
In summary, we have described a green and ecofriendly
method for the synthesis of 2,3-disubstituted indoles or N-
substituted-2-amino-1,3-benzothiazoles by cross-coupling
reactions in the presence of magnetic nanoparticles func-
tionalized with a Schiff base–copper complex as a catalyst.
Ease of workup, the use of water as solvent, good yields, and
short reaction times in comparison with other methods are
the main advantages of these protocols.
Me
+
temperature
O
O
N
H
4
a
Me
OMe
3a
Entry Catalyst Additive
Base
(equiv)
Temp
(°C)
Yielda
(%)
(
mg)
(mol%)
1
2
3
4
5
6
7
8
9
20
20
20
15
25
20
20
20
20
20
20
20
20
20
20
20
20
–
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (15)
CTAB (5)
TBAF (10)
TBAB (10)
SDS (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
CTAB (10)
–
K
2
CO
3
(1 equiv)
(0.5 equiv)
(1.5 equiv)
(1 equiv)
(1 equiv)
(1 equiv)
(1 equiv)
(1 equiv)
(1 equiv)
(1 equiv)
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
60
40
50
50
50
85
56
81
69
85
85
73
55
68
72
80
20
35
50
trace
85
70
–
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
1
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
1
1
1
1
DABCO (1 equiv)
K
3
PO
4
(1 equiv)
(1 equiv)
Acknowledgment
Na
2
CO
3
py (1 equiv)
We are grateful to the Islamic Azad University Central Tehran Branch
for partial financial support of this work.
NaOH (1 equiv)
K
K
K
–
K
2
2
2
CO
CO
CO
3
3
3
(1 equiv)
(1 equiv)
(1 equiv)
Supporting Information
Supporting information for this article is available online at
20
20
–
http://dx.doi.org/10.1055/s-0035-1561405.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
2
2
CO
3
(1 equiv)
–
a
Isolated yield.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Synlett
F. K. Moghadam et al.
Letter
References
external magnet, and the solution was extracted with EtOAc (3
×
10 mL). The extracts were dried (MgSO ), filtered, and concen-
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(1) (a) Tanimori, S.; Ura, H.; Kirihata, M. Eur. J. Org. Chem. 2007,
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(
(
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White solid; yield: 210 mg (93%); mp 157–160 °C. IR (KBr):
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2
008, 10, 3535. (e) Ghosh, M.; Mishra, S.; Hajra, A. J. Org. Chem.
015, 80, 5364. (f) Liu, J.; Zhang, X.; Peng, H.; Jiang, H.; Yin, B.
−1
1
3
3
7
(
459, 1635 cm
.
H NMR (400 MHz, CDCl ): δ = 7.02 (t, JHH
=
3
3
.2 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.30–7.41 (m, 3 H), 7.15
d, J = 7.7 Hz, 1 H), 7.76–7.84 (m, 3 H), 10.48 (s, 1 H). C NMR
HH
Adv. Synth. Catal. 2015, 357, 727. (g) Kim, Y. S.; Kwak, S. H.;
Gong, Y.-D. ACS Comb. Sci. 2015, 17, 365. (h) Qiu, J.-W.; Hu, B.-L.;
Zhang, X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Org. Biomol. Chem.
3
13
HH
(
100 MHz, CDCl ): δ = 118.2, 119.7, 121.5, 122.5, 122.8, 126.4,
3
129.5, 130.5, 141.2, 152.6, 162.1.
2015, 13, 3122. (i) Zeng, W.; Dang, P.; Zhang, X.; Liang, Y.; Peng,
(
4) 2,3-Disubstituted Indoles 4a–f; General Procedure
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A mixture of the appropriate 1,3-dicarbonyl compound 3 (1.1
equiv), 2-iodoaniline (1 equiv), CTAB (10 mol%), K CO3 (1
2
equiv), and magnetic catalyst (20 mg) in H O (4 mL) was stirred
2
(
2) (a) Ghanbaripour, R.; Mohammadpoor-Baltork, I.; Moghadam,
M.; Khosropour, A. R.; Tangestaninejad, S.; Mirkhani, V. Polyhe-
dron 2012, 31, 721. (b) Ghanbaripour, R.; Mohammadpoor-Bal-
tork, I.; Moghadam, M.; Khosropour, A. R.; Tangestaninejad, S.;
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at 50 °C for 3 h then cooled to r.t. The catalyst was removed by
using an external magnet, and the solution was extracted with
EtOAc (3 × 10 mL). The extracts were dried (MgSO ), filtered,
4
and concentrated under vacuum to give a crude product that
was purified by column chromatography.
Methyl 2-Methyl-1H-indole-3-carboxylate (4a)
Beige solid; yield: 160 mg (85%); mp 164–166 °C. IR (KBr):
−1
1
3
016, 1690, 1449, 1209, 10905 cm . H NMR (400 MHz, CDCl ):
3
(3) N-Substituted 1,3-Benzothiazol-2-amines 2a–f; General Pro-
cedure
δ = 2.72 (s, 3 H), 3.93 (s, 3 H), 7.16−7.30 (m, 3 H), 8.08 (d, J= 7.7
13
Hz, 1 H), 8.67 (br s, 1 H). C NMR (100 MHz, CDCl ): δ = 14.2,
3
A mixture of the appropriate isothiocyanate 1 (1.1 equiv), 2-
iodoaniline (1 equiv), CTAB (10 mol%), DABCO (2 equiv), and
5
1
0.8, 104.3, 110.4, 121.2, 121.7, 122.3, 127.2, 134.5, 144.2,
66.7.
magnetic catalyst (15 mg) in H O (4 mL) was stirred at 50 °C for
2
2
h then cooled to r.t. The catalyst was removed by using an
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D