An efficient synthesis of N-substituted indoles from indoline/indoline carboxylic acid via aromatization followed by C-N cross-coupling reaction by using nano copper oxide as a recyclable catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.04.012

A new and elegant protocol for the synthesis of 1-substituted indoles was developed via aromatization of indoline/indoline carboxylic acid followed by C-N cross-coupling with various aryl halides in the presence of nano CuO as a recyclable catalyst, Cs₂CO₃ as a base in DMSO at 80 °C. 1-Substituted indoles were obtained in good to excellent yields and the catalytic system can be recycled up to four cycles without loss of catalytic activity.

Full text of DOI:10.1016/j.tetlet.2012.04.012

Tetrahedron Letters 53 (2012) 3061–3065
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An efficient synthesis of N-substituted indoles from indoline/indoline
carboxylic acid via aromatization followed by C–N cross-coupling reaction
by using nano copper oxide as a recyclable catalyst
⇑
K. Harsha Vardhan Reddy, G. Satish, K. Ramesh, K. Karnakar, Y.V.D. Nageswar
Organic Chemistry Divison-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and elegant protocol for the synthesis of 1-substituted indoles was developed via aromatization of
indoline/indoline carboxylic acid followed by C–N cross-coupling with various aryl halides in the pres-
ence of nano CuO as a recyclable catalyst, Cs2CO3 as a base in DMSO at 80 °C. 1-Substituted indoles were
obtained in good to excellent yields and the catalytic system can be recycled up to four cycles without
loss of catalytic activity.
Received 7 March 2012
Revised 3 April 2012
Accepted 4 April 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-substituted indoles
Indoline/indoline carboxylicacid
CuO nanoparticles
C–N cross-coupling
Recyclability
Over the years, N-substituted indoles have gained prominence
due to their presence in a wide variety of natural products and
bioactive compounds (Fig. 1). They have also played an important
role as building blocks in organic synthesis, pharmaceutical, agro-
chemical, and material sciences.1 N-aryl indoles are given special
emphasis for exhibiting diverse activities such as antipsychotic,2
antiallergic,3 herbicidal,4 COX-2 inhibition,5 angiotensin II antago-
nism,6 and melatonin receptor MT1 agonism.7
of nucleophilic N-heterocycles with aryl halides. However, high
reaction temperatures, use of more than stoichiometric amount
of copper reagents, longer reaction times, and low product yields
are some of the limitations, in these methodologies. Several
catalytic systems, such as Pd,9 Fe,10 Fe/Cu,11 Ni,12 Cd,13 and other
copper mediated catalytic systems in combination with numerous
ligands,14 have been reported in recent literature.
Venkataraman and co-workers15 reported the C–N bond
formation from the corresponding nitrogen nucleophiles and aryl
halides employing CuBr as a catalyst in combination with 1,
Traditional methods for the synthesis of these N-substituted
heterocyclic compounds involve Ullmann type coupling reaction8
MeO
F
O
NH
OH
O
O
N
Cl
N
Cl
N
O
O
N
NH
N
N
O
Sertindole
Pravadoline
hGCGR IC50 = 52 nM
Figure 1. Bio active compounds with N-substituted indole skeleton.
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.012

3062
K. H. V. Reddy et al. / Tetrahedron Letters 53 (2012) 3061–3065
10-phenanthroline as ligand. Zou et al.16 reported multinuclear
(a)
nano CuO, Cs2CO3
DMSO, 80 O
copper complex catalyst for the C–N cross-coupling reaction to
get access to a library of N-aryl heterocyclic compounds. Recently,
our own research group presented CuI as a recyclable catalyst for
N-arylation of indoles using both aryl iodide and aryl bromides
as coupling partners in water.17 In continuation of our interest in
the field of cross-coupling reactions and heterogeneous catalysis,18
herein we disclose recyclable nano copper oxide catalyzed N-aryla-
tion of indole, which in turn is obtained from the aromatization of
indoline/indoline carboxylic acid (Scheme 1).
RX
N
H
N
R
C
X = I, Br
R = Aromatic, Aliphatic, Hetero cyclic
nano CuO, Cs2CO3
R1X
(b)
DMSO, 80 O
X = I, Br
C
N
H
COOH
1 = Aromatic
N
R1
Initially, a model reaction was conducted at room temperature
to examine the feasibility of the reaction. When we reacted indo-
line with iodobenzene using nano copper oxide as catalyst, Cs2CO3
as a base and DMSO as a reaction medium, only trace amount of N-
substituted indole formation was observed via aromatization of
indoline precursor,19 followed by N-arylation. However, our at-
tempts toward this reaction gave rise to the desired product in
good overall yield when conducted at a temperature of 70–80 °C.
To the best of our knowledge, this is the first CuO nano particles-
catalyzed coupling of aryl halides with indoline to result in
N-substituted indoles. While optimizing the reaction conditions,
the influence of different bases and solvents on the synthesis of
N-substituted indoles was studied. The reaction was screened for
the effect of different bases such as K2CO3, K3PO4, Na2CO3,
KO-tBu, and Cs2CO3. Cs2CO3 was found to be efficient and produced
the desired product in good yield (Table 1, entry 8) whereas, K2CO3
and K3PO4 were less effective (Table 1, entries 1 and 2), and other
bases such as Na2CO3 and KO-tBu gave trace amounts of N-substi-
tuted indoles (Table 1, entries 3 and 4). The coupling reaction did
not occur in the absence of the catalyst as well as the base (Table
1, entries 9 and 11). DMSO appeared to be a better choice as
solvent than DMF and PhMe, which were less effective (Table 1,
entries 5 and 6). Reaction in water medium did not result in the
product formation.
R
Scheme 1. Synthesis of N-substituted indoles.
Table 1
Screening study of different bases and solventsa
I
nano CuO
base, solvent
N
N
H
Entry
Base
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
K2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMF
PhMe
Water
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
80
Rt
57
20
Na2CO3
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
None
Trace
Trace
35
Trace
0
89
0c
10
11
Trace
0
80
a
While expanding the scope of the reaction, a series of aryl halides
were employed as coupling partners to investigate the generality of
the reaction and the results are depicted in Table 2. It was observed
that the N-arylation of indolines happened via aromatization
followed by C–N cross-coupling reaction with a broad range of aryl
Reaction conditions: Indoline (1.0 mmol), iodobenzene (1.0 mmol), base
(2.0 equiv) in the presence of nano CuO (5.0 mol %) in 2.0 mL of solvent at 80 °C, 8 h.
b
Isolated yield.
In the absence of catalyst.
c
Table 2
Synthesis of N-substituted indoles from indolinea
CuO, Cs2CO3
DMSO,80 O
RX
C
N
R
N
H
Entry
1
Indoline
RX
Product
Yieldb (%)
89
I
N
H
N
N
N
N
Br
2
3
4
N
H
80c
87
85
I
N
H
I
N
H

K. H. V. Reddy et al. / Tetrahedron Letters 53 (2012) 3061–3065
3063
Table 2 (continued)
Entry
Indoline
RX
Product
Yieldb (%)
I
5
6
7
8
9
N
H
82
80
N
N
N
Cl
Cl
N
H
I
F
I
I
N
H
82
F
I
79d
84
N
H
N
N
N
N
N
F3C
F3C
I
N
H
CF3
CF3
N
H
10
11
12
80
75
70
I
I
I
N
H
6
N
H
N
6
O2N
O2N
O2N
O2N
O2N
O2N
I
N
H
13
14
15
16
17
82
78c
80
N
N
N
N
N
O2N
O2N
O2N
O2N
Br
N
H
I
N
H
I
N
H
77
F3C
N
H
I
CF3
74
69
I
N
H
18
N
S
S
a
Reaction conditions: Indoline (1 mmol), aryl halides (1.0 mmol), nano CuO (5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 80 °C, 8 h.
Isolated yield.
After 10 h, 100 °C.
2.0 mmol/indoline.
b
c
d

3064
K. H. V. Reddy et al. / Tetrahedron Letters 53 (2012) 3061–3065
Table 3
Synthesis of N-substituted indoles from indoline carboxylic acida
CuO, Cs2CO3
R1X
DMSO, 80 O
C
N
R1
N
H
COOH
Entry
1
Indoline carboxylic acid
R1X
Product
Yieldb (%)
85
I
COOH
N
H
N
Br
COOH
N
H
2
80c
N
I
I
I
COOH
3
4
5
6
7
8
9
N
H
82
80
78
73
75
80
78
N
N
N
N
N
N
N
COOH
N
H
COOH
N
H
Cl
F
Cl
COOH
N
H
I
I
COOH
N
H
F
F3C
F3C
I
COOH
N
H
CF3
CF3
COOH
N
H
I
a
b
c
Reaction conditions: Aryl halides (1.0 mmol), indoline carboxylic acid (1.0 mmol), nano CuO (5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 80 °C, 8 h.
Isolated yield.
After 10 h, 100 °C.
iodides (e.g., electron-rich, electron-deficient, electron-neutral, and
functionalized iodoarenes), affording the corresponding products in
good to excellent yields (Table 2, entries 1–18). The reactions were
conducted with commercially available and diversely substituted
aryl iodides and aliphatic iodides. The presence of substituents like
Me, Et, and t-Bu groups on aryl iodide part gave increased product
yield (Table 2, entries 3–5, 15, and 16) whereas, F, Cl, and CF3 func-
tional groups at para-position afforded slightly lower yields due to
electronic factors (Table 2, entries 6, 7, 9, 10, and 17).
It was generally observed that iodobenzene was more reactive
when compared to other halobenzene. (Table 2, entries 6 and 7).
The coupling process was also investigated with hetero aromatic
iodides resulting in the corresponding N-substituted indoles in
impressive yields (Table 2, entry 18).In the case of the reaction of
aryl bromides with indoline the process required longer reaction
times and elevated reaction temperatures to obtain the desired
product (Table 2, entries 2 and 14). Interestingly, when 1,4-diiodo-
benzene was reacted with indoline, 1,4-diindolyl benzene was ob-
tained in moderate yield (Table 2, entry 8). The substrate scope
was expanded to include the synthesis of N-substituted indoles
using aliphatic iodides and it was observed that as the chain length
of aliphatic iodide increased the product was formed in lower
yields (Table 2, entries 11 and 12).
Indoline-2-carboxylic acid was also reacted with various aryl io-
dides and the respective results are summarized in Table 3. In all
these cases the reaction gave rise to unexpected products.
The reusability of the nano copper oxide catalyst was examined
and the results are summarized in Table 4. After the reaction, the
reaction mass was centrifuged and the catalyst was separated from
the reaction mixture, washed with ethyl acetate and acetone, air
dried, and used directly for further catalytic reactions. No signifi-
cant loss of catalyst activity was observed up to four cycles. The na-
tive and used CuO nanoparticles were analyzed by powder XRD
and TEM analysis. It was observed from the TEM studies that the
used CuO nanoparticles were intact in size and shape even after
four cycles compared to the native catalyst. The powder XRD spec-
tra also confirmed the intactness of the particles after four cycles
(Supplementary data).
In conclusion, we have developed an efficient synthesis of 1-
substituted indoles using copper oxide nanoparticles without the

K. H. V. Reddy et al. / Tetrahedron Letters 53 (2012) 3061–3065
3065
Table 4
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Nageswar, Y. V. D. Org. Bio. Chem. 2011, 9, 5989; (c) Reddy, V. P.; Shankar, J.;
Madhav, B.; Kumar, B. S. P. A.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52,
2679; (d) Reddy, K. H. V.; Reddy, V. P.; Madhav, B.; Shankar, J.; Nageswar, Y. V.
D. Synlett 2011, 9, 1268; (e) Reddy, K. H. V.; Kumar, A. A.; Kranthi, G.; Nageswar,
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nano CuO, Cs2CO3
DMSO, 80 O
N
N
H
C
Recycle
Yield (%)
Catalyst recovery (%)
Native
89
87
84
80
94
92
89
82
1
2
3
a
Reaction conditions: Indoline (1 mmol), iodobenzene (1.0 mmol), nano CuO
(5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 80 °C, 8 h.
use of any external ligands. The copper oxide nanoparticles can be
easily recovered and reused up to four cycles without loss of activity.
Acknowledgments
We are grateful to the CSIR, New Delhi, for research fellowships
to K.H.V.R., G.S., and K.K. and to the UGC, New Delhi, for fellowship
to K.R.
Supplementary data
19. (a) Preedasuriyachai, P.; Chavasiri, W.; Sakurai, H. Synlett, 2011, 1121; (b)
Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem., 2001, 66, 1403.
Representative experimental procedure for the synthesis of N-substituted indoles:
To a stirred solution of aryl halides (1.0 mmol) and indoline/indoline carboxylic
acid (1.0 equiv) in dry DMSO (2.0 mL) at rt was added nano CuO (5.0 mol %)
followed by CS2CO3 (2.0 equiv) and heated at 80 °C for 10 h. The progress of the
reaction was monitored by TLC. After the reaction was complete, the reaction
mixture was cooled to room temperature and catalyst was filtered, the crude
residue was extracted with ethyl acetate (3 Â 10 mL). The combined organic
layers were extracted with water, saturated brine solution, and dried over
anhydrous Na2SO4. The organic layers were evaporated under reduced
pressure and the resulting crude product was purified by column
chromatography by using ethyl acetate/hexane (7:3) as eluent to give the
corresponding N-substituted indoles in excellent yields. The identity and
purity of the product were confirmed by 1H, 13C NMR, and mass spectra.
Data of representative examples: 1-(4-(tert-butyl)phenyl)-1H-indole (Table 2,
entry 5): 1H NMR (300 MHz, CDCl3) d 7.64–7.59 7.65 (m, 1H), 7.59–7.41 (m,
5H), 7.30 (t, J = 5.7 Hz, 1H), 7.23–7.10 (m, 2H), 6.66 (d, J = 2.7 Hz, 1H), 1.45 (s,
9H).13C NMR (75 MHz, CDCl3): d 149.4, 137.2, 129.1, 128.0, 126.4, 123.9, 122.1,
121.0, 120.1, 110.5, 103.1, 34.6, 31.3. EI-MS: m/z 249.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
012.
References and notes
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5-Nitro-1-phenyl-1H-indole (Table 2, entry 13): 1H NMR (300 MHz, CDCl3): d
8.44 (d, J = 1.7 Hz, 1H), 8.06 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H),
7.63–7.38 (m, 7H), 6.84–6.71 (m, 1H). 13C NMR (75 MHz, CDCl3): d 143.4,
133.4, 129.9, 127.6, 124.5, 120.9, 115.6, 107.4, 104.0. EI-MS: m/z 238.
5-Nitro-1-(p-tolyl)-1H-indole (Table 2, entry 15): 1H NMR (300 MHz, CDCl3): d
8.36 (s, 1H), 8.06–7.96 (m, 1H), 7.79–7.62 (m, 2H), 7.48–7.35 (m, 4H), 6.80 (d,
J = 3.1 Hz, 1H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3): d 142.3, 136.8, 134.7,
133.7, 129.6, 123.5, 120.1, 114.4, 106.4, 103.0, 20.1. EI-MS: m/z 252.
1-(4-Ethylphenyl)-5-nitro-1H-indole (Table 2, entry 16): 1H NMR (300 MHz,
CDCl3): d 8.42 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 (d,
J = 2.6 Hz, 1H), 7.40 (s, 4H), 6.76 (d, J = 2.1 Hz, 1H), 2.77 (q, J = 7.5 Hz, 2H), 1.33
(t, J = 7.6 Hz, 3H).13C NMR (75 MHz, CDCl3): d 144.1, 143.5, 135.9, 134.8, 133.6,
129.3, 124.7, 120.9, 115.6, 107.6, 103.8, 28.4, 15.4. EI-MS: m/z 266.
5-Nitro-1-(3-(trifluoromethyl)phenyl)-1H-indole (Table 2, entry 17): d1H NMR
(300 MHz, CDCl3) d 8.40 (d, J = 1.8 Hz, 1H), 8.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.76 (d,
J = 6.9 Hz, 5H), 7.62 (d, J = 3.3 Hz, 1H), 6.84 (dd, J = 3.2, 0.6 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 143.9, 138.9, 134.5, 133.9, 133.1, 130.7, 127.8, 124.4, 121.3,
116.1, 107.0, 105.0. EI-MS: m/z 306.