Indium-HI-mediated one-pot reaction of 1-(2-arylethynyl)-2-nitroarenes to 2-arylindoles

Article abstract of DOI:10.1016/j.tetlet.2008.04.032

While 1-(2-arylethynyl)-2-nitroarenes were reduced to 2-(2-arylethynyl)anilines in the presence of indium and InCl₃ in THF/H₂O (v/v = 5/1) at 50 °C, 1-(2-arylethynyl)-2-nitroarenes were reductively cyclized to 2-arylindoles with good yields in the presence of indium and aqueous HI in benzene.

Full text of DOI:10.1016/j.tetlet.2008.04.032

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3733–3738
Indium-HI-mediated one-pot reaction of
1-(2-arylethynyl)-2-nitroarenes to 2-arylindoles
Ji Sook Kim a, Joon Hee Han a, Jung June Lee a, Young Moo Jun a
Byung Min Lee b, Byeong Hyo Kim a,*
a Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea
b Korea Research Institute of Chemical Technology, Taejon 305-600, Republic of Korea
Received 28 February 2008; revised 31 March 2008; accepted 7 April 2008
Available online 9 April 2008
Abstract
While 1-(2-arylethynyl)-2-nitroarenes were reduced to 2-(2-arylethynyl)anilines in the presence of indium and InCl3 in THF/H2O (v/
v = 5/1) at 50 °C, 1-(2-arylethynyl)-2-nitroarenes were reductively cyclized to 2-arylindoles with good yields in the presence of indium
and aqueous HI in benzene.
Ó 2008 Elsevier Ltd. All rights reserved.
Indole rings have been well known as the basic skeletons
of pharmacologically and biologically active molecules.1
Because of the wide-ranging applications of indoles, the
development of efficient synthetic methods has continu-
ously attracted the attention of many synthetic chemists
since the classic Fischer indole synthesis was developed as
a good tool for synthesizing bioactive indole compounds.
Among the various indole syntheses, the metal-2 or base3-
catalyzed preparation of indoles starting from 2-alkynylan-
ilines is one of the most efficient approaches for indole
synthesis. However, one-pot reductive cyclizations of
1-(2-arylethynyl)-2-nitroarenes to indoles, which involves
both the reductive reaction of the nitro group and follow-
ing up with intramolecular cyclization, has not been
reported yet, despite many studies have been performed
on intramolecular metal-catalyzed hydroamination of
alkynes leading to indoles. Even two-step cyclizations start-
ing from 2-nitroarylacetylenes to indoles are shown rarely
in the literature.4
interest in the past decade for economic and environmental
reasons.5 In particular, the reactions mediated and cata-
lyzed by indium in aqueous media have been focused on
synthetic applications because of the ease of reactions that
obviate the need for inflammable anhydrous organic sol-
vents and inert atmosphere and also because of indium’s
green chemistry characteristics.5b Worth noting is the fact
that the toxicity observed in many metals is little observed
in indium, lending the metal its attractive green chemistry.
Consequently, considering the importance of bioactive
indoles and the attractive green chemistry of indium, we
combined them to develop a new synthetic methodology.
Based on our previous work concerning the reductive het-
erocyclizations such as 2,1-benzisoxazoles,6a,b benzimidaz-
oles,6c quinolines,6d and indazoles,6b we designed a new
path for the indole ring formation starting from 2-ethynyl
group substituted nitroarenes using indium metal, which
can be triggered by the reductive reaction between the nitro
group and indium toward indoles. Herein, we report the
development of one-pot indole synthesis via indium-pro-
moted reductive heterocyclization reactions.
In the view of synthetic tools, the use of indium for var-
ious organic transformations has been receiving increasing
Thus, the reductive cyclizations of 1-(2-arylethynyl)-2-
nitroarenes using indium either in aqueous or in organic
solution were examined for the development of a new
synthetic path with indoles. Firstly, we attempted the
*
Corresponding author. Fax: +82 2 942 4635.
E-mail address: bhkim@kw.ac.kr (B. H. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.032

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J. S. Kim et al. / Tetrahedron Letters 49 (2008) 3733–3738
Table 1
Reductive reaction of 1-(2-arylethynyl)-2-nitroarene derivatives to 2-(2-arylethynyl)anilines in the presence of 4 equiv of indium and 0.4 equiv of InCl3 in
THF/H2O (v/v = 5/1) at 50 °Ca
R2
R2
In (4 equiv), InCl3 (0.4 equiv)
R1
R3
R1
R3
THF / H2O (5 mL : 1 mL), 50 ºC
NO2
NH2
Time (h)
Entry
Substrate
R2
Product yieldb (%)
R1
R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a
H
CH3
OCH3
Cl
H
F
H
CH3
OCH3
Cl
H
F
H
CH3
OCH3
Cl
H
F
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
5
4
3
6
7
10
5
4
87
92
90
86
81
86
83
82
83
80
84
72
83
86
76
88
86
69
3
14
14
15
6
6
3
14
14
16
0.5 mmol of substrate was used.
Isolated yield.
b
heterocyclizations of 1-(2-arylethynyl)-2-nitroarenes such
as 1-nitro-2-(2-phenylethynyl)benzene in the presence of
indium/indium(III) chloride as we believe that indium
can transfer the electron to trigger the reductive reaction
of the nitro group. Moreover, the InCl3 may act as a Lewis
to 2-(2-arylethynyl)anilines in excellent yields as shown in
Eq. 1 and Table 1. Although indole formation was failed
with the In/InCl3 condition, it will be worth to apply for
the synthesis of anilines from nitroarenes as the reaction
condition is quite mild with good yields.
THF/H2O (v/v = 5/1)
R'
+
In
+
InCl3
R'
R"
50 ºC
R"
NO2
NH2
R' = H, Me, F, Cl, OMe
R" = H, Me, CF3
ð1Þ
R'
N
H
R"
acid to activate the triple bond to accept the anionic species
of the reduced intermediate of the nitro group. Unfortu-
nately, although various reaction conditions were exam-
ined, simply reduced products, 2-(2-arylethynyl)anilines,
were obtained as a major product instead of indole forma-
tion. However, it is worth mentioning that it can be utilized
as a useful methodology, if the simple reduction of nitro
moiety is concerned. Thus, the reduction of 1-(2-arylethyn-
yl)-2-nitroarenes was optimized for the synthesis of 2-(2-
arylethynyl)anilines. In the presence of 4 equiv of indium
and 0.4 equiv of InCl3 in THF/H2O (v/v = 5/1) at 50 °C,
1-(2-arylethynyl)-2-nitroarenes derivatives were reduced
To discover the appropriate reaction condition for the
reductive cyclization of 1-(2-arylethynyl)-2-nitroarenes to
indoles, not only wide range of Lewis acids or acids such
as InBr3, I2, Br2, AcOH, and HCl but also various solvents
such as H2O, alcohols, glycol, THF, CH2Cl2, pyridine,
benzene, toluene, and some co-solvents were examined.
However, any of the combination was not successful
toward the desired cyclization reaction. After the various
reaction conditions were examined, we could finally find
out a proper acid and solvent for the reductive one-pot syn-
thesis of indoles, that is, an optimized new condition for
indium-catalyzed heterocyclizations to indoles. As shown

J. S. Kim et al. / Tetrahedron Letters 49 (2008) 3733–3738
3735
Table 2
Reductive cyclization reaction of 1-nitro-2-(2-phenylethynyl)benzene (0.5 mmol) to 2-phenylindole in the presence of indium/hydriodic acid under the
various reaction conditions
In / X
solvent
N
H
NO2
Molar equiv
Entry
Aliquat 336
Solvent (mL)/temp (°C)
Time (h)
Yielda (%)
In
I2
HI
HCl
40
1
2
3
4
5
6
7
8
9
10
11
12
13
a
4
4
4
4
4
4
4
4
4
4
4
4
4
1 drop
Benzene(15)/reflux
Benzene(15)/reflux
Benzene(15)/reflux
Toluene(15)/50
CH2Cl2(15)/reflux
Benzene(15)/50
24
24
10
24
24
24
24
24
7
24
8
24
12
NRc
NR
43
4
4
40
40
40
40
20
20
20
30
40
40
60
36
19c
16b
NRc
14c
32
1 drop
1 drop
1 drop
1 drop
1 drop
Benzene(15)/rt
Benzene(15)/50
Benzene(15)/reflux
Benzene(15)/reflux
Benzene(15)/reflux
Benzene(15)/reflux
Benzene(15)/reflux
43
52
35
44
GC yield with an internal standard.
NMR yield.
b
c
Substrate was remained (entry 1: 50%, entry 5: 40%, entry 7: 20%, entry 8: 24%).
in Table 2, the cyclization of 2-nitroethynylbenzene to
indole occurs in the presence of the hydriodic acid in ben-
zene, whereas it does not occur even in the presence of the
hydrochloric acid (Table 2, entry 1).
methyl)phenylethynyl]]-2-nitrobenzene (entry 12) were
retarded significantly and the yield was drastically lowered.
In the case of 4-chloro-1-[2-[4-(trifluoromethyl)phenyleth-
ynyl]]-2-nitrobenzene, no major product was observed even
with the extended reaction time of up to 2 days. The sub-
stitution of highly electronegative halogen atom such as
fluoro atom on the phenyl ring also slowed down the reac-
tion and lowered the yield as shown in entries 16, 17, and
18 in Table 3. Therefore, the hyperconjugation effect and
electronegativity of the substituent seem to affect the reac-
tivity, which may come from the variations in electron den-
sity of the triple bond between the two phenyl groups.
Although the reaction path is not disclosed yet, it is obvi-
ous that 1-amino-2-(2-arylethynyl)arene is not a reaction
intermediate, since 1-amino-2-arylethynylarene is not
transformed into the corresponding indole by treating with
HI or HI-In3+ (In3+ could be formed from the reduction of
nitro group by indium) in aliquat 336/benzene at reflux.
We presume that more reactive intermediate such as
nitroso radical anion species may trigger the heteroannula-
tion. We are now studying on theoretical calculations to
explain the mechanistic considerations.
A typical procedure for the reductive heterocyclization
is as follows: 2-Nitroethynylarene derivative (0.5 mmol)
was added to a mixture of indium powder (230 mg,
2.0 mmol) and aliquat 336 (1 drop) in benzene (10 mL),
and then hydriodic acid (4.5 mL, 20 mmol) in benzene
(5 mL) was added. The reaction mixture was stirred at
reflux under a nitrogen atmosphere. After the reaction
was complete, the reaction mixture was diluted with diethyl
ether (30 mL), filtered through Celite, poured into 10%
NaHCO3 solution (30 mL), and extracted with diethyl
ether (30 mL x 3). The combined organic extracts were
As indium in the presence of hydriodic acid turned out
to have a reasonable reductive ability and trigger the cycli-
zation toward indoles, the indium/hydriodic acid-pro-
moted cyclization of 1-nitro-2-(2-phenylethynyl)benzene
to indole was extended to cyclizations of variously substi-
tuted 1-(2-arylethynyl)-2-nitroarenes to test the synthetic
utilization. Thus, the heterocyclizations of variously substi-
tuted 1-(2-arylethynyl)-2-nitrobenzene were examined
using the optimized reaction conditions, that is, indium
(4 equiv)/aq HI (40 equiv)/aliquat 336 (1 drop) in benzene
at reflux (Table 3, entries 1–18). In most cases, the cycliza-
tion reaction appears to be generally applicable, as most of
the substrates were consumed within 1–8 hours to give the
corresponding indoles with reasonable yields.
As shown in Table 3, an interesting tendency of the sub-
stituent was observed. In general, the hyperconjugative
electron-donating methyl group on either of the phenyl
rings seems to enhance the reactivity in terms of fast reac-
tion time and (similar or) improved yield compared with a
similar compound that has no methyl group on the phenyl
ring (e.g., entry 1 vs entries 2, 3; entry 5 vs entries 6, 7; entry
9 vs entries 10, 11; entry 13 vs entries 14, 15). On the other
hand, the electronegative group or heteroatom on either of
the phenyl rings tends to retard the reaction and reduce the
yield as well. Especially, the reactions of trifluoromethyl
substituted 1-nitro-2-(2-phenylethynyl)arenes such as 1-[2-
[4-(trifluoromethyl)phenylethynyl]]-2-nitrobenzene (entry 4),
1-[2-[4-(trifluoromethyl)phenylethynyl]]-4-methyl-2-nitro-
benzene (entry 8), and 4-chloro-1-[2-[4-(trifluoro-

3736
J. S. Kim et al. / Tetrahedron Letters 49 (2008) 3733–3738
Table 3
Synthesis of 2-phenylindole derivatives under the optimized condition
R''
R''
In (4 equiv) , HI (aq, 40 equiv)
Aliquat 336 (1 drop) , Benzene (15 mL), reflux
R'
N
R'
NO2
H
(0.5 mmol)
Entry
1
Substrate
Time (h)
8
Product
Yielda (%)
50
N
H
NO2
NO2
CH3
CH3
2
3
4
2
2
60
55
18
N
H
N
H
NO2
CH3
CH3
CF3
CF3
16
N
H
NO2
H3C
5
6
6
1
64
58
N
H
H3C
H3C
H3C
NO2
NO2
H3C
CH3
CH3
N
H
H3C
H3C
Cl
7
8
1
12
6
63
17
50
50
N
H
NO2
NO2
NO2
NO2
CH3
CH3
CF3
CF3
N
H
H3C
Cl
9
N
H
Cl
CH3
CH3
10
4
N
H
Cl
Cl
11
12
13
4
48
8
53
N
H
Cl
NO2
NO2
CH3
CH3
Cl
Cl
CF3
—
No major product
Cl
54
N
H
NO2

J. S. Kim et al. / Tetrahedron Letters 49 (2008) 3733–3738
3737
Table 3 (continued)
Entry
Substrate
Time (h)
3
Product
Yielda (%)
Cl
Cl
CH3
14
15
16
17
18
57
61
44
45
35
CH3
N
H
NO2
Cl
Cl
3
12
3
N
H
CH3
NO2
CH3
F
F
F
N
F
H
NO2
CH3
CH3
N
H
F
F
NO2
NO2
6
N
H
CH3
CH3
a
Isolated yield.
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dried over MgSO4, filtered, and concentrated. The residue
was eluted with ethyl acetate/hexane (v/v = 2/98–20/80)
through a silica gel column to give the corresponding 2-
phenylindole, for the structures of 2-arylindoles were fully
1
characterized by H NMR, 13C NMR, FTIR, MS, and
HRMS.7
In conclusion, we have described a simple and efficient
method for one-pot transformation of 2-nitroethynylarenes
to the corresponding 2-arylindoles with good yields in the
presence of indium and aqueous HI in benzene.
Acknowledgment
This work was supported by the RRC program of the
Ministry of Commerce, Industry and Energy and partly
by the Kwangwoon University in the year 2007.
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7. Representative
spectroscopic
data
of
6-fluoro-2-(4-methyl-
phenyl)indole; TLC (20% ethyl acetate/hexane) R f 0.45; mp 225–
227 °C; 1H NMR (400 MHz, CDCl3) d 8.30 (br s, 1H), 7.48–7.53 (m,
3H), 7.24 (d, 2H, J = 8.3 Hz), 7.06 (dd, 1H, J = 9.7, 2.3 Hz) 6.87 (ddd,
1H, J = 9.8, 8.7, 2.3 Hz) 6.73 (br s, 1H) 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 161.10, 158.74, 138.56, 138.53, 137.69, 136.67,
136.55, 129.73, 129.33, 125.84, 124.88, 121.19, 121.09, 108.98, 108.74,
99.23, 97.35, 97.09, 21.2; IR (Nujol) 3441, 3058, 2990, 1498, 1415, 1348,
1261, 908 cmꢀ1;GC–MS m/z (rel. intensity) 225 (M+, 100), 209 (6), 196
(7), 183 (5), 112 (6), 99 (3); HRMS (EI) calcd for C15H12FN 225.0953,
found 225.0950.
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