Synthesis of indoles from o,β-dinitrostyrenes via indium/acetic acid-mediated Reductive heterocyclizations

Article abstract of DOI:10.3987/COM-12-12605

Reductive heterocyclization reactions of various 1-nitro-2-(2-nitroaryl) ethenes to indoles were investigated. In the presence of indium/AcOH in toluene or benzene, 1-nitro-2-(2-nitroaryl)ethenes were cyclized to give corresponding indoles in good yields.

Full text of DOI:10.3987/COM-12-12605

HETEROCYCLES, Vol. 87, No. 1, 2013
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HETEROCYCLES, Vol. 87, No. 1, 2013, pp. 155 - 162. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 11th October, 2012, Accepted, 26th November, 2012, Published online, 28th November, 2012
DOI: 10.3987/COM-12-12605
SYNTHESIS OF INDOLES FROM -DINITROSTYRENES VIA
INDIUM/ACETIC ACID-MEDIATED REDUCTIVE
HETEROCYCLIZATIONS
Geunsoo Lee, Jaehwan Choi, Byung Min Lee,† and Byeong Hyo Kim*
Department of Chemistry, Kwangwoon University, Seoul, 139-701, Korea
E-mail: bhkim@kw.ac.kr
†Korea Research Institute of Chemical Technology, Taejon 305-600, Korea
Abstract – Reductive heterocyclization reactions of various 1-nitro-2-
(2-nitroaryl)ethenes to indoles were investigated. In the presence of indium/AcOH
in toluene or benzene, 1-nitro-2-(2-nitroaryl)ethenes were cyclized to give
corresponding indoles in good yields.
Indole rings have been continuously investigated since the early days of heterocycles given their
pharmacological and biological activity and potential application.1 Since the discovery of Fischer indole
synthesis, many synthetic chemists have investigated methods for the efficient synthesis of indole
compounds including various metal-catalyzed preparations.2
Various indium-mediated organic transformations were found in the literature in the past decades as they
were found to be environmentally favorable.3 Moreover, given that environmental issues are becoming
increasingly important to society, the green chemistry characteristics of indium are noteworthy.3b
Therefore we made continuous efforts recently for the development of new synthetic methodologies using
indium-mediated
reaction
conditions
including
reductive
heterocyclizations
towards
2,1-benzisoxazoles,4a,b benzimidazoles,4c quinolines,4d indazoles,4b and indoles.4e Herein, we report the
development of one-pot indole synthesis from o,β-dinitrostyrenes via indium-promoted reductive
heterocyclization reactions.
We examined a one-pot reaction for the preparation of indoles from o,β-dinitrostyrenes since only a few
examples of indole synthesis starting from o,β-dinitrostyrenes have been reported in the literature.2a,5
While a range of transformation from various starting substrates is well documented in the literature,
yields of the indole products by conventional conditions using reducing agents such as zinc, iron, titanium,

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HETEROCYCLES, Vol. 87, No. 1, 2013
or tin reagent usually remain in low to middle range. Moreover, most of these reported reactions are not
environmentally favorable and/or use harsh conditions.2b,2o Prior to study on heterocyclization reactions
of o,β-dinitrostyrenes, the o,β-dinitrostyrene substrates were prepared by one-step synthesis starting from
corresponding o-nitrobenzaldehyde derivatives (Eq. 1).6
O
NO2
MeNO2 (2.5 equiv), NH4OAc (2.5 equiv)
AcOH, reflux
H
R
R
NO2
NO2
Based on our previous heterocyclization reaction conditions, the initial indium-mediated experiments
were tested with synthesized o,β-dinitrostyrene substrate by varying solvents and additives to find an
optimum reaction condition (Table 1). The reaction conditions (indium/HI in benzene)4e that we
developed to transform 1-(2-arylethynyl)-2-nitroarenes into 2-arylindoles were not successful for
heterocyclization of o,β-dinitrostyrene (entry 1, Table 1). The use of a strong acid such as hydrochloric
acid as an additive for indium-mediated reductive cyclization was also unsuccessful. Reactions performed
in protic solvents in the presence of indium/acetic acid did produce indole rings, but only in poor yield
(entries 2, 3). Various reaction conditions including indium/2-bromo-2-nitropropane,4c indium/indium(III)
chloride, and indium/iodine4b in diverse solvent systems failed to produce the indole as a desired major
product. However, the reaction of o,β-dinitrostyrene in the presence of indium/acetic acid in non-polar
aprotic solvent, such as benzene or toluene, produced the desired indole product with reasonably high
yields (entries 4~16). Ratio of indium and acetic acid, amount of the solvent, and type of aprotic solvent
were examined to obtain optimum conditions for indole formation from o,β-dinitrostyrenes (Table 1). The
reaction condition including o,β-dinitrostyrenes (1 mmol)/indium (5 equiv)/acetic acid (10 equiv) in
benzene (5 mL) at reflux (entry 5) or in toluene (5 mL) at 80 oC (entry 15) was the most practical reaction
condition. We recommend a toluene solvent over benzene given the potential decrease in environmental
and health risk.
Indium in the presence of acetic acid proved to be successful for the reductive cyclization of
o,β-dinitrostyrenes toward indole. Given this observation, the indium/acetic acid-mediated reductive
cyclization of o,β-dinitrostyrene to indole was extended to heterocyclizations of variously substituted
indoles in order to examine for its synthetic utilizations. The heterocyclizations of substituted
o,β-dinitrostyrenes were tested using the optimized reaction conditions of indium (5 equiv)/acetic acid (10
equiv) in benzene or toluene. Since reaction yields were not significantly different in benzene or toluene

HETEROCYCLES, Vol. 87, No. 1, 2013
157
solvent, we applied both sets of reaction conditions to various o,β-dinitrostyrenes. Table 2 summarizes the
reactions performed. In most cases, heterocyclization of o,β-dinitrostyrenes was successful with
reasonable yield in the range of 65 - 90%, regardless of the solvent applied. The reaction was completed
in 1 - 5 hours and yield did not vary significantly depending on whether the substrate was substituted with
hyperconjugative alkyl group (or with entries 7, 8) or electronegative heteroatom (entries 2 - 6). Without
doubt, this methodology can be utilized to synthesize substituted indole derivatives with ease.
Table 1. Indium-mediated reductive cyclization reaction of o,β-dinitrostyrene to indole under various
conditions
NO2
In, additive
solvent / temp
N
NO2
1 mmol
H
1
Molar equiv.
additive (equiv)
HI (40)
Yielda (%)
1
Substrate
(eq)
Solvent (mL)/
Temp (oC)
Time
(h)
Entry
In
5
4
4
5
4
5
6
5
5
5
5
5
5
5
5
5
1b
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
benzene (5)/reflux
MeOH (5)/reflux
H2O (5)/ reflux
2
3
tracec
26c
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (5)
3
2
6d
4
THF (5)/reflux
1
14
5
benzene (5)/reflux
benzene (5)/reflux
benzene (5)/reflux
benzene (5)/reflux
benzene (5)/reflux
benzene (2.5)/reflux
benzene (10)/reflux
benzene (5)/50
2
65
6
2
77
7
2
73
8
24
2
36d
9
AcOH (20)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
68
10
11
12
13
14
15
16
2
59
3
69
5
30d
26d
45d
83 (80)e
43c
benzene (5)/rt
24
24
5
toluene (5)/50
toluene (5)/80
toluene (5)/reflux
2
aGC yield with an internal standard(octane). bAliquat 336 (1 drop) was added.
cSeveral by-products were observed on GC analysis. dUnreacted initial substrate was remained. eIsolated yield.

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HETEROCYCLES, Vol. 87, No. 1, 2013
Table 2. Indium-mediated reductive cyclization of o,β-dinitrostyrenes to indole derivatives under
optimized conditions (o,β-dinitrostyrene (1 mmol)/indium (5 mmol)/AcOH (10 mmol)/benzene (5 mL,
method A) or toluene (5 mL, method B)
NO2
In, AcOH
R
R
method A or B
N
NO2
H
Entry
1
Time (h)
Product
Yield (%)a
Substrate
NO2
Method
NO2
A
B
2
5
75
80
N
H
NO2
O
O
O
O
A
B
3
3
71
65
2
3
N
H
NO2
NO2
A
B
3
2
84
90
N
H
NO2
OMe
OMe
Cl
Cl
NO2
A
B
4
3
80
89
4
5
N
H
NO2
NO2
Cl
Cl
74
69
A
B
1
2
N
H
NO2
NO2
A
B
69
69
3
2
6
7
N
H
Cl
Cl
NO2
NO2
5
4
A
B
76
71
N
H
NO2
NO2
A
B
4
4
78
65
8
N
H
NO2
a Isolated yield.
Based on our previous results and related literature,5b a plausible reaction mechanism is depicted in
Scheme 1. The mechanistic picture consists of sequential processes of: 1) single electron transfer by
indium metal; 2) proton transfer by acetic acid; and 3) isomerization in acidic medium to form
intermediate A (Scheme 1). Intermediate A can be transformed into indole via cyclization by the
nucleophilic addition of amine to protonated imine followed by proton transfer, loss of NH3, and
aromatization by acid-base chemistry.
A new, mild, environmentally friendly, and efficient one-pot synthetic protocol was developed to obtain

HETEROCYCLES, Vol. 87, No. 1, 2013
159
variously substituted indoles directly from corresponding o,β-dinitrostyrenes using indium/acetic acid
under mild conditions. This one-pot cyclization method can be utilized to introduce the biologically active
indole moiety starting with a proper dinitro compound.
NH
NH2
NH2
H+
NO2
SET & PT
NH2
NH3
R
NH2
NH2
NO2
R
R
R
R
A
H
1) -H+
2) +H+
NH3
-NH4
-NH3
NH2
N
H
N
N
H
N
H
R
R
R
H
H
Scheme 1
EXPERIMENTAL
1. General consideration
Most of the chemical reagents were purchased from Sigma-Aldrich Co. (St. Louis, Missouri, USA) and
were used without further purification, in most cases. Solvents were purchased and dried using standard
1
methods. H and 13C NMR spectra were recorded at 400 (JEOL, Tokyo, Japan) and 100 MHz,
respectively. Chemical shifts were reported in parts per million relative to the residual solvent as an
internal standard. GC-MS spectra were recorded on an Agilent 6890N GC connected to an Agilent 5975
mass selective detector (Hewlett-Packard Co., Palo Alto, California, USA). Infrared (IR) spectra were
recorded using an MB104 FTIR (ABB Bomem, Inc., Zurich, Switzerland). Melting points were
determined on an electrothermal apparatus and were uncorrected. All the major products were isolated by
flash column chromatography on silica gel (230-400 mesh ATSM, purchased from Merck & Co., Inc.
(Whitehouse Station, New Jersey, USA)) with eluent of mixed solvents (EtOAc/hexane).
2. General procedure for indium-mediated reductive reaction of 1-nitro-2-(2-nitroethenyl)-
benzenes to indoles
A mixture of 1-nitro-2-(2-nitroethenyl)benzene derivatives (1.0 mmol), indium (0.574 g, 5.0 mmol), and
o
acetic acid (0.601 g, 10 mmol) in benzene (5 mL) or toluene (5 mL) was stirred at 80 C under nitrogen
atmosphere. After reaction completion, the reaction mixture was diluted with DCM (30 mL), filtered
through Celite, poured into 10% aqueous NaHCO3 (30 mL), and extracted with DCM (30 mL x 3). The
combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted
with EtOAc/hexane (v/v=30/70) through a silica gel column to give the corresponding pure indoles.
Indole structures were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS.

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HETEROCYCLES, Vol. 87, No. 1, 2013
1H-Indole2l
Mp 55.5-57.8 oC; TLC (40% EtOAc/hexane) Rf 0.62; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.76 (d,
J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.32-7.21 (m, 3H), 6.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
135.66, 127.74, 124.12, 121.91, 120.67, 119.74, 110.99, 102.49; IR (KBr) 3408, 3087, 1616, 1455 cm-1;
GC-MS m/z (rel. intensity) 117 (M, 100), 90 (44), 63 (12).
5H-[1,3]Dioxolo[4,5-f]indole2o
Mp 115.8-116.5 oC; TLC (50% EtOAc/hexane) Rf 0.60; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.03
13
(d, J = 18.8 Hz, 2H), 6.83 (s, 1H), 6.42 (s, 1H), 5.92 (s, 2H); C NMR (100 MHz, CDCl3) δ 144.88,
142.99, 130.58, 122.76, 121.61, 102.77, 100.53, 99.10, 91.84; IR (KBr) 3406, 3134, 3105, 2883, 1700,
1609, 1460, 1308 cm-1; GC-MS m/z (rel. intensity) 161 (M, 100), 103 (32), 76 (22), 50 (8).
7-Methoxy-1H-indole7
Oil; TLC (50% EtOAc/hexane) Rf 0.67; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.47 (d, J = 7.9 Hz,
13
1H), 7.26-7.20 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.71 (t, J = 2.6 Hz, 1H), 4.08 (s, 3H); C NMR (100
MHz, CDCl3) δ 146.02, 129.09, 126.27, 123.69, 120.02, 113.04, 102.62, 101.60, 55.12; IR (KBr) 3418,
3051, 2944, 1623, 1581, 1253 cm-1; GC-MS m/z (rel. intensity) 147 (M, 100), 132 (67), 104 (81), 89 (11),
77 (18), 63 (6), 51 (9).
5-Chloro-1H-indole2m
Mp 75.8-78.4 oC; TLC (50% EtOAc/hexane) Rf 0.63; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.50 (d,
13
J = 1.7 Hz, 1H), 7.12-7.02 (m, 3H), 6.37-6.36 (m, 1H); C NMR (100 MHz, CDCl3) δ 133.99, 128.80,
125.56, 125.27, 122.15, 119.97, 111.99, 102.20; IR (KBr) 3387, 3108, 3035, 1444, 1315, 1092 cm-1;
GC-MS m/z (rel. intensity) 151 (M, 100), 124 (13), 116 (25), 89 (32), 75 (8), 63 (9).
4-Chloro-1H-indole2o
1
TLC (50% EtOAc/hexane) Rf 0.58; H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.31-7.17 (m, 4H), 6.76
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 136.33, 126.59, 125.83, 124.77, 122.45, 119.43, 109.71, 101.01;
IR (KBr) 3418, 3109, 1706, 1600, 1564 cm-1; GC-MS m/z (rel. intensity) 151 (M, 100), 124 (14), 116
(24), 89 (38), 75 (8), 63 (13).
6-Chloro-1H-indole2o
Mp 89.4-90.7 oC; TLC (50% EtOAc/hexane) Rf 0.62; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.52 (d,
13
J = 8.5 Hz, 1H), 7.27 (s, 1H), 7.10-7.07 (m, 2H), 6.50 (s, 1H); C NMR (100 MHz, CDCl3) δ 135.99,
127.67, 126.31, 124.87, 121.47, 120.45, 110.91, 102.59; IR (KBr) 3403, 3107, 3066, 1719, 1609, 1575
cm-1; GC-MS m/z (rel. intensity) 151 (M, 100), 124 (15), 116 (21), 89 (34), 75 (8), 63 (10).
7-Methyl-1H-indole8
Mp 62.0-63.8 oC; TLC (50% EtOAc/hexane) Rf 0.55; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.53 (s,
1H), 7.25 (d, J = 8.3 Hz, 1H), 7.13-7.08 (m, 2H), 6.54 (s, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3)

HETEROCYCLES, Vol. 87, No. 1, 2013
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δ 133.95, 128.86, 127.97, 124.26, 123.47, 120.22, 110.66, 101.80, 21.36; IR (KBr) 3396, 3104, 3049,
2934, 2859, 1722, 1588 cm-1; GC-MS m/z (rel. intensity) 130 (M-1, 100), 103 (12), 77 (13), 65 (5), 51
(5).
5-Methyl-1H-indole2m
Mp 87.2-89.0 oC; TLC (50% EtOAc/hexane) Rf 0.57; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.58 (d,
J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.14-7.06 (m, 2H), 6.63 (s, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 135.39, 127.34, 123.82, 122.47, 120.19, 119.99, 118.44, 103.07, 16.69; IR (KBr) 3396, 3061, 2973,
2941, 1588, 1423, 1345, 1106 cm-1; GC-MS m/z (rel. intensity) 130 (M-1, 100), 103 (12), 77 (15), 65 (6),
51 (6).
ACKNOWLEDGEMENTS
This work was supported by Kwangwoon University in 2012.
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