Solid-state synthesis of novel 3-substituted indoles

Article abstract of DOI:10.1016/j.crci.2013.02.001

Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] and N,N,N',N'-tetrabromobenzene-1,3-disulfonamide [TBBDA] were used as efficient catalysts for the one-pot synthesis of 3-substituted indoles in good to high yields from indole, aldehydes, and arylami

Full text of DOI:10.1016/j.crci.2013.02.001

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Full paper/Memoire
Solid-state synthesis of novel 3-substituted indoles
*
Ramin Ghorbani-Vaghei , Hajar Shahbazi, Zahra Toghraei-Semiromi
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65174 Hamedan, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] and N,N,N’,N’-tetrabromoben-
zene-1,3-disulfonamide [TBBDA] were used as efficient catalysts for the one-pot synthesis
of 3-substituted indoles in good to high yields from indole, aldehydes, and arylamines
under solid-state conditions at room temperature.
Received 11 November 2012
Accepted after revision 4 February 2013
Available online xxx
´
ß 2013 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Multi-component reaction
3-Substituted indoles
TBBDA
PBBS
1. Introduction
2. Experimental
Multi-component reactions (MCRs) are powerful and
useful synthetic tools to produce complex molecules from
simple precursors by a one-pot procedure [1]. Since they
are performed without the need to isolate any intermedi-
ate during their processes, this reduces time and saves
both energy and raw materials [2]. Therefore, the design of
novel MCRs has attracted great attention from research
groups working in the field of medicinal chemistry, drug
discovery, and materials science [3].
Indole and its derivatives are known as an important
class of heterocyclic compounds and bioactive intermedi-
ates in R&D and pharmaceutical industry [4–12]. 3-
Substituted indoles are important building blocks for the
synthesis of various biologically active molecules [13–18].
The immense potential of indole nucleus as drug
candidates prompted the synthetic chemists to explore
different methods suitable for the synthesis of 3-substi-
tuted indoles. One such method is MCR. The atom-
economy, convergent character, operational simplicity,
structural diversity, and complexity of the molecules are
the major advantages associated with MCRs.
All commercially available chemicals were obtained
from Merck and Fluka companies, and used without
further purification unless otherwise stated. Nuclear
magnetic resonance, 1H- and 13C-NMR spectra were
recorded on Bruker Avance 300 FT NMR spectrometers.
Infrared (IR) spectroscopy was conducted on a Perkin
Elmer GX FT-IR spectrometer. Mass spectra were recorded
on a Shimadzu QP 1100 BX Mass Spectromet. Elemental
analyzes (C, H, N) were performed with a Heraeus CHN-
Rapid analyzer.
2.1. Typical procedure for the preparation of N-((1H-indol-3-
yl)(p-tolyl)methyl)2-amino-4,6-dimethylpyrimidin
To a stirred mixture of 4-methylbenzaldehyde (1 mmol,
0.120 g) and N,N,N’,N’-tetrabromobenzene-1,3-disulfona-
mide [TBBDA] (0.05 g, 0.09 mmol) or poly(N-bromo-N-
ethyl-benzene-1,3-disulfonamide) [PBBS] (0.12 g) at room
temperature, was added 2-amino-4,6-dimethylpyrimidin
(1 mmol, 0.123 g). Then, indole (1 mmol, 0.12 g) was added
to the mixture after 10 min. The progress of the reaction
was monitored by TLC (n-hexane/acetone, 17:2). After
completion of the reaction, EtOH (5 mL) was added to
the reaction mixture and the colorless precipitate was
filtered (after evaporation of the ethanol, cool methylene
* Corresponding author.
E-mail address: rgvaghei@yahoo.com (R. Ghorbani-Vaghei).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.02.001
Please cite this article in press as: Ghorbani-Vaghei R, et al. Solid-state synthesis of novel 3-substituted indoles. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.02.001

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dichloride (2 mL) was added, and the catalyst was
recovered), washed with EtOH and dried and purified by
recrystallization from ethanol.
28 (49). Anal. Calcd. for C21H20N4: C, 76.80; H, 6.14; N,
17.06%. Found: C, 76.56; H, 6.14; N, 17.08%.
2.2.4. N-((2,6-dichlorophenyl)(1H-indol-3-yl)methyl)2-
aminopyrimidine (Table 2, 4h)
2.2. Physical and spectroscopic data
Mp: 161–162 8C Yield: 83%. IR (KBr): 3428, 3181, 1586,
2.2.1. N-((1H-indol-3-yl)(p-tolyl)methyl) 2-amino-4,6-
dimethylpyrimidine (Table 2, 4b)
Mp: 154–156 8C. Yield: 93%. IR (KBr): 3427, 1631, 1587,
1568, 1511, 1456, 1384, 1340, 1121, 743, 802, 743,
1567, 1509, 1485, 1455, 1340, 1121, 1070, 1009, 804 cmÀ1
.
1H-NMR (FT-90 MHz, DMSO-d6):
6.88–8.30 (12H, m), 11.02 (1H, s). 13C-NMR (FT-400 MHz,
DMSO-d6): (ppm) 49.7, 105.6, 111.5, 112.2, 112.5, 118.9,
d (ppm) 6.66 (1H, s),
d
663 cmÀ1
.
1H-NMR (FT-400 MHz, DMSO-d6):
d
(ppm)
2.20 (9H, s), 6.36 (1H, s), 6.60 (1H, s), 6.62–7.63 (10H,
m), 10.89 (1H, s). 13C-NMR (FT-400 MHz, DMSO-d6):
119.3, 121.7, 124.1, 124.3, 126.3, 129.9, 137.0, 137.3, 158.5,
161.6, 162.5. MS, m/z: 368 (M+, 2), 238 (5), 176 (11), 175
(71), 94 (37), 28 (100), 26 (27). Anal. Calcd. for
d
(ppm) 21.1, 24.1, 51.1, 109.3, 111.9, 117.9, 118.9, 119.4,
121.5, 123.5, 123.6, 126.5, 127.7, 129.0, 135.8, 136.7, 136.9,
141.6, 162.0, 167.2. MS, m/z: 342 (M+, 27), 220 (73), 117
(50), 42 (100), 28 (40). Anal. Calcd. for C22H22N4: C, 77.16;
H, 6.48; N, 16.36%. Found: C, 77.04; H, 6.36; N, 16.35%.
C21H18Cl2N4: C, 61.80; H, 3.82; N, 15.17%. Found: C,
54.73; H, 3.38; N, 25.23%.
2.2.5. N-((1H-indol-3-yl)(4-nitrophenyl)methyl)2-
aminopyrimidine (Table 2, 4i)
Mp 184–185 8C. Yield: 76%. IR (KBr): 3415, 3225, 1590,
1515, 1449, 1414, 1344, 1252, 1106, 1012, 870, 802, 739,
2.2.2. N-((2,3-dichlorophenyl)(1H-indol-3-yl)methyl)2-
amino-4,6-dimethylpyrimidine (Table 2, 4c)
Mp: 209–211 8C. Yield: 87%. IR (KBr): 3424, 1588, 1563,
1507, 1451,1341, 1194, 1123, 830, 793, 740, 580 cmÀ1. 1H-
605, 425 cmÀ1. 1H-NMR (FT-400 MHz, DMSO-d6):
d
(ppm)
6.62 (1H, s), 6.64 (1H, s), 6.68–8.32 (12H, m), 10.05 (1H, s).
13C-NMR (FT-400 MHz, DMSO-d6):
(ppm) 51.4, 111.2,
d
NMR (FT-400 MHz, DMSO-d6):
(1H, s), 6.41 (1H, s), 6.79–7.79 (9H, m), 10.95 (1H, s). 13C-
NMR (FT-400 MHz, DMSO-d6): (ppm) 24.0, 59.6, 109.8,
112.1, 115.7, 119.1, 119.2, 121.8, 124.1, 124.3, 126.6, 127.7,
128.4, 129.1, 130.9, 131.9, 136.8, 136.9, 144.9, 161.7, 167.3.
MS, m/z: 396 (M+, 12), 361 (58), 238 (50), 173 (100), 29
(38).
d
(ppm) 2.20 (6H, s), 6.40
112.1, 116.1, 119.1, 119.3, 121.9, 123.9, 124.1, 124.3, 126.3,
128.7, 136.8, 146.7, 152.3, 158.5, 161.9. MS, m/z: 345 (M+,
4), 298 (2), 204 (10), 117 (39), 28 (100), 27 (46). Anal. Calcd.
for C19H15N5O2: C, 66.08; H, 4.38; N, 20.28%. Found: C,
65.91; H, 4.24; N, 20.18%.
d
3. Results and discussion
2.2.3. N-((1H-indol-3-yl)(phenyl)methyl)2-amino-4,6-
dimethylpyrimidine (Table 2, 4d)
Mp: 200–201 8C. Yield: 80%. IR (KBr): 3426, 3240, 1586,
1567, 1508, 1489, 1455, 1340, 1121, 1013, 832, 806, 744,
In continuation of our interest in the application of
TBBDA and [PBBS] [16] in organic synthesis [19–31], we
wish to report here a facile and improved protocol for the
preparation of new 3-substituted indoles from heteroar-
ylamines, aromatic aldehydes, and indole in the presence
of TBBDA and PBBS as catalysts under solid-state condi-
tions at room temperature (Scheme 1).
619, 479 cmÀ1. 1H-NMR (FT-400 MHz, DMSO-d6):
d
(ppm)
2.21 (6H, s), 6.38 (1H, s), 6.60 (1H, s), 6.62–7.76 (10H, m),
10.95 (1H, s). 13C-NMR (FT-400 MHz, DMSO-d6):
(ppm)
d
23.9, 50.9, 109.6, 112.0, 117.1, 119.0, 119.3, 119.9, 121.6,
123.8, 123.8, 126.3, 130.0, 131.3, 136.9, 144.1, 161.9, 167.2.
MS, m/z: 328 (M+, 18), 251 (5), 206 (38), 118 (50), 42 (100),
The advantages of TBBDA and PBBS are as follows:
ꢀ
the preparation of TBBDA and PBBS is easy;
Scheme 1. Three-component synthesis of 3-substituted indoles.
Please cite this article in press as: Ghorbani-Vaghei R, et al. Solid-state synthesis of novel 3-substituted indoles. C. R.
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3
Table 1
Optimization of reaction conditions for the synthesis of 3-substituted indoles.
H3C
N
NH2
N
CHO
CH3
N
Cl
N
TBBDA
r.t.
+
+
H3C
NH
Cl
N
CH3
H
N
H
Entry
Solvent/Condition
Catalyst TBBDA (g)
Time (min)
Yield (%)a
1
EtOH/rt
EtOH/rt
EtOH/rt
EtOH/rt
Neat/rt
Neat/rt
Neat/rt
Neat/rt
Neat/rt
Neat/rt
Neat/rt
Neat/rt
No Catalyst
0.05
380
70
70
70
340
60
55
35
25
25
25
25
27
52
65
76
30
56
67
78
98
96
88
95
2
3
0.08
4
0.1
5
No Catalyst
0.02
6
7
0.03
8
0.04
9
0.05
10
11
12
0.06
0.07
0.08
rt: room temperature; TBBDA: N,N,N’,N’-tetrabromobenzene-1,3-disulfonamide.
a
Standardization of reaction conditions: 2-chlorobenzaldehyde (1 mmol, 0.140 g), 2-amino-4,6-dimethylpyrimidine (1 mmol, 0.12 g), indole (1 mmol,
0.12 g).
ꢀ
ꢀ
TBBDA and PBBS are stable under atmospheric condi-
tions for two months;
after completion of the reaction, the catalysts are
recovered and can be reused several times without
decreasing the yield.
All these reactions underwent smoothly to provide the
corresponding 3-substituted indole, in moderate to good
yields (Table 2, entries 1–10). The present method failed to
furnish the expected 3-substituted indole derivative with
4-aminopyridine. In general, aromatic aldehydes bearing
electron-donating or electron-withdrawing functional
groups at different positions reacted smoothly with
arylamine in the presence of TBBDA and indole to generate
Initially, we decided to explore the role of our catalyst in
EtOH as a solvent system for the preparation of 3-
substituted indoles. In the absence of catalyst, no 3-
substituted indole was observed, even after prolonged
reaction time. Since the synthesis of 3-substituted indole
failed in the absence of catalyst, the effect of the catalyst
was also investigated in various conditions, and the results
are presented in Table 1.
In the solvent system, the best results were achieved
using 0.1 g, 0.18 mmol of catalyst (Table 1, entry 4). In
recent years, there has been an increasing interest in
reactions that proceeded in the absence of a solvent due to
reduced pollution, low cost, simplicity in process and
handling. Therefore, we decided to test this reaction in the
solid state and in various ratio of catalyst. We found that
the reaction was rapid and gave excellent yields of the
product when catalyzed by TBBDA (25 min, 98%, entry 9).
These results encouraged us to investigate the scope
and generality of this new protocol for various 3-
substituted indoles under optimized conditions in the
presence of catalytic amounts of either TBBDA or PBBS. As
shown in Table 2, a series of aromatic aldehydes containing
either electron-withdrawing or electron-donating substi-
tuents successfully reacted with indole and various
amines, such as 2-amino-4,6-dimethylpyrimidine, 2-ami-
nopyrimidine, 2-aminopyridine, affording good to high
yields of products with high purity, at room temperature
under solid-state conditions. Our attempt for the reaction
of aromatic aldehyde with OMe substituents failed.
Scheme 2. Suggested mechanism for synthesis of 3-substituted indoles.
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Table 2
Synthesis of various 3-substituted indoles using TBBDA and PBBS at room temperature.
Structure
Aldehyde
Amine
Producta
TBBDA
Time (min) Yield (%) Time (min) Yield (%)
25 98 40 85
PBBS
Reference
[18]
4a
NH2
N
H3C
N
CHO
Cl
N
CH3
CH3
CH3
N
H3C
H3C
H3C
H3C
H3C
CH3
CH3
CH3
CH3
CH3
NH
Cl
N
H
4b
4c
4d
4e
25
93
45
90
–
NH2
N
CHO
CHO
CHO
H3C
N
Me
N
N
N
N
N
NH
N
H
40
30
20
87
80
92
60
60
35
88
75
87
–
NH2
N
H3C
N
Cl
Cl
Cl
Cl
N
N
N
NH
N
H
–
NH2
N
H3C
N
CH3
NH
N
H
[18]
NH2
N
H3C
N
CHO
Br
Br
CH3
NH
N
H
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Table 2 (Continued )
Structure
Aldehyde
Amine
Producta
TBBDA
Time (min) Yield (%) Time (min) Yield (%)
55 87 90 85
PBBS
Reference
[18]
4f
CHO
NH2
N
H3C
N
O2N
N
CH3
N
N
H3C
CH3
NH
NO2
N
H
4g
70
63
90
66
[18]
NH2
CHO
Cl
Cl
N
N
N
NH
N
H
4h
40
83
60
76
–
CHO
NH2
N
Cl
Cl
Cl
N
N
N
Cl
N
H
N
N
H
4i
40
76
70
70
–
NH2
N
O2N
CHO
N
N
NH
NO2
N
H
4j
35
86
50
63
[18]
CHO
NH2
N
Cl
N
NH
Cl
N
H
TBBDA: N,N,N’,N’-tetrabromobenzene-1,3-disulfonamide; PBBS: poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide).
a
Products were characterized from their physical properties, by comparison with authentic samples, and by spectroscopic methods.
the corresponding products in good to excellent yields. The
products were characterized by IR, 1H-NMR, 13C-NMR
spectra and mass spectra.
TBBDA and PBBS are stable, non-volatile, inexpensive,
and safe catalysts.
It is likely that these catalysts release Br+ in situ, which
can act as an electrophilic species [19–31]. Therefore, the
mechanism shown in Scheme 2 can be suggested for the
conversion of the indole, aldehyde, and arylamine, to 3-
substituted indole [4].
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heteroarylamines derivatives from the reaction of alde-
hydes, indole, and arylamine compounds using TBBDA and
PBBS under solvent-free conditions. The catalysts are
heterogeneous, recyclable, non-corrosive and environ-
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We are thankful to Bu-Ali Sina University, the Center of
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Methods for Chemical Synthesis (CEDEFMCS) for financial
support.
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Please cite this article in press as: Ghorbani-Vaghei R, et al. Solid-state synthesis of novel 3-substituted indoles. C. R.
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