PANI-HBF4: A reusable polymer-based solid acid catalyst for three-component, one-pot synthesis of 3-substituted amino methyl indoles under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.542535

A simple, fast, efficient, high-yielding, and green process is developed for one-pot, three-component synthesis of 3-substituted amino methyl indoles under solvent-free conditions using polyaniline salt as polymer-based reusable solid acid catalyst at room temperature. The advantages of polyaniline salt catalyst are ease of synthesis and handling, low cost, versatality, and recyclability. Copyright Taylor & Francis Group, LLC.

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PANI-HBF4: A Reusable Polymer-
Based Solid Acid Catalyst for Three-
Component, One-Pot Synthesis of 3-
Substituted Amino Methyl Indoles Under
Solvent-Free Conditions
Chebrolu Lavanya Devi a , Vaidya Jayathirtha Rao a & Srinivasan
Palaniappan b
a Organic Chemistry Division II, Indian Institute of Chemical
Technology, Hyderabad, India
b Organic Coatings and Polymers Division, Indian Institute of
Chemical Technology, Hyderabad, India
Accepted author version posted online: 28 Nov 2011.Version of
record first published: 03 Feb 2012.
To cite this article: Chebrolu Lavanya Devi , Vaidya Jayathirtha Rao & Srinivasan Palaniappan (2012):
PANI-HBF4: A Reusable Polymer-Based Solid Acid Catalyst for Three-Component, One-Pot Synthesis of
3-Substituted Amino Methyl Indoles Under Solvent-Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:11, 1593-1603
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Synthetic Communications1, 42: 1593–1603, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.542535
PANI-HBF4: A REUSABLE POLYMER-BASED SOLID
ACID CATALYST FOR THREE-COMPONENT, ONE-POT
SYNTHESIS OF 3-SUBSTITUTED AMINO METHYL
INDOLES UNDER SOLVENT-FREE CONDITIONS
Chebrolu Lavanya Devi,1 Vaidya Jayathirtha Rao,1 and
Srinivasan Palaniappan2
1Organic Chemistry Division II, Indian Institute of Chemical Technology,
Hyderabad, India
2Organic Coatings and Polymers Division, Indian Institute of Chemical
Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A simple, fast, efficient, high-yielding, and green process is developed for one-pot,
three-component synthesis of 3-substituted amino methyl indoles under solvent-free
conditions using polyaniline salt as polymer-based reusable solid acid catalyst at room tem-
perature. The advantages of polyaniline salt catalyst are ease of synthesis and handling, low
cost, versatality, and recyclability.
Keywords Multicomponent reaction; polyaniline salt catalyst; reusable catalyst; 3-substi-
tuted amino methyl indoles
INTRODUCTION
Multicomponent reactions have offered many fascinating and challenging
transformations in organic synthesis.[1–7] The atom-economy, convergent character,
operational simplicity, structural diversity, and complexity of the molecules are the
Received June 30, 2010.
Address correspondence to Srinivasan Palaniappan, Organic Coatings and Polymers Division,
Indian Institute of Chemical Technology, Hyderabad 500607, India. E-mail: palani74@rediffmail.com
1593

1594
C. L. DEVI, V. J. RAO, AND S. PALANIAPPAN
Figure 1. Biologically active 3-substituted indoles.
major advantages associated with multicomponent reactions. These multicomponent
reactions are emerging as a powerful tool in the synthesis of biologically important
compounds.[8,9]
Indole derivatives have become increasingly useful and important in the field of
pharmaceuticals.[10–13] Substituted 3-alkyl indole moieties are of much importance as
they are widely distributed in nature and reveal a broad range of biological
activity.[14,15] Indoles with substituents at the 3-position are considered as venerable
pharmacophores[16–19] in drug discovery and are found in various natural products
such as 5-HT1B=1D receptor agonist activities used in the treatment of migraines
(Fig. 1a), aromatase inhibitors for breast cancer (Fig. 1b),[20] HIV-1 integrase inhibi-
tor (Fig. 1c),[29] and Gramine (Fig. 1d).
The immense potential of the indole nucleus as drug candidates prompted us to
synthesize substituted 3-alkyl indoles based on multicomponent reactions. Literature
reports[22–28] for the synthesis of 3-substituted amino methyl indole derivatives by
various pathways are given in Table 1. Most of the methods have shortcomings such
as use of strongly acidic conditions, long reaction times, poor yields, and solvents
that are not acceptable in the context of green synthesis. Therefore, the discovery
of facile, efficient, and environmentally benign approaches for the synthesis of indole
derivatives is highly desirable.
Heterogeneous catalysts have gained much importance in organic synthesis.
Recently, we have been establishing the use of polymer-based solid acid catalyst in
various organic synthesis.[29] In this work, 3-substituted amino methyl indole
derivatives were synthesized efficiently by multicomponent reaction of aldehydes,
Table 1. Literature reports on the synthesis of amino methyl inldoles
No.
1
Reactants; catalyst, solvent, condition
Time
6 h
Yield (%) Ref.
Aldehyde, trimethyl silyl dialkyl amine, indole; LiClO4; diethyl
ether; rt
65–84
22
2
3
4
5
6
7
Aryl imine, indole; cinchona alkaloid; ethyl acetate; 50 ꢀC
N-Sulfonyl aldemines, indole; Cu(OTf)2; DCM; 20 ꢀC
Immonium salts, indole (or) N-methyl indole; DCM, toluene; rt
Tosyl aldemine, 3-bromo indole; THF; rt
8–72 h
3–5 days
2–15 h
86–98
47–94
73–92
15–73
30–57
65–85
85–95
23
24
25
26
27
28
12–18 h
10–24 h
3–4.5 h
Aldemines, indole; Dy(OTf)3; ionic liquid; rt
Aldehyde, amine, indole; PMA-SiO2; rt CH3CN; neat
1.75–2.75 h

AMINOMETHYLINDOLE SYNTHESIS USING POLYANILINE SALT
1595
Scheme 1. Synthesis of 3-substituted indoles catalyzed by PANI-HBF4.
N-methyl aniline, and indoles under solvent-free conditions at room temperature
using PANI-HBF4 as polymer-based solid acid catalyst (Scheme 1).
RESULTS AND DISCUSSION
Initially the reaction was conducted with benzaldehyde (0.01 mol), N-methyl
aniline (0.013 mol), and indole (0.01 mol) under solvent-free conditions at room tem-
perature for 30 min. The reaction gave 20% product of 3-substituted indole, 30% side
product of bisindolylmethane, and remainders of starting material (Table 2). This
reaction was carriedout with increasing amounts of PANI-HBF4 catalyst with
respect to the amount of benzaldehyde, and the results are included in Table 2. By
Table 2. Effect of catalyst amount on the product yield
No.
Catalyst (wt%)a
Product yield (%)b
By-product (%)b
1
2
3
4
5
6
0
1
2
3
4
5
20
45
60
70
80
95
30
18
10
5
2
0
aWith respect to aldehyde.
bIsolated yields.
Scheme 2. Possible mechanism for the formation of 3-substituted indoles.

1596
C. L. DEVI, V. J. RAO, AND S. PALANIAPPAN
Table 3. Three-component reaction of N-methyl aniline, indoles, and aldehydes catalyzed by PANI-
HBF4 for synthesis of 3-substituted amino methyl indoles
Time Isolated
(min) yield (%)
No.
Indole
Aldehyde
Product
1
30
95
2
30
97
3
30
94
4
45
90
5
40
92
(Continued )

AMINOMETHYLINDOLE SYNTHESIS USING POLYANILINE SALT
1597
Table 3. Continued
Time Isolated
(min) yield (%)
No.
Indole
Aldehyde
Product
6
40
92
7
45
93
8
45
90
9
50
92
10
50
88
(Continued )

1598
C. L. DEVI, V. J. RAO, AND S. PALANIAPPAN
Table 3. Continued
Time Isolated
(min) yield (%)
No.
Indole
Aldehyde
Product
11
12
13
45
45
45
90
93
90
increasing the amount of catalyst from 1 to 4 wt%, the desired product formation
was increased with decrease in by-product (bisindolylmethane formation) and start-
ing material quantity. The reaction of benzaldehyde with N-methyl aniline in the
presence of catalyst proceeds via the formation of immonium ion intermediate,
which then reacts with indole and gives the product (3-substituted indole). Simulta-
neously, benzaldehyde reacts with indole to give the side product (bisindolylmethane
formation) (Scheme 2). With the increase of catalyst amount of polyaniline salt (i.e,
increasing the Hþ concentration in the catalyst), the formation of immonium ion
increases and subsequently the desired product formation also increases. The pro-
duct in 95% yield was obtained without side product with the use of 5 wt% of catalyst
(Table 2). Increase in catalyst amount (>5 wt%), reaction time, and temperature of
the reaction did not improve the product yield.
The amount of dopants, both fluoroboric acid and dodecylhydrogensulfate
together, present in polyaniline salt was reported (47 wt%). However, it is difficult
to find out the percentage of individual dopant present on polyaniline salt. The acid

AMINOMETHYLINDOLE SYNTHESIS USING POLYANILINE SALT
1599
groups such as fluoroboric acid and dodecyl hydrogen sulfate present in the polyani-
line salt take part in organic transformation.
To evaluate the generality of this procedure, a variety of aromatic aldehydes
(having electron-withdrawing and electron-donating groups) and heterocyclic alde-
hyde were reacted with a different indoles (indole, 5-bromo indole, 5-methoxy
indole) and N-methyl aniline in the presence of a very low amount of PANI-HBF4
catalyst (5 wt%) under solvent-free conditions and gave products in excellent yields.
Results of these experiments are presented in Table 3. Electron-donating groups on
the aromatic ring react faster than electron-withdrawing substituents and gave better
yields. This indicates that the 3-substituted amino methyl indoles can be produced in
greater yield in less reaction time when compared to the reported procedures.[22–28]
All the synthesized compounds are well characterized by spectral data, and the char-
acterization data for four new compounds (Table 3, entries 6, 7, 9, and 12) were
reported in the experimental section.
To verify the recyclability of the PANI-HBF4 catalyst, the reaction of benzal-
dehyde (0.01 mol), N-methyl aniline (0.013 mol), and indole (0.01 mol) was per-
formed under solvent-free condition at room temperature for 30 min using 5 wt%
of PANI-HBF4 catalyst (with respect to the amount of benzaldehyde). After the
reaction, ethyl acetate was added to the reaction mixture, and the catalyst was
removed by filtration, washed thoroughly with ethyl acetate, dried in an oven, and
reused for the next cycle. The reaction proceeded smoothly with yields of 95, 95,
94, 93, 91, and 93%. This result indicates that the activity of the catalyst was not
affected by reusing the catalyst.
CONCLUSION
In conclusion, a simple, efficient, and green process was developed for the
synthesis of 3-substituted amino methyl indoles using polyaniline salt. Easy syn-
thesis of the catalyst, stability of catalyst, easy handling, convenient workup
procedure, mild reaction conditions, versatility, low cost, reusability, and the eco-
friendly nature of the catalyst make this method a valid contribution to the existing
methods.
EXPERIMENTAL
Analytical thin-layer chromatography (TLC) was performed using Merck
silica-gel 60 F glass plates. Flash chromatography was performed using Merck silica
gel (60–120 mesh). Melting points were determined using a Mel-Temp II melting-
point apparatus. NMR spectra were recorded using a Gemini 200-MHz Varian
instrument and an Avance 300-MHz Bruker UX 300 Fourier transform (FT)NMR.
NMR data were obtained in CDCl3=DMSO-d6 solution, and chemical shifts (d) were
given in parts per million (ppm) relative to tetramethylsilane (TMS). Mass spectra
were recorded using electrospray ionization (ESI) ion trap mass spectrometer
(Thermofinnigan, Sanzox, CA, USA). High-resolution mass spectra (HRMS) were
recorded using an Applied Biosystems QSTAR XL spectrometer. Infrared (IR) spec-
tra were recorded using a Shimadzu 435 IR spectrophotometer.

1600
C. L. DEVI, V. J. RAO, AND S. PALANIAPPAN
Synthesis and Characterization of Polyaniline Salt Catalyst
A polyaniline salt, polyaniline-fluoroboricacid-dodecylhydrogensulfate salt
(PANI-HBF4), was synthesized via emulsion polymerization pathway and character-
ized in our earlier report.[30] Aniline was oxidized to polyaniline salt by benzoyl
peroxide in the presence of sodium lauryl sulfate and fluoroboric acid. This polymer-
ization pathway leads to incorporation of both acid and surfactant groups, into the
polyaniline chain as dopants.
In a typical experiment, 3 g of benzoyl peroxide were dissolved in 30 ml chloro-
form in a 250-ml round-bottomed flask. Sodium lauryl sulfate (1 g) in 20 mL water
was added to the solution. The mixture was stirred at 40 ꢀC. Fluoroboric acid
(5.5 ml) and aniline (1 mL) were dissolved in 50 ml water. This solution was added
dropwise to the solution during 15–20 min under constant stirring, and the reaction
was continued for 8 h. The chloroform layer containing polyaniline salt was sepa-
rated from the aqueous layer and washed three times with distilled water. Polyaniline
salt in the chloroform layer was precipitated by adding 300 ml of acetone. Polyani-
line salt powder was filtered, washed with water followed by acetone, and dried at
70 ꢀC until a constant mass.
Formation of polyaniline salt was confirmed from FTIR spectroscopy, elec-
tronic absorption spectroscopy, and x-ray diffraction studies. Polyaniline salt
showed aggregated granular morphology with viscosity in dimethyformamide
solvent (1.3 dL=g) and conductivity (0.03 S=cm).
General Experimental Procedure for the Synthesis of 3-Substitute
Amino Methyl Indoles
In a typical experiment, benzaldehyde (0.01 mol, 1 mL) was added to N-methyl
aniline (0.013 mol, 1.4 mL) in a 10-mL round-bottomed flask. PANI-HBF4 (5 wt%)
catalyst with respect to aldehyde (50 mg) was added, and the reaction mixture was
stirred at room temperature for 5 min. Then indole (0.01 mol, 1.17 g) was added
and stirred at room temperature. Completion of the reaction was monitored by
TLC. After completion, ethyl acetate (2 ꢁ 10 mL) was added to the reaction mixture.
The mixture was filtered, and the catalyst was removed. The solvent was evaporated
under reduced pressure, and the crude product was purified by silica-gel column
chromatography (eluent: n-hexane=EtOAc, 4=1) to furnish [(1H-indol-3-yl)-phenyl-
methyl]-methyl-phenyl-amine (3.28 g, 95%). A similar procedure was adopted for the
preparation of other 3-substituted amino methyl indoles. Authenticity of the pro-
1
ducts was confirmed from mp, H NMR, and mass spectral data.
Spectral Data for New Compounds
[(4-Bromo-phenyl)-(1H-indol-3-yl)-methyl]-methyl-phenyl-amine
(6).
1
Brick red solid; mp ¼ 126–130 ꢀC. H NMR (300 MHz, CDCl3): d 2.84 (s, 3H), 5.5
(s, 1H), 6.58–6.60 (m, 3H), 7.00 (d, 2H), 7.18–7.22 (m, 4H), 7.24–7.28 (m, 3H),
7.36 (s, 1H), 7.98 (s, 1H). 13C NMR (CDCl3): d 30.75, 47.43, 111.13, 112.41,
119.45, 119.67, 122.19, 123.68, 123.98, 124.27, 126.70, 129.64, 130.81, 133.90,
136.72, 148.02, 149.49, 153.82. IR (KBr): 423, 517, 741, 1009, 1177, 1452, 1515,

AMINOMETHYLINDOLE SYNTHESIS USING POLYANILINE SALT
1601
1613, 2854, 2879, 3036, 3377 cmꢂ1. ESIMS: m=z 391 (Mþ þ H). HRMS calcd. for
C22H20N2Br, 391.0809. Found 391.0794.
[(1H-Indol-3-yl)-pyridin-4-yl-methyl]-methyl-phenyl-amine
(7). Light
1
brick red solid; mp ¼ 95–98 ꢀC. H NMR (300 MHz, CDCl3): d 2.83 (s, 3H), 5.48
(s, 1H), 6.47–6.49 (d, 2H), 6.53 (s, 1H), 6.93–6.98 (m, 3H), 7.10–7.15 (m, 4H),
7.30 (d, 1H), 8.0 (s 1H), 8.46 (d, 2H). 13C NMR (CDCl3): d 30.82, 47.36, 111.00,
112.35, 119.34, 119.75, 119.89, 122.07, 123.93, 126.82, 129.58, 130.66, 131.19,
132.14, 136.67, 143.74, 147.74. IR (KBr): 425, 606, 743, 1004, 1183, 1454, 1518,
1599, 2870, 2920, 3038, 3406 cmꢂ1. ESIMS: m=z 314 (Mþ þ H). HRMS calcd. for
C21H20N3, 314.1657. Found 314.1667.
[(5-Bromo-1H-indol-3-yl)-phenyl-methyl]-methyl-phenyl-amine
(9).
1
Brick red solid; mp ¼ 140–145 ꢀC. H NMR (300 MHz, CDCl3): d 2.84 (s, 3H), 5.5
(s, 1H), 6.57–6.60 (q, 3H), 7.00 (d, 2H), 7.18–7.22 (m, 4H), 7.24–7.28 (q, 3H), 7.36
(s, 1H), 7.98 (s, 1H). 13C NMR (CDCl3): d 30.75, 47.43, 111.15, 112.44, 119.41,
119.76, 122.24, 123.76, 123.98, 124.32, 126.87, 129.70, 130.85, 133.96, 136.78,
148.12, 149.54, 153.92. IR (KBr): 477, 525, 748, 1009, 1103, 1450, 1514, 1611,
2879, 3022, 3061, 3380 cmꢂ1. ESIMS: m=z 391 (Mþ þ H). HRMS calcd. for
C22H20N2Br, 391.0801. Found 391.0796.
[(5-Methoxy-1H-indol-3-yl)-phenyl-methyl]-methyl-phenyl-amine (12).
Brick red solid; mp ¼ 186–190 ꢀC. 1H NMR (300 MHz, CDCl3): d 2.83 (s, 3H),
3.78 (s, 3 H), 5.48 (s, 1H), 6.48–6.50 d, 2H), 6.76–6.79 (t, 2H), 6.92–7.00 (m, 3H),
7.09–7.13 (m, 3H), 7.18–7.22 (q, 1H), 7.25–7.28 (q, 1H), 7.33–7.35 (d, 1H), 7.78
(s, 1H). 13C NMR (CDCl3): d 31.04, 47.10, 55.22, 111.1, 112.41, 113.57, 119.19,
119.25, 120.00, 120.12, 121.89, 123.51, 123.87, 129.63, 129.84, 133.30, 136.24,
136.96. IR (KBr): 428, 480, 719, 1023, 1171, 1208, 1485, 1584, 1621, 2829, 2934,
3001, 3391 cmꢂ1. ESIMS: m=z 343 (Mþ þ H). HRMS calcd. for C23H23N2O,
343.1810. Found 343.1818.
ACKNOWLEDGMENTS
The authors thank Dr. J. S. Yadav, director, Indian Institute of Chemical
Technology, for facilities under the Projects MLP0007 and MLP0013 and encour-
agement. CLD thanks the Council of Scientific and Industrial Research, New Delhi,
for a research fellowship.
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