Chemoselective synthesis of bis(indolyl)methanes using sulfonic acid-functionalized chitosan

Article abstract of DOI:10.1007/s11696-019-00846-2

Abstract: Herein, we describe the electrophilic substitution reaction of indole with aldehydes and ketone using sulphonic acid functional group containing chitosan for the synthesis of bis(indolyl)methanes. The reaction is chemoselective affording a produ

Full text of DOI:10.1007/s11696-019-00846-2

Chemical Papers
https://doi.org/10.1007/s11696-019-00846-2
ORIGINAL PAPER
Chemoselective synthesis of bis(indolyl)methanes using sulfonic
acid‑functionalized chitosan
Amit Kumar1 · Chetananda Patel1 · Pooja Patil1 · Shivam Vyas1 · Abha Sharma1
Received: 2 January 2019 / Accepted: 7 June 2019
© Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
Herein, we describe the electrophilic substitution reaction of indole with aldehydes and ketone using sulphonic acid func-
tional group containing chitosan for the synthesis of bis(indolyl)methanes. The reaction is chemoselective afording a product
from aldehydes and indole. The catalyst can be reused up to three times without great loss in yields. Hence, chitosan–SO3H
(CTSA) proved to be a heterogeneous, efcient, chemoselective, and reusable catalyst for the synthesis of bis(indolyl)meth-
ane derivatives.
Graphic abstract
Keywords Bis(indolyl)methanes · Chemoselective · CTSA · Recyclable
Introduction
ramiforine, deoxytopsentin, bromodeoxytopsentin have
been isolated from plants and sponges (Oh et al. 2006;
Tanaka et al. 2006; Wright et al. 1992; Wright and Phillip-
son 1990). Some novel bis- and tris-indole derivatives such
as arundine, 1,1,3-tris(3-indolyl)butane, 3,3-bis(3-indolyl)
butane-2-one, and 1,1,1-tris(3-indolyl)methane isolated
from a bacteria Vibrio parahaemolyticus Bio249, reported
by Veluri et al. (2003). Predominantly, bis(indolyl)meth-
ane (BIM) and their derivatives exhibit anti-bacterial(Kaur
et al. 2015), anticancer (Ichite et al. 2009; Jamsheena et al.
2016), antioxidant (Simha et al. 2017) analgesic and anti-
infammatory activities (Sarva et al. 2016), acts as HIV-1
integrase inhibitor (Contractor et al. 2005), used in estro-
gen metabolism regulation in humans (Karthik et al. 2005),
in the treatment of chronic fatigue, fbromyalgia, irritable
A structurally diverse range of molecules has been isolated
from plants and microorganisms which possess a wide
range of biological activities (Bao et al. 2005; Casapullo
et al. 2000; Garbe et al. 2000). Bis-indole alkaloids such
as macrocarpamine, macralstonine acetate, villastonine,
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-019-00846-2) contains
supplementary material, which is available to authorized users.
* Abha Sharma
abha.sharma@niperraebareli.edu.in
1
Department of Medicinal Chemistry, National Institute
of Pharmaceutical Education and Research, Raebareli, India
Vol.:(0123456789)
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Chemical Papers
bowel syndrome (Kamble et al. 2007), food industry (Shi-
moda and Shibamoto 1990), optics, and polymers (Lafzi
et al. 2018; Shchepinov and Korshun 2003). It has also been
developed as a molecular sensor for selective detection of
copper and mercury ions (Liao et al. 2015; Martınez et al.
2008). Figure 1 shows the structure of some biologically
important bis(indolyl)methane derivatives.
silica-supported catalyst; although product yield obtained
was excellent, this protocol is not environmentally friendly
(Boroujeni and Parvanak 2011). The other method of syn-
thesis of BIM is the reaction of indole with benzyl alcohol
and Bartoli indole reaction (Abe et al. 2013; Hikawa and
Yokoyama 2013).
In recent years, the utilization of natural polymer-bound
catalysts has been well explored owing to cost-efective,
easy separation of catalysts and products (Bailey and Langer
1981; Dash et al. 2011; Xie et al. 2016). One such natural
polymer is chitosan (CT, Fig. 2a) as it is a polysaccharide,
biodegradable, biocompatible and can be chemically modi-
fed because of the presence of amine and hydroxyl groups.
Chitosan can be made acidic by sulfonation, yielding chi-
tosan–SO3H (CTSA, Fig. 2b). Few reports show the utiliza-
tion of biodegradable solid acid–chitosan as catalysts for an
organic transformation (Khan and Siddiqui 2015; Moham-
madi and Kassaee 2013; Reddy et al. 2013). Other modifed
forms of chitosan have been used in Suzuki cross-coupling
(Martina et al. 2011), Ullmann reaction (Zeng et al. 2012),
Michael addition reaction (Khalil et al. 2010), [3+2] Huis-
gen cycloaddition (Chtchigrovsky et al. 2009), Heck reac-
tion (Calò et al. 2004), C–C bond formation (Kühbeck et al.
2012) and cycloaddition of CO2 (Sun et al. 2012). Herein,
we wish to report an efcient and practical synthesis of BIM
catalyzed by CTSA (Scheme 1).
The most simple and straightforward approach for the
synthesis of BIM is the brønsted acid-catalyzed electrophilic
substitution reaction of indoles with aldehydes (Chakrabarty
et al. 2006; Ke et al. 2005; Veisi et al. 2011). Other than
acids, a variety of reagents such as iodine (Ji et al. 2004),
modifed zirconia (Nadkarni et al. 2008), InCl3 and In(OTf)3
(Nagarajan and Perumal 2002), tetramethyl guanidinium
chlorosulfonate (Kalla et al. 2014), aluminum dodecatung-
stophosphate (Firouzabadi et al. 2006), silica-supported
AlCl3 (Boroujeni and Parvanak 2011), ionic liquids (Yadav
et al. 2008; Ying et al. 2015), and BF3·OEt2 (Swetha et al.
2015) have also been used for the synthesis of BIM. The
reported methodologies are associated with some draw-
backs such as the use of costly, toxic reagent/solvents and
tedious workup process; for example, there is a report of
the synthesis of bis(indolyl)methane in the presence of
iodine, the workup process of this protocol is not straight-
forward, and requires special treatment during the workup
process (Ji et al. 2004). There are many reports of use of
Fig. 1 Some biologically active
bis(indolyl)methane derivatives
A
B
Fig. 2 Structures of a chitosan and b CTSA
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Chemical Papers
Scheme 1 Synthesis of
bis(indolyl)methane derivatives
catalyzed by CTSA
showed the carbon, nitrogen and sulfur content 28.43%
5.33% and 7.45%, respectively. The SEM micrograph of
the CT, CTSA and recovered CTSA showed homogene-
ous nature of the material. The surface of CT appeared
smooth and homogeneous. After modifcation of CT to
CTSA, SEM image showed homogeneous nature of the
material which remained as such for recovered CTSA. The
surface of the CTSA and recovered CTSA appeared to
be unafected after modifcation. The SEM images of CT,
CTSA and recovered CTSA are shown in Fig. 3.
Results and discussion
Our study started with the modifcation of chitosan with
chlorosulfonic acid led to the formation of CTSA (Fig. 2b).
The functionalization of CT to CTSA was confirmed
by analyzing FT-IR spectra. The IR spectrum of CTSA
showed a broad band at 2400–3400 cm−1 due to stretching
vibration of acidic OH bond. The sulphonic acid group
is introduced at OH as well as NH2 group of chitosan;
its S=O stretching bands appeared at 1216 cm−1 and
1069 cm−1 for –O–SO3H and –NH–SO3H, respectively.
The S–N bond stretching vibration in the –HN–SO3H
appeared at 669 cm−1. The appearance of these bands con-
frmed the introduction of sulphonic acid groups in CTSA
which are absent in CT (Fig. 2a). CTSA elemental analysis
After the preparation and characterization of CTSA,
we checked the possibility of CTSA to act as a catalyst for
the synthesis of BIM. A reaction between indole (117 mg,
1 mmol) and benzaldehyde (53 mg, 0.5 mmol) in EtOH
(2 mL) in the presence of CTSA (100 mg) was selected as a
model reaction (78 °C). A promising result was obtained and
Fig. 3 SEM image of the CT
and catalyst
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Chemical Papers
Table 1 Screening of solvents for the synthesis of bis(indolyl)meth-
Table 2 Optimization of temperature and amount of catalyst for the
anes on the model reaction
synthesis of bis(indolyl)methanes in EtOH
Entry
Solvents
Temperature
Timea
Yieldb
Entry
CTSAa (mg)
Temp °C
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
EtOH
Refux
Refux
Refux
Refux
80 °C
80 °C
80 °C
Refux
RT
1 h 30 min
2 h
2 h
6 h
7 h
7 h
7 h
1 h
1 h
87
82
80
82
65
63
59
1.
2.
3.
4.
5.
6.
7.
8.
10
10
20
30
40
50
60
70
80
90
100
40
50
60
70
80
90
rt
24
21
17
15
12
10
9
8
7
8
8
8
33
40
45
56
60
65
73
75
76
77
78
66
72
78
80
83
87
87
85
84
MeOH
iPrOH
H2O
PEG-200
PEG-400
PEG-600
EtOHc
Neat
60
60
60
60
60
60
60
60
60
60
78
78
78
78
78
78
78
78
78
No reaction
Trace product
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Indole (1 mmol), benzaldehyde (0.5 mmol), 100 mg CTSA and 2 mL
solvent
aReaction progress monitored by TLC
bIsolated yield
4
2 h 45 min
2
1 h 50 min
1 h 40 min
1 h 30 min
1 h 45 min
1 h 50 min
dWithout a catalyst
this encouraged us to study further. The study was directed
further by taking diferent solvents such as methanol, etha-
nol, water, PEG200, PEG400 and PEG600, and the results
are summarized in Table 1. We observed that the best sol-
vent in terms of reaction time and yield was EtOH (Table 1,
entry 1). In water (Table 1, entry 4) also yield was found
near to EtOH but a drawback associated with this was the
difculty in recovery of the catalyst. The product obtained
in water was in the precipitate form and catalyst was also not
soluble. At the time of workup, frst, we had to add EtOH to
dissolve the product which was then fltered. In polyethylene
gylcol (Table 1, entries 5–7), more time was required for
the reaction and less yield of products was obtained, but in
MeOH and iPrOH, i.e., in protic solvents (Table 1, entries
2–3), yield of the products was found to be good.
100
120
140
Indole (1 mmol), benzaldehyde (0.5 mmol), and 2 mL solvent
bAmount of CTSA groups
catalyst was found to be 100 mg and reaction ended in 1 h
and 30 min (Table 2, entry 14). The result of the optimiza-
tion of reaction conditions is listed in Table 2.
Then the optimized protocol was extended to the reaction
of indole with diferent aromatic aldehydes and ketones. The
result showed that this method applicable to a wide range of
aromatic aldehydes gave the corresponding products in good
to very good yield in 30 min–3 h. Unsubstituted aromatic
benzaldehyde furnished the product in 1 h and 30 min with
87% yield. The various substituted aromatic aldehydes bear-
ing electron-donating and -withdrawing groups produced
derivatives with the yield from 71 to 87% (Table 3). Further,
rate of reaction was infuenced by the nature of substitu-
ent present on aromatic aldehyde. We found slow rate with
electron-withdrawing group-bearing aromatic aldehydes.
On the other hand, we found the diference in the yield of
product with the position of substituent on the aromatic alde-
hydes. Slightly greater yield was found for indole reaction
with para-substituted aromatic aldehydes. All the prepared
products were characterized by 1H-NMR and 13C-NMR. The
1H NMR spectrum of novel compound 3q showed multiplets
in the range of δ 7.57–6.81 for all the aromatic protons. The
two NH protons have appeared at δ 7.84 and singlet for two
protons appeared at δ 6.56 which is for indole ‘pyrrole’ ring.
The peak at δ 6.25 appeared as singlet for CH proton. The
After fnding out the best solvent for the reaction, a study
has been done for optimization of reaction temperature and
amount of catalyst. This was carried out with the reaction
of indole (1a, 1 mmol), benzaldehyde (2a, 0.5 mmol) and
10 mg CTSA in EtOH (2 mL) at room temperature (rt). We
observed that the reaction ended in 24 h with 33% yield
(Table 2, entry 1). This study showed that it is efective as
a catalyst. Now, to determine the best reaction condition,
i.e., the amount of CTSA, temperature and reaction time,
reaction was proceeded with the same amount of catalyst at
60 °C. It was found that at this temperature reaction com-
pleted in 21 h with 40% yield (Table 2, entry 2). Now at
this temperature, we varied the amount of catalyst, 20 mg,
and observed that reaction time decrease to 17 h with 45%
yield (Table 2, entry 3) and carried out the reaction up to
100 mg of catalyst with 10 mg of diference in each reac-
tion (Table 2, entries 4–7). After this, we increased the tem-
perature to 100 °C and observed that optimum quantity of
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Producta
Time
Yield (%)
Table 3 Synthesis of
Entry Aldehyde
1.
bis(indolyl)methanes derivatives
catalyzed by CTSA
1 h 30 min
87
3a
3b
3c
2.
1h
1h
81
85
3.
4.
2 h
78
3d
5.
2h
79
3e
6.
1 h
81
3f
7.
8.
2 h
2 h
72
74
3g
3h
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Chemical Papers
Producta
Time
Yield (%)
Table 3 (continued)
Entry Aldehyde
9.
2 h 30 min
79
3i
10.
1 h 20 min
72
3j
11.
3 h
77
3k
3l
12.
13.
50 min
71
1h 15 min
75
3m
14.
15.
30 min
45min
81
78
3n
3o
13C NMR spectrum showed signals at δ 163.9 for carbon-
bearing fuoro group and at δ 145.7 for carbon attached to
bromo substituent. The signal at δ 39.9 was for sp3-hybrid-
ized carbon in 3q derivative.
The various reported catalysts used for the synthesis of
bis(indolyl)methane are tabulated in Table 4. The present
protocol is recyclable, eco-friendly and in some aspects
superior to some reported methods.
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Chemical Papers
Producta
Time
Yield (%)
Table 3 (continued)
Entry Aldehyde
16.
1 h 10 min
74
3p
17.
1 h 30 min
75
3q
aProducts were identifed by 1H and 13C NMR, and known products were matched with the literature data
(Swetha et al. 2015; Khalil et al. 2010; Chtchigrovsky et al. 2009)
Table 4 Efciency of reported catalyst used for the synthesis of
3,3′-(phenylmethylene)bis(1H-indole)
indole (Scheme 2). The result of this reaction indicated
that the formation of ‘3a’ alone suggests that the reaction
is chemoselective.
Catalysts
Time (h)
Yield (%)
References
Heterogeneous catalyst was recovered and its efciency
again for the synthesis of 4a was checked for three subse-
quent runs (Fig. 4). The catalyst was easily recovered by
fltering the reaction mixture followed by washing with
ethanol, acetone and kept for air drying. There was some
decrease in catalytic activity of CTSA in the third run of
reaction. In the present protocol, we utilized natural prod-
uct-modifed catalyst which is a biodegradable and reusable
catalyst, therefore, fulflling some aspects of green chemistry
principle.
Ln(OTf)3
LiClO4
I2
SiO2–H2SO4
SiO2–NaHSO4
Heteropolyacid
Zeolite
Zeokarb-225
In(OTf)3
12
95
90
76
92
89
84
80
95
71
Chen et al. (1996)
Yadav et al. (2001)
Ji et al. (2004)
Pore et al. (2006)
Ramesh et al. (2003)
Azizi et al. (2007)
Karthik et al. (2004)
Magesh et al. (2004)
2.5
0.16
0.75
2.5
2
2
7.5
0.41
Nagarajan and Perumal
(2002)
SbCl3
1.15
94
Srinivasa et al. (2008)
Conclusion
In conclusion, the CTSA proved to be an efective, chem-
oselective, heterogeneous and recyclable catalyst for the
synthesis of bis(indolyl)methane derivatives thus making
methodology clean and simple for its synthesis.
After testing various aromatic aldehydes, protocol
extended for the reaction of a ketone with indole, no prod-
uct was observed. This observation prompted us to per-
form the reaction with benzaldehyde, acetophenone and
Scheme 2 Chemoselective synthesis of bis(indolyl)methane (3a)
1 3

Chemical Papers
was fltered to separate the catalyst. The fltrate was con-
centrated and after addition of water, the solid product was
obtained.
Selected spectroscopic data
3,3′‑(Phenylmethylene)bis(1H‑indole) (3a) Red solid;
mp=149-152 °C (Ref; 148–152 °C); yield: 90%; 1H NMR
(300 MHz, CDCl3): δ 7.82 (s, 1H), 7.38–7.12 (m, 11H), 6.98
(t, J = 7.5 Hz, 2H), 6.60 (s, 2H), 5.86 (s, 1H)). 13C NMR
(CDCl3, 100 MHz): 144.7, 136.8, 129.6, 128.8, 126.7, 126.4,
125.8, 123.8, 122.1, 121.2, 119.3, 111.3, 40.6. MS-ESI: 322
[M]+.
3,3′‑((2‑Chlorophenyl)methylene)bis(1H‑indole) (3b) 1H
NMR (300 MHz, DMSO) δ 10.78 (s, 2H), 7.34 (d,
J=8.1 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 7.19 (s, 1H), 7.16–
7.13 (m, 2H), 7.06–6.96 (m, 3H), 6.90–6.84 (m, 2H), 6.82
(dd, J=4.8, 1.4 Hz, 2H), 5.78 (s, 1H), 2.24 (s, 2H), MS-ESI:
336.1 [M]+.
Fig. 4 Percentage conversion with time
Experimental
Methods and materials
3,3′‑(p‑Tolylmethylene)bis(1H‑indole) (3c) Pink solid;
1
mp=103-105 °C (Lit. 103-104 °C); yield: 85%; H-NMR
All reagents and solvents used in this work are available
commercially and used as such without further purifca-
tion. Reaction progress was monitored by TLC aluminum
sheet and silica gel 60 F254.1H NMR and 13C NMR spectra
were recorded on 300 and 100 MHz Brucker instrument,
respectively, using CDCl3 as solvent and Me4Si as an inter-
nal standard.
(300 MHz, CDCl3): δ 7.78 (s, 2H), 7.39 (d, J=9 Hz, 2H),
7.32 (d, J=9 Hz, 2H), 7.22–6.96 (m, 8 H), 6.60 (s, 2H), 5.83
(s, 1H), 2.30 (s, 3H). 13C NMR (CDCl3, 100 MHz): 141.3,
136.3, 135.7, 129.3, 128.5, 126.7, 122.8, 122.2, 121.5,
120.2, 119.2, 110.3, 39.8, 21.5. MS-ESI: 336.1 [M]+.
3,3′‑((2‑Chlorophenyl)methylene)bis(1H‑indole) (3d) 1H
NMR (300 MHz, DMSO): δ 10.86 (s, 2H), 7.50–7.43 (m,
1H), 7.36 (d, J=8.1 Hz, 2H), 7.25 (m, 6H), 7.10–7.00 (m,
2H), 6.93–6.84 (m, 2H), 6.76 (d, J =1.9 Hz, 2H), 6.22 (s,
1H). MS-ESI: 322.41 [M]+.
Modifcation of CT to CTSA
CTSA was synthesized by the reported method (Khan and
Siddiqui 2015). In round-bottom fask, 2.00 g of chitosan
was taken in 20 mL of dry dichloromethane and then 4 mL
chlorosulfonic acid was added dropwise at 0 °C in 2 h. After
its whole addition, the mixture was stirred for another 4 h at
room temperature until HCl was removed from the reaction
vessel. Then the mixture was fltered and washed many times
with methanol until a neutral pH level was accomplished.
Then the product was dried at room temperature to obtain a
white powder of CTSA.
3,3′‑((4‑Bromophenyl)methylene)bis(1H‑indole) (3i) 1H
NMR (300 MHz, DMSO): δ 10.83 (s, 2H), 7.48–7.42 (m,
2H), 7.37–7.24 (m, 6H), 7.08–7.00 (m, 2H), 6.91–6.81 (m,
4H), 5.83 (s, 1H), MS-ESI: 401.31 [M]+.
3,3′‑((4‑Fluorophenyl)methylene)bis(1H‑indole) (3j) 1H
NMR (300 MHz, DMSO): δ 10.82 (s, 2H), 7.40–7.32 (m,
4H), 7.27 (d, J=7.8 Hz, 2H), 7.12–6.99 (m, 4H), 6.90–6.80
(m, 4H), 5.85 (s, 1H), MS-ESI: 340.14 [M]+.
General procedure for the synthesis of bis(indolyl)
methanes
1
3,3′‑(Thiophene‑2‑ylmethylene)bis(1H‑indole) (3o) H NMR
(300 MHz, DMSO): δ 10.84 (s, 2H), 7.35 (dd, J = 11.3,
4.2 Hz, 4H), 7.30 (dd, J=4.4, 2.0 Hz, 1H), 7.07–6.99 (m,
4H), 6.94–6.84 (m, 4H), 6.13 (s, 1H), MS-ESI: 328.10 [M]+.
For the synthesis of bis(indolyl) methane derivatives, indole
(1 mmol) and diferent aldehydes (0.5 mmol) were taken in
2.0 mL of EtOH in a 25-mL round-bottom fask containing
a magnetic stir bar. Then 100 mg of the CTSA was added to
the reaction mixture and the reaction mixture was refuxed.
After the completion of the reaction, the reaction mixture
3,3′‑((2‑Bromo‑5‑fluorophenyl)methylene)bis(1H‑indole)
1
(3q) Pink solid; mp = 135-136 °C H NMR (300 MHz,
CDCl3): δ 7.84 (s, 2H); 7.57-7.53 (1H, m); 7.40–7.35 (4H,
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Chemical Papers
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m); 7.18 (t, J =7.5 Hz, 2H); 7.03 (t, J =7.5 Hz, 2H); 6.93
(dd, J=6 Hz, 1H); 6.81 (1H, m); 6.56 (s, 2H), 6.25 (1H,s).
13C NMR (CDCl3, 100 MHz): 163.9 (C–F), 160.68(C–F),
145.7, 136.9 134.0 123.9, 122.4, 119.9, 119.6, 118.0, 117.5
39.9. 19F-NMR (CD3OD, 282 MHz): -116.97; MS–ESI:
418.04[M]+.
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Acknowledgements We are grateful to Dr. S.J.S. Flora Director,
NIPER-Raebareli for their support and motivation. The authors Amit
Kumar, Chetananda Patel, Pooja Patil and Shivam Vyas are thankful to
Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers,
Government of India, for granting fellowship. SAIF-CSIR-CDRI, Luc-
know, is greatly acknowledged for providing spectral data. NIPER-R/
Communications/035.
Jamsheena V, Shilpa G, Saranya J, Harry NA, Lankalapalli RS, Priya
S (2016) Anticancer activity of synthetic bis(indolyl)methane-
ortho-biaryls against human cervical cancer (HeLa) cells. Chem
Biol Interact 247:11–21
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room temperature under solvent-free conditions. Tetrahedron
60:2051–2055
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chlorosulfonate as a highly efcient and recyclable organocata-
lyst for the preparation of bis(indolyl)methane derivatives. Catal
Commun 57:55–59
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