Metal-free oxidative coupling of arylmethylamines with indoles: A simple, environmentally benign approach for the synthesis of 3,3′-bis(indolyl)methanes

Article abstract of DOI:10.1039/d0ra03221b

The efficient metal-free oxidative coupling of arylmethylamines with indoles has been developed using molecular oxygen as a green oxidant. The present reaction provides a novel route towards the synthesis of 3,3′-bis(indolyl)methanes in excellent yields of up to 95% via C-C and C-N bond formation. This attractive and environmentally friendly one-pot protocol is a simple procedure that features inexpensive acetic acid as the catalyst and molecular oxygen as the sole oxidant, and it supports a wide substrate scope with the good tolerance of functional groups.

Full text of DOI:10.1039/d0ra03221b

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Metal-free oxidative coupling of arylmethylamines
with indoles: a simple, environmentally benign
approach for the synthesis of 3,30-bis(indolyl)
methanes†
Cite this: RSC Adv., 2020, 10, 23254
a
b
a
*
Vikas D. Kadu,
Sankala Naga Chandrudu,
Mahesh G. Hublikar,
Dattatraya G. Rauta and Raghunath B. Bhosalea
The efficient metal-free oxidative coupling of arylmethylamines with indoles has been developed using
molecular oxygen as a green oxidant. The present reaction provides a novel route towards the synthesis
of 3,30-bis(indolyl)methanes in excellent yields of up to 95% via C–C and C–N bond formation. This
attractive and environmentally friendly one-pot protocol is a simple procedure that features inexpensive
acetic acid as the catalyst and molecular oxygen as the sole oxidant, and it supports a wide substrate
scope with the good tolerance of functional groups.
Received 10th April 2020
Accepted 25th May 2020
DOI: 10.1039/d0ra03221b
rsc.li/rsc-advances
dysplasia.12,13 Therefore, their preparation has generated addi-
tional interest from synthetic organic chemists and biologists.
Traditionally, 3,30-bis(indolyl)methanes have been synthesized
Introduction
The indole scaffold is the most ubiquitous nitrogen heterocycle
and is present in various natural products, alkaloids, hormones,
neurotransmitters, pharmaceuticals and agrochemicals.1 This
useful structural scaffold has been established as an essential
component of heterocyclic compounds in pharmacology and
medicinal chemistry.2 Typically, along with various indole deriva-
tives, bis(indolyl)methanes have been extensively recognized as
a privileged class due to their presence in natural products2 and
their wide-ranging applications in pharmaceuticals.1,3 In the last
few years, a large number of bis(indolyl)methanes (BIMs) have
been referred to as extremely privileged structures due to their
presence in various terrestrial and marine natural sources, where
they exhibit a wide range of biological applications.4–7
Biologically active bis(indolyl)methanes are depicted in
Fig. 1. Simple 3,30-bis(indolyl)methanes, such as arundine, have
been used in cancer chemotherapy, while vibrindole A displays
excellent antibacterial activity8 and arsindoline A shows excel-
lent antitumor activity towards various cancer cell lines.9
Bis(indolyl)methanes are also efficacious at preventing cancer
owing to their capability to modify established cancer-causing
estrogen metabolites.10 Recently, the M. Shiri group have
reviewed the cancer chemotherapy effectiveness and various
biological activities of BIMs.11 Also, these compounds may
normalize the anomalous cell growth that is related to cervical
via the condensation of aldehydes with indoles in the presence of
diverse catalysts and strong acids.14–16 Alternatively, 3,30-bis(indolyl)
methanes can be synthesized from alkynes and indoles using
ruthenium catalysts.17 Also, a primary alcohol can undergo transfer
hydrogenation in the presence of precious metal complexes, fol-
lowed by condensation with indoles to furnish BIMs.18–20 Then, Xiang
et al. demonstrated the decarboxylative deamination of amino acids
using an I2/PTA catalyst, and the Zhang research group described the
utility of a tetramethylethylenediamine (TMEDA) carbon source in
the presence of CuCl2 for BIM synthesis with indoles.21,22 Previously,
the Sankala research group reported the synthesis of 3,30-benzyli-
denebis(1H-indole), using an iron(II) triate catalyst, from benzyl-
amine with indoles.23 Furthermore, the platinum-catalyzed
bisindolylation reaction of indoles and allenes has also led to the
construction of 3,30-bis(indolyl)methanes (Scheme 1).24
Although these methods are effective for 3,30-bis(indolyl)
methane synthesis, they all have at least one shortcoming, such as
the use of toxic or precious metals, high catalyst loadings, expen-
sive ligands, volatile solvents, large amounts of promoters, and/or
hydrophobic oxidants; long reaction times; lower yields; tedious
work-up procedures; and the formation of byproducts under
microwave and ultrasound conditions. Moreover, removing metal
impurities from the desired products is a highly challenging task
for chemists and biologists. In this context, the versatile applica-
tions of BIMs have attracted great demand for the development of
a new modied method. Herein, the present protocol provides
a simple, attractive and environmentally friendly one-pot approach
for the synthesis of functionalized bis(indolyl)methanes with the
good tolerance of a wide range of functional groups.
aSchool of Chemical Sciences, Punyashlok Ahilyadevi Holkar Solapur University,
Solapur-413255, Maharashtra, India. E-mail: vikaskadu1@gmail.com
bDepartment of Chemistry, College of Engineering, Rayalseema University, Kurnool-
518002, Andhra Pradesh, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra03221b
23254 | RSC Adv., 2020, 10, 23254–23262
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 1 Some biologically active bis(indolyl)methanes.
(10 mol%) secured the same yield (92%) of product 3aa.
However, further lowering the amount of AcOH catalyst
(5 mol%) reduced the yield of product 3aa from 92% to 79%.
Also, the reaction was executed under atmospheric air, and this
furnished 3aa in 81% yield (Table 1, entry 12). Next, the reaction
was performed under a nitrogen atmosphere, and this afforded
a 35% yield of the desired product 3aa (Table 1, entry 13). Aer
that, a decrease in the reaction temperature from 120 ꢀC to
80 ꢀC was also studied, and this resulted in a lower yield of 3aa
(Table 1, entry 14). Overall, the optimal conditions were iden-
tied as: 1a: 1.1 mmol; 2a: 2.0 mmol; AcOH: 10 mol%; toluene: 1
mL; 120 ꢀC; and under an O2 atmosphere.
With the optimized conditions in hand, we investigated the
scope of amines as coupling partners (Table 2). To our delight,
a wide range of amines (1a–1r), with electron-donating and
electron-withdrawing groups, furnished the desired products
(3aa–3ra) without any difficulties under the optimized reaction
conditions. Moreover, a variety of functional groups, such as
methoxy, methyl, halogen, triuoromethyl, naphthyl and thio-
phene, could be signicantly maintained under the optimized
reaction conditions. Electronic factors slightly inuenced the
yields of the desired products. Benzylamines with electron-
donating groups at the para position (1b–1e) furnished the
corresponding 3,30-BIMs in slightly higher yields than benzyl-
amines with electron-withdrawing groups (1f–1g). Furthermore,
benzylamines with halogen substituents also afforded the
desired products in good to moderate yields. Sterically hindered
benzylamines (1i–1n), such as those with 2-chloro, 2-methoxy,
Results and discussion
We commenced our investigation with benzylamine 1a (1.1
mmol) and indole 2a (2 mmol) as model substrates to optimize
the reaction parameters, as depicted in Table 1.
Initially, a series of toluene-mediated acid systems was
tested. For this, benzylamine 1a (1.1 mmol) and indole 2a (2
mmol) were studied in the presence of triuoroacetic acid (TFA)
ꢀ
(30 mol%) and toluene (1 mL) at 120 C for 12 h under an O2
atmosphere; this gratifyingly afforded the 3,30-bis(indolyl)
methane 3aa in 62% yield (Table 1, entry 1). Then, reaction
optimization was carried out with different acids, such as
MsOH, TfOH, AcOH and PivOH, under similar reaction condi-
tions; the desired product 3aa was obtained and yields are re-
ported in Table 1 (entries 2–5). All the toluene/acid systems
promoted 3,30-bis(indolyl)methane 3aa formation, and the
AcOH/toluene combination was observed to be most effective
(yield of 3aa: 71%; entry 4). For further yield improvements, the
reaction conditions were optimized using the polar solvents
ethylene glycol and DMF in AcOH (30 mol%) at 120 ꢀC, but 3,30-
bis(indolyl)methane 3aa was procured in low yields of 25% and
31%, respectively (Table 1, entries 6 and 7). Then, the trans-
formation was accelerated in the non-polar solvent chloroben-
zene and, signicantly, the anticipated product 3,30-bis(indolyl)
methane 3aa was produced in 91% yield (Table 1, entry 8). Aer
that, neat reaction conditions were tested, and the yield of
product 3aa shied from 91% to 75% (Table 1, entry 9).
Subsequently, we attempted various catalyst loading levels from
30 mol% to 10 mol% to further optimize the reaction conditions
(Table 1, entries 10–11). A lesser amount of AcOH catalyst
4-chloro-2-uoro,
2-chloro-4-uoro,
and
2,3-dichloro
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 23254–23262 | 23255

View Article Online
RSC Advances
Paper
Scheme 1 Approaches for the synthesis of 3,30-bis(indolyl)methanes.
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
TFA
Toluene
Toluene
Toluene
Toluene
Toluene
Ethylene glycol
DMF
Chlorobenzene
—
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
12
12
12
12
12
12
12
9
9
9
9
9
62
50
35
71
65
25
31
92
75
92
79
81
35
76
MsOH
TfOH
AcOH
PivOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
9
10c
11d
12c,e
13c,f
14c,g
12
12
a
Reaction conditions: 1a (1.1 mmol), 2a (2.0 mmol), catalyst (30 mol%), solvent (1 mL), at 120 ꢀC, under an O2 balloon unless otherwise mentioned.
b
Isolated yield. c 10 mol% of catalyst was used. d 5 mol% catalyst was used. e Under atmospheric air. f Under N2. g Reaction was carried out at 80 ꢀC.
23256 | RSC Adv., 2020, 10, 23254–23262
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 2 Substrate scopea,b
a
Reaction conditions: 1 (1.1 mmol), 2 (2.0 mmol), AcOH (10 mol%), chlorobenzene (1 mL), at 120 ꢀC, under an O2 balloon unless otherwise
mentioned. b Isolated yield.
substituents on the benzene rings, also imparted the corre- resulted in 3,30-[3,5-bis(triuoromethyl)-benzylidene]bis(1H-
sponding 3,30-BIMs with up to 85–75% yields (3ia–3ma,Table 2). indole) (3na) in good yield.
Excitingly, having a strong electron-withdrawing group at the
To expand the scope of the reaction, heteroaryl methyl-
meta position of 3,5-bis(triuoromethyl)benzylamine (1n) also amines, such as 4-picolylamine, 3-picolylamine and 2-
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 23254–23262 | 23257

View Article Online
RSC Advances
Paper
Scheme 2 Control experiments.
Scheme 3 The proposed reaction mechanism.
thiophene-methylamine, were further investigated, and the mechanism for the synthesis of a bis(indolyl)methane from
desired products (3pa–3ra) could be obtained with notable benzylamine 1a and indole 2a under metal-free conditions
yields of 80%, 75%, and 85%, respectively. In addition, 5-bromo (Scheme 3). At rst, an oxidative process involving benzylamine
indole (2b) tolerated various substituted arylmethylamines well 1a results in the formation of the corresponding aldimine 8.
and furnished 3,30-BIMs (3sa–3wa) in good to high yields of Then, this aldimine 8 undergoes further transamination with
91%, 83%, 89%, 80%, and 76%, respectively.
another molecule of amine to furnish the corresponding homo-
To gain more insight into the reaction mechanism, we con- coupled product N-benzylidinebenzylamine 5. In the next step,
ducted some control experiments (Scheme 2). Initially, N-4- indole 2a undergoes a Mannich reaction with N-benzylidine-
methyl-N-(4-methylbenzylidene)benzylamine was prepared benzylamine 5 to afford the C-3 alkylated intermediate 9, which
from 4-methylbenzylamine at 120 ꢀC in chlorobenzene under undergoes further oxidation resulting in the formation of the
a molecular oxygen atmosphere using acetic acid (10 mol%) (I). azafulvene intermediate 10. In the nal step, azafulvene 10
Aerwards, this intermediate was treated with two equivalents reacts with another molecule of indole 2a, resulting in the
of indole, furnishing a bis(indolyl)methane (II) (Scheme 2); this formation of the desired product 3,30-bis(indolyl)methane 3aa.
was also achieved using 1.5 mmol of benzylamine and 2.0 mmol For testing the practicability of the reaction on a large scale, the
of indole. From previous literature reports and the above reaction of benzylamine (1a, 19.5 mmol) and indole (2a, 30
control experiments, we propose
a
tentative reaction mmol) was investigated, and it afforded 4.59 g of 3aa in 91%
23258 | RSC Adv., 2020, 10, 23254–23262
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
yield, showing no major loss of efficiency. As a result, this reduced pressure, and the resulting residue was puried via
protocol has utility as a practical process for preparing bis(in- silica gel column chromatography using a hexane/ethyl acetate
dolyl)methanes.
mixture to afford the corresponding bis(indolyl)methane
Additionally, we studied the ability of our methodology to products 3.
synthesize some biologically active bis(indolyl)methanes, such
as 3,30-(4-methoxybenzylidene)bis(1H-indole) (3ca), 3,30-(4-
Characterization data from the pure bis(indolyl)methanes
products
Synthesis of 4-methyl-N-(4-methylbenzylidene)benzylamine
hydroxybenzylidene)bis(1H-indole) (3da), and 3,30-(4-tert-butyl-
benzylidene)bis(1H-indole) (3ea) (Table 2). The compounds 3ca
and 3da induce nuclear NR4A1-dependent apoptosis and
inhibit the growth of colon, bladder, lung and pancreatic cancer (4). 4-Methylbenzylamine (1a) (350 mg, 2.89 mmol), AcOH
cells25–27 through the activation or deactivation of receptors. (10 mol%), and dry chlorobenzene (2 mL) were added to a 25 mL
Compound 3ea inhibits the proliferation of the invasive round bottom ask. The round bottom ask was equipped with
estrogen receptor-negative MDA-MB-231 and MDA-MB-453 an O2 balloon, and the reaction mixture was stirred at 110 ꢀC for
human breast cancer cell lines.28
3.4 h. The reaction mixture was cooled to room temperature and
adsorbed on basic alumina. It was puried via column chro-
matography over basic alumina using a hexane/ethyl acetate
(9 : 1) mixture as the eluent to afford 4-methyl-N-(4-methyl-
benzylidene)benzylamine (4) (232 mg, 72% yield) as a pale
yellow solid.
Conclusions
In summary, we have developed a simple AcOH-catalyzed novel
metal-free oxidative coupling reaction between benzylamines
and indoles to synthesize a diverse range of functionalized
bis(indolyl)methanes. The synthesis of bis(indolyl)methanes
involves aerobic oxidative addition, cleavage, and sequential
coupling in a one-pot procedure using green molecular oxygen
as the oxidant, making the transformation very economical and
environmentally benign.
IR (cmꢂ1): 3022, 2923, 2853, 1646, 1514, 1174, 1021, 811, 711;
1H NMR (400 MHz, CDCl3): d 8.24 (s, 1H), 7.07–7.26 (m, 8H,
ArH), 4.5 (d, J ¼ 5.6 Hz, 2H), 2.35 (s, 3H), 2.34 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3): d 160.9, 137.5, 134.5, 129.6, 129.5,
129.3, 129.2, 127.8, 126.9, 41.97, 21.1 ppm; 13C NMR DEPT-135
(100 MHz, CDCl3): 160.9 (]CH, up), 129.6, 129.5, 127.8, 126.9,
41.9 (CH2, down), 21.1 (2 ꢁ CH3, up) ppm.
Synthesis of 3,30-benzylidenebis(1H-indole) (3aa). Yield:
296 mg (92%) as a pink solid; mp: 148–151 ꢀC (lit.29 151–152 ꢀC);
IR (cmꢂ1): 3416, 3058, 2924, 1601, 1456, 1337, 1217, 1093, 745,
701, 597; 1H NMR (400 MHz, CDCl3): d 7.86 (br s, 2H, NH), 7.45–
7.24 (m, 9H, ArH), 7.22 (t, J ¼ 8.4 Hz, 2H), 7.05 (t, J ¼ 8.0 Hz, 2H),
6.64 (s, 2H), 5.93 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d 144.0, 137.7, 128.8, 128.3, 127.1, 126.2, 123.7, 121.9, 120.0,
119.2, 111.0, 40.2 ppm; 13C NMR DEPT-135 (100 MHz, CDCl3):
128.8, 128.3, 126.2, 123.7, 121.9, 120.0, 119.2, 111.09 (up, ]CH,
sp2), 40.2 (up, CH, sp3) ppm.
Experimental section
General information
All reactions were carried out in oven-dried glassware using dry
solvents under a molecular oxygen atmosphere, unless stated
otherwise. Iron salts were purchased from Sigma-Aldrich and
were used as received. All other chemicals were used as received
from commercial sources. Reactions were monitored via TLC on
0.25 mm Merck silica gel plates (60 F254) using UV light for
visualization. Column chromatography purication was per-
formed using silica gel (100–200 mesh). Melting points were
Synthesis of 3,30-(4-methylbenzylidene)bis(1H-indole) (3ba).
Yield: 313 mg (93%) as a pink solid; mp: 95–96 C (lit.29 94–96
ꢀ
¨
measured using Buchi melting point apparatus and are uncor-
ꢀC); IR (cmꢂ1): 3414, 3055, 2920, 2850, 1618, 1456, 1417, 1216,
1093, 776, 744, 598; 1H NMR (400 MHz, CDCl3): d 7.81 (br s, 2H,
NH), 7.32 (d, J ¼ 8.4 Hz, 2H), 7.27 (d, J ¼ 8.4 Hz, 2H), 7.16 (t, J ¼
6.8 Hz, 2H), 7.08 (t, J ¼ 6.8 Hz, 2H), 7.00 (d, J ¼ 7.6 Hz, 2H), 6.92
(t, J ¼ 6.8 Hz, 2H), 6.58 (d, J ¼ 1.6 Hz, 2H), 5.77 (s, 1H), 2.24 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): d 140.9, 136.6, 135.4,
128.9, 128.5, 127.0, 123.5, 121.8, 119.9, 119.8, 119.1, 111.0, 39.7,
21.0 ppm.
rected. IR spectra were recorded using a Spectrum FT-IR spec-
trophotometer. NMR spectra were recorded using a Bruker 400
MHz spectrometer (1H: 400 MHz, 13C: 100 MHz), using DMSO-
d6 or CDCl3 as the solvent with TMS as the internal standard at
room temperature. Mass spectra were recorded using a 6530
Accurate-Mass Q-TOF LC/MS (Agilent Technologies).
General procedure for the synthesis of bis(indolyl)methanes
(3)
Synthesis of 3,30-(4-methoxybenzylidene)bis(1H-indole)
(3ca). Yield: 334 mg (95%) as a light orange solid mp: 187–
Benzylamine 1 (1.1 mmol), indole 2 (2.0 mmol), AcOH 190 ꢀC (lit.30 187–189 ꢀC); IR (cmꢂ1): 3408, 1609, 1507, 1455,
(10 mol%), and dry chlorobenzene (2 mL) were added to a 25 mL 1416, 1337, 1300, 1242, 1173, 1124, 1092, 1027, 813, 793, 740; 1H
round bottom ask. The round bottom ask was equipped with NMR (400 MHz, CDCl3): d 7.94 (br s, 2H, NH), 7.41 (d, J ¼ 7.6 Hz,
ꢀ
an O2 balloon, and the reaction mixture was stirred at 110 C 2H, ArH), 7.38 (d, J ¼ 8.4 Hz, 2H, ArH), 7.28 (d, J ¼ 6.6 Hz, 2H,
until the complete consumption of indole 2 occurred, as ArH), 7.19 (t, J ¼ 7.8 Hz, 2H, ArH), 7.03 (t, J ¼ 7.5 Hz, 2H, ArH),
monitored via TLC. Aer the reaction was nished, the reaction 6.84 (d, J ¼ 6.8 Hz, 2H, ArH), 6.68 (s, 2H, ArH), 5.87 (s, 1H), 3.81
mixture was cooled to room temperature, diluted with CH2Cl2 (s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3): d 157.8, 136.6,
(10 mL), and washed with water (2 ꢁ 10 mL). The organic extract 136.2, 129.6, 127.1, 123.5, 121.9, 120.0, 119.9, 119.2, 113.5,
was dried over anhydrous Na2SO4 and concentrated under 111.0, 55.2, 39.3 ppm.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 23254–23262 | 23259

View Article Online
RSC Advances
Synthesis of
Paper
1
3,30-(4-hydroxybenzylidene)bis(1H-indole)
1093, 1038, 743, 599; H NMR (400 MHz, CDCl3): d 7.84 (br s,
2H), 7.36–7.28 (m, 5H), 7.16–7.01 (m, 5H), 6.94 (t, J ¼ 6.8 Hz,
2H), 6.57 (d, J ¼ 1.6 Hz, 2H), 6.27 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3): d 141.3, 136.7, 133.9, 130.3, 129.4, 127.5, 127.0,
126.6, 123.7, 122.0, 119.8, 119.3, 118.3, 111.0, 36.6 ppm.
3,30-((4-chloro-2-uorophenyl)methylene)
bis(1H-indole) (3ka). Yield: 295 mg (79%) as a light orange solid;
(3da). Yield: 300 mg (89%) as a pink solid; mp: 214–216 ꢀC (lit.14
210–212 ꢀC); IR (cmꢂ1): 3412, 2924, 2853, 1611, 1510, 1456,
1338, 1217, 1093, 786, 744, 598; 1H NMR (400 MHz, CDCl3):
d 7.90 (br s, 2H, NH), 7.37–7.32 (m, 4H), 7.19–7.12 (m, 4H), 6.98
(t, J ¼ 6.8 Hz, 2H), 6.72 (d, J ¼ 11.2 Hz, 2H), 6.63 (t, J ¼ 1.2 Hz,
2H), 5.81 (s, 1H), 4.80 (br s, 1H, OH) ppm; 13C NMR (100 MHz,
CDCl3): d 154.5, 136.6, 135.5, 129.4, 126.9, 123.5, 121.3, 119.7,
118.6, 114.8, 110.9, 60.2 ppm.
Synthesis
of
1
ꢀ
mp: 187–190 C; H NMR (400 MHz, CDCl3): d 7.98 (br s, 2H,
NH), 7.41–7.39 (m, 4H, ArH), 7.21 (m, 2H, ArH), 7.16 (m, 2H,
ArH), 7.07–6.99 (m, 3H, ArH), 6.73 (d, J ¼ 1.2 Hz, 2H, ArH), 6.19
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d 159.2, 136.7, 132.6,
131.2, 129.8, 126.7, 124.3, 124.2, 123.6, 122.2, 119.7, 117.7,
116.2, 111.1, 60.4 ppm.
Synthesis of 3,30-(4-tert-butylbenzylidene)bis(1H-indole)
(3ea). Yield: 340 mg (90%) as a yellow solid; mp: 88–91 ꢀC (lit.23
86–89 C); IR (cmꢂ1): 3412, 2959, 2923, 2852, 1457, 1419, 1338,
ꢀ
1217, 1092, 1010, 795, 742, 600; 1H NMR (400 MHz, CDCl3):
d 7.69 (br s, 2H, NH), 7.49–7.46 (m, 2H), 7.37–7.32 (m, 6H), 7.24–
7.20 (m, 2H), 7.09–7.04 (m, 2H), 6.60 (s, 2H), 5.92 (s, 1H), 1.37 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): d 148.7, 140.8, 136.6,
128.2, 127.1, 125.0, 123.5, 121.7, 119.9, 119.8, 119.0, 111.0, 39.5,
34.3, 31.4 ppm.
Synthesis
of
3,30-((2-chloro-4-uorophenyl)methylene)
bis(1H-indole) (3la). Yield: 292 mg (78%) as a faint pink solid;
mp: 98–99 ꢀC; IR (cmꢂ1): 3407, 3060, 1603, 1484, 1456, 1417,
1337, 1260, 1216, 1124, 1093, 1035, 1010, 903, 858, 795; 1H NMR
(400 MHz, CDCl3): d 8.01 (br s, 2H, NH), 7.40 (d, J ¼ 8.4 Hz, 4H,
ArH), 7.342–7.19 (m, 4H, ArH), 7.07–7.03 (m, 2H, ArH), 6.86 (t, J
¼ 8.4 Hz, 1H, ArH), 6.64 (d, J ¼ 2.4, 2H, ArH), 6.30 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3): d 162.2, 159.7, 137.3, 137.2, 136.7,
134.4, 134.3, 131.2, 131.1, 126.8, 123.7, 122.1, 119.8, 119.4,
118.2, 116.8, 116.6, 113.8, 113.6, 111.1, 36.2 ppm; HRMS: m/z [M
+ H]+ calcd for C23H16ClFN2: 374.0986, found: 374.1039.
Synthesis of 3,30-(4-uorobenzylidene)bis(1H-indole) (3fa).
Yield: 313 mg (92%) as an orange solid; mp: 72–74 ꢀC (lit.14 71–
73 ꢀC); IR (cmꢂ1): 3413, 3056, 2926, 1603, 1506, 1456, 1217,
1094, 863, 744, 582; 1H NMR (400 MHz, CDCl3): d 7.88 (br s, 2H,
NH), 7.30 (d, J ¼ 8.4 Hz, 4H), 7.23–7.19 (m, 2H), 7.11 (t, J ¼
6.8 Hz, 2H), 6.96–6.87 (m, 4H), 6.58 (d, J ¼ 2.4 Hz, 2H), 5.80 (s,
1H) ppm; 13C NMR (100 MHz, CDCl3): d 139.7, 136.7, 130.1,
130.0, 126.9, 123.5, 122.0, 119.8, 119.6, 119.3, 115.0, 114.8,
111.0, 39.4 ppm.
Synthesis of 3,30-((2,3-dichlorophenyl)methylene)bis(1H-
indole) (3ma). Yield: 293 mg (75%) as a violet-pink solid; mp:
110–113 ꢀC; IR (cmꢂ1): 3408, 1455, 1416, 1337, 1216, 1176, 1154,
1
Synthesis of 3,30-((4-chlorophenyl)methylene)bis(1H-indole)
1124, 1092, 1040, 1010, 794, 769, 738, 711, 686; H NMR (400
(3ga). Yield: 313 mg (88%) as a pink solid; mp: 78–80 C (lit.14
ꢀ
MHz, CDCl3): d 7.98 (br s, 2H, NH), 7.41–7.36 (m, 4H, ArH),
7.09–7.03 (m, 3H, ArH), 7.23–7.15 (m, 3H, ArH), 6.66 (d, J ¼
1.2 Hz, 2H, ArH), 5.32 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d 143.7, 136.6, 133.0, 132.2, 128.4, 128.4, 126.9, 126.8, 123.8,
122.1, 119.7, 119.4, 117.8, 111.1, 37.8 ppm; HRMS: m/z [M + H]+
calcd for C23H16Cl2N2: 391.2925, found: 391.3125.
77–79 C); IR (cmꢂ1): 3411, 3055, 2923, 2848, 1617, 1417, 1337,
ꢀ
1
1089, 1013, 743; H NMR (400 MHz, CDCl3): d 5.86 (s, 1H, Ar-
CH), 6.63 (s, 2H, Ar-H), 6.97 (t, 2H, Ar-H), 7.02 (t, 2H, Ar-H),
7.14–7.36 (m, 8H, Ar-H), 7.91 (br, s, 2H, NH) ppm; 13C NMR
(100 MHz, CDCl3): d 142.5, 136.7, 131.9, 130.0, 128.3, 126.9,
123.4, 122.1, 119.8, 119.4, 119.2, 111.0, 39.6 ppm.
Synthesis
of
3,30-[3,5-bis(triuoromethyl)benzylidene]
bis(1H-indole) (3na). Yield: 353 mg (77%) as a dark red solid;
mp: 64–66 ꢀC (lit.23 65–67 ꢀC); IR (cmꢂ1): 3415, 2923, 2852, 1620,
1458, 1373, 1278, 1171, 1133, 901, 745, 682; 1H NMR (400 MHz,
CDCl3): d 7.99 (br s, 2H, NH), 7.81 (s, 2H), 7.75 (s, 1H), 7.38–7.33
(m, 4H), 7.20 (t, J ¼ 7.6 Hz, 2H), 7.03 (t, J ¼ 7.2 Hz, 2H), 6.62 (d, J
¼ 1.6 Hz, 2H), 6.01 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d 146.7, 136.7, 131.5, 131.2, 128.7, 126.5, 124.8, 123.7, 122.4,
122.1, 120.5, 119.6, 119.4, 117.9, 111.3, 40.0 ppm; HRMS: m/z [M
+ H]+ calcd for C25H16F6N2: 457.1145, found: 457.1129.
Synthesis of 3,30-(1-naphthylmethylene)bis(1H-indole) (3oa).
Yield: 391 mg (86%) as a brown solid; mp: 218–221 ꢀC (lit.31 218–
220 ꢀC); IR (cmꢂ1): 3414, 3052, 2923, 1618, 1452, 1341, 1255,
1217, 1094, 778, 744; 1H NMR (400 MHz, DMSO-d6): d 10.63
(br s, 2H), 8.13 (d, J ¼ 8.4 Hz, 1H), 7.81 (d, J ¼ 8.0 Hz, 1H), 7.67
(d, J ¼ 8.4 Hz, 1H), 7.38–7.21 (m, 5H), 7.15 (d, J ¼ 7.6 Hz, 2H),
6.96 (t, J ¼ 7.6 Hz, 2H), 6.76 (t, J ¼ 7.6 Hz, 2H), 6.63 (d, J ¼ 1.2 Hz,
2H), 6.52 (s, 1H), 5.53 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-
d6): d 140.9, 137.3, 134.3, 131.9, 129.3, 127.4, 127.2, 126.7, 126.2,
126.0, 124.9, 124.4, 121.9, 119.6, 119.2, 118.5, 112.4, 55.3 ppm.
Synthesis of 3,30-(4-pyridylmethylene)bis(1H-indole) (3pa).
Yield: 258 mg (80%) as a brown solid; mp: 158–161 ꢀC (lit.32 160–
162 ꢀC); IR (cmꢂ1): 3408, 3169, 3056, 2975, 2922, 1597, 1456,
Synthesis of 4-(di(1H-indol-3-yl)methyl)benzonitrile (3ha).
Yield: 284 mg (82%) as a pink solid; mp: 209–211 ꢀC (lit.14 209–
1
210 ꢀC); IR (cmꢂ1): 3396, 3165, 2940, 2253, 1602, 1407, 757; H
NMR (400 MHz, CDCl3): d 7.96 (br s, 2H, NH), 7.56 (d, J ¼
8.18 Hz, 2H, Ar-H), 7.44 (d, J ¼ 8.18 Hz, 2Ar-H), 7.1–7.5 (m, 8H,
Ar-H), 6.63 (s, 2H, Ar-CH), 5.92 (s, 1H, CH) ppm; 13C NMR (100
MHz, CDCl3): d 149.7, 136.7, 132.2, 129.5, 126.7, 123.7, 122.3,
119.6, 119.5, 119.2, 118.2, 111.2, 110.0, 40.4 ppm.
Synthesis of 3,30-(2-methoxybenzylidene)bis(1H-indole)
(3ia). Yield: 299 mg (85%) as a white solid; mp: 136–137 ꢀC (lit.14
136–138 ꢀC); IR (cmꢂ1): 3414, 3057, 2933, 1597, 1489, 1456,
1
1338, 1243, 1092, 1028, 743, 600; H NMR (400 MHz, CDCl3):
d 7.83 (br s, 2H, NH), 7.39 (d, J ¼ 8.4 Hz, 2H), 7.32 (d, J ¼ 7.6 Hz,
2H), 7.15–7.11 (m, 4H), 6.97 (t, J ¼ 6.8 Hz, 2H), 6.92 (d, J ¼
8.4 Hz, 1H), 6.79 (t, J ¼ 8.0 Hz, 1H), 6.63 (s, 2H), 6.34 (s, 1H), 3.80
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d 156.9, 136.7, 132.3,
129.7, 127.2, 127.1, 123.5, 121.7, 120.4, 120.0, 119.6, 119.0,
110.9, 110.6, 55.7, 32.0 ppm.
Synthesis of 3,30-(2-chlorobenzylidene)bis(1H-indole) (3ja).
Yield: 284 mg (80%) as an orange solid; mp: 72–74 ꢀC (lit.14 72–
73 ꢀC); IR (cmꢂ1): 3413, 3057, 2924, 1618, 1456, 1337, 1216,
23260 | RSC Adv., 2020, 10, 23254–23262
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
1416, 1339, 1242, 1012, 801, 743; 1H NMR (400 MHz, CD3- 135.4, 134.5, 134.4, 130.8, 130.7, 128.4, 125.2, 124.8, 122.1, 117.5,
COCD3): d 10.18 (br s, 2H, NH), 8.50 (t, J ¼ 5.2 Hz, 2H), 7.46–7.42 117.2, 116.9, 114.0, 113.8, 112.8, 112.7, 35.5 ppm; HRMS: m/z
(m, 4H), 7.04–6.98 (m, 7H), 6.75–6.71 (m, 2H) ppm; 13C NMR calculated: 53.6301, found: 533.6301 [M + H]+.
(100 MHz, CD3COCD3): d 156.3, 149.7, 138.2, 128.2, 125.7, 122.3,
Synthesis of 3,30-((2,3-dichlorophenyl)methylene)bis(5-
121.8, 119.1, 112.2, 49.0 ppm.
bromo-1H-indole) (3wa). Yield: 417 mg (76%) as an orange red
Synthesis
of
3,30-(pyridin-3-ylmethylene)bis(1H-indole) solid; mp: 220–222 ꢀC; IR (cmꢂ1): 3431, 3415, 3075, 1708, 1614,
(3qa). Yield: 242 mg (75%) as a reddish brown solid; mp: 137– 1580, 1564, 1458, 1449, 1413, 1339, 1318, 1292, 1256, 1268,
1
ꢀ
ꢀ
139 C (lit. 138–140 C); H NMR (400 MHz, CDCl3): d 8.43 (d, 1213, 1176, 1154, 1133, 1095, 1041, 964, 903, 881, 864, 835, 802,
1
1H, J ¼ 7.6 Hz, ArH), 8.18 (brs, 2H, NH), 7.40–7.03 (m, 11H, 786, 780, 767, 749, 736, 714, 701, 668, 657; H NMR (400 MHz,
ArH), 6.69 (s, 2H, ArH), 5.89 (s, 1H, Ar-CH) ppm; 13C NMR (100 CDCl3): d 8.03 (s, 2H), 7.47 (s, 2H), 7.46–7.381 (m, 1H), 7.30–7.24
MHz, CDCl3): d 149.5, 147.0, 140.2, 136.5, 135.5, 126.3, 123.6, (m, 4H), 7.08–7.03 (m, 2H), 6.62 (d, J ¼ 1.6 Hz, 2H), 6.22 (s,
123.2, 121.0, 118.8, 118.2, 117.1, 111.5, 54.8 ppm.
1H) ppm; 13C NMR (100 MHz, CDCl3): d 142.8, 135.3, 133.4,
Synthesis of 3,30-(2-thienylmethylene)bis(1H-indole) (3ra). 132.3, 128.8, 128.4, 128.0, 127.0, 125.2, 124.9, 122.0, 117.2,
Yield: 278 mg (85%) as a red solid; mp: 180–182 C (lit.31 185– 112.9, 112.7, 37.4 ppm; HRMS: m/z calculated: 546.8909 [M +
ꢀ
188 ꢀC); IR (cmꢂ1): 3414, 2923, 2852, 1456, 1338, 1217, 1094, H]+, found 546.8886 [M + H]+.
1010, 853, 742, 592; 1H NMR (400 MHz, CDCl3): d 7.91 (br s, 2H,
NH), 7.45 (d, J ¼ 8.4 Hz, 2H), 7.34 (d, J ¼ 8.4 Hz, 2H), 7.18–7.13
Conflicts of interest
(m, 3H), 7.02 (t, J ¼ 7.6 Hz, 2H), 6.92–6.89 (m, 2H), 6.82 (s, 2H),
6.15 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d 148.6, 136.5,
126.7, 126.4, 125.1, 123.6, 123.1, 122.0, 119.7, 119.6, 119.3,
111.1, 35.3 ppm.
There are no conicts to declare.
Synthesis of 3,30-benzylidenebis(5-bromo-1H-indole) (3sa).
References
Yield: 437 mg (91%) as a red solid; mp: 243–247 C (lit.30 246–
ꢀ
248 ꢀC); IR (cmꢂ1): 3248, 2920, 2850, 1610, 1463, 1261, 1098,
1 R. Tjalkens and S. Safe, US Pat., 8580843, 2013.
2 S. A. Morris and R. J. Andersen, Tetrahedron, 1990, 46, 715–720.
3 A. Ramirez, S. Garcia-Rubio, A. Ramırez and S. Garcıa-Rubio,
885, 798, 700; 1H NMR (400 MHz, CDCl3): d 7.90 (br s, 2H, NH),
7.38 (s, 2H), 7.20–7.12 (m, 9H), 6.56 (s, 2H), 5.66 (s, 1H) ppm; 13
C
´
´
NMR (100 MHz, CDCl3): d 143.2, 135.3, 128.5, 128.4, 128.1,
Curr. Med. Chem., 2003, 10, 1891–1915.
126.2, 124.9, 124.4, 121.9, 118.5, 112.6, 112.1, 38.7 ppm.
4 J. K. Porter, C. W. Bacon, J. D. Robbins, D. S. Himmelsbach
and H. C. Higman, J. Agric. Food Chem., 1977, 25, 88–93.
5 T. R. Garbe, M. Kobayashi, N. Shimizu, N. Takesue,
M. Ozawa and H. Yukawa, J. Nat. Prod., 2000, 63, 596–598.
6 K.-B. Oh, W. Mar, S. Kim, J.-Y. Kim, T.-H. Lee, J.-G. Kim,
D. Shin, C. J. Sim and J. Shin, Biol. Pharm. Bull., 2006, 29,
570–573.
Synthesis
of
4-(bis(5-bromo-1H-indol-3-yl)methyl)
benzonitrile (3ta). Yield: 419 mg (83%) as a dark red solid;
mp: 230–232 ꢀC; IR (cmꢂ1): 3444, 3393, 3332, 3053, 2922, 2852,
2230, 1651, 1604, 1562, 1488, 1457, 1416, 1336, 1315, 1303,
1242, 1220, 1207, 1173, 1134, 1100, 1043, 1019, 933, 885, 863,
1
852, 825, 790, 774, 762, 744, 726, 700, 683, 667; H NMR (400
MHz, CDCl3): d 9.38 (s, 2H), 7.53 (d, J ¼ 8.4 Hz, 2H), 7.35 (dd, J ¼
5.2 and 3.6 Hz, 4H), 7.20–7.17 (m, 4H), 6.59 (d, J ¼ 2 Hz, 2H),
5.76 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): d 149.2, 135.5,
132.2, 129.4, 128.3, 125.2, 124.7, 121.6, 119.1, 116.9, 113.0,
112.4, 110.1, 40.2 ppm.
7 E. Fahy, B. C. M. M. Potts, D. J. Faulkner and K. Smith, J. Nat.
Prod., 1991, 54, 564–569.
8 R. Bell, S. Carmeli and N. Sar, J. Nat. Prod., 1994, 57, 1587–
1590.
9 S. X. Cai, D. H. Li, T. J. Zhu, F. P. Wang, X. Xiao and Q. Q. Gu,
Helv. Chim. Acta, 2010, 93, 791–795.
Synthesis of 3,30-((4-chlorophenyl)methylene)bis(5-bromo-
1H-indole) (3ua). Yield: 457 mg (89%) as a red solid; mp: 110– 10 M. A. Zelgis, J. Med. Food, 1998, 1, 67–82.
112 ꢀC; IR (cmꢂ1): 3397, 3053, 2923, 2852, 1656, 1617, 1562, 11 M. Shiri, M. A. Zolgol, H. G. Kruger and Z. Tanbakouchian,
1487, 1459, 1418, 1338, 1302, 1219, 1165, 1133, 1091, 1014, 925,
Chem. Rev., 2010, 110, 2250–2293.
882, 867, 791, 744, 726, 700, 675, 653; 1H NMR (400 MHz, 12 C. Thomas, US Pat., 4500689, 1985.
CDCl3): d 8.01 (s, 2H), 7.46 (t, J ¼ 1.2 Hz, 2H), 7.28–7.21 (m, 8H), 13 M. C. Bell, P. Crowley-Nowick, H. L. Bradlow, D. W. Sepkovic,
6.63 (dd, J ¼ 2.4 & 0.8 Hz, 2H), 5.74 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3): d 141.6, 135.3, 132.2, 129.9, 128.6, 128.5, 125.1,
124.8, 122.2, 118.5, 112.8, 112.7, 39.3 ppm; HRMS: m/z calcu-
lated: 511.9291, found: 512.9225 [M + H]+.
D. Schmidt-Grimminger, P. Howell, E. J. Mayeaux, A. Tucker,
E. A. Turbat-Herrera and J. M. Mathis, Gynecol. Oncol., 2000,
78, 123–129.
14 V. D. Kadu, D. N. Nadimetla, M. G. Hublikar, D. G. Raut and
R. B. Bhosale, Lett. Org. Chem., 2020, 17, 61–67.
Synthesis of 3,30-((2-chloro-4-uorophenyl)methylene)bis(5-
bromo-1H-indole) (3va). Yield: 426 mg (80%) as an orange solid; 15 R. M. N. Kalla, J. V. John, H. Park and I. Kim, Catal.
mp: 98–100 ꢀC; IR (cmꢂ1): 3429, 1682, 1596, 1579, 1484, 1457,
Commun., 2014, 57, 55–59.
1417, 1394, 1338, 1318, 1260, 1215, 1165, 1095, 1060, 1041, 903, 16 S. A. R. Mulla, A. Sudalai, M. Y. Pathan, S. A. Siddique,
883, 861, 791, 768, 747, 682, 653; 1H NMR (400 MHz, CDCl3): d 8.01
(s, 2H), 7.46 (t, J ¼ 0.8 Hz, 2H), 7.30–7.20 (m, 5H), 7.09 (dd, J ¼ 8.8 &
S. M. Inamdar, S. S. Chavan and R. S. Reddy, RSC Adv.,
2012, 2, 3525.
6.4 Hz, 1H), 6.88–6.83 (m, 1H), 6.61 (d, J ¼ 1.6 Hz, 2H), 6.14 (s, 17 D. Xia, Y. Wang, Z. Du, Q. Y. Zheng and C. Wang, Org. Lett.,
1H) ppm; 13C NMR (100 MHz, CDCl3): d 162.4, 159.9, 136.4, 136.3,
2012, 14, 588–591.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 23254–23262 | 23261

View Article Online
RSC Advances
Paper
18 S. Zhang, W. Fan, H. Qu, C. Xiao, N. Wang, L. Shu, Q. Hu and 26 S. Dae Cho, S.-O. Lee, S. Chintharlapalli, M. Abdelrahim,
L. Liu, Curr. Org. Chem., 2012, 16, 942–948.
19 A. E. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe and T. Ohta,
Eur. J. Org. Chem., 2013, 6344–6354.
20 T. Nobuta, A. Fujiya, N. Tada, T. Miura and A. Itoh, Synlett,
2012, 23, 2975–2979.
S. Khan, K. Yoon, A. M. Kamat and S. Safe, Mol.
Pharmacol., 2010, 77, 396–404.
27 S.-O. Lee, X. Li, E. Hedrick, U.-H. Jin, R. B. Tjalkens,
D. S. Backos, L. Li, Y. Zhang, Q. Wu and S. Safe, Mol.
Endocrinol., 2014, 28, 1729–1739.
21 J. Xiang, J. Wang, M. Wang, X. Meng and A. Wu, Org. Biomol. 28 K. Vanderlaag, Y. Su, A. E. Frankel, R. C. Burghardt,
Chem., 2015, 13, 4240–4247.
R. Barhoumi, G. Chadalapaka, I. Jutooru and S. Safe, BMC
Cancer, 2010, 10, 669.
29 B. P. Bandgar, A. V. Patil and V. T. Kamble, ARKIVOC, 2007,
252–259.
30 B. S. Liao, J. T. Chen and S. T. Liu, Synthesis, 2007, 2007,
3125–3128.
22 L. Zhang, C. Peng, D. Zhao, Y. Wang, H. J. Fu, Q. Shen and
J. X. Li, Chem. Commun., 2012, 48, 5928–5930.
23 K. Gopalaiah, S. N. Chandrudu and A. Devi, Synthesis, 2015,
47, 1766–1774.
˜
24 M. P. Munoz, M. C. De La Torre and M. A. Sierra, Chem.–Eur.
J., 2012, 18, 4499–4504.
25 D. C. Sung, K. Yoon, S. Chintharlapalli, M. Abdelrahim,
31 R. Ghorbani-Vaghei and S. M. Malaekehpoor, Org. Prep.
Proced. Int., 2010, 42, 175–182.
P. Lei, S. Hamilton, S. Khan, S. K. Ramaiah and S. Safe, 32 A. Zare, A. Parhami, A. R. Moosavi-Zare, A. Hasaninejad,
Cancer Res., 2007, 67, 674–683.
A. Khala-Nezhad and M. H. Beyzavi, Can. J. Chem., 2009,
87, 416–421.
23262 | RSC Adv., 2020, 10, 23254–23262
This journal is © The Royal Society of Chemistry 2020