Utilization of flow chemistry in catalysis: New avenues for the selective synthesis of Bis(indolyl)methanes

Article abstract of DOI:10.1016/j.tet.2017.02.026

Flow chemistry enables the preparation of bis(indolyl)methanes from various indoles and structurally divergent aldehydes using Sc(OTf)₃ catalysis. The reaction is regioselective for C-3 functionalization of the indoles, occurring over short reaction times allowing for rapid investigation of scope with straightforward work up facilitating product isolation.

Full text of DOI:10.1016/j.tet.2017.02.026

Accepted Manuscript
Utilization of flow chemistry in catalysis: New avenues for the selective synthesis of
Bis(indolyl)methanes
Swapna S. Mohapatra, Zoe E. Wilson, Sujit Roy, Steven V. Ley
PII:
S0040-4020(17)30158-8
10.1016/j.tet.2017.02.026
TET 28467
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 December 2016
Revised Date: 1 February 2017
Accepted Date: 13 February 2017
Please cite this article as: Mohapatra SS, Wilson ZE, Roy S, Ley SV, Utilization of flow chemistry in
catalysis: New avenues for the selective synthesis of Bis(indolyl)methanes, Tetrahedron (2017), doi:
10.1016/j.tet.2017.02.026.
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Utilization of Flow Chemistry in Catalysis:
New Avenues for the Selective Synthesis of
Bis(indolyl)methanes.
Leave this area blank for abstract info.
Swapna S. Mohapatraa,b, Zoe E. Wilsona, Sujit Royb
and Steven V. Leya*
a Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge, CB2 1EW, UK
b Organometallics & Catalysis Laboratory, School of
Basic Sciences, Indian Institute of Technology,
Bhubaneswar 751013, India

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Utilization of flow chemistry in catalysis: new avenues for the selective synthesis of
Bis(indolyl)methanes.
Swapna S. Mohapatraa,b, Zoe E. Wilsona, Sujit Royb and Steven V. Leya*
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Flow chemistry enables the preparation of bis(indolyl)methanes from various indoles and
structurally divergent aldehydes using Sc(OTf)3 catalysis. The reaction is regioselective for C-3
functionalization of the indoles, occurring over short reaction times allowing for rapid
investigation of scope with straightforward work up facilitating product isolation.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Alkylation
Scandium Triflate
Bis(indolyl)methanes
Flow
Catalysis
1. Introduction
is highly soluble in a range of organic solvents while being stable
in the presence of water, unlike the majority of Lewis acids,
meaning that it can be recovered and reused if desired.37
Flow chemistry has emerged as an excellent technique for
reaction profiling and optimization, and has the benefit of
additionally aiding in the scale up of reactions, with its
characteristic rapid and controlled mixing and excellent
temperature control often leading to higher yields and or
selectivity over batch processes.1,2 In this work, we report a
scandium triflate (Sc(OTf)3) catalyzed flow chemistry
preparation of bis(indolyl) alkanes, which are structural motifs
frequently found in natural products, pharmaceuticals, and other
functional materials3. Particularly, bis(indolyl) methane (BIM)
derivatives possess promising biological effects such as anti-
Prior to this work there was a single report of the use of
Sc(OTf)3 proceeding by an acid catalyzed mechanism5,39 to
prepare 3a (Scheme 1).38 It was envisaged that by using flow
methodology it would be possible to rapidly optimise and explore
the scope of this process leading to decorated tri-substituted
methanes with an indole core using Sc(OTf)3 catalysis.
pyretic,
anti-fungal,
anti-inflammatory,
anti-convulsant,
cardiovascular, and selective COX-2 inhibitory activities.4,5 In
addition, oxidized forms of BIMs are utilized as dyes as well as
colorimetric chemosensors.5
Owing to their wide spread occurrence, there has been
significant interest in the synthesis of BIMs. To date, most
methods have employed conventional Lewis acids as well as
protic acids as catalysts to promote the electrophilic substitution
reaction of indoles with various aldehydes or carbonyl
compounds.5–8 A variety of organo-9–13, transition metal14–20, ionic
liquid21–26 and nanomaterial27–32 catalysts have also been
reported. However, many of these reported methods suffer
disadvantages such as requiring high catalyst loading, long
reaction times and/or monotonous work-up procedures.33–36 The
development of a more sustainable alternative protocol for the
preparation of BIMs would therefore be desirable. Scandium
triflate is an attractive Lewis acid to employ for this purpose as it
Scheme 1. Synthesis of BIM 3a in batch by Sato and Sato.38
2. Results and Discussion
Initially, the assembly of BIM 3a from benzaldehyde 1a (0.66
mmol) and indole 2a (1.32 mmol) was repeated in batch by
Sato’s method to afford the desired product in a comparable 91%
yield with 3.5 h reaction time, confirming the robustness of this
process.
Next, we transferred this reaction to flow. Initially the flow
equipment was set up according to the scheme of Table 1, using

2
Tetrahedron
ACCEPTED MANUSCRIPT
Syrris Asia syringe pumps. Indole 2a and benzaldehyde 1a
reacted with benzaldehyde 1a to form the corresponding products
were taken up in acetonitrile and filled into loop 1. Sc(OTf)3 (5
mol%) was taken up in acetonitrile and filled into loop 2. The
two loops were simultaneously injected into streams of
acetonitrile and the plugs met at a T- piece before passing
through a 5 mL reactor coil, for a reaction time of 30 min. The
reaction stream was pressurised by a 100 psi back pressure
regulator (BPR) and the outflow collected. The solvent was
removed in vacuo and the crude directly purified by flash
chromatography to afford the desired product in 54% yield (entry
1). When the concentration of reactants and catalyst was doubled,
the yield was found to improve to 81% (entry 2) but further
increasing the concentration led to a drop in yield to 75% (entry
3). Increasing the flow rate (halving the reaction time) at the
optimized concentration resulted in a decrease in yield to 72%
(entry 4) whereas increasing reaction time to 45 min resulted in a
slight increase to 82% (entry 5). At this point the reaction coil
was changed to a 20 mL coil to allow a reaction time of 60 min
with faster flow rates and resulted in an unchanged yield of 82%
(entry 6). Next the solvent was changed to tetrahydrofuran
(THF), resulting in the yield of the desired product 3a increasing
to 92% (entry 7). As before, when the concentration was lowered
the yield of desired product 3a was reduced to 89% (entry 8).
When the reaction was performed at 40 °C at the optimal
concentration, the yield of the desired product 3a was decreased
to 82% (entry 9). Therefore, it was decided to carry out all
reactions at room temperature (entry 7), using THF as a solvent.
3b (89%) and 3c (95%) respectively. Similarly, benzaldehyde 1a
reacted with 5-nitro indole 2d to form 3d as the product with
83% yield (entry 4). It was found that the reaction of 1a with 4-
methoxy indole 2e (entry 5), resulted in a modest 50% of 3e.
Pleasingly, it was found that N-methyl indole 2f reacted to form
the product 3f (88%) with 4-chloro benzaldehyde 1b (entry 6).
Additionally, it was found that a wide range of substituted
benzaldehydes such as 2,3,4,5,6-pentafluoro benzaldehyde 1c
(entry 7), 3-nitro benzaldehyde 1d (entry 8), and 4-chloro
benzaldehyde 1e (entry 9) reacted with indole 2a to form the
corresponding products 3g, 3h, and 3i in yields ranging from 80-
97%. It was even seen that one equivalent of terephthalaldehyde
1f reacted with four equivalents of 2a to form 3j in 65% yield
(entry 10). Due to poor solubility, when reacting 10-chloro-9-
anthraldehyde 1g and 4-methoxy indole 2e in THF the
concentration of the solution was lowered to 0.08 M (entry 11),
with the corresponding novel BIM 3k obtained in a modest 20%
yield.
When
5-methoxy
indole
2c
reacted
with
3-chlorobenzaldehyde 1h, 4-nitrobenzaldehyde 1i, and
mesitaldehyde 1j (entries 12-14), the products formed in 80%
(3l), 97% (3m), 83% (3n) yield respectively. Finally, the scope
was further extended by exchanging the benzaldehyde for a
heterocyclic aldehyde. It was found that using furfural 1k (entry
15) and 2-thiophene carboxaldehyde 1l (entry 16) as the aldehyde
coupling partners resulted in 78% and 93% of the desired
products 3o and 3p respectively. However, when 2-pyridine
carboxaldehyde 1m and 3-pyridine carboxaldehyde 1n were
used, the reactions did not go to completion in the time frame of
the flow reaction, with yields reduced to 30% (3q) and 10% (3r)
With optimized flow conditions established, the scope of the
reaction was evaluated with a variety of aldehydes (1) and
indoles (2) employed as detailed in Table 2. It was seen that 5-
bromo indole 2b (entry 2), and 5-methoxy indole 2c (entry 3)
(entries
17
and
18).
Table 1. Optimization of conditions for the synthesis of bis(indolyl)methane 3a.
Reaction
time (min)
Yield 3a
(%)
54
Flow rate
(ꢀL/min/pump)
Conc.
(M)
Vol.
(mL)
entry
Solvent
Temp.
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
83
83
83
166
55
166
166
166
83
30
30
30
15
45
60
60
60
60
0.33
0.66
0.99
0.66
0.66
0.66
0.66
0.33
0.66
5
5
5
5
5
20
20
20
10
RT
RT
RT
RT
RT
RT
RT
RT
81
75
72
82
82
92
89
82
THF
THF
40 °C

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Table 2. Substrate scope for Sc(OTf)3 catalyzed flow synthesis of bis(indolyl)methanes.
Yield
(%)
Yield
(%)
entry
1
Aldehyde
Indole
Product
entry
5
Aldehyde
Indole
Product
92
1a
50
2a
1a
1a
2e
3e
3a
2
89
6
88
2f
2b
1b
3b
3f
3
4
1a
1a
95
83
7
8
2a
96
96
2c
1c
3c
3g
3h
2a
2d
1d
3d

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4
Tetrahedron
Yield
entry
(%)
Yield
(%)
entry
9
Aldehyde
Indole
Product
Aldehyde
Indole
Product
2a
96
65
14
15
2c
83
1j
1e
3n
3o
3i
10
2a1
2a
78
1k
1f
3j
11
2e
20
16
2c
93
1l
3p
1g
3k
3l
12
13
2c
2c
80
97
17
18
2a
2a
30
10
1m
1n
1h
1i
3q
3r
3m
1 Four equivalents of the indole were used.

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Scheme 3. Continuous flow synthesis of 3b.
Additionally, as proof of scalability the synthesis of 3b was
run continuously for 5 h 46 min on 28.6 mmol scale (determined
by our laboratories supply of indole 2b) to afford 12.4 g of
product (91% yield). For the purposes of this reaction the flow
equipment used was changed to acid-resistant Vapourtec R-series
pumps. The reaction coil volume was increased to 60 mL to
allow the pumps to be run with flow rates of 0.5 mL.min-1 per
pump without changing the reaction time, and a 40 psi BPR was
used to pressurize the reaction stream (Scheme 3).
(13C). All 13C NMR spectra were run with broadband proton
decoupling. Multiplicity of a signal in 1H NMR is indicated by: s
= singlet, d = doublet, t = triplet, m = multiplet, or a combination
thereof. Multiplets are reported as the range of ppm values
covered by the signals, otherwise the center of the signal is given.
Coupling constants, J, are quoted in Hz and recorded to the
nearest 0.1 Hz. Assignments (detailed in the supporting
information) were confirmed using Distortionless Enhanced
Polarisation Transfer NMR (DEPT 135) and two dimensional
NMR (1H–1H Correlation Spectroscopy (COSY), Heteronuclear
Single Quantum Coherence (HSQC) and Heteronuclear Multiple
Bond Correlation (HMBC)) experiments gave information used
to assign both the 1H NMR and 13C NMR spectra.
3. Conclusions
Flow chemistry has been found to be an effective method for
the synthesis of bis(indolyl)methanes from a range of indoles
with structurally diverse aldehydes using Sc(OTf)3 as catalyst in
both plug and continuous flow modes. It was found that shorter
reaction times were needed and only a straightforward work up
required. The successful synthesis of a library of 18 BIMs,
including novel structures 3e, 3k, 3l and 3n, provides the
opportunity to further explore the bioactivity of this family of
compounds.
Infrared spectra were recorded neat as thin films on a Perkin-
Elmer Spectrum One FTIR spectrometer. Absorbances were
1
recorded in the range 4000 650 cm .
High resolution mass spectrometry (HRMS) was performed
using positive/negative electrospray ionisation (ESI+/ESI-), on
either a Waters Micromass LCT Premier spectrometer or using a
Bruker Bioapex 47e FTICR spectrometer. All m/z values are
reported to 4 decimal places and are within ± 5 ppm of
theoretical values.
4. Experimental Details
4.1. General Experimental Details
Melting points were measured on a Stuart Scientific SMP3
melting point apparatus using a gradient of 0.5 °C.min-1. Samples
were recrystallized from ethanol and water prior to measuring.
Reactions were performed using oven-dried glassware (200
°C) under an atmosphere of argon unless otherwise stated. All
plug flow reactions were performed using a Syrris Asia flow
system40 and a Polar Bear Plus cooling/heating unit (Cambridge
reactor design)41. The continuous flow reaction was carried out
using a Vapourtec R-series flow machine with acid resistant
pumps42. Solvents were freshly distilled over calcium hydride
and lithium aluminium hydride (tetrahydrofuran) or calcium
hydride (acetonitrile, ethyl acetate and 40-60 petroleum ether).
All additional reagents and solvents were obtained from
commercial sources and used without further purification. Flash
column chromatography was performed using high-purity grade
silica gel (grade 9385) with 60-120 mesh particle size under air
pressure. Analytical thin layer chromatography (TLC) was
performed using silica gel 60 F254 pre-coated glass backed plates
and visualized by ultraviolet radiation (254 nm).
Additional data related to this publication is available at the
University of Cambridge Institutional Data Repository
(https://doi.org/10.17863/CAM.6695).
4.2. Batch Procedure for the synthesis of 3,3'-
(phenylmethylene)bis(1H-indole) (3a)
Benzaldehyde 1a (70 mg, 0.66 mmol), indole 2a (154 mg,
1.32 mmol) and ScOTf3 (8 mg, 0.02 mmol) were taken up in
acetonitrile (4 mL) and was stirred at room temperature (20 °C)
for 3.5 h. The solvent was removed in vacuo and the mixture was
purified by flash column chromatography using 40-60 petroleum
ether:ethyl acetate (4:1) as eluent to afford the title compound 3a
(193 mg, 0.60 mmol, 91%) as an off white solid. See below for
characterization.
All NMR spectra except 3d were recorded on a 600 MHz
1
Avance 600 BBI Spectrometer. H and 13C NMR spectra of 3d
4.3. General Procedure for the synthesis of BIMs in Flow (plug
flow)
were recorded on a Bruker-AC 400 MHz Spectrometer. Unless
otherwise stated, all samples were run at room temperature in
deuterated solvent, with chemical shift (δ) reported to the nearest
0.01 (1H)/0.1 (13C) ppm, relative to the residual protic solvent;
δ(CDCl3) = 7.26 (1H)/77.16 (13C) ppm, δ(CD3COCD3) = 2.05
(1H)/ 29.84, 206.26 (13C) or δ(CD3SOCD3) = 2.50 (1H)/39.52
The flow equipment was set up according to Table 2. Indole 2
(1.65 mmol) and aldehyde 1 (0.82 mmol) were taken up in THF
(5 mL) and filled into loop 1. Sc(OTf)3 (5 mol%, 0.041 mmol)
was taken up in THF (5 mL) and filled into loop 2. The two loops
were simultaneously injected and the plugs met at a T-piece

6
Tetrahedron
ACCEPTED MANUSCRIPT
before passing through a 20 mL reactor coil, pressurised by a
2H), 7.42 (dd, J = 7.3, 1.4 Hz, 2H), 7.29 – 7.17 (m, 4H), 7.18 (d,
100 psi back pressure regulator and the outflow collected. The
solvent was removed in vacuo and the mixture purified by flash
column chromatography using 40-60 petroleum ether:ethyl
acetate as eluent to afford the title compound 3.
J = 7.4 Hz, 1H), 6.86 – 6.79 (m, 4H), 6.74 (dd, J = 8.8, 2.4 Hz,
2H), 5.84 (s, 1H), 3.62 (s, 6H); 13C NMR (150 MHz,
CD3COCD3): δ 154.4, 146.0, 133.2, 129.5, 128.8, 128.5, 126.6,
125.3, 119.5, 112.7, 112.0, 102.5, 55.7, 41.2; FTIR (νmax, cm-1):
3392, 3317, 3008, 2964, 2936, 1623, 1583, 1484, 1453, 1441,
1292, 1207, 1171, 1126, 1038, 1021, 923, 832, 808, 719; HRMS
(ESI): found 383.1737, [M+H]+ C25H23N2O2 requires 383.1754.
All spectroscopic data was in agreement with that published in
the literature.44
4.4. Continuous flow synthesis of 3,3'-(phenylmethylene)bis(5-
bromo-1H-indole) (3b)
The flow equipment was set up according to Scheme 3.
5-bromoindole 2b (11.2 g, 57.1 mmol) and benzaldehyde 1a (2.9
mL, 28.6 mmol) were taken up in THF (173 mL). Sc(OTf)3
(0.81 g, 1.6 mmol) was taken up in THF (200 mL, 0.034 M). The
pump for the catalyst solution was started 30 s before the other
pump to ensure overlap of streams. The reaction streams met at a
T-piece before passing through a 60 mL reactor coil, pressurised
by a 40 psi back pressure regulator and the outflow collected,
with the lines being flushed out with THF once the solution has
all been passed through the system. The solvent was removed in
vacuo and the mixture purified by flash column chromatography
using 40-60 petroleum ether:ethyl acetate (4:1, Rf = 0.32) as
eluent to afford the title compound 3b (12.4 g, 25.9 mmol, 91%)
as an off white solid. See below for characterization.
4.5.4. 3,3'-(phenylmethylene)bis(5-nitro-1H-indole)
(3d)
According to the flow general method indole 2d was coupled
to benzaldehyde 1a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.46) as eluent to afford the title compound 3d (280 mg, 0.68
mmol, 83%) as a yellow solid, mp = >300 °C, lit. mp = >300
°C47. 1H NMR (400 MHz, CD3SOCD3): δ 11.66 (s, 2H), 8.30 (d,
J = 2.2 Hz, 2H), 7.97 (dd, J = 9.0, 2.3 Hz, 2H), 7.54 (d, J = 9.0
Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.22
(t, J = 7.3 Hz, 1H), 7.13 (d, J = 1.9 Hz, 2H), 6.19 (s, 1H); 13C
NMR (101 MHz, CD3SOCD3): δ 144.1, 140.6, 140.2, 128.9,
128.6, 128.0, 126.8, 126.2, 120.9, 117.0, 116.6, 112.5, 38.9;
FTIR (νmax, cm-1): 3368, 1623, 1580, 1514, 1470, 1424, 1377,
1324, 1239, 1090, 1040, 893, 817, 739, 701; HRMS (ESI):
found 413.1232, [M+H]+ C23H17N4O4 requires 413.1244. All
spectroscopic data was in agreement with that published in the
literature.48
4.5. Characterization of BIMs synthesized in flow.
4.5.1. 3,3'-(phenylmethylene)bis(1H-indole) (3a)
According to the flow general method indole 2a was coupled
to benzaldehyde 1a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (4:1,
Rf = 0.4) as eluent to afford the title compound 3a (243 mg, 0.75
mmol, 92%) as a pink solid, mp = 91.6 – 92.7 °C, lit. mp = 93 –
95 °C.43 1H NMR (600 MHz, CDCl3): δ 7.63 (s, 2H), 7.47 (d, J
= 8.0 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 7.38 – 7.19 (m, 7H), 7.09
(t, J = 8.0 Hz, 2H), 6.55 (s, 2H), 5.95 (s, 1H); 13C NMR (150
MHz, CDCl3): δ 144.1, 136.6, 128.7, 128.3, 127.1, 126.2, 123.7,
121.9, 119.9, 119.5, 119.2, 111.2, 40.2; FTIR (νmax, cm-1): 3405,
3055, 3024, 2833, 1723, 1599, 1492, 1455, 1417, 1336, 1216,
1092, 1040, 1009, 762, 739, 700; HRMS (ESI): found 321.1399,
[M-H]- C23H17N2 requires 321.1397. All spectroscopic data was
in agreement with that published in the literature.44
4.5.5. 3,3'-(phenylmethylene)bis(4-methoxy-1H-
indole) (3e)
According to the flow general method indole 2e was coupled
to benzaldehyde 1a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.8) as eluent to afford the title compound 3e (156 mg, 41
mmol, 50%) as a white solid, mp = 268 – 270 °C (decomposes).
1H NMR (600 MHz, CD3COCD3): δ 9.82 (s, 2H), 7.32 (d, J =
7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H),
6.98 – 6.92 (m, 4H), 6.79 (s, 1H), 6.54 (d, J = 1.7 Hz, 2H), 6.43 –
6.34 (m, 2H), 3.61 (s, 6H); 13C NMR (151 MHz, CD3COCD3):
δ 155.9, 148.3 , 139.5, 129.6, 128.2, 125.7, 123.1, 122.7, 122.1,
118.3, 105.5, 100.1, 55.4, 42.1; FTIR (νmax, cm-1): 3438, 3398,
3020, 2837, 1611, 1581, 1504, 1462, 1453, 1358, 1259, 1118,
1085, 1038, 766, 728; HRMS (ESI): found 382.1676, [M]+
C25H22N2O2 requires 382.1673.
4.5.2. 3,3'-(phenylmethylene)bis(5-bromo-1H-
indole) (3b)
According to the flow general method indole 2b was coupled
to benzaldehyde 1a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (4:1,
Rf = 0.32) as eluent to afford the title compound 3b (350 mg, 0.73
mmol, 89%) as an off white solid, mp = 253.4 – 255.0 °C, lit. mp
= 246 – 248 °C.45 1H NMR (600 MHz, CD3COCD3): δ 10.27 (s,
2H), 7.54 (s, 2H), 7.45 – 7.37 (m, 4H), 7.31 (t, J = 7.7 Hz, 2H),
7.22 – 7.19 (m, 3H), 6.89 (s, 2H), 5.95 (s, 1H); 13C NMR (150
MHz, CD3COCD3): δ 145.0, 136.7, 129.7, 129.3, 129.0, 127.0,
126.2, 124.8, 122.5, 119.2, 114.1, 112.3, 40.5; FTIR (νmax, cm-1):
3418, 1720, 1597, 1564, 1492, 1443, 1417, 1373, 1241, 1225,
1095, 1040, 977, 881, 793, 745, 705; HRMS (ESI): found
476.9609, [M-H]- C23H15Br2N2 requires 476.9596. All
spectroscopic data was in agreement with that published in the
literature.44
4.5.6. 3,3'-((4-chlorophenyl)methylene)bis(1-
methyl-1H-indole) (3f)
According to the flow general method indole 2f was coupled
to benzaldehyde 1b and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.91) as eluent to afford the title compound 3f (277 mg, 0.72
mmol, 88%) as a light pink solid, mp = 208.2 – 209.3 °C, lit. mp
= 208 – 209 °C43. 1H NMR (600 MHz, CD3COCD3): δ 7.42 (d,
J = 7.7 Hz, 2H), 7.39 – 7.23 (m, 8H), 7.07 (t, J = 7.7 Hz, 2H),
6.58 (s, 2H), 5.92 (s, 1H), 3.73 (s, 6H); 13C NMR (150 MHz,
CD3COCD3): δ 143.1, 137.5, 131.7, 130.1, 128.4, 128.3, 127.3,
121.6, 112.0, 118.8, 117.8, 109.2, 39.6, 32.8; FTIR (νmax, cm-1):
3024, 3050, 2998, 2865, 2817, 1731, 1616, 1548, 1472, 1484,
1422, 1370, 1329, 1223, 1199, 1152, 1128, 1085, 1056, 1010,
920, 862, 800, 734; HRMS (ESI): found 383.1311, [M-H]-
C25H20N2Cl requires 383.1310. All spectroscopic data was in
agreement with that published in the literature.18
4.5.3. 3,3'-(phenylmethylene)bis(5-methoxy-1H-
indole) (3c)
According to the flow general method indole 2c was coupled
to benzaldehyde 1a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (4:1,
Rf = 0.3) as eluent to afford the title compound 3c (297 mg, 0.78
mmol, 95%) as an off white solid, mp = 218.0 – 220.0 °C, lit. mp
= 217 – 218 °C.46 1H NMR (600 MHz, CD3COCD3): δ 9.83 (s,
4.5.7. 3,3'-((perfluorophenyl)methylene)bis(1H-
indole) (3g)

4.5.11. 3,3'-((10-chloroanthracen-9-
According to the flow general method indoAle C2aCwEasPcTouEplDed MANUSCRIPT
yl)methylene)bis(4-methoxy-1H-indole) (3k)
to benzaldehyde 1c and purified by flash column chromatography
using 40-60 petroleum ether:ethyl acetate (1:1, Rf = 0.8) as eluent
to afford the title compound 3g (324 mg, 0.78 mmol, 96%) as an
off white solid, mp = 125.4 – 127.0 °C, lit. mp = 129 – 130 °C49.
1H NMR (600 MHz, CD3COCD3): δ 10.25 (s, 2H), 7.45 (d, J =
8.2 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 1.6 Hz, 2H),
7.13 (m, 2H) 7.05 – 6.97 (m, 2H), 6.41 (s, 1H); 13C NMR (150
MHz, CD3COCD3): δ 147.0, 145.3, 139.5, 137.8, 127.6, 124.8,
According to the flow general method indole 2e was coupled
to benzaldehyde 1g and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.8) as eluent to afford the title compound 3k (85 mg, 0.16
1
mmol, 20%) as an off white solid, mp = 202.8 – 204.3 °C. H
NMR (600 MHz, CDCl3): δ 8.84 (d, J = 8.6 Hz, 2H), 8.56 (d, J
= 8.7 Hz, 2H), 8.00 (s, 1H), 7.81 (s, 2H), 7.48 (s, 2H), 7.27 (s,
2H), 7.02 (s, 2H), 6.91 (d, J = 7.9 Hz, 2H), 6.69 (s, 2H), 6.31 (s,
2H), 3.13 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 154.9, 139.1,
138.2, 131.0, 129.0, 127.2, 126.9, 125.7, 124.9, 124.4, 122.5,
117.5, 104.1, 99.7, 54.6, 37.4; FTIR (νmax, cm-1): 3409, 3385,
2925, 2833, 1614, 1582, 1504, 1434, 1360, 1323, 1253, 1118,
1083, 928, 770, 740; HRMS (ESI): found 515.1516, [M-H]-
C33H24N2O2Cl requires 515.1521.
122.4, 119.9, 119.6, 119.3, 115.1, 112.4, 39.6, 32.8; FTIR (νmax
,
cm-1): 3407, 3048, 1718, 1651, 1621, 1519, 1497, 1457, 1418,
1338, 1114, 1045, 986, 950, 774, 740; HRMS (ESI): found
411.0911, [M-H]- C23H12N2F5 requires 411.0915. All
spectroscopic data was in agreement with that published in the
literature.49,50
4.5.8. 3,3'-((3-nitrophenyl)methylene)bis(1H-
indole) (3h)
4.5.12. 3,3'-((3-chlorophenyl)methylene)bis(5-
methoxy-1H-indole) (3l)
According to the flow general method indole 2c was coupled
to benzaldehyde 1h and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.7) as eluent to afford the title compound 3l (273 mg, 0.65
According to the flow general method indole 2a was coupled
to benzaldehyde 1d and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.76) as eluent to afford the title compound 3h (289 mg, 0.78
mmol, 96%) as an off white solid, mp = 255.1 – 258.3 °C, lit. mp
= 261 – 263 °C.51 1H NMR (600 MHz, CDCl3): δ 8.23 (s, 1H),
8.16 – 8.02 (m, 1H), 7.90 (s, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.45 –
7.33 (m, 5H), 7.23 (t, J = 7.6 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H),
6.59 (d, J = 2.2 Hz, 2H), 6.00 (s, 1H); 13C NMR (150 MHz,
CDCl3): δ 148.4, 146.4, 136.7, 135.0, 129.2, 126.6, 123.8, 123.6,
122.3, 121.5, 119.5, 118.2, 111.4, 40.0; FTIR (νmax, cm-1): 3406,
3057, 2976, 1723, 1618, 1522, 1488, 1456, 1417, 1345, 1243,
1216, 1124, 1093, 1040, 1010, 927, 832, 793, 739, 728; HRMS
(ESI): found 366.1236, [M-H]- C23H16N3O2 requires 366.1237.
All spectroscopic data was in agreement with that published in
the literature.52
1
mmol, 80%) as an off white solid, mp = 242.6 – 243 °C. H
NMR (600 MHz, CD3COCD3): δ 9.90 (s, 2H), 7.43 (s, 1H), 7.38
(d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 17.7 Hz,
2H), 7.24 – 7.20 (m, 1H), 6.90 – 6.85 (m, 4H), 6.77 (dd, J = 8.8,
2.4 Hz, 2H), 5.90 (s, 1H), 3.64 (s, 6H); 13C NMR (150 MHz,
CD3COCD3): δ 154.4, 148.6, 134.2, 133.2, 130.4, 129.3, 128.2,
128.0, 126.7, 125.3, 118.6, 112.8, 112.1, 102.3, 55.7, 40.8; FTIR
(νmax, cm-1): 3393, 2992, 2948, 2825, 1624, 1584, 1484, 1453,
1440, 1287, 1207, 1172, 1127, 1091, 1041, 1025, 926, 832, 812,
767, 737, 704.52; HRMS (ESI): found 415.1203, [M-H]-
C25H20N2O2Cl requires 415.1208.
4.5.9. 3,3'-((4-chlorophenyl)methylene)bis(1H-
indole)(3i)
4.5.13. Bis(5-methoxyindol-3-yl)(4′-
nitrophenyl)methane (3m)
According to the flow general method indole 1a was coupled
to benzaldehyde 2a and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.78) as eluent to afford the title compound 3i (281 mg, 0.78
mmol, 96%) as an off white solid, mp = 102.7 – 104.2 °C, lit. mp
= 104 – 106 °C.53 1H NMR (600 MHz, CDCl3): δ 7.73 (s, 2H),
7.44 (d, J = 7.5 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.33 – 7.27 (m,
4H), 7.25 (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.5 Hz, 2H), 6.57 (s,
2H), 5.90 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 142.6, 136.7,
131.8, 130.1, 128.4, 126.9, 123.7, 122.1, 119.8, 119.4, 119.1,
111.2, 39.6; FTIR (νmax, cm-1): 3408, 3054, 2837, 1722, 1617,
1550, 1487, 1455, 1416, 1336, 1243, 1215, 1088, 1038, 1012,
856, 785, 738; HRMS (ESI): found 355.0998, [M-H]-
C23H16N2Cl requires 355.0997. All spectroscopic data was in
agreement with that published in the literature.54
According to the flow general method indole 2c was coupled
to benzaldehyde 1i and purified by flash column chromatography
using 40-60 petroleum ether:ethyl acetate (1:1, Rf = 0.67) as
eluent to afford the title compound 3m (340 mg, 0.79 mmol,
97%) as off white solid, mp =138.5 – 140.0 °C, lit. mp = 142
1
°C57. H NMR (600 MHz, CDCl3): δ 8.12 (d, J = 8.6 Hz, 2H),
8.02 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H),
6.89 (dd, J = 8.8, 2.0 Hz, 2H), 6.81 (d, J = 2.0 Hz, 2H), 6.65 (d, J
= 1.3 Hz, 2H), 5.90 (s, 1H), 3.74 (s, 6H); 13C NMR (150 MHz,
CDCl3): δ 153.9, 151.9, 146.4, 131.9, 129.5, 127.1, 124.6, 123.6,
117.5, 112.12, 112.13, 101.8, 55.9, 40.2; FTIR (νmax, cm-1):
3411, 2938, 2830, 1624, 1583, 1513, 1482, 1453, 1438, 1341,
1292, 1206, 1170, 1106, 1040, 925, 834, 795, 749, 721; HRMS
(ESI): found 428.1602, [M+H]+ C25H22N3O4 requires 428.1605.
All spectroscopic data was in agreement with that published in
the literature.57
4.5.10. 1,4-bis(di(1H-indol-3-yl)methyl)benzene (3j)
4.5.14. 3,3'-(mesitylmethylene)bis(5-methoxy-1H-
indole) (3n)
According to the flow general method 4 equivalents of indole
2a were coupled to benzaldehyde 1f and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.65) as eluent to afford the title compound 3j (302 mg, 0.53
mmol, 65%) as an off white solid, mp = 246.5 – 248.0 °C, lit. mp
According to the flow general method indole 2c was coupled
to benzaldehyde 1j and purified by flash column chromatography
using 40-60 petroleum ether:ethyl acetate (1:1, Rf = 0.92) as
eluent to afford the title compound 3n (289 mg, 0.68 mmol, 83%)
1
= 194 – 195 °C55. H NMR (600 MHz, CDCl3): δ 7.40 (d, J =
1
7.6 Hz, 4H), 7.18 (s, 4H), 7.15 (t, J = 7.6 Hz, 4H), 7.08 – 7.05
(m, 8H), 6.67 (s, 4H), 5.79 (s, 4H), 5.69 (s, 2H); 13C NMR (150
MHz, CDCl3): δ 141.5, 136.5, 128.6, 127.0, 123.8, 121.7, 119.9,
119.2, 118.9, 111.4, 39.9; FTIR (νmax, cm-1): 3408, 3051, 1615,
1455, 1417, 1337, 1215, 1092, 1010, 738; HRMS (ESI): found
565.2378, [M-H]- C40H29N4 requires 565.2387. All spectroscopic
data was in agreement with that published in the literature.56
as an off white solid, mp = 204.0 – 205.0 °C. H NMR (600
MHz, CDCl3): δ 7.83 (s, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.88 (dd,
J = 8.8, 2.4 Hz, 2H), 6.75 (d, J = 2.4 Hz, 2H), 6.67 (d, J = 1.0 Hz,
2H), 6.16 (s, 1H), 3.72 (s, 6H), 2.32 (s, 3H), 2.18 (br. s, 6H); 13
C
NMR (150 MHz, CDCl3): δ 153.6, 137.2, 136.6, 135.4, 131.9,
130.1, 127.9, 124.5, 117.4, 111.83, 111.75, 102.0, 55.9, 35.8,
21.4, 20.9; FTIR (νmax, cm-1): 3412, 2942, 1722, 1622, 1581,

8
Tetrahedron
ACCEPTED MANUSCRIPT
1
1482, 1439, 1207, 1171, 1041, 925, 794, 707; HRMS (ESI):
= 150 °C61. H NMR (600 MHz, CD3COCD3): δ 10.13 (s, 2H),
8.71 (s, 1H), 8.43 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.41 (d, J =
8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (dd, J = 7.7, 4.8 Hz),
7.09 (t, J = 7.6 Hz, 2H), 6.92 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 1.4
Hz, 2H), 6.01 (s, 1H); 13C NMR (150 MHz, CD3COCD3): δ
150.9, 148.0, 141.3, 138.1, 136.6, 127.8, 124.6, 124.0, 122.2,
120.1, 119.5, 118.8, 112.2, 38.6; FTIR (νmax, cm-1): 3405, 2921,
2853, 1671, 1580, 1456, 1420, 1338, 1217, 1103, 1033, 1011,
743; HRMS (ESI): found 324.1507, [M+H]+ C22H18N3 requires
324.1495. All spectroscopic data was in agreement with that
published in the literature.61,62
found 423.2060, [M-H]- C28H27N2O2 requires 423.2067.
4.5.15. 3,3'-(furan-2-ylmethylene)bis(1H-indole)
(3o)
According to the flow general method indole 2a was coupled
to benzaldehyde 1k and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (4:1,
Rf = 0.38) as eluent to afford the title compound 3o (199 mg, 0.63
mmol, 78%) as a brown solid, mp = >300 °C, lit. mp = 322 - 324
°C. 1H NMR (600 MHz, CDCl3): δ 7.64 (s, 2H), 7.57 (d, J = 8.0
Hz, 2H), 7.41 (d, J = 0.9 Hz, 1H), 7.30 – 7.21 (m, 4H), 7.17 –
7.11 (m, 2H), 6.73 (d, J = 2.1 Hz, 2H), 6.37 (dd, J = 3.1, 1.9 Hz,
1H), 6.13 (d, J = 3.1 Hz, 1H), 6.00 (s, 1H); 13C NMR (150 MHz,
CDCl3): δ 157.1, 141.2, 136.4, 126.7, 123.2, 121.9, 119.7, 119.4,
116.9, 111.3, 110.2, 106.7, 34.1; FTIR (νmax, cm-1): 3405, 3119,
3053, 1719, 1615, 1589, 1548, 1504, 1455, 1418, 1336, 1240,
1216, 1147, 1092, 1038, 1092, 1008, 927, 781, 738; HRMS
(ESI): found 311.1186, [M-H]- C21H15N2O requires 311.1179. All
spectroscopic data was in agreement with that published in the
literature.44
Acknowledgements
We gratefully acknowledge funding from the British Council,
UK and DST-Inspire, India (Newton-Bhabha Ph.D Placement
Programme, SSM) and the Engineering and Physical Sciences
Research Council (grants EP/K009494/1 and EP/K039520/1).
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(3p)
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3.
According to the flow general method indole 1a was coupled
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6.
7.
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= 180 - 182 °C58. H NMR (600 MHz, CDCl3): δ 7.86 (s, 2H),
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(3q)
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to benzaldehyde 1m and purified by flash column
chromatography using 40-60 petroleum ether:ethyl acetate (1:1,
Rf = 0.28) as eluent to afford the title compound 3q (79 mg, 0.24
mmol, 30%) as a brown solid, mp = 232.5 – 235.1 °C, lit. mp =
1
238.0 – 240.0 °C45. H NMR (600 MHz, CDCl3): δ 8.59 (d, J =
4.3 Hz, 1H), 8.08 (s, 2H), 7.60 (dd, J = 10.9, 4.4 Hz, 1H), 7.39
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(150 MHz, CDCl3+ CD3SOCD3): δ 162.9, 147.7, 135.7, 135.2,
125.7, 122.6, 121.6, 120.0, 119.9, 118.1, 117.3, 116.0, 110.3,
42.0; FTIR (νmax, cm-1): 3449, 3144, 2922, 1587, 1567, 1471,
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