Base-promoted three-component cascade approach to unsymmetrical bis(indolyl)methanes

Article abstract of DOI:10.1016/j.tetlet.2017.04.032

Here we report a base-catalyzed reaction of two different indoles with aldehydes under heating to produce unsymmetrical bis(indolyl)methanes (BIMs), in which one of the indole ring must be N-substituted. Mixture of EtOH-H₂O is used as solvent. The reaction did not give symmetrical BIMs of N-substituted indoles or N–H indoles. However, traces of latter were formed in few cases, especially when electron-rich aldehydes were used. Diversely substituted indoles and aldehydes were used for the reaction. The reaction proceeds via 3-indolylalcohol, which we confirmed through isolation. The method also gives good yield on multigram scale reaction.

Full text of DOI:10.1016/j.tetlet.2017.04.032

Accepted Manuscript
Base-promoted three-component cascade approach to unsymmetrical bis(indol-
yl)methanes
Mohit L. Deb, Bhaskar Deka, Prakash J. Saikia, Pranjal K. Baruah
PII:
S0040-4039(17)30465-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.032
TETL 48824
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 February 2017
4 April 2017
8 April 2017
Please cite this article as: Deb, M.L., Deka, B., Saikia, P.J., Baruah, P.K., Base-promoted three-component cascade
approach to unsymmetrical bis(indolyl)methanes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.04.032
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Base-promoted three-component cascade
approach to unsymmetrical
bis(indolyl)methanes
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Mohit L. Deb,*a Bhaskar Deka,a Prakash J. Saikiab and Pranjal K. Baruah*a

1
Tetrahedron Letters
journal homepage: www.els evier.com
Base-promoted three-component cascade approach to unsymmetrical
bis(indolyl)methanes
Mohit L. Deb,*a Bhaskar Deka,a Prakash J. Saikiab and Pranjal K. Baruah*a
a Department of Applied Sciences, GUIST, Gauhati University, Guwahati-781014, Assam, India
b Analytical Chemistry Division, CSIR-NEIST, Jorhat-785006
ARTICLE INFO
ABSTRACT
Article history:
Received
Here we report a base-catalyzed reaction of two different indoles with aldehydes under heating
to produce unsymmetrical bis(indolyl)methanes (BIMs), in which one of the indole ring must be
N-substituted. Mixture of EtOH-H2O is used as solvent. The reaction did not give symmetrical
BIMs of N-substituted indoles or N-H indoles. However, traces of latter were formed in few
cases, especially when electron-rich aldehydes were used. Diversely substituted indoles and
aldehydes were used for the reaction. The reaction proceeds via 3-indolylalcohol, which we
confirmed through isolation. The method also gives good yield on multigram scale reaction.
Received in revised form
Accepted
Available online
Keywords:
Multi-component
2009 Elsevier Ltd. All rights reserved.
Cascade approach
Unsymmetrical bis(indolyl)methanes
Base catalyzed
Alkylideneindolenine intermediate
Introduction
straightforward and provides always symmetrical BIMs.10 But the
synthesis of unsymmetrical BIMs is still highly desired in
During the last few decades, multi-component process (MCP),
a green technology achieved much interest in synthetic chemistry
due to their advantages of atom economy, simplified mode of
operation, and energy savings.1 Moreover, reduced reaction steps,
waste, and cost are the additional advantages of the MCPs.1
There has also been an increasing interest to replace hazardous
solvents with environment friendly solvents such as water,
ethanol, PEG, etc.2 The cascade reaction which is also known as
domino or tandem reaction is arguably first reported through the
synthesis of tropinone.3 Thereafter, the use of cascade reactions
has flourished in the area of total synthesis, which is reflected by
the numbers of published review articles.4
synthetic chemistry. There are only few reports for the synthesis
of unsymmetrical BIMs, and all the methods use pre-
functionalized indole derivative which reacts with a different
indole molecule to form unsymmetrical BIMs.11 However, they
have a number of disadvantages and limitations such as use of
two or more synthetic steps, expensive catalysts and highly
unstable starting material. In continuation of our work on BIMs,12
here we disclose an efficient base-catalyzed three-component
cascade approach to unsymmetrical BIMs (Scheme 1). We
believe this is the first report of three-component one-pot
synthesis of unsymmetrical BIMs.
The importance of indole and their derivatives is well
recognized by the synthetic as well as biological chemists.5 3,3-
Bisindolylmethane (BIM) is one such important indole derivative
has attracted lot of chemists and biologists due to its enormous
bioactivity. For example, BIM increases the 2-hydroxylation of
estrogen metabolites that helps to reduce the risk of breast and
prostate cancer.6 It is also under clinical trials for Cervical
Dysplasia, a pre-cancerous condition caused by the Human
Papilloma Virus.7 It worked as HIV-1 integrase inhibitor,8 and
exhibit antibacterial activity.9 It has been reported that the
reaction of indoles with aldehydes or ketones can easily afford
BIMs in the presence of a catalyst. The strategy is very simple,
Results and discussion
We started our study with the reaction of indole (1a),
benzaldehyde (2a) and 1-methylindole (3a), which we considered
as our model reaction, in the presence of different catalysts and
solvents. After a careful screening of variety of catalysts, we
established the optimum conditions for the synthesis of 4a, in
which sodium hydroxide (1.0 eq.) was used as catalyst in EtOH-
H2O (1:1) as solvent at 90 ºC furnishing 85 % yield (entry 9,
Table 1).13 A trace of 5a was also detected in the crude product.
Decreasing the loading of base catalyst decreased the product
yield, whereas increase of the same did not affect the yield
(entries 10-11, Table 1). Using of either pure ethanol or water as
solvent afforded lower yield (entries 5 and 7, Table 1). There was
also a decrease in the product yield with the increase in the ratio
∗Corresponding
mohitdd.deb@gmail.com; baruah.pranjal@gmail.com
author.
Tel.:
+91-8876998905;
e-mail:

2
Tetrahedron Letters
Scheme 1. Synthesis of unsymmetrical BIMs
Table 1. Optimization of the reaction condition[a]
Entry[c]
Catalyst (eq)
Solvent
Temp. (ºC)
Time (h)
Yield 4a (%)
1
p-TsOH.H2O (0.1)
LiCl (0.1)
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
90
3
3
1
3
3
3
3
3
2
2
2
2
2
20
2
2
4
4
4
4
Trace[b]
Trace[b]
Trace[b]
Trace[b]
58
2
EtOH
3
I2 (0.1)
EtOH
4
L-Proline (0.2)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
NaOH (0.8)
NaOH (1.3)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
KOH (1.0)
K2CO3 (1.0)
Et3N (1.0)
EtOH
5
EtOH
6
MeOH
40
7
H2O
20
8
CH3CN
24
9
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:2)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
EtOH-H2O (1:1)
85
10
11
12
13
14
15
16
17
18
19
20
90
60
90
85
100
80
84
68
RT
38
90
42
90
83
90
30
90
NR[d]
DMAP (1.0)
Cs2CO3
90
NR
90
NR
[a] Unless otherwise mentioned, all the reactions were performed by using 1a (1.0 mmol, 117 mg), 2a (1.0 mmol, 106 mg), 3a (1.0 mmol, 131 mg). [b] 5a and 6a
were formed predominantly. [c] Entries 5-17 also produced traces of 5a. [d] NR: no reaction.
4 than electron-deficient aldehydes as the former produced minor
amount of symmetrical BIM 5 along with 4 (e.g., 4b vs. 4e,
Scheme 2). Functional groups on the phenyl ring such as -NO2, -
Br, -Me, -OMe were very much compatible. Heterocyclic
aldehydes such as thiophene-2-carboxaldehyde also furnished the
desired product in good yield (4h, Scheme 2). 2-Phenylindole
produced the product with relatively lower yield (4q, Scheme 2).
Though minor amount of 5 was formed in the few cases,
however, we did not observe 6 in the crude product. When N-
substituted indoles such as N-Boc/-acyl/-tosylindoles were
separately treated with NH-indole and benzaldehyde under
optimized condition, we obtained only 5 and no cross reaction
of water in the solvent mixture (entry 15, Table 1). Polar aprotic
solvent such as CH3CN gave poor yield (entry 8, Table 1). At
room temperature, the reaction produced only 38 % of yield after
20 h of stirring (entry 14, Table 1). We found KOH is nearly as
good as NaOH to catalyze the reaction (entry 16, Table 1).
With the optimized condition in hand, we subsequently
investigated the substrate scope for the synthesis of 4 by
employing a variety of aldehydes and indoles. To our delight,
compound 4 containing a broad range of substituents were
formed in moderate to good yield, as summarized in Scheme 2.
We also noticed that electron-rich aldehydes gave lower yield of

3
was observed. We believe that the reason must be due to the
poor nucleophilicity of the mentioned N-substituted indoles. Our
model reaction gave us 88 % of 4a when performed on 10 g scale
showing that the reaction could be easily scaled up to multigram
scale. Products were characterized by NMR and mass
spectroscopy as well as single crystal X-ray crystallography
(Figure 1).14
A tentative mechanism is proposed for the reaction (Scheme
3). First, the base abstracts the N-H proton of indole 1 and the
resulting anion attacks the aldehyde to generate the 3-
indolylalcohol 7. NaOH again deprotonates the N-H proton of 7
and finally eliminates the -OH group to generate the
alkylideneindolenine intermediates A. A was then attacked by N-
alkylindole 3 to give the desired product 4. Additionally, A reacts
with indole 1 to furnish small amount of symmetrical
bisindolylmethanes 5 as side product in few cases. To support the
mechanism, we isolated the indolylalcohol 7 (by stopping the
reaction before completion) and characterized. Since the presence
of water in the reaction enhanced the yield of 4, we believe that
the water might help to solubilize the base catalyst into the
reaction medium. However, water alone as solvent gave only
poor yield due to insolubility of organic substrates into it.
Scheme 3. Tentative mechanism proposed for the reaction
Scheme 2. Substrate scope for the synthesis of 4. Reaction conditions: 1 (1.0
mmol), 2 (1.0 mmol), 3 (1.0 mmol), NaOH (1.0 eq, 40 mg), EtOH-H2O (1:1,
2.0 mL) at 90 ºC. Products were purified by column chromatography using
silica gel (100-200 mesh) and yields are for the isolated products. In case of
4e, 4f and 4k, little amount of 5e (12 %), 5f (9 %) and 5k (7 %) were also
formed.
In conclusion, we have successfully developed a 3-component
cascade approach for the synthesis of unsymmetrical
bis(indolyl)methanes. The reaction proceeds through the
formation of alkylideneindolenine intermediate. The reaction is
free from hazardous metal or Lewis acid catalyst and uses
environment-friendly solvent. The reaction could easily be scaled
up to multigram scale with good yield. To the best of our
knowledge, this is the first report of one-pot multi-component
synthesis of unsymmetrical bis(indolyl)methanes. We anticipate
that this method would offer efficient and cost effective way to
obtain this important class of compounds.
Acknowledgments
MLD is thankful to Science and Engineering Research Board
(SERB), India (Grant No. SB/FT/CS-073/2014) for the financial
support under Fast Track Scheme. PKB is thankful to DST,
India, (Grant No. SB/FT/CS-100/2012) for the financial support.
BD thanks DST for research fellowship. The authors
Figure 1. Single crystal X-ray structure of 4g

4
Tetrahedron
(DCM). Removed the DCM under vacuum and the crude product
was purified by column chromatography (silica gel 100-200 mesh,
hexane-ethyl acetate as eluent) to obtain 4 as pure product. For
multigram scale reaction, the same procedure has been followed.
14. Crystallographic data for compound 4g have been deposited with
CCDC 1532121 and can be obtained free of charge from the
acknowledge Dr. Ranjit Thakuria, Dept. of Chemistry, Gauhati
University for X-ray structure analysis.
References and notes
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13. General procedure for the synthesis of compound 4: 1 (1.0
mmol), 2 (1.0 mmol), 3 (1.0 mmol) and NaOH (1.0 mmol, 40 mg)
were taken in a screw-top V-vial. EtOH-H2O (1:1, 2.0 mL) as
solvent was added to this. Closed the vial and heated at 90 oC in an
oil bath for specified time. The progress of the reaction was
monitored by TLC. After completion of the reaction, solvent was
removed under vacuum and extracted with dichloromethane

5
Highlights
The main highlights of the manuscript are-
•
•
Metal-free cascade approach to unsymmetrical
bis(indolyl)methanes.
Base catalyzed reaction using EtOH-H2O as
solvent.
•
•
The reaction could be easily scaled up.
First report of their synthesis by multi-
component strategy.