An efficient and clean synthesis of bis(indolyl)methanes in a protic solvent at room temperature

Article abstract of DOI:10.1016/j.tetlet.2005.12.093

Electrophilic substitution reactions of indoles with various aldehydes were carried out in a protic solvent at room temperature in the absence of any other catalyst to afford bis(indolyl)-methanes in excellent yields.

Full text of DOI:10.1016/j.tetlet.2005.12.093

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1441–1443
An efficient and clean synthesis of bis(indolyl)methanes in a
protic solvent at room temperature
Mohit L. Deb and Pulak J. Bhuyan*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785 006, Assam, India
Received 21 October 2005; revised 5 December 2005; accepted 15 December 2005
Abstract—Electrophilic substitution reactions of indoles with various aldehydes were carried out in a protic solvent at room tem-
perature in the absence of any other catalyst to afford bis(indolyl)-methanes in excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The importance of indoles and their derivatives is well
recognized by synthetic as well as biological chemists.
icals and heterocyclic compounds of biological impor-
tance, we report here the first example of the synthesis
of bis(indolyl)methanes from the condensation of vari-
ous aldehydes and indoles in a protic solvent at room
temperature in the absence of any added catalyst. In
fact, we concentrated our study on the effect of solvents
on condensation processes of aldehydes and indoles.
The reactions were studied in various aprotic, protic, po-
lar and non-polar solvents. Remarkably, we found that
the condensation of aldehydes and indoles to bis(indol-
yl)methanes required no catalyst when performed in a
suitable protic solvent, for example, methanol or water
(in the presence of surfactants). Moreover, the reactions
occur at room temperature giving good to excellent
yields of the desired products.
1
Bis(indolyl)methanes, which contain two indole or
substituted indole units in a molecule, feature widely
in bioactive metabolites of terrestrial and marine ori-
2
gin. Therefore, significant efforts have been directed to-
wards the synthesis of these molecules. Synthetically,
these compounds are obtained from the condensation
of indoles with aldehydes and ketones in the presence
3
of protic (e.g., HCl) or Lewis acids (e.g., AlCl3,
4
BF ). Generally, traditional Lewis acid catalysts are
3
moisture sensitive and are easily decomposed or deacti-
vated in the presence of even a small amount of water.
In many reactions, more than stoichiometric amounts
5
of Lewis acids are required because these acids are
trapped by the nitrogen-containing reactants. These
problems can be solved to some extent by using expen-
sive lithium perchlorate but this also requires long reac-
First, we examined the reaction using methanol as a sol-
1
1
vent. In a simple experimental procedure, equimolar
amounts of indole 1 and benzaldehyde 2 in methanol
were allowed to react with stirring at room temperature
for 12 h, to give, after workup, a 70% yield of compound
3a (Scheme 1). The structure of 3a was confirmed from
spectroscopic data and by comparison with an authentic
sample. Similarly, compounds 3b–o were synthesized
6
tion times. NaHSO –SiO , I and NBS have been used
4
2
2
7
to catalyze these reactions. Recently, rare earth cata-
lysts have been recognized as possible environmentally
friendly alternatives to conventional Lewis acids in
many organic reactions. Hence, LnCl , Ln(OTf) and
3
3
Re(PFO) have been successfully used in the synthesis
3
8
of bis(indolyl)methanes. Similarly, the use of ionic liq-
uids is of interest for such organic synthesis.
9
Ph
In our continued interest in the development of a highly
expedient methodology for the synthesis of fine chem-
O
1
0
+
Ph
H
N
H
N
H
N
H
Keywords: Indoles; Bis(indolyl)methanes; Aldehydes; Protic solvent;
Aqueous medium.
1
2
3a
*
Corresponding author. Fax: +91 376 2370011;
pulak_jyoti@yahoo.com
e-mail:
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.093

1442
M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 47 (2006) 1441–1443
and characterized (Table 1). 2-Methylindole was found
to be the most reactive giving the product in excellent
yields in 2.5 h. 3-Methylindole on the other hand did
not react under these reaction conditions. Interestingly,
when the condensation reaction was carried out using
acetonitrile, chloroform, THF or toluene as the solvent,
no reaction occurred at all.
Presuming the insolubility of the reactant was the prob-
lem, we considered the use of SDS (sodium dodecylsul-
fate) as a surfactant, since it forms micelles in water and
can solubilize organic compounds, which are otherwise
insoluble in water. Accordingly, we studied the reaction
by utilizing equimolar amounts of the indoles and alde-
hydes in water in the presence of a small amount of
1
2
SDS. The indoles dissolved in a very short time and
it was exciting to observe that the reaction occurred
immediately on stirring the reaction mixture at room
temperature and was complete in 2.5–5 h giving 55–
96% yields of bis(indolyl)methanes. Our observations
are recorded in Table 1.
Encouraged by the effect of a protic solvent and to re-
duce the reaction time, we studied the reaction using
water as the solvent. Unfortunately, it was observed that
indoles were insoluble in water and no reaction occurred
even after stirring the reaction mixture for a long time.
Table 1. Synthesis of bis(indolyl)methanes from the condensation of aldehydes and indoles
Entry
1
Indole
Aldehyde
Product
Mp (°C)
Reaction time (h)
Yield (%)
2
MeOH H O
MeOH
H
2
O
CHO
13
3a
149–150
12
2.5
70
95
N
H
CHO
CHO
CHO
1
4
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
3g
3h
3i
93–94
12
18
20
18
17
16
18
20
14
2.5
3.5
2.5
5
65
78
60
75
72
65
61
50
60
90
70
96
80
60
55
60
60
—
—
65
94
60
N
H
H C
3
1
5
5
185–187
217–220
N
H
H CO
3
1
5
N
H
O N
2
CHO
1
4
4
76–77
70–71
5
N
H
Cl
CHO
Cl
1
4
N
H
H CO
CHO
3
126–127
4
N
H
HO
15
>300
—
—
2
N
H
O
S
CHO
CHO
14
150–153
N
H
15
CHO
10
11
12
3j
98–99
N
H
CHO
CHO
3k
3l
247–248
174–175
1
N
H
CH3
CH3
CHO
1
N
H
H C
3
H C
3
13
14
15
3m
3n
3o
195–196
148–150
123–126
12
16
17
1
70
65
60
88
—
—
N
H
1
5
5
3
CH CHO
—
—
N
H
CHO
1
N
H
CH3

M. L. Deb, P. J. Bhuyan / Tetrahedron Letters 47 (2006) 1441–1443
1443
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We studied the reaction by utilizing a variety of aro-
matic, heterocyclic and aliphatic aldehydes with a num-
ber of substituted indoles in both solvents (Table 1).
Both solvents had their own advantages in terms of reac-
tion simplicity, time required, workup and overall yields.
The reactivity increased with increasing order of acidity
of the solvents (H O > CH OH). However, the reaction
8
9
1
996, 37, 4467; (b) Nagarajan, R.; Perumal, P. T.
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2
3
was highly chemoselective and applicable only to alde-
hydes and not to ketones.
A reasonable mechanism for the reaction is outlined in
Scheme 2, which is applicable for both solvents in the
present study.
10. (a) Devi, I.; Bhuyan, P. J. Synlett 2004, 283; (b) Deb, M.
L.; Bhuyan, P. J. Tetrahedron 2005, 46, 6453.
1
1. Experimental procedure: Indole 1 (0.234 mg, 2 mmol) and
benzaldehyde 2 (0.106 mg, 1 mmol) were taken in meth-
anol (10 ml) and stirred at rt for 12 h. The solvent was
removed under reduced pressure and the crude product
was purified by column chromatography using hexane–
In conclusion, we have demonstrated a simple, efficient
and clean synthesis of bis(indolyl)methanes from the
condensation of indoles and aldehydes in a protic sol-
vent at room temperature. The results demonstrate that
the effect of solvent on this condensation process is
remarkable.
chloroform (5:2) as eluent. Product 3a: Solid, mp 149–
13
1
50 °C (lit., 150–152 °C), yield 70% (225 mg).
12. Experimental procedure: Indole 1 (0.234 mg, 2 mmol) and
benzaldehyde 2 (0.106 mg, 1 mmol) were taken up in water
(
10 ml). A small amount of surfactant (sodium dodecyl
Acknowledgements
sulfate) was added to the reaction mixture, which was
stirred for 2.5 h. at rt. The organic material was extracted
with ethyl acetate and the surfactant was precipitated by
M.L.D. thanks CSIR (India) for the award of a Junior
Research Fellowship.
the slow addition of CaCl
2
to the vigorously stirred
mixture of the micellar solution and ethyl acetate. The
solvent was removed under reduced pressure and the
product was purified by column chromatography using
hexane–chloroform (5:2) as eluent. Product 3a: yield 95%
(306 mg).
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