Glycerin and CeCl3·7H2O: a new and efficient recyclable medium for the synthesis of bis(indolyl)methanes

Article abstract of DOI:10.1016/j.tetlet.2009.08.062

Glycerin and CeCl₃·7H₂O were successfully used in recyclable catalytic system for the synthesis of several bis(indolyl)methanes in good to excellent yields through the reaction of indoles with aldehydes. The method is applicable to a

Full text of DOI:10.1016/j.tetlet.2009.08.062

Tetrahedron Letters 50 (2009) 6060–6063
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Tetrahedron Letters
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Glycerin and CeCl3ꢀ7H2O: a new and efficient recyclable medium
for the synthesis of bis(indolyl)methanes
a
a
b
b
Claudio C. Silveira a, , Samuel R. Mendes , Francieli M. Líbero , Eder J. Lenardão , Gelson Perin
*
a Departamento de Química, Universidade Federal de Santa Maria, UFSM, 97105-900 Santa Maria, RS, Brazil
b Instituto de Química e Geociências, LASOL, Universidade Federal de Pelotas, UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Glycerin and CeCl3ꢀ7H2O were successfully used in recyclable catalytic system for the synthesis of several
bis(indolyl)methanes in good to excellent yields through the reaction of indoles with aldehydes. The
method is applicable to aliphatic and aromatic aldehydes, and the mixture of glycerin and CeCl3ꢀ7H2O
can be reused up to five times without special treatment and with comparable yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 May 2009
Revised 18 August 2009
Accepted 19 August 2009
Available online 23 August 2009
Keywords:
Glycerin
Bis(indolyl)methanes
Cerium(III) chloride
Indoles and their derivatives are widely present in bioactive
metabolites of compounds of both terrestrial and marine origin.1 Re-
cent studies have shown that bis(indolyl)methanes can act as highly
selective fluorescent molecular sensors for Cu2+ cations2 and also as
colon cancer cell and tumor growth inhibitors.3 Because of their ver-
satile biological activities, in particular the pharmacological activity,
various methods are mentioned for the preparation of bis(indo-
lyl)methanes. The most common protocol involves the Lewis or
protic acid-promoted electrophilic substitution reaction of indoles
with carbonyl compounds.4 Despite the high atomic efficiency of
these reactions, a drawback of most of the described methods is
the use of expensive and toxic reagents and volatile solvents. Re-
cently, some improvements on the preparation of bis(indolyl)meth-
anes have been described.5 These comprise the use of I2,5a modified
zirconia,5b HBF4–SiO2,5c ZnO,5d oxalic acid,5e trityl chloride,5f and
CeCl3ꢀ7H2O–NaI–SiO25g under solvent-free conditions, dodecylsulf-
onic acid in the presence of water,5h PEG-supported sulfonic acid,5i
catalytic [bmim][MeSO4],5j or ionic liquid in the absence of any cat-
alyst.5k In general, these reactions occur under mild conditions, are
simple and clean, and give yields comparable to the conventional
methods. In spite of these advantages, the direct reuse of the cata-
lytic system is not possible in most of the described methods.
Recently, glycerin, which is easily available as a co-product in
the biodiesel production, has attracted attention as it is a versatile,
cheap, and renewable feedstock in synthetic organic chemistry.6
Because of our interest in the use of glycerin as a solvent,7 and in
new applications of cerium(III) in organic synthesis,8 we decided
to study the electrophilic substitution reaction of indoles 1 with
carbonyl compounds 2 to obtain bis(indolyl)methanes 3 (Scheme
1, Tables 1 and 2).
Initially, we chose indole (1a, 1 mmol) and benzaldehyde
(2a, 0.5 mmol) as standard starting materials to establish the best
conditions for the reaction. We examined the temperature,
amount of CeCl3ꢀ7H2O, and reaction time using glycerin as a recy-
clable solvent (Table 1). It was found that by using 0.5 equiv of
CeCl3ꢀ7H2O and 2.0 mL of glycerin at room temperature, the reac-
tion proceeded slowly and in 95% yield after stirring for 24 h
(Table 1, entry 1). However, when the mixture was heated at
60 and 75 °C, the desired product 3a was obtained in similar
yields, after 3 and 1.5 h, respectively (entries 2 and 3). At higher
temperatures no products were isolated, even after stirring for
several hours (entry 4). The effect of the amount of the catalyst
was also evaluated. When only 0.1 equiv of CeCl3ꢀ7H2O was used,
3a was obtained in excellent yield after stirring at 75 °C for 1.5 h
(entry 5). On the other hand, by using 1.0 equiv of CeCl3ꢀ7H2O, no
increase in yield or reduction in time was observed (entry 6).
R
CeCl3.7H2O, 75 o
glycerin
C
RCHO
X
X
+
N
H
X
N
H
N
H
1a,b
2a-j
3a-n
1 X = (a) H, (b) Br
2 R = (a) C6H5, (b) 4-NO2C6H4, (c) 4-ClC6H4, (d) 4-CH3OC6H4, (e) 2-ClC6H4,
(f) 2-CH3C6H4, (g) C6H5CH=CH, (h) 3,4-OCH2O-C6H3, (i) 2-furyl, (j) C4H9.
* Corresponding author. Tel./fax: +11 55 55 220 8754.
E-mail address: silveira@quimica.ufsm.br (C.C. Silveira).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.062

C. C. Silveira et al. / Tetrahedron Letters 50 (2009) 6060–6063
6061
Table 1
When the reaction was performed in glycerin, without
CeCl3ꢀ7H2O, at room temperature or by heating (75 °C), incom-
plete consumption of the starting materials and poor yields were
observed (entries 7 and 8). We also used other solvents instead of
glycerin, such as CH3CN, CH3NO2, PrOH, and PEG-400. However,
only PEG-400 afforded the product, but in modest yield (30%),
even after 24 h (Table 1, entry 10).
Since the best conditions were established (Table 1, entry 5), the
protocol was extended to other aromatic and aliphatic aldehydes,
reacting with indole and 6-bromoindole (Table 2, Scheme 1).9
For all the tested examples, the bis(indolyl)methanes 3 were
obtained in good to excellent yields after stirring at 75 °C for
1.5–5 h, except for p-chlorobenzaldehyde (2c), which needed 8–
10 h of reaction (Table 2). When 6-bromo-1H-indole (1b) was used,
the respective brominated products were obtained in slightly low-
er yields, compared to 1a (entries 2, 4, 6 and 8, Table 2). For substi-
tuted benzaldehydes containing either NO2 (2b, entries 3 and 4) or
Optimization of the synthesis of bis(indolyl)methanes according to Scheme 1a
Entry
Solvent
CeCl3ꢀ7H2O (equiv)
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Glycerin
Glycerin
Glycerin
Glycerin
Glycerin
Glycerin
Glycerin
Glycerin
CH3CN
PEG-400
PEG-400
iC3H7OH
CH3NO2
0.5
0.5
0.5
0.5
0.1
1.0
0
rt
24
3
95
95
94
—
96
i
60
75
100
75
75
rt
75
rt
rt
1.5
24
1.5
1.5
24
24
24
24
24
24
24
b
94
31
0
32
0.5
0.5
0
0.5
0.5
N.R.c
30
rt
rt
rt
N.R.c
N.R.c
N.R.c
a
b
c
Reaction conditions: indole (1a, 1.0 mmol); benzaldehyde (2a, 0.5 mmol).
A complex mixture was obtained.
No reaction.
Table 2
Synthesis of bis(indolyl)methanes 3 using the mixture of glycerin/CeCl3ꢀ7H2O
Entry
Indoles 1
Aldehydes 2
Product 3
C6H5
Time (h)
1.5
Yielda (%)
96
CHO
1
N
H
N
H
N
H
2a
1a
3a
C6H5
Br
Br
Br
Br
Br
2
3
4
5
6
7
8
2a
1.5
85
79
73
88
77
87
N
H
Br
N
H
N
H
1b
3b
4-NO2C6H4
NO2
CHO
1a
5
N
N
H
2b
H
3c
4-NO2C6H4
Br
1b
1a
1b
1a
1b
2b
5
N
N
H
H
3d
4-ClC6H4
Cl
CHO
8
N
H
N
H
2c
3e
4-ClC6H4
Br
2c
10
N
N
H
H
3f
CH3OC6H4
CH3O
CHO
2
N
N
H
2d
H
3g
CH3OC6H4
Br
2d
4
73
N
N
H
H
3h
(continued on next page)

6062
C. C. Silveira et al. / Tetrahedron Letters 50 (2009) 6060–6063
Table 2 (continued)
Entry
Indoles 1
Aldehydes 2
Cl
Product 3
2-ClC6H4
Time (h)
5
Yielda (%)
84
9
1a
CHO
N
H
N
H
2e
2f
3i
2-CH3C6H4
CHO
10
1a
1a
2
2
96
75
N
N
H
H
3j
C6H5
11
CHO
2g
N
N
H
H
3k
O
O
CHO
O
12
1a
5
72
O
2h
N
H
N
H
3l
O
O
CHO
2i
13
1a
1a
2
5
86
75
N
H
N
H
3m
3n
CHO
14
2j
N
H
N
H
Yields of pure products isolated by column chromatography (hexanes/AcOEt) and identified by mass spectrometry, 1H and 13C NMR, Refs. 4 and 5.
a
Cl (2c, entries 5 and 6; and 2e, entry 9), longer reaction times were
needed to completely consume the starting materials. The aliphatic
aldehyde pentanal (2j) reacted with indole 1a under our conditions
to afford, after 5 h, 3,30-pentane-1,1-diylbis-1H-indole (3n) in 75%
(entry 14).
Acknowledgments
This project is funded by MCT/CNPq, CAPES and FAPERGS.
References and notes
The glycerin/CeCl3ꢀ7H2O mixture can be successfully reused up
to five times without any treatment with excellent results. Thus,
for example, after the completion of the reaction of indole 1a and
benzaldehyde 2a (Table 2, entry 1), the product 3a was simply ex-
tracted with ethyl acetate (3 ꢁ 5 mL) and the glycerin/catalyst
mixture was reused in a new electrophilic substitution. The prod-
uct was obtained in 95%, 94%, 96%, 94%, and 95% yields after suc-
cessive cycles.
In conclusion, the mixture of glycerin/CeCl3ꢀ7H2O has proved to
be an effective, recyclable catalytic system for the synthesis of
bis(indolyl)methanes. The method is simple, clean, and general
for the reaction of aromatic and aliphatic aldehydes with indole.
The use of low-cost, renewable feedstock glycerin as a solvent
and of a small amount of the catalyst, together with the possibility
of their direct reuse for several cycles, is particularly relevant to the
green chemistry concept.
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9. General procedure for the synthesis of bis(indolyl)methanes: To a mixture of
glycerin (2 mL), indole (1a, 0.117 g, 1.0 mmol), and benzaldehyde (2a, 0.053 g,
0.5 mmol) was added 0.1 equiv of CeCl3ꢀ7H2O (0.0186 g, 0.05 mmol) at room
temperature. The temperature was slowly raised to 75 °C, under magnetic
stirring. The reaction progress was followed by TLC, and after 1.5 h (see Table 2)
the oil bath was removed. Then, at room temperature, ethyl acetate (3 ꢁ 5 mL)
was added and the upper organic phase was separated from the glycerin/
catalyst mixture, dried with MgSO4, and the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography (ethyl
acetate:hexanes, 1:9) yielding 3a as a light pink solid (0.155 g, 96%). Mp 123–
125 °C (Lit.4a 124–125 °C); 1H NMR (200 MHz, CDCl3) d (ppm) 7.89 (br s, 2H);
7.40–7.30 (m, 6H); 7.28–7.23 (m, 2H); 7.23–7.12 (m, 3H); 6.98 (t, J = 6.8 Hz, 2H);
6.64 (s, 2H); 5.87 (s, 1H).
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