Facile synthesis of bis(indolyl)methanes using LaCl3 7H2O as a mild and efficient catalyst in molten salt media

Article abstract of DOI:10.1080/00397910802604224

Efficient electrophilic substitution reaction of indole with various carbonyl compounds were carried out using a catalytic amount of LaCl37H2O in molten tetraethylammonium chloride as an ionic liquid to afford the corresponding bis(indolyl)methanes in exc

Full text of DOI:10.1080/00397910802604224

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Facile Synthesis of
Bis(indolyl)methanes Using
LaCl3 · 7H2O as a Mild and
Efficient Catalyst in Molten Salt
Media
Neda Seyedi a , Kazem Saidi a & Hojatollah
Khabazzadeh a
a Department of Chemistry, Shahid Bahonar
University of Kerman, Kerman, Iran
Version of record first published: 15 Apr 2009.
To cite this article: Neda Seyedi , Kazem Saidi & Hojatollah Khabazzadeh (2009):
Facile Synthesis of Bis(indolyl)methanes Using LaCl3 · 7H2O as a Mild and Efficient
Catalyst in Molten Salt Media, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:10, 1864-1870
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Synthetic Communications1, 39: 1864–1870, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802604224
Facile Synthesis of Bis(indolyl)methanes Using
LaCl3 ꢀ 7H2O as a Mild and Efficient Catalyst
in Molten Salt Media
Neda Seyedi, Kazem Saidi, and Hojatollah Khabazzadeh
Department of Chemistry, Shahid Bahonar University of Kerman,
Kerman, Iran
Abstract: Efficient electrophilic substitution reaction of indole with various
carbonyl compounds were carried out using a catalytic amount of LaCl3 ꢀ 7H2O
in molten tetraethylammonium chloride as an ionic liquid to afford the corres-
ponding bis(indolyl)methanes in excellent yields.
Keywords: Bis(indolyl)methane, lanthanum chloride, molten salt, tetraethyl-
ammonium chloride
INTRODUCTION
Indole fragment is featured widely in a wide variety of pharmacologically
and biologically active compounds.[1] For example, bis(indolyl)alkanes
and their derivatives are found in bioactive metabolites of terrestrial and
marine origin.[2]
The acid-catalyzed condensations of indole with carbonyl com-
pounds have been a useful route for preparation of bis(indolyl)methanes.
The protic acids[3] and Lewis acids[4] usually have been used in excess, and
drastic conditions are required. To decrease the environmental pollution
of the disposal of the excess acids and improvement of the condensation
reactions of indole and carbonyl compounds, a number of catalytic sys-
tems such as NaHSO4 ꢀ SiO2,[5] 12-tungstophosphoric acid,[6] AlPW12O40,[7]
Received September 27, 2008.
Address correspondence to Kazem Saidi, Department of Chemistry, Shahid
Bahonar University of Kerman, 76169, Kerman, Iran. E-mail: saidik@mail.uk.ac.ir
1864

Synthesis of Bis(indolyl)methanes
1865
Scheme 1. Synthesis of bis(indolyl)methanes using LaCl3 Á 7H2O.
[10]
zeolites,[8] ionic liquids,[9] and I2 have been successfully utilized. These
methods have their own advantages and disadvantages, but it is always
interesting to develop a new method with desirable features such as
efficiency, short reaction time, easy workup, and ecofriendly catalyst for
the organic transformation.
Recently, catalytic reactions using ionic liquids have attracted con-
siderable interest[11] because they possess unique advantages of negligible
vapor pressure, excellent thermal stability, and interesting intrinsic phy-
sicochemical characteristics. Ionic liquids have been used as effective sol-
vents for clean chemical reactions, namely as replacements for volatile
organic and dipolar aprotic solvents. They may provide a medium for
clean reactions with minimal waste and efficient product extraction. It
has been found that catalytic activity and product selectivity are acceler-
ated when they are used. However, the high cost of most conventional
room-temperature ionic liquids has led us to explore the use of more
benign salts in the molten state as practical alternatives. Previously, mol-
ten tetraalkylammonium halides were used as cost-effective ionic liquids
in a number of useful synthetic transformations.[12,13]
In the context of developing environmentally friendly green chem-
istry and on the basis of our previous work on lanthanum chloride,[14]
we decided to look at the use of this salt in a one-pot synthesis of
bis(indolyl)methanes in molten tetraethylammonium chloride as an ionic
liquid (Scheme 1).
RESULTS AND DISCUSSION
First, the reaction of benzaldehyde with indole was carried out with 1:2
molar ratios to optimize the reaction conditions with respect to tempera-
ture, time, and the molar ratios of lanthanum chloride and tetraethyl-
ammonium chloride with respect to the substrate. We found that
10 mol% of LaCl3 Á 7H2O and 2:1 molar ratio of tetraethyl ammonium
chloride was sufficient to obtꢀain the desired bis(indolyl)methane in
92% yield within 30 min at 100 C.

1866
N. Seyedi, K. Saidi, and H. Khabazzadeh
These optimized conditions have been applied successfully for the
condensation of a variety of aldehydes with indole. The results are sum-
marized in Table 1.
The influence of electron-withdrawing and electron-donating sub-
stituents on the aromatic ring of aldehydes upon results of the reaction
was investigated. Surprisingly, the results showed that both electron-
withdrawing and electron-donating substituents had no significant effect
on the reaction times and the yields (Table 1, entries 2–4 and 7). The pre-
sence of a substituent on the ortho position of aromatic aldehydes caused
an increase in the reaction times (Table 1, entries 5, 6, and 10). In the case
of aliphatic aldehydes such as butyraldehyde, the reaction took a longer
time and lower yield was produced in comparison with aromatic alde-
hydes (Table 1, entry 12). To extend the scope of this method, the rate
of the reaction of several ketones such as cyclohexanone and acetophe-
none was also investigated. Because of the lower reactivity of ketones
relative to the aldehydes, longer reaction times and greater amounts of
catalyst were used for the reaction of cyclohexanone with indole in
comparison with the aliphatic and aromatic aldehydes (Table 1, entry 13).
Attempts to bring indole into a reaction with acetophenone in the pre-
sence of this catalyst were mostly unsuccessful, and after a prolonged
reaction time, most of the starting materials were recovered (Table 1,
entry 14).
Table 1. Synthesis of bis(indolyl)methanes via the condensation of indole with
carbonyl compounds using LaCl3 ꢀ 7H2O in molten tetraethylammonium chloride
Catalyst
(mol%)
Time
(min)
Yield
(%)
Entry
Product[ref.]
R
R0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a[15]
3b[16]
3c[16]
3d[16]
3e[17]
3f[18]
3g[16]
3h[18]
3i[19]
3j[20]
3k[21]
3l[19]
3m[15]
3n
C6H5
4-CH3O-C6H4
4-CH3-C6H4
4-Cl-C6H4
2-CH3O-C6H4
2-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
1-Naphthyl
2, 4-Di-Cl-C6H3
2-HO-C6H5
CH3CH2CH2
-(CH2)5-
H
H
H
H
H
H
H
H
H
H
H
H
10
10
10
10
10
10
10
10
10
10
10
10
30
30
30
30
20
20
40
30
20
30
30
40
15
40
120
180
92
92
93
93
90
88
93
93
84
88
91
70
60
00
C6H5
CH3

Synthesis of Bis(indolyl)methanes
1867
Table 2. Comparative results of condensation of indole with benzaldehyde using
the reported methods versus the present method
Entry
Catalyst
Solvent
Time (min)
Yield(%)[ref.]
1
2
3
4
5
LaCl3 ꢀ 7H2O
PPh3 ꢀ HClO4
ZrOCl2 ꢀ 8H2O
In(OTf)3
Molten Et4NCl
CH3CN
Solventfree
CH3CN
Water
30
30
40
25
92
61[22]
84[23]
71[24]
84[20]
H3PW12O40
120
To assess the capability of the present method with respect to the
reported methods for the preparation of bis(indolyl)methanes from
indoles and carbonyl compounds, the synthesis of compound 3a was
compared with some of the reported methods (Table 2). As is clear from
Table 2, the present method is more efficient.
The following sequence of reactions appears to afford a satisfactory
explanation of the mode of formation of products for the synthesis of
bis(indolyl)methanes catalyzed by LaCl3 ꢀ 7H2O from carbonyl com-
pounds (Scheme 2). The carbonyl group was first activated by La3þ
and carried out an electrophilic substitution reaction at C-3 of indole.
After loss of water, an intermediate was generated. The intermediate
was further activated by La3þ and served as an electrophile to attack a
second molecule of indole to form the final product.
In conclusion, we have demonstrated a simple, convenient, and effi-
cient protocol for the synthesis of a wide range of bis(indolyl)methane in
molten salt media. The simplicity, efficiency, mild reaction conditions,
high yields of products, easy workup procedure, lack of waste produced,
Scheme 2. Mechanism of LaCl3 ꢀ 7H2O-catalyzed reaction indole with carbonyl
compounds.

1868
N. Seyedi, K. Saidi, and H. Khabazzadeh
water as the only by-product, good generality, and use of a small amount
of catalyst make it the preferred procedure for the preparation of
different kinds of bis(indolyl)methanes. Other important features of this
methodology are the use of molten tetraethylammonium chloride as a
low-cost ionic liquid and the avoidance of hazardous organic solvent.
EXPERIMENTAL
All products are known compounds and were characterized by compar-
ison of thier physical properties and spectral data with authentic samples.
All reagents were purchased from Merck Chemical Company and were
1
used without further purification. H NMR and 13C NMR spectra were
recorded on a Bruker DRX-500 Avance spectrometer in dimethyl
sulfoxide (DMSO-d6).
Typical Experimental Procedure
A mixture of 1 mmol of appropriate aldehyde, 2ꢁmmol indole, 2 mmol
Et4NCl, and 10 mol% of LaCl3 was heated at 100 C for the appropriate
time. After the completion of the reaction (monitored by thin-layer chroma-
tography, TLC) the mixture was dissolved in ethanol and poured in water.
The resulting precipitate was recrystallized by ethanol to give pure product 3.
Spectral Data for Selected Compounds
2-((1H-Indol-2-yl)(phenyl)methyl)-1H-indole (3a)
1H NMR: d (ppm) 5.94 (s, 1H, CH), 6.68 (d, J ¼ 1.6 Hz, 2H), 7.06 (t,
J ¼ 7.2 Hz, 4H), 7.21–7.46 (m, 9H, arom), 7.89 (s, br, 2H, NH). 13C
NMR: d (ppm) 40.7, 111.4, 119.8, 120.3, 122.3, 123.8, 126.3, 127.5,
127.7, 128.4, 128.6, 137.1, 144.4.
2-((1H-Indol-2-yl)(4-methoxyphenyl)methyl)-1H-indole (3b)
1H NMR: d (ppm) 3.84 (s, 3H, OCH3), 5.90 (s, 1H, CH), 6.64 (d,
J ¼ 1.6 Hz, 1H), 6.88 (d, J ¼ 8.6 Hz, arom), 7.07 (t, J ¼ 7.4 Hz, arom),
7.23 (t, J ¼ 7.2 Hz, arom), 7.30 (t, J ¼ 6.7 Hz, arom), 7.37 (d, J ¼ 8.1 Hz,
arom), 7.45 (d, J ¼ 7.9 Hz, arom), 7.82 (s, br, 2H, NH). 13C NMR: d
(ppm): 39.7, 55.6, 111.5, 114.0, 119.6, 120.4, 120.4, 122.3, 123.9, 127.5,
130.0, 136.7, 137.1, 158.3.

Synthesis of Bis(indolyl)methanes
1869
2-((1H-Indol-2-yl)(p-tolyl)methyl)-1H-indole (3c)
1H NMR: d (ppm) 2.37 (s, 3H, CH3), 5.90 (s, 1H, CH), 6.70 (t, J ¼ 1.4 Hz,
2H), 7.05 (t, J ¼ 7.5 Hz, 2H, arom), 7.44 (d, J ¼ 7.9 Hz, 2H, arom), 7.90
(s, br, 2H, NH). 13C NMR: d (ppm): 21.5, 40.2, 111.4, 119.6, 120.3,
120.4, 122.3, 123.9, 127.5, 128.9, 129.3, 135.9, 137.1, 141.4.
ACKNOWLEDGMENT
The authors express their gratitude for the Shahid Bahonar University
of Kerman Faculty Research Grant which provided support for this
investigation.
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