Antimony(III) sulfate catalyzed condensation reaction of indoles with carbonyl compounds

Article abstract of DOI:10.1007/s00706-007-0697-z

Antimony sulfate was found to be on effective catalyst for the condensation reaction of indoles with carbonyl compounds at room temperature. This catalyst is inexpensive, easily available and it was also found that this catalyst could be recovered quantitatively and reused without much loss of catalytic activity.

Full text of DOI:10.1007/s00706-007-0697-z

Monatshefte fu¨r Chemie 139, 111–115 (2008)
DOI 10.1007/s00706-007-0697-z
Printed in The Netherlands
Antimony(III) Sulfate Catalyzed Condensation Reaction
of Indoles with Carbonyl Compounds
Aswathanarayana Srinivasa1, Putta Prabhakar Varma1, Vijaykumar Hulikal2,
and Kittappa M. Mahadevan1;ꢀ
1
Department of Post Graduate Studies and Research in Chemistry, School of Chemical Sciences,
Kuvempu University, Shankaraghatta, Karnataka, India
2
BioOrganics and Applied Materials Pvt. Ltd., Peenya, Bangalore, India
Received March 27, 2007; accepted (revised) April 16, 2007; published online November 16, 2007
# Springer-Verlag 2007
Summary. Antimony sulfate was found to be on effective
moisture sensitive and get easily decomposed or de-
catalyst for the condensation reaction of indoles with carbonyl
compounds at room temperature. This catalyst is inexpensive,
easily available and it was also found that this catalyst could
be recovered quantitatively and reused without much loss of
catalytic activity.
activated in the presence of even trace amounts of
water and are thus difficult to handle. Further dispo-
sal of these acids leads to environmental pollution.
The other catalysts used for this condensation are
hexamethylene-bromine [5], trichloro-1,3,5-triazine
[6], PPh3 ꢁ HClO4 [7].
Keywords. Antimony sulfate; Indoles; Aldehydes; Bis(indo-
lyl)methanes; 3-Indolyl ketones.
With the rapid development in the field of catalyt-
ic and synthetic chemistry, researchers have started
to pay more attention to develop eco-friendly and
reusable catalysts to avoid or minimize these harm-
ful environmental pollution problems. Particularly,
the condensation of indoles and carbonyl compounds
has been carried out successfully using catalysts like,
KHSO4 [8], I2 [9], ion exchange resin [10], NBS
[11], NaHSO4 ꢁ SiO2 [12], montmorillonite K-10 clay
[13], ionic liquids [14], and rare earth catalysts [15].
However, some of the reported methods have the
following drawbacks: for example use of expensive
reagents [4c, g, 15], excess of catalyst [3a, e], long
reaction time [3b, c, 4g, 10], low yield of product
[3a], and use of additional microwave [4d].
To circumvent the environmental problems and
limitations of the above-mentioned catalysts, we
thought of using a Lewis acid, which is efficient as
a catalyst, stable under the reaction conditions, and
insoluble in common organic solvents. Since it will
be insoluble in common solvents, it can be filtered
off after the reaction and is suited for recycling.
Introduction
Bis(indolyl)alkanes and their derivatives are at-
tractive compounds as the bioactive metabolites of
terrestrial and marine origin [1]. Vibrindole A has
been demonstrated for the first time to exhibit an-
tibacterial activity against Staphylococcus aureus,
S. albus, and B. subtilis; gentamycin is in use as a
standard drug [2]. Consequently, numerous methods
have been reported for the preparation of bis(indo-
lyl)methanes. Of these methods, the acid-catalyzed
condensation of indoles with carbonyl compounds is
one of the most common and straightforward ap-
proaches for the synthesis of bis(indolyl)methanes.
The acids utilized in this type of reaction are protic
acids [3] and Lewis acids [4], usually used in excess
and require long hours for the completion of the
reaction. Generally, these Lewis acid catalysts are
ꢀ
Corresponding author. E-mail: mady_kmm@yahoo.co.uk

112
A. Srinivasa et al.
Scheme 1
Antimony salts are stable and insignificantly solu-
action between indole and carbonyl compounds,
Sb2(SO4)3 gave good results (Table 1, entry 5).
Further it was noticed that 5 mol% of the catalyst
gave the best result, though increasing the concen-
tration of catalyst resulted in marginal increase in the
yield without significant reduction in the reaction
time (Table 1, entry 6).
Encouraged by this result, we further examined
the catalytic activity of Sb2(SO4)3 in different reac-
tion media to investigate the solvent effect on re-
action. The results are summarized in Table 2 and
show that polar solvents such as MeOH and EtOH
are better solvents than non-polar ones. Although the
reaction proceeds in water, the isolated yields are low
(60%) (Table 2, entry 11). Also, we examined the re-
action in an alcohol=water system. Remarkably, the
condensation proceeded smoothly in MeOH=H2O
(3=1, v=v), EtOH=H2O (3=1, v=v) system and afford-
ed the desired product in good yield (90%) (Table 2,
entries 12, 13). However, methanol was found to be
ble in common organics solvents. We expected their
catalytic activity to be similar to bismuth salts as
both bismuth and antimony are positioned in the
same group in the periodic table. Bismuth salts have
been extensively used in various organic syntheses
and found to be versatile catalysts in some organic
reactions [16]. There are only few reports where an-
timony salts are used as catalysts, antimony chloride
in particular has been used in Friedel-Crafts acyla-
tion [17]. Hence, we planned to explore the possibil-
ity of using various antimony salts in the synthesis of
bis(indolyl)alkanes. The results of these experiments
using various antimony salts as catalysts in the con-
densation reaction between indoles and carbonyl
compounds are described in this paper.
Results and Discussions
Initial studies were aimed at the investigation of
various antimony salts in the model reaction of
indole with benzaldehyde (Scheme 1) for their cata-
lytic activity in methanol. The results are shown in
Table 1. Among the antimony salts used in this re-
Table 2. Screening of the catalytic activity of antimony
sulfate for the synthesis of bis(indolyl)methane at room
temperature
Entry
Solvent
Amount of
catalyst
Time= Yield=%a
h
Table 1. Effect of catalysts in the reaction of indole with
benzaldehyde in MeOH at room temperature
1
2
3
4
5
6
7
8
9
10
11
12
13
MeOH
EtOH
CH2Cl2
Toluene
CH3CN
DMF
5% Sb2(SO4)3
5% Sb2(SO4)3
5% Sb2(SO4)3
5% Sb2(SO4)3
5% Sb2(SO4)3
5% Sb2(SO4)3
5% Sb2(SO4)3
2.5% Sb2(SO4)3 2.30
10% Sb2(SO4)3 0.50
5% Sb2(SO4)3
5% Sb2(SO4)3
1.30
1.30
1.30
2.00
1.30
2.30
3.45
96
88
82
78
86
72
60
88
94
Entry
Amount of catalyst
Time=h
Yield=%a
1
2
3
4
5
6
7
8
9
5% SbPO4
16.00
12.00
12.00
2.30
1.30
0.50
3.00
2.00
2.30
1.45
3.00
1.50
60
65
72
88
96
97
55
65
75
88
60
68
10% SbPO4
20% SbPO4
2.5% Sb2(SO4)3
5% Sb2(SO4)3
10% Sb2(SO4)3
5% SbCl3
THF
MeOH
MeOH
MeOH
H2O
1.30 (96, 90, 85)b
4.00
1.50
1.50
10% SbCl3
60
90
90
5% Sb(NO3)3
10% Sb(NO3)3
5% SbF3
MeOH=H2O 5% Sb2(SO4)3
EtOH=H2O 5% Sb2(SO4)3
10
11
12
a
Isolated yields
10% SbF3
b
The same catalyst recovered and reused for each of the three
runs
a
Isolated yields

Antimony(III) Sulfate Catalyzed Condensation Reaction
113
Scheme 2
the best for the catalytic reaction at room tempera-
ture in terms of yield and reaction time.
bis(indolyl)methanes in good yield in short reaction
time. It was observed that the electronic properties
of the aromatic ring have an effect on the rate of the
condensation reaction. The rate is accelerated if an
electron-donating group is present on the aromatic
ring compared to electron-withdrawing group. Thus
anisaldehyde and hydroxybenzaldehyde (Table 3,
3b, 3c) reacted faster compared to nitrobenzalde-
hyde (Table 3, 3d) and also gave better yields. In
addition, n-butanal and n-hexanal (Table 3, 3l, 3n)
reacted with indoles to afford the product in good
yield with prolonged reaction time. In the case of
ketones (Table 3, 3q, 3r, 3t), the isolated yields are
less compared to those for aldehydes. The indoles
reacted with cinnamaldehyde (Table 3, 3p) in a rela-
tively short reaction time to produce the correspond-
ing bis(indolyl)methanes with high yields.
As expected, antimony sulfate could be easily re-
covered by filtration and recycled without significant
decrease in the activity of the catalyst (Table 2, entry
10, 1st run 96%, 2nd run 88%, and 3rd run 82%).
Having established the optimum reaction condi-
tions, various aromatic and aliphatic aldehydes and
ketones were reacted with indole to investigate the
scope of the reaction (Scheme 2) and several repre-
sentative results are summarized in the Table 3.
In all these cases, the condensation reaction of
indoles with aromatic aldehydes proceeded smoothly
at room temperature to produce the corresponding
Table 3. The synthesis of bis(indolyl)methanes using anti-
mony sulfate at room temperature
Product R1
R2
R3
Time= Yield=
%
It is reported that, contrary to ꢀ,ꢁ-unsaturated
aldehydes, ꢀ,ꢁ-unsaturated ketones undergo a 1,4-
addition reaction with indoles in presence of acid
catalysts (protic and Lewis acid) [18] to yield indolyl
ketones. These indolyl ketones have received a lot of
interest for more than a century, as a number of their
derivatives occur in nature and possess a variety of
biological activities [19]; especially 3-indolyl ke-
tones are very interesting.
As expected, in the presence of 10 mol% Sb2(SO4)3,
the indoles underwent 1,4-addition with ꢀ,ꢁ-unsatu-
rated ketones (Scheme 3) to afford 3-indolyl ke-
tones. The results are represented in the Table 4.
In conclusion, the condensation reaction of indole
with carbonyl compounds were successfully carried
out in presence of a catalytic amount of reusable
Sb2(SO4)3 at room temperature in methanol. This
method offers several significant advantages such as
high conversions, easy handling, cheaper catalyst,
cleaner reaction profiles, short reaction time, and
the reaction conditions are environmental friendly
and might be amenable for upscaling.
h
3a
3b
3c
3d
3e
3f
H
H
H
H
H
Ph
4-MeOPh
4-HOPh
4-NO2Ph
4-ClPh
4-N(Me2)Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
1.30
1.10
1.20
2.00
1.30
1.15
1.30
2.00
2.20
3.00
1.50
3.00
3.00
3.30
3.30
1.10
8.00
9.00
5.00
5.00
96
95
93
88
92
96
94
85
82
85
90
92b
90
90b
85
95
80
75
84b
78
H
3g
3h
3i
3j
3k
3l
Me
H
Me
Ph
H
2-furyl
2-furyl
Ph
2-hydroxynaphthyl
C3H7
C3H7
H
3m
3n
3o
3p
3q
3r
3s
H
H
H
H
H
H
H
C5H11
C5H11
PhCH¼CH
Ph
–C5H10–
Ph
Me
Me
Me
3t
H
a
Isolated yields
10 mol% catalyst was loaded
b

114
A. Srinivasa et al.
Scheme 3
3,30-Bis(2-phenylindolyl)phenylmethane (3j, C35H26N2)
Table 4. Antimony sulfate catalyzed 1,4-addition of indoles
with ketones at room temperature
Mp 266–268ꢃC; IR (KBr): ꢂꢀ¼ 3425, 3099, 2955, 1645, 1600,
1480, 750 cmꢄ1; 1H NMR (CDCl3): ꢃ ¼ 7.945 (br s, 2H, NH),
7.23–7.28 (m, 4H), 7.16 (d, J ¼ 7.8 Hz, 2H), 7.01–7.14 (m,
13H), 6.91 (d, J ¼ 8.0 Hz, 2H), 6.75 (t, J ¼ 7.2, 2.8 Hz, 2H),
6.05 (s, 1H) ppm; MS: m=z ¼ 474 (Mþ).
Product
R1
R4
R5
Time=h
Yield=%a
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
Ph
Ph
H
Ph
Ph
Me
Ph
9.00
10.00
8.00
85
80b
90
82
68
76
86
78
84
86
90
3,30-Bisindolyl(2-hydroxynaphthyl)methane (3k, C27H20N2O)
Yellow solid; mp 203–205ꢃC; IR (KBr): ꢂꢀ¼ 3415, 3020,
Me
9.00
–C3H6–
–C2H4–
Ph Ph
–C2H4–
Me
Ph
12.00
12.00
9.00
12.00
6.00
9.00
1
1605, 1460, 1290, 1068, 1004, 750 cmꢄ1; H NMR (CDCl3):
H
ꢃ ¼ 12.2 (s, 1H), 8.15 (d, J ¼ 8.6 Hz, 1H), 8.06 (br s, 2H,
NH), 7.83 (d, J ¼ 8.0 Hz, 1H), 7.73 (d, J ¼ 8.0 Hz, 1H), 7.3–
7.45 (m, 7H), 7.2 (t, J ¼ 7.2 Hz, 2H), 7.02 (t, J ¼ 7.6Hz, 2H),
6.82 (s, 1H), 6.76 (s, 1H), 6.5 (s, 1H, CH) ppm; MS:
m=z ¼ 388 (Mþ).
Me
Me
Me
Me
Me
Ph
Me
Me
5j
5k
H
6.00
a
Isolated yields
7.5 mol% catalyst was loaded
General Procedure for the Synthesis of 3-Indolyl ketones 5
Sb2(SO4)3 (0.1mmol) was added to a mixture of 1.0mmol
indole and 1.0mmol ꢀ,ꢁ-unsaturated ketone in 2 cm3 meth-
anol. The reaction mixture was stirred at room temperature
for appropriate time. After completion, the reaction mixture
was quenched with 20 cm3 water and extracted with 3ꢂ
10cm3 ethyl acetate. The combined organic layer was dried
(Na2SO4), concentrated, and purified by column chromato-
graphy on SiO2 with an ethyl acetate and petroleum ether
mixture as eluent to afford the 3-indolyl ketones.
b
Experimental
All melting points were recorded in open capillaries. The
purity of the compounds was checked by TLC on silica gel
1
and they were purified by column chromatography. H NMR
spectra were recorded on a Bruker-400Hz spectrometer using
TMS as an internal standard. IR spectra were obtained using a
FTS-135 spectrometer instrument. Mass spectra were recorded
on a JEOL SX 102=DA-6000 (10 kV) FAB mass spectrometer.
The compounds 3a [3d], 3b [10], 3c [5], 3d [10], 3e [4f], 3f
[5], 3g [3d], 3h [3d], 3i [3d], 3l [5], 3n [10], 3p [5], 3q [5],
3r [4c], 3t [10], 5a [18i], 5c [18e], 5d [18i], 5e [18e], 5f [18i],
5g [18i], 5h [18i], 5i [18i], 5j [18i], and 5k [18e] are known,
their identities were proven by means of IR, NMR, and mass
spectra. Herein we give melting points and spectral data for 3j,
and 3k, which could not be found in literature.
Acknowledgements
The authors are thankful to the Department of Post Graduate
Studies and Research in Chemistry and Industrial Chemistry,
Kuvempu University, Shankaraghatta, for providing laboratory
facilities. The authors are also thankful to the Indian Institute
of Science, Bangalore, and CDRI, Lucknow, for spectral data.
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Sb2(SO4)3 (0.05 mmol) was added to a mixture of 2.0 mmol
indole and 1.0 mmol aldehyde or ketone in 2 cm3 methanol.
The reaction mixture was stirred at room temperature for
the appropriate time. After completion, the reaction mixture
was quenched with 20 cm3 H2O and extracted with 3ꢂ
10cm3 ethyl acetate. The combined organic layer was dried
(Na2SO4), concentrated, and purified by column chromatogra-
phy on SiO2 with an ethyl acetate and petroleum ether mixture
as eluent to afford the bis(indolyl)methanes.
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