Silica-supported LiHSO4 as a highly efficient, mild, heterogeneous, and reusable catalytic system for the solvent-free synthesis of bis(indolyl)methanes

Article abstract of DOI:10.1080/10426500802466056

Silica-supported LiHSO₄ (LiHSO₄/SiO₂) is used as a green, cheap, and efficient catalytic system for the synthesis of bis(indolyl)methanes via the condensation of indoles with carbonyl compounds under solvent-free condition

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Phosphorus, Sulfur, and Silicon
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Silica-Supported LiHSO4
as a Highly Efficient, Mild,
Heterogeneous, and Reusable
Catalytic System for the
Solvent-Free Synthesis of
Bis(indolyl)methanes
a
b
Alireza Hasaninejad , Abdolkarim Zare , Hashem
c
c
a
Sharghi , Reza Khalifeh & Mohsen Shekouhy
a
Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr, Iran
b
Department of Chemistry, Payame Noor University
(
PNU), Iran
c
Department of Chemistry, College of Sciences,
Shiraz University, Shiraz, Iran
Version of record first published: 21 Sep 2009.
To cite this article: Alireza Hasaninejad , Abdolkarim Zare , Hashem Sharghi , Reza
Khalifeh & Mohsen Shekouhy (2009): Silica-Supported LiHSO as a Highly Efficient,
4
Mild, Heterogeneous, and Reusable Catalytic System for the Solvent-Free Synthesis
of Bis(indolyl)methanes, Phosphorus, Sulfur, and Silicon and the Related Elements,
184:10, 2508-2515
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Phosphorus, Sulfur, and Silicon, 184:2508–2515, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802466056
Silica-Supported LiHSO as a Highly Efficient, Mild,
4
Heterogeneous, and Reusable Catalytic System for the
Solvent-Free Synthesis of Bis(indolyl)methanes
1
2
Alireza Hasaninejad, Abdolkarim Zare, Hashem
3
3
1
Sharghi, Reza Khalifeh, and Mohsen Shekouhy
Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
Department of Chemistry, Payame Noor University (PNU), Iran
Department of Chemistry, College of Sciences, Shiraz University,
1
2
3
Shiraz, Iran
Silica-supported LiHSO4 (LiHSO4/SiO2) is used as a green, cheap, and efficient
catalytic system for the synthesis of bis(indolyl)methanes via the condensation of
indoles with carbonyl compounds under solvent-free conditions. The reactions pro-
ceed rapidly at room temperature, and the title compounds are obtained in high to
excellent yields.
Keywords Bis(indolyl)methane; carbonyl compound; indole; LiHSO4/SiO2; solvent-free
INTRODUCTION
In recent years, the use of solid-supported catalysts has become popu-
lar due to their unique properties such as enhanced reactivity as well
as selectivity, straightforward workup, recyclability of the catalyst, and
the ecofriendly reaction conditions.1 Silica gel is one of the most in-
teresting solid supports, because it has surface properties that sug-
gest that very rich organic reactions may occur there. SiO2 is an inex-
pensive, reusable, commercially available, and environmentally benign
support that, accompanied with different catalysts, has been used in a
,2
Received 4 June 2008; accepted 10 September 2008.
The authors thank Persian Gulf University and Payame Noor University Research
Councils for financial support of this work.
Address correspondence to Alireza Hasaninejad, Department of Chemistry, Fac-
ulty of Sciences, Persian Gulf University, Bushehr 75169, Iran. E-mail: ahassanine-
jad@yahoo.com or Abdolkarim Zare, Department of Chemistry, Payame Noor University
(PNU), Iran. E-mail: abdolkarimzare@yahoo.com
2508

Synthesis of Bis(indolyl)methanes
2509
2
variety of organic transformations. Nevertheless, most of the existing
processes in organic synthesis involve toxic and volatile organic sol-
vents as reaction media, and these are environmentally unacceptable
from a green chemistry view point. One of the most effective tech-
niques to solve this problem is solvent-free conditions, which makes
synthesis simpler, saves energy, and prevents solvent waste, hazards,
3
and toxicity. Consequently, it is important to note that the combina-
tion of safe catalysis with the use of solventless technology represents
a suitable way toward so-called “ideal synthesis.” In this article, we
wish to introduce silica-supported LiHSO4 as a new catalyst for or-
+
+
−
ganic synthesis. The strong oxophilicity of Li as well as H of HSO4
powerfully activates oxygen-containing electrophiles for nucleophilic
4
attack.
Bis(indolyl)methanes are very important compounds, as they have
5
various biological and pharmaceuticals activities. The synthesis of
bis(indolyl)methanes via the condensation of indoles with carbonyl
compounds is one of the more significant and well-known transfor-
6,7
mations in organic synthesis. In general, this transformation re-
6
7
quires a protic or a Lewis acid to activate carbonyl compounds. For
6
a
this purpose, several reagents and catalysts such as acetic acid,
silica sulfuric acid,6a H3PMo12O40.xH2O, HY-Zeolite, M(HSO4)n
6c
6d
6
e
7a
7b
7c
7f
(
M = Zn, Mg and Ca), ZrOCl2.8H2O, AlPW12O40, In(OTf)3,
7d 7e
Dy(OTf)3, La(PFO)3 (PFO = perfluorooctanoates), Zeokarb-225,
7
g
7h
7i
MgSO4, trityl chloride, P2O5/SiO2, and silica chloride have been
7
j
used. However, most of the reported methods are associated with
one or more of the following disadvantages: (i) the use of expen-
sive reagents, (ii) the necessity of a large or stoichiometric amount
of reagent, (iii) long reaction times, and (iv) moderate yields. More-
over, metal hydrogen sulfates have been previously employed for
bis(indolyl)methane synthesis,6e but this reaction has been performed
in solution conditions (EtOH and DMSO) and in relatively long re-
action times. Thus, the need for a more efficient and practical alter-
native use of an inexpensive, copious, and available catalyst is still
urgent.
Considering the above facts and also in extension of our previ-
ous studies on the application of silica-supported catalysts in or-
ganic synthesis,2
a–2h,7i,7j
we introduce here LiHSO4/SiO2 as a new
catalyst for the preparation of bis(indolyl)methanes via the conden-
sation of indoles with aldehydes as well as ketones under solvent-
free conditions at room temperature (Scheme 1). It is worth not-
ing that this method has none of the mentioned disadvantages at
all.

2510
A. Hasaninejad et al.
SCHEME 1
RESULTS AND DISCUSSION
In order to obtain optimal reaction conditions, the condensation of in-
dole with benzaldehyde was selected as a model reaction, and firstly
it was examined in the presence of LiHSO4 (20 mol%) under solvent-
free conditions at room temperature. However, in these conditions, a
highly sticky orange reaction mixture was obtained, and the desired
product was produced in 81% yield after 70 min. Prolonging the reac-
tion time did not improve the yield. The yield considerably increased
and the reaction time decreased when the reaction was carried out in
the presence of silica-supported LiHSO4 (Scheme 1). In this case, the
product was obtained in 94% yield within 30 min. Thus, LiHSO4/SiO2
was applied as catalyst for all other reactions.
The condensation of indole with benzaldehyde was also examined in
the presence of LiHSO4/SiO2 at room temperature in different solvents
including H2O, EtOH, CHCl3, THF, and CH3CN (Table I). As it can be
seen from Table I, the solvent-free method is more efficient.
To recognize the efficiency and the capacity of the catalyst, indoles
were reacted with structurally diverse aldehydes as well as ketones.
TABLE I Comparison of the Reaction of Indole with Ben-
zaldehyde in the Presence LiHSO
4 2
/SiO Under Solution
Conditions Versus the Solvent-Free Method
Entry
Solvent
Solvent-free
Time (min)
Yield (%)a
1
2
3
4
5
6
30
120
60
120
120
120
94
23
89
36
65
59
H2O
EtOH
CHCl3
THF
CH3CN
aIsolated yield.

Synthesis of Bis(indolyl)methanes
2511
TABLE II Synthesis of Bis(indolyl)methanes via the Condensation
of Indoles with Carbonyl Compounds
Time
(min)
Yield
(%)
a
◦
Entry
X
R
R’
Mp C (Lit.)
g
1
2
3
4
5
6
7
8
9
H
CH3
H
H
H
CH3
H
H
H
CH3
H
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
30
50
25
25
25
40
30
30
30
50
25
35
30
30
94
89
90
88
92
88
96
93
87
91
92
90
94
92
140–142 (140–142)7
244–246 (245–247)
216–218 (217–219)
7
j
i
7
p-NO2C6H4
m- NO2C6H4
m-CNC6H4
p-NO2C6H4
p-CH3C6H4
p-OMeC6H4
p-OHC6H4
p-CH3C6H4
p-ClC6H4
o-ClC6H4
7
6
6
g
219–221 (218–220)
7
h
99–101 (102–104)
241–243 (240–242)
94–96 (97–99)
d
6
b
b
186–188 (178–181)
119–121 (119–121)
7i
7g
10
11
12
13
14
175–177 (176–178)
7
i
78–80 (78–80)
73–75 (69–71)
7h
H
H
H
7
j
i
4-Pyridyl
2-Furyl
161–163 (161–163)
317–319 (316–318)
7
15
H
H
40
91
163, dec. (162, dec.)7i
7
i
16
17
18
19
20
H
H
H
H
E-C6H5CH=CH
CH3(CH2)3CH2
C6H5
3-Pyridyl
−CH2(CH2)3CH2−
H
H
CH3
CH3
50
50
120
120
60
90
88
74
76
85
99–101 (100–102)
7g
71–73 (71–73)
163–165 (164–166)
251–252 (251–252)
161–163 (163–165)
7
j
7
h
7
i
aIsolated yield.
The results are summarized in Table II. As Table II indicates, indoles
were efficiently condensed with a structurally diverse variety of aldehy-
des including aromatic aldehydes possessing electron-withdrawing and
electron-releasing substituents as well as halogen on their aromatic
rings and aliphatic aldehydes (Table II, entries 1–17). The reaction
of indoles with ketones gave the corresponding bis(indolyl)methanes
in lower yields and longer reaction times (Table II, entries 18–20).
Our catalyst was also successfully applied for condensation of indole

2512
A. Hasaninejad et al.
SCHEME 2
with terephthaldehyde. When, 2.1 equivalents of indole were reacted
with terephthalaldehyde, bis(indolyl)methane was obtained as the ma-
jor product; however, the use of 4.2 equivalents of indole afforded di-
bis(indolyl)methane as the main product (Scheme 2).
One of the most interesting properties of LiHSO4/SiO2 is its ease
of recycling. It can be reused after simple washing with Et2O, thus
rendering the process more economical. The yields of the condensation
of indole with benzaldehyde in the 2nd, 3rd, and 4th uses of the catalyst
were almost as high as in the first use (please see Table III).
TABLE III The Condensation of Indole with Benzalde-
hyde in the Presence of Recycled LiHSO /SiO
4 2
Entry
Cycle
Time (min)
Yield (%)a
1
2
3
4
1st use
2nd use
3rd use
4th use
30
35
40
50
94
91
90
88
aIsolated yield.

Synthesis of Bis(indolyl)methanes
2513
In conclusion, we have introduced LiHSO4/SiO2 as a new, efficient,
green, heterogeneous, and reusable catalyst for organic synthesis. Effi-
cient synthesis of bis(indolyl)methanes via the condensation of indoles
with carbonyl compounds is the first application of this cheap catalyst.
EXPERIMENTAL
All chemicals were purchased from Merck or Fluka chemical compa-
nies. H2SO4 98% was used for the preparation of LiHSO4. Silica gel 60,
0
.063–0.200 mm (7–230 mesh ASTM) was applied as support. All prod-
ucts are known, and their structures were identified by comparison of
their spectral data and melting points with those in the authentic sam-
ples. The H NMR (250 MHz) and C NMR (62.5 MHz) were run on
a Bruker Avance DPX-250 FT-NMR spectrometer. Microanalyses were
performed on a Perkin-Elmer 240-B microanalyzer. Melting points were
recorded on a B u¨ chi B-545 apparatus in open capillary tubes and are
uncorrected.
1
13
General Procedure for the Preparation of LiHSO4
A mixture of LiCl (0.848 g, 20 mmol) and H2SO4 (2.002 g, 20 mmol) was
stirred under N2 gas for 120 min to give LiHSO4 (2.080 g) as a white
powder. The HCl gas produced was trapped with NaOH solution.
General Procedure for the Preparation of LiHSO /SiO
4
2
Catalytic System
A mixture of LiHSO4 (0.5 g) and SiO2 (9.5 g) was ground vigorously to
give LiHSO4/SiO2 catalytic system as a white powder (10 g).
General Procedure for the Synthesis of Bis(indolyl)methanes
To a mixture of carbonyl compound (1 mmol) and LiHSO4/SiO2 (0.416
g, 20 mol%) in a mortar, indole (2.1 mmol) was added, and the result-
ing mixture was ground at room temperature for the times reported
in Table II. Then, the reaction mixture was suspended in EtOAc (25
mL), filtered, and the filtrate was washed with a saturated solution
of NaHCO3 (2 × 20 mL), saturated solution of NaHSO3 (2 × 20 mL),
and water (2 × 20 mL). The organic layer was separated and dried
with CaCl2. The solvent was evaporated, and the crude product was
purified by recrystallization from EtOAc:petroleum ether (1:2) or plate
chromatography on silica gel eluted with EtOAc:petroleum ether (1:2).

2514
A. Hasaninejad et al.
After isolation of the products, the remaining LiHSO4/SiO2 was dried
and used for the next run under identical reaction conditions.
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