[Fe(III)(salophen)]Cl in Molten Tetrabutylammonium Bromide as a New Homogeneous Catalytic System for the Electrophilic Reaction of Indole with Carbonyl Compounds

Article abstract of DOI:10.1002/cjoc.201090119

[Fe(III)(salophen)]Cl in molten tetrabutylammonium bromide was used as a cost effective and efficient catalytic system for the electrophilic reaction of indole with carbonyl compounds. The remarkable features of this new procedure are high conversions, sh

Full text of DOI:10.1002/cjoc.201090119

FULL PAPER
[Fe(III)(salophen)]Cl in Molten Tetrabutylammonium Bromide
as a New Homogeneous Catalytic System for the Electrophilic
Reaction of Indole with Carbonyl Compounds
Saeidnia, Samira
Sheikhshoaie, Iran*
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
[Fe(III)(salophen)]Cl in molten tetrabutylammonium bromide was used as a cost effective and efficient catalytic
system for the electrophilic reaction of indole with carbonyl compounds. The remarkable features of this new pro-
cedure are high conversions, short reaction time, clean reaction profiles and simple experimental and work-up pro-
cedures.
Keywords [Fe(III)(salophen)]Cl, tetrabutylammonium bromide, transition metal complex, carbonyl compound,
electrophilic reaction, indole, ionic liquid
Introduction
induce both receptor-dependent and -independent
growth inhibitory and proapoptotic pathways in cancer
cells and tumors including activation of ER stress in
both pancreatic and ovarian cancer cell lines.19
Schiff bases are considered as a very important class
of organic compounds. Since the first report of their
metal complexes,1 symmetrical and nonsymmetrical
Schiff bases have been extensively studied and used as
ligands in many complex species.2 The complexes of di-
and trivalent transition metals involving derivatives of
salicylaldehyde and aliphatic or aromatic amines are of
immense importance because of their potential as cata-
lyst for some catalytic reactions3-5 and biological activi-
ties.6-8 N,N'-Bis(salicylidene)-1,2-phenylenediamine (salo-
phen), which is one of the most popular symmetrical
tetradentate ligand, forms complexes with various metal
ions and organic compounds.9 The complexation reac-
tions of this ligand in nonaqueous matrices could be
used as an efficient strategy to design the analytical
systems such as potentiometric sensors,10-12 bulk liquid
membrane transports,13 optical sensors,14 solid phase
extraction15 and biochemistry fields.16
Indole fragment is featured widely in a wide variety
of pharmacologically and biologically active com-
pounds.17 For example, bis(indolyl)alkanes and their
derivatives are found in bioactive metabolites of terres-
trial and marine origin.18 Some of ring-substituted
bis(indolyl)methanes such as 1,1-bis(3-indolyl)-1-(para-
substituted phenyl)methanes are cytotoxic to cancer
cells and inhibit tumor growth in vivo. For instance,
bis(indolyl)methanes containing p-trifluoromethyl,
tert-butyl and cyano activate peroxisome prolifera-
tor-activated receptor c (PPARc), whereas the methoxy
and unsubstituted analogs activate nerve growth factor
induced-Ba (Nur77), an orphan nuclear receptor. Both
PPARc-active and Nur77-active bis(indolyl)methanes
Consequently, numerous methods have been re-
ported for the synthesis of bis(indolyl)methanes.20 Of
these methods, the acid-catalysed electrophilic substitu-
tion reaction of indoles with aldehydes is one of the
most simple and straightforward approaches for the
synthesis of bis(indolyl)methanes. A variety of reagents
such as InCl3,21 In(OTf)3,22 La(OTf)3,23 LiClO4,24
FeCl3•6H2O,25
NaHSO4•SiO2,26
zeolites27
and
H3PMo12O40•xH2O28 have been employed to accomplish
this transformation. However, some of the reported
methods have the following drawbacks: for example,
use of expensive reagents, longer reaction time and low
yields of products.
It was of interest to us, therefore, to investigate the
catalytic effect of some of transition metal salophen
complexes on the electrophilic reaction of indole with
carbonyl compounds (Scheme 1).
Results and discussion
At first, we investigated the catalytic ability of 5
mol% of different transition metal salophen complexes
in molten TBAB as an ionic liquid at 110 ℃ on the
reaction of indole with benzaldehyde. The results are
presented in Table 1.
As Table 1 shows, initial screening studies identified
Fe(III) salophen as the most efficient catalyst. Encour-
aged by these results, [Fe(III)(salophen)]Cl was chosen
as the best catalyst.
*
E-mail: sheikhshoaie_i@yahoo.com; Tel./Fax: 0098-341-322-2033
Received June 18, 2009; revised November 1, 2009; accepted December 8, 2009.
Project supported by Research Council of Shahid Bahonar University of Kerman.
Chin. J. Chem. 2010, 28, 601— 604
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
601

Saeidnia & Sheikhshoaie
FULL PAPER
Scheme 1 [M(salophen)]-catalyzed reaction of indole with
Table 3 Condensation of carbonyl compounds with indole
carbonyl compounds
catalyzed by [Fe(III)(salophen)]Cl
Time/ Yield/
References to
known compounds
Entry Carbonyl compound
min
40
30
40
20
20
15
20
50
70
40
120
%
98
97
98
90
97
95
98
95
98
96
96
1
2
3
4
5
6
7
8
9
2,4-Di-ClC6H3CHO
2-OHC6H4CHO
4-ClC6H4CHO
[29]
[30]
[31]
[32]
[33]
[31]
[34]
[31]
[35]
[33]
[36]
3-NO2C6H4CHO
C6H5CHO
4-CH3C6H4CHO
2-CH3OC6H4CHO
4-NO2C6H4CHO
1-Naphthaldehyde
Table 1 Catalytic effect of different salophen catalysts on the
reaction of indole with benzaldehyde
10 Cyclohexanone
11 Acetophenone
Entry
Catalyst
Time/min
Yield/%
97
1
2
3
4
5
6
VO(salophen)
55
30
30
35
60
30
(Entry 6). Similarly, for a strong electron-withdrawing
group, such as nitro, para to the carbonyl group, re-
quired a longer reaction time and gave a lower yield
(Entry 8).
[Mn(III)(salophen)]Cl
[Fe(III)(salophen)]Cl
Co(II)(salophen)
Ni(II)(salophen)
Cu(II)(salophen)
90
97
87
91
To show the merit of this work in comparison with
reported results in the literature, we compared our re-
sults with FeCl3•6H2O,25 phosphated zirconia37 and
ZrOCl2•8H2O38 in the synthesis of bis(indolyl)methane
derivatives.
As shown in Table 4, [Fe(III)(salophen)]Cl in mol-
ten TBAB can act as an effective catalytic system with
respect to reaction times and yields.
91
In the next step, we studied the influence of the
amount of [Fe(III)(salophen)]Cl on the reaction time
and yield. As shown in Table 2, there is small difference
between 10 mol% and 15 mol% of catalyst. So we in-
ferred that 10 mol% of [Fe(III)(salophen)]Cl was suffi-
cient for this reaction.
We think that [Fe(III)(salophen)]Cl as a homogene-
ous catalyst might activate the carbonyl group as well as
indole moiety to promote the reaction.
Table 2 Effect of different amounts of [Fe(III)(salophen)]Cl on
the reaction
Experimental
Carbonyl
compound
[Fe(III)(salophen)]Cl/ Time/ Yield/
Entry
mol%
5
min
30
%
97
97
98
95
96
97
All chemicals used for the synthesis of the ligands
and metal complexes, indole and carbonyl compounds
were of reagent grade. All products are known and were
identified by comparing their spectral data and physical
properties with those of the authentic samples. NMR
spectra were recorded on a Bruker DRX-500 AVANCE
NMR spectrometer using CDCl3 as solvent. All salo-
phen complexes were synthesized according to the lit-
eratures.39-42
1
2
3
4
5
6
Benzaldehyde
Benzaldehyde
Benzaldehyde
Acetophenone
Acetophenone
Acetophenone
10
15
5
20
20
120
120
120
10
15
With the optimized reaction conditions, we next
studied the reaction of a series of aldehydes and ketones
with indole. In order to show the general applicability of
this method, various carbonyl compounds were effi-
ciently reacted with two equivalents of indole in the
same conditions. As shown in Table 3, yields are almost
quantitative in most cases.
The substituents on the carbonyl compound play a
significant role in the reaction. The presence of an elec-
tron-releasing group, such as methyl in para position to
the carbonyl group, enhances the product formation as
indicated by a shorter reaction time and higher yield
General procedure for the [Fe(III)(salophen)]Cl-
catalyzed reaction of indole with carbonyl com-
pounds
A mixture of indole (2 mmol), aldehyde or ketone (1
mmol) and [Fe(III)(salophen)]Cl (0.1 mmol) in tetrabu-
tylammonium bromide (1 mmol) was stirred at 110 ℃
for the appropriate time (Table 1). The progress of the
reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was dissolved in
ethanol and poured into water. The resulting precipitate
was filtered and purified by silica gel column chroma-
602
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 601— 604

[Fe(III)(salophen)]Cl in Molten Tetrabutylammonium Bromide as a Catalytic System
Table 4 Comparison of the results of iron(III)(salophen)Cl complex as a catalyst in electrophilic reaction of carbonyl compounds and
indole with literatures
Entry
1
Carbonyl compound
C6H4CHO
Catalyst
Catalyst ratio
Solvent
Condition Time/min Yield/%
[Fe(III)(salophen)]Cl
FeCl3•6H2O
Phosphated zirconia
ZrOCl2•8H2O
10 mol%
5 mol%
20 wt%
5 mol%
Molten TBAB 100 ℃
20
90
20
40
97
98
93
84
[OMIm]PF6
Solvent-free
Solvent-free
r.t.
80 ℃
50 ℃
[Fe(III)(salophen)]Cl
Phosphated zirconia
ZrOCl2•8H2O
10 mol%
20 wt%
5 mol%
Molten TBAB 100 ℃
40
150
180
96
79
80
2
3
Cyclohexanone
Acetophenone
Solvent-free
Solvent-free
80 ℃
50 ℃
[Fe(III)(salophen)]Cl
FeCl3•6H2O
Phosphated zirconia
10 mol%
5 mol%
20 wt%
Molten TBAB 100 ℃
120
600
12 h
96
00
[OMIm]PF6
Solvent-free
r.t.
80 ℃
Trace
tography using chloroform as eluent, to afford the de-
sired compound in pure form.
attractive process for the rapid synthesis of substituted
bis(indolyl)methanes.
Spectral data of selected compounds
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indole with carbonyl compounds was successfully car-
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[Fe(III)(salophen)]Cl in molten TBAB as an ionic liquid.
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Chin. J. Chem. 2010, 28, 601— 604