Diammonium hydrogen phosphate as an efficient and inexpensive catalyst for the synthesis of bis(indolyl)methanes under solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0658-6

Bis(indolyl)methanes were synthesized by the reaction of indole derivatives and aromatic and aliphatic aldehydes in the presence of diammonium hydrogen phosphate as a solid catalyst under solvent-free conditions. This methodology offers significant improv

Full text of DOI:10.1007/s00706-007-0658-6

Monatshefte fu¨r Chemie 138, 595–597 (2007)
DOI 10.1007/s00706-007-0658-6
Printed in The Netherlands
Diammonium Hydrogen Phosphate as an Efficient and Inexpensive Catalyst
for the Synthesis of Bis(indolyl)methanes under Solvent-Free Conditions
Minoo Dabiri1;ꢀ, Peyman Salehi2;ꢀ, Mostafa Baghbanzadeh1, Yasamin Vakilzadeh1, and Shadi Kiani1
1
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Evin, Tehran, Iran
2
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute,
Shahid Beheshti University, Evin, Tehran, Iran
Received January 22, 2007; accepted (revised) January 25, 2007; published online April 23, 2007
# Springer-Verlag 2007
Summary. Bis(indolyl)methanes were synthesized by the
reaction of indole derivatives and aromatic and aliphatic alde-
hydes in the presence of diammonium hydrogen phosphate as
a solid catalyst under solvent-free conditions. This methodol-
The methods which are used are based on the re-
action of indole and aldehydes or ketones catalyzed
by an acidic catalyst. There are several catalysts re-
ported that promote this reaction, such as protic acids
ogy offers significant improvements for the synthesis of bis(in-
[7], Lewis acids [8, 9], heterogeneous acidic cata-
lysts [10–13], and reagents like iodine [14], NBS
[15], CAN [16], and hexamethylenetetramine bro-
mine [17]. However, many of these methods still
suffer from some drawbacks, such as long reaction
time, expensive reagents, low yields of products in
some cases, high catalyst loading, corrosive reagents,
and large amounts of solid supports, which would
eventually result in the generation of large amounts
of toxic waste. For these reasons, superior catalysts,
which are cheap, less toxic, easily available, air sta-
ble, and water-tolerant are desirable.
dolyl)methanes with regard to the yield of products, simplicity
in operation, and green aspects by avoiding toxic catalysts and
solvents.
Keywords. Indole; Heterocycle; Solvent-free; Aldehyde.
Introduction
Indole and its derivatives are important intermedi-
ates in organic synthesis and exhibit various physio-
logical properties and pharmacological activities [1],
such as beneficial estrogen metabolism promoter [2],
inhibitory of human prostate cancer cells [3], and
radical scavenging activities associated with cancer
cells [4]. These compounds are also used as dietary
supplements, which promote healthy estrogen meta-
bolism in human by converting both estrone and
estradiol to their respective 2-hydroxy derivatives
[5]. Over the past decade, a number of natural prod-
ucts containing bis(indolyl)methanes (BIMs) have
been isolated from marine sources indeed [6]. There-
fore, there is a great deal of interest in the synthesis
of these class of compounds.
In continuation of our interest in the synthesis of
heterocyclic compounds [18] we examined diammo-
nium hydrogen phosphate (DAHP) [19] for the syn-
thesis of BIMs under solvent free-conditions.
Results and Discussion
Initially, we carried out the reaction of indole with
4-chlorobenzaldehyde in the presence of different
amounts of DAHP at 80ꢁC. It was found that the best
result was obtained with 30 mol% of DAHP. It is
worthy to note that in the absence of DAHP the
reaction did not yield any product at 80ꢁC even after
ꢀ
p-salehi@sbu.ac.ir
Corresponding authors. E-mail: m-dabiri@sbu.ac.ir and

596
M. Dabiri et al.
Scheme 1
Table 1. Synthesis of BIMs by the reaction of indole derivatives and aldehydes in the presence of DAHP at 80ꢁC
Entry
Aldehyde
Indole
Time=h
Yield=%a
Ref.b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
benzaldehyde
4-nitrobenzaldehyde
4-methoxybenzaldehyde
3-nitrobenzaldehyde
2-nitrobenzaldehyde
cinnamaldehyde
terephthaldialdehyde
anthracene-5-carbaldehyde
heptanal
indole-3-carbaldehyde
furfural
pyrrole-3-carbaldehyde
pyridine-2-carbaldehyde
4-nitrobenzaldehyde
4-methoxybenzaldehyde
indole
indole
indole
indole
indole
indole
indole
indole
indole
indole
2
2
2
2
2.5
3
2
3.5
3.5
4
3.5
3.5
3
87
89
83
91
92
93
86
80
81
83
84
82
87
89
85
[9]
[9]
[9]
[9]
[9]
[9]
[9]
[9]
[9]
[11]
[11]
[11]
[11]
[11]
[12]
2-methylindole
2-methylindole
2-methylindole
2-methylindole
2-methylindole
3
3
a
b
Isolated yield. The products were characterized by comparison of their spectroscopic and physical data with authentic
samples synthesized by the procedures given in the references
a long reaction time. Thus, the work was focused on
the synthesis of desired compounds with the opti-
mized amounts of DAHP (30 mol%) under solvent-
free conditions at 80ꢁC (Scheme 1).
philic substitution of indoles with aldehydes using
DAHP as an efficient and broadly available catalyst.
The mildness of the reaction conditions, low cost of
the reagents, and ease of work-up make the present
methodology useful for the synthesis of compounds
in drug discovery studies.
As shown in Table 2, a series of aromatic, alipha-
tic, and heterocyclic aldehydes underwent the elec-
trophilic substitution reaction with indole smoothly
to afford a wide range of substituted BIMs in good
to excellent yields. Many of the pharmacologically
relevant substitution patterns on the aromatic ring
could be introduced with high efficiency by using
this procedure. Furthermore, even an unsaturated
aldehyde (cinnamaldehyde) gave the correspond-
ing BIM without polymerization (Table 1, entry 6).
The heterocyclic aldehydes also worked well with-
out the formation of any side products (Table 1,
entries 10–13). The work-up procedure was very
simple including addition of cold water at the end
of the reaction to the mixture and filtration of the
product.
Experimental
Melting points were obtained in open capillary tubes and were
measured on an electrothermal 9200 apparatus. Mass spectra
were recorded on a Shimadzu QP 1100 BX mass spectro-
meter. IR spectra were recorded on KBr pellets on a Shimadzu
IR-470 spectrophotometer. 1H and 13C NMR spectra were
determined on a Bruker 300 DRX Avance instrument at 300
and 75MHz.
General Procedure for the Synthesis of BIMs
Aldehyde (2mmol), and 1 mmol indole were mixed with
0.396 g DAHP (0.3mmol) and placed in a round bottomed
flask. The mixture was stirred at 80ꢁC. After the completion
of the reaction confirmed by TLC (eluent: n-hexane=ethyl
acetate ¼ 3=1), cold H2O was added to the mixture and the pre-
cipitated product was separated by simple filtration. Finally,
In conclusion, we showed that BIMs can be syn-
thesized by a simple and highly efficient electro-

Synthesis of Bis(indolyl)methanes
597
the crude product was recrystallized from ethyl acetate=n-
hexane or ethanol.
[11] Zolfigol MA, Salehi P, Shiri M, Tanbakouchian Z (2007)
Catal Commun 8: 173
[12] Magesh CJ, Nagarajan R, Karthik M, Perumal PT (2004)
Appl Catal A 266: 1
Acknowledgement
[13] Bartoli G, Bosco M, Foglia G, Giuliani A, Marcantoni E,
Sambri L (2004) Synthesis 895
[14] Ji SJ, Wang SY, Zhang Y, Loh TP (2004) Tetrahedron
60: 2051
Financial support by the Research Council of Shahid Beheshti
University is gratefully acknowledged.
[15] Koshima H, Matsuaka W (2002) J Heterocycl Chem
39: 1089
[16] Ramesh C, Ravindranath N, Das B (2003) J Chem
Res (S) 72
[17] Bandgar BP, Bettigeri SV, Joshi NS (2004) Monatsh
Chem 135: 1265
[18] a) Salehi P, Dabiri M, Zolfigol MA, Baghbanzadeh M
(2005) Synlett 1155; b) Dabiri M, Salehi P, Otokesh S,
Baghbanzadeh M, Kozehgary Gh, Mohammadi AA
(2005) Tetrahedron Lett 46: 6123; c) Baghbanzadeh
M, Salehi P, Dabiri M, Kozehgary Gh (2006) Syn-
thesis 344; d) Salehi P, Dabiri M, Zolfigol MA,
Baghbanzadeh M (2005) Tetrahedron Lett 46: 7051;
e) Salehi P, Dabiri M, Zolfigol MA, Otokesh S,
Baghbanzadeh M (2006) Tetrahedron Lett 47: 2557;
f) Dabiri M, Salehi P, Baghbanzadeh M, Bahramnejad
M (2006) Tetrahedron Lett 47: 6983; g) Dabiri M,
Arvin-Nezhad H, Khavasi HR, Bazgir A (2007) Tet-
rahedron 63: 1170
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