An efficient and green synthetic protocol for the preparation of bis(indolyl)methanes catalyzed by H6P2W18O 62·24H2O, with emphasis on the catalytic proficiency of Wells-Dawson versus Keggin heteropol

Article abstract of DOI:10.1016/j.molcata.2011.09.029

A simple, atom economy, and a highly well-organized green protocol has been developed for the synthesis of bis(indolyl)methanes. Wells-Dawson diphosphooctadecatungsticacid (H₆P₂W₁₈O ₆₂·24H₂O) was empl

Full text of DOI:10.1016/j.molcata.2011.09.029

Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
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An efficient and green synthetic protocol for the preparation of
bis(indolyl)methanes catalyzed by H6P2W18O62·24H2O, with emphasis on the
catalytic proficiency of Wells-Dawson versus Keggin heteropolyacids
Reza Tayebeea,∗, Farzaneh Nehzata, Esmail Rezaei-Sereshta, Farokhzad Z. Mohammadia, Ezzat Rafieeb
a Department of Chemistry, School of Sciences, Sabzevar Tarbiat Moallem University, Sabzevar 96179-76487, Iran
b Department of Chemistry, School of Science, Razi University, Kermanshah 67149, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, atom economy, and a highly well-organized green protocol has been developed for the
synthesis of bis(indolyl)methanes. Wells-Dawson diphosphooctadecatungsticacid (H6P2W18O62·24H2O)
was employed as a proficient, a highly water tolerant, and green heteropolyacid catalyst for the elec-
trophilic substitution reactions of indole with various aldehydes and ketones to afford the corresponding
bis(indolyl)methane derivatives under solvent-free condition. Presumably, discrepancies observed in the
reactivity patterns of various heteropolyacids would be explained concerning differences in the acidity,
structural diversity, and dissimilarities in the approach of the substrates to the bulk of the heteropoly-
acid catalysts. It is confirmed that the identity of the catalyst was retained almost completely during the
catalytic reaction.
Received 13 August 2011
Received in revised form
27 September 2011
Accepted 28 September 2011
Available online 5 October 2011
Keywords:
Heteropolyacid
Wells-Dawson
Keggin
© 2011 Elsevier B.V. All rights reserved.
Bis(indolyl)methanes
Synthesis
1. Introduction
indole compounds [7]. One of the simplest and direct methods for
the synthesis of three-substituted indoles is through the reaction of
There has been a lot of interest to the development of highly effi-
cient transformations for the preparation of organic compounds, as
well as, biologically active materials, with potential application in
pharmaceutical or agrochemical industries. There is also a need for
synthetic chemists to find new, efficient, and strategically accept-
able protocols, which are environmentally benign and lead to the
greater structural variations with high yields and simple work-up
procedures. For these reasons, enormous advances have been made
to chemical processes to achieve the ultimate goal of waste-free and
energy-efficient synthesis over the last few decades [1].
The reactions of indole have received much interest due to their
vast applications in material sciences, occurrence of a number of
their derivatives in nature and many applications in the field of
pharmaceuticals and agrochemicals [2–4]. Particularly, the sub-
strates including bis(indolyl)methane moieties such as secondary
metabolites [5], and marine sponge alkaloids [6], are of remarkable
significance. The third position of indole is the preferred site for
electrophilic substitution reaction and three-substituted indoles
are versatile intermediates for the synthesis of a wide range of
two equivalents of indole with one equivalent of the carbonyl group
in the presence of either protic [8] or Lewis acids [9] in excess and
under drastic conditions.
To abate the environmental impacts of the pollutions result-
ing from harmful acids used for the condensation of indole with
carbonyl compounds and to improve the efficacy of the protocol,
a number of catalytic systems such as NaHSO4/SiO2 [10], Zeolites
[11], ionic liquids [12], and LiClO4 [13] have been successfully uti-
lized. Also, rare earth catalysts such as La(OTf)3 [14], and InCl3 [15]
have been employed for the promotion of this reaction. Nonethe-
less, it has been reported that many Lewis acids are deactivated
or sometimes decomposed by nitrogen atom of indoles [16] and,
therefore, may be consumed in more than stoichiometric amount.
Moreover, the acids commonly applied are generally toxic catalysts,
difficult to handle, and require tedious work-up, along with the use
of environmentally harmful organic solvents. Therefore, cheaper
Lewis acid catalysts that secure catalytic activity, low toxicity, high
stability towards humidity, and air tolerance have been considered
to prepare bis(indolyl)alkane derivatives under green solvent-free
conditions.
Generally, stronger acidity and greater stability of many Keg-
gin type polyoxoanions in comparison with other structural
types of polyoxometalates guarantees their wide applications as
∗
Corresponding author.
E-mail address: rtayebee@yahoo.com (R. Tayebee).
1381-1169/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2011.09.029

R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
155
Scheme 1.
resin. Characterization of this product with 31P- and 183W NMR,
confirmed that 90–95% of the solid product is in the ␣-form. 31P
NMR: ˛ = −12.7 ppm, ˇ = −11 and −11.6 ppm, 183W NMR: ˛ = −125
and −170 ppm, ˇ = −112, −131, −171 and −191 ppm.
homogeneous and heterogeneous catalysts in many organic trans-
formations [17,18]. However, because of the distinct features of
the Wells-Dawson heteropolyacids, such as greater selectivity and
higher reactivity in some acid catalyzed reactions [19], these com-
pounds had been the target of several research groups during the
past decade [20–23].
2.2. General procedure for the preparation of
Solvent-free condensation of indole with carbonyl com-
pounds is scarce in the literature [24]. Due to our interest to
explore new catalytic activities for structurally different het-
eropolyacids [25–34], an efficient carbon–carbon bond formation
between indole and carbonyl compounds to achieve various
bis-(indolyl)methanes catalyzed by Wells-Dawson diphospho-
octadecatungstic acid H6P2W18O62·24H2O under solvent free
condition is introduced (Scheme 1). To the best of our knowledge,
this announcement is the first systematic study on the application
of Well-Dawson heteropolyacid, H6P2W18O62·24H2O, as a power-
ful catalyst for this transformation.
H6P2W18O62·24H2O is prepared as per standard procedure from
commercially available cheap starting materials. This compound is
stable and tolerant towards humidity and air, having low toxicity
and is not corrosive. Handling of H6P2W18O62·24H2O is easy and
does not need special precautions.
bis-(indolyl)methanes using H6P2W18O62·24H2O
A mixture of carbonyl compound (1 mmol), indole (0.234 g,
2 mmol) and the catalyst (2–7 mol%) was stirred at the elevated
temperature (120 ◦C) for the appropriate reaction time. After com-
pletion of the reaction, as indicated by TLC, chloroform (3 ml) was
added to the reaction mixture and the catalyst was filtered off. Then,
silica gel (∼1 g) was added to the filtrate, and after evaporation of
the solvent, a dark pinkish solid mixture was obtained. Purification
of the product was performed by a short column chromatography
eluted with ethylacetate/petroleum ether (1/9) to give a pinkish
solid product in high yields. Products were known compounds and
were identified by means of IR and 1H NMR spectroscopy and/or
comparison of their melting points with those reported in the lit-
erature.
3. Results and discussion
2. Experimental
In order to optimize the reaction conditions, 2 mol% of
H6P2W18O62·24H2O was employed as catalyst in the condensation
of benzaldehyde (1 mmol) and indole (2.1 mmol) in the absence
of solvent at 120 ◦C. A highly sticky orange mixture including the
desired bis(3-indolyl)phenylmethane was obtained in a maximum
yield of 78% after 15 min. Conducting the same reaction, but with-
out catalyst, led to only a trace amount of the desired product (<5%)
after 4 h. Expanding the reaction time to 24 h did not improve the
yield of the desired product.
Reagents and starting materials were purchased from com-
mercial resources and were used as received. All products were
characterized by comparison of their spectral and physical data
with those previously reported. Silica gel 60 (70–230 mesh) was
performed for column chromatography. Progress of the reactions
were monitored by TLC. Infrared spectra were recorded (KBr pel-
lets) on a 8700 Shimadzu Fourier Transform spectrophotometer.
1H and 13C NMR spectra were recorded on a Bruker AVANCE 300-
MHz instrument using TMS as an internal reference. The catalysts
were prepared and characterized according to literature proce-
dures [35–42].
3.1. Effect of heteropolyacid nature, role of structure and acidity
on the catalytic activity
2.1. Preparation of K6P2W18O62·10H2O and its acidic form
H6P2W18O62·24H2O
To compare the reactivity of H6P2W18O62·24H2O with other
indicative familiar heteropolyoxomatalates for the catalytic prepa-
ration of bis(indolyl)methane, different heteropolyacids and their
salts were inspected in the model reaction (Table 1 and Fig. 1).
Almost, all of the introduced acids were strong and have been
applied as active catalysts both for acidic and oxidative reactions
in different catalytic organic transformations. Heteropolyacid cat-
alysts introduced in Table 1 could be structurally divided into two
important subclasses, Keggin and Wells-Dawson. Both structures
are formed from close-packed frameworks of MO6 octahedra. These
octahedra are joined by common edges and form the M3O13 sub-
units. These subunits joined by common vertices and could form
Td (Keggin) or D3h (Wells-Dawson) symmetry structures. The het-
eropoly atom in Keggin anion occupied a tetrahedral position and
Na2WO4·2H2O (100 g) was added to 350 ml of water and the
solution was heated to boiling. Then, 150 ml of 85% H3PO4 was
added and the resulting yellow-green solution was refluxed for
13 h. The solution was cooled, and the product was precipitated
by addition of 100 g of solid KCl. The light green precipitate was
collected and re-dissolved in a minimum amount of hot water
and allowed to crystallize at 5 ◦C overnight. The typical yield was
70 g after drying at 80 ◦C under vacuum for several hours. The
K6P2W18O62 prepared by this way is always a mixture of ␣ and ␤
isomers. The acid H6P2W18O62·24H2O was prepared from an aque-
ous solution of ␣/␤ K6P2W18O62 salt by passing of it from a cationic

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Table 1
polarized oxygen atoms are weakly basic and weakly attract pro-
tons [43–46].
Synthesis of bis(3-indolyl)phenylmethane in the presence of some Keggin and
Wells-Dawson heteropolyoxometalates.
After
a concise review on the acidic characteristics of
Entry
Catalyst
Time (h)
Yield (%)
heteropolyacids, it is the time to discuss the relevance of het-
eropolyacid strength to the efficiency of the catalytic condensation
of indole with carbonyl group to afford the correspond-
ing three-substituted indole. H6P2W18O62·24H2O, as a strong
acid (pK1 = 4.39), behaved as the most familiar heteropolyacid,
H3PW12O40 (pK1 = 4.7), and was capable of converting indole to
bis(indolyl)methane with 78% yield after 15 min. A little less effi-
ciency of H6P2W18O62·24H2O compared to H3PW12O40 could not
be explained regarding more acidity of H6P2W18O62·24H2O [47].
Furthermore, despite a little difference between the acidity of
H3PW12O40 and H3PMo12O40 (pK1 = 4.68), both with Keggin struc-
ture, the molybdenum analogue was distinctly less efficient than
H3PW12O40 and produced 58% of conversion after long time 2 h.
Another indicator which confirmed the present protocol is
not totally acid catalyzed, is based on the high catalytic activity
of vanadium substituted mixed metal heteropolyacids. Vana-
dium substituted mixed metal heteropolyacids were comparatively
effective and furnished 40–65% of products in 20–45 min. Findings
have shown that the acidity of heteropolyacids diminishes with
replacement of MoVI or WVI atoms by VV [46,48,49]. Although,
H5PW10V2O40 is considerably a weaker acid than H3PW12O40, this
compound behaved as efficient as H3PW12O40 and furnished 80%
of conversion after 15 min. Albeit H5PMo10V2O40 is only slightly
less acidic than H5PW10V2O40 [45], the former was completely
ineffectual and furnished 40% of conversion after 45 min. Surpris-
ingly, substitution of two vanadium atoms in H3PMo12O40 to obtain
less acidic H5PMo10V2O40, did not change the Keggin structure,
whereas, an enhancement (>three times) was observed in the cat-
alytic activity of the later. H5PMo10V2O40 led to 40% conversion
after 45 min; whereas, in the case of H3PMo12O40 the correspond-
ing conversion was reached to 58% after 120 min.
1
2
3
4
5
6
7
8
9
10
11
12
13
H5PW10V2O40·xH2O
H3PW12O40·xH2O
15 min
15 min
15 min
20 min
45 min
45 min
2
4
2
3
3
4
4
80
83
78
58
65
40
58
40b
50
30b
15
7b
H6P2W18O62·24H2O
H7SiW9V3O40·xH2O
H5SiW9Mo2VO40·xH2O
H5PMo10V2O40·xH2O
H3PMo12O40·xH2O
H3PMo12O40·xH2O
2Na2OP2O5·12WO3
2Na2OP2O5·12WO3
K6P2W18O62·10H2O
K6P2W18O62·10H2O
H14NaP5W30O110·xH2O
15
A mixture of carbonyl compound (1 mmol), indole (2 mmol) and catalyst (2 mol%)
was stirred under solvent free condition at 120 ◦C. At the end of the reaction, the cat-
alyst was separated and the crude product was purified by column chromatography
as is explained in Section 2.
b
At room temperature.
is coordinated by ␮3O atoms belonging to four different M3O13
subunits; whereas, in the Wells-Dawson structure, the heteropoly
atom is coordinated only to three Oa atoms. As shown in Fig. 1, there
are four different positions for oxygen in both structures: Oa atom
in the P–O bonds, Ob atoms joining [M3O13] subunits, Oc atoms in
M3O13 subunits and Od terminal atoms in M O double bond [43].
Generally, polyoxometalate anions having charge densities con-
siderably lower than those observed in non-coordinative inorgan−ic
−
anions possess low charge density, such as ClO4 and NO3
.
Accordingly, the extensive application of heteropolyacids in acid
catalysis organic transformations originates from their very high
acidity. The simplest explanation for this abnormally high acid
strength is based on the fact that the negative charge of the anion is
smeared over the numerous (36 in Keggin and 56 in Wells-Dawson
structure) external oxygen atoms and the attraction of protons is
very much weaker than, for example, in the case of sulphuric acid.
It has been demonstrated that, the MO6 octahedra, which bearing
one terminal oxygen Od, are strongly distorted. Hence, the partial
negative charges residing on the outermost terminal oxide ligands,
Substitution of PV with SiIV in the vanadium substituted
H5PW10V2O40, afforded the less acidic H7SiW9V3O40 heteropoly-
acid [44]. Anyhow, H7SiW9V3O40 showed comparatively good
catalytic activity and produced 58% of product after 20 min.
H5SiW9Mo2VO40 as a mixed metal Si-substituted Keggin type het-
eropolyacid, showed good catalytic activity and produced 65% of
bis(indolyl)methane after 45 min. Sodium phosphotungstate diba-
sic hydrate, 2Na2OP2O5·12WO3, potassium salt K6P2W18O62, and
preyssler H14NaP5W30O110 were unproductive in this catalytic sys-
tem and provided only (15–50%) of the desired product after long
time (2–4 h).
M
Od double bond, are generally lower than those on the bridging
oxide anions embedded within the clusters. Therefore, the cation
is shifted towards the exterior of the anion. This shift results in
the formation of a layer of oxygen atoms, strongly polarized (due
to d␲–p␲ interactions) towards the inside of the polyanion. Such
Several studies have shown that the acidity of heteropoly-
acids slightly is affected by their structural composition. Many
heteropolyacids, in particular those possessing the Keggin struc-
ture, are close to the spherical shape. According to the electrostatic
laws of Marcus, this structural geometry affects the acid strength
of heteropolyacids [48,49]. Hence, it is expected that heteropoly-
acids with Keggin structure should be intrinsically stronger acids
than Wells-Dawson and Preyssler types. Higher efficiency of the
Keggin heteropolyacids than Preyssler types in the synthesis of
bis(indolyl)methanes would be explained considering Marcus pos-
tulation.
As mentioned above, H6P2W18O62·24H2O showed higher
activity than the other structurally different heteropolyacids in
this catalytic system (Fig. 2). This behavior could be demonstrated
regarding the approach of substrate absorption into the bulk of the
heteropolyacid. This trend differs from the activity series obtained
for many catalytic systems using heteropolyacid as catalyst under
liquid-phase conditions. It seems that polar reactant molecules
penetrate into the bulk of the heteropolyacid crystallites, then,
after chemical transformation, the products release to the outside
of the solid bulk. So, the diffusion and the reaction in the bulk of
Fig. 1. Keggin (a) and Wells–Dawson (b) structures [43].

R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
157
Fig. 3. Effect of H6P2W18O62·24H2O (mol%) on the preparation of
bis(indolyl)phenylmethane.
Fig. 2. Comparing the catalytic activity of different Keggin and Wells-Dawson het-
eropolyoxometalates in the preparation of bis(indolyl)phenylmethane. H6P2W18O62
bearing 24H2O and other catalysts have xH2O molecules.
3.2. Effect of catalyst mol%
Expectedly, the catalytic system should be influenced by various
reaction parameters, such as the kind and amount of the employed
catalyst, solvent system, and temperature. To establish the opti-
mal reaction conditions, a set of experiments varying the amount
of H6P2W18O62·24H2O, changing quantities of indole with respect
to aromatic aldehyde, and effect of temperature were taken into
account.
At first, different mol% of H6P2W18O62·24H2O were examined
as described in Fig. 3. As mentioned before, the synthetic route
is drastically dependent on the presence of the catalyst and very
low conversion was attained in the absence of H6P2W18O62·24H2O.
The optimum catalyst mol% was found to be 2. More or fewer
amount of catalyst resulted in a pronounced decrease in conversion.
H6P2W18O62·24H2O supplied 53 and 40% of conversion, respec-
tively, after 60 min (for 1 mol%) and 40 min (for 10 mol%).
3.3. Comparing the catalytic activity of heteropolyacids with
other catalysts
Scheme 2. Pseudo-liquid catalysis on the bulk of the heteropolyacid crystallites.
The superiority of the present method over reported method-
ologies can be seen by comparing our results with those reported
previously (Table 2). The reaction of benzaldehyde with indole for
the synthesis of bis(3-indolyl)methane was selected as a model
reaction and the comparison was in terms of mol% of the cata-
lysts, temperature, reaction time, and percentage yields. Although,
other introduced additives catalyzed the reaction, even though at
room temperature, they required longer reaction times and higher
mol% of catalyst. The present methodology utilized a low amount
(2 mol%) of Keggin and/or Wells-Dawson heteropolyacid under sol-
vent free condition and distinctly required shorter reaction time.
the heteropolyacid are faster than the reaction occurring on the
external surface of the catalyst and occurrence of the catalytic
reaction in the pseudo liquid phase would be a crucial step [43].
In this case, solid heteropolyacid behaves in some respects like
liquid. According to the polarity and size of the reactants in the
preparation of the desired products by the mediation of Keggin
and Wells-Dawson heteropolyacids under solvent free condition,
the bulk type I reactions (or pseudo-liquid catalysis) proposed by
Misono would be followed (Scheme 2) [50].
Table 2
Comparison of the catalytic efficiency of H6P2W18O62·24H2O and H5PW10V2O40 with some different catalysts reported for the reaction of indole with benzaldehyde.
Entry
20
Catalyst
Catalyst (mol%)
2
Time (min)
15
Yield (%)
>80
Condition
Ref.
H6P2W18O62·24H2O
H5PW10V2O40·xH2O
ZrOCl2·8H2O
TiO2 (nano)
LiClO4
Solvent free/120 ◦
C
This work
21
22
23
24
25
5
10
10
5
40
84
64
90
90
71
Solvent free/50 ◦
CH2Cl2/r.t
CH3CN/r.t
CH3CN/r.t
CH3CN/r.t
C
[24]
[51]
[52]
[53]
[54]
12 h
5 h
30
La(PFO)3
Ln(OTF)3
5
25

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R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
Table 3
Moreover, simple ketones like cyclohexanone, cyclohepentanone,
and 2-butanone reacted in the same manner albeit with longer
reaction time. The reaction of indole with acetophenone in the
presence of H6P2W18O62·24H2O was not successful and most of
the starting materials remained intact after a prolonged reaction
time.
Effect of different solvents on the synthesis of bis(indolyl)methane in the presence
of H6P2W18O62·24H2O (2 mol%) at 60 ◦C.
Entry
Solvent
Boiling point
Time (h)
Yield (%)
26
27
28
29
30
31
H2O
100
3
1
0.7
1.5
1
19
64
51
56
50
68
CH3CN
CH3OH
C2H5OH
CHCl3
–
81
65
78
61
–
3.7. The excellence of H6P2W18O62·24H2O over some well-known
0.7
metal/non-metal oxides
Reaction condition is described in Table 1 legend.
Table 6 tabulates the excellence of H6P2W18O62·24H2O in com-
parison with other catalysts used in the similar reaction. Evidently,
the required mole ratio for most of the introduced catalysts was
>2% and the reaction times were much longer (1–12 h). Silicon
dioxide family behaved as effective catalysts in the synthesis of
bis(indolyl)methane. 0.1 g, ∼20 mol%, of MCM-41 and MCM-48,
with hexagonal and cubic structures, respectively, disclosed very
good activity and produced 60–70% of conversion under solvent
free conditions after 25 min. While, the same amount of bulk SiO2
(silica gel 60, 70–230 mesh) provided only 35% of product under
the same condition after 35 min. Higher amounts of the bulk sili-
con dioxide (50 mol%) was needed to obtain high conversion (85%)
after 25 min. It is noteworthy that this catalyst was effective in room
temperature and 50 mol% of SiO2 provided 84% of conversion in ace-
tonitrile at room temperature after 40 min. It seems that crystalline
structure, pore size, and surface area of silicon dioxide strongly
affected its catalytic activity. Proficiency of titanium dioxide was
also investigated in comparison with other catalysts introduced in
Table 6. 50 mol% of TiO2 led to 45% of conversion under solvent free
condition after 40 min. Zirconium dioxide, potassium dihydrogen-
phosphate, zinc oxide, and copper oxide showed low activity in this
catalytic system and did not give an appreciable amount of product
even after long times.
Table 4
Effect of temperature on the synthesis of bis(indolyl)methane in the presence of
H6P2W18O62·24H2O (2 mol%) under solvent free condition.
Entry
Time (min)
Yield (%)
Temperature (◦C)
32
33
34
35
60
45
15
10
50
65
78
82
25
50
120
140
Reaction condition is described below Table 1 legend.
3.4. Effect of solvent
Despite the fact that, this methodology is under solvent free con-
ditions even though the effect of different solvents such as water,
ethanol, methanol, and chloroform were studied on the model reac-
tion and the obtained results were compared with solvent free case
(Table 3). This study was carried out at a fixed temperature, 60 ◦C,
in all cases. Obviously, the solvent free approach was found to be
more effective than the solvent system. Almost all reactions in the
introduced solvents were less efficient than the solvent free case,
considering the reaction time and the obtained yield.
3.5. Effect of temperature
3.8. Chemoselectivity of the protocol
The effect of temperature on the synthesis of
bis(indolyl)methane in the presence of H6P2W18O62·24H2O
(2 mol%) under solvent free condition was also studied (Table 4).
Results revealed that yield% was enhanced by increasing reaction
temperature from 25 to 140 ◦C. Even though, the product yield at
140 ◦C was slightly higher than 120 ◦C, considering technical limita-
tions, the lower temperature was selected as the best temperature
for all the reactions. Additionally, it should be mentioned that
besides the type of the catalyst, the catalytic solvent free system is
generally more effective at 120 ◦C than in room temperature. The
reactivity pattern obtained for K6P2W18O62, 2Na2OP2O5·12WO3,
and H3PMo12O40 illustrated that the conversion% was diminished
to ∼half amount in room temperature in comparison with the
elevated temperature.
This methodology is also highly chemoselective for aldehy-
des. For example, when a 1:1 mixture of benzaldehyde and
acetophenone was allowed to react with indole in the presence
of H6P2W18O62·24H2O, it was found that only phenyl-3,3-
bis(indolyl)methane was obtained, while acetophenone was intact
under the reported reaction condition (Scheme 3). This reaction
was clean and the corresponding product was obtained in high yield
without formation of any side reactions such as N-alkylation.
The catalytic system is capable of selective condensation of
1,4-dicarboxaldehydebenzene, as a di-aldehyde, to the correspond-
ing bis-(indolyl)methane via controlling the molar ratio of indole
(Scheme 4). The results showed that (1) would be achieved in
the presence of 2 equivalents of indole; whereas, treatment of 4
equivalents of indole with terephthaldialdehyde led selectively to
appearance of the corresponding di [bis-(indolyl)methane] (2).
3.6. Condensation of different carbonyl compounds with indole
This methodology is effective for a series of structurally diverse
aldehydes bearing electron withdrawing or donating substituents
on phenyl ring and provides substituted bis(indolyl)methanes
in good to excellent yields (Table 5). A series of aromatic and
aliphatic aldehydes, along with some simple ketones, underwent
electrophilic substitution reaction with indole smoothly to afford
a wide range of products. This method is equally effective for alde-
hydes bearing electron withdrawing or donating substituents in
the aromatic rings. Furthermore, acid sensitive aldehydes, such
as salysilaldehyde, worked well without any decomposition or
polymerization under the reported reaction conditions. Aliphatic
aldehydes also achieved their corresponding bis(indolyl)methanes
satisfactorily under these conditions, but needed longer times.
3.9. Reaction pathway
A reasonable pathway for the reaction of indole with carbonyl
compounds in the presence of H6P2W18O62·24H2O is presented
by Scheme 5. The reaction between aldehyde and indole most
probably takes place via the formation of indolyl carbinol which
further converts to azafulvenium salt. The produced azafulvenium
salt, as an electrophile, can undergo further addition with the sec-
ond indole molecule giving the corresponding bis(indolyl)methane
derivative [64,65]. It may be assumed that polar benzaldehyde
molecule could penetrate the bulk of H6P2W18O62·24H2O crystal-
lites and catalytic reaction occurs in the pseudoliquid phase.

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159
Table 5
Synthesis of different bis(indolyl)methanes in the presence of H6P2W18O62·24H2O (2 mol%) under solvent free condition.
Entry
Aldehyde
Product
Time (min)
Yield (%)
M.P.
Ref.
H
C
N
H
H
C
N
O
H
1
15
78
149–150
[55]
H
C
MeO
H
N
H
C
O
N
OMe
H
2
20
87
139–141
[56]
MeO
MeO
H
C
H
N
C
MeO
MeO
H
O
N
H
3
20
91
195 (Dec.)
[57]
H
C
HO
H
C
N
H
O
N
H
OH
4
35
71
122–123
[58]
H
HO
C
H
C
N
H
O
N
OH
H
5
10
91
98 (clear melt.)
[57]
H
C
NO2
H
N
C
H
O
N
NO2
H
6
15
93
139–141
[59]
O2N
H
C
N
H
H
C
O2N
N
O
H
7
15
86
218–220
[57]

160
R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
Table 5 (Continued )
Entry
Aldehyde
Product
Time (min)
Yield (%)
M.P.
Ref.
H
O2N
C
H
C
N
O
H
N
NO2
H
8
15
93
220–222
[60]
H
Br
C
H
C
N
H
O
N
Br
H
9
15
90
189–191
This work
CH3
O
H3C
C
C
N
H
N
H
10
360
10
189–190
[45]
Me
O
CH3
H3C
C
C
N
H
N
H
H3C
11
300
20
195–197
[59]
Cl
H
C
N
H
H
Cl
C
N
O
H
12
35
70
76–77
[61]
Cl
H
C
Cl
Cl
Cl
H
N
C
H
O
N
H
13
20
75
108–109
[59]
H
C
Me
H
N
H
C
O
N
Me
H
14
45
67
95–97
[59]

R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
161
Table 5 (Continued )
Entry
Aldehyde
Product
Time (min)
Yield (%)
M.P.
Ref.
O
N
H
N
H
15
120
60
118–120
[62]
O
N
H
N
H
16
180
50
116–119
This work
Et
Et
C
O
C
N
H
N
E t
E t
H
17
160
40
129–130
This work
H
nPr
C
N
H
O
CH3CH2CH2C
N
H
H
18
60
70
118–119
This work
H3C
H3C-H2C
C
O
C
N
H
CH3
N
H
CH3CH2
19
120
50
198–200
This work
H
CH3
C
O
N
H
CH
3C
N
H
H
20
85
55
92–93
[63]
Reaction condition is described below Table 1 legend. Products were identified by means of IR and 1H NMR spectroscopy and/or comparison of their melting points with
those reported in the literature.
O
H
H
C
C
Ph
O
CH3
C
C
H6P2W18O62.24H2O (2 mol%)
Solvent Free, 120 oC, 15 min.
+
N
2
O
+
H
CH3
N
N
H
H
100%
78%
Scheme 3.

162
R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
2
H
N
H
NH
C
NH
H
O
(1)
C
C
O
H
HN
H
NH
HN
C
C
4
H
N
H
NH
(2)
Scheme 4.
3.10. Characterization and reusability of H6P2W18O62·24H2O
which are assigned to stretching absorption modes of oxygen
atom bonded to tungsten and phosphorous (W· · ·O), (P–O) and
(W–O–W). The band at 1093 cm−1 assigned to the stretching
frequency of the PO4 tetrahedron and, by comparison with the
Keggin structure, the band at 965 cm−1 corresponded to the W· · ·O
FTIR spectroscopy was employed for the confirmation of the sta-
bilization of Wells-Dawson catalyst (Fig. 4). H6P2W18O62·24H2O
exhibited four major bands at 1093, 965, 912 and 776 cm−1
(PW)
H
N
H
R
C
O
H
N
H
(PW)
H
H
H
O
C
R
O
H
O
C
H
C
R
(PW)
N
R
H
H
H
R
C
2O
H
.24
O62
W18
P2
H6
N
H
R
N
H
C
H
OH
H
(PW)
N
H
H
C
H
R
N
H
N
H
(PW)
R
H
R
H
C
C
N
N
H
H2O
N
(PW)H
(PW)
H
N
H
Scheme 5. Proposed reaction pathway for the condensation of indole with aldehyde by the mediation of H6P2W18O62·24H2O.

R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
163
Table 6
Effect of some additives as catalyst on the synthesis of bis(indolyl)methane.
Entry Catalyst
mol% Condition
CH3CN Solvent
Time
(min)
Yield
(%)
RT
free
120 ◦C
56
57
–
–
2
*
*
240
15
<5
78
H6P2W18O62
24H2O
ZrO2
ZrO2
SiO2
SiO2
SiO2
MCM-41
MCM-48
ZnO
ZnO
TiO2
TiO2
KH2PO4
KH2PO4
CuO (nano)
·
58
59
60
61
62
63
64
65
66
67
68
69
70
71
50
50
60
20
60
20
20
50
50
50
50
50
50
4 mg
*
*
240
180
40
35
25
25
25
120
90
90
<5
7
*
84
35
85
70
60
7
20
25
45
<5
30
<5
*
*
*
*
*
*
*
*
*
40
360
180
120
*
*
Reaction condition is described below Table 1 legend.
(terminal bonds). The vibration bands at 912 and 776 cm−1 were
assigned to the ‘inter’ and ‘intra’ W–O–W bridges, respectively [66].
In order to prove the reusability of H6P2W18O62·24H2O, it was
separated from the reaction mixture and washed with chloroform.
The catalyst was dried in vacuum and reused for fresh lot of ben-
zaldehyde (2 mmol) with indole (4 mmol). The catalyst was found
to be reusable for five cycles without significant loss in activity.
Reusability studies showed that the activity of the exhausted cata-
lyst was almost similar to the new one, demonstratingthe efficiency
of the catalyst (Fig. 5).
The FTIR spectrum of the recovered H6P2W18O62·24H2O after
the 5th run confirmed any significant change in the Wells-Dawson
structure of the catalyst (Fig. 4, bottom). Therefore, the identity of
the catalyst was retained almost completely during the catalytic
reaction. Reusability studies showed that the activity of the spent
catalyst was almost the same as the new one, clearly demonstrating
the efficiency of the catalyst.
3.11. Spectral data for selected bis(indolyl)methanes [67,68]
Fig. 4. FTIR spectrum of the new (up) and the recovered (bottom) Wells-Dawson
heteropolyacid H6P2W18O62·24H2O.
Bis(indolyl)phenylmethane. 1H NMR (CDCl3, 300 MHz), ı(ppm):
5.91 (s, 1H, CH), 6.68 (s, 2H), 7.10 (t, J = 7.3 Hz, 2H, arom), 7.22 (t,
J = 7.3 Hz, 2H, arom), 7.23 (t, J = 7.2 Hz, 1H, arom), 7.30–7.40 (m, 2H,
arom), 7.35–7.45 (m, 4H, arom), 7.41 (d, J = 7.9 Hz, 2H, arom), 7.90
(s, br, 2H, NH). 13C NMR, ı(ppm): 40.6, 111.4, 119.7, 120.2, 120.4,
122.4, 124.1, 126.6, 127.5, 128.6, 129.2, 137.1, and 144.4. IR (KBr,
cm−1) ꢀmax: 760, 820, 890, 960, 1080, 1200, 1410, 1640, 2380, 2880,
2900, 3340.
80
70
60
50
40
30
20
10
0
Bis(indolyl)-4-nitrophenylmethane. 1H NMR (CDCl3, 300 MHz),
ı(ppm): 5.92 (s, 1H, CH), 6.63 (s, 2H), 6.91 (t, J = 7.3 Hz, 2H, arom),
7.08 (t, J = 7.3 Hz, 2H, arom), 7.25 (d, J = 7.9 Hz, 2H, arom), 7.32 (d,
J = 8.1 Hz, 2H, arom), 7.44 (d, J = 8.6 Hz, 2H, arom), 8.04 (d, J = 8.6 Hz,
2H, arom), 9.31 (s, br, 2H, NH). 13C NMR, ı(ppm): 40.5, 111.8, 117.8,
119.4, 119.7, 122.1, 123.8, 124.4, 127.0, 129.9, 137.3, 146.7, 152.8;
IR (KBr, cm−1) ꢀmax: 736, 1086, 1343, 1416, 1457, 1506, 1636, 3447.
Bis(indolyl)-4-chlorophenylmethane. 1H NMR (CDCl3, 300 MHz),
ı(ppm): 5.82 (s, 1H), 6.54 (brs, 2H), 7.0 (t, 2H), 7.15 (t, 2H), 7.25–7.35
(m, 8H), 7.81 (brs, 2H, NH); 13C NMR, ı(ppm): 39.4, 111.2, 129.2,
129.4, 129.8, 122.0, 123.2, 126.4, 128.0, 130.0, 131.4, 136.2, 142.5;
IR (KBr, cm−1) ꢀmax: 667, 761, 856, 1012, 1040, 1091, 1124, 1216,
1338, 1416, 1455, 1486, 1518, 1616, 1726, 2853, 2925, 3011, 3056,
3413.
1
2
3
4
5
No of cycles
Fig. 5. Studying reusability of H6P2W18O62·24H2O in the reaction of benzaldehyde
with indole.

164
R. Tayebee et al. / Journal of Molecular Catalysis A: Chemical 351 (2011) 154–164
Bis(indolyl)-2,6-dichlorophenylmethane. 1H NMR (CDCl3,
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H), 7.09 (d, 2 H, J = 7.8 Hz), 7.41 (d, 2 H, J = 7.8 Hz), 7.71 (brs, NH);
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124.7, 127.2, 128.2, 128.6, 136.3, 138.7.
Bis(indolyl)-2-nitrophenylmethane. 1H NMR (CDCl3, 300 MHz),
ı(ppm): 6.12 (s, 1 H), 6.91 (s, 2 H), 7.08–7.17 (m, 4 H), 7.29 (d, 2
H, J = 7.8 Hz), 7.47 (d, 2 H, J = 7.9 Hz), 7.57–7.66 (m, 2H), 7.79–7.90
(m, 2H), 8.21 (d, 2H, J = 8.6 Hz).
Bis(indolyl)-(1-Methyl)methanediyl. 1H NMR (CDCl3, 300 MHz),
ı(ppm): ı 1.91 (d, 3H, J = 6.8 Hz), 4.50 (m, 1H), 6.85 (t, 2H, J = 6.8 Hz),
7.03 (m, 2H), 7.07 (t, 2H, J = 8 Hz), 7.25 (d, 2H, J = 8 Hz), 7.40 (d, 2H,
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Bis(indolyl)-Cyclohexanediyl. 1H NMR (CDCl3, 300 MHz), ı(ppm):
ı 1.61 (m, 6H), 2.54 (m, 4H), 3.25 (m, 1H), 4.60 (s, 1H), 6.89 (t, 2H,
J = 7.2 Hz), 7.07 (m, 4H), 7.29 (d, 2H, J = 8.1 Hz), 7.55 (d, 2H, J = 8.1 Hz),
7.92 (brs, 2H); IR (KBr, cm−1) ꢀmax: 3450, 3030, 2929, 1658, 1550,
1461, 740.
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1H
NMR
(CDCl3,
300 MHz), ı(ppm): ı 3.79 (s, 1H), 5.83 (s, 1H), 6.67 (d, 2H),
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(m, ArH, 12H), 7.80 (br s, NH, 2H); (KBr, cm−1) ꢀmax: 3408, 3056,
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Acknowledgement
The researchers greatly appreciate the Research Council of
Sabzevar Tarbiat Moallem University for their partial financial sup-
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