Synthesis of bis(indolyl) methanes using aluminium oxide (acidic) in dry media

Article abstract of DOI:10.1016/j.cclet.2009.07.010

Heterogeneous catalyst aluminium oxide (acidic) is found to be an effective catalyst for the solvent-free condensation reaction of indole with aldehydes in microwave irradiation with shorter reaction time and higher yields.

Full text of DOI:10.1016/j.cclet.2009.07.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 39–42
www.elsevier.com/locate/cclet
Synthesis of bis(indolyl) methanes using aluminium
oxide (acidic) in dry media
*
Sandip A. Sadaphal, Amol H. Kategaonkar, Vilas B. Labade, Murlidhar S. Shingare
Organic Research Laboratory, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, MS 431001, India
Received 15 May 2009
Abstract
Heterogeneous catalyst aluminium oxide (acidic) is found to be an effective catalyst for the solvent-free condensation reaction of
indole with aldehydes in microwave irradiation with shorter reaction time and higher yields.
#
2009 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aluminium oxide (acidic); Indole; Aldehydes; Bis(indolyl) methanes; Microwave irradiation; Dry media
In recent years, a large trend towards synthesis of bis(indolyl) methanes and their derivatives has attracted much
attention due to their synthetic as well as biological applications [1]. Bis(indolyl) methanes are most active cruciferous
substances for promoting beneficial estrogen metabolism and inducing apoptosis in human cancer cells [2].
Because of their wide occurrence as natural products and various biological activities, synthesis of these
bis(indolyl) methanes has attracted attention. Recently, oxidized bis(indolyl) methanes containing a conjugated
bis(indolyl) skeleton have acted as colorimetric sensors and chromogenic sensors [3]. Solvent-free reactions have been
established an efficient technique for various organic reactions avoiding harmful solvents. The acid-catalyzed
condensations of indole with carbonyl compounds have been of concern as a useful route for preparation of
bis(indolyl) methanes. The protic acids [4] and Lewis acids [4] have been used in excess and drastic conditions. To
abate the environmental pollution of the disposal of excess acids with the improvement of reaction condition a number
of catalytic systems were used, which were rare earth perfluorooctanoate [RE(PFO) ] [5], trichloro-1,3,5-triazine [6],
3
hexamethylenetetramine-bromine [7], ion-exchange resin [8]. Ionic liquids in conjugation with In(OTf)3 or
FeCl ꢀ6H O [9] were also found to promote this reaction. Recently, phosphate zirconia [10], heteropoly acids [11],
3
2
fluoroboric acid [12], amberlyst [13a], silica sulfuric acid [13b], ZrOCl ꢀ2H O/SiO [14], and protic solvents [15]
2
2
2
were also reported to promote the synthesis of bis(indolyl) methanes.
However, many of these methods suffer from the drawback like use of expensive reagents [16–18], excess of
catalyst [19], long reaction time [7,16,19] and low yield of products [23]. In order to develop a new method for the
synthesis of bis(indolyl) methanes and to overcome all the problems on previous work of Posner et al., we use alumina
(
acidic) as a catalyst. The role of aluminium oxide as a heterogeneous catalyst on several organic reactions, such as
*
Corresponding author.
E-mail address: prof_msshingare@rediffmail.com (M.S. Shingare).
1001-8417/$ – see front matter # 2009 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.07.010

40
S.A. Sadaphal et al. / Chinese Chemical Letters 21 (2010) 39–42
oxidation, reduction and displacement reactions is known from the previous work of Posner et al. [20–23]. Keeping all
these facts in mind, we go for synthesis of bis(indolyl) methanes using heterogeneous catalyst aluminium oxide
(
acidic) which gives clean, efficient and fast reactions.
1
. Experimental
Melting points were determined in open capillaries and are uncorrected. The completion of reactions was
1
monitored by TLC. IR spectra were recorded on a matrix of KBr with PerkinElmer 1430 spectrometer. H NMR
spectra were recorded in CDCl using TMS as an internal standard on Varian NMR spectrometer, Model Mercury Plus
3
(
400 MHz), mass spectra [ES-MS] were recorded on a Water-Micro Mass Quattro-II. Microwave oven equipped with
a turntable was used (LG Smart Chef MS-255R operating at 2450 MHz having maximum output of 900 W).
Aluminium oxide (acidic) (0.5 g) was added to a mixture of (2.0 mmol) indole and (1.0 mmol) aldehyde in a beaker
and the reaction mixture irradiated in microwave at 450 W for appropriate time. The completion of the reaction was
monitored by TLC. All compounds were characterized by spectral analysis.
0
3
69 cm ; H NMR (CDCl ): d 5.89 (s, 1H), 6.67 (s, 2H), 7.09–7.58 (m, 13H), 7.94 (bs, 2H, NH); ES-MS m/z 322 (M ).
,3 -Bis(indolyl) phenylmethane 3a: IR (KBr): 3478, 3019, 1601, 1522, 1456, 1419, 1215, 1093, 1017, 757,
+
ꢁ1 1
6
3
2
. Results and discussion
For the aforementioned reasons and in light of our general interest to synthesize bis(indolyl) methanes using various
catalysts [24], in this paper, we report a simple procedure for the synthesis of bis(indolyl) methanes under solvent-free
conditions using acidic aluminium oxide in microwave irradiation.
In order to study the optimization of reaction conditions for the synthesis of bis(indolyl) methanes, initially we have
chosen various aluminium oxides for the condensation reaction of benzaldehyde and indole in the mole ratio of 1:2 as a
standard example and we found that the reaction forward rapidly with acidic aluminium oxide rather than other
catalysts (Table 1).
Then we performed a reaction with aluminium oxide (acidic) as catalyst (0.5 g) and carried out the reaction of
benzaldehyde and indole in the mole ratio of 1:2 as a standard example (Scheme 1) in a domestic microwave oven at
4
50 W.
To explain the actual role of aluminium oxide (acidic) in the synthesis of bis(indolyl) methanes we explore probable
mechanism of the reaction in Scheme 2.
The reaction proceeded smoothly and the desired product (Table 2, entry 3a) was obtained in high yield (97%) and
in a shorter reaction time (5 min). The obtained results are encouraging results, we extended the procedure for the
synthesis of different substituted bis(indolyl) methanes (3a-l) using substituted benzaldehydes and heterocyclic
aldehydes. The results described in Table 2 indicate the scope and generality of the method. The reported method is
Table 1
Comparative study of catalysts using benzaldehyde as a substrate (3a).
Entry
Aluminium oxide
Time (min)
Yield (%)
1
2
3
4
Without
Neutral
Basic
25
20
25
5
45
60
55
97
Acidic
Scheme 1. Aluminium oxide (acidic) catalyzed solvent-free synthesis of bis(indolyl) methanes.

S.A. Sadaphal et al. / Chinese Chemical Letters 21 (2010) 39–42
41
Scheme 2. Mechanistic role of aluminium oxide (acidic) in solvent-free synthesis of bis(indolyl) methanes.
Table 2
Characterization of bis(indolyl) methanes (3a-l).
a
Entry Aromatic
Time (min)
M.P. (8C)
Yield (%)
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
C
6
H
5
5
14
15
17
6
124–126
97–99
97
90
89
88
95
88
96
88
91
85
86
90
4-Me C
6
H
4
4-Meo C
6
H
4
191–193
220–222
104–105
123–125
221–223
111–113
137–139
319–321
278–280
98–99
6 3
3,4-MeO C H
4-Cl C
4-OH C
4-NO
6
H
4
6
H
4
18
5
g
h
i
2
C
6
H
4
3-MeO, 4-OH C
2-Pyridyl
6
H
3
10
11
19
16
17
j
2-Furyl
k
l
2-Thiophyl
2-Piperanyl
a
Melting points compared with physical data in Refs. [16–20].
efficient for various aromatic and heterocyclic aldehydes to obtain the bis(indolyl) methanes with yields greater than
8
5% (Table 2).
Aluminium oxide (acidic) is found to be the choice of catalyst for this reaction. Moreover, the reaction proceeded in
the absence of catalyst to give the product in fewer yields (45%) over a prolonged period of time (25 min) as indicated
in Table 1 (entry 1). In summary, we have demonstrated that aluminium oxide (acidic) can act as an efficient catalyst
for the condensation reaction of aldehydes with indole under solvent-free condition using microwave irradiation
through an environmentally acceptable process. The products were obtained in high yields and isolated very easily by
dissolving the reaction mixture in dichloromethane to affect the separation of the catalyst. The dichloromethane layer
was evaporated under reduced pressure. The crude product was recrystallized by using ethanol. All the prepared
compounds were unequivocally characterized by their spectral analysis. In our next investigation we check the
reusability of catalyst. For reusability experiment we have performed an experiment with same reaction condition
considering benzaldehyde as a standard, the obtained results are illustrated in Table 3.
Table 3
The recycling of aluminium oxide (acidic) for benzaldehyde derivative.
a
Entry
Time (min)
Yield (%)
0
1
2
3
12
14
16
20
92
90
87
85
a
Isolated yields.

42
S.A. Sadaphal et al. / Chinese Chemical Letters 21 (2010) 39–42
Aluminium oxide (acidic) has proved to be an efficient catalyst for the one pot synthesis of different bis(indolyl)
methanes. The performed reaction gives excellent yields in shorter reaction time under solvent-free conditions using
microwave irradiation. The method developed may find extensive use in combinatorial chemistry for the synthesis of
different bis(indolyl) methanes.
3
. Conclusions
Using aluminium oxide (acidic) the reaction goes through solvent-free and indicates the green concepts in organic
synthesis with better yields and shorter reaction time.
Acknowledgment
The authors are thankful to The Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, for providing laboratory facilities.
References
[1] (a) T. Osawa, M. Namiki, Tetrahedron Lett. 24 (1983) 4719;
(
(
b) J.K. Porter, C.W. Bacon, J.D. Robbin, et al. J. Agric. Food Chem. 25 (1977) 88;
c) T.R. Garbe, M. Kobayashi, N. Shimizu, et al. J. Nat. Prod. 63 (2000) 596.
[
[
[
2] X. Ge, S. Yannai, G. Rennert, et al. Biochem. Biophys. Res. Commun. 228 (1996) 153.
3] H. Xiaoming, H. Shuzhen, K. Liu, et al. Org. Lett. 8 (2006) 333.
4] (a) A. Chatterjee, S. Manna, J. Benerji, et al. J. Chem. Soc., Perkin Trans. I (1980) 553;
(
(
(
(
(
b) W.E. Noland, M.R. Venkiteswaran, C.G. Richards, J. Org. Chem. 264 (1961) 241;
c) G. Babu, N. Sridhar, P.T. Perumal, Synth. Commun. 301 (2000) 609;
d) J.S. Yadav, B.V.S. Reddy, C.V.S.R. Mueth, et al. Synthesis (2001) 783;
e) J. Banerji, A. Chatterjee, S. Manna, et al. Heterocycles 15 (1981) 325;
f) A. Chatterjee, R. Chakrabarthi, B. Das, et al. Heterocycles 34 (1992) 259.
[
[
[
[
[
5] L.M. Wang, J.W. Han, H. Tian, et al. Synlett (2005) 337.
6] G.V.M. Sharma, J.J. Reddy, P.S. Lakshmi, et al. Tetrahedron Lett. 45 (2004) 7729.
7] B.P. Bandgar, S.V. Bettigeri, N.S. Joshi, Monatsh. Chem. 135 (2004) 1265.
8] X.L. Feng, C.J. Guan, C.X. Zhao, Synth. Commun. 34 (2004) 487.
9] (a) S.J. Ji, M.F. Zhou, D.G. Gu, et al. Synlett (2003) 2077;
(b) S.J. Ji, M.F. Zhou, D.G. Gu, et al. Eur. J. Org. Chem. (2004) 1584.
[
[
[
[
10] S.V. Nadkarni, M.B. Gawande, R.V. Jayaram, et al. Catal. Commun. 9 (2008) 1728.
11] N. Azizi, L. Torkian, M.R. Saidi, J. Mol. Catal. A: Chem. 275 (2007) 109.
12] V.T. Kamble, A.V. Patil, B.P. Bandgar, Arkivoc 16 (2007) 252.
13] (a) B. Ke, Y. Qin, Y. Wang, et al. Synth. Commun. 35 (2005) 1209;
(b) D.M. Pore, U.V. Desai, T.S. Thopate, et al. Arkivoc 12 (2006) 75.
[
[
[
[
[
14] H. Firouzabadi, N. Iranpoor, M. Jafarpour, et al. Mol. Catal. A: Chem. 253 (2006) 249.
15] M.L. Deb, P.J. Bhuyan, Tetrahedron Lett. 47 (2006) 1441.
16] J.S. Yadav, B.V.S. Reddy, V.S.R. Murthy, et al. Synthesis (2003) 783.
17] B.P. Bandgar, K.A. Shaikh, Tetrahedron Lett. 44 (2003) 1959.
18] (a) X.L. Mi, S.Z. Luo, J.Q. He, et al. Tetrahedron Lett. 45 (2004) 4567;
(
b) D. Chen, L. Yu, P.G. Wang, Tetrahedron Lett. 37 (1996) 4467.
19] (a) A. Kamal, A. Qureshi, Tetrahedron 19 (1963) 513;
b) R.S. Pankajkumar, U.S. Devendrapratap, D.S. Shriniwas, Synth. Commun. 35 (2005) 2133.
[
(
[
[
[
[
20] B.K. Karale, V.P. Chavan, A.S. Mane, et al. Synth. Commun. 32 (4) (2002) 497.
21] R.S. Varma, J. Chem. Soc., Perkin Trans. I (1993) 999.
22] R.S. Varma, Tetrahedron Lett. 38 (1997) 4337.
23] (a) G.H. Posner, D.Z. Rogers, C.M. Kinzing, et al. Tetrahedron Lett. 16 (1975) 3597;
(
(
(
b) G.H. Posner, A.W. Runquist, Tetrahedron Lett. 16 (1975) 3601;
c) G.H. Posner, R.B. Perfetti, A.W. Runquist, Tetrahedron Lett. 17 (1976) 3499;
d) G.H. Posner, M.J. Chapdelaine, Tetrahedron Lett. 18 (1977) 3227.
[24] (a) S.A. Sadaphal, K.F. Shelke, S.S. Sonar, et al. Cent. Eur. J. Chem. 6 (2008) 622;
(b) S.A. Sadaphal, M.N. Ware, S.S. Sonar, et al. Green Chem. Lett. Rev. 1 (4) (2008) 191.