Synthesis of bis(indolyl) methanes catalyzed by Schiff base-Cu(II) complex

Article abstract of DOI:10.1016/j.cclet.2011.04.014

Schiff base-Cu(II) complex is found to be an effective catalyst for the condensation reaction of indole with aldehydes using ethanol as the solvent. The characterization of the catalysts was carried out using XRD and FT-IR.

Full text of DOI:10.1016/j.cclet.2011.04.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1071–1074
www.elsevier.com/locate/cclet
Synthesis of bis(indolyl) methanes catalyzed by Schiff
base–Cu(II) complex
Yong Lei Yang a,b, Ning Ning Wan a,b, Wen Ping Wang a,b,
b,
Zheng Feng Xie a, , Ji De Wang
*
*
a College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, China
b Key Laboratory of Oil & Gas Fine Chemicals of Education of Ministry, Xinjiang University, Urumqi 830046, China
Received 11 January 2011
Abstract
Schiff base–Cu(II) complex is found to be an effective catalyst for the condensation reaction of indole with aldehydes using
ethanol as the solvent. The characterization of the catalysts was carried out using XRD and FT-IR.
# 2011 Zheng Feng Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Schiff base complex; Bis(indolyl) methanes; Indole; Aldehydes
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 (BIM) are the most active
cruciferous substances for promoting beneficial estrogen metabolism and preventing cancer in human [2].
Because of their wide occurrence as natural products and various biological activities, synthesis of these
bis(indolyl) methanes has received an increasing attention. One of the simplest and direct methods used for the
preparation of this class of compounds is via condensation of two molecules of indoles with one molecule of aldehyde
in the presence of Lewis [3] or protic [4] acids. In view of that, several synthetic methods for the preparation of BIMs
have been reported by using catalysts such as InCl3 [5], I2 [6], ionic liquid [7], anthanide triflate [8], aminosulfonic
acid under ultrasound [9], trichloro-1,3,5-triazine [10], ZrOCl2Á8H2O/silica gel [11], ammonium chloride [12],
heteropoly acids [13], Zr(DS4) [14], Sc(OTf)3 [15], Cu(OTf)2 [16], and gold [17].
However, many of these methods suffer from one or more disadvantage like use of expensive reagents [8,14–17],
excess of catalyst [16], complicated manipulations along with the involving of environmentally toxic media [10]. In
order to develop a new method for the synthesis of bis(indolyl) methanes and to overcome all the problems on previous
work, we use Schiff bases complex as catalyst. The role of Schiff bases complex as catalyst on several organic
reactions, such as oxidation [18], reduction [19] and aldol reaction [20] is known from the previous work. Keeping all
these facts in mind, we go for synthesis of BIM using Schiff base–Cu(II) complex as catalyst giving the desired
products in good to excellent yield.
* Corresponding authors.
E-mail addresses: xiezhf@sohu.com (Z.F. Xie), awangjd@xju.edu.cn (J. De Wang).
1001-8417/$ – see front matter # 2011 Zheng Feng Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.04.014

1072
Y.L. Yang et al. / Chinese Chemical Letters 22 (2011) 1071–1074
1. Experimental
Melting points were determined in open capillaries and are uncorrected. The completion of reactions was
monitored by TLC. Purification of reaction products was carried out by column chromatography using Qingdao silica
gel (300–400 mesh). Analytical thin-layer chromatography (TLC) was performed on silica gel GF254 (Qingdao,
China) with ethyl acetate and petroleum ether (60–90 8C) and detected by UV light or iodine vapor. Melting points
were recorded on an elemental digital melting points apparatus and were uncorrected. The 1H and 13C NMR spectra
were recorded on an INOVA 400 MHz FT-NMR spectrometer, The IR spectrum was recorded on a Bruker Equinox 55
FT-IR spectrophotometer. Elemental analyses were performed on a Thermo Flash EA1112 elemental analyzer. X-ray
diffraction data obtained with XRD, D8, Advance, Bruker, axs.
XRD pattern of the Schiff base complex is shown in Fig. 1. The strongest peak of the XRD pattern corresponds to
the planes of amorphous complex matrix, while other peaks reveal a single phase of the supported cooper particles. IR
spectrum of the complex showed a strong absorption bands at 3482 cmÀ1 and 3041 cmÀ1, 2905 cmÀ1 were
disappeared (Fig. 2). These variations could be confirmed the coordination of cooper salt with the Schiff base ligand.
2. Results and discussion
In continuation of our ongoing interest [21], in this paper, we report a simple procedure for the synthesis of BIM via
electrophilic substitution reaction of indoles with aldehydes using ethanol as the solvent.
In order to study the optimization of reaction conditions for the synthesis of bis(indolyl) methanes, initially we have
chosen various Schiff base (L1–L7) (Fig. 3) 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 L2 rather than other catalysts using
ethanol as the solvent.
Following, severalmetalsalts are investigatedinTable 1. All complexesofmetal salt withL2 could effectively catalyze
the model reaction. When the L2 (5 mol%) and CuSO4Á5H2O (5 mol%) as the catalyst, the yield of BIM was obtained in
high yield of 98% (Table 1, entry 7), the products was only achieved in 60% yield when the catalyst was CuSO4Á5H2O.
[(Fig._1)TD$FIG]
L
L+M
0
10
20
30
40
50
60
Fig. 1. XRD patterns of L2 and L2 and L2–Cu complex.
[(Fig._2)TD$FIG]
L
L+M
0
500 1000 1500 2000 2500 3000 3500 4000 4500
Fig. 2. FT-IR spectra of L2 and L2–Cu complex.

[(Fig._3)TD$FIG]
Y.L. Yang et al. / Chinese Chemical Letters 22 (2011) 1071–1074
1073
Fig. 3. Structure of ligands.
To explain the actual role of Schiff base–Cu(II) complex in the synthesis of bis(indolyl) methanes we explore
probable mechanism of the reaction in Scheme 1 [22]. An aldehyde was activated by the catalyst and then carried out
an electrophilic substitution at C-3 of an indole. After ring-opening reaction, the intermediate 3 was served as an
electrophile to attack a second molecule of indole, the target products were formed after loss of water.
The reaction proceeded smoothly and the desired products were obtained in high yield (up to 98%). The obtained
results are encouraging results, we extended the procedure for the synthesis of different substituted BIM (3a–o) using
substituted benzaldehydes and heterocyclic aldehydes. Both electron-withdrawing, electron-donating substituted
groups and heterocyclic imines can obtain BIM in high yield (Table 2, entries 2–5, 8–9, 12, 14, 15). However, nitro is
deactivating group and hydroxyl is easy to form hydrogen bonding, which may be the reason of nitro and hydroxyl
substituted products yield are relative low (Table 2, entries 6, 7, 10, 11).
In summary, we have demonstrated that Schiff base complex can act as an efficient catalyst for the condensation
reaction of aldehydes with indole using ethanol as the solvent through an environmentally acceptable process. The
products were obtained in high yields (up to 98%). the solution diluted with saturated sodium chloride solution and
extracted with ethyl acetate (3Â 5 mL), dried by magnesium sulfate, solvent was removed under reduced pressure to
give a crude product which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1:15)
to furnish the product 3a–3o. All compounds were characterized by spectral analysis. The protocol offers several
Table 1
Comparative study of L2 + metal salt using benzaldehyde as a substrate in ethanol.
Entry
Cat. (5 mol%)
Time (h)
Isolated yield (%)
Entry
Cat. (5 mol%)
Time (h)
Isolated yield (%)
1
2
3
4
L2 + Mn(CH3COO)2Á2H2O
L2 + Co(NO3)2Á6H2O
15
15
15
15
47
43
35
85
5
6
7
8
L2 + Zn(ClO4)2Á2H2O
L2 + Mg(ClO4)2
L2 + CuSO4Á5H2O
CuSO4Á5H2O
15
15
15
15
43
25
98
60
L2 + Zn(CH3COO)2Á2H2O
L2 + Cu(ClO4)2Á6H2O
[(Scheme_1)TD$FIG]
Cat.
Cat.
O
H
O
O
H
cat.
R
H
N
Ar
R
R
NH
3
1
2
indole
HO
Ar
H
N
N
N
N
H2O
H
H
H
H
5
4
Scheme 1. The probably mechanistic role of Schiff base complex in synthesis of bis(indolyl) methanes.

1074
Y.L. Yang et al. / Chinese Chemical Letters 22 (2011) 1071–1074
Table 2
Characterization of bis(indolyl) methanes (3a–o).[TD$INLE]
.
Entry
R
Products
Yield (%)
Mp. (8C) Ref.
Entry
R
Products
Yield (%)
Mp.(8C) Ref.
1
2
3
4
5
6
H
3a
3b
3c
3d
3e
3f
98
93
91
92
95
85
118–120 [1]
92–94
9
10
11
12
13
14
2-OCH3
3i
3j
94
81
82
88
80
93
133–135 [10]
103–104 [12]
106–108 [1]
101–103 [1]
111–113 [6]
121–123
4-F
2-OH
4-Cl
97–99 [1]
3-OCH3, 4-OH
4-CH3
3k
3l
4-Br
106–107 [6]
147–148 [6]
235–237 [1]
2,4-Dichloride
4-NO2
4-N(CH3)2
3m
3n
[DT$INLE]
7
8
2-NO2
3g
3h
82
95
210–212 [8]
185–186 [1]
15
3o
97
78–80
[DT$INLE]
4-OCH3
advantages such as high yield of product, short reaction time, simple work up procedures and environmental friendly.
Further work is in progress to extrapolate the catalytic activity of Schiff base complex to other organic transformation.
Acknowledgment
We appreciate the financial support from the National Natural Science Foundation of China (Nos. 20962018,
20862015, 20762009 and 20562011).
References
[1] (a) T. Osawa, M. Namiki, Tetrahedron Lett. 24 (1983) 4719;
(b) S.A. Sadaphal, A.H. Kategaonkar, V.B. Labade, et al. Chin. Chem. Lett. 21 (2010) 39.
[2] M. Karthik, A.K. Tripathi, N.M. Gupta, et al. Catal. Commun. 5 (2004) 371.
[3] (a) S.M. Ma, S.C. Yu, Org. Lett. 7 (2005) 5063;
(b) W.E. Noland, M.R. Venkiteswaran, C.G. Richards, J. Org. Chem. 26 (1961) 4241.
[4] X.M. He, S.H. Hu, K. Liu, et al. Org. Lett. 8 (2006) 333.
[5] J.S. Yadav, B.V.S. Reddy, G. Satheesh, et al. Tetrahedron Lett. 44 (2003) 2221.
[6] B.P. Bandgar, K.A. Shaikh, Tetrahedron Lett. 44 (2003) 1959.
[7] S.J. Ji, M.F. Zhou, D.G. Gu, et al. Eur. J. Org. Chem. 7 (2004) 1584.
[8] D.P. Chen, L.B. Yu, P.G. Wang, Tetrahedron Lett. 37 (1996) 4467.
[9] J.T. Li, H.G. Dai, W.Z. Xu, et al. Ultrason. Sonochem. 13 (2006) 24.
[10] G.V.M. Sharma, J.J. Reddy, P.S. Lakshmi, et al. Tetrahedron Lett. 45 (2004) 7729.
[11] H. Firouzabadi, N. Iranpoor, M. Jafarpour, et al. J. Mol. Catal. A: Chem. 253 (2006) 249.
[12] J. Azizian, F. teimouri, M.R. Mohammadizadeh, Catal. Commun. 8 (2007) 1117.
[13] N. Azizi, L. Torkian, M.R. Saidi, J. Mol. Catal. A: Chem. 275 (2007) 109.
[14] M.A. Zolfigol, P. Salehi, M. Shiri, et al. Catal. Commun. 8 (2007) 173.
[15] S. Sato, T. Sato, Carbohydr. Res. 340 (2005) 2251.
[16] M.H. Xie, F.D. Xie, G.F. Lin, et al. Tetrahedron Lett. 51 (2010) 1213.
[17] C. Praveen, Y.W. Sagayaraj, P.T. Perumal, Tetrahedron Lett. 50 (2009) 644.
[18] (a) J.Y. Mao, N. Li, H. Li, et al. J. Mol. Catal. A: Chem. 258 (2006) 178;
(b) A. Robert, A. Tsapara, B. Meunier, J. Mol. Catal. A: Chem. 85 (1993) 13;
(c) S. Rayati, S. Zakavi, M. Koliaei, et al. J. Mol. Catal. A: Chem. 13 (2010) 203.
[19] (a) S.M. Islam, B.K. Palit, D.K. Mukherjee, et al. J. Mol. Catal. A: Chem. 124 (1997) 5;
(b) V. Arun, N. Sridevi, P.P. Robinson, et al. J. Mol. Catal. A: Chem. 304 (2009) 191.
[20] N. Yoshikawa, M. Shibasaki, J. Mol. Catal. A: Chem. 58 (2002) 8289.
[21] J.Z. Zhang, Z.H. Xie, R.R. Wang, et al. J. Chem. Chem. Eng. 4 (2010) 27.
[22] (a) B. Ke, Y. Qin, Q.F. He, et al. Tetrahedron Lett. 46 (2005) 1751;
(b) R. Nagarajan, P.T. Perumal, Synth. Commun. 32 (2002) 105.