Table of Contents
ISRN Organic Chemistry
Volume 2013, Article ID 616932, 5 pages
http://dx.doi.org/10.1155/2013/616932
Research Article

An Eco-Friendly Improved Protocol for the Synthesis of Bis(3-indolyl)methanes Using Poly(4-vinylpyridinium)hydrogen Sulfate as Efficient, Heterogeneous, and Recyclable Solid Acid Catalyst

1Department of Chemistry, National Institute of Technology, Warangal, Andhra Pradesh 506 004, India
2Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

Received 2 July 2013; Accepted 1 August 2013

Academic Editors: E. Bertounesque, F. C. Pigge, and Z. Wimmer

Copyright © 2013 Janardhan Banothu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Highly efficient and eco-friendly protocol for the synthesis of bis(3-indolyl)methanes by the electrophilic substitution reaction of indole with aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate was described. Excellent yields, shorter reaction times, simple work-up procedure, avoiding hazardous organic solvents, and reusability of the catalyst are the most obvious advantages of this method.

1. Introduction

Indole derivatives have emerged as important class of nitrogen containing heterocycles and are known to possess broad spectrum of biological and pharmacological activities [1, 2]. In particular, bis(indolyl)methanes (BIMs) which are isolated from terrestrial and marine natural sources such as parasitic bacteria, tunicates, and sponge are found as possible antibacterial, anticarcinogenic, genotoxic, and DNA-damaging agents [3]. BIMs are active cruciferous substances for promoting estrogen metabolism [4] and have the ability to prevent cancer by modulating certain cancer-causing estrogen metabolites [5].

Owing to their diverse biological properties, many methods have been developed for their synthesis using various catalytic systems such as amberlyst-15 [6], iodine [7], boric acid [8], fluoroboric acid [9], sulfamic acid [10], NbCl5 [11], silica sulfuric acid [12], cellulose sulfuric acid [13], zeolite [14], ceric ammonium nitrate [15], polyvinylsulfonic acid [16], dodecylsulfonic acid [17], dodecylbenzenesulfonic acid [18], HClO4-SiO2 [19], ZrOCl2 8H2O [20], Dy(OTf)3 [21], protic solvent [22], and ionic liquids [23]. However, most of these reported methods suffer from one or several drawbacks such as low yields, prolonged reaction times, use of hazardous, expensive, moisture-sensitive, and large quantity of reagents, involving harsh reaction conditions, tedious workup procedure, and difficulty in recovery, and reusability of the catalysts. Therefore, still there is a need to develop an efficient, eco-friendly, and versatile method for the synthesis of bis(indolyl)methanes.

In continuation of our research towards the synthesis of biologically important molecules using novel methodologies [24], we report herein a simple, highly efficient, and eco-friendly method for the synthesis of bis(3-indolyl)methanes using poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4] [25] as heterogeneous and reusable solid acid catalyst.

2. Results and Discussion

The electrophilic substitution reaction of indole with aryl aldehydes catalyzed by P(4-VPH)HSO4 is shown in Scheme 1. The reaction smoothly proceeds at room temperature under grinding technique to provide the corresponding bis(3-indolyl)methane with good yields in shorter reaction times.

616932.sch.001
Scheme 1: P(4-VPH)HSO4 catalyzed synthesis of bis(3-indolyl)methanes.

In order to synthesize bis(3-indolyl)methanes under solvent-free conditions, a model reaction was performed between indole and benzaldehyde using P(4-VPH)HSO4 as catalyst (Scheme 2). Indole (2 mmol) and benzaldehyde (1 mmol) were taken in a mortar and ground at room temperature with pestle by the different amount of catalyst (Table 1). After completion of the reaction shown by TLC (monitored every 2 min), we observed 94% yield in 12 min in the presence of 15 mg of the catalyst. Decreasing the amount of the catalyst results in; low yield of the product (3a) even after prolonged reaction times than the higher amount of catalyst does not show any effect on product yield and reaction time. At the optimized conditions (15 mg of catalyst, grinding at room temperature), the reaction was carried out with substituted aldehydes and the corresponding bis(3-indolyl)methanes were obtained in good yields (Table 2). All the synthesized compounds were well characterized by their analytical and spectral studies and compared with the literature values.

tab1
Table 1: Optimizing the reaction conditionsa.
tab2
Table 2: Synthesis of bis(3-indolyl)methanes catalyzed by P(4-VPH)HSO4 under solvent-free conditions.
616932.sch.002
Scheme 2: Synthesis of bis(3-indolyl)phenylmethane catalyzed by P(4-VPH)HSO4.

We investigated the efficiency of P(4-VPH)HSO4 compared to other acid catalysts based on the synthesis of bis(indol-3-yl)phenylmethane (3a). The results show that P(4-VPH)HSO4 is an efficient catalyst in terms of product yield and reaction time (Table 3). The catalyst was recovered after completion of the reaction; the catalyst was washed with dichloromethane, dried, and reused for subsequent reactions for additional five times. We observed a slight decrease in its activity in terms of product yield (Table 4).

tab3
Table 3: Comparing the efficiency of P(4-VPH)HSO4 with some reported acid catalysts for the synthesis of bis(3-indolyl)phenylmethane (3a).
tab4
Table 4: Reusability of P(4-VPH)HSO4 for the synthesis of bis(3-indolyl)phenylmethanea.

A plausible mechanism for the formation of bis(3-indolyl)methanes catalysed by P(4-VPH)HSO4 is proposed in Scheme 3. In the presence of catalyst, the electrophilicity of carbonyl carbon has increased and it readily reacts with indole, affording the corresponding 3-arylidine-3H-indole [A] via dehydration. Intermediate [A] on reaction with second mole of indole followed by rearrangement affords the final product in good yield.

616932.sch.003
Scheme 3: Plausible mechanism for the formation of bis(3-indolyl)methanes catalyzed by P(4-VPH)HSO4.

3. Experimental

All the reagents and solvents were purchased from Aldrich/Merck and used without further purification. Melting points were determined in open capillaries using Stuart SMP30 apparatus and are uncorrected. The progress of the reactions as well as purity of compounds was monitored by thin layer chromatography with F254 silica-gel precoated sheets using hexane, ethyl acetate (8 : 2) as eluent; UV light and iodine vapors were used for detection. Products were characterized by comparison with authentic samples and by spectroscopy data (IR and 1H NMR). IR spectra were recorded on Perkin-Elmer 100S spectrometer using KBr disk, and values are expressed in cm−1. 1H NMR spectra were recorded with Bruker 400 MHz spectrometer and chemical shifts are expressed in ppm. Elemental analyses were performed on a Carlo Erba modal EA1108 and Mass spectra were recorded on a Jeol JMSD-300 spectrometer.

3.1. General Procedure for the Synthesis of Bis(3-indolyl)methanes (3a–n)

Poly(4-vinylpyridinium)hydrogen sulfate (15 mg) was added to a mixture of indole (2 mmol) and aryl aldehyde (1 mmol) in a mortar and ground with a pestle in appropriate time as shown in Table 2. After completion of the reaction monitored by TLC, 5 mL of water was added and stirred at room temperature for additional 5 min. Thus, the solid obtained was filtered, washed with water, dried, and recrystallized from ethanol to afford the analytically pure product. Aqueous layer containing catalyst was recovered under reduced pressure, washed with dichloromethane, dried, and reused for subsequent reactions.

3.2. Spectral Data for Selected Compounds
3.2.1. Bis(3-indolyl)-4-chlorophenylmethane (3c)

IR (KBr) (cm−1): 3472 (NH), 1598 (C=C), 678 (C–Cl); 1H NMR (400 MHz, DMSO- ): δ 5.87 (s, 1H), 6.62 (s, 2H), 7.02–7.72 (m, 12H), 7.91 (s, 2H); MS (ESI) m/z: 357 (M+H)+; Anal. Calcd. for C23H17ClN2: C, 77.41; H, 4.80; N, 7.85; Found: C, 77.62; H, 4.57; N, 7.93.

3.2.2. Bis(3-indolyl)-3,4-dimethoxyphenylmethane (3i)

IR (KBr) (cm−1): 3478 (NH), 1604 (C=C), 1035 (C–O–C); 1H NMR (400 MHz, DMSO- ): δ 3.76 (s, 3H), 3.85 (s, 3H), 5.85 (s, 1H), 6.43–6.52 (m, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.70 (s, 2H), 6.78 (d, J = 8.0 Hz, 1H), 7.03–7.45 (m, 8H), 7.92 (s, 2H); MS (ESI) m/z: 405 (M + Na)+; Anal. Calcd. for C25H22N2O2: C, 78.51; H, 5.80; N, 7.32; Found: C, 78.70; H, 5.64; N, 7.51.

3.2.3. Bis(3-indolyl)furylmethane (3n)

IR (KBr) (cm−1): 3477 (NH), 1602 (C=C), 1093 (C–O–C); 1H NMR (400 MHz, DMSO- ): δ 5.94 (s, 1H), 6.07 (d,  Hz, 1H), 6.72 (s, 2H), 7.03–7.48 (m, 10H), 7.96 (s, 2H); MS (ESI) m/z: 313 (M + H)+; Anal. Calcd. for C21H16N2O: C, 80.75; H, 5.16; N, 8.97; Found: C, 80.90; H, 5.33; N, 8.79.

4. Conclusion

In conclusion, we have developed a simple and efficient method for the preparation of bis(3-indolyl)methanes utilizing poly(4-vinylpyridinium)hydrogen sulfate as solid acid catalyst under solvent-free conditions at ambient temperature. This protocol offers several advantages in terms of product yield, operational simplicity, and reusability of the catalyst and it obeys the green chemistry conditions by avoiding hazardous organic solvents. We believe that this method is superior to existing methods.

Acknowledgments

The authors would like to thank the Director of the National Institute of Technology, Warangal, for roviding facilities under RSM Project. Janardhan Banothu thanks the Ministry of Human Resource Development; Rajitha Gali and Ravibabu Velpula give thanks to UGC for providing research fellowships.

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