ISRN Organic Chemistry

Volume 2013 (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

Janardhan Banothu,¹ Rajitha Gali,¹ Ravibabu Velpula,¹ Rajitha Bavantula,¹ and Peter A. Crooks²

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], ZrOCl₂8H₂O [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.

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.

Table 1: Optimizing the reaction conditionsa.

Entrya
P(4-VPH)HSO₄ (mg)
Time (min)
Yieldb (%)

1
—
60
Trace

2
5
30
51

3
10
30
76

4
15
12
94

5
20
12
94

Reaction conditions: indole (2 mmol) and benzaldehyde (1 mmol), grinding at RT.

Isolated yields of the product 3a.

Table 2: Synthesis of bis(3-indolyl)methanes catalyzed by P(4-VPH)HSO₄ under solvent-free conditions.

Entrya
Aldehyde
Product
Time (min)
Yieldb (%)
Melting points (°C)

Found
Lit. Reference

1
Benzaldehyde
3a
12
94
150–152
150–152 [7]

2
2-Chlorobenzaldehyde
3b
14
92
71–73
72–74 [7]

3
4-Chlorobenzaldehyde
3c
12
96
76–78
76-77 [7]

4
4-Fluorobenzaldehyde
3d
10
90
78–80
80–82 [9]

5
2-Nitrobenzaldehyde
3e
14
88
140–142
140-141 [18]

6
3-Nitrobenzaldehyde
3f
14
89
262–264
264-265 [20]

7
4-Methylbenzaldehyde
3g
10
92
95–97
94–96 [7]

8
4-Methoxybenzaldehyde
3h
10
92
186–188
187–189 [7]

9
3,4-Dimethoxybenzaldehyde
3i
10
94
195–197
197-198 [19]

10
2-Hydroxybenzaldehyde
3j
12
89
342–344
340–342 [18]

11
4-Hydroxybenzaldehyde
3k
10
90
124–126
124–126 [20]

12
4-Hydroxy-3-methoxybenzaldehyde
3l
10
91
126–128
126-127 [22]

13
4-(Dimethylamino)benzaldehyde
3m
14
90
168–171
170–172 [20]

14
Furan-2-carbaldehyde
3n
16
89
321–323
322–325 [7]

Reaction conditions: indole (2 mmol), aldehyde (1 mmol), and P(4-VPH)HSO₄ (15 mg), grinding at RT.

Isolated yields.

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).

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

Entrya
Catalyst (g)
Reaction conditions
Time (min)
Yield (%) reference

1
Boric acid (0.0124 g)
Neat, 80°C
60
94 [8]

2
Oxalic acid (0.09 g)
H₂O, 80°C
40
96 [26]

3
Sulfamic acid (0.0485 g)
MeOH, RT
180
90 [10]

4
PEG-SO₃H (0.045 g)
H₂O, RT
20
92 [27]

5
Dodecyl sulfonic acid (0.025 g)
H₂O, RT
25
95 [17]

6
Polyvinylsulfonic acid (0.0216 g)
EtOH, RT
120
93 [16]

7
Silica sulfuric acid (0.1 g)
Neat, RT
40
92 [12]

8
Cellulose sulfuric acid (0.1 g)
Grinding, RT
8
93 [13]

9
P(4-VPH)HSO₄ (0.015 g)
Grinding, RT
12
94 [present work]

Note: For comparison, mole percentages were converted into grams.

Table 4: Reusability of P(4-VPH)HSO₄ for the synthesis of bis(3-indolyl)phenylmethanea.

Run
Cycle
Yieldb (%)

1
0
94

2
1
93

3
2
92

4
3
92

5
4
90

6
5
88

Reaction conditions: indole (2 mmol), benzaldehyde (1 mmol), and P(4-VPH)HSO₄ (15 mg), grinding at RT for 12 min.

Isolated yields.

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.

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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