International Scholarly Research Notices

International Scholarly Research Notices / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 616932 | https://doi.org/10.1155/2013/616932

Janardhan Banothu, Rajitha Gali, Ravibabu Velpula, Rajitha Bavantula, Peter A. Crooks, "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", International Scholarly Research Notices, vol. 2013, Article ID 616932, 5 pages, 2013. https://doi.org/10.1155/2013/616932

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

Academic Editor: F. C. Pigge
Received02 Jul 2013
Accepted01 Aug 2013
Published02 Sep 2013

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

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.


EntryaP(4-VPH)HSO4 (mg)Time (min)Yieldb (%)

160Trace
253051
3103076
4151294
5201294

Reaction conditions: indole (2 mmol) and benzaldehyde (1 mmol), grinding at RT.
Isolated yields of the product 3a.

EntryaAldehydeProductTime (min)Yieldb (%)Melting points (°C)
FoundLit. Reference

1Benzaldehyde3a1294150–152150–152 [7]
22-Chlorobenzaldehyde3b149271–7372–74 [7]
34-Chlorobenzaldehyde3c129676–7876-77 [7]
44-Fluorobenzaldehyde3d109078–8080–82 [9]
52-Nitrobenzaldehyde3e1488140–142140-141 [18]
63-Nitrobenzaldehyde3f1489262–264264-265 [20]
74-Methylbenzaldehyde3g109295–9794–96 [7]
84-Methoxybenzaldehyde3h1092186–188187–189 [7]
93,4-Dimethoxybenzaldehyde3i1094195–197197-198 [19]
102-Hydroxybenzaldehyde3j1289342–344340–342 [18]
114-Hydroxybenzaldehyde3k1090124–126124–126 [20]
124-Hydroxy-3-methoxybenzaldehyde3l1091126–128126-127 [22]
134-(Dimethylamino)benzaldehyde3m1490168–171170–172 [20]
14Furan-2-carbaldehyde3n1689321–323322–325 [7]

Reaction conditions: indole (2 mmol), aldehyde (1 mmol), and P(4-VPH)HSO4 (15 mg), grinding at RT.
Isolated yields.
616932.sch.002

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).


EntryaCatalyst (g)Reaction conditionsTime (min)Yield (%) reference

1Boric acid (0.0124 g)Neat, 80°C6094 [8]
2Oxalic acid (0.09 g)H2O, 80°C40 96 [26]
3Sulfamic acid (0.0485 g)MeOH, RT18090 [10]
4PEG-SO3H (0.045 g)H2O, RT2092 [27]
5Dodecyl sulfonic acid (0.025 g)H2O, RT2595 [17]
6Polyvinylsulfonic acid (0.0216 g)EtOH, RT12093 [16]
7Silica sulfuric acid (0.1 g)Neat, RT4092 [12]
8Cellulose sulfuric acid (0.1 g)Grinding, RT893 [13]
9P(4-VPH)HSO4 (0.015 g)Grinding, RT1294 [present work]

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

RunCycleYieldb (%)

1094
2193
3292
4392
5490
6588

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.

616932.sch.003

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.

References

  1. R. J. Sundberg, The Chemistry of Indoles, Academic Press, New York, NY, USA, 1996.
  2. S. V. Laxmi, B. Janardhan, B. Rajitha, P. Raghavaiah, and P. Srinivas, “Synthesis, single crystal X-ray studies and antimicrobial activities of novel Indole barbiturates,” Medicinal Chemistry Research, vol. 21, no. 10, pp. 2896–2901, 2012. View at: Publisher Site | Google Scholar
  3. T. Osawa and M. Namiki, “Structure elucidation of streptindole, a novel genotoxic metabolite isolated from intestinal bacteria,” Tetrahedron Letters, vol. 24, no. 43, pp. 4719–4722, 1983. View at: Google Scholar
  4. M. A. Zeligs, “Diet and estrogen status: the cruciferous connection,” Journal of Medicinal Food, vol. 1, no. 2, pp. 67–82, 1998. View at: Google Scholar
  5. J. J. Michnovicz, H. L. Bradlow, M. J. Huang et al., “Food phytochemicals for cancer prevention 1: fruits and vegetables,” American Chemical Society, pp. 282–293, 1994. View at: Google Scholar
  6. K. Singh, S. Sharma, and A. Sharma, “Unique versatility of Amberlyst 15. An acid and solvent-free paradigm towards synthesis of bis(heterocyclyl)methane derivatives,” Journal of Molecular Catalysis A, vol. 347, no. 1-2, pp. 34–37, 2011. View at: Publisher Site | Google Scholar
  7. S.-J. Ji, S.-Y. Wang, Y. Zhang, and T.-P. Loh, “Facile synthesis of bis(indolyl)methanes using catalytic amount of iodine at room temperature under solvent-free conditions,” Tetrahedron, vol. 60, no. 9, pp. 2051–2055, 2004. View at: Publisher Site | Google Scholar
  8. J. S. Yadav, M. K. Gupta, R. Jain, N. N. Yadav, and B. V. S. Reddy, “A practical synthesis of bis(indolyl)methanes employing boric acid,” Monatshefte fur Chemie, vol. 141, no. 9, pp. 1001–1004, 2010. View at: Publisher Site | Google Scholar
  9. B. P. Bandgar, A. V. Patil, and V. T. Kamble, “Fluoroboric acid adsorbed on silica gel catalyzed synthesis of bisindolyl alkanes under mild and solvent-free conditions,” Arkivoc, vol. 2007, no. 16, pp. 252–259, 2007. View at: Google Scholar
  10. W.-J. Li, X.-F. Lin, J. Wang, G.-L. Li, and Y.-G. Wang, “A mild and efficient synthesis of bis-indolylmethanes catalyzed by sulfamic acid,” Synthetic Communications, vol. 35, no. 21, pp. 2765–2769, 2005. View at: Publisher Site | Google Scholar
  11. M. M. Heravi, F. Nahavandi, S. Sadjadi, H. A. Oskooie, and M. Tajbakhsh, “Convenient synthesis of bis(indol)alkanes by niobium(V) chloride,” Synthetic Communications, vol. 39, no. 18, pp. 3285–3292, 2009. View at: Publisher Site | Google Scholar
  12. D. M. Pore, U. V. Desai, T. S. Thopate, and P. P. Wadgaonkar, “A mild, expedient, solventless synthesis of bis(indolyl)alkanes using silica sulfuric acid as a reusable catalyst,” Arkivoc, vol. 2006, no. 12, pp. 75–80, 2006. View at: Google Scholar
  13. S. A. Sadaphal, S. S. Sonar, M. N. Ware, and M. S. Shingare, “Cellulose sulfuric acid: reusable catalyst for solvent-free synthesis of bis(indolyl)methanes at room temperature,” Green Chemistry Letters and Reviews, vol. 1, no. 4, pp. 191–196, 2008. View at: Publisher Site | Google Scholar
  14. M. Karthik, C. J. Magesh, P. T. Perumal, M. Palanichamy, B. Arabindoo, and V. Murugesan, “Zeolite-catalyzed ecofriendly synthesis of vibrindole A and bis(indolyl)methanes,” Applied Catalysis A, vol. 286, no. 1, pp. 137–141, 2005. View at: Publisher Site | Google Scholar
  15. X.-F. Zeng, S.-J. Ji, and S.-Y. Wang, “Novel method for synthesis of unsymmetrical bis(indolyl)alkanes catalyzed by ceric ammonium nitrate (CAN) under ultrasonic irradiation,” Tetrahedron, vol. 61, no. 43, pp. 10235–10241, 2005. View at: Publisher Site | Google Scholar
  16. S. S. Ekbote, K. M. Deshmukh, Z. S. Qureshi, and B. M. Bhanage, “Polyvinylsulfonic acid as a novel Brønsted acid catalyst for the synthesis of bis(indolyl)methanes,” Green Chemistry Letters and Reviews, vol. 4, no. 2, pp. 177–183, 2011. View at: Publisher Site | Google Scholar
  17. P. Hazarika, S. D. Sharma, and D. Konwar, “Efficient synthesis of bis- and tris-indolylalkanes catalyzed by a Brønsted acid-surfactant catalyst in water,” Synthetic Communications, vol. 38, no. 17, pp. 2870–2880, 2008. View at: Publisher Site | Google Scholar
  18. Y.-Y. Peng, Q.-L. Zhang, J.-J. Yuan, and J.-P. Cheng, “A facile aqueous synthesis of bis(indol-3-yl)alkanes catalyzed by dodecylbenzenesulfonic acid,” Chinese Journal of Chemistry, vol. 26, no. 12, pp. 2228–2232, 2008. View at: Publisher Site | Google Scholar
  19. V. T. Kamble, K. R. Kadam, N. S. Joshi, and D. B. Muley, “HClO4-SiO2 as a novel and recyclable catalyst for the synthesis of bis-indolylmethanes and bis-indolylglycoconjugates,” Catalysis Communications, vol. 8, no. 3, pp. 498–502, 2007. View at: Publisher Site | Google Scholar
  20. S. Mishra and R. Ghosh, “Ecofriendly and sustainable efficient synthesis of bis(indolyl)methanes based on recyclable Broønsted (CSA) or Lewis (ZrOCl2.8H2O) acid catalysts,” Indian Journal of Chemistry B, vol. 50, no. 11, pp. 1630–1636, 2011. View at: Google Scholar
  21. X. Mi, S. Luo, J. He, and J.-P. Cheng, “Dy(OTf)3 in ionic liquid: an efficient catalytic system for reactions of indole with aldehydes/ketones or imines,” Tetrahedron Letters, vol. 45, no. 23, pp. 4567–4570, 2004. View at: Publisher Site | Google Scholar
  22. M. L. Deb and P. J. Bhuyan, “An efficient and clean synthesis of bis(indolyl)methanes in a protic solvent at room temperature,” Tetrahedron Letters, vol. 47, no. 9, pp. 1441–1443, 2006. View at: Publisher Site | Google Scholar
  23. J. S. Yadav, B. V. S. Reddy, and S. Sunitha, “Efficient and eco-friendly process for the synthesis of bis(1H-indol-3-yl)methanes using ionic liquids,” Advanced Synthesis and Catalysis, vol. 345, no. 3, pp. 349–352, 2003. View at: Publisher Site | Google Scholar
  24. B. Janardhan and B. Rajitha, “Brønsted acidic ionic liquid catalyzed highly efficient synthesis of chromeno pyrimidinone derivatives and their antimicrobial activity,” Chinese Chemical Letters, vol. 23, no. 9, pp. 1015–1018, 2012. View at: Google Scholar
  25. N. G. Khaligh and F. Shirini, “Ultrasound assisted the chemoselective 1, 1-diacetate protection and deprotection of aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate salt as a eco-benign, efficient and reusable solid acid catalyst,” Ultrasonics Sonochemistry, vol. 20, no. 1, pp. 19–25, 2013. View at: Google Scholar
  26. N. D. Kokare, J. N. Sangshetti, and D. B. Shinde, “Oxalic acid as a catalyst for efficient synthesis of bis-(indolyl)methanes, and 14-aryl-14H-dibenzo[a,j]xanthenes in water,” Chinese Chemical Letters, vol. 19, no. 10, pp. 1186–1189, 2008. View at: Publisher Site | Google Scholar
  27. A. Hasaninejad, M. Shekouhy, A. Zare, S. M. S. Hoseini Ghattali, and N. Golzar, “PEG-SO3H as a new, highly efficient and homogeneous polymeric catalyst for the synthesis of bis(indolyl)methanes and 4, 4′-(Arylmethylene)- bis(3-methyl-1-phenyl-1hpyrazol-5-ol)s in water,” Journal of the Iranian Chemical Society, vol. 8, no. 2, pp. 411–423, 2011. View at: Google Scholar

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.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views1502
Downloads672
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.