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Tungstic acid-catalyzed synthesis of 3,3-bis (1H-indol-3-yl)indolin-2-one derivatives

  • Gautam M. Patel and Pradeep T. Deota EMAIL logo
Published/Copyright: November 22, 2013
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 19 Issue 6

Abstract

Tungstic acid was used as a low-cost and readily available heterogeneous catalyst for the synthesis of 3,3-bis(1H-indol-3-yl)indolin-2-one derivatives from indoles. The reaction parameters, including catalyst quantity, solvents, temperature, and time were optimized. The present method has several advantages, such as mild conditions, simple work-up, elimination of anhydrous condition, easy recovery of catalyst and its recyclability as compared with existing methods.

Keywords: indole; isatin; oxindole; tungstic acid

Introduction

Among biologically active heterocyclic compounds [1–3], derivatives of oxindole [3,3-bis(1H-indol-3-yl) indolin-2-one, 3a in Scheme 1) attract much attention as anti-inflammatory [4], anti-HIV [5],andantitumor [6] agents, among other things [7, 8]. Oxindole is also an integral component of many natural products including convolutamydines [9], arundaphine [10], donaxaridine [11], paratunamide [12], and maremycins [13].

Scheme 1
Scheme 1

There are many reactions known for the synthesis of oxindole derivatives by condensation of isatins and indoles in the presence of various catalysts [14–30]. Although these methods work well, many of them involve harsh reaction conditions, long reaction time, or the use of corrosive acids. Most of the Lewis acid catalysts, being moisture sensitive, require usually more than stoichiometric amounts, the use of inert atmosphere, and easily undergo decomposition.

We have been involved in the study of the catalytic activity of tungstic acid in organic reactions. Many tungstic acid-catalyzed organic transformations are known [31–33]. Tungstic acid, a low-cost and readily available heterogeneous catalyst, exhibits high catalytic efficiency. We found that tungstic acid efficiently catalyzes condensation of indoles with isatins to form corresponding oxindole derivatives in high yields. The present method involves relatively mild conditions and easy work-up procedure (Scheme 1).

The reaction of indole 1a with isatin 2a in the presence of tungstic acid to form of 3,3-bis(indol-3-yl)indolin-2-one 3a was taken as model for the optimization study. To evaluate the catalyst quantity, a reaction of 1a and 2a was carried out using various amounts of catalyst (2.5, 5, 7.5, 10, 12.5, and 15 mol%). It was found that 10 mol% of catalyst gave a maximum yield in minimum time. Larger amounts of the catalyst loading neither increased the yield nor shortened the conversion time. For solvent optimization, various solvents such as toluene, chloroform, N,N-dimethylformamide, dichloromethane, methanol, t-butyl alcohol, and ethanol were used. Among the solvents studied, ethanol gave the best yield (92%) at 30°C. The use of methanol was avoided because of its toxicity. There was an increase in the yield of 3a up to 6 h; however, no substantial increase in the yield of 3a was noted when the reaction was continued beyond 6 h. A marginal increase in the yield was also recorded as temperature was increased from 30°C to refluxing in ethanol. The catalyst reusability study showed that tungstic acid can be reused up to three cycles without a substantial decrease in yield. Thus, the yield of 3a was 91% in the first cycle, 83% in the second cycle, and 71% for using the catalyst for the third time.

Conclusion

An efficient and expeditious method is reported for the synthesis of 3,3-bis(indol-3-yl)indolin-2-one derivatives 3a–h using tungstic acid as a heterogeneous catalyst. The method has the advantages of operational simplicity and mild conditions. The catalyst can be easily regenerated and reused up to three cycles without significant loss in the yield.

Experimental

1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were determined in DMSO-d6 on a Bruker-400 FT NMR spectrometer (Bruker India Scientific Pvt. Ltd., India). For regeneration and reusability, the catalyst was heated in dry ethanol at reflux temperature for half an hour, washed with dry ethanol, and dried at room temperature (~30°C).

General procedure

A mixture of indole 1a–d (1.59 g, 13.58 mmol), corresponding isatin 2a–b (1.0 g, 6.79 mmol), and tungstic acid (10 mol%) in ethanol (10 mL) was stirred for 6 h at room temperature. Then, the mixture was filtered through a celite pad to remove the suspended catalyst. Concentration on a rotary evaporator followed by silica gel chromatography eluting with mixtures of light petroleum and ethyl acetate furnished the 3,3-bis(1H-indol-3-yl)indolin-2-one 3a–h.

3,3-Bis(1H-indol-3-yl)indolin-2-one (3a) [34]

White solid, 92% (lit. 92%), mp >300°C; 1H NMR: δ 6.78 (t, 2H, J = 7 Hz), 6.81 (s, 2H), 6.95 (m, 4H), 7.22 (t, 4H, J = 8 Hz), 7.34 (d, 2H, J = 8 Hz), 10.61 (s, 1H), 10.97 (s, 2H).

3,3-Bis(5-bromo-1H-indol-3-yl)indolin-2-one (3b) [35]

White solid, 92% (lit. 70%), mp 264–266°C; 1H NMR: δ 6.92 (s, 2H), 7.00 (m, 2H), 7.16 (m, 3H), 7.27 (t, 1H, J = 7.6 Hz), 7.36 (m, 4H), 10.77 (s, 1H) 11.25 (s, 2H); 13C NMR: δ52.6, 110.3, 111.5, 114.2, 114.3, 122.3, 123.1, 124.1, 125.3, 126.4, 127.7, 128.7, 134.0, 136.1, 141.6, 178.9.

3,3-Bis(5-methoxy-1H-indol-3-yl) indolin-2-one (3c) [36]

White solid, 92% (lit. 95%), mp 240–244°C; 1H NMR: δ 3.52 (s, 6H, OCH3), 6.69 (m, 4H), 6.85 (s, 2H), 6.97 (m, 2H), 7.23 (m, 4H), 10.62 (s, 1H), 10.82 (s, 2H); 13C NMR: δ 52.9, 55.5, 103.8, 109.9, 110.9, 112.5, 114.0, 122.0, 125.4, 125.6, 126.5, 128.3, 132.6, 135.0, 141.8, 152.8, 179.2.

3,3-Bis(1-methyl-1H-indol-3-yl)indolin-2-one (3d) [37]

White solid, 89% (lit. 83%), mp >300°C; 1H NMR: δ 3.70 (s, 6H, CH3), 6.83 (m, 2H), 6.88 (s, 2H), 6.95 (m, 2H), 7.08 (m, 2H), 7.22 (m, 4H), 7.37 (d, 2H, J = 8.4 Hz), 10.63 (s, 1H); 13C NMR: δ 32.8, 52.8, 110.1, 110.2, 113.8, 118.9, 121.3, 121.5, 122.1, 125.3, 126.4, 128.4, 128.9, 134.9, 137.7, 141.6, 179.0.

3,3-Bis(5-bromo-1H-indol-3-yl)-1-methylindolin-2-one (3e)

White solid, 91%, mp 280–284°C; 1H NMR: δ 3.25 (s, 3H, CH3), 6.91 (s, 2H), 7.07 (m, 3H), 7.14 (m, 2H), 7.26 (m, 2H), 7.38 (m, 3H), 11.25 (s, 2H). 13C NMR: δ 26.8 (CH3), 52.2, 109.5, 111.5, 114.0, 114.3, 123.0, 124.1, 125.0, 126.4, 127.6, 129.0, 133.1, 136.1, 143.0, 177.2. Anal. Calcd for C25H17Br2N3O: C, 56.10; H, 3.20; N, 7.85. Found: C, 56.12; H, 3.24; N, 7.82.

3,3-Bis(5-methoxy-1H-indol-3-yl)-1-methylindolin-2-one (3f)

White solid, 88%, mp 236–240°C; 1H NMR: δ 3.27 (s, 3H, CH3), 3.51 (s, 6H, OCH3), 6.58 (s, 2H), 6.76 (m, 2H), 6.84 (d, 2H, J = 2.4 Hz), 7.03 (m, 2H), 7.27 (m, 4H), 10.84 (s, 2H); 13C NMR: δ 26.6, 52.5, 55.5, 103.3, 109.0, 111.0, 112.6, 113.8, 122.7, 125.1, 125.6, 126.4, 128.5, 132.6, 134.0, 143.3, 152.9, 177.4. Anal. Calcd for C27H23N3O3: C, 74.12; H, 5.30; N, 9.60. Found: C, 74.08; H, 5.32; N, 9.58.

3,3-Bis(1H-indol-3-yl)-1-methylindolin-2-one (3g) [37]

White solid, 90% (lit. 85%), mp >300°C; 1H NMR: δ 3.26 (s, 3H, CH3), 6.78 (m, 2H), 6.80 (s, 2H), 6.99 (m, 3H), 7.09 (m, 3H), 7.36 (m, 4H), 10.99 (s, 2H); 13C NMR: δ 26.7, 52.6, 109.2, 112.1, 114.5, 118.8, 121.1, 121.4, 122.8, 124.8, 126.0, 128.6, 134.2, 137.3, 143.3, 177.4.

1-Methyl-3,3-bis(1-methyl-1H-indol-3-yl)indolin-2-one (3h) [37]

White solid, 88% (lit. 80%), mp 230–232°C; 1H NMR: δ 3.25 (s, 3H, CH3), 3.70 (s, 6H, CH3), 6.81 (m, 2H), 6.87 (s, 2H), 7.00 (m, 1H), 7.04 (m, 2H), 7.08 (m, 3H), 7.17 (m, 1H), 7.30 (m, 3H); 13C NMR: δ 26.7,32.8, 52.4, 109.2, 110.3, 113.6, 119.0, 121.3, 121.6, 122.8, 125.0, 126.4, 128.5, 128.9, 134.0, 137.8, 143.1, 177.2.

Corresponding author: Pradeep T. Deota, Faculty of Technology and Engineering, Applied Chemistry Department, The Maharaja Sayajirao University of Baroda, Vadodara 390 001, India, e-mail:

G.M. Patel thanks UGC, New Delhi, India, for the award of a research fellowship under the RFSMS Scheme.

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Received: 2013-9-10
Accepted: 2013-10-23
Published Online: 2013-11-22
Published in Print: 2013-12-01

©2013 by Walter de Gruyter Berlin Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2013-0142
Keywords for this article
indole; isatin; oxindole; tungstic acid
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Reviews
  4. Polyoxin and nikkomycin analogs: recent design and synthesis of novel peptidyl nucleosides
  5. Synthesis of fused heterocycles derived from 2H-1,4-benzoxazin-3(4H)-ones
  6. Research Articles
  7. Green synthesis of 1-monosubstituted 1,2,3-triazoles via ‘click chemistry’ in water
  8. Synthesis of a novel fused tricyclic heterocycle, pyrimido[5,4-e][1,4]thiazepine, and its derivatives
  9. Synthesis of 2-[(quinolin-8-yloxy)methyl]quinoline-3-carboxylic acid derivatives
  10. Pyrimidine-5-carbonitriles – part III: synthesis and antimicrobial activity of novel 6-(2-substituted propyl)-2,4-disubstituted pyrimidine-5-carbonitriles
  11. Tungstic acid-catalyzed synthesis of 3,3-bis (1H-indol-3-yl)indolin-2-one derivatives
  12. One-pot synthesis of dihydropyrano[c]chromene derivatives by using BF3•SiO2 as catalyst
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