Feng Guoliang, Geng Lijun, Zhang Hongli
(School of Science, Hebei University of Science and Technology, Shijiazhuang 050018)

Abstract An efficient synthesis of symmetrical 3,3-di(indolyl)indolin-2-ones is achieved via a reaction of isatin and indoles catalyzed by ZrO₂/S₂O₈^2- solid superacid under solvent-free conditions at room temperature on grinding, which provides an efficient route to the synthesis of symmetrical 3,3-di(indolyl)indolin-2-ones. Their chemical formula was confirmed by means of ¹H NMR, IR Spectra and elementary analysis. The key advantages are the not hazardous organic solvent, high yields, simple workup and the catalyst also inexpensive and reusable.
Keywords 3,3-di(indolyl)indolin-2-ones, ZrO₂/S₂O₈^2- solid superacid, isatin, indoles, grinding

The indole moiety is probably the most well-known heterocycle, a common and important feature of a variety of natural products,^[1] as well as in many compounds that show pharmacological and biological activities.^[2-4] Oxindole derivatives are known to possess a bariety of bilolgical activity.^[5,6] The 3,3-diaryloxindoles have been shown to possess mechanism-specific antiproliferative, antibacterial, antiprotozoal, and antiinflammatory activies.^[7] In view of the biological importance of 3,3-di(indolyl)indolin-2-ones, several methods for their synthesis have been reported. The classical method involves the reaction of isatin and indoles in acid conditions for long reaction times or promoted by KAl(SO₄)₂ under microwave conditions.^[8-10] Some of these methods have not been entirely satisfactory owing to such drawbacks as long reaction times, cumbersome experimental and non-recoverable catalysts. Therefore, the search for a better method for the synthesis of 3,3-di(indolyl)indolin-2-ones is still the need of the day.
In recent times, the progress in the field of solvent-free reactions is gaining significance because of their high efficiency, operational simplicity and environmentally benign processes. Solventless organic reactions based on grinding have been investigated for the intensive subject in recent years. The grinding mode for the solid-state reactions has earlier been reported for Grignard reaction, Reformatsky reaction, Aldol condensation, Dieckmann condensation, Knoevenagel condensation, reduction, etc.^[11-14] Most of these reactions are carried out at room temperature in absolutely solvent-free environment using only a mortar and pestle. Solid superacid have received considerable attention as powerful reaction media for effecting various transformations.^[15,16] In addition solid superacids are attractive because they are stable, reusable, green and cheap. Recently, we have developed efficient and convenient procedures for the preparation of some organic compounds catalysed by ZrO₂/S₂O₈^2- solid superacid.^[17,18] As a part of ongoing work on grinding and solid superacid catalysis, we now describe a facile and solvent-free, simple and practical method for synthesis 3,3-di(indolyl)indolin-2-ones from isatin with indoles catalyzed by ZrO₂/S₂O₈^2- solid superacid under solvent-free conditions at room temperature on grinding, which provide an efficient route to the synthesis of symmetrical 3,3-di(indolyl)indolin-2-ones derivatives (Scheme 1).
The optimized procedure for reaction for indole to isatin was found to be as follows: the mixture of isatin (1 mmol), indole (2.1 mmol) and ZrO₂/S₂O₈^2- (20 mg) was grinded at room temperature. Representative results of this study are summarized in Table 1. As shown in Table 1, isatin in the presence of ZrO₂/S₂O₈^2- were grinded with indoles in free solvent, the corresponding 3,3-di(indolyl)indolin-2-ones were obtained in good to excellent yield. The reaction proceeded cleanly and work-up was simple, involving only filtration of the catalyst to obtain the product.

Scheme 1

Table 1 The reaction of isatin with indoles catalyzed by ZrO₂/S₂O₈^2- under grinding

Entry	Isatins	Indoles	Products	Time(min)	Yieldsa(%)
1			3a	8	89
2			3b	8	90
3			3c	8	87
4			3d	8	85
5			3e	8	89
6			3f	8	86
7			3g	12	76
8			3h	8	90
9			3i	8	85
10			3j	8	87

กก^aYield of pure isolated products.

We were pleased to find that the conversion rate of the indoles bearing electron-withdrawing group (5-nitro-1H-indole) provided lower conversion rate (especially for 7-nitro-1H-indole, no reaction) than the indoles bearing donate group (5-methyl-1H-indole, 6-methyl-1H-indole, 7-methyl-1H-indole and 5-(benzyloxy)-1H-indole), this indicated that electron-donating groups had increased reaction yields. On the other hand electron-withdrawing groups, which deactivated the indole ring, had decreased yields. This reaction also tolerated different substituents such as bromo and methyl group at the ring in isatin.
It is known that the 3-position of the indole is the preferred site for electrophilic attack. In the presence of ZrO₂/S₂O₈^2-, the electrophilic attack uniquely occurred at the 3-position of the indole ring. As anticipated if the 3-position was occupied, the reaction could not proceed. In our experiments, 3-carbaldehyde indole and 3-cyanoindole were used for the reaction, they all remained intact with isatin under given condition even after 30 minutes.
It should be noted that in the absence of catalyst lower yields of product were observed even with prolonged reaction time. For example, entry 2 without catalyst after 20 minutes 32% yield of product was obtained, whereas 90% yield was obtained with catalyst for 8 minutes. The catalyst was easily regenerated by washing with ethanol followed by drying at 100^oC for 4h. The catalyst could be reused five times for the synthesis 3,3-Di(5-methyl-1H-indol-3-yl)indolin-2-one (3b) without significant loss of activity.
In summary, we have developed a practical and efficient method for the synthesis of 3,3-di(indolyl)indolin-2-ones under solvent-free conditions using isatin and indoles in the presene of ZrO₂/S₂O₈^2-. This method is superior from the view of operation simplicity, high yields, non-corrosion, and friendliness to the environment than previously reported methods.
Melting points were determined by an XT-5A micro-melting point apparatus and are uncorrected. ¹H NMR spectra were determined on a Varian VXP-400s spectrometer using CDCl₃ or DMSO as solvent and tetramethylsilane (TMS) as internal reference. IR Spectra was obtained on a Nicolet FT-IR500 spectrophotometer using KBr pellets. Elementary analyses were performed by a Carlo-Erba EA1110 CNNO-S analyzer. The catalyst ZrO₂/S₂O₈^2- solid superacid was prepared as follows. Zr(OH)₄ was infused in an aqueous (NH₄)₂S₂O₈ solution (1 mol/l) for 4 hours, then filtered off, dried at 110^oC for 2 hours, crushed over 150 mesh, dried and calcined in a furnace at 600^oC for 4 hours and finally stored in a desiccaor until used.
A mixture of isatin 1 (1 mmol), indole 2 (2.1 mmol) and ZrO₂/S₂O₈^2- (20 mg) were ground by mortar and pestle at room temperature for 8 min, and was kept for a period. The process of the reaction was determined by TLC. After the completion of the reaction, the mixture was extracted with ethyl acetate (10 mLกม3) and dried over MgSO₄. Evaporation of the solvent under reduced pressure afforded the crude product. After column chromatography on silica gel eluting with PE : EA (5:1), pure compounds 3(a–j) were obtained.
3,3-Di(1H-indol-3-yl)indolin-2-one(3a): m.p.: >300 ^oC; IR (KBr) n : 741, 1100, 1467, 1616, 1690, 3056, 3125, 3399, 3442 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 6.91-7.00 (m, 6H), 7.10-7.23 (m, 3H), 7.34-7.39 (m, 5H), 7.73 (s, 1H, NH), 8.09 (s, 2H, NH); Anal. Calcd. for C₂₄H₁₇N₃O: C, 79.32; H, 4.72; N, 11.56. Found: C, 79.30; H, 4.75; N, 11.64.
3,3-Di(5-methyl-1H-indol-3-yl)indolin-2-one(3b): m.p.: >300 ^oC; IR (KBr) n : 750, 1109, 1235, 1466, 1615, 1712, 2858, 2924, 3389, 3421 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 2.41 (s, 6H, CH₃), 6.78 (d J=7.6 Hz, 2H), 6.92-7.01 (m, 5H), 7.12-7.38 (m, 5H), 7.53 (s, 1H, NH), 7.92 (s, 2H, NH); Calcd. for C₂₆H₂₁N₃O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.59; H, 5.55; N, 10.64.
3,3-Di(6-methyl-1H-indol-3-yl)indolin-2-one(3c): m.p.: 296-298 ^oC; IR (KBr) n : 743, 1100, 1235, 1472, 1620, 1698, 2853, 2910, 3172, 3320, 3429 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 2.31 (s, 6H, CH₃), 6.94-7.0 (m, 7H), 7.14-7.32 (m, 5H) 7.50 (s, 1H, NH), 7.96 (s, 2H, NH); Anal. Calcd. for C₂₆H₂₁N₃O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.62; H, 5.50; N, 10.64.
3,3-Di(7-methyl-1H-indol-3-yl)indolin-2-one(3d): m.p.: 197-198.5.^oC; IR (KBr) n :750, 1100, 1343, 1472, 1617, 1700, 3054, 3413 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 2.45 (s, 6H, CH₃), 6.85-6.98 (m, 8H), 7.18-7.23 (m, 3H), 7.40 (d, J=7.2 Hz, 1H), 7.72 (s, 1H, NH), 8.00 (s, 2H, NH); Anal. Calcd. for C₂₆H₂₁N₃O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.72; H, 5.32; N, 10.84.
3,3-Di(1-methyl-1H-indol-3-yl)indolin-2-one(3e): m.p.: >300 ^oC; IR (KBr) n : 1207, 1245, 1455, 1618, 1693, 2874, 2939, 3057, 3320, 3438 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 3.70 (s, 6H, CH₃), 6.85 (s, 2H), 6.88-7.40 (m, 12H), 7.76 (s, 1H, NH); Anal. Calcd. for C₂₆H₂₁N₃O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.81; H, 5.40; N, 10.79.
3,3-Di(5-(benzyloxy)-1H-indol-3-yl)indolin-2-one(3f): m.p.: 198-199.5 ^oC; IR (KBr) n : 744, 1100, 1382, 1469, 1480, 1699, 2914, 3027, 3385, 3423 cm^-1; ¹H NMR (CDCl₃, 400 MHz,) d: 6.83-7.01 (m, 8H), 7.10-7.50 (m, 18H), 7.92 (s, 1H, NH), 7.98 (s, 2H, NH); Anal. Calcd. for C₃₈H₂₉N₃O₃: C, 79.28; H, 5.08; N, 7.30. Found: C, 79.41; H, 5.18; N, 7.39.
3,3-Di(5-nitro-1H-indol-3-yl)indolin-2-one(3g): m.p.: >300 ^oC; IR (KBr) n : 742, 1092, 1251, 1260, 1468, 1620, 1710, 3343 cm^-1; ¹H NMR (DMSO-d₆, 400 MHz) d: 7.00-7.08 (m, 2H), 7.20-7.31 (m, 4H), 7.58 (d, J=8.0 Hz, 2H), 8.0 (d, J=8.0 Hz, 2H), 8.21 (s, 2H), 10.92 (s, 1H, NH), 11.80 (s, 2H, NH); Anal. Calcd. for C₂₄H₁₅N₅O₅: C, 63.58; H, 3.33; N, 15.45. Found: C, 63.44; H, 3.18; N, 15.37.
4-Bromo-3,3-di(1H-indol-3-yl)indolin-2-one(3h): m.p.: >300 ^oC; IR (KBr) n : 735, 1106, 1614, 1702, 3049, 3330, 3383 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 6.96 (d, J=7.0 Hz, 1H), 7.0-7.06 (m, 4H), 7.10-7.20 (m, 4H), 7.39 (d, J=8.0 Hz, 2H), 7.50 (d, J=9.2 Hz, 2H), 8.0 (s, 1H, NH), 8.10 (s, 2H, NH); Anal. Calcd. for C₂₄H₁₆BrN₃O: C, 65.17; H, 3.65; N, 9.50. Found: C, 65.24; H, 3.55; N, 9.42.
6-Bromo-3,3-di(1H-indol-3-yl)indolin-2-one(3i): m.p.: >300 ^oC; IR (KBr) n : 741, 1117, 1449, 1605, 1709, 3027, 3112, 3398, 3440 cm^-1; ¹H NMR (DMSO-d₆, 400 MHz) d: 6.80 (d, J=7.6 Hz, 2H), 6.82 (d, J=2.4 Hz, 2H), 7.0 (t, J=7.6 Hz, 2H), 7.10-7.15 (m, 3H), 7.19 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 10.72 (s, 1H, NH), 11.00 (s, 2H, NH); Anal. Calcd. for C₂₄H₁₆BrN₃O: C, 65.17; H, 3.65; N, 9.50. Found: C, 65.34; H, 3.52; N, 9.45.
3,3-Di(1H-indol-3-yl)-1-methylindolin-2-one(3j): m.p.: >300 ^oC; IR (KBr) n : 743, 1092, 1350, 1613, 1668, 2925, 3043, 3116, 3352, 3440 cm^-1; ¹H NMR (CDCl₃, 400 MHz) d: 3.34 (s, 3H, CH₃), 6.90-7.05 (m, 6H), 7.10 (t, J=7.2 Hz, 3H), 7.32 (t, J=6.8 Hz, 4H), 7.43 (d, J=7.2 Hz, 1H), 8.02 (s, 2H, NH); Anal. Calcd. for C₂₅H₁₉N₃O: C, 79.55; H, 5.07; N, 11.13. Found: C, 79.42; H, 5.22; N, 11.25.