Facile synthesis of 3,3-di(indolyl)indolin-2-one derivatives catalyzed by ZrO2/S2O82- solid superacid under grinding condition Feng Guoliang, Geng Lijun, Zhang Hongli Keywords 3,3-di(indolyl)indolin-2-ones, ZrO2/S2O82- 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.
Table 1 The reaction of isatin with indoles catalyzed by ZrO2/S2O82- under grinding
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. 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/S2O82-. 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/S2O82- 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 110oC for 2 hours, crushed over 150 mesh, dried and calcined in a furnace at 600oC 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/S2O82- (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 mL×3) 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. REFERNECES 固体超强酸ZrO2/S2O82-催化无溶剂研磨条件下对称3,3-二(吲哚基)吲哚-2-酮的合成 |