Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 21 Aqueous Phase Supramolecular Synthesis of 3-spirocyclic oxindoles Catalyzed by -cyclodextrin Subhendu Naskar and Suprakash Roy2* Department of Chemistry, Bandwan Polytechnic (under DTET-WB), Purulia, West Bengal, INDIA. Department of Chemistry, Raja Ranjit Kishore Government Polytechnic College (under DTET-WB), West Midnapore, West Bengal, INDIAAvailable online at: www.isca.in, www.isca.me Received 24th October 2014, revised 23rd November 2014, accepted 14th December 2014 AbstractA high yielding green protocol is described for the synthesis of 3-spirocyclic oxindoles by [3+2] cycloaddition reaction of azomethine ylides to the 12 double bond of andrographolide (a natural product isolated from Andrographis paniculata Nees) in water catalyzed by -cyclodextrin. Keywords: -Spirocyclic oxindole; -cyclodextrin; andrographolide; [3+2] cycloaddition reaction; azomethine ylide; reactions in water. Introduction In recent years considerable interest has been noticed among the synthetic organic chemists to perform organic reactions in water because it is cheap, non-toxic, non-inflammable and safe. Moreover, the unique physical and chemical properties of water often increase the reactivity as well as selectivity which is unattainable in common organic solvents and the product may be easily isolated by simple filtration or recrystallization. But most of the organic compounds are hydrophobic in nature and their limited solubility in water is the prime obstacle in performing reactions in aqueous media. The strategy that has contributed to some extent to overcome this obstacle is the introduction of supramolecular catalysts, as for example cyclodextrin. -Cyclodextrin(-CD) are torus-shaped cyclic oligosaccharides and they have considerable hydrophobic cavities, which bind substrates selectively and catalyze chemical reactions by a supramolecular interaction2,3Due to these unique structural properties -CDs have been widely used in food and cosmetics industries, as well as pharmaceutical chemistry5,6. As a part of our concerted research for establishing novel methodologies for the synthesis of bioactive heterocycles in water6-8. We were intrigued by the unique characteristics of -CDs and contemplated to utilize -CD as catalyst for the synthesis of 3-spirocyclic oxindoles which have a wide range of biological activities9,10. 3-spirocyclic oxindole ring systems are found in a number of bioactive alkaloid like horsifiline, spirotryprostatin A and B, elacomine and so on. The varied biological activities of 3-spirocyclic oxindole derivatives have attracted the attention of organic chemists and a number of synthetic methodologies have been developed for the preparation of them11-13. Recently N.B. Mondal et. al. reported a method for the synthesis of 3spirocyclic oxindoles by [3+2] cycloaddition reaction of azomethine ylide to the conjugated double bond of andrographolide14. However, their methodology had some shortcomings, like poor yields of the products (50-60%), long reaction time (22 h) and use of environmentally hazardous different organic solvents and lenghthy usual work up to get pure final product. To overcome these problems we have now successfully develop a truly green protocol for the synthesis of 3-spirocyclic oxindoles with excellent yields in short reaction time using -cyclodextrin -CD) as catalyst in aqueous media, without the use of any organic solvent and clean cut pure compounds. Material and Methods Experimental: Melting points were determined with a capillary melting point apparatus. IR spectra were recorded on a JASCO FTIR (model 410) in KBr pellets. ESI-MS (positive) was conducted using LC-ESI-Q-TOF micro Mass spectrometer. H and 13C NMR spectra were taken on a Bruker 600 MHz DPX spectrometer at 600 and 150 MHz respectively, with tetramethylsilane (TMS) as internal standard and the chemical shifts are reported in units. Andrographolide was isolated from the leaves of Andrographis paniculata Nees by the method described in the literature. Isatin derivatives, proline and sarcosine were purchased from Aldrich Chemical Ltd (USA). General procedure for the synthesis of 3-spirocyclic oxindoles: -cyclodextrin (1 mmole) was dissolved in water (20 ml) by warming to 60 ºC until a clear solution was formed. Then, isatin derivative (1mmole) was added portion wise with constant stirring followed by L-proline/sarcosine (1 mmole) and andrographolide (1 mmole); the mixture was stirred at 80 ºC until the reaction was complete (monitored by TLC). After completion of the reaction (monitored by TLC), the contents of the reaction mixture were poured into a separating funnel and extracted with ethyl acetate (3x25 ml). The organic layer was washed thoroughly with hot water until free from cyclodextrin, dried over sodium sulfate, and evaporated to Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 22 dryness in a rotary evaporator under reduced pressure. The residue was chromatographed over a column of silica gel (100-200 mesh) eluting with a mixture of hexane and ethyl acetate in different ratios, to yield the 3-spirocyclic oxindoles. Spectral characterization of the compounds: Compound3a: Colourless needles, m.p. 182-184ºC (lit.14 180-182ºC); IR (KBr, max) 3353, 2938, 2873, 1766, 1698, 1620, 1472 cm-1; H NMR (CDOD) 7.36 (1H, dd, =1.2, 7.8Hz), 7.17 (2H, m), 6.98 (1H, d, =7.8 Hz), 4.81 (1H, t, =8.4 Hz), 4.61 (1H, t, =8.4 Hz), 4.52 (1H, s), 4.15 (1H, m) 3.99 (1H, d, =10.8 Hz), 3.94 (1H, t, =9 Hz), 3.61 (1H, s), 3.35 (2H, dd, =3.0, 11.4 Hz), 3.25 (1H, d, =10.8 Hz), 2.86 (1H, m), 2.69 (1H, m), 2.22 (1H, m), 1.92 (1H, m), 1.71(9H, m), 1.26 (1H, m), 1.19 (1H, m), 1.16 (1H, m), 1.14 (3H, s), 1.00 (2H, m), 0.45 (3H, s); 13C NMR (CDOD) 15.1 (CH), 20.8 (CH), 23.5 (CH), 25.7 (CH), 26.4 (CH), 29.1 (CH), 29.7 (CH), 38.3 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.6 (CH), 50.2 (CH), 54.0 (CH), 56.8 (CH), 57.6 (C), 65.0 (CH), 66.3 (CH), 68.4 (CH), 70.4 (CH), 77.8 (C), 80.9 (CH), 107.3 (CH), 112.1 (CH), 124.0 (CH), 127.8 (CH), 129.0 (C), 131.4 (CH), 143.8 (C), 148.2 (C), 179.7 (C), 183.9 (C); MS (ESI-MS, positive ion) m/z 551 [M+H], 573 [M+Na]; HRMS m/z 573.2940 [M+Na] [calcd. 573 .2941]. Compound3b: Colourless prisms, m.p. 180-182ºC (lit.14 182-184ºC); IR (KBr, max) 3352, 2941, 1775, 1698, 1617, 1474 cm; H NMR (CDOD) 7.53 (1H, dd, =1.8Hz, 7.8Hz), 7.29 (1H, d, =1.8Hz), 6.92 (1H, d, =7.8Hz), 4.80 (1H, m), 4.60 (2H, m), 4.17 (1H, m), 3.99 (1H, d, =10.8Hz), 3.93 (1H, t, =9Hz), 3.64 (1H, s), 3.35 (1H, m), 3.28 (2H, m), 2.82 (1H, m), 2.71 (1H, m), 2.25 (1H, m), 1.92 (1H, m), 1.69 (9H, m), 1.26 (1H, d, =11.4Hz), 1.17 (5H, m), 1.15 (3H, s), 1.14 (1H, m), 1.01 (2H, m), 0.46 (3H, s); 13C NMR (CDOD) 15.1 (CH), 20.9 (CH), 23.5 (CH), 25.7 (CH), 26.5 (CH), 29.1 (CH), 29.6 (CH), 38.3 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.7 (CH), 50.1 (CH), 54.0 (CH), 56.9 (CH), 57.8 (C), 65.0 (CH), 66.2 (CH), 68.4 (CH), 70.5 (CH), 77.7 (C), 80.9 (CH), 106.9 (CH), 113.8 (CH), 116.4 (C), 130.7 (CH), 131.5 (C), 134.3 (CH), 143.1 (C), 148.5 (C), 179.6 (C), 183.3 (C); MS (ESI-MS, positive ion) m/z 629 [M+H], 631 [(M+2)+H], 651 [M+Na], 653 [(M+2)+Na]; HRMS m/z 651.2007 [M+Na] [calcd. 651.2046]. Compound 3c: Colourless needles, m.p. 208-210ºC (lit.14 208-210ºC); IR (KBr, max) 3321, 2950, 2885, 1771, 1700, 1610, 1469 cm-1; H NMR (CDOD) 7.47 (1H, m), 7.25 (2H, m), 7.10 (1H, d, =7.8 Hz), 4.82 (1H, dd, =8.4, 9Hz), 4.61 (1H, t, =7.8 Hz), 4.53 (1H, s), 4.17 (1H, dd, =6.6, 9Hz), 3.97 (1H, d, =11.4 Hz), 3.94 (1H, t, =9 Hz), 3.69 (1H, s), 3.37 (1H, dd, =4.2, 10.2 Hz), 3.32 (1H, m), 3.24 (1H, d, =11.4 Hz), 3.19 (3H, s), 2.83 (1H, m), 2.66 (1H, m), 2.19 (1H, m), 1.93 (1H, m), 1.71 (7H, m), 1.57 (2H, m), 1.20 (1H, m), 1.15 (1H, m), 1.13 (1H, m), 1.12 (3H, s), 0.99 (1H, m), 0.93 (1H, dd, =2.4, 12.6 Hz), 0.43 (3H, s); 13C NMR (CDOD) 15.0 (CH), 21.1 (CH), 23.5 (CH), 25.6 (CH), 26.3 (CH), 26.8 (CH), 29.0 (CH), 29.6 (CH), 38.1 (CH), 39.3 (CH), 40.8 (C), 43.7 (C), 49.8 (CH), 50.2 (CH), 53.9 (CH), 56.9 (CH), 58.0 (C), 65.0 (CH), 66.1 (CH), 68.5 (CH), 70.5 (CH), 77.2 (C), 80.9 (CH), 107.1 (CH), 110.9 (CH), 124.5 (CH), 127.4 (CH), 128.7 (C), 131.5 (CH), 145.6 (C), 148.5 (C), 179.6 (C), 181.6 (C); MS (ESI-MS, positive ion) m/z 565 [M+H], 587 [M+Na]; HRMS m/z 565.3285 [M+H] [calcd 565.3278], 587.3078 [M+Na] [calcd. 587.3097]. Compound3d: Colourless needles, m.p. 180-182ºC (lit.14 181-183ºC); IR (KBr, max) 3376, 2937, 1769, 1694, 1624, 1491 cm; H NMR (CDOD) 7.18 (1H, dd, =0.6, 8.4 Hz), 6.99 (1H, s), 6.87 (1H, d, =7.8 Hz), 4.80 (1H, dd, =8.4, 9.0 Hz), 4.60 (1H, t, =7.8 Hz), 4.53 (1H, s), 4.17 (1H, m), 3.99 (1H, d, =11.4 Hz), 3.93 (1H, t, =9.0 Hz), 3.61 (1H, s), 3.32 (2H, m), 3.25 (1H, d, =11.4Hz), 2.88 (1H, m), 2.69 (1H, m), 2.37 (3H, s), 2.23 (1H, m), 1.92 (1H, m), 1.71 (10H, m), 1.26 (1H, m), 1.14 (4H, m), 1.00 (2H, m), 0.45 (3H, s); 13C NMR (CDOD) 15.1 (CH), 20.8 (CH), 21.4 (CH), 23.5 (CH), 25.7 (CH), 26.4 (CH), 29.1 (CH), 29.7 (CH), 38.3 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.7 (CH), 50.2 (CH), 54.0 (CH), 56.9 (CH), 57.8 (C), 65.0 (CH), 66.2 (CH), 68.4 (CH), 70.4 (CH), 77.9 (C), 80.9 (CH), 107.1 (CH), 111.9 (CH), 128.4 (CH), 129.1 (C), 131.6 (CH), 133.8 (C), 141.3 (C), 148.3 (C), 179.8 (C), 183.8 (C); MS (ESI-MS, positive ion) m/z 565 [M+H], 587 [M+Na]; HRMS m/z 565.3283 [M+H] [calcd 565.3278], 587.3094 [M+Na] [calcd. 587.3097]. Compound3e: Colourless needles, m.p. 181-183ºC (lit.14 180-182ºC); IR (KBr, max) 3347, 2938, 1767, 1695, 1490 cm-1; H NMR (DMSO-) 10.69 (1H, s, -NH), 6.93 (1H, dd, =2.4, 9.0 Hz), 6.87 (1H, d, =8.4 Hz), 6.68 (1H, s), 6.60 (1H, d, =2.4 Hz), 5.04 (1H, d, =4.8 Hz), 4.62 (2H, m), 4.48 (1H, s), 4.06 (1H, m), 3.99 (1H, m), 3.84 (1H, t, =8.4 Hz), 3.75 (3H, s), 3.72 (1H, d, =9.6 Hz), 3.51 (1H, s), 3.15 (3H, m), 2.69 (1H, m), 2.56 (1H, m), 2.15 (1H, m), 1.83 (1H, m), 1.58 (8H, m), 1.46 (1H, m), 1.17 (2H, m), 1.10 (1H, m), 1.00 (3H, s), 0.90 (1H, dd, J=1.8, 12.6 Hz), 0.83 (1H, m), 0.36 (3H, s); 13C NMR (DMSO-) 14.1 (CH), 18.9 (CH), 23.0 (CH), 24.3 (CH), 25.1 (CH), 27.8 (CH), 28.1 (CH), 36.4 (CH), 37.8 (CH), 42.2 (C), 47.5 (CH), 48.3 (CH), 51.7 (CH), 54.8 (CH), 55.4 (C), 55.8 (CH, C) 62.6 (CH), 64.5 (CH), 66.4 (CH), 68.6 (CH2), 76.1 (C), 78.2 (CH), 105.4 (CH), 111.3 (CH), 112.4 (CH), 114.9 (CH), 128.8 (C), 135.4 (C), 147.0 (C), 155.3 (C), 177.1 (C), 181.5 (C); MS (ESI-MS, positive ion) m/z 581 [M+H], 603 [M+Na]; HRMS m/z 603.2988 [M+Na] [calcd. 603.3046]. Compound3f: Colourless needles, m.p. 180-182ºC (lit.14 179-181ºC); IR (KBr, max) 3374, 2938, 1767, 1700, 1630, 1486 cm; H NMR (CDOD) 7.13 (1H, dt, =2.4, 9.0 Hz), 6.97 (2H, m), 4.81 (1H, dd, =7.8, 9.0 Hz), 4.61 (1H, t, =7.8 Hz), 4.58 (1H, s), 4.15 (1H, dd, =5.4, 9.6 Hz), 3.99 (1H, d, =11.4Hz), 3.94 (1H, t, =9Hz), 3.63 (1H, s), 3.35 (1H, dd, =3.6, 11.4 Hz), 3.27 (2H, m), 2.83 (1H, m), 2.72 (1H, m), 2.24 (1H, m), 1.93 (1H, m), 1.76 (3H, m), 1.71 (3H, m), 1.63 (1H, m), 1.27 (1H, d, =11.4 Hz), 1.19 (5H, m), 1.01 (2H, m), 0.46 (3H, s); 13C NMR (CDOD) 15.1 (CH), 20.8 (CH), 23.5 (CH), 25.7 (CH), 26.4 (CH), 29.1 (CH), 29.6 (CH), 38.3 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.7 (CH), 50.0 (CH), 54.0 (CH), 56.8 (CH), 57.6 (C), 65.0 (CH), 66.4 (CH), 68.4 (CH), 70.4 (CH), Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 23 78.1 (C), 80.9 (CH), 106.9 (CH), 113.0 (CH, C-F 7.5 Hz), 115.2 (CH, C-F 25.5 Hz ), 117.7 (CH,C-F 24 Hz ), 131.0 (C, C-F 7.5 Hz), 139.8 (C), 148.4 (C), 160.64 (C, C-F 238.5 Hz), 179.6 (C), 183.8 (C); MS (ESI-MS, positive ion) m/z 569 [M+H], 591 [M+Na]; HRMS m/z 569.3010 [M+H] [calcd 569.3027], 591.2856 [M+Na] [calcd. 591.2846]. Compound3g: Colourless needles, m.p. 179-181ºC (lit.14 178-180ºC); IR (KBr, max) 3346, 2940, 1773, 1699, 1619, 1477 cm; H NMR (CDOD) 7.39 (1H, dd, =2.4, 8.4 Hz), 7.16 (1H, d, =2.4 Hz), 6.97 (1H, d, =8.4 Hz), 4.80 (1H, dd, =8.4, 9 Hz), 4.61 (1H, t, =8.4 Hz), 4.58 (1H, s), 4.17 (1H, dd, =6.0, 10.2 Hz), 3.99 (1H, d, =10.8 Hz), 3.93 (1H, t, =9 Hz), 3.63 (1H, s), 3.35 (1H, dd, =3.6, 11.4 Hz), 3.27 (2H, m), 2.82 (1H, m), 2.71 (1H, m), 2.25 (1H, m), 1.93 (1H, m), 1.76 (5H, m), 1.65 (4H, m), 1.27 (1H, d, J=11.4 Hz), 1.20 (1H, dt, =4.8, 12.6 Hz), 1.15 (4H, m), 1.00 (2H, m), 0.46 (3H, s); 13C NMR (CDOD) 15.1 (CH), 20.9 (CH), 23.5 (CH), 25.7 (CH), 26.4 (CH), 29.1 (CH), 29.6 (CH), 38.3 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.7 (CH), 50.1 (CH), 54.0 (CH), 56.9 (CH), 57.7 (C), 65.0 (CH), 66.3 (CH), 68.4 (CH), 70.5 (CH), 77.7 (C), 80.9 (CH), 106.9 (CH), 113.4 (CH), 127.9 (CH), 129.4 (C), 131.1 (C), 131.3 (CH), 142.6 (C), 148.5 (C), 179.6 (C), 183.5 (C); MS (ESI-MS, positive ion) m/z 585 [M+H], 587 [(M+2)+H] 607 [M+Na], 609 [(M+2)+Na]; HRMS m/z 607.2518 [M+Na][calcd. 607.2551]. Compound3h: Colourless needles, m.p. 184-186ºC (lit.14 184-186ºC); IR (KBr, max) 3406, 2938, 1766, 1703, 1613, 1472 cm; H NMR (CDOD) 7.72 (1H, dd, =1.2, 8.4 Hz), 7.46 (1H, d, J=1.2 Hz), 6.81 (1H, d, =8.4 Hz), 4.79 (1H, dd, =7.8, 9 Hz), 4.60 (3H, m), 4.17 (1H, dd, =5.4, 9.6 Hz), 3.99 (1H, d, =11.4 Hz), 3.93 (1H, t, =9 Hz), 3.66 (1H, s), 3.36 (1H, m), 3.27 (2H, m), 2.81 (1H, m), 2.70 (1H, m), 2.25 (1H, m), 1.91 (1H, m), 1.73 (6H, m), 1.61 (2H, m), 1.26 (1H, d, =10.8Hz), 1.20 (1H, m), 1.14 (4H, m), 1.02 (2H, m), 0.46 (3H, s); 13C NMR (CDOD) 15.1 (CH), 21.0 (CH), 23.5 (CH), 25.7 (CH), 26.5 (CH), 29.1 (CH), 29.6 (CH), 38.2 (CH), 39.4 (CH), 40.7 (C), 43.8 (C), 49.7 (CH), 50.2 (CH), 54.0 (CH), 56.9 (CH), 57.8 (C), 65.0 (CH), 66.2 (CH), 68.4 (CH), 70.5 (CH), 77.4 (C), 80.9 (CH), 85.7 (C), 107.0 (CH), 114.2 (CH), 131.8 (C), 136.6 (CH), 140.3 (CH), 143.6 (C), 148.5 (C), 179.6 (C), 183.0 (C); MS (ESI-MS, positive ion) m/z 677 [M+H], 699 [M+Na]; HRMS m/z 677.2083 [M+H] [calcd 677.2088]. Compound4a: Colourless needles, m.p. 232-234ºC (lit.14 234-236ºC); IR (KBr, max) 3374, 2938, 2851, 1724, 1619, 1471 cm; H NMR (CDOD) 7.30 (1H, dt, =1.2, 7.8 Hz), 7.14 (1H, d, =7.2 Hz), 7.01 (1H, dt, =0.6, 7.8 Hz), 6.85 (1H, d, =7.8 Hz), 4.82 (2H, d, =12 Hz), 4.43 (1H, d, =2.4 Hz), 4.13 (1H, d, =11.4 Hz), 3.76 (1H, d, =10.2 Hz), 3.41 (2H, m), 3.35 (1H, m), 3.18 (1H, dd, =2.4, 10.2 Hz), 3.03 (1H, dd, =6.0, 9.0 Hz), 2.90 (1H, m), 2.53 (1H, m), 2.41 (1H, m), 2.26 (1H, t, =12.6 Hz), 2.04 (1H, m), 2.01 (1H, m), 1.97 (3H, s), 1.82 (3H, m), 1.56 (1H, d, =11.4 Hz), 1.34 (1H, m), 1.28 (2H, m), 1.22 (3H, s), 0.69 (3H, s); 13C NMR (CDOD) 15.9 (CH), 23.6 (CH), 25.6 (CH), 26.3 (CH), 29.3 (CH), 35.7 (CH), 38.6 (CH), 39.7 (CH), 40.4 (CH), 40.5 (C), 43.9 (C), 56.3 (CH), 57.0 (CH), 61.1 (CH), 65.3 (CH), 66.7 (C), 73.3 (CH), 75.4 (CH), 76.8 (C), 81.4 (CH), 108.6 (CH), 111.0 (CH), 123.9 (CH), 126.9 (CH), 127.0 (C), 131.5 (CH), 144.2 (C), 148.7 (C), 179.1 (CO), 180.7 (CO); MS (ESI-MS, positive ion) m/z 525 [M+H], 547 [M+Na]; HRMS m/z 525.2943 [M+H] [calcd. 525.2965]. Compound4b: Colourless needles, m.p. 208-210ºC (lit.14 209-211ºC); IR (KBr, max) 3398, 2941, 2850, 1760, 1725, 1617, 1472 cm-1; H NMR (CDOD) 7.46 (1H, dd, =2.4, 8.4 Hz), 7.24 (1H, d, =1.8 Hz), 6.79 (1H, d, =8.4 Hz), 4.82 (2H, d, =10.2 Hz), 4.61 (1H, s), 4.42 (1H, m), 4.13 (1H, d, =10.8 Hz), 3.82 (1H, d, =10.2 Hz), 3.41 (2H, m), 3.34 (1H, d, =10.8 Hz), 3.23 (1H, dd, =2.4, 10.2 Hz), 3.00 (1H, m), 2.90 (1H, m) 2.51 (1H, m), 2.40 (1H, m), 2.24 (1H, m), 1.98 (3H, s), 1.96 (1H, m), 1.82 (5H, m), 1.56 (1H, d, =11.4 Hz), 1.33 (1H, m), 1.26 (2H, m), 1.22 (3H, s), 0.69 (3H, s); 13C NMR (CDOD) 15.9 (CH), 23.6 (CH), 25.6 (CH), 26.3 (CH), 29.3 (CH), 35.7 (CH), 38.6 (CH), 39.7 (CH), 40.3 (CH), 40.5 (C), 43.9 (C), 56.3 (CH), 57.0 (CH), 61.2 (CH), 65.3 (CH), 66.9 (C), 73.1 (CH), 75.5 (CH), 76.6 (C), 81.4 (CH), 108.6 (CH), 112.7 (CH), 116.3 (C), 129.5 (C), 130.0 (CH), 134.4 (CH), 143.5 (C), 148.7 (C), 178.6 (CO), 180.3 (CO); MS (ESI-MS, positive ion) m/z 603 [M+H], 605 [(M+2)+H], 625 [M+Na], 627 [(M+2)+Na]; HRMS m/z 625.1905 [M+Na]+ [calcd. 625.1889]. Compound 4c: Colourless needles, m.p. 230-232ºC (lit.14 231-233ºC); IR (KBr, max) 3430, 2942, 2855, 1770, 1698, 1625 cm; H NMR (CD3OD) 7.11 (1H, d, =7.8 Hz), 6.98 (1H, s), 6.74 (1H, d, =8.4 Hz), 4.82 (2H, d, =9 Hz), 4.42 (1H, d, =1.8 Hz), 4.13 (1H, d, =10.8 Hz), 3.76 (1H, d, =10.2 Hz), 3.41 (2H, m), 3.34 (1H, d, =11.4 Hz), 3.19 (1H, dd, =2.4, 10.2 Hz), 3.02 (1H, dd, =6.0, 8.4 Hz), 2.89 (1H, m), 2.53 (1H, m), 2.41 (1H, m), 2.27 (3H, s), 2.23 (1H, d, =12.6 Hz), 2.00 (2H, m), 1.96 (3H, s), 1.81 (3H, m), 1.56 (1H, d, =11.4 Hz), 1.31 (3H, m), 1.22 (3H, s), 0.69 (3H, s); 13C NMR (CDOD) 15.9 (CH), 21.3 (CH), 23.6 (CH), 25.6 (CH), 26.3 (CH), 29.3 (CH), 35.7 (CH), 38.6 (CH), 39.7 (CH), 40.3 (CH), 40.4 (C), 43.9 (C), 56.3 (CH), 57.0 (CH), 61.2 (CH), 65.3 (CH), 66.7 (C), 73.3 (CH), 75.5 (CH), 76.9 (C), 81.4 (CH), 108.6 (CH), 110.8 (CH), 127.1 (C), 127.5 (CH), 131.8 (CH), 133.7 (C), 141.7 (C), 148.7 (C), 179.1 (CO), 180.7 (CO); MS (ESI-MS, positive ion) m/z 539 [M+H], 561 [M+Na]; HRMS m/z 539.3111 [M+H][calcd. 539.3121]. Compound4d: Colourless needles, m.p. 226-228ºC (lit.14 224-226ºC); IR (KBr, max) 3462, 2944, 2854, 1750, 1706, 1642, 1491 cm-1; H NMR (DMSO-) 10.40 (1H, s, -NH), 6.84 (1H, dd, =2.4, 8.4 Hz), 6.73 (1H, d, =8.4 Hz), 6.57 (1H, d, =3 Hz), 5.77 (1H, d, =4.2 Hz, 14-OH), 5.08 (1H, d, =4.8 Hz, 3-OH), 4.75 (2H, d, =10.8 Hz), 4.29 (1H, m), 4.13 (1H, dd, =2.4, 7.8 Hz, 19-OH), 3.86 (1H, dd, =2.4, 10.8 Hz), 3.72 (1H, d, =10.2 Hz), 3.66 (3H, s), 3.29 (1H, t, =8.4 Hz), 3.26 (1H, dd, =4.2, 10.2 Hz), 3.22 (1H, m), 3.01 (1H, m), 2.85 (1H, dd, =6, 8.4 Hz), 2.63 (1H, qn, =6 Hz), 2.36 (1H, t, =11.4 Hz), 2.31 (1H, d, =12.6 Hz), 2.14 (1H, t, =12.6 Hz), 1.90 (1H, m), 1.85 (4H, m), 1.73 (1H, m), 1.66 (2H, m), 1.45 (1H, d, =11.4 Hz), 1.29 (1H, m), 1.15 (2H, m), 1.09 (3H, s), 0.59 (3H, s); 13C Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 24 NMR (DMSO-) 14.9 (CH), 23.1 (CH), 24.1 (CH), 24.5 (CH), 28.0 (CH), 34.9 (CH), 36.8 (CH), 38.0 (CH), 38.5 (CH), 38.8 (C), 42.3 (C), 54.4 (CH), 54.8 (CH), 55.3 (CH), 59.7 (CH), 62.8 (CH), 64.9 (C), 71.1 (CH), 73.4 (CH), 74.6 (C), 78.6 (CH), 107.4 (CH), 109.9 (CH), 112.1 (CH), 114.3 (CH), 127.0 (C), 136.1 (C), 147.6 (C), 154.7 (C), 176.5 (CO), 177.7 (CO); MS (ESI-MS, positive ion) m/z 555 [M+H], 577 [M+Na]; HRMS m/z 577.2880 [M+Na] [calcd. 577.2890]. Compound4e: Colourless needles, m.p. 210-212ºC (lit.14 210-212ºC); IR (KBr, max) 3400, 2941, 2852, 1762, 1715, 1634, 1486 cm-1; H NMR (DMSO-) 10.63 (1H, s, -NH), 7.13 (1H, m), 6.82 (1H, dd, =4.8, 8.4 Hz), 6.72 (1H, dd, =2.4, 8.4 Hz), 5.84 (1H, d, =3.6 Hz, 14-OH), 5.08 (1H, d, J=4.8 Hz, 3-OH), 4.75 (2H, d, =10.2 Hz), 4.30 (1H, dd, =2.4, 3.6 Hz), 4.13 (1H, m, 19-OH), 3.85 (1H, dd, =2.4, 10.8 Hz), 3.76 (1H, d, =9.6 Hz), 3.31 (1H, t, =8.4 Hz), 3.25 (2H, m), 3.03 (1H, dd, =2.4, 10.2 Hz), 2.85 (1H, dd, =6, 8.4 Hz), 2.63 (1H, m), 2.36 (1H, m), 2.31 (1H, m), 2.13 (1H, t, =12.6 Hz), 1.90 (1H, dd, =4.2, 12.6 Hz), 1.87 (3H, s), 1.84 (1H, m), 1.73 (1H, m), 1.66 (2H, m), 1.45 (1H, d, =10.8 Hz), 1.30 (1H, m), 1.15 (2H, m), 1.09 (3H, s), 0.60 (3H, s); 13C NMR (DMSO-) 14.9 (CH), 23.1 (CH), 24.1 (CH), 24.4 (CH), 28.0 (CH), 34.9 (CH), 36.8 (CH), 38.0 (CH), 38.5 (CH), 38.8 (C), 42.3 (C), 54.3 (CH), 54.8 (CH), 59.6 (CH), 62.8 (CH), 65.0 (C), 70.9 (CH), 73.5 (CH), 74.4 (C), 78.6 (CH), 107.3 (CH), 110.5 (CH, C-F7.5 Hz), 112.6 (CH, C-F 24 Hz), 116.5 (CH, C-F 22.5 Hz), 127.5 (C, C-F 7.5 Hz), 139.2 (C), 147.6 (C), 157.8 (C, C-F 23.7 Hz), 176.6 (CO), 177.6 (CO); MS (ESI-MS, positive ion) m/z 543 [M+H], 565 [M+Na]; HRMS m/z 543.2888 [M+H][calcd. 543.2870]. Compound4f: Colourless needles, m.p. 210-212ºC (lit.14 211-213ºC); IR (KBr, max) 3402, 2940, 2851, 1757, 1720, 1620, 1474 cm-1; H NMR (CDOD) 7.31 (1H, dd, =2.4, 7.8 Hz), 7.11 (1H, d, =2.4 Hz), 6.84 (1H, d, =7.8 Hz), 4.82 (2H, d,=10.8 Hz), 4.61 (1H, s), 4.42 (1H, d, =1.8 Hz), 4.13 (1H, d, =11.4 Hz), 3.82 (1H, d, =10.2 Hz), 3.41 (2H, m), 3.35 (1H, m), 3.23 (1H, dd, =1.8, 10.2 Hz), 3.00 (1H, dd, =6.0, 7.8 Hz), 2.88 (1H, m), 2.51 (1H, m), 2.41 (1H, m), 2.24 (1H, t, =12.6 Hz), 2.03 (1H, m), 1.98 (3H, s), 1.82 (3H, m), 1.56 (1H, d, =11.4 Hz), 1.33 (1H, m), 1.27 (2H, m), 1.22 (3H, s), 0.69 (3H, s); 13C NMR (CDOD) 15.9 (CH), 23.6 (CH), 25.6 (CH), 26.3 (CH), 29.3 (CH), 35.7 (CH), 38.6 (CH), 39.7 (CH), 40.3 (CH), 40.5 (C), 43.9 (C), 56.3 (CH), 57.0 (CH), 61.2 (CH), 65.3 (CH), 66.9 (C), 73.1 (CH), 75.5 (CH), 76.7 (C), 81.4 (CH), 108.6 (CH), 112.3 (CH), 127.2 (CH), 129.1 (C), 129.3 (C), 131.5 (CH), 143.0 (C), 148.7 (C), 178.7 (CO), 180.3 (CO); MS (ESI-MS, positive ion) m/z 559 [M+H], 581 [M+Na]; 583 [(M+2)+H] HRMS m/z 559.2580 [M+H][calcd. 559.2575]. Compound 4g: Colourless needles, m.p. 212-214ºC (lit.14 213-215ºC); IR (KBr, max) 3412, 2940, 2855, 1722, 1614, 1470 cm; H NMR (CDOD) 7.65 (1H, dd, =1.8, 8.4 Hz), 7.41 (1H, d, =1.8 Hz), 6.68 (1H, d, =8.4 Hz), 4.82 (2H, d, =9.0 Hz), 4.61 (2H, s), 4.41 (1H, d, =2.4 Hz), 4.13 (1H, d, =11.4 Hz), 3.82 (1H, d, =10.2 Hz), 3.38 (3H, m), 3.22 (1H, dd, =1.8, 10.2 Hz), 2.99 (1H, m), 2.87 (1H, m), 2.51 (1H, m), 2.40 (1H, m), 2.23 (1H, t, =12.6 Hz), 2.01 (1H, m), 1.98 (3H, s), 1.82 (2H, m), 1.56 (1H, d, =11.4 Hz), 1.29 (3H, m), 1.22 (3H, s), 0.69 (3H, s); 13C NMR (CDOD) 15.9 (CH), 23.6 (CH), 25.6 (CH), 26.3 (CH), 29.3 (CH), 35.7 (CH), 38.6 (CH), 39.7 (CH), 40.3 (CH), 40.5 (C), 43.9 (C), 56.3 (CH), 57.0 (CH), 61.2 (CH), 65.3 (CH), 66.9 (C), 73.1 (CH), 75.5 (CH), 76.4 (C), 81.4 (CH), 85.8 (C), 108.6 (CH), 113.1 (CH), 129.7 (C), 135.8 (CH), 140.4 (CH), 144.1 (C), 148.7 (C), 178.3 (CO), 180.3 (CO); MS (ESI-MS, positive ion) m/z 651 [M+H], 673 [M+Na]; HRMS m/z 651.1926 [M+H] [calcd. 651.1931]. Results and Discussion Initially, we attempted the synthesis of 3-spirocyclic oxindole 3a in order to optimize the reaction conditions (table-1). The reaction was carried out by forming the -CD complex of isatin (2a) in water at 60 ºC, followed by the addition of L-proline and andrographolide (1) with constant stirring at 80 ºC H H OH HO Me O HO O + N O O R1 R2 N COOH Water, Beta-cyclodextrin80 H H OH HO Me N N O O HO O R1 R2 12a-h3a-hWhere 2a, 3a : R = R = H; 2b, 3b: R = H, R = Br; 2c, 3c: R = Me, R = H; 2d, 3d: R = H, R = Me; 2e, 3e: R = H, R = OMe; 2f, 3f: R = H, R = F; 2g, 3g: R = H, R = Cl; 2h, 3h: R = H, R = I; Figure-1 -CD catalyzed synthesis of dispiropyrrolizidinooxindoles (3a-h) in water Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 25 H H OH HO Me O HO O + N O O R H HOOC Water, Beta-cyclodextrin80 H H OH HO Me N N O O HO O R 12a-h4a-g Where 2a, 4a : R = H; 2b, 4b : R = Br; 2c, 4c : R = Me; 2d, 4d : R = OMe; 2e, 4e : R = F; 2f, 4f : R = Cl; 2g, 4g : R = I; Figure-2 -CD catalyzed synthesis of di-spiropyrrolidino-oxindoles (4a-g) in water After several attempts (varying the catalyst loading and time period), it was revealed that the reaction yielded maximum amount of 3-spirocyclic oxindole 3a within 65 minutes with the mole ratio 1:1:1:1 of -CD, isatin, L-proline and andrographolide respectively (table-1, entry 8). With lesser amount of catalyst, the yield was lower, however, higher yield was not obtained even when higher amount of catalyst was employed and with longer reaction time (table-1, entry 11). It is noteworthy that without -CD (table-1, entry 1), the reaction was unsuccessful even after conducting the reaction for a long period. On the other hand the reaction also did not proceed when it was carried out below 80 ºC (table-1, entry 12). The structure of the final product was confirmed by IR, NMR, and Mass spectroscopy which clearly indicated that the product was a dispiropyrrolizidino-oxindole adduct of andrographolide. Table-1 Optimization of catalysis content and reaction timeEntry-CD (equiv.) T C) Time (min) Yields (%) 1 0 80 240 NR b 2 0.25 80 120 42 3 0.25 80 240 44 4 0.50 80 80 53 5 0.50 80 160 56 6 0.75 80 75 60 7 0.75 80 150 62 8 1 80 65 96 9 1 80 100 96 10 1.5 80 60 96 11 5 100 100 96 12 5 70 240 NR b Isolated yields of pure products, bNo reaction In order to establish the generality and scope of this new methodology, we used different derivatives of isatin (2b-h). The results were summarized in table-2. All the reactions proceeded very cleanly at optimum temperature to afford dispiropyrrolizidino-oxindole adduct of andrographolide (3a-h) with high yield and no undesirable side product was obtained. Table-2 -CD catalyzed synthesis of 3-spirocyclic oxindoles (3a-h) in water EntryIsatinProductTime (min) Yields (%) 1 2a 3a 65 96 2 2b 3b 68 90 3 2c 3c 65 92 4 2d 3d 65 94 5 2e 3e 70 95 6 2f 3f 68 94 7 2g 3g 65 95 8 2h 3h 65 92 aAll the reactions were performed using -CD (1 mmol), isatin (1 mmol), L-proline (1mmol) and andrographolide (1mmol) at 80 ºC in water. Isolated yield of pure products. Next we attempted the synthesis of 3-spirocyclic oxindole by using isatin (2a), sarcosine (as a source of amino acid) and andrographolide (1), following the above reaction protocol (figure-2). Gratifyingly, in this case also the reaction proceeded cleanly to yield dispiropyrrolidino-oxindole adduct of andrographolide (confirmed by IR, NMR and Mass spectroscopy). The above reaction was then performed with different isatin derivatives (2b-g) in order to observe the effect of substituent (table-3). In these cases also the reactions proceeded with high yield to afford dispiropyrrolidino-oxindole adducts of Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 26 andrographolide (4a-g). The possibility of using recycled CD was studied in the synthesis of 3a. After completion of the reaction the product was isolated by filtration in hot condition. The aqueous filtrate was cooled to 5 C to crystallize out the catalyst which was recovered by filtration. This catalyst was recycled several times without noticeable change in yield of 3a. Table-3 -cyclodextrin catalyzed synthesis of 3-spirocyclic oxindoles (4a-j) in water EntryIsatinProductTime (min) Yields (%) 1 2a 4a 65 96 2 2b 4b 68 92 3 2c 4c 65 96 4 2d 4d 65 96 5 2e 4e 70 95 6 2f 4f 68 94 7 2g 4g 65 92 All the reactions were performed using -cyclodextrin (1 mmol), isatin (1 mmol), sarcosin (1mmol) and andrographolide (1mmol) at 80 ºC in water. b Isolated yield of pure products. A plausible reaction mechanism for the formation of 3spirocyclic oxindole 3a is depicted in figure-3. It is presumed that isatin dissolved in water after forming an inclusion complex with -CD from its secondary side15. Now an oxazolidinone intermediate A was formed, by the reaction of isatin and L-proline, which undergoes loss of CO forming the azomethine ylide intermediate B16. The dienophile also dissolved in water by forming an inclusion complex with CD17. So, both azomethine ylide intermediate B and andrographolide came in close proximity in the -CD cavity facilitating the 1,3-dipolar cycloaddition to the desired 3spirocyclic oxindole 3a. Conclusion In summary, we have developed a green protocol for the synthesis of 3-spirocyclic oxindoles with excellent yields using -cyclodextrin as supramolecular catalyst in aqueous medium. The study demonstrates minimization of reaction time with maximization of yields of the products. This high yielding process can be considered as a green protocol, as it fulfils many required criteria of green chemistry e.g., the use of an environmentally friendly solvent (water), reusability of catalyst, minimum chemical waste and minimization of reaction time. N O O 2a N COOH N N O O O - CO N O ON O A N O B N H H OH HO Me O HO O Water, Beta-cyclodextrin80 H H O H HO Me N N O O HO O R 3aFigure-3 Plausible pathway for the formation of 3-spirocyclic oxindole3a Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 27 Figure-4 13CNMR of Compound-4a in MeOD Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 28 Figure-5 COSY of Compound-4a Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 29 Figure-6 NOESY of Compound-4a Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 30 Figure-7 HNMR of Compound-3a in MeOD Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 31 Figure-8 13CNMR of Compound-3a in MeOD Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 32 Figure-9 HMBC of Compound 3a Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(12), 21-33, December (2014) Res. J. Chem. Sci.International Science Congress Association 33 Acknowledgements We like to thank Department of Technical Education and Training (DTET), West Bengal, India and UGC, India for financial support of the work. References 1.Li C.J. and Chen L., Chem. Soc. Rev., 35, 68-73 (2006)2.Villiers A., Compt. Rend., 112, 536-540 (1891)3.Nayek S., Choudhury I.H., Jaishee N. and Roy S., Res. J. Chem. Sci.,4(9), 63-69, (2014)4.Szejtli J. and Osa T., In Comprehensive Supramoleculer Chemistry: Cyclodextrins,eds., Pergamon Press: New York, 3,(1996)5.Hashimoto H., J. Inclusion Phenomena and Macrocyclic Chem., 44, 57-62 (2002)6.Naskar S., Roy S. and Sarkar S., Syn. Comm., 44, 1629-1634 (2014) 7.Naskar S., Hazra A., Paira P., Sahu K.B., Banerjee S. and Mondal N.B., J. Chem. Res., 10, 568-573 (2008)8.Naskar S., Saha P., Paira R., Paira P.A., Hazra S., Banerjee S. and Mondal N.B., J. Chem. Res., 3, 174-177 (2009) 9.Lopez-Gresa M.P., Gonzalez M.C., Ciavatta L., Ayala I., Moya P., Primo J., J. 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