Representative procedures for synthesis of spirooxindoles (compounds 4a to f) and bis-spirooxindoles (compounds 6a to f).

The spirooxindoles 4a to f were synthesized by a modified routes and the representative procedure for synthesis is as follows. To a solution of isatin (compound 1a) (147 mg, 1 mmol) in CH₃CN (5 ml) with stirring, l-proline (compound 2a) (115.06 mg, 1 mmol) was added, followed by the addition of 4-Å molecular sieves (MS) (200 mg), and the solution was left with stirring at room temperature (28°C) for 30 min. A deep green reaction mass appeared, to which methyl acrylate (compound 3a) (84 μl, 1 mmol) was added, and the stirring was continued at room temperature (28°C). The progress of the reaction was monitored by thin-layer chromatography (TLC) by using 40% ethyl acetate in petroleum ether as the solvent system. After 6 h, the starting materials completely disappeared, and then the 4-Å MS were filtered off over a thin pad of celite and the filtrate was evaporated in a rotary evaporator. The residue was then diluted with water (15 ml) and extracted with ethyl acetate (3 times, 25 ml). The organic layer was separated, washed with brine, and then dried over anhydrous Na₂SO₄. Removal of solvent resulted in a sticky brownish mass which was chromatographed over silica gel (60-120 mesh) using petroleum ether with an increasing proportion of ethyl acetate as the eluent. Elution with 25% ethyl acetate in petroleum ether gave the desired compound 4a (259 mg, 91%) as a white solid, which was crystallized in chloroform.

The representative procedure for synthesis of compounds 6a to f is as follows. To a solution of N-benzyl isatin (compound 1b) (118.5 mg, 0.5mmol) in CH₃CN (3 ml) with stirring, l-proline (compound 2a) (57.5 mg, 0.5mmol) was added followed by the addition of 4-Å MS (100 mg), and the solution was left with stirring at room temperature (30°C) for 30 min. A light yellow reaction mass appeared, and to the reaction mass dipolarophile (compound 5a) (93.5 mg, 0.5mmol) was added and subjected to stirring at room temperature (30°C). The progress of the reaction was monitored by TLC by using 50% ethyl acetate in petroleum ether solvent system. After 6 h of reaction, there was very little starting material, which was not consumed on further continuation of the reaction. The MS were then filtered off over a thin pad of celite, and the filtrate was evaporated in a rotary evaporator. The residue was then diluted with water (15 ml) and extracted with ethyl acetate (3 times, 25 ml). The organic layer was separated, washed with brine, and then dried over anhydrous Na₂SO₄. Removal of solvent resulted in a sticky solid which was chromatographed over silica gel (60-120 mesh) using petroleum ether with an increasing proportion of ethyl acetate as the eluent. Elution with 30% ethyl acetate in petroleum ether gave compound 6a (202 mg, 85%) as a gray solid.