AN IMPROVED SYNTHESIS OF DIOXINDOLE-3-PROPIONIC ACID AND SOME TRANSFORMATIONS OF THE C-3 HYDROXYL GROUP

Dioxindole-3-propionic acid lactone (3) is obtained in 80% yield by oxidative cyclization of indole-3-propionic acid with t-BuBr/DMSO. In the presence of 18-crown-6 in DMSO, KCN opens the spirolactone ring of 3 at C-3 with the formation of 3-cyanooxindole-3-propionic acid (4a) in 14% yield. Methanolysis of the lactone is strongly promoted by DMAP, and the resulting 3-hydroxy ester (5) is converted into the 3-fluoro ester (6) with methyl DAST. Every attempt to isolate 3-fluorooxindole-3-propionic acid resulted in rapid intramolecular displacement of fluorine by the free carboxyl group to reform the spirolactone. The 3-hydroxy ester is converted into the 3-chloro ester (9) with SOCl2/Et3N. The halogen is readily displaced by nucleophiles (e.g., N3-, CN-, NH3, AcO-, H2O) to generate the corresponding methyl 3-X-oxindole-3-propionate. Saponification of the ester function provides the corresponding 3-X-oxindole-3-propionic acid. Acetylation of the 3-hydroxy ester provides a separable mixture of the O-acetyl (16) and N-acetyl (17) derivatives. As in the case of 3, the O-acetyl derivative undergoes hydrogenolysis at C-3, while the 3-hydroxyl function is stable to removal by hydrogenolysis.