N-benzyloxindole [7135-32-2] (1) is the starting material. Base facilitated alkylation with 2 molar equivalents of methyl halide (via the enolate stabilized carbanion) gives 1-benzyl-3,3-dimethylindol-2-one, PC11086219. Dissolving metal reduction (sodamide generated in situ) was the reaction medium which was employed to cleave the benzyl protecting group to give 3,3-dimethyloxindole [19155-24-9] (2). Nitration of this can obviously be achieved by the nitronium ion (generated in situ from nitric and sulfuric acids) to give 3,3-dimethyl-5-nitro-oxindole [100511-00-0]. Catalytic hydrogenation over palladium then reduces the nitro group to give 3,3-dimethyl-5-amino-oxindole [31523-05-4] (3). Treatment with acetic anhydride protects amino groups as the acetamide. Treatment with nitric acid is then able to add a nitro group on to the aromatic ring which is probably sterically directed. Treatment with acid hydrolyses the acetamide protecting groups to give 3,3-dimethyl-5-amino-6-nitro-oxindole, PC22162178 (4). Catalytic hydrogenation over platinum oxide reduces the nitro group to give 3,3-dimethyl-5,6-diamino-oxindole [100568-79-4]. The last step of the reaction sequence is a condensation with Isonicotinaldehyde [872-85-5], thus completing the synthesis of adibendan (5), respectively.
↑Mertens, A.; Mueller-Beckmann, B.; Kampe, W.; Hoelck, J. P.; Von der Saal, W. (August 1987). "Nonsteroidal cardiotonics. 1. 2-Pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-ones, a novel class of cardiotonic agents". Journal of Medicinal Chemistry. 30 (8): 1279–1287. doi:10.1021/jm00391a004.
