Isatins with ketone reagents

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

Carbonyl not adjacent to heteroatom. Carbonyl groups not adjacent to a heteroatom are less stabilized by resonance and react with the relatively weakly nucleophilic ketonic reagents. If carbonyl groups of both types are present, as in 319 (Z = O, NH), then the carbonyl group not adjacent to the heteroatom is preferentially attacked. Thus, isatin and indoxyl and their O- and S-analogues (319, 322) react with hydroxylamine, hydrazine, phenylhydrazine, semicarbazide, etc., to give oximes, hydrazones, phenylhydrazones, semicarbazones, etc. (322 323 319 324). 

Conversion of isatins into oxindoles can be achieved by catalytic reduction in acid, or by the Wolff-Kischner process.3-Substituted indoles result from Grignard addition at the ketone carbonyl, followed by lithium aluminium hydride reduction of the residual amide, then dehydration. The reaction of isatin with triphenylphosphine provides an easy synthesis of 3-(triphenylphosphorylidene)oxindole, a Wittig reagent. ... 

They selected the isatin-derived 3-hydroxy-3-indolyoxindole as a good alkylation reagent for the direct alkylation reaction. Quite remarkably, the stereoselective reaction promoted by chiral phosphoric acid was described with ketones and not with aldehydes, owing to the major tendency of ketones to form the enol by acid... 

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