3- methylene-2-indolone

N-Methyl-4-hydroxy-2-quinolone 183 in a three-component reaction gives spiro pyrano[3,2-c]qionoline-2-ones (02MI2), but indolones 213 with 4-hydroxy-6-methyl-2-pyridone 177 react in a complicated way (97BCJ1625). Ethoxycarbonyl-methylene indolone (Z = COOEt) forms pyrans 224, while dicyano analogs (Z = CN) yield substituted quinoline 225 (Scheme 85). 

Isatogens (1) and indolones (2) are brightly colored solids that do not occur naturally. Isatogens (I) are more comprehensively named as 3-oxo-3//-indole 1-oxides, or as the 1-oxides of indolones (2), 3-oxo-3H-indoles, or 3//-indol-3-ones. Both series of compounds are numbered in accordance with IUPAC rules. Isatogens were first reported in 18811,2 and the first indolone in 1912.3 Isatogens (1), indolones (2) and indoxyls (3) form an interrelated redox system. Indolones in which there is a methylene or methine substituent in the 2-position tautomerize to the preferred 2-methylene-3//-indol-3-one (indogenide) structures (4).4 Only passing reference will be made to 3 and 4 in this review. 

In contrast, the structure of the diindoxyls (141) is controversial. Kalb and Bayer,3 followed by Jones,24 supported structure 146. On the other hand, Hassner and Haddadin94 and Bond,18 from a comparison of the UV spectra with those of 2,2-disubstituted indoxyls95 have argued for 141. Chemical evidence has also been presented in favor of 141.18 Indolones (138) do not form adducts with phenols, and their water and alcohol adducts are unstable. The adducts with active methylene compounds are more stable (Section V,A). The stability of the diindoxyls corresponds to a C—C rather than a C—O linkage at the 2-position of the indolone adducts. The present evidence overwhelmingly supports 141 as the correct structure for these compounds. 

Heterocyclization of a-mercapto acids with (azolylimino)indolones 182 (Scheme 36) afforded the spirocyclic thiadiazepinones 183 <1989IJB639, 1994PS27>. gem-Dithiol addition to bis(methylene)-substituted diketopiper-azine 168 afforded the bridged bicyclic structure 169 featuring two dithiazepane rings (Scheme 33) <1981JHC1545>. 

The synthesis of a structurally somewhat more complex indolone tyrosine kinase inhibitor starts with the construction of the pyrrole ring. Reaction of tert-butyl acetoacetate (87) with nitrous acid leads to nitrosa-tion on the activated methylene carbon. This reaction introduces the nitrogen atom that will appear in the target pyrrole. Condensation of 88 with... 

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