Carbon Dioxide → 2-fluoro-9H-fluorene-9-carboxylic acid

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The novel spiro-tricyclicthiazolidinedione derivatives of the present invention are readily prepared from appropriate fluorene and heterocyclic analogs of fluorene derivatives of Formula III, wherein A and B are previously defined. For example, spiro-thiazolidinedione derivative (26) is prepared from 5H-indeno[1,2-b]pyridine: ##STR25## Likewise, the spiro-thiazolidinedione of example (12) is prepared from its starting material 2-fluoro-9H-fluorene: ##STR26## The synthesis of a spiro-thiazolidinedione from the corresponding tricyclic fluorene or heterocyclic fluorene derivative is a multistepped synthesis as depicted in Example IV. The first step involves metalation with a lower alkyl lithium reagent such as n-butyllithium in an inert aprotic solvent such as diethyl ether or tetrahydrofuran under an inert atmosphere of nitrogen or argon, e.g., metalation of 2-fluoro-9H-fluorene: ##STR27## Metalation occurs primarily at the methylene bridge. Reaction with carbon dioxide results in carbonation of the bridge carbon to yield upon isolation the carboxylic acid, e.g., 2-fluoro-9H-fluoren-9-carboxylic acid: ##STR28## Isolation of the carboxylic acid derivative can be accomplished by a process including acidification, simple column chromatography and solvent recrystallization similar to the process cited in Example IV. In contrast to this general case, metalation and carbonation of 8H-indeno[1,2-c] thiophene results in a significant formation of 8H-indeno[1,2-c] thiophene-1-carboxylic acid and 8H-indeno[1,2-c] thiophene-3-carboxylic acid in addition to the desired 8H-indeno [1,2-c] thiophene-8-carboxylic acid, MacDowell and Jefferies; J. Org. Chem., 35 (1970) 871. The tricyclic carboxylic acid product is then esterified with a lower alkylalcohol such as methanol in the presence of an acid catalyst such as a hydrogen halide, such as hydrochloric acid. In a typical procedure, the acid (e.g., 2-fluoro-9H-fluorene-9-carboxylic acid) is esterified by the addition of acetyl chloride to methanolic solution of the carboxylic acid with reflux: ##STR29## Proton abstraction from the acidic methine bridge of the carboxylic ester by an alkali alkoxide such as sodium metal in methanol or alkali hydride such as potassium hydride in DMSO or DMF generates a carbanion. Introduction of purified dry oxygen results in oxidation of the methine carbon. Bisulfite reduction and a simple work-up involving filtration results in the isolation of an α-hydroxy ester product, e.g., 2-fluoro-9-hydroxy-9H-fluoren-9-carboxylic acid methyl ester: ##STR30## α-Halogenation of the α-hydroxy ester by a thionyl halide such as thionyl chloride at reflux transforms 2-fluoro-9-hydroxy-9H-fluoren-9-carboxylic acid methyl ester into 9-chloro-2-fluoro-9H-fluoren-9-carboxylic acid methyl ester: ##STR31##

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