Pyrazolidine-3,5-diones, methylation

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

Synthesis Feprazone is prepared by the condensation of acetic acid 3-methyl-but-2-enyl ester with the lithium salt of 1,2-diphenyl-pyrazolidine-3,5-dione in the presence of tetrakis(triphenylphosphin)palladium in anhydrous tetra-hydrofuran. 

Earlier, Kutterer et al. (05BMCL2527) (Scheme 80) reported that 4-methyl-1,2-fazs(4-chlorophenyl)pyrazolidine-3,5-dione 348 with 2-bromo-l-(2,4-difluoro-phenyl)ethanone 349 in toluene containing DIPEA under MW heating (900 W) for 1 min gave 4 -alkyl-4-methyl-pyrazolidine-3,5-dione 350 and 4-methyl-5-alkyloxy-pyrazol-3-one 351. Although compound 351 was evaluated as new inhibitor of bacterial cell wall biosynthesis, no separation and yields of 350 and 351 were reported. 

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