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Please login or sign up for a free trial to access the full content. Variation 1: From Saturated 4-Oxo Acids and Derivatives, with Subsequent Oxidation

DOI: 10.1055/sos-SD-016-00192

Haider, N.; Holzer, W.Science of Synthesis, (200416133.

4-Oxoalkanoic acids 19 both with alkyl or aryl/hetaryl residues as R3, with or without further substituents R1 and R2, have been employed for condensation reactions with hydrazine. Typical examples are the transformation of ethyl 4-oxopentanoate (19, R1=R2=H; R3=Me; R4=Et) into 6-methyl-4,5-dihydropyridazin-3(2H)-one (20, R1=R2=H; R3=Me),[‌122‌,‌123‌] which is subsequently oxidized with bromine in acetic acid into 6-methylpyridazin-3(2H)-one (21, R1=R2=H; R3=Me),[‌122‌] and the condensation of 4-(substituted phenyl)-4-oxobutanoic acids with hydrazine, again followed by aromatization using bromine in acetic acid (Scheme 9).[‌124‌,‌125‌] Whereas in most cases the free carboxylic acids (R4=H) are employed for the preparation of compounds of type 20, esters are also frequently used. For the latter case, a protocol suitable for high-throughput organic synthesis was developed, which is based on construction of the oxo ester by silver(I)-catalyzed addition of zirconocenes to epoxy esters (including esters of polyfluorinated alcohols, which can be efficiently purified by liquidliquid extraction schemes).[‌126‌] Another interesting alternative is the use of 5-(2-substituted 2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4,6-diones 22 (Meldrum's acids). These compounds are easily available and cyclize with hydrazine already at room temperature under decarboxylation to provide the 4,5-dihydropyridazin-3(2H)-ones 23 (Scheme 9).[‌127‌]

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