5-Pyrazolones amides

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Amino polystyrene pyrazolone linker resin 58 provided various amide products 59 with a high conversion rate and good purity under mild conditions the resin linker was stable under the reaction conditions, resistant to hydrolysis, and reused repeatedly without loss of activity <03TL8063>. The preparation of pyrazoline derivatives 61 was accomplished with traceless solid-phase sulfone linker 60 with phenylhydrazine <030L1067>. Aniline cellulose-bound enaminones 62 reacted with phenylhydrazine under microwave irradiation to produce pyrazolocarboxylic acid derivatives 63 in high yields <03JCO465>. 

Coupling 5-isopropyl-l-methylpyrazol-3-ol 333 with 2-bromothi-azole, 5-bromo-pyrimidine and 3-bromoquinoline under Buchwald-type amidation gave pyrazolones 334a-c, in modest yields (06BMCL3713) (Scheme 76). 

CijHjjNsOjS, rBenzol-5ulfons4ure-(l)]-<2 azo 4)-[l-(3- u]famoyl-phenyl)-pyrazolon-(5)-oarbaiis ure-[3)] 2S U 247, Ea8i nie-[bis-(2.6-dinitro-benz]rl)-amid] 181467. 

Oximliio-3-methyl-pyrazolon>(5)-tUocarbonsaure (l)-amid 24 II176. 

Pyrazolones from y -ketocarboxylic acid amides via y -ketocarboxylic acid amide hydrazones... 

A comprehensive theoretical smdy of some pyrazolones has been presented. The predicted tautomeric equilibrium constants of these compounds were found to be in good agreement with existing experimental data, indicating that the oxo tautomers are present in aqueous solution whereas, in the main, the hydroxy tautomers predominate in the gas phase. It has been shown that, in solution, the most abundant tautomer of both l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one and its 1-phenyl derivative is dependent on the solvent used, while an NMR study of a number of l(2)//-dihydropyrazolo[3,4-fc]pyridin-6-ones has revealed that they all exist as 2//-tautomers both in solution and in the solid state. DFT and ab initio calculations have been carried out to investigate the stability of different tautomers of 2-hydroxy- and 2,3-dihydroxy-pyrazine in the gas phase and in different media. The data obtained indicated that 2-hydroxypyrazine is more stable than its 2-keto tautomer in the gas phase, whereas in solution the stability order is reversed. For 2,3-dihydroxypyrazine it appears that the intramolecular hydrogen-bonded hydroxyoxo and the a-diketo tautomers are the most stable species at all theoretical levels in the gas phase. Both spectroscopic and theoretical studies of the tautomerism of 2,1,3-benzothiadiazinone 2,2-dioxides and other related fused heterocyclic amides have predicted that the keto form (415) is the most abundant tautomer in the gas phase, whereas the NH hydroxy form (416) is the preferred tautomer in solution and in the solid state. 

Cyclative cleavage of polymer-bound substrates is also a known procedure for amide resins. Recently, Dodd et al. released 5-aminopyrazoles 176 from resins linked to /i-ketoamides (Scheme 27) [181]. As a side reaction, they found the formation of 5-pyrazolones 175 which are formed via cyclative cleavage from the resins prior to product isolation. The whole synthesis has been performed on 4-formyl-3-(methoxyphenoxy)methylpolystyrene (FMP) resin with immobilized amines that react with /8-ketoamides to give 172. 

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