3.4- Disubstituted pyrazolin-5-ones

IV-Alkyl-substituted phthalimides 9 were easily transformed into mono-, di- or trisubslituted pyrazoles 10 via a one-pot addition/decyclization/cyclocondensation sequence <02JCS(P1)207>. 5-Silylpyrazoles can be prepared from condensation of silylalkynones with hydrazines <02T4975>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted pyrazolin-5-ones <02T3639>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

The photorearrangement of pyrazoles to imidazoles is probably analogous, proceeding via iminoylazirines (82AHC(30)239) indazoles similarly rearrange to benzimidazoles (67HCA2244). 3-Pyrazolin-5-ones (56) are photochemically converted into imidazolones (57) and open-chain products (58) (70AHC(ll)l). The 1,2- and 1,4-disubstituted imidazoles are interconverted photochemically. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Disubstituted hydrazines and semicarbazones react with a-haloacyl halides under two-phase catalytic conditions to produce l,2-diazetidin-3-ones (20-85%) [35], whereas (3-haloacyl halides react with hydrazines to form pyrazolin-3-ones (ca. 30%). 

This important section deals with pyrazolenines, isopyrazoles and 4,4-disubstituted 2-pyrazolin-5-ones whose thermal and photochemical reactions will be discussed in this order. 

Chattaway and co-workers287-290,294 have synthesized a number of l-aryl-2-pyrazolin-4-ones which, as a rule, have been considered to have the 4-hydroxypyrazole structures. However, some of these must have the 2-pyrazolin-4-one structure due to disubstitution at C-5. Emerson and Beegle425 have synthesized some 2-pyrazolin-4-ones unsubstituted at N-l permitting more possibilities for isomerism. These will be discussed later. 

N-2.984,988 993 A modification of this consists of using a symmetrically substituted hydrazine to give l,2-disubstituted-3-pyrazolin-5-ones.54... 

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with jS-ketoesters forms 2-aryl-3-pyrazolin-5-ones.679,849,984,988,1001 The aeyl group is lost in the cyclization and these products have no N-l substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3-pyrazoIin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus penta-chloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a j8-ketoester to give l,2-disubstituted-3-pyrazolin-5-ones.54,370 The sub-... 

Alkoxy-2-pyrazolin-5-ones have been prepared by two methods. In one of these a hydrazine is condensed with a -substituted ester (eq. 160).598,1143 The second is O-alkylation of a 4,4-disubstituted-l-... 

A variety of 4-amino-5-alkoxy- and acyloxy-l,3-disubstituted-pyrazoles have been treated with alkylating agents such as alkyl halides to give 4-dialkylamino-3-pyrazolin-5-ones.525 There is a simultaneous alkylation of ring nitrogen and extranuclear nitrogen. 

A group of Italian workers has claimed that 1,3-disubstituted-2-methyl-5-oxo-3-pyrazolin-4-carboxaldehydes can be prepared through methylation of the Schiff bases derived from aromatic amines and l,3-disubstituted-2-pyrazolin-5-ones.1097 The methylation is carried out with methyl iodide which methylates the ring at N-2, and this is followed by hydrolysis of the Schiff bases with alkaline solutions (eq. 221). Passerini and Losco1092,1093-1097 and Ridi1181 claimed to have... 

Derivatives of Y-hydroxyacetylenic acids, which are useful intermediates in the synthesis of butenolides, are prepared from propiolic acid and ester anions. Alk-2-ynoic and 2-allenic esters are prepared by the oxidation of 3,4-disubstituted 2-pyrazolin-5-ones with lead(iv) tetra-acetate in the absence and presence of BF3 respectively. Py-Unsaturated esters are produced in high yield by the palladium-catalysed decarboxylation-carbonylation of allylic carbonates. Magnesium enolates of esters react with nitriles to give (Z)-3-amino-alk-2-enoates. Enol lactones react with diethyl methoxycarbonylmethylphosphonate to give cyclic unsaturated keto-esters (Scheme 66). ... 

A new acetylene synthesis involves the reaction of 3,4-disubstituted 4-haIo-2-pyrazolin-5-ones with aqueous sodium hydroxide and potassium ferricyanide. The reaction proceeds particularly well for arylacetylenes and is believed to involve the oxidation of an intermediate vinyl radical to a vinyl cation (Scheme 69). A similar reaction mechanism may be involved also in the thallium(iii) nitrate oxidation of pyrazolones prepared from -ketoesters and hydrazine. Full experimental details of this procedure have now been published with yields in the range 68—7-1 % (Scheme 70). 

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