4- Acyl-3-pyrazolin-5-ones

A number of syntheses of compounds having nitrogen on a carbon attached to 2-pyrazolin-5-one rings have already been mentioned, but several others are known. The most important of these is the reaction of 4-formyl- or 4-acyl-2-pyrazolin-5-ones with hydroxylamine, hydrazines, semicarbazide and similar chemicals.559 1841 These compounds can also be obtained by direct synthesis from an appropriate /3-ketoester or derivative and a hydrazine (eq. 50).138 512-1100 An interesting syn-... 

Acylation of 2-pyrazolin-5-ones leads to 4-acyl-2-pyrazolin-5-ones. This has been done by treatment with aromatic acid chlorides110 and with ethyl oxalate in the presence of potassium. A modification of this procedure is acylation of 2-pyrazolin-5-ones to give 4-acyl-5-acyloxy-pyrazoles 591,977 or 2,4-diacyl-3-pyrazolin-5-ones1058 followed by hydrolytic removal of the A-acyl or O-acyl groups. The 4-acyl compounds can also be prepared by hydrolysis of their Schiff bases as shown in eq. 215. 

The reaction of hydrazine with appropriately substituted isoxazo-lones or isoxazolinones also forms 4-acyl-2-pyrazolin-5-ones (eq. 218).947,1295... 

Acyl-, 4-alkoxycarbonyl- and 4-phenylazo-pyrazolin-5-ones present the possibility of a fourth tautomer with an exocyclic double bond and a chelated structure. The molecular structure of (138) has been determined by X-ray crystallography (Table 5). It was shown that the hydroxy group participates in an intramolecular hydrogen bond with the carbonyl oxygen atom of the ethoxycarbonyl group at position 4 (8OCSCII21). On the other hand, the fourth isomer is the most stable in 4-phenylazopyrazolones (139), a chelated phenyl-hydrazone structure. 

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>. 

Pyrazol-5-ones are widely used in medicine, color photography, analytical chemistry, and agriculture. The tautomeric equilibria between the CFI, OH, and NH forms in a series of 4-substituted-l-phenyl-3-methyl-pyrazolin-5-ones 100-102 have been studied using ab initio calculations at various levels of theory and comparison made with the experimental results obtained from C NMR measurements <2001JP0566>. The tautomerism of 4-acyl-2-phenyl-2-pyrazolidin-3-ones 103 and 104 was studied by C NMR spectroscopy <1999CHE748>. The tautomerism of... 

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>. 

L-f/ireo-glycerol-l-yl)-pyrazoline-5-one (49) when its solution in alkali was acidified with acetic acid (50). The reaction was further extended to other bis(arylhydrazones) (51), The structure of the phenyl analogue (49) was established by oxidation to the known 3-carboxy-l-phenyl-4-phenylazopyrazolin-5-one (50). Later, on the basis of NMR data (39), the structure of this group of compounds was formulated as the hydra-zones (51). Acylation of 51 aflForded the tri-O-acylated derivatives (51), while periodate oxidation of 51 gave 3-formyl-l-aryl-4,5-pyrazoledione-... 

Pyrazolin-5-ones can be readily acylated at C-4 with acid chlorides,110 esters1841 and anhydrides.1279 Very few reactions with acid chlorides and esters have been reported but the product is the ketone (XXI), as expected. Phthalic anhydride reacts with two moles... 

Acylation of 2-pyrazolin-5-ones having no substituent at N-l occurs readily with such agents as acetyl chloride,1499,1598 acetic anhydride,1499,1598 benzoyl chloride1056,1598 and aryl sulfonyl chlorides.1199 The usual product is a l-acyl-2-pyrazolin-5-one, but acylation may also occur on oxygen, or both on oxygen and at N-2.1598... 

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-... 

The vast majority of reactions undergone by 3-pyrazolin-5-ones occur at the 4-position. These pyrazolinones react by direct substitution, very much as do activated benzene rings. Such reactions as halogenation, nitrosation, sulfonation, acylation, the Mannich reaction and many others give 4-substituted-3-pyrazolin-5-ones. 

One method of preparing acyloxy-2-pyrazolin-5-ones has already been mentioned (eq. 159). The second method is acylation of 3,5-pyrazolidinediones having no N-2 substituent (eq. 162). The acylations... 

Most 4-amido-3-pyrazolin-5-ones have been prepared either by acylation of secondary amines537 618,1471 (4-alkylimino-3-pyrazol-idinones) or by acylation of the primary amine1471 followed by alkylation.537 Shimidzu1297 has reported the replacement of a methyl group by a cyano group and conversion of this to a thiourea (eq. 198). 

A large number of 2-pyrazolin-5-one aldehydes and ketones are known. These are listed in Table XXX. It is possible to have both 3-and 4-formyl and acyl substituents and both are known, although only one 5-oxo-2-pyrazoline-3-carboxaldehyde has been reported. There has been very little study of the effect of 4-acyl substituents on the structure of 2-pyrazolin-5-ones, but it seems probable that such compounds would tend to exist to a large extent as the 5-hydroxypyrazoles since they would be 1,3-dicarbonyl compounds. 

Acyl-2-pyrazoIin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-ones and conversion of other heterocycles. As might be expected the reaction of /J-ketoesters with hydrazines has been utilized.124,1124,1532,1533 In this case the /J-ketoester has an a-acyl substituent (eq. 216). Both Borsche and Lewinsohn124 and Vila1533... 

The 4-formyl and 4-acyl-3-pyrazolin-5-ones react like normal carbonyl compounds with active methylene groups,898-1190 amines,107,1190 hydroxylamine,196 hydrazines196-201 and semicarba-zide,201 although some fail to react with thiosemicarbazide.799 They... 

Various bis(3-pyrazolin-5-ones) having acyl substituents are known. In all cases the acyl group is part of a 4,4 -bridge between the 3-... 

Acyl-3-pyrazolin-5-ones dimerize by an aldol condensation.901... 

Functional group substituents on N-l of 2-pyrazolin-5-ones (Table XXXVII) are acyl, sulfonyl and various carboxyl derivatives, such as carbalkoxy, amides, thioamides, hydrazides, thiohydrazides and amidines. The usual synthesis of these compounds is by the classical 2-pyrazolin-5-one synthesis, reaction of a /J-ketoester with a hydrazine. In these cases the hydrazines are special types such as hydrazide,... 

N-l and 0. Other acylating agents used have been arylsulfonyl chlorides1199 and alkylchloroformates.61 Isocyanates react with N-l of 2-pyrazolin-5-ones having no 1-substituent to form 5-oxo-2-pyrazolin-1-carboxanilides. Treatment of l-acyl-5-acyloxypyrazoles with piperidine in ethanol removes the 0-acyl to give l-acyl-2-pyrazolin-5-ones.1898... 

The N-l acyl substituted 2-pyrazolin-5-ones react as do the other classes of 2-pyrazolin-5-ones since the hydrogen atoms at C-4 are active.519,1296 The jV-acyl substituents are readily removed by hydrolysis284,355 or treatment with aniline.6 Pyridine and acetic acid cause a rearrangement of iV-acetyl groups to the oxygen atom.1598... 

A few bis(l-acyl-2-pyrazolin-5-ones) are known. Those linked through N-l have been prepared by reaction of carbazide with two equivalents of a /J-ketoester1037,1632 either with255 or without isolation of the intermediate hydrazone. The bis compounds linked at C-3 or C-4 are prepared by reaction of bis(/3-ketoesters) with semicarbazide.357,1222... 

The 5-imino-2-pyrazolines having no N-l substituents can be acylated with acetic anhydride to form the 1-acyl derivatives,301,342,391 as can their 5-oxo analogs. Compounds of this type having a 3-acetoxy substituent have been prepared by reaction of 3-amino-2-pyrazolin-5-ones (5-imino-3-pyrazolidinones) with acetic anhydride (eq. 237).594,1598 Cusmano and Sprio343,344 have treated a-benzylidene-j8-ketonitriles... 

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