2- Pyrazolin-5-one synthesis

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,... 

A few other methods of preparing 4-amino-3-pyrazolin-5-ones have been reported but none has been used extensively. Methylation of the N-2 of 2-pyrazolin-5-ones, the classical 3-pyrazolin-5-one synthesis, has been reported only once.536 Emerson and co-workers426 have hydrolyzed iminotoluquinone substituted by antipyrine to give the... 

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>. 

By far the most widely used synthesis for 2-pyrazolin-5-ones is the condensation of a /3-ketoester with a hydrazine (eq. l).6 11-6 269-303-805... 

Perhaps the most common procedure for preparing 3-pyrazolin-5-ones is alkylation of a 2-pyrazolin-5-one at N-2 as shown for the synthesis of antipyrine (eq. 2).806 Other alkylating agents such as dimethyl... 

In summarizing this method of synthesis it can be said that it is so extremely general that almost any non-substituted or monosubstituted /3-ketoester will react with almost any monosubstituted hydrazine to form a 2-pyrazolin-5-one. 

A very important reaction in the synthesis of merocyanine dyes is the alkylation of 2-pyrazolin-5-ones with various heterocyclic rings as illustrated in eqs. 33-35.166-238,239 2-Pyrazolin-5-ones other than the... 

Most of the syntheses of a-hydroxyalkyl and a-alkoxyalkyl-2-pyrazolin-5-ones have been discussed in connection with the reactions of 2-pyrazolin-5-ones. However, there is one synthesis by which compounds of this type are obtained directly. This is by reaction of the appropriate alkoxy- or phenoxymethylacetoacetic esters with hydrazines (eq. 48).532,1314,1313,1316,1562 The reactions of these compounds... 

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-... 

The most widely used synthesis of 4,4 -bis(2-pyrazolin-5-ones) is mild oxidation of monocyclic 2-pyrazolin-5-ones, which has already been discussed in the section devoted to reactions of 2-pyrazolin-5-ones (eq. 45). These compounds can also be synthesized by reaction of a,a -diacylsuccinic esters with hydrazines (eq. 54).357.807.8i5 a number... 

Only a very few 4,4 -bis(2-pyrazolin-5-ones) linked by a double bond have been prepared. The parent compound of this series, 4-(3-methyl -1 -phenyl - 5 - oxo - 2 - pyrazolin - 4-ylidene)-3-methyl-l-phenyl-2-pyrazolin-5-one (XXII-D), is known as pyrazole blue.323,807,809,816, 1090,1091 was so nameci by Knorr because of its great resemblance to indigo blue. All these compounds are strongly colored. The usual synthesis is by ferric chloride oxidation of monomeric 2-pyrazolin-5-ones (eq. 61)296,809 or by oxidation of the corresponding bis compounds... 

Westoo has reported the synthesis of complex bispyrazolinones which he has called furlones.1608,1610,1611 These have two 2-pyrazolin-5-one rings connected through a dihydrofuran ring which in turn is fused with a pyrazole ring. These were prepared by condensation of 4-halogenated-2-pyrazolin-5-ones, together, with l-aryl-2-pyrazolin-5-ones, or with pyrazole blue (XXII-D) in the presence of a base and copper sulfate (eq. 87). These compounds are listed in Table X. 

Lecher, Parker and Conn885 report that the cyclization of the hydrazone hydrazide, as in eq. 106, is the preferred synthesis for 2-aryl-3-methyl-3-pyrazolin-5-ones. 

In one case the substituents on the nitrogen atoms were both phenyl.789 Two other methods of synthesis of the 3-pyrazolin-5-thiones have been reported. Michaelis992 has claimed the conversion of l,2-dimethyl-3-phenyl-3-pyrazolin-5-one to the thione analog by reaction with potassium hydrogen sulfide. Worrall1653 has reported the synthesis shown in eq. 150. 

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /9-ketoester with hydrazines according to the classical method for preparation of 2-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /9-substituents whose reaction is equivalent to that of a /9-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,1027 ethyl phenylpenaldate243 and the acetal of an a-amido-/9-formyl ester.59,243 Cornforth has isomerized 2-phenyl-4-hydrazino-methylidyneoxazolidone to 4-benzamido-2-pyrazolin-5-one. The same compound was obtained by treatment of 1-ethoxyvinyl-2-phenyl-oxazolidone with phenylhydrazine.319... 

The synthesis of 4-azo-3-methyl-l-phenyl-2-pyrazolin-5-one is shown in eq. 176.1144 The 4-hydrazones of 2-pyrazolin-4,5-diones have... 

The standard /3-ketoester-hydrazine reaction for preparation of 2-pyrazolin-5-ones has been used for direct synthesis of the 4-oximino derivatives by starting with an a-oximino-jS-ketoester.269,1125,1534,1536 In a modification of this by Biilow and Bozenhardt258 a hydrazone of the a-oximino-j8-ketoester was used. Ponzio and Ruggeri1125 have used a-oximino-j8-hydrazonohydroxamic acids and hydrazines, and other oximino compounds, as illustrated in eq. 209. 

Freri478,480 has reported a very interesting synthesis of 4-oximino-3-methyl-2-pyrazolin-5-one. This consisted in the treatment of citra-conic acid hydrazide with nitrous acid (eq. 211). The physical data which... 

The reduction of 4-nitroso-3-pyrazolin-5-ones has already been discussed in connection with the synthesis of 4-dialkylamino-3-pyra-zolin-5-ones. This reduction occurs readily to give the corresponding amine when catalytic hydrogenation or various chemical combina-tions461,092,1174 1175 are used. Oxidation of nitroso to nitro occurs in the presence of excess of nitrous acid or by use of nitric acid.984-992... 

The usual synthesis of the 4-nitro-2-pyrazolin-5-ones is by nitration of 2-pyrazolin-5-ones under mild conditions (eq. 2 1 4).61-872-690 1004-1683... 

There has been considerable interest in the preparation of 5-oxo-3-pyrazolin-4-carboxaldehydes (listed in Table XXXI) because of their close relationship to antipyrine (2,3-dimethyl-l-phenyl-3-pyrazolin-5-one). The most frequently used preparation of these compounds has already been mentioned (eq. 135, p. 54). This consists of treating the condensation products of 3-pyrazoIin-5-ones and chloral with base.107,196,889,893,896,901,1190 The McFadyen-Stevens aldehyde synthesis has been applied to the preparation of both 5-oxo-3-pyrazolin-3-carboxaldehydes698 and -4-carboxaldehydes.204,892,1634 This is illustrated in eq. 220. The final step is usually carried out in glycerol at... 

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