Pyrazolones, preparation from

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). 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Imidazo[l,5-i]pyrazoles (269) have also been prepared from imidazole intermediates. Thus, treatment of 295 with sufuryl chloride gives 296 (69JOC3213). Perhydroimidazo[l,5-l>]pyrazolones (299) are obtained as... 

Heterocyclic azo couplers have also featured prominently in disperse dye chemistry, especially in the production of yellows. Cl Disperse Yellow I (B-71MI11202) is in fact an azo dye prepared from benzenediazonium chloride and l-phenyl-3-methyl-5-pyrazolone, and pyrazolone couplers continue to appear in patents. However, the most important recent development has been the introduction of 2,6-dihydroxypyridine couplers in azo dyes such as (54). Although the couplers had been disclosed some time ago, their development by... 

This is the simplest member of the pyrazolone dyes which are prepared in two ways (a) from dihydroxytartaric acid and phenylhy-drazine (tartrazines), and (b) from phenylmethylpyrazolones by coupling with diazo compounds. The second method is simpler and has largely displaced the older, first method. The pyrazolone is prepared from a given phenylhydrazine (e.g., phenylhydrazinesulfonic acid, page 128) and acetoacetic ester, and coupled with diazotized aniline ... 

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>. 

Turchi and Cullen described the first examples of pyrazoles prepared from oxazoles (Scheme 1.231). Treatment of 5-ethoxy-p-oxo-2-phenyl-4-oxazolepropa-noic acid ethyl ester 857 with hydrazine did not afford the expected pyrazolone 858. Instead, the authors isolated ethyl-4-(benzoylamino)-5-ethoxy-l//-pyrazole-3-acet-ate 860 (R = H) in good yield. Similarly, reaction of 857 with methyUiydrazine produced 860 (R = CH3) in comparable yield. 

This reaction was first reported by Knorr in 1883. It is the preparation of pyrazole derivatives from 1,3-dicarbonyl compounds and hydrazines. Similarly, pyrazole derivatives can also be prepared from hydrazines and equivalent molecules of 1,3-dicarbonyl compounds, such as a-ethoxymethylene a-phenylacetone. In a special case, -carbonyl aldehyde reacts with a simple hydrazine to afford tautomers of 3- and 5-substituted pyra-zoles, of which the proton oscillates rapidly back and forth between two nitrogen atoms. These two tautomers are distinguishable only at sufficiently low temperatures." It should be pointed out that the reaction of hydrazine with j8-carbonyl ester leads to the formation of pyrazolone. ... 

Five-membered aromatic heterocycles can be prepared from silylhydrazines and ethyl acetate (Scheme 5). Condensation of ethanol leads to pyrazolones. Starting with organohydrazines, for example, with phenylhydrazine three isomeric rings are known. The CH form is isolated in nonpolar solvents. In water 90 % of the NH form with 10 % of the OH form exist in an equilibrium. The hitherto unknown Si form could be isolated by starting with silylhydrazines. 

The TV-substituted thiosaccharine derivatives (106) are formed with LR. The ester group is not attacked by LR and the yields are higher than those obtained with phosphorus pentasulfide. 4-TV2-Arylhydrazono-5-methylpyrazole-3-thiones have been prepared from the corresponding pyrazolones. Thionation of the... 

Various derivatives of this ring system—pyrano[2,3-c]pyrazole (X)—have recently been prepared from 4-acetyl-1-aryl-3-methyl-5-pyrazolones and suitable carbonyl compounds by means of base-catalyses, followed by ring closure [7]. Some of these compounds are being evaluated for pharmacological activity. 

A soln. of benzenediazonium salt prepared from aniline, NaNOa, and 4%-HCl added portionwise with cooling at 0° to a stirred soln. of 3-ethoxycarbonylamino-l phenyl-5-pyrazolone in pyridine, and the product isolated after 12 hrs. -> 3-ethoxycarbonylamino-4-phenylhydrazono-l-phenyl-5-pyrazolone (Y 97%) refluxed in cw-decalin until crystals separate after 5-10 min. ->tetrahydro-2,6-di-phenylpyrazolo[3,4-e][l,2,4]triazine-3,7-dione (Y 94%). F. e. s. J. Slouka and P. Pec, M. 103, 1444 (1972). 

In a related piece of work, imidazolines have been prepared from A -chloro-N-phenyl amidines and enamines. (Scheme 79). Pyrazomycins have been synthesized by the Roche group, the key step being the preparation of the pyrazolone ring by the addition of toluene- -sulphonyl azide to the anion from diethyl acetone dicarboxylate (Scheme 80). Imidazolidines (201) have been prepared by the action of isocyanates and isothiocyanates with an aziridine ester a dipolar intermediate is implicated. Imidazolidine-4,5-diones have been prepared by the... 

The preparation of methyl-phenyl-pyrazolone illustrates one of the synthetic uses of ethyl acetoacetate, as distinct from those involving the hydrolysis of substitution derivatives. 

Mix 6 2 ml. (6 4 g.) of pure ethyl acetoacetate and 5 ml. of pure phenylhydrazine in an evaporating-basin of about 75 ml. capacity, add 0 5 ml. of acetic acid and then heat the mixture on a briskly boiling water-bath (preferably in a fume-cupboard) for I hour, occasionally stirring the mixture with a short glass rod. Then allow the heavy yellow syrup to cool somewhat, add 30-40 ml. of ether, and stir the mixture vigorously the syrup may now dissolve and the solution shortly afterwards deposit the crystalline pyrazolone, or at lower temperatures the syrup may solidify directly. Note. If the laboratory has been inoculated by previous preparations, the syrup may solidify whilst still on the water-bath in this case the solid product when cold must be chipped out of the basin, and ground in a mortar with the ether.) Now filter the product at the pump, and wash the solid material thoroughly with ether. Recrystallise the product from a small quantity of a mixture of equal volumes of water and ethanol. The methyl-phenyl-pyrazolone is obtained... 

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

Another sequence involving an anionic and a Pd-catalyzed step was described by the groups of Rossi and Arcadi [477]. These authors prepared substituted tetrahy-dro-2H-pyrrolo[3,2-c]pyrazolones 2-934 starting from hydrazones 2-932 and aryl-halides or alkenyl triflates 2-933 (Scheme 2.208). The first step is the formation of a pyrazolone. There follows cleavage of the urea moiety with piperidine and an inter-as well as an intramolecular Heck-type reaction with 2-933. 

The first commercial synthetic dye, Mauveine (3), discovered by Perkin in 1856, was also a heterocycle, an azine of the Safranine class prepared by oxidation of aniline containing o- and p-toluidines. Since that time the contribution to colour chemistry from heterocyclic synthesis has been considerable and the present review can only hope to present some of the more salient features and at that only briefly. As an illustration it can be noted that since the late 1960s there have been in excess of 230 patents covering the use of azo dye couplers based on 2,6-dihydroxypyridine alone and the number of disclosures describing pyrazolones is probably greater than 1000. 

---