Pyrazolones, preparation

A standard pyrazolone preparation applied to piperidone esters is shown in Scheme 109 (34JA700). Standard procedures for the preparation of saturated and partially unsaturated pyrazolo[l,2-a]pyridazines are shown in Schemes 110 (68BSF4222), 111 (70CPB1526) and 112 <65CR(261)1872). 

As anti-inflammatory drugs, pyrazolone preparations have been used topically for superficial phlebitis and similar inflammatory conditions. Krook (1975) described three cases of contact allergy, one sensitive to oxyphenbutazone, the two others sensitive to phenylbutazone. Phenylbutazone did not cause cross-sensitivity to oxyphenbutazone, while cross-sensitivity the opposite way was found. Vooys and Van Ketel (1977) added one more case of phenylbutazone allergy, and Thormann and Kaaber (1978) recorded four, emphasizing the increased risk of developing hypersensitivity in patients with preexisting skin disorders. 

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 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... 

P Keto esters (t.g., ethyl ocetoacetate) are soluble in solutions of caustic alkalis but not in sodium carbonate solution. They give colours with freshly prepared ferric chloride solution a little alcohol should be added to bring the ester into solution. Sodium ethoxide solution reacts to yield sodio compounds, which usually crystallise out in the cold. Phenylhydrazine yields pyrazolones. They are hydrolysed by boiling sulphuric acid to the Corresponding ketones, which can be identified as usual (Section 111,74). 

Another important reduction process is that of aryldiazonium salts with sulfite/bisulfite at controlled pH to produce aryUiydrazines. AryUiydrazines are important intermediates for the preparation of pyrazolones and indoles. 

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. 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

Phosphorus derivatives of different structures have been prepared including pyrazol-1-ylphosphines PPzs, PhPPz2 and Ph2PPz (Pz for pyrazolate anion (72CRV497,80MI40402)). By transamination with tris(dimethylamino)phosphine, pyrazoles and indazole are converted into (291) and (292), respectively (67CR(C)(265)1507). 3,5-Dimethylpyrazole reacts with amidodichlorophosphates to yield triamides (293) whereas 1-substituted pyrazolones yield amidophosphates (294) (71LA(750)39). 

The reaction is very common in pyrazolone chemistry. Since alkoxypyrazoles and tautomerizable pyrazolones undergo this reaction and 3-pyrazolin-5-ones, like antipyrine, do not, it is assumed that the reaction takes place at C-4 of the OH tautomer. Pyrazolone diazo coupling is an important industrial reaction since the resulting azo derivatives are used as dyestuffs. For instance, tartrazine (Section 4.04.4.1.3) has been prepared this way. 3,5-Pyrazolidinediones react with aryldiazonium salts resulting in the introduction of a 4-arylazo group. As has been described in Section 4.04.2.1.4(v), diazonium salts couple in the 3-position with indazole to give azo compounds. 

Some active 5-pyrazolone derivatives (707) and (708) in which the 1-phenyl substituent of antipyrine was replaced by 2 -, 3 - and 4 -pyridyl groups have been prepared (66HCA272). A series of aminoesters substituted at the nitrogen atom of the ester grouping with an antipyryl residue (709) were found to possess local anesthetic properties (69MI40400). 

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. ... 

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. ... 

The preparation of the selenazolyl-pyrazolones was then effected by a second method, in which first the pyrazolone ring and afterward the selenazole ring was formed. For this purpose -ketoester seleno-semicarbazones were first converted to the corresponding 1-seleno-carbamoyl-3-aIkylpyrazol-5-one. These, by condensation with a-halo-genocarbonyl compounds according to the Hantzsch synthesis, formed the selenazole ring as a second step (17). 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

DERIVATIVES OF PYRAZOLE Pyrazolones rank among some of the more venerable nonsteroidal antiinflammatory agents. The activity of antipyrine (154) was discovered not too long after that of aspirin. The preparation of a plethora of analogues of that compound, all bearing additional substitution at the 4-position, was described in some detail in the earlier volume. 

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. 

Pyrazolones have been prepared by palladium promoted cyclization of a,/ -unsaturated carboxylic acid hydrazides but yields are only moderate (Scheme 91)15 6 and no attempt has been made to effect a catalytic conversion. 

Oxidation of 1 -(alkylamino)pyrazolones 1 allowed the preparation of monocyclic 1,2,3-triazin-4(3i/)-ones 2, which are a new class of heterocycles <06EJ03021>. 

The l-arylpyrazol-5-ones (4.9), prepared by the two-step condensation of an arylhydrazine with ethyl acetoacetate, are the most commonly used coupling components for the synthesis of greenish yellow azo dyes. Coupling occurs at the 4-position of the pyrazolone ring which, as in the case of the acetoacetarylamides discussed above, is activated towards electrophilic attack by the two flanking unsaturated carbon atoms (Scheme 4.14). 

Closely related to the pyrazolones, but less commonly used, are the 5-aminopyrazoles (4.10). Again, these compounds give greenish yellow dyes when coupled at the activated 4-position indicated by the arrow in Scheme 4.15. The aminopyrazoles are prepared by condensation of an arylhydrazine with 3-aminobut-2-enenitrile (diacetonitrile), which is itself produced by dimerisation of ethanenitrile (acetonitrile) over a nickel catalyst. 

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... 

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