Pyrazolidine-3,5-diones

Sulfinpyrazone Sulfinpyrazone, l,2-diphenyl-4,2-(phenylsulfinil)ethyl-3,5-pyrazolidine-dione (3.2.8), is an analog of phenylbutazone that is synthesized in the analogous manner of condensing hydrazobenzol with 2-(2-phenyltioethyl)malonic ester into pyrazolidinedione (3.2.7), and the subsequent oxidation of thiol ether by hydrogen peroxide in acetic acid into the sulfoxide, sulfinpyrazone (3.2.8) [70,71]. 

Bromination occurs readily with formation of 4-bromo-3,5-pyrazolidine-diones.1031 1032 1048 A 4-phenyliminomethinyl substituent can be introduced1190 by reaction with A,jV -diphenylformamidine (eq. 257). 

Diazo-Meldrum s acid does have one serious drawback it sublimates out of the coating during the prebake step. Enormous efforts were made with a view to finding related chromophores that do not sublimate. Successful candidates include diazo-pyrazolidine dione (DPD) (XIV), diazotetramic acid (XV), and diazopiperidine dione (XVI). ... 

Figure 1. Summary ofthe aryl-pyrazolidine-dione optimization demonstrating key fragment contributions to activity level against grass weed species (aryl moiety) and tolerance in cereal crops (hydrazine moiety).

General access to analogs Aryl-pyrazolidine-diones, precursors of the target molecules, were primarily prepared via a thermal condensation reaction between hydrazines and aryl malonates. While scouting for a technical synthesis of pinoxaden, it was moreover discovered that aryl malonamides will react with equal efficacy (NH3 extrusion), a reaction unprecedented in the literature [8]. 

Synthesis of pinojaden A convergent synthetic route leads to the pyrazolidine-dione NO A 407854, which is esterihed in the last step with pivaloyl chloride. Pinoxaden is prepared effectively in a total of 5 (longest linear sequence) + 3 (oxadiazepane synthesis), total 8 steps. Key reachons are an efficient malononitrile arylation via cross-coupling [12] to access a sterically hindered aryl malononitrile and the unprecedented condensation of its malonamide derivative with [l,4,5]oxa-diazepane [8], This sequence fits feasibility criteria for a technical application. 

In Zurich, IS cases of pseudo-lupus eiythema-todes syndrome were observed in patients treated for long periods with Venocuran . It was subsequently found that among pseudo-LE cases in Germany there were many patients who had been taking a similar product (Venopytonum). Both products contain, alongside the natural extracts, a quantity of phenopyrazone (1,2-diphenyl-3,5-pyrazolidine-dione) which may well have been responsible for this complication. The trade name Venopytonum is, however, also in use for other products in the series to which phenopyrazone has not been added (14). 

Neither pyrazolidines (9), which have no double bonds, nor pyrazoline diones (10), with two double bonds, and pyrazoUdine triones (11), which have three double bonds, are covered in this article. 

Three double bonds. The most fully oxidized pyrazoles, the typical non-aromatic representatives of which are the pyrazoline-4,5-diones (1) and the pyrazolidine-3,4,5-triones (2), should be included here. 

A Hammett relationship of the form ApK = 5.8am has been proposed for 4-substituted pyrazoles (74TL1609) in order to explain the effect of 4-nitro ApK = 4.5, am = 0.71) and 4-diazo groups (Apiifa = 10.0, am = 1.76). The acidity constants of a series of pyrazolidine-3,5-diones have been determined (75AJC1583) and the 4- -butyl-1,2-diphenyl derivative phenylbutazone has a pK of 4.33. 

A variety of mono- and bi-cyclic /3-lactams have also been prepared by oxidative ring contraction of pyrrolidine-2,3-diones (180) (75JOC2356), and by the photolysis of pyrazolidin-3-ones (181) (78T1731, 75JOC3510, 75JOC3502, 75CC725). 

Pyrazolidine-3,5-dione, 4,4-diethyl-1,2-dimethyl- CNMR, 5, 194 (80CB3910) Pyrazolidine-3,5-dione, 4-(dimethylaminomethylene)-1,2-diphenyl-... 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

Voigt-Martin et al. [13] have used MICE to solve the stmcture of 4-(4 -(N,N-dimethyl)aminobenzylidene)-pyrazolidine-3,5-dione at 1.4A in projection using 42 reflections. The potential maps do not resolve atoms with these data and models have to be fitted to the map density in a way reminiscent of macromolecular crystallography. This can pose problems in structure validation which were overcome in this case by simulation calculations. There is an excellent agreement between the solution and independent model building and high resolution electron microscopy studies. 

Treatment of phenylbutazone and sulfinpyrazone with one equivalent of iV-fluorobis(trifluoro-methylsulfonyl)amine (1 d) in acetic acid and chloroform solution, respectively, results in clean fluorination at position four, and the corresponding 4-butyl-4-fluoro-l, 2-diphenylpyrazolidine-3,5-dione (22a) and 4-fluoro-1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]pyrazolidine-3,5-dione (22b) are obtained in 95 and 90% isolated yield.148... 

Acidic enolic compounds (pyrazolidine-3,5-diones, oxicams)... 

Synthesis Feprazone is prepared by the condensation of acetic acid 3-methyl-but-2-enyl ester with the lithium salt of 1,2-diphenyl-pyrazolidine-3,5-dione in the presence of tetrakis(triphenylphosphin)palladium in anhydrous tetra-hydrofuran. 

Butyl-1-phenyl-pyrazolidine-3,5-dione, C13H16N202, Mr 232.28, mp 102-103 °C sodium salt [41468-34-2], C13Hi5N2Na02, Mr 254.27... 

Comm. Farmaceutica Milanese Preparation of 4-n-butyl-2-phenyl-pyrazolidine-3,5-dione and 1-alkyl substituents thereof, GB 839 057,1957. 

As another important mechanistic type, fragmentation into at least three products that are formed more or less simultaneously has to be mentioned. Such [5 - 2 + 2 + 1] reactions were encountered in 2-pyrrolidinones (65, 67), certain pyrazolidine derivatives (68, 72, 73), l,2,4-triazolidine-3-ones (69) and l,2,4-triazolidine-3,5-diones (70), 2//-pyrrol-2-ones (71), 1,3-dithiolane 1-oxides (78), 1,2,3,4-thiatriazoles (74), 1,2,4-oxadiazolines (75), and in several rings containing sulfur in an oxidized state (76-79,82). Most of these molecules have an exocyclic double bond. 

A mixture comprising 108 g of phenyl hydrazine and 216 g of the diethyl ester of n-butylmalonic acid is heated on an oil bath at 170°-180°C for 12 hours. The residue is taken up with water in which an alkaline compound has been dissolved and acetic acid is added to precipitate 4-n-butyl-2-phenyl-pyrazolidine-3,5-dione. The product is a white crystalline solid having a MP 103°C. It is soluble in acetone and benzene, soluble in hot condition in methanol and ethanol and insoluble in water. 

The C—N bond of (56 A = B = O) is easily cleaved in alkaline media to form pyrazolidine-3,5-diones (58) (71CHE1028). The product of the reaction of hydroxide ion with a typical syn-bimane was shown to be the 2-pyrazolinonylacrylic acid (82JOC4222). 

A large number of diazetidinones 15 have been synthesized by an intramolecular cyclization of haloacetylhydrazones 14 with suitable bases (Scheme 11) . A photochemical Wolff rearrangement of 4-diazo-pyrazolidine-3,5-diones 16 in the presence of some nucleophiles (H20 or alcohols) leads to diazetidinones 17 in moderate yields (Scheme 12) <1987J(P1)899>. 

The anionic [3,3] sigmatropic rearrangement of cyclic diacyl pyrazolidines resulted in poor to good yields of 1,5-diazonane-6,9-diones <2000H(53)151 >. 

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