Pyrazolidine

Flavazin L has already been described as a textile dye derived from pyrazolone. Tartrazine 5 is one of the few synthetic dyes which are approved for colouring foodstuffs and cosmetics. The yellow compound, which is the trisodium salt, is produced by coupling 2,4-dihydro-3//-pyrazol-3-ones with diazo-tized sulfanilic acid. The required pyrazole is accessible from diethyl 2-oxobutanedioate and 4-hydrazinobenzene-1-sulfonic acid. 

4-Dihydro-3//-pyrazol-3-ones are also used as couplers in colour photography. During the chro-mogenic development of the exposed colour film, they react with the developer, e.g. iV,iV-diethyl-p-phenylenediamine, to give a purple dye 6. 

3-Diaryl-4,5-dihydropyrazoles are used as optical brighteners, e.g. the l-[4-(aminosulfonyl)-phenyl]-3-(4-chlorophenyl)-4,5-dihydropyrazole [140]. 

Several oxo compounds are derived from pyrazolidine, a cyclic iy,iV-disubstituted hydrazine. Pyra-zolidin-3-ones, as well as pyrazolidin-4-ones are known [141]. The anti-inflammatory phenylbutazone 1 is a substituted pyrazolidine-3,5-dione. It is made by C-alkylation of l,2-diphenylpyrazolidin-3,5-dione. For the industrial synthesis, cyclocondensation of 1,2-diphenylhydrazine with diethyl 2-butyl-malonate is preferred  

Phenylbutazone, pKa = 4.5, is soluble in sodium hydroxide and forms the salt 2. 

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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. 

C3N2 N N — — — Pyrazole substituted pyrazoles A - and A -pyrazolines pyrazolinones pyrazolidines pyrazolidinones... 

Cationic rings are readily reduced by complex hydrides under relatively mild conditions. Thus isoxazolium salts with sodium borohydride give the 2,5-dihydro derivatives (217) in ethanol, but yield the 2,3-dihydro compound (218) in MeCN/H20 (74CPB70). Pyrazolyl anions are reduced by borohydride to pyrazolines and pyrazolidines. Thiazolyl ions are reduced to 1,2-dihydrothiazoles by lithium aluminum hydride and to tetrahydrothiazoles by sodium borohydride. The tetrahydro compound is probably formed via (219), which results from proton addition to the dihydro derivative (220) containing an enamine function. 1,3-Dithiolylium salts easily add hydride ion from sodium borohydride (Scheme 20) (80AHC(27)151). 

Some tetrahydro azoles can be aromatized, but this is more difficult than in the corresponding dihydro series. Thus the conversion of pyrazolidines into pyrazoles is accomplished with chloranil. Imidazolidines are aromatized with great difficulty. 

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. 

One double bond. The three pyrazolines, A - (15), A - (16) and A -pyrazoline (17), and the carbonyl derivatives of pyrazolidines like (18), are the most representative compounds of this group. 

Without double bonds. Pyrazolidines (19) are the only representative of this group. 

Following the classification of Chapter 4.01, three classes will be considered, (a) Compounds isomeric with aromatic compounds (6), (7) and (8). The quaternary, non-aromatic salts (Scheme 7, Chapter 4.01) will be discussed only in connection with protonation studies which lead to the conclusion of their non-existence. The carbonyl derivatives (9), (10), (13) and (14) will also be included here because it is possible to write an aromatic tautomer for each one, (9 )-(14 ), even if it is energetically unfavoured, (b) Dihydro compounds. In this class not only pyrazolines (15), (16) and (17) but also pyrazolidinones (18) and pyrazolinediones like (1) are included, (c) Tetrahydro compounds. Besides the pyrazolidines (19), the pyrazolidinetriones (2) are included here. 

Pyrazolidine 2-AcetyI-5-(methoxycarbonyImethyI)-l-methyI-3,4,5-pyrazolidinetricarboxylic acid, trimethyl ester 79CB1719... 

The fully saturated pyrazolidines have been utilized as models for the study of the nitrogen inversion of hydrazines. For instance, (75), a 2,3-diazabicyclo[2.2.1]heptene derivative, presents a consecutive inversion process at two nitrogen atoms with an activation barrier... 

The conformation of heteroethylenic rings. A - and A -pyrazolines, and the nitrogen inversion and preferred orientation of the IV-methyl groups in pyrazolidines (71T123) have been discussed in connection with their NMR spectra (Section 4.04.1.3.3). 

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 -Pyrazolines are obtained by the reduction of pyrazoles with sodium and alcohol, by catalytic hydrogenation on palladium or by electrochemical means (B-76MI40402). In some cases the reduction proceeds further yielding pyrazolidines and open-chain compounds. 

The stereochemistry of pyrazolines and pyrazolidines has already been discussed (Section 4.04.1.4.3). Optically active A - and A -pyrazolines have seldom been described (77JA2740, 79CJC360), but cis-trans isomeric pairs are common. The C-4 acid-catalyzed epimerization involves the mechanism shown in Scheme 38 (70TL3099), but in spite of some inconclusive arguments the C-5 epimerization has never been established with certainty. 

Pyrazolidines are cyclic hydrazones and their reactivities are comparable, the main difference being found in the oxidation of pyrazolidines to pyrazolines and pyrazoles. 

Analogous to the oxidation of hydrazones to azo compounds, A-unsubstituted pyrazolidines are oxidized to A -pyrazolines. For example, the blcyclic pyrazolidine (415) when treated with silver oxide yields the pyrazoline (416) (65JA3023). Pyrazolidine (417) is transformed into the perchlorate of the pyrazolium salt (411) by reaction with mercury(II) acetate in ethanol followed by addition of sodium perchlorate (69JOU1480). 

The pyrazole (420) is formed when the pyrazolidine (418) is heated with chloranil and the intermediate A -pyrazoline (419) (one of the rare A(l)-unsubstituted derivatives) can be isolated (78TL4503). 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

The stereochemistry of pyrazolidines has briefly been discussed in Section 4.04.1.4.3. The pyrazolidine ring in (429) in the crystal state is not planar and the configuration about the amide bond is E as represented. 

Azomethines add with great ease and stereospecificity to carbon-carbon double bonds affording pyrazolidines. They also add to carbon-carbon triple bonds with the formation of pyrazolines. Benzimidazolium iV-imines, e.g. (622), are a special case of azomethines. Its reaction with DMAD yields l-(2-methylaminophenyl)pyrazole (624), which is formed by cleavage of the initial adduct (623) (75JHC225). 

Monosubstituted hydrazones react with alkenes and alkynic compounds to yield pyrazolidines and pyrazolines, respectively (71LA(743)50, 79JOC218). Oxidation often occurs during the reaction and pyrazoles are isolated as the end product. 

The synthesis of l-phenyl-2-(phenylcarbamoyl)pyrazolidines (721) afforded a new series of anticonvulsant agents (79JPS377). 

Formal addition products of 1,3-dipoles are compiled in a recent review (79AHC(24)63). Examples include addition to a nitrone forming a six-membered ring, to an enamine forming a pyrazolidine ring, and to the C=0 bond of diphenylcyclopropenone. 

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-... 

Pyrazolidine, l,2-diethyl-3-hydroxymethyl-biological activity, 5, 297 Pyrazolidine, 2-ethoxycarbonyl-l-phenyl-reactions, 5, 257 Pyrazolidine, 4-hydroxy-synthesis, 5, 155 Pyrazolidine, 1-phenyl-... 

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