1- Pyrazolines, 3-substituted synthesis

Pyrazolines substituted at position 4 or 5 with hydroxy or amino groups readily eliminate a molecule of water or amine yielding pyrazoles. The 4-substituted derivatives are relatively more stable than the 5-substituted ones, because for the last group the lone pair at N-1 assists the elimination (407) -> (408) -> (409). The sulfonyl group at position 1 is also easily eliminated and this property is taken advantage of in Dorn s elegant synthesis of 3-aminopyrazole (Section 4.04.3.3.1). 

The general method for the preparation of diphenylpyrazolines is shown in Scheme 11.8, in which X is a suitable leaving group, usually chloro but sometimes dialkylamino. This reaction normally proceeds readily, although pH control may be important. Preparation of the substituted ketone and hydrazine intermediates needed for the synthesis may involve lengthy and complicated sequences. Further reactions are often required to modify the substitution in ring B after formation of the pyrazoline ring. The preparation of compound 11.26 shown in Scheme 11.9 illustrates one of the simpler instances. 

Rurack K, Bricks JL, Schulz B et al (2000) Substituted l,5-diphenyl-3-benzothiazol-2-yl-A2-pyrazolines synthesis, X-ray structure, photophysics, and cation complexation properties. J Phys Chem A 104 6171-6188... 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

On the other hand, pyrazoline and pyrazole derivatives are successfully used for material science tasks. For example, triarylpyrazolines are used in the synthesis of green electroluminescent polymers for light-emitting diodes [18], Some aromatic substituted 2-pyrazolines are effective organic luminophores [19,20], fluorophores [21] and scintillating materials [20, 22]. 

To accelerate the reactions rates and to increase their yields, sometimes microwave-assisted procedures are applied. The first mention of using a solvent-free microwave procedure was in [55]. The authors described the synthesis of 1,3,5-triarylpyrazoline by the cyclization of chalcones with phenylhydrazine on a basic alumina solid support. The target heterocycles were synthesized under microwave irradiation in high yields (up to 85%) in 1-2 min instead of 3 h in the case of thermal activation. Another publication [56] deals with the rapid (2-12 min) solvent-phase cyclization of naphthyl-substituted chalcones 41 and hydrazines 42 in a microwave field yielding the appropriate pyrazolines 43 quantitatively (Scheme 2.10). 

Access to alkyl substituted derivatives of the homotropylidene complexes is provided via the / -tropone iron complex by reaction with diazoalkanes, followed by mild thermolysis of the 3+2 pyrazoline adduct to give the corresponding homotropone complexes (equation 149)217,218 jYiQ 8,8-dimethyl derivative was used as starting material for the preparation of the fluxional ( -2,8,8-trimethylbicyclo[5.1.0]octa-2,4-dienylium)Fe(CO)3 cation com-plex More recently (homotropone)Fe(CO)3 was used for the synthesis of unique chiral 1,2-homoheptafulvene iron complexes . ... 

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>. 

The addition of hydrazines to chalcones gives dihydropyrazoles, which can be functionalized further. Eor example, a,/3-unsaturated ketones 643 were condensed with arylhydrazines to yield dihydropyrazoles 644 these can be further alkylated and oxidized to l,3,5-triaryl-4-alkylpyrazoles 645, which are novel ligands for the estrogen receptor (Scheme 80) <20000L2833>. A parallel solution-phase synthesis of an N-substituted 2-pyrazoline library 648... 

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. 

Only two procedures are known for direct synthesis of the 2-pyrazolin-4-one ring system and one of these has been used very little. The chief method employed has been cyclization of the 1-arylhydrazone of 3-substituted-l,2-dioxo compounds (eq. 242) using basic cyclizing... 

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... 

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