1- Pyrazolines, 3-substituted

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). 

Scheme 1.16. Thermal extrusion-rearrangement of the first isolated fullerene-fused pyrazoline substituted at C(3), affording diastereoisomeric 6-5 open homo[60]fullerene derivatives, of which the major isomer has the bulkier group located above the former pentagon.

Double addition of diazomethane to cinnamylidene cyanoacetic ester 50 (EWG = COOR ) and corresponding dinitriles (51) (EWG = CN) followed by thermolysis gave rise to pyrazoline-substituted cyclopropanes (52) which upon photolysis and acid treatment afforded biscyclopropanes (53) and tricyclic compounds (54) respectively. ... 

Pyrazole can be prepared by addition of diazomethane to acetylene, and ethylene analogously gives pyrazoline. Substituted ethylenes, cyclenes, 1,3-dienes, and, / -unsaturated carbonyl compounds can also add diazomethane.107 In these reactions 1-pyrazolines are the primary products, but these are converted by basic or acidic reagents or by light into the 2-pyrazo-lines 108... 

The intramolecular Diels-Alder reaction of 2(lH)-pyrazolines substituted at the 3-position with a phenylalkyne-containing side-chain (175) will lead to either benzofuro-[2,3- ]pyridines (176) or benzofuro[2,3-c]pyridin-l(2-H)-ones (177) depending on the substitution pattern on the pyrazoline moiety (Scheme 67). " ... 

PyraZolines. l,3-Diphenyl-2-pyia2olines (7) (Table 2) aie obtainable from appiopiiately substituted phenyUiydiazines by the Knoii reaction with either P-chloro- or P-dimethylaminopropiophenones (30,31). They are employed for brightening synthetic fibers such as polyamides, cellulose acetates, and polyacrylonitriles. 

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

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Together with pyridones, the tautomerism of pyrazolones has been studied most intensely and serves as a model for other work on tautomerism (76AHC(Sl)l). 1-Substituted pyrazolin-5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), (DH (78b) and NH (78c). In the vapour phase the CH tautomer predominates and in the solid state there is a strongly H-bonded mixture of OH and HN tautomers (Section 4.04.1.3.1). However, most studies of the tautomerism of pyrazolones correspond to the determination of equilibrium constants in solution (see Figure 20). 

The problem of tautomerism is simpler in the case of 1-substituted pyrazolin-3-ones since only two forms, the OH (140a) and the NH (140b), are possible. The OH form is the more stable and is the only one present in the crystal (Section 4.04.1.3.1). In protic solvents, like water or methanol, the equilibrium position is much more evenly balanced between the OH and NH forms. Finally, 4-hydroxypyrazoles (141) exist as such. A CNDO/2 calculation justifies the result that 4-hydroxy tautomers are relatively more stable than... 

A mechanism has been proposed to rationalize the results shown in Figure 23. The relative proportion of the A -pyrazolines obtained by the reduction of pyrazolium salts depends on steric and electronic effects. When all the substituents are alkyl groups, the hydride ion attacks the less hindered carbon atom for example when = Bu only C-5 is attacked. The smaller deuterohydride ion is less sensitive to steric effects and consequently the reaction is less selective (73BSF288). Phenyl substituents, both on the nitrogen atom and on the carbon atoms, direct the hydride attack selectively to one carbon atom and the isolated A -pyrazoline has the C—C double bond conjugated with the phenyl (328 R or R = Ph). Open-chain compounds are always formed during the reduction of pyrazolium salts, becoming predominant in the reduction of amino substituted pyrazoliums. 

Isopyrazole quaternary salts (363) are key intermediates leading to the highly substituted A -pyrazolines. Lithium aluminum hydride gives the pentasubstituted derivatives (364 R = H) and Grignard reagents provide access to the fully substituted A -pyrazolines (364 R H) (68BSF3866, 70BSF1121). 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

However, in the case of a-substituted unsaturated esters (4), as for example methacrylic or tiglic acid esters, diazomethane addition results in the formation of stable A pyrazolines (5). The latter products require halogen acids for conversion to the isomeric nonconjugated A -pyrazolines (6). 

In the substituted 2-pyrazoline ring (27) both nitrogen atoms have lone pairs of electrons available those on N-1 are no longer involved in an aromatic system, and in the two cases so far reported the salt... 

Substituted pyrazolin-5-ones have only three and -substituted pyrazolin-3-ones only two tautomers, since now the corresponding 19c and 19d structures are isomers. The calculations involved l-methylpyrazolin-5-one (PM3/6-3H-G, anions and cations), l-phenyl-3-methyl-2-pyrazolin-5-one (DFT, radical reactions) [97JPC(A)3769], and l-(2, 4 -dinitrophenyl)-3-methyl-2-pyrazolin-5-one [B3LYP/6-31G and the crystal structure (Section V,D,2)] (98NJC1421). 

Reaction of substituted hydrazine analogue with protected 3-dicarbonyl compound 67 leads to a ring-forming two-site reaction and formation of the pyrazoline diuretic agent, muzolimine (68). ... 

Diazomethane and 1 -substituted 1 //-azepine-4,5-dicarboxylates 44 yield the C4 — C5 pyrazoline adducts, e. g. 45.234 In contrast, the 1-mesyl and the 1-tosyl derivatives yield only adducts of the benzene imine valence tautomers of the l//-azepines. 

Alkenyl-substituted diarylnitrilimines 325, generated by photolysis or thermolysis of corresponding tetrazoles 324, undergo a regioselective INIC reaction to yield fused 2-pyrazolines (Scheme 34) [93]. Similarly, with alkynyl derivatives... 

Cellulose acetate and triacetate fibres are brightened with disperse-type FBAs, including derivatives of 1,3-diphenylpyrazoline (11.19). These form a commercially important group of FBAs. If suitably substituted they can be applied to substrates other than acetate and triacetate. The commercially more important products of this type are used to brighten nylon and acrylic fibres. Their preparation and other aspects of pyrazoline chemistry are discussed in section 11.8. Examples of pyrazolines used to brighten acetate and triacetate... 

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. 

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