1-(1H-Pyrazol-1-yl)ethanone CAS 10199-64-1

Pyrazole is a π-excess aromatic heterocycle. Electrophilic substitution reactions occur preferentially at position 4 and nucleophilic attacks at positions 3 and 5.

The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. we will study this evolution and present the methods generally used to access substituted pyrazoles, that is to say:

Cyclocondensation of hydrazine and similar derivatives with carbonyl systems.
Dipolar cycloadditions.
Multicomponent reactions.
Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems
The leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an α,β-unsaturated ketone.

From 1,3-Diketones
The cyclocondensation of the 1,3-dicarbonyl compounds with the hydrazine derivatives is a simple and rapid approach to obtain polysubstituted pyrazoles. The first synthesis of the substituted pyrazoles was carried out in 1883 by Knorr et al. who reacted β-diketone 1 with hydrazine derivatives to give two regioisomers 2 and 3.

Indeed, the authors have found that the cyclocondensation of an aryl hydrochloride hydrazine with 1,3-diketones in aprotic dipolar solvents gives better results than in the polar protic solvents (like ethanol) generally used for this type of reaction. After optimization of the conditions, the addition of a solution of HCl 10 N to the amide solvent (DMF, NMP, DMAc) or urea (DMPU, TMU) makes it possible to increase the yields by accelerating the dehydration steps. The cyclocondensation of the diketones with hydrazine thus takes place at ambient temperature in N,N-dimethylacetamide, in an acid medium, to give the corresponding pyrazoles with good yields and good regioselectivity.

The condensation of various arylhydrazine with 4,4,4-trifluoro-1-arylbutan-1,3-diketones 9, afforded two isomers 11, 12 with 74–77% yields. The selectivity obtained is of the order of 98:2 in favor of the isomer 11. By comparison, the reactions carried out under conventional conditions in ethanol, at ambient temperature, give equimolar mixtures of the regioisomers. Nevertheless, a loss of control of the regioselectivity is observed when the CF3 group is replaced by a CH3 or CHF2. Finally, the condensations of aryl hydrazines with the 1,3-diketones 13 that are 2-substituted by an alkyl group give the trisubstituted pyrazoles 14 and 15 in 79–89% yields and a regioselectivity greater than 99.8:0.2 in favor of isomer 15 in all cases.

From Acetylenic Ketones
The cyclocondensation reaction of hydrazine derivatives 17 on acetylenic ketones 16 to form pyrazoles has been known for more than 100 years. However, the reaction again results in a mixture of two regioisomers 18 and 19.

The diacetylene ketones 20 reacted with phenylhydrazine 5 in ethanol to give two regioisomeric pyrazoles 21 and 22. When phenylhydrazine was used, a mixture of regio-isomers 21/22 was generated in approximately 3:2 ratio. When hydrazine hydrate was used as the nucleophile, only regioisomer 21 was isolated, presumably due to hydrogen bonding to the ethyl ester group.

The difference in regioselectivity observed when using methylhydrazine (ratio 27/28 = 93:3 to 97:3) or an arylic hydrazine (ratio 28/27 = 87:13 to 99:1) is explained by the fact that the nitrogen carrying a methyl group is much more nucleophilic and will react by Michael addition on the triple bond of the acetylenic ketone followed by the intramolecular formation of an imine. In the case of a hydrazine substituted by an aryl group, the primary amine is the most nucleophilic and will react on the triple bond followed by the attack of the secondary amine on the carbonyl.

From Vinyl Ketones
The cyclocondensation reaction between an α,β-ethylenic ketone and a hydrazine derivative results in the synthesis of pyrazolines which, after oxidation, provide the pyrazole ring.

The condensation of an α,β-ethylenic ketone 29 with p-(4-(tert-butyl)phenyl)hydrazine 30 in the presence of copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] (PF6) as catalysts, to access pyrazoline 31. The corresponding 1,3,5-trisubstituted pyrazole 32 was obtained after oxidation in situ of this pyrazoline. The reaction protocol gave 1,3,5-triarylpyrazoles in good yields (about 82%) via a one-pot addition–cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization stands without the requirement of an additional oxidizing reagent. The catalyst can be reused more than four cycles without much loss in the catalytic activity.

The synthesis of 3,5-diaryl-1H-pyrazoles from the reaction β-arylchalcones 33 with hydrogen peroxide that gave epoxides 34. Then, addition of hydrazine hydrate afforded pyrazoline intermediates 35, dehydration of which yielded desired 3,5-diaryl-1H-pyrazoles 36.