Pyrazole. alkylation tautomerism

But when Begtrup (88BSB573) (Scheme 7) treated the pyrazol-3-one 19/pyrazole 20 tautomeric mixture with 4-methoxybenzyl chloride he obtained 5% of O-alkylated pyrazole derivative 21 and 70% of l-(4-methoxybenzyl)pyrazol-3-one 22. 

Unsymmetrical pyrazoles can exist in two tautomeric forms, which on complete alkylation give the same methiodide. 

When the pyrazole is substituted by an electron-withdrawing group in the 3- or 5-position, alkylation usually proceeds on the nitrogen atom nearer to the electron acceptor, although a number of exceptions to this rule are known.83,88 With different substituents in the 3- and 5-positions, one of the two tautomeric forms may be expected to predominate. A separation of the isomeric alkylation products is usually quite laborious. Differences in steric hindrance682 or basicity714 have been used, and also fractional crystallization of salts or distillation.663... 

Since an asymmetric pyrazole such as 3(5)-Mepz can exist in two tautomeric structures in solution the reaction of asymmetric pyrazole with alkylation agents under P.T.C. conditions yields the three isomers I, II, and III shown in Scheme 14. Generally, the relative amounts of isomeric RR C(pz)2 (I II III) correspond to (a + b)2. Reaction of 3-(2-pyridyl)pyrazole with CH2Br2 affords only two isomers I and II,218 whereas 3-(tertbutyl)pyrazole under analogous conditions gives only isomer I.219... 

Khalil et al. (05PS479) reacted hydrazine hydrate with ethyl acetoacetate, ethyl benzoylacetate or ethyl nicotinoylacetate in boiling ethanol and obtained 5-substituted pyrazol-3-ols la-c (Scheme 75). The existence of pyrazoles 325a-c predominantly in their enol tautomeric form was confirmed by spectroscopic data as well as by phase-transfer catalysis (PTC) alkylations, affording O-monoalkylated or O- and... 

Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a-d/pyrazol-5-ol 79a d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,... 

Pyrazol-3-ones 116a d are converted into the more stable O-alkyl-5-hydroxy-pyrazole-4-carbothioates 117a-d instead of their tautomeric pyrazol-3-ones 118a-d by treatment with calcium hydroxide and then with 0,0-diethyl- or 0,0-di-n-butyltrithiotricarbonate in 1,4-dioxane. The yield of the products is 38, 22, 20 and 16% respectively (95JHC1377) (Scheme 37). 

Thiadiazine 1,1-dioxides (389) have been synthesized by Ochoa s group and a comparative study of their physiochemical properties with that of pyrazoles 390 has been made371,372. Rough parallels are observed in the tautomeric equilibria of (389) and (390) with 13C chemical shifts and the reactivity of the 4-position while differences in their aromaticity have been observed. The 1,2,6-thiadiazine-1,1-dioxides 389 are prepared either by reaction of sulphamide or substituted sulphamides with 1,3-dicarbonyl compounds or their acetal derivatives or by AT-alkylation of the unsubstituted derivatives. 

The ramification of the tautomerization is that alkylation of unsymmetrically substituted pyrazoles often gives rise to a mixture of two isomers, one is the iV-1 alkylation and the other is the N-2 alkylation. The ratio depends on the nature of the substrate and the electrophile as well as on the solvent and base (vide infra). 

The high m.p. and b.p. of p3rrazole compared with 1-alkyl or aryl substituted pyrazoles are due to intermolecular hydrogen bonding which results in the dimmer. It is a tautomeric substance. Pyrazole is a weak basic and forms salts with inorganic adds the imino hydrogen... 

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