Pyrazole ring reactivities

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

According to Section 4.02.3.1.8 substituents removed from the pyrazole ring by two or more saturated carbon atoms and substituents on the benzene ring of indazoles are similar in reactivity to the corresponding aromatic derivatives. For instance, chloromethyl-pyrazoles are comparable to benzyl chlorides and 5-hydroxyindazoles to /3-naphthols in their reactivity. 

Fused ring systems containing a pyrazole unit can be prepared either from the heterocyclic moiety by formation of a pyrazole ring or from the reaction between a pyrazole derivative and a suitably functionalized reagent. The ring systems thus obtained are discussed in detail in other chapters (Chapters 4.05, 4.35, 4.36) but it is of interest to discuss here those methods which start from a pyrazole derivative as the reactions involved can be considered as examples of the reactivity of pyrazoles. The most widely studied fused ring systems are the [5.6] systems and the examples described in this section will be chosen from this group and, occasionally, from [5.5] and [5.7] systems. 

There are slight differences in the reactivity of the acetylenic groups depending on their position in the pyrazole ring. This can be followed using py-razole diethynyl derivatives as an example. In the case of 4,5-diethynyl- and... 

Although in theory vinylpyrazoles can react with dienophiles to give Diels-Alder adducts, the reaction destroys the aromaticity of the pyrazole ring, and these dienic systems show a very low reactivity toward dienophiles. 

The reaction of l-aryl-4,6,6-trimethyl-3-phenyl-l,6-dihydropyrano[2,3-cjpyrazoles 88a-d with DMAD in dimethylformamide (DMF) at reflux is the first example of a Diels-Alder reaction involving the pyrazole ring. The reaction afforded an indazole 89 by elimination of a molecule of acetone from the intermediate cycloadduct (83S852). The s-cis conformation of the reactive diene fixed by the dihydropyran and the aromatization process to afford the indazole by elimination of acetone could be the driving force for this reaction. 

Since the reactions involve only the olefinic substituent, with no participation in the cycloaddition reaction of the pyrazole ring, the authors considered important the preparation of l-phenyl-5-vinylpyrazole 96 and the study of its reactivity. Differences in electron densities and steric hindrance for the 4- and 5-positions of the 1-phenylpyrazole made it difficult to predict possible similarities in reactivity between l-phenyl-5-vinylpyrazole 96 and l-phenyl-4-vinylpyrazole 90a and the study showed that the reactivity of 1-phenyl-5-vinylpyrazole was lower, with reaction times longer than those required for the vinylpyrazole 90a. With all the dienophiles used, included DEAZD, Diels-Alder adducts were obtained exclusively [90JCS(P1)2749]. 

Practically all linear 1,3-diketones13 7-142 give the corresponding pyrazoles with hydrazine104 143 and its derivatives.144-149 The reaction of aliphatic diketones should be moderated by dilution, cooling, or the addition of acid.137 Since pyrazole rings are stable, severe conditions may be used in their preparation where necessary. For details of the hydrazine/acetylacetone reaction see Wiley and Hexner.150 Evidently the reaction proceeds via the formation of the monohydrazone (11)151 which, when aryl-substituted, is less reactive and may be isolated.83,152-159 (However, see reference 159a.) It is not known if the monohydrazones are cyclic (12) or not, but they are... 

A pyrazole ring also serves as a directing group (Eq. 29) [46]. The reactivity of N-phenylpyrazole is much higher than expected on the basis of the basicity of the pyrazole. 

The tautomerism of these compounds has already been discussed (Section 4.04.1.5.2). Owing to the extra functionality they have a complex reactivity, and to the reactions of the substituent must be added those of the pyrazole ring itself (Section 4.04.2.3), which are different for each tautomer. In addition to the three neutral tautomers, one has to bear in mind that the NH and OH tautomers of 5-pyrazolones can be written as betaines as in formula (158) which is important in understanding their reactivity. 

Pyrazole rings are formed from 2-alkylpyridine-Af-imines and acid chlorides under basic conditions. For example, the 1-aminopyridinium salt (336) gives first (337) but this is very reactive and is acetylated under the reaction conditions to (338 Scheme 95) (68JOC3766). The 2-hydroxymethylpyridine (339) shows similar reactions (Scheme 96) (73CPB2146). 

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