Pyrazole ring

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

At Merck Research Laboratories, the imidazole ring ia losartan (81, K = n — butyl), a novel clinical candidate against hypertension, was replaced with a pyrazole ring (52). Some of the best compounds are represented by formula (82), where K = n — butyl and R = 2,6-dichlorophenyl, 2-chlorophenyl, or... 

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. 

The pyrazole ring is generally stable to oxidation and side chains are oxidized to carbonyl groups (66AHC(6)347). l-Aryl-3-methylpyrazoles (134) react with ozone to yield 1,3,4-oxadiazolinones (135) (66AHC(7)183). 

The pyrazole ring is particularly difficult to cleave and, amongst the azoles, pyrazoles together with the 1,2,4-triazoles are the most stable and easiest to work with. This qualitative description of pyrazole stability covers the neutral, anionic and cationic aromatic species. On the other hand, the saturated or partially saturated derivatives can be considered as hydrazine derivatives their ring opening reactions usually involve cleavage of the N—C bond and seldom cleavage of the N—N bond. It should be noted, however, that upon irradiation or electron impact the N—N bond of pyrazoles can be broken. 

For )V-unsubstituted pyrazoles the tautomeric proton was generally located without ambiguity. 3-Substituted tautomers were favoured in the solid state (45), (46) and (48) (Table 5). For the pyrazolyltriazole (47) the authors (77JHC65) concluded that the X-ray analysis indicates that the proton on the pyrazole ring populates either nitrogen atom to... 

Hi) Pyrazole rings containing carbonyl groups In this subsection compounds with a pyrazole C—O bond will be discussed independently of their aromatic character. In solution the tautomers of pyrazolinones, e.g. (78a), (78b) and (78c), are easily identified by their IR spectra (Figure 18) (76AHC(Sl)l). 

From studies reported in the references in Table 5 (Section 4.04.1.3.1) the dihedral angle between a phenyl and a pyrazole ring in the crystalline state, falls between 4° and 22° when the phenyl group is in the 3- or 4-position. The planar conformation of C-formylpyrazoles (57) and the resonance interaction between them (87) has already been discussed in connection with H NMR (Section 4.04.1.3.3(i)) and IR studies (Section 4.04.1.3.7(iii)). 

The principal results on the nitration of pyrazoles are shown in Scheme 23. If the substituent is a phenyl group, it can compete with the pyrazole ring and para-nitration is often observed (Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i)). 

The mechanism of the reaction is now well known due to a series of kinetic studies by Katritzky et al. (Table 31). The nature, free base or conjugate acid, of the substrate depends on the substituents in the pyrazole ring and on the acidity of the nitrating mixture. 

Nitration of 4-(2-thienyl)- (301) and 4-(3-thienyl)-pyrazoles (302) mainly occurs on the thiophene ring, but when acetyl nitrate is used as the nitration agent small quantities of products nitrated on the pyrazole ring are isolated (position of the nitro group uncertain) (80CS( 15)102). Pyrazol-l -ylpyridines (303) undergo electrophilic reactions (bromination, chlorination and nitration) preferentially in the pyrazole ring. Thus, the nitration of (303 R = R = = H) either with a mixture of nitric acid and sulfuric acid at 10-15 °C or with... 

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. 

When the pyrazole ring bears two adjacent functional substituents, it reacts like an o-substituted benzene. For example, 4,5-diaminopyrazoles behave similarly to... 

Some tricyclic systems have been prepared by intramolecular cyclization from A-aryl-pyrazoles carrying substituents both in the pyrazole ring at C-5 and in the phenyl ring at the o-position. Thus pyrazolo[l,5-n]quinazolines (563) (69JHC947) and pyrazolo[l,5-n]-[l,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable precursors. 

The different possibilities for the creation of the pyrazole ring according to the bonds formed are shown in Scheme 46. It should be noted that this customary classification lacks mechanistic significance actually, only two procedures have mechanistic implications the formation of one bond, and the simultaneous formation of two bonds in cycloaddition reactions (disregarding the problem of the synchronous vs. non-synchronous mechanism). 

Nitrilimines (621) are another class of 1,3-dipoles which provide a useful entry into the pyrazole ring. They are often generated by cycloreversion (79AG(E)72l) of tetrazoles, triazolopyridines and oxadiazolones (79JOC2957) (Scheme 55). Pyrazolines of known stereochemistry, pyrazoles and indazoles (Section 4.04.3.1.1(iii)) have all been prepared from nitrilimines. 

Organophosphates and carbamates containing a pyrazole ring, useful as insecticides as discussed earlier (Section 4.04.4.1.2), are metabolized mainly through hydrolysis of the ester function (B-80MI40406). 

Quaternary salt formation in a 1-substituted pyrazole ring (cf. 23) can occur only at N-2 to give the fully resonance-stabilized symmetrical salt 24. This reaction, which proceeds very readily, has been known for many years and therefore will not be commented on here. 

Two ring systems derived from pyrazole have been studied more recently. The 4 -pyrazole ring (25) forms quaternary salts (26) with fair ease, and, as in the case of pyridazine (see Section IV, C), the direction of quatemization is controlled by the nature of R and... 

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

The different nucleophilicities of 3,5-dimethyl- and 3,5-bis(trifluoromethyl) pyrazoles are shown by their reactions widi lraas-[Rh(CO)Cl(Ph3P)2]. The dimethyl derivative gives die dinuclear species similar to 111. The less nucleophilic fluorine derivative gives 116, where die pyrazole ring is monodentate. The fluoro compound similar to 111 [L2 = (CO)2l may be obtained in the absence... 

The above method can also be used to simultaneously transform two acetyl groups into acetylenic ones in positions 3 and 5 of the pyrazole ring. This is demonstrated by the synthesis of 3,5-diethynyl- 1-methylpyrazole (yield 62%) from 3,5-diacetyl-1-methylpyrazole (Scheme 30). 

Eberle and Schaub (93EUP571326) describe the synthesis of a large series of 3-hydroxy-2-(2-methyl-4-prop-l-ynyl-2//-pyrazol-3-yl)acrylic acid methyl esters 26 and methoxyimino-(2-methyl-4-prop-l-ynyl-2//-pyrazol-3-yl)acetic acid methyl esters 27 by dehydrohalogenation of the corresponding chloroolefins 25 under the action of bases. In this case, the functional groups in position 5 of the pyrazole ring undergo dehydrobromination (Scheme 34). 

To ascertain the possibility of inserting more than one acetylenic moiety into the pyrazole ring, the replacement of two and three iodine atoms in the appropriate halides by different alk-l-ynes was carried out. To increase the total rate, the cross-coupling of diiodopyrazoles and triiodopyrazole was performed with higher initial concentrations of the reactants than for the monoiodides. The reaction of diiodopyrazoles with the acetal was completed for the most part in 40 h, and in 64 h in the case of triiodopyrazole. The yields of the di- and triacetals reached 70-90% (Table XTTT). 

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