N-phenylpyrazole

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. 

Table 26 Dihedral Angles Between the Pyrazole and the Phenyl Ring in N-Phenylpyrazoles Determined by X-Ray Crystallography (for References see Table 5)...

Marzinzik and Felder [34] also performed a pyraz.ole synthesis as a possible transformation of polymer-bound enones. A single enone was treated with 2,3-dimethylphenyl-hydrazine under regioselective formation of the N-phenylpyrazole shown in Figure 6.26 (a, b). The crude product had a purity of 83 %, and the isolated yield was 73 %. 

The results obtained for 1-phenylpyrazole (32) and its conjugate acid (34) are consistent with those of Minkin. The bond order between thd two rings decreases by protonation (from 0.341 to 0.241) and this is in agreement with the expected effect of the N-2 positive charge on the delocalization of the lone pair on N-1 over the phenyl ring. 

The study of tautomerism using H NMR spectroscopy is simple when the tautomers give separate signals (84B2906) otherwise, interpolation methods need to be applied, which entail several sources of imprecision [83JPR(325)238]. A paper reports the observation of two NH signals for the N-labeled tautomers of 3(5)-methyl-5(3)-phenylpyrazole (45) in toluene-dg at 190 K (Scheme 15) [92JCS(P2)1737]. 

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (80JHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3-ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates—66a-f, 68a-f, 69a-f, and 70a-f— were proposed for this reaction. 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

Another type of substituted pyrazole is obtained by refluxing osazones with acetic anhydride during the acetylation, two molecules of water per molecule are removed. The structure of the resulting 5-(D-g/ycero-diacetoxyethyl)-3-formyl-l-phenylpyrazole 2-acetyl-2-phenylhydrazone (71) was determined by deacetylation followed by oxidation with (a) periodate to a pyrazolaldehyde (72), and (b) permanganate to the known l-phenyl-pyrazole-3,5-dicarboxylic acid (73), as well as by a study of its n.m.r. spectrum, which confirmed the pres-... 

Generally speaking, 2-aminothiazoles, -oxazoles, and N-substituted imidazoles react with or-halogenoketones more easily than NH compounds, though 2-amino-4,5-dimethyloxazole and 3-amino-l-methyl-4-phenylpyrazole are reported214 not to undergo the Tschitschibabin reaction. 

N-Heteroarylhydrazonoyl halides 5a,d,f react in a similar manner with ethyl cyanoacetate and cyanoacetanilide to give the corresponding 5-aminopyrazole derivatives 235A and B (77HCA2171 80JHC209 83MI1). In contrast, the reaction of the hydrazonoyl halide 35 with ethyl cyanoacetate was reported to yield 3-benzo[d)isoxazolyl-4-cyano-5-hydroxy-l-phenylpyrazole 236 in 59% yield [90ZN(B)1067]. 

The nitration of 3-methoxy-5-methyl-l-phenylpyrazole with nitric acids sulfuric acid at 0°C, followed by 3 h at 50°C, gives 3-methoxy-5-methyl-(4-nitrophenyl) pyrazole (51%), but reaction with mixed acid at 40°C for 24 h gives the 4-nitro-l-(4-nitrophenyl) product (85%). The preparative nitrations (using mixed acid) of the dinitro products are summarized in Table III. No n.m.r. evidence was found for the presence of ortho or meta nitrophenyl isomers. 

In neutral and alkaline media, pyrazoles unsubstituted in the 1-position undergo hydroxymethylation at that position.653,667 Polymeric material of unknown structure is obtained in acid media, but from 3,5-dimethylpyrazole a small yield of l,4-bis(hydroxy-methyl)-3,5-dimethylpyrazole was isolated.653 Hydroxymethylation was used in the synthesis of the naturally occurring pyrazolyl-alanine.657 When the reaction is carried out in hydrochloric acid on 1 -phenylpyrazole,350 1,1, 5,5 -tetraphenyl-3,3 -dipyrazolyl,219 and other N-substituted pyrazoles,656 it is found that W-alkylpyrazoles give hydroxymethyl, and iV-arylpyrazoles chloromethyl derivatives. The 4-position is always the site of substitution. A side reaction is the linking of pyrazoles by methylene bridges.656... 

The halogen atom of quaternary salts of 3- and 5-halogeno-l-phenylpyrazoles may be replaced easily at 80-100° by hydroxyl, alkoxyl, sulfhydryl, thioalkyl, amino, alkylamino, dialkylamino, arylamino, or cyano groups.565,675-683 The chlorine atom of quaternary salts of N-substituted 5-chloropyrazoIes may be replaced by bromine541,550,579,684,685 or by iodine265,550, 662,684-887 by heating... 

In contrast, in the photolysis of3,6-diphenylpyridazine-N-oxide 28 (R1 = R2 = Ph), a mixture of 3-benzoyl-5-phenylpyrazole 31 and 2,5-diphenylfuran 32 is formed. Diazoketone 29 (R1 = R2 = Ph) undergoes two competing reactions (i) thermal internal cyclization into the pyrazole 31 or (ii) photoinduced formation of a carbene leading to the final furan 32 (Scheme 12.9) therefore, the product distribution depends heavily on the reaction conditions. Thus, the formation of pyrazole 31 (75%) is favored over that of furan 32 (3%) by irradiation in acetone in a Rayonet reactor equipped with lamps irradiating at 350 nm. On the other hand, by irradiation with a Hanovia immersion lamp the yield of 31 decreases to 27%, whereas the yield of 32 increases to 67%. Moreover, the exclusive formation of the furan derivative 32 (43%) was observed by irradiation in the Rayonet reactor at low temperatures (—65 °C) [27]. 

The reaction of the tetrafluoroethylene trimer with phenylhydrazine in the presence of three equivalents of triethylamine leads to the formation of E and Z octafluoro-3-trifluoromethyl-4-(N-phenylhydrazino)pent-3-enes, which further undergo intramolecular cyclization into 3,4,5-tris(trifluoro-methyl)-1 -phenylpyrazole 63 (98JFC(88)169). 

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