Arylpyrazole

Another example of the analogy between pyrazole and chlorine is provided by the alkaline cleavage of l-(2,4-dinitrophenyl)pyrazoles. As occurs with l-chloro-2,4-dinitrobenzene, the phenyl substituent bond is broken with concomitant formation of 2,4-dinitrophenol and chlorine or pyrazole anions, respectively (66AHC(6)347). Heterocyclization of iV-arylpyrazoles involving a nitrene has already been discussed (Section 4.04.2.1.8(i)). Another example, related to the Pschorr reaction, is the photochemical cyclization of (515) to (516) (80CJC1880). An unusual transfer of chlorine to the side-chain of a pyrazole derivative was observed when the amine (517 X = H, Y = NH2) was diazotized in hydrochloric acid and subsequently treated with copper powder (72TL3637). The product (517 X = Cl, Y = H) was isolated. 

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>. 

The l-arylpyrazol-5-ones (4.9), prepared by the two-step condensation of an arylhydrazine with ethyl acetoacetate, are the most commonly used coupling components for the synthesis of greenish yellow azo dyes. Coupling occurs at the 4-position of the pyrazolone ring which, as in the case of the acetoacetarylamides discussed above, is activated towards electrophilic attack by the two flanking unsaturated carbon atoms (Scheme 4.14). 

The data about MCRs involving 5-amino-3-arylpyrazoles are more discrepant. Quiroga et al. [82] reported three-component treatment of this pyrazole with dime-done and aromatic aldehydes in boiling ethanol, yielding only pyrazoloquinolinones... 

However, further a possibility of the formation of several different reaction products in similar processes was reported [97-99]. With the help of microwave irradiation and ultrasonication, the problem of selectivity was also touched in these communications. It was found that three-component reaction of equimolar mixture of 5-amino-Al-arylpyrazole-4-carboxamides, aldehydes, and cyclic (3-diketones in DMF under conventional thermal heating or under microwave irradiation at 150°C yielded pyrazoloquinazolines 68. The treatment at room temperature under ultrasonication gave the same reaction products, although addition of catalytic amounts of hydrochloric acid changed direction and positional isomeric quinazolines 69 were only isolated in this case. 

Thermal dimerization of several arylazoethynylarenes in cyclohexane gave mesoionic pyrazolo[4,3-c]pyrazoles (116) in fair yield. The structure of one product 116 (Ar1 = Ph Ar2 = p-ClC6H4) was supported by thermal degradation (500°) to cr-(p-chlorophenylimino)-phenylacetonitrile and hydrogenation to give two iV-arylpyrazoles.115... 

Treatment of arylidenepyruvic acids 236 with 5-amino-3-arylpyrazoles 222 (R is Ar, Ri is H) in most cases was not regioselective and yielded mixtures of several regioisomers and products of their heteroaromatization 2,7-diaryl-4,7-dihydropyrazolo[l,5-tf]pyrimidine-5-carboxylic acids 246 (main product), 3,4-diaryl-4,7-dihydropyrazolo[3,4-Z ]pyridine-6-carboxylic acids 247 and their heteroaromatized derivatives 248 (Scheme 3.68). 

Dinitration of 1,3- or 1,5-diphenylpyrazole in sulfuric acid yields the corresponding bis (4-nitrophenyl) products, whereas nitric acid acetic anhydride yields 4-nitro-l-(4-nitrophenyl) materials. Mononitration of the diphenylpyrazoles, and several other 1-arylpyrazoles, occurs at the 4-position in nitric acid acetic anhydride at 0°C. 

A recent patent has reported the preparation of several l-(3-nitrophenyl) pyrazoles, as intermediates leading to potential herbicides, by nitration of some 1-arylpyrazoles of the type (29). This indicates meta nitration of a 1-arylpyrazole in yields of 88% (87JAP62/I23173). 

The Friedel-Crafts reaction has limited application in pyrazole chemistry, as the acyl group can be introduced only in the 4-position. The reaction is easier with 1-arylpyrazoles which are less inclined to form pyrazole cations.822,828 Heating N-substituted pyrazoles with benzoyl chloride at 200-230° for some hours gives high yields of 4-benz-oylpyrazoles (60) even in the absence of catalysts.48,505,647,624,825... 

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... 

Sodium and alcohol can only be used to remove a halogen atom from the 5-position in 1-arylpyrazoles the ring is reduced to a pyrazoline during the reaction.550,582,663 The halogen may be removed from... 

Arylpyrazoles mercuriate in the 4-position (54JCS2293 55JCS1205 60ZOB2931), and 3-phenyl-1,2,4-oxadiazole mercuriates in the 5-position (64HCA838), the only electrophilic substitution reported in this hetero-cylic ring. 

Intramolecular alkylation at N(2) of benzotriazole derivative 107 results from Pummerer reaction giving salt 108 which, on hydrogenolysis, leads to fV-arylpyrazole 109 <2002EJ0493>. 

Cyano-4-trifluoromethyl-6-aryl-2(l//)-pyridones 100 react with hydrazine hydrate to give exclusively 5-trifluoro-methyl-3-arylpyrazoles 101 (Scheme 55) <2002JFC(115)9>. 

COX-II inhibiting agents consisting of sulfamoylheteroaryl-, (I), and arylpyrazole derivatives, (II), were prepared by Ando (4,5) and used in treating anti-inflammatory disorders without gastric side effects associated with COX-I inhibition. 

Cheng et al. [14] introduced an amidinyl group into the C-5 position of N-arylpyrazoles by the use of commercially available amide solvents and phosphorus oxychloride under microwave irradiation and a series of A,A-disubstituted-A -[i-aryl-l//-pyrazol-5-yl]-methnimidamides (v) were obtained. 

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