Pyrazole ring alkylation

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). 

Since l-heterobut-l-en-3-ynes are readily alkylated and functionalized at the terminal acetylenic carbon atom, their reaction with hydrazines makes it possible to introduce diverse (including functional) substituents into the pyrazole ring. For instance, from benzylated methoxybutenyne 112, isomeric 2-phenylethylpyrazoles 113 were obtained in 74% yield (81H146). 

Only a few reports have dealt with the behavior of tetra-azaindenes toward electrophiles, and the reactions reported involved the pyrazole ring. Thus, alkylation of 336 with alkyl halides affords a mixture of the A-alkylated derivatives 337 and 338. Compound 336 is produced by alkylation of 339. Bromination of 339 (R = H) affords the 7-bromo derivative 340 (82JHC817) (Scheme 34). Nitration of 2-methylpyrazolo[3,4-c] pyridazine occured at pyrazole C-3 (73JAP76893). Bromination of 341 with bromine in acetic acid gives 342 (83AP697). 

The aromatic 2-substituted pyrazole 1-oxides 74 are derived from pyrazoles 89 by appending an oxygen atom to the pyridine type ring nitrogen atom of the pyrazole nucleus. The second nitrogen atom of the pyrazole ring can be attached to an alkyl, aryl, hydroxy, or amino group. 

Alkyl- and aryl-pyrazoles themselves have a sharply pronounced sedative action on the central nervous system.27,28 Steroidal compounds whose structures include pyrazole rings are of interest as possible psychopharmacological agents.29,30 Pyrimidinopyrazoles are being studied in the fight against cancer.31... 

Deprotonation can occur at the -GH of pyrazole A-alkyl groups for example 1-methylpyrazole with -BuLi. Such proton loss is facilitated in cationic azido rings, and the ylides so formed sometimes undergo rearrangement. Thus, quaternized 1,2-benzisoxazoles 796 lose a proton and then rearrange to 1,3-benzoxazines, e.g., 797. Quaternized derivatives of benzofuroxan formed in situ undergo rearrangement to 1-hydroxybenzimidazole A-oxides 798. Reactions of this type are also known for A-alkylazolinones. 

When pyrazole rings are bridged by larger alkyl group (isopropylidene) the ligands were better prepared by acid-catalyzed reaction of pyrazole or C-substituted pyrazole with acetals or ketals (Scheme 12).215... 

Tris(pyrazolyl)methanes alkylated on the methyne carbon atom have been synthesized.255,256 Methylation of (HC(pz)3) was carried out according to Scheme 20. The synthesis of alkylated tris(pyrazolyl)methanes was only successful when the pyrazole rings contained no alkyl substituents on the 5-position (Scheme 20). 

Nur ein Ring-C-Atom fur den sich bildenden Pyrazol-Ring liefert das 1,3-Thiazol-Geriist von 2-(2-Oxo-alkyl)- oder 2-(l-Acyl-ethenyl)-l,3-thiazolen in Reaktionen mit Hydrazinen. Die Transformation ist gegcbcnenfalls von einer Retroaldol-Spaltungen begleitet8n,8 ... 

The source of the regiochemistry for the methylation reaction to give pyrazole 3 was intriguing. Subsequent work in chemical research and development showed that under basic conditions the main product was the N-2 regioisomer. Literature reports have shown that 5-alkylpyrazole-3-carboxylates such as 2 exist in the tautomer like 2b, both in the solid state and solution. Hence, it was proposed that in solution the majority of the pyrazole exists as the N-2 isomer 2b and under acidic or neutral conditions the lone pair of electrons on the N-2 isomer is delocalized into the pyrazole ring and reaction takes place on the pyridine-like nitrogen to give the N- alkylated isomer 3 as the main product. Under basic conditions, there is formation of an anion which leads to the more stable N-2 isomer (Scheme 16.2). 

The preparation of tebufenpyrad and tolfenpyrad (see below) are outlined in Scheme 28.3.4. The pyrazole ring is prepared from a Claisen condensation of 2-butanone with diethyl oxalate followed by treating the resulting acylpyruvate with hydrazine [45, 46]. The pyrazole ring is then alkylated with dimethyl sulfate at 50-60 °C without base to give, selectively, the l-methylpyrazole-5[Pg.893]

The formation of a pyrazole ring at the 17 -position in the androstane molecule (7) is accomplished by condensing pre enolone with ethyl formate or diethyl oxalate followed by reaction with hydrazine. The 17g-hydroxy-17a isoxazolyl derivatives in the estrone and androstane series were prepared by the addition of an alkyl... 

SCHEME 21 Alkylation of pyrazole ring with different reactive aUcyl bromides. 

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