Pyrazole Vilsmeier formylation

Substituted pyrazoles are formylated (Vilsmeier-Haack reaetion) and aeetylated (Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in positions 3 and 5 facilitate the reaetion (80ACH(105)127,80CHE1), but the heteroatoms eompete with the C-substitution. For instanee, when the amino derivative (91 R = = Ph, R = H)... 

Pyrazoles substituted with an aminovinyl or isocyanatovinyl group are useful precursors. For example, the Vilsmeier formylation product 148 on treatment with ammonium chloride, hydroxylamine, or ammonium acetate affords the aldehyde 149, oxime 150, or the 7,7 -dimer 151, respectively.142... 

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

Six years later Wrzeciono and Szostak-Rzepiak (75PHA582) (Scheme 40) repeated the Vilsmeier formylation of compound 120a but neutralized the reaction mixture with a solution of ammonium hydroxide instead of potassium carbonate. They obtained a mixture of products consisting of pyrazole-3-ones 124, 125, 126 and 127/128 in 48, 2, 4 and 5% yield, respectively. 

Acylation and metallation studies on monomers, dimers, trimers, and tetramers containing linked thiophen, pyridine, pyrimidine, furan, benzofuran, benzothiophen, and indole moieties have been published/ Deuteriation, halogenation, and diazo-coupling reactions of 2-oxo- and 2-thioxo-l,2-dihy-dropyrimidinium salts have been studied and compared with results for 2,2-dialkyl-1,2-dihydropyrimidinium and 2,3-dihydro-1,4-diazepinium salts in order to demonstrate the effect of an adjacent 0x0- or thioxo-group on the properties of a 1,5-diazopentadienium system/ Vilsmeier formylation of, and tautomerism in, 2-hydroxypyrazolo[5,l-h]quinazolone and l-phenylpyrazolo[5,l-A]-quinazoline-2,9-dione have been studied/ The pyrazolo[3,4-c]pyrazole (71) has been methylated and acetylated, the major products being (72)/ ... 

Recent work by Kvitko et a/.409 on thieno[2,3-c]pyrazoles 393 has shown that bromination and formylation (Vilsmeier reaction) take place at C-2, i.e., a to sulfur, though benzothiophene generally substitutes in the / -position.4090 These Russian workers argue that, for 393, a transition state such as 395 will be less unfavorable than the corresponding transition state 394 for benzothiophenes, since 394 has to adopt a quinonoid structure (see 90c and 282b, Section IV,A,1). 

Bei Verwendung von einem Mol Vilsmeier-Haak-Reagenz pro Mol Hydrazon kommt es zur 1 H-Pyrazol-Ringbildung ohne Einfuhrung der Formyl-Gruppe (Ausbeuten 20-30%)887. 

Die Vilsmeier-Haack-Reaktion mit Acetophenon-azin und 2 mol Dimethylformamid-Phos-phoroxychlorid-Komplex fuhrt praktisch quantitativ zu 4-Formyl-3-phenyl-l-( 1-phenyl-ethe-nyl)-lH-pyrazol (Schmp. 62°)738. 

The corresponding 4-halopyrazoles are produced by the action of chlorine or bromine in acetic acid. Nitrating acid yields 4-nitropyrazoles and, dependent on the substituents in the pyrazole ring, reaction takes place either with pyrazole itself or the pyrazolium ion. Sulfonation involves the pyrazolium ion. For this reason, heating in oleum is necessary, which leads to pyrazole-4-sulfonic acid. Pyrazoles with substituents in the 1-position yield pyrazole-4-carbaldehyde in the Vilsmeier-Haack formylation and are amenable to Friedel-Crafts acylation. 4- and 5-aminopyrazoles can be diazotized. 

---