Pyrazoles, 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)... 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Pyrazole, 3-ethoxycarbonyl-3 (5 ),5-dimethyl-5 (3 )-pyrazol-l-yl-reduction, 5, 260 Pyrazole, ethynyl-reactions, 5, 261 Pyrazole, 4-formyl-IR spectra, S, 201 NMR... 

Pyrazole, C-formyl-conformation, 5, 209 Pyrazole, fluoro-reactions, 5, 263, 267 Pyrazole, 4-fluoro-5-hydroxy-tautomerism, 5, 214 Pyrazole, 1-germyl-synthesis, 5, 236 Pyrazole, halo-halogenation by, 5, 54 reactions, 5, 104, 105, 266 reduction, S, 105, 106, 266 Pyrazole, 3-halo-1-phenyl-quaternary salts... 

Acyl-4,5-dihydro-pyrazole mit exo-cyclischer Carbonyl-Gruppe werden zu 1 -Alkyl-4,5 -dihydro-pyrazolen reduziert, mit Ausnahme der 1-Formyl-Derivate, die... 

The formation of pyrazoles from reactions of suitably substituted 2-arylazirines and molybdenum hexacarbonyl has been discussed earlier in this section (see Schemes 89, 90)47 an analogous procedure depicting the transformation of 2-formyl-3-phenyl-2H-azirine into 3-phenylisoxazole is illustrated in Scheme 109.47... 

Similarly l-phenyl-3-methyl-4-formyl-5-chloropyrazole reacts with thioglycollic acid in the presence of alkali to yield a mercaptopyrazole derivative that could be cyclized to thieno[2,3-c]pyrazole in the presence of alkali (69KGS760, 69ZOR1498). Similar to this is the reported formation, via 311, of 312 from 310 and mercaptoacetanilide (73ZOR2416). 

Stanozol Stanozol, 17a-methyl-5a-androstano[3,2-c]pyrazol-17j3-ol (29.3.13), is made by reducing the double bond at C4-C5 in methyltestosterone, which has independent interest as an anabolic drug of mestanolone (29.3.11). Mestanolone undergoes formylation with ethylformate in the presence of sodium ethoxide, forming a 2-formyl (oxymethylene) derivative (29.3.12), which upon reaction with hydrazine easily cyclizes to the desired stanazole (29.3.13), which is a pyrazol-condensed steroid system [33,34]. 

CH3 OHC CsHs H2S/H3C—OH/wenig Piperidin 10-20°, 30 min 5-Amino-4-formyl-l-me- thyl-3-phenyl-pyrazol 64 2... 

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-... 

Thermolysis of the (Z)-acraldehyde 265 gives a mixture of the pyridyl-pyrazoles 266 and 267.258 From the (JS )-acraldehyde only compound 266 was obtained. In this reaction the diazoalkane is presumably trapped by the side-chain double bond, with subsequent formyl migration. 

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). 

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... 

Cyanomethylbenzo[6]thiophene condenses with 2-methylthio-1-naphthaldehyde to give 199,571 and it affords 200 on formylation with ethyl formate and sodium methoxide.524 Compound 200 reacts with hydrazine under suitable conditions to give either 201 or 3-amino-4-(3-benzo[6]thienyl)pyrazole (202).524 With ethylene-... 

Treatment of 348 with Na[EIBEt3] has also been reported, affording initially the Pt(II) formyl complex anion [Tp PtMe C(0)H ] (355 ), as determined by 1EI and 13C NMR spectroscopic data that again reveal a chiral metal center. At 193 K two formyl environments (2 1 ratio) are apparent, which coalesce at 201 K. These are attributed to restricted rotation about the Pt—C linkage, and AG for conversion of the minor to major isomer was calculated at 8.8 kcal mol-1.120 Protonation of 355 affords exclusively the Pt(IV) formyl complex Tp PtMe C(0)H H (356), with no evidence for protonation of either pyrazole or the formyl, or... 

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). 

A further example of electrophilic substitution is the synthesis of pyrazole aldehydes by formylation with dimethylformamide.620,628... 

Poorer results were obtained when methylformanilide was used in place of dimethylformamide.629 Formylation was unsuccessful with pyrazoles acylated or unsubstituted in the 1-position.620,630... 

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