Pyrazole-4-carbaldehyde

Synthesis The pyrazole-4-carbaldehyde synthesized according to Vilsmeier is reduced to the alcohol, which is chlorinated. The chloro derivative is reacted with sodium cyanide to give the nitrile, which is hydrolyzed to Lonazolac. The calcium salt, slightly soluble in water, is formed by adding calcium chloride to the free acid (Rainer et al., 1981 Unterhalt, 1982 Rainer et al. (Byk Gulden), 1969 1982 Kleemann et al., 1999). 

The Pd-catalysed Miyaura-Suzuki coupling of aryltrifluoroborates with 4-tosyloxycoumarins in aqueous conditions offers an attractive route to 4-arylcoumarins <06TL1525> and 4-hydroxycoumarins have been converted into a mixture of predominantly thiopyrano[5, 4 3,4]- pyrano[5,6-c]coumarins and [6,5-c]chromones in a one-pot tandem Knoevenagel - HDA sequence with an S-prenylated 1-phenyl-lff-pyrazole-4-carbaldehyde <06TL2265>. The benzopyrano[4,3-c]benzopyranone system can be obtained from 3-aryl-4-methylcoumarins by deprotonation of the methyl function and subsequent elaboration <06TL5909>. 

Additions of Dialkylzinc Reagents. (lR,2S)-A/-Pyrrolidinyl-norephedrine (1) is an effective catalyst for the enantioselective addition of dialkylzinc reagents to aromatic aldehydes (eq 1). Optimized conditions involve reaction in toluene at 0°C with 10 mol % of the ligand and 2.2 equiv of the dialkylzinc reagent. Normal work-up after 20 h affords the product from addition to the Si face of the aldehyde. Product yields for a variety of alkylzinc reagents (1° and 2°) and an array of aromatic aldehydes are normally 80-100% with ee being nearly 90%. While similar results can be obtained for pyrazole-4-carbaldehydes, aliphatic aldehydes, and 1,2-phthalic dicarbaldehydes, the optimal ligand structure may involve variation of the amine substitution pattern (aliphatic tertiary amine rather than pyrrolidine structure). 

There are only a few reports in this area. Reaction of a pyrazolyl disulfide 377 with bromotrifluoromethane and ethyl bromide in the presence of sodium dithionite at room temperature afforded pyrazolyl sulfides 378. Oxidation of these with hydrogen peroxide in trifluoroacetic acid afforded sulfenylpyrazoles 379 in excellent yields (Scheme 41) <2006JFC(127)948>. Pyrazole-4-carbaldehyde 380 has been utilized in the efficient synthesis of... 

Hydrazones (166) react with chloromethyleneiminium salt (I) giving, after hydrolysis, aldehydes (167 Scheme 12). In this transformation the hydrazones (166) are clearly behaving as aza-enamines. - Hydrazones (168) and (169) react with chloromethyleneiminium salt (1) at both the methyl group and at nitrogen to yield the corresponding iminium salts (170) and (171), which cyclize with loss of dimethylamine to provide iminium salts (172) and (173), respectively. Hydrolysis of these salts (172) and (173) affords pyrazole-4-carbaldehyde derivatives (174) and (175 72-96% Scheme 13). Pr uct (174) can also be prepared from semicaibazone (176). 

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. 

Shelke et al. [80] S5mthesized various fluorine-containing compounds by conventional and nonconventional procedures by ultrasonication and microwave techniques. Various 3-substituted-l-phenyl-lH-pyrazole-4-carbaldehydes were treated with 3-(trifluoromethyl)-l-phenyl-lH-pyrazol-5(4H)-one (83) to give 4-((3-(4-aryl)-l-phenyl-lH-pyrazol-4-yl) methylene)-3-(trifluoromethyl)-l-phenyl-lH-pyrazol-5(4H)-one (85). Equivalent mole of 3-formylchromone and 3-(trifluoromethyl)-l-phenyl-lH-pyrazol-5(4H)-one by conventional method and nonconventional methods gave 3-(trifluoromethyl)-4-(4-oxo-4H chromon-3-yl)-methylene-l-phenyl-lH-pyrazol-(4H)-one (84) (Scheme 21). Compounds 84 and 85 were obtained in slightly better yields within 5-10 min under ultrasonication than in 2-3 min with microwave irradiation. 

A simple protocol for synthesis of a series of l-(4-substituted phenyl)-3-phe-nyl-lH-pyrazole-4-carbaldehyde has been developed under microwave irradiation (Selvam et al., 2011). 

Pyrazole, N-vinyl-polymerization, 5, 269 3H-Pyrazole, 3,3,5-trimethyl-irradiation, 5, 251 Pyrazole carbaldehydes reactions, 5, 260 Pyrazole carbinols dehydration, 5, 261... 

Ligand abbreviations bi = 2,2 -bi-2-imidazoline bt = 2,2 -bi-2-thiazoline bpy = 2,2 -bipyridine phen = 1,10-phenanthroline phy = l,10-phenanthroline-2-carbaldehyde phenylhydrazone bpp = 2,6-bis(pyrazol-3-yl)pyridine paptH = 2-(2-pyridylamino)-4-(2-pyridyl)thiazole 2-pic = 2-picolylamine L = macrocyclic ligand derived from condensation of 2,6-diacetylpyridine with 3,6-dioxaoctane-1,8-diamine Hjthpu = pyruvic acid thiosemicarbazone Hjthpx = pyridoxal thiosemicarbazone salen = dianion of W,iV -ethylenebis(salicylideneimine) H2fsa2en = dianion of fV,JV -ethylenebis(3-carboxysalicylaldimine). 

Acetylenedicarboxylic acid esters and related activated alkynes are routinely used as dipolarophiles for diazo dipoles. Recent examples include the use of diazo compounds 20 (49), 23 (51), and 24 (52) (Scheme 8.7), 25 (56) (Scheme 8.8), diazoacetaldehyde dimethylacetal (41) (which after cycloaddition and deprotection gave the corresponding pyrazole-3-carbaldehyde), ethyl 3-diazopyruvate (270), p-tolyl-trifluoromethyldiazomethane (271), bis(trifluoromethyl)diazomethane (272), and diazomethylenephosphoranes (60). 

Oxidation of the pyrazole carboxaldehydes 294 using potassium permanganate in aqueous pyridine gave satisfactory yields of the carboxylic acids 295 (Equation 56) <2001CHE467>. Condensation of AT-alkylpyrazole-4-carbaldehyde 296 with 2,3-bis(hydroxyamino)-2,3-dimethylbutane sulfate, then sodium periodate oxidation of 1,3-dihydroxyimi-dazolidine 297 afforded pyrazolyl nitronyl nitroxides 298 (Scheme 26) <2001ARK55>. Another approach to... 

Similar conditions were used to condense pyrazol-3-one 30 with 5-[4 -(5-formylfuran-2-yl)biphenyl-4-yl]furan-2-carbaldehydes 175a c to give ( /Z)-4- [5-(4 -substituted biphenyl-4-yl)furan-2-ylmethylene]-amino pyrazol-3-ones 176a-c in 45%, 52% and 20% yields, respectively (92JOU431) (Scheme 46). 

Tietze et al. (88LA9) (Scheme 77) alkylated 2-hydroxybenzaldehyde with 5-bromo-2-methylpent-2-ene and 1 //-pyrrole-2-carbaldehyde with l-bromo-3-methyl-but-2-ene and obtained the corresponding aryl aldehydes 246 and 248. Condensation of the latter with pyrazol-3-one 262 in acetonitrile containing ethylenediamine diacetate as a catalyst provided (7 /Z)-4- 2-[(4-methylpent-3-enyl)oxy]benzylidine -pyrazol-3-one 247 and ( /Z)-4- [l-(3-methylbut-2-enyl)-177-pyrrol-2-yl]methylene -pyrazol-3-one 249, in 67 and 99% yield, respectively. 

Wrzeciono et al. (78PHA264) (Scheme 89) presented the only example of condensation between an aromatic heterocyclic aldehyde and a 2,4-dihydropyrazol-3-one. Thus reaction of pyrazol-3-ones 289a c with furan-2-carbaldehydes 290d,e afforded the furfurylidene derivatives 291f,g. 

Pyrazole derivatives can be prepared analogously from alkynes e.g., reaction of propynal with ethereal diazomethane gives 84% of pyrazole-3-carbaldehyde and that with diazoacetic ester gives 86% of ethyl 5-formyl-pyrazole-3-carb-oxylate.18 Further, pyrazole itself is readily accessible from acetylene and diazomethane.19... 

Reaction of pyrazole-3-carbaldehyde with Meldrum s acid gave the condensation product (31), which was pyrolyzed in the gas phase to give 6-oxopyrrolo[l,2-fe]pyrazole (24) in low yield (18%) (Equation (1)) <87JCS(P1)653>. 

---