Sodium pyrazolate, reaction with chloride

Reaction of ethyl 5-amino-3-methylthio-l//-pyrazol-4-carboxylate 267 with sodium nitrite in the presence of hydrochloric acid gives the diazo intermediate 268, which on treatment with active methylenic compounds such as ethyl a-chloroacetate or a-chloroacetylacetone affords the hydrazonyl chlorides 269 and 270, respectively, whose reaction with triethylamine in refluxing ethanol convert them into ethyl 4-hydro-2-methylthiopyrazolo[5,l-c]-[l,2,4]triazole-3,6-dicarboxylate 271 and ethyl 6-acetyl-4-hydro-2-methylthiopyrazolo[5,l-c][l,2,4]triazole-3-carboxy-late 272 (Scheme 23) <2001MI1>. 

The product of the reaction of 3-methyl-l-phenyl-5-pyrazolone with chloride 21c in ethanol in the presence of sodium ethoxide was assigned structure 232 (83MI1). Neither spectral nor elemental analysis data were given to support such an ambiguous assignment, however. As the 5-pyrazolone derivative is an active methylene compound, its reaction with hydrazonoyl halides 21c is expected to give pyrazolo[3,4-c]pyrazole derivative 233, not 232. 

A few halogenated 3-pyrazolin-5-thiones are known (Table XVIII). These are prepared from the methyl chlorides of 3- or 4,5-dichloro-pyrazole by reaction with sodium sulfide or potassium hydrogen sulfide.795,981 Michaelis988,992 has reported that 3-pyrazolin-5-selenones form dichlorides and di- and tetrabromides when treated with chlorine or bromine. No specific structures were suggested. 

A similar cyclization leading to pyrazol-3-one 266 was described by Brugel et al. (06TL3195) (Scheme 59). Beginning with 4-fluorophenyla-cetyl chloride 261, reaction with methylhydrazine at — 78 °C led to the selective formation of 2-(4-fluorophenyl)-N-methylacetohydrazide 262 in 61% yield. Reductive amination with piperidone 263 afforded 264 in excellent yield. A second acylation with 2-methylsulfanylpyrimidine-4-carbonyl chloride 265 in pyridine gave the bis-acylated precycliza-tion intermediate 266 that was cyclized with sodium hydride... 

The synthesis, characterization, and energetic properties of various heterocycles containing azide groups are reported. Compound 105 is prepared by the reaction of cyanuric chloride with sodium azide. The preparation of 106 utilizes the conversion of a pyrazole derivative by reaction with hydrazine to form the hydrazo intermediate which is subsequently reacted with NaN02. 2,5,8-Trichloro-s-heptazine is converted quantitatively into 2,5,8-triazido-s-heptazine (107) with trimethylsilyl azide. The nucleophilic reaction of hydrazine with 4,4, 6,6 -tetra(chloro)hydrazo-l,3,5-triazine... 

The reaction is cooled to room temperature and approximately 50 mL of toluene and 35 mL of 5% sodium carbonate solution are added. The organic layer is separated, extracted with 3 x 50 mL of 5% sodium carbonate solution, dried over MgS04, and filtered. The toluene is removed on a rotary evaporator and the residue dissolved in 20 mL of methylene chloride. The concentrated solution is absorbed at the top of a column of alumina (2 x 20 cm ca. 100 g of activity III) and eluted with 150 mL of CH2C12 to remove any unreacted pyrazole. The solvent is removed on a rotary evaporator and the solid is recrystallized from 100 mL hexanes to give 10.28 g of the product as white crystals melting at 84-86°C. A second crop of product (0.60 g) can be obtained by concentration of the filtrate, giving an overall yield of 10.88 g (62%) based on 2,2-dimethoxypropane. 

Various benzimidazole derivatives can be fused between the C-2 and N-1 positions in order to build novel heterocyclic ring systems. For example, the reaction of 2-cyanomethylbenzimidazole 73 with hydrazonoyl halides 74 in the presence of triethylamine led to the formation of pyrrolo[l,2-a]benzimid-azoles 76 (Scheme 16) [60]. It has been suggested that the reaction starts with the nucleophilic substitution of the halogen by the benzimidazole carban-ion to give intermediate 75, which upon cyclization via elimination of water gives the desired cyclic pyrrolobenzimidazoles 76. On the other hand, the reaction of hydrazonoyl chlorides 77 with 2-cyanomethylbenzimidazole 73 in sodium ethoxide afforded pyrazole-3-carboxylate 80, which upon treatment under triethylamine yielded the pyrazolopyrrolobenzimidazole 81. The product was also obtained by the direct reaction of 2-cyanomethylbenzimidazole 73 with hydrazonoyl chlorides 77 in the presence of triethylamine. 

Tautomeric lactose hydrazone 77/78 was obtained from 2,2,2-trifluoroethyl-3-oxobutanoate 76 with hydrazine tautomers 74/74 in a 1 3 ratio using acetonitrile and water to give, after lyophilization, a mixture of pyrazol-3-one 79 and l-lactosylpyrazol-3-one 80 (00CAR169) (Scheme 19). They were identified by HPLC-ESIMS, their stability being limited due to rapid atmospheric oxidation. Further reaction of this mixture with 4-methylbenzenediazonium chloride in aqueous sodium bicarbonate followed by addition of 2,4-pentadione gave, after purification by HPLC, stable 2-/)-D-lactosyl-4-[2-(methylphenyl)diazenyl]pyra-zol-3-one 81 in 15% yield. 

The reaction of pyrazol-3-one 62 with iminium salts is similar to the above addition-elimination process involving pyrazol-3-one C4/H4. In the first example, two equivalents of pyrazol-3-one 62 react with iminium perchlorate 599 in tetrahydrofuran containing sodium hydride to afford the (77/Z)-bipyrazol-3-one derivative 600 in only 32% yield (82AG559). Without the use of basic conditions one equivalent of 62 reacted with iminium chloride 601 in acetonitrile to give (Z)-4-(3,3-dichloroprop-2-enylidene)pyrazol-3-one 602 in 84% yield (97S573) (Scheme 178). 

Reaction of 3,4,6-tri-0-acetyl-2-deoxy-2-nitroso-a-D-hexo-pyranosyl chloride with pyrazole gave as major product (30),together with epimers at C-1 and C-3, the latter epimerization presumed to occur via the 2-nitroso-2-ene. Treatment of (30) with sodium azide in ethanol (Scheme 8) gave (31) as major product, presumably also... 

To a stirred solution of aldehyde (1 1 mmol), active methylene cyano derivative (2 1.2 mmol) and Bestmann-Ohira reagent (3 1.5 mmol) in distilled methanol (4 mL), was added molecular sieves followed by powdered KOH (2 mmol) and the reaction mixture was stirred at room temperature for one hour. Upon completion of the reaction (TLC monitoring), methanol was distilled off under reduced pressure. The crude residue was dissolved in ethyl acetate (50 mL) and washed with saturated ammonium chloride (2 x 20 mL). Finally the organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulphate. After removal of the solvent, column chromatographic purification was carried out using 0-30% acetone-dichloromethane as eluent to afford phosphonyl pyrazole 4. All the products were characterized based on spectral studies. 

Reactions of Other Derivatives.—Condensation of 2-methyl-benzothiazoles with aromatic aldehydes may be carried out in 50% aqueous sodium hydroxide at room temperature in the presence of triethylbenzylammonium chloride. In some cases the intermediate carbinols are isolable under these conditions. 2-Methylbenzothiazoles undergo the Vilsmeier-Haack reaction to give products [1 R = C( CHOH)CHO] that can be converted into other heterocycles e.g., alkyl- or aryl-hydrazines furnish pyrazoles. ... 

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