Sodium pyrazolate, reaction with carbonyls

The semicarbiizoiic " " and para-loluenesulfonylhydrazonc " of diethyl l-formylmeth-ylphosphonate can be metallated with NaH in THF or DME for reaction with carbonyl compounds at room temperature, whereas the oxazine and dimethylhydra/inc -derivatives require metallation with n-BuLi in THF at low temperature. The oxazine protecting group is removed by sequential treatment with NaBH4 and aqueous oxalic acid at reflux. The pora-toluenesulfonyl-hydrazone participates in cyclization reactions with the release of sodium para-toluenesulfinate to produce pyrazoles (Scheme... 

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... 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

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