Pyrazole nitrosation

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

The behaviour of pyrazoles towards nitrosation is similar to their behaviour described above towards diazo coupling, i.e. aminopyrazoles and pyrazolones readily react with nitrosation agents, like alkyl nitrites (81FES1019), to afford stable nitroso derivatives. Some simple nitrosopyrazoles have been isolated, for example the blue-green 3,5-dimethyl-4-nitrosopyrazole, and many others have been proposed as reactive intermediates in the direct conversion of pyrazoles into diazonium or diazo derivatives (Scheme 25) (B-76MI40402). 

The nitrosation of oximes can also serve to produce N-hydroxy-N-nitrosamines (Scheme 3.9). The acidified nitrite procedure can be applied to oximes derived from terpenes [132] and hydroxyguanidine [133] for the synthesis of N-hydroxy-N-nitrosamines. However, some a, 5-uri saturated oximes were converted into pyrazole-1,2-dioxides [134]. The alkyl nitrites under basic conditions have produced interesting results. Quinone dioximes yielded only monodiazeniumdiolates [135], while simple aliphatic oximes gave products resulting from addition to the imine double bond... 

Similar synthesis of l-hydroxypyrazole-2-oxides was realized in the presence of Co(II) ions or HN02 as nitrosating agent. Pyrazole-Af-oxides were successfully obtained from 1,3-dioximes and SOCI2 . 

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. 

Direct nitrosation of pyrazoles cannot be accomplished to obtain 4-nitrosopyrazoles, j9-diketones are nitrosated and then treated with hydrazine or a hydrazine derivative.594 Nitrosation of 3- and 5-hydroxypyrazoles (pyrazolinones) takes place readily in the 4-position,595 but 4-hydroxypyrazoles yield 5-nitroso derivatives.598 The following compounds are also nitrosated at the 4-position 1,3-dimethyl-5-methylthiopyrazole,542 3-methyl-5-ethoxypyrazole,597... 

In a strongly acidic medium the pyrazole nucleus exists as a cation from which the hydrogen atom at position 4 cannot be displaced by electrophilic substitution such as nitrosation. In a less acidic medium the weakly basic 2-nitrogen atom of a 1-phenylpyrazole is not pro-tonated, and the pyrazole activated by the electron-donating amino group is readily nitrosated in position 4. See also Grandberg and Klyuchko.600 Nitrosation in the 4-position of l-phenyl-3-methyl-5-sulfanilamidopyrazole occurred successfully.601... 

In the presence of sulfuric acid 1-nitroso-3-pyrazolidinones lose nitrous acid by elimination, giving 2-pyrazolin-5-ones which are then nitrosated at C-4.335,1028 The amino group in 4-amino-3-pyrazol-idinones is diazotizable and the resulting diazonium salt undergoes coupling.12... 

Nitrosation of 1-unsubstituted pyrazol-3-ones 167a j in aqueous hydrochloric acid at 5 °C with sodium nitrite afforded the corresponding pyrazol-3-one 4-oximes 169a j in good yields (65ZOR133) (Scheme 55). The reaction most likely takes place via the intermediate nitroso compound 168 that tautomerises to the product because of the available proton at Nl. 

The pyrrole (114) reacts with dimethyl acetylenedicarboxylate to form the pyrazole (116) in a complex process involving an intermediate pyrazoline (IIS). Nitrosation of the hydroxypyrrole (117) results in the ring-expanded product (118). °... 

Methods of Synthesis. C-Nitrosierungen Qber Silyl-derivate [nitrosation of (trimethyl-silyl)benzene, p-(trimethylsilyl)toluene, and 4-(trimethylsilyl)pyrazole with alkyl nitrite-CFj-COaH or NaNOa-CFj COaH gives nitrosobenzene, p-nitrosotoluene, and 4-nitrosopyrazole, respectively]. Dimethyl Sulphoxide Oxidations A New Method for the Conversion of C = S and C=Se Groups into a Carbonyl Group [CFj-COaH catalyses the conversion of thio- or seleno-carbonyl groups into C=0 via reaction... 

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