Pyrazole dihydro-, tautomerism

Pyrazole, 4-[(2,5-dichlorophenyl)azo]-5-hydroxy-3-methyl-l-phenyl-as dyestuff, 5, 299 Pyrazole, difluoro-synthesis, 5, 263 Pyrazole, dihydro-tautomerism, 5, 78... 

Unfortunately, 4,5-dihydro-32/-pyrazoles can not only produce cyclopropanes but also tautomeric 4,5-dihydro-l//-pyrazoles (d -pyrazolines) and acyclic constitutional isomers of the cyclopropanes. This is illustrated for the 4,5-dihydro-3//-pyrazoles 11 which result from [3-1-2] cycloaddition of a-diazo esters to electron-deficient alkenes. If = H, they undergo rapid tautomerism to form 4,5-dihydro-l//-pyrazoles 12 or 13, both of which are not subsequently... 

Additions of diazoalkanes to the cumulated double-bond systems of ketenes and allenes yield cyclopropanones (Houben-Weyl, Vol. 4/3, pp 65 and 66) and alkylidenecyclopropanes respectively. For example, methylenecyclopropane (53) was made by the addition of diazomethane to allene. The intermediate 4-methylene-4,5-dihydro-3//-pyrazole is exeeptionally sensitive to tautomerism and poor yields were obtained under all but strictly neutral conditions. 

Most often in these reactions, however, the monoadduct is isolated and used to prepare the alkylidenecyclopropane, as in the case of the 1 1 allene-2-diazopropane adduct, which on thermolysis generated the singlet trimethylenemethane diradical 59, which closed to give a mixture of l,l-dimethyl-2-methylenecyclopropane (60) and isopropylidenecyclopropane (61). Although a wide variety of alkylidenecyclopropanes have been made in this way (see Table 2), the involvement of trimethylenemethane intermediates in the deazetization step means that mixtures of isomers are normally produced. Attempted syntheses of alkylidenecyclopropanes by this route have sometimes been frustrated by tautomerism and autoxidation of the intermediate 4,5-dihydro-3i/-pyrazole or by a reversal in the regiochemistry of the diazoalkane and allene addition reaction leading to 3-alkylidene-4,5-dihydro-3//-pyrazoles. ... 

Some insight into the nature of these catalyzed cyclizations is provided by the synthesis of benzobicyclo[3.1.0]hexene 17. Intramolecular cycloaddition under base catalysis (from the tosylhydrazone 14) or by heating compound 18 gave the [3.3.0] bicyclic product 16 but, in the boron trifluoride catalyzed reaction, the [3.2.1] bicyclic product 13 was formed. In the base-catalyzed reaction the intermediate 4,5-dihydro-3//-pyrazole 16 suffered tautomerization (to give 19). The diazo compound 13 cannot tautomerize, and gave a quantitative yield of benzobicyclohexene 17 when heated. These boron trifluoride catalyzed addition reactions do not involve the free diazo compound and in this particular case the cyclic A -tosyl intermediate 12 could be isolated from the reaction mixture. ... 

Reactions like the conversion of compound 7c to 7d are relatively uncommon. Most 4,5-dihydro-3//-pyrazoles are chemically too sensitive to permit extensive structural modification before deazetization. Those that can be modified are normally persubstituted at C3 and C5 or these positions are bridgehead carbons so that in either case tautomerism is avoided. Hence, in making optically active 1-hydroxymethyl-1-methyl-2,2-diphenylcyclopropane (10), the ester group of the diphenyldiazomethane, menthyl 2-methylprop-2-enoate adduct 9 was reduced... 

Michael addition of water to 4-methylenepyrazol-3-ol 312, derived from 5-methyl-l,2-dihydro-3H-pyrazol-3-one and neat N,N-dimethylfor-mamide dimethylacetal in the presence of acid, gave 4-formylpyrazol-3-one 315 via intermediate 313 which loses dimethylamine to form, after tautomerization, aldehyde 314 (02EJOC1763) (Scheme 71). The slow reaction is complete in 2 days. 

The equilibrium position depends on the type of substituent and on the solvent used. In the gas phase and in apolar solvents, the 2,4-dihydro-3//-pyrazol-3-one dominates. Substituent tautomerism in heterocycles is observed in oxo compounds as well as in the corresponding thiones and imines. 

Acylation and metallation studies on monomers, dimers, trimers, and tetramers containing linked thiophen, pyridine, pyrimidine, furan, benzofuran, benzothiophen, and indole moieties have been published/ Deuteriation, halogenation, and diazo-coupling reactions of 2-oxo- and 2-thioxo-l,2-dihy-dropyrimidinium salts have been studied and compared with results for 2,2-dialkyl-1,2-dihydropyrimidinium and 2,3-dihydro-1,4-diazepinium salts in order to demonstrate the effect of an adjacent 0x0- or thioxo-group on the properties of a 1,5-diazopentadienium system/ Vilsmeier formylation of, and tautomerism in, 2-hydroxypyrazolo[5,l-h]quinazolone and l-phenylpyrazolo[5,l-A]-quinazoline-2,9-dione have been studied/ The pyrazolo[3,4-c]pyrazole (71) has been methylated and acetylated, the major products being (72)/ ... 

The cover picture presents schematically the 3-way tautomerism of the neuroprotective agent 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one enolisation, ketonisation and switching from imine to enamine. 

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