Pyrazole 3 -, isomerization

The reaction between a diazocarbonyl compound and an electron-deficient alkene is carried out in the presence of an additive that suppresses the 4,5-dihydro-3 f-pyrazole to 4,5-dihydro-l/f-pyrazole isomerization, thus allowing the ring contraction of the 4,5-dihydro-3//-pyrazole by thermal nitrogen elimination to occur under the reaction conditions. 

Alkenylcyclopropane-l -carbonitriles were obtained in moderate to good yields, in some cases even with good diastereoselectivity, by the photolysis of 3/f-pyrazole-5-carbonitriles in unsaturated solvents (Table 4). On UV irradiation, the pyrazoles isomerize to jS,> -unsaturated a-diazocarbonitriles, which cannot be isolated but decompose rapidly to l-alkenyl(cyano)car-benes, which then either cyclize to cyclopropenecarbonitriles 1 or react with the alkene substrate to give 1 -alkenylcyclopropane-1 -carbonitriles 2. As a rule, the cyclopropanation of electron-rich alkenes, dienes, thiophene, and furan dominates the intramolecular carbene reaction. A generalized procedure can be found in Houben-Weyl, Vol. 19b, p 1209. 

Cycloaddition of 1,3-dipolarophiles to alkynes for the synthesis of diazo compounds can also be applied to reaction of diazoalkanes with alkynes (2-91). 2-Diazopropane and 1,2-diarylethynes readily form 3//-pyrazoles (2.229). These pyrazoles isomerize photochemically to the 4-diazo-2-methyl-3,4-diarylbutenes (2.230), i.e., to a vinyldiazo compound (Pincock et al., 1973 Arnold et al., 1976 Leigh and Arnold, 1979). Some cyclopropene (2.231) is formed in a consecutive dediazoniation, i. e., by cyclization of the carbene formed. The method is not useful for unsymmetrically substituted alkynes because these cycloadditions are not regiospecific. It is, however, applicable to the synthesis of diazoalkenes with alicyclic... 

PYRAZOLES, PYRAZOLINES AND PYRAZOLONES] (Vol 20) MVPI. See Mobil s Vapor Phase Isomerization Process. 

The compounds of this article, ie, ftve-membered heterocycles containing two adjacent nitrogen atoms, can best be discussed according to the number of double bonds present. Pyrazoles contain two double bonds within the nucleus, imparting an aromatic character to these molecules. They are stable compounds and can display the isomeric forms, (1) and (2), when properly substituted. Pyrazoles are scarce ia nature when compared to the imidazoles (3), which are widespread and have a central role ia many biological processes. 

If 7 Rg, a mixture of the two isomeric pyrazoles is obtained. An excellent method to prepare pyrazole [288-13-1] consists in treating 1,1,3,3-tetramethoxypropane (masked malondialdehyde) with hydrazine (eq. 2). 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

Azole 7V-oxide groups are readily removed by reduction with Zn/HOAc, HI or PCI3, e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isomerize on irradiation to the corresponding 2-oxides. 

The systems discussed here are aromatic systems which undergo a variety of isomerizations on irradiation. Irradiation of imidazoles led to a scrambling of substituents, whereas such scrambling has not been observed in the pyrazoles which undergo photoisomerization to imidazoles. 

Irradiation of the substituted pyrazole (523) gave the imidazoles (524) and (525). The amount of each isomer formed is solvent dependent. In ethanol 7% of (524) was formed together with 2% of (525). In cyclohexane, however, isomerization was more efficient, the percentages of the two isomers being 20% and 10%, respectively. 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

From UV studies of 4-phenyl-, 4-nitro- and 4-nitroso-pyrazoles, Habraken et al. (67RTC1249,72JHC939) conclude that the 4-pyrazolyl group acts as an electron-donating group. UV spectra of pairs of 1-aryl- and 2-aryl-indazoles and their utility in the determination of isomeric structures are discussed in (67BSF2619) many other UV data on indazole derivatives can be found in (71PMH(3)67). 

The fact that the isomeric structure of azolides is thermodynamically controlled has been used by Olofson and Kendall to prepare 1-alkylazoles regioselectively (70JOC2246). An asymmetric pyrazole yields two alkylated derivatives (Scheme 21 see Section 4.04.2.1.3 (viii)), but the alkylation with a powerful alkylating agent of the acetylated derivative leads to the less abundant isomer via the salt (249), which is too unstable to be isolated. 

JA173) illustrates this possibility (Scheme 34). Thus 3,3,5-trimethyl-3//-pyrazole (371 R = H) on irradiation in pentane solution gives 1,3,3-trimethylcyclopropene (372 R = H) the intermediate diazoalkene (373) has been characterized. The tetramethyl derivative (371 R" = Me) when irradiated at -50 °C in methylene chloride leads to a species believed to be a l,2-dlazablcyclo[2.1.0]pent-2-ene (374). This isomerization is thermally reversible, the 3H- pyrazole being regenerated at room temperature. 

The 1,2-diazepine ring system is related, thermally and photoehemieally, to two pyrazole [4.5] bicyclie systems (511) and (512). A large number of publieations by Moore, Sharp, Snieekus and Streith deal with these isomerizations (72CC827, 80CC444). 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Burger s criss-cross cycloaddition reaction of hexafluoracetone-azine (76S349) is also a synthetic method of the [CNN + CC] class. In turn, the azomethines thus produced, (625) and (626) (79LA133), can react with alkenes and alkynes to yield azapentalene derivatives (627) and (628), or isomerize to A -pyrazolines (629) which subsequently lose HCF3 to afford pyrazoles (630 Scheme 56) (82MI40401). 

Pyrazole, 3-(trifluoromethyl)-4,5-trimethylene as amebicide, 5, 291 Pyrazole, 3-triflyl-4-phenyl-synthesis, 5, 282 Pyrazole, 1,3,4-triiodo-synthesis, 5, 234 Pyrazole, 1,3,5-trimethyl-isomerization, 5, 221 Pyrazole, 3,4,5-trimethyl-bromination, 5, 240 halogenation, 5, 89 reactions... 

A recent paper by Singh et al. summarized the mechanism of the pyrazole formation via the Knorr reaction between diketones and monosubstituted hydrazines. The diketone is in equilibrium with its enolate forms 28a and 28b and NMR studies have shown the carbonyl group to react faster than its enolate forms.Computational studies were done to show that the product distribution ratio depended on the rates of dehydration of the 3,5-dihydroxy pyrazolidine intermediates of the two isomeric pathways for an unsymmetrical diketone 28. The affect of the hydrazine substituent R on the dehydration of the dihydroxy intermediates 19 and 22 was studied using semi-empirical calculations. ... 

Apart from the IH and 2H tautomers 2a and 2b, isomeric forms in which the migrating proton takes up its position on one of the carbon atoms in the ring are formally possible. For the case of unsubstituted pyrazole 2, R = r2 = r3 = tjjg tautomeric equilibrium should be represented by the scheme involving 4H 2e and a pair of degenerate 5H species 2c and 2d (Scheme 2). 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

Asano and co-workers have reported die kinetic effects of pressure, solvent, and substituent on geometric isomerization about die carbon-nitrogen double bond for pyrazol-3-one azomethines 406 (R = H), 406 (R = NO2) and 407, (Scheme 93). The results demonstrate the versatility of die inversion mechanism. The rotation mechanism has been invalidated. First-wder rate constants and activating volumes for diermal E-Z isomerization for 406 (R = H) and 406 (R = NO2) are given at 25°C in benzene and methanol (89JOC379). 

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