Tautomeric pyrazoles

Holzer and Plagens (97H309) (Scheme 24) studied the alkylation of pyrazol-3-ones 62 and of the tautomeric pyrazol-3-one 78a-d/pyrazol-5-ol 79a d mixtures by applying the Mitsunobu reaction [triphenylphosphine, diethyl azodicarboxylate (DEAD), alcohol, solvent]. The reactions were performed in various solvents. Using methanol as the alkylating agent the reaction of 62 in dichloromethane or THF,... 

Pyrazol-3-ones 116a d are converted into the more stable O-alkyl-5-hydroxy-pyrazole-4-carbothioates 117a-d instead of their tautomeric pyrazol-3-ones 118a-d by treatment with calcium hydroxide and then with 0,0-diethyl- or 0,0-di-n-butyltrithiotricarbonate in 1,4-dioxane. The yield of the products is 38, 22, 20 and 16% respectively (95JHC1377) (Scheme 37). 

Cycloaddition of diazomethane with 159 proceeded readily in EtaO at 0 C to give a mixture of the tautomeric pyrazoles 163 and 164 in 60/40 ratio as was established by NMR spectroscopy data (Scheme 48). 

Uracil reacts with hydrazine to give pyrazol-3(2if)-one (944) and urea N-methyl- and dimethyl-hydrazine behave similarly to give the 2-methyl- and 1,2-dimethyl derivatives. The reactions of hydrazines with uridine and related nucleosides and nucleotides is well studied (67JCS(C)1528). The tautomerism and predominant form of uracil are discussed in Section 2.13.1.8.4. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as examples of other possible structures. A detailed investigation of this system disclosed that in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) (150) or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) (149) or (150). 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Only three systems belong to this group pyrazole (3), l//-indazole (4) and 2//-indazole (isoindazole 5). The fused carbon atoms in indazoles are numbered 3a and 7a. When R = H, annular tautomerism (76AHC(Si)i) makes the 3- and 5-positions of pyrazoles equivalent and thus the name 3(5)-R-pyrazole means that the compound is a mixture of tautomers with the substituent R in position 3 and in position 5. The same applies to TV-unsubstituted indazoles however, the numbering is identical in both tautomers and thus 3-R-indazole means either (4) or (5) (R or R = H). Since the indazole tautomer is largely predominant (Section 4.04.1.5.1), indazoles are usually represented by the formula (4). 

Theoretical methods ranging from the now obsolete HMO studies to ab initio calculations have been used extensively on pyrazoles. Although not emphasized in earlier reviews (66AHC(6)347,67HC(22)l), the most recent publications (B-76MI40402,79RCR289) contain several references to theoretical studies. Some publications related to structural studies are to be found in the following sections, especially in connection with NMR spectroscopy (Section 4.04.1.3.4), UV spectroscopy (Section 4.04.1.3.6), PE spectroscopy (Section 4.04.1.3.9) and tautomerism (Section 4.04.1.5). 

For )V-unsubstituted pyrazoles the tautomeric proton was generally located without ambiguity. 3-Substituted tautomers were favoured in the solid state (45), (46) and (48) (Table 5). For the pyrazolyltriazole (47) the authors (77JHC65) concluded that the X-ray analysis indicates that the proton on the pyrazole ring populates either nitrogen atom to... 

The mean chemical shifts of A- unsubstituted pyrazoles have been used to determine the tautomeric equilibrium constant, but the method often leads to erroneous conclusions (76AHC(Sl)l) unless the equilibrium has been slowed down sufficiently to observe the signals of individual tautomers (Section 4.04.1.5.1). When acetone is used as solvent it is necessary to bear in mind the possibility (depending on the acidity of the pyrazole and the temperature) of observing the signals of the 1 1 adduct (55) whose formation is thermodynamically favoured by lowering the solution temperature (79MI40407). A similar phenomenon is observed when SO2 is used as solvent. 

After the publication of a book on the prototropic tautomerism of aromatic heterocycles (76AHC(Sl)l) which covered the literature up to 1975, the study of the tautomerism of pyrazoles has not made great strides. In this section the main conclusions of this earlier review will be summarized and comments on a few recent and significant references added. 

Aromatic pyrazoles and indazoles, in the broad sense defined in Sections 4.04.1.1.1 and 4.04.1.1.2, will be discussed here. Tautomerism has already been discussed (Section 4.04.1.5) and acid-base equilibria will be considered in Section 4.04.2.1.3. These two topics are closely related (Scheme 10) as a common anion (156a) or a common cation (156b) is generally involved in the mechanism of proton transfer (e.g. 78T2259). For aromatic pyrazoles with exocyclic conjugation there is also a common anion (157) for the three tautomeric forms... 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

Two points must be stressed that a 3-R-pyrazole (199a) gives a 1,5-disubstituted derivative (200) and that often the less abundant tautomeric species (Section 4.04.1.5.1) is the more reactive. It is theoretically possible to use the tautomeric composition to direct the synthesis towards one or another derivative. For instance, if (199a) is the more abundant tautomer, the condition to obtain a large proportion of (200) is that The factors... 

Often electrophilic reagents can attack both nitrogen atoms of the mesomeric pyrazolate and indazolate anions. In this case there is no simple relationship between the tautomeric constant and the product composition. 

Azocrown ethers pyrazoles, 5, 228 Azo dyes, 1, 328-331 colour and constitution, 1, 342 heterocyclic, 1, 325-326 Azo-hydrazone tautomerism, 1, 331, 334 Azoles acetic acids decarboxylation, 5, 92 acetoxymercurio reactions, 5, 107 acetyl... 

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... 

Pyrazole, C-formyl-conformation, 5, 209 Pyrazole, fluoro-reactions, 5, 263, 267 Pyrazole, 4-fluoro-5-hydroxy-tautomerism, 5, 214 Pyrazole, 1-germyl-synthesis, 5, 236 Pyrazole, halo-halogenation by, 5, 54 reactions, 5, 104, 105, 266 reduction, S, 105, 106, 266 Pyrazole, 3-halo-1-phenyl-quaternary salts... 

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