Indazoles tautomerism

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). 

The indazole molecular structure (Figure 11) shows the tautomeric proton bonded to N-1 (1//-indazole. Section 4.04.1.5.1). A linear correlation between the bond lengths and the bond orders calculated by the CNDO/2 method was observed (74T2903). 

A well-known example of non-prototropic tautomerism is that of azolides (acylotropy). The acyl group migrates between the different heteroatoms and the most stable isomer (annular or functional) is obtained after equilibration. In indazoles both isomers are formed, but 2-acyl derivatives readily isomerize to the 1-substituted isomer. The first order kinetics of this isomerization have been studied by NMR spectroscopy (74TL4421). The same publication described an experiment (Scheme 8) that demonstrated the intermolecular character of the process, which has been called a dissociation-recombination process. 

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... 

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. 

Indazole, 5,5-dimethyl-3-trifluoromethyl-4,5-dihydro-trichomonacidal activity, 5, 291 Indazole, 2-ethoxycarbonyl-reactions, 5, 269 Indazole, 3-fluoro-synthesis, S, 263 Indazole, 1-germyl-synthesis, 5, 236 Indazole, 1-glycosyl-synthesis, 5, 289 Indazole, 2-glycosyl-synthesis, 5, 289 Indazole, halo-reactions, S, 266 Indazole, 2-hydroxy-methylation, 5, 269 Indazole, 3-hydroxy-reactions, S, 264 Indazole, 6-hydroxy-diazo coupling, 5, 86 Indazole, hydroxyphenyl-synthesis, S, 288 Indazole, 3-iodo-synthesis, S, 241 Indazole, l-isopropyl-3-phenyl-reduction, 5, 243 Indazole, 3-mercapto-1 -substituted tautomerism, 5, 265 Indazole, methoxy-... 

Palmer devoted several papers to simple azoles [77JST(40)191 78JST(43)33, 78JST(43)203 81ZN(A)1246 87CPH(111)249], succeeding in definitely establishing the tautomeric predominance of 2//-1,2,3-triazole, 1//-1,2,4-triazole, 2//-tetrazole, and l//-indazole in the gas phase. 

In the field of azoles, Catalan, Abboud, and Elguero [87AHC(41)187] carried out a series of studies which show the interest of the ICR method for a case where the correction always corresponds to an N-methylation effect which can be estimated accurately. This is the case for (1) the annular tautomerism of indazole and its relationship with the annulation effect... 

Fyrazoles and indazoles, imidazoles and benzimidazoles/ and benzotriazoles which possess a free NH group are associated and have been considered to exhibit mesohydric tautomerism see discussion in Volume 1, article I, Section I,C. 

Cycloproparenes may be prepared by formation of one of the lateral cyclopropane o-bonds either via biradical closing, or via 1/3/elimination. The first reported synthesis of a benzocyclopropene derivative (see Section 1)" is an application of the former of these approaches. Upon irradiation, 3//-pyrazoles 70 loose Nj, and the intermediate biradical 71 cyclizes to 72. There is evidence that the intermediate biradical is in the triplet state, but an alternative interpretation in favor of an excited singlet state has also been presented. A variety of 1,1-disub-stituted benzocyclopropenes has been synthesized by the 3ff-indazole route, which is however limited. Cycloproparenes lacking substituents at Cl are not accessible in this way, because the required indazoles occur in the IH tautomeric form 73. 

Annular tautomerism (e.g. 191 192) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (191 R = H) and pyrazole (193 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. However, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (195) than in (196), and UV spectral comparisons show that indazole exists predominantly as (195). 

The 3//-indazole route is limited to 3,3-disubstituted derivatives because the mono-substituted analogues tautomerize to the aromatic 1 /7-isomer (equation 5). Moreover, 3,3-... 

Finally, the case of indazole (36) was theoretically studied and the tautomerism compared to that of 31 [48], Since now there is no lone-pair/lone-pair... 

Sometimes one tautomeric form predominates for indazole the aromaticity of the benzenoid ring is greater in tautomer 243 than in 244, and UV spectral comparisons show that indazole exists predominantly as tautomer 243. 

Tautomeric processes in some nitroindazoles, 6-nitroindazole-based complexes, and other nitrated indazoles have been investigated by vibration spectroscopy [583, 645, 655, 1080-1084],... 

Structure and reactivity of neutral pyrazole, its anion and its cation. 2.2 Structure and reactivity of substituted pyrazoles. 2.3 Structure and reactivity of indazoles. 2.4 Dipole moments Structural Methods. 3.1 X-Ray diffraction. 3.2 Microwave spectroscopy. 3.3 H NMR spectroscopy. 3.4 C NMR spectroscopy. 3.5 Nitrogen NMR spectroscopy 3.6 UV spectroscopy. 3.7 JR spectroscopy. 3.8 Mass spectrometry. 3.9 Photoelectron spectroscopy. 3.10 Electron spin resonance spectroscopy Thermodynamic Aspects. 4.1 Intermolecular forces. 4.2 Stability and stabilization. 4.3 Conformation and configuration Tautomerism... 

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