Indazole acylation

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. 

Infrared spectral evidence indicates that indazol 3-one probably exists in the oxo form (cf. 77). 4-Monosubstituted-l,3-diphenylpyrazol-5-ones have been assigned an oxo structure (cf. 78) on the basis of infrared (presence of a v C=N band) and ultraviolet spectral data. The structure of certain iV-acylated pyrazolones has been discussed on the basis of their infrared spectra, but in these cases the possibility of acyl migration is a complicating factor. 

Acylation of 270 with certain cyclic anhydrides 433 in acetic acid affords 4-oxobutyric acid derivatives 434. Cyclocondensation of these acids with acetic anhydride gives pyridazino[l,2- ]indazole-6,9,ll-triones 435 (Scheme 70) <2003MI1>. 

Rearrangements of 3-(o-aminophenyl)-l,2,4-oxadiazoles (44) or their A-acyl derivatives (R = acyl) to indazoles (45) require drastic conditions (Equation (10)) <82JCS(p1)759, 90ACH795>, for related reactions see also <82H(19)339,83T823>. 

The preceding method is that of Huisgen and Nakaten and is based on the preparation of indazole (ca. 40% yield) from N-nitroso-fl-benzotoluidide discovered by Jacobson and Huber. Mechanistic studies showed this reaction to be an intramolecular azo coupling with an initial acyl shift as the determining step. The yield of indazole from N-nitroso-o-benzotoluidide can be made almost quantitative. Since the low solubility of o-benzo-toluidide makes large quantities of acetic acid and acetic anhydride necessary, the method using the N-acetyl compound described here is more convenient. 

Alkylation of 6-methylindazole with dihydropyran and acid produces the A-l-tetrahydropyranyl derivative as in N-l-acylation of indazoles, this 1-substituted product may be a thermodynamic product resulting from reversible alkylation. 

Acid anhydrides, with or without pyridine, bring about A-acylation of benzimidazoles, A-l-acylation of indazoles, and 1,3-diacylation of benzimidazol-2-one. A-2-Acylation of indazole can be achieved in the presence of a hindered base. ... 

H-Indazol-l -oxide sind durch Umsetzung von 2-Acyl-l-nitro-arenen, z. B. 2-Nitro-benzal-dehyden718 oder 2-Nitro-phenyl-glyoxylsaure-nitril718,719, mit Aminen zuganglich (s.a. Bd. X/ 3, S. 767). 

Wird statt des 2,6-Dinitro-benzaldehyds ein 2-Halogen-5-nitro-benzaldehyd bzw. 3-Acyl-4-ha-logen-l-nitro-aren eingesetzt, so fungiert das Halogen-Atom als Abgangsgruppe175,573- 715 und fiihrt ebenfalls zum Indazol z. B. ... 

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