Indazoles 3- indazolones

Two double bonds. This is the most important class which includes the aromatic compounds pyrazole (3), indazole (4) and isoindazole (5), their non-aromatic isomers, pyrazolenines (or 3iL-pyrazoles 6), isopyrazoles (or 4JT-pyrazoles 7) and 3JT-indazoles (8), and the carbonyl derivatives of pyrazolines with the endocyclic double bond in positions 1, 2 or 3, i.e. (9), (10) and (11), respectively. The indazolones (12) and the pyrazolidinediones (13) and (14) also belong to this group. 

Substituted indazolones exist in the OH form (143b) and 2-substituted indazolones exist in the NH form (144a), whereas the structure of AC-unsubstituted indazolones varies with the physical state. This difference of behaviour, depending on the position of the A -R substituent, corresponds to the aromatic structure of the indazole derivatives compared with the quinonoid structure of isoindazoles. 

Indazoles can also be prepared by the [CCC + NN] method. For instance indazolones have been obtained rather simply by the action of hydrazine hydrate on 2-halobenzoic esters (78S633). 

Some of these indazoles showed analgesic activity greater than that of aspirin and several possessed significant antiinflammatory action. Both properties were the most striking and characteristic ones of the series. In a few cases the authors isolated the corresponding indazolones (705) which were less active than (704) in terms of analgesic and antiinflammatory properties. 

From a qualitative viewpoint there is no doubt that the compounds classified as aromatic in Section 4.04.1.1 (pyrazoles, indazoles, isoindazoles, pyrazolones, indazolones, mesoionic derivatives) indeed have aromatic properties to a greater or lesser extent. Dihy-drobenz[cd]indazole (115) is also formally an aromatic compound since it has an odd number of electron pairs (n =7). However, due to the presence of two adjacent nitrogen atoms the aromatic tautomer (115a) is not stable, and the compound exists as the 1,5- or 1,3-dihydro tautomers (115b) or (115c) <72JCS(P2)68). The antiaromatic benz[cd]indazole (116), although unstable, has been fully characterized by N, H and NMR spectroscopy... 

Similar ring contractions in which the nitrogen-nitrogen bond is cleaved are found in the reductive ring contractions of pyridazines to pyrroles [148, 149], phthalazines to isoindoles [150], 5,6-diphenyl-1,2,4-triazinones to imidazolones [151], benzo-l,2,4-triazines to benzimidazoles [71], benzo-l,2,3-triazinone to indazolone [la, 152], benzo-l,2,3-triazin-3-oxide to indazole [la], benzo-2,3-diazepines to isoquinolines [153], benzo-l-pyrano-[4,3-e ]-as-triazin-3-one to benzopyranoimidazolone [154], and 2-methyl-4,5-dihydropyridazin-3-ones to pyrrolin-2-ones [155]. 

The preparations of ()-hydrazinobenzoic acid hydrochloride and indazolone are essentially those given by Pfannstiel and Janecke. The procedure for the conversion of indazolone to indazole is a modification of that of Fischer and Seuffert. A procedure involving the decarboxylation of indazole-3-carboxylic acid is described by Schad and by von Auwers. ... 

Indazoles have been used as the biosteres of indoles in drug discovery. In the synthesis of the nonsteroidal anti-inflammatory drug (NSAID) bendazac, benzylaniline was used as its starting material. Nitrosolation was accomplished using nitrous acid. The resulting A-nitroso intermediate was reduced with sodium thiosulfate to the corresponding hydrazine, which cyclized to the indazolone. Subsequent alkylation with methyl chloroacetate was followed by hydrolysis to deliver bendazac. 

Two other Cu-catalyzed reactions have been reported for preparing 2-aryl-2//-indazoles 114 (Scheme 40) [76] and 1-substituted indazolones 116 (Scheme 41) [77]. The first one started from protected hydrazines 112, which underwent intramolecular amidation and subsequent deacylation and oxidation to afford 114 with moderate yields. In this case, if base was switched from K2CO3 to CS2CO3, no ligand was required. The secondary one using amides 115 as substrates, which were catalyzed by CuI/L-proline to provide 116 with good yields. 

---