Indazole ring

The partition coefficient P, defined as the equilibrium concentration of the compound in n-octanol divided by that in the aqueous phase, has been measured for pyrazole and indazole (B-79MI40416). It was found that log F = 0.13-0.26 for pyrazole and 1.82 for indazole, clearly showing the greater hydrophobicity (lipophilicity) of the indazole ring, due to the benzenoid moiety. 

Similarly, the hydrogen atom at the 3-position of the indazole ring has been replaced by NHa, NHMe, NMea and NEta upon irradiation in the presence of the appropriate nucleophile (80T3523). 

This section deals with reactions taking place at positions 4, 5, 6 and 7 of the indazole ring. The reactivity of position 3 has already been discussed with that of pyrazoles. 

Substituents in the indazole ring may direct a given reaction towards another position either by their R and I electronic properties or simply by protecting the most reactive position. Examples of both types are found in sulfonation studies (67HC(22)l). As indicated before (Section 4.04.2.3.2(i)), sulfonation takes place at position 7. However, the presence of an amino group at positions 5 or 7 directs the attack towards the 4-position (Scheme 40). To obtain the indazole-5-sulfonic acid a more complicated procedure has been used but it is still based on the same ideas. 

A much improved synthesis of a dioxino[23-e]indolemethanol was described. This procedure now allows the preparation of multigram quantities of the enantiomerically pure compound. Application of this methodology to different 5-hydroxy heterocycles enables access to furo[33- [l,4]benzodioxin, thieno[33-/l[l,4]benzodioxin and l,4-dioxino[23-e]indazole ring systems <99S1181>. 

Patey, A. L. Waldron, N. M. A new indazole ring synthesis. Tetrahedron Lett. 1970, 3375-3376. 

The synthesis of pazopanib (1) involves sequential animation of 2,4-dichloropyrimidine 25 with 6-amino-2,3-dimethylindazole 24 and 5-amino-2-methyl-benzenesulfonamide 28. The 6-amino-2,3-dimethylindazole 24, on the other hand, was prepared from 2-ethylphenylamine 20 via 5-nitration with fuming nitric acid and concentrated sulfuric acid, followed by treatment with isoamyl nitrite and acetic acid to produce 6-nitro-3-methylindazole 22. The 6-nitro group was reduced with stannous chloride and concentrated HC1 in glyme and subsequently methylated at the C2 position of the indazole ring with trimethyloxonium tetrafluoroborate in acetone to produce 6-amino-2,3-dimethylindazole 24. The resultant indazole 24 was condensed with 2,4-dichloropyrimidine 25 in the presence of sodium bicarbonate in ethanol/THF and subsequent iV-methylation with iodomethane and cesium carbonate to produce 27. The 2-chloro group of pyrimidine was then allowed to react with 5-amino-2-methyl-benzenesulfonamide 28 in catalytic HCl/isopropanol and heated to reflux to deliver pazopanib hydrochloride (1) in good yield. 

The alkaline hydrolysis of isatin is the first step of a method for the construction of the indazolic ring system354. This method has been applied to the synthesis of serotonin... 

The nitration of 2-phenylindazole at 0°C with sulfuric-nitric acid mixture leads to 5-nitro-2-phenylindazole and 7-nitro-2-phenylindazole. These compounds have been identified using NMR spectroscopy [19]. In spite of the fact that the indazole positions 5 and 7 are most reactive with respect to electrophilic substitution [20] it is difficult to know beforehand the competition between the aromatic positions of the indazole ring (C-4, C-5, C-6, C-7) and the /V-phcnyl ring. 

As an alternative to the diradical ring closure that occurs with the 3 -indazole ring contraction, the employment of a 1,3-elimination from an ortho, a-disubstituted aromatic has much appeal for cycloproparene formation, not least because of the simplicity of the process and the ready availability of the starting materials. It is not surprising, therefore, that such a report appeared as early as 1974. Radlick and Crawford found that 1-bromo-2-(methoxymethyl)benzene (33) underwent lithium-halogen exchanged and cyclization to 1 upon treatment with butyllithium. The yield was a modest but acceptable 30%. In similar vein, the cyclization methodology provided rocketene (34) albeit in 5% yield (equation 7a). ... 

Die Oxidation spielt in der Indazol-Reihe keine groBe Rolle, da dadureh zumeist der heterocy-clische Ring zcrstort wird. C-Methyl-indazole konnen mit Kaliumpermanganat zu den ent-sprechenden Carbonsauren oxidiert werden, aber unter etwas drastischeren Bedingungen wird der Indazol-Ring abgebaut 192 717. 

The 3,3 -isomer (54) has been prepared by two routes (71JOC1563) (Scheme 21) cyclization of bibenzyl-2,2 -bisdiazoacetate and dehydrogenation of an octahydro derivative made, in two steps, from cyclohexanone. A 1,1 -diaryl derivative of 54 had previously been prepared, with formation of one indazole ring, by oxidation of a benzoylarylhydrazone with lead tetraacetate and treatment with a Lewis acid [66JCS(C)1527j. Lead tetraacetate oxidation of 54 leads to A- - -bi-3H-indazole (71JOC1563). 

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