Indazole, nitration

Benzimidazole (viii) and indazole (ix) differ from the azanaphthalenes in being nitrated at the / -position [C(g)] of the carbocyclic ring. ... 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

The only approaches to fluorinated indazoles seem to be via the diazonium fluoroborates [77BSF171 90AHC(48)65]. 5-Fluoroindazole has been nitrated (92PHA22). 

Dinitro-6-nitramino-indazole, (02N)2C7HtN2 -NH(N02), mw 268.15, N 31 34%. Refs to this compd and higher nitrated derivs, which undoubtedly would be expl were not found in... 

The nitration of indazoles seems to have been little studied. The nitration of 1-phenylindazole (32) in 86% nitric acid gives 4-nitro-1-phenylindazole (33) but an uncharacterized dinitro derivative is obtained with potassium nitrate in sulfuric acid (36LA285). 

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. 

Amination at an azole ring nitrogen is known for N-unsubstituted azoles. Thus, 1,2,3-triazole and 4,5-diphenyl-l,2,3-triazole with hydroxylamine-O-sulfonic acid give 1-amino 145 and 2-amino 146 derivatives in a ratio of 4 1 and 1 3, respectively. 3-Amino-5-/isy/-butylpyrazole affords 147 and indazole and tetrazole give comparable amounts of the 1- and 2-amino derivatives, and ethyl benzothiazol-2-ylcarboxylate reacts at room temperature <2001JOC8528>. Pyrazole is easily N-nitrated with nitrogen dioxide in the presence of ozone <1996JCR(S)388>. 

Indazoles are nitrated, mainly into the position 5 by a mixture of sulfuric and nitric acids or just by nitric acid (Scheme 2.1) with formation of 5-nitroindazole derivatives that are a part of so-called universal nucleosides [9],... 

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. 

Kinetics and mechanism of nitration of indazoles with acetyl nitrate have not been specially investigated. In the sulfuric-nitric mixture indazoles are nitrated in the cation form [39],... 

The nitration of benzazoles is usually effected using concentrated (65%) to fuming (100%) nitric acid generally at temperature between 0 and 5°C. Indazoles are usually nitrated into 5 position, benzimidazoles - as a rule - into 5- or 6-position of the phenylene fragment whereas benzotriazole into position 4 or 7. For the preparation of other nitrobenzazoles the reaction of heterocyclization is used. 

NMR spectra of vicarious /V-alkylation products of 7-nitroinduzoles [672], l-benzylamino-3-nitroindazole [673], 1- and 6-nitroglucosylindazoles [674], l-acetyl-3-chloro-6-nitroindazole [675], the products of methylation and acetylation of 5- and 6-nitroindazoles in various solvents (CDC13, DMSO, acetone) [676], 5-nitro-7-methylindazole [677], 2-substituted 4,6-dinitroindazole [678], several dinitro indazoles [679], 6-nitroindazole derivatives [680], 44 nitrated 1- and 2-methylindazoles having H, Cl, and Br substituents in position 3 [681] have been obtained. II NMR data of some nitroindazoles are presented in a few studies [682-684],... 

The substituent electron effects in indazole and other azoles essentially influence the nitro group vas (Table 3.60). The valence vibration bands of the C-nitro group in nitrated indazoles are in a frequency range of 1560-1510 (vj and 1380-1310 cm-1 (vs) [644, 657-664, 668, 669, 673, 679, 680], The introduction of the nitro group into position 1 in indazole displaces the asymmetric band to higher frequencies (-1620-1610 cm-1), and symmetric frequency, on the contrary, to lower frequencies (-1280-1240 cm-1) in comparison with C-nitroindazoles (Table 3.61) [657, 659, 663, 664], Similar changes are observed in 5-membered nitroazoles. 

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

The 1993 review by Hurst <93AHC(58)215>, The Nitration of Phenyl-substituted Heterocycles, covers the case of pyrazoles and indazoles. Chapter references are up to 1991, but its most recent reference concerning nitration of 1 -arylpyrazoles is <88CHE353>, which is a review on nitropyrazoles. 

The only known C-substitutions in the heterocyclic rings of any benzo-azole are the 2-bromination of benzimidazole with A-bromosuccinimide, the 2-substimtion of benzothiazole with bromine at 450 °C ° and the 3-nitration of indazole." The general rnle is that electrophilic nitrations and halogenations can be achieved only in the benzene ring at the 5-, or 6- or 7-positions, for example 5-bromobenzimidazole can be obtained in high yield from the unsubstituted heterocycle." The efficient conversion of indazole into 3-iodoindazole" is achieved in the presence of base and probably involves iodination of the indazolyl anion (see 26.3). 

Hydroxy-indazole werden glatt mit Thallium(III)-nitrat in Orthoamciscnsaure-triester zu den entsprechenden Chinonen oxidiert467 z. B. ... 

Bis-[cyanamino-(l-indazolo)-methylenamino]-aus Kupfer(II)-nitrat/Kalium-di-cyanamid/lH-Indazol 837... 

It seems that treatment of the parent compound with NBS or NCS in DMF, or reaction with aqueous sodium hypobromite, results in halogena-tion at the 3-position. The ring system has been described as being as inert to electrophilic substitution as indazole but more reactive than quinoxaline. Nitration under imspecified conditions of the heterocycle results in a mixture of mononitro compounds, the major product being either the 6- or 7-nitro derivative and the minor product having a nitro group in either the 5- or the 8-position. Both nitro compounds were reduced to the corresponding primary amines with stannous chloride. 

Halogenation of indazole occurs preferentially in the 5-position. Nitration with filming nitric acid gives 5-nitroindazole. Sulfonation with oleum, however, yields indazole-7-sulfonic acid. Indazole couples with diazonium salts in the 3-position. 

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