Indazoles bromination

Partial rate factors calculated for indazole bromination indicate that the benzo derivative is less reactive than pyrazole a positional reactivity order of 5 > 3 > 7 (in the ratio 10.7 6.9 I) was obtained [78JCS(P2)865]. 

Aqueous bromination of indazole shows the relative order of reactivity for various positions to be 5>7 others, 5 >3 >7 others, and 3 others for reactions of cationic. 

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 mercuration of thiophene, which presumably goes by way of a coordination compound, gives an initial attack in the 2 position as expected from the reactions of thiophene itself (67). The bromination (or chlorination) of indazole or its silver salt also leads to the same products (82). 

Within a given series of heterocycles, differences in reactivity and stability are found compared to their corresponding benzo analogues (see Section 7.02.5). For example, 2,1-benzoisoxazoles are stable in mineral acids, while thieno[3,2-c]isoxazoles (1) and selenolo[3,2-c]isoxazoles (2) are not. Further, 2,1-benzoisoxazoles react with activated methylene synthons to afford quinoline V-oxides <67TL2337> whereas compounds (1) and (2) are inert. The isomer distribution from the pH dependent bromination of thieno[3,2-c]pyrazole (3) is similar to that found for indazole, while thieno[3,2-c]isoxazole (4) is relatively inert <76CS165,77CSi>. 

Scheme 8.8. Partial rate factors for bromination benzimidazole, 5-bromobenimidazole, and indazole.

Bromination of 2-phenyl-2//-indazole occurs mainly in the 3-position (89% yield) and subsequently in the 5- and 7-positions (84JOC3401). The high reactivity of the 3-position here may be attributed to the gain of ben-zenoid aromaticity on forming the transition state 8.82. 

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). 

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