Indazoles halogenation

A patent (95JAP07196655) deseribed the preparation of a 2//-indazole derivative of speeifie formula 109 useful as a therapeutie agent for a eireulatory disease sueh as hypertension, having angiotensin II antagonism and antihypertensive aetion. In formula 109 r = lower alkyl or alkenyl R, R = H, halogen, lower... 

Because the reactive 4-position of pyrazole is substituted in indazole (benzo[b]pyrazole), substitution by electrophiles occurs by default in the 3-position initially, and then in the 5- and 7-positions of the fused benzene ring (ortho and para to the N-l). Anionic indazoles always halogenate at C-3 (84MI22). 

The above considerations do not necessarily apply to reactions of electrophilic reagents with pyrazole and imidazole anions (134, 135). The imidazole anion is sometimes (diazo coupling, halogenation, deuterium exchange) substituted in the 2-position (139) and the indazole anion in the 3-position (cf. Section 3.4.1.4.5). 

Metal-promoted approaches have been investigated for the preparation of indazoles. A copper(II) oxide-catalyzed regioselective synthesis of 1-alkyl- and 1-aryi-1 //-indazoles 25 from ortho-halogenated alkanoylphenones, benzophenones, and arylcarboxylic acids 24 with hydrazines in the presence of potassium carbonate has been developed <07OL525>. A... 

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). ... 

Chromium tricarbonyl-complexed aryl fluorides undergo nucleophilic substitution reactions. The substitution is not a straightforward SNAr mechanism as can be seen using, for example, 4-methoxy-l-fluorobenzene complex (71). Reaction of (71) with acetylide (72) gives a 1 2 mixture of the 1,2 and 1,3 products (73) and (74) (Scheme 115). Other leaving groups include halogens, alkoxides, and amines. Indazoles can be prepared by reaction with hydrazine followed by acidic deprotection-decomplexation (Scheme 116). 

The benzo-1,3- and -1,2-azoles do not undergo electrophilic substitution on the hetero-ring some examples of electrophilic halogenations are known in the benzene ring. These bicyclic systems are slightly weaker bases than the azoles, but react easily with alkyl halides to give salts. N-Deprotonation of indazoles or benzimidazoles allows substitution on nitrogen. 

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). 

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. ... 

Eine nukleophile Photosubslilution an 3-Halogen-lH-indazolen wird bei der Photolyse in Aminen beobachtet, wobei aus 3-Brom-l-methyl-5-nitro-l H-indazol in Dimethylamin 3-Dimethyl-amino-I-metkyl-5-nitro-lH-indazol292, (20% Schmp. 253-255°) gebildet wird. 

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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