Halogenation of pyrazoles

A stepwise halogenation of pyrazole and substituted pyrazoles has been carried out via their silver salts. Thus silver pyrazolide yields 4-halopyrazoles and 5-methylpyrazole gave 4-halo-5-methylpyrazole (equation 5).60,61... 

Halogenation of pyrazole gives 4-monohalo-pyrazoles, for example 4-iodo-, or 4-bromopyrazole under controlled conditions. Poor yields are obtained on reaction of isothiazole and isoxazole " with bromine, again with attack at C-4, but with stabilising groups present, halogenation proceeds betteC and efficient... 

Stefani et al. [56] synthesized 4-halo-3,5-dimethyl pyrazoles (31) in good yields, in short reaction times, and in the absence of a catalyst, by reaction the of 3,5-dimethyl pyrazoles (30) with N-halosuccinimides (NBS, NCS, and NIS) xmder ultrasoxmd irradiation. In addition, the halogenation of pyrazoles with Br2, ICl, and I2 was shown in similar conditions. The procedure is not only simple to operate but also efficient (Scheme 9). 

In the preceding parts of Section 4.04.2.1.3 the electrophilic attack on pyrazolic nitrogen with the concomitant formation of different classes of N—R bond has been examined N—H (iv, v), N—metal (vi), N—C(sp ) (vii, viii, xi), N—C(sp ) (be, x, xi), N—SO2R (x), N—halogen (xii), N—O (xiii) and N—-N (xiv). In this last part the reaction with other Lewis acids leading to the formation of pyrazole N—metalloid bonds will be discussed, and the study of their reactivity will be dealt with in Section 4.04.2.3.lO(viii). 

Halogenation is one of the most studied electrophilic substitutions in the pyrazole series (67HC(22)1, B-76MI40402). The results concern chlorination, bromination and iodination since there is no report on direct fiuorination of pyrazoles (fiuoropyrazoles are prepared by other... 

It is neeessary to emphasize that the direet amination of the methyl group at position 5 of pyrazoles is impossible. Neither 1,3,5-tiimethyl- nor4-ethynyl-l,3,5-trimethylpyrazole undergoes sueh transformations under the reaetion eonditions and starting materials are reeovered nearly quantitatively. Moreover, 4-bromo-ethynyl-l,3,5-trlmethyl- and 4-iodoethynyl-l,3,5-trimethylpyrazole with sodium amide in ammonia exehange the halogen for metal almost quantitatively and in this respeet are similar to phenylehloroaeetylene (Seheme 102). 

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). 

Halogen at ring positions of pyrazole 1-oxides can be activated by palladium toward cross-coupling reactions. However, no examples of nucleophilic displacement of such halogen have been reported. 

Halogenation of phenylpyrazoles always takes place in the pyrazole ring to give 4-halogeno derivatives.60,76,266,350 641> 545-554... 

In the halogenation of benzo derivatives under neutral conditions, the position ortho to the heteroatom is taken with lessened facility (quinoline yielding the 3,6-dibromo product, little 3,8-BB 1-substituted pyrazoles undergoing attack at C-446). 

---