Pyrazole halogen-metal exchange

The halogen migration is completely suppressed by halogen-metal exchange when the chloroethynyl group is in position 5 of the pyrazole ring. The concentrations of 3-pyrazolyl and 4-pyrazolyl anions are probably small, and they cannot compete with NH2 anions for chlorine bonded to the acetylenic carbon. 

Nucleophilic addition to a ketone by a pyrazole-3-one can also take place via a pyrazolon-4-yl anion generated from a halogen-metal exchange reaction. Akgiin and Pindur (84M197) (Scheme 106) reported one such example, namely the addition of pyrazole-3-one lithium salt 342, obtained by treating 4-bromopyrazol-3-one 341 with n-BuLi in THF at —78 °C, to benzophenone. The addition product 343 was quenched with tetrafluoroboric acid-diethyl ether complex to afford, after loss of water, (3-oxopyrazol-4-yl) (diphenyl)methylium tetrafluoroborate 344. 

Metal-halogen exchange can be achieved in the formation of 3-lithio-l-methylpyrazole from the bromo-pyrazole, and reaction of 4-bromopyrazole with two equivalents of n-butyllithium produces a 1,4-dilithio-pyrazole that reacts with electrophiles at C-4. ° 4-Iodoisothiazole can be converted into a magnesium compound that shows normal nucleophilic Grignard properties. ... 

It is necessary to emphasize that the direct amination of the methyl group at position 5 of pyrazoles is impossible. Neither 1,3,5-trimethyl- nor4-ethynyl-l,3,5-trimethylpyrazole undergoes such transformations under the reaction conditions and starting materials are recovered nearly quantitatively. Moreover, 4-bromo-ethynyl-l,3,5-trlmethyl- and 4-iodoethynyl-l,3,5-trimethylpyrazole with sodium amide in ammonia exchange the halogen for metal almost quantitatively and in this respect are similar to phenylchloroacetylene (Scheme 102). 

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