Science of Synthesis

Stanovnik, B.; Svete, J., Science of Synthesis, (2002) 12, 22.

The synthesis of pyrazoles from 1,3-dicarbonyl compounds and hydrazines is probably the most widely used and the most general method for pyrazole synthesis. A single pyrazole is obtained with symmetrical 1,3-dicarbonyl compounds and with hydrazine itself, using unsymmetrical 1,3-dicarbonyl reagents can give two isomeric pyrazoles and occasionally both can be isolated from the reaction mixture. Many structural and experimental factors influence the preferred formation of one or the other of the two possible isomers. In many cases steric interactions seems to play the major role (see the relevant examples in ‌Schemes 10‌, ‌11‌, and ‌14‌). The high reactivity of many 1,3-dicarbonyl compounds has led to the use of adequately protected precursors like the O,O-acetals or the in situ synthesis of the 1,3-dicarbonyl compound. The substituent on the hydrazines can be widely varied: alkylhydrazine, arylhydrazines, and also acylhydrazines have been successfully used. Yields are generally high and the experimental procedures are simple, provided that the synthesis yields one major regioisomer and that the separation of the products does not result in loss of product. The condensation of hydrazines with 1,3-dicarbonyl compounds is usually performed in polar protic solvents, like alcohols or water/alcohol mixtures. In many cases the reaction mixture is refluxed in the presence of mineral acids or acetic acid. Highly activated 1,3-dicarbonyl compounds react even in the absence of Brønsted acids to give the corresponding pyrazole in good yields.

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