Pyrazole Knorr synthesis

Similar to the Paal-Knorr pyrrole synthesis, the Knorr pyrazole synthesis entails the reaction of hydrazine, or substituted hydrazine, with 1,3-dicarbonyl compounds to provide the pyrazole ring systems.  

Presumably, the Knorr pyrazole synthesis begins with formation of the hydrazone with the more active one of the two carbonyls. In reality, a mixture of the two regioisomers would arise. The hydrazones then cyclize to afford a mixture of regioismeric pyrazoles. 

The Knorr pyrazole synthesis has bestowed a futile ground for medicinal chemists to practice their craft in drug discovery. The most conspicuous example is the synthesis of celecoxib (Celebrex), a selective COX-2 inhibitor prescribed as an analgesic. As shown below, the substrate dione was prepared by the Claisen condensation of 4-methylacetophenone with ethyl trifluoroacetate in the presence of NaOMe in methanol under reflux. Subsequent diarylpyrazole formation from the condensation of the dione and 4-sulfonamidophenyl-hydrazine hydrochloride then delivered celecoxib.  

Tepoxalin is a potent inhibitor of both the cyclcooxygenase and lipoxygenase pathways of the arachidonic acid cascade. In a facile and more environmentally friendly synthesis, condensation between methoxyphenyl-hydrazine and the bis-ketone with a pendant hydroxamic acid group at the end of the molecule delivered tepoxalin in 70% yield. 

Another important application of the Knorr pyrazole synthesis is the preparation of rimonabant. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 148, Springer International Publishing Switzerland 2014 

1 (a) Knorr, L. Ber 1883,16, 2597. Ludwig Knorr (1859-1921) was bom near Munich, Germany. After studying under VoUiard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone dmg, pyrine. (b) Knorr, L. Ber 1884,17, 546,2032. (c) Knorr, L. Ber. 1885,18,3. (d) Knorr, L. Ann. 1887, 238,137. 

7 Sakya, S. M. Knorr Pyrazole Synthesis. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Corey, E. J., Eds, Wiley Hoboken, NJ, 2005, pp 292-300. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 139, Springer-Verlag Berlin Heidelberg 2009 

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The Knorr pyrazole synthesis has been extensively utilized in the preparation of a number of pyrazoles as metal chelators, photographic dyes, herbicides, and biologically active... 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

Reaction between 1,4-ketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 331). 

KNORR Pyrazole synthesis 206 KNORR Quinoline synthesis 206 Knorr 209,284 Knowles 180... 

The Knorr pyrazole synthesis with 1,1,3,3-tetraethoxypropane and amin-oguanidine readily gave praxadine (292) which is an anti-inflammatory and analgesic agent [359, 360]. 

In addition to 1,3-dicarbonyl as a reactant for the Knorr pyrazole synthesis, several variants exist as the 1,3-dicarbonyl group surrogate. Enaminone is one example. Reaction between ethyl-4-iodobenzylacetate and I. N-dimethylformamide dimethylacetal (DMFDMA) provided the enaminone. Subsequent condensation between the enaminone and 2,4-dichlorophenyl-hydrazine afforded the pyrazole as an advanced intermediate for 1,5-diarylpyrazole derivatives as CBi receptor antagonists. 

Other references related to the Knorr pyrazole synthesis are cited in the literature. ... 

Knorr Pyrazole Synthesis James Kempson 5.6.1 Description... 

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