Variations of the Knorr Pyrazole Synthesis

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. 

The tactic of using the enaminone as the 1,3-dicarbonyl variant was also successfully applied to the synthesis of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as ATi selective angiotensin II receptor antagonists.  

Another 1,3-dicarbonyl equivalent is keto-enol. Treatment of the ketone with ethyl formate in the presence of NaH afforded the keto-enol as the 2-hydroxy-methylene ketone. Condensation of the keto-enol with hydrazines provided the corresponding pyrazole fused bile acid methyl ester 

Enone may also serve as a substrate for preparing pyrazolines, which epoxy ketone has been used to make hydroxyl-pyrazolines. For instance, the enone-ester substrate was used to make diaryl dihydropyrazole-3-carboxamides as CB] receptor antagonists.  

Methoxyimino-ketones are not only variants of the 1,3-dicarbonyl group, but also they have the advantage of affording excellent regioselectivity for the pyrazole formation. Chemoselective condensation between the diketoester and methoxyamine hydrochloride produced 

---

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

---