Pyrazole reaction with formaldehyde

Thus a support-bound benzylpiperazine (282) was allowed to undergo a Man-nich reaction with formaldehyde and a-keto-aldehyde hydrazones. Upon addition of 1,2-dibromo-ethane (388) the support-bound piperazine tether is N, N -dialky-lated to give a quinuclidinium species (389). Subsequent Hoffmann elimination released a diazaalkadiene (390) from the polymeric support, allowing it to react with isonitriles to give pyrazoles (395). With electron-rich dienophiles, HDA reactions were also reported to have been performed to yield compound (393) (Scheme 80). 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

Bis(pyrazole) (169) was prepared by the reaction of 3,5-dimethylpyrazole with formaldehyde (a 4-CH2OH derivative is the probable intermediate) (84ICA99). 

The hydrogen atom of the imino group of pyrazoles is sufficiently active to take part in Mannich reactions. Thus, pyrazoles unsubstituted on nitrogen, with formaldehyde and secondary amines, react smoothly to give high yields of dialkylaminomethyl derivatives (64) which are acid labile.653-656 Pyrazoles substituted on nitrogen give... 

More recently formaldehyde or paraformaldehyde in the classical Mannich reaction has been replaced by methylene chloride. Reaction of pyrazol-3-one (antipyrine) 70 with dimethylamine or piperidine in methylenene chloride at 40 °C or with morpholine in a 1 1 v/v methylene chloride/acetonitrile mixture at 50 °C,... 

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