Determining the Synthesis of Pyrazoles via Multi-Component Reaction and Cyclization Cascade of Hydrazono Ugi Adducts

Abstract

Multicomponent reactions (MCR) and cascade reactions are widely applied in organic synthesis. These two synthetic routes are used to access different substituted pyrazoles. In the first part, we are interested in the study of the preparation of aminocyanopyrazoles via a multicomponent reaction. The present research describes a useful protocol for the multicomponent reaction (MCRs) between malononitrile with an orthoester and hydrazine derivatives, under acid catalyst. Indeed, the preparation, isolation and characterization of series of aminocyanopyrazoles 4 were conducted. Such pyrazoles reacted with sodium nitrite followed by secondary amine reagent and with formic acidpyrazolotriazines 6 and pyrazolopyrimidinones 7. Some of the aminopyrazoles were converted into the matching sulfamides by reaction with sulfamoyl chloride. The testing of aminopyrazoles incorporating phenyl and tosyl moieties as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII was performed. Thus, lots of them revealed low micromolar or submicromolar inhibition of these enzymes. The corresponding sulfamides were low nanomolar CA inhibitors. In the second part, acidic hydrolysis of Ugi adducts formed from \(\alpha\)-hydrazonocarboxylic acids and amino acetaldehyde dimethyl acetal leads to the fragmentation of aminoacetaldehyde residues with final formation of pyrazoles. An aldol-type reaction of the hydrazone is proposed as the key step of the cascade. MCR multicomponent reactions and Ugi cascade synthesis constitute efficient and interesting methods for the synthesis of pyrazoles obtained in good to moderate yields.