Davana S. Gonçalves

Theoretical and experimental investigation of the polyeletrophilic β-enamino diketone: straightforward and highly regioselective synthesis of 1,4,5-trisubstituted pyrazoles and pyrazolo[3,4-d]pyridazinones

Obtaining a new precursor enamino diketone with five electrophilic centers is reported, along with theoretical and experimental studies of its reactivity against mono- or dinucleophiles. The Fukui function showed that the β-carbon is the most electrophilic center, followed by the carbonyl ketone and the carbonyl ester, respectively. The reaction of enamino diketone with aniline and hydrazines allowed for the synthesis of a new enamino diketone and 1,4-disubstituted pyrazoles-5-carboxylates, respectively. The regiochemistry and mechanism of syntheses of 1,4-disubstituted pyrazoles-5-carboxylates were determined from reaction monitoring by ESI-MS, NMR analysis and crystallographic data, and fully agreed with the theoretical results. The versatility and efficiency of the enamino diketone was demonstrated by the reaction with hydrazines furnishing multi-functionalized pyrazoles and pyrazolo[3,4-d]pyridazinone derivatives with high regioselectivity.

Theoretical aspects of the unexpected regiospecific synthesis of pyrazole-5-carboxylates from unsymmetrical enaminodiketones

Pyrazoles are heterocycles with economic importance because of the wide applications of such compounds in the pharmaceutical and agrochemical industries. Pyrazoles can be prepared from the cyclocondensation of unsymmetrical enaminodiketones with hydrazines. However, this method often suffers from the formation of a regioisomeric mixture of pyrazoles with generally poor selectivity. Only in few cases, the regiospecific synthesis was possible. Nevertheless, up to now, the factors behind the regiospecificity of this reaction were unknown. Thus, in this work, we use density functional theory (M06-2X/6-31++G(d,p)) to analyze the reaction mechanism. Our results show that the activation-free energy leading to the possible products are similar, but the products present very different stabilities which explain the formation of a single regioisomer experimentally observed. In this way, the regiospecificity is governed by thermodynamical factors.

Unconventional Method for Synthesis of 3-Carboxyethyl-4-formyl(hydroxy)-5-aryl-N-arylpyrazoles

An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of β-enamino diketones with arylhydrazines. Structural modifications in the β-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the β-enamino diketone and arylhydrazine substrates is described.