Quantum-Chemical Modeling of One-Pot Assembly of 1-Formyl-2-Pyrazolines from Alkylaryl Ketones, Arylacetylenes, Hydrazine, and Formic Acid

The assembly mechanism of 1-formyl-2-pyrazoline from alkylaryl ketones, arylacetylenes, hydrazine and formic acid has been investigated in some detail using the B2PLYP-D2/6-311+G**//B3LYP/6-31+G* quantum-chemical approach. We ascertained that the first stage of the assembly involves the C-vinylation reaction of acetophenone with phenylacetylene catalyzed by the KOBu^t/DMSO superbase, followed by the Z-E isomerization of the dienolate ion. Neutralization of the latter leads to a mixture of α,β- and β,γ-unsaturated ketones. The kinetically most favorable route for the subsequent assembly of 1-formyl-2-pyrazoline is found to involve (i) addition of hydrazine to the C═C bond of the α,β-unsaturated ketone, (ii) cyclization of the β-hydrazinyl ketone, and (iii) formylation of 2-pyrazoline. The β,γ-unsaturated ketone is found to convert into the β,γ-unsaturated formylhydrazone, which is consistent with experiment. The transformation of β,γ-unsaturated formylhydrazone to 1-formyl-2-pyrazoline proceeds through the hydration of formylhydrazone, resulting in the formation of β,γ-unsaturated ketone, which subsequently isomerizes into the α,β-unsaturated ketone. The high barrier of the isomerization accounts for the long duration of the corresponding stage of the synthesis (1 h, 100 °C).