Copper(I)-Catalyzed 1,3-Dipolar Cycloaddition of Ketonitrones to Dialkylcyanamides: A Step toward Sustainable Generation of 2,3-Dihydro-1,2,4-oxadiazoles

Abstract

Cu^I-catalyzed cycloaddition (CA) of the ketonitrones, Ph₂C=N⁺(R')O^- (R' = Me, CH₂Ph), to the disubstituted cyanamides, NCNR₂ (R = Me₂, Et₂, (CH₂)₄, (CH₂)₅, (CH₂)₄O, C₉H₁₀, (CH₂Ph)₂, Ph(Me)), gives the corresponding 5-amino-substituted 2,3-dihydro-1,2,4-oxadiazoles (15 examples) in good to moderate yields. The reaction proceeds under mild conditions (CH₂Cl₂, RT or 45 °C) and requires 10 mol % of [Cu(NCMe)₄](BF₄) as the catalyst. The somewhat reduced yields are due to the individual properties of 2,3-dihydro-1,2,4-oxadiazoles, which easily undergo ring opening via N-O bond splitting. Results of density functional theory calculations reveal that the CA of ketonitrones to Cu^I-bound cyanamides is a concerted process, and the copper-catalyzed reaction is controlled by the predominant contribution of the HOMO_dipole-LUMO_{dipolarophile} interaction (group I by Sustmann's classification). The metal-involving process is much more asynchronous and profitable from both kinetic and thermodynamic viewpoints than the hypothetical metal-free reaction.