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

High Resolution Image Download MS PowerPoint Slide Cu I -catalyzed cycloaddition (CA) of the ketonitrones, Ph 2 C═N + (R′)O – (R′ = Me, CH 2 Ph), to the disubstituted cyanamides, NCNR 2 (R = Me 2, Et 2, (CH 2 ) 4, (CH 2 ) 5, (CH 2 ) 4 O, C 9 H 10, (CH 2 Ph) 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 (CH 2 Cl 2, RT or 45 °C) and requires 10 mol % of [Cu(NCMe) 4 ](BF 4 ) 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.