1,3-Dipolar [3 + 2] cycloaddition reactions of N,C,C-trisubstituted nitrones with ring-acceptor...

1,3-Dipolar [3 + 2]-cycloaddition of nitrones to the carbon-carbon double bonds of methylenecyclopropanes yields a mixture of regioisomeric 4- and 5-isoxazolidines. The mechanisms of the reactions of N,C,C-trisubstituted nitrones with ring acceptor substituted dimethyl methylenecyclopropanes-1,2-dicarboxylate and aryl methylidene cyclopropanes-1,1-dicarboxylate have been investigated with the Becke 3-Parameter Lee-Yang-Par exchange-correlation functional, a Hartree-Fock DFT hybrid functional, to delineate the factors responsible for the regioselectivity of these class of reactions.

The energetics of the reaction of the phenyl-substituted nitrone with unsubstituted methylenecyclopropane indicate that the formation of the 5-spirocyclopropane is favored over the 4-spirocyclopropane kinetically and thermodynamically. However, the energetics of the reaction of the same phenyl nitrone with vicinal ester (-CO₂CH₃)-substituted methylenecyclopropane show an inversion in the regioselectivity favoring the formation of the 4-regioisomer over the 5-regioisomer. For the reactions of N,C,C-trisubstituted nitrone with vicinal ester (-CO₂CH₃)-substituted methylenecyclopropane (-R₁=H, -R₂=Ph and -R₁=CH₃ and -R₂=CO₂CH₃) and geminal ester (-CO₂CH₃)-substituted methylenecyclopropane (R₃=H, R₄=H; R₃=OCH₃, R₄=CH₃; and R₃=H, R₄=Cl), the energetics indicate that the 5-spirocyclopropane is favored over the 4-spirocyclopropane. The calculations also indicate that electron-donating groups increase regioselectivity of the 5-regioisomers over the 4-regioisomers.

The regioselectivity of these reactions is determined by both electronic and steric factors. The pathways with the lower activation barrier leads to the more stable regioisomer in all cases, implying that the pathways that are kinetically favored are also thermodynamically favored. However, it is also clear from the energetics that these reactions are not reversible and are therefore under kinetic control. Therefore the selectivity of the reactions is governed solely by the difference in activation barriers leading to the two isomers and not in any way by the thermodynamic stability of the isomers formed.