Understanding the role of the trifluoromethyl group in reactivity and regioselectivity in [3+2] cycloaddition reactions of enol acetates with nitrones. A DFT study.

The mechanism of the [3+2] cycloaddition (32CA) reaction of C-phenyl-N-methylnitrone with ethyl trifluoroacetoacetate has been theoretically studied at the MPWB1K/6-311G(d,p) level. This 32CA reaction, in which the enol form of the β-keto ester participates as the ethylene component, takes place with complete ortho regioselectivity and exo stereoselectivity. The presence of the CF3 group in the β-position in the enol acetate accelerates the 32CA reaction, but it does not modify the regioselectivity, which is controlled by the presence of the ester group. While ortho regioselectivity is reproduced by the MPWB1K calculations, the endo selectivity is not. The inclusion of solvent effects slightly decreases the reactivity but does not modify the gas phase selectivities. Analysis of the DFT global reactivity indices and the Parr functions in reagents provide a rationalization for the participation of ethyl trifluoroacetoacetate and the regioselectivity in this zw-type 32CA reaction.