Spirocycles are important structures in drug development due to their inherent biological activity. Their complex architecture usually presents many synthetic difficulties which are efficiently resolved with detailed theoretical studies. The chemo-, regio- and stereoselectivities of the formation of spiroheterocyclic compounds via the (3 + 2) cycloaddition (32CA) reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one (A1) derivatives with diazomethane and nitrone derivative have been studied at the M06-2X/6-311G(d,p) level of theory. The reactions of diazomethane (A2) and N-methyl-C-phenyl nitrone (A3) derivatives with 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one derivatives (A1) occurs chemoselectively along the olefinic bond of A1 via an asynchronous one-step mechanism. Analysis of the electrophilic ( and nucleophilic ( Parr functions at the different reaction sites in A1 shows that A2 and A3 add across the atomic centers with the largest Mulliken and NBO atomic spin densities. Both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the A3 molecule do not affect the observed preferred pathway in its 32CA reaction with A1 whereas the electronic and steric nature of the substituent on the A2 molecule influences the preferred pathway in the 32CA reaction of A1 and A2. The title reaction proceeds via forward electron denisity flux (FEDF), where electron density fluxes from the three-atom components (A2 and A3) to A1. The computed global electron density transfer (GEDT) values suggest that the 32CA of A1 with diazomethane is a polar reaction while the 32CA reaction of A1 with N-methyl-C-phenyl nitrone is a non-polar reaction, and an inverse relationship has been established between the polar character of the reactions and activation barriers. In all the reactions studied, the selectivities are kinetically controlled.
A molecular electron density theory study of the [3 + 2] cycloaddition reaction of nitrones with ketenes
