Exploring the chemo-, regio-, and stereoselectivities of the (3 + 2) cycloaddition reaction of 5,5-dimethyl-3-methylene-2-pyrrolidinone with C,N-diarylnitrones and nitrile oxide derivatives: a DFT study.

The (3 + 2) cycloaddition (32CA) reaction is an efficient method for the synthesis of many biologically active heterocyclic compounds, but there are several regio- and stereochemical issues that must be fully understood to exploit the full utility of its synthetic power. We herein explored the chemo-, regio-, and stereoselectivities of the 32CA reaction of 5,5-dimethyl-3-methylene-2-pyrrolidinone (B1) to C,N-diarylnitrones (B2), and nitrile oxide derivatives (B3) with DFT at the M06/6-311G(d,p) level of theory. The reactions occur via an asynchronous one-step mechanism, with the chemoselective addition of the C,N-diarylnitrones, and nitrile oxide derivatives across the olefinic bond of 5,5-dimethyl-3-methylene-2-pyrrolidinone being the most preferred kinetically and thermodynamically. The regio- and stereoselectivities of the reactions are affected by the electronic and steric nature of substituents on B2 but they are not affected by the electronic and steric nature of substituents on B3. The C,N-nitrones and the nitrile oxide derivatives add across the atomic centers with the largest atomic spin densities on 5,5-dimethyl-3-methylene-2-pyrrolidinone as seen through the local electrophilic ([Formula: see text]) and nucleophilic ([Formula: see text]) Parr functions of the various reaction centers. Results from the global electron density transfer (GEDT) reveal the low polar nature of the reactions.