Mechanistic study on the NHC-catalyzed [3+4] annulation of enals and thiazolones

Abstract

The possible mechanism and origin of stereoselectivity of the NHC-catalyzed [3+4] annulation reaction between an enal and 5-alkenyl thiazolone leading to ε-lactone have been investigated using density functional theory (DFT) calculations. The reaction is identified to proceed via six elementary steps: the nucleophilic addition of the NHC to the enal (step 1), followed by the 1,2-proton transfer to form the Breslow intermediate (step 2). Addition to the other substrate 5-alkenyl thiazolone in which a new C–C bond is formed (step 3). Another proton transfer (step 4) followed by intramolecular cyclization leads to the [3+4] cycloadduct (step 5). The NHC regeneration completes the catalytic cycle and affords the desired product ε-lactone (step 6). DFT results show that the C–C bond formation step (step 3) is the stereoselective step and the RS-configurational isomer is the predominant product. The distortion–interaction analysis indicates that interactions between the two fragments control the stereoselectivity of the reaction. Further non-covalent interaction analysis shows that the cumulative interactions such as CH⋯N, CH⋯π, OH⋯O and CH⋯S are responsible for the stereochemistry of the reaction. The mechanistic insights gained in the present work should be useful for the rational design of a new catalytic reaction in the future.