A DFT study of NHC-catalyzed reactions of [3+3] annulations of 2-bromoenals and thioamides: mechanisms and regio- and stereoselectivities

We present a density functional theory study to characterize the possible mechanisms and origins of regio- and stereoselectivities of N-heterocyclic carbene (NHC)-catalyzed reactions of 2-bromoenals with thioamides leading to the formation of 1,3-thiazin-4-ones. According to DFT results, the energetically favorable mechanism involves the following elementary steps: formation of a Breslow intermediate via coordination of the NHC to 2-bromoenal followed by 1,2-proton transfer. Debromination followed by 1,3-proton transfer generates the α,β-unsaturated acylazolium intermediate, which further undergoes thia-Michael addition to thioamide forming the enolate intermediate. Subsequent 1,5-proton transfer and intramolecular cyclization give the six-membered ring intermediate, which upon elimination of NHC leads to the formation of 1,3-thiazin-4-one. The thia-Michael addition step was identified as the regio- and stereoselectivity-determining step, affording the S-configurational product preferentially, in agreement with previous experimental observations. According to NCI analysis, the stronger non-covalent interactions such as CH⋯π, LP⋯π and π⋯π interactions lead to the lower energy of the transition state that corresponds to the major stereoisomer of 1,3-thiazin-4-one.