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 alpha,beta-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 CHMIDLINE HORIZONTAL ELLIPSIS pi, LPMIDLINE HORIZONTAL ELLIPSIS pi and pi MIDLINE HORIZONTAL ELLIPSIS pi interactions lead to the lower energy of the transition state that corresponds to the major stereoisomer of 1,3-thiazin-4-one. The mechanisms and regio- and stereoselectivities of NHC-catalyzed [3+3] annulations of 2-bromoenals and thioamides are investigated.