Reaction Mechanism and Origin of Stereoselectivity in the Fluorination and Trifluoromethylthiolation of 2-Bromoamides with AgF and AgSCF3

Reactions of chiral alpha-bromoamides with AgF readily gave the corresponding 2-fluorinated amide with retention of configuration. The mechanism and origin of the stereochemistry were rationalized using density functional theory calculations, which suggested a double-inversion pathway via the formation of an aziridinone intermediate. The computed reaction pathway is consistent with the experimental results. In addition, the stereochemistry in base-promoted trifluoromethylthiolation of alpha-bromoamides using AgSCF3 was examined. The experimental results showed that the reaction proceeds through the generation of a neutral aziridinone intermediate, following the attack of a trifluoromethylthiolate anion at C-3. The stereoselectivity of C-3 attack on the aziridinone depended on the steric bulk of substitutes on the alpha-position and nitrogen of the amide. The study results show the potential utility of AgF and AgSCF3 in the synthesis of chiral 2-functionalized amide derivatives and provide mechanistic insights for nucleophilic substitution of 2-bromoamides.