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

Abstract

AbstractReactions of chiral α‐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 α‐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 α‐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.