Synthesis of β-Fluoro-α,β-Unsaturated Amides from the Fragmentation of Morpholine 3,3,3-Trifluoropropanamide by Grignard Reagents

Fluoroalkenes serve as bioisosteres to peptide bonds and are resistant to hydrolytic enzymes in vivo. Currently, alpha-fluoro-alpha,beta-unsaturated carbonyl compounds are readily accessible via general synthetic methods; however, beta-fluoro-alpha,beta-unsaturated carbonyl groups are more challenging to construct. To address this need, we have designed a reagent, morpholine 3,3,3-trifluoropropanamide, that creates (E)-beta-fluoro-alpha,beta-unsaturated amides upon the addition of many commonly used Grignard reagents. Reactions with this reagent enable a high level of stereocontrol in the fluoroalkene product.