Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp³)─F Bonds Functionalization

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Fluorine Chemistry

Background:

• Expanding structural diversity and improving molecular properties are key goals in organic chemistry.
• Introducing unique functional groups is essential for developing new molecules.

Purpose of the Study:

• To develop a novel defluorinative cyclization reaction for constructing fluoroalkenyl oxazoles.
• To utilize perfluoroalkyl halides (PFAH) as a novel coupling partner in organic synthesis.

Main Methods:

• A new reaction involving enamides and perfluoroalkyl halides (PFAH) was developed.
• The reaction proceeds via selective, two-fold cleavage of vicinal C(sp3)−F bonds in PFAH.
• This process achieves C(sp2)−H functionalization of enamides without metal catalysts, photocatalysts, oxidants, or light.

Main Results:

• The study successfully synthesized fluoroalkenyl oxazoles using a novel defluorinative cyclization.
• The reaction demonstrated the introduction of a 1,2-difluoroalkenyl moiety.
• Mechanistic studies suggest a radical perfluoroalkylation followed by heterolytic C−F bond cleavage and cyclization.

Conclusions:

• A new, metal-free synthetic route to fluoroalkenyl oxazoles has been established.
• The developed method is applicable to late-stage modification of complex molecules and synthesis of biologically relevant oxazole analogs.
• The protocol shows potential for scale-up synthesis, highlighting its practical utility.