Synthesis of 5-alkyl-3,4-difluorofuran-2(5H)-ones by lactonisation. Effects of substituents on cyclisation ability of fluorinated 4-hydroxyalkanoates. DFT calculations of the cyclisation energies

•The synthesis of 5-alkyl-3,4-difluorofuran-2(5H)-ones was developed.•The first synthetic step was radical addition of ethers to 2,3,3-trifluoroacrylate.•The effects of alkyl and fluoro substituents on lactonisation were studied.•DFT calculations of the cyclisations of 4-hydroxyalkanoates were carried out.•Cyclisations became more feasible with increasing number of alkyls at C5.

5-Alkyl-3,4-difluorofuran-2(5H)-ones were synthesised starting with radical addition of ethers to methyl 2,3,3-trifluoroprop-2-enoate, followed by alkyloxy bond cleavage, acid-catalyzed lactonisation and dehydrofluorination. For a study of substituent effects on lactonisation, methyl 4-bromo-2-chloro-2-fluorodecanoate and 2-chloro-2-fluoro-4,4-dimethoxybutanoate based on radical additions of methyl 2-bromo-2-chloro-2-fluoroacetate to oct-1-ene or vinyl acetate were prepared. DFT calculations of the transition state energies of the exo-trig cyclisations confirmed the observation that the ring closure became more feasible with increasing number of alkyls at C4 of the fluorinated 4-hydroxyesters.

Graphical abstractThe synthesis begins with radical addition of ethers to trifluoroacrylate, followed by ether bond clavage to form 4-hydroxyalkanoates, which cyclise under strong acid catalysis and afford the butenolides by dehydrofluorination.Figure optionsDownload full-size imageDownload as PowerPoint slide