Access to Uncharted (Ethoxy)difluoromethylated-Containing Tetrahydrofurans by Hydrogenation

Fluorinated (hetero)cyclic compounds have garnered attention over the years, offering key building blocks in medicinally relevant molecules. However, the synthesis of fluorinated tetrahydrofurans remains a synthetic challenge to reach. Herein, we developed an efficient and robust approach for the synthesis of cis-(ethoxycarbonyl)difluoromethylated tetrahydrofurans. Using the inexpensive Pd/C catalyst, the diastereoselective hydrogenation of functionalized CF₂CO₂Et-containing furans was achieved under mild reaction conditions. Access to unprecedented cis-fluorinated tetrahydrofurans with isolated yields of up to 74% and diastereomeric ratios up to 95:5 (12 examples) was reached. Pleasingly, under slightly modified reaction conditions, 5-arylated CF₂CO₂Et-containing furans were smoothly converted into the valuable α,α-difluoro-β-hydroxyesters (five examples, up to 66% yield). Overall, the protocol exhibited good functional-group tolerance and was easily scaled up. The synthetic utility of the CF₂CO₂Et moiety was further illustrated by its conversion into various other fluorinated groups.