The introduction of a trifluoromethyl functional group (CF3) is a common strategy in medicinal chemistry to impart favorable changes in reactivity, metabolic stability, and solubility. Moreover, the CF3 group is receiving increased attention due to its role as a synthetic intermediate. Trifluoromethylalkene derivatives containing C(sp2)–CF3 bonds are particularly attractive and versatile intermediates in medicinal and materials chemistry. However, methods to prepare such derivatives are scarce and suffer from narrow substrate scope. We report the synthesis of α–trifluoromethylacrylates from shelf-stable α–trifluoroborylacrylates via a stereoretentive radical trifluoromethylation with inexpensive reagents NaSO2CF3 and TBHP at room temperature (Scheme 1). Under these conditions, a wide substrate scope afforded the (E)–diastereomer exclusively in moderate to good yield. The utility of the reaction products is demonstrated in the synthesis of phenyl–4H–pyran, a potent and selective class of IKCa channel blockers.

Copper-catalyzed synthesis of α–trifluoromethylacrylates from trifluoroborylacrylates via stereoretentive radical trifluoromethylation

ACS Fall 2021

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