Synthesis of β-CF3 Ethers by Base-Catalyzed Anti-Markovnikov Addition of Alcohols to Trifluoromethyl Alkenes

Abstract

The oxa-Michael-type addition of alcohols to trifluoromethyl alkenes represents a straightforward synthetic route to trifluoromethyl ethers, but it remains a challenge in organic synthesis. Herein, we present an intermolecular anti-Markovnikov addition of alcohols to azole-substituted trifluoromethyl alkenes in the presence of catalytic DBU. A wide array of β-trifluoromethyl ethers is obtained with up to 98% yield under mild reaction conditions. The utility of this protocol was demonstrated through a scale-up synthesis and various synthetic transformations. Reversibility studies suggested that the resulting adducts are stable to resist elimination through a retro-Michael reaction or alcohol exchange at 50 °C.