Combined Photocatalysis and Lewis Acid Catalysis Strategy for the Oxa-Pictet-Spengler Reactions of Ethers

Saturated oxygen-containing heterocycles are present in numerous natural products and biologically active compounds. While the oxa-Pictet-Spengler reaction conventionally serves as a traditional synthetic strategy for preparing arene-fused tetrahydropyrans (THPs), existing methods typically involve harsh conditions. Disclosed herein is the development of a mild photocatalytically triggered oxa-Pictet-Spengler reaction of ethers providing a synthetic approach to fused THP compounds. The tuned dual photo/hydrogen-atom transfer (HAT) catalysis enables site- and chemoselective C-H functionalization at the benzylic ether, which results in the formation of a benzoate acetal intermediate. The key intermediate is then exposed to subsequent Lewis acid catalysis, thus facilitating oxocarbenium ion generation and ring closure. Notably, this combination strategy successfully addresses concerns related to the overoxidation inherent in photocatalytic systems.