Regioselective synthesis of substituted 3,6-dihydropyran from 3-butene-1-ol and aromatic aldehydes via Prins cyclization mediated by TfOH (triflic acid)

We present a streamlined one-pot method to synthesize biologically relevant 3,6-dihydropyrans key scaffolds in natural products and pharmaceuticals using a three-component Prins cyclization. This approach combines 3-butene-1-ol with diverse aromatic aldehydes under mild conditions (0 °C to room temperature), leveraging triflic acid (TfOH) as both a Brønsted acid and nucleophilic promoter. The reaction exhibits broad functional group tolerance (-NO₂, -CN, halides, -OMe) and delivers substituted 3,6-dihydro-2 H-pyrans in 52–78% isolated yields. Notably, the method introduces a double bond at the 4-position of the dihydropyran core, enabling further derivatization via cross-coupling reactions a strategic advantage for drug discovery. Mechanistic studies suggest TfOH activates aromatic aldehydes to form an oxocarbenium intermediate, triggering regioselective oxonium-ene cyclization. TfOH outperformed conventional catalysts (p-TsOH, In(OTf)₃, Sc(OTf)₃), achieving 76% yield with 1.2 equivalents. While a diverse range of aromatic aldehydes performed well, sterically hindered substrates (e.g., 2,4- and 2,6-dichlorobenzaldehydes) showed reduced efficiency. Structural confirmation was achieved through NMR, HRMS, and X-ray crystallography. This protocol simplifies access to dihydropyran libraries, offering a versatile platform for synthesizing complex molecules and accelerating medicinal chemistry efforts. By combining efficiency, regioselectivity, and post-synthetic flexibility, the method addresses a critical need in organic synthesis, bridging the gap between natural product inspiration and pharmaceutical innovation.