Synthesis of 3,6-Dihydro-2H-Thiopyrans via Diffusion-Controlled Generation of Thioaldehydes as Dienophiles for [4+2] Cycloaddition

In this work we propose a mild, diffusion-controlled method for generating unstable thioaldehydes from stable precursors (Bunte salts or thiocyanates) using tertiary amine vapors (NEt3 or DIPEA). The reactions were conducted in a closed system consisting of two nested vials, allowing slow amine evaporation to maintain a low steady-state concentration of thiocarbonyl intermediates in the reaction mixture. This technique effectively suppressed unwanted side processes and enabled efficient trapping by cyclopentadiene, 2,3-dimethylbutadiene, and isoprene at room temperature. While thiocyanates served as alternatives for low-polarity solvents, Bunte salts proved superior, providing a wider substrate range and higher cycloadduct yields (up to 84%). Additionally, rapid transesterification of the thiocarbonyl intermediate was observed when using methanol as a solvent. Overall, the diffusion mixing technique avoids thermal activation, offering a mild and efficient synthetic route to 3,6-dihydro-2H-thiopyrans, particularly when employing less reactive dienes.