Synthesis of 3,3-Disubstituted Thietane Dioxides.

4-Membered heterocycles have been increasingly exploited in medicinal chemistry and, as small polar motifs, often show important influence on activity and physicochemical properties. Thietane dioxides similarly offer potential in both agricultural and pharmaceutical applications but are notably understudied. Here we report a divergent approach to 3,3-disubstituted thietane dioxide derivatives by forming carbocations on the 4-membered ring with catalytic Lewis or Brønsted acids. Benzylic tertiary alcohols of the thietane dioxides are coupled directly with arenes, thiols, and alcohols.

Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols.

Oxetanes and azetidines continue to draw significant interest in medicinal chemistry, as small, polar and non-planar motifs. Oxetanes also represent interesting surrogates for carbonyl-containing functional groups. Here we report a synthesis of 3,3-disubstituted oxetane- and azetidine-ethers, with comparisons made to the ester functional group. The tertiary benzylic alcohols of the 4-membered rings are selectively activated using Brønsted acid catalysis and reacted with simple alcohols to form the ethers and maintain the oxetane ring intact. This approach avoids the use of strong bases and halide alkylating agents and allows alcohol libraries to be leveraged. Oxetane ethers demonstrate excellent chemical stability across a range of conditions and an improved stability vis-à-vis analogous esters under basic and reducing conditions.