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

Organic & Biomolecular Chemistry Pub Date: 2023-06-15 DOI: 10.1039/D3OB00731F

Abstract

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 Br?nsted 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.

Graphical abstract: Synthesis of oxetane and azetidine ethers as ester isosteres by Br?nsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols
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