Modular synthesis of 3,3-diaryloxetanes

Abstract Oxetanes are strained four-membered oxygen heterocycles that are valuable motifs for modulating lipophilicity, metabolic stability and three-dimensional structure of pharmaceuticals. Diaryloxetanes with 3,3-substitution are recognized as bioisosteres of diaryl ketones that preserve key electronic features while exhibiting distinct reactivity. However, synthesis of this motif largely relies on Lewis acid-promoted Friedel–Crafts reactions, which are restricted to electron-rich arenes and often suffer from low functional-group tolerance and competing side reactions. Here we report a method for the synthesis of 3,3-substituted diaryloxetanes from readily available 3-oxetanone through a cross-coupling reaction with tetrafluoropyridone as leaving group. The difunctionalization through subsequent addition of two aryl groups, one from an aryl halide, the other from an arylboronic ester, provides access to a variety of benzophenone bioisosteres. The nickel-catalysed cross-coupling at a fully substituted carbon centre is enabled through oxetanyl C–O bond oxidative addition and establishes programmable entry to 3,3-diaryloxetane bioisosteres that are synthetically challenging to access via traditional polar bond disconnection strategies. Mechanistic studies support a Ni(0)-mediated oxidative addition of the oxetanyl tetrafluoropyridine ester.