3,3-Disubstituted oxetanes and azetidines are valuable motifs with attractive physichochemical properties and are potential replacement groups for gem-dimethyl, carbonyls and larger heterocycles. The development of robust methods to access such scaffolds is highly desirable. In this thesis, novel 3,3-disubstituted oxetanes and azetidines are prepared through the in situ generation of carbocations and radicals. The suitability of these new motifs for drug discovery programmes is also evaluated.
In this regard, 3,3-diaryloxetanes are first assessed as replacement groups for diarylketones and 1,1-diarylalkanes in part 3. These oxetanes are synthesised through a Friedel–Crafts reaction with oxetanols. The comparison of the physicochemical properties between 3,3-diaryloxetanes, benzophenones and 1,1-diarylalkanes shows that these oxetanes are suitable replacements groups for medicinal chemistry application.
The preparation of new 3,3-diarylazetidines and 3-arylsulfanyl-azetidines is then described in part 4. This was achieved through in situ generation of azetidinyl carbocations from NCbz-azetidin-3-ols using Ca and Fe catalysts. These carbocations can react with nucleophiles such as (hetero)aromatics and thiols giving new azetidine scaffolds in high yields.
The generation of oxetanyl and azetidinyl carbocations required the alcohol precursors to bear electron-rich aromatics. An alternative Fe-catalysed Friedel–Crafts reaction is then described in part 5, where the use of hexafluoroisopropanol as solvent enables oxetanyl carbocation formation from oxetanols bearing phenyl and electron-poor aromatics. Previously inaccessible 3,3-diaryloxetanes are synthesised as well as one example of 3,3-diarylazetidine and 3-arylsulfanyl-oxetane.
New oxetane and azetidine scaffolds are then prepared through in situ generation of radicals in part 6. This was achieved through photoredox-catalysed decarboxylation of oxetane and azetidine carboxylic acid precursors. The radicals are trapped with alkenes to give new 3-aryl-3-alkyl oxetanes and azetidines. A two-step protocol is also described to efficiently access the acid precursors. This involves the preparation of 3-aryl-3-furanyl intermediates through Friedel–Crafts reaction followed by oxidative cleavage of the furan.