The development of novel chemical motifs and building blocks is essential to enable the rapid generation of molecular complexity and the exploration of new chemical space. Fluorinated cycloalkyl building blocks have garnered particular attention, including the gem-difluorocyclobutane moiety. This motif has been employed in drug discovery campaigns to modulate physicochemical properties, as seen in FDA-approved anti-cancer medication Ivosidenib. Nonetheless, synthetic strategies to access 1,1-disubstituted 3,3-gem-difluorocyclobutanes remain extremely limited. This presentation will describe the synthesis, reactivity, and stability of 3,3-gem-difluorocyclobutanols as a new difluorocyclobutane building block and their utility in accessing novel 1,1-disubstituted-3,3-gem-difluorocyclobutane fragments.

Starting from commercially available difluorocyclobutanone, a La-mediated nucleophilic addition of (hetero)aromatic and alkynyl metal reagents affords difluorocyclobutanols as novel building blocks. The use of organolanthanum reagents was crucial to avoid undesired elimination of HF by controlling nucleophile basicity. We also report a Lewis acid-catalyzed Friedel-Crafts reaction of difluorocyclobutanols with arene nucleophiles to access 1,1-diaryl-3,3-difluorocyclobutane fragments. Other nucleophiles, such as thiols, are effective under the same catalytic system to give previously inaccessible difluorocyclobutane derivatives. We have also generated the difluorocyclobutane radical by homolytic cleavage of the difluorocyclobutanol C–O bond using a low-valent titanium catalyst. The resulting radical undergoes Giese-type addition with Michael acceptors to give alkyl difluorocyclobutane fragments. Further diversification of the resulting products has been demonstrated and the stability of these novel motifs has been studied.

Callum S. Begg

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