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. 2025 Jul 25;90(29):10425-10433.
doi: 10.1021/acs.joc.5c01175. Epub 2025 Jul 10.

Synthesis of gem-Difluorocyclobutanes: Organolanthanum Enabled Synthesis and Divergent Catalytic Functionalization of gem-Difluorocyclobutanols

Hikaru Ishikura  1 , Juan J Rojas  1 , Callum S Begg  1 , Chulho Choi  2 , James A Bull  1
Affiliations

Synthesis of gem-Difluorocyclobutanes: Organolanthanum Enabled Synthesis and Divergent Catalytic Functionalization of gem-Difluorocyclobutanols

Hikaru Ishikura et al. J Org Chem. .

Abstract

Fluorinated cycloalkyl motifs continue to receive intense interest in medicinal chemistry due to their potential to modulate physicochemical properties. In recent years, this interest has extended to gem-difluorocyclobutanes as small, polar, yet lipophilic moieties. However, strategies to access gem-difluorocyclobutanes remain limited, presenting opportunities for the development of new synthetic methods. Here, we report the synthesis and divergent functionalization of gem-difluorocyclobutanols to generate a diverse range of 1,1-disubstituted-3,3-difluorocyclobutanes. The use of organolanthanum reagents is crucial to achieve the addition of carbon nucleophiles to commercially available difluorocyclobutanone to avoid the undesired elimination of HF by controlling nucleophile basicity. The generated difluorocyclobutanols enable functionalization through carbocation and radical intermediates, providing diverse 1,1-disubstituted difluorocyclobutanes and expediting access to new design options for medicinal or materials chemistry.

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Figures

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(A) gem-Difluorocyclobutane-containing bioactive molecules. (B) Current synthetic strategies to access 1,1-disubstituted gem-difluorocyclobutanes. (C) This work: double functionalization of 3,3-difluorocyclobutanone to access a diverse range of 1,1-disubstituted gem-difluorocyclobutanes.
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1. Preparation of Difluorocyclobutanols from Transmetalation of Organolithium Reagents to Organolanthanum Reagents
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2. Reaction Scope of Difluorocyclobutanols with Arene, Thiol, and Azide Nucleophiles Using Iron Catalysis to Generate Carbocation Intermediates
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3. Further Functionalization of 1,1,-Disubstituted gem-Difluorocyclobutanes
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4. Low-Valent Titanium Catalyzed Giese Addition of Difluorocyclobutanols
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