Synthesis of gem-Difluorocyclobutanes: Organolanthanum Enabled Synthesis and Divergent Catalytic Functionalization of gem-Difluorocyclobutanols
Hikaru Ishikura, Juan J. Rojas, Callum S. Begg, Chulho Choi, James A. Bull
TL;DR
This paper presents a new method to synthesize gem-difluorocyclobutanes, useful structures in drug and materials design, using organolanthanum reagents to improve efficiency and diversity.
Contribution
A novel organolanthanum-enabled synthesis and divergent functionalization of gem-difluorocyclobutanols is introduced.
Findings
Organolanthanum reagents prevent HF elimination during the synthesis of gem-difluorocyclobutanols.
Difluorocyclobutanols can be functionalized via carbocation and radical pathways to yield diverse products.
The method provides new design options for medicinal and materials chemistry.
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…
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Taxonomy
TopicsFluorine in Organic Chemistry · Inorganic Fluorides and Related Compounds · Radical Photochemical Reactions