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

## 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.

## Key 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 intermediates, providing diverse 1,1-disubstituted difluorocyclobutanes
and expediting access to new design options for medicinal or materials
chemistry.