Synthesis of gem-difluorinated cyclobutane and cyclopentane building blocks

Herein, we describe a concise and scalable strategy for the preparation of gem-difluorinated cyclobutanes and cyclopentanes from simple, commercially available precursors under mild deoxyfluorination conditions. Optimization of the fluorination step enabled direct access to key intermediates, such as gem-difluorocyclobutyl bromides and boronates in two to three steps and on up to 77 g scale, avoiding the mercury-mediated or high-temperature processes typical of earlier methodologies. The developed protocol exhibits broad functional-group tolerance, allowing the preparation of amino-, hydroxy-, and sulfonyl-substituted derivatives, as (including deoxyfluorination of certainly functionalized cyclobutanones or by rearrangement of methylenecyclopropanes), remain hardly accessible due to lengthy synthetic procedures or limited scalability. Their higher homologues, gem-difluorinated cyclopentanes, are described significantly well as novel cis- and trans-difluorocyclopentane scaffolds including diols, diamines, and carboxylic acid analogues. The operational simplicity, scalability, and structural diversity of the resulting building blocks make this approach a valuable platform for the exploration of CF₂-containing fragments in medicinal and materials chemistry