Practical Approach toward gem-Difluorinated Ring Expansion of Exocyclic Alkenes

Keywords

gem-difluorination - ring expansion - exocyclic alkenes - F₅-PIDA

Significance

Incorporation of fluorine atoms into drug molecules represents a common strategy in medicinal chemistry. Fluorination can affect metabolic stability, lipophilicity and pK _a while preserving pharmacological effects. Consequently, significant efforts have been devoted to developing efficient reactions for the fluorination of C–H bonds. This article introduces a new protocol for the gem-difluorinated ring expansion of exocyclic alkenes A. The electronically fine-tuned iodine(III) reagent, F₅-PIDA, enables a 1,2-alkyl shift of intermediate B, generating an α-fluoro-stabilized cation, which is subsequently trapped by a fluoride anion to complete the difluorinated ring homologation to produce C. This approach provides medicinal chemists with easy access to saturated gem-difluorinated cycles with diverse ring sizes and types.

Comment

This article presents a practical method for converting exocyclic alkenes to gem-difluorinated ring-expansion products. To determine the optimal reaction conditions, various iodine(III) reagents were screened to ultimately identify F₅-PIDA. The reaction was successfully applied to diverse cyclic ring systems, demonstrating compatibility with monocyclic, macrocyclic, bridged cyclic and spirocyclic rings. It also exhibited tolerance for various functional groups such as amines, esters, nitriles, carbamates, halogens and ketones. However, the standard conditions were not compatible with heteroatom-containing rings, such as protected azetidines, piperidines and thiopyrans. Additionally, the effect of gem-difluorination on the functional group’s acidity and basicity was explored. Given the growing importance of fluorine atoms in small-molecule drug discovery, this approach is expected to find broad application in medicinal chemistry research.

Publication History

Article published online:
25 March 2025