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Bench-stable azidodifluoromethyl imidazolium reagents unlock the synthetic potential of carbonimidic difluorides

Year: 2025

Type: article

Abstract: N-fluoroalkyl compounds are highly valuable in medicinal chemistry. While carbonimidic difluorides have been recognized as valuable intermediates for N-CF3 compounds synthesis, their broader synthetic potential remains largely unexplored due to the limitations of current methodologies, particularly in expanding the scope of N-fluoroalkyl derivatives. Herein, we report the design and synthesis of azidodifluoromethyl imidazolium reagents that enable the in situ generation of carbonimidic difluorides. These intermediates undergo a series of controlled transformations, including chlorination, fluorination, monodefluorination, didefluorination, and subsequent derivatization of N-chlorodifluoromethyl compounds, providing an efficient strategy for the synthesis of structurally diverse N-fluoroalkane and amine derivatives. Here, the authors report the design and synthesis of azidodifluoromethyl imidazolium reagents that enable the in situ generation of carbonimidic difluorides. These intermediates undergo a series of controlled transformations, including chlorination, fluorination, monodefluorination, didefluorination, and subsequent derivatization of N-chlorodifluoromethyl compounds, providing an efficient strategy for the synthesis of structurally diverse N-fluoroalkane and amine derivatives.

Source: Nature Communications

DOI: 10.1038/s41467-025-66605-y