Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy

The C-F bond cleavage and C-C bond formation (i.e., carbodefluorination) of readily accessible (per)fluoroalkyl groups constitutes an atom-economical and efficient route to partially fluorinated compounds. However, the selective mono-carbodefluorination of trifluoromethyl (CF3) groups remains a challenge, due to the notorious inertness of C-F bond and the risk of overdefluorination arising from C-F bond strength decrease as the defluorination proceeds. Herein, we report a carbene-initiated rearrangement strategy for the carbodefluorination of fluoroalkyl ketones with alpha,gamma-unsaturated alcohols to provide skeletally and functionally diverse alpha-mono- and alpha,,-difluoro-gamma,delta-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a beta,gamma-unsaturated alcohol to form key silver-coordinated oxonium ylide intermediates, which triggers selective C-F bond cleavage by HF elimination and C-C bond formation through Claisen rearrangement of in situ generated difluorovinyl ether. The origin of chemoselectivity and the reaction mechanism are determined by experimental and DFT calculations. Collectively, this strategy by an intramolecular cascade process offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, functional group tolerance, etc.

Automated summary

A carbene-initiated rearrangement strategy has been developed for the selective carbodefluorination of fluoroalkyl ketones, providing diverse alpha-fluorinated ketones. This strategy offers significant advances over existing stepwise strategies in terms of selectivity, efficiency, and functional group tolerance.