Carbodefluorination of fluoroalkyl ketones via a carbene-initiated rearrangement strategy

Linxuan Li, Xinyu Zhang, Yongquan Ning, Xiaolong Zhang, Binbin Liu, Zhansong Zhang, Paramasivam Sivaguru, Giuseppe Zanoni, Shuang Li, Edward A. Anderson and Xihe Bi ()
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Linxuan Li: Northeast Normal University
Xinyu Zhang: Northeast Normal University
Yongquan Ning: Northeast Normal University
Xiaolong Zhang: Northeast Normal University
Binbin Liu: Northeast Normal University
Zhansong Zhang: Northeast Normal University
Paramasivam Sivaguru: Northeast Normal University
Giuseppe Zanoni: University of Pavia
Shuang Li: Northeast Normal University
Edward A. Anderson: University of Oxford
Xihe Bi: Northeast Normal University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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 over-defluorination 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 β,γ-unsaturated alcohols to provide skeletally and functionally diverse α-mono- and α,α-difluoro-γ,δ-unsaturated ketones. The reaction starts with the formation of silver carbenes from fluoroalkyl N-triftosylhydrazones, followed by nucleophilic attack of a β,γ-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.

Date: 2022
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DOI: 10.1038/s41467-022-31976-z

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