General alkyl fluoride functionalization via short-lived carbocation-organozincate ion pairs

D. Lucas Kane, Bryan C. Figula, Kaluvu Balaraman, Jeffery A. Bertke and Christian Wolf ()
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D. Lucas Kane: Georgetown University, Chemistry Department
Bryan C. Figula: Georgetown University, Chemistry Department
Kaluvu Balaraman: Georgetown University, Chemistry Department
Jeffery A. Bertke: Georgetown University, Chemistry Department
Christian Wolf: Georgetown University, Chemistry Department

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing β-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization.

Date: 2024
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DOI: 10.1038/s41467-024-45756-4

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