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. 2022 Dec 2;24(47):8719-8723.
doi: 10.1021/acs.orglett.2c03775. Epub 2022 Nov 17.

Organocuprate Cross-Coupling Reactions with Alkyl Fluorides

Bryan C Figula  1 , D Lucas Kane  1 , Kaluvu Balaraman  1 , Christian Wolf  1
Affiliations

Organocuprate Cross-Coupling Reactions with Alkyl Fluorides

Bryan C Figula et al. Org Lett. .

Abstract

Cross-coupling of alkyl fluorides and organocuprates is accomplished via aluminum halide mediated C-F bond activation and subsequent Csp2-Csp3 and Csp3-Csp3 bond formation. Relatively mild conditions allow for smooth activation of notoriously challenging primary and secondary alkyl fluorides while competing alkyl chain rearrangement, HF elimination, and homocoupling reactions are effectively controlled. The utility and functional group tolerance are demonstrated with 23 examples and a variety of coupling products obtained in up to 88% yield.

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Conflict of interest statement

CONFLICT OF INTERESTS

The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
Scope and challenges of cross-coupling reactions with alkyl fluorides and organocuprates.
Scheme 2.
Scheme 2.. Reaction Scope of Organocuprate Cross-Coupling with Primary and Secondary Fluorides.a
aR-F (1 equiv.) and AlI3 (0.5 equiv.) stirred in 600 μL DBE at room temperature. Ph2CuCNLi2 (2 equiv.) added and stirred for 18 hours at room temperature. b0.75 equiv. AlI3 used. cAlI3 and R-F heated at 50 °C for two hours. dCuprate addition at 35 °C, 5 days. All reported yields are for isolated products. See SI for details.
Scheme 3.
Scheme 3.. Diversification of Organocuprates in the Cross-Coupling with Alkyl Fluorides.a
aR-F (1 equiv.) and AlI3 (0.5 equiv.) stirred in 600 μL DBE at 25 °C. Ph2CuCNLi2 (2 equiv.) added and stirred for 18 hours at room temperature. bCuprate addition at 50 °C. c0.75 equiv. of AlI3. dCuprate addition performed at 35 °C, 5 days. All reported yields are for isolated products. See SI for details.
Scheme 4.
Scheme 4.. Organocuprate C–C Coupling with Enantioenriched Fluoride 26.
See SI for details.
See this image and copyright information in PMC

References

    1. Terao J; Ikumi A; Kuniyasu H; Kambe N Ni- or Cu-Catalyzed Cross-Coupling Reaction of Alkyl Fluorides with Grignard Reagents. J. Am. Chem. Soc. 2003, 125, 5646–5647. - PubMed
    1. Matsubara K; Ishibashi T; Koga Y C-F Bond Cleavage Reactions of Fluoroalkanes with Magnesium Reagents and without Metal Catalysts. Org. Lett. 2009, 11, 1765–1768. - PubMed
    1. Blessley G; Holden P; Walker M; Brown JM; Gouverneur V Palladium-Catalyzed Substitution and Cross-Coupling of Benzylic Fluorides. Org. Lett. 2012, 14, 2754–2757. - PubMed
    1. Erickson LW; Lucas EL; Tollefson EJ; Jarvo ER Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides: Stereospecific Synthesis of Vinylcyclopropanes. J. Am. Chem. Soc. 2016, 138, 14006–15011. - PubMed
    1. Iwasaki T; Yamashita K; Kuniyasu H; Kambe N Co-Catalyzed Cross-Coupling Reaction of Alkyl Fluorides with Alkyl Grignard Reagents. Org. Lett. 2017, 19, 3691–3694. - PubMed