Transition metal difluorocarbene complexes (LnM=CF2) are highly promising intermediates for the synthesis of fluorine-containing compounds. Despite their potential utility, however, only a limited number of reactions of difluorocarbene complexes are reported in the past year. Our continuous interest in difluorocarbene complexes prompted us to apply them to catalytic synthesis. Thus, we have accomplished the regioselective syntheses of α- and β-, di- and mono-fluorinated cyclopentanone derivatives by using Ni and Cu difluorocarbene complexes as key intermediates. Recently, we succeeded in the synthesis of 5,5-difluorocyclopent-1-en-1-yl silyl ethers (α,α-difluorocyclopentanone derivatives). Silyl dienol ethers prepared from α,β-unsaturated ketones underwent the nickel-catalyzed difluorocyclopropanation of the electron-rich alkene moiety with trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (FSO2CF2CO2SiMe3, TFDA). The subsequent vinylcyclopropane–cyclopentene (VCP) rearrangement proceeded via regioselective C–C bond cleavage to afford 5,5-difluorocyclopent-1-en-1-yl silyl ethers. We next accomplished the [4 + 1] cycloaddition of copper difluorocarbene complexes and silyl dienol ethers, affording 4,4-difluorocyclopent-1-en-1-yl silyl ethers (β,β-difluorocyclopentanone derivatives). The key copper difluorocarbene complex was generated from a copper(I) salt and sodium bromodifluoroacetate (CBrF2CO2Na). Unlike the nickel(II) complex, copper(I) difluorocarbene complex was electrophilic enough to be attacked by silyl dienol ethers, leading to alkyl copper(I) species. The copper intermediates in turn underwent a Michael-type ring closure to afford 4,4-difluorocyclopent-1-en-1-yl silyl ethers. The two five-membered silyl enol ethers obtained above are versatile intermediates for α- and β-fluorocyclopentenones. Silyl dienol ethers also underwent proton sponge-catalyzed difluorocyclopropanation with TFDA, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes, which were in turn subjected to fluoride ion-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e., Nazarov precursors). Treatment of the precursors with Me3SiB(OTf)4 regioselectively promoted the Nazarov cyclization.

Syntheses of fluorinated cyclopentanone derivatives via regioselective CF2 insertion using transition metal difluorocarbene complexes

253rd National Meeting (2017)

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