First Stereospecific Synthesis of (E)- or (Z)-α-Fluoroenones via a Kinetically Controlled Negishi Coupling Reaction

Abstract

A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).

ChemInform Abstract: Palladium‐ and Copper‐Catalyzed Stereocontrolled Direct C—H Fluoroalkenylation of Heteroarenes Using gem‐Bromofluoroalkenes.

“…Both isomers could be separated using standard chromatographic techniques, resulting in the isolation of (E)-3 aA' (15 % yield) and (Z)-3 aA (40 % yield), as well as (E)-3 aD' (31 % yield) and (Z)-3 aD (39 % yield). As already observed in different cross-coupling reactions, [9,18] the (E)-monofluoroalkenes 3 aA and 3 aD could be produced alone in good yield, when two equivalents of a mixture of (E/Z)-gem-bromofluoroalkenes 2 A/2 A' or 2 D/ 2 D' were employed. In this case, the (Z)-gem-bromofluoroalkenes 2 A' and 2 D' were recovered (2 A'/3 aA = 2:7 and 2 D'/3 aD = 9:11, as determined by 19 F NMR analyses of the crude products), owing to the faster oxidative addition of the less steric hindered (E)-gem-bromofluoroalkenes to the Pd 0 complex (Scheme 3 b).…”

Stereoselective One‐Pot Sequential Dehydrochlorination/trans‐Hydrofluorination Reaction of β‐Chloro‐α,β‐unsaturated Aldehydes or Ketones: Facile Access to (Z)‐β‐Fluoro‐β‐arylenals/β‐Fluoro‐β‐arylenones

“…The bromofluoroalkenes are highly attractive as intermediates for the preparation of more functionalized fluoroalkenes ,,,. With a facile and viable approach towards ( Z )‐β‐fluoroenals 3 , we then worked on transforming Z ‐ 3 into bromofluoroenals, and exploring their potential applications as building blocks for the synthesis of highly substituted alkenes.…”

Synthetic Methods for Fluorinated Olefins

“…Pannecoucke and co-workers developed a highly stereospecific synthesis of (Z)-or (E)-α-fluoro-α,β-unsaturated ketones 49 through kinetically controlled Negishi cross-coupling (Scheme 36). [63] Scheme 36. Kinetically controlled Negishi cross-couplings of compounds 47.…”