Stereoselective Palladium-Catalyzed
Base-Free Suzuki–Miyaura Cross-Coupling of Tetrasubstituted gem-Difluoroalkenes: An Experimental and Computational Study
Palladium-catalyzed Suzuki–Miyaura
cross-coupling reactions are among the most powerful tools for constructing
carbon–carbon bonds. Moreover, the selective coupling between gem-difluoroalkenes and boronic acids via the C–F
bond activation can lead to pharmaceutically relevant monofluoroalkene
compounds. Therefore, synthetic methods that produce multisubstituted
monofluoroalkenes with high levels of stereocontrol are of significance.
We herein describe the diastereoselective synthesis of a wide range
of densely functionalized tetrasubstituted (E)-monofluoroalkenes
via Pd(0)-catalyzed base-free Suzuki–Miyaura cross-couplings.
The reaction design was supported by computational studies of the
key C–F bond activation step. Density functional theory (DFT)
calculations elucidated an intriguing reaction pathway favoring a
formal [4 + 1] cycloaddition of Pd(0), followed by 1,5-sigmatropic
fluoride migration, assisted by the chelation of the ester-substituent
group to Pd center. This mechanism fittingly rationalizes the decreased
C–F bond strength for subsequent cleavage (rate-determining
step) and the complete control of stereoselectivity, which are consistent
with the experimental observations. The C–F bond activation
generates a vinylpalladium(II) fluoride intermediate, which readily
undergoes transmetalation with boronic acids and therefore does not
require assistance from an extraneous base.