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Stereoselective Palladium-Catalyzed Base-Free Suzuki–Miyaura Cross-Coupling of Tetrasubstituted gem-Difluoroalkenes: An Experimental and Computational Study

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posted on 2021-04-05, 19:34 authored by Yanhui Wang, Xiaotian Qi, Qiao Ma, Peng Liu, Gavin Chit Tsui
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.

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