Ligand-controlled selectivity in palladium(0)-catalyzed C(sp2)-C(sp3) Negishi cross-coupling reactions

Over the past decades, transition-metal-catalyzed cross-coupling reactions have witnessed considerable growth and emerged as a powerful tool for the construction of carbon-carbon bonds. These reactions have found numerous applications in assembling structurally complex molecules ranging from medicines to materials. While the C(sp2)-C(sp2) cross-coupling reactions have seen a tremendous development, less effort has been devoted to the more challenging C(sp2)-C(sp3) couplings.
The selectivity control in the palladium(0)-catalyzed cross-coupling of alkyl nucleophiles is an important topic of research in the Baudoin group. Both direct and migrative cross-couplings can be achieved by simply switching the ligand involved.
Following the long-standing interest in this field, we firstly extended the migrative cross-coupling reactions to simple and easily available secondary alkyl bromides under Barbier conditions. Moreover, the terminal-selective functionalization of simple alkanes could be achieved when this reaction was coupled to a non-selective radical monobromination process.
On the other hand, a series of azole-based bulky phosphine ligands was designed and applied to direct C(sp2)-C(sp3) Barbier-Negishi cross-coupling reactions, successfully preventing the β-hydride elimination process while favouring the direct reductive elimination.
Finally, the ‘‘ligand-controlled selectivity’’ strategy was applied to the divergent synthesis of enantioenriched β-amino acid derivatives.