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Keywords:

  • allylic substitution;
  • asymmetric catalysis;
  • enantioselectivitiy;
  • ligand effects;
  • palladium

Abstract

We have expanded the ligand design of one of the most successful phosphite-oxazoline ligands, derived from hydroxyl amino acid derivatives, in Pd-catalyzed allylic alkylation by replacing the oxazoline group with a thiazoline moiety. These phosphite-thiazoline ligands have been evaluated in the Pd-catalyzed allylic substitution of a wide range of mono-, di-, and trisubstituted substrates with several carbon nucleophiles, such as the less studied α-substituted malonates and β-diketones. For comparison we have also expanded our previous work on phosphite-oxazoline to carbon nucleophiles other than dimethyl malonate and to the alkylation of trisubstituted substrates. For hindered substrates such as disubstituted rac-1,3-diphenyl-3-acetoxyprop-1-ene and trisubstituted rac-1,1,-diphenyl-1-hepten-3-yl acetate and rac-1,3,3-triphenylprop-2-enyl acetate, enantioselectivities (ee values up to >99 %) are best obtained with phosphite-oxazoline ligands, whereas for unhindered cyclic substrates such as rac-3-acetoxycyclohexene, rac-3-acetoxycyclopentene, and rac-3-acetoxycycloheptene, enantioselectivities (ee values up to 94 %) improved considerably with phosphite-thiazoline ligands. In the case of monosubstituted substrates, the regio- and enantioselectivities obtained with both ligand types were comparable and excellent (regioselectivities up to 90 % and ee values up to 95 %). Therefore, by correctly combining substrate and ligand type (phosphite-oxazoline or phosphite-thiazoline), we have identified one of the few catalytic systems that provide high regio- and enantioselectivities in both enantiomers of the alkylation product for a wide range of hindered and unhindered mono-, di-, and trisubstituted substrates with several carbon nucleophiles. We have also discussed the synthesis and characterization of Pd-π-allyl intermediates to provide greater insight into the origin of enantioselectivity in these catalytic systems.