Bifunctional Amine-Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of beta,gamma-Unsaturated alpha-Ketoesters and alpha,beta-Unsaturated Ketones with 4-Hydroxycoumarins

The catalytic efficiency of various amine-squaramides was tested in Michael/hemiketalization reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide organocatalysts afforded the best results regarding both activity and enantioselectivity when beta,gamma-unsaturated alpha-ketoesters were used as the Michael acceptors (yields up to 98%, enantioselectivities up to 90% ee). On the other hand, the primary amine-squaramides are the best choice for related reactions of 4-hydroxycoumarins with enones. The corresponding pyrano[3,2-c]chromen-S-on products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-hydroxycoumarin to 4-phenyl-but-3-en-2-on directly produced chiral anticoagulant drug (S)warfarin in 92% ee when green solvent 2-MeTHF and catalyst (S,S)-C8 were used. Moreover, an enantiomeric catalyst (R,R)-C8 gave (R)-warfarin in >99% ee.