Primary Amine Attached to an N‐(Carboxyalkyl)imidazolium Cation: A Recyclable Organocatalyst for the Asymmetric Michael Reaction

Abstract

A (1S,2S)‐1,2‐diphenylethane‐1,2‐diamine derivative modified with an N‐(4‐carboxybutyl)imidazolium cation and PF6– anion has been developed and applied as a recyclable organocatalyst of the asymmetric 1,4‐conjugate addition of 4‐hydroxy‐2H‐chromen‐2‐one to 1‐substituted buten‐3‐ones or cyclohexen‐3‐one to afford corresponding Michael adducts in high yields (up to 97 %) and enantioselectivities (up to 90 % ee). The most active (S) enantiomer of the clinically useful anticoagulant warfarin was prepared in this way. The catalyst exhibited better recyclability than its known analog, which does not contain a carboxy group: it could be recycled 5 times in the reaction without a significant decrease in product yield or ee values. Gradual deactivation of the catalyst was caused by leaching during workup rather than by off‐cycle reactions between the catalyst and reagents.

Ionic Liquids in Asymmetric Synthesis: An Overall View from Reaction Media to Supported Ionic Liquid Catalysis

“…Despite the reasonable activity and enantioselectivity obtained in the reaction between4 -hydroxycoumarin and benzylideneacetone by using 70,t he performance of this catalyst decreases progressively after three cycles.T oc onquer this problem,acarboxylic group can be introduced directly into the alkyl chain of the imidazolium ionicl iquid in the chiral catalyst system( Scheme44). [110] Catalyst 71 containing ac arboxy group can be recycled five times with just as mall decrease in the product yield and enantioselectivity in the same transformation.…”

Asymmetric Michael Addition Mediated by Chiral Ionic Liquids

“…The catalytic efficacy of 42 progressively declines after the third cycle plausibly because of its deactivation by the irreversible reaction with the Michael adduct. To suppress this Brønsted-acid-sensitive undesired off-cycle reaction, structurally-modified catalyst 43 was designed [ 44 ]. In the presence of 43 , the Michael adducts are obtained in high yields (up to 97%) and enantioselectivities (up to 90% ee).…”

Bifunctional Amine-Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of β,γ-Unsaturated α-Ketoesters and α,β-Unsaturated Ketones with 4-Hydroxycoumarins

“…Later, Feng and coworkers used chiral amide catalyst derived from proline in warfarin synthesis . Primary amine-based organocatalysts were recognized as useful for Michael additions of coumarins. , Mlynarski and recently Zlotin described the synthesis of warfarin in water using ( S , S )-diphenylethylenediamine or quinoline-based 1,2-diamine organocatalysts. − Primary amine organocatalysts were also tagged with suitable ionic groups to ensure their recyclability. , Warfarin synthesis using quinine as a catalyst was also adopted for flow setup . Several other efficient asymmetric methods based on primary amine catalysts derived from cinchona and primary amine thiourea catalysts have been introduced for the preparation of ( S )-warfarin. , Although bifunctional amine-squaramide organocatalysts were used for activation of related compounds, they were not used in the asymmetric synthesis of warfarin and its analogues.…”

“…18−20 Primary amine organocatalysts were also tagged with suitable ionic groups to ensure their recyclability. 21,22 Warfarin synthesis using quinine as a catalyst was also adopted for flow setup. 23 Several other efficient asymmetric methods based on primary amine catalysts derived from cinchona and primary amine thiourea catalysts have been introduced for the preparation of (S)-warfarin.…”