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

Abstract

The catalytic efficiency of various aminesquaramides 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 β,γunsaturated α-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-5-on products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-hydroxycoumarin to 4-phenylbut-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.

Green Asymmetric Organocatalysis

“…If CPME and squaramide catalyst C72 were used, product 105 was obtained in 90 % ee . Other classical solvents (dioxane, dioxane/CH 3 CN, CH 2 Cl 2 /MeOH) gave lower enantioselectivities (Scheme ) …”

“…Our research group found that 2‐MeTHF was the most suitable reaction medium for the organocatalytic synthesis of 105 (Scheme ). Under optimized conditions, the substrate scope was extended, and eight different warfarin derivatives with potential anticoagulant activities were synthetized …”

“…In the synthesis of 105 , we also used PEG‐600 and product 105 was obtained at room temperature in 40 % yield and 97 % ee …”

Asymmetric organocatalyzed synthesis of coumarin derivatives

“…Sebesta and colleagues described an enantioselective Michael/hemiketalization addition of hydroxycoumarins 1 to enones 2 and ketoesters 86 using squaramide 85 [ 62 ]. The methodology developed made it possible to obtain a mixture of open and closed forms of ( R )-warfarin ( 3a ) from a bifunctional catalyst of squaramide by the formation of an iminium ion intermediate with enone and hydrogen bonding with hydroxycoumarin ( Scheme 27a ).…”

Ring opening of 2,6‐diaryl‐3,5‐diphenyl piperidine‐4‐one by acetic acid: Structural studies and Hirshfeld surface analysis of (E)‐4‐aryl‐1,3‐diphenylbut‐3‐en‐2‐ones

“…α,β‐Unsaturated ketones are widely used in the field of synthetic chemistry as valuable intermediates in building complex organic molecules 1–6 . They have also drawn attention due to their broad applications in the field of food, agriculture, and medicinal industries 7–10 .…”