| More than 100 years ago,pyrazolone compounds have been used as medicines by humans,and then they have been successively used in pesticide science and so on.Pyrazolinones have different reaction sites,such as C3 is electrophilic,C4 is nucleophilic,the carbonyl oxygen of pyrazolone is nucleophilic,and there are three tautomers（CH form,NH form,OH form）.Due to its different reaction sites,pyrazolones can participate in many reactions,such as: Michael addition,Mannich addition,Michael/Mannich,Michael/Conia-ene cascade cyclization,Michael/Hemiketalization cyclization,aza-Friedel-Crafts and other reactions.In recent years,there have been many reports of asymmetric catalytic reactions involving pyrazolones,but relatively few asymmetric catalytic reactions involving pyrazolones substituted with aryl groups at the C3 position.Fluorine atoms have strong electronegativity,the introduction of fluorine atoms into drug molecules can change the properties of the original drugs,and can improve the lipophilicity,metabolic stability and bioavailability of the drug molecules.So,we report the asymmetric Michael addition reaction of pyrazolones substituted with aryl groups at the C3 position and β-trifluoromethyl-α,β-unsaturated ketones,resulting in chiral and continuous tertiary and quaternary carbons center.Herein,we report the catalytic asymmetric Michael addition of 4-substituted-5-pyrazolones to β-trifluoromethyl-α,β-unsaturated ketones using a dipeptide-based urea-amide tertiary amine as a multifunctional Br（?）nsted base organocatalyst.The reaction generated chiral compounds containing both pyrazolone and trifluoromethyl moieties bearing vicinal quaternary and tertiary stereocenters in good yields with good to excellent enantioselectivity and diastereoselectivity.In addition,the reaction system is also applicable to substrates substituted with aryl or alkyl at the C3 position of pyrazolone.After confirming the reaction conditions,we expanded the types of reaction substrates for pyrazolone and β-trifluoromethyl-α,β-unsaturated ketones respectively,and achieved high enantioselectivity and diastereoselectivity.This proved the universality of the reaction conditions.We also expanded the reaction to a gram scale,and also obtained 92% ee,> 20:1 d.r.,95% yield products,which provides a certain possibility for future industrial production.We have also carried out further derivatization of the chiral products,and can obtain derivatized products with the ee value and d.r.value maintained.The report of the asymmetric Michael addition reaction of pyrazolones and β-trifluoromethyl-α,β-unsaturated ketones provides a new method for obtaining highly stereoselective compounds containing pyrazolones and trifluoromethyl fragments. |
