Chiral Squaramide Catalyzed Asymmetric [3+2] Cycloaddition Reaction for Synthesis of Trifluoromethylated Barbituric Acid Derivatives

Abstract

A squaramide catalyzed asymmetric Michael/Mannich [3+2] cycloaddition reaction between N‐2,2,2‐trifluoroethyl isatin ketimines and barbiturate‐based olefins was developed. The corresponding trifluoromethylated dispirobarbituric acid derivatives containing three stereocenters were obtained in excellent yields and stereoselectivities (up to 99% yield, 99:1 dr and >99% ee). In addition, the gram‐scale reaction also achieved with excellent yield and stereoselectivity.

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…This 1,3‐dipolar annulation could install four contiguous stereocenters in single steps among which two are vicinal spiroquaternery and one is trifluoromethylated stereocenter (Scheme 54e) [85] . The same type of ketimine 207 was merged with barbiturate derived olefins leading to the formation of barbituric acid based bispirocyles (not shown in scheme) [86] . Methyleneoxindolinone 218 has been exploited in formal (3+2) annulation with 207 in course of synthesizing bispirocyclic frameworks 219 bearing four contiguous stereocenters.…”

“…[85] The same type of ketimine 207 was merged with barbiturate derived olefins leading to the formation of barbituric acid based bispirocyles (not shown in scheme). [86] Methyleneoxindolinone 218 has been exploited in formal (3 + 2) annulation with 207 in course of synthesizing bispirocyclic frameworks 219 bearing four contiguous stereocenters. Squaramide K' promoted cycloaddition proceeds through stereoselective intermolecular Michael followed by intramolecular Mannich reaction (Scheme 54f).…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…we envisaged whether the barbituric acid could be introduced into the cycloaddition reaction with N ‐2,2,2‐trifluoroethyl isatin‐derived ketimines 53 . In the next year our group [51] developed an enantioselective Michael/Mannich cascade cycloaddition reaction of barbiturate‐based olefins 61 with N ‐2,2,2‐trifluoroethyl isatin‐derived ketimines 53 to build trifluoromethylated barbituric acid derivatives 62 bearing three stereocenters. Under the optimized condition that catalyzed by squaramide catalyst C6 in CH 2 Cl 2 at room temperature for 2 h (Scheme 26), the reaction tolerated a wide range of substrates and the desired products were obtained in good to high yields (62–99%) with good to excellent enantio‐ and diastereoselectivities (71:29–99:1 dr, 72–>99% ee).…”

Phase‐Transfer Catalytic Strategy: Rapid Synthesis of Spiro‐Fused Heterocycles, Integrated with Four Pharmacophores‐Succinimide, Pyrrolidine, Oxindole, and Trifluoromethyl Group

“…N ‐2,2,2‐trifluoroethylisatin ketimine is a type of versatile reagent that it could act as nucleophile [12] or azomethine ylide precursor [13] in organic synthesis. Since it was firstly utilized in organocatalytic 1,3‐dipolar [3+2] cycloaddition with α,β‐unsaturated aldehydes for the formation of CF 3 ‐substituted spiropyrrolidinyl‐2,3′‐oxindoles by Wang′s group, [14] many kinds of canonical electron‐deficient alkenes had been employed as variants to react with this synthon, delivering large amount of more structurally diverse trifluoromethyl spiropyrrolidinyl‐2,3′‐oxindoles, such as nitroalkenes, [15] 3‐alkenyl‐5‐arylfuran‐2(3 H )‐ones, [16] 3‐alkylideneoxindoles, [17] α,β‐unsaturated ketone, [18] arylidene azlactone, [19] 5‐alkylidenerhodanine, [20] 5‐alkylidenethiazolones„ [21] barbiturate‐based olefin, [22] aurone olefin, [23] 4‐alkylidenepyrazolinones, [24] 2,3‐dioxopyrrolidine, [25] cyclic 2,4‐dienones [26] . However, these seminal studies all suffered from long reaction time, and this insuperable defect impeded their potential applications in the medicinal industry because of the high production costs.…”