Enantioselective Synthesis of CF₃‐Containing 3,2’‐Pyrrolidinyl Spirooxindoles and Dispirooxindoles via Thiourea‐Catalyzed Domino Michael/Mannich [3+2] Cycloaddition Reactions

Abstract

An efficient and practical organocatalytic asymmetric domino Michael/Mannich [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and arylidene azlactones by using a hydroquinine-derived thiourea as the catalyst has been disclosed. Under mild conditions, a broad range of CF 3 -containing 3,2'pyrrolidinyl spirooxindole/ dispirooxindole derivatives bearing four adjacent stereogenic centers including two vicinal spiro quaternary chiral centers were obtained in high yields (up to 99% yield) with excellent diastereoselectivities (> 20:1 dr, in all case) and enantioselectivities (up to > 99% ee).

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

“…Du and coworkers used a similar cascade process to obtain CF 3 -containing 3,2'-pyrrolidinylspirooxindoles and dispirooxindoles. [101] Fluorinated isatin ketimines 94 were in this case reacted with arylidene azlactones 97 in the presence of hydroquinine-derived thiourea C25 bearing a 4-CF 3 group on the aromatic ring, and spirocyclic products 98 were obtained in > 20 : 1 dr, with high yields and excellent ees (Figure 33). One gram-scale synthesis could also perform, which shows the potentialities of the method.…”

“…Synthesis of CF 3 -containing 3,2'-pyrrolidinyl spirooxindoles and dispirooxindoles. [101] attempted purification. Therefore, subsequently, once the starting materials were consumed, 3 M HCl in MeOH was added to hydrolyze the products to the corresponding 3,2'-pyrrolidinyl spirooxindoles 98, which were obtained in high yields as previously mentioned.…”

Recent Advances in the Construction of Trifluoromethyl‐Containing Spirooxindoles through Cycloaddition Reactions

“…In 2018, Du's group used rhodanine derivatives (Scheme 4, c); In 2019, Du's group used arylidene azlactones (Scheme 4, d); in 2019, Yan's group used N-2,2,2-trifluoroethylisatin ketimines and aurones (Scheme 4, e) to construct certain chiral spirooxindoles, respectively. [11][12][13] The spirooxindoles obtained from Du's methodology in 2019 (Scheme 4, d) were not stable and could be easily converted into hydrolysates by the treatment of HCl. In 2019, Yan's group reported a catalytic asymmetric cyclization of N-2,2,2-trifluoroethylisatin ketimines and α,β-unsaturated pyrazolones and Cinchona alkaloid-derived squaramide C-6 was adopted to be the best chiral catalyst in the reaction (Scheme 4, f).…”

“…Similarly, Cinchona alkaloid‐derived squaramide C‐5 were adopted in the catalytic asymmetric cyclizations with N ‐2,2,2‐trifluoroethylisatin ketimines. In 2018, Du's group used rhodanine derivatives (Scheme , c); In 2019, Du's group used arylidene azlactones (Scheme , d); in 2019, Yan's group used N ‐2,2,2‐trifluoroethylisatin ketimines and aurones (Scheme , e) to construct certain chiral spirooxindoles, respectively . The spirooxindoles obtained from Du's methodology in 2019 (Scheme , d) were not stable and could be easily converted into hydrolysates by the treatment of HCl.…”

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.…”