Recent Advances of N-2,2,2-Trifluoroethylisatin Ketimines in Organic Synthesis

The special properties of fluorine atoms and fluorine-containing groups have led to an increasing number of applications for fluorine-containing organic compounds, which are also extremely widely used in the field of new drug development. Unfortunately, naturally fluorinated organics are rare in nature, so the selective introduction of fluorine atoms or fluorine-containing groups into organic molecules is very important for pharmaceutical/synthetic chemists. N-2,2,2-trifluoroethylisatin ketimines have received the attention of many chemists since they were first developed as fluorine-containing synthons in 2015. This paper reviews the organic synthesis reactions in which trifluoroethyl isatin ketimine has been involved in recent years, focusing on the types of reactions and the stereoselectivity of products, and also provides a prospect of its application in this field.


Introduction
The special properties of fluorinated compounds make them have important application value in medicinal chemistry, pesticides, functional materials, and other fields [1]. Among these fluorinated compounds, trifluoromethylation products account for a large proportion. Trifluoromethyl (CF 3 ) is an important fluorine-containing group. The introduction of this functional group into drug molecules often significantly changes the fat solubility of the parent compound, enhances the metabolic stability of the molecule, and affects its biological activities such as drug absorption, distribution, and donor-receptor interaction [2]. Trifluoromethyl is widely found in a variety of bioactive molecules and lead compound structures, with protease inhibition, anticancer, anti-tumor, anti-HIV, and other activities (Figure 1) [3][4][5][6]. For example, as a drug for the treatment of osteoporosis, odanacatib can effectively and selectively inhibit the activity of cathepsin K [7,8]. Fludelone has the same anti-tumor activity as Epothilone D without trifluoromethyl, and the drug has a longer action time and less toxicity and side effects [9]. CJ-17493, as a new NK-1 receptor antagonist, has become a potential therapeutic drug for the treatment of chemotherapy-induced vomiting, arthritis, migraine, and other diseases [10]. In view of the fact that trifluoromethyl can improve and enhance the activity of drugs, the synthesis of trifluoromethyl compounds is becoming a hot topic for many pharmacologists and chemists. rize the latest research progress on this type of compound, this review describes the plication of trifluoroethyl isatin ketimine in organic synthesis based on the stereosele ity of the products and their reaction types (Scheme 1). This article aims to provide port for the development of trifluoroethyl isatin ketimines in this field by summari and analyzing their advantages and disadvantages, reaction mechanisms, and app tions in organic synthesis.

Organocatalytic Reactions Involving N-2,2,2-Trifluoroethylisatin Ketimines
As an important synthon of trifluoromethylation, trifluoroethyl isatin ketimines h become attractive partners in organocatalytic reactions in recent years. In order to facil combing and better understanding, this review mainly consists of two main parts accor to the stereoselectivity of the product, namely the chiral part and the racemic part. As an important synthetic "building block" containing trifluoromethyl, trifluoroethylamine has made great achievements in the application of organic synthesis [11][12][13][14][15][16]. However, there are few studies on the direct use of trifluoroethylamine in the construction of functionalized α-trifluoromethyl amine compounds. Until 2015, Wang and co-workers synthesized N-2,2,2-trifluoroethylisatin ketimine derivatives as 1,3-dipoles for the first time and successfully applied them in an organocatalytic asymmetric [3 + 2] cycloaddition reaction [17]. From then on, the door to the application of trifluoroethyl isatin ketimine in organocatalytic synthesis has been opened. In recent years, with the continuous efforts of organic chemists, many efficient new catalytic systems have been developed, expanding the application range of this type of compound in organic synthesis. In order to summarize the latest research progress on this type of compound, this review describes the application of trifluoroethyl isatin ketimine in organic synthesis based on the stereoselectivity of the products and their reaction types (Scheme 1). This article aims to provide support for the development of trifluoroethyl isatin ketimines in this field by summarizing and analyzing their advantages and disadvantages, reaction mechanisms, and applications in organic synthesis.
Molecules 2023, 28, x FOR PEER REVIEW 2 of 4 However, there are few studies on the direct use of trifluoroethylamine in the construction of functionalized α-trifluoromethyl amine compounds. Until 2015, Wang and co-workers synthesized N-2,2,2-trifluoroethylisatin ketimine derivatives as 1,3-dipoles for the firs time and successfully applied them in an organocatalytic asymmetric [3 + 2] cycloaddition reaction [17]. From then on, the door to the application of trifluoroethyl isatin ketimine in organocatalytic synthesis has been opened. In recent years, with the continuous efforts o organic chemists, many efficient new catalytic systems have been developed, expanding the application range of this type of compound in organic synthesis. In order to summa rize the latest research progress on this type of compound, this review describes the ap plication of trifluoroethyl isatin ketimine in organic synthesis based on the stereoselectiv ity of the products and their reaction types (Scheme 1). This article aims to provide sup port for the development of trifluoroethyl isatin ketimines in this field by summarizing and analyzing their advantages and disadvantages, reaction mechanisms, and applica tions in organic synthesis.

Organocatalytic Reactions Involving N-2,2,2-Trifluoroethylisatin Ketimines
As an important synthon of trifluoromethylation, trifluoroethyl isatin ketimines have become attractive partners in organocatalytic reactions in recent years. In order to facilitate combing and better understanding, this review mainly consists of two main parts according

Organocatalytic Reactions Involving N-2,2,2-Trifluoroethylisatin Ketimines
As an important synthon of trifluoromethylation, trifluoroethyl isatin ketimines have become attractive partners in organocatalytic reactions in recent years. In order to facilitate combing and better understanding, this review mainly consists of two main parts according to the stereoselectivity of the product, namely the chiral part and the racemic part. In 2015, Wang and co-workers synthesized N-2,2,2-trifluoroethylisatin ketimines for the first time and used it as a cascade reaction reagent to undergo an asymmetric cycloaddition reaction with cinnamaldehyde under the catalysis of prolinol silyl ether (Scheme 2) [17]. This reaction is concise and efficient to obtain chiral spirooxindole derivatives 3 with excellent diastereoselectivities (10:1->20:1 dr) and enantioselectivities (88->99% ee) in moderate to excellent yields (58-98%). In addition, researchers proposed a possible transition state model for the reaction based on the absolute configuration of the product. As shown in Scheme 2, prolinol silyl ether reacts with cinnamaldehyde to generate the iminium ion intermediate TS-1. Due to the steric hindrance of the aryl group on the Re-face, the cycloaddition reaction takes place on the Si-face of oxindole-derived azomethine ylides. Then, the intermediate TS-3 is hydrolyzed to release the product from the catalytic cycle and regenerate the catalyst.
Molecules 2023, 28 In 2015, Wang and co-workers synthesized N-2,2,2-trifluoroethylisatin ketimines for the first time and used it as a cascade reaction reagent to undergo an asymmetric [3 + 2] cycloaddition reaction with cinnamaldehyde under the catalysis of prolinol silyl ether (Scheme 2) [17]. This reaction is concise and efficient to obtain chiral spirooxindole derivatives 3 with excellent diastereoselectivities (10:1->20:1 dr) and enantioselectivities (88->99% ee) in moderate to excellent yields (58-98%). In addition, researchers proposed a possible transition state model for the reaction based on the absolute configuration of the product. As shown in Scheme 2, prolinol silyl ether reacts with cinnamaldehyde to generate the iminium ion intermediate TS-1. Due to the steric hindrance of the aryl group on the Re-face, the cycloaddition reaction takes place on the Si-face of oxindole-derived azomethine ylides. Then, the intermediate TS-3 is hydrolyzed to release the product from the catalytic cycle and regenerate the catalyst. Scheme 2. Asymmetric [3 + 2] cycloaddition of trifluoroethyl isatin ketimines to cinnamaldehydes.
In the same year, Wang and co-workers again reported a [3 + 2] cycloaddition reaction for the synthesis of 5′-trifluoromethyl-spiro[pyrrolidin-3,2′-oxindoles] 5 from nitroolefins 4 and N-2,2,2-trifluoroethylisatin ketimines 1 catalyzed by squaramide C2 (Scheme 3) [18]. A series of chiral fluorospiroindole derivatives were synthesized by this An efficient, highly asymmetric [3 + 2] cycloaddition reaction catalyzed by the thioureatertiary amine catalyst C3 for the synthesis of spiro[pyrrolidin-3,2 -oxindoles] 8 was developed by the Yuan group in 2016 (Scheme 4) [19]. This cascade reaction proceeded well at low catalyst loading (1 mol%) with a broad substrate scope, furnishing the desired products in high yields (81-99%) with excellent stereoselectivities (12:1->20:1 dr and 83->99% ee) under mild conditions. The practicability of this process was further verified by preparative-scale experiments. Regardless of the catalyst loading of 5 mol% or 1 mol%, the gram-scale reaction can achieve satisfactory results. Subsequently, product 8a was converted to other spirocyclic oxindoles by treatment with different reagents. Treatment of product 8a with DMAP in methanol afforded the ring-opened esterified derivative 9 with excellent stereoselectivity (>20:1 dr, 98% ee) in 97% yield. Furthermore, product 8a could also be converted by hydrazinolysis to the intermediate hydrazide 10, which was directly treated with a mixture of HCl/AcOH (v/v 4:1) to give the spirocyclic compound 11 with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (>99% ee) in 99% yield. Based on the experimental data and the absolute configuration of the product, a transition state model of the reaction was proposed, which further explained that the reaction was catalyzed by a tertiary amine-thiourea bifunctional activation mode to achieve substrate activation and stereoselectivity control.  [19]. This cascade reaction proceeded well at low catalyst loading (1 mol%) with a broad substrate scope, furnishing the desired products in high yields (81-99%) with excellent stereoselectivities (12:1->20:1 dr and 83->99% ee) under mild conditions. The practicability of this process was further verified by preparative-scale experiments. Regardless of the catalyst loading of 5 mol% or 1 mol%, the gram-scale reaction can achieve satisfactory results. Subsequently, product 8a was converted to other spirocyclic oxindoles by treatment with different reagents. Treatment of product 8a with DMAP in methanol afforded the ring-opened esterified derivative 9 with excellent stereoselectivity (>20:1 dr, 98% ee) in 97% yield. Furthermore, product 8a could also be converted by hydrazinolysis to the intermediate hydrazide 10, which was directly treated with a mixture of HCl/AcOH (v/v 4:1) to give the spirocyclic compound 11 with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (>99% ee) in 99% yield. Based on the experimental data and the absolute configuration of the product, a transition state model of the reaction was proposed, which further explained that the reaction was catalyzed by a tertiary amine-thiourea bifunctional activation mode to achieve substrate activation and stereoselectivity control.
In 2016, Lu and co-workers disclosed a highly efficient asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with methyleneindolinones 12 catalyzed by a bifunctional squaramide-tertiary amine catalyst C4 (Scheme 5) [20]. This method can synthesize a series of potentially biologically active trifluoromethyl-containing spirooxindole derivatives 13 in excellent yields (84-99%) and stereoselectivities (all >20:1 dr and 62->99% ee). In addition, the researchers also provided the catalytic reaction model. The squaramide catalyst plays a double activation role, which is similar to the process described in Scheme 3, so it will not be described too much here.
In 2016, Lu and co-workers disclosed a highly efficient asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with methyleneindolinones 12 catalyzed by a bifunctional squaramide-tertiary amine catalyst C4 (Scheme 5) [20]. This method can synthesize a series of potentially biologically active trifluoromethyl-containing spirooxindole derivatives 13 in excellent yields (84-99%) and stereoselectivities (all >20:1 dr and 62->99% ee). In addition, the researchers also provided the catalytic reaction model. The squaramide catalyst plays a double activation role, which is similar to the process described in Scheme 3, so it will not be described too much here. Subsequently, Enders' group and Wang's group reported the asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with methyleneindolinones 12 in 2017 and 2020, respectively, using different organic catalysts (Scheme 6) [21,22]. Whether it is a bifunctional thiourea catalyst or an acid-base synergistic catalyst, both of them can efficiently synthesize a series of potentially biologically active trifluoromethyl-containing bispiro indolinone derivatives, which provides a new method for expanding the construction of complex chiral pyrrolidine bispirooxindole skeletons. Subsequently, Enders' group and Wang's group reported the asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with methyleneindolinones 12 in 2017 and 2020, respectively, using different organic catalysts (Scheme 6) [21,22]. Whether it is a bifunctional thiourea catalyst or an acid-base synergistic catalyst, both of them can efficiently synthesize a series of potentially biologically active trifluoromethylcontaining bispiro indolinone derivatives, which provides a new method for expanding the construction of complex chiral pyrrolidine bispirooxindole skeletons.
In 2019, Jiang and co-workers disclosed a highly asymmetric [3 + 2] cycloaddition between N-2,2,2-trifluoroethylisatin ketimines 1 and 2,3-dioxopyrrolidines 27 (Scheme 12) [28]. Under optimal conditions, all reactions proceeded smoothly and afforded a series of chiral spirobipyrrolidine derivatives 28 with two adjacent spiro-quaternary carbon centers in moderate to excellent yields (63-96%) with good diastereoselectivities (2.3:1-19:1 dr) and enantioselectivities (62-97% ee). The practicality of this catalytic reaction was demonstrated by gram-scale and derivatization experiments. It is worth noting that this method can obtain single-configuration diastereoisomers by controlling the reaction time under single catalytic conditions. The researchers thoroughly studied the diastereoselective conversion mechanism through controlled experiments. The squaramide activates pyrrolidine 27a and indoleketimine 1b through dual activation modes and controls the stereoselectivity of the Michael(Si-face)/Mannich(Re-face) cascade reaction (TS-8) to obtain compound 28a . Meanwhile, equivalent diastereomer 28a (Path A) can also be obtained by Michael(Siface)/Mannich(Si-face) cascade reaction (TS-9). If the reaction time is prolonged, the carbon-carbon bond between adjacent spiro-quaternary carbons in 28a will be broken under acidic conditions, and the intramolecular Mannich reaction (Si-face) will occur again to convert to 28a (TS-3, Path B).
A chiral secondary amine catalyzed asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with vinyl substituted aryl aldehydes (37,39,41) was reported by the Chen group in 2019 (Scheme 16) [32]. This reaction has mild conditions and excellent substrate tolerance, making it suitable for trifluoroethylisatin ketimine substrates with different electronegativity and positional substitution. However, for vinyl substituted aromatic aldehydes, the position of the aldehyde group and the vinyl group has a great influence on the reaction activity and stereoselectivity. For the o-vinyl benzaldehyde substrate, NO2 must be introduced at the 3-position to make the reaction go smoothly. Based on the experimental data and the absolute configuration of the product, the researchers proposed the corresponding catalytic mechanism. The reaction utilizes a Scheme 13. Phosphonium salt-catalyzed [3 + 2] cycloaddition between N-2,2,2-trifluoroethylisatin ketimines and 2,3-dioxopyrrolidines.  A chiral secondary amine catalyzed asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with vinyl substituted aryl aldehydes (37,39,41) was reported by the Chen group in 2019 (Scheme 16) [32]. This reaction has mild conditions and excellent substrate tolerance, making it suitable for trifluoroethylisatin ketimine substrates with different electronegativity and positional substitution. However, for vinyl substituted aromatic aldehydes, the position of the aldehyde group and the vinyl group has a great influence on the reaction activity and stereoselectivity. For the o-vinyl benzaldehyde substrate, NO 2 must be introduced at the 3-position to make the reaction go smoothly. Based on the experimental data and the absolute configuration of the product, the researchers proposed the corresponding catalytic mechanism. The reaction utilizes a chiral prolinol silyl ether catalyst to achieve the activation of vinyl-substituted aromatic aldehydes through a strategy of lowering the lowest unoccupied molecular orbital (LUMO) of polyconjugated imine ions.
In the same year, Du and co-workers developed squaramide-catalyzed asymmetric cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with barbiturate-based olefins 43 (Scheme 17) [33]. This reaction proceeds smoothly under mild conditions and has good substrate universality, and spiroheterocyclic derivatives 44 with good diastereoselectivities (87:13-99:1 dr) and enantioselectivities (74-98% ee) can be constructed in moderately excellent yields (62-99%). Meanwhile, the reaction can be carried out smoothly without losing its stereoselectivity by enlarging the scale to 20 times on the basis of the experimental model. Furthermore, the researchers discussed in detail the catalytic model of the dual activation mechanism (TS-14) in the reaction based on the experimental data and the absolute configuration of the product.
In 2020, Han and co-workers described the squaramide-catalyzed asymmetric cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with (Z)-α-bromonitroalkenes 49 (Scheme 20) [36]. This cascade reaction has good substrate tolerance and can construct pyrrolidine-fused spirooxindole derivatives 50 with good diastereoselectivities (8:1->20:1 dr) and excellent enantioselectivities (93->99%) in moderate to high yields (48-84%) under optimal conditions. In order to increase the potential drug activity of the product, a derivatization experiment was carried out on it. When product 50a was treated with the sulfhydryl-containing nucleophiles reagent benzyl mercaptan or N-protected cysteine methyl ester, its sulfurized derivatives could be synthesized in moderate yields without loss of its stereoselectivity.

EER REVIEW
17 of 42 methyl ester, its sulfurized derivatives could be synthesized in moderate yields without loss of its stereoselectivity.
A highly efficient asymmetric [3 + 2] annulation reaction of N-2,2,2-trifluoroethylisatin ketimines 1 and 2-nitroindoles or 2-nitrobenzofurans was presented by the Wang group in 2021 (Scheme 21) [37]. This reaction has a wide range of substrates, and the CF3containing polycyclic spirooxindole derivatives 54 with excellent diastereoselectivities (all >20:1 dr) and good enantioselectivities (70-96% ee) can be obtained in high yields (80-97%) by dipeptided phosphonium salt catalysis (C22 or C23). Pleasantly, the gram-scale preparation was able to isolate the product with an 87% yield while maintaining its stereoselectivity. Chiral compound 55 was obtained in 93% yield with 96% ee by treating product 54a with trifluoroacetic acid. This catalytic reaction mechanism is similar to that described in Scheme 13, and the product stereoselectivity is mainly controlled by the ionpair and H-bonding interactions between chiral phosphonium salts and substrates.
A highly efficient asymmetric [3 + 2] annulation reaction of N-2,2,2-trifluoroethylisatin ketimines 1 and 2-nitroindoles or 2-nitrobenzofurans was presented by the Wang group in 2021 (Scheme 21) [37]. This reaction has a wide range of substrates, and the CF 3 -containing polycyclic spirooxindole derivatives 54 with excellent diastereoselectivities (all >20:1 dr) and good enantioselectivities (70-96% ee) can be obtained in high yields (80-97%) by dipeptided phosphonium salt catalysis (C22 or C23). Pleasantly, the gram-scale preparation was able to isolate the product with an 87% yield while maintaining its stereoselectivity. Chiral compound 55 was obtained in 93% yield with 96% ee by treating product 54a with trifluoroacetic acid. This catalytic reaction mechanism is similar to that described in Scheme 13, and the product stereoselectivity is mainly controlled by the ion-pair and H-bonding interactions between chiral phosphonium salts and substrates.
An efficient and practical squaramide-catalyzed asymmetric domino Micheal/Mannich [3 + 2] annulation reaction of N-2,2,2-trifluoroethylisatin ketimines 1 and 3-methyl-4-nitro-5-isatylidenyl-isoxazoles 61 was reported by the Du group in 2022 (Scheme 23) [40]. This asymmetric reaction can obtain a series of CF 3 -containing 3,2 -pyrrolidinyl dispirooxindole derivatives 62 with excellent diastereoselectivities (all >20:1 dr) and good enantioselectivities (53-96% ee) in moderate to excellent yields (42-99%). The practicability of the asymmetric catalytic reaction was proved by the preparation experiment on the gram scale. Moreover, the comprehensive applicability of this method was further proved by the derivative transformation experiment of the product. The nitro group was selectively reduced with tin chloride in a THF/HCl mixed solution at room temperature, and its amine derivative 63 was obtained with a 40% yield. However, by slightly changing the reaction temperature and reagent, the ring-opening product 64 can be obtained with a yield of 43% by a two-step reaction, and its stereoselectivity can be maintained. The researchers detailed the dual activation of the catalyst based on the experimental results and the absolute configuration of the products (TS-18). An efficient and practical squaramide-catalyzed asymmetric domino Micheal/Man nich [3 + 2] annulation reaction of N-2,2,2-trifluoroethylisatin ketimines 1 and 3-methyl-4 nitro-5-isatylidenyl-isoxazoles 61 was reported by the Du group in 2022 (Scheme 23) [40] This asymmetric reaction can obtain a series of CF3-containing 3,2′-pyrrolidinyl dispiroox indole derivatives 62 with excellent diastereoselectivities (all >20:1 dr) and good enanti oselectivities (53-96% ee) in moderate to excellent yields (42-99%). The practicability o the asymmetric catalytic reaction was proved by the preparation experiment on the gram scale. Moreover, the comprehensive applicability of this method was further proved by the derivative transformation experiment of the product. The nitro group was selectively reduced with tin chloride in a THF/HCl mixed solution at room temperature, and it amine derivative 63 was obtained with a 40% yield. However, by slightly changing th reaction temperature and reagent, the ring-opening product 64 can be obtained with a yield of 43% by a two-step reaction, and its stereoselectivity can be maintained. The re searchers detailed the dual activation of the catalyst based on the experimental results and the absolute configuration of the products (TS-18).

Catalytic Asymmetric Reaction of Trifluoroethylisatin Ketimines as Nucleop Reagent
A highly efficient asymmetric SN2′-SN2′ reaction between N-2,2,2-trifluoroeth ketimines 1 and Morita-Baylis-Hillman (MBH) carbonates 69 was disclosed by th group in 2016 (Scheme 25) [42]. In this reaction, a series of chiral α-trifluoromethy 70 with good diastereoselectivities (15:1->20:1 dr) and enantioselectivities (75-98% be synthesized with moderate to excellent yields (46-93%) by using the catalysts from cinchona base. In the mixed solution of concentrated HCl/EtOH, the adduct easily remove the N-methyl isatin group. The remaining product fraction underg cyclization and conversion to the pharmacophore α-methylenelactams 71. Rese proposed a possible mechanism model for the catalytic reaction based on the a configuration of the product. β-ICD acts as a Lewis base chiral catalyst to attac carbonate through the SN2′ process to remove a molecule of CO2 and a tert-butano Isatinketimine was deprotonated and activated by the tert-butanol anion, and place in another SN2′ reaction as a nucleophilic reagent. Scheme 24. Chiral secondary amine catalyzed asymmetric [3 + 4] cycloaddition between N-2,2,2trifluoroethylisatin ketimines and α-vinylenals.

Catalytic Asymmetric Reaction of Trifluoroethylisatin Ketimines as Nucleophilic Reagent
A highly efficient asymmetric S N 2 -S N 2 reaction between N-2,2,2-trifluoroethylisatin ketimines 1 and Morita-Baylis-Hillman (MBH) carbonates 69 was disclosed by the Wang group in 2016 (Scheme 25) [42]. In this reaction, a series of chiral α-trifluoromethylamines 70 with good diastereoselectivities (15:1->20:1 dr) and enantioselectivities (75-98% ee) can be synthesized with moderate to excellent yields (46-93%) by using the catalysts derived from cinchona base. In the mixed solution of concentrated HCl/EtOH, the adduct 70a can easily remove the N-methyl isatin group. The remaining product fraction undergoes self-cyclization and conversion to the pharmacophore α-methylenelactams 71. Researchers proposed a possible mechanism model for the catalytic reaction based on the absolute configuration of the product. β-ICD acts as a Lewis base chiral catalyst to attack MBH carbonate through the S N 2 process to remove a molecule of CO 2 and a tert-butanol anion. Isatinketimine was deprotonated and activated by the tert-butanol anion, and it takes place in another S N 2 reaction as a nucleophilic reagent.
In 2019, Wang and co-workers described for the first time that trifluoroethylisatin ketimines have the characteristics of polarity reversal and developed a chiral iridium-catalyzed allylation/2-aza-Cope rearrangement cascade reaction between trifluoroethylisatin ketimine 1a and allylic carbonates 72 (Scheme 26) [43]. This asymmetric catalytic reaction has broad substrate tolerance and provides a new method for the synthesis of α-trifluoromethyl homoallylic amine derivatives 73 with good to excellent enantioselectivities (75-99% ee) in high yields (82-99%). The gram-scale preparation proceeded smoothly under optimal conditions, which further proves the practicability of this synthetic method. The adduct 73a was hydrolyzed under acidic conditions to obtain its primary amine derivative 74 in 97% yield and 94% ee. Subsequent treatment of primary amines 74 with I2 allowed the construction of biologically important trifluoromethylpyrrolidine 75, containing three stereocenters with exclusive diastereoselectivity at 92% yield. In addition, the researchers proposed a possible transition-state model for the catalytic reaction. First, allylic carbonate 72a undergoes a coordination reaction with iridacycle TS-20, followed by oxidative addition-decarboxylation to generate Ir-π-allyl species TS-21 and the anion MeO − , and the latter serves as the base for the deprotonation of ketimine 1a. Then, enantioselective umpolung allylation occurs between the substrates to form branched allylation intermediates. The steric congestion caused by the adjacent oxindole ring and phenyl group facilitates a Scheme 25. Catalyzed asymmetric S N 2 -S N 2 reaction between N-2,2,2-trifluoroethylisatin ketimines and MBH carbonates.
In 2019, Wang and co-workers described for the first time that trifluoroethylisatin ketimines have the characteristics of polarity reversal and developed a chiral iridiumcatalyzed allylation/2-aza-Cope rearrangement cascade reaction between trifluoroethylisatin ketimine 1a and allylic carbonates 72 (Scheme 26) [43]. This asymmetric catalytic reaction has broad substrate tolerance and provides a new method for the synthesis of αtrifluoromethyl homoallylic amine derivatives 73 with good to excellent enantioselectivities (75-99% ee) in high yields (82-99%). The gram-scale preparation proceeded smoothly under optimal conditions, which further proves the practicability of this synthetic method. The adduct 73a was hydrolyzed under acidic conditions to obtain its primary amine derivative 74 in 97% yield and 94% ee. Subsequent treatment of primary amines 74 with I 2 allowed the construction of biologically important trifluoromethylpyrrolidine 75, containing three stereocenters with exclusive diastereoselectivity at 92% yield. In addition, the researchers proposed a possible transition-state model for the catalytic reaction. First, allylic carbonate 72a undergoes a coordination reaction with iridacycle TS-20, followed by oxidative addition-decarboxylation to generate Ir-π-allyl species TS-21 and the anion MeO − , and the latter serves as the base for the deprotonation of ketimine 1a. Then, enantioselective umpolung allylation occurs between the substrates to form branched allylation intermediates. The steric congestion caused by the adjacent oxindole ring and phenyl group facilitates a spontaneous 2-aza-Cope rearrangement reaction, ultimately delivering the observed linear α-trifluoromethyl homoallylic amine derivatives. A novel palladium-catalyzed highly regioselective asymmetric hydroalkylation reaction between trifluoroethylisatin ketimine 1a and terminal dienes 76 was presented by the Malcolmson group in 2020 (Scheme 27) [44]. This method was the first to efficiently and stereoselectively synthesize α-trifluoromethyl homoallylamine derivatives using internal olefins and further expands the synthesis strategy of this type of chiral compound. Interestingly, the coupling reaction with 1a undergoes diene isomerization when using hexadienoate 78a, providing homoallylamine with an ester-conjugated, ethyl-substituted stereogenic center. However, its internal diene analogues 78b can also be used to synthesize acrylate with similar stereoselectivity but lower conversion. The gram-scale reaction obtained the target product in 82% yield under optimal conditions while maintaining its stereoselectivity. In addition, the isatin moiety can be removed from the adduct under acidic conditions to obtain a free primary amine derivative 80 with a 77% yield. A novel palladium-catalyzed highly regioselective asymmetric hydroalkylation reaction between trifluoroethylisatin ketimine 1a and terminal dienes 76 was presented by the Malcolmson group in 2020 (Scheme 27) [44]. This method was the first to efficiently and stereoselectively synthesize α-trifluoromethyl homoallylamine derivatives using internal olefins and further expands the synthesis strategy of this type of chiral compound. Interestingly, the coupling reaction with 1a undergoes diene isomerization when using hexadienoate 78a, providing homoallylamine with an ester-conjugated, ethyl-substituted stereogenic center. However, its internal diene analogues 78b can also be used to synthesize acrylate with similar stereoselectivity but lower conversion. The gram-scale reaction obtained the target product in 82% yield under optimal conditions while maintaining its stereoselectivity. In addition, the isatin moiety can be removed from the adduct under acidic conditions to obtain a free primary amine derivative 80 with a 77% yield. In 2020, Lu and co-workers established the cross-Mannich reaction of trifluoroethylisatin ketimines 1 with cyclic ketimines 81 under the catalysis of the chiral bifunctional squaramide catalyst C8 through a polarity inversion strategy (Scheme 28) [45]. Under the optimal catalytic conditions, chiral vicinal tetrasubstituted diamine derivatives with excellent diastereoselectivities (all >20:1 dr) and enantioselectivities (88->99% ee) were synthesized in excellent yields (85-98%). This method has the characteristics of wide substrate tolerance, is suitable for gram-scale preparation, and has high chemical/regioselectivity, which provide prerequisites for its practical application in biological activity evaluation research. Furthermore, the researchers proposed a possible catalytic reaction mechanism based on the absolute configuration of the products. The catalyst plays a dual activation role in this reaction (TS-22). The trifluoroethylisatin ketimine was partially deprotonated by the tertiary amine of the catalyst and activated by double hydrogen bonds. Meanwhile, the carbonyl and ketimine groups of the isatin-derived N-Boc ketimine are immobilized and activated by hydrogen bonds formed by the squaramide moiety of the catalyst. Activated trifluoroethylisatin ketamine attacks the isatin-derived N-Boc ketimine from Re-face to form the observed product. In 2020, Lu and co-workers established the cross-Mannich reaction of trifluoroethylisatin ketimines 1 with cyclic ketimines 81 under the catalysis of the chiral bifunctional squaramide catalyst C8 through a polarity inversion strategy (Scheme 28) [45]. Under the optimal catalytic conditions, chiral vicinal tetrasubstituted diamine derivatives with excellent diastereoselectivities (all >20:1 dr) and enantioselectivities (88->99% ee) were synthesized in excellent yields (85-98%). This method has the characteristics of wide substrate tolerance, is suitable for gram-scale preparation, and has high chemical/regioselectivity, which provide prerequisites for its practical application in biological activity evaluation research. Furthermore, the researchers proposed a possible catalytic reaction mechanism based on the absolute configuration of the products. The catalyst plays a dual activation role in this reaction (TS-22). The trifluoroethylisatin ketimine was partially deprotonated by the tertiary amine of the catalyst and activated by double hydrogen bonds. Meanwhile, the carbonyl and ketimine groups of the isatin-derived N-Boc ketimine are immobilized and activated by hydrogen bonds formed by the squaramide moiety of the catalyst. Activated trifluoroethylisatin ketamine attacks the isatin-derived N-Boc ketimine from Re-face to form the observed product. A highly efficient asymmetric Michael addition reaction between N-2,2,2-trifluoroethylisatin ketimines 1 and ethylene sulfonyl fluoride 83 was realized by the Yan group in 2021 (Scheme 29) [46]. This method utilizes quinine-derived squaramide catalysts C8 to obtain a series of isatin-derived α-(trifluoromethyl)imine derivatives 84 with diverse structures and excellent enantioselectivities (91-99% ee) in excellent yields (79-97%). The gram-scale reaction proceeded well under optimal conditions, further demonstrating the applicability of the method. In addition, the derivatization experiment on the product was carried out. The product 84a was hydrolyzed under acidic conditions to obtain a chiral γtrifluoromethyl-γ-sultam heterocyclic compound 85 with excellent enantioselectivity, which is a useful skeleton in drug research. On the other hand, the adduct 84a gave the secondary amine derivative 86 with good stereoselectivity and a 76% yield by catalytic hydrogenation. Further treatment of product 86 with TFA allowed intramolecular cyclization to synthesize sultam derivative 87 in 83% yield. Based on the experimental results, the researchers proposed a possible transition state model (TS-23).

Scheme 28. Catalytic asymmetric umpolung cross-Mannich reaction of trifluoroethylisatin ketimines.
A highly efficient asymmetric Michael addition reaction between N-2,2,2trifluoroethylisatin ketimines 1 and ethylene sulfonyl fluoride 83 was realized by the Yan group in 2021 (Scheme 29) [46]. This method utilizes quinine-derived squaramide catalysts C8 to obtain a series of isatin-derived α-(trifluoromethyl)imine derivatives 84 with diverse structures and excellent enantioselectivities (91-99% ee) in excellent yields (79-97%). The gram-scale reaction proceeded well under optimal conditions, further demonstrating the applicability of the method. In addition, the derivatization experiment on the product was carried out. The product 84a was hydrolyzed under acidic conditions to obtain a chiral γ-trifluoromethyl-γ-sultam heterocyclic compound 85 with excellent enantioselectivity, which is a useful skeleton in drug research. On the other hand, the adduct 84a gave the secondary amine derivative 86 with good stereoselectivity and a 76% yield by catalytic hydrogenation. Further treatment of product 86 with TFA allowed intramolecular cyclization to synthesize sultam derivative 87 in 83% yield.

Catalytic Diastereoselectic [3 + 2] Cycloaddition Reaction
In 2016, Carretero and co-workers reported a case of silver-catalyzed [3 + 2] cycloaddition reactions of N-2,2,2-trifluoroethylisatin ketimine 1a with maleimide 88a (Scheme 30) [47]. By using AgOAc/(±)BINAP as the catalyst system, the desired product 89a was obtained with 87% yield and >20:1 dr. A highly efficient base-catalyzed diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with methyleneindolinones 12 was developed by the Lin group in 2017 (Scheme 31) [48]. The reaction has broad substrate tolerance under mild conditions, and CF 3 -containing 3,3 -pyrrolidinyl-dispirooxindole derivatives 13 with good diastereoselectivities (3:1-18:1 dr) can be obtained in excellent yields (86-98%). In 2018, Shi and co-workers disclosed a catalyst-free, self-catalyzed [3 + 2] cycloaddition reaction of trifluoroethylisatin ketimines 1 with vinylpyridines 90 (Scheme 32) [49]. This reaction provides a facile and feasible method for the construction of a series of CF3containing spiropyrrolidin-3,2′-oxindole derivatives 91 with moderate to good yields (32-88%) and good diastereoselectivities (9:1-20:1 dr). The researchers studied the reaction mechanism through control experiments, DFT calculations of pKa values, and kinetic curves, revealing that this reaction is completed by mutual activation between the substrates. First, substrate 1a is deprotonated by vinylpyridine 90a to produce protonated In order to increase the practicability of the product, a derivatization experiment was carried out on it. Treating the adduct with Pd/H2 in methanol can reduce its nitro group to an amino group with a yield of 90%. Subsequently, the product 92 was condensed with amino acids, and a derivative 93 with potential application value in biomolecular synthesis was constructed at a 27% yield. In 2018, Shi and co-workers disclosed a catalyst-free, self-catalyzed [3 + 2] cycloaddition reaction of trifluoroethylisatin ketimines 1 with vinylpyridines 90 (Scheme 32) [49]. This reaction provides a facile and feasible method for the construction of a series of CF 3 -containing spiropyrrolidin-3,2 -oxindole derivatives 91 with moderate to good yields (32-88%) and good diastereoselectivities (9:1-20:1 dr). The researchers studied the reaction mechanism through control experiments, DFT calculations of pKa values, and kinetic curves, revealing that this reaction is completed by mutual activation between the substrates. First, substrate 1a is deprotonated by vinylpyridine 90a to produce protonated to produce the required product 91a. In order to increase the practicability of the product, a derivatization experiment was carried out on it. Treating the adduct with Pd/H 2 in methanol can reduce its nitro group to an amino group with a yield of 90%. Subsequently, the product 92 was condensed with amino acids, and a derivative 93 with potential application value in biomolecular synthesis was constructed at a 27% yield. A novel strategy for the [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 to benzynes 94 was described by the Ko group in 2018 (Scheme 33) [50]. This reaction proceeds smoothly in the presence of a weak base such as TBAF or TBAT, and spiro[oxindole-3,2′-pyrrolidine] derivatives 95 can be constructed in good yields (32-88%). Furthermore, the researchers proposed a possible catalytic mechanism based on the experimental results. When the imine 1a is treated with a weak base such as fluoride, it can be deprotonated and transformed into the azomethine ylide 1a′. Subsequently, the intermediate 1a′ of azomethine ylide reacted with the in-situ generated benzyne 94a′ to form the desired product by the [3 + 2] cycloaddition reaction. However, two molecules of the azomethine ylide intermediate 1a′ can be transformed into a dimer 95a′ by a [3 + 3] cycloaddition reaction in the presence of TBAF. A novel strategy for the [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 to benzynes 94 was described by the Ko group in 2018 (Scheme 33) [50]. This reaction proceeds smoothly in the presence of a weak base such as TBAF or TBAT, and spiro[oxindole-3,2 -pyrrolidine] derivatives 95 can be constructed in good yields (32-88%). Furthermore, the researchers proposed a possible catalytic mechanism based on the experimental results. When the imine 1a is treated with a weak base such as fluoride, it can be deprotonated and transformed into the azomethine ylide 1a . Subsequently, the intermediate 1a of azomethine ylide reacted with the in-situ generated benzyne 94a to form the desired product by the [3 + 2] cycloaddition reaction. However, two molecules of the azomethine ylide intermediate 1a can be transformed into a dimer 95a by a [3 + 3] cycloaddition reaction in the presence of TBAF. An efficient DMAP-catalyzed decarboxylative [3 + 2] annulation of N-2,2,2trifluoroethylisatin ketimines 1 with 3-carboxylic acid chromones 98 was established by the Zhou group in 2020 (Scheme 35) [52]. A series of trifluoromethylated chromanone-fused pyrrolidinyl spirooxindoles 99 with high diastereoselectivities (5:1-15:1 dr) and potential bioactivity were synthesized in good yields (70-87%). In addition, the researchers also preliminarily attempted the asymmetric decarboxylation [3 + 2] cycloaddition reaction catalyzed by chiral bifunctional squaramide catalysts. However, preliminary experimental results are not satisfactory. According to the absolute configuration of the product, the researchers believe that the cycloaddition reaction mainly proceeds through the endo'transition state. An efficient DMAP-catalyzed decarboxylative [3 + 2] annulation of N-2,2,2-trifluoroethylisatin ketimines 1 with 3-carboxylic acid chromones 98 was established by the Zhou group in 2020 (Scheme 35) [52]. A series of trifluoromethylated chromanone-fused pyrrolidinyl spirooxindoles 99 with high diastereoselectivities (5:1-15:1 dr) and potential bioactivity were synthesized in good yields (70-87%). In addition, the researchers also preliminarily attempted the asymmetric decarboxylation [3 + 2] cycloaddition reaction catalyzed by chiral bifunctional squaramide catalysts. However, preliminary experimental results are not satisfactory. According to the absolute configuration of the product, the researchers believe that the cycloaddition reaction mainly proceeds through the endo'-transition state. Scheme 34. Phosphine-catalyzed [3 + 2] annulation of N-2,2,2-trifluoroethylisatin ketimines with γ-substituted allenoates.
Subsequently, Han's group synthesized a series of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives 101 in the same way [54]. The difference is that the researchers evaluated its pharmacological activity as a glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitor and found that the resulting compound exhibited strong activity against both targets. Through in-depth experimental research, compounds with the same activity in vitro and in vivo were selected.
A highly efficient and practical diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with maleimides 88 was reported by the Chen group in 2021 (Scheme 37) [55]. This reaction affords a series of complex trifluoromethyl spirofused[succinimide-pyrrolidine-oxindole] derivatives 89 with good diastereoselectivities (67:33->99:1 dr) in moderate to excellent yields (69-96%) in the presence of a phase transfer catalyst. The gram-scale preparation and derivatization experiments demonstrated the application prospects of this synthetic strategy. The Suzuki-Miyaura cross-coupling reaction between the adduct and arylboronic acid was carried out under optimized conditions, and the target product 105 was obtained in moderate yields. In addition, the researchers proposed a possible reaction mechanism based on the absolute configuration of the product and previous studies. Initially, THAB undergoes a displacement reaction with Cs 2 CO 3 on its solid surface to produce THAC. The trifluoroethyl imine 1b is then deprotonated by the carbonate anion of THAC and transferred into the DCM liquid phase. Subsequently, the imine moiety of the intermediate TS-33 captures the proton of tetrahexylammonium bicarbonate to generate the reactive azomethine ylide TS-34 and release THAC. Finally, yelide TS-34 and maleimide 88b undergo cycloaddition conversion to deliver the desired product.
A highly efficient and practical diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with maleimides 88 was reported by the Chen group in 2021 (Scheme 37) [55]. This reaction affords a series of complex trifluoromethyl spirofused[succinimide-pyrrolidine-oxindole] derivatives 89 with good diastereoselectivities (67:33->99:1 dr) in moderate to excellent yields (69-96%) in the presence of a phase transfer catalyst. The gram-scale preparation and derivatization experiments demonstrated the application prospects of this synthetic strategy. The Suzuki-Miyaura cross-coupling reaction between the adduct and arylboronic acid was carried out under optimized conditions, and the target product 105 was obtained in moderate yields. In addition, the researchers proposed a possible reaction mechanism based on the absolute configuration of the product and previous studies. Initially, THAB undergoes a displacement reaction with Cs2CO3 on its solid surface to produce THAC. The trifluoroethyl imine 1b is then deprotonated by the carbonate anion of THAC and transferred into the DCM liquid phase. Subsequently, the imine moiety of the intermediate TS- 33  In 2021, Wang and co-workers developed an efficient diastereoselective [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with, β,γ-unsaturated α-keto esters 106 in the presence of the catalyst DABCO (Scheme 38) [56]. This strategy enables the construction of CF 3 -containing spiro[pyrrolidin-3,2 -oxindole] derivatives 107 with good diastereoselectivities (7:1->20:1 dr) and moderate-to-excellent yields (61-93%) under optimal conditions. Subsequently, the researchers conducted a preliminary exploration of this asymmetric catalytic reaction using a bifunctional thiourea catalyst. In addition, the researchers screened the biological activity of these compounds on K562 leukemia cells by the MTT method. 106 in the presence of the catalyst DABCO (Scheme 38) [56]. This strategy enables the construction of CF3-containing spiro[pyrrolidin-3,2′-oxindole] derivatives 107 with good diastereoselectivities (7:1->20:1 dr) and moderate-to-excellent yields (61-93%) under optimal conditions. Subsequently, the researchers conducted a preliminary exploration of this asymmetric catalytic reaction using a bifunctional thiourea catalyst. In addition, the researchers screened the biological activity of these compounds on K562 leukemia cells by the MTT method. Scheme 38. Highly diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with β,γ-unsaturated α-keto esters.
A new strategy for the synthesis of trifluoromethyl bispiro-[oxindole-pyrrolidinechromanone] derivatives with diverse structures was disclosed by the Tian group in 2021 (Scheme 39) [57]. The method uses DABCO to catalyze the diastereoselective [3 + 2] cycloaddition reaction of trifluoroethylisatin ketimines 1 and benzylidenechromanones 108 and obtains the target products 109 with good diastereoselectivities (10:1->20:1 dr) in high yields (70-91%). The researchers also preliminarily explored the catalytic effect of chiral organocatalysts in this reaction. However, the selected catalysts cannot achieve satisfactory results. In addition, the biological activity of the selected compounds was tested by the MTT method.
In 2021, Chen and co-workers described a new method for the rapid construction of bispiro heterocycles with five pharmacophores by using phase transfer catalysis (Scheme 40) [58]. Under mild conditions, the diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with (Z)-4-((chromone-3-yl)methylene)oxazolones 110 took place, and the desired product with excellent diastereoselectivities (92:8->99:1 dr) was produced in moderate to excellent yields (51-94%). The kinetic control mechanism of the catalytic reaction was explored through different catalytic systems. In addition, the researchers also discussed the catalytic mechanism of PTC in depth, but since it has been described in Scheme 37, it will not be repeated here. A new strategy for the synthesis of trifluoromethyl bispiro-[oxindole-pyrrolidinechromanone] derivatives with diverse structures was disclosed by the Tian group in 2021 (Scheme 39) [57]. The method uses DABCO to catalyze the diastereoselective [3 + 2] cycloaddition reaction of trifluoroethylisatin ketimines 1 and benzylidenechromanones 108 and obtains the target products 109 with good diastereoselectivities (10:1->20:1 dr) in high yields (70-91%). The researchers also preliminarily explored the catalytic effect of chiral organocatalysts in this reaction. However, the selected catalysts cannot achieve satisfactory results. In addition, the biological activity of the selected compounds was tested by the MTT method. In 2021, Chen and co-workers described a new method for the rapid construction of bispiro heterocycles with five pharmacophores by using phase transfer catalysis (Scheme 40) [58]. Under mild conditions, the diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with (Z)-4-((chromone-3-yl)methylene)oxazolones 110 took place, and the desired product with excellent diastereoselectivities (92:8->99:1 dr) was produced in moderate to excellent yields (51-94%). The kinetic control mechanism of the catalytic reaction was explored through different catalytic systems. In addition, the researchers also discussed the catalytic mechanism of PTC in depth, but since it has been described in Scheme 37, it will not be repeated here. The unexpected gold-catalyzed diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with yne enones 112 was presented by the Su group in 2021 (Scheme 41) [59]. The catalytic reaction can obtain diastereoisomers (113 or 113 ) with good diastereoselectivities in moderate to excellent yields under different catalytic systems. The practicability of the method was further demonstrated by gram-scale preparation and derivatization experiments. Treatment of adduct 113a with Pd/C and H 2 in methanol afforded the alkene derivative 114 in a 93% yield. More interestingly, in the presence of IPrAuCl/AgSbF 6 , cycloadduct 113a can undergo 1,2 -alkyl migration at a relatively higher temperature to generate furan-fused spiroindole 115. In addition, the researchers proposed the catalytic mechanism of the reaction based on the experimental results and previous studies. The reaction synthesized its diastereoisomers separately through two different pathways.
The unexpected gold-catalyzed diastereoselective [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with yne enones 112 was presented by the Su group in 2021 (Scheme 41) [59]. The catalytic reaction can obtain diastereoisomers (113 or 113′) with good diastereoselectivities in moderate to excellent yields under different catalytic systems. The practicability of the method was further demonstrated by gram-scale preparation and derivatization experiments. Treatment of adduct 113a with Pd/C and H2 in methanol afforded the alkene derivative 114 in a 93% yield. More interestingly, in the presence of IPrAuCl/AgSbF6, cycloadduct 113a can undergo 1,2′-alkyl migration at a relatively higher temperature to generate furan-fused spiroindole 115. In addition, the researchers proposed the catalytic mechanism of the reaction based on the experimental results and previous studies. The reaction synthesized its diastereoisomers separately through two different pathways. Scheme 41. Diastereoselectivity-switchable gold-catalyzed formal [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with yne enones.
In 2022, Duan and co-workers established a new method for the diastereoselective construction of fully disubstituted spiro[indoline-3,2 -pyrrolidin]-2-one derivatives through base-promoted [3 + 2] cycloaddition reactions (Scheme 42) [60]. Interestingly, different configurations of products were obtained when different bases were used as catalysts. Whether Lewis base (PCy 3 ) or Brøwns base (K 2 CO 3 ) was used as the catalyst, both of them could obtain spiroheterocyclic derivatives (117 or 117 ) with excellent diastereoselectivity in good yields. The difference is that the products obtained by the two catalytic reactions are diastereoisomers. Based on the experimental results and previous studies, two plausible catalytic mechanisms were proposed. When PCy 3 was used as the catalyst, the phosphine catalyst first underwent nucleophilic addition with conjugated diene 116a to obtain the zwitterionic intermediate TS- 41 In 2022, Duan and co-workers established a new method for the diastereoselective construction of fully disubstituted spiro[indoline-3,2′-pyrrolidin]-2-one derivatives through base-promoted [3 + 2] cycloaddition reactions (Scheme 42) [60]. Interestingly, different configurations of products were obtained when different bases were used as catalysts. Whether Lewis base (PCy3) or Brøwns base (K2CO3) was used as the catalyst, both of them could obtain spiroheterocyclic derivatives (117 or 117′) with excellent diastereoselectivity in good yields. The difference is that the products obtained by the two catalytic reactions are diastereoisomers. Based on the experimental results and previous studies, two plausible catalytic mechanisms were proposed. When PCy3 was used as the catalyst, the phosphine catalyst first underwent nucleophilic addition with conjugated diene 116a to obtain the zwitterionic intermediate TS- 41 [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines with conjugated dienes.

Catalytic Diastereoselectic [3 + 3] Cycloaddition Reaction
A highly efficient diastereoselective [3 + 3] cycloaddition reaction of N-2,2,2trifluoroethylisatin ketimines 1 with N,N -dialkyloxyureas 118 was realized by the Zhao group in 2019 (Scheme 43) [61]. This reaction has a broad substrate scope and enables the synthesis of spiro-1,3,5-triazinan-2-one derivatives 119 with excellent diastereoselectivities (all >99:1 dr) in moderate to good yields (50-81%). Furthermore, the researchers proposed a possible catalytic mechanism based on the experimental results to elucidate the reaction. First, substrate 1 was deprotonated to form its ylide, TS-48, while substrate 118 was oxidized to afford its diaza-allyl cation, TS-49. The in situ-generated intermediate undergoes a [3 + 3] cycloaddition via two possible transition states to generate the product. However, there is a strong steric repulsion between the CF 3 and OR 3 groups in the transition state TS-51. Therefore, TS-50 was thermodynamically more stable and was dominated by the formation of trans-119.
A similar diastereoselective [3 + 5] cycloaddition reaction of trifluoroethylisatin ketimines 1 with vinyloxiranes 127 was established by the Zhou group in 2021 (Scheme 46) [66]. In the presence of Pd 2 (dba) 3 ·CHCl 3 , PPh 3, and 60% NaH, this reaction enables the synthesis of medium-heterocycle-fused spirooxindole compounds with excellent diastereoselectivities (all >20:1 dr) in moderate to good yields (52-87%). To explain the formation of the cis-products, the researchers proposed a possible catalytic reaction mechanism. First of all, the imine is deprotonated by NaH to provide the azomethine ylide TS-52, which readily resonates into its enolate TS-52 . At the same time, the ring-opening reaction of vinyloxirane 127 under the catalysis of the in situ-formed PdL n complex produces the Pd-π-allyl complex TS-53. Then, the generated enolate TS-52 attacks the zwitterionic Pd-π-allyl complex TS-53 via transition state TS-54 to provide intermediate TS-55. At this time, there are two possible pathways for the intermediate to deliver the cyclization products. However, due to the strong repulsion between CF 3 and benzene groups in the transition state TS-57, the transition state TS-56 is thermodynamically more stable, so the formation of cis-products dominates.

Conclusions
In summary, N-2,2,2-trifluoroethylisatin ketimines have been widely used in organocatalytic reactions as a 1,3-dipole, nucleophile, and synthetic "building block" containing trifluoromethyl groups with excellent activity. In order to facilitate readers' understanding, we classify them according to the two major parts of asymmetric catalysis and dia-

Conclusions
In summary, N-2,2,2-trifluoroethylisatin ketimines have been widely used in organocatalytic reactions as a 1,3-dipole, nucleophile, and synthetic "building block" containing trifluoromethyl groups with excellent activity. In order to facilitate readers' understanding, we classify them according to the two major parts of asymmetric catalysis and diastereoselective synthesis and refine them according to their reaction types. So far, researchers have mainly focused on the application of trifluoroethylketoimine in the [3 + 2] cycloaddition reaction, while the studies of [3 + 3], [3 + 4], and [3 + 5] cycloaddition are relatively limited. In particular, the application of developed synthetic methodologies to the synthesis of active drug molecules or complex natural products has rarely been reported. With the deepening of organic synthesis research, further exploration and expansion of trifluoroethylisatin ketimines in the construction of active drug molecules or their skeletons under the action of various types of organic catalysts and even its application in the synthesis of natural product molecules will become hot and challenging research topics in the future. We believe that in the near future, more and more unexpected organic synthesis methods involving trifluoroethylisatin ketimines will be established and applied to the construction of some important pharmaceutical skeletons.