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

Abstract

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.

1. 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 (CF₃) 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.

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.

2. 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.

2.1. Catalytic Asymmetric Reaction of Trifluoroethyl Isatin Ketimines

2.1.1. Organocatalytic Asymmetric [3 + 2] Cycloaddition Reaction

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.

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 reaction in high yields (70–95%) with excellent diastereo- and enantioselectivities (all >20:1 dr and 94–>99% ee). In order to increase the practicability of the product, the adduct 5a was reduced to its amino derivative 6 in a 64% yield by using NiCl₂·6H₂O and NaBH₄ in methanol, and its stereoselectivity was maintained. In order to better clarify the reaction, the researchers gave a possible reaction mechanism. As shown in Scheme 3, the squaramide catalyst plays a dual activation role. The ketamine 1a combines with the tertiary amine moiety of the catalyst to form a five-membered ring, and the nitroalkene 4a is simultaneously fixed and activated by the N-H bond of the squaramide. Subsequently, the product 5a with a specific configuration was formed after two Re-face attacks, and the catalytic cycle was completed.

An efficient, highly asymmetric [3 + 2] cycloaddition reaction catalyzed by the thiourea-tertiary 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.

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.

An efficient asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with rhodamine derivatives 14 was described by the Du group in 2018 (Scheme 7) [23]. This asymmetric reaction proceeded well with 5 mol% bifunctional cinchona-derived squaramide catalyst C7 to give CF₃-containing bispiro heterocyclic compounds 15 in high yields (65–99%) with good diastereo- and enantioselectivities (86:14–>99:1 dr and 57–>99% ee). Based on the experimental results and the absolute configuration of the products, the researchers proposed a possible transition state model for this catalytic cycle. Furthermore, the feasibility of this method was proven by the preparation of the gram scale. At the same time, the practicability of this method was proven by the derivative transformation reaction of the product. Treatment of product 15a with CH₃I and NaH in DMF afforded its methylated derivative 15b a 96% yield while maintaining its stereoselectivity. Treatment of the heterocyclic product 15c with CrO₃ in AcOH can readily oxidize its thiocarbonyl group to an oxycarbonyl group.

In 2018, Yuan and co-workers presented bifunctional squaramide-catalyzed [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines with β-trifluoromethyl electron-deficient alkenes (Scheme 8) [24]. Under the catalysis of cinchona base-derived squaramide, the vicinally bis(trifluoromethyl)-substituted 3,2′-pyrrolidinyl spirooxindoles with excellent stereoselectivities (all >20:1 dr and 92–>99% ee) can be obtained in good yields (75–99%) using β-trifluoromethyl enones as electron-deficient alkenes. Notably, under the catalysis of cyclohexanediamine-derived squaramide, a series of vicinally bis(trifluoromethyl)-substituted 3,2′-pyrrolidinyl spirooxindoles with four contiguous stereocenters, including two vicinal spiro-quaternary chiral center atoms, can be obtained in high yields (78–99%) with excellent diastereoselectivities (all >20:1 dr) and enantioselectivities (87–95% ee) by using 3-trifluoroethylidene oxindole and 3-trifluoroethylidene benzofuranone as substrates. In addition, the practicability of this method is proved by the derivation experiment. Treatment of product 18a with NaBH₄ in methanol afforded the tertiary alcohol derivative 21 in a 99% yield without loss of its stereoselectivity.

Subsequently, Lu and co-workers also reported the asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 to 3-(trifluoroethylidene)oxindoles 19′ catalyzed by squaramide C10 (Scheme 9) [25]. This process enables the preparation of highly functionalized vicinally bis(trifluoromethyl)-substituted 3,3′-pyrrolidinyl spirooxindoles 20′ in excellent yields (85–99%) with excellent diastereo- and enantioselectivities (all >20:1 dr and 80–99% ee).

In 2019, Du and co-workers established an efficient organocatalytic asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with arylidene azlactones 22 (Scheme 10) [26]. Under mild conditions, this reaction can easily obtain CF₃-containing 3,2′-pyrrolidinyl spirooxindole derivatives 23 with excellent diastereoselectivities (all >20:1 dr) and enantioselectivities (78–99% ee) in moderate to excellent yields (60–99%). It is worth noting that CF₃-containing 3,2′-pyrrolidinyl dispirooxindole derivatives 24 with excellent diastereo- and enantioselectivities (all >20:1 dr and 92–>99% ee), can be obtained in high yields (66–83%) by slightly changing the reaction conditions.

The thiourea-catalyzed asymmetric [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with aurones 25 was developed by the Yan group in 2019 (Scheme 11) [27]. This process enables the construction of a novel spiro [benzofuran-pyrrolidine-oxindole] skeleton with excellent diastereoselectivities (all >20:1 dr) and good enantioselectivities (2–>99% ee) in moderate to excellent yields (27–99%). In addition, researchers described a possible catalytic reaction model. The researchers believe that under the dual activation, the reactants undergo intermolecular Michael addition and intramolecular Mannich reaction to deliver cyclization products.

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(Si-face)/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).

An alternative method for enantioselective synthesis of CF₃-containing spirooxindoles via [3 + 2] cycloaddition between N-2,2,2-trifluoroethylisatin ketimines 1 and 2,3-dioxopyrrolidines 27 was developed by the Wang group in 2020 (Scheme 13) [29]. The researchers developed a class of chiral bifunctional quaternary phosphonium phase transfer catalysts (C14) based on chiral dipeptides and successfully applied them to this reaction. Under mild reaction conditions, this reaction can obtain CF₃-containing 3,2′-pyrrolidinyl spirooxindole derivatives with excellent stereoselectivities (all >20:1 dr and 68–94% ee) in excellent yields (82–99%). In addition, the researchers confirmed through controlled experiments that chiral quaternary phosphonium salts activate substrates and control stereoselectivity through a synergistic ion-pair/H-bonding effect (TS-11, TS-12).

In 2019, Du and co-workers synthesized structurally novel cinnamoyl-3-ylideneoxindoles 31 and successfully applied them in a one-pot, three-component cascade reaction (Scheme 14) [30]. By using a quinine-derived bifunctional squaramide catalyst C15, a variety of CF₃-containing bispirooxindole-spirooxindoles 33 with seven stereocenters were synthesized in high yields (82–95%) with excellent diastereo- and enantioselectivities (8:1–>20:1 dr and 97–99% ee). Furthermore, the comprehensive practicability of this asymmetric catalytic process was further demonstrated by the gram-scale preparation and derivative transformation experiments of product 33a. Product 33a was readily reacted with iodomethane under mild conditions to give another family of bispirooxindole-spirooxindole analogues, 34, with excellent enantioselectivity (98% ee) in 91% yield.

In 2019, Yan and co-workers presented squaramide-catalyzed asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with α,β-unsaturated pyrazolones 35 (Scheme 15) [31]. A series of novel spiro-oxindole-pyrrolidine-pyrazolone derivatives 36 with excellent diastereoselectivities (all >20:1 dr) and moderate to excellent enantioselectivities (42–96% ee) were synthesized in high yields (66–94%) under mild conditions. In addition, the researchers also described the dual activation mechanism involved in the reaction in detail.

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 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 [3 + 2] 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 2019, Ye and co-workers reported the use of chiral primary amine C20 as a catalyst to catalyze the remote regioselective asymmetric [3 + 2] cycloaddition reaction between N-2,2,2-trifluoroethyl isatin ketimines 1 and cyclic 2,4-dienones 45 (Scheme 18) [34]. This asymmetric cascade reaction can construct a series of chiral pyrrolidine spirocyclic indole derivatives 46 with good to excellent diastereo- and enantioselectivities (3:1–>19:1 dr and 82–95% ee) in high yields (26–95%).

Hydroquinine-derived organocatalysts catalyzed the asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with 5-alkenyl thiazolones 47, as disclosed by the Jiang group in 2020 (Scheme 19) [35]. This method synthesized a series of novel pyrrolidinyl spirooxindole derivatives 48 with excellent stereoselectivities (all >20:1 dr and 86–98% ee) in moderate to excellent yields (62–98%). Interestingly, optically pure products 48 or their racemates can easily undergo configuration conversion under acidic conditions to obtain their diastereoisomers 48′ with high stereoselectivity. The researchers believe that the product 39 undergoes retro-Mannich synthesis under acidic conditions to generate the intermediate TS-15, delivering the sterically advantageous 48′ as the only product.

In 2020, Han and co-workers described the squaramide-catalyzed asymmetric [3 + 2] 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.

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 CF₃-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.

Subsequently, Wang’s group reported a similar reaction for binuclear zinc-catalyzed enantioselective dearomatization [3 + 2] cycloaddition [38]. This strategy provides a series of 2,3-fused dihydrobenzofuran (or dihydrobenzothiophene) derivatives with excellent diastereoselectivities and enantioselectivities in high yields under mild conditions.

In 2021, Knipe and co-workers established the organocatalytic asymmetric [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with benzylidenemalononitriles 56 catalyzed by a cinchona-derived thiourea catalyst C24 (Scheme 22) [39]. Under mild conditions, this reaction can provide a series of functionalized spiro-pyrrolidinoxindole derivatives with three to four chiral centers in high yields (67–98%) with good diastereo- and enantioselectivities (2:1–>100:1 dr and 73–97% ee). In addition, the researchers also tried the asymmetric cycloaddition reaction of isatin-derived ketimines 1b and benzylidene-indanediones 58 under the same reaction conditions. The experimental results showed that no matter whether indenedione or indanone was used as the substrate, the bisspirooxindole derivative could be constructed with moderate yield and diastereoselectivity. Unfortunately, the enantioselectivity of indanone-based products has not been determined.

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 CF₃-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).

2.1.2. Organocatalytic Asymmetric [3 + 4] Cycloaddition Reaction

In 2021, Chen and co-workers developed a highly asymmetric [3 + 4] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 and α-vinylenals 65 catalyzed by prolinol silyl ethers C25 (Scheme 24) [41]. Under optimal conditions, a series of CF₃-containing spirooxindole derivatives 66 incorporating an azepane motif were synthesized with excellent stereoselectivities (all >19:1 dr and 80–96% ee) and high yields (60–90%). In addition, the α,β-unsaturated aldehyde moiety of the cyclization product 66a can undergo a [3 + 3] cycloaddition reaction with cyclohexane-1,3-dione 67 under mild conditions and construct a more complex product 68 in 87% yield without losing its stereoselectivity.

2.1.3. Catalytic Asymmetric Reaction of Trifluoroethylisatin Ketimines as Nucleophilic Reagent

A highly efficient asymmetric S_N2′-S_N2′ 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_N2′ process to remove a molecule of CO₂ and a tert-butanol anion. Isatinketimine was deprotonated and activated by the tert-butanol anion, and it takes place in another S_N2′ 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 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.

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 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. Based on the experimental results, the researchers proposed a possible transition state model (TS-23).

2.2. Catalytic Racemization Reaction of Trifluoroethyl Isatin Ketimines

2.2.1. 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 CF₃-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 CF₃-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 vinylpyridine TS-24 and intermediate TS-25. Then the intermolecular Michael addition reaction occurs to produce the intermediate TS-26. The intermediate TS-27 was obtained by the intramolecular Mannich reaction of carbanion attacking the imine moiety of 1b from Re-face. Finally, the intermediate TS-27 undergoes intramolecular proton transfer 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/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.

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.

In 2019, Shi and co-workers presented a phosphine-catalyzed [3 + 2] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with γ-substituted allenoates 96 (Scheme 34) [51]. This reaction can construct spiro[indoline-3,2′-pyrrole] skeleton compounds 97 in moderate to good yields (35–85%) with acceptable diastereoselectivities (1:1–4:1 dr) in the presence of triphenylphosphine. In addition, researchers proposed a possible mechanism for this novel [3 + 2] cycloaddition reaction catalyzed by phosphine. First, the phosphine catalyst attacks the β-position of allenoates 96a to eliminate the acetate group to generate intermediate TS-28. Then, substrate 1a was deprotonated by the generated ⁻OAc to obtain intermediate TS-29, which further underwent an intermolecular Michael addition reaction with intermediate TS-28 to generate intermediate TS-30. Subsequently, the intermediate undergoes an intramolecular Mannich reaction to form intermediate TS-31, which is transferred by protonation to obtain intermediate TS-32. Finally, the desired product is produced, and the catalyst is regenerated, completing the catalytic cycle.

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.

In 2021, Huang and co-workers realized a highly diastereoselective [3 + 2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with styrylisoxa-zoles 100 (Scheme 36) [53]. A series of CF₃-containing 3′-(nitroisoxazol)spiro [pyrrolidin-3,2′-oxindole] derivatives 101 with excellent diastereoselectivities (all >20:1 dr) were obtained in good to excellent yields (76–93%) under mild conditions. In addition, the comprehensive practicality of this catalytic reaction is demonstrated by gram-scale preparation and derivatization experiments. Treatment of the adduct with Zn and HCl in DCM/EtOH (1:6) could reduce it to the amino derivative 102 with an 80% yield. When the adduct was treated with HCl and SnCl₂ in THF/H₂O (1:1), the ring-opened product 103 could be obtained with a 75% yield. Either strategy does not affect its diastereoselectivity.

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 spiro-fused[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 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.

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 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.

A new strategy for the synthesis of trifluoromethyl bispiro-[oxindole-pyrrolidine-chromanone] 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 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.

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. Then intermediate TS-41 attacks the trifluoroethylisatin ketimine 1a from a specific direction to undergo a nucleophilic addition reaction to generate intermediate TS-43. Finally, intermediate TS-44 undergoes the S_N2 substitution reaction to form the desired product endo-117a and regenerates the phosphine catalyst. However, when K₂CO₃ was used as the Brønsted base, substrate 1a was deprotonated to form the intermediate TS-45. Then an intermolecular Michael addition reaction with conjugated dienes was carried out to afford intermediate TS-46. Subsequently, the intramolecular Mannich reaction and protonation reaction occurred to produce the corresponding product, exo’-117a, and regenerate the catalyst.

2.2.2. Catalytic Diastereoselectic [3 + 3] Cycloaddition Reaction

A highly efficient diastereoselective [3 + 3] cycloaddition reaction of N-2,2,2-trifluoroethylisatin 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 CF₃ and OR³ groups in the transition state TS-51. Therefore, TS-50 was thermodynamically more stable and was dominated by the formation of trans-119.

In 2021, Ko and co-workers reported a one-pot process of umpolung allylation/aza-Prins cyclization of N-2,2,2-trifluoroethylisatin ketimines 1 with allyl bromide (Scheme 44) [62]. This reaction enables the reaction with allyl bromide 120 at lower temperatures to synthesize spiro[indoline-3,2′-piperidin]-2-one derivatives 121 in moderate to excellent yields (36–99%). However, this reaction with a substituted allyl bromide 122 enables the synthesis of 5′,6′-dihydro-1′H-spiro[indoline-3,2′-pyridin]-2-one derivatives 123 in moderate yields (12–74%) at elevated temperatures. This reaction is the first reported aza-Prins cyclization, taking advantage of the umpolung property of N-2,2,2-trifluoroethylisatin ketimines.

Remarkably, this study was not compatible with TMSX (X=Cl, I, etc.) in the one-pot method. To solve this problem, Ko’s group also developed a step-by-step process based on this study in the same year that overcame the limitations of the one-pot method and successfully performed the [3 + 3] aza-Prins cyclization reaction with TMSX (X=Cl, I, etc.) [63].

2.2.3. Catalytic Diastereoselectic [3 + 5] Cycloaddition Reaction

An efficient Pd-catalyzed diastereoselective formal [3 + 5] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 with aryl substituted vinylethylene carbonates (VECs) 124 was disclosed by the Shi group in 2019 (Scheme 45) [64]. This reaction exhibits good substrate tolerance in the presence of Brønsted acid and constructs CF₃-containing spirooxindole derivatives fused with an eight-membered ring in high yields (27–85%). The researchers tried using t-Bu-RuPhos as a chiral phosphine ligand, and the asymmetric reaction synthesized a chiral spiro compound 125′ with 63% ee in 80% yield. In addition, the adduct 125a treated with m-chloroperoxybenzoic acid (m-CPBA) in DCM can be converted into the spiroxyindole derivative 126 with a 63% yield.

Subsequently, Zhao and co-workers also presented a diastereoselective [3 + 5] cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines 1 with VECs 119 [65]. Differently from before, the reaction was carried out under the catalyst system of Pd(PPh₃)₄, PPh₃, and pyridine. However, this catalytic system enables the synthesis of the desired product with excellent diastereoselectivities (all >20:1 dr) and good to excellent yields (75–97%).

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 Pd₂(dba)₃·CHCl₃, 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 CF₃ 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.

3. 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.