Diastereoselective Formal 1,3-Dipolar Cycloaddition of Trifluoroethyl Amine-Derived Ketimines Enables the Desymmetrization of Cyclopentenediones

In this research, a metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones which can efficiently lead to the desymmetrization of cyclopentene-1,3-diones is developed. With the developed protocol, a series of tetracyclic spirooxindoles containing pyrrolidine and cyclopentane subunits can be smoothly obtained with good results (up to 99% yield and 91:9 dr). Furthermore, the methodology can be extended to trifluoromethyl-substituted iminomalonate, and the corresponding formal [3+2] cycloaddition reaction affords bicyclic heterocycles containing fused pyrrolidine and cyclopentane moieties in moderate yields with >20:1 dr. The synthetic potential of the methodology is demonstrated by the scale-up experiment and by versatile transformations of the products.


Optimization Studies
Initially, we selected the N-2,2,2-trifluoroethylisatin ketimine 1a and cyclopentene-1,3-dione 2a as model substrates for the optimization of reaction conditions. As shown in Table 1, to our delight, when using 1,1,3,3-tetramethylguanidine (TMG) as the base the reaction could proceed well in 1,2-dicholorethane (DCE) at 30 °C, providing the tetracyclic spirooxindole containing pyrrolidine and cyclopentane subunits 3aa in 73% yield with 81:19 dr (Table 1, entry 1). By screening different organic bases (Table 1,  , we found that DBU was the best candidate and that the corresponding cycloaddition product 3aa could be obtained in 87% yield with good diastereoselectivity (Table 1, entry 2). In the presence of the inorganic base CS2CO3, the reaction took place but yielded the cycloaddition product 3aa with poor results (only 30% yield and 71:29 dr) after 96 h (Table 1, entry 5). Next, different solvents, including toluene, THF, MeCN, and MeOH, were investigated, and it was found that DCE was the optimal solvent in terms of yield and diastereoselectivity (  13). By altering the ratio of substrates 1a:2a from 1.2:1 to 1.5:1, the isolated yield of product 3aa could be slightly improved to 92% (Table 1, entry 14). Finally, the product 3aa was obtained in 96% yield with 85:15 dr at 50 °C for 24 h by increasing the amount of DABCO from 1.0 equivalent to 1.5 equivalents (Table 1, entry 15). Scheme 1. 1,3-Dipolar cycloaddition reaction of trifluoroethyl amine-derived ketimines enabling the desymmetrization of cyclopentene-1,3-diones.

Optimization Studies
Initially, we selected the N-2,2,2-trifluoroethylisatin ketimine 1a and cyclopentene-1,3-dione 2a as model substrates for the optimization of reaction conditions. As shown in Table 1, to our delight, when using 1,1,3,3-tetramethylguanidine (TMG) as the base the reaction could proceed well in 1,2-dicholorethane (DCE) at 30 • C, providing the tetracyclic spirooxindole containing pyrrolidine and cyclopentane subunits 3aa in 73% yield with 81:19 dr (Table 1, entry 1). By screening different organic bases (Table 1,  , we found that DBU was the best candidate and that the corresponding cycloaddition product 3aa could be obtained in 87% yield with good diastereoselectivity (Table 1, entry 2). In the presence of the inorganic base CS 2 CO 3 , the reaction took place but yielded the cycloaddition product 3aa with poor results (only 30% yield and 71:29 dr) after 96 h (Table 1, entry 5). Next, different solvents, including toluene, THF, MeCN, and MeOH, were investigated, and it was found that DCE was the optimal solvent in terms of yield and diastereoselectivity (

Substrate Scope Studies
With the optimized reaction conditions in hand, we set out to investigate the substrate scope and generality of the metal-free diastereoselective formal 1,3-dipolar cycloaddition of different N-2,2,2-trifluoroethylisatin ketimines 1 and various cyclopentene-1,3-diones 2. First, the substrate scope of N-2,2,2-trifluoroethylisatin ketimines was explored; the results are shown in Scheme 2. The reaction system was applicable to different substituents (Me-, Et-, and allyl-) at the N1 position of the isatin-derived ketimines. These substrates were able to react smoothly with cyclopentene-1,3-dione 2a to afford the corresponding tetracyclic spirooxindoles 3ba-da in high yields and good diastereoselectivities (up to 96% yield and 90:10 dr). Furthermore, the introduction of an electron-withdrawing group, such as F-, Cl-, or Br-, into the oxindole skeleton of ketimines allowed these substrates to react effectively with 2a regardless of their different positions, resulting in the corresponding products 3ea-la in yields ranging from 62-91% with acceptable dr values. Moreover, the substrate with trifluoromethyl at the C7-position of the N-2,2,2-trifluoroethylisatin ketimine provided cycloaddition product 3ma in 69% yield with 83:17 dr. In addition, a variety of isatin-derived ketimines with electron-donating groups (-OMe and -Me) worked well, affording the corresponding products 3na-pa with good results (91-96% yields and 80:20-85:15 dr). Disubstituted substrate, such as 5,7-dimethyl-substituted trifluoroethylisatin ketimine, was successfully employed in this transformation under the standard conditions, generating product 3qa in 80% yield with 83:17 dr.

Substrate Scope Studies
With the optimized reaction conditions in hand, we set out to investigate the substrate scope and generality of the metal-free diastereoselective formal 1,3-dipolar cycloaddition of different N-2,2,2-trifluoroethylisatin ketimines 1 and various cyclopentene-1,3-diones 2. First, the substrate scope of N-2,2,2-trifluoroethylisatin ketimines was explored; the results are shown in Scheme 2. The reaction system was applicable to different substituents (Me-, Et-, and allyl-) at the N1 position of the isatin-derived ketimines. These substrates were able to react smoothly with cyclopentene-1,3-dione 2a to afford the corresponding tetracyclic spirooxindoles 3ba-da in high yields and good diastereoselectivities (up to 96% yield and 90:10 dr). Furthermore, the introduction of an electron-withdrawing group, such as F-, Cl-, or Br-, into the oxindole skeleton of ketimines allowed these substrates to react effectively with 2a regardless of their different positions, resulting in the corresponding products 3ea-la in yields ranging from 62-91% with acceptable dr values. Moreover, the substrate with trifluoromethyl at the C7-position of the N-2,2,2-trifluoroethylisatin ketimine provided cycloaddition product 3ma in 69% yield with 83:17 dr. In addition, a variety of isatinderived ketimines with electron-donating groups (-OMe and -Me) worked well, affording the corresponding products 3na-pa with good results (91-96% yields and 80:20-85:15 dr). Disubstituted substrate, such as 5,7-dimethyl-substituted trifluoroethylisatin ketimine, was successfully employed in this transformation under the standard conditions, generating product 3qa in 80% yield with 83:17 dr.
Next, a range of differently substituted cyclopentenediones 2 were examined by reaction with N-2,2,2-trifluoroethylisatin ketimine 1a to further explore the substrate scope of the 1,3-dipolar cycloaddition reaction (Table 2). With electron-donating groups such as methyl and methoxy on the phenyl moiety of 2-benzyl-2-methylcyclopentenediones 2, the reactions afforded cycloaddition products 3ab-ad in almost quantitative yields (94-96%), with good diastereoselectivities (up to 85:15 dr) in the reaction with N-2,2,2trifluoroethylisatin ketimine 1a ( Table 2, entries 1-3). Similarly, the reaction system showed good compatibility with cyclopentenediones with different electron-withdrawing groups (such as F-, Cl-and Br-) on the phenyl moiety, as demonstrated by the synthesis of cycloaddition products 3ae-ai in good to excellent yields and high diastereoselectivities ( Table 2, entries 4-8). Meanwhile, when the aromatic ring of the benzyl group of 2 was substituted with bulky naphthyl groups, the reactions furnished the corresponding tetracyclic spirooxindoles 3aj and 3ak in 98% yield with 89:11 dr and 99% yield with 86:14 dr, respectively (Table 2, entries 9 and 10). In addition, the change of the R 2 group of cyclopentenediones from methyl to ethyl was tolerated by the reaction system, providing efficient access to products 3al-an with acceptable results (up to 88% yield and 88:12 dr) (  Next, a range of differently substituted cyclopentenediones 2 were examined by reaction with N-2,2,2-trifluoroethylisatin ketimine 1a to further explore the substrate scope of the 1,3-dipolar cycloaddition reaction (Table 2). With electron-donating groups such as methyl and methoxy on the phenyl moiety of 2-benzyl-2-methylcyclopentenediones 2, the reactions afforded cycloaddition products 3ab-ad in almost quantitative yields (94-96%), with good diastereoselectivities (up to 85:15 dr) in the reaction with  N-2,2,2-trifluoroethylisatin ketimine 1a (Table 2, entries 1-3). Similarly, the reaction system showed good compatibility with cyclopentenediones with different electron-withdrawing groups (such as F-, Cl-and Br-) on the phenyl moiety, as demonstrat-  of the R 2 group of cyclopentenediones from methyl to ethyl was tolerated by the reaction system, providing efficient access to products 3al-an with acceptable results (up to 88% yield and 88:12 dr) (  Having established the general scope of the metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 and diverse cyclopentene-1,3-diones 2, we next attempted the formal 1,3-dipolar cycloaddition of trifluoromethyl-substituted iminomalonate 4 and cyclopentenediones 2 through a desymmetrization strategy. As illustrated in Scheme 3, using Cs2CO3 as a catalyst in DCE at room temperature for 16 h, the reaction of 2-benzyl-2-methylcyclopentenedione 2a and trifluoromethyl-substituted iminomalonate 4 proceeded well, providing the desired bicyclic heterocyclic product 5a in 57% yield with >20:1 dr. The generality of this transformation of various cyclopentene-1,3-diones 2 and trifluoromethyl-substituted iminomalonate 4 was then investigated, and it was found that all reactions resulted in the corresponding cyclization products with excellent diastereoselectivities (all cases > 20:1 dr) (Scheme 3). As cyclopentenediones bearing different electron-donating substituents such as methyl and methoxyl on the phenyl, these substrates worked well in the reaction with trifluoromethyl-substituted iminomalonate 4 under the standard conditions, providing the desired cycloaddition products 5b-d in moderate yields (42-54% yield). Likewise, cyclopentenediones with various electron-withdrawing substituents (F-, Cl, and Br-) on the phenyl ring, regardless of the position, were compatible with the catalytic system in the reaction with 4, affording the desired cycloaddition products 5e-g in yields ranging from 44-60%. Cyclopentenedione substrates bearing a sterically hindered naphthyl group proceeded successfully as well, yielding the corresponding bicyclic heterocycle products 5h and 5i in 59% and 50% yield, respectively. The structure and the relative configuration of product 5a was unambiguously determined by single-crystal X-Ray Having established the general scope of the metal-free diastereoselective formal 1,3dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines 1 and diverse cyclopentene-1,3-diones 2, we next attempted the formal 1,3-dipolar cycloaddition of trifluoromethylsubstituted iminomalonate 4 and cyclopentenediones 2 through a desymmetrization strategy. As illustrated in Scheme 3, using Cs 2 CO 3 as a catalyst in DCE at room temperature for 16 h, the reaction of 2-benzyl-2-methylcyclopentenedione 2a and trifluoromethylsubstituted iminomalonate 4 proceeded well, providing the desired bicyclic heterocyclic product 5a in 57% yield with >20:1 dr. The generality of this transformation of various cyclopentene-1,3-diones 2 and trifluoromethyl-substituted iminomalonate 4 was then investigated, and it was found that all reactions resulted in the corresponding cyclization products with excellent diastereoselectivities (all cases > 20:1 dr) (Scheme 3). As cyclopentenediones bearing different electron-donating substituents such as methyl and methoxyl on the phenyl, these substrates worked well in the reaction with trifluoromethyl-substituted iminomalonate 4 under the standard conditions, providing the desired cycloaddition products 5b-d in moderate yields (42-54% yield). Likewise, cyclopentenediones with various electron-withdrawing substituents (F-, Cl, and Br-) on the phenyl ring, regardless of the position, were compatible with the catalytic system in the reaction with 4, affording the desired cycloaddition products 5e-g in yields ranging from 44-60%. Cyclopentenedione substrates bearing a sterically hindered naphthyl group proceeded successfully as well, yielding the corresponding bicyclic heterocycle products 5h and 5i in 59% and 50% yield, respectively. The structure and the relative configuration of product 5a was unambiguously determined by single-crystal X-ray analysis, and the configurations of all other products in Scheme 3 were assigned by analogy due to their formation through a common reaction pathway [45].
Molecules 2023, 28, x FOR PEER REVIEW analysis, and the configurations of all other products in Scheme 3 were assi analogy due to their formation through a common reaction pathway [45]. Scheme 3. Substrate scope investigation of 1,3-dipolar cycloaddition of trifluoromethyl-su iminomalonate and different cyclopentenediones. The dr values were determined by analysis of the crude product. The yields refer to isolated yields as a mixture of diastereoi

Scale-Up Experiment and Versatile Transformations of the Products
In order to demonstrate the synthetic potential and utility of the metal-f stereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin k and cyclopentene-1,3-diones, a gram-scale experiment between 1a and 2a was out under standard reaction conditions, which was 25-fold larger than the sca model reaction. As shown in Scheme 4, the reaction was able to proceed to comp 50 °C after 24 h in DCE, smoothly providing product 3aa in 90% yield with 84:16 structure and the relative configuration of the product 3aa were unambiguous mined by single-crystal X-ray analysis. Assuming a common reaction pathway, tive configuration of the other products in Scheme 2 and Table 2 was assigned b gy [45]. Next, various transformations of the products to other heterocyclic com were investigated. When 3aa was treated with NaBH4 in MeOH for 4 h, the re product 6 was obtained in 86% yield with 83:17 dr. The structure and relative co tion of product 6 were determined with certainty by NMR and NOESY spe Supporting Information). The treatment of 3aa with m-CPBA in CH2Cl2 for 48 h g to the formation of the hydroxylamine product 7 in 42% yield with >20:1 dr. In a product 8 was obtained with acceptable results from 3aa with (CH2O)n and NaB the mixed solvents of MeOH and THF at 50 °C for 48 h. Notably, the structure uct 8 was unambiguously determined by single-crystal X-Ray analysis [45]. Ult the Suzuki coupling reaction between 3ka and phenylboronic acid was conducte mol % Pd(PPh3)4 as the catalyst to afford the product 9 in 91% yield with >20:1 dr Scheme 3. Substrate scope investigation of 1,3-dipolar cycloaddition of trifluoromethyl-substituted iminomalonate and different cyclopentenediones. The dr values were determined by 1 H NMR analysis of the crude product. The yields refer to isolated yields as a mixture of diastereoisomers.

Scale-Up Experiment and Versatile Transformations of the Products
In order to demonstrate the synthetic potential and utility of the metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones, a gram-scale experiment between 1a and 2a was carried out under standard reaction conditions, which was 25-fold larger than the scale of the model reaction. As shown in Scheme 4, the reaction was able to proceed to completion at 50 • C after 24 h in DCE, smoothly providing product 3aa in 90% yield with 84:16 dr. The structure and the relative configuration of the product 3aa were unambiguously determined by single-crystal X-ray analysis. Assuming a common reaction pathway, the relative configuration of the other products in Scheme 2 and Table 2 was assigned by analogy [45]. Next, various transformations of the products to other heterocyclic compounds were investigated. When 3aa was treated with NaBH 4 in MeOH for 4 h, the reduction product 6 was obtained in 86% yield with 83:17 dr. The structure and relative configuration of product 6 were determined with certainty by NMR and NOESY spectra (see Supporting Information). The treatment of 3aa with m-CPBA in CH 2 Cl 2 for 48 h gave rise to the formation of the hydroxylamine product 7 in 42% yield with >20:1 dr. In addition, product 8 was obtained with acceptable results from 3aa with (CH 2 O) n and NaBH 3 CN in the mixed solvents of MeOH and THF at 50 • C for 48 h. Notably, the structure of product 8 was unambiguously determined by single-crystal X-ray analysis [45]. Ultimately, the Suzuki coupling reaction between 3ka and phenylboronic acid was conducted with 5 mol % Pd(PPh 3 ) 4 as the catalyst to afford the product 9 in 91% yield with >20:1 dr.

Proposed Mechanism for the 1,3-Dipolar Cycloaddition Reaction Accompanied by Desymmetrization Process
Based on our experimental results and previous related reports [30][31][32][33], a p catalytic mechanism involving a stepwise reaction process was assumed to exp stereoselectivity of the 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ke and cyclopentene-1,3-diones. As depicted in Scheme 5, the N-2,2,2-trifluoroeth ketimine 1 is deprotonated under a basic condition to yield the 2-azaallyl anion i diate I. As illustrated in transition state II, the α-carbon anion of intermedia proaches the carbon-carbon double bond of cyclopentene-1,3-diones, resulting tion of the intermediate III. Subsequently, intramolecular cyclization from the anion to the C=N of azomethine-ylide occurs, delivering the intermediate IV, w protonated to form products 3.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin-layer chromatography (TLC). 1 H NMR and 13 C NMR spectra were recorded in CDCl3 and DMSO-d6. 1 H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS), with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS), with the solvent resonance as the internal standard (CDCl3 at 77.20 ppm, DMSO-d6 at 39.52 ppm). Melting points of the products were recorded on a Büchi Melting Point B-545. The HRMS were recorded by The HRMS were recorded using an Agilent 6545 LC/Q-TOF mass spectrometer. Table 2) N-2,2,2-trifluoroethylisatin ketimines 1 (0.3 mmol) and DABCO (33.6 mg, 0.3mmol, 1.5 equiv.) were added to a solution of cyclopentene-1,3-diones 2 (40.2 mg, 0.2 mmol, 1.0 equiv.) in DCE (2.0 mL), then the mixture was stirred for 24 h at 50 °C. After completion, the reaction mixture was directly purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 15:1-10:1) to yield the corresponding products 3.

General Information
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin-layer chromatography (TLC). 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 and DMSO-d 6 . 1 H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS), with the solvent resonance employed as the internal standard (CDCl 3 at 7.26 ppm, DMSO-d 6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), and integration. 13 C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS), with the solvent resonance as the internal standard (CDCl 3 at 77.20 ppm, DMSO-d 6 at 39.52 ppm). Melting points of the products were recorded on a Büchi Melting Point B-545. The HRMS were recorded by The HRMS were recorded using an Agilent 6545 LC/Q-TOF mass spectrometer.

Procedure for the Synthesis of Compound 9
To an oven-dried Schlenk tube, 3ak (119.2 mg, 0.20 mmol), PhB(OH) 2 (36.6 mg, 0.30mmol), and Cs 2 CO 3 (130.4 mg, 0.40 mmol) were combined and then the mixture solvents ethanol (0.4 mL) and toluene (2.0 mL) were added to the reaction tube. The reaction mixture was stirred at 120 • C under N 2 atmosphere for 12 h. The heat source was an oil bath. When the mixture was cooled to room temperature, the brine (10 mL) was added to quench the reaction. The aqueous layer was extracted with DCM (2×10.0 mL) and the combined organic layers were dried over anhydrous Na 2 SO 4 . After filtration, the organic phase was concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 15:1) to afford product 9 as a white solid (108.1 mg, 91% yield).

Conclusions
In conclusion, we have developed a highly diastereoselective formal 1,3-dipolar cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones that affords a series of tetracyclic spirooxindoles with good results (up to 96% yield and 91:9 dr). This reaction can lead to the desymmetrization of cyclopentene-1,3-diones, and provides an efficient method for constructing tetracyclic spirooxindoles containing fused pyrrolidine-cyclopentane subunits, which could be useful in the development of new pharmaceuticals. In addition, this 1,3-dipolar cycloaddition reaction could be extended to trifluoromethyl-substituted iminomalonate for the synthesis of bicyclic heterocycles bearing fused pyrrolidine-cyclopentane moieties in moderate yields with >20:1 dr under mild conditions. The potential applications of the protocol have been demonstrated by performing the gram-scale reaction and versatile transformations of the products. We believe that these novel compounds based on fused pyrrolidine-cyclopentane scaffolds can provide novel therapeutic agents and useful biological tools for the research and development of new drugs. Efforts toward the development of a catalytic asymmetric version of this 1,3-dipolar cycloaddition reaction and the application of this strategy to synthesize more promising drug discovery candidates, as well as the biological evaluation of these compounds, are currently underway in our laboratory.