Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles

N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76–95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.


Results and Discussion
In this study, we describe a substrate-controlled 1,3-dipolar cycloaddition reaction of isatins 5, α-amino acids (6), and 1,4-enedione derivatives to access divergent N-fused pyrrolidinyl spirooxindoles. To establish the feasibility of this strategy, as well as to optimize the reaction conditions, the three-component reaction of isatin 5a (0.5 mmol), L-proline (6a, 0.6 mmol), and N-ethylmaleimide (11a, 0.6 mmol) was selected as the model reaction (Table 1). Initially, the model reaction was performed in a range of organic solvents

Results and Discussion
In this study, we describe a substrate-controlled 1,3-dipolar cycloaddition reaction of isatins 5, α-amino acids (6), and 1,4-enedione derivatives to access divergent N-fused pyrrolidinyl spirooxindoles. To establish the feasibility of this strategy, as well as to optimize the reaction conditions, the three-component reaction of isatin 5a (0.5 mmol), L-proline (6a, 0.6 mmol), and N-ethylmaleimide (11a, 0.6 mmol) was selected as the model reaction (Table 1). Initially, the model reaction was performed in a range of organic With the optimal reaction conditions in hand, we then explored the scope of this three-component 1,3-dipolar cycloaddition reaction. Initially, an array of maleimides (11) were fixed as dipolarophiles to test a variety of isatin-derived azomethine ylides generated in situ from isatins (5) and α-amino acids (6), the results of which are presented in Scheme 2. Under the optimized conditions, this three-component 1,3-dipolar cycloaddition reaction was tolerated by all the tested isatins (5), α-amino acids (6), and maleimides (11) bearing various different electron properties and substitution patterns, affording the corresponding products (7) in 76-95% yields with excellent diastereoselectivities (17:1-> 99:1 dr). For the isatins (5), the aromatic ring bearing either electron-donating (Me, OMe) or electron-withdrawing functional groups (F, Cl, Br, NO 2 ) and the various N-substituted groups (R 2 ) could form the target products in high yields with excellent diastereoselectivities (up to >99:1 dr) (7a-7k). For the substitution patterns of isatins (5), 5-substitution and 6-substitution were proven to be the preferred substitution position (87-95% yields) compared with 7-substitution (76-79% yields). The results clearly show that the types of N-hydrocarbyl of maleimides (11) and α-amino acids (6) have no obvious effect on the reaction efficiency and diastereoselectivities (7l-7y). D-proline was also employed and led to high-purity 7a in 91% yield. Furthermore, the structure and relative configuration of product 7a (CCDC 2201643) were unequivocally established by X-ray crystallographic analysis.
With the optimal reaction conditions in hand, we then explored the scope of this three-component 1,3-dipolar cycloaddition reaction. Initially, an array of maleimides (11) were fixed as dipolarophiles to test a variety of isatin-derived azomethine ylides generated in situ from isatins (5) and α-amino acids (6), the results of which are presented in Scheme 2. Under the optimized conditions, this three-component 1,3-dipolar cycloaddition reaction was tolerated by all the tested isatins (5), α-amino acids (6), and maleimides (11) bearing various different electron properties and substitution patterns, affording the corresponding products (7) in 76-95% yields with excellent diastereoselectivities (17:1-> 99:1 dr). For the isatins (5), the aromatic ring bearing either electron-donating (Me, OMe) or electron-withdrawing functional groups (F, Cl, Br, NO2) and the various N-substituted groups (R 2 ) could form the target products in high yields with excellent diastereoselectivities (up to >99:1 dr) (7a-7k). For the substitution patterns of isatins (5), 5-substitution and 6-substitution were proven to be the preferred substitution position (87-95% yields) compared with 7-substitution (76-79% yields). The results clearly show that the types of Nhydrocarbyl of maleimides (11) and α-amino acids (6) have no obvious effect on the reaction efficiency and diastereoselectivities (7l-7y). D-proline was also employed and led to high-purity 7a in 91% yield. Furthermore, the structure and relative configuration of product 7a (CCDC 2201643) were unequivocally established by X-ray crystallographic analysis.

Scheme 2.
The synthesis of product 7: a All reactions were carried out with isatins 5 (0.5 mmol), aamino acids (6, 0.6 mmol) and maleimides 11 (0.6 mmol) in EtOH (3 mL) at room temperatures for 4 h. Isolated or recrystallizated yields based on isatin 5a and all >25:1 dr (except for 7c and 7s) by 1 H NMR analysis. b D-proline was used instead of 6a. c 20:1 dr. d 17:1 dr. Encouraged by the above results, we further screened different types of 1,4-enedione derivatives as dipolarophiles. When various methylene indolinones (12) were employed, this three-component 1,3-dipolar cycloaddition reaction occurred smoothly and afforded the corresponding products (8) in 85-94% yields with excellent diastereoselectivities (17:1-Scheme 2. The synthesis of product 7: a All reactions were carried out with isatins 5 (0.5 mmol), a-amino acids (6, 0.6 mmol) and maleimides 11 (0.6 mmol) in EtOH (3 mL) at room temperatures for 4 h. Isolated or recrystallizated yields based on isatin 5a and all >25:1 dr (except for 7c and 7s) by 1 H NMR analysis. b D-proline was used instead of 6a. c 20:1 dr. d 17:1 dr. Encouraged by the above results, we further screened different types of 1,4-enedione derivatives as dipolarophiles. When various methylene indolinones (12) were employed, this three-component 1,3-dipolar cycloaddition reaction occurred smoothly and afforded the corresponding products (8) in 85-94% yields with excellent diastereoselectivities (17:1->99:1 dr) (Scheme 3a). It is worth noting that the 7-substitution pattern and steric hindrance of isatins (5) had no significant effect on the reaction efficiency and diastereoselectivities. Based on this 1,3-dipolar cycloaddition reaction, a series of complex N-fused pyrrolidinyl-dispirooxindoles (8) bearing two spiro-quaternary centers were obtained. Subsequently, maleic anhydride (13) was employed as the dipolarophile under the optimal reaction conditions. However, the use of EtOH as the solvent does not seem to favor the formation of the products (9), and only moderate yields (67% and 72%) were obtained. When MeOH was employed as the reaction solvent, the decyclization products 9a and 9b could be obtained in 89% and 91% yield, respectively (Scheme 3b), which may undergo a dehydration-decarboxylation-cycloaddition-hydrolysis-methylesterification sequence reaction [69]. In addition, we noticed that the diastereoselectivities of product 9 were tightly affected by the N group of isatins (5) (9:1 vs. >99:1 dr), which may be related to the hydrogen bonding between NH and the hydroxyl group.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 6 of 21 >99:1 dr) (Scheme 3a). It is worth noting that the 7-substitution pattern and steric hindrance of isatins (5) had no significant effect on the reaction efficiency and diastereoselectivities. Based on this 1,3-dipolar cycloaddition reaction, a series of complex N-fused pyrrolidinyl-dispirooxindoles (8) bearing two spiro-quaternary centers were obtained. Subsequently, maleic anhydride (13) was employed as the dipolarophile under the optimal reaction conditions. However, the use of EtOH as the solvent does not seem to favor the formation of the products (9), and only moderate yields (67% and 72%) were obtained. When MeOH was employed as the reaction solvent, the decyclization products 9a and 9b could be obtained in 89% and 91% yield, respectively (Scheme 3b), which may undergo a dehydration-decarboxylation-cycloaddition-hydrolysis-methylesterification sequence reaction [69]. In addition, we noticed that the diastereoselectivities of product 9 were tightly affected by the N group of isatins (5) (9:1 vs. >99:1 dr), which may be related to the hydrogen bonding between NH and the hydroxyl group. Subsequently, we investigated the substrate scopes by choosing 1,4-naphthoquinone (14) as the dipolarophile (Scheme 4a). Surprisingly, we did not observe the expected products (15). Instead, polycyclic N-fused-pyrrolidinyl spirooxindoles (10) bearing an unsaturated structure unit were obtained in 83-92% yields with excellent diastereoselectivities (50:1->99:1 dr), regardless of the positions and electronic properties of the substituents on Subsequently, we investigated the substrate scopes by choosing 1,4-naphthoquinone (14) as the dipolarophile (Scheme 4a). Surprisingly, we did not observe the expected products (15). Instead, polycyclic N-fused-pyrrolidinyl spirooxindoles (10) bearing an unsaturated structure unit were obtained in 83-92% yields with excellent diastereoselectivities (50:1->99:1 dr), regardless of the positions and electronic properties of the substituents on the phenyl ring of the R 1 group and N-hydrocarbyl group (R 2 ) of isatins (5). Based on our previous work [73,74] and other studies [34,40,66,70], a plausible mechanism was proposed to explain the reaction process (Scheme 4b). The two nucleophilic carbons of the mentioned isatin-derived azomethine ylides (I-1) add to the corresponding electron-deficient carbons of the dipolarophile during the cycloadditions via 1,3-cycloaddition reactions (TS-1), lead-ing to the formation of compound 15. Then, the intermediates I-2 were formed via the tautomerization of compounds 15, which subsequently underwent rapid oxidation under air conditions to afford the product 10.

Conclusions
In conclusion, we developed a chemically sustainable and dipolarophile-controlled three-component 1,3-dipolar cycloaddition reaction to construct a broad range of (40 examples) functionalized N-fused pyrrolidinyl spirooxindoles in 76-95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This reaction can be scaled-up to the gram level, and the products can be purified by filtering and recrystallization without compromising the chemical outcome, inferring an efficient synthetic method for achieving diverse, complex natural spirooxindole alkaloids and biologically active spirooxindole derivatives. This reaction not only realizes a concise dipolarophile-controlled, catalysis-free 1,3-dipolar cycloaddition under green conditions but also provides a practical strategy for the construction of functionalized N-fused pyrrolidinyl spirooxindoles. Further investigations of the synthesized N-fused pyrrolidinyl spirooxindoles are ongoing in our laboratory.