A Facile One-Pot Construction of Succinimide-Fused Spiro[Pyrrolidine-2,3′-Oxindoles] via 1,3-Dipolar Cycloaddition Involving 3-Amino Oxindoles and Maleimides

Increasing interests have been invested in the development of synthetic strategies toward the construction of spiro[pyrrolidine-2,3′-oxindole], which is the core structural skeleton in some compounds with diverse biological activities. In this work, an efficient diastereoselective 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from 3-amino oxindoles and aldehydes with maleimides has been described. The protocol provides a facile and efficient access to structurally diverse succinimide-fused spiro[pyrrolidine-2,3′-oxindole] compounds in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of cycloaddition products has been assigned by X-ray diffraction analysis.


Results and Discussion
We commenced our studies with the three-component reaction of 3-amino-1-methylindolin-2-one hydrochloride 1a, 2a, and N-phenylmaleimide 3a (Scheme 2) as model substrates for surveying the reaction parameters, and the results are summarized in Table 1. Initially, the reaction was performed in the presence of 1 equivalent of weak inorganic base NaHCO 3 and the desired product 4a could be obtained in 60% yield with 74:26 diasteromeric excess (dr, Table 1, entry 1). Other two weak inorganic bases, K 2 CO 3 and KF/Al 2 O 3 , did not provide better results (Table 1, entries 2 and 3). When the strong base NaOH was employed, only trace product was detected (Table 1, entry 4). A further study showed that organic base TEA could afford 4a in 68% yield and 83:17 dr (Table 1, entry 6), and prolonging reaction time would benefit the reaction yield (Table 1, entry 7). Subsequently, a series of solvents were also screened. As seen from Table 1, with chlorinated alkane-type solvents, ether-type solvents, alcohol-type solvents, toluene or acetonitrile, the current strategy could afford the desired product 4a in various yields and diastereoselectivities (Table 1, entries [8][9][10][11][12][13][14][15][16]. In terms of diastereoselectivity, CH 2 Cl 2 was selected as the optimal reaction solvent ( Under optimum conditions, a variety of aldehyde substrates 2 were firstly investigated (Scheme 3). As shown in Table 2, all tested aldehydes underwent the reaction smoothly to afford the corresponding products with good to excellent results. Both electron-withdrawing and electron-donating substituents on the aryl ring of R 2 groups could be well tolerated ( Table 2, entries [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. It was shown that the positions of the substituents on the aryl ring of R 2 groups seem to play a significant influence on the reaction results. The ortho-and para-substituents exhibit more beneficial impact on reaction yield and diastereoselectivity than meta-substituents (   Under optimum conditions, a variety of aldehyde substrates 2 were firstly investigated (Scheme 3). As shown in Table 2, all tested aldehydes underwent the reaction smoothly to afford the corresponding products with good to excellent results. Both electron-withdrawing and electron-donating substituents on the aryl ring of R 2 groups could be well tolerated ( Table 2, entries [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. It was shown that the positions of the substituents on the aryl ring of R 2 groups seem to play a significant influence on the reaction results. The orthoand para-substituents exhibit more beneficial impact on reaction yield and diastereoselectivity than meta-substituents (   To extend the utility of this procedure, we then screened a series of 3-amino oxindoles1 and maleimides 3 (Scheme 4). As can be seen from Table 3, the electronic property of the substituent R 1 on aromatic ring of 3-amino oxindole seems to show significant influence on the diastereoselectivity of the reaction, and electron-donating group gave better dr value than electron-withdrawing group ( Table 3, entry 1 vs. entry 3, entry 2 vs. entry 4). Additionally, the N-protecting group R of 3-amino oxindole has also been found to have a major impact on the reaction result. When methyl-substituted 1a was replaced with benzyl-substituted 1e, the diastereoselectivity of the reaction was decreased from 88:12 to 83:17 ( Table 2, entry 1 vs. Table 3, entry 6). Unprotected 1d came to the worst results (Table 3, entry 5). Next, to further validate the compatibility of this strategy, the scope of maleimides 3 was also explored. It was found that substrates 3 with either electron-withdrawing or electron-donating substituents R 3 could be amenable to this reaction system ( Table 3, entries 8-13).  To extend the utility of this procedure, we then screened a series of 3-amino oxindoles 1 and maleimides 3 (Scheme 4). As can be seen from Table 3, the electronic property of the substituent R 1 on aromatic ring of 3-amino oxindole seems to show significant influence on the diastereoselectivity of the reaction, and electron-donating group gave better dr value than electron-withdrawing group ( Table 3, entry 1 vs. entry 3, entry 2 vs. entry 4). Additionally, the N-protecting group R of 3-amino oxindole has also been found to have a major impact on the reaction result. When methyl-substituted 1a was replaced with benzyl-substituted 1e, the diastereoselectivity of the reaction was decreased from 88:12 to 83:17 ( Table 2, entry 1 vs. Table 3, entry 6). Unprotected 1d came to the worst results (Table 3, entry 5). Next, to further validate the compatibility of this strategy, the scope of maleimides 3 was also explored. It was found that substrates 3 with either electron-withdrawing or electron-donating substituents R 3 could be amenable to this reaction system ( Table 3,   The relative configuration of 1,3-dipolar cycloaddition product 4k was established by X-ray diffraction analysis ( Figure 2) [22], the relevant data shown in supplementary materials and the relative configurations of other succinimide-fused spiro[pyrrolidine-2,3′-oxindole] products were assigned by analogy.   The relative configuration of 1,3-dipolar cycloaddition product 4k was established by X-ray diffraction analysis (Figure 2) [22], the relevant data shown in Supplementary Materials and the relative configurations of other succinimide-fused spiro[pyrrolidine-2,3 -oxindole] products were assigned by analogy.

Scheme 4.
Screening of a series of 3-amino oxindoles 1 and maleimides 3. The relative configuration of 1,3-dipolar cycloaddition product 4k was established by X-ray diffraction analysis (Figure 2) [22], the relevant data shown in supplementary materials and the relative configurations of other succinimide-fused spiro[pyrrolidine-2,3′-oxindole] products were assigned by analogy.

Experimental
All reactions were carried out in reaction tubes with magnetic stirring and no special precautions were taken to exclude air from the reaction vessels. TLC was performed on pre-coated silica gel plates (Qingdao Marine Chemistry Company, Qingdao, China). Column chromatography was carried out with silica gel (200-300 mesh, Qingdao Marine Chemistry Company, Qingdao, China) eluting with ethyl acetate and petroleum ether. NMR spectra were recorded with a Bruker Avance II 400 NMR spectrometer (Bruker Biospin, Fällanden, Switzerland). Chemical shifts are reported in parts per million (ppm) downfield from TMS (Aladdin, Shanghai, China) with the solvent resonance as the internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications. High Resolution Mass Spectrometer (HRMS) was recorded on a Bruker micrOTOF-Q II mass spectrometer (Bruker Daltonics Inc., Billerica, Massachusetts, MA, USA). X-ray diffraction analysis was recorded with a Bruker Apex-II spectrometer (Bruker AXS, Karlsruhe, Germany).

General Procedure forthe Preparation of Succinimide-Fused Spiro[Pyrrolidine-2,3 -Oxindoles] 4 and 5
3-Amino oxindoles 1 (0.2 mmol), aldehydes 2 (0.2 mmol) and TEA (0.2 mmol) were put into an ordinary test tube equipped with a magnetic stirring bar and then sealed in the air. Then, CH 2 Cl 2 (1 mL) was added. After being stirred at room temperature for 30 min, maleimides 3 (0.22 mmol) and CH 2 Cl 2 (1 mL) were added and the resulting mixture was stirred at reflux for 24 h. The crude reaction mixture was directly purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 7:1-3:1) to give the correspondingsuccinimide-fused spiro[pyrrolidine-2,3 -oxindole] products 4 or 5. All the products were confirmed by 1 H-NMR, 13 C-NMR and HRMS spectroscopic analysis. The diastereomeric ratio was determined by crude NMR analysis.

Conclusions
In summary, we have developed a simple and efficient strategy for diastereoselective construction of structurally diverse succinimide-fused spiro[pyrrolidine-2,3 -oxindoles] by a one-pot three-component 1,3-dipolar cycloaddition reaction ofazomethine ylides generated in situ from 3-amino oxindolesand aldehydes with maleimides. A series of succinimide-fused spiro[pyrrolidine-2,3 -oxindole] compounds have been obtained in good to high yields (up to 93%) with moderate to excellent diastereoselectivities (up to >95:5). The relative stereochemistry of products has been assigned by X-ray diffraction analysis. Further biological applications of 3-aminooxindoles are currently underway.