Next Article in Journal
Oxidative Stress and Inflammation in Osteoporosis: Molecular Mechanisms Involved and the Relationship with microRNAs
Previous Article in Journal
A Proposed Methodology to Deal with the Impact of In Vitro Cellular Matrix on the Analytical Performances of a Targeted Metabolomic LC-HRMS Method
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 4
10.3390/ijms24043771
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Yongchao Wang
1,*,
Lijun Yan
1,
Yuxin Yan
1,
Sujin Li
1,
Hongying Lu
1,
Jia Liu
1 and
Jianwei Dong
2,*
1
Colleage of Vocational and Technical Education, Yunnan Normal University, Kunming 650092, China
2
Colleage of Chemistry and Environmental Science, Qujing Normal University, Qujing 655011, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(4), 3771; https://doi.org/10.3390/ijms24043771
Submission received: 7 January 2023 / Revised: 10 February 2023 / Accepted: 10 February 2023 / Published: 13 February 2023
(This article belongs to the Section Biochemistry)
Browse Figures
Versions Notes

Abstract

:
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.

1. Introduction

The spirooxindole system belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules [1,2,3,4]. As a representative subclass of spirooxindoles, N-fused pyrrolidinyl spirooxindoles are gradually became appealing synthetic targets as the diverse biological activities [5,6,7,8] (Figure 1). Spirotryprostatin A (1) was first isolated from the fermentation broth of Aspergillus fumigatu, which can inhibit the G2/M progression of mammalian tsFT210 cells [9]. Strychnofoline (2) is a representative alkaloid and displays high antimitotic activity against cultures of mice melanoma and Eurlich tumor cells [10,11]. Synthetic N-fused pyrrolidinyl spirooxindoles SYNAZO-1 (3) [12] and MI-219 (4) [13] are promising antifungal synergizer and anticancer drug candidate, respectively. Other N-fused pyrrolidinyl spirooxindoles have also displayed a broad range of biological activities, such as antitumor, antiviral, anti-HIV activities, etc. [14,15,16,17].
Due to the diverse biological activities and the challenge of the simultaneous creation of spiro-quaternary centers, the development of cyclizations, cycloadditions, and cascade reactions for the construction of N-fused pyrrolidinyl spirooxindoles has continuously attracted the attention of synthetic chemists [18,19,20,21,22,23]. Among all the reported synthetic methodologies, multicomponent 1,3-dipolar cycloaddition [24,25,26,27] has been proven to be one of the most efficient and straightforward pathways for the construction of these unique nitrogen-containing skeletons [28,29,30] (Scheme 1a). Isatin-derived azomethine ylides were recognized as typical dipoles and generally generated in situ by decarboxylative condensation of α-amino acids with isatins, which then react with dipolarophiles [31]. Significantly, diverse dipolarophiles have proven highly fruitful, including electron-deficient alkenes (activated by nitro [32,33,34,35,36], carbonyl [37,38,39,40], or other electron-withdrawing groups [41,42,43]), alkynes [44,45,46], arylacetylenes [47], allenes [48], N-heteroenes [49,50], and strained cyclopropenes [51]. However, previously reported methods mainly focused on the traditional ‘single target’ approach, and thus, only one type of spirooxindole skeleton can be prepared via the 1,3-dipolar cycloaddition of isatin-derived azomethine ylides to monogroup-activated dipolarophiles. Fortunately, the switchable divergent synthesis strategy provides a straightforward method whereby the products can be switched by changing the reaction conditions or using common pluripotent substrates [52,53,54,55]. In this context, the scaffolds of N-fused pyrrolidinyl spirooxindoles can be regulated and switched via the dipole-controlled or dipolarophile-controlled strategy. To date, several powerful dipole-controlled multicomponent 1,3-dipolar cycloadditions have been explored selectively to access N-fused pyrrolidinyl spirooxindoles by using diverse α-amino acids as precursors to furnish isatin-derived azomethine ylides [40,56,57,58,59] (Scheme 1b). Noticeably, 1,4-enedione derivatives [60,61,62], such as maleimides [63,64], methylene indolinones [65,66,67], 1,4-naphthoquinone [68,69,70,71], maleic anhydride, etc., can be activated by two carbonyl groups, which can enhance the flexibility and diversity of cyclization in synthetic chemistry. To the best of our knowledge, only individual multicomponent dipolarophile-controlled methods have been elegantly developed to synthesize N-fused pyrrolidinyl spirooxindoles, while designated catalysts are necessary for this synthetic strategy [72]. Therefore, to fully take advantage of the library of 1,4-enedione derivatives and fill the gap of structural diversity, the development of efficient reactions to access biologically important N-fused pyrrolidinyl spirooxindoles is urgent in the field of chemical synthesis and drug discovery. Herein, we disclose a dipolarophile-controlled, catalysis-free, and eco-friendly 1,3-dipolar cycloaddition of in situ generated isatin-derived azomethine ylides with 1,4-enedione derivatives in EtOH at room temperature (Scheme 1c). An array of 1,4-enedione derivatives (including maleimides, methylene indolinones, maleic anhydride, and 1,4-naphthoquinone) were successfully utilized in the assembly of diversely substituted and functionalized N-fused pyrrolidinyl spirooxindoles. 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.

2. 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 (including proton solvents and aprotic solvents) at room temperature for 4 h (entries 1–16). The model reaction proceeded smoothly in the screened solvents with excellent diastereoselectivity (all >20:1 dr), with yields ranging from 18 to 81% (entries 1-14). Pleasingly, the 1,3-dipolar cycloaddition reaction produced the desired product in excellent yield in the presence of MeOH or EtOH (entries 15 and 16). Taking the toxicity and green synthesis into consideration, we chose EtOH as the optimal solvent to further optimize the reaction temperature and time. When the reaction temperature rose from room temperature to 40 °C or reflux, the product yields were not significantly changed (entries 16–18). In addition, there was no significant increase in yield when the reaction time was extended from 4 h to 8 h or 24 h (entries 16, 20 and 21), while the product yield declined to 81% when the reaction time was reduced to 2 h. The target product, N-fused-pyrrolidinyl spirooxindole (7a), could be easily precipitated from the reaction solution and purified by filtering and recrystallization or column chromatography separation. Overall, the optimal reaction conditions for synthesizes of N-fused-pyrrolidinyl spirooxindoles were achieved via a ‘one-pot’ reaction of isatins (5), α-amino acids (6), and 1,4-enedione derivatives in EtOH at room temperature for 4 h.
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 (R2) 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.
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.
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 R1 group and N-hydrocarbyl group (R2) 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), leading 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.
We also explored the 1,3-dipolar cycloaddition reactions by employing acenaphthenequinone-derived azomethine ylide as dipole, which was generated in situ from acenaphthenequinone (16) and L-proline (6a) (Scheme 5). Under reaction conditions similar to those described above, the reactions of 1,4-enedione derivatives (11) with azomethine ylide proceeded smoothly, and the corresponding products (17a–17d) were furnished in 87–93% yields with all >99:1 dr levels. This 1,3-dipolar cycloaddition reaction also occurred smoothly when methylene indolinone (12a) was used as the dipolarophile, affording product 17e with an 85% yield with 50:1 dr.
To further demonstrate the synthetic utility of the 1,3-dipolar cycloaddition reaction, a gram-scale synthesis of 7g was carried out (Scheme 6). Under the optimized conditions, this three-component reaction of 6-bromoisatin (5b, 3.0 mmol), L-proline (6a, 3.6 mmol), and N-ethylmaleimide (11a, 3.6 mmol) proceeded smoothly and led to the desired product (7g) in 94% yield with excellent diastereoselectivity (>99:1 dr). It is worth noting that visible color changes were observed during the reaction process, which were and accompanied by precipitation. Finally, the high-purity target compound (7g) was obtained by simple filtration and recrystallization.

3. Materials and Methods

3.1. General Information

Reagents and materials (Adamas, Shanghai, China) were of the highest commercial grade and were used without further purification. NMR spectra were recorded on a Bruker DRX 400 (1H: 400 MHz, 13C: 100 MHz) with TMS as the internal standard. Chemical shifts (δ) were expressed in ppm, J values were given in Hz, and deuterated DMSO-d6 was used as a solvent. IR spectra were recorded by FT-IR on a Thermo Nicolet Avatar 360 using a KBr pellet. The mass spectroscopic data were obtained from an Agilent 6550 Q-TOF and a Thermo Fisher-QE spectrometer. Melting points were determined with an SGWX-4 melting-point apparatus. The reactions were monitored by thin-layer chromatography (TLC) with silica gel GF254, and all compounds were visualized by UV and sprayed with H2SO4 (10%) in ethanol, followed by heating. A suitable single crystal was selected and analyzed with Rigaku XtaLab Synergy. Supplementary Materials: 1H-NMR, 13C-NMR spectra and HRMS of compounds 7, 8, 9,10, 17; Single crystal X-ray diffraction study data of compound 7a.

3.2. General Procedure for the Synthesis of Compounds 7–10

The target compounds were obtained by a ‘one-pot’ reaction of isatins (5, 0.5 mmol), α-amino acids (6, 0.6 mmol) and 1,4-enedione derivatives (11–14, 0.6 mmol) in EtOH or MeOH (3 mL) at room temperature for 4 h. The resulting precipitate was collected by filtration and washed with cold EtOH 2–3 times. The crude product was further purified by recrystallization (in EtOH or MeOH) or column chromatography (the mixtures of petroleum ether and ethyl acetate were used as eluents) to afford the pure corresponding compound.
2′-Ethyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo [3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7a). White solid; 93% yield; >99:1 dr; mp 231–232 °C; IR (KBr) 750, 1138, 1350, 1375, 1474, 1618, 1690, 1717, 2365, 2884, 2978, 3088, 3148 cm−1; HRMS (ESI) calcd for C18H19N3O3 [M + H]+ 326.1499, found 326.1508; 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H, NH), 7.25 (t, J = 14.8 Hz, 1H, ArH), 6.94 (t, J = 15.2 Hz, 1H, ArH), 6.89 (d, J = 7.6 Hz, 1H, ArH), 6.84 (d, J = 7.6 Hz, 1H, ArH), 4.26–4.21 (m, 1H, CH), 3.58 (d, J = 7.6 Hz, 1H, CH), 3.49 (t, J = 16.0 Hz, 1H, CH), 3.45–3.43 (m, 2H, CH2), 2.41–2.29 (m, 2H, CH2), 1.94–1.75 (m, 4H, CH2), 1.11 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.2, 177.1, 175.4, 143.0, 129.9, 127.4, 125.4, 121.6, 110.1, 69.1, 64.4, 55.5, 46.2, 45.3, 33.6, 25.9, 23.8, 13.0.
2′-Ethyl-5-methyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7b). Brown solid; 88% yield; >99:1 dr; mp 240–241 °C; IR (KBr) 1219, 1339, 1491, 1624, 1695, 1711, 2995, 3177 cm−1; HRMS (ESI) calcd for C19H21N3O3 [M + H]+ 340.1656, found 340.1662; 1H-NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H, NH), 7.06–7.04 (m, 1H, ArH), 6.74 (d, J = 8.0 Hz, 1H, ArH), 6.66 (s, 1H, ArH), 4.22–4.17 (m, 1H, CH), 3.57 (d, J = 8.0 Hz, 1H, CH), 3.48 (d, J = 8.0 Hz, 1H, CH), 3.45–3.41 (m, 2H, CH2), 2.39–2.25 (m, 2H, CH2), 2.21 (m, 3H, CH3), 1.90–1.79 (m, 4H, CH2), 1.12 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.3, 177.0, 175.4, 140.6, 130.2, 130.1, 127.7, 125.6, 109.9, 68.8, 64.5, 56.1, 46.0, 44.7, 33.6, 26.1, 23.8, 21.2, 13.1.
2′-Ethyl-5-methoxy-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7c). White solid; 87% yield; 20:1 dr; mp 241–242 °C; IR (KBr) 1207, 1224, 1348, 1400, 1491, 1690, 1701, 2957 cm−1; HRMS (ESI) calcd for C19H21N3O4 [M + H]+ 356.1605, found 356.1604; 1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H, NH), 6.86–6.83 (m, 1H, ArH), 6.76 (d, J = 8.8 Hz, 1H, ArH), 6.41 (d, J = 2.4 Hz, 1H, ArH), 4.24–4.19 (m, 1H, CH), 3.68 (s, 3H, OCH3), 3.59 (d, J = 7.6 Hz, 1H, CH), 3.48 (d, J = 8.0 Hz, 1H, CH), 3.47–3.42 (m, 2H, CH2), 2.38–2.27 (m, 2H, CH2), 1.86–1.80 (m, 4H, CH2), 1.11 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.1, 177.0, 175.4, 154.7, 136.2, 126.8, 114.4, 114.3, 110.3, 69.0, 64.5, 56.0, 55.8, 45.9, 44.6, 33.6, 26.1, 23.7, 13.1.
2′-Ethyl-5-fluoro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7d). Orange solid; 90% yield; >99:1 dr; mp 225–226 °C; IR (KBr) 768, 1173, 1221, 1462, 1487, 1695, 1730, 1770, 2704, 2821, 2976 cm−1; HRMS (ESI) calcd for C18H18FN3O3 [M + H]+ 344.1405, found 344.1414; 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H, NH), 7.15–7.10 (m, 1H, ArH), 6.86–6.82 (m, 1H, ArH), 6.68–6.66 (m, 1H, ArH), 4.25–4.20 (m, 1H, CH), 3.62 (d, J = 7.6 Hz, 1H, CH), 3.49 (d, J = 8.0 Hz, 1H, CH), 3.47–3.42 (m, 2H, CH2), 2.40–2.27 (m, 2H, CH2), 1.88–1.81 (m, 4H, CH2), 1.10 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.1, 176.9, 175.4, 159.0, 156.6, 139.2, 139.2, 127.2, 127.1, 116.6, 116.4, 115.0, 114.8, 110.9, 110.8, 68.9, 64.5, 55.8, 45.9, 44.9, 33.7, 25.9, 23.7, 13.1.
2′-Ethyl-5-nitro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7e). Khaki solid; 89% yield; >99:1 dr; mp 267–268 °C; IR (KBr) 1099, 1217, 1339, 1406, 1628, 1680, 1736, 2965, 3233 cm−1; HRMS (ESI) calcd for C18H18N4O5 [M + H]+ 371.1350, found 371.1356; 1H-NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H, NH), 8.20–8.18 (m, 1H, ArH), 7.60 (d, J = 2.4 Hz, 1H, ArH), 7.00 (d, J = 8.8 Hz, 1H, ArH), 4.16–4.11 (m, 1H, CH), 3.67 (d, J = 7.6 Hz, 1H, CH), 3.46 (d, J = 8.0 Hz, 1H, CH), 3.43–3.37 (m, 2H, CH2), 2.37–2.19 (m, 2H, CH2), 1.87–1.75 (m, 4H, CH2), 1.11 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.4, 176.6, 175.4, 149.5, 142.2, 127.3, 126.5, 122.5, 110.6, 67.8, 64.8, 56.2, 45.5, 44.3, 33.7, 26.1, 23.6, 13.1.
6-Chloro-2′-ethyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7f). White solid; 94% yield; 25:1 dr; mp 270–271 °C; IR (KBr) 806, 1219, 1346, 1400, 1466, 1616, 1694, 1719, 2932, 2982 cm−1; HRMS (ESI) calcd for C18H18ClN3O3 [M + H]+ 360.1109, found 360.1113; 1H-NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H, NH), 7.02–6.99 (m, 1H, ArH), 6.87 (t, J = 10.4 Hz, 2H, ArH), 4.24–4.19 (m, 1H, CH), 3.60 (d, J = 8.0 Hz, 1H, CH), 3.49 (d, J = 8.0 Hz, 1H, CH), 3.47–3.40 (m, 2H, CH2), 2.40–2.27 (m, 2H, CH2), 1.88–1.79 (m, 4H, CH2), 1.10 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.1, 177.0, 175.4, 144.5, 134.3, 128.9, 124.3, 121.4, 110.2, 68.6, 64.5, 55.6, 46.1, 45.2, 33.6, 25.9, 23.8, 13.1.
6-Bromo-2′-ethyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7g). White solid; 95% yield; >99:1 dr; mp 200–201 °C; IR (KBr) 758, 804, 1219, 1398, 1466, 1589, 1701, 1722, 2928, 2947, 2984, 3030, 3122 cm−1; HRMS (ESI) calcd for C18H18BrN3O3 [M + H]+ 404.0604, found 404.0625; 1H-NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H, NH), 7.14 (d, J = 8.4 Hz, 1H, ArH), 6.99 (s, 1H, ArH), 6.81 (d, J = 8.0 Hz, 1H, ArH), 4.23–4.18 (m, 1H, CH), 3.60 (d, J = 7.6 Hz, 1H, CH), 3.49 (d, J = 8.0 Hz, 1H, CH), 3.46–3.42 (m, 2H, CH2), 2.39–2.29 (m, 2H, CH2), 1.86–1.80 (m, 4H, CH2), 1.09 (t, J = 13.6 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.0, 177.0, 175.4, 144.7, 129.2, 124.7, 124.3, 122.8, 113.0, 68.6, 64.5, 55.6, 46.0, 45.1, 33.7, 25.9, 23.8, 13.1.
2′-Ethyl-7-fluoro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7h). White solid; 76% yield; >99:1 dr; mp 210–211 °C; IR (KBr) 729, 1206, 1225, 1341, 1686, 1701, 2363, 2799, 2968, 2974 cm−1; HRMS (ESI) calcd for C18H18FN3O3 [M + H]+ 344.1405, found 344.1413; 1H-NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H, NH), 7.19 (t, J = 18.0 Hz, 1H, ArH), 6.99–6.94 (m, 1H, ArH), 6.72 (d, J = 7.2 Hz, 1H, ArH), 4.25–4.20 (m, 1H, CH), 3.64 (d, J = 8.0 Hz, 1H, CH), 3.51 (d, J = 7.6 Hz, 1H, CH), 3.48–3.41 (m, 2H, CH2), 2.40–2.28 (m, 2H, CH2), 1.86–1.79 (m, 4H, CH2), 1.10 (t, J = 14.0 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.0, 176.9, 175.2, 148.0, 145.6, 130.2, 130.1, 128.4, 128.3, 123.4, 123.3, 122.4, 122.4, 117.0, 116.8, 69.0, 69.0, 64.5, 56.0, 46.0, 45.0, 33.6, 26.0, 23.9, 13.1.
2′-Ethyl-5,7-dimethyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7i). Yellow solid; 79% yield; >99:1 dr; mp 227–228 °C; IR (KBr) 1221, 1342, 1400, 1624, 1697, 1719, 2851, 2918, 2957, 3198 cm−1; HRMS (ESI) calcd for C20H23N3O3 [M + H]+ 354.1812, found 354.1823; 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H, NH), 6.79 (s, 1H, ArH), 6.40 (s, 1H, ArH), 4.13 (t, J = 12.8 Hz, 1H, CH), 3.49 (d, J = 8.0 Hz, 1H, CH), 3.39 (d, J = 7.6 Hz, 1H, CH), 3.36–3.33 (m, 2H, CH2), 2.30–2.16 (m, 2H, CH2), 2.10 (s, 3H, CH3), 2.08 (s, 3H, CH3), 1.78–1.72 (m, 4H, CH2), 1.04 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 178.8, 177.0, 175.4, 139.0, 131.6, 130.1, 125.3, 124.9, 119.0, 68.8, 64.5, 56.3, 45.9, 44.5, 33.6, 26.1, 23.7, 21.1, 16.7, 13.1.
2′-Ethyl-1-methyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4’-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7j). White solid; 94% yield; >99:1 dr; mp 247–249 °C; IR (KBr) 758, 1341, 1398, 1612, 1697, 2365, 2822, 2963 cm−1; HRMS (ESI) calcd for C19H21N3O3 [M + H]+ 340.1656, found 340.1664; 1H-NMR (400 MHz, DMSO-d6): δ 7.39–7.35 (m, 1H, ArH), 7.05–7.01 (m, 2H, ArH), 6.96 (t, J = 7.6 Hz, 1H, ArH), 4.29–4.24 (m, 1H, CH), 3.58 (d, J = 8.0 Hz, 1H, CH), 3.51 (t, J = 15.6 Hz, 1H, CH), 3.47–42 (m, 2H, CH), 3.36 (s, 3H, NCH3), 2.40–2.23 (m, 2H, CH2), 1.95–1.75 (m, 4H, CH2), 1.11 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 177.1, 176.2, 175.4, 144.5, 130.1, 127.2, 124.6, 122.3, 109.1, 68.8, 64.5, 55.5, 46.3, 45.5, 33.6, 26.3, 25.8, 23.8, 13.0.
2′-Ethyl-1-phenyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7k). Bright-yellow solid; 92% yield; >99:1 dr; mp 239–241 °C; IR (KBr) 750, 1225, 1373, 1400, 1499, 1611, 1699, 2940, 2955 cm−1; HRMS (ESI) calcd for C24H23N3O3 [M + H]+ 402.1812, found 402.1810; 1H-NMR (400 MHz, DMSO-d6): δ 7.61–7.51 (m, 2H, ArH), 7.49–7.45 (m, 3H, ArH), 7.33–7.29 (m, 1H, ArH), 7.11–7.04 (m, 2H, ArH), 6.74 (d, J = 8.0 Hz, 1H, ArH), 4.30–4.25 (m, 1H, CH), 3.80 (d, J = 7.6 Hz, 1H, CH), 3.45 (d, J = 8.0 Hz, 1H, CH), 3.52–3.46 (m, 2H, CH2), 2.48–2.39 (m, 2H, CH2), 1.93–1.83 (m, 4H, CH2), 1.17 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 177.0, 175.6, 175.4, 144.3, 134.2, 130.1, 130.1, 130.1, 128.8, 127.8, 127.4, 127.4, 124.5, 122.8, 109.4, 68.7, 64.5, 55.7, 46.1, 45.1, 33.7, 25.9, 23.8, 13.1.
3a′,6′,7′,8′,8a′,8b′-Hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7l). Light-yellow solid; 89% yield; >99:1 dr; mp >300 °C; IR (KBr) 751, 1194, 1474, 1701, 2345, 2365, 2965, 3086, 3186 cm−1; HRMS (ESI) calcd for C16H15N3O3 [M + H]+ 298.1186, found 298.1187; 1H-NMR (400 MHz, DMSO-d6): δ 11.33 (s, 1H, NH), 10.52 (s, 1H, NH), 7.26–7.22 (m, 1H, ArH), 6.98–6.91 (m, 2H, ArH), 6.83 (d, J = 7.6 Hz, 1H, ArH), 4.19–4.14 (m, 1H, CH), 3.53 (d, J = 8.0 Hz, 1H, CH), 3.45 (t, J = 15.6 Hz, 1H, CH), 2.46–2.26 (m, 2H, CH2), 1.99–1.81 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.9, 178.3, 177.1, 142.9, 129.9, 127.2, 125.7, 121.6, 110.0, 68.5, 64.4, 57.2, 47.2, 44.7, 26.1, 23.7.
2′-Phenyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7m). Light-yellow solid; 90% yield; >99:1 dr; mp 230–232 °C; IR (KBr) 748, 1194, 1219, 1387, 1474, 1707, 1740, 2363, 2828, 2957, 3065 cm−1; HRMS (ESI) calcd for C22H19N3O3 [M + H]+ 374.1499, found 374.1502; 1H-NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H, NH), 7.54 (t, J = 15.2 Hz, 2H, ArH), 7.46 (t, J = 14.8 Hz, 1H, ArH), 7.30–7.24 (m, 3H, ArH), 7.02 (d, J = 7.2 Hz, 1H, ArH), 6.95 (t, J = 14.8 Hz, 1H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 4.38–4.32 (m, 1H, CH), 3.74 (t, J = 18.0 Hz, 1H, CH), 3.69 (d, J = 8.0 Hz, 1H, CH), 2.56–2.39 (m, 2H, CH2), 1.96–1.82 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.2, 176.5, 174.7, 143.1, 132.8, 130.0, 129.6, 128.9, 128.9, 127.5, 127.4, 127.4, 125.3, 121.7, 110.2, 69.7, 64.8, 55.8, 46.7, 45.9, 25.9, 24.1.
2′-Benzyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7n). Light-yellow solid; 87% yield; >99:1 dr; mp 269–270 °C; IR (KBr) 758, 1344, 1400, 1476, 1701, 1728, 2363, 2681, 2828, 2940, 3065 cm−1; HRMS (ESI) calcd for C23H21N3O3 [M + H]+ 388.1656, found 388.1660; 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H, NH), 7.42–7.32 (m, 5H, ArH), 7.22–7.18 (m, 1H, ArH), 6.81 (d, J = 8.0 Hz, 1H, ArH), 6.74–6.70 (m, 1H, ArH), 6.40 (d, J = 7.6 Hz, 1H, ArH), 4.66–4.53 (m, 2H, CH2), 4.28–4.23 (m, 1H, CH), 3.62 (d, J = 7.6 Hz, 1H, CH), 3.56 (t, J = 15.6 Hz, 1H, CH), 2.18–2.14 (m, 2H, CH2), 1.94–1.89 (m, 2H, CH2), 1.88–1.83 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.1, 177.1, 175.3, 143.0, 136.1, 129.8, 129.0, 129.0, 128.8, 128.8, 128.3, 127.6, 125.2, 121.4, 110.0, 69.2, 64.4, 55.4, 46.5, 45.4, 42.2, 25.6, 23.6.
6-Chloro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7o). White solid; 83% yield; >99:1 dr; mp 279–281 °C; IR (KBr) 761, 1192, 1327, 1458, 1618, 1717, 2710, 2922, 3134, 3192 cm−1; HRMS (ESI) calcd for C16H14ClN3O3 [M + H]+ 332.0796, found 332.0796; 1H-NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H, NH), 10.68 (s, 1H, NH), 7.02–6.99 (m, 1H, ArH), 6.96 (d, J = 8.0 Hz, 1H, ArH), 6.86 (d, J = 1.6 Hz, 1H, ArH), 4.17–4.12 (m, 1H, CH), 3.56 (d, J = 7.6 Hz, 1H, CH), 3.45 (t, J = 15.6 Hz, 1H, CH), 2.45–2.24 (m, 2H, CH2), 1.89–1.80 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.7, 178.2, 177.0, 144.4, 134.3, 128.6, 124.6, 121.4, 110.1, 68.1, 64.5, 57.3, 47.0, 44.5, 26.2, 23.7.
6-Bromo-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7p). Light-pink solid; 87% yield; >99:1 dr; mp >300 °C; IR (KBr) 1120, 1321, 1449, 1609, 1709, 2828, 3063, 3132, 3163 cm−1; HRMS (ESI) calcd for C16H14BrN3O3 [M - H+]- 374.0146, found 374.0138; 1H-NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H, NH), 10.70 (s, 1H, NH), 7.16–7.13 (m, 1H, ArH), 6.98 (d, J = 1.6 Hz, 1H, ArH), 6.89 (d, J = 8.0 Hz, 1H, ArH), 4.16–4.11 (m, 1H, CH), 3.56 (d, J = 8.0 Hz, 1H, CH), 3.44 (t, J = 15.6 Hz, 1H, CH), 2.44–2.25 (m, 2H, CH2), 1.91–1.81 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.8, 178.1, 177.0, 144.6, 128.9, 125.0, 124.4, 122.7, 112.9, 68.1, 64.5, 57.3, 47.0, 44.5, 26.2, 23.7.
5-Fluoro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7q). White solid; 91% yield; >99:1 dr; mp 254–256 °C; IR (KBr) 814, 899, 1194, 1321, 1489, 1717, 2706, 2967, 3088, 3184 cm−1; HRMS (ESI) calcd for C16H14FN3O3 [M - H]- 314.0946, found 314.0945; 1H-NMR (400 MHz, DMSO-d6): δ 11.38 (s, 1H, NH), 10.57 (s, 1H, NH), 7.13–7.08 (m, 1H, ArH), 6.85–6.81 (m, 1H, ArH), 6.76–6.73 (m, 1H, ArH), 4.18–4.13 (m, 1H, CH), 3.57 (d, J = 7.6 Hz, 1H, CH), 3.44 (t, J = 15.6 Hz, 1H, CH), 2.46–2.42 (m, 1H, CH2), 2.28–2.24 (m, 1H, CH2), 1.93–1.79 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.7, 178.2, 177.0, 159.1, 156.7, 139.1, 139.1, 127.6, 127.5, 116.5, 116.3, 114.7, 114.4, 110.8, 110.8, 68.4, 68.4, 64.5, 57.5, 46.8, 44.2, 26.2, 23.5.
5-Methoxy-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7r). White solid; 84% yield; 50:1 dr; mp 291–292 °C; IR (KBr) 1209, 1491, 1717, 2365, 2959, 3254 cm−1; HRMS (ESI) calcd for C17H17N3O4 [M - H]- 326.1146, found 326.1158; 1H-NMR (400 MHz, DMSO-d6): δ 11.34 (s, 1H, NH), 10.35 (s, 1H, NH), 6.85–6.82 (m, 1H, ArH), 6.74 (d, J = 8.4 Hz, 1H, ArH), 6.53 (d, J = 2.4 Hz, 1H, ArH), 4.17–4.12 (m, 1H, CH), 3.68 (s, 3H, OCH3), 3.54 (d, J = 7.6 Hz, 1H, CH), 3.44 (t, J = 15.2 Hz, 1H, CH), 2.44–2.24 (m, 2H, CH2), 1.92–1.78 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.8, 178.2, 177.0, 154.7, 136.2, 127.1, 114.2, 114.2, 110.2, 68.5, 64.5, 57.7, 55.9, 46.9, 44.2, 26.3, 23.7.
5-Nitro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7s). Light-yellow solid; 79% yield; 17:1 dr; mp 255–256 °C; IR (KBr) 1194, 1341, 1522, 1624, 1717, 2365, 2967, 3231 cm−1; HRMS (ESI) calcd for C16H14N4O5 [M - H]- 341.0891, found 341.0898; 1H-NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1H, NH), 11.27 (s, 1H, NH), 8.27–8.24 (m, 1H, ArH), 7.77 (d, J = 2.0 Hz, 1H, ArH), 7.06 (d, J = 8.8 Hz, 1H, ArH), 4.19–4.13 (m, 1H, CH), 3.68 (d, J = 7.6 Hz, 1H, CH), 3.48 (t, J = 15.6 Hz, 1H, CH), 2.49–2.24 (m, 2H, CH2), 1.97–1.79 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.5, 178.4, 177.1, 149.5, 142.2, 127.2, 126.6, 122.5, 110.5, 67.6, 64.7, 57.5, 46.6, 44.0, 26.2, 23.5.
2′-Benzyl-6-chloro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7t). White solid; 80% yield; >99:1 dr; mp 211–213 °C; IR (KBr) 704, 1167, 1339, 1395, 1616, 1697, 1740, 2363, 2693, 2808, 2965 cm−1; HRMS (ESI) calcd for C23H20ClN3O3 [M - H]- 420.1120, found 420.1125; 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H, NH), 7.42–7.38 (m, 2H, ArH), 7.35–7.32 (m, 3H, ArH), 6.83 (d, J = 2.0 Hz, 1H, ArH), 6.76–6.74 (m, 1H, ArH), 6.33 (d, J = 8.0 Hz, 1H, ArH), 4.64 (d, J = 14.4 Hz, 1H, CH), 4.54 (d, J = 14.4 Hz, 1H, CH2), 4.25–4.20 (m, 1H, CH), 3.65 (d, J = 7.6 Hz, 1H, CH), 3.56 (t, J = 15.6 Hz, 1H, CH), 2.18–2.13 (m, 2H, CH2), 1.90–1.86 (m, 2H, CH2), 1.84–1.73 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.0, 176.9, 175.2, 144.5, 136.1, 134.3, 129.0, 129.0, 128.9, 128.9, 128.3, 128.3, 124.1, 121.1, 110.2, 68.7, 64.6, 55.5, 46.2, 45.2, 42.3, 25.7, 23.6.
2′-Benzyl-6-bromo-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7u). White solid; 81% yield; >99:1 dr; mp 270–272 °C; IR (KBr) 704, 1167, 1339, 1395, 1612, 1697, 1736, 2363, 2965 cm−1; HRMS (ESI) calcd for C23H20BrN3O3 [M + H]+ 466.0761, found 466.0766; 1H-NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H, NH), 7.40 (t, J = 14.8 Hz, 2H, ArH), 7.35 (t, J = 10.8 Hz, 3H, ArH), 6.96 (d, J = 1.6 Hz, 1H, ArH), 6.90–6.88 (m, 1H, ArH), 6.26 (d, J = 8.0 Hz, 1H, ArH), 4.64 (d, J = 14.8 Hz, 1H, CH2), 4.54 (d, J = 14.4 Hz, 1H, CH2), 4.25–4.19 (m, 1H, CH), 3.65 (d, J = 7.6 Hz, 1H, CH), 3.56 (t, J = 15.6 Hz, 1H, CH), 2.17–2.13 (m, 2H, CH2), 1.89–1.83 (m, 2H, CH2), 1.82–1.73 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 177.9, 176.9, 175.2, 144.7, 136.1, 129.2, 129.2, 129.0, 129.0, 128.9, 128.3, 124.6, 124.0, 122.7, 112.9, 68.8, 64.6, 55.5, 46.2, 45.1, 42.3, 25.7, 23.6.
2′-Benzyl-5-fluoro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7v). White solid; 89% yield; >99:1 dr; mp >300 °C; IR (KBr) 707, 1159, 1202, 1391, 1489, 1701, 1730, 2818, 2856, 2967, 3032 cm−1; HRMS (ESI) calcd for C23H20FN3O3 [M + H]+ 406.1561, found 406.1564; 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H, NH), 7.40–7.31 (m, 5H, ArH), 7.08–7.03 (m, 1H, ArH), 6.83–6.79 (m, 1H, ArH), 6.19–6.16 (m, 1H, ArH), 4.67 (d, J = 14.8 Hz, 1H, CH2), 4.55 (d, J = 14.4 Hz, 1H, CH2), 4.28–4.23 (m, 1H, CH), 3.67 (d, J = 8.0 Hz, 1H, CH), 3.55 (t, J = 15.6 Hz, 1H, CH), 2.16 (t, J = 14.8 Hz, 2H, CH2), 1.88–1.82 (m, 2H, CH2), 1.80–1.73 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 177.9, 176.9, 175.3, 158.8, 156.5, 139.2, 136.2, 129.1, 129.1, 128.6, 128.6, 128.3, 127.0, 126.9, 116.5, 116.3, 115.2, 115.0, 110.8, 110.7, 69.1, 64.5, 55.6, 46.0, 44.9, 42.3, 25.7, 23.4.
2′-Benzyl-5-methoxy-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7w). White solid; 87% yield; >99:1 dr; mp 211–212 °C; IR (KBr) 742, 1217, 1395, 1491, 1688, 1717, 2857, 2967, 3032, 3177 cm−1; HRMS (ESI) calcd for C24H23N3O4 [M + H]+ 418.1761, 418.1757; 1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H, NH), 7.39–7.28 (m, 5H, ArH), 6.81–6.78 (m, 1H, ArH), 6.73 (d, J = 8.8 Hz, 1H, ArH), 6.18 (d, J = 2.4 Hz, 1H, ArH), 4.62 (d, J = 4.4 Hz, 2H, CH2), 4.31–4.26 (m, 1H, CH), 3.64 (d, J = 7.6 Hz, 1H, CH2), 3.55 (t, J = 16.0 Hz, 1H, CH2), 3.45 (s, 3H, OCH3), 2.19 (t, J = 13.2 Hz, 2H, CH2), 1.88–1.84 (m, 2H, CH2), 1.80–1.72 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 177.9, 177.1, 175.3, 154.5, 136.2, 136.2, 129.1, 129.1, 128.2, 128.2, 128.1, 126.4, 114.9, 114.3, 110.3, 69.3, 64.3, 55.6, 55.6, 46.1, 44.9, 42.1, 25.7, 23.6.
2′-Benzyl-5-nitro-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H-spiro[indoline-3,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (7x). White solid; 85% yield; >99:1 dr; mp 201–202 °C; IR (KBr) 739, 1339, 1398, 1522, 1624, 1686, 1734, 2372, 2947, 3128 cm−1; HRMS (ESI) calcd for C23H20N4O5 [M - H]- 431.1361, found 431.1379; 1H-NMR (400 MHz, DMSO-d6): δ 11.33 (s, 1H, NH), 8.25 (d, J = 2.4 Hz, 1H, ArH), 8.23 (d, J = 2.4 Hz, 1H, ArH), 7.58–7.38 (m, 4H, ArH), 7.35–7.31 (m, 1H, ArH), 7.05 (d, J = 8.4 Hz, 1H, ArH), 4.67–4.57 (m, 2H, CH2), 4.31–4.25 (m, 1H, CH), 3.78 (d, J = 8.0 Hz, 1H, CH), 3.58 (t, J = 16.0 Hz, 1H, CH), 2.22–2.07 (m, 2H, CH2), 1.86–1.79 (m, 2H, CH2), 1.69–1.57 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 178.1, 176.8, 175.4, 149.7, 142.0, 135.9, 129.1, 129.1, 128.6, 128.6, 128.3, 127.3, 125.8, 123.4, 110.5, 68.9, 64.6, 54.9, 46.3, 45.7, 42.4, 25.3, 23.6.
7′-Ethyl-2′,3′,8a′,8b′-tetrahydrospiro[indoline-3,5′-pyrrolo[3′,4′:3,4]pyrrolo[2,1-b]thiazole]-2,6′,8′(5a′H,7′H)-trione (7y). Yellow solid; 84% yield; >99:1 dr; mp 199–201 °C; IR (KBr) 752, 1227, 1686, 1701, 2365, 2976, 3265 cm−1; HRMS (ESI) calcd for C17H17N3O3S [M + H]+ 344.1063, found 344.1069; 1H-NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H, NH), 7.32–7.24 (m, 1H, ArH), 6.98–6.94 (m, 1H, ArH), 6.86–6.80 (m, 2H, ArH), 4.44–4.38 (m, 1H, CH), 3.76 (d, J = 8.0 Hz, 1H, CH), 3.68–3.64 (m, 1H, CH2), 3.48–3.42 (m, 2H, CH2), 3.38–3.36 (m, 1H, CH2), 3.19 (d, J = 6.0 Hz, 1H, CH), 3.02–2.98 (m, 1H, CH2), 2.77–2.72 (m, 1H, CH2), 1.12 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 177.6, 175.9, 174.6, 142.8, 130.3, 126.5, 124.6, 122.2, 110.4, 68.0, 67.3, 56.9, 45.8, 44.2, 33.9, 29.7, 13.4.
Ethyl 7″ -bromo-2,2″-dioxo-5′,6′,7′,7a′-tetrahydro-1′H-dispiro[indoline-3,2′-pyrrolizine-3′,3″-indoline]-1′-carboxylate (8a). White solid; 87% yield; >99:1 dr; mp >300 °C; IR (KBr) 1234, 1479, 1631, 1724, 2378, 3279 cm−1; HRMS (ESI) calcd for C24H22BrN3O4 [M + H]+ 496.0866, found 496.0869; 1H-NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H, NH), 10.30 (s, 1H, NH), 7.63 (d, J = 7.2 Hz, 1H, ArH), 7.24–7.21 (m, 2H, ArH), 7.07 (t, J = 14.8 Hz, 1H, ArH), 6.66 (d, J = 7.6 Hz, 1H, ArH), 6.45 (t, J = 15.6 Hz, 1H, ArH), 6.22 (d, J = 7.6 Hz, 1H, ArH), 4.37 (s, 2H, CH2), 3.84–3.76 (m, 1H, CH2), 3.68–3.60 (m, 1H, CH2), 2.62 (t, J = 15.2 Hz, 1H, CH), 2.46 (d, J = 6.8 Hz, 1H, CH), 2.21–2.15 (m, 2H, CH2), 2.13–2.03 (m, 2H, CH2), 0.68 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 177.9, 173.5, 169.9, 142.9, 142.2, 132.7, 129.6, 127.8, 127.3, 126.7, 124.7, 122.6, 121.5, 109.7, 102.0, 77.7, 66.5, 66.1, 60.3, 51.1, 47.2, 31.4, 30.5, 13.7.
Ethyl 7-bromo-2,2″-dioxo-2′,3′,7′,7a′-tetrahydrodispiro[indoline-3,5′-pyrrolo[2,1-b]thiazole-6′,3″-indoline]-7′-carboxylate (8b). White solid; 85% yield; 33:1 dr; mp >300 °C; IR (KBr) 1221, 1465, 1644, 1718, 2385, 3274 cm−1; HRMS (ESI) calcd for C23H20BrN3O4S [M + H]+ 514.0431, found 514.0435; 1H-NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H, NH), 10.31 (s, 1H, NH), 7.59 (d, J = 7.6 Hz, 1H, ArH), 7.44–7.39 (m, 2H, ArH), 7.18–7.14 (m, 1H, ArH), 6.95–6.89 (m, 2H, ArH), 6.69 (d, J = 7.6 Hz, 1H, ArH), 4.94–4.89 (m, 1H, CH), 3.87 (d, J = 8.8 Hz, 1H, CH), 3.77–3.71 (m, 2H, CH2), 3.69–3.53 (m, 2H, CH2), 3.24–3.11 (m, 2H, CH2), 0.60 (t, J = 15.0 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 174.9, 174.8, 169.0, 142.2, 141.6, 132.9, 129.3, 128.6, 128.0, 126.2, 126.2, 122.6, 121.1, 109.4, 102.2, 76.5, 68.5, 66.0, 60.6, 54.2, 49.8, 35.2, 13.6.
Ethyl 5-methyl-2,2″-dioxo-5′,6′,7′,7a′-tetrahydro-1′H-dispiro[indoline-3,2′-pyrrolizine-3′,3″-indoline]-1′-carboxylate (8c). White solid; 91% yield; 17:1 dr; mp >300 °C; IR (KBr) 1200, 1342, 1474, 1618, 1719, 2345, 3119, 3277 cm−1; HRMS (ESI) calcd for C25H25N3O4 [M + H]+ 432.1918, found 432.1924; 1H-NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H, NH), 10.11 (s, 1H, NH), 7.53 (d, J = 7.6 Hz, 1H, ArH), 7.19–7.15 (m, 2H, ArH), 6.95–6.88 (m, 2H, ArH), 6.61 (d, J = 7.6 Hz, 1H, ArH), 6.49 (d, J = 8.0 Hz, 1H, ArH), 4.94–4.89 (m, 1H, CH), 3.74–3.69 (m, 2H, CH2), 3.68–3.58 (m, 1H, CH2), 3.43–3.39 (m, 1H, CH2), 2.59 (d, J = 6.8 Hz, 1H, CH), 2.18 (s, 3H, CH3), 2.16–2.01 (m, 2H, CH2), 1.84–1.76 (m, 2H, CH2), 0.57 (t, J = 14.0 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 178.6, 176.2, 170.1, 143.0, 140.2, 129.9, 129.6, 129.0, 128.7, 128.5, 127.0, 125.2, 121.3, 109.6, 108.7, 77.6, 66.8, 65.7, 60.2, 57.7, 47.6, 30.0, 26.3, 21.4, 13.7.
Ethyl 5,7-dimethyl-2,2″-dioxo-5′,6′,7′,7a′-tetrahydro-1′H-dispiro[indoline-3,2′-pyrrolizine-3′,3″-indoline]-1′-carboxylate (8d). White solid; 94% yield; 50:1 dr; mp >300 °C; IR (KBr) 679, 750, 1115, 1202, 1325, 1474, 1616, 1715, 2961, 3092, 3157, 3308 cm−1; HRMS (ESI) calcd for C26H27N3O4 [M + H]+ 446.2074, found 446.2095; 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H, NH), 10.11 (s, 1H, NH), 7.54 (d, J = 7.6 Hz, 1H, ArH), 7.17 (t, J = 16.8 Hz, 1H, ArH), 7.00 (s, 1H, ArH), 6.93 (t, J = 14.8 Hz, 1H, ArH), 6.72 (s, 1H, ArH), 6.62 (d, J = 7.6 Hz, 1H, ArH), 4.87 (s, 1H, CH), 3.73–3.67 (m, 2H, CH2), 3.60 (d, J = 8.8 Hz, 2H, CH2), 3.35 (d, J = 7.6 Hz, 2H, CH2), 2.54 (d, J = 22.8 Hz, 1H, CH), 2.15 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.81 (s, 2H, CH2), 0.55 (t, J = 13.2 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 178.7, 176.2, 170.1, 142.9, 138.8, 130.5, 129.8, 129.4, 128.9, 126.6, 125.9, 125.3, 121.2, 117.7, 109.7, 77.4, 66.9, 65.6, 60.1, 57.7, 47.5, 30.1, 26.6, 21.3, 16.7, 13.6.
Ethyl 5-methoxy-2,2″-dioxo-5′,6′,7′,7a′-tetrahydro-1′H-dispiro[indoline-3,2′-pyrrolizine-3′,3″-indoline]-1′-carboxylate (8e). White solid; 90% yield; 17:1 dr; mp >300 °C; IR (KBr) 812, 1209, 1474, 1709, 1719, 2345, 3275 cm−1; HRMS (ESI) calcd for C25H25N3O5 [M + H]+ 448.1867, found 448.1879; 1H-NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H, NH), 10.17 (s, 1H, NH), 7.54 (d, J = 7.6 Hz, 1H, ArH), 7.17 (t, J = 14.8 Hz, 1H, ArH), 6.95–6.68 (m, 2H, ArH), 6.66 (d, J = 1.2 Hz, 1H, ArH), 6.61 (d, J = 7.6 Hz, 1H, ArH), 6.50 (d, J = 8.4 Hz, 1H, ArH), 4.96–4.91 (m, 1H, CH), 3.76–3.64 (m, 2H, CH2), 3.59 (s, 3H, OCH3), 3.50–3.43 (m, 2H, CH2), 2.60 (d, J = 6.8 Hz, 1H, CH), 2.18–2.11 (m, 2H, CH2), 2.09–1.74 (m, 2H, CH2), 0.60 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 178.8, 176.2, 170.2, 154.4, 143.0, 136.0, 130.0, 128.7, 128.1, 125.1, 121.4, 115.4, 113.0, 109.6, 109.1, 77.8, 67.0, 65.8, 60.2, 57.9, 55.8, 47.7, 29.8, 26.0, 13.7.
2′-(Methoxycarbonyl)-2-oxo-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indoline-3,3′-pyrrolizine]-1′-carboxylic acid (9a). White solid; 89% yield; 9:1 dr; mp 225–226 °C; IR (KBr) 764, 1182, 1202, 1381, 1595, 1740, 2365, 2986, 3370 cm−1; HRMS (ESI) calcd for C17H18N2O5 [M + H]+ 331.1288, found 331.1281; 1H-NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H, CO2H), 10.43 (s, 1H, NH), 7.35 (d, J = 7.6 Hz, 1H, ArH), 7.26–7.22 (m, 1H, ArH), 6.94 (t, J = 15.2 Hz, 1H, ArH), 6.82 (t, J = 11.2 Hz, 1H, ArH), 4.05–4.00 (m, 2H, CH2), 3.49 (d, J = 8.0 Hz, 1H, CH), 3.17 (s, 3H, CO2CH3), 3.12–3.06 (m, 1H, CH), 2.28 (t, J = 14.0 Hz, 1H, CH), 1.94–1.87 (m, 2H, CH2), 1.86–1.83 (m, 1H, CH2), 1.71–1.66 (m, 1H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 179.5, 173.1, 171.6, 143.4, 129.9, 127.7, 125.6, 121.5, 110.2, 70.6, 65.9, 54.4, 51.6, 49.1, 48.1, 48.0, 28.4, 27.2.
2′-(Methoxycarbonyl)-2-oxo-1-phenyl-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indoline-3,3′-pyrrolizine]-1′-carboxylic acid (9b). White solid; 91% yield; >99:1 dr; mp 163–165 °C; IR (KBr) 750, 1177, 1204, 1375, 1499, 1609, 1717, 1734, 2365, 2951, 3391 cm−1; HRMS (ESI) calcd for C23H22N2O5 [M + H]+ 407.1601, found 407.1615; 1H-NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H, CO2H), 7.60–7.55 (m, 3H, ArH), 7.49 (d, J = 1.2 Hz, 1H, ArH), 7.48–7.41 (m, 2H, ArH), 7.31–7.27 (m, 1H, ArH), 7.10–7.07 (m, 1H, ArH), 7.11 (d, J = 7.2 Hz, 1H, ArH), 4.12–3.96 (m, 2H, CH2), 3.77 (d, J = 8.0 Hz, 1H, CH), 3.41 (s, 3H, CO2CH3), 3.18–3.13 (m, 1H, CH), 2.40 (t, J = 14.4 Hz, 1H, CH), 1.96–1.94 (m, 2H, CH2), 1.93–1.92 (m, 1H, CH2), 1.78–1.75 (m, 1H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 177.3, 173.1, 171.3, 144.6, 134.5, 130.1, 130.1, 130.0, 128.7, 128.1, 127.4, 127.4, 125.0, 122.8, 109.5, 70.5, 66.1, 55.3, 51.7, 47.9, 47.7, 28.4, 27.4.
1,2,3,11b-Tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10a). Reddish-brown solid; 91% yield; 50:1 dr; mp 265–267 °C; IR (KBr) 762, 1177, 1348, 1472, 1589, 1665, 1740, 2345, 2967, 3349 cm−1; HRMS (ESI) calcd for C22H16N2O3 [M + H]+ 357.1234, found 357.1249; 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H, NH), 8.06 (d, J = 7.6 Hz, 1H, ArH), 7.91–7.83 (m, 3H, ArH), 7.31–7.27 (m, 1H, ArH), 7.15 (d, J = 7.6 Hz, 1H, ArH), 6.95–6.91 (m, 2H, ArH), 4.78 (t, J = 14.8 Hz, 1H, CH), 2.67–2.61 (m, 1H, CH2), 2.55–2.51 (m, 1H, CH2), 2.25–2.20 (m, 1H, CH2), 1.91–1.88 (m, 1H, CH2), 1.87–1.78 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.6, 181.5, 177.7, 152.5, 146.1, 143.3, 134.8, 134.7, 133.1, 132.7, 130.4, 127.1, 126.5, 126.3, 126.1, 121.7, 110.6, 77.0, 70.7, 47.8, 30.9, 27.7.
1′-Methyl-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10b). Orange solid; 89% yield; >99:1 dr; mp 265–266 °C; IR (KBr) 1474, 1560, 1653, 1719, 2345, 3366 cm−1; HRMS (ESI) calcd for C23H18N2O3 [M + H]+ 371.1390, found 371.1396; 1H-NMR (400 MHz, DMSO-d6): δ 8.07 (t, J = 8.4 Hz, 1H, ArH), 7.91 (t, J = 6.8 Hz, 1H, ArH), 7.89–7.80 (m, 2H, ArH), 7.42–7.38 (m, 1H, ArH), 7.21 (d, J = 6.8 Hz, 1H, ArH), 7.12 (d, J = 7.6 Hz, 1H, ArH), 7.04–7.00 (m, 1H, ArH), 4.81 (t, J = 14.8 Hz, 1H, CH), 3.19 (s, 3H, NCH3), 2.66–2.60 (m, 1H, CH2), 2.52–2.51 (m, 1H, CH2), 2.27–2.21 (m, 1H, CH2), 1.94–1.90 (m, 1H, CH2), 1.89–1.77 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.6, 181.4, 176.0, 152.5, 145.9, 144.6, 134.9, 134.7, 133.1, 132.6, 130.6, 126.8, 126.5, 126.3, 125.3, 122.4, 109.6, 76.6, 70.8, 47.8, 30.9, 27.8, 26.8.
1′-Phenyl-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10c). Reddish-brown solid; 83% yield; >99:1 dr; mp 275–276 °C; IR (KBr) 698, 756, 1375, 1458, 1670, 1734, 2345, 2877, 3266 cm−1; HRMS (ESI) calcd for C28H20N2O3 [M + H]+ 433.1547, found 433.1558; 1H-NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 7.2 Hz, 1H, ArH), 7.91–7.84 (m, 3H, ArH), 7.65–7.61 (m, 2H, ArH), 7.52–7.47 (m, 3H, ArH), 7.36–7.30 (m, 2H, ArH), 7.10–7.01 (m, 1H, ArH), 6.82 (d, J = 7.6 Hz, 1H, ArH), 4.86 (t, J = 15.2 Hz, 1H, CH), 2.77–2.74 (m, 1H, CH), 2.68–2.64 (m, 1H, CH2), 2.28–2.26 (m, 1H, CH2), 2.01–1.96 (m, 1H, CH2), 1.94–1.88 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.5, 181.6, 175.7, 152.4, 146.1, 144.4, 134.9, 134.8, 134.8, 133.2, 132.6, 130.7, 130.3, 130.3, 128.7, 127.4, 127.1, 126.6, 126.6, 126.3, 125.0, 123.1, 110.1, 76.9, 71.2, 47.6, 31.0, 28.1.
5′-Fluoro-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10d). Light-yellow solid; 92% yield; >99:1 dr; mp 277–278 °C; IR (KBr) 791, 1184, 1341, 1489, 1668, 1744, 2345, 3431 cm−1; HRMS (ESI) calcd for C22H15FN2O3 [M + H]+ 375.1139, found 375.1143; 1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H, NH), 8.05 (t, J = 7.2 Hz, 1H, ArH), 7.91–7.84 (m, 3H, ArH), 7.16–7.11 (m, 2H, ArH), 6.93–6.90 (m, 1H, ArH), 4.78 (t, J = 15.2 Hz, 1H, CH), 2.67–2.61 (m, 1H, CH2), 2.58–2.53 (m, 1H, CH2), 2.24–2.19 (m, 1H, CH2), 1.94–1.91 (m, 1H, CH2), 1.90–1.86 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.6, 181.5, 177.7, 159.2, 156.9, 152.7, 145.5, 139.5, 134.8, 134.7, 133.2, 132.7, 127.7, 127.6, 126.4, 126.3, 116.9, 116.7, 115.2, 114.9, 111.3, 111.2, 77.1, 70.8, 47.8, 30.7, 27.8.
5′-Bromo-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10e). Brown solid; 87% yield; >99:1 dr; mp 274–275 °C; IR (KBr) 814, 1288, 1344, 1474, 1667, 1748, 2345, 3431 cm−1; HRMS (ESI) calcd for C22H15BrN2O3 [M + H]+ 435.0339, found 435.0339; 1H-NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H, NH), 8.07–8.05 (m, 1H, ArH), 7.91–7.88 (m, 1H, ArH), 7.87–7.84 (m, 2H, ArH), 7.49–7.43 (m, 1H, ArH), 7.43 (s, 1H, ArH), 6.90 (d, J = 8.8 Hz, 1H, ArH), 4.80–4.76 (m, 1H, CH), 2.65–2.54 (m, 2H, CH), 2.24–2.18 (m, 1H, CH2), 1.95–1.93 (m, 1H, CH2), 1.91–1.89 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.6, 181.6, 177.3, 152.8, 145.3, 142.6, 134.8, 134.7, 133.3, 133.2, 132.7, 129.9, 128.4, 126.4, 126.3, 113.6, 112.5, 76.8, 70.9, 47.9, 30.6, 27.8.
6′-Chloro-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10f). Orange solid; 86% yield; >99:1 dr; mp 289–190 °C; IR (KBr) 1130, 1319, 1449, 1663, 1726, 2345, 3385 cm−1; HRMS (ESI) calcd for C22H15ClN2O3 [M + H]+ 391.0844, found 391.0847; 1H-NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H, NH), 8.04 (t, J = 7.2 Hz, 1H, ArH), 7.90–7.86 (m, 1H, ArH), 7.84–7.82 (m, 2H, ArH), 7.19 (d, J = 8.0 Hz, 1H, ArH), 7.01–6.95 (m, 1H, ArH), 6.94 (s, 1H, ArH), 4.78 (t, J = 14.8 Hz, 1H, CH), 2.65–2.53 (m, 2H, CH2), 2.24–2.20 (m, 1H, CH2), 1.92–1.90 (m, 1H, CH2), 1.89–1.83 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.5, 181.5, 177.6, 152.7, 145.5, 144.8, 134.9, 134.7, 134.7, 133.1, 132.6, 128.7, 126.5, 126.3, 124.9, 121.4, 110.7, 76.5, 70.8, 47.8, 30.8, 27.7.
6′-Bromo-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10g). Bright-yellow solid; 84% yield; 50:1 dr; mp 273–274 °C; IR (KBr) 1132, 1458, 1560, 1663, 1724, 2345, 3422 cm−1; HRMS (ESI) calcd for C22H15BrN2O3 [M + H]+ 435.0339, found 435.0341; 1H-NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H, NH), 8.05 (d, J = 7.2 Hz, 1H, ArH), 7.89–7.83 (m, 3H, ArH), 7.13 (s, 2H, ArH), 7.08 (s, 1H, ArH), 4.78 (t, J = 14.8 Hz, 1H, CH), 2.66–2.53 (m, 2H, CH2), 2.24–2.19 (m, 1H, CH2), 1.91–1.77 (m, 3H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.5, 181.5, 177.5, 152.7, 145.5, 144.9, 134.8, 134.7, 133.1, 132.6, 129.0, 126.5, 126.3, 125.4, 124.3, 123.2, 113.5, 76.5, 70.8, 47.9, 30.8, 27.7.
5′,7′-Dimethyl-1,2,3,11b-tetrahydrospiro[benzo[f]pyrrolo[2,1-a]isoindole-5,3′-indoline]-2′,6,11-trione (10h). Reddish-brown solid; 88% yield; >99:1 dr; mp 276–278 °C; IR (KBr) 708, 1296, 1341, 1481, 1670, 1719, 2345, 3387, 3399 cm−1; HRMS (ESI) calcd for C24H20N2O3 [M + H]+ 385.1547, found 385.1556; 1H-NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H, NH), 8.04 (d, J = 7.2 Hz, 1H, ArH), 7.90–7.83 (m, 3H, ArH), 6.91 (s, 1H, ArH), 6.78 (s, 1H, ArH), 4.77 (t, J = 14.8 Hz, 1H, CH), 2.69–2.63 (m, 1H, CH2), 2.53–2.48 (m, 1H, CH2), 2.24 (s, 3H, CH3), 2.16 (s, 3H, CH3), 1.91–1.84 (m, 2H, CH2), 1.83–1.76 (m, 2H, CH2); 13C-NMR (100 MHz, DMSO-d6): δ 182.7, 181.5, 178.1, 152.3, 146.3, 139.4, 134.8, 134.7, 133.1, 132.7, 132.2, 130.4, 126.4, 126.3, 125.8, 124.9, 119.5, 77.3, 70.7, 47.7, 31.0, 27.8, 21.0, 16.8.

3.3. General Procedure for the Synthesis of Compound 17

The reaction was performed by a mixture of acenaphthenequinone (16, 0.5 mmol), L-proline (6a, 0.6 mmol), and maleimides (11, 0.6 mmol) or methylene indolinone (12) in EtOH (3 mL) at room temperature for 4 h. The resulting precipitate was collected by filtration and washed with cold EtOH 2–3 times. The crude product was purified by recrystallization (in EtOH or MeOH) or column chromatography (the mixtures of petroleum ether and ethyl acetate were used as eluents) to afford the pure corresponding compounds (17).
3a′,6′,7′,8′,8a′,8b′-Hexahydro-1′H,2H-spiro[acenaphthylene-1,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (17a). Reddish-brown solid; 87% yield; >99:1 dr; mp 178–179 °C; IR (KBr) 768, 918, 1177, 1325, 1595, 1695, 1732, 2737, 2949, 3462 cm−1; HRMS (ESI) calcd for C20H16N2O3 [M + H]+ 333.1234, found 333.1240; 1H-NMR (400 MHz, DMSO-d6): δ 11.40 (s, 1H, NH), 8.32 (d, J = 8.0 Hz, 1H, ArH), 8.06 (d, J = 8.8 Hz, 1H, ArH), 7.95 (t, J = 6.8 Hz, 1H, ArH), 7.87–7.83 (m, 1H, ArH), 7.75–7.71 (m, 1H, ArH), 7.46 (d, J = 6.8 Hz, 1H, ArH), 4.26–4.20 (m, 1H, CH), 3.68–3.62 (m, 2H, CH2), 2.56–2.53 (m, 1H, CH), 2.31–2.26 (m, 1H, CH), 2.11–1.70 (m, 4H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 203.7, 179.2, 177.8, 142.1, 134.9, 132.7, 130.6, 130.2, 128.9, 128.7, 126.0, 124.5, 122.4, 73.3, 65.2, 56.0, 48.7, 46.9, 25.9, 24.1.
2′-Ethyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H,2H-spiro[acenaphthylene-1,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (17b). Yellow solid; 93% yield; >99:1 dr; mp 248–249 °C; IR (KBr) 792, 1215, 1354, 1686, 1724, 2361, 2978 cm−1; HRMS (ESI) calcd for C22H20N2O3 [M + H]+ 361.1547, found 361.1551; 1H-NMR (400 MHz, DMSO-d6): δ 8.34 (d, J = 8.0 Hz, 1H, ArH), 8.07 (d, J = 8.8 Hz, 1H, ArH), 7.98 (d, J = 6.8 Hz, 1H, ArH), 7.86 (t, J = 15.2 Hz, 1H, ArH), 7.73 (t, J = 15.6 Hz, 1H, ArH), 7.38 (d, J = 7.2 Hz, 1H, ArH), 4.31–4.26 (m, 1H, CH), 3.72 (d, J = 8.0 Hz, 1H, CH), 3.65 (t, J = 16.4 Hz, 1H, CH), 3.63–3.45 (m, 2H, CH2), 2.50–2.46 (m, 1H, CH2), 2.35–2.30 (m, 1H, CH2), 2.12–2.06 (m, 1H, CH2), 1.98–1.90 (m, 1H, CH2), 1.80–1.69 (m, 2H, CH2), 1.15 (t, J = 14.4 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 203.2, 177.4, 176.1, 142.1, 134.6, 132.7, 130.6, 130.2, 129.0, 128.7, 126.1, 124.9, 122.5, 73.8, 65.2, 54.3, 47.7, 47.5, 33.7, 25.6, 24.2, 13.0.
2′-Phenyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H,2H-spiro[acenaphthylene-1,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (17c). Yellow solid; 89% yield; >99:1 dr; mp 201–203 °C; IR (KBr) 1188, 1389, 1700, 1717, 2367, 2957 cm−1; HRMS (ESI) calcd for C26H20N2O3 [M + H]+ 409.1547, found 409.1540; 1H-NMR (400 MHz, DMSO-d6): δ 8.34 (d, J = 8.0 Hz, 1H, ArH), 8.07 (d, J = 8.0 Hz, 1H, ArH), 8.01 (d, J = 6.8 Hz, 1H, ArH), 7.87 (t, J = 8.0 Hz, 1H, ArH), 7.74 (t, J = 8.4 Hz, 1H, ArH), 7.71–7.54 (m, 2H, ArH), 7.51–7.46 (m, 2H, ArH), 7.36 (t, J = 8.8 Hz, 2H, ArH), 4.42–4.37 (m, 1H, CH), 3.90 (d, J = 8.0 Hz, 1H, CH), 3.86 (t, J = 16.0 Hz, 1H, CH), 2.67–2.51 (m, 1H, CH2), 2.47–2.41 (m, 1H, CH2), 2.18–2.15 (m, 1H, CH2), 2.01–1.98 (m, 1H, CH2), 1.88–1.86 (m, 1H, CH2), 1.79–1.74 (m, 1H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 203.1, 176.8, 175.4, 142.2, 134.5, 132.8, 132.8, 130.7, 130.2, 129.6, 129.6, 129.0, 129.0, 128.8, 127.4, 127.4, 126.2, 125.0, 122.7, 74.4, 65.5, 54.6, 48.2, 48.1, 25.6, 24.5.
2′-Benzyl-3a′,6′,7′,8′,8a′,8b′-hexahydro-1′H,2H-spiro[acenaphthylene-1,4′-pyrrolo[3,4-a]pyrrolizine]-1′,2,3′(2′H)-trione (17d). Yellow solid; 90% yield; >99:1 dr; mp 207–209 °C; IR (KBr) 702, 779, 1165, 1346, 1395, 1694, 1701, 1712, 2828, 2933, 2951 cm−1; HRMS (ESI) calcd for C27H22N2O3 [M + H]+ 423.1703, found 423.1713; 1H-NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 8.0 Hz, 1H, ArH), 8.01 (d, J = 8.0 Hz, 1H, ArH), 7.95 (t, J = 6.8 Hz, 1H, ArH), 7.84 (t, J = 8.0 Hz, 1H, ArH), 7.50 (t, J = 8.8 Hz, 1H, ArH), 7.48–7.36 (m, 5H, ArH), 6.82 (d, J = 7.2 Hz, 1H, ArH), 4.69 (d, J = 14.4 Hz, 1H, CH2), 4.58 (d, J = 14.4 Hz, 1H, CH2), 4.31–4.26 (m, 1H, CH), 3.76 (d, J = 8.0 Hz, 1H, CH), 3.72 (t, J = 16.0 Hz, 1H, CH), 2.20–2.13 (m, 2H, CH2), 2.11–2.08 (m, 1H, CH2), 1.93–1.88 (m, 1H, CH2), 1.65–1.59 (m, 2H, CH2); 13C-NMR (400 MHz, DMSO-d6): δ 203.0, 177.3, 175.9, 142.1, 136.1, 134.5, 132.7, 130.6, 130.2, 129.1, 129.1, 129.0, 129.0, 129.0, 128.5, 128.4, 126.0, 124.9, 122.6, 74.0, 65.2, 54.2, 47.9, 47.6, 42.4, 25.2, 23.9.
Ethyl 5″-methoxy-2,2″-dioxo-5′,6′,7′,7a′-tetrahydro-1′H,2H-dispiro[acenaphthylene-1,3′-pyrrolizine-2′,3″-indoline]-1′-carboxylate (17e). Yellow solid; 85% yield; 50:1 dr; mp 277–279 °C; IR (KBr) 743, 1212, 1347, 1434, 1700, 1756, 2825, 2998 cm−1; HRMS (ESI) calcd for C29H26N2O5 [M + H]+ 483.1914, found 483.1921; 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H, NH), 8.16 (d, J = 8.0 Hz, 1H, ArH), 7.84–7.75 (m, 3H, ArH), 7.34 (t, J = 15.2 Hz, 2H, ArH), 6.84–6.76 (m, 2H, ArH), 6.49 (d, J = 8.4 Hz, 1H, ArH), 4.48–4.42 (m, 1H, CH), 4.22 (d, J = 8.8 Hz, 1H, CH), 3.81 (s, 3H, OCH3), 3.69–3.63 (m, 2H, CH2), 2.59–2.55 (m, 2H, CH2), 2.38–2.23 (m, 2H, CH2), 2.14–2.10 (m, 2H, CH2), 0.69 (t, J = 14.0 Hz, 3H, CH3); 13C-NMR (400 MHz, DMSO-d6): δ 207.2, 173.6, 169.8, 154.8, 141.0, 136.4, 135.9, 132.1, 131.8, 130.3, 129.3, 128.7, 128.5, 125.7, 122.2, 120.4, 114.0, 113.6, 109.9, 79.5, 68.2, 66.2, 60.4, 56.2, 52.2, 46.5, 31.4, 30.4, 13.8.

4. 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.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms24043771/s1.

Author Contributions

Conceptualization, Y.W. and L.Y.; methodology, Y.W. and Y.Y.; validation, Y.W., S.L., H.L. and J.L.; formal analysis, Y.W. and L.Y.; investigation, Y.Y., S.L., H.L. and J.L.; resources, Y.W., L.Y. and J.D.; data curation, Y.W., S.L., H.L. and J.L.; writing—original draft preparation, Y.W.; writing—review and editing, Y.W., L.Y. and J.D.; visualization, Y.W.; supervision, Y.W. and J.D.; project administration, Y.W. and L.Y.; funding acquisition, Y.W., L.Y. and J.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Yunnan Fundamental Research Projects (Nos. 202001AT070054 and 202001AT070062), the first-class curriculum construction project of Yunnan Normal University (No. 2020hhkc08), and the Special Basic Cooperative Research Programs of Yunnan Provincial Undergraduate Universities (No. 2019FH001–109).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Recent advances in organocatalytic methods for the synthesis of disubstituted 2- and 3-indolinones. Chem. Soc. Rev. 2012, 41, 7247–7290. [Google Scholar] [CrossRef] [PubMed]
  2. Singh, G.S.; Desta, Z.Y. Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks. Chem. Rev. 2012, 112, 6104–6155. [Google Scholar] [CrossRef] [PubMed]
  3. Mei, G.J.; Shi, F. Catalytic asymmetric synthesis of spirooxindoles: Recent developments. Chem. Commun. 2018, 54, 6607–6621. [Google Scholar] [CrossRef]
  4. Nasri, S.; Bayat, M.; Mirzaei, F. Recent strategies in the synthesis of spiroindole and spirooxindole scaffolds. Top. Curr. Chem. 2021, 379, 25–62. [Google Scholar] [CrossRef] [PubMed]
  5. Rana, S.; Blowers, E.C.; Tebbe, C.; Contreras, J.I.; Radhakrishnan, P.; Kizhake, S.; Zhou, T.; Rajule, R.N.; Arnst, J.L.; Munkarah, A.R.; et al. Isatin derived spirocyclic analogues with α-Methylene-γ-butyrolactone as anticancer agents: A structure–activity relationship study. J. Med. Chem. 2016, 59, 5121–5127. [Google Scholar] [CrossRef]
  6. Nivetha, N.; Martiz, R.M.; Patil, S.M.; Ramu, R.; Sreenivasa, S.; Velmathi, S. Benzodioxole grafted spirooxindole pyrrolidinyl derivatives: Synthesis, characterization, molecular docking and anti-diabetic activity. RSC Adv. 2022, 12, 24192–24207. [Google Scholar] [CrossRef] [PubMed]
  7. Al-Rashood, S.T.; Hamed, A.R.; Hassan, G.S.; Alkahtani, H.M.; Almehizia, A.A.; Alharbi, A.; Al-Sanea, M.M.; Eldehna, W.M. Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity. J. Enzyme Inhib. Med. Chem. 2020, 35, 831–839. [Google Scholar] [CrossRef]
  8. Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; et al. A Potent amall-molecule inhibitor of the MDM2–p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J. Med. Chem. 2013, 56, 5553–5561. [Google Scholar] [CrossRef] [PubMed]
  9. Cui, C.B.; Kakeya, H.; Osada, H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996, 52, 12651–12666. [Google Scholar] [CrossRef]
  10. Dideberg, O.; Lamotte-Brasseur, J.; Dupont, L.; Campsteyn, H.; Vermeire, M.; Angenot, L. Structure cristalline et moléculaire d’un nouvel alcalöide bisindolique: Complexe moléculaire 1:2 strychnofoline-ethanol (C30H34N4O2·2C2H6O). Acta Crystallogr. B 1977, 33, 1796–1801. [Google Scholar] [CrossRef]
  11. Yu, Q.; Guo, P.; Jian, J.; Chen, Y.; Xu, J. Nine-step total synthesis of (-)-strychnofoline. Chem. Commun. 2018, 54, 1125–1128. [Google Scholar] [CrossRef]
  12. Premachandra, I.D.U.A.; Scott, K.A.; Shen, C.T.; Wang, F.Q.; Lane, S.; Liu, H.Q.; Vranken, D.L.V. Potent synergy between spirocyclic pyrrolidinoindolinones and fluconazole against calbicans. ChemMedChem 2015, 10, 1672–1686. [Google Scholar] [CrossRef] [PubMed]
  13. Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R.S.; Qiu, S.; Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl. Acad. Sci. USA 2008, 105, 3933–3938. [Google Scholar] [CrossRef]
  14. Yu, B.; Zheng, Y.-C.; Shi, X.-J.; Qi, P.-P.; Liu, H.-M. Natural product-derived spirooxindole fragments serve as privileged substructures for discovery of new anticancer agents. Anticancer Agents Med. Chem. 2016, 16, 1315–1324. [Google Scholar] [CrossRef] [PubMed]
  15. Yu, B.; Yu, Z.; Qi, P.-P.; Yu, D.-Q.; Liu, H.-M. Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: Success and challenges. Eur. J. Med. Chem. 2015, 95, 35–40. [Google Scholar] [CrossRef] [PubMed]
  16. Ye, N.; Chen, H.; Wold, E.A.; Shi, P.-Y.; Zhou, J. Therapeutic potential of spirooxindoles as antiviral agents. ACS Infect. Dis. 2016, 2, 382–392. [Google Scholar] [CrossRef]
  17. Yu, B.; Yu, D.-Q.; Liu, H.-M. Spirooxindoles: Promising scaffolds for anticancer agents. Eur. J. Med. Chem. 2015, 97, 673–698. [Google Scholar] [CrossRef] [PubMed]
  18. Gui, H.-Z.; Wei, Y.; Shi, M. Recent advances in the construction of trifluoromethyl-containing spirooxindoles through cycloaddition reactions. Chem-Asian J. 2020, 15, 1225–1233. [Google Scholar] [CrossRef] [PubMed]
  19. Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C.F. Organocatalytic asymmetric assembly reactions: Synthesis of spirooxindoles via organocascade strategies. ACS Catal. 2014, 4, 743–762. [Google Scholar] [CrossRef]
  20. Hong, L.; Wang, R. Recent advances in asymmetric organocatalytic construction of 3,3′-spirocyclic oxindoles. Adv. Synth. Catal. 2013, 355, 1023–1052. [Google Scholar] [CrossRef]
  21. Galliford, C.V.; Scheidt, K.A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. [Google Scholar] [CrossRef] [PubMed]
  22. Boda, S.; Dharavath, R.; Madhavaram, M.; Adem, K.; Palithapu, M.; Maloth, G.; Parthasarathy, T. A conventional and solid-state synthesis, biological activity, and molecular docking studies of 6-arylbenzo[4,5]imidazo[1,2-a] [1,8]naphthyridin-10-ols. Synth. Commun. 2019, 49, 1–11. [Google Scholar] [CrossRef]
  23. Shen, P.; Guo, Y.; Wei, J.; Zhao, H.; Zhai, H.; Zhao, Y. Straightforward synthesis of succinimide-fused pyrrolizidines by a three-component reaction of α-diketone, amino acid, and maleimide. Synthesis 2020, 53, 1262–1270. [Google Scholar]
  24. Hashimoto, T.; Maruoka, K. Recent advances of catalytic asymmetric 1,3-dipolar cycloadditions. Chem. Rev. 2015, 115, 5366–5412. [Google Scholar] [CrossRef] [PubMed]
  25. Kissane, M.; Maguire, A.R. Asymmetric 1,3-dipolar cycloadditions of acrylamides. Chem. Soc. Rev. 2010, 39, 845–883. [Google Scholar] [CrossRef] [PubMed]
  26. Adrio, J.; Carretero, J.C. Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Chem. Commun. 2014, 50, 12434–12446. [Google Scholar] [CrossRef] [PubMed]
  27. Li, J.; Ye, Y.; Zhang, Y. Cycloaddition/annulation strategies for the construction of multisubstituted pyrrolidines and their applications in natural product synthesis. Org. Chem. Front. 2018, 5, 864–892. [Google Scholar] [CrossRef]
  28. Yan, L.-J.; Wang, Y.-C. Recent advances in green synthesis of 3,3′-spirooxindoles via isatin-based one-pot multicomponent cascade reactions in aqueous medium. ChemistrySelect 2016, 1, 6948–6960. [Google Scholar] [CrossRef]
  29. Karcev, D.D.; Efremova, M.M.; Molchanov, A.P.; Rostovskii, N.V.; Kryukova, M.A.; Bunev, A.S.; Khochenkov, D.A. Selective and reversible 1,3-dipolar cycloaddition of 2-(2-oxoindoline-3-ylidene)acetates with nitrones in the synthesis of functionalized spiroisoxazolidines. Int. J. Mol. Sci. 2022, 23, 12639. [Google Scholar] [CrossRef] [PubMed]
  30. Wang, Y.; Cobo, A.A.; Franz, A.K. Recent advances in organocatalytic asymmetric multicomponent cascade reactions for enantioselective synthesis of spirooxindoles. Org. Chem. Front. 2021, 8, 4315–4348. [Google Scholar] [CrossRef]
  31. Haddad, S.; Boudriga, S.; Porzio, F.; Soldera, A.; Askri, M.; Knorr, M.; Rousselin, Y.; Kubicki, M.M.; Golz, C.; Strohmann, C. Regio- and stereoselective synthesis of spiropyrrolizidines and piperazines through azomethine ylide cycloaddition reaction. J. Org. Chem. 2015, 80, 9064–9075. [Google Scholar] [CrossRef]
  32. Arumugam, N.; Almansour, A.I.; Kumar, R.S.; Periasamy, V.S.; Athinarayanan, J.; Alshatwi, A.A.; Govindasami, P.; Altaf, M.; Menéndez, J.C. Regio- and diastereoselective synthesis of anticancer spirooxindoles derived from tryptophan and histidine via three-component 1,3-dipolar cycloadditions in an ionic liquid. Tetrahedron 2018, 74, 5358–5366. [Google Scholar] [CrossRef]
  33. Mali, P.R.; Chandrasekhara Rao, L.; Bangade, V.M.; Shirsat, P.K.; George, S.A.; Jagadeesh Babu, N.; Meshram, H.M. A convenient and rapid microwave-assisted synthesis of spirooxindoles in aqueous medium and their antimicrobial activities. New J. Chem. 2016, 40, 2225–2232. [Google Scholar] [CrossRef]
  34. Puerto Galvis, C.E.; Kouznetsov, V.V. Regio- and stereoselective synthesis of spirooxindole 1′-nitro pyrrolizidines with five concurrent stereocenters under aqueous medium and their bioprospection using the zebrafish (Danio rerio) embryo model. Org. Biomol. Chem. 2013, 11, 7372–7386. [Google Scholar] [CrossRef] [PubMed]
  35. Barkov, A.Y.; Zimnitskiy, N.S.; Korotaev, V.Y.; Kutyashev, I.B.; Moshkin, V.S.; Sosnovskikh, V.Y. Highly regio- and stereoselective 1,3-dipolar cycloaddition of stabilised azomethine ylides to 3,3,3-trihalogeno-1-nitropropenes: Synthesis of trihalomethylated spiro[indoline-3,2′-pyrrolidin]-2-ones and spiro[indoline-3,3′-pyrrolizin]-2-ones. Tetrahedron 2016, 72, 6825–6836. [Google Scholar] [CrossRef]
  36. Alimohammadi, K.; Sarrafi, Y.; Tajbakhsh, M.; Yeganegi, S.; Hamzehloueian, M. An experimental and theoretical investigation of the regio- and stereoselectivity of the polar [3 + 2] cycloaddition of azomethine ylides to nitrostyrenes. Tetrahedron 2011, 67, 1589–1597. [Google Scholar] [CrossRef]
  37. Anusha Rani, M.; Vivek Kumar, S.; Malathi, K.; Muthu, M.; Almansour, A.I.; Suresh Kumar, R.; Ranjith Kumar, R. A One-pot multicomponent 1,3-dipolar cycloaddition strategy: Combinatorial synthesis of dihydrothiophenone-engrafted dispiro hybrid heterocycles. ACS Comb. Sci. 2017, 19, 308–314. [Google Scholar] [CrossRef] [PubMed]
  38. Lin, B.; Zhou, G.; Gong, Y.; Wei, Q.-D.; Tian, M.-Y.; Liu, X.-L.; Feng, T.-T.; Zhou, Y.; Yuan, W.-C. Molecular hybridization-guided one-pot multicomponent synthesis of turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles via a 1,3-dipolar cycloaddition reaction. Molecules 2017, 22, 645. [Google Scholar] [CrossRef] [PubMed]
  39. Revathy, K.; Lalitha, A. An efficient green chemistry protocol for the synthesis of novel spiropyrrolizidine compounds. RSC Adv. 2014, 4, 279–285. [Google Scholar] [CrossRef]
  40. Xiao, J.A.; Zhang, H.G.; Liang, S.; Ren, J.W.; Yang, H.; Chen, X.Q. Synthesis of pyrrolo(spiro-[2.3′]-oxindole)-spiro-[4.3″]-oxindole via 1,3-dipolar cycloaddition of azomethine ylides with 3-acetonylideneoxindole. J. Org. Chem. 2013, 78, 11577–11583. [Google Scholar] [CrossRef]
  41. Palomba, M.; De Monte, E.; Mambrini, A.; Bagnoli, L.; Santi, C.; Marini, F. A three-component [3 + 2]-cycloaddition/elimination cascade for the synthesis of spirooxindole-pyrrolizines. Org. Biomol. Chem. 2021, 19, 667–676. [Google Scholar] [CrossRef]
  42. Sankar, U.; Surya Kumar, C.V.; Subramanian, V.; Balasubramanian, K.K.; Mahalakshimi, S. Stereo-, regio-, and chemoselective [3 + 2]-cycloaddition of (2E,4E)-ethyl 5-(phenylsulfonyl)penta-2,4-dienoate with various azomethine ylides, nitrones, and nitrile oxides: Synthesis of pyrrolidine, isoxazolidine, and isoxazoline derivatives and a computational study. J. Org. Chem. 2016, 81, 2340–2354. [Google Scholar]
  43. Tiwari, K.N.; Pandurang, T.P.; Pant, S.; Kumar, R. Highly efficient and regioselective synthesis of spirooxindolo pyrrolizidines by reaction of isatin, proline and acrylonitrile/methyl acrylate in water. Tetrahedron Lett. 2016, 57, 2286–2289. [Google Scholar] [CrossRef]
  44. Cao, J.; Yang, F.; Sun, J.; Huang, Y.; Yan, C.-G. Construction of unique eight- or nine-membered polyheterocyclic systems via multicomponent reaction of l-proline, alkyl propiolate, and isatin. J. Org. Chem. 2019, 84, 622–635. [Google Scholar] [CrossRef]
  45. Mali, P.R.; Shirsat, P.K.; Khomane, N.; Nayak, L.; Nanubolu, J.B.; Meshram, H.M. 1,3-Dipolar cycloaddition reactions for the synthesis of novel oxindole derivatives and their cytotoxic properties. ACS Comb. Sci. 2017, 19, 633–639. [Google Scholar] [CrossRef] [PubMed]
  46. Shi, G.; He, X.; Shang, Y.; Xie, M. Combinatorial synthesis of spiro[indoline-3,2′-pyrrole] derivatives via a three-component reaction under catalyst-free conditions. RSC Adv. 2016, 6, 10412–10418. [Google Scholar] [CrossRef]
  47. Kolle, S.; Barak, D.S.; Ghosh, A.; Jaiswal, V.; Kant, R.; Batra, S. Dehydrative transformation of spirooxindoles to pyrido[2,3-b]indoles via POCl3. ACS Omega 2019, 4, 5617–5629. [Google Scholar] [CrossRef] [PubMed]
  48. Wang, C.-S.; Zhu, R.-Y.; Zheng, J.; Shi, F.; Tu, S.-J. Enantioselective construction of spiro[indoline-3,2′-pyrrole] framework via catalytic asymmetric 1,3-dipolar cycloadditions using allenes as equivalents of alkynes. J. Org. Chem. 2015, 80, 512–520. [Google Scholar] [CrossRef]
  49. Qian, Y.-L.; Xia, P.-J.; Li, J.; Zhao, Q.-L.; Xiao, J.-A.; Xiang, H.-Y.; Yang, H. Diversity-driven and facile 1,3-dipolar cycloaddition to access dispirooxindole-imidazolidine scaffolds. Org. Biomol. Chem. 2017, 15, 8705–8708. [Google Scholar] [CrossRef]
  50. Angyal, A.; Demjén, A.; Harmat, V.; Wölfling, J.; Puskás, L.G.; Kanizsai, I. 1,3-Dipolar cycloaddition of isatin-derived azomethine ylides with 2H-azirines: Stereoselective synthesis of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles. J. Org. Chem. 2019, 84, 4273–4281. [Google Scholar] [CrossRef] [PubMed]
  51. Filatov, A.S.; Knyazev, N.A.; Molchanov, A.P.; Panikorovsky, T.L.; Kostikov, R.R.; Larina, A.G.; Boitsov, V.M.; Stepakov, A.V. Synthesis of functionalized 3-spiro[cyclopropa[a]pyrrolizine]- and 3-spiro[3-azabicyclo[3.1.0]hexane]oxindoles from cyclopropenes and azomethine ylides via [3 + 2]-cycloaddition. J. Org. Chem. 2017, 82, 959–975. [Google Scholar] [CrossRef]
  52. Beletskaya, I.P.; Nájera, C.; Yus, M. Chemodivergent reactions. Chem. Soc. Rev. 2020, 49, 7101–7166. [Google Scholar] [CrossRef]
  53. Chintawar, C.C.; Yadav, A.K.; Kumar, A.; Sancheti, S.P.; Patil, N.T. Divergent gold catalysis: Unlocking molecular diversity through catalyst control. Chem. Rev. 2021, 121, 8478–8558. [Google Scholar] [CrossRef] [PubMed]
  54. Wei, Y.; Shi, M. Divergent synthesis of carbo- and heterocycles via gold-catalyzed reactions. ACS Catal. 2016, 6, 2515–2524. [Google Scholar] [CrossRef]
  55. Neufeldt, S.R.; Sanford, M.S. Controlling site selectivity in palladium-catalyzed C–H bond functionalization. Acc. Chem. Res. 2012, 45, 936–946. [Google Scholar] [CrossRef]
  56. Gong, P.; Ma, Y.; Wang, X.; Yu, L.; Zhu, S. A facile and diverse synthesis of coumarin substituted spirooxindole and dispiro oxindole-pyrrolizidine/pyrrolothiazole/pyrrolidine derivatives via 1, 3-dipolar cycloaddition. Tetrahedron 2021, 91, 132221–132231. [Google Scholar] [CrossRef]
  57. Rajesh, S.M.; Perumal, S.; Menéndez, J.C.; Yogeeswari, P.; Sriram, D. Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition. MedChemComm 2011, 2, 626–630. [Google Scholar] [CrossRef]
  58. Wang, K.-K.; Li, Y.-L.; Chen, R.; Wang, Z.-Y.; Li, N.-B.; Zhang, L.L.; Gu, S. Substrate-controlled regioselectivity switchable [3 + 2] annulations to access spirooxindole skeletons. J. Org. Chem. 2022, 87, 8158–8169. [Google Scholar] [CrossRef] [PubMed]
  59. Wang, K.-K.; Li, Y.-L.; Chen, R.-X.; Sun, A.-L.; Wang, Z.-Y.; Zhao, Y.-C.; Wang, M.-Y.; Sheng, S. Substrate-controlled regioselectivity switch in a three-component 1,3-dipolar cycloaddition reaction to access 3,3′-pyrrolidinyl-spirooxindoles derivatives. Adv. Synth. Catal. 2022, 364, 2047–2052. [Google Scholar] [CrossRef]
  60. Brandão, P.; Marques, C.; Burke, A.J.; Pineiro, M. The application of isatin-based multicomponent-reactions in the quest for new bioactive and druglike molecules. Eur. J. Med. Chem. 2021, 211, 113102. [Google Scholar] [CrossRef]
  61. Ganesh, M.; Suraj, S. Expeditious entry into carbocyclic and heterocyclic spirooxindoles. Org. Biomol. Chem. 2022, 20, 5651–5693. [Google Scholar] [CrossRef] [PubMed]
  62. Qin, N.; Lu, X.; Liu, Y.; Qiao, Y.; Qu, W.; Feng, F.; Sun, H. Recent research progress of Uncaria spp. based on alkaloids: Phytochemistry, pharmacology and structural chemistry. Eur. J. Med. Chem. 2021, 210, 112960. [Google Scholar] [CrossRef]
  63. Azizian, J.; Asadi, A.; Jadidi, K. One-pot highly diastereo-selective synthesis of new 2-substituted 8-(sprio-3′- indolino-2′-one)-pyrrolo[3,4-a]-pyrrolizine-1,3-diones mediated by azomethine ylide induced by microwave irradiation. Synth. Commun. 2001, 31, 2727–2733. [Google Scholar] [CrossRef]
  64. Rehn, S.; Bergman, J.; Stensland, B. The three-component reaction between isatin, α-amino acids, and dipolarophiles. Eur. J. Org. Chem. 2004, 2004, 413–418. [Google Scholar] [CrossRef]
  65. Xu, Q.; Wang, D.; Wei, Y.; Shi, M. Highly efficient and stereoselective construction of bispirooxindole derivatives via a three-component 1,3-dipolar cycloaddition reaction. ChemistryOpen 2014, 3, 93–98. [Google Scholar] [CrossRef]
  66. Qian, Y.-L.; Li, B.; Xia, P.-J.; Wang, J.; Xiang, H.-Y.; Yang, H. Diastereospecific entry to pyrrolidinyldispirooxindole skeletons via three-component 1,3-dipolar cycloadditions. Tetrahedron 2018, 74, 6821–6828. [Google Scholar] [CrossRef]
  67. Lin, B.; Zhang, W.-H.; Wang, D.-D.; Gong, Y.; Wei, Q.-D.; Liu, X.-L.; Feng, T.-T.; Zhou, Y.; Yuan, W.-C. 3-Methyl-4-nitro-5-isatylidenyl-isoxazoles as 1,3-dipolarophiles for synthesis of polycyclic 3,3′-pyrrolidinyl-dispirooxindoles and their biological evaluation for anticancer activities. Tetrahedron 2017, 73, 5176–5188. [Google Scholar] [CrossRef]
  68. Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P.T. Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity. Eur. J. Med. Chem. 2012, 51, 79–91. [Google Scholar] [CrossRef] [PubMed]
  69. Dandia, A.; Jain, A.K.; Laxkar, A.K. Ethyl lactate as a promising bio based green solvent for the synthesis of spiro-oxindole derivatives via 1,3-dipolar cycloaddition reaction. Tetrahedron Lett. 2013, 54, 3929–3932. [Google Scholar] [CrossRef]
  70. Chen, H.; Wang, S.-Y.; Xu, X.-P.; Ji, S.-J. Facile three-component synthesis of spirooxindolepyrrololine ring systems via 1,3-dipolar cycloaddition with 1,4-naphthoquinone. Synth. Commun. 2011, 41, 3280–3288. [Google Scholar] [CrossRef]
  71. Dandia, A.; Jain, A.K.; Sharma, S.; Singh, R. Task-specific ionic liquid mediated eco-compatible approach for the synthesis of spirooxindole derivatives and their DNA cleavage activity. J. Heterocycl. Chem. 2018, 55, 1419–1425. [Google Scholar] [CrossRef]
  72. Zhang, X.; Liu, M.; Qiu, W.; Evans, J.; Kaur, M.; Jasinski, J.P.; Zhang, W. One-pot synthesis of polycyclic spirooxindoles via montmorillonite K10-catalyzed C–H functionalization of cyclic amines. ACS Sustain. Chem. Eng. 2018, 6, 5574–5579. [Google Scholar] [CrossRef]
  73. Wang, Y.-C.; Wang, J.-L.; Burgess, K.S.; Zhang, J.-W.; Zheng, Q.-M.; Pu, Y.-D.; Yan, L.-J.; Chen, X.-B. Green synthesis of new pyrrolidine-fused spirooxindoles via three-component domino reaction in EtOH/H2O. RSC Adv. 2018, 8, 5702–5713. [Google Scholar] [CrossRef] [PubMed]
  74. Yan, L.-J.; Wang, J.-L.; Xu, D.; Burgess, K.S.; Zhu, A.-F.; Rao, Y.-Y.; Chen, X.-B.; Wang, Y.-C. Chemically sustainable and green one-pot multicomponent synthesis of highly functionalized polycyclic N-fused-pyrrolidine heterocycles. ChemistrySelect 2018, 3, 662–665. [Google Scholar] [CrossRef]
Ijms 24 03771 g001 550
Figure 1. Representative natural and synthetic N-fused pyrrolidinyl spirooxindoles.
Figure 1. Representative natural and synthetic N-fused pyrrolidinyl spirooxindoles.
Ijms 24 03771 g001
Ijms 24 03771 sch001 550
Scheme 1. Three-component 1,3-dipolar cycloaddition reactions.
Scheme 1. Three-component 1,3-dipolar cycloaddition reactions.
Ijms 24 03771 sch001
Ijms 24 03771 sch002 550
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 1H NMR analysis. b D-proline was used instead of 6a. c 20:1 dr. d 17:1 dr.
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 1H NMR analysis. b D-proline was used instead of 6a. c 20:1 dr. d 17:1 dr.
Ijms 24 03771 sch002
Ijms 24 03771 sch003 550
Scheme 3. The synthesis of products 8 and 9.
Scheme 3. The synthesis of products 8 and 9.
Ijms 24 03771 sch003
Ijms 24 03771 sch004 550
Scheme 4. The synthesis of product 10.
Scheme 4. The synthesis of product 10.
Ijms 24 03771 sch004
Ijms 24 03771 sch005 550
Scheme 5. The synthesis of product 17.
Scheme 5. The synthesis of product 17.
Ijms 24 03771 sch005
Ijms 24 03771 sch006 550
Scheme 6. Scale-up of the 1,3-dipolar cycloaddition reaction.
Scheme 6. Scale-up of the 1,3-dipolar cycloaddition reaction.
Ijms 24 03771 sch006
Table
Table 1. Optimization of reaction conditions for the model reaction a.
Table 1. Optimization of reaction conditions for the model reaction a.
Ijms 24 03771 i001
EntrySolventTemperature (°C)Time (h)Yield b (%)
1Toluener.t. c472
2Benzener.t.457
3Acetonitriler.t.449
4Etherr.t.432
5DCEr.t.467
6DCMr.t.461
7CHCl3r.t.458
8THFr.t.445
9Acetoner.t.424
101,4-Dioxaner.t.464
11DMSOr.t.438
12DMFr.t.425
13H2Or.t.418
14iPrOHr.t.481
15MeOHr.t.494
16EtOHr.t.493
17EtOH40493
18EtOHreflux494
19EtOHr.t.278
20EtOHr.t.893
21EtOHr.t.2494
a All reactions were carried out with isatin 5a (0.5 mmol), L-proline (6a, 0.6 mmol), and N-ethylmaleimide (11a, 0.6 mmol) in corresponding solvents (3 mL) at corresponding temperatures. b Isolated or recrystallized yields based on isatin (5a); >20:1 dr by 1H NMR analysis. c Room temperature.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, Y.; Yan, L.; Yan, Y.; Li, S.; Lu, H.; Liu, J.; Dong, J. Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles. Int. J. Mol. Sci. 2023, 24, 3771. https://doi.org/10.3390/ijms24043771

AMA Style

Wang Y, Yan L, Yan Y, Li S, Lu H, Liu J, Dong J. Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles. International Journal of Molecular Sciences. 2023; 24(4):3771. https://doi.org/10.3390/ijms24043771

Chicago/Turabian Style

Wang, Yongchao, Lijun Yan, Yuxin Yan, Sujin Li, Hongying Lu, Jia Liu, and Jianwei Dong. 2023. "Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles" International Journal of Molecular Sciences 24, no. 4: 3771. https://doi.org/10.3390/ijms24043771

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop