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Article

Efficient Synthesis of Fully Substituted Pyrrolidine-Fused 3-Spirooxindoles via 1,3-Dipolar Cycloaddition of Aziridine and 3-Ylideneoxindole

by
Wen Ren
1,†,
Qian Zhao
2,†,
Chuan Zheng
2,
Qiong Zhao
2,
Li Guo
1,* and
Wei Huang
2,*
1
Key Laboratory of Drug Targeting and Drug Delivery Systems of Ministry of Education, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
2
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
*
Authors to whom correspondence should be addressed.
Molecules 2016, 21(9), 1113; https://doi.org/10.3390/molecules21091113
Submission received: 26 July 2016 / Revised: 12 August 2016 / Accepted: 18 August 2016 / Published: 24 August 2016
(This article belongs to the Special Issue Pericyclic Reactions)
Browse Figures
Versions Notes

Abstract

:
Drug-like spirocyclic scaffolds have been prepared by fusing fully functionalized pyrrolidine with oxindoles in an approach based on 1,3-dipolar cycloaddition. Reaction between aziridine and 3-ylideneoxindole generated diverse spirooxindole-pyrrolidines in good yield (up to 95%) with high diastereoselectivity (up to >20:1). The reaction also proceeded smoothly with several other synthetically useful activated trisubstituted olefins. The mild reaction conditions, short reaction times, and high tolerance for various substitutions make this approach attractive for constructing pharmacologically interesting spiro-architectures.

1. Introduction

Since the first report of Steven rearrangement in 1928 [1], nitrogen ylides have attracted considerable attention from organic chemists because of their distinctive properties and usefulness in preparative organic syntheses [2,3,4,5,6]. As nitrogen-based 1,3-dipoles, they play important roles in organic synthesis, particularly in cycloadditions [7,8,9,10]. Nitrogen ylides have been used to achieve (3 + 2) annulation [11,12,13,14,15] and (3 + 3) annulation [16,17], providing a direct route to various nitrogen-containing heterocycles, including pyrrolidine [18,19,20,21,22], piperidine [23,24], and piperazine [25]. This strategy has proven powerful for synthesizing natural products as well as other biologically interesting compounds [26,27,28,29].
Spirooxindole-pyrrolidine, a privileged framework with crucial biological activities, is present in a large family of alkaloid and natural products (Figure 1) [30,31,32,33]. For example, spirotryprostatins A and B, both isolated from Aspergillus fumigatus, completely inhibit progression from G2 to M phase in mammalian tsFT210 cells [30]. The synthetic analogues of these natural products are often more efficacious and selective than the natural molecules [34,35,36,37]. For example, spirooxindole-pyrrolidine derivative MI-77301, an inhibitor of murine double minute 2 (MDM2), entered its second Phase I clinical trial in 2013 [37].
Various elegant studies have generated molecules with spirooxindole-pyrrolidine skeletons [38,39,40,41,42] using diverse reactions, including 1,3-dipolar cycloaddition [43,44,45,46,47,48,49,50,51,52], ring-enlargement [53,54,55], intramolecular Mannich reaction [56], rearrangement [57] and alkylation [58]. Nitrogen ylides have been used to synthesize spirooxindole-pyrrolidines via 1,3-dipolar addition; this process shows high reactivity, high yield, and excellent stereoselectivity (Scheme 1a [43,44,45,46,47] and Scheme 1b [48,49,50,51,52]). In this approach, two steps are required to modify the nitrogen by alkylation, acylation, or, under harsh conditions, arylation. Developing a one-step strategy for constructing spirooxindoles containing a fully substituted pyrrolidine remains an important challenge.
To construct functionalized spirooxindoles in a straightforward, single-step reaction, we envisioned 1,3-dipolar cycloaddition between 3-ylideneoxindole 1 and aziridine 2 (Scheme 1c). Aziridine could generate a 1,3-dipole through thermolysis, and then 1,3-dipolar cycloaddition of the 1,3-dipole with dipolarophile 1 would yield (3 + 2) cycloadduct 2 (Scheme 2). If successful, this approach would broaden the applications of aziridine and provide an alternative method for preparing pharmacologically interesting spirooxindole-pyrrolidines.

2. Results and Discussion

Our investigation began with 3-ylideneoxindole 1a and 1,3-dipolar aziridine 2a in MeCN at 90 °C (Table 1, entry 1). The 1,3-dipolar cycloaddition proceeded rapidly, affording 3a in 40% yield. Encouraged by this result, we optimized the reaction conditions, first by replacing MeCN with other solvents while keeping other conditions the same (Table 1, entries 2–5). Toluene led to the best yield (Table 1, entry 3), but it did not improve the dr value. Varying temperature did not increase yield, though it did accelerate the reaction (Table 1, entries 6, 7). Therefore, we examined whether acid or alkali additive might promote the conversion from aziridine to 1,3-dipole and thereby increase yield (Table 1, entries 8–15) [59,60]. Among the acid additives tested, acetic acid afforded the highest yield (Table 1, entry 8), whereas no reaction was observed with trifluoroacetic acid (Table 1, entry 11). Base additives increased yield more than acid additives, with triethylamine giving the best result (Table 1, entry 15). When we carried out this model reaction under 90 °C using TEA as base additive, a similar good result was also obtained, but the reaction did not proceed quickly enough. Obviously, thermodynamic factor played an important role in the 1,3-dipole generation (Table 1, entry 16). Finally, we found that a different configuration of aziridine also participated in the reaction, giving the product 3a in moderate yield (Table 1, entry 17).
Using the optimized reaction conditions, we evaluated the substrate scope and limitations of 1,3-dipolar cycloaddition (Table 2). We first examined the reaction of 1,3-dipolar aziridine 2a with 1. The nature of the functional group at position R1 on the oxindole core did not affect the reaction: both electron-deficient and electron-rich groups gave the corresponding products 3b–d in high yield. Isopropoxyformoxyl, phenoxyformoxyl or dicyano groups at R2 barely affected reaction efficiency, leading to satisfying yields and dr values for the corresponding products 3e–g. Aryl or polycyclic aryl groups at R2 afforded the products 3h–n in moderate yield with high diastereoselectivity; yield was higher for electron-withdrawing substituents (Table 2, 3i–k) than for electron-donating ones (Table 2, 3l–m). A heteroaryl group at R2 led to the corresponding products 3o and 3p in slightly lower yield. Various protecting groups, including benzyl and Boc groups, were well tolerated and enhanced the dr values obtained for products 3q and 3r. Finally, we made substitutions on the aziridine 2 that led to good yield of products 3s and 3t. The relative configuration of product 3a was unambiguously determined by X-ray crystallographic analysis (Figure 2) [61].
To further probe the usefulness of this single-step reaction, we examined whether it was compatible with synthetically useful activated trisubstituted olefins. The reaction proceeded smoothly with several such substrates, including olefinic acenaphthene, indenedione, pyrazolone, and rhodanine, providing the corresponding pharmacologically important spirocyclic products (Scheme 3, 3u–x) in good yields (up to 95%) with moderate to high diastereoselectivities (up to >20:1).

3. Materials and Methods

3.1. General Information

NMR data was obtained for 1H at 400 MHz (Varian, Palo Alto, CA, USA) and for 13C at 100 MHz. Chemical shifts were reported in ppm from tetramethylsilane using solvent resonance in CDCl3 solution as the internal standard. ESI HRMS (Electrospray Ionization, High Resolution Mass Spectrum) was performed on a Waters SYNAPT G2 (Milford, MA, USA). Column chromatography was performed on silica gel (200–300 mesh) using an eluent of ethyl acetate and petroleum ether. TLC was performed on glass-backed silica plates; products were visualized using UV light and I2. Melting points were determined on a Mel-Temp apparatus (Electrothermal, Staffordshire, UK) and were not corrected. All chemicals were used from Adamas-beta (Adamas, Shanghai, China) without purification unless otherwise noted.

3.2. Synthesis

3.2.1. General Procedure for the Synthesis of Spirooxindole-Pyrrolidines 3a–t

A mixture of 3-ylideneoxindole 1 (1.1 mmol), aziridine 2 (1.0 mmol) and additive TEA (0.5 mmol) in toluene (2 mL) was refluxed at 110 °C under an open atmosphere. The reaction mixture stirred for a specified reaction time until most of 3-ylideneoxindole 1 was consumed (monitored by TLC). Then, the reaction mixture was concentrated and the residue was purified by elaborative chromatography on silica gel to give the final products 3a–t in good yield (up to 77%) with high diastereoselectivity (up to >20:1). The products were further identified by 1H-NMR, 13C-NMR and HRMS (See supplementary materials).
Triethyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3a). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 78% yield (71.3 mg). The dr value was calculated to be 5:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3a was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 65% yield (59.4 mg). m.p. 130–132 °C; 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.25–7.18 (m, 3H), 6.99 (t, J = 7.6 Hz, 1H), 6.85 (dd, J = 13.2, 7.6 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 5.42 (d, J = 8.4 Hz, 1H), 5.11 (s, 1H), 4.09–3.99 (m, 3H), 3.88–3.82 (m, 1H), 3.80–3.66 (m, 3H), 0.99 (t, J = 7.2 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.14, 171.80, 167.35, 167.32, 145.26, 141.23, 129.59, 128.73, 126.28, 125.67, 122.71, 120.26, 116.39, 109.40, 68.76, 64.88, 61.45, 61.41, 61.08, 58.06, 54.64, 13.85, 13.49, 13.42; HRMS: m/z calcd. for C26H28N2O7 + Na, 503.1794; found, 503.1790.
Triethyl-4-bromo-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3b). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 82% yield (86.7 mg). The dr value was calculated to be 2.5:1 from crude 1H-NMR analysis of the mixture. The pure major isomer 3b could not be separated in pure form after elaborative chromatography; the yield of 3b was calculated to be 59% based on the total yield and dr value. m.p. 128–130 °C; 1H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.24–7.14 (m, 4H), 6.87–6.82 (m, 2H), 6.72 (d, J = 8.0 Hz, 2H), 5.49 (s, 1H), 5.40 (d, J = 8.8 Hz, 1H), 4.81 (d, J = 8.8 Hz, 1H), 4.18–4.08 (m, 4H), 4.06–4.02 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.33, 172.46, 168.35, 168.22, 144.79, 144.09, 130.81, 128.81, 128.67, 127.02, 119.60, 118.46, 116.37, 115.42, 109.43, 64.93, 64.31, 61.69, 61.40, 58.94, 51.01, 14.01, 13.68, 13.62; HRMS: m/z calcd. for C26H27BrN2O7 + Na, 581.0899; found, 581.0901.
Triethyl-5-fluoro-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3c). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 83% yield (78.2 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3c was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 67% yield (62.6 mg). m.p. 120–122 °C; 1H-NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.13 (dd, J = 8.0, 2.4 Hz, 1H), 6.99–6.92 (m, 1H), 6.89–6.84 (m, 2H), 6.76 (d, J = 8.0 Hz, 2H), 5.38 (d, J = 8.0 Hz, 1H), 5.11 (s, 1H), 4.09–4.01 (m, 3H), 3.94–3.72 (m, 4H), 1.01 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.48, 171.68, 167.25, 167.13, 158.64 (d, JCF = 243.4 Hz), 145.09, 137.56 (d, JCF = 2.0 Hz), 128.78, 127.28 (d, JCF = 8.1 Hz), 120.59, 116.60, 116.12 (d, JCF = 23.2 Hz), 114.21 (d, JCF = 25.3 Hz), 110.26 (d, JCF = 8.1 Hz), 68.70, 64.70, 61.59, 61.54, 61.21, 58.60, 54.52, 13.86, 13.50, 13.48; HRMS: m/z calcd. for C26H27FN2O7 + Na, 521.1700; found, 521.1696.
Triethyl-5-methyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3d). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 81% yield (75.7 mg). The dr value was calculated to be 6:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3d was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 69% yield (64.9 mg). m.p. 120–123 °C; 1H-NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.21 (dd, J = 8.4, 7.6 Hz, 2H), 7.15 (s, 1H), 7.02 (dd, J = 8.0, 0.8 Hz, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.79–6.74 (m, 3H), 5.42 (d, J = 8.8 Hz, 1H), 5.11 (s, 1H), 4.10–4.01 (m, 3H), 3.90–3.82 (m, 1H), 3.78–3.74 (m, 1H), 3.72–3.69 (m, 2H), 2.27 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.60, 171.87, 167.38, 167.34, 145.31, 138.99, 132.18, 129.90, 128.74, 126.73, 125.68, 120.09, 116.19, 109.32, 68.71, 64.90, 61.44, 61.37, 61.02, 58.23, 54.68, 21.09, 13.86, 13.48, 13.40; HRMS: m/z calcd. for C27H30N2O7 + Na, 517.1951; found, 517.1954.
2′,5′-Diethyl-4′-isopropyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3e). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 81% yield (76.3 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3e was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 65% yield (61.2 mg). m.p. 110–115 °C; 1H-NMR (400 MHz, CDCl3) δ 8.27 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.25–7.20 (m, 3H), 7.05 (td, J = 7.6, 0.8 Hz, 1H), 6.89–6.83 (m, 2H), 6.67 (d, J = 8.0 Hz, 2H), 4.97 (d, J = 10.8 Hz, 1H), 4.70 (s, 1H), 4.66–4.58 (m, 1H), 4.50 (d, J = 10.8 Hz, 1H), 4.48–4.40 (m, 1H), 4.30–4.21 (m, 1H), 4.16–4.04 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.56 (d, J = 6.4 Hz, 3H). 13C-NMR (101 MHz, CDCl3) δ 175.43, 171.37, 169.77, 166.74, 145.38, 140.19, 130.54, 129.42, 129.03, 126.41, 123.49, 119.91, 114.74, 109.18, 71.32, 69.04, 62.16, 61.54, 61.42, 57.63, 52.95, 21.42, 20.56, 14.04, 13.99; HRMS: m/z calcd. for C27H30N2O7 + Na, 517.1951; found, 517.1948.
2′,5′-Diethyl-4′-phenyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3f). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 87% yield (86.9 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3f was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 70% yield (69.5 mg). m.p. 135–137 °C; 1H-NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.30 (td, J = 7.6, 0.8 Hz, 1H), 7.23–7.14 (m, 4H), 7.13–7.05 (m, 2H), 6.91–6.84 (m, 2H), 6.78 (d, J = 8.0 Hz, 2H), 6.28–6.25 (m, 2H), 5.51 (d, J = 8.0 Hz, 1H), 5.19 (s, 1H), 4.30 (d, J = 8.0 Hz, 1H), 4.11–4.03 (m, 2H), 3.75–3.65 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.74 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.29, 171.74, 167.25, 166.36, 149.72, 145.16, 141.62, 129.88, 129.33, 128.80, 126.46, 126.20, 125.62, 122.97, 120.96, 120.50, 116.59, 109.99, 68.88, 64.87, 61.60, 61.20, 58.22, 54.62, 13.88, 13.50; HRMS: m/z calcd. for C30H28N2O7 + Na, 551.1794; found, 551.1798.
Diethyl-4′,4′-dicyano-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3g). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 86% yield (75.3 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3g was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 69% yield (60.2 mg). m.p. 140–142 °C; 1H-NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29–7.25 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 8.0 Hz, 2H), 5.44 (s, 1H), 5.23 (s, 1H), 4.36–4.24 (m, 2H), 3.83 (q, J = 7.2 Hz, 2H), 1.25–1.21(m, 3H), 0.78 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 172.46, 166.81, 165.21, 143.61, 141.50, 131.86, 129.18, 126.81, 123.48, 121.60, 121.55, 116.69, 111.71, 111.27, 109.85, 69.27, 66.25, 63.14, 61.89, 59.31, 45.06, 13.82, 13.46; HRMS: m/z calcd. for C25H22N4O5 + Na, 481.1488; found, 481.1489.
Diethyl-2-oxo-1′,4′-diphenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3h). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 63% yield (57.6 mg). The dr value was calculated to be >20:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3h was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 61% yield (55.8 mg). m.p. 130–132 °C; 1H-NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 8.4, 7.6 Hz, 2H), 7.12–7.04 (m, 6H), 7.01–6.97 (m, 1H), 6.81 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 7.6 Hz, 1H), 5.39 (d, J = 10.4 Hz, 1H), 5.33 (s, 1H), 4.30 (d, J = 10.4 Hz, 1H), 4.00–3.89 (m, 2H), 3.80–3.65 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.48, 171.79, 167.85, 145.42, 140.58, 132.31, 129.10, 128.77, 128.34, 128.04, 128.01, 126.86, 125.52, 122.24, 119.40, 115.35, 109.64, 67.54, 67.20, 61.68, 61.26, 60.93, 57.21, 13.79, 13.46; HRMS: m/z calcd. for C29H28N2O5 + Na, 507.1896; found, 507.1900.
Diethyl-4′-(4-bromophenyl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3i). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 68% yield (73.2 mg). The dr value was calculated to be 6:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3i was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 58% yield (62.7 mg). m.p. 79–82 °C; 1H-NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.24–7.20 (m, 4H), 7.14 (t, J = 7.6 Hz, 1H), 7.02–6.94 (m, 3H), 6.83 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 7.6 Hz, 1H), 5.33–5.31 (m, 2H), 4.24 (d, J = 10.4 Hz, 1H), 3.99–3.93 (m, 2H), 3.80–3.65 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.26, 171.62, 167.74, 145.25, 140.61, 131.41, 131.27, 130.02, 129.37, 128.81, 126.72, 125.12, 122.38, 122.24, 119.55, 115.34, 109.95, 67.49, 67.16, 61.46, 61.42, 61.02, 56.59, 13.82, 13.45; HRMS: m/z calcd. for C29H27BrN2O5 + Na, 585.1001; found, 585.1003.
Diethyl-4′-(2-fluorophenyl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3j). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 66% yield (63.1 mg). The dr value was calculated to be >20:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3j was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 63% yield (60.2 mg). m.p. 137–140 °C; 1H-NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.16–7.11 (m, 2H), 7.09–7.06 (m, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.88–6.80 (m, 3H), 6.73 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.41 (d, J = 9.6 Hz, 1H), 5.34 (s, 1H), 4.66 (d, J = 9.6 Hz, 1H), 4.04–3.92 (m, 2H), 3.79–3.66 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.82, 171.65, 167.92, 161.00 (d, JCF = 249.5 Hz), 145.44, 141.01, 129.78 (d, JCF = 3.0 Hz), 129.55 (d, JCF = 9.1 Hz), 129.21, 128.81, 126.98, 125.44, 123.60 (d, JCF = 3.0 Hz), 122.04, 120.17 (d, JCF = 14.1 Hz), 119.51, 115.46, 115.39 (d, JCF = 23.2 Hz), 109.71, 67.75, 67.11, 61.32, 60.98, 60.78, 49.67, 13.75, 13.43; HRMS: m/z calcd. for C29H27FN2O5 + Na; 525.1802; found, 525.1804.
Diethyl-4′-(4-nitrophenyl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3k). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 62% yield (62.8 mg). The dr value was calculated to be 5:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3k was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 52% yield (52.3 mg). m.p. 90–93 °C; 1H-NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 2H), 7.94–7.89 (m, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 7.6 Hz, 1H), 5.41 (d, J = 10.0 Hz, 1H), 5.34 (s, 1H), 4.38 (d, J = 10.4 Hz, 1H), 4.02–3.92 (m, 2H), 3.82–3.67 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 175.72, 171.33, 167.55, 147.58, 145.05, 140.37, 140.00, 129.69, 129.31, 128.88, 126.70, 124.65, 123.26, 122.61, 119.84, 115.42, 109.97, 67.58, 66.90, 61.63, 61.41, 61.13, 56.49, 13.81, 13.46; HRMS: m/z calcd. for C29H27N3O7 + Na, 552.1747; found, 552.1744.
Diethyl-2-oxo-1′-phenyl-4′-(p-tolyl)spiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3l). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 58% yield (55.3 mg). The dr value was calculated to be >20:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3l was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 56% yield (53.4 mg). m.p. 85–88 °C; 1H-NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.95–6.80 (m, 5H), 6.73 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.0 Hz, 1H), 5.35 (d, J = 10.4 Hz, 1H), 5.31 (s, 1H), 4.25 (d, J = 10.0 Hz, 1H), 4.00–3.89 (m, 2H), 3.80–3.65 (m, 2H), 2.13 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.55, 171.87, 167.89, 145.47, 140.63, 137.59, 132.16, 129.25, 129.06, 128.76, 127.83, 126.92, 125.33, 122.14, 119.38, 115.37, 109.69, 67.54, 67.44, 61.68, 61.23, 60.92, 57.20, 21.24, 13.79, 13.46; HRMS: m/z calcd. for C30H30N2O5 + Na, 521.2052; found, 521.2056.
Diethyl-4′-(3,4-dimethoxyphenyl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3m). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 57% yield (59.4 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3m was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 46% yield (47.5 mg). m.p. 100–103 °C; 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.22 (dd, J = 8.0, 7.6 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H), 6.66–6.63 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 5.30 (s, 1H), 5.24 (d, J = 10.4 Hz, 1H), 4.22 (d, J = 10.4 Hz, 1H), 4.02–3.91 (m, 2H), 3.83–3.79 (m, 1H), 3.75 (s, 3H), 3.71–3.67 (m, 1H), 3.61 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 175.17, 172.71, 168.64, 148.59, 148.03, 145.23, 141.06, 129.07, 128.81, 128.74, 124.30, 123.10, 122.96, 120.62, 118.92, 114.75, 111.36, 110.49, 109.64, 68.45, 65.15, 61.66, 61.29, 61.13, 58.39, 55.60, 55.49, 13.98, 13.64; HRMS: m/z calcd. for C31H32N2O7 + Na, 567.2107; found, 567.2110.
Diethyl-4′-(naphthalen-2-yl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3n). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 55% yield (55.7 mg). The dr value was calculated to be >20:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3n was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 53% yield (53.5 mg). m.p. 105–107 °C; 1H-NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.67–7.65 (m, 2H), 7.59–7.51 (m, 3H), 7.41–7.37 (m, 2H), 7.24–7.14 (m, 3H), 7.07–6.99 (m, 2H), 6.82 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 7.2 Hz, 1H), 5.50 (d, J = 10.4 Hz, 1H), 5.37 (s, 1H), 4.47 (d, J = 10.0 Hz, 1H), 3.96–3.88 (m, 2H), 3.81–3.62 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H), 0.66 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.39, 171.83, 167.84, 145.44, 140.61, 132.89, 132.87, 129.93, 129.18, 128.79, 128.14, 127.96, 127.62, 127.44, 126.91, 126.12, 126.02, 125.71, 125.47, 122.25, 119.46, 115.41, 109.78, 67.62, 67.48, 61.75, 61.31, 60.96, 57.42, 13.80, 13.46; HRMS: m/z calcd. for C33H30N2O5 + Na, 557.2052; found, 557.2049.
Diethyl-4′-(furan-2-yl)-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3o). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 46% yield (41.3 mg). The dr value was calculated to be 3:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3o was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 35% yield (31.1 mg). m.p. 140–143 °C; 1H-NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 8.0 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.85–6.77 (m, 2H), 6.72 (d, J = 8.0 Hz, 2H), 6.07–6.01 (m, 2H), 5.27 (d, J = 10.0 Hz, 1H), 5.25 (s, 1H), 4.43 (d, J = 9.6 Hz, 1H), 4.11–3.94 (m, 2H), 3.79–3.66 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H), 0.71 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.58, 171.71, 167.64, 147.90, 145.28, 142.35, 140.79, 129.15, 128.80, 126.74, 125.63, 122.31, 119.66, 115.53, 110.03, 109.57, 107.99, 67.67, 66.83, 61.47, 61.02, 60.03, 50.42, 13.81, 13.48; HRMS: m/z calcd. for C27H26N2O6 + Na, 497.1689; found, 497.1687.
Diethyl-2-oxo-1′-phenyl-4′-(thiophen-2-yl)spiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3p). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 52% yield (48.1 mg). The dr value was calculated to be 3:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3p was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 39% yield (36.2 mg). m.p. 192–194 °C; 1H-NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.23–7.18 (m, 3H), 7.06–7.01 (m, 2H), 6.84–6.70 (m, 6H), 5.29 (s, 1H), 5.17 (d, J = 10.4 Hz, 1H), 4.59 (d, J = 10.0 Hz, 1H), 4.05–3.93 (m, 2H), 3.82–3.67 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.14, 171.42, 167.67, 145.21, 141.10, 134.68, 129.51, 128.77, 127.24, 127.05, 126.19, 125.70, 125.39, 122.54, 119.60, 115.44, 109.82, 69.71, 67.23, 61.41, 61.21, 61.01, 53.06, 13.82, 13.47; HRMS: m/z calcd. for C27H26N2O5S + Na, 513.1460; found, 513.1458.
Triethyl-1-benzyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-2′,4′,5′-tricarboxylate (3q). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 88% yield (95.5 mg). The dr value was calculated to be 7:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3q was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 77% yield (83.6 mg). m.p. 170–172 °C; 1H-NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.36–7.34 (m, 3H), 7.31–7.29 (m, 1H), 7.24–7.16 (m, 3H), 6.96 (t, J = 7.6 Hz, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.76 (t, J = 8.4 Hz 3H), 5.44 (dd, J = 8.0, 1.0 Hz, 1H), 5.18 (s, 1H), 4.98 (d, J = 5.2 Hz, 2H), 4.10 (d, J = 8.4 Hz, 1H), 4.06–4.02 (m, 2H), 3.79–3.75 (m, 1H), 3.64–3.55 (m, 3H), 1.01–0.98 (m, 3H), 0.56–0.50 (m, 6H); 13C-NMR (101 MHz, CDCl3) δ 174.83, 171.78, 167.32, 167.28, 145.35, 143.43, 135.68, 129.38, 128.72, 128.68, 128.08, 127.92, 125.95, 125.38, 122.68, 120.20, 116.41, 108.67, 68.94, 65.08, 61.40, 60.99, 57.50, 54.78, 44.65, 22.66, 13.86, 13.30, 13.24; HRMS: m/z calcd. for C33H34N2O7 + Na, 593.2264; found, 593.2266.
1-(Tert-butyl)-2′,4′,5′-triethyl-2-oxo-1′-phenylspiro(indoline-3,3′-pyrrolidine)-1,2′,4′,5′-tetracarboxylate (3r). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 82% yield (90.3 mg). The dr value was calculated to be 6:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3r was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 71% yield (77.4 mg). m.p. 150–153 °C; 1H-NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.6, 0.8 Hz, 1H), 7.35–7.30 (m, 1H), 7.21 (dd, J = 8.0, 7.2 Hz, 2H), 7.12 (dd, J = 8.0, 7.6 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H), 5.39 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 4.08–3.96 (m, 3H), 3.78–3.65 (m, 4H), 1.68 (s, 9H), 0.97 (t, J = 6.8 Hz, 3H), 0.81–0.76 (m, 6H); 13C-NMR (101 MHz, CDCl3) δ 173.34, 171.55, 167.06, 166.75, 149.01, 145.13, 140.31, 129.80, 129.21, 128.73, 125.31, 124.64, 120.07, 116.70, 114.59, 84.73, 69.08, 64.90, 61.88, 61.49, 61.12, 58.18, 55.31, 42.99, 28.10, 14.15, 13.83, 13.38, 13.26; HRMS: m/z calcd. for C31H36N2O9 + Na, 603.2319; found, 603.2314.
Diethyl-2-oxo-4′-phenyl-1′-(m-tolyl)spiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3s). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 70% yield (62.3 mg). The dr value was calculated to be 5:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3s was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 58% yield (52.1 mg). m.p. 135–138 °C; 1H-NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.41 (d, J = 8.4 Hz, 1H), 5.11 (s, 1H), 4.09–4.02 (m, 3H), 3.88–3.84 (m, 1H), 3.77–3.68 (m, 3H), 2.27 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H), 0.81–0.74 (m, 6H); 13C-NMR (101 MHz, CDCl3) δ 176.66, 171.99, 167.45, 167.38, 145.19, 141.42, 138.41, 129.59, 128.56, 126.21, 125.70, 122.69, 121.19, 117.19, 113.43, 109.63, 68.72, 64.81, 61.42, 61.22, 61.07, 58.14, 54.64, 21.65, 13.90, 13.49, 13.40; HRMS: m/z calcd. for C27H30N2O7 + Na, 517.1951; found, 517.1954.
Diethyl-2-oxo-4′-phenyl-1′-(4-(trifluoromethyl)phenyl)spiro(indoline-3,3′-pyrrolidine)-2′,5′-dicarboxylate (3t). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 67% yield (55.4 mg). The dr value was calculated to be 5:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3t was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 56% yield (46.2 mg). m.p. 145–147 °C; 1H-NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.29–7.24 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 5.45 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 4.16–4.07 (m, 2H), 4.03 (d, J = 8.4 Hz, 1H), 3.90–3.84 (m, 1H), 3.81–3.69 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 176.21, 171.26, 166.92, 166.85, 147.99, 141.39, 129.90, 126.10, 126.09, 125.22, 124.54 (d, JCF = 272.7 Hz), 122.82, 121.67 (d, JCF = 33.3 Hz), 115.51, 109.75, 68.63, 64.62, 61.86, 61.61, 61.46, 58.06, 54.78, 13.90, 13.45, 13.40; HRMS: m/z calcd. for C27H27F3N2O7 + Na, 571.1668; found, 571.1671.

3.2.2. Synthetic Transformations to Access Other Drug-Like Spirocyclic Scaffolds 3u–x

A mixture of trisubstituted olefins (1.1 mmol), aziridine 2a (1.0 mmol) and additive TEA (0.5 mmol) in toluene (2 mL) was refluxed at 110 °C under an open atmosphere. The reaction mixture would be cooled to room temperature until most of the 3-ylideneoxindole 1 was consumed (monitored by TLC). Then, the reaction mixture was concentrated and the residue was purified by elaborative chromatography on silica gel to give the final products 3u–x in good yield (up to 78%) with moderate to high diastereoselectivity (up to >20:1). The products were further identified by 1H-NMR, 13C-NMR and HRMS.
Diethyl-2-oxo-1′,4′-diphenyl-2H-spiro(acenaphthylene-1,3′-pyrrolidine)-2′,5′-dicarboxylate (3u). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 76% yield (75.4 mg). The dr value was calculated to be 8:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3u was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 68% yield (66.9 mg). m.p. 154–156 °C; 1H-NMR (400 MHz, CDCl3) δ 7.94–7.91 (m, 2H), 7.76–7.71 (m, 2H), 7.61–7.55 (m, 2H), 7.23 (t, J = 8.0 Hz, 2H), 7.00–6.97 (m, 2H), 6.87–6.81 (m, 4H), 6.76 (d, J = 8.0 Hz, 2H), 5.53 (d, J = 10.4 Hz, 1H), 5.44 (s, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.03–3.93 (m, 2H), 3.46–3.36 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H), 0.04 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 201.65, 171.97, 168.09, 145.61, 142.19, 134.83, 132.95, 132.84, 131.87, 130.23, 128.76, 128.22, 128.05, 127.81, 127.76, 127.62, 125.07, 123.99, 121.86, 119.30, 115.42, 68.07, 67.71, 66.11, 61.22, 60.41, 57.32, 13.82, 12.78; HRMS: m/z calcd. for C33H29NO5 + Na, 542.1943; found, 542.1945.
Diethyl-1,3-dioxo-1′,4′-diphenyl-1,3-dihydrospiro(indene-2,3′-pyrrolidine)-2′,5′-dicarboxylate (3v). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 90% yield (85.3 mg). The dr value was calculated to be 4:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3v was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 72% yield (68.2 mg). m.p. 133–135 °C; 1H-NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 1H), 7.75–7.67 (m, 3H), 7.22–7.15 (m, 4H), 7.10–7.05 (m, 3H), 6.79 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 5.57 (d, J = 10.0 Hz, 1H), 5.33 (s, 1H), 4.23 (d, J = 10.4 Hz, 1H), 4.01–3.92 (m, 2H), 3.84–3.72 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 198.08, 197.65, 171.57, 168.05, 145.09, 142.18, 142.05, 136.00, 135.74, 131.84, 128.71, 128.64, 128.46, 128.30, 123.27, 123.08, 119.11, 115.14, 66.58, 66.13, 65.76, 61.23, 61.18, 56.29, 13.82, 13.33; HRMS: m/z calcd. for C30H27NO6 + Na, 520.1736; found, 520.1733.
Diethyl-1-methyl-4-oxo-3,7,9-triphenyl-2,3,7-triazaspiro(4.4)non-1-ene-6,8-dicarboxylate (3w). The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 93% yield (92.4 mg). The dr value was calculated to be 5:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3w was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 78% yield (76.8 mg). m.p. 165–167 °C; 1H-NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H), 7.27 (s, 1H), 7.25–7.20 (m, 6H), 7.09 (t, J = 7.2 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 5.62 (d, J = 9.6 Hz, 1H), 5.12 (s, 1H), 4.08–4.05 (m, 1H), 4.01 (d, J = 7.2 Hz, 1H), 3.98–3.90 (m, 3H), 2.47 (s, 3H), 0.94 (q, J = 6.8 Hz, 6H); 13C-NMR (101 MHz, CDCl3) δ 172.16, 169.60, 167.44, 157.03, 144.78, 137.18, 131.10, 128.86, 128.82, 128.64, 128.39, 125.23, 119.48, 118.97, 115.12, 65.83, 64.85, 64.69, 61.71, 61.43, 55.14, 13.88, 13.82, 13.74; HRMS: m/z calcd. for C31H31N3O5 + Na, 548.2161; found, 548.2159.
Diethyl-3-benzyl-4-oxo-7,9-diphenyl-2-thioxo-1-thia-3,7-diazaspiro(4.4)nonane-6,8-dicarboxylate (3x): The mixed two isomers were isolated by flash chromatography (petroleum ether/ethyl acetate = 5:1) in 72% yield (78.1 mg). The dr value was calculated to be >20:1 from crude 1H-NMR analysis of the mixture. After which, the pure major isomer 3x was obtained as a white solid after elaborative chromatography (petroleum ether/ethyl acetate = 10:1) in 69% yield (74.9 mg). m.p. 162–165 °C; 1H-NMR (400 MHz, CDCl3) δ 7.31–7.27 (m, 5H), 7.25–7.10 (m, 7H), 6.85 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.6 Hz, 2H), 5.54 (s, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.69 (dd, J = 41.6, 14.0 Hz, 2H), 4.55 (d, J = 10.0 Hz, 1H), 4.07–4.03 (m, 1H), 3.94–3.85 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H); 13C-NMR (101 MHz, CDCl3) δ 172.68, 170.92, 169.02, 166.92, 144.85, 134.51, 131.38, 128.96, 128.88, 128.82, 128.78, 128.68, 128.66, 128.29, 120.49, 116.10, 69.76, 66.62, 61.87, 61.51, 57.08, 45.52, 43.00, 13.87, 13.74; HRMS: m/z calcd. for C31H30N2O5S2 + Na, 597.1494; found, 597.1497.

4. Conclusions

In summary, we have developed an efficient single-step reaction between aziridines and 3-ylideneoxindoles to synthesize diverse spirooxindole-pyrrolidines. This is a straightforward technique for constructing fully substituted pyrrolidines bearing phenyl substituents on the nitrogen atom. The reaction also proceeded smoothly with several other synthetically useful activated trisubstituted olefins to afford some pyrrolidine-fused drug-like spirocyclic scaffolds. Further studies on the biological activities of the resulting spiro-architectures are underway in our laboratory.

Supplementary Materials

Supplementary Materials can be accessed at: https://www.mdpi.com/1420-3049/21/9/1113/s1.

Acknowledgments

We are grateful for financial support from the National Natural Science Foundation of China (81303208, 21472130, 81373531 and 81573589), and the Science & Technology Department of Sichuan Province (2014JY0013).

Author Contributions

W.H. and L.G. conceived and designed the experiments; W.R. and Q.Z. performed the experiments; C.Z analyzed the data; Q.Z. contributed reagents and materials; W.H. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

DBU1,8-Diazabicyclo(5.4.0)undec-7-ene
DABCO1,4-Diazabicyclo(2.2.2)octane
TEATriethylamine

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  • Sample Availability: All samples are available from the authors.
Molecules 21 01113 g001 550
Figure 1. Examples of the spirooxindole-pyrrolidine framework in biologically active molecules.
Figure 1. Examples of the spirooxindole-pyrrolidine framework in biologically active molecules.
Molecules 21 01113 g001
Molecules 21 01113 sch001 550
Scheme 1. 1,3-Dipolar cycloaddition-based synthesis of spirooxindole-pyrrolidines.
Scheme 1. 1,3-Dipolar cycloaddition-based synthesis of spirooxindole-pyrrolidines.
Molecules 21 01113 sch001
Molecules 21 01113 sch002 550
Scheme 2. Synthetic strategy.
Scheme 2. Synthetic strategy.
Molecules 21 01113 sch002
Molecules 21 01113 sch003 550
Scheme 3. Synthesis of pharmacologically important spiro-pyrrolidines.
Scheme 3. Synthesis of pharmacologically important spiro-pyrrolidines.
Molecules 21 01113 sch003
Molecules 21 01113 g002 550
Figure 2. X-ray structure of 3a.
Figure 2. X-ray structure of 3a.
Molecules 21 01113 g002
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 21 01113 i001
EntrySolventt (h) bT (°C) cAdditiveYield (%) ddr e
1MeCN490-40 (30)3:1
2EtOH490-33 (25)3:1
3toluene490-45 (36)4:1
41,4-dioxane490-35 (26)3:1
5DCM490-37 (28)3:1
6toluene1270-<10-
7toluene0.5110-55 (37)2:1
8toluene0.5110CH3COOH67 (51)3:1
9toluene0.5110HCOOH34 (27)4:1
10toluene0.5110ClCH2COOH47 (38)4:1
11toluene0.5110CF3COOHn.r.-
12toluene0.5110DBU52 (42)4:1
13toluene0.5110DABCO65 (49)3:1
14toluene0.5110K2CO357 (43)3:1
15toluene0.5110TEA78 (65)5:1
16toluene490TEA72 (58)4:1
17 ftoluene0.5110TEA66 (53)4:1
a Reaction conditions: additive (0.5 mmol) was added to a solution of 3-ylideneoxindole 1a (1.1 mmol) and aziridine 2a (1.0 mmol) in solvent (2 mL) at the indicated temperature. b Time for one-step reaction. c Temperature of one-step reaction. d Total yield of the mixed two isomers; the yield of the isolated major isomer 3a was shown in parentheses. e Based on crude 1H-NMR analysis of the mixed two isomers. f 2a′ was used. MeCN = acetonitrile; DCM = dichloromethane; TEA = triethylamine.
Table
Table 2. Evaluation of substrate scope under optimized reaction conditions a.
Table 2. Evaluation of substrate scope under optimized reaction conditions a.
Molecules 21 01113 i002
EntryR1R2R3R4ProductYield (%) bdr c
1HCOOEtHPh3a78 (65)5:1
24-BrCOOEtHPh3b82 (59)2.5:1
35-FCOOEtHPh3c83 (67)4:1
45-CH3COOEtHPh3d81 (69)6:1
5HCOOiPrHPh3e81 (65)4:1
6HCOOPhHPh3f87 (70)4:1
7H(CN)2HPh3g86 (69)4:1
8HPhHPh3h63 (61)>20:1
9H4-Br-C6H4HPh3i68 (58)6:1
10H2-F-C6H4HPh3j66 (63)>20:1
11H4-NO2-C6H4HPh3k62 (52)5:1
12H4-Me-C6H4HPh3l58 (56)>20:1
13H3,4-(MeO)2-C6H4HPh3m57 (46)4:1
14H2-naphthylHPh3n55 (53)>20:1
15H2-furylHPh3o46 (35)3:1
16H2-thienylHPh3p52 (39)3:1
17HCOOEtBnPh3q88 (77)7:1
18HCOOEtBocPh3r82 (71)6:1
19HCOOEtH3-Me-C6H43s70 (58)5:1
20HCOOEtH4-CF3-C6H43t67 (56)5:1
a See entry 15 and footnote “a” in Table 1. b Total yield of the mixed two isomers; the yield of the isolated major isomer 3 was shown in parentheses. c Based on crude 1H-NMR analysis of the mixed two isomers.

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MDPI and ACS Style

Ren, W.; Zhao, Q.; Zheng, C.; Zhao, Q.; Guo, L.; Huang, W. Efficient Synthesis of Fully Substituted Pyrrolidine-Fused 3-Spirooxindoles via 1,3-Dipolar Cycloaddition of Aziridine and 3-Ylideneoxindole. Molecules 2016, 21, 1113. https://doi.org/10.3390/molecules21091113

AMA Style

Ren W, Zhao Q, Zheng C, Zhao Q, Guo L, Huang W. Efficient Synthesis of Fully Substituted Pyrrolidine-Fused 3-Spirooxindoles via 1,3-Dipolar Cycloaddition of Aziridine and 3-Ylideneoxindole. Molecules. 2016; 21(9):1113. https://doi.org/10.3390/molecules21091113

Chicago/Turabian Style

Ren, Wen, Qian Zhao, Chuan Zheng, Qiong Zhao, Li Guo, and Wei Huang. 2016. "Efficient Synthesis of Fully Substituted Pyrrolidine-Fused 3-Spirooxindoles via 1,3-Dipolar Cycloaddition of Aziridine and 3-Ylideneoxindole" Molecules 21, no. 9: 1113. https://doi.org/10.3390/molecules21091113

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