Diversity-oriented one-pot multicomponent synthesis of spirooxindole derivatives and their biological evaluation for anticancer activities

Tetrahedron 72 (2016) 8523e8536

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Diversity-oriented one-pot multicomponent synthesis of spirooxindole derivatives and their biological evaluation for anticancer activities Jun Yang a, 1, Xiong-Wei Liu a, 1, Dan-Dan Wang a, Min-Yi Tian a, Shuo-Nan Han a, Ting-Ting Feng a, Xiong-Li Liu a, *, Ren-Qiang Mei b, Ying Zhou a, ** a

Guizhou Engineering Center for Innovative Traditional Chinese Medicine and Ethnic Medicine, Guizhou University, Guiyang, 550025, China State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 August 2016 Received in revised form 8 October 2016 Accepted 14 October 2016 Available online 2 November 2016

Described herein is a facile and efficient methodology for diversity-oriented one-pot multicomponent synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 via knoevenagel condensation/Michael/cyclization and then aminomethylation reaction. A wide variety of products with varying degrees of substitution around it, were obtained smoothly with high efficiency (up to overall yield 73% and >20:1 diastereoselectivity). In particular, their biological activities against these three cell lines K562, A549 and PC-3 have been evaluated. These results suggested that most of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 showed equipotent or more potent than the positive control of Cisplatin (up to 3.4 times). © 2016 Elsevier Ltd. All rights reserved.

Keywords: Five-membered carbocyclic spirooxindoles One-pot multicomponent synthesis Knoevenagel condensation/Michael/ cyclization Aminomethylation Antitumor activity

1. Introduction Multifunctional spiropyrrolidine oxindoles possessing interesting structural characteristics and strong bioactivity profiles, such as antibacterial,1 antiviral2 and local anaesthetic activities,3 have particularly emerged as attractive synthetic targets, since they serve as useful molecular scaffolds for the exploration and exploitation of pharmacophore space via diversity-oriented synthesis (DOS), which has led to the findings of new drug leads.4 Especially, five-membered carbocyclic spirooxindoles possess interesting structural properties found in a number of biologically active synthetic5 and natural products6 with activities in a variety of disease areas (Fig. 1). On the other hand, many natural products and pharmaceuticals ((S)-(
)-spirobrassinin, horsfiline,7 (þ)-Dioxibrassinin and coerulescine,8 etc.), share a common 3-aminomethyl

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (X.-L. Liu), [email protected] (Y. Zhou). 1 These two authors contributed equally to this work. http://dx.doi.org/10.1016/j.tet.2016.10.050 0040-4020/© 2016 Elsevier Ltd. All rights reserved.

quaternary carbon oxindole unit and exhibit significant biological activities.9 In this context, on account of the good biological activities of five-membered carbocyclic spirooxindole scaffolds and 3aminomethyl quaternary carbon oxindole scaffolds, which are considered “privileged structures”, we wondered if a hybrid of these two motifs for the construction of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 might generate novel drug-like molecules for biological screenings (Scheme 1). Stereoselective construction of spiropyrrolidine oxindoles is one of the most challenging work in catalytic organic reactions10,11. Generally, isatin and its derivatives have been employed as starting materials in 1,3-dipolar cycloaddition reactions yielding the spirooxindole core12e16 due to the facile preparation of the corresponding azomethine ylides in the presence of a-amino acids,17 and a variety of 1,3-dipolarophiles such as a, b-unsaturated ketones,18e20 arylidenemalono-dinitriles,21 a, b-unsaturated lactones,22 nitrostyrenes,23 acrylamides24 and various other electron deficient alkenes25e27 have been documented. Although many synthetic methods have been developed for the selective synthesis of spiropyrrolidine oxindoles, but existing stereoselective catalytic

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J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

Fig. 1. X-ray crystallographic structures of 4b and 5k.

Scheme 1. Design of diversity-oriented spirooxindole derivatives for drup discovery.

syntheses of substituted five-membered carbocyclic spirooxindoles from simple substrates and catalysts are very few.28,29 In particular, their high-yielding synthesis with multiple stereocenters and a spiro-quaternary carbon is a still demanding task.30 Therefore, the development of a catalytic stereoselective protocol for the diversity-oriented synthesis of functionalized five-membered carbocyclic spirooxindoles is a significant challenge. On the other hand, oxindoles containing a aminomethyl group at the C3 position are very attractive and valuable synthetic targets. Due to the ease of transforming aminomethyl group to other functionalities, aminomethylation oxindoles can act as potential intermediates for further elaboration. In this context, as a continuing effort to develop new methodology for the construction of complex oxindole-containing drug-like molecules,31 we report herein a facile diversity-oriented one-pot multicomponent synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 via knoevenagel condensation/michael/cyclization and then aminomethylation reaction (Scheme 2). In particular, their biological activity against human prostate cancer cells PC-3, human lung cancer cells A549 and human leukemia cells K562 have been evaluated. 2. Results and discussion In our initial endeavor, we screened different tertiary amines

and secondary amines (e.g., DABCO, Et3N, Et2NH, pyrrolidine and piperidine, entries 1e5, Table 1) as organocatalysts in the reaction of N-CH3-oxindole 1a with phthalaldehyde 2a to substantiate the feasibility of the strategy, as shown in Table 1. We were pleased to discover that the commonly used secondary amine catalyst of piperidine, was shown to catalyze the reaction more successfully, delivering the desired product 4a with 67% yield (Table 1, entry 5). Further solvent screening demonstrated that the reaction could deliver the product 4a (71% yield) preferentially with MeOH as the solvent (Table 1, entry 9). However, when the reaction was performed in toluene and CH3CN, only along with intractable product mixtures from which no main product could be identified by the HRMS spectra analysis (Table 1, entries 7 and 8). Extending the reaction time from 10 h to 16 h had a little positive effect on the yield of 4a with high diastereoselectivity (Table 1, entry 10). With this promising result in hand, the temperature effect of the reaction was further examined (Table 1, entries 11 and 12). The reaction also occurs at 40  C but extended reaction time (24 h) is required, albeit, much lower yield (25%) of product 4a was obtained (Table 1, entry 11). Thus, the optimal reaction conditions for synthetic intermediate oxindole 4a we established were, N-CH3-oxindole 1a (0.9 mmol), phthalaldehyde 2a (0.3 mmol), piperidine (10 mol%) in 6.0 mL of MeOH at reflux for 16 h. With this promising result in hand and considering the fact that oxindoles containing a aminomethyl group at the C3 position may

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

8525

Scheme 2. The synthesis of dioxindole derivatives.

Table 1 Optimization of reaction conditions for intermediate 4a.

Entrya 1 2 3 4 5 6 7 8 9 10e 11 12

Catalyst (10 mol%) DABCO Et3N Et2NH pyrrolidine piperidine piperidine piperidine piperidine piperidine piperidine piperidine piperidine

Solvent EtOH EtOH EtOH EtOH EtOH EtOAc Toluene CH3CN CH3OH CH3OH CH3OH CH3OH

T ( C) reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux 40 rt

Time(h) 10 10 10 10 10 10 10 10 10 16 24 30

Table 2 Optimization of reaction conditions for product 5a.

Yieldb (%) trace 17 58 55 67 18 trace trace 71 82 25 <5

Drc d

e 15:1 16:1 20:1 >20:1 17:1 ed ed >20:1 >20:1 >20:1 ed

a Unless noted, reactions were carried out with 0.9 mmol of 1a and 0.3 mmol of 2a in 6.0 mL of solvent. b Isolated yield after chromatographic purification. c Determined by 1H NMR analysis of the crude products. d Not determined. e The optimal reaction conditions in Table 1.

be beneficial for the biological activity. We then continue pursuing aminomethylation approach to access a series of oxindoles bearing an aminomethyl group at the C3 position via Mannich reaction. Because formaldehyde does not form stable imines, in an attempt to avoid this issue, we chose to examine the three-component reaction of the above synthetic intermediate 3-substituted oxindole 4a, secondary amine, and formaldehyde (Table 2). We envisioned that the iminium ion, generated in situ from formaldehyde and secondary amine, was attacked by the C3-position of 3-substituted oxindole 4a to form the corresponding aminomethylation product 5a. We initially investigated the three-component Mannich reaction of the intermediate oxindole 4a (0.3 mmol), piperidine 3a (0.6 mmol) and paraformaldehyde (1.2 mmol) in various solvents

Entrya

Solvent

T ( C)

Time (h)

Yieldb (%)

Drc

1 2 3 4 5 6 7 8 9d

(ClCH2)2 CH2Cl2 CHCl3 CH3CN EtOH Toluene EtOAc EtOAc EtOAc

40 reflux 40 40 40 40 40 50 70

48 48 48 48 48 48 48 30 24

45 47 35 51 28 47 75 87 93

20:1 >20:1 >20:1 15:1 14:1 19:1 >20:1 >20:1 >20:1

a Unless noted, reactions were carried out with 0.3 mmol of 4a, 0.6 mmol of 3a and 1.2 mmol of paraformaldehyde in 6.0 mL of solvent. b Isolated yield after chromatographic purification. c Determined by 1H NMR analysis of the crude products. d The optimal reaction conditions in Table 2.

(6.0 mL) at 40  C (Table 1, entries 1e8). It was found that ethyl acetate (EtOAc) was superior to other examined solvents like chlorinated solvents, toluene, CH3CN and EtOH in view of the yield and diastereoselectivity (Table 2, entry 7 vs entries 1e6). To our delight, further improvement to 93% yield and >20:1 dr of 5a has been achieved by increasing the reaction temperature from 40  C to 70  C with trace amount of other products observed by TLC in shortened reaction time (Table 2, entry 10). With the best reaction conditions in hands, we next turned our interest to the reaction scope, and the results were summarized in Table 3. The piperidine 3a was first used as a model substrate to probe the reactivity of different oxindole derivatives 1 in this reaction. It clearly indicated that all of the reactions proceeded smoothly under the optimal conditions, producing the desired products 5 in good yields with good diastereoselectivities (Table 3, entries 1e7). In addition, we explored the effects of displacement of the piperidine with a variety of secondary amines 3 (pyrrolidine,

Table 3 Synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5a, and their biological evaluation on human prostate cancer cells K562b, c.

a

Isolated overall yield after chromatographic purification.

b

The IC50 concentration represents the concentration which results in a 50% decrease in cell growth after two days

of incubation. The given values are mean values of three experiments. c

Cisplatin as a positive control, and its IC50 concentration was 25.4 μM.

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

dihydropyrrolidine, morpholine, thiomorpholine and Et2NH) in this reaction. It was found that the reaction could be conducted without affecting obviously the good yields and diastereoselectivities, and significant structural variation in the oxindoles 1 could be well accommodated. For example, electron-rich (CH3) and electronpoor (Cl, Br or F) substituents incorporated on the benzo moiety of oxindoles 1 were tolerated under the conditions (Table 3, entries 8e37). All the target spiropyrrolidine oxindoles 4a, 4b and 5a-5k′ were determined by nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy, and further confirmed by X-ray crystallographic studies of single crystals of 4b and 5k32(Fig. 1). Subsequently, to further demonstrate the potential activities of these synthesized 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5, following the literature precedent by Mosmann and coworkers33a with minor modification (Alley et al.),33b the activity of all the afforded spirooxindole derivatives 5 were evaluated in vitro against human leukemia cells K562 by the MTT-based assay using the commercially available broad-spectrum anticancer drug of Cisplatin as a positive control, and their IC50 concentration were depicted in Table 3. The results demonstrated that most of the compounds 5 showed considerable cytotoxicities to the cell lines K562. Although a general structure-activity relationship of the 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 to anticancer effect could not be summarized only from these in vitro inhibitory activity data, the following points were noteworthy: there is a trend that substituent at the 7-position of benzo moiety of compounds 5 improve the potency; the compounds 5c, 5f, 5p, 5x, 5y, 5b′, 5j′, 5i′ and 5k′ showed IC50 ranging from 7.4 mM to 32.8 mM in vitro inhibitory activity against human leukemia cells K562, and showed equipotent or more potent than the positive control of Cisplatin (up to 3.4 times). Subsequently, the seven compounds 5c, 5p, 5x, 5y, 5b′, 5j′, and 5i′ that displayed good activity against human leukemia cells K562 were evaluated against human prostate cancer cells PC-3 and human lung cancer cells A549 (Table 4). Compounds 5y, 5b′ and 5i′ had comparable in vitro inhibitory activity against human lung cancer cells A549, and Compounds 5y, 5b′, 5i′ and 5j′ had comparable in vitro inhibitory activity against human prostate cancer cells PC-3 with the positive control Cisplatin. The results also indicated that 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 may be useful leads for further biological screenings. Next, to prove the importance of the a aminomethyl group located in the 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 for biological activity, we compared with products 5 in Table 3, compounds 4a and 4b showed lower inhibitory activity towards the cell lines K562 due to higher IC50 datas (Scheme 3). These results suggested deletion of this a aminomethyl group from products 5 could obviously impact the activity, and a aminomethyl moiety located in the 3aminomethyl quaternary carbon oxindole fused five-membered

Table 4 Cytotoxicity of the nine compounds 5b, 5f, 5p, 5x, 5y, 5b′, 5j′, 5i′ and 5k′ on human prostate cancer cells PC-3 and human lung cancer cells A549a. Compound

5c

5p

5x

5y

5b′

5j′

5i′

Cisplatin

A549 IC50 (mM) PC-3 IC50 (mM)

>100.0

>100.0

>100.0

37.2

24.4

98.4

18.1

24.7

>100.0

98.9

>100.0

39.7

27.9

21.4

17.7

23.1

a

The IC50 concentration represents the concentration which results in a 50% decrease in cell growth after two days of incubation. The given values are mean values of three experiments.

8527

Scheme 3. Inhibitory activities of compounds 4a and 4b towards the cell lines K562.

carbocyclic spirooxindoles 5 is a beneficial structural requirement for the activity. 3. Conclusion In conclusion, we have developed a facile and efficient methodology for the synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 via a Knoevenagel condensation/Michael/cyclization and then aminomethylation reaction. A wide variety of products, which is hybridization of two key structural skeletons of five-membered carbocyclic spirooxindole and 3-aminomethyl quaternary carbon oxindole found in a large number of biologically active natural products and pharmaceutical compounds, were obtained smoothly with high efficiency (up to overall yield 73% and >20:1 diastereoselectivity). Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human leukemia cells K562 by the MTT-based assays using the commercially available broad-spectrum anticancer drug Cisplatin as a positive control. These results suggested that most of 3aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 showed equipotent or more potent than the positive control of Cisplatin (up to 3.4 times), which suggested these synthesized spirooxindole derivatives 5 may be potential leads for synthesizing new compounds that possess better activity. Moreover, efforts are in progress to improve the antitumor activities of these novel drug-like skeletons, and their other biological activity evaluation including antibacterial, antiviral activities are also underway in our laboratory. 4. Experimental section 4.1. General The 1H and 13C NMR spectra were recorded on Bruker Avance DMX 400 MHz NMR spectrometers in CDCl3 or DMSO-d6 using TMS as internal standard. Chemical shifts were reported as d values (ppm). High-resolution mass spectra (HRMS-ESI) were obtained on a Micro™ Q-TOF Mass Spectrometer. Melting points were uncorrected and recorded on an Electothermal 9100 digital melting point apparatus. Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin layer chromatography using silica gel GF254 plates. Column chromatography was performed on silica gel (300e400 mesh). 4.2. General procedure for synthesis of 3-aminomethyl quaternary carbon oxindole fused five-membered carbocyclic spirooxindoles 5 A solution of oxindole derivatives 1 (0.9 mmol), phthalaldehyde 2a (0.3 mmol) and piperidine (10 mol%) in MeOH (6.0 mL) was stirred at reflux for 16 h. After completion of the reaction, as indicated by TLC, the removal of solvent and purification by flash

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column chromatography (hexane/EtOAc ¼ 4:1e2:1) were carried out to furnish the corresponding intermediate oxindoles 4. In an ordinary vial equipped with a magnetic stirring bar, to the mixture of the above synthetic intermediate oxindoles 4 (0.3 mmol), secondary amines 3 (0.6 mmol) and in 6.0 mL EtOAc was added paraformaldehyde (1.2 mmol). The reaction mixture was stirred at 70  C for 24 h. After completion of the reaction, as indicated by TLC, the removal of solvent, purification by flash column chromatography (hexane/EtOAc ¼ 3:1e2:1) was carried out to furnish the corresponding products 5. 4.2.1. 1-Hydroxy-1'-methyl-3-(1-methyl-2-oxoindolin-3-yl)-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (4a)

White solid; m.p. 231.6e231.9  C; yield: 82%, dr: >20/1; 1H NMR (CDCl3, 400 MHz) d: 1.84 (d, J ¼ 11.2 Hz, 1H), 2.50 (s, 3H), 2.63 (s, 3H), 4.15 (d, J ¼ 2.0 Hz, 1H), 4.68 (d, J ¼ 6.0 Hz, 1H), 5.51 (d, J ¼ 10.8 Hz, 1H), 6.37 (d, J ¼ 8.0 Hz, 1H), 6.42 (d, J ¼ 7.8 Hz, 1H), 6.66 (d, J ¼ 7.2 Hz, 1H), 6.77e6.81 (m, 1H), 6.99e7.03 (m, 1H), 7.08e7.15 (m, 2H), 7.29 (s, 1H), 7.39e7.47 (m, 3H), 7.72 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.5, 25.9, 43.0, 50.0, 66.3, 80.6, 107.1, 107.7, 121.3, 121.5, 125.4, 125.6, 127.9, 128.0, 128.1, 138.0, 142.1, 144.2, 144.8, 174.7, 177.9; HRMS (ESI-TOF) m/z: Calcd. for C26H22N2NaO3 [MþNa]þ: 433.1528; Found: 433.1527. 4.2.2. 1'-Ethyl-1-(1-ethyl-2-oxoindolin-3-yl)-3-hydroxy-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (4b)

White solid; m.p. 132.1e133.3  C; overall yield: 68%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 1.22e1.28 (m, 6H), 2.25e2.29 (m, 4H), 2.53 (s, 3H), 2.69 (s, 3H), 2.94 (d, J ¼ 14.1 Hz, 1H), 3.25 (d, J ¼ 14.1 Hz, 1H), 4.72 (s, 1H), 5.37 (s, 1H), 6.20 (d, J ¼ 7.6 Hz, 1H), 6.30 (d, J ¼ 8.0 Hz, 1H), 6.44 (d, J ¼ 7.8 Hz, 1H), 6.68e6.71 (m, 1H), 6.90e6.92 (m, 1H), 7.01e7.03 (m, 2H), 7.31e7.33 (m, 2H), 7.39e7.42 (m, 2H), 8.16 (d, J ¼ 14.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 23.9, 25.5, 26.2, 26.5, 51.0, 55.0, 56.8, 65.2, 67.3, 81.3, 106.8, 107.8, 120.8, 121.2, 123.2, 126.7, 127.6, 127.7, 127.8, 138.2, 142.9, 143.8, 144.8, 177.3, 178.2; HRMS (ESI-TOF) m/z: Calcd. for C32H33N3NaO3 [MþNa]þ: 530.2420; Found: 530.2424. 1

4.2.4. 1'-Ethyl-1-(1-ethyl-2-oxo-3-(piperidin-1-ylmethyl)indolin-3yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5b)

colorless oil; overall yield: 65%, dr: 10/1; 1H NMR (CDCl3, 400 MHz) d: 0.92e0.96 (m, 3H), 0.99e1.03 (m, 3H), 1.17e1.25 (m, 8H), 2.15e2.19 (m, 2H), 2.31e2.38 (m, 2H), 2.50e2.55 (m, 1H), 2.73e2.76 (m, 1H), 3.10 (d, J ¼ 13.2 Hz, 1H), 3.24 (d, J ¼ 14.0 Hz, 1H), 3.43e3.49 (m, 1H), 3.58e3.68 (m, 1H), 4.57 (s, 1H), 5.37e5.39 (m, 1H), 6.21 (d, J ¼ 7.8 Hz, 1H), 6.34 (d, J ¼ 8.0 Hz, 1H), 6.41 (d, J ¼ 6.8 Hz, 1H), 6.65e6.68 (m, 1H), 6.85e6.89 (m, 1H), 6.98e7.04 (m, 2H), 7.29e7.40 (m, 5H), 8.14 (d, J ¼ 6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d:12.5, 12.9, 24.0, 26.4, 34.4, 34.9, 51.4, 54.8, 56.8, 65.7, 67.3, 81.4, 106.8, 107.9, 120.5, 121.0, 123.1, 126.7, 127.5, 127.6, 127.7, 138.0, 143.0, 143.3, 144.0, 177.0, 177.5; HRMS (ESI-TOF) m/z: Calcd. for C34H37N3NaO3 [MþNa]þ: 558.2733; Found: 558.2733. 4.2.5. 1'-Benzyl-1-(1-benzyl-2-oxo-3-(piperidin-1-ylmethyl) indolin-3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]-2'one (5c)

White solid; m.p. 224.5e225.3  C; yield: 78%, dr: 12/1; 1H NMR (DMSO-d6, 400 MHz) d: 0.77e0.84 (m, 6H), 2.68e2.73 (m, 1H), 2.89e2.94 (m, 1H), 3.14e3.20 (m, 1H), 3.27e3.35 (m, 1H), 4.34 (d, J ¼ 5.2 Hz, 1H), 4.47 (d, J ¼ 5.2 Hz, 1H), 5.30 (d, J ¼ 6.4 Hz, 1H), 5.52 (d, J ¼ 10.0 Hz, 1H), 6.44 (d, J ¼ 6.8 Hz, 1H), 6.54e6.57 (m, 2H), 6.62e6.65 (m, 1H), 6.88e6.92 (m, 1H), 7.02e7.06 (m, 1H), 7.09e7.13 (m, 2H), 7.27e7.34 (m, 3H), 7.61e7.63 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) d: 12.4, 12.6, 33.6, 34.0, 42.6, 49.7, 66.0, 79.6, 107.1, 107.2, 119.8, 120.7, 124.9, 125.3, 126.9, 127.0, 127.2, 138.6, 142.9, 143.1, 143.2, 173.7, 177.2; HRMS (ESI-TOF) m/z: Calcd. for C28H26N2NaO3 [MþNa]þ: 461.1841; Found: 461.1844. 4.2.3. 1-Hydroxy-1'-methyl-3-(1-methyl-2-oxo-3-(piperidin-1ylmethyl)indolin-3-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5a)

White solid; m.p. 185.7e186.2  C; overall yield: 64%, dr: 12/1; 1H NMR (CDCl3, 400 MHz) d: 1.24e1.26 (m, 8H), 2.26e2.28 (m, 2H), 2.36e2.37 (m, 2H), 3.23 (d, J ¼ 14.0 Hz, 1H), 3.34 (d, J ¼ 16.0 Hz, 1H), 3.41 (d, J ¼ 14.0 Hz, 1H), 3.63 (d, J ¼ 16.0 Hz, 1H), 4.68 (s, 1H), 4.85 (d, J ¼ 16.0 Hz, 1H), 5.09 (d, J ¼ 15.8 Hz, 1H), 5.51 (d, J ¼ 11.8 Hz, 1H), 6.10 (d, J ¼ 7.6 Hz, 1H), 6.19 (d, J ¼ 8.0 Hz, 1H), 6.50 (d, J ¼ 7.8 Hz, 1H), 6.74e6.78 (m, 1H), 6.95e7.02 (m, 3H), 7.08e7.11 (m, 2H), 7.15e7.24 (m, 9H), 7.34e7.36 (m, 2H), 7.41e7.44 (m, 2H), 8.25 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 23.9, 26.0, 43.5, 43.6, 51.8, 55.0, 57.1, 65.9, 67.4, 81.8, 108.1, 109.1, 121.4, 123.1, 124.3, 124.8, 126.6, 127.0, 127.2, 127.4, 127.5, 127.7, 127.9, 128.4, 128.7, 128.9, 129.3, 135.6, 136.1, 137.8, 142.9, 177.4, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C44H41N3NaO3 [MþNa]þ: 682.3046; Found: 682.3045. 4.2.6. 1,7-Dimethyl-2-oxo-3-(piperidin-1-ylmethyl)indolin-3-yl)-3hydroxy-1',7'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]-2'one (5d)

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

8529

4.2.9. 1'-Ethyl-1-(1-ethyl-7-methyl-2-oxo-3-(piperidin-1-ylmethyl) indolin-3-yl)-3-hydroxy-7'-methyl-1,3-dihydrospiro[indene-2,3'indolin]-2'-one (5g)

White solid; m.p. 231.1e232.3  C; overall yield: 62%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 1.23e1.32 (m, 6H), 2.18 (s, 3H), 2.24 (s, 3H), 2.29e2.31 (m, 4H), 2.85 (s, 3H), 2.88 (d, J ¼ 13.2 Hz, 1H), 3.03 (s, 3H), 3.23 (d, J ¼ 14.0 Hz, 1H), 4.69 (s, 1H), 5.35 (d, J ¼ 11.2 Hz, 1H), 6.27e6.29 (m, 1H), 6.58e6.62 (m, 1H), 6.80e6.85 (m, 3H), 7.25e7.39 (m, 5H), 8.16 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 18.9, 19.0, 24.0, 26.5, 28.8, 29.6, 52.1, 54.0, 56.8, 65.3, 66.4, 81.4, 118.0, 119.2, 120.5, 121.0, 122.8, 123.2, 124.9, 125.1, 127.5, 127.6, 127.7, 130.2, 131.3, 132.5, 138.4, 141.8, 142.8, 143.0, 178.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C34H37N3NaO3 [MþNa]þ: 558.2733; Found: 558.2731. 1

4.2.7. 1,5-Dimethyl-2-oxo-3-(piperidin-1-ylmethyl)indolin-3-yl)-3hydroxy-1',5'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]-2'one (5e)

White solid; m.p. 208.7e209.6  C; overall yield: 67%, dr: 9/1; 1H NMR (CDCl3, 400 MHz) d: 0.96e0.99 (m, 3H), 1.03e1.06 (m, 3H), 1.21e1.26 (m, 6H), 2.14 (s, 3H), 2.20e2.24 (m, 5H), 2.32e2.34 (m, 2H), 2.87e2.92 (m, 1H), 3.09e3.13 (m, 2H), 3.22 (d, J ¼ 13.6 Hz, 1H), 3.54e3.60 (m, 1H), 3.75e3.81 (m, 1H), 4.54 (s, 1H), 5.36 (d, J ¼ 12.0 Hz, 1H), 5.26 (d, J ¼ 7.8 Hz, 1H), 6.54e6.58 (m, 1H), 6.78e6.82 (m, 3H), 7.18 (d, J ¼ 7.0 Hz, 1H), 7.30e7.39 (m, 4H), 8.18 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 14.6, 15.0, 18.8, 18.9, 24.0, 26.4, 36.1, 36.7, 52.8, 53.7, 56.8, 65.9, 66.2, 81.6, 117.2, 118.5, 120.3, 120.9, 122.9, 123.1, 124.9, 125.2, 127.4, 127.5, 128.7, 130.5, 131.4, 132.7, 138.1, 141.4, 142.0, 143.2, 177.8, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C36H41N3NaO3 [MþNa]þ: 586.3046; Found: 586.3044. 4.2.10. 1-Hydroxy-1'-methyl-3-(1-methyl-3-(morpholinomethyl)2-oxoindolin-3-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5h)

White solid; m.p. 191.4e192.1  C; overall yield: 67%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 1.26e1.30 (m, 6H), 2.12 (s, 3H), 2.25e2.31 (m, 4H), 2.34 (s, 3H), 2.53 (s, 3H), 2.70 (s, 3H), 2.92 (d, J ¼ 14.0 Hz, 1H), 3.22 (d, J ¼ 14.0 Hz, 1H), 4.67 (s, 1H), 5.38 (d, J ¼ 11.8 Hz, 1H), 6.11 (d, J ¼ 8.0 Hz, 1H), 6.21 (d, J ¼ 8.0 Hz, 1H), 6.28 (s, 1H), 6.82e6.86 (m, 2H), 7.33e7.42 (m, 4H), 8.15 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 21.1, 21.4, 24.0, 25.2, 25.9, 26.5, 29.8, 50.9, 55.0, 56.8, 65.0, 67.5, 81.2, 106.4, 107.5, 125.7, 127.5, 127.7, 127.8, 127.9, 129.2, 130.0, 138.5, 141.6, 142.7, 142.9, 177.3, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C34H37N3NaO3 [MþNa]þ: 558.2733; Found: 558.2734. 1

4.2.8. 7'-Chloro-1-(7-chloro-1-methyl-2-oxo-3-(piperidin-1ylmethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5f)

White solid; m.p. 164.4e165.7  C; overall yield: 70%, dr: 13/1; 1H NMR (CDCl3, 400 MHz) d: 2.24e2.26 (m, 2H), 2.40e2.44 (m, 2H), 2.56 (s, 3H), 2.70 (s, 3H), 3.19e3.29 (m, 2H), 3.32e3.39 (m, 4H), 4.63 (s, 1H), 5.38 (d, J ¼ 7.2 Hz, 1H), 6.24 (d, J ¼ 6.4 Hz, 1H), 6.34 (d, J ¼ 6.0 Hz, 1H), 6.46 (d, J ¼ 6.0 Hz, 1H), 6.71e6.74 (m, 1H), 6.92e6.95 (m, 1H), 7.03e7.07 (m, 2H), 7.34e7.43 (m, 5H), 8.14 (d, J ¼ 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.5, 26.1, 51.2, 54.8, 55.3, 65.1, 67.3, 67.4, 81.1, 106.9, 107.7, 120.8, 123.2, 124.8, 126.3, 127.5, 127.9, 128.7, 137.6, 142.9, 144.1, 144.6, 177.0, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C31H31N3NaO4 [MþNa]þ: 532.2212; Found: 532.2215. 4.2.11. 5'-Fluoro-1-(5-fluoro-1-methyl-3-(morpholinomethyl)-2oxoindolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro[indene2,3'-indolin]-2'-one (5i)

White solid; m.p. 156.5e157.6  C; overall yield: 66%, dr: 17/1; 1H NMR (CDCl3, 400 MHz) d: 1.24e1.30 (m, 6H), 2.29e2.30 (m, 4H), 2.94e3.01 (m, 4H), 3.14e3.23 (m, 4H), 4.67 (s, 1H), 5.39 (d, J ¼ 10.4 Hz, 1H), 6.32e6.35 (m, 1H), 6.64e6.68 (m, 1H), 6.86e6.91 (m, 1H), 7.07e7.11 (m, 2H), 7.25e7.41 (m, 5H), 8.13 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 23.9, 26.5, 28.9, 29.7, 52.2, 54.6, 56.8, 65.3, 66.8, 81.6, 114.4, 115.6, 121.5, 122.0, 123.3, 123.4, 125.3, 127.2, 127.8, 127.9, 128.6, 130.5, 131.6, 132.1, 137.5, 139.8, 140.4, 142.5, 177.5, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C32H31Cl2N3NaO3 [MþNa]þ: 598.1640; Found: 598.1642.

White solid; m.p. 149.3e149.9  C; overall yield: 63%, dr: 16/1; 1H NMR (CDCl3, 400 MHz) d: 2.26e2.28 (m, 2H), 2.39e2.43 (m, 2H), 2.65 (s, 3H), 2.80 (s, 3H), 3.18e3.19 (m, 2H), 3.36e3.38 (m, 4H), 5.35 (d, J ¼ 9.6 Hz, 1H), 6.16e6.18 (m, 1H), 6.24e6.27 (m, 2H), 6.74e6.76 (m, 2H), 7.11 (d, J ¼ 6.4 Hz, 1H), 7.25e7.34 (m, 4H), 8.08 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.5, 26.1, 51.2, 55.4, 55.5, 65.1, 67.3, 67.6, 81.3, 107.1, 107.2, 107.9, 113.1 (d, JCF ¼ 25.1 Hz), 114.0, 114.2,

8530

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

114.3, 114.4, 114.9, 123.4, 127.9, 128.0, 128.5, 131.0 (d, JCF ¼ 9.2 Hz), 136.9, 140.1 (d, JCF ¼ 2.0 Hz), 142.3, 158.1 (d, JCF ¼ 239.0 Hz), 176.8, 178.3; HRMS (ESI-TOF) m/z: Calcd. for C31H29F2N3NaO4 [MþNa]þ: 568.2024; Found: 568.2027. 4.2.12. 7'-Chloro-1-(7-chloro-1-methyl-3-(morpholinomethyl)-2oxoindolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro[indene2,3'-indolin]-2'-one (5j)

2.18e2.22 (m, 2H), 2.30e2.33 (m, 2H), 2.47e2.51 (m, 2H), 2.57e2.59 (m, 1H), 2.68e2.71 (m, 2H), 2.78e2.80 (m, 1H), 3.11 (d, J ¼ 11.6 Hz, 1H), 3.45e3.53 (m, 2H), 3.62e3.67 (m, 1H), 4.50 (s, 1H), 5.39 (s, 1H), 6.26e6.29 (m, 1H), 6.37e6.42 (m, 2H), 6.68e6.71 (m, 1H), 6.88e6.92 (m, 1H), 7.03e7.08 (m, 2H), 7.22e7.25 (m, 1H), 7.32e7.42 (m, 3H); 13C NMR (CDCl3, 100 MHz) d: 12.6, 12.7, 28.1, 34.4, 34.8, 51.5, 54.9, 56.9, 65.8, 67.2, 81.3, 106.9, 107.9, 120.5, 121.0, 123.1, 126.3, 127.4, 127.5, 127.8, 137.5, 142.9, 143.5, 143.8, 176.7, 177.3; HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3S [MþNa]þ: 576.2297; Found: 576.2297. 4.2.15. 1,5-Dimethyl-2-oxo-3-(thiomorpholinomethyl)indolin-3yl)-3-hydroxy-1',5'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5m)

White solid; m.p. 146.2e146.7  C; overall yield: 64%, dr: 10/1; 1H NMR (CDCl3, 400 MHz) d: 2.24e2.27 (m, 2H), 2.40e2.43 (m, 2H), 2.97 (s, 3H), 3.13e3.17 (m, 4H), 3.27 (d, J ¼ 14.0 Hz, 1H), 3.37e3.41 (m, 4H), 4.57 (s, 1H), 5.36e5.38 (m, 1H), 6.31e6.33 (m, 1H), 6.64e6.68 (m, 1H), 6.86e6.90 (m, 1H), 7.07e7.12 (m, 2H), 7.19e7.25 (m, 1H), 7.31e7.42 (m, 4H), 8.09 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 29.0, 29.7, 52.5, 54.5, 55.5, 65.3, 66.7, 67.3, 81.5, 114.7, 115.6, 121.6, 122.1, 123.3, 123.5, 124.9, 127.1, 127.9, 128.1, 128.4, 130.8, 131.6, 131.8, 137.0, 104.1, 140.4, 142.5, 177.3, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C31H29Cl2N3NaO4 [MþNa]þ: 600.1433; Found: 600.1433. 4.2.13. 1-Hydroxy-1'-methyl-3-(1-methyl-2-oxo-3(thiomorpholinomethyl)indolin-3-yl)-1,3-dihydrospiro[indene-2,3'indolin]-2'-one (5k)

White solid; m.p. 116.3e117.5  C; overall yield: 68%, dr: 10/1; 1H NMR (CDCl3, 400 MHz) d: 2.13 (s, 3H), 2.21e2.25 (m, 2H), 2.28e2.33 (m, 2H), 2.35 (s, 3H), 2.49e2.53 (m, 2H), 2.56 (s, 3H), 2.66e2.70 (m, 5H), 3.15 (d, J ¼ 11.2 Hz, 1H), 3.34 (d, J ¼ 11.6 Hz, 1H), 4.51 (s, 1H), 5.38 (s, 1H), 6.15 (d, J ¼ 6.0 Hz, 1H), 6.24 (d, J ¼ 6.4 Hz, 1H), 6.28 (s, 1H), 6.85e6.88 (m, 2H), 7.14 (s, 1H), 7.35e7.44 (m, 4H), 8.11 (d, J ¼ 6.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 21.0, 21.2, 25.2, 25.7, 28.3, 51.1, 55.1, 56.8, 65.4, 67.3, 81.0, 106.5, 107.4, 123.2, 125.6, 127.1, 127.5, 128.1, 129.1, 129.9, 137.8, 141.9, 142.5, 142.9, 177.0, 177.9; HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3S [MþNa]þ: 576.2297; Found: 576.2294. 4.2.16. 1,7-Dimethyl-2-oxo-3-(thiomorpholinomethyl)indolin-3yl)-3-hydroxy-1',7'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5n)

White solid; m.p. 212.3e213.1  C; overall yield: 72%, dr: 14/1; 1H NMR (CDCl3, 400 MHz) d: 2.15e2.21 (m, 2H), 2.25e2.29 (m, 2H), 2.47e2.55 (m, 5H), 2.64e2.69 (m, 5H), 3.16 (d, J ¼ 14.0 Hz, 1H), 3.35 (d, J ¼ 14.0 Hz, 1H), 4.54 (s, 1H), 5.36 (d, J ¼ 10.0 Hz, 1H), 6.22 (d, J ¼ 7.8 Hz, 1H), 6.31 (d, J ¼ 8.0 Hz, 1H), 6.42e6.44 (m, 1H), 6.69e6.73 (m, 1H), 6.91e6.94 (m, 1H), 7.02e7.06 (m, 2H), 7.28e7.41 (m, 5H), 8.11 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.6, 26.2, 28.4, 51.3, 55.2, 56.9, 65.7, 67.3, 81.2, 107.0, 107.9, 120.8, 121.3, 124.8, 127.6, 127.7, 128.0, 128.9, 137.6, 142.9, 144.3, 144.7, 177.2, 178.2; HRMS (ESITOF) m/z: Calcd. for C31H31N3NaO3S [MþNa]þ: 548.1984; Found: 548.1985. 4.2.14. 1'-Ethyl-1-(1-ethyl-2-oxo-3-(thiomorpholinomethyl) indolin-3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]-2'one (5l)

White solid; m.p. 173.5e174.3  C; overall yield: 69%, dr: 6/1; 1H NMR (CDCl3, 400 MHz) d: 0.98e1.00 (m, 3H), 1.03e1.03 (m, 3H),

White solid; m.p. 218.9e219.6  C; overall yield: 67%, dr: 15/1; 1H NMR (CDCl3, 400 MHz) d: 2.22 (s, 3H), 2.26 (s, 3H), 2.27e2.33 (m, 4H), 2.53e2.57 (m, 2H), 2.68e2.72 (m, 2H), 2.88 (s, 3H), 3.04 (s, 3H), 3.17 (d, J ¼ 11.6 Hz, 1H), 3.32 (d, J ¼ 11.2 Hz, 1H), 4.53 (s, 1H), 3.36 (d, J ¼ 8.8 Hz, 1H), 6.29 (d, J ¼ 5.6 Hz, 1H), 6.61e6.64 (m, 1H), 6.83e6.87 (m, 3H), 7.14e7.16 (m, 1H), 7.33e7.42 (m, 4H), 8.14 (d, J ¼ 6.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 18.7, 18.8, 28.2, 28.7, 29.4, 52.3, 54.2, 56.8, 65.7, 66.2, 81.2, 118.1, 119.2, 120.4, 120.9, 122.7, 123.2, 124.4, 124.7, 127.4, 127.5, 128.4, 129.5, 131.4, 132.4, 137.6, 142.2, 142.6, 142.9, 177.7, 178.8; HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3S [MþNa]þ: 576.2297; Found: 576.2297. 4.2.17. 5'-Fluoro-1-(5-fluoro-1-methyl-2-oxo-3(thiomorpholinomethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (5o)

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

8531

4.2.20. 1-Hydroxy-3-(2-oxo-1-phenyl-3-(pyrrolidin-1-ylmethyl) indolin-3-yl)-1'-phenyl-1,3-dihydrospiro[indene-2,3'-indolin]-2'one (5r)

White solid; m.p. 184.0e185.1  C; overall yield: 58%, dr: 15/1; 1H NMR (CDCl3, 400 MHz) d: 2.21e2.26 (m, 2H), 2.29e2.34 (m, 2H), 2.49e2.56 (m, 2H), 2.66e2.71 (m, 5H), 2.81 (s, 3H), 3.16 (d, J ¼ 14.0 Hz, 1H), 3.30 (d, J ¼ 14.0 Hz, 1H), 4.51 (s, 1H), 5.35 (d, J ¼ 6.0 Hz, 1H), 6.15e6.18 (m, 1H), 6.23e6.27 (m, 2H), 6.74e6.80 (m, 2H), 7.05e7.08 (m, 1H), 7.31e7.42 (m, 3H), 8.08 (d, J ¼ 8.0 Hz, 1H); 13 C NMR (CDCl3, 100 MHz) d: 25.5, 26.1, 28.4, 51.2, 55.7, 57.0, 65.7, 67.6, 81.3, 107.9, 108.0, 113.0 (d, JCF ¼ 25.1 Hz), 114.0, 114.1, 114.2, 114.4, 115.0 (d, JCF ¼ 23.1 Hz), 123.4, 127.9, 128.1, 128.5, 130.8, 136.8, 140.2, 142.3, 158.1 (d, JCF ¼ 240.0 Hz), 176.8, 178.3; HRMS (ESI-TOF) m/z: Calcd. for C31H29F2N3NaO3S [MþNa]þ: 584.1795; Found: 584.1798. 4.2.18. 7'-Chloro-1-(7-chloro-1-methyl-2-oxo-3(thiomorpholinomethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (5p)

White solid; m.p. 191.8e192.5  C; overall yield: 55%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 1.46e1.54 (m, 4H), 2.07e2.10 (m, 2H), 2.32e2.34 (m, 2H), 3.12 (d, J ¼ 12.0 Hz, 1H), 3.41 (d, J ¼ 12.4 Hz, 1H), 4.26 (s, 1H), 5.52 (d, J ¼ 10.4 Hz, 1H), 5.97e5.99 (m, 1H), 6.22e6.24 (m, 1H), 6.60 (d, J ¼ 7.8 Hz, 1H), 6.68e6.78 (m, 3H), 7.05e7.12 (m, 2H), 7.27e7.37 (m, 11H), 7.50e7.58 (m, 4H); 13C NMR (CDCl3, 100 MHz) d: 24.3, 55.1, 55.8, 57.0, 65.0, 67.4, 80.7, 108.8, 109.5, 121.8, 122.6, 127.4, 127.7, 127.8, 127.9, 128.0, 128.4, 129.3, 129.4, 130.3, 130.8, 134.6, 135.3, 140.6, 144.1, 145.5, 146.3, 175.0, 178.7; HRMS (ESI-TOF) m/z: Calcd. for C41H35N3NaO3 [MþNa]þ: 640.2576; Found: 640.2580. 1

4.2.21. 1'-Ethyl-1-(1-ethyl-2-oxo-3-(pyrrolidin-1-ylmethyl)indolin3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5s)

White solid; m.p. 138.9e139.6  C; overall yield: 57%, dr: 14/1; 1H NMR (CDCl3, 400 MHz) d: 2.25e2.31 (m, 4H), 2.48e2.53 (m, 2H), 2.65e2.68 (m, 2H), 2.98 (s, 3H), 3.12e3.17 (m, 4H), 3.36 (d, J ¼ 14.0 Hz, 1H), 4.50 (s, 1H), 5.36 (d, J ¼ 9.2 Hz, 1H), 6.31e6.33 (m, 1H), 6.65e6.67 (m, 1H), 6.88e6.91 (m, 1H), 7.07e7.10 (m, 2H), 7.14e7.16 (m, 1H), 7.33e7.42 (m, 4H), 8.08 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 28.4, 29.0, 29.7, 52.5, 54.9, 57.0, 65.8, 66.7, 81.5, 114.6, 115.6, 121.5, 122.1, 123.3, 123.5, 124.8, 127.1, 127.8, 128.1, 128.4, 130.7, 131.6, 131.7, 136.9, 140.2, 140.3, 142.6, 177.3, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C31H29Cl2N3NaO3S [MþNa]þ: 616.1204; Found: 616.1207. 4.2.19. 1-Hydroxy-1'-methyl-3-(1-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5q)

White solid; m.p. 141.5e142.3  C; overall yield: 65%, dr: 19/1; 1H NMR (CDCl3, 400 MHz) d: 0.87e0.91 (m, 3H), 1.01e1.04 (m, 3H), 1.44e1.47 (m, 4H), 2.15e2.17 (m, 2H), 2.38e2.41 (m, 2H), 2.48e2.53 (m, 1H), 2.72e2.77 (m, 1H), 3.22 (d, J ¼ 13.6 Hz, 1H), 3.46e3.51 (m, 1H), 3.61e3.68 (m, 2H), 4.59 (s, 1H), 5.39 (d, J ¼ 11.6 Hz, 1H), 6.20 (d, J ¼ 7.8 Hz, 1H), 6.35 (d, J ¼ 7.8 Hz, 1H), 6.42e6.44 (m, 1H), 6.66e6.70 (m, 1H), 6.87e6.91 (m, 1H), 6.99e7.06 (m, 2H), 7.27e7.41 (m, 5H), 8.15 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 12.1, 12.9, 24.1, 34.3, 34.9, 51.7, 54.8, 56.1, 63.9, 67.3, 81.4, 106.9, 107.9, 120.7, 121.0, 123.1, 125.1, 127.5, 127.7, 128.8, 138.0, 142.9, 143.3, 144.0, 177.0, 177.5; HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3 [MþNa]þ: 544.2576; Found: 544.2581. 4.2.22. 1'-Ethyl-1-(1-ethyl-2-oxo-3-(pyrrolidin-1-ylmethyl)indolin3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5t)

White solid; m.p. 116.7e118.3  C; overall yield: 63%, dr: 20/1; 1H NMR (CDCl3, 400 MHz) d: 1.51e1.54 (m, 4H), 2.26e2.29 (m, 2H), 2.41e2.45 (m, 2H), 2.50 (s, 3H), 2.68 (s, 3H), 3.32e3.41 (m, 2H), 4.72 (s, 1H), 5.37 (d, J ¼ 11.2 Hz, 1H), 6.19 (d, J ¼ 8.0 Hz, 1H), 6.32 (d, J ¼ 8.0 Hz, 1H), 6.44 (d, J ¼ 7.8 Hz, 1H), 6.69e6.72 (m, 1H), 6.91e6.95 (m, 1H), 7.02e7.04 (m, 2H), 7.31e7.36 (m, 4H), 8.17 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 24.2, 25.6, 26.2, 51.7, 55.0, 56.5, 63.9, 67.4, 81.3, 106.9, 107.8, 121.0, 121.3, 123.2, 124.8, 126.7, 127.6, 127.8, 138.0, 142.8, 143.9, 144.8, 177.3, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C31H31N3NaO3 [MþNa]þ: 516.2263; Found: 516.2263.

White solid; m.p. 201.2e202.4  C; overall yield: 67%, dr: 20/1; H NMR (CDCl3, 400 MHz) d: 1.49e1.52 (m, 4H), 2.11 (s, 3H), 2.26e2.29 (m, 2H), 2.33 (s, 3H), 2.41e2.45 (m, 2H), 2.50 (s, 3H), 2.68 (s, 3H), 3.30 (d, J ¼ 7.2 Hz, 1H), 3.40 (d, J ¼ 12.8 Hz, 1H), 4.65 (s, 1H), 5.36 (d, J ¼ 11.2 Hz, 1H), 6.09e6.11 (m, 1H), 6.22e6.24 (m, 1H), 6.28 (s, 1H), 6.82e6.86 (m, 2H), 7.17 (s, 1H), 7.32e7.42 (m, 4H), 8.15 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 21.1, 21.4, 24.2, 25.3, 25.9, 51.7, 55.0, 56.4, 63.9, 67.5, 81.3, 106.5, 107.6, 123.2, 125.6, 127.5, 127.6, 127.7, 128.0, 130.8, 138.3, 141.7, 142.7, 142.8, 177.3, 178.0; 1

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HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3 [MþNa]þ: 544.2576; Found: 544.2577. 4.2.23. 1-(1,7-Dimethyl-2-oxo-3-(pyrrolidin-1-ylmethyl)indolin-3yl)-3-hydroxy-1',7'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5u)

1.42e1.44 (m, 4H), 2.07e2.13 (m, 5H), 2.29e2.37 (m, 5H), 2.51 (s, 1H), 2.74 (s, 1H), 3.12e3.14 (m, 1H), 3.48e3.53 (m, 1H), 3.63e3.68 (m, 2H), 4.51 (d, J ¼ 5.2 Hz, 1H), 5.34e5.38 (m, 1H), 6.10e6.12 (m, 1H), 6.24 (s, 2H), 6.79e6.84 (m, 2H), 7.03 (s, 1H), 7.30e7.36 (m, 4H), 8.09 (br s, 1H); 13C NMR (CDCl3, 100 MHz) d: 12.1, 12.9, 21.1, 21.2, 24.1, 33.9, 34.5, 51.8, 54.9, 56.0, 63.8, 67.3, 81.3, 106.5, 107.7, 123.1, 125.9, 127.4, 127.6, 128.0, 129.2, 129.8, 138.2, 141.1, 141.7, 141.8, 143.0, 177.0, 177.5; HRMS (ESI-TOF) m/z: Calcd. for C35H39N3NaO3 [MþNa]þ: 572.2889; Found: 572.2888. 4.2.26. 1'-Ethyl-1-(1-ethyl-7-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-7'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5x)

White solid; m.p. 201.1e202.6  C; overall yield: 69%, dr: 9/1; 1H NMR (CDCl3, 400 MHz) d: 1.50e1.56 (m, 4H), 2.18 (s, 3H), 2.26 (s, 3H), 2.29e2.34 (m, 2H), 2.42e2.45 (m, 2H), 2.83 (s, 3H), 3.02 (s, 3H), 3.30e3.39 (m, 2H), 4.68 (s, 1H), 5.34 (d, J ¼ 11.8 Hz, 1H), 6.29 (d, J ¼ 7.8 Hz, 1H), 6.59e6.63 (m, 1H), 6.81e6.84 (m, 3H), 7.19e7.21 (m, 1H), 7.31 (d, J ¼ 4.6 Hz, 2H), 7.36e7.41 (m, 1H), 8.17 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 18.8, 19.0, 24.2, 28.9, 29.6, 52.9, 54.0, 56.5, 64.1, 66.3, 81.5, 118.1, 119.2, 120.7, 121.1, 122.7, 123.1, 124.8, 125.0, 127.5, 128.7, 130.5, 131.4, 132.5, 138.1, 141.8, 142.7, 142.9, 177.8, 178.9; HRMS (ESI-TOF) m/z: Calcd. for C33H35N3NaO3 [MþNa]þ: 544.2576; Found: 544.2573. 4.2.24. 1'-Benzyl-1-(1-benzyl-7-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-7'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5v)

White solid; m.p. 218.5e219.3  C; overall yield: 56%, dr: 15/1; 1H NMR (CDCl3, 400 MHz) d: 1.55e1.61 (m, 4H), 1.84 (s, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.18e2.21 (m, 2H), 2.46e2.53 (m, 2H), 3.16e3.20 (m, 1H), 3.84e3.88 (m, 1H), 4.08e4.13 (m, 2H), 4.18 (s, 1H), 4.55 (s, 1H), 5.01 (d, J ¼ 16.2 Hz, 1H), 5.22 (d, J ¼ 16.6 Hz, 1H), 5.49 (d, J ¼ 12.4 Hz, 1H), 6.41 (d, J ¼ 7.8 Hz, 1H), 6.70e6.75 (m, 1H), 6.82e6.84 (m, 2H), 6.91e6.95 (m, 1H), 7.03e7.25 (m, 13H), 7.36e7.43 (m, 4H), 8.27 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 18.5, 18.7, 24.0, 44.7, 45.0, 53.8, 54.4, 56.6, 64.9, 66.4, 82.0, 118.3, 119.5, 120.7, 121.4, 122.8, 123.2, 125.0, 125.1, 125.5, 125.8, 126.7, 127.0, 127.6, 127.8, 128.4, 128.9, 129.0, 130.2, 131.9, 132.9, 137.5, 138.2, 142.1, 142.2, 143.0, 178.3, 179.2; HRMS (ESI-TOF) m/z: Calcd. for C45H43N3NaO3 [MþNa]þ: 696.3202; Found: 696.3207. 4.2.25. 1'-Ethyl-1-(1-ethyl-5-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-5'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5w)

White solid; m.p. 202.3e203.7  C; overall yield: 68%, dr: 6/1; 1H NMR (CDCl3, 400 MHz) d: 0.87e0.89 (m, 3H), 1.00e1.02 (m, 3H),

White solid; m.p. 199.5e200.6  C; overall yield:72%, dr: 7/1; 1H NMR (CDCl3, 400 MHz) d: 0.87e0.91 (m, 3H), 1.02e1.06 (m, 3H), 1.44e1.46 (m, 4H), 2.12 (s, 3H), 2.13e2.18 (m, 2H), 2.21 (s, 3H), 2.36e2.40 (m, 2H), 2.85e2.90 (m, 1H), 3.07e3.12 (m, 1H), 3.16 (d, J ¼ 13.6 Hz, 1H), 3.58e3.63 (m, 1H), 3.72 (d, J ¼ 13.2 Hz, 1H), 3.76e3.80 (m, 1H), 4.52 (s, 1H), 5.35 (d, J ¼ 12.0 Hz, 1H), 6.27e6.29 (m, 1H), 6.54e6.58 (m, 1H), 6.77e6.83 (m, 4H), 7.11e7.14 (m, 1H), 7.30e7.40 (m, 4H), 8.18 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 14.1, 15.1, 18.8, 18.9, 24.1, 35.9, 36.7, 53.2, 53.7, 56.1, 64.2, 66.2, 81.6, 117.3, 118.5, 120.5, 120.9, 123.0, 123.1, 124.8, 125.2, 127.4, 127.5, 128.7, 131.0, 131.5, 132.7, 137.9, 141.5, 142.0, 143.1, 177.9, 178.6; HRMS (ESI-TOF) m/z: Calcd. for C35H39N3NaO3 [MþNa]þ: 572.2889; Found: 572.2891. 4.2.27. 7'-Chloro-1-(7-chloro-1-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5y)

White solid; m.p. 173.2e174.1  C; overall yield: 66%, dr: 18/1; 1H NMR (CDCl3, 400 MHz) d: 1.57 (s, 4H), 2.34e2.35 (m, 2H), 2.45e2.47 (m, 2H), 2.96 (s, 3H), 3.13 (s, 3H), 3.34 (d, J ¼ 10.8 Hz, 1H), 3.44 (d, J ¼ 10.8 Hz, 1H), 4.67 (s, 1H), 5.38 (s, 1H), 6.33e6.35 (m, 1H), 6.65e6.67 (m, 1H), 6.89e6.91 (m, 1H), 7.08e7.11 (m, 2H), 7.23e7.35 (m, 5H), 8.15 (d, J ¼ 6.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 24.1, 28.8, 29.5, 52.7, 54.5, 56.3, 64.0, 66.7, 81.4, 114.2, 115.3, 121.5, 121.9, 123.1, 123.2, 125.1, 127.2, 127.6, 127.7, 128.3, 130.4, 131.3, 132.3, 137.1, 139.6, 140.1, 142.3, 177.3, 178.5; HRMS (ESI-TOF) m/z: Calcd. for C31H29Cl2N3NaO3 [MþNa]þ: 584.1484; Found: 584.1487. 4.2.28. 5'-Chloro-1-(5-chloro-1-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5z)

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

8533

4.2.31. 1-(3-((2,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-methyl-2oxoindolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro[indene2,3'-indolin]-2'-one (5c0 )

White solid; m.p. 121.1e122.4  C; overall yield: 56%, dr: 20/1; 1H NMR (CDCl3, 400 MHz) d: 1.54e1.57 (m, 4H), 2.32e2.34 (m, 2H), 2.45e2.47 (m, 2H), 2.67 (s, 3H), 2.86 (s, 3H), 3.36 (s, 2H), 4.69 (s, 1H), 5.38 (s, 1H), 6.16 (d, J ¼ 8.0 Hz, 1H), 6.28 (d, J ¼ 8.4 Hz, 1H), 6.48 (d, J ¼ 5.0 Hz, 1H), 7.03e7.04 (m, 2H), 7.24e7.444 (m, 5H), 8.12 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 24.3, 25.7, 26.3, 51.6, 55.3, 56.6, 64.0, 67.4, 81.6, 107.8, 108.6, 123.3, 125.1, 126.4, 126.5, 126.8, 126.9, 127.8, 127.9, 128.0, 128.6, 128.9, 131.7, 137.2, 142.1, 142.6, 143.4, 176.8, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C31H29Cl2N3NaO3 [MþNa]þ: 584.1484; Found: 584.1484. 4.2.29. 5'-Fluoro-1-(5-fluoro-1-methyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-3-hydroxy-1'-methyl-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5a0 )

White solid; m.p. 192.1e193.0  C; overall yield: 73%, dr:10/1; 1H NMR (CDCl3, 400 MHz) d: 2.52 (s, 3H), 2.70 (s, 3H), 3.18e3.22 (m, 2H), 3.41e3.45 (m, 2H), 3.51 (d, J ¼ 13.6 Hz, 1H), 3.76 (d, J ¼ 14.0 Hz, 1H), 4.65 (s, 1H), 5.38 (d, J ¼ 10.4 Hz, 1H), 5.51 (s, 2H), 6.20 (d, J ¼ 7.6 Hz, 1H), 6.34 (d, J ¼ 7.8 Hz, 1H), 6.45e6.47 (m, 1H), 6.70e6.73 (m, 1H), 6.94e6.96 (m, 1H), 7.04e7.05 (m, 2H), 7.32e7.34 (m, 4H), 8.20 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.7, 26.2, 51.8, 55.7, 63.4, 66.0, 67.4, 81.4, 106.9, 107.9, 121.0, 121.4, 123.2, 127.2, 127.6, 127.7, 127.9, 137.8, 142.8, 144.2, 144.8, 177.2, 178.1; HRMS (ESITOF) m/z: Calcd. for C31H29N3NaO3 [MþNa]þ: 514.2107; Found: 514.2109. 4.2.32. 1-(3-((2,5-Dihydro-1H-pyrrol-1-yl)methyl)-1-ethyl-2oxoindolin-3-yl)-1'-ethyl-3-hydroxy-1,3-dihydrospiro[indene-2,3'indolin]-2'-one (5d0 )

White solid; m.p. 126.3e127.5  C; overall yield: 62%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 1.56e1.59 (m, 4H), 2.35e2.37 (m, 2H), 2.47e2.49 (m, 2H), 2.65 (s, 3H), 2.82 (s, 3H), 3.34e3.41 (m, 2H), 4.71 (s, 1H), 5.39 (s, 1H), 6.16e6.17 (m, 1H), 6.28e6.30 (m, 2H), 6.78e6.79 (m, 2H), 7.13e7.15 (m, 1H), 7.28e7.42 (m, 3H), 8.15 (d, J ¼ 6.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 24.1, 25.4, 25.9, 51.4, 55.4, 56.4, 63.9, 67.5, 81.3, 106.7, 106.8, 107.7, 107.8, 112.9 (d, JCF ¼ 20.5 Hz), 113.9 (d, JCF ¼ 19.4 Hz), 114.3, 114.7, 123.1, 126.3, 127.7, 128.5, 131.6, 137.1, 139.7, 140.6, 142.1, 158.0 (d, JCF ¼ 205.4 Hz), 176.8, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C31H29F2N3NaO3 [MþNa]þ: 552.2075; Found: 552.2078. 1

4.2.30. 7'-Chloro-1-(7-chloro-1-ethyl-2-oxo-3-(pyrrolidin-1ylmethyl)indolin-3-yl)-1'-ethyl-3-hydroxy-1,3-dihydrospiro [indene-2,3'-indolin]-2'-one (5b0 )

White solid; m.p. 104.6e105.3  C; overall yield: 69%, dr: 8:1; 1H NMR (CDCl3, 400 MHz) d: 0.84e0.89 (m, 3H), 1.00e1.04 (m, 3H), 2.48e2.57 (m, 1H), 2.73e2.79 (m, 1H), 3.13 (d, J ¼ 9.6 Hz, 2H), 3.39e3.49 (m, 4H), 3.59e3.69 (m, 1H), 3.86 (d, J ¼ 13.6 Hz, 1H), 4.58 (s, 1H), 5.39 (d, J ¼ 11.2 Hz, 1H), 5.48 (s, 2H), 6.21 (d, J ¼ 7.8 Hz, 1H), 6.36 (d, J ¼ 8.0 Hz, 1H), 6.43 (d, J ¼ 7.2 Hz, 1H), 6.66e6.70 (m, 1H), 6.88e6.92 (m, 1H), 7.00e7.06 (m, 2H), 7.26e7.42 (m, 5H), 8.16 (d, J ¼ 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 12.2, 12.9, 34.3, 34.9, 51.7, 55.5, 63.1, 65.9, 67.3, 81.4, 106.9, 108.0, 109.4, 120.7, 121.1, 123.2, 127.1, 127.6, 127.8, 137.9, 143.0, 143.4, 144.0, 177.1, 177.5; HRMS (ESITOF) m/z: Calcd. for C33H33N3NaO3 [MþNa]þ: 542.2420; Found: 542.2424. 4.2.33. 5'-Chloro-1-(5-chloro-3-((2,5-dihydro-1H-pyrrol-1-yl) methyl)-1-methyl-2-oxoindolin-3-yl)-3-hydroxy-1'-methyl-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (5e0 )

White solid; m.p. 172.5e173.4  C; overall yield: 64%, dr: 7/1; 1H NMR (CDCl3, 400 MHz) d: 0.95e0.98 (m, 3H), 1.08e1.11 (m, 3H), 1.48e1.50 (m, 4H), 2.20e2.22 (m, 2H), 2.42e2.44 (m, 2H), 3.20 (d, J ¼ 14.8 Hz, 1H), 3.32e3.37 (m, 1H), 3.53e3.58 (m, 2H), 3.74e3.78 (m, 2H), 4.51 (s, 1H), 5.41 (s, 1H), 6.32e6.33 (m, 1H), 6.61e6.64 (m, 1H), 6.84e6.88 (m, 1H), 7.08e7.10 (m, 2H), 7.17 (d, J ¼ 6.0 Hz, 1H), 7.32e7.35 (m, 3H), 7.39e7.41 (m, 1H), 8.16 (d, J ¼ 6.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 14.1, 15.0, 24.0, 35.9, 36.7, 52.9, 54.2, 56.0, 64.1, 66.5, 81.4, 113.6, 114.8, 121.4, 121.7, 123.1, 123.3, 124.8, 127.4, 127.5, 127.6, 128.4, 130.5, 131.5, 132.8, 137.0, 139.3, 139.6, 142.5, 177.2, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C33H33Cl2N3NaO3 [MþNa]þ: 612.1797; Found: 612.1795.

White solid; m.p. 187.9e188.6  C; overall yield: 63%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 2.68 (s, 3H), 2.86 (s, 3H), 3.25e3.27 (m, 2H), 3.45e3.52 (m, 3H), 3.72 (d, J ¼ 13.6 Hz, 1H), 4.61 (s, 1H), 6.16 (d, J ¼ 8.4 Hz, 1H), 6.28 (d, J ¼ 8.4 Hz, 1H), 6.47 (d, J ¼ 2.0 Hz, 1H), 7.02e7.07 (m, 2H), 7.29e7.45 (m, 5H), 8.15 (d, J ¼ 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 25.8, 26.3, 51.7, 56.0, 63.6, 66.3, 67.4, 81.6, 1

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107.8, 108.7, 123.4, 125.1, 126.4, 126.5, 126.7, 126.8, 127.1, 127.9, 128.0, 128.6, 128.9, 131.4, 136.9, 142.1, 142.8, 143.4, 176.7, 178.1; HRMS (ESITOF) m/z: Calcd. for C31H27Cl2N3NaO3 [MþNa]þ: 582.1327; Found: 582.1331. 4.2.34. 1-(3-((2,5-Dihydro-1H-pyrrol-1-yl)methyl)-5-fluoro-1methyl-2-oxoindolin-3-yl)-5'-fluoro-3-hydroxy-1'-methyl-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (5f0 )

White solid; m.p. 176.1e176.6  C; overall yield: 66%, dr: 20:1; 1H NMR (CDCl3, 400 MHz) d: 2.63 (s, 3H), 2.80 (s, 3H), 3.23e3.26 (m, 2H), 3.43e3.52 (m, 3H), 3.67e3.69 (m, 1H), 4.61 (s, 1H), 5.37 (s, 1H), 5.52 (s, 2H), 6.12e6.15 (m, 1H), 6.25e6.28 (m, 2H), 6.73e6.79 (m, 2H), 7.08e7.10 (m, 1H), 7.31e7.43 (m, 3H), 8.15 (d, J ¼ 8.0 Hz, 1H); 13 C NMR (CDCl3, 100 MHz) d: 25.6, 26.1, 51.7, 56.2, 63.6, 66.2, 67.6, 81.5, 100.0, 107.0, 112.9, 114.1(d, JCF ¼ 24.1 Hz), 114.3, 123.3, 127.1, 127.9, 128.0, 128.7, 137.0, 140.2, 142.2, 142.3, 158.3 (d, JCF ¼ 224.4 Hz), 159.3, 176.9, 178.3; HRMS (ESI-TOF) m/z: Calcd. for C31H27F2N3NaO3 [MþNa]þ: 550.1918; Found: 550.1918. 4.2.35. 1'-Benzyl-1-(1-benzyl-5-bromo-3-((2,5-dihydro-1H-pyrrol1-yl)methyl)-2-oxoindolin-3-yl)-5'-bromo-3-hydroxy-1,3dihydrospiro[indene-2,3'-indolin]-2'-one (5g0 )

6.43e6.45 (m, 1H), 6.69e6.72 (m, 1H), 6.90e6.94 (m, 1H), 7.00e7.05 (m, 2H), 7.31e7.42 (m, 5H), 8.17 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 11.3, 25.5, 26.2, 47.8, 51.6, 55.4, 62.5, 67.4, 81.4, 106.8, 107.8, 120.7, 121.3, 126.9, 127.6, 127.7, 127.8, 128.8, 138.0, 142.9, 144.1, 144.8, 177.4, 178.2; HRMS (ESI-TOF) m/z: Calcd. for C31H33N3NaO3 [MþNa]þ: 518.2420; Found: 518.2416. 4.2.37. 1'-Benzyl-1-(1-benzyl-3-((diethylamino)methyl)-2oxoindolin-3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5i0 )

White solid; m.p. 172.8e173.1  C; overall yield: 56%, dr: 7/1; 1H NMR (CDCl3, 400 MHz) d: 0.65e0.68 (m, 6H), 2.33e2.46 (m, 4H), 3.27 (d, J ¼ 14.0 Hz, 1H), 3.35 (d, J ¼ 16.0 Hz, 1H), 3.63 (d, J ¼ 16.0 Hz, 1H), 3.83 (d, J ¼ 14.0 Hz, 1H), 4.62 (s, 1H), 4.88 (d, J ¼ 16.0 Hz, 1H), 5.11 (d, J ¼ 16.4 Hz, 1H), 5.51 (d, J ¼ 12.0 Hz, 1H), 6.07e6.09 (m, 1H), 6.19 (d, J ¼ 8.0 Hz, 1H), 6.50e6.52 (m, 1H), 6.75e6.79 (m, 1H), 6.98e7.03 (m, 3H), 7.15e7.22 (m, 11H), 7.34e7.45 (m, 4H), 8.24 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 10.7, 43.3, 43.6, 47.7, 52.1, 55.7, 62.6, 67.5, 81.8, 108.1, 109.1, 126.6, 127.1, 127.2, 128.4, 128.7, 129.1, 135.6, 136.0, 137.7, 143.0, 143.8, 143.9, 177.6, 178.2; HRMS (ESITOF) m/z: Calcd. for C43H41N3NaO3 [MþNa]þ: 670.3046; Found: 670.3047. 4.2.38. 1-(3-((Diethylamino)methyl)-1,7-dimethyl-2-oxoindolin-3yl)-3-hydroxy-1',7'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5j0 )

White solid; m.p. 205.6e206.3  C; overall yield: 59%, dr: >20:1; H NMR (CDCl3, 400 MHz) d: 3.08e3.12 (m, 2H), 3.40e3.47 (m, 3H), 3.59 (d, J ¼ 15.8 Hz, 1H), 3.78 (d, J ¼ 16.0 Hz, 1H), 4.26 (d, J ¼ 13.6 Hz, 1H), 4.55 (s, 1H), 5.20e5.28 (m, 1H), 5.40 (d, J ¼ 15.6 Hz, 1H), 5.51 (d, J ¼ 11.2 Hz, 1H), 5.56 (s, 2H), 5.91 (d, J ¼ 8.4 Hz, 1H), 6.10 (d, J ¼ 7.8 Hz, 1H), 6.68 (s, 1H), 7.10e7.25 (m, 13H), 7.35e7.48 (m, 4H), 8.20 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 43.5, 43.8, 51.8, 56.3, 63.1, 65.8, 67.4, 82.0, 109.6, 110.4, 113.6, 114.2, 126.6, 126.7, 126.8, 127.1, 127.2, 127.6, 127.9, 128.2, 128.6, 128.9, 131.0, 131.7, 135.1, 135.3, 136.6, 142.2, 143.1, 177.0, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C43H35Br2N3NaO3 [MþNa]þ: 822.0943; Found: 822.0944. 1

4.2.36. 1-(3-((Diethylamino)methyl)-1-methyl-2-oxoindolin-3-yl)3-hydroxy-1'-methyl-1,3-dihydrospiro[indene-2,3'-indolin]-2'-one (5h0 )

White solid; m.p. 218.3e219.4  C; overall yield: 70%, dr: >20/1; H NMR (CDCl3, 400 MHz) d: 0.69e0.73 (m, 6H), 2.18 (s, 3H), 2.24 (s, 3H), 2.36e2.41 (m, 4H), 2.84 (s, 3H), 3.03 (s, 3H), 3.26e3.32 (m, 2H), 4.59 (s, 1H), 5.34 (d, J ¼ 11.2 Hz, 1H), 6.28 (d, J ¼ 7.6 Hz, 1H), 6.57e6.60 (m, 1H), 6.62e6.83 (m, 3H), 7.17e7.19 (m, 1H), 7.25e7.33 (m, 4H), 8.16 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 11.2, 18.9, 19.0, 28.8, 29.6, 47.7, 52.8, 54.5, 62.6, 66.4, 81.5, 118.0, 119.3, 120.4, 121.0, 122.8, 123.2, 124.9, 125.2, 127.5, 127.6, 128.7, 130.0, 131.3, 132.5, 138.2, 142.1, 142.7, 143.0, 178.0, 179.0; HRMS (ESI-TOF) m/z: Calcd. for C33H37N3NaO3 [MþNa]þ: 546.2733; Found: 546.2735. 1

4.2.39. 1-(3-((Diethylamino)methyl)-1,5-dimethyl-2-oxoindolin-3yl)-3-hydroxy-1',5'-dimethyl-1,3-dihydrospiro[indene-2,3'-indolin]2'-one (5k0 )

White solid; m.p. 229.8e230.4  C; overall yield: 69%, dr: 18/1; H NMR (CDCl3, 400 MHz) d: 0.68e0.71 (m, 6H), 2.34e2.39 (m, 4H), 2.53 (s, 3H), 2.70 (s, 3H), 3.27e3.35 (m, 2H), 4.64 (s, 1H), 5.37 (d, J ¼ 11.2 Hz, 1H), 6.19 (d, J ¼ 7.8 Hz, 1H), 6.31 (d, J ¼ 7.6 Hz, 1H), 1

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

White solid; m.p. 106.7e107.3  C; overall yield: 71%, dr: 18/1; 1H NMR (CDCl3, 400 MHz) d: 0.67e0.71 (m, 6H), 2.11 (s, 3H), 2.33e2.37 (m, 7H), 2.52 (s, 3H), 2.69 (s, 3H), 3.28e3.30 (m, 2H), 4.57 (s, 1H), 5.36 (d, J ¼ 11.2 Hz, 1H), 6.10 (d, J ¼ 8.0 Hz, 1H), 6.22 (d, J ¼ 8.0 Hz, 1H), 6.27 (s, 1H), 6.81e6.86 (m, 2H), 7.19e7.21 (m, 1H), 7.30e7.35 (m, 4H), 8.15 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d: 11.4, 21.1, 21.3, 25.2, 25.9, 47.9, 51.6, 55.4, 62.4, 67.6, 81.2, 106.4, 107.5, 127.5, 127.8, 127.9, 129.2, 129.3, 129.9, 130.7, 138.3, 141.9, 142.6, 142.9, 177.4, 178.1; HRMS (ESI-TOF) m/z: Calcd. for C33H37N3NaO3 [MþNa]þ: 546.2733; Found: 546.2733.

5.

6.

7. 8. 9.

4.3. Cytotoxicity assay Three human cancer cell lines, K562, A549 and PC-3 were purchased from Chinese Academy of Sciences, Kunming Cell Bank and Chinese Academy of Sciences, Shanghai Cell Bank respectively. All the cells were cultured in RPMI-1640 medium (GIBICO, USA), supplemented with 10% fetal bovine serum (Hyclone, USA) and Penicillin-Streptomycin (respectively 100 U/mL) in 5% CO2 at 37  C. The cytotoxicity assay was performed according to the MTT (3-(4,5dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) method in 96-well microplates. Briefly, 5000 cells were seeded into each well of 96-well cell culture plates and allowed to grow for 24 h before drug addition. Each tumor cell line was exposed to the test compound at the concentrations of 6.25, 12.5, 25, 50, and 100 mmol$L
1. in triplicates for 48 h, comparable to cisplatin (Aladdin, China). Then the MTT reagent was added to reaction with the cancer cells for 4 h. At least, measure the OD value at 490 wavelengths. IC50 of all the compounds were calculated by IBM SPSS Statistics (version 19).

10.

11.

Acknowledgements We are grateful for the financial support from the National Natural Science Foundations of China (No. 21302024, No. 81560563 and No. 81660576); Excellent creative talents of science and technology support plan in guizhou province colleges and universities ([(2015)491] Qian Jiao He KY Zi); Guizhou chinese medicine and pharmaceutical engineering professional degree graduate student workstation (JYSZ [2014]002); Science and technology major project of Guizhou province (Qian Ke He J Zhong Da Zi ([2015]20023-4) and Mutual funds of Guizhou province and Guizhou university ([2014]7662] Qian Ke He LH Zi).

12.

13. 14. 15. 16.

Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2016.10.050. References 1. (a) Dandia A, Sati M, Arya K, Sharma R, Loupy A. Chem Pharm Bull. 2003;51: 1137e1141; (b) Chande MS, Verma RS, Barve PA, Khanwelkar RR. Eur J Med Chem. 2005;40: 1143e1148; (c) Kumar RR, Perumal S, Senthilkumar P, Yogeeswari PP, Sriram D. J Med Chem. 2008;51:5731e5735; (d) Kumar RR, Perumal S, Yogeeswari P, Sriram D. Tetrahedron. 2008;64: 2962e2971. 2. Lundahl K, Schut J, Schlatmann JLMA, Paerels GB, Peters A. J Med Chem. 1972;15:129e132. 3. Kornet MJ, Thio AP. J Med Chem. 1976;19:892e898. 4. (For selected examples, see): (a) MacClean D, Schullek JR, Murphy MM, Ni Z-J, Gordon EM, Gallop MA. Proc Natl Acad Sci. 1997;94:2805e2810; (b) Hanessian S, Bayrakdarian M. Bioorg Med Chem Lett. 2000;10:427e431; (c) Hanessian S, Bayrakdarian M. Tetrahedron Lett. 2002;43:9441e9444; (d) Lo M-C, Neimann CS, Nagayama S, Perlstein EO, Schreiber SL. J Am Chem Soc. 2004;126:16077e16086;

17.

18. 19. 20. 21. 22. 23. 24.

8535

(e) Han W-Y, Zhao J-Q, Zuo J, Xu X-Y, Zhang X-M, Yuan W-C. Adv Synth Catal. 2015;357:3007e3031; (f) Yu J-S, Zhou F, Liu Y-L, Zhou. J Synlett. 2015;26:2491e2504. (a) Fensome A, Adams WR, Adams AL, et al. J Med Chem. 2008;51:1861; (b) Shangary S, Qin D, McEachern D, et al. Proc Natl Acad Sci USA. 2008;105: 3933. (a) Bond RF, Boeyens JCA, Holzapfel CW, Steyn PS. J Chem Soc, Perkin Trans. 1979;1:1751; (b) Greshock TJ, Grubbs AW, Jiao P, Wicklow DT, Gloer JB, Williams RM. Angew Chem, Int Ed. 2008;47:3573; (c) Mugishima T, Tsuda M, Kasai Y, et al. J Org Chem. 2005;70:9430. Jossang A, Jossang P, Hadi HA, Sevenet T. J Org Chem. 1991;56:6527e6530. James MNG, Williams GJB. Can J Chem. 1972;50:2407e2412. (a) Bindra JS. In: Manske RHF, ed. The Alkaloids. vol. 14. New York: Academic. Press; 1973:84; (b) Galliford CV, Scheidt KA. Angew Chem Int Ed. 2007;46:8748e8758; (c) Li N, Xia Q, Ruan J, Fu PP, Lin G. Curr Drug Metab. 2011;12:823; (d) Roeder E, Wiedenfeld H. Pharmazie. 2011;66:637; (e) Roeder E, Wiedenfeld H. Pharmazie. 2009;64:699; (f) Coulombe Jr RA. Adv Food Nutr Res. 2003;45:61; (g) Smith LW, Culvenor CCJ. J Nat Prod. 1981;44:129. (For selected examples, see): (a) Liu T-L, Xue Z-Y, Tao H-Y, Wang C-J. Org Biomol Chem. 2011;9:1980e1986; (b) Antonchick AP, Schuster H, Bruss H, et al. Tetrahedron. 2011;67: 10195e10202; (c) Hanhan NV, Ball-Jones NR, Tran NT, Franz AK. Angew Chem. 2012;124: 1013e1016. Angew. Chem. Int. Ed. 2012, 51, 989e992; (d) Dugal-Tessier J, O‘Bryan EA, Schroeder TBH, Cohen DT, Scheidt KA. Angew Chem. 2012;124:5047e5051. Angew. Chem. Int. Ed. 2012, 51, 4963e4967; (e) Li G-L, Liang T, Wojtas L, Antilla JC. Angew Chem. 2013;125:4726e4730. Angew. Chem. Int. Ed. 2013, 52, 4628e4632. (For selected examples, see): (a) Grouleff J, Chen Y-C, JFgensen KA. J Am Chem Soc. 2011;133:5053e5061; (b) Lan Y-B, Zhao H, Liu Z-M, Liu G-G, Tao J-C, Wang X-W. Org Lett. 2011;13: 4866e4869; (c) Tan B, Candeias NR, Barbas III CF. J Am Chem Soc. 2011;133:4672e4675; (d) Tan B, Hernndez-Torres G, Barbas III CF. J Am Chem Soc. 2011;133: 12354e12357; (e) Liu Y-K, Nappi M, Arceo E, Vera S, Melchiorre P. J Am Chem Soc. 2011;133: 15212e15218; (f) Tan B, Zeng X-F, Leong WWY, Shi Z-G, Barbas III CF, Zhong G-F. Chem Eur J. 2012;18:63e67; (g) Noole A, Jrving I, Werner F, Lopp M, Malkov A, Kanger T. Org Lett. 2012;14: 4922e4925; (h) Sun W-S, Zhu G-M, Wu C-Y, Hong L, Wang R. Chem Eur J. 2012;18: 6737e6741; (i) Shen L-T, Jia W-Q, Ye S. Angew Chem. 2013;125:613e616. Angew. Chem. Int. Ed. 2013, 52, 585e588. (For selected examples, see): (a) Rajesh R, Suresh M, Selvam R, Raghunathan R. Tetrahedron Lett. 2014;55:4047e4053; (b) Senthil Kumar G, Satheesh kumar R, Kaminsky W. Tetrahedron Lett. 2014;55:5475e5480. Peng C, Ren J, Jun-An X, Honggang Z, Yangand H, Yiming L. Beilstein J Org Chem. 2014;10:352e360. Lanka S, Thennarasu S, Perumal PT. Tetrahedron Lett. 2012;53:7052e7055. Al Mamari K, El Mokhtar E. Tetrahedron Lett. 2012;53:2328e2331. (For selected examples, see): (a) Raj AA, Raghunathan R. Tetrahedron. 2001;57: 10293e10298; (b) Kumar RR, Perumal S, Senthilkumar P, Yogeeswari P, Sriram D. Eur J Med Chem. 2009;44:3821e3829; (c) Coulter T, Grigg R, Malone JF, Sridharan V. Tetrahedron Lett. 1991;32: 5417e5420; (d) Naga Siva Rao J, Raghunathan R. Tetrahedron Lett. 2015;56:1539e1544; (e) Hemamalini A, Nagarajan S, Ravinder P, Subramanian V, Das TM. Synthesis. 2011:2495e2504; (f) Hu XF, Feng YQ. Synth Commun. 2005;35:1747e1752; (g) Arumugam N, Periyasami G, Raghunathan R, Kamalraj S, Muthumary J. Eur J Med Chem. 2011;46:600e607; (h) Purushothaman S, Prasanna R, Raghunathan R. Tetrahedron. 2013;69: 9742e9750; (i) Li G, Wu M, Liu F, Jiang J. Synthesis. 2015;47:3783e3796. (For some recent reviews, see): (a) Santos MMM. Tetrahedron. 2014;70: 9735e9757; (b) Hong L, Wang R. Adv Synth Catal. 2013;355:1023e1053; (c) Hong L, Wang R. Adv Synth Catal. 2013;355:1023e1052; (d) Zhou F, Liu YL, Zhou J. Adv Synth Catal. 2010;352:1381e1407; (e) Ball-Jones NR, Badillo JJ, Franz AK. Org Biomol Chem. 2012;10:5165e5181; (f) Xia M, Ma RZ. J Heterocycl Chem. 2014;51:539e554. Abdel-Aziz S, El-Ahl. Heteroat Chem. 2002;13:324e329. Hazra A, Paira P, Sahu Kr B, et al. Tetrahedron Lett. 2010;51:1585e1588. Babu SR, Raghunathan R. Tetrahedron Lett. 2008;49:4618e4620. Dandia A, Jain AK, Bhati DS. Tetrahedron Lett. 2011;52:5333e5337. Naga Siva Rao J, Raghunatha R. Tetrahedron Lett. 2012;53:854e858. Poornachandran M, Raghunathan R. Synth Commun. 2007;37:2507e2517. Pavlovskaya TL, Yaremenko FG, Lipson VV, et al. Org Chem. 2014;10:117e126.

8536

J. Yang et al. / Tetrahedron 72 (2016) 8523e8536

25. Kumar RS, Rajesh SM, Perumal S, Banerjee D, Yogeeswari P, Sriram D. Eur J Med Chem. 2010;45:411e422. 26. Prasanna P, Balamurugan K, Perumal S, Yogeeswari P, Sriram D. Eur J Med Chem. 2010;45:5653e5661. 27. Ranjith KR, Perumal S, Senthilkumar P, Yogeeswari P, Sriram D. Eur J Med Chem. 2009;44:3821e3829. 28. (a) Albertshofer K, Tan B, Barbas III CF. Org Lett. 2012;14:1834; (b) Sun W, Zhu G, Hong C, Wu L, Wang R. Chem.Eur J. 2012;18:6737; (c) Tan B, Candeias NR, Barbas III CF. Nat Chem. 2011;3:473; (d) Zhong F, Han X, Wang Y, Lu Y. Angew Chem, Int Ed. 2011;50:7837; (e) Tan B, Candeias NR, Barbas III CF. J Am Chem Soc. 2011;133:4672; (f) Deng H-P, Wei Y, Shi M. Org Lett. 2011;13:3348; (g) Voituriez A, Pinto N, Neel M, Retailleau R. Chem Eur J. 2010;16:12541. 29. (a) Tan B, Zeng X, Leong WWY, Shi Z, Barbas III CF, Zhong G. Chem Eur J. 2012;18:63; (b) Shi F, Tao Z-L, Luo S-W, Tu S-J, Gong L-Z. Chem Eur J. 2012;18:6885; (c) Bergonzini G, Melchiorre P. Angew Chem, Int Ed. 2012;51:971; (d) Cao Y, Jiang X, Liu L, Shen F, Zhang F, Wang R. Angew Chem, Int Ed. 2011;50: 9124; (e) Chen X-H, Wei Q, Luo S-W, Xiao H, Gong L-Z. J Am Chem Soc. 2009;131: 13819. 30. (For some recent reviews, see): (a) Honga L, Wang R. Adv Synth Catal. 2013;355:1023; (b) Dalpozzo R, Bartolib G, Bencivenni G. Chem Soc Rev. 2012;41:7247; (c) Singh GS, Desta ZY. Chem Rev. 2012;112:6104; (d) Tessier JD, O'Bryan EA, Schroeder TBH, Cohen DT, Scheidt KA. Angew Chem,

Int Ed. 2012;51:4963; (e) Jiang X, Cao Y, Wang Y, Liu L, Shen F, Wang R. J Am Chem Soc. 2010;132: 15328. 31. (Our some representative examples relevant to the construction of oxindole drug-like molecules, see): (a) Liu X-L, Han W-Y, Zhang X-M, Yuan W-C. Org Lett. 2013;12:1246e1249; (b) Liao Y-H, Liu X-L, Wu Z-J, Cun L-F, Zhang X-M, Yuan W-C. Chemistry-A Eur J. 2012;18:6679e6687; (c) Yu Z-B, Liu X-L, Pan B-W, Chen B, Zhou Y, Wang H-L. Synth Commun. 2014;44:530e539; (d) Liu X-W, Han W-Y, Liu X-L, Zhou Y, Zhang X-M, Yuan W-C. Tetrahedron. 2014;70:9191e9197; (e) Liu X-W, Yang J, Yang C, et al. Tetrahedron Lett. 2014;55:7110e7113; (f) Feng T-T, Huang X, Liu X-L, et al. Org Biomol Chem. 2014;12:9366e9374; (g) Liu X-L, Pan B-W, Zhang W-H, et al. Org Biomol Chem. 2015;13:601e611; (h) Liu X-L, Yu Z-B, Pan B-W, Chen L, Feng T-T, Zhou Y. J Heterocycl Chem. 2015;52:628e634; (i) Liu X-L, Jing D-H, Yao Z, et al. Tetrahedron Lett. 2015;56:5637e5645; (j) Liu X-L, Zhang W-H, Yao Z, et al. Tetrahedron. 2015;71:9483e9485; (k) Wang H-J, Pan B-W, Zhang W-H, et al. Tetrahedron. 2015;71:8131e8139. 32. CCDC 1501485 and CCDC 1501486 contain the supplementary crystallographic datas for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. 33. (a) Mosman T. J Immunol Methods. 1983;65:55e63; (b) Alley MC, Scudiero DA, Monks A, et al. Cancer Res. 1988;48:589e601.