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Organic & Biomolecular Chemistry

Highly Regioselective Syntheses of 3-Alkenyl-Oxindole Ring-fused 3,3′-disubstituted Oxindoles via Direct Gamma-substitution of

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Morita-Baylis-Hillman Carbonates of Isatins with 3-substituted Oxindoles Ting-Ting Feng,a,c Xuan Huang, a ,c Xiong-Li Liu,*a De-Hong Jing, a Xiong-Wei Liu,a Feng-Ming Guo,a Ying Zhou*a and Wei-Cheng Yuan b a

Guizhou Engineering Center for Innovative Traditional Chinese Medicine and Ethnic Medicine, College of Pharmacy, Guizhou University, Guiyang, 550025, China b Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China c These two authors contributed equally to this work. * Corresponding author. For Xiong-Li Liu: Tel.: 86-8513853800; fax: 86-8513851091. For Ying Zhou: Tel.: 86-8518297907; fax: 86-8518297907. * E-mail address: [email protected] † Electronic supplementary information (ESI) available. See DOI:

ABTRACT The phase transfer-catalysed the first direct γ-substitution of Morita-Baylis-Hillman carbonates of isatins with 3-substituted oxindoles has been developed, which affords 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindoles in up to 83% yield under mild reaction condition. Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3 and human leukemia cells K562 by the MTT-based assays, using the commercially available standard drugs Cisplatin as a positive control. Gratifyingly, compounds 3aa, 3ba and 3ca exhibited comparable in vitro inhibitory activity against human prostate cancer cells (PC-3) with the positive control Cisplatin. What’s more, 3ba also had good inhibition ability against human leukemia cells K562. These results indicated that 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindole analogs may be potential lead compounds for further biological screenings.

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DOI: 10.1039/C4OB01523A

3-alkenyl-oxindoles are ubiquitous framework found in many natural products and pharmaceuticals.1 For instance, Sunitinib I is a tyrosine kinase inhibitor that was approved in 2006 for the treatment of renal cell carcinoma and gastrointestinal stromal tumours.2 Woodard et al. Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

identified a series of selective plasmodial CDK inhibitors (e.g. II).3 Khosla and co-workers described 3-acylidene-oxindoles (e.g. III) as inhibitors of human transglutaminase-2.4 Meisoindigo IV is also an anti-cancer drug.5 On the other hand, 3,3′-disubstituted oxindoles also have attracted significant attention in both synthetic and medicinal chemistry communities because of the prevalence of them in a wide variety of structurally complex and biologically active compounds.6 For instance, V and MI-219 VI are inhibitors of MDM2-p53 interaction for the treatment of cancer.7 On account of the good biological activities of 3-alkenyl-oxindoles and 3,3′-disubstituted oxindoles, thus a hybrid of these two motifs could potentially lead to a series of structurally and biologically interesting alkaloids for biological screenings (Scheme 1).8 In particular, construction of diindoles is also attractive and imperative, because numerous compounds of marine origin bear two isolated indoles (Scheme 2), such as NITD609 VII, which was found to display potent antimalarial activity in a mouse model. The dragmacidins (e.g. VIII, IX) possess antitumor,9,

10

phosphatase inhibitory,11 and antiviral12 activities. Several natural

products with anticancer activity (vibrindole A XI, streptindole XII, etc.) share a common 3,3-diindolylmethane (DIM) X molecular unit.13 Diazonamide A XIII 14 is also a antitumoral natural product. In this context, the development of an efficient synthetic method for the expedient construction of 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindole scaffolds with general formula 3 is particularly attractive for the preparation of compound libraries for biological screenings.

Scheme 1. Design strategy for 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindoles by a hybrid of two separate active alkaloids.

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Introduction

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Organic & Biomolecular Chemistry

N

O

N

N O

N H

O Cl

N H O

F

O

Br

N H

N H TG2 inhibitor; III

N H

Sunitinib; I

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O N H

O

O

CDK inhibitor; II

Meisoindigo; IV

Fragment 1 OH Cl

OH R3

MeO

N H V anti-cancer agent

Cl

Fragment 2

F

O

O Cl

N Boc

O

NH O

Cl

R2

H N

O

N H

R1 O

5

R

O N 3 4 R a hybrid of these two motifs

MI-219; VI anti-cancer agent

Scheme 2. Structures of some indole alkaloids containing two isolated indole moieties.

Recently, it has been shown that upon conversion of the alcohol to a leaving group, Morita-Baylis-Hillman (MBH) adducts become substrates for allylic substitution.15 The reaction of MBH adducts of aldehydes with a nucleophile could proceed allylic substitution to afford α- or γ-substituted products (Scheme 3).16-19 Furthermore, various O-, N-, P-, S- and C-based nucleophiles have been achieved to provide the nucleophilic α- or γ-substitution products via palladium catalysis16 and with phosphine or tertiaryamine related organocatalysis17-19. Chen and co-workers20 have also successfully applied the MBH carbonates of isatins (ketone) as substrates which be successfully applied in the Lewis base-catalyzed allylic alkylation reaction, thus an elegant electrophilic approach to α-substituted oxindoles had been realized (Scheme 4). However, the use of MBH carbonates of isatins (ketone) as substrates to afford γ-substituted oxindoles has not yet been reported. In this context, as a continuing effort to develop new methodology for the construction of complex structural oxindole scaffolds,21 we report herein the facile construction of

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F

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carbonates of isatins with 3-substituted oxindoles (Scheme 4). In particular, their biological activity against human prostate cancer cells PC-3 and human leukemia cells K562 have been

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evaluated. Scheme 3. The reaction of MBH adducts of aldehydes with a nucleophile.

Scheme 4. Regioselectivity in the Substitution of Morita–Baylis–Hillman Carbonates of Isatins

Results and discussion In our initial study, our attempts to identify an effective catalyst from literature-reported cinchona alkaloid catalysts for the direct γ-substitution of MBH carbonates of isatin 2a with 3-phenyl oxindole 1a were unsuccessful. As summarized in Table 1, natural cinchona alkaloids (Table 1, entries 2-5) failed to afford the desired product 3aa. In the absence of catalyst, the reaction did not occur under otherwise identical conditions (Table 1, entry 1). We also screened other tertiary amines (e.g., DABCO, DBU, and DMAP) as organocatalyst in the reaction, however, no γ-substitution product was obtained (Table 1, entries 6-8). To our delight, the commonly used phase transfer catalysts, containing hexadecyltrimethylammonium bromide (CTMAB) and tetrabutylammonium bromide (TBAB), were shown to catalyze the reaction successfully, delivering the regioselective γ-substituted product 3aa, along with intractable product mixtures from which no α-substituted product could be identified by the HRMS spectra analysis (Table 1, 4

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Organic & Biomolecular Chemistry

stereocenter in α-substituted product. In the absence of quaternary ammonium salts, the reaction only afforted the desired product 3aa in 24% yield (Table 1, entry 14). To explore the effect of solvent, DCM, toluene, AcOEt, CH3CN and EtOH were examined, the results were summarized in Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

Table 1. As the data indicated in Table 1, the use of nonpolar solvents, such as DCM and toluene led to higher yields than polar solvents, such as AcOEt CH3CN and EtOH (Table 1, entries 15-18). Finally, toluene was found to be the best choice among all the solvents. Thus, the optimal reaction conditions we established were, 3-phenyl oxindole 1a (0.3 mmol), MBH carbonates of isatin 2a (0.2 mmol), 20 mol% of TBAB and 3.0 eq. of NaOH in 5.0 mL toluene at room temperature for 24 h. With the best reaction conditions in hands, we next turned our interest to the reaction scope, and the results were summarized in Table 2. 3-phenyl oxindole 1a was first used as a standard substrate to probe the reactivity of different MBH carbonates of isatins 2 in this reaction. It clearly indicated that all of the reactions proceeded smoothly under the optimal conditions, producing the desired products 3 in moderate to good yields (Table 2, entries 1-10), regardless of the electronic nature on the MBH adduct 2. In addition, the MBH adducts derived from methyl or ethyl acrylate also gave good results under the optimal conditions (Table 2, entries 5 and 10). Gratifyingly, N-Boc MBH adduct 2k led to almost no deleterious effects on the reactivity and give the corresponding product in the best yield (Table 2, entry 11, 83%). The generality of the reaction was further demonstrated by using a variety of 3-substituted oxindoles 1, significant structural variation in the oxindole system could be accommodated in this reaction. For example, electron-rich (Table 2, entries 12-17, 19 and 20) and electron-poor (Table 2, entry 18) substituent incorporated on the phenyl group or the benzo moiety of oxindole core were tolerated under the conditions. It is noteworthy that benzyl groups with electron-poor (Table 2, entry 22) and electron-rich (Table 2, entries 23 and 24) substituent were also well tolerated (Table 2, entry 21), affording the desired products in good yields (65-72%). Next, to stress the synthetic utility of this developed methodology, removal of the Boc protecting group of 3aa with F3CCOOH has been realized, the pure N-H 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindole 3aa-1 was obtained in 90% yield, (Scheme 5).

5

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Organic & Biomolecular Chemistry

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a

DOI: 10.1039/C4OB01523A

Entry

Catalyst (20 mol %)

Base (3.0 eq)

Solvent (5 mL)

Time (h)

Yieldb (%)

1

No

No

toluene

48

0

2

quinine

No

toluene

48

0

3

quinidine

No

toluene

48

0

4

cinchonine

No

toluene

48

0

5

cinchonidine

No

toluene

48

0

6

DABCO

No

toluene

48

0

7

DBU

No

toluene

48

0

8

DMAP

No

toluene

48

0

9

TBAB

NaOH

toluene

24

61

10

CTMAB

NaOH

toluene

24

49

11

TBAB

Na2CO3

toluene

24

15

12

TBAB

NaOH

toluene

48

56

13

TBAB

NaOH

toluene

12

48

14

No

NaOH

toluene

24

24

15

TBAB

NaOH

DCM

24

44

16

TBAB

NaOH

AcOEt

48

15

17

TBAB

NaOH

CH3CN

48

0

18

TBAB

NaOH

EtOH

48

100

3

1a

Ph

H

2c

CH3

CH3

5-F

3ac

72

>100 d

4

1a

Ph

H

2d

CH3

CH3

5-CH3

3ad

69

>100 d

5

1a

Ph

H

2e

CH3

CH3

7-Cl

3ae

74

87.2

6

1a

Ph

H

2f

CH3

Bn

H

3af

72

>100

7

1a

Ph

H

2g

CH3

Bn

5-F

3ag

53

>100

8

1a

Ph

H

2h

CH3

Bn

5-Cl

3ah

71

>100

9

1a

Ph

H

2i

CH3

Bn

5-CH3

3ai

64

>100

10

1a

Ph

H

2j

Et

CH3

7-Cl

3aj

66

>100

11

1a

Ph

H

2k

Et

Boc

H

3ak

83

>100

12

1b

4-MeC6H4

H

2a

CH3

CH3

H

3ba

60

30.9

13

1b

4-MeC6H4

H

2b

CH3

CH3

5-Cl

3bb

60

>100

14

1b

4-MeC6H4

H

2h

CH3

Bn

5-Cl

3bh

61

>100

15

1c

3,5-(Me)2C6H3

H

2a

CH3

CH3

H

3ca

56

30.4

16

1c

3,5-(Me)2C6H3

H

2h

CH3

Bn

5-Cl

3ch

75

>100

17

1c

3,5-(Me)2C6H3

H

2j

Et

CH3

7-Cl

3cj

60

>100

18

1d

Ph

F

2a

CH3

CH3

H

3da

52

73.8

19

1e

Ph

CH3

2a

CH3

CH3

H

3ea

54

>100

20

1e

Ph

CH3

2b

CH3

CH3

5-Cl

3eb

64

>100

21

1f

Bn

H

2h

CH3

Bn

5-Cl

3fh

72

>100

22

1g

4-CF3C6H4CH2

H

2e

CH3

CH3

7-Cl

3ge

65

>100

23

1h

4-MeOC6H4CH2

H

2e

CH3

CH3

7-Cl

3he

71

>100

24

1i

4,5-(MeO)2C6H3CH2

H

2e

CH3

CH3

7-Cl

3ie

67

>100

25

3aa-1

53.8

23

Cisplatin

28.4

Unless otherwise specified, the reactions were carried out in 5.0 mL solvent with 0.3 mmol 1, 0.2 mmol 2 in the

presence of 20 mol % TBAB and 3.0 eq NaOH at rt for 24 h. b

Isolated yield after chromatographic purification.

c

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. d

The compound is not good water-soluble. 8

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evaluation on human prostate cancer cells PC-3a

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Table 3 Cytotoxicity of compounds 3aa, 3ba, 3ca and 3aa-1 on human leukemia cells K562 Compound

3aa

3ba

3ca

3aa-1

Cisplatin

K562

72.1

31.3

52.5

63.9

20.6

IC50 (μM)

Conclusions In conclusion, we have developed a highly regioselective method for the syntheses of 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindoles via the phase transfer-catalysed direct the first γ-substitution of MBH carbonates of isatins with 3-substituted oxindoles in up to 83% yield under mild reaction conditions. Furthermore, their biological activity has been preliminarily demonstrated by in vitro evaluation against human prostate cancer cells PC-3 and human leukemia cells K562 by the MTT-based assays, using the commercially available standard drugs Cisplatin as a positive control. Gratifyingly, compounds 3aa, 3ba and 3ca exhibited comparable in vitro inhibitory activity against human prostate cancer cells (PC-3) with the positive control Cisplatin. What’s more, 3ba also had good inhibition ability against human leukemia cells K562. Moreover, efforts are in progress to improve the antitumor activities of these 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindole analogs, and their other biological activity evaluation including antibacterial, antiviral activities are also underway in our laboratory.

Experimental section General procedure for synthesis of 3-alkenyl-oxindole ring-fused 3,3′-disubstituted oxindoles In an ordinary vial equipped with a magnetic stirring bar, to the mixture of 3-substituted oxindoles 1 (0.3 mmol) , 20 mol % TBAB (12.9 mg) and MBH carbonates of isatins 2 (0.2

mmol) in 5.0 mL toluene was added 3.0 eq NaOH (24 mg). The reaction mixture was stirred at rt for 24 h. After completion of the reaction, as indicated by TLC, the removal of solvent, purification by flash column chromatography (hexane/EtOAc) was carried out to furnish the corresponding products 3. 9

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Organic & Biomolecular Chemistry

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in-doline-1-carboxylate (3aa). Light yellow solid, yield 61%; mp: 149.1-150.4 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.63 (s, 9 Hz), 3.15 (s, 3H), 3.60 (s, 3H), 4.27 (d, J = 13.6 Hz, 1H), 4.74 (d, J = 13.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 7.10 Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

(t, J = 7.6 Hz, 1H), 7.22-7.33 (m, 5H), 7.43 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H). 7.90 (d, J = 8.4 Hz, 1H);

13

C NMR (CDCl3, 100 MHz) δ: 25.9, 28.1, 35.4, 52.3, 56.8, 84.1, 108.0, 115.3,

120.0, 122.2, 122.6, 124.0, 126.0, 127.2, 127.8, 128.6, 128.7, 130.2, 139.4, 139.9, 142.9, 149.3, 167.1, 168.1, 175.8. HRMS (ESI-TOF) m/z: Calcd. for C32H30N2NaO6 [M+Na]+: 561.2002; Found: 561.2008.

(E)-tert-butyl 3-(2-(5-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-phenylindoline-1-carboxylate (3ab). Light yellow solid, yield 63%; mp: 156.0-156.9 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.06 (s, 3H), 3.55 (s, 3H), 4.22 (d, J = 13.6 Hz, 1H), 4.64 (d, J = 13.6 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H). 7.01-7.05 (m, 1H), 7.10-7.13 (m. 1H), 7.17-7.25 (m, 4H), 7.33-7.39 (m, 3H), 7.83 (d, J = 8.0 Hz, 1H);

13

C NMR

(CDCl3, 100 MHz) δ: 26.0, 28.1, 35.6, 52.5, 56.7, 84.2, 108.9, 115.2, 121.3, 123.1, 124.0, 125.9, 127.1, 127.6, 127.9, 128.6, 128.7, 128.9, 129.9, 139.2, 139.9, 141.0, 141.3, 149.2, 166.6, 167.7, 175.6. HRMS (ESI-TOF) m/z: Calcd. for C32H29ClN2NaO6 [M+Na]+: 595.1612; Found: 595.1613.

(E)-tert-butyl 3-(2-(5-fluoro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-phenylindoline-1-carboxylate (3ac). Light yellow solid, yield 72%; mp: 156.2-156.3 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.14 (s, 3H), 3.63 (s, 3H), 4.28-4.32 (m, 1H), 4.74 (d, J = 13.2Hz, 1H), 6.62-6.66 (m, 1H), 6.76-6.80 (m, 1H), 6.92-6.97 (m, 1H), 7.09-7.13 (m, 1H), 7,24-7.33 (m, 4H), 7.41-7.48 (m, 3H), 7.91(d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 26.0, 28.0, 35.5, 52.5, 56.7, 84.2, 108.3, 108.4, 110.6 (d, JCF = 26.7 Hz), 115.2, 116.5 (d, JCF =

23.7 Hz), 120.8, 124.0, 125.7, 125.9, 126.8, 127.1, 127.8, 128.5, 128.6, 128.8, 138.9, 139.1, 139.9, 140.8, 149.2, 158.6 (d, JCF = 238.1 Hz), 166.8, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C32H29FN2NaO6 [M+Na]+: 579.1907; Found: 579.1908.

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(E)-tert-butyl

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phenylindoline-1-carboxylate (3ad). Light yellow solid, yield 69%; mp: 164.2-165.0 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.64 (s, 9H), 2.13 (s, 3H), 3.06 (s, 3H), 3.54 (s, 3H), 4.18 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.95-7.04 (m, 2H), 7.18-7.26 Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

(m, 4H), 7.34-7.42(m, 3H), 7.83 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 21.2, 25.9, 28.1, 35.4, 52.3, 56.7, 84.1, 107.7, 115.1, 120.0, 123.4, 124.0, 126.0, 127.2, 127.3, 127.7, 128.6, 128.7, 130.6, 131.4, 139.0, 139.4, 139.9, 140.7, 149,3, 167.1, 168.2, 175.8, 177.3. HRMS (ESI-TOF) m/z: Calcd. for C33H32N2NaO6 [M+Na]+: 575.2158; Found: 575.2159.

(E)-tert-butyl 3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-phenylindoline-1-carboxylate (3ae). Light yellow solid, yield 74%; mp: 153.0-154.9 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.54 (s, 3H), 3.60 (s, 3H), 4.24 (d, J = 13.2 Hz, 1H), 4.77 (d, J = 13.2 Hz, 1H), 6.77 (t, J = 7.8 Hz, 1H), 6.89-6.91 (m, 1H). 7.10-7.16 (m, 2H), 7.24-7.33 (m, 4H), 7.39-7.42 (m, 2H), 7.45-7,47 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H);

13

C NMR

(CDCl3, 100 MHz) δ: 28.0, 29.3, 35.6, 52.5, 56.7, 84.2, 115.1, 115.6, 120.9, 122.6, 122.7, 124.0, 125.8, 125.9, 127.1, 127.8, 128.5, 128.6, 128.8, 132.3, 138.6, 139.2, 139.8, 140.7, 149.2, 167.2, 168.0, 175.6. HRMS (ESI-TOF) m/z: Calcd. for C32H29ClN2NaO6 [M+Na]+: 595.1612; Found: 595.1612.

(E)-tert-butyl 3-(2-(1-benzyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo-3-phenylindoline-1-carboxylate (3af). Light yellow solid, yield 72%; mp: 158.8-158.9 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.65 (s, 9H), 3.66 (s, 3H), 4.30 (d, J = 13.6 Hz, 1H), 4.83-4.94 (m, 3H), 6.64 (d, J = 7.6 Hz, 1H), 6.85-6.89 (m 1H), 7.07-7.16 (m, 3H), 7.23(t, J = 4.2 Hz, 2H), 7.28-7.37 (m, 7H), 7.47-7.49 (m 2H), 7.55-7.57 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 28.1, 35.5, 43.3, 52.4, 56.9, 84.2, 108.9, 115.2, 122.3, 122.7, 124.0, 126.1, 127.1, 127.2, 127.7, 127.8, 128.6, 128.7, 128.8, 130.2, 135.6, 139.2, 139.8, 139.9, 142.0, 149.3, 167.2, 168.2, 175.8. HRMS (ESI-TOF) m/z: Calcd. for C38H34N2NaO6 [M+Na]+: 637.2315; Found: 637.2317.

(E)-tert-butyl 3-(2-(1-benzyl-5-fluoro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo-3phenylindoline-1-carboxylate (3ag). Light yellow solid, yield 53%; mp: 155.4-156.6 oC; 1H NMR 11

Organic & Biomolecular Chemistry Accepted Manuscript

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Organic & Biomolecular Chemistry

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6.49-6.53 (m 1H), 6.76-6.85 (m, 2H), 7.07-7.11 (m, 1H), 7.16-7.25 (m, 2H), 7.25-7.36 (m, 7H), 7.35-7.50 (m, 2H), 7.49-7.52 (m, 1H), 7.92 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 28.0, 35.5, 43.3, 52.6, 84.2, 109.3, 109.4, 110.7 (d, JCF = 25.9 Hz), 115.2, 116.5 (d, JCF = 23.6 Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

Hz), 120.9, 123.9, 126.0, 126.7, 127.0, 127.1, 127.7, 127.8, 128.5, 128.6, 128.8, 135.2, 137.9, 138.9, 139.9, 141.2, 149.2, 158.6 (d, JCF = 238.1 Hz), 166.9, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C38H33FN2NaO6 [M+Na]+: 655.2220; Found: 655.2229.

(E)-tert-butyl 3-(2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-phenylindoline-1-carboxylate (3ah). Light yellow solid, yield 71%; mp: 150.7-150.9 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.62 (s, 9H), 3.65 (s, 3H), 4.28 (d, J = 13.2 Hz, 1H), 4.78-4.91 (m, 3H), 6.52 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 7.07-7.11 (m, 2H), 7.15 (d, J = 6.8 Hz, 2H), 7.25-7.35 (m, 7H), 7.42-7.44 (m, 2H), 7.48-7.50 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H);

13

C NMR

(CDCl3, 100 MHz) δ: 28.0, 35.6, 43.3, 52.6, 56.8, 84.2, 109.8, 115.2, 121.3, 123.2, 123.9, 125.9, 126.2, 127.0, 127.1, 127.7, 127.8, 127.9, 128.4, 128.6, 128.8, 129.9, 135.1, 138.9, 139.9, 140.3, 141.4, 149.2, 166.7, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C38H33ClN2NaO6 [M+Na]+: 671.1925; Found: 671. 1920.

(E)-tert-butyl 3-(2-(1-benzyl-5-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-phenylindoline-1-carboxylate (3ai). Light yellow solid, yield 64%; mp: 257.8-258.4 oC; 1H NMR (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1.64 (s, 9H), 2.09 (s, 3H), 3.56 (s, 3H), 4.16 (d, J = 13.6 Hz, 1H), 4,70-4.82 (m, 3H), 6.42 (d, J = 8.0 Hz, 1H), 6.48 (t, J = 9.0 Hz, 1H), 6.74 (s, 1H), 6.84 (t, J = 4.0 Hz, 1H), 6.90-7.01 (m, 2H), 7.07-7.25 (m, 6H), 7,35-7.46 (m 4H), 7.84(d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 21.2, 27.7, 28.1, 35.5, 43.3, 52.3, 56.9, 84.2, 108.7, 115.2, 123.5, 123.9, 126.2, 127.1, 127.2, 127.6, 127.7, 127.8, 128.6, 128.7, 128.8, 130.6, 131.5, 135.7, 139.4, 149.3, 167.2, 168.3, 175.8. HRMS (ESI-TOF) m/z: Calcd. for C39H36N2NaO6 [M+Na]+: 651.2471; Found: 651.2472.

(E)-tert-butyl 3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-ethoxy-3-oxopropyl)-2-oxo-3phenylindoline-1-carboxylate (3aj). Light yellow solid, yield 66%; mp: 150.8-152.5 oC; 1H NMR 12

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(CDCl3, 400 MHz) δ: 1.61 (s, 9H), 3.65 (s, 3H), 4.28 (d, J = 13.2 Hz, 1H), 4.78-4.91DOI: (m,10.1039/C4OB01523A 3H),

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Organic & Biomolecular Chemistry

3.99-4.05 (m, 2H), 4.27 (d, J = 13.6 Hz, 1H), 4.77 (d, J = 13.6 Hz, 1H), 6.77 (t, J = 8.0 Hz., 1H), 6.95-6.97 (m, 1H), 7.10-7.17 (m, 2H), 7.24-7.33 (m, 4H), 7.40-7.47 (m, 3H), 7.91 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 13.6, 28.0. 29.3, 35.6, 56.7, 62.0, 84.1, 115.2, 115.5, 121.1, Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

122.6, 122.8, 124.1, 125.6, 125.8, 127.1, 127.8, 128.6, 128.7, 128.8, 132.2, 138.6, 139.3, 139.9, 141.3, 149.3, 167.3, 167.6, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1769.

(E)-tert-butyl

3-(2-(1-(tert-butoxycarbonyl)-2-oxoindolin-3-ylidene)-3-ethoxy-3-oxopropyl)-2-

oxo-3-phenylindoline-1-carboxylate (3ak). Light yellow solid, yield 83%; mp: 148.7-149.8 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.06 (t, J = 7.2 Hz, 3H), 1.60 (d, J = 7.6 Hz, 18H), 2.19-2.28 (m, 1H), 3.45-3.53 (m, 1H), 3.83-3.87 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 7,04 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.25-7.32 (m, 5H), 7.43 (t, J = 6.6 Hz, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4Hz, 1H).13C NMR (CDCl3, 100 MHz) δ: 13.2, 28.0, 28.1, 39.1, 55.9, 61.7, 84.5, 84.6, 114.9, 115.3, 120.7, 123.7, 123.9, 124.4, 126.0, 127.2, 127.3, 127.8, 128.1, 128.7, 129.1, 130.4, 137.9, 139.8, 140.2, 140.4, 148.7, 149.1, 163.6, 168.6, 175.2. HRMS (ESI-TOF) m/z: Calcd. for C37H38N2NaO8 [M+Na]+: 661.2526; Found: 661.2527.

(E)-tert-butyl 3-(3-methoxy-2-(1-methyl-2-oxoindolin-3-ylidene)-3-oxopropyl)-2-oxo-3-p-tolylindoline-1-carboxylate (3ba). Light yellow solid, yield 60%; mp: 177.2-177.3 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.52 (s, 9H), 2.22 (s, 3H), 3.07 (s, 3H), 3.53 (s, 3H), 4.17 (d, J = 13.6 Hz, 1H), 4.66 (d, J = 13.6 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.77-6.81 (m, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.01-7.04 (m, 3H), 7.12-7.23 (m, 4H), 7,39-7.41 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 20.9, 25.9, 28.1, 35.4, 52.3, 56.5, 84.0, 108.0, 115.1, 120.1, 122.1, 122.6, 123.9, 125.9, 127.0, 128.6, 128.9, 129.3, 130.2, 136.5, 137.5, 139.5, 139.9, 142.9, 149.3, 167.1, 168.2, 175.9. HRMS (ESI-TOF) m/z: Calcd. for C33H32N2NaO6 [M+Na]+: 575.2158; Found: 575.2159.

(E)-tert-butyl

3-(2-(5-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-

oxo-3-p-tolylindoline-1-carboxylate (3bb). Light yellow solid, yield 60%; mp: 172.9-173.1 oC; 1H 13

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DOI:(s, 10.1039/C4OB01523A (CDCl3, 400 MHz) δ: 1H NMR (CDCl3, 400 MHz) δ: 1.22-1.30 (m, 3H), 1.61 (s, 9H), 3.54 3H),

Organic & Biomolecular Chemistry

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Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 7.08-7.12 (m, 3H), 7.19-7.21 (m, 1H), 7.26-7.33 (m, 3H), 7.43-7.45 (m, 1H), 7.90 (d. J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 20.9, 26.0, 28.0, 35.5, 52.5, 56.4, 84.1, 108.8, 115.1, 121.2, 123.1, Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

123.9, 125.8, 126.3, 127.0, 127.5, 128.6, 128.7, 129.3, 129.8, 136.2, 137.6, 139.8, 141.1, 141.2, 149.2, 166.6, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1773.

(E)-tert-butyl 3-(2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo3-p-tolylindoline-1-carboxylate (3bh). Light yellow solid, yield 61%; mp: 166.9-167.7 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 2.29 (s, 3H), 3.66 (s, 3H), 4.14 (d, J = 13.2 Hz, 1H), 4.90 (d, J = 13.6 Hz, 1H), 5.29-5.39 (m, 2H), 6.78 (t, J = 8.0 Hz, 1H), 6.94-6.96 (m, 1H), 7.02-7.04 (m, 1H), 7.06-7.12 (m, 5H), 7.24-7.27 (m, 2H), 7.28-7.38 (m, 4H), 7,45-7.47 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 20.9, 28.1, 35.7, 44.5, 52.5, 56.6, 84.1, 115.1, 115.5, 121.1, 122.8, 122.9, 123.9, 125.4, 125.9, 126.3, 126.9, 127.1, 128.5, 128.6, 128.7, 129.3, 132.5, 136.2, 137.2, 137.6, 137.8, 139.8, 141.5, 149.3, 167.6, 168.1, 175.9. HRMS (ESI-TOF) m/z: Calcd. for C39H35ClN2NaO6 [M+Na]+: 685.2081; Found: 685.2085.

(E)-tert-butyl 3-(3,5-dimethylphenyl)-3-(3-methoxy-2-(1-methyl-2-oxoindolin-3-ylidene)-3-oxopropyl)-2-oxoindoline-1-carboxylate (3ca). Light yellow solid, yield 56%; mp: 291.0-292.5 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.61 (s, 9H), 2.24-2.28 (m, 6H), 3.16 (s, 3H), 3.64 (s, 3H), 4.16 (d, J = 13.6 Hz, 1H), 4.82 (d, J = 13.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.84-6.89 (m, 2H), 7.02 (t, J = 7.8 Hz, 2H), 7.07-7.11 (m, 1H), 7.21-7.31 (m, 2H), 7.45-7.47 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H); 13

C NMR (CDCl3, 100 MHz) δ: 21.5, 25.8, 28.1, 35.3, 52.3, 56.6, 84.0, 107.9, 115.0, 120.0, 122.1,

122.5, 123.9, 124.8, 126.0, 126.9, 128.6, 128.9, 129.4, 130.1, 138.0, 139.3, 139.7, 139.8, 142.8, 149.3, 167.0, 168.1, 175.9. HRMS (ESI-TOF) m/z: Calcd. for C34H34N2NaO6 [M+Na]+: 589.2315; Found: 589.2311.

(E)-tert-butyl 3-(2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-3-(3,5dimethylphenyl)-2-oxoindoline-1-carboxylate (3ch). Light yellow solid, yield 75%; mp: 14

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NMR (CDCl3, 400 MHz) δ: 1.60 (s, 9H), 2.30 (s, 3H), 3.14 (s, 3H), 3.63 (s, 3H), 4.27(d,DOI: J =10.1039/C4OB01523A 13.2

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Organic & Biomolecular Chemistry

= 13.6 Hz, 1H), 5.01 (d, J = 13.6 Hz, 1H), 5.29-5.39 (m, 2H), 6.76-6.80 (m, 1H), 6.88 (s, 1H), 6.94-6.96 (m, 3H), 7.02-7.06 (m, 1H), 7.07-7.12 (m, 3H). 7.24-7.33 (m, 4H), 7.44-7,46 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H) ; 13C NMR (CDCl3, 100 MHz) δ: 21.4, 28.2, 35.7, 44.5, 52.5, 56.8, 84.1, Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

115.1, 115.5, 121.1, 122.8, 122.9, 123.9, 124.7, 125.3, 126.0, 126.2, 126.9, 127.1, 128.5, 128.7, 128.8, 129.5, 132.5, 137.3, 137.8, 138.0, 139.1, 139.8, 141.7, 149.3, 167.7, 168.1, 176.0. HRMS (ESI-TOF) m/z: Calcd. for C40H37ClN2NaO6 [M+Na]+: 699.2238; Found: 699.2238.

(E)-tert-butyl

3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-ethoxy-3-oxopropyl)-3-(3,5-

dimethylphenyl)-2-oxoindoline-1-carboxylate (3cj). Light yellow solid, yield 60%; mp: 169.8-169.9 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.24 (t, J = 7.2 Hz, 3H), 1.61 (s, 9H), 2.26 (s, 6H), 1.54 (s, 3H), 4.03-4.08 (m, 2H), 4.15 (d, J = 13.2 Hz, 1H), 4.83 (d, J = 13.2 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.94-6.97 (m, 3H), 7.08-7.16 (m, 2H), 7.26-7.32 (m, 1H), 7.42-7.44 (m, 1H),7.91(d, J = 8.0 Hz, 1H);

13

C NMR (CDCl3, 100 MHz) δ: 13.6, 21.5, 28.0, 29.3, 35.5, 56.6,

62.0, 84.0, 115.0, 115.5, 121.0, 122.6, 122.8, 123.9, 124.7, 125.4, 125.8, 128.6, 128.9, 129.5, 132.1, 138.0, 138.5, 139.3, 139.9, 141.6, 149.3, 167.3, 167.6, 175.8. HRMS (ESI-TOF) m/z: Calcd. for C35H35ClN2NaO6 [M+Na]+: 637.2081; Found: 637.2084.

(E)-tert-butyl

5-fluoro-3-(3-methoxy-2-(1-methyl-2-oxoindolin-3-ylidene)-3-oxopropyl)-2-oxo-

3-phenylindoline-1-carboxylate (3da). Light yellow solid, yield 52%; mp: 211.4-212.5 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.09 (s, 3H), 3.58 (s, 3H), 4.06 (d, J = 13.6 Hz, 1H), 4.79(d, J = 13.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.79-6.83 (m, 1H), 6.89-6.96 (m, 2H), 7.14-7.27 (m, 5H), 7.32-7.34 (m, 2H), 7.80-7.83 (m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ: 25.9, 28.1, 35.2, 52.4, 57.1, 84.3, 108.2, 113.4 (d, JCF = 37.5 Hz), 115.3, 115.5, 116.4, 119.9, 122.4 (d,

JCF = 24.8 Hz), 127.0, 128.0, 128.8, 130.4, 130.6, 135.9, 138.8, 142.9, 159.5 (d, JCF = 241.4 Hz), 167.1, 168.1, 175.5. HRMS (ESI-TOF) m/z: Calcd. for C32H29FN2NaO6 [M+Na]+: 579.1907; Found: 579.1909.

(E)-tert-butyl 3-(3-methoxy-2-(1-methyl-2-oxoindolin-3-ylidene)-3-oxopropyl)-5-methyl-2-oxo3-phenylindoline-1-carboxylate (3ea). Light yellow solid, yield 54%; mp: 246.1-246.4 oC; 1H 15

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151.9-152.7 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.62 (s. 9H), 2.23 (s. 6H), 3.69 (s. 3H), DOI: 4.0610.1039/C4OB01523A (d, J

Organic & Biomolecular Chemistry

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13.6Hz, 1H), 4.78 (d, J = 13.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.88-6.92 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.10-7.12 (m, 1H), 7.23-7.35 (m, 5H), 7.46 (t, J = 4.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 21.1, 25.8, 28.1, 35.4, 52.3, 57.0, 83.9, 107.9, 114.9, 120.1, Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

122.1, 122.7, 126.5, 127.2, 127.7, 128.6, 128.7, 129.2, 130.2, 133.4, 137.6, 139.4, 139.6, 142.8, 149.3, 167.1, 168.1, 175.9. HRMS (ESI-TOF) m/z: Calcd. for C33H32N2NaO6 [M+Na]+: 575.2158; Found: 575.2168.

(E)-tert-butyl

3-(2-(5-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-5-

methyl-2-oxo-3-phenylindoline-1-carboxylate (3eb). Light yellow solid, yield 64%; mp: 168.9-169.0 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.60 (s, 9H), 2.25 (s, 3H), 3.15 (s, 3H), 3.64 (s, 3H), 4.29 (d, J = 13.2 Hz, 1H), 4.69(d, J = 13.2 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 7.09-7.12 (m, 1H), 7.19-7.22 (m, 1H), 7.25-7.34 (m, 4H). 7.41-7.44 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 21.0, 25.9, 28.0, 35.5, 52.5, 55.9, 84.0, 108.7, 114.9, 121.2, 123.2, 126.4, 127.1, 127.5, 127.8, 128.5, 128.6, 129.3, 129.8, 133.4, 137.5, 139.3, 141.0, 141.2, 149.2, 166.6, 167.7, 175.7. HRMS (ESI-TOF) m/z: Calcd. for C33H31ClN2NaO6 [M+Na]+: 609.1768; Found: 609.1781.

(E)-tert-butyl 3-benzyl-3-(2-(1-benzyl-5-chloro-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl) -2-oxoindoline-1-carboxylate (3fh). Light yellow solid, yield 72%; mp: 120.4-123.2 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.14 (d, J = 12.8 Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.74 (s, 3H), 4.94 (d, J = 13.6 Hz, 1H), 5.36-5.49 (m, 2H), 6.70-6.78 (m, 3H), 6.91 (d, J = 0.8 Hz, 1H), 6.91-6.93 (m, 5H), 6.98-6. 7.17 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.48 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 28.0, 34.0, 44.6, 47.3, 52.5, 55.5, 83.5, 114.4, 115.5, 121.0, 122.8, 123.8, 124.2, 124.8, 126.2, 126.8, 127.1, 127.5, 128.1, 128.4, 128.6, 129.7, 132.4, 134.1, 137,1, 137.7, 139.7, 141.5, 148.5, 168.0, 177.0. HRMS (ESI-TOF) m/z: Calcd. for C39H35ClN2NaO6 [M+Na]+: 685.2081; Found: 685.2081.

(E)-tert-butyl

3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-2-oxo

-3-(4-(trifluoromethyl)benzyl)indoline-1-carboxylate (3ge). Light yellow solid, yield 65%; mp: 16

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DOI:(d, 10.1039/C4OB01523A NMR (CDCl3, 400 MHz) δ: 1 .62 (s, 9H), 2.17 (s, 3H), 3.18 (s, 3H), 3,65 (s, 3H), 4.17 J=

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Organic & Biomolecular Chemistry

12.8 Hz, 1H), 3.63 (s, 3H), 3.70 (s, 3H), 3.77 (d, J = 13.6 Hz, 1H), 4.70 (d, J = 14 Hz, 1H), 6.77 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.90-6.92 (m, 1H), 7.11-7.20 (m, 3H), 7.27 (t, J = 4.0 Hz, 2H), 7.44-7.46 (m, 1H), 7.50-7.52 (m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ: 27.9, 29.4, 34.0, Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

46.5, 52.5, 55.0, 83.9, 114.5, 115.7, 121.0, 122.6, 122.8, 123.5 (q, J = 270.9 Hz), 124.0, 124.1, 124.0 (q, J = 3.3 Hz), 125.6, 127.9, 128.7 (q, J = 32.9 Hz), 130.1, 132.3, 138.4, 138.6, 139.7, 140.4, 148.2, 167.6, 167.9, 176.6. HRMS (ESI-TOF) m/z: Calcd. for C34H30ClF3N2NaO6 [M+Na]+: 677.1642; Found: : 677.1649.

(Z)-tert-butyl

3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-3-

(4-methoxybenzyl)-2-oxoindoline-1-carboxylate (3he). Light yellow solid, yield 71%; mp: 142.5-143.8 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.54 (s, 9H), 3.09 (d, J = 12.8 Hz, 1H), 3.21 (d, J = 12.8 Hz, 1H), 3.61 (s, 3H), 3.67(s, 3H), 3.68 (s, 3H), 3.73 (d, J = 14.0 Hz, 1H), 4.68 (d, J = 13.6 Hz, 1H), 6.54-6.56 (m, 2H), 6.62-6.65 (m, 2H), 6.74 (t, J = 8.0 Hz, 1H), 6.87-6.89 (m, 1H), 7.07-7.18 (m, 3H), 7.43-7.45 (m, 1H), 7.48-7.50 (m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ: 28.0, 29.3, 33.8, 46.4, 52.4, 55.0, 55.2, 83.5, 112.9, 114.5, 115.5, 120.9, 122.7, 123.8, 124.0, 125.2, 126.2, 128.3, 130.8, 132.1, 138.5, 139.8, 141.0, 148.6, 158.4, 167.5, 168.0, 177.0. HRMS (ESI-TOF) m/z: Calcd. for C34H33ClN2NaO7 [M+Na]+: 639.1874; Found: : 639.1877.

(Z)-tert-butyl

3-(2-(7-chloro-1-methyl-2-oxoindolin-3-ylidene)-3-methoxy-3-oxopropyl)-3-

(3,4-dimethoxybenzyl)-2-oxoindoline-1-carboxylate (3ie). Light yellow solid, yield 67%; mp: 146.0-147.4 oC; 1H NMR (CDCl3, 400 MHz) δ: 1.53 (s, 9H), 3.09 (d, J = 12.8 Hz, 1H), 3.24 (d, J = 12.8 Hz, 1H), 3.55 (s, 3H), 3.62 (s, 3H), 3.70 (t, J = 6.8 Hz, 4H), 3.75 (s, 3H), 4.72 (d, J = 14.0 Hz, 1H), 6.11 (d, J = 2.0 Hz, 1H), 6.35-6.38 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 6.89-6.91 (m, 1H), 7.09-7.18 (m, 3H), 7.48 (t, J = 4.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 28.0, 29.4, 34.0, 46.8, 52.5, 55.4, 55.6, 83.6, 110.2, 112.3, 114.6, 115.6, 120.9, 122.1, 122.6, 122.7, 122.8, 124.1, 125.3, 126.6, 128.3, 128.6, 132.2, 138.5, 140.0, 140.9, 147.7, 147.8, 148.5, 167.6, 168.0, 177.1. HRMS (ESI-TOF) m/z: Calcd. for C35H35ClN2NaO8 [M+Na]+: 669.1980; Found: 669.1982.

17

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DOI:(d, 10.1039/C4OB01523A 241.1-241.9 oC; 1H NMR (CDCl3, 400 MHz) δ:1.51 (s, 9H), 3.20 (d, J = 12.4 Hz, 1H), 3.33 J=

Organic & Biomolecular Chemistry

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DOI: 10.1039/C4OB01523A 2-(1-methyl-2-oxoindolin-3-ylidene)-3-(2-oxo-3-phenylindolin-3-yl)propanoate

(3aa-1). Light yellow solid, yield 90%; mp: 218.2-218.7 oC; 1H NMR (DMSO-d6, 400 MHz) δ: 3.12 (s, 3H), 3.50 (s, 3H), 4.08 (d, J = 13.2 Hz, 1H), 4.52 (d, J = 13.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.88-6.95 (m, 3H), 6.98 (d, J = 8.0 Hz, 1H), 7.14-7.18 (m, 1H), 7.25-7.39 (m, 7H), 10.54 (br Published on 02 October 2014. Downloaded by KUNGL TEKNISKA HOGSKOLAN on 12/10/2014 12:24:07.

s, 1H);

13

C NMR (DMSO-d6, 100 MHz) δ: 25.9, 33.8, 52.2, 56.3, 108.9, 109.8, 119.1, 121.3,

121.9, 122.2, 125.4, 125.8, 126.5, 127.4, 128.5, 130.5, 130.6, 139.9, 140.4, 142.3, 142.5, 166.4, 167.5, 178.2. HRMS (ESI-TOF) m/z: Calcd. for C27H22N2NaO4 [M+Na]+: 461.1477; Found: 461.1468.

Cytotoxicity assay Two human cancer cell lines, K562 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-(4,5-dimethylthiazol-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 μmol·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 hours. At least, measure the OD value at 490 wavelengths. IC50 of all the compounds were calculated by IBM SPSS Statistics (version 19).

Acknowledgements We are grateful for the financial support from the National Natural Science Foundation of China (No. 21302024); Program for New Century Excellent Talents in University of Ministry of Education of China (NCET-11-0926); Project for Structure Determination of the Novel Active Components in Guizhou Ethnic Medicines and Application of NMR Spectrometer R&D (No: 2011YQ12003506)and Modernization of Traditional Chinese Medicine Special of Guizhou ([2013(3010)] Qian Ke He Zi). 18

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(E)-methyl

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Highly regioselective synthesis of 3-alkenyl-oxindole ring-fused 3,3'-disubstituted oxindoles via direct gamma-substitution of Morita-Baylis-Hillman carbonates of isatins with 3-substituted oxindoles.

The first phase transfer-catalysed direct γ-substitution of Morita-Baylis-Hillman carbonates of isatins with 3-substituted oxindoles has been develope...
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