English

• 1.   Introduction

  Coumarin is an important compound in pharmaceutical synthesis^[1~6] because of the pyranone skeleton, which possesses extensive pharmacological activities such as anti-inflammatory, anti-tuberculosis, antioxidants, anti- virus, antibacterial, anti-cancer, anti-depression and anti-hyperlipidemia, etc.^[7~13] Various methods for the synthesis of substituted coumarins have been reported, for example, pyrano[3, 2-c]coumarins have been reported in the literature that utilize different catalytic systems including nanoparticles, H₆P₂W₁₈O₆₂·18H₂O, nanosilica, sodium carbonate, ionic liquids, and proline-melamine.^[14~16] Recently, chromeno[3', 4':5, 6]pyrano[2, 3-b]indole derivatives have been obtained via a two-step reaction sequence, but more efficient protocol still need to be developed.^[17] Furthermore, as the significant biological and pharmacological activities of coumarin, more attention should be paid to the extension of coumarin derivatives.

  Tröger's base (TB, Figure 1) which was firstly found in 1887^[18] has aroused wide attention in molecular recognition, bioorganic chemistry, supramolecular chemistry and other fields.^[19~21] Their distinctive non-twisted V-shape nitrogen-containing eight-member fused skeleton enables TB and its derivatives to capture appropriate molecules efficiently and display great potential as catalyst.^[22]

  Figure 1

  

  Figure 1.  Structure of Tröger's base

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  It is worth noting that the structural advantages of TB and its derivatives are far from being developed. The weak alkalescence, limited active sites (only two bridgehead N atoms) and single hydrogen bond acceptor restricted their application as organocatalyst or ligands.

  To take full structural advantage of TB and further promote their catalysis by increasing catalytic active sites and enhancing the basicity, herein 1, 7-bis(N-substituted-amino- methyl)-2, 8-dihydroxy type Tröger's bases were designed and synthesized from available raw materials through simple hydrolysis and Mannich reaction. They were then used as efficient organocatalyst for the Aldol reaction of 4-hy- droxylcoumarin and 2-benzylidenemalononitrile (or methyl(ethyl)-2-cyano-3-phenylacrylate) to afford 2-amino- 4-aryl-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitri-les (carboxylates) (8). Subsequently, they were used as the efficient ligand to promote the Pd-catalyzed Aldol-Ullmann reaction to give 7-aryl-7, 12-dihydro-6H-chromeno[3', 4': 5, 6]pyrano[2, 3-b]indol-6-one (10) and 5'(or 5', 7')-substi- tuted-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano[2, 3-b]in-dole-7, 3'-indoline]-2', 6-dione (12), respectively. The anti- cancer and anti-bacterial activities of catalysts and products in vitro were tested preliminary.

  2.   Results and discussion

  2.1   Synthesis

  Firstly, a series of catalyst TBs 4 based on TB derivatives was synthesized via simple process (Scheme 1) with high yields (83%~95%).

  Scheme 1

  

  Scheme 1.  Synthesis of series of TBs 4

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  Then their pH values was tested. It can be seen from Table 1 that the pH values of TBs 4 are in the range of 6.30~7.33, indicated their stronger alkalinity than that of TB (6.07).

  Table 1

  

  Table 1.  Synthesis and pH value of TBs 4

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  Compd.	R	Yield/%	pHa
  TB	—	80	6.07
  4a	Cyclohexyl	83	6.30
  4b	Methyl	87	6.25
  4c	Butyl	85	6.16
  4d	1-Phenylmethyl	89	7.18
  4e	Pyridin-2-methyl	90	7.33
  4f	1-Cyclohexyl-1-methyl	95	7.24
  4g	4-Methylcyclohexyl-	91	6.95
  4h	3, 3-DiMethyl-2-butyl	93	7.14
  4i	tert-Butyl	87	6.94
  a Test solution was prepared by dissolving 0.01 mmol of compounds in apropos amount of anhydrous ethanol and diluting to 10.0 mL with anhydrous ethanol.

  Next, catalyst 4 was used as catalyst for the synthesis of 2-amino-4-aryl-5-oxo-4H, 5H-pyrano-[3, 2-c]chromene-3-carbonitriles (8) (Scheme 2).

  Scheme 2

  

  Scheme 2.  Synthesis of 2-amino-4-aryl-5-oxo-4H, 5H-pyrano- [3, 2-c]chromene-3-carbonitriles (8)

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  The reaction conditions were then optimized based on the yield of 8a from 7a and 4-hydroxycoumarin subsequently (Table 2). Firstly, the catalysts were screened. As shown in Table 2, the reaction could not occur without catalyst (Entry 1). Tröger's base could promote the reaction (Entry 2) but give low yield (15%). After the addition of TB derivative 4, the yield increased to 43%~81% (Entries 3~10). 4e (Entry 7, 81%) was obviously efficient than others (Entry 3~6, 8~10) due to its strongest basicity and two pyridine rings. Increasing the loading of 4e from 1 mol% to 10 mol% led to a significant enhancement of the yield of 8a from 53% to 92% (Entry 13 vs. Entries 15, 16), which showed the importance of the catalyst loading for the reaction. However, no further yield increase was observed when the catalyst loading was increased to 20 mol% (Entry 7, 93%). Secondly, the solvents were screened (Entries 11~14) and it was found that the best result was obtained in anhydrous EtOH because of its suitable solubility for the substrates and polarity for the reaction. Finally, the reaction time was screened (Entries 18~20). The yield increased with the prolongation of reaction time. When the reaction time was over 8 h, the yield almost did not increase. Above all, using 10 mol% of 4e as catalyst in anhydrous EtOH at room temperature for 8 h was the optimum condition.

  Table 2

  

  Table 2.  Synthesis of product 8a under different condition^a

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  Entry	4	Cat./mol%	Solvent	t/h	Yield/%
  1	—	—	CH3CN	12	—
  2	TB	10	CH3CN	12	15
  3	4a	10	CH3CN	12	43
  4	4b	10	CH3CN	12	56
  5	4c	10	CH3CN	12	52
  6	4d	10	CH3CN	12	49
  7	4e	10	CH3CN	12	81
  8	4f	10	CH3CN	12	59
  9	4g	10	CH3CN	12	47
  10	4h	10	CH3CN	12	55
  11	4e	10	CH2Cl2	12	53
  12	4e	10	Et2O	12	78
  13	4e	10	EtOH	12	92
  14	4e	10	CHCl3	12	47
  15	4e	1	EtOH	12	53
  16	4e	5	EtOH	12	70
  17	4e	20	EtOH	12	93
  18	4e	10	EtOH	6	75
  19	4e	10	EtOH	8	92
  20	4e	10	EtOH	10	92
  a Unless otherwise noted, the reactions were carried out by using 7a (1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) at room temperature.

  Under the optimized conditions, the scope of substrates was explored (Table 3). The results in Table 3 showed that the reaction afforded desired products in high yields (84%~95%) with wide substrate scope, which showed the high efficiency and universality of the catalyst. There was no regular relationship between the yield and the steric hindrance and electronic effect of substituents.

  Table 3

  

  Table 3.  Synthesis of product 8 under the optimum condition

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  Compd.	R1	R2	Yield/%
  8a	p-Br	CN	92
  8b	p-OCH3	CN	93
  8c	p-F	CN	87
  8d	o-OCH3	CN	85
  8e	2, 4-Cl2	CN	95
  8f	p-CH3	CN	93
  8g	CN	COOMe	84
  8h	p-OCH3	COOEt	85
  8i	CN	COOEt	87
  8j	CN	CN	93
  8k	p-Cl	CN	90
  8l	o-Cl	CN	92
  8m	o-F	CN	84
  8n	o-Br	CN	90
  8o	H	CN	95
  8p	3, 4-(OCH3)2	CN	90
  8q	3, 4, 5-(OCH3)3	CN	93
  8r	2, 3-(OCH3)2	CN	89
  8s	o-NO2	COOEt	81
  8t	o-NO2	CN	86
  8u	2, 4-Cl2	COOMe	88

  Encouraged by the exciting results, catalyst 4 was then used as ligands for the Pd-catalyzed Aldol-Ullmann reaction of aromatic aldehyde (5), 2-(2-iodo(or bromo)phenyl)- acetonitrile (9) and 4-hydroxycoumarin successfully to afford 7-aryl-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano-[2, 3-b]indol-6-one (10) in high yields (Scheme 3). The reaction conditions were optimized based on the reaction of product 10a (Table 4). From Table 4, the optimum condition is that substrates and 5 mol% of 4e were stirred in toluene at 110 ℃ for 16 h.

  Scheme 3

  

  Scheme 3.  Synthesis of product 10

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  Table 4

  

  Table 4.  Synthesis of product 10a under different conditions^a

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  Entry	4	Cat./mol%	t/h	Yield/%
  1	—	—	12	—
  2	TB	10	12	37
  3	4a	10	12	63
  4	4b	10	12	71
  5	4c	10	12	59
  6	4d	10	12	53
  7	4e	10	12	76
  8	4f	10	12	69
  9	4g	10	12	75
  10	4h	10	12	58
  11	4e	1	12	53
  12	4e	5	12	73
  13	4e	5	10	55
  14	4e	5	14	82
  15	4e	5	16	95
  16	4e	5	18	95
  a Unless otherwise noted, the reactions were carried out by using aromatic aldehyde (5, 1.0 mmol), 2-(2-iodo(or bromo)phenyl)acetonitrile (9, 1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) in toluene at room temperature.

  The results of Table 5 showed that the reaction afforded high yields (90%~95%) of the desired products 10.

  Table 5

  

  Table 5.  The result of synthesis of product 10 under the opti- mum condition

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  Product	R	X	Yield/%
  10a	2-OCH3	2-I	95
  10b	2, 3-(OCH3)2	2-I	93
  10c	4-OH	2-I	92
  10d	4-Br	2-I	90
  10e	4-CH3	2-Br	96
  10f	4-F	2-Br	94
  10g	4-Br	2-Br	96
  10h	4-CN	2-Br	92
  10i	3-NO2	2-Br	90

  Subsequently, isatins with lower reactivity than aldehydes were used as carbonyl compounds (Scheme 4). As expect, they reacted smoothly and gave relative product 5' (or 5', 7')-substituted-6H, 12H-spiro[chromeno[3', 4':5, 6]py- rano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12) in DMSO (Table 6).

  Scheme 4

  

  Scheme 4.  Synthesis of product 12

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  Table 6

  

  Table 6.  The result of synthesis of product 12^a

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  Compd.	R	Yield/%
  12a	5-Cl	88
  12b	5, 7-(CH3)2	85
  12c	5-Br	90
  12d	5-CH3	82
  12e	5-OCH3	89
  12f	5-NO2	85
  a Unless otherwise noted, the reactions were carried out by using isatins (11, 1.0 mmol), 2-(2-iodo(or bromo)phenyl)acetonitrile (9, 1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) and 4e (5 mol %) as ligand, PbCl2 (5 mol %) as catalysts in DMSO (3 mL) at 110 ℃.

  2.2   Possible mechanism

  Based on our previous catalytic mechanistic study^{[20, 21]} and literature reports, ^[10] a possible mechanism for the formation of product 8 was suggested in Scheme 5. Firstly, the catalyst 4e isomerized as I, a inner salt containing two oxygen anions and two nitrogen cations in the pyridine rings. One of the oxygen anion in I took away a proton of 4-hydroxycoumarin and formed intermediate A. Meanwhile, catalyst I changed to II. A reacted to arylmethylenemalononitrile through an 1, 4-electron transfer process to form intermediate B. B took away a proton in II to form C, while II changed back to I. Then one of the oxygen anion in I attacked C to take away a proton and formed intermediate D. D yielded the final product 8 via intramolecular condensation in the presence of II, meanwhile II changed back to I to complete the catalyst cycle.

  Scheme 5

  

  Scheme 5.  A possible mechanism for the synthesis of product 8

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  Above all, we speculated that the key role of catalyst came from its ability to form a bipolar ion. It provided or captured proton efficiently and conveniently.

  A possible mechanism for the formation of product 10 was also proposed based on the literature (Scheme 6).^[23] Firstly, palladium complex A was generated from PdCl₂ and catalyst 4e. A captured the iodine atom on D to form complex B. B then took off a molecule of 4e under the effect of alkali to form complex C and 4e-OH^－. The reduction and elimination of C formed product 10.

  Scheme 6

  

  Scheme 6.  A possible mechanism for the synthesis of product 10

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  2.3   Biological activity

  In the last, the anti-cancer activities on human three positive breast cancer cells (MCF-7), human three negative breast cancer cells (MDA-MB-231), human hepatoma cells (HepG2), human hepatoma cells (MHCC-97H) and cytotoxicity on human hepatocyte cells (LO2) of catalyst 4 and all products in vitro were evaluated (Table 7) according to the method of Alamar Blue, while paclitaxel was used as positive control (1 μg/mL). The cells were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences (Shanghai, China) and maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin and 100 μg/mL streptomycin at 37 ℃ in 5% CO₂ atmosphere. Cell viability was determined by the Alamar Blue method. Briefly, cancer cells with same number were inoculated into each well in 96-well plates (Costar, Charlotte, NC) in 100 mL of culture medium. After an overnight incubation, 25 μg/mL compounds were added for 48 h. Thereafter, 200 μL of Alamar Blue solution was added to each well after removal of the sample solution and washing with phosphate-buffered saline and cultured for an additional 4 h. The absorbance was measured using SpectraMax M2 (Molecular Devices) at λ_ex＝530 nm and λ_em＝590 nm. Growth inhibition rate was calculated by the following formula and the results were shown in Table 7.

  $ \begin{gathered} {\text{Growth}}\;\;{\text{inhibition}}\;\;{\text{rate}} = \left[ {1 - \left( {{\text{O}}{{\text{D}}_{{\text{dosing }}\;\;{\text{cell }}}} - {\text{O}}{{\text{D}}_{{\text{blank }}\;\;{\text{group }}}}} \right)/} \right. \hfill \\ \left. {\left( {{\text{O}}{{\text{D}}_{{\text{control }}\;\;{\text{cell }}}} - {\text{O}}{{\text{D}}_{{\text{blank }}\;\;{\text{group }}}}} \right)} \right] \times 100\% \hfill \\ \end{gathered} $

  Table 7

  

  Table 7.  Inhibition rate (%) of compounds 4 and 8^a

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  Compd.	LO2	MCF-7	231	HepG2	MHCC97H
  4b	34.29	30.84	—	—	—
  4d	32.09	—	37.00	—	—
  4e	47.14	—	40.93	—	—
  8a	76.28	50.21	32.45	80.21	63.08
  8c	46.02	—	—	38.70	34.16
  8d	44.16	33.31	33.35	—	—
  8e	89.06	71.62	82.23	79.64	61.09
  8l	41.92	30.91	—	—	—
  8m	72.64	40.45	42.62	82.43	75.21
  8n	74.90	48.60	53.01	78.97	74.61
  8q	68.63	36.81	—	85.94	70.40
  Paclitaxel	47.86	89.70	65.83	80.09	42.37
  a Data less than 30% was showed as "—".

  Products 10 and 12 did not show any bioactivity owing to their poor solubility in the test solvent.

  The results in Table 7 showed that compounds 4d and 4e had selective inhibition on MDA-MB-231 cells. It will be possible to develop them as specific drug for triple negative breast cancer by the further systematic study.

  Compound 8q had strong inhibitory effects on three kinds of cancer cells except MDA-MB-231 and had no obvious structure-activity relationship. Compounds 8a, 8e, 8m and 8n had strong inhibitory effects on four kinds of cancer cells. However, they also inhibited LO2 cells which prompt the necessary of structural modification to reduce their toxicity.

  3.   Conclusions

  In summary, a new series of catalysts was synthesized and used to promote the Aldol and Aldol-Ullmann reaction of 4-hydroxylcoumarin and three different electrophiles. Correspondingly, three series of products with complex structure were synthesized efficiently. The key role of catalyst maybe came from its ability to form a bipolar ion, which provided or captured proton efficiently and conveniently. The results confirmed the rationality and our design. Some compounds showed anti-cancer activity, indicated their potential in new drug development. The study on the specific role of the catalyst is underway.

  4.   Experimental

  4.1   Materials and methods

  All the reagents were purchased commercially. Human three positive breast cancer cells (MCF-7), human three negative breast cancer cells (MDA-MB-231), human hepatoma cells (HepG2), human hepatoma cells (MHCC- 97H) and Human hepatocyte (LO2) were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences (Shanghai, China).

  All melting points were determined with an electrothermal digital melting point apparatus and were uncorrected. NMR spectra were measured using a Bruker 400 MHz spectrometer. Mass spectra were recorded on a Micro TOF-Q (ESI) instrument. The methyl thiazolyl tetrazolium assay (MTT) assay was performed on a microplate reader (SpectraMax M2).

  4.2   General procedure for 1, 7-bis(N-substituted- aminomethyl)-2, 8-dihydroxy-Tröger's Bases (TBs 4)

  p-Methoxyaniline (30.0 mmol) and polyformaldehyde (60.0 mmol) were added dropwise into 60 mL of trifluoroacetic acid (TFA) at －15 ℃. After the addition, the reaction temperature was increased slowly to room temperature. After 2 d (TLC), the reaction mixture was poured into ice water, adjusted the pH value to 9 with ammonia water, extracted with CH₂Cl₂ for three times and dried the organic layer with anhydrous sodium sulfate. The crude product was given by removing solvents under vacuum. It was then purified by column chromatography (V_{petroleum ether}:V_{ethyl acetate}＝1:3 gradient elution) to give 2, 8-dimethoxy-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine (1).^{[24] 1}H NMR (400 MHz, CDCl₃) δ: 7.13 (d, J＝8 Hz, 2H), 6.86~6.80 (m, 2H), 6.62 (d, J＝7.6 Hz, 2H), 4.61 (d, J＝16.8 Hz, 2H), 4.28 (s, 2H), 4.13 (d, J＝16.8 Hz, 2H), 3.81 (s, 3H).

  1 (5.0 mmol) and 10 mL of CH₂Cl₂ were added into a 100 mL dry flask. BBr₃ (10.0 mmol) dissolved in 30 mL of CH₂Cl₂ was added dropwise into the flask at －15 ℃. Then the temperature increased slowly to room temperature after grey solid precipitated out. After the completion (TLC), the reaction mixture was poured into ice water, adjusted the pH to 5 with ammonia water, extracted with ethyl acetate for three times, dried and concentrated the organic layer to give 6H, 12H-5, 11-methanodibenzo[b, f]- [1, 5]diazocine-2, 8-diol (2).^{[24] 1}H NMR (400 MHz, CDCl₃) δ: 9.01 (s, 2 H), 6.86 (d, J＝8.0 Hz, 2 H), 6.57~6.54 (m, 2 H), 6.29 (d, J＝2.4 Hz, 2 H), 4.46 (d, J＝16.0 Hz, 2 H), 4.10 (s, 2 H), 3.89 (d, J＝16.0 Hz, 2 H).

  Formaldehyde (1.2 mmol), amine (1.2 mmol), glacial acetic acid (1 mol%) and anhydrous ethanol (3 mL) were successively added to a 50 mL dry flask to react at 80 ℃ for 2 h, then compound 2 (1.0 mmol) was added. Until the completion (TLC), the excess solvent was removed by vacuum and TBs 4 was obtained by recrystallized with EtOH.

  1, 7-Bis((cyclohexylamino)methyl)-6H, 12H-5, 11-meth-anodibenzo[b, f][1, 5]diazocine-2, 8-diol (4a): Yield 83% (0.3958 g). White solid, m.p. 153.5~154.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.95 (d, J＝8.8 Hz, 2H), 6.66 (d, J＝8.8 Hz, 2H), 4.89 (d, J＝9.4 Hz, 1H), 4.81 (d, J＝10.0 Hz, 1H), 4.44 (d, J＝16.6 Hz, 2H), 4.24 (s, 2H), 3.93 (d, J＝16.4 Hz, 2H), 3.79 (s, 4H), 2.67 (s, 2H), 2.07 (s, 1H), 1.94 (s, 4H), 1.80~1.59 (m, 8H), 1.24 (d, J＝10.2 Hz, 8H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.9, 134.5, 123.9, 122.6, 114.9, 107.4, 71.9, 59.7, 58.6, 47.9, 43.5, 34.3, 25.7, 25.1. HRMS (ESI) calcd for C₂₉H₄₀N₄O₂ 477.3230 [M+H]⁺, found 477.3267 [M+H]⁺.

  1, 7-Bis((methylamino)methyl)-6H, 12H-5, 11-methano-dibenzo[b, f][1, 5]diazocine-2, 8-diol (4b): Yield 87% (0.2965 g). White solid, m.p. 244.3~247.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.97 (d, J＝8.8 Hz, 2H), 6.71 (d, J＝8.8 Hz, 2H), 4.67 (s, 4H), 4.42 (d, J＝16.8 Hz, 2H), 4.23 (s, 2H), 3.92 (d, J＝16.8 Hz, 2H), 3.69 (s, 4H), 2.58 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 141.9, 137.5, 124.0, 122.6, 115.9, 107.4, 71.9, 55.8, 44.4, 35.8. HRMS (ESI) calcd for C₁₉H₂₄N₄O₂ 341.1978 [M+H]⁺, found 341.1977.

  1, 7-Bis((butylamino)methyl)-6H, 12H-5, 11-methanodi-benzo[b, f][1, 5]diazocine-2, 8-diol (4c): Yield 85% (0.3613 g). White solid, m.p. 159.3~161.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.95 (d, J＝8.8 Hz, 2H), 6.68 (d, J＝8.8 Hz, 2H), 4.74 (d, J＝2.4 Hz, 4H), 4.42 (d, J＝16.8 Hz, 2H), 4.22 (s, 2H), 3.91 (d, J＝17.2 Hz, 2H), 3.75 (s, 4H), 2.71 (s, 4H), 1.72 (s, 2H), 1.54 (s, 5H), 1.36 (d, J＝7.6 Hz, 6H), 1.27 (d, J＝7.0 Hz, 4H), 0.94 (t, J＝7.3 Hz, 7H); ¹³C NMR (100 MHz, CDCl₃) δ: 141.1, 139.2, 124.2, 122.8, 115.9, 107.4, 81.6, 55.8, 51.6, 47.5, 30.1, 20.3, 13.9. HRMS (ESI) calcd for C₂₅H₃₆N₄O₂ 425.2917 [M+H]⁺, found 425.2917.

  1, 7-Bis(((1-phenylethyl)amino)methyl)-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine-2, 8-diol (4d): Yield 89% (0.4654 g). White solid, m.p. 217.2~220.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.35~7.27 (m, 10H), 6.85 (d, J＝8.8 Hz, 2H), 6.64 (d, J＝8.8 Hz, 2H), 5.03 (d, J＝10.0 Hz, 2H), 4.73 (d, J＝10.2 Hz, 2H), 4.13 (t, J＝8.4 Hz, 4H), 3.90 (q, J＝6.4 Hz, 2H), 3.74~3.61 (m, 4H), 3.44~3.36 (m, 2H), 1.44 (t, J＝7.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 150.9, 144.4, 128.5, 127.3, 127.2, 125.6, 124.1, 117.3, 115.5, 79.31, 57.9, 55.8, 45.8, 21.4. HRMS (ESI) calcd for C₃₃H₃₆N₄O₂ 521.2915 [M+H]⁺, found 521.2917.

  1, 7-Bis(((pyridin-2-ylmethyl)amino)methyl)-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine-2, 8-diol (4e): Yield 90% (0.4461 g). White solid, m.p. 106.5~110.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.59 (s, 2H), 7.69 (s, 2H), 7.38 (d, J＝7.8 Hz, 2H), 7.22 (s, 2H), 6.92 (d, J＝8.8 Hz, 2H), 6.71 (d, J＝8.8 Hz, 2H), 4.80 (s, 4H), 4.33 (d, J＝16.8 Hz, 2H), 4.19 (s, 2H), 4.03 (s, 4H), 3.82~3.68 (m, 4H), 2.10 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 158.1, 150.3, 149.6, 136.7, 124.3, 123.1, 122.4, 116.9, 116.0, 82.1, 57.8, 55.8, 47.1. HRMS (ESI) calcd for C₂₉H₃₀N₆O₂ 495.2508 [M+H]⁺, found 495.2505.

  1, 7-Bis(((1-cyclohexylethyl)amino)methyl)-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine-2, 8-diol (4f): Yield 95% (0.5072 g). White solid, m.p. 172.0~173.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.92 (d, J＝8.8, 2H), 6.65 (d, J＝8.8 Hz, 2H), 4.81~4.70 (m, 4H), 4.41~4.36 (m, 2H), 4.22 (s, 2H), 3.91 (d, J＝16.8 Hz, 2H), 3.75~3.59 (m, 4H), 1.84~1.63 (m, 8H), 1.44~1.33 (m, 2H), 1.27~1.09 (m, 11H), 1.00~0.89 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 143.0, 136.9, 124.1, 123.8, 115.9, 81.9, 80.7, 66.1, 62.1, 61.4, 55.8, 44.7, 41.7, 41.4, 30.8, 28.8, 26.6, 26.4, 14.7, 14.1 HRMS (ESI) calcd for C₃₃H₄₈N₄O₂ 533.3856 [M+H]⁺, found 533.3885.

  1, 7-Bis(((4-methylcyclohexyl)amino)methyl)-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine-2, 8-diol (4g): Yield 91% (0.4613 g). White solid, m.p. 183.1~185.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.95 (d, J＝8.6 Hz, 2H), 6.65 (d, J＝8.8 Hz, 2H), 4.98~4.72 (m, 4H), 4.42 (d, J＝16.8 Hz, 2H), 4.23 (s, 2H), 3.95~3.66 (m, 6H), 2.60 (d, J＝12.2 Hz, 2H), 1.94 (d, J＝11.2 Hz, 4H), 1.72 (d, J＝12.2 Hz, 5H), 1.41~1.17 (m, 8H), 0.89~0.76 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.1, 137.8, 124.2, 122.8, 115.9, 106.8, 71.9, 60.0, 58.6, 43.5, 33.0, 31.8, 31.3, 20.7. HRMS (ESI) calcd for C₃₁H₄₄N₄O₂ 505.3543 [M+H]⁺, found 505.3594.

  1, 7-Bis(((3, 3-dimethylbutan-2-yl)amino)methyl)-6H, 12H-5, 11-methanodibenzo[b, f][1, 5]diazocine-2, 8-diol (4h): Yield 93% (0.4480 g). White solid, m.p. 176.3~178.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.86 (t, J＝7.8 Hz, 2H), 6.57~6.43 (m, 2H), 4.75~4.61 (m, 4H), 4.38~4.26 (m, 2H), 4.16 (d, J＝5.6 Hz, 2H), 3.84~3.50 (m, 6H), 2.61~2.54 (m, 2H), 0.95~0.76 (m, 24H); ¹³C NMR (100 MHz, CDCl₃) δ: 151.9, 123.7, 120.3, 119.8, 116.2, 84.5, 82.9, 67.0, 66.2, 66.1, 55.6, 47.1, 44.8, 36.6, 36.5, 26.6, 12.7, 12.5. HRMS (ESI) calcd for C₂₉H₄₄N₄O₂ 481.3579 [M+H]⁺, found 481.3543.

  1, 7-Bis((tert-butylamino)methyl)-6H, 12H-5, 11-meth-anodibenzo[b, f][1, 5]diazocine-2, 8-diol (4i): Yield 87% (0.3698 g). White solid, m.p. 165.4~167.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 6.94 (d, J＝8.8 Hz, 2H), 6.66 (d, J＝8.8 Hz, 2H), 4.90 (d, J＝9.8 Hz, 2H), 4.76 (d, J＝10.0 Hz, 2H), 4.44 (d, J＝16.8 Hz, 2H), 4.24 (s, 2H), 3.95 (d, J＝16.8 Hz, 2H), 3.84~3.70 (m, 2H), 2.06 (s, 2H), 1.29~1.21 (m, 18H); ¹³C NMR (100 MHz, CDCl₃) δ: 140.9, 138.5, 123.9, 122.8, 114.9, 109.4, 71.9, 61.2, 58.6, 40.4, 29.7. HRMS (ESI) calcd for C₂₅H₃₆N₄O₂ 425.2917 [M+H]⁺, found 425.2967.

  4.3   General procedure for compound 8

  Aromatic aldehyde 5 (1.0 mmol), propylene nitrile 6 (1.0 mmol), anhydrous ethanol 3 mL and KOH (10 mol%) were successively added to a 100 mL dry round-bottom flask. 7 was obtained by simple filtration after the completion and recrystallization with anhydrous EtOH.

  7 (1.0 mmol), 4-hydroxycoumarin (1.0 mmol), anhydrous ethanol 3 mL and 4e (10 mol%) were added to a 100 mL dry flask in turn, the target compound 8 was obtained by column chromatography (V_{petroleum ether}:V_{ethyl acetate}＝5:1 gradient elution) after the reaction was completed (TLC) at room temperature.

  2-Amino-4-(4-bromophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8a): Yield 92% (0.3647 g). White solid, m.p. 255.2~257.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J＝7.8 Hz, 1H), 7.73 (t, J＝7.6 Hz, 1H), 7.49~7.31 (m, 5H), 7.24 (s, 1H), 5.77 (s, 2H), 4.48 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.5, 157.9, 153.5, 152.1, 142.7, 133.2, 131.3, 129.9, 124.9, 122.4, 120.1, 116.5, 112.9, 103.3, 57.3, 54.9, HRMS (ESI) calcd for C₁₉H₁₁BrN₂O₃ 361.0699 [M－H]^－, found 361.0678.

  2-Amino-4-(4-methoxyphenyl)-5-oxo-4H, 5H-pyrano-[3, 2-c]chromene-3-carbonitrie (8b): Yield 93% (0.3228 g). White solid, m.p. 179.3~184.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.83 (d, J＝7.6 Hz, 2H), 7.65 (t, J＝7.6 Hz, 2H), 7.36~7.28 (m, 4H), 5.77 (s, 1H), 5.59 (s, 2H), 3.72 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 163.7, 157.2, 153.6, 136.4, 129.1, 128.6, 124.2, 121.4, 121.1, 115.4, 112.3, 97.2, 54.8, 20.2. HRMS (ESI) calcd for C₂₀H₁₄N₂O₄ 345.0875 [M－H]^－, found 345.0911.

  2-Amino-4-(4-fluorophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8c): Yield 87% (0.2921 g). White solid, m.p. 264.1~267.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J＝7.8 Hz, 1H), 7.72 (t, J＝7.4 Hz, 1H), 7.49~7.37 (m, 4H), 7.32~7.25 (m, 2H), 7.14 (t, J＝8.8 Hz, 2H), 4.49 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.2, 157.9, 153.9, 152.2, 139.3, 132.5, 129.6 (d, J＝8.4 Hz), 124.6, 122.8, 119.1, 116.6, 115.7, 115.2, 112.4, 103.4, 57.2. HRMS (ESI) calcd for C₁₉H₁₁FN₂O₄ 333.0675 [M－H]^－, found 333.0738.

  2-Amino-4-(3-methoxyphenyl)-5-oxo-4H, 5H-dihydro-pyrano[3, 2-c]chromene-3-carbonitrile (8d): Yield 85% (0.2947 g). White solid, m.p. 226.7~234.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J＝7.0 Hz, 1H), 7.73 (t, J＝7.4 Hz, 1H), 7.53~7.41 (m, 4H), 7.24 (t, J＝7.8 Hz, 1H), 6.86~6.77 (m, 3H), 4.43 (s, 1H), 3.73 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.5, 158.5, 157.9, 153.9, 152.5, 132.4, 130.69, 129.1, 128.4, 124.6, 122.6, 120.3, 116.4, 112.9, 111.3, 103.7, 56.9, 55.1, 32.1. HRMS (ESI) calcd for C₂₀H₁₄N₂O₄ 345.0875 [M－H]^－, found 345.0839.

  2-Amino-4-(2, 4-dichlorophenyl)-5-oxo-4H, 5H-dihydro-pyrano[3, 2-c]chromene-3-carbonitrile (8e): Yield 95% (0.3667 g). White solid, m.p. 234.9~239.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93~7.87 (m, 1H), 7.78~7.71 (m, 1H), 7.60 (d, J＝1.8 Hz, 1H), 7.57~7.47 (m, 4H), 7.37~7.25 (m, 2H), 4.98 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.3, 158.2, 154.6, 152.2, 133.5, 131.2, 128.7, 124.6, 122.5, 116.4, 112.5. HRMS (ESI) calcd for C₁₉H₁₀Cl₂N₂O₃ 382.9990 [M－H]^－, found 382.9929.

  2-Amino-5-oxo-4-(p-tolyl)-4H, 5H-pyrano[3, 2-c]chro-mene-3-carbonitrile (8f): Yield 93% (0.3082 g). White solid, m.p. 218.6~220.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90~7.87 (m, 1H), 7.75~7.68 (m, 1H), 7.49~7.28 (m, 2H), 7.42 (s, 2H), 7.15~7.09 (m, 4H), 5.77 (s, 2H), 4.40 (s, 1H), 2.26 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.1, 157.7, 153.3, 152.7, 140.7, 136.5, 132.9, 129.4, 127.8, 124.6, 122.3, 116.5, 112.4, 104.9, 58.2, 54.7, 20.9. HRMS (ESI) calcd for C₂₀H₁₄N₂O₃ 329.0926 [M－H]^－, found 329.0951.

  Methyl-2-amino-4-(4-cyanophenyl)-5-oxo-4H, 5H-Pyrano[3, 2-c]chromene-3-carboxylate (8g): Yield 84% (0.3152 g). White solid, m.p. 199.9~203.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.96 (s, 2H), 7.71 (s, 2H), 7.45 (s, 4H), 5.77 (s, 2H), 4.77 (s, 1H), 3.51 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.4, 159.4, 158.7, 153.8, 152.7, 150.9, 132.9, 132.8, 131.9, 129.8, 124.6, 123.9, 123.1, 122.7, 118.8, 116.6, 116.3, 113.0, 109.6, 105.4, 90.4, 75.2, 59.1, 14.1. HRMS (ESI) calcd for C₂₁H₁₄N₂O₅ 373.0824 [M－H]^－, found 373.0768.

  Ethyl-2-amino-4-(4-methoxyphenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carboxylate (8h): Yield 85% (0.3356 g). White solid, m.p. 179.6~181.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.08~7.74 (m, 2H), 7.58~7.33 (m, 2H), 7.31~7.03 (m, 4H), 6.78 (s, 2H), 5.29 (s, 1H), 4.90 (s, 2H), 3.77~3.52 (m, 6H), 2.51 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 163.6, 157.2, 153.6, 136.4, 129.1, 128.6, 124.62, 121.4, 121.1, 115.2, 112.3, 97.2, 54.8, 20.2, HRMS (ESI) calcd for C₂₂H₁₉N₁O₆ 392.1134 [M－H]^－, found 392.1127.

  Ethyl-2-amino-4-(4-cyanophenyl)-5-oxo-4H, 5H-pyrano-[3, 2-c]chromene-3-carboxylate (8i): Yield 87% (0.3387 g). White solid, m.p. 128.1~130.4 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.97 (s, 2H), 7.73 (s, 2H), 7.47 (s, 4H), 5.78 (s, 2H), 4.77 (s, 1H), 4.00 (s, 2H), 1.10 (s, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 167.5, 159.8, 158.6, 153.5, 152.6, 150.8, 132.6, 132.2, 129.5, 124.7, 122.7, 118.9, 116.6, 113.0, 109.4, 105.6, 75.4, 54.8, 50.4, HRMS (ESI) calcd for C₂₂H₁₆N₂O₅ 387.0981 [M－H]^－, found 387.1034.

  2-Amino-4-(4-cyanophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8j): Yield 93% (0.3188 g). White solid, m.p. 241.3~242.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.95 (d, J＝8.4 Hz, 2H), 7.84~7.81 (m, 1H), 7.65~7.57 (m, 3H), 7.38~7.31 (m, 2H), 5.54 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 165.7, 162.7, 153.6, 141.8, 132.7, 132.4, 129.6, 123.9, 123.4, 118.3, 116.4, 115.6, 112.6, 90.2, 52.5. HRMS (ESI) calcd for C₂₂H₁₆N₂O₅ 340.0722 [M－H]^－, found 340.0840.

  2-Amino-4-(4-chlorophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8k): Yield 90% (0.3164 g). White solid, m.p. 246.2~248.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.92~7.87 (m, 1H), 7.76~7.70 (m, 1H), 7.54~7.44 (m, 4H), 7.37 (d, J＝8.6 Hz, 2H), 7.31 (d, J＝8.6 Hz, 2H), 5.76 (s, 1H), 4.49 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.2, 157.1, 153.2, 152.4, 142.1, 133.1, 131.6, 129.1, 128.1, 124.8, 122.9, 119.7, 116.7, 112.1, 103.4, 57.4, 54.8. HRMS (ESI) calcd for C₁₉H₁₁Cl- N₂O₃ 349.0380 [M－H]^－, found 349.0399.

  2-Amino-4-(3-chlorophenyl)-5-oxo-4H, 5H-dihydro-pyrano[3, 2-c]chromene-3-carbonitrile (8l): Yield 92% (0.3238 g). White solid, m.p. 274.1~276.7 ℃; ¹HNMR (400 MHz, DMSO-d₆) δ: 7.91 (d, J＝7.2 Hz, 1H), 7.72 (d, J＝7.2 Hz, 1H), 7.57~7.44 (m, 4H), 7.30~7.12 (m, 4H), 4.52 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.5, 157.7, 153.3, 152.7, 140.7, 136.5, 132.9, 129.4, 127.8, 124.6, 122.3, 116.4, 112.4, 104.9, 58.2, 54.7, 36.2, 20.9. HRMS (ESI) calcd for C₁₉H₁₁ClN₂O₃ 349.0380 [M－H]^－, found 349.0352.

  2-Amino-4-(3-fluorophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8m): Yield 84% (0.2818 g). White solid, m.p. 219.6~222.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93~7.88 (m, 1H), 7.72 (s, 1H), 7.53~7.45 (m, 4H), 7.36 (s, 1H), 7.10~6.93 (m, 3H), 4.52 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.7, 157.4, 153.0, 152.8, 132.8, 130.3 (d, J＝8.2 Hz), 129.1, 124.6, 123.7, 122.5, 119.6, 116.5, 115.0, 114.9, 114.4, 112.7, 103.4, 57.4. HRMS (ESI) calcd for C₁₉H₁₁FN₂O₃ 333.0675 [M－H]^－, found 333.0763.

  2-Amino-4-(3-bromophenyl)-5-oxo-4H, 5H-dihydropy-rano[3, 2-c]chromene-3-carbonitrile (8n): Yield 90% (0.3565 g). White solid, m.p. 231.1~248.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J＝7.4 Hz, 1H), 7.73 (t, J＝7.4 Hz, 1H), 7.53~7.44 (m, 6H), 7.29 (d, J＝4.6 Hz, 2H), 4.50 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.6, 157.4, 153.1, 152.1, 146.2, 133.1, 131.9, 130.9, 130.5, 126.3, 124.5, 122.5, 121.8, 116.7, 112.8, 103.1, 57.2, 36.9. HRMS (ESI) calcd for C₁₉H₁₁BrN₂O₃ 392.9875 [M－H]^－, found 392.9854.

  2-Amino-5-oxo-4-phenyl-4H, 5H-pyrano[3, 2-c]chro-mene-3-carbonitrile (8o): Yield 95% (0.3011 g). White solid, m.p. 217.5~219.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 7.91 (d, J＝7.8 Hz, 1H), 7.72 (s, 1H), 7.53~7.41 (m, 4H), 7.34~7.29 (m, 2H), 7.27~7.21 (m, 3H), 4.45 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.3, 157.3, 153.4, 152.1, 143.1, 132.4, 128.9, 127.9, 126.7, 124.8, 122.5, 119.1, 116.6, 112.3, 103.6, 57.9. HRMS (ESI) calcd for C₁₉H₁₂N₂O₃ 315.0770 [M－H]^－, found 315.0772.

  2-Amino-4-(3, 4-dimethoxyphenyl)-5-oxo-4H, 5H-py-rano[3, 2-c]chromene-3-carbonitrile (8p): Yield 90% (0.3402 g). White solid, m.p. 159.4~164.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.80~7.78 (m, 1H), 7.42~7.29 (m, 3H), 7.05~6.68 (m, 3H), 5.76 (s, 1H), 4.41 (s, 1H), 3.88~3.64 (m, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.9, 151.80, 146.6, 136.0, 135.0, 132.5, 124.3, 123.6, 121.8, 120.0, 119.2, 116.5, 113.9, 103.2, 59.1, 55.7, 32.7, 25.6, 20.2. HRMS (ESI) calcd for C₂₁H₁₆N₂O₅ 375.0981 [M－H]^－, found 375.0951.

  2-Amino-5-oxo-4-(3, 4, 5-trimethoxyphenyl)-4H, 5H-dihydropyrano[3, 2-c]chromene-3-carbonitrile (8q): Yield 93% (0.3792 g). White solid, m.p. 226.6~228.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.90 (d, J＝7.8 Hz, 1H), 7.74 (s, 1H), 7.55~7.46 (m, 2H), 7.41 (s, 2H), 6.52 (s, 2H), 4.44 (s, 1H), 3.72 (s, 6H), 3.63 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.4, 159.1, 157.3, 153.9, 152.9, 152.1, 139.4, 136.8, 132.3, 131.1, 124.9, 122.1, 119.5, 116.1, 113.5, 104.7, 103.1, 59.8, 57.1, 55.5, 40.7, 39.8, 39.5, 39.4, 39.3, 39.2, 38.8, 36.8. HRMS (ESI) calcd for C₂₂H₁₈N₂O₆ 405.1087 [M－H]^－, found 405.1066.

  2-Amino-4-(2, 3-dimethoxyphenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carbonitrile (8r): Yield 89% (0.3353 g). White solid, m.p. 206.9~210.7 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.91 (d, J＝6.8 Hz, 1H), 7.83~7.80 (m, 1H), 7.72 (t, J＝7.2 Hz, 1H), 7.47 (d, J＝8.2 Hz, 1H), 7.40~7.30 (m, 2H), 7.11 (s, 1H), 6.99~6.90 (m, 2H), 4.70 (s, 1H), 3.78 (d, J＝4.2 Hz, 3H), 3.71 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 159.9, 151.8, 146.6, 136.0, 135.7, 132.5, 124.3, 123.6, 122.8, 120.9, 119.6, 116.2, 113.1, 103.2, 59.1, 55.7, 20.2. HRMS (ESI) calcd for C₂₁H₁₆N₂O₅ 375.0981 [M－H]^－, found 375.0954.

  Ethyl-2-amino-4-(3-nitrophenyl)-5-oxo-4H, 5H-pyrano-[3, 2-c]chromene-3-carboxylate (8s): Yield 81% (0.3316 g). White solid, m.p. 253.5~255.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.05 (d, J＝7.4 Hz, 2H), 8.00 (d, J＝7.5 Hz, 3H), 7.72~7.68 (m, 2H), 7.59~7.49 (m, 3H), 7.47 (d, J＝8.4 Hz, 1H), 4.82 (s, 2H), 3.98 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 160.8, 158.8, 156.3, 153.7, 146.5, 128.7, 122.8, 122.7, 120.9, 116.4, 115.8, 59.3. HRMS (ESI) calcd for C₂₁H₁₆N₂O₇ 407.0879 [M－H]^－, found 407.0880.

  2-Amino-4-(3-nitrophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]-chromene-3-carbonitrile (8t): Yield 86% (0.3121 g). White solid, m.p. 219.6~222.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J＝8.8 Hz, 2H), 7.92 (s, 1H), 7.82 (d, J＝7.8 Hz, 1H), 7.77(s, 1H), 7.63~7.56 (m, 3H), 7.55~7.47 (m, 2H), 4.74 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 184.4, 159.5, 157.7, 153.3, 152.7, 140.7, 136.5, 132.9, 129.4, 127.8, 124.6, 122.3, 116.4, 112.4, 104.9, 58.2, 54.7, 20.9. HRMS (ESI) calcd for C₁₉H₁₁N₃O₅ 361.0699 [M－H]^－, found 361.0678.

  Methyl-2-amino-4-(3, 5-dichlorophenyl)-5-oxo-4H, 5H-pyrano[3, 2-c]chromene-3-carboxylate (8u): Yield 88% (0.3689 g). White solid, m.p. 168.3~171.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.93 (s, 1H), 8.62 (s, 1H), 8.44 (t, J＝6.6 Hz, 2H), 7.94~7.77 (m, 1H), 7.48 (s, 1H), 7.23 (t, J＝8.2 Hz, 1H), 4.82 (s, 1H), 3.89 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.2, 162.7, 159.2, 158.6, 147.0, 128.3, 125.7, 123.1, 122.4, 121.1, 117.5, 115.6, 108.4, 79.5, 56.4, 39.0. HRMS (ESI) calcd for C₂₀H₁₃Cl₂NO₅ 416.0093 [M－H]^－, found 416.0436.

  4.4   General procedure for compound 10

  Aromatic aldehyde 5 (1.0 mmol), compound 9 (1.0 mmol), 4-hydroxycoumarin (1.0 mmol), catalyst 4e (5 mol%), palladium dichloride (5 mol%) and toluene 3 mL were added to a 50 mL dry round-bottom flask in turn and stirred at 110 ℃. By the end of the reaction (TLC), a small amount of water was added, extracted with ethyl acetate, combined with organic phase, removed excess solvent and purified by column chromatography (V_{petroleum ether}:V_{ethyl acetate}＝1:1 gradient elution) to give compound 10.

  7-(2-Methoxyphenyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano[2, 3-b]indol-6-one (10a): Yield 95% (0.3761 g). White solid, m.p. 213.1~215.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.79 (d, J＝7.6 Hz, 2H), 7.46 (t, J＝7.8 Hz, 2H), 7.21 (d, J＝8.4 Hz, 5H), 7.07 (s, 1H), 6.78 (s, 2H), 6.21 (s, 1H), 3.53 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.4, 164.8, 152.7, 131.5, 130.4, 129.4, 126.8, 124.5, 123.6, 120.6, 119.8, 115.6, 111.8, 104.1, 55.9, 19.2. HRMS (APCI) calcd for C₂₅H₁₇NO₄ 396.1236 [M+H]⁺, found 396.1218.

  7-(2, 3-Dimethoxyphenyl)-7, 12-dihydro-6H-chromeno-[3', 4':5, 6]pyrano[2, 3-b]indol-6-one (10b): Yield 93% (0.3969 g). White solid, m.p. 210.7~215.8 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.80 (d, J＝6.4 Hz, 2H), 7.45 (s, 2H), 7.21 (s, 4H), 6.87~6.77 (m, 3H), 6.28 (s, 1H), 3.71 (s, 3H), 3.43 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.3, 164.2, 152.7, 146.7, 137.7, 131.3, 124.3, 123.2, 122.5, 121.6, 120.4, 115.7, 110.7, 104.2, 59.7, 55.9. HRMS (APCI) calcd for C₂₆H₁₉NO₅ 426.1341 [M+H]⁺, found 426.1309.

  7-(4-Hydroxyphenyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano[2, 3-b]indol-6-one (10c): Yield 92% (0.3520 g). White solid, m.p. 188.8~190.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (s, 1H), 7.80~7.69 (m, 2H), 7.57~7.43 (m, 2H), 7.23 (s, 4H), 6.86 (d, J＝7.8 Hz, 2H), 6.55 (d, J＝8.6 Hz, 2H), 6.14 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.2, 165.3, 152.2, 131.3, 127.8, 124.4, 120.48, 115.6, 114.4, 104.6, 56.4.

  7-Phenyl-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano-[2, 3-b]indol-6-one (10d): Yield 90% (0.3296 g). White solid, m.p. 181.5~184.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.81 (d, J＝6.8 Hz, 2H), 7.50~7.41 (m, 2H), 7.24 (s, 4H), 7.19~7.13 (m, 2H), 7.07~6.91 (m, 3H), 6.26 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.6, 165.3, 152.6, 142.3, 131.6, 128.4, 127.1, 125.5, 124.8, 123.3, 120.9, 115.1, 103.6.

  7-(p-Tolyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]py-rano[2, 3-b]indol-6-one (10e): Yield 96% (0.3657 g). Yellow solid, m.p. 189.7~190.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.80 (d, J＝7.4 Hz, 2H), 7.50 (t, J＝7.2 Hz, 2H), 7.23~7.18 (m, 4H), 6.96 (s, 4H), 6.21 (s, 1H), 2.22 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 165.1, 152.9, 131.2, 128.7, 127.3, 124.5, 123.3, 120.4, 115.8, 103.9, 55.3, 20.9.

  7-(4-Fluorophenyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano[2, 3-b]indol-6-one (10f): Yield 94% (0.3611 g). Yellow solid, m.p. 183.6~185.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.81~7.73 (m, 2H), 7.53~7.47 (m, 2H), 7.22-7.03 (m, 4H), 7.09~7.02 (m, 2H), 6.97 (t, J＝8.8 Hz, 2H), 6.23 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.1, 164.9, 152.9, 138.7 (d, J＝7.8 Hz), , 131.4, 128.7, 123.3, 120.3, 115.9, 114.7, 103.8, 55.3, 14.5.

  7-(4-Bromophenyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]pyrano[2, 3-b]indol-6-one (10g): Yield 96% (0.4278 g). Yellow solid, m.p. 196.4~197.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.86~7.78 (m, 2H), 7.54~7.43 (m, 2H), 7.34 (d, J＝8.6 Hz, 2H), 7.29~7.18 (m, 4H), 7.04 (d, J＝7.6 Hz, 2H), 6.20 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.2, 164.8, 152.9, 131.4, 130.9, 129.4, 124.5, 123.3, 120.2, 115.9, 55.3.

  4-(6-oxo-7, 12-Dihydro-6H-chromeno[3', 4':5, 6]pyrano-[2, 3-b]indol-7-yl)benzonitrile (10h): Yield 92% (0.3596 g). White solid, m.p. 188.3~187.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.81~7.69 (m, 2H), 7.64 (d, J＝8.4 Hz, 2H), 7.56~7.50 (m, 2H), 7.31~7.22 (m, 6H), 6.31 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.1, 164.8, 152.9, 132.2, 131.7, 128.2, 124.5, 123.5, 119.9, 116.5, 103.2, 55.3.

  7-(2-Nitrophenyl)-7, 12-dihydro-6H-chromeno[3', 4':5, 6]-pyrano[2, 3-b]indol-6-one (10i): Yield 90% (0.3702 g). Yellow solid, m.p. 186.4~187.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.00 (d, J＝8.0 Hz, 1H), 7.88 (s, 1H), 7.82~7.68 (m, 2H), 7.59~7.54 (m, 2H), 7.50~7.41 (m, 2H), 7.33~7.26 (m, 2H), 7.22~7.14 (m, 2H), 6.35 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.4, 153.5, 148.2, 131.7, 124.6, 123.5, 121.1, 116.5, 103.8, 55.3, 14.5.

  4.5   General procedure for compound 12

  Product 12 was obtained by repeating the synthesis process of 10 via replacing aldehyde with isatin.

  5'-Chloro-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12a): Yield 88% (0.3884 g). White solid, m.p. 220.5~222.1 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.00 (s, 1H), 8.48 (d, J＝6.8 Hz, 2H), 7.87~7.80 (m, 2H), 7.59 (t, J＝7.4 Hz, 2H), 7.53 (d, J＝8.4 Hz, 2H), 7.47 (d, J＝2.0 Hz, 1H), 7.26 (s, 1H), 6.86 (d, J＝8.4 Hz, 1H), 5.76 (s, 1H); ¹³C NMR (100 MHz, DMSO-d6) δ 168.2, 161.9, 152.5, 151.9, 136.5, 133.2, 130.4, 129.6, 129.2, 128.3, 127.9, 127.4, 125.4, 123.3, 121.7, 119.8, 118.8, 117.4, 116.4, 111.3, 108.8, 97.9, 54.2.

  5', 7'-Dimethyl-6H, 12H-spiro[chromeno[3', 4':5, 6]py-rano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12b): Yield 85% (0.3702 g). Red solid, m.p. 187.5~189.3 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.37 (s, 1H), 8.47 (s, 1H), 7.87~7.75 (m, 2H), 7.63~7.52 (m, 2H), 7.55 (s, 1H), 7.37 (s, 2H), 7.22 (s, 1H), 6.86 (s, 1H), 2.16~1.96 (m, 3H), 1.41~1.21 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.1, 160.2, 154.2, 152.4, 133.9, 131.9, 129.5, 128.7, 128.1, 126.8, 125.7, 124.4, 121.4, 119.8, 118.5, 116.9, 115.6, 113.3, 105.8, 91.4, 42.7, 30.6, 22.6, 19.1, 15.8, 11.7.

  5'-Bromo-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12c): Yield 90% (0.4387 g). White solid, m.p. 179.5~181.9 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.01 (s, 1H), 8.47 (d, J＝6.8 Hz, 2H), 7.82~7.74 (m, 2H), 7.58 (t, J＝7.6 Hz, 3H), 7.52 (d, J＝8.2 Hz, 2H), 7.38 (s, 1H), 6.82 (d, J＝8.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.2, 165.6, 155.3, 154.1, 133.1, 131.2, 130.6, 129.6, 129.1, 127.3, 127.1, 126.5, 125.8, 121.2, 119.7, 118.5, 117.8, 115.3, 110.3, 109.6.

  5'-Methyl-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12d): Yield 82% (0.3464 g). Yellow solid, m.p. 185.3~188.6 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.75 (s, 1H), 8.47 (d, J＝7.0 Hz, 2H), 7.82 (t, J＝7.2 Hz, 2H), 7.58 (t, J＝7.6 Hz, 2H), 7.51 (d, J＝8.4 Hz, 2H), 7.07 (s, 1H), 7.00 (d, J＝7.8 Hz, 1H), 6.73 (d, J＝7.8 Hz, 1H), 2.12 (s, 2H), 1.91 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.2, 161.9, 152.5, 151.9, 138.1, 136.5, 134.5, 131.7, 128.3, 125.4, 123.3, 121.7, 119.8, 118.8, 117.4, 116.4, 115.3, 111.1, 108.8, 97.9, 55.0, 21.6.

  5'-Methoxy-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano-[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12e): Yield 89% (0.3897 g). Yellow solid, m.p. 197.5~199.2 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.67 (s, 1H), 8.47 (d, J＝8.0 Hz, 2H), 7.82 (t, J＝7.8 Hz, 2H), 7.58 (t, J＝7.4 Hz, 2H), 7.52 (d, J＝8.2 Hz, 2H), 6.98 (s, 1H), 6.75 (s, 2H), 3.59 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.2, 161.9, 156.7, 152.5, 151.9, 136.5, 133.4, 128.8, 128.3, 127.4, 125.4, 121.7, 119.8, 118.8, 117.4, 116.4, 111.5, 108.8, 97.9, 55.0, 55.8.

  5'-Nitro-6H, 12H-spiro[chromeno[3', 4':5, 6]pyrano[2, 3-b]indole-7, 3'-indoline]-2', 6-dione (12f): Yield 85% (0.3841 g). Red solid, m.p. 195.4~197.5 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.51 (d, J＝7.8 Hz, 1H), 7.85~7.78 (m, 2H), 7.51~7.43 (m, 2H), 7.24 (s, 3H), 7.19~7.13 (m, 1H), 7.12~7.03 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.1, 161.9, 152.5, 151.9, 147.2, 144.1, 136.5, 133.9, 131.9, 128.3, 127.4, 126.2, 125.4, 124.1, 123.0, 121.7, 119.8, 118.8, 116.8, 91.4, 42.7, 11.2.

  Supporting Information ¹H NMR and ¹³C NMR spectra of compounds 4, 8, 10 and 12. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
• 1. [1]

     Hassanpour, A.; Hosseinzadeh-Khanmiri, R.; Ghorbanpour, K.; Abolhasani, J.; Oskoei, Y. M. Iran. J. Chem. Chem. Eng. 2016, 35, 39.

  2. [2]

     Manvar, A.; Bavishi, V.; Radadiya, A.; Patel, J.; Vora, V.; Dodia, N.; Rawal, K.; Shah, A. Bioorg. Med. Chem. 2011, 16, 4728.

  3. [3]

     Vekariya, H. R.; Patel, D. H. Synth. Commun. 2014, 44, 2756. doi: 10.1080/00397911.2014.926374

  4. [4]

     Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem. 2011, 7, 1937.

  5. [5]

     Zheng, Y.; Qiu, L.; Hong, K.; Dong, S.; Xu, X. Chem. Eur. J. 2018, 24, 6705. doi: 10.1002/chem.201704759

  6. [6]

     Zaki, R. M.; Elossaily, Y. A.; Kamal El-Dean, A. M. Russ. J. Bioorg. Chem. 2012, 38, 639. doi: 10.1134/S1068162012040152

  7. [7]

     Zolfigol, M. A.; Safaiee, M.; Bahraminejad, N. J. New J. Chem. 2016, 40, 5071. doi: 10.1039/C6NJ00243A

  8. [8]

     Brahmachari, G.; Banerjee, B. ACS Sustain. Chem. Eng. 2013, 2, 411.

  9. [9]

     Keri, R. S.; Sasidhar, B. S.; Nagaraja, B.; Santos, M. M. Eur. J. Org. Chem. 2015, 100, 257.

  10. [10]

      Chen, C.; Lu, M.; Liu, Z.; Wan, J.; Tu, Z.; Zhang, T.; Yan, M. Open J. Med. Chem. 2013, 3, 128.

  11. [11]

      Nasr, T.; Bondock, S.; Youns, M. Eur. J. Med. Chem. 2014, 76, 539. doi: 10.1016/j.ejmech.2014.02.026

  12. [12]

      Wickel, S. M.; Citron, C. A.; Dickschat, J. S. Eur. J. Org. Chem. 2013, 14, 2906.

  13. [13]

      Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. A. Eur. J. Med. Chem. 2009, 44, 3805. doi: 10.1016/j.ejmech.2009.04.017

  14. [14]

      Khaleghi-Abbasabadi, M.; Azarifar, D. Res. Chem. Intermed. 2019, 45, 2095. doi: 10.1007/s11164-018-03722-y

  15. [15]

      Sabbaghan, M.; Sofalgar, P. Comb. Chem. High Throughput Screening 2015, 18, 901. doi: 10.2174/1386207318666150224112853

  16. [16]

      Nagaraju, S.; Paplal, B.; Sathish, K.; Giri, S.; Kashinath, D. Tetrahedron Lett. 2017, 58, 4200. doi: 10.1016/j.tetlet.2017.09.060

  17. [17]

      Chen, Z. W.; Zhang, N.; Wang, Z. H.; Su, W. K. Chin. Chem. Lett. 2013, 24, 199. doi: 10.1016/j.cclet.2013.01.033

  18. [18]

      Tröger, J. J. Prakt. Chem. 1887, 36, 225. doi: 10.1002/prac.18870360123

  19. [19]

      Veale, E. B.; Frimannsson, D. O.; Lawler, M.; Gunnlaugsson, T. Org. Lett. 2009, 11, 4040. doi: 10.1021/ol9013602

  20. [20]

      Li, W.; Michinobu, T. Chem. Phys. 2016, 217, 863.

  21. [21]

      李明琪, 硕士论文, 江苏师范大学, 徐州, 2018.Li, M. Q. M.S. Thesis, Jiangsu Normal University, Xuzhou, 2018 (in Chinese).

  22. [22]

      Yuan, R.; Li, M. Q.; Xu, J. B.; Huang, S. Y.; Zhou, S. L.; Zhang, P.; Liu, J. J.; Wu, H. Tetrahedron 2016, 72, 4081. doi: 10.1016/j.tet.2016.05.042

  23. [23]

      Lo, Q. A.; Sale, D.; Braddock, D. C.; Davies, R. P. ACS Catal. 2018, 8, 101. doi: 10.1021/acscatal.7b03664

  24. [24]

      Malik, Q. M.; Ijaz, S.; Craig, D. C.; Try, A. C. Tetrahedron 2011, 67, 5798. doi: 10.1016/j.tet.2011.05.128

• 

  Figure 1  Structure of Tröger's base

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  Scheme 1  Synthesis of series of TBs 4

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  Scheme 2  Synthesis of 2-amino-4-aryl-5-oxo-4H, 5H-pyrano- [3, 2-c]chromene-3-carbonitriles (8)

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  Scheme 3  Synthesis of product 10

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  Scheme 4  Synthesis of product 12

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  Scheme 5  A possible mechanism for the synthesis of product 8

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  Scheme 6  A possible mechanism for the synthesis of product 10

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  Table 1.  Synthesis and pH value of TBs 4

  Compd.	R	Yield/%	pHa
  TB	—	80	6.07
  4a	Cyclohexyl	83	6.30
  4b	Methyl	87	6.25
  4c	Butyl	85	6.16
  4d	1-Phenylmethyl	89	7.18
  4e	Pyridin-2-methyl	90	7.33
  4f	1-Cyclohexyl-1-methyl	95	7.24
  4g	4-Methylcyclohexyl-	91	6.95
  4h	3, 3-DiMethyl-2-butyl	93	7.14
  4i	tert-Butyl	87	6.94
  a Test solution was prepared by dissolving 0.01 mmol of compounds in apropos amount of anhydrous ethanol and diluting to 10.0 mL with anhydrous ethanol.

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  Table 2.  Synthesis of product 8a under different condition^a

  Entry	4	Cat./mol%	Solvent	t/h	Yield/%
  1	—	—	CH3CN	12	—
  2	TB	10	CH3CN	12	15
  3	4a	10	CH3CN	12	43
  4	4b	10	CH3CN	12	56
  5	4c	10	CH3CN	12	52
  6	4d	10	CH3CN	12	49
  7	4e	10	CH3CN	12	81
  8	4f	10	CH3CN	12	59
  9	4g	10	CH3CN	12	47
  10	4h	10	CH3CN	12	55
  11	4e	10	CH2Cl2	12	53
  12	4e	10	Et2O	12	78
  13	4e	10	EtOH	12	92
  14	4e	10	CHCl3	12	47
  15	4e	1	EtOH	12	53
  16	4e	5	EtOH	12	70
  17	4e	20	EtOH	12	93
  18	4e	10	EtOH	6	75
  19	4e	10	EtOH	8	92
  20	4e	10	EtOH	10	92
  a Unless otherwise noted, the reactions were carried out by using 7a (1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) at room temperature.

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  Table 3.  Synthesis of product 8 under the optimum condition

  Compd.	R1	R2	Yield/%
  8a	p-Br	CN	92
  8b	p-OCH3	CN	93
  8c	p-F	CN	87
  8d	o-OCH3	CN	85
  8e	2, 4-Cl2	CN	95
  8f	p-CH3	CN	93
  8g	CN	COOMe	84
  8h	p-OCH3	COOEt	85
  8i	CN	COOEt	87
  8j	CN	CN	93
  8k	p-Cl	CN	90
  8l	o-Cl	CN	92
  8m	o-F	CN	84
  8n	o-Br	CN	90
  8o	H	CN	95
  8p	3, 4-(OCH3)2	CN	90
  8q	3, 4, 5-(OCH3)3	CN	93
  8r	2, 3-(OCH3)2	CN	89
  8s	o-NO2	COOEt	81
  8t	o-NO2	CN	86
  8u	2, 4-Cl2	COOMe	88

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  Table 4.  Synthesis of product 10a under different conditions^a

  Entry	4	Cat./mol%	t/h	Yield/%
  1	—	—	12	—
  2	TB	10	12	37
  3	4a	10	12	63
  4	4b	10	12	71
  5	4c	10	12	59
  6	4d	10	12	53
  7	4e	10	12	76
  8	4f	10	12	69
  9	4g	10	12	75
  10	4h	10	12	58
  11	4e	1	12	53
  12	4e	5	12	73
  13	4e	5	10	55
  14	4e	5	14	82
  15	4e	5	16	95
  16	4e	5	18	95
  a Unless otherwise noted, the reactions were carried out by using aromatic aldehyde (5, 1.0 mmol), 2-(2-iodo(or bromo)phenyl)acetonitrile (9, 1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) in toluene at room temperature.

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  Table 5.  The result of synthesis of product 10 under the opti- mum condition

  Product	R	X	Yield/%
  10a	2-OCH3	2-I	95
  10b	2, 3-(OCH3)2	2-I	93
  10c	4-OH	2-I	92
  10d	4-Br	2-I	90
  10e	4-CH3	2-Br	96
  10f	4-F	2-Br	94
  10g	4-Br	2-Br	96
  10h	4-CN	2-Br	92
  10i	3-NO2	2-Br	90

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  Table 6.  The result of synthesis of product 12^a

  Compd.	R	Yield/%
  12a	5-Cl	88
  12b	5, 7-(CH3)2	85
  12c	5-Br	90
  12d	5-CH3	82
  12e	5-OCH3	89
  12f	5-NO2	85
  a Unless otherwise noted, the reactions were carried out by using isatins (11, 1.0 mmol), 2-(2-iodo(or bromo)phenyl)acetonitrile (9, 1.0 mmol) and 4-hydroxycoumarin (1.0 mmol) and 4e (5 mol %) as ligand, PbCl2 (5 mol %) as catalysts in DMSO (3 mL) at 110 ℃.

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  Table 7.  Inhibition rate (%) of compounds 4 and 8^a

  Compd.	LO2	MCF-7	231	HepG2	MHCC97H
  4b	34.29	30.84	—	—	—
  4d	32.09	—	37.00	—	—
  4e	47.14	—	40.93	—	—
  8a	76.28	50.21	32.45	80.21	63.08
  8c	46.02	—	—	38.70	34.16
  8d	44.16	33.31	33.35	—	—
  8e	89.06	71.62	82.23	79.64	61.09
  8l	41.92	30.91	—	—	—
  8m	72.64	40.45	42.62	82.43	75.21
  8n	74.90	48.60	53.01	78.97	74.61
  8q	68.63	36.81	—	85.94	70.40
  Paclitaxel	47.86	89.70	65.83	80.09	42.37
  a Data less than 30% was showed as "—".

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