Diastereoselective Construction of Indole-Bridged Chroman

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Diastereoselective Construction of Indole-Bridged Chroman Spirooxindoles through a TfOH-Catalyzed Michael Addition-Inspired Cascade Reaction Jiaomei Guo, Xuguan Bai, Qilin Wang, and Zhanwei Bu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00035 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 14, 2018

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The Journal of Organic Chemistry

Diastereoselective Construction of Indole-Bridged Chroman Spirooxindoles through a TfOH-Catalyzed Michael Addition-Inspired Cascade Reaction

Jiaomei Guo, Xuguan Bai, Qilin Wang,* and Zhanwei Bu*

Institute of Functional Organic Molecular Engineering, College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475004, China. E-mail: [email protected]; [email protected] Table of Contents Graphic

Abstract: The first highly diastereoselective Michael addition/condensation/Friedel-Crafts alkylation cascade reaction of 3-indolyl substituted oxindoles with ortho-hydroxychalcones was established, which afforded a wide range of polycyclic indole-bridged chroman spirooxindoles with novel and complex scaffolds in moderate to excellent yields.

INTRODUCTION

Cascade reaction, in which two or more consecutive reactions occur to form multiple bonds in a one-pot fashion and only a single solvent, workup procedure and purification step is needed, has become an attractive tool to achieve promising molecules containing biologically relevant structures.1 Polycyclic indoles represent an important and unique class of privileged structural cores with wide distribution in

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natural products and pharmaceuticals as well as material science.2 Consequently, considerable efforts have been directed toward the development of efficient approaches for their synthesis and many great achievements have been made, including Fischer indolizaiton,3 cycloadditions of vinylindoles4 and 2- or 3-indolylmethanols,5 Friedel-Crafts alkylation of indole derivatives,6 Pictet-Spengler reaction of tryptamines and tryptophols,7 and others.8 Despite these elegant works, expensive reagents and harsh reaction conditions are often needed in these reactions. Moreover, most of them focused on the construction of polycyclic indoles with only one additional new-formed cycle beside indolic ring via cyclization process. To our knowledge, however, studies on the synthesis of polycyclic indoles with the concomitant formation of two rings, one of which is a bridged ring, through a one-pot domino reaction from simple starting materials, have not been reported. The lack of efficient methods for the synthesis of polycyclic indoles fused with a bridged ring may be due to the structural complexity, diversity and rigidity although they often possess important bioactivities.9 Thus, development of a general and robust approach for the synthesis of this kind of compound with more complex and rigid bridged-ring skeletons would be highly desirable and challenging.

On the other hand, spirooxindoles are also attractive structural units both from synthetic and biological points of view.10 As such, the construction of such scaffolds has gained much attention from organic chemists and numerous elegant protocols have been achieved. However, these protocols mainly focused on the synthesis of spiro monocyclic oxindoles11 and spiro fused oxindoles.12 And creation of spiro bridged cyclic oxindoles has lagged far behind,13 although they often show significant bioactivities.14 Moreover, among the existing limited methods for the synthesis of spiro bridged cycle oxindoles, only one new ring was formed in most cases, which may restrict the diversity and complexity of the final products. Thus, establishing a facile method for the synthesis of more complex and diverse spirooxindoles with concomitant formation of multiple rings, one of which is bridged ring, remains a compelling objective.


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In light of the medicinal relevance of bridged polycyclic indoles and spirooxindoles, we envisioned that the combination of them into one molecule would generate a kind of new compounds with more complex and diverse structures, which will not only inherit the structures and properties of both scaffolds, but also award unforeseen benefits to medicinal chemistry. However, a protocol for the construction of this kind of compounds has not been established till now. To fill the void and as a continuation of our interest in the construction of spirooxindoles,15 3-indolyl substituted oxindoles16 were firstly employed as competent 1,3-bisnucleophiles to react with ortho-hydroxychalcones via a Michael addition-inspired quadruple cascade reaction, enabling the efficient and highly diastereoselective synthesis of a series of novel indole-bridged chroman spirooxindoles. As outlined in Scheme 1, the reaction was proposed to be initiated by a Michael addition to generate intermediate A, and sequentially, an intramoleculer condensation occurred, affording an oxocarbenium ion B. Finally, a Friedel-Crafts alkylationtook place between the C2 position of indole ring and the oxocarbenium ion to yield the desired polycyclic indole-bridged chroman spirooxindoles. In this transformation, two new rings, including a bridged ring, were constructed simultaneously in a one-pot manner. However, some inherent challenges still remain to be addressed in this transformation. For example, the C3-position of the oxindole core of 3-indolyl substituted oxindole had relatively low reactivity due to the presence of indole moiety. Herein, for the first time we report a highly diastereoselective synthesis of polycyclic indole-bridged chroman spirooxindoles by a TfOH-catalyzed Michael addition-inspired quadruple cascade reaction.

Scheme 1 Our synthetic design for the synthesis of polycyclic indole-bridged chroman spirooxindoles via a Michael addition-inspired quadruple cascade



RESULTS AND DISCUSSION Initially, 3-(1H-indol-3-yl)-1-methylindolin-2-one 1a and ortho-hydroxychalcone 2a were selected as the model substrates to examine the feasibility of the Michael addition-inspired quadruple cascade reaction. To our delight, the reaction proceeded well in the presence of Cu(OTf)2 in acetonitrile at 60 oC, delivering the desired product 3a in 28% yield (Table 1, entry 1). Apart from the polycyclic indole spirooxindole scaffold, a chroman core was incorporated into 3a, which was also important structural unit frequently encountered in biologically active natural products and pharmaceuticals.17 To improve the synthetic efficiency, some other catalysts, including Lewis acid and protonic acids, were tested (Table 1, entries 2-8). The reactions could not occur in the presence of FeCl3, Zn(OTf)2 and TFA. Among them, TfOH proved to be the best of choice, giving 3a in 45% yield (Table 1, entry 6). The substrate ratios had a profound influence on the yield. When 2.2 equivalent of 1a was employed, the yield could be improved to 64% (Table 1, entry 9). A much better result was obtained when the reaction was conducted in 80 oC for 48 h (71% yield, Table 1, entry 10). Subsequently, the reaction media, including toluene, dioxane and 1,2-DCE, was investigated to further improve the yield. Unfortunately, all gave inferior results compared with the one obtained in CH3CN (Table 1, entries 10 vs 11-13). Prolonged reaction time was beneficial, and 82% yield was achieved when the reaction was conducted at 80 oC for 72 h (Table 1, entries 10 vs 14).

Table 1. Optimization of reaction conditionsa


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entry

Cat.

solvent

time (h)

yieldb (%)

1

Cu(OTf)2

CH3CN

48

28

2

Fe(OTf)3

CH3CN

48

31

3

FeCl3

CH3CN

48

n.r.

4

Zn(OTf)2

CH3CN

48

n.r.

5

TFA

CH3CN

48

n.r.

6

TfOH

CH3CN

48

45

7

MsOH

CH3CN

48

27

8

p-TSA

CH3CN

48

34

c

TfOH

CH3CN

48

64

10c,d

TfOH

CH3CN

48

71

c,d

TfOH

toluene

48

66

c,d

12

TfOH

dioxane

48

44

13c,d

TfOH

1,2-DCE

48

66

c,d

TfOH

CH3CN

72

82

9

11

14 a

Unless otherwise noted, the reaction was conducted with 0.12 mmol 2a and 1.2 equivalent of

1a in 1 mL specified solvent at 60 oC. b Isolated yield obtained by column chromatography. c The ratio of 1a to 2a is 2.2:1. d At 80 oC. TfOH = trifluoromethanesulfonic acid; TFA = trifluoroacetic acid; p-TSA = p-toluenesulfonic acid.

With the optimized reaction condition in hand, the substrate scope with 3-indolyl oxindoles 1 bearing different substitution patterns was investigated and the results were outlined in Table 2. Generally, the reactions proceeded smoothly for all cases, delivering 3a-s in moderate to excellent yields. Initially, the effect of the N-protecting group of oxindole core was studied and the results indicated that the bulkiness of the N-substituents had significant influence on the yields. The yields dropped sharply with the increase of the bulkiness. When N-benzyl substituted 3-indolyl



oxindole 1f was employed, only 42% yield of 3f was obtained. When the R2 substituents on the aromatic rings of 1 were altered, regardless of the substitution patterns and electronic nature, moderate to good yields (56-85%) were obtained for products 3g-o. In addition, 1p-s bearing Cl, Br and methyl group at the indole moiety were also compatible, allowing the synthesis of 3p-s in 45-90% yields. Table 2. Scope of substrates with respect to 3-indolyl oxindolesa

a

Unless otherwise noted, the reaction was conducted with 0.12 mmol 2a and 2.2 equivalent of 1 in 1 mL CH3CN

at 80 oC for 72 h.

b

Isolated yield obtained by column chromatography. c Isolated yield obtained by filtration of

precipitate.


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Then, we turned our attention to further investigate the scope by reacting 1a with a variety of ortho-hydroxychalcones 2 bearing different substituents. As highlighted in Table 3, a wide range of ortho-hydroxychalcones underwent the Michael addition-inspired quadruple cascade smoothly, thus affording the corresponding polycyclic indole-bridged chroman spirooxindoles 3t-ag in 51-81% yields. Firstly, we determined the effect of the R4 substituent. Both the substrates with electron-withdrawing groups and the ones with electron-donating groups participated in this cascade reaction smoothly to give 3t-aa in reasonable yields. Notably, 2-naphthyl substituted ortho-hydroxychalcone was also proved to be suitable reaction partners and 3ab was obtained in 81% yield. Subsequently, substrates bearing with different R5 substituents were examined to further extend the generality of this cascade reaction. Delightfully, all of them could react with 1a successfully to generate 3ac-ag in 51-70% yields. Remarkably, the reaction proceeded in a highly diastereoselective fashion.Only one diastereoisomer was obtained for all cases, although the products contained three stereocenters, two of which were quaternary carbon centers. Of particular note, some of the products, such as 3h-i, 3m-n, 3p-q, 3t-x, 3aa and 3ad-af, were precipitated from the original homogeneous reaction system. To purify them, only a direct filtration was needed, thus avoiding the employment of the chromatography. The structure and the relative configuration of 3a were unequivocally assigned by X-ray diffraction.18 And the relative configurations of other products 3 were determined by analogy.

Table 3. Scope of substrates with respect to ortho-hydroxychalconesa



a

Unless otherwise noted, the reaction was conducted with 0.12 mmol 2 and 2.2 equivalent of 1a in 1 mL CH3CN

at 80 oC for 72 h.

b

Isolated yield obtained by column chromatography. c Isolated yield obtained by filtration of

precipitate. d For 48 h.

To demonstrate the synthetic utility of this methodology, some chemical transformations were conducted to further decorate the products (Scheme 2). By treatment 3i and 3v with 4-chlorophenylboronic acid, the Suzuki coupling occurred under the catalysis of palladium acetate, delivering 4 and 5 in 89% and 57% yields, respectively.

Scheme 2. Chemical transformations of 3i and 3v


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Scheme 3. Plausible reaction pathway Ph O

HO

OHO 2a

Ph Si-face attack NH

O O

Michael addition

NH

NH

+ O N CH3 A

NH

O

O

NH

N CH3

N CH3

O N CH3

C

B

3a

N H3C

O

condensation

O 1a

Based on the experimental results, a plausible reaction mechanism was proposed to explain the reaction pathway and the stereochemistry (Scheme 3). As exemplified by the formation of 3a, initially, a Michael addition occurred between 3-indolyl oxindole 1a and ortho-hydroxychalcone 2a in the presence of catalytic amount of TfOH to generate intermediate A. Later, an intramolecular condensation took place with the formation of an oxocarbenium B, which was equivalent to intermediate C. Finally, the oxocarbenium was attacked by the indole core from the Si-face of the oxocarbenium due to that the equatorial position is more thermodynamic preference, thus delivering the desired product 3a.

In

summary,

we

have

established

a

TfOH-catalyzed

addition/hemiketalization/dehydration/oxa-Pictet-Spengler

highly

quadruple

diastereoselective

cascade

reaction

of

Michael 3-indolyl

substituted oxindoles with ortho-hydroxychalcone, which provides a facile and robust method to access a variety of polycyclic indole-bridged chroman spirooxindoles with novel and strained structure. Moreover, chemical conversions were performed for further modification of the target products. This protocol not only represents the first example of the employment of 3-indolyl substituted oxindoles as 1,3-bisnucleophiles to



participate in a cascade reaction, but also provides a simple and efficient route for the construction of bridged spirooxindoles with structural complexity and diversity. Further endeavours toward the application of this protocol are ongoing in our laboratory.

EXPERIMENTAL SECTION General methods. NMR spectra were recorded with tetramethylsilane as the internal standard. 1H NMR spectra were recorded at 400 MHz, and 13C NMR spectra were recorded at 100 MHz (Bruker Avance). 1

H NMR chemical shifts (δ) are reported in ppm relative to tetramethylsilane (TMS) with the solvent signal

as the internal standard (CDCl3 at 7.26 ppm, (CD3)2SO at 2.50 ppm). 13C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.00 ppm, (CD3)2SO at 39.52 ppm). Data are given as: s (singlet), d (doublet), t (triplet), q (quartet), dd (double of doublet), br (broad) or m (multiplets), coupling constants (Hz) and integration. Flash column chromatography was carried out using silica gel eluting with ethyl acetate and petroleum ether. High resolution mass spectra were obtained with the Q-TOF-Premier mass spectrometer. Reactions were monitored by TLC and visualized with ultraviolet light. IR spectra were recorded on a Thermo Fisher Nicolet Avatar 360 FTIR spectrometer on a KBr beam splitter. All the solvents were used directly without any purification. Substrates 1 were prepared according to literatures.16

General Procedure for the Synthesis of polycyclic indole-bridged chroman spirooxindole 3. To a 5.0 mL vial were successively added 3-indolyl substituted oxindole 1 (0.26 mmol), ortho-hydroxychalcone 2 (0.12 mmol), TfOH (3.6 mg, 0.024 mmol) and 1.0 mL CH3CN. The resulting mixture was stirred at 80 oC for 72 h, and then the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ ethyl acetate) to afford the corresponding products 3. For products 3h-i, 3m-n, 3p-q, 3t-x, 3aa and 3ad-af, the precipitate was generated, and only a simple filtration was needed to purify the product.


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For all products, only one single diastereoisomer was obtained and the dr value was determined by 1H NMR of the crude reaction mixtures.

1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino [3,4-b]indol]-2-one (3a). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 25:1 to 20:1); 46.2 mg, 82% yield; reaction time = 72 h; mp 250.9-252.5 oC; 1H NMR (400 MHz, CDCl3), δ 7.82 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.40 (q, J = 8.0 Hz, 2H), 7.20-7.14 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.99 (q, J = 8.0 Hz, 2H), 6.81 (t, J = 8.0 Hz, 1H), 6.69 (q, J = 8.0 Hz, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 2H), 4.10 (dd, J1 = J2 = 4.0 Hz, 1H), 3.37 (s, 3H), 3.21 (t, J = 4.0 Hz, 1H), 2.15 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.8, 143.9, 141.9, 137.0, 136.1, 133.3, 129.9, 128.9 (2C), 128.6, 128.0, 126.2, 125.0, 122.6, 121.4, 121.3, 119.5, 119.4, 118.6, 117.1, 111.3, 111.1, 111.0, 107.7, 74.0, 58.4, 53.3, 40.2, 33.0. IR (KBr) ν 3308, 1706, 1609, 1489, 1452, 1345, 1236, 752 cm-1. HRMS (ESI) calcd for C32H25N2O2 [M+H]+ 469.1911, found 469.1901. 1-ethyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino[3 ,4-b]indol]-2-one (3b). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 45.7 mg, 79% yield; reaction time = 72 h; mp 248.5-250.1 oC; 1H NMR (400 MHz, CDCl3), δ 7.74 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.12-7.04 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 2H), 6.71 (t, J = 8.0 Hz, 1H), 6.62 (q, J = 8.0 Hz, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 4.0 Hz, 2H), 4.02 (d, J = 16.0 Hz, 1H), 3.87-3.80 (m, 2H), 3.12 (s, 1H), 2.07 (d, J = 12.0 Hz, 1H), 1.29 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.7, 153.8, 142.9, 141.9, 137.0, 136.1, 133.3, 130.1, 129.1, 128.9, 128.5, 128.4, 128.0, 126.2, 125.0, 122.6, 121.3, 121.2, 119.6, 119.3, 118.6, 117.1, 111.3, 111.1, 107.8,



74.0, 53.3, 40.2, 35.0, 33.0, 12.7. IR (KBr) ν 3403, 1700, 1609, 1486, 1453, 1227, 752 cm-1. HRMS (ESI) calcd for C33H27N2O2 [M+H]+ 483.2067, found 483.2051. 6'-phenyl-1-propyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino [3,4-b]indol]-2-one (3c). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 38.8 mg, 65% yield; reaction time = 72 h; mp 254.2-255.7 oC; 1H NMR (400 MHz, CDCl3), δ 7.82 (d, J = 8.0 Hz, 2H), 7.75 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.42-7.34 (m, 2H), 7.19-7.12 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (q, J = 8.0 Hz, 2H), 6.78 (t, J = 8.0 Hz, 1H), 6.69 (q, J = 8.0 Hz, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 2H), 4.10 (dd, J1 = J2 = 4.0 Hz, 1H), 3.83 (t, J = 8.0 Hz, 2H), 3.18 (s, 1H), 2.14 (dd, J1 = J2 = 4.0 Hz, 1H), 1.86-1.81 (m, 2H), 1.01 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.8, 143.3, 141.9, 137.0, 136.1, 133.3, 130.0, 129.1, 128.9, 128.5, 128.4, 128.0, 126.2, 125.0, 122.6, 121.3, 121.2, 119.5, 119.3, 118.6, 117.1, 111.3, 111.1, 108.0, 74.0, 53.3, 41.8, 40.4, 33.0, 20.9, 11.5. IR (KBr) ν 3333, 1690, 1607, 1487, 1455, 1358, 747 cm-1. HRMS (ESI) calcd for C34H29N2O2 [M+H]+ 497.2224, found 497.2224. 1-allyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino[3 ,4-b]indol]-2-one (3d). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 35.9 mg, 61% yield; reaction time = 72 h; mp 245.1-246.8 oC; 1H NMR (400 MHz, CDCl3), δ 7.72 (t, J = 8.0 Hz, 3H), 7.38 (t, J = 8.0 Hz, 2H), 7.32-7.24 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 8.0 Hz, 2H), 6.71 (t, J = 8.0 Hz, 1H), 6.60 (q, J = 8.0 Hz, 2H), 6.35 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 8.0 Hz, 2H), 5.88-5.80 (m, 1H), 5.21 (q, J = 12.0 Hz, 2H), 4.39 (d, J = 4.0 Hz, 2H), 4.01 (d, J = 16.0 Hz, 1H), 3.13 (s, 1H), 2.06 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 153.8, 143.0,


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141.8, 137.0, 136.1, 133.3, 131.4, 129.8, 129.0, 128.9, 128.5, 128.4, 128.0, 126.2, 125.0, 122.6, 121.4, 121.2, 119.6, 119.3, 118.6, 117.5, 117.1, 111.4, 111.0, 108.6, 74.0, 53.3, 42.5, 40.4, 33.0. IR (KBr) ν 3332, 1694, 1607, 1486, 1456, 1349, 750 cm-1. HRMS (ESI) calcd for C34H27N2O2 [M+H]+ 495.2067, found 495.2066. 1-butyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino[ 3,4-b]indol]-2-one (3e). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 35:1 to 30:1); 28.1 mg, 46% yield; reaction time = 72 h; mp 241.6-243.2 oC; 1H NMR (400 MHz, CDCl3), δ 7.82 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.42-7.36 (m, 2H), 7.15 (dd, J1 = J2 = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (q, J = 8.0 Hz, 2H), 6.78 (t, J = 8.0 Hz, 1H), 6.69 (q, J = 8.0 Hz, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 2H), 4.10 (dd, J1 = J2 = 4.0 Hz, 1H), 3.85 (t, J = 8.0 Hz, 2H), 3.18 (s, 1H), 2.14 (dd, J1 = J2 = 4.0 Hz, 1H), 1.80-1.74 (m, 2H), 1.49-1.40 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H);

13

C NMR (100 MHz,

CDCl3) δ 178.0, 153.8, 143.3, 141.9, 137.0, 136.1, 133.3, 130.1, 129.1, 128.9, 128.5, 128.4, 128.0, 126.2, 125.0, 122.6, 121.3, 121.1, 119.5, 119.3, 118.6, 117.1, 111.3, 111.2, 108.0, 74.0, 53.3, 40.4, 40.1, 33.0, 29.6, 20.3, 13.8. IR (KBr) ν 3326, 1690, 1607, 1483, 1456, 1360, 750 cm-1. HRMS (ESI) calcd for C35H31N2O2 [M+H]+ 511.2380, found 511.2379. 1-benzyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino [3,4-b]indol]-2-one (3f). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 27.1 mg, 42% yield; reaction time = 72 h; mp 193.7-195.0 oC; 1H NMR (400 MHz, CDCl3), δ 7.83 (d, J = 4.0 Hz, 2H), 7.79 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.32-7.21 (m, 4H), 7.17 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.01-6.96 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.76-6.64 (m, 3H), 6.43 (d, J = 8.0 Hz, 1H),



6.06 (d, J = 8.0 Hz, 2H), 5.18 (d, J = 16.0 Hz, 1H), 4.94(d, J = 16.0 Hz, 1H), 4.13 (dd, J1 = J2 = 4.0 Hz, 1H), 3.27 (s, 1H), 2.18 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.3, 153.8, 142.8, 141.8, 137.0, 136.1, 136.0, 133.4, 129.9, 129.0 (2C), 128.8, 128.6, 128.0, 127.6, 127.3, 126.2, 125.0, 122.7, 121.4, 121.2, 119.5 (2C), 118.6, 117.1, 111.4, 111.1, 108.8, 74.0, 53.4, 44.0, 40.3, 33.0. IR (KBr) ν3296, 1694, 1610, 1488, 1456, 1352, 750 cm-1. HRMS (ESI) calcd for C38H29N2O2 [M+H]+ 545.2224, found 545.2224. 5-fluoro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8 ]oxocino[3,4-b]indol]-2-one (3g). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 25:1 to 15:1); 44.1 mg, 76% yield; reaction time = 72 h; mp 267.2-268.8 oC; 1

H NMR (400 MHz, CDCl3), δ 7.90 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H),

7.35 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.09-7.05 (m, 2H), 6.99-6.91 (m, 3H), 6.75-6.68 (m, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 5.82 (dd, J1 = J2 = 4.0 Hz, 1H), 4.05 (dd, J1 = J2 = 4.0 Hz, 1H), 3.31 (s, 3H), 3.19 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 158.3 (d, J = 239.0 Hz, 1C), 153.8, 141.7, 139.8, 137.0, 136.0, 133.0, 131.8 (d, J = 8.0 Hz, 1C), 129.2, 128.5, 128.0, 126.1, 124.7, 122.7, 120.7, 119.7, 119.1, 118.7, 117.2, 116.7 (d, J = 25.0 Hz, 1C), 114.8 (d, J = 24.0 Hz, 1C), 111.5, 110.3, 108.0 (d, J = 8.0 Hz, 1C), 73.9, 53.7, 40.1, 32.9, 26.6. IR (KBr) ν3450, 1708, 1614, 1490, 1451, 1346, 752 cm-1. HRMS (ESI) calcd for C32H24FN2O2 [M+H]+ 487.1816, found 487.1817. 5-chloro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3h). White solid obtained by filtration of the precipitate; 48.3 mg, 80% yield; reaction time = 72 h; mp 299.4-301.1 oC; 1H NMR (400 MHz, CDCl3), δ 7.80 (d, J = 8.0 Hz, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.43-7.36 (m, 2H), 7.24-7.14 (m, 2H), 7.04-6.96 (m, 3H),


Page 14 of 33

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6.79-6.71 (m, 2H), 6.41 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 4.0 Hz, 1H), 4.02 (dd, J1 = J2 = 4.0 Hz, 1H), 3.35 (s, 3H), 3.18 (s, 1H), 2.15 (dd, J1 = J2 = 4.0 Hz, 1H);

13

C

NMR (100 MHz, CDCl3) δ 177.6, 153.8, 142.4, 141.7, 137.1, 136.0, 133.1, 131.6, 129.3, 129.0, 128.6, 128.4, 128.0, 127.0, 126.2, 124.8, 122.8, 120.7, 119.8, 119.1, 118.6, 117.3, 111.5, 110.2, 108.5, 73.9, 53.6, 40.2, 32.9, 26.7. IR (KBr) ν3306, 1701, 1608, 1486, 1456, 752 cm-1. HRMS (ESI) calcd for C32H24ClN2O2 [M+H]+ 503.1521, found 503.1520. 5-bromo-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3i). White solid obtained by filtration of the precipitate; 51.8 mg, 79% yield; reaction time = 72 h; mp 302.9-304.3 oC; 1H NMR (400 MHz, CDCl3), δ 7.80 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 7.54-7.47 (m, 3H), 7.42 (t, J = 8.0 Hz, 1H), 7.24-7.15 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.81-6.72 (m, 2H), 6.40 (dd, J1 = J2 = 4.0 Hz, 1H), 6.15 (dd, J1 = 8.0 Hz, J2 = 4.0 Hz, 2H), 4.02 (dd, J1 = J2 = 4.0 Hz, 1H), 3.35 (s, 3H), 3.18 (t, J = 4.0 Hz, 1H), 2.16 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.5, 153.8, 142.9, 141.7, 137.1, 136.0, 133.1, 131.9, 131.7, 131.3, 129.3, 128.6, 128.1, 126.2, 124.8, 122.8, 120.7, 119.9, 119.2, 118.6, 117.3, 114.4, 111.5, 110.2, 109.1, 73.9, 53.6, 40.2, 32.9, 26.6. IR (KBr) ν3306, 1702, 1608, 1483, 1456, 1341, 757 cm-1. HRMS (ESI) calcd for C32H24BrN2O2 [M+H]+ 547.1016, found 547.1018. 7-chloro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3j). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1); 34.0 mg, 56% yield; reaction time = 72 h; mp 272.1-273.8 oC; 1H NMR (400 MHz, CDCl3), δ 7.80 (d, J = 8.0 Hz, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 4.0 Hz, 1H), 7.15 (q, J = 8.0 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz,



Page 16 of 33

1H), 6.73 (t, J = 8.0 Hz, 1H), 6.68 (t, J = 8.0 Hz, 2H), 6.34 (d, J = 8.0 Hz, 1H), 6.19 (d, J = 8.0 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.02 (dd, J1 = J2 = 4.0 Hz, 1H), 3.74 (s, 3H), 3.17 (s, 1H), 2.14 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.3, 153.8, 141.7, 139.7, 137.2, 136.0, 133.3, 132.7, 130.9, 129.1, 128.6, 128.0, 127.5, 126.1, 124.8, 122.8, 122.0, 120.8, 119.7, 119.4, 118.6, 117.2, 115.0, 111.4, 110.4, 73.9, 53.3, 40.6, 32.9, 30.0. IR (KBr) ν 33931689, 1602, 1456, 1227, 751 cm-1. HRMS (ESI) calcd for C32H24ClN2O2 [M+H]+ 503.1521, found 503.1519. 6-chloro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3k). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 37.1 mg, 62% yield; reaction time = 72 h; mp 287.2-289.1 oC; 1

H NMR (400 MHz, CDCl3), δ 7.79 (d, J = 8.0 Hz, 3H), 7.47 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0

Hz, 1H), 7.19-7.12 (m, 2H), 7.06 (s, 1H), 7.02-6.94 (s, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.74-6.69 (m, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 4.03 (dd, J1 = J2 = 4.0 Hz, 1H), 3.34 (s, 3H), 3.18 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 177.9, 153.8, 145.1, 141.7, 137.1, 136.0, 134.4, 133.1, 129.7, 129.1, 128.6, 128.3, 128.0, 126.1, 124.8, 122.8, 121.3, 121.0, 119.7, 119.2, 118.7, 117.2, 111.4, 110.4, 108.5, 73.9, 53.1, 40.2, 32.9, 26.6. IR (KBr) ν3318, 1710, 1605, 1488, 1454, 1365, 751 cm-1. HRMS (ESI) calcd for C32H24ClN2O2 [M+H]+ 503.1521, found 503.1520. 6-bromo-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3l). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 43.5 mg, 66% yield; reaction time = 72 h; mp 295.1-296.9 oC; 1


Hz, 1H), 7.20-7.11 (m, 3H), 7.00 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.74-6.69 (m, 2H),


Page 17 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6.43 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.93 (d, J = 8.0 Hz, 1H), 4.02 (dd, J1 = J2 = 4.0 Hz, 1H), 3.33 (s, 3H), 3.18 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 153.8, 145.2, 141.7, 137.1, 136.0, 133.1, 130.0, 129.1, 128.8, 128.6, 128.0, 126.1, 124.7, 124.2, 122.8, 122.3, 121.0, 119.7, 119.2, 118.7, 117.2, 111.4, 111.2, 110.2, 73.9, 53.2, 40.1, 32.9, 26.6. IR (KBr) ν3312, 1712, 1600, 1487, 1455, 1364, 752 cm-1. HRMS (ESI) calcd for C32H24BrN2O2 [M+H]+ 547.1016, found 547.1017. 1,5-dimethyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxo cino[3,4-b]indol]-2-one (3m). White solid obtained by filtration of the precipitate; 39.7 mg, 69% yield; reaction time = 72 h; mp 295.6-296.7 oC; 1H NMR (400 MHz, CDCl3), δ 7.82 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.18-7.13 (m, 3H), 6.96 (tt, J1 = J2 = 8.0 Hz, 3H), 6.70 (t, J = 8.0 Hz, 2H), 6.40 (d, J = 8.0 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 4.08 (dd, J1 = J2 = 4.0 Hz, 1H), 3.34 (s, 3H), 3.17 (t, J = 4.0 Hz, 1H), 2.14 (dd, J1 = J2 = 4.0 Hz, 1H), 2.06 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 178.0, 153.9, 141.9, 141.5, 137.0,

136.0, 133.4, 130.8, 129.8, 129.7, 128.9, 128.6, 128.5, 128.0, 126.2, 125.1, 122.6, 121.3, 119.5, 118.2, 117.1, 111.4, 111.3, 111.2, 107.3, 74.1, 53.4, 40.3, 33.0, 26.5, 20.9. IR (KBr) ν3290, 1698, 1611, 1493, 1454, 1354, 1236, 749 cm-1. HRMS (ESI) calcd for C33H27N2O2 [M+H]+ 483.2067, found 483.2069. 1,5,7-trimethyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]o xocino[3,4-b]indol]-2-one (3n). White solid obtained by filtration of the precipitate; 46.8 mg, 79% yield; reaction time = 72 h; mp 329.6-331.1 oC; 1H NMR (400 MHz, CDCl3), δ 7.81 (d, J = 4.0 Hz, 2H), 7.73 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.18-7.12 (m, 2H), 7.02-6.94 (m, 2H), 6.90 (s, 1H), 6.73-6.65 (m, 2H), 6.33 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 5.64 (s,



1H), 4.06 (dd, J1 = J2 = 4.0 Hz, 1H), 3.61 (s, 3H), 3.12 (s, 1H), 2.70 (s, 3H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H), 1.98 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 178.7, 153.8, 142.0, 139.0, 137.0, 136.0,

133.6, 132.5, 130.4 (2C), 128.8, 128.5, 127.9, 127.7, 126.2, 125.1, 122.5, 121.2, 119.7, 119.5, 118.6, 118.1, 117.0, 111.4, 111.3, 74.1, 52.9, 40.7, 33.0, 29.9, 20.6, 19.1. IR (KBr) ν3297, 1688, 1606, 1480, 1453, 1346, 1235, 749 cm-1. HRMS (ESI) calcd for C34H29N2O2 [M+H]+ 497.2224, found 497.2227. 5-methoxy-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[ 7,8]oxocino[3,4-b]indol]-2-one (3o). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 20:1 to 18:1); 51.1 mg, 85% yield; reaction time = 72 h; mp 209.9-211.5 oC; 1

H NMR (400 MHz, CDCl3), δ 7.74 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.41 (t, J = 8.0 Hz, 2H),

7.33 (t, J = 8.0 Hz, 1H), 7.09 (q, J = 8.0 Hz, 2H), 6.94-6.84 (m, 4H), 6.68-6.61 (m, 2H), 6.41 (d, J = 8.0 Hz, 1H), 6.07 (d, J = 8.0 Hz, 1H), 5.62 (d, J = 4.0 Hz, 1H), 4.03 (dd, J1 = J2 = 4.0 Hz, 1H), 3.33 (s, 3H), 3.26 (s, 3H), 3.13 (t, J = 4.0 Hz, 1H), 2.06 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 154.8, 153.9, 141.8, 137.4, 136.9, 136.0, 133.4, 131.0, 128.9, 128.6, 128.0, 126.2, 125.0, 122.6, 121.2, 119.7, 119.5, 118.5, 117.3, 115.0, 114.6, 111.3, 110.9, 108.2, 74.1, 55.7, 53.8, 40.2, 33.0, 26.6. IR (KBr) ν3311, 1703, 1606, 1492, 1456, 1235, 752 cm-1. HRMS (ESI) calcd for C33H27N2O3 [M+H]+ 499.2016, found 499.2020. 10'-chloro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7 ,8]oxocino[3,4-b]indol]-2-one (3p). White solid obtained by filtration of the precipitate; 54.3 mg, 90% yield; reaction time = 72 h; mp 344.4-346.1 oC; 1H NMR (400 MHz, CDCl3), δ 7.80 (d, J = 4.0 Hz, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.95 (t, J = 8.0 Hz, 2H), 6.84 (t, J = 8.0 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 6.40 (d, J =


Page 18 of 33

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4.0 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 4.06 (dd, J1 = J2 = 4.0 Hz, 1H), 3.37 (s, 3H), 3.19 (t, J = 4.0 Hz, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 153.7, 143.8, 141.5, 138.5, 134.4, 133.3, 129.3, 129.0, 128.9, 128.7, 128.6, 128.1, 126.1, 126.0, 125.1, 123.0, 121.6, 121.1, 118.8, 118.7, 117.1, 112.4, 110.8, 108.0, 73.9, 53.2, 40.2, 32.8, 26.6. IR (KBr) ν3283, 1691, 1609, 1482, 1456, 1238, 753 cm-1. HRMS (ESI) calcd for C32H24ClN2O2 [M+H]+ 503.1521, found 503.1520. 10'-bromo-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7 ,8]oxocino[3,4-b]indol]-2-one (3q). White solid obtained by filtration of the precipitate; 44.5 mg, 68% yield; reaction time = 72 h; mp 349.4-351.6 oC; 1H NMR (400 MHz, CDCl3), δ 7.80 (d, J = 4.0 Hz, 3H), 7.49 (t, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.09-7.06 (m, 2H), 6.99 (q, J = 8.0 Hz, 2H), 6.85 (t, J = 8.0 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.15 (s, 1H), 6.06 (d, J = 8.0 Hz, 1H), 4.07 (dd, J1 = J2 = 4.0 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 153.7, 143.8, 141.5, 138.4, 134.7, 133.3, 129.2, 129.0, 128.9, 128.7 (2C), 128.1, 126.7, 126.1, 125.6, 122.0, 121.6, 121.2, 118.8, 117.1, 112.8, 112.7, 110.7, 108.0, 73.9, 53.2, 40.2, 32.7, 26.6. IR (KBr) ν3280, 1688, 1609, 1482, 1238, 753 cm-1. HRMS (ESI) calcd for C32H24BrN2O2 [M+H]+ 547.1016, found 547.1015. 9'-bromo-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3r). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 49.4 mg, 75% yield; reaction time = 72 h; mp 311.4-312.8 oC; 1

H NMR (400 MHz, CDCl3), δ 7.80 (t, J = 8.0 Hz, 3H), 7.48 (t, J = 8.0 Hz, 2H), 7.39 (q, J = 8.0

Hz, 2H), 7.28 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H),



6.80 (q, J = 8.0 Hz, 2H), 6.70 (t, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.90 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 12.0 Hz, 1H), 3.36 (s, 3H), 3.20 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 153.7, 143.8, 141.5, 137.7, 136.8, 133.3, 129.6, 129.0, 128.7 (2C), 128.6, 128.1, 126.1, 123.8, 122.9, 121.5, 121.1, 120.5, 118.7, 117.1, 116.2, 114.3, 111.3, 107.8, 73.9, 53.1, 40.1, 32.9, 26.6. IR (KBr) ν3337, 1704, 1609, 1487, 1452, 1235, 757 cm-1. HRMS (ESI) calcd for C32H24BrN2O2 [M+H]+ 547.1016, found 547.1012. 1,10'-dimethyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]ox ocino[3,4-b]indol]-2-one (3s). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 26.0 mg, 45% yield; reaction time = 72 h; mp 302.9-303.8 oC; 1


7.39 (t, J = 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.04 (dd, J1 = J2 = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.81 (t, J = 8.0 Hz, 2H), 6.69 (t, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 5.81 (s, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.37 (s, 3H), 3.19 (s, 1H), 2.12 (dd, J1 = J2 = 4.0 Hz, 1H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.2, 153.9, 143.9, 142.0, 137.1, 134.4, 133.3, 129.9, 129.0, 128.9, 128.6, 128.5, 128.4, 127.9, 126.2, 125.2, 124.2, 121.4, 119.1, 118.5, 117.0, 111.0, 110.5, 107.6, one carbon missing in the aromatic region, 74.1, 53.4, 40.3, 32.9, 26.5, 21.3. IR (KBr) ν3310, 1696, 1608, 1486, 1236, 754 cm-1. HRMS (ESI) calcd for C33H27N2O2 [M+H]+ 483.2067, found 483.2069. 1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocino[3,4-b]ind ol]-2-one (3t). White solid obtained by filtration of the precipitate; 42.0 mg, 72% yield; reaction time = 72 h; mp 335.1-336.7 oC; 1H NMR (400 MHz, CDCl3), δ 7.80-7.74 (m, 3H), 7.39 (t, J = 8.0 Hz, 1H), 7.19-7.13 (m, 4H), 7.05 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0


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Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.73-6.67 (m, 2H), 6.43 (dd, J1 = J2 = 4.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 2H), 4.06 (dd, J1 = J2 = 4.0 Hz, 1H), 3.36 (s, 3H), 3.20 (s, 1H), 2.11 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.0, 162.5 (d, J = 245.0 Hz, 1C), 153.7, 143.9, 137.7 (d, J = 3.0 Hz, 1C), 136.6, 136.1, 133.3, 129.8, 129.0 (d, J = 6.0 Hz, 1C), 128.6, 128.1, 128.0, 124.9, 122.8, 121.5, 121.2, 119.6, 119.4, 118.7, 117.0, 115.4 (d, J = 21.0 Hz, 1C), 114.4, 111.2, 107.8, 73.8, 53.3, 40.2, 33.1, 26.5. IR (KBr) ν3296 1692, 1610, 1488, 1454, 1232, 751 cm-1. HRMS (ESI) calcd for C32H24FN2O2 [M+H]+ 487.1816, found 487.1816. 6'-(4-chlorophenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3u). White solid obtained by filtration of the precipitate; 38.9 mg, 64% yield; reaction time = 72 h; mp 361.6-363.3 oC; 1H NMR (400 MHz, CDCl3), δ 7.67 (d, J = 8.0 Hz, 3H), 7.37-7.30 (m, 3H), 7.11-7.05 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H), 6.66-6.59 (m, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.00 (t, J = 8.0 Hz, 2H), 3.99 (dd, J1 = J2 = 4.0 Hz, 1H), 3.29 (s, 3H), 3.13 (t, J = 4.0 Hz, 1H), 2.04 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.0, 153.6, 143.9, 140.5, 136.4, 136.1, 133.9, 133.3, 129.7, 129.0, 128.9, 128.7, 128.6, 127.7, 124.9, 122.8, 121.5, 121.2, 119.6, 119.4, 118.8, 117.0, 111.4, 111.3, 107.8, 73.8, 53.3, 40.1, 33.0, 26.5. IR (KBr) ν3298, 1690, 1610, 1488, 1233, 751 cm-1. HRMS (ESI) calcd for C32H24ClN2O2 [M+H]+ 503.1521, found 503.1511. 6'-(4-bromophenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3v). White solid obtained by filtration of the precipitate; 52.0 mg, 79% yield; reaction time = 72 h; mp 362.4-363.9 oC; 1H NMR (400 MHz, CDCl3), δ 7.67 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.11-7.05 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 8.0 Hz, 1H),



6.66-6.59 (m, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.00 (t, J = 8.0 Hz, 2H), 3.98 (dd, J1 = J2 = 4.0 Hz, 1H), 3.29 (s, 3H), 3.13 (t, J = 4.0 Hz, 1H), 2.04 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.0, 153.6, 143.9, 141.0, 136.3, 136.1, 133.3, 131.7, 129.7, 129.0, 128.9, 128.6, 128.1, 124.9, 122.8, 122.1, 121.5, 121.2, 119.6, 119.4, 118.8, 117.0, 111.4, 111.3, 107.8, 73.8, 53.3, 40.1, 32.9, 26.5. IR (KBr) ν3299, 1691, 1610, 1486, 1455, 1233, 752 cm-1. HRMS (ESI) calcd for C32H23BrN2NaO2 [M+Na]+ 569.0835, found 569.0833. 1-methyl-6'-(p-tolyl)-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxocin o[3,4-b]indol]-2-one (3w). White solid obtained by filtration of the precipitate; 40.7 mg, 70% yield; reaction time = 72 h; mp 329.2-331.5 oC; 1H NMR (400 MHz, CDCl3), δ 7.74 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.19-7.12 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.98 (q, J = 8.0 Hz, 2H), 6.81 (t, J = 8.0 Hz, 1H), 6.69 (q, J = 8.0 Hz, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.07 (t, J = 8.0 Hz, 2H), 4.08 (dd, J1 = J2 = 4.0 Hz, 1H), 3.36 (s, 3H), 3.20 (t, J = 4.0 Hz, 1H), 2.43 (s, 3H), 2.12 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.9, 143.9, 138.9, 137.7, 137.2, 136.0, 133.3, 129.9, 129.2, 128.9 (2C), 128.5, 126.1, 125.0, 122.6, 121.4 (2C), 119.5, 119.4, 118.5, 117.1, 111.3, 110.9, 107.7, 73.9, 53.3, 40.2, 32.9, 26.5, 21.2. IR (KBr) ν3309, 1693, 1610, 1487, 1454, 1235, 748 cm-1. HRMS (ESI) calcd for C33H26N2NaO2 [M+Na]+ 505.1886, found 505.1878. 6'-(4-isopropylphenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo [7,8]oxocino[3,4-b]indol]-2-one (3x). White solid obtained by filtration of the precipitate; 46.1 mg, 75% yield; reaction time = 72 h; mp 303.4-305.3 oC; 1H NMR (400 MHz, CDCl3), δ 7.77 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.40-7.33 (m, 3H), 7.18-7.13 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.97 (q, J = 8.0 Hz, 2H), 6.80 (t, J = 8.0 Hz, 1H), 6.68 (q, J = 8.0 Hz, 2H), 6.42 (d, J = 8.0 Hz, 1H),


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6.06 (q, J = 4.0 Hz, 2H), 4.07 (dd, J1 = J2 = 4.0 Hz, 1H), 3.36 (s, 3H), 3.20 (s, 1H), 3.02-2.95 (m, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H), 1.32 (d, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.9, 148.6, 143.9, 139.2, 137.2, 136.0, 133.3, 129.9, 128.9 (2C), 128.5, 126.6, 126.1, 125.0, 122.5, 121.4, 121.3, 119.5, 119.4, 118.5, 117.1, 111.3, 110.9, 107.7, 74.0, 53.3, 40.2, 33.9, 32.9, 26.5, 24.0. IR (KBr) ν3309, 1700, 1610, 1487, 1455, 1235, 749 cm-1. HRMS (ESI) calcd for C35H30N2NaO2 [M+Na]+ 533.2199, found 533.2214. 6'-(4-methoxyphenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[ 7,8]oxocino[3,4-b]indol]-2-one (3y). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 10:1); 41.8 mg, 70% yield; reaction time = 72 h; mp 311.6-313.5 oC; 1

H NMR (400 MHz, CDCl3), δ 7.77 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 1H),

7.18-7.14 (m, 2H), 7.06-6.96 (m, 5H), 6.81 (t, J = 8.0 Hz, 1H), 6.69 (q, J = 8.0 Hz, 2H), 6.42 (d, J = 8.0 Hz, 1H), 6.07 (t, J = 8.0 Hz, 2H), 4.06 (dd, J1 = J2 = 4.0 Hz, 1H), 3.87 (s, 3H), 3.36 (s, 3H), 3.20 (s, 1H), 2.12 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 159.3, 153.9, 143.9, 137.2, 136.0, 133.9, 133.3, 129.9, 128.9 (2C), 128.5, 127.4, 125.1, 122.6, 121.4, 121.3, 119.5, 119.4, 118.5, 117.0, 113.9, 111.3, 110.9, 107.7, 73.8, 55.4, 53.3, 40.3, 33.0, 26.5. IR (KBr) ν3312, 1698, 1610, 1512, 1487, 1240, 751 cm-1. HRMS (ESI) calcd for C33H26N2NaO3 [M+Na]+ 521.1836, found 521.1826. 6'-(3,4-dimethylphenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenz o[7,8]oxocino[3,4-b]indol]-2-one (3z). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 20:1); 40.7 mg, 68% yield; reaction time = 48 h; mp 289.6-291.6 oC; 1H NMR (400 MHz, CDCl3), δ 7.69 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (q, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (q, J



= 8.0 Hz, 2H), 6.73 (t, J = 8.0 Hz, 1H), 6.61 (q, J = 8.0 Hz, 2H), 6.34 (d, J = 8.0 Hz, 1H), 6.00 (dd, J1 = J2 = 4.0 Hz, 2H), 4.02 (dd, J1 = J2 = 4.0 Hz, 1H), 3.29 (s, 3H), 3.13 (s, 1H), 2.26 (s, 6H), 2.05 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.9, 143.9, 139.3, 137.3, 136.8, 136.3, 136.0, 133.3, 130.0, 129.8, 128.9, 128.8, 128.5, 127.2, 125.0, 123.5, 122.5, 121.4 (2C), 119.4 (2C), 118.5, 117.1, 111.3, 110.7, 107.7, 73.8, 53.4, 40.2, 32.8, 26.5, 20.0, 19.5. IR (KBr) ν 3311, 1695, 1610, 1486, 1454, 1241, 747 cm-1. HRMS (ESI) calcd for C34H28N2NaO2 [M+Na]+ 519.2043, found 519.2035. 6'-(3,4-dimethoxyphenyl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobe nzo[7,8]oxocino[3,4-b]indol]-2-one (3aa). White solid obtained by filtration of the precipitate; 39.6 mg, 63% yield; reaction time = 48 h; mp 309.3-311.1 oC; 1H NMR (400 MHz, CDCl3), δ 8.09 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 12.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 2H), 6.82 (t, J = 8.0 Hz, 1H), 6.70 (q, J = 8.0 Hz, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.08 (t, J = 8.0 Hz, 2H), 4.07 (dd, J1 = J2 = 4.0 Hz, 1H), 3.91 (d, J = 8.0 Hz, 6H), 3.37 (s, 3H), 3.20 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.2, 153.9, 148.9, 148.5, 143.9, 137.1, 136.1, 134.5, 133.3, 129.9, 128.9 (2C), 128.5, 125.0, 122.5, 121.4 (2C), 119.4 (2C), 118.6, 118.5, 117.0, 111.4, 110.9, 110.8, 109.2, 107.7, 73.9, 55.9 (2C), 53.4, 40.3, 33.1, 26.5. IR (KBr) ν3322, 1708, 1610, 1515, 1456, 1246, 753 cm-1. HRMS (ESI) calcd for C34H28N2NaO4 [M+Na]+ 551.1941, found 551.1949. 1-methyl-6'-(naphthalen-2-yl)-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7 ,8]oxocino[3,4-b]indol]-2-one (3ab). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 20:1); 50.2 mg, 81% yield; reaction time = 48 h; mp 311.2-313.1 oC; 1

H NMR (400 MHz, CDCl3), δ 8.43 (s, 1H), 7.97-7.88 (m, 3H), 7.76 (d, J = 8.0 Hz, 2H), 7.54 (t, J


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= 4.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.21 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.06 (q, J = 8.0 Hz, 3H), 6.98 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.74-6.66 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 6.10 (t, J = 8.0 Hz, 2H), 4.22 (d, J = 16.0 Hz, 1H), 3.37 (s, 3H), 3.24 (s, 1H), 2.19 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.9, 143.9, 139.1, 136.9, 136.1, 133.3, 133.2, 133.0, 129.9, 128.9, 128.6, 128.4, 127.7, 126.4, 126.3, 125.0, 124.9, 124.4, 122.7, 121.5, 121.4, 119.6, 119.4, 118.7, 117.1, 111.4, 111.1, 107.7, two carbons missing in the aromatic region, 74.1, 53.4, 40.2, 32.7, 26.5. IR (KBr) ν 3310, 1693, 1609, 1476, 1462, 1232, 746 cm-1. HRMS (ESI) calcd for C36H26N2NaO2 [M+Na]+ 541.1886, found 541.1887. 2'-fluoro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3ac). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 25:1 to 20:1); 40.6 mg, 70% yield; reaction time = 72 h; mp 273.2-274.1 oC; 1


Hz, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.80 (dd, J1 = J2 = 4.0 Hz, 3H), 6.61 (t, J = 8.0 Hz, 1H), 6.06 (d, J = 8.0 Hz, 2H), 6.00 (d, J = 8.0 Hz, 1H), 4.00 (dd, J1 = J2 = 4.0 Hz, 1H), 3.28 (s, 3H), 3.08 (s, 1H), 2.02 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.8, 155.2 (d, J = 237.0 Hz, 1C), 149.8 (d, J = 2.0 Hz, 1C), 143.9, 141.6, 136.4 (d, J = 67.0 Hz, 1C), 129.5, 128.8, 128.6 (2C), 128.0, 126.1, 124.9, 122.7, 122.2 (d, J = 7.0 Hz, 1C), 121.6, 119.6, 119.4, 119.0 (d, J = 23.0 Hz, 1C), 117.9, 117.8, 115.7 (d, J = 23.0 Hz, 1C), 111.4, 110.9, 107.9, 74.1, 53.2, 40.3, 32.6, 26.5. IR (KBr) ν3306, 1710, 1692, 1611, 1491, 1222, 743 cm-1. HRMS (ESI) calcd for C32H23FN2NaO2 [M+Na]+ 509.1636, found 509.1623. 2'-chloro-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3ad). White solid obtained by filtration of the precipitate; 41.0 mg,



Page 26 of 33

68% yield; reaction time = 72 h; mp 305.4-306.7 oC; 1H NMR (400 MHz, CDCl3), δ 7.78 (d, J = 8.0 Hz, 3H), 7.48-7.37 (m, 4H), 7.13-7.05 (m, 3H), 6.98 (t, J = 8.0 Hz, 1H), 6.89 (t, J = 8.0 Hz, 2H), 6.68 (t, J = 8.0 Hz, 1H), 6.37 (d, J = 4.0 Hz, 1H), 6.10 (t, J = 8.0 Hz, 2H), 4.07 (dd, J1 = J2 = 4.0 Hz, 1H), 3.35 (s, 3H), 3.13 (s, 1H), 2.10 (dd, J1 = J2 = 4.0 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 177.7, 152.4, 143.8, 141.4, 136.6, 136.1, 133.8, 132.6, 129.4, 128.9, 128.7, 128.6, 128.1, 126.1, 124.8, 123.4, 122.8 (2C), 121.5, 119.6, 119.4, 118.4, 111.4, 110.9, 108.0, 74.3, 53.2, 40.0, 32.6, 26.5. IR (KBr) ν3318, 1701, 1610, 1474, 1236, 747 cm-1. HRMS (ESI) calcd for C32H23ClN2NaO2 [M+Na]+ 525.1340, found 525.1355. 2'-bromo-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7, 8]oxocino[3,4-b]indol]-2-one (3ae). White solid obtained by filtration of the precipitate; 36.5 mg, 56% yield; reaction time = 72 h; mp 289.6-291.5 oC; 1H NMR (400 MHz, CDCl3), δ 7.79 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.51-7.40 (m, 4H), 7.27 (t, J = 4.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 8.0 Hz, 1H), 6.51 (d, J = 4.0 Hz, 1H), 6.11 (t, J = 8.0 Hz, 2H), 4.09 (dd, J1 = J2 = 4.0 Hz, 1H), 3.37 (s, 3H), 3.14 (s, 1H), 2.11 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.7, 153.0, 143.8, 141.4, 136.6, 136.1, 135.6, 131.6, 129.4, 128.9, 128.7, 128.6, 128.1, 126.1, 124.9, 123.3, 122.9, 121.5, 119.7, 119.5, 118.9, 111.4, 111.0, 110.7, 108.0, 74.4, 53.2, 40.0, 32.5, 26.6. IR (KBr) ν3312, 1696, 1610, 1471, 1368, 1236, 747 cm-1. HRMS (ESI) calcd for C32H23BrN2NaO2 [M+Na]+ 569.0835, found 569.0843. 1-methyl-2'-nitro-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8] oxocino[3,4-b]indol]-2-one (3af). White solid obtained by filtration of the precipitate; 31.2 mg, 51% yield; reaction time = 72 h; mp 295.3-296.9 oC; 1H NMR (400 MHz, CDCl3), δ 8.10 (dd, J1 = J2 =


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4.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 3H), 7.53 (t, J = 8.0 Hz, 2H), 7.48-7.43 (m, 2H), 7.38 (d, J = 4.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 (dd, J1 = J2 = 8.0 Hz, 2H), 6.83 (t, J = 8.0 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 4.20 (dd, J1 = J2 = 4.0 Hz, 1H), 3.39 (s, 3H), 3.28 (s, 1H), 2.16 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.4, 159.4, 143.8, 140.5, 139.7, 136.1, 136.0, 129.3, 129.2, 129.0, 128.8, 128.5, 127.9, 126.0, 124.7, 123.2, 122.1, 121.9, 119.9, 119.6, 117.9, 111.5, 111.0, 108.4, one carbon missing in the aromatic region, 75.8, 53.0, 40.1, 32.5, 26.6. IR (KBr) ν 3306, 1685, 1611, 1520, 1492, 1241, 749 cm-1. HRMS (ESI) calcd for C32H23N3NaO4 [M+Na]+ 536.1581, found 536.1584. 1,2'-dimethyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methanobenzo[7,8]oxo cino[3,4-b]indol]-2-one (3ag). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1 to 25:1); 40.6 mg, 70% yield; reaction time = 72 h; mp 193.3-195.4 oC; 1


7.39 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 2H), 6.86-6.79 (m, 2H), 6.67 (t, J = 8.0 Hz, 1H), 6.18 (s, 1H), 6.07 (t, J = 8.0 Hz, 2H), 4.05 (dd, J1 = J2 = 4.0 Hz, 1H), 3.36 (s, 3H), 3.14 (s, 1H), 2.13 (dd, J1 = J2 = 4.0 Hz, 1H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.1, 151.6, 143.8, 142.0, 137.0, 136.0, 133.7, 129.9, 129.4, 129.0, 128.5 (2C), 127.9, 127.5, 126.2, 125.0, 122.5, 121.0, 120.8, 119.4 (2C), 116.7, 1113, 111.0, 107.7, 73.9, 53.3, 40.2, 33.0, 26.5, 20.3. IR (KBr) ν3323, 1708, 1610, 1493, 1233, 746 cm-1. HRMS (ESI) calcd for C33H26N2NaO2 [M+Na]+ 505.1886, found 505.1896. General procedure for the synthesis of 4. Under nitrogen atmosphere, compound 3i (82.1 mg, 0.15 mmol), 4-chlorophenylboronic acid (1.5 equiv), Cs2CO3 (2.0 equiv), Pd(OAc)2 (0.05 equiv)



and butyl di-1-adamantylphosphine (0.06 equiv) were successively added to a 15 mL dried tube, followed by adding 2.0 mL DME. The resulting mixture was stirred at 80 oC for 22 h till almost full consumption of 3i monitored by thin layer chromatography, and then the reaction mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ ethyl acetate) to afford the corresponding product 4. 5-(4-chlorophenyl)-1-methyl-6'-phenyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]methan obenzo[7,8]oxocino[3,4-b]indol]-2-one (4). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 25:1 to 20:1); 77.6 mg, 89% yield; reaction time = 22 h; mp 300.8-302.0 oC; 1H NMR (400 MHz, CDCl3), δ 7.81 (d, J = 8.0 Hz, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.48-7.43 (m, 3H), 7.40-7.35 (m, 2H), 7.19 (t, J = 8.0 Hz, 3H), 7.09 (q, J = 4.0 Hz, 2H), 7.02 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 6.49 (dd, J1 = 4.0 Hz, J1 = 8.0 Hz, 1H), 6.27 (s, 1H), 6.17 (t, J = 8.0 Hz, 1H), 4.08 (dd, J1 = 4.0 Hz, J1 = 8.0 Hz, 1H), 3.38 (s, 3H), 3.23 (s, 1H), 2.17 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.0, 154.0, 143.5, 141.7, 139.0, 137.1, 136.0, 133.2, 133.0, 132.6, 130.6, 129.0, 128.8, 128.6, 128.0, 127.8, 127.2, 127.0, 126.2, 124.9, 122.6, 121.4, 119.6, 119.3, 118.5, 117.4, 111.4, 110.6, 108.0, 74.0, 53.5, 40.3, 33.0, 26.7. IR (KBr) ν 3438, 1709, 1611, 1483, 1452, 1349, 1237, 752 cm-1. HRMS (ESI) calcd for C38H28ClN2O2 [M+H]+ 579.1834, found 579.1837. General procedure for the synthesis of 5. Under nitrogen atmosphere, compound 3v (82.1 mg, 0.15 mmol), 4-chlorophenylboronic acid (1.5 equiv), Cs2CO3 (2.0 equiv), Pd(OAc)2 (0.05 equiv) and butyl di-1-adamantylphosphine (0.06 equiv) were successively added to a 15 mL dried tube, followed by adding 2.0 mL DME. The resulting mixture was stirred at 80 oC for 22 h till almost full consumption of 3v monitored by thin layer chromatography, and then the reaction


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mixture was directly subjected to flash column chromatography on silica gel (petroleum ether/ ethyl acetate) to afford the corresponding product 5. 6'-(4'-chloro-[1,1'-biphenyl]-4-yl)-1-methyl-6',7'-dihydro-13'H-spiro[indoline-3,12'-[6,13]me thanobenzo[7,8]oxocino[3,4-b]indol]-2-one (5). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 60:1 to 40:1); 49.9 mg, 57% yield; reaction time = 22 h; mp 343.3-344.9 oC; 1H NMR (400 MHz, CDCl3), δ 7.81 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 4.0 Hz, 1H), 7.10 (q, J = 8.0 Hz, 2H), 6.98 (d, J = 4.0 Hz, 1H), 6.92 (q, J = 8.0 Hz, 2H), 6.74 (t, J = 8.0 Hz, 1H), 6.63 (q, J = 8.0 Hz, 2H), 6.36 (d, J = 8.0 Hz, 1H), 6.01 (t, J = 8.0 Hz, 2H), 4.05 (d, J = 12.0 Hz, 1H), 3.30 (s, 3H), 3.15 (s, 1H), 2.09 (dd, J1 = J2 = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 178.1, 153.8, 143.9, 141.3, 139.7, 139.1, 136.8, 136.1, 133.6, 133.3, 129.8, 129.0 (2C), 128.9, 128.6, 128.4, 127.1, 126.8, 125.0, 122.7, 121.5, 121.3, 119.6, 119.4, 118.7, 117.1, 111.3, 111.2, 107.7, 74.0, 53.3, 40.2, 32.9, 26.6. IR (KBr) ν3308, 1698, 1609, 1482, 1234, 750 cm-1. HRMS (ESI) calcd for C38H28ClN2O2 [M+H]+ 579.1834, found 579.1837. ASSOCIATED CONTENT Supporting Information Copies of NMR spectra for the products, and single crystal X-ray crystallographic data for products 3a. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected]. Notes



The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for the financial support from National Natural Science Foundation of China (U1504206), the Foundation of He’nan Educational Committee (18A150002) and Henan University (yqpy20170008). We also thank Prof. Zhi-Yong Jiang from Key Laboratory of Natural Medicine and Immune-Engineering of Henan Province, Henan University for helpful advice. REFERENCES (1) For selected reviews, see: (a) Zhou, J. Chem. Asian J. 2010, 5, 422. (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390. (c) Wang, Y.; Lu, H.; Xu, P. F. Acc. Chem. Res. 2015, 48, 1832. (2) For selected reviews, see: (a) Bonjoch, J.; Solé, D. Chem. Rev. 2000, 100, 3455. (b) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. (3) (a) Butkus, E.; Malinauskienė, J.; Stončius, S. Org. Biomol. Chem. 2003, 1, 391. (b) Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534. (4) For selected examples, see: (a) Wang, X.-F.; Chen, J.-R.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. Org. Lett. 2010, 12, 1140. (b) Tan, B.; Hernández-Torres, G.; Barbas III, C. F. J. Am. Chem. Soc. 2011, 133, 12354. (c) Zeng, H.-F.; He, P.; Liu, Y.-B.; Zhang, Y.-L.; Liu, X.-H.; Lin, L.-L.; Feng, X.-M. Chem. Commun. 2014, 50, 8794. (d) Tian, X.; Hofmann, N.; Melchiorre, P. Angew. Chem. Int. Ed. 2014, 53, 2997. (e) Wang, Y.; Tu, M.-S.; Yin, L.; Sun, M.; Shi, F. J. Org. Chem. 2015, 80, 3223. (5) For selected examples, see: (a) Han, X.-P.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem. Int. Ed. 2012, 51, 10390. (b) Hao, W.-J.; Wang, S.-Y.; Ji, S.-J. ACS Catal. 2013, 3, 2501. (c) Shi, F.;


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