Diastereoselective Construction of Indole-Bridged Chroman

Mar 13, 2018 - (1) Polycyclic indoles represent an important and unique class of .... the reaction was conducted at 80 °C for 72 h (Table 1, entries ...
1 downloads 0 Views 1MB Size
Download PDF
Article Cite This: J. Org. Chem. 2018, 83, 3679−3687

pubs.acs.org/joc

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 S Supporting Information *

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 A 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 are 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 a wide distribution in 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 3indolylmethanols,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 an indolic ring via a 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 a more complex and rigid bridged-ring skeleton would be highly desirable and challenging. On the other hand, spirooxindoles are also attractive structural units from both a synthetic and biological point of view.10 As such, the construction of such scaffolds has gained © 2018 American Chemical Society

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 The 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 a more complex and diverse spirooxindole with a concomitant formation of multiple rings, one of which is a bridged ring, remains a compelling objective. 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 compound with a more complex and diverse structure, which not only will 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 compound has not been established until now. To fill the void and as a continuation of our interest in the construction of spirooxindoles,15 3-indolyl-substituted oxindoles16 were first employed as competent 1,3-bisnucleophiles to react with orthohydroxychalcones via a Michael addition-inspired triple 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 Received: January 5, 2018 Published: March 13, 2018 3679

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

Scheme 1. Our Synthetic Design for the Synthesis of Polycyclic Indole-Bridged Chroman Spirooxindoles via a Michael Addition-Inspired Triple Cascade

Friedel−Crafts alkylation took place between the C2 position of the 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 the 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 triple cascade reaction.

entry

cat.

solvent

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9c 10c,d 11c,d 12c,d 13c,d 14c,d

Cu(OTf)2 Fe(OTf)3 FeCl3 Zn(OTf)2 TFA TfOH MsOH p-TSA TfOH TfOH TfOH TfOH TfOH TfOH

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN toluene dioxane 1,2-DCE CH3CN

48 48 48 48 48 48 48 48 48 48 48 48 48 72

28 31 n.r. n.r. n.r. 45 27 34 64 71 66 44 66 82

a

Unless otherwise noted, the reaction was conducted with 0.12 mmol of 2a and 1.2 equiv of 1a in 1 mL of the specified solvent at 60 °C. b Isolated yield was obtained by column chromatography. cThe ratio of 1a:2a is 2.2:1. dAt 80 °C. TfOH = trifluoromethanesulfonic acid; TFA = trifluoroacetic acid; and p-TSA = p-toluenesulfonic acid.

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 the oxindole core was studied, and the results indicated that the bulkiness of the Nsubstituents had significant influence on the yields. The yields dropped sharply with the increase of the bulkiness. When Nbenzyl-substituted 3-indolyl oxindole 1f was employed, only a 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 a methyl group at the indole moiety, were also compatible, allowing the synthesis of 3p−s in 45−90% yields. 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 triple cascade smoothly, thus affording the corresponding polycyclic indole-bridged chroman spirooxindoles 3t−ag in 51−81% yields. First, we determined the effect of the R4 substituent. Both the substrates with electronwithdrawing 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 proven to be a suitable reaction partner, and 3ab was obtained in 81% yield. Subsequently, substrates bearing 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 of the cases, although the

■

RESULTS AND DISCUSSION Initially, 3-(1H-indol-3-yl)-1-methylindolin-2-one 1a and orthohydroxychalcone 2a were selected as the model substrates to examine the feasibility of the Michael addition-inspired triple cascade reaction. To our delight, the reaction proceeded well in the presence of Cu(OTf)2 in acetonitrile at 60 °C, 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 an important structural unit frequently encountered in biologically active natural products and pharmaceuticals.17 To improve the synthetic efficiency, some other catalysts, including Lewis acids 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 choice, giving 3a in a 45% yield (Table 1, entry 6). The substrate ratios had a profound influence on the yield. When 2.2 equiv 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 at 80 °C 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 a 82% yield was achieved when the reaction was conducted at 80 °C for 72 h (Table 1, entries 10 vs 14). With the optimized reaction condition in hand, the substrate scope with 3-indolyl oxindoles 1 bearing different substitution patterns was investigated, and the results are outlined in Table 3680

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry Table 3. Scope of Substrates with Respect to orthoHydroxychalconesa

Table 2. Scope of Substrates with Respect to 3-Indolyl Oxindolesa

a

Unless otherwise noted, the reaction was conducted with 0.12 mmol of 2 and 2.2 equiv of 1a in 1 mL of CH3CN at 80 °C for 72 h. b Isolated yield was obtained by column chromatography. cIsolated yield was obtained by the filtration of precipitate. dFor 48 h. a

Scheme 2. Chemical Transformations of 3i and 3v

Unless otherwise noted, the reaction was conducted with 0.12 mmol of 2a and 2.2 equiv of 1 in 1 mL of CH3CN at 80 °C for 72 h. b Isolated yield was obtained by column chromatography. cIsolated yield was obtained by the filtration of precipitate.

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 The relative configurations of other products 3 were determined by analogy. To demonstrate the synthetic utility of this methodology, some chemical transformations were conducted to further decorate the products (Scheme 2). By treatment of 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. 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 a 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 has more thermodynamic preference, thus delivering the desired product 3a. In summary, we have established a TfOH-catalyzed highly diastereoselective Michael addition/condensation/FriedelCrafts alkylation cascade reaction of 3-indolyl-substituted oxindoles with ortho-hydroxychalcone, which provides a facile and robust method to access a variety of polycyclic indole3681

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry Scheme 3. Plausible Reaction Pathway

53.3, 40.2, 33.0. IR (KBr) ν 3308, 1706, 1609, 1489, 1452, 1345, 1236, 752 cm−1. HRMS (ESI): [M + H]+ calcd for C32H25N2O2, 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 = 30:1−25:1); 45.7 mg, 79% yield; reaction time = 72 h; mp 248.5− 250.1 °C. 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): [M + H]+ calcd for C33H27N2O2, 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 = 30:1−25:1); 38.8 mg, 65% yield; reaction time = 72 h; mp 254.2−255.7 °C. 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): [M + H]+ calcd for C34H29N2O2, 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 °C. 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, 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): [M + H]+ calcd for C34H27N2O2, 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 = 35:1−30:1); 28.1 mg, 46% yield; reaction time = 72 h; mp 241.6− 243.2 °C. 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),

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 3indolyl-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 endeavors 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). 1H 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. Substrate 1 was prepared according to literatures.16 General Procedure for the Synthesis of Polycyclic IndoleBridged Chroman Spirooxindole 3. 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 of CH3CN were successively added to a 5.0 mL vial. The resulting mixture was stirred at 80 °C 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 product 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. For all of the 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 = 25:1−20:1); 46.2 mg, 82% yield; reaction time = 72 h; mp 250.9−252.5 °C. 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, 3682

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry 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): [M + H]+ calcd for C35H31N2O2, 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 = 30:1−25:1); 27.1 mg, 42% yield; reaction time = 72 h; mp 193.7−195.0 °C. 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): [M + H]+ calcd for C38H29N2O2, 545.2224; found, 545.2224. 5-Fluoro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3g). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 25:1−15:1); 44.1 mg, 76% yield; reaction time = 72 h; mp 267.2−268.8 °C. 1H 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): [M + H]+ calcd for C32H24FN2O2, 487.1816; found, 487.1817. 5-Chloro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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), 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). 13C 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): [M + H]+ calcd for C32H24ClN2O2, 503.1521; found, 503.1520. 5-Bromo-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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): [M + H]+ calcd for C32H24BrN2O2, 547.1016; found, 547.1018. 7-Chloro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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, 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): [M + H]+ calcd for C32H24ClN2O2, 503.1521; found, 503.1519. 6-Chloro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 1H 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). 13C 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): [M + H]+ calcd for C32H24ClN2O2, 503.1521; found, 503.1520. 6-Bromo-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3l). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 30:1−25:1); 43.5 mg, 66% yield; reaction time = 72 h; mp 295.1−296.9 °C. 1H 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), 7.20−7.11 (m, 3H), 7.00 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.74−6.69 (m, 2H), 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): [M + H]+ calcd for C32H24BrN2O2, 547.1016; found, 547.1017. 1,5-Dimethyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline-3,12′[6,13]methanobenzo[7,8]oxocino[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 °C. 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). 13C 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): [M + H]+ calcd for C33H27N2O2, 483.2067; found, 483.2069. 1,5,7-Trimethyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[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 °C. 1H NMR (400 MHz, 3683

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry 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). 13C 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): [M + H] calcd for C34H29N2O2,+ 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]-2one (3o). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 20:1−18:1); 51.1 mg, 85% yield; reaction time = 72 h; mp 209.9−211.5 °C. 1H 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): [M + H]+ calcd for C33H27N2O3, 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]-2one (3p). White solid obtained by filtration of the precipitate; 54.3 mg, 90% yield; reaction time = 72 h; mp 344.4−346.1 °C. 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 = 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): [M + H]+ calcd for C32H24ClN2O2, 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]-2one (3q). White solid obtained by filtration of the precipitate; 44.5 mg, 68% yield; reaction time = 72 h; mp 349.4−351.6 °C. 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): [M + H]+ calcd for C32H24BrN2O2, 547.1016; found, 547.1015. 9′-Bromo-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3r). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 30:1−25:1); 49.4 mg, 75% yield; reaction time = 72 h; mp 311.4−312.8 °C. 1H 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): [M + H]+ calcd for C32H24BrN2O2, 547.1016; found, 547.1012. 1,10′-Dimethyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3s). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 30:1−25:1); 26.0 mg, 45% yield; reaction time = 72 h; mp 302.9−303.8 °C. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 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): [M + H]+ calcd for C33H27N2O2, 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]indol]-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 °C. 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 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): [M + H]+ calcd for C32H24FN2O2, 487.1816; found, 487.1816. 6′-(4-Chlorophenyl)-1-methyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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). 13 C 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): [M + H]+ calcd for C32H24ClN2O2, 503.1521; found, 503.1511. 6′-(4-Bromophenyl)-1-methyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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): [M + Na] calcd for C32H23BrN2NaO2,+ 569.0835; found, 569.0833. 1-Methyl-6′-(p-tolyl)-6′,7′-dihydro-13′H-spiro[indoline-3,12′[6,13]methanobenzo[7,8]oxocino[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 °C. 1H NMR (400 MHz, 3684

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry 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): [M + Na]+ calcd for C33H26N2NaO2, 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]-2one (3x). White solid obtained by filtration of the precipitate; 46.1 mg, 75% yield; reaction time = 72 h; mp 303.4−305.3 °C. 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), 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): [M + Na]+ calcd for C35H30N2NaO2, 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]-2one (3y). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1−10:1); 41.8 mg, 70% yield; reaction time = 72 h; mp 311.6-313.5 °C. 1H 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): [M + Na]+ calcd for C33H26N2NaO3, 521.1836; found, 521.1826. 6′-(3,4-Dimethylphenyl)-1-methyl-6′,7′-dihydro-13′H-spiro[indoline-3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2one (3z). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1−20:1); 40.7 mg, 68% yield; reaction time = 48 h; mp 289.6−291.6 °C. 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): [M + Na]+ calcd for C34H28N2NaO2, 519.2043; found, 519.2035. 6′-(3,4-Dimethoxyphenyl)-1-methyl-6′,7′-dihydro-13′H-spiro[indoline-3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2one (3aa). White solid obtained by filtration of the precipitate; 39.6 mg, 63% yield; reaction time = 48 h; mp 309.3−311.1 °C. 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): [M + Na]+ calcd for C34H28N2NaO4, 551.1941; found, 551.1949. 1-Methyl-6′-(naphthalen-2-yl)-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3ab). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 30:1−20:1); 50.2 mg, 81% yield; reaction time = 48 h; mp 311.2−313.1 °C. 1H 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 = 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): [M + Na]+ calcd for C36H26N2NaO2, 541.1886; found, 541.1887. 2′-Fluoro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3ac). White solid obtained by column chromatography (petroleum ether/ ethyl acetate = 25:1−20:1); 40.6 mg, 70% yield; reaction time = 72 h; mp 273.2−274.1 °C. 1H NMR (400 MHz, CDCl3, δ): 7.72 (d, J = 4.0 Hz, 3H), 7.40 (t, J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 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): [M + Na]+ calcd for C32H23FN2NaO2, 509.1636; found, 509.1623. 2′-Chloro-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3ad). White solid obtained by filtration of the precipitate; 41.0 mg, 68% yield; reaction time = 72 h; mp 305.4−306.7 °C. 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). 13C 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): [M + Na]+ calcd for C32H23ClN2NaO2, 525.1340; found, 525.1355. 2′-Bromo-1-methyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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 °C. 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): [M + Na]+ calcd for C32H23BrN2NaO2, 569.0835; found, 569.0843. 1-Methyl-2′-nitro-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline3,12′-[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% 3685

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry yield; reaction time = 72 h; mp 295.3−296.9 °C. 1H NMR (400 MHz, CDCl3, δ): 8.10 (dd, J1 = J2 = 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): [M + Na]+ calcd for C32H23N3NaO4, 536.1581; found, 536.1584. 1,2′-Dimethyl-6′-phenyl-6′,7′-dihydro-13′H-spiro[indoline-3,12′[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]-2-one (3ag). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 30:1−25:1); 40.6 mg, 70% yield; reaction time = 72 h; mp 193.3−195.4 °C. 1H NMR (400 MHz, CDCl3, δ): 7.81 (d, J = 4.0 Hz, 2H), 7.76 (s, 1H), 7.47 (t, J = 8.0 Hz, 2H), 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): [M + Na]+ calcd for C33H26N2NaO2, 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 the addition of 2.0 mL of DME. The resulting mixture was stirred at 80 °C for 22 h until 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]methanobenzo[7,8]oxocino[3,4-b]indol]-2one (4). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 25:1−20:1); 77.6 mg, 89% yield; reaction time = 22 h; mp 300.8−302.0 °C. 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): [M + H]+ calcd for C38H28ClN2O2, 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 the addition of 2.0 mL of DME. The resulting mixture was stirred at 80 °C for 22 h until almost full consumption of 3v( 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 5. 6′-(4′-Chloro-[1,1′-biphenyl]-4-yl)-1-methyl-6′,7′-dihydro-13′Hspiro[indoline-3,12′-[6,13]methanobenzo[7,8]oxocino[3,4-b]indol]2-one (5). White solid obtained by column chromatography (petroleum ether/ethyl acetate = 60:1−40:1); 49.9 mg, 57% yield;

reaction time = 22 h; mp 343.3−344.9 °C. 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): [M + H]+ calcd for C38H28ClN2O2, 579.1834; found, 579.1837.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00035. Copies of NMR spectra for the products and single crystal X-ray crystallographic data for product 3a (PDF) X-ray crystallographic data of product 3a (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qilin Wang: 0000-0003-4637-0392 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (U1504206), the Foundation of He’nan Educational Committee (18A150002), and Henan University (yqpy20170008). We also would like to 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, C. F., III J. Am. Chem. Soc. 2011, 133, 12354. (c) Zheng, 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.; Zhang, H.-H.; Sun, X.-X.; Liang, J.; Fan, T.; Tu, S.-J. Chem. - Eur. J. 2015, 21, 3465. (d) Zhang, H.-H.; Zhu, Z.-Q.; Fan, T.; Liang, J.; Shi, F. Adv. Synth. Catal. 2016, 358, 1259. (e) Sun, X.-X.; Zhang, H.-H.; Li, G.-H.; He, Y.3686

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687

Article

The Journal of Organic Chemistry Y.; Shi, F. Chem. - Eur. J. 2016, 22, 17526. (f) Zhu, Z.-Q.; Shen, Y.; Sun, X.-X.; Tao, J.-Y.; Liu, J.-X.; Shi, F. Adv. Synth. Catal. 2016, 358, 3797. (6) For selected examples, see: (a) Chen, J.-R.; Li, C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-Y.; Xiao, W.-J. Angew. Chem., Int. Ed. 2008, 47, 2489. (b) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem., Int. Ed. 2009, 48, 7428. (c) Huang, H.-X.; Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604. (7) For selected examples, see: (a) Gobé, V.; Guinchard, X. Org. Lett. 2014, 16, 1924. (b) Zhao, C.-F.; Chen, S. B.; Seidel, D. J. Am. Chem. Soc. 2016, 138, 9053. (c) Wang, S.-G.; Xia, Z.-L.; Xu, R.-Q.; Liu, X.-J.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 7440. (8) For selected examples, see: (a) Zhou, L.-J.; Xu, B.; Zhang, J.-L. Angew. Chem., Int. Ed. 2015, 54, 9092. (b) Hansen, C. L.; Ohm, R. G.; Olsen, L. B.; Ascic, E.; Tanner, D.; Nielsen, T. E. Org. Lett. 2016, 18, 5990. (c) Xu, J.-F.; Yuan, S.-R.; Miao, M.-Z. Org. Lett. 2016, 18, 3822. (d) Wang, G.-P.; Chen, M.-Q.; Zhu, S.-F.; Zhou, Q.-L. Chem. Sci. 2017, 8, 7197. (9) For selected examples, see: (a) Liu, X.-X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339. (b) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534. (c) Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113. (10) For selected reviews, see: (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (b) Hong, L.; Wang, R. Adv. Synth. Catal. 2013, 355, 1023. (c) Cheng, D.-J.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014, 4, 743. (11) For selected examples, see: (a) Liu, X.-L.; Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2013, 15, 1246. (b) Su, J.-H.; Ma, Z.-L.; Li, X.-Y.; Lin, L.; Shen, Z.-Q.; Yang, P.-J.; Li, Y.; Wang, H.-L.; Yan, W.J.; Wang, K.-R.; Wang, R. Adv. Synth. Catal. 2016, 358, 3777. (c) Zhang, L.; Lu, H.; Xu, G.-Q.; Wang, Z.-Y.; Xu, P.-F. J. Org. Chem. 2017, 82, 5782. (d) Huang, N.; Zou, L.-L.; Peng, Y.-G. Org. Lett. 2017, 19, 5806. (12) For selected examples, see: (a) Pérez, M.; Ramos, C.; Massi, L.; Gazzola, S.; Taglienti, C.; Yayik, N.; Molins, E.; Viayna, A.; Luque, F. J.; Bosch, J.; Amat, M. Org. Lett. 2017, 19, 4050. (b) Huang, J.-R.; Sohail, M.; Taniguchi, T.; Monde, K.; Tanaka, F. Angew. Chem., Int. Ed. 2017, 56, 5853. (c) Jiang, X.-L.; Liu, S.-J.; Gu, Y.-Q.; Mei, G.-J.; Shi, F. Adv. Synth. Catal. 2017, 359, 3341. (13) For selected examples, see: (a) Zhou, Z.; Wang, Z.-X.; Zhou, Y.C.; Xiao, W.; Ouyang, Q.; Du, W.; Chen, Y.-C. Nat. Chem. 2017, 9, 590. (b) Zhou, Y.-H.; Lu, Y.; Hu, X.-Y.; Mei, H.-J.; Lin, L.-L.; Liu, X.H.; Feng, X.-M. Chem. Commun. 2017, 53, 2060. (14) For selected examples, see: (a) Stephen, M. R.; Rahman, M. T.; Tiruveedhula, V. V. N. P. B.; Fonseca, G. O.; Deschamps, J. R.; Cook, J. M. Chem. - Eur. J. 2017, 23, 15805. (b) Zhang, W.; Xu, W.; Wang, G.-Y.; Gong, X.-Y.; Li, N.-P.; Wang, L.; Ye, W.-C. Org. Lett. 2017, 19, 5194. (15) (a) Wang, Q.-L.; Peng, L.; Wang, F.-Y.; Zhang, M.-L.; Jia, L.-N.; Tian, F.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2013, 49, 9422. (b) Wang, Q.-L.; Cai, T.; Zhou, J.; Tian, F.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2015, 51, 10726. (c) Zhu, Y.-S.; Zhou, J.; Jin, S.-J.; Dong, H.-H.; Guo, J.-M.; Bai, X.-G.; Wang, Q.-L.; Bu, Z.-W. Chem. Commun. 2017, 53, 11201. (d) Zhu, Y.-S.; Wang, W.-B.; Yuan, B.-B.; Li, Y.-N.; Wang, Q.-L.; Bu, Z.-W. Org. Biomol. Chem. 2017, 15, 984. (e) Zhu, Y.-S.; Yuan, B.-B.; Guo, J.-M.; Jin, S.-J.; Dong, H.-H.; Wang, Q.-L.; Bu, Z.-W. J. Org. Chem. 2017, 82, 5669. (16) For the application of 3-indolyl-substituted oxindoles as mononucleophiles at the C3-position of oxindole ring, see: (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548. (b) Trost, B. M.; Zhang, Y. Chem. - Eur. J. 2010, 16, 296. (c) Ghosh, S.; Chaudhuri, S.; Bisai, A. Chem. - Eur. J. 2015, 21, 17479. (d) Trost, B. M.; Chan, W. H.; Malhotra, S. Chem. - Eur. J. 2017, 23, 4405. (17) (a) Pratap, R.; Ram, V. J. Chem. Rev. 2014, 114, 10476. (b) Kumar, M.; Chauhan, P.; Valkonen, A.; Rissanen, K.; Enders, D. Org. Lett. 2017, 19, 3025. (18) CCDC 1563889 (3a).

3687

DOI: 10.1021/acs.joc.8b00035 J. Org. Chem. 2018, 83, 3679−3687