Enantioselective Construction of Cyclopenta[b]indole Scaffolds via the

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Enantioselective Construction of Cyclopenta[b]indole Scaffolds via the Catalytic Asymmetric [3 + 2] Cycloaddition of 2‑Indolylmethanols with p‑Hydroxystyrenes Meng-Meng Xu, Hai-Qing Wang, Ying Wan, Shu-Liang Wang, and Feng Shi* School of Chemistry & Material Science, Jiangsu Normal University, Xuzhou, 221116, China S Supporting Information *

ABSTRACT: The catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols to p-hydroxystyrenes was established in the presence of a chiral phosphoramide, and this reaction provided chiral cyclopenta[b]indole scaffolds in generally high yields and with good enantioselectivities (up to 98% yield, 99:1 er). The control experiments demonstrated that the dual hydrogen-bonding activation mode of the chiral catalyst toward the two substrates played an important role in the reaction. In addition, the largescale reaction indicated that this catalytic asymmetric [3 + 2] cycloaddition could be scaled up for the synthesis of chiral cyclopenta[b]indole derivatives.

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cycloaddition of 2-indolylmethanols to 3-vinylindoles,11 which afforded chiral cyclopenta[b]indole scaffolds in high regio-, diastereo-, and enantioselectivities (Scheme 1, eq 1).10b However, in this approach, 3-vinylindoles, a specific type of alkene, were employed as substrates. We considered whether a more general class of alkenes such as styrenes could be utilized as reactants in this catalytic asymmetric [3 + 2] cycloaddition with 2-indolylmethanols. On the basis of our previous work on CPA-catalyzed asymmetric reactions,12 we envisioned that phydroxystyrenes could act as a more general class of alkenes that would be activated by chiral Brønsted acids (B*-H) via remote activation through hydrogen-bonding interactions, thus undergoing enantioselective [3 + 2] cycloaddition with 2indolylmethanols to construct chiral cyclopenta[b]indole scaffolds (Scheme 1, eq 2). On the basis of this design, we achieved the catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols with phydroxystyrenes, which afforded cyclopenta[b]indole scaffolds in generally high yields and good enantioselectivities (up to 98% yield, 99:1 er). Herein, we report the details of our investigation.

INTRODUCTION The chiral cyclopenta[b]indole scaffold represents one of the most popular heterocyclic frameworks, and it is found in the cores of many natural alkaloids and pharmaceuticals (Figure 1).1,2 For instance, yuehchukene and bruceolline I are natural

Figure 1. Natural alkaloids and pharmaceuticals containing the cyclopenta[b]indole scaffold.

alkaloids containing the cyclopenta[b]indole scaffold.1 Compound I is a selective androgen receptor modulator, and compound II can inhibit platelet aggregation.2 Therefore, the enantioselective construction of cyclopenta[b]indole scaffolds has received significant attention from the chemistry community. Recently, catalytic asymmetric reactions involving indolylmethanol have been recognized as powerful methods for constructing chiral indole-fused frameworks.3−8 Specifically, 2indolylmethanols have emerged as a new class of versatile reactants for enantioselective synthesis of indole-containing heterocycles.9,10 In our previous work, we established a chiral phosphoric acid (CPA)-that catalyzed the asymmetric [3 + 2] © 2017 American Chemical Society

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RESULTS AND DISCUSSION At the outset, the reaction of 2-indolylmethanol (1a) with phydroxystyrene (2a) was chosen as a model reaction for examining the potential of our design (Table 1). Indeed, the reaction with CPA catalyst 4a underwent the desired [3 + 2] Received: July 11, 2017 Published: September 18, 2017 10226

DOI: 10.1021/acs.joc.7b01731 J. Org. Chem. 2017, 82, 10226−10233

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The Journal of Organic Chemistry

Scheme 1. Design of the Catalytic Asymmetric [3 + 2] Cycloaddition of 2-Indolylmethanols to p-Hydroxystyrenes for the Construction of Cyclopenta[b]indole Scaffolds

enantioselectivity to 85:15 er (entry 13). This result could be attributed to the fact that the reaction speed would be decreased by diluting the reaction, which would provide more time for the chiral catalyst to activate the substrates, thus improving the enantioselectivity. Finally, at this concentration, the catalyst loading was altered (entries 18−20). However, neither decreasing nor increasing the catalyst loading could enhance the enantioselectivity. Therefore, the optimal reaction conditions were set as illustrated in entry 13. Using the determined optimal conditions, we then carried out an investigation into the substrate scope of the catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols 1 with p-hydroxystyrenes 2 (Table 3). First, the scope of 2indolylmethanols 1 was studied (entries 1−8). A series of substrates 1 bearing various R substituents at different positions on the indole ring were well tolerated in the reaction (entries 1−6) and afforded the cyclopenta[b]indole products 3 in generally high yields (50−87%) and with good enantioselectivities (85:15 to 91:9 er). In addition, the two Ar groups in 1 could be changed from phenyl groups to meta-fluorosubstituted phenyl groups, which generated the corresponding products 3ga and 3ha with considerable enantioselectivities, albeit with moderate yields (entries 7−8). Second, the scope of p-hydroxystyrenes 2 was examined (entries 9−15). It was found that this reaction was amenable to not only halogen-substituted substrates 2b and 2c (entries 9 and 10) but also substrates 2d− 2f bearing electron-rich R1 groups (entries 11−15). Except for substrate 2e, the [3 + 2] cycloaddition occurred smoothly to give products 3 in high yields (59−98%) and with good enantioselectivities (85:15 to 99:1 er). Therefore, this synthetic method will provide an easy route to chiral cyclopenta[b]indoles. Notably, in most cases, substrate 2d, which has a pOMeC6H4 substituent (R1), participated in the [3 + 2] cycloaddition to afford the corresponding products 3ad and 3ed with excellent enantioselectivities (entries 11 and 13). This result indicated that the p-OMeC6H4 substituent might be important for achieving the observed high enantioselectivities.

cycloaddition to give the cyclopenta[b]indole product 3aa in a high yield (83%) but with essentially no enantioselectivity (entry 1). Then, a series of BINOL-derived CPAs 4 and 5 were screened in ethyl acetate at 50 °C (entries 1−8), and we found that CPA 4e, which has two bulky 3,3′-(9-anthracenyl) groups, could catalyze the reaction with high enantioselectivity (73:27 er, entry 5). Then, other typical solvents were evaluated in conjunction with CPA 4e (entries 9−13). However, these solvents were inferior to ethyl acetate in terms of controlling the enantioselectivity of the reaction (entries 9−13 vs 5). For the enantioselectivity to be improved further, catalysts 6−8, analogues of CPA 4e with two bulky 9-anthracenyl groups, were tested in the reaction (entries 14−16). Although catalysts 6 and 7 failed to promote the reaction (entries 14 and 15), chiral phosphoramide (CPN) 8 increased the enantioselectivity up to 76:24 er and greatly improved the yield (79%, entry 16). Therefore, CPN 8 was selected as the optimal catalyst for further detailed evaluation of solvents (entries 17−24). Because of the good performance of 1,2-dichloroethane (entry 18), different chloro-containing solvents were carefully screened at 25 °C (entries 19−24), and dichloromethane was the most suitable solvent with regard to enantioselective control (entry 20). Next, using the optimal catalyst/solvent combination (8/ dichloromethane), other reaction parameters were modulated to improve the enantioselectivity (Table 2). We changed the reaction temperature (entries 1−4) and found that lowering the temperature to −30 °C could increase the enantioselectivity of the reaction to 84:16 er without obvious sacrifices in yield (entry 3 vs Table 1, entry 20). Thus, −30 °C was determined to be the best temperature for further optimization reactions. The addition of additives such as molecular sieves (MS) and anhydrous sulfates was detrimental to both the yield and enantioselectivity (entries 5−9). Then, we attempted to decrease the concentration of the reaction to enhance the enantioselectivity (entries 10−17). It was found that properly diluting the reaction to 0.125 M could slightly improve the 10227

DOI: 10.1021/acs.joc.7b01731 J. Org. Chem. 2017, 82, 10226−10233

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The Journal of Organic Chemistry Table 1. Screening of Catalysts and Optimization of the Reaction Conditionsa

entry

cat.

solvent

yield (%)b

erc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d 20d 21d 22d 23d 24d

4a 4b 4c 4d 4e 4f 4g 5 4e 4e 4e 4e 4e 6 7 8 8 8 8 8 8 8 8 8

EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc toluene CH3CN 1,4-dioxane acetone CH2ClCH2Cl EtOAc EtOAc EtOAc toluene CH2ClCH2Cl CH2ClCH2Cl CH2Cl2 CHCl3 CH3CCl3 CH2ClCHCl2 CHCl2CHCl2

83 77 93 22 48 trace trace 37 35 80 trace 44 77 trace trace 79 66 85 60 77 75 72 80 77

51:49 54:46 61:39 60:20 73:27

58:42 61:39 51:49 56:44 69:31

76:24 73:27 76:24 77:23 80:20 76:24 79:21 79:21 76:24

a Unless otherwise indicated, the reaction was carried out on a 0.1 mmol scale and catalyzed by 10 mol % 4−8 in 1 mL of solvent for 12 h, and the molar ratio of 1a:2a was 1:1.5. bIsolated yield. cThe er was determined by HPLC. dPerformed at 25 °C.

On one hand, the electron-donating p-OMeC6H4 substituent would make the terminal position of the alkenyl group in substrate 2d more nucleophilic, thus facilitating the [3 + 2] cycloaddition. On the other hand, in the possible transition state, the presence of p-OMeC6H4 as the R1 substituent might stabilize the favorable steric configuration, which would contribute to the excellent enantioselectivity. The structures of products 3 were determined by 1H NMR, 13 C NMR, IR, and HR-MS. The proposed mode by which CPN 8 activates the substrates is shown in Scheme 2. Specifically, the anion of CPN 8 simultaneously formed an ion pair interaction

and a hydrogen-bonding interaction with the carbocation formed in situ from 2-indolylmethanols 1 as well as a hydrogenbonding interaction with the OH group of p-hydroxystyrenes 2. The dual activation of both substrates by the catalyst allowed the enantioselective [3 + 2] cycloaddition, which afforded the chiral cyclopenta[b]indole skeleton. For verifying the suggested dual hydrogen-bonding activation mode, two control experiments were carried out by using N-methyl protected 2indolylmethanol (1i) and O-methyl-protected p-hydroxystyrene (2g) (Scheme 2, eqs 3 and 4). In these two cases, no reaction (N.R.) occurred, which demonstrated that the free N−H group in 2-indolylmethanols 1 and the free O−H group in p10228

DOI: 10.1021/acs.joc.7b01731 J. Org. Chem. 2017, 82, 10226−10233

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The Journal of Organic Chemistry Table 2. Further Optimization of Reaction Conditionsa

entry

x

T (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d 19e 20f

1 1 1 1 1 1 1 1 1 2 4 6 8 10 14 18 20 8 8 8

0 −10 −30 −50 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30 −30

additives

3 Å MS 4 Å MS 5 Å MS Na2SO4 MgSO4

yield (%)b

erc

74 74 75 57 19 trace 24 25 25 75 70 68 68 64 64 63 63 32 68 73

81:19 82:18 84:16 82:18 73:27

hydroxystyrenes 2 play an important role in forming hydrogen bonds with the anion of CPN 8. The monohydrogen-bonding activation mode of the catalyst to the substrate in the two control experiments led to failure of the reaction. Furthermore, to investigate whether the position of the hydroxyl group in substrates 2 would affect the reaction, we carried out two more control experiments using o-hydroxystyrene (2h) and m-hydroxystyrene (2i) as substrates (Scheme 3). However, no reaction occurred in either case (eqs 5 and 6). This outcome implied that the position of the hydroxyl group on substrates 2 played a crucial role in the catalytic asymmetric [3 + 2] cycloaddition with 2-indolylmethanols. Finally, to demonstrate the utility of the catalytic asymmetric [3 + 2] cycloaddition, we carried out a large-scale synthesis of product 3ca (Scheme 4). Compared with the small-scale reaction (Table 3, entry 3), this large-scale reaction smoothly afforded desired product 3ca in a nearly maintained high yield of 80% and with good enantioselectivity (90:10 er). This result indicated that this catalytic asymmetric [3 + 2] cycloaddition could be scaled up for the synthesis of chiral cyclopenta[b]indole derivatives.

71:29 81:19 82:18 83:17 83:17 84:16 85:15 81:19 79:21 75:25 75:25 80:20 83:17 83:17

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CONCLUSIONS In summary, we established the catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols with p-hydroxystyrenes in the presence of a chiral phosphoramide, which afforded chiral cyclopenta[b]indole scaffolds in generally high yields and with good enantioselectivities (up to 98% yield and 99:1 er, respectively). The control experiments demonstrated that the dual hydrogen-bonding activation mode of the chiral catalyst toward the two substrates played an important role in the reaction. In addition, the large-scale reaction indicated that this catalytic asymmetric [3 + 2] cycloaddition could be scaled up for the synthesis of chiral cyclopenta[b]indole derivatives. This

a

Unless otherwise indicated, the reaction was carried out on a 0.1 mmol scale and catalyzed by 10 mol % 8 in dichloromethane with additives (100 mg) for 12 h, and the molar ratio of 1a:2a was 1:1.5. b Isolated yield. cThe er was determined by HPLC. dCatalyzed by 5 mol % 8. eCatalyzed by 20 mol % 8. fCatalyzed by 30 mol % 8.

Table 3. Substrate Scope of Catalytic Asymmetric [3 + 2] Cycloadditiona

entry

3

R\Ar (1)

R2\R1 (2)

yield (%)b

erc

1 2 3 4 5 6 7 8 9e 10e 11 12e,f 13d 14e,g 15e

3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ab 3ac 3ad 3cd 3ed 3ae 3af

H\C6H5 (1a) 5-Br\C6H5 (1b) 5-Cl\C6H5 (1c) 6-Cl\C6H5 (1d) 6-Br\C6H5 (1e) 4,6-Cl2\C6H5 (1f) 6-Cl\m-FC6H4 (1g) H\m-FC6H4 (1h) H\C6H5 (1a) H\C6H5 (1a) H\C6H5 (1a) 5-Cl\C6H5 (1c) 6-Br\C6H5 (1e) H\C6H5 (1a) H\C6H5 (1a)

H\H (2a) H\H (2a) H\H (2a) H\H (2a) H\H (2a) H\H (2a) H\H (2a) H\H (2a) Cl\H (2b) F\H (2c) H\p-OMeC6H4 (2d) H\p-OMeC6H4 (2d) H\p-OMeC6H4 (2d) H\m,p-(OMe)2C6H3 (2e) H\m-Me,p-OMeC6H3 (2f)

68 87 84 83 74 50 45 48 70 80 85 98 98 38 59

85:15 90:10 91:9 90:10 85:15 91:9 90:10 88:12 85:15 85:15 97:3 85:15 99:1 87:13 85:15

a Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale in the presence of 10 mol % (S)-8 in dichloromethane (8 mL) at −30 °C for 12 h, and the molar ratio of 1:2 was 1:1.5. bIsolated yield. cThe er was determined by HPLC. dPerformed at 0 °C. ePerformed at 25 °C. fIn the presence of 20 mol % (R)-9. gIn the presence of 10 mol % (R)-8.

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reaction not only enriches the field of catalytic asymmetric transformations involving 2-indolylmethanol but also provides a useful method for constructing chiral cyclopenta[b]indole skeletons.

Scheme 2. Suggested Activation Mode and Control Experiments

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EXPERIMENTAL SECTION

1

H and 13C NMR spectra were measured at 400 and 100 MHz, respectively. The solvent used for NMR spectroscopy was CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by an HRMS/MS instrument. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography (chiral HPLC). The chiral columns used for the determination of enantiomeric ratios by chiral HPLC were Chiralpak OD-H and AD-H columns. Optical rotation values were measured with instruments operating at λ = 589 nm corresponding to the sodium D line at the temperatures indicated. Analytical grade solvents for the column chromatography were distilled before use. All starting materials commercially available were used directly. Substrates 1 were synthesized according to the literature method.10d General Procedure for the Synthesis of Cyclopenta[b]indoles 3. To the mixture of 2-indolylphenylmethanols 1 (0.1 mmol), p-hydroxylstyrenes 2 (0.15 mmol), and catalyst (S)-8 (0.01 mmol) was added dichloromethane (8 mL), which was stirred at −30 °C for 12 h. After the completion of the reaction, which was indicated by TLC, the reaction mixture was directly purified through preparative thin layer chromatography on silica gel to afford pure products 3. 4-(3,3-Diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3aa). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 68% yield (27.3 mg); white solid; mp 101−102 °C; [α]D20 −23.6 (c 0.36, acetone); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.61−7.56 (m, 3H), 7.37 (t, J = 7.5 Hz, 2H), 7.34−7.27 (m, 2H), 7.20−7.13 (m, 2H), 7.12−7.05 (m, 1H), 6.99 (t, J = 7.5 Hz, 2H), 6.69 (d, J = 7.9 Hz, 2H), 6.49 (d, J = 7.8 Hz, 2H), 6.42 (d, J = 8.0 Hz, 2H), 5.07 (t, J = 7.8 Hz, 1H), 4.55 (s, 1H), 3.31 (dd, J = 14.2, 7.2 Hz, 1H), 3.09 (dd, J = 14.2, 8.3 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 153.9, 146.4, 145.1, 142.1, 140.5, 133.1, 130.6, 129.7, 128.5, 128.0, 127.2, 126.6, 126.2, 124.5, 121.3, 119.8, 119.2, 117.7, 114.2, 111.9, 62.2, 59.5, 31.0; IR (KBr) 3734, 3019, 2359, 1513, 1303 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H22NO 400.1696, found 400.1699; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak OD-H, hexane/ isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 9.920 min (major); tR = 13.753 min (minor). 4-(7-Bromo-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3ba). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 87% yield (41.6 mg); white solid; mp 126−127 °C; [α]D20 −7.9 (c 0.69, acetone); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 6.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 6.49 (d, J = 8.1 Hz, 2H), 6.38 (d, J = 7.9 Hz, 2H), 5.06 (t, J = 7.8 Hz, 1H), 4.59 (s, 1H), 3.26 (dd, J = 14.3, 7.3 Hz, 1H), 3.04 (dd, J = 14.3, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.0, 147.8, 144.7, 141.8, 139.0, 132.7, 130.6, 129.6, 128.6, 128.0, 127.3, 126.7, 126.4, 126.1, 124.0, 121.8, 117.3, 114.3, 113.2, 113.1, 62.1, 59.4, 30.7; IR (KBr) 3749, 2341, 1516, 1137, 1026 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21BrNO 478.0801, found 478.0813; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0

Scheme 3. Control Experiments to Investigate the Role of the Position of the Hydroxyl Group

Scheme 4. A Large-Scale Synthesis of Product 3ca

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Article

The Journal of Organic Chemistry

Chiralpak OD-H, hexane/isopropanol = 95:5, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 23.620 min (major), tR = 31.703 min (minor). 4-(6-Chloro-3,3-bis(3-fluorophenyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3ga). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 45% yield (21.2 mg); white solid; mp 104−105 °C; [α]D20 −29.6 (c 0.31, acetone); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39−7.29 (m, 3H), 7.23 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07−6.91 (m, 2H), 6.80 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.17 (d, J = 7.8 Hz, 1H), 6.11 (d, J = 10.7 Hz, 1H), 4.97 (t, J = 7.6 Hz, 1H), 4.64 (s, 1H), 3.30 (dd, J = 14.5, 7.3 Hz, 1H), 3.07 (dd, J = 14.5, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.4, 162.9 (d, J = 246.5 Hz), 161.0, 154.3, 147.1, 147.0, 145.7, 144.2, 144.1, 140.8, 132.2, 130.4, 130.2, 130.1, 128.7, 128.6, 127.6, 125.2, 123.6, 123.6, 122.8, 120.8, 120.1, 118.3, 116.7, 116.5, 115.1 (d, J = 22.7 Hz), 114.5, 114.0, 113.8, 113.6, 113.4, 111.9, 62.1, 60.0, 30.7; IR (KBr) 3853, 3735, 2360, 1733, 1558, 1457, 1062 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H19ClF2NO 470.1118, found 470.1133; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 4.480 min (major), tR = 5.103 min (minor). 4-(3,3-Bis(3-fluorophenyl)-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3ha). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 48% yield (21.0 mg); white solid; mp 95−96 °C; [α]D20 −36.7 (c 0.48, acetone); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.38− 7.30 (m, 3H), 7.27−7.25 (m, 1H), 7.23−7.13 (m, 2H), 7.02−6.92 (m, 2H), 6.83−6.75 (m, 1H), 6.70 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 8.2 Hz, 2H), 6.22 (d, J = 7.9 Hz, 1H), 6.18−6.13 (m, 1H), 4.98 (t, J = 7.6 Hz, 1H), 4.67 (s, 1H), 3.34 (dd, J = 14.5, 7.3 Hz, 1H), 3.11 (dd, J = 14.5, 7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.4, 162.9 (d, J = 246.2 Hz), 161.0, 154.3, 147.1, 147.0, 145.7, 144.2, 144.1, 140.8, 132.2, 130.4, 130.1 (d, J = 8.3 Hz), 128.7, 128.6, 127.6, 125.2, 123.7, 123.6, 122.8, 120.8, 120.1, 118.3, 116.7, 116.5, 115.1 (d, J = 22.6 Hz), 114.5, 114.0, 113.8, 113.6, 113.4, 111.9, 62.1, 60.0, 30.7; IR (KBr) 3853, 3735, 2360, 1716, 1558, 1456, 1230 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H20F2NO 436.1507, found 436.1523; Enantiomeric ratio = 88:12, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 80:20, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 5.320 min (major), tR = 6.113 min (minor). 2-Chloro-4-(3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3ab). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 70% yield (30.6 mg); white solid; mp 98−99 °C; [α]D20 −34.7 (c 0.52, acetone); 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.62−7.53 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.35−7.27 (m, 2H), 7.22−7.14 (m, 2H), 7.15−7.08 (m, 1H), 7.03 (t, J = 7.6 Hz, 2H), 6.68 (d, J = 8.2 Hz, 3H), 6.45 (d, J = 8.0 Hz, 2H), 5.34 (s, 1H), 5.03 (t, J = 7.7 Hz, 1H), 3.34 (dd, J = 14.3, 7.3 Hz, 1H), 3.06 (dd, J = 14.3, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.7, 146.1, 144.9, 141.9, 140.6, 134.3, 129.8, 129.7, 129.4, 128.6, 127.9, 127.3, 126.7, 126.6, 124.4, 121.4, 119.9, 119.2, 118.8, 117.4, 115.0, 111.9, 62.2, 59.1, 31.2; IR (KBr) 3054, 2925, 2360, 1498, 1260, 1180 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21ClNO 434.1306, found 434.1301; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 80:20, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.570 min (minor), tR = 18.473 min (major). 4-(3,3-Diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)-2-fluorophenol (3ac). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 80% yield (33.5 mg); orange solid; mp 87−88 °C; [α]D20 −32.3 (c 0.53, acetone); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.58 (t, J = 8.3 Hz, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.35−7.28 (m, 2H), 7.21−7.14 (m, 2H), 7.10 (t, J = 7.2 Hz, 1H), 7.02 (t, J = 7.5 Hz, 2H), 6.67 (t, J = 8.7 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 6.50−6.39 (m, 3H), 5.04 (t, J = 7.7 Hz, 1H), 4.92 (s, 1H), 3.34 (dd, J = 14.3, 7.3 Hz, 1H), 3.06 (dd, J = 14.3, 8.1 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 150.1 (d, J = 236.2 Hz), 146.1, 144.9, 141.8, 141.7, 140.6, 134.2, 134.1, 129.6, 128.6, 127.9, 127.3, 126.7, 126.5, 125.8, 125.7, 124.4, 121.4, 119.9, 119.2, 117.4, 116.3 (d, J = 18.3 Hz), 115.9, 115.9, 111.9, 62.2, 59.2, 31.0; IR (KBr) 3649, 2926, 2360,

mL/min, T = 30 °C, 254 nm); tR = 6.870 min (major), tR = 8.787 min (minor). 4-(7-Chloro-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3ca). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 84% yield (36.6 mg); white solid; mp 114−115 °C; [α]D20 −12.8 (c 0.67, acetone); 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.61−7.51 (m, 3H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.14−7.05 (m, 2H), 7.00 (t, J = 7.5 Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 7.6 Hz, 2H), 5.06 (t, J = 7.8 Hz, 1H), 4.63 (s, 1H), 3.26 (dd, J = 14.3, 7.2 Hz, 1H), 3.04 (dd, J = 14.3, 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.4, 153.3, 147.5, 146.1, 140.1, 139.9, 139.5, 129.3, 129.1, 128.3, 128.2, 128.0, 126.4, 125.8, 125.4, 125.1, 121.7, 119.0, 114.6, 113.2, 112.8, 65.5, 57.1, 55.4, 55.2; IR (KBr) 3735, 2923, 2360, 1513, 1444, 1290, 1055 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21ClNO 434.1306, found 434.1300; Enantiomeric ratio = 91:9, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.550 min (major), tR = 7.697 min (minor). 4-(6-Chloro-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3da). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 83% yield (36.1 mg); white solid; mp 103−104 °C; [α]D20 −13.6 (c 0.59, acetone); 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.41−7.34 (m, 2H), 7.29 (s, 2H), 7.16−7.05 (m, 2H), 7.05−6.94 (m, 2H), 6.67 (d, J = 8.1 Hz, 2H), 6.49 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 8.0 Hz, 2H), 5.06 (t, J = 7.8 Hz, 1H), 4.60 (s, 1H), 3.28 (dd, J = 14.3, 7.3 Hz, 1H), 3.05 (dd, J = 14.3, 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 154.0, 147.1, 144.8, 141.9, 140.7, 132.8, 130.6, 129.6, 128.6, 128.0, 127.2, 127.1, 126.7, 126.4, 123.0, 120.5, 119.9, 117.7, 114.3, 111.8, 62.2, 59.5, 30.8; IR (KBr) 3853, 3751, 2359, 1734, 1513 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21ClNO 434.1306, found 434.1305; Enantiomeric ratio = 90:10, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.713 min (major), tR = 9.760 min (minor). 4-(6-Bromo-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol2-yl)phenol (3ea). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 74% yield (35.4 mg); yellow solid; mp 119−120 °C; [α]D20 −14.2 (c 0.43, acetone); 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.48−7.33 (m, 4H), 7.32−7.28 (m, 1H), 7.24 (s, 1H), 7.11−7.05 (m, 1H), 7.05−6.94 (m, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 8.0 Hz, 2H), 5.06 (t, J = 7.8 Hz, 1H), 4.63 (s, 1H), 3.27 (dd, J = 14.4, 7.3 Hz, 1H), 3.05 (dd, J = 14.4, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.1, 147.1, 144.8, 141.5, 141.1, 132.7, 130.6, 129.7, 128.6, 128.0, 127.2, 126.7, 126.4, 123.3, 123.1, 120.3, 117.7, 114.8, 114.6, 114.3, 62.2, 59.5, 30.8; IR (KBr) 3735, 2922, 2359, 1717, 1514, 1175 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21BrNO 478.0801, found 478.0807; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.983 min (major), tR = 10.330 min (minor). 4-(6,8-Dichloro-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3fa). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 50% yield (23.5 mg); white solid; mp 122−123 °C; [α]D20 −19.2 (c 0.48, acetone); 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 7.01 (t, J = 7.5 Hz, 2H), 6.67 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 8.0 Hz, 2H), 6.37 (d, J = 7.9 Hz, 2H), 5.06 (t, J = 7.9 Hz, 1H), 4.63 (s, 1H), 3.50 (dd, J = 14.7, 7.2 Hz, 1H), 3.22 (dd, J = 14.7, 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.1, 147.7, 144.5, 141.5, 140.7, 132.5, 130.6, 129.6, 128.6, 128.0, 127.3, 126.9, 126.8, 126.5, 125.9, 120.3, 117.3, 114.3, 110.6, 62.0, 59.5, 31.6; IR (KBr) 2926, 2360, 1550, 1513, 1105 cm−1; HRMS (ESITOF) m/z [M − H]− calcd for C29H20Cl2NO 468.0916, found 468.0905; Enantiomeric ratio = 91:9, determined by HPLC (Daicel 10231

DOI: 10.1021/acs.joc.7b01731 J. Org. Chem. 2017, 82, 10226−10233

Article

The Journal of Organic Chemistry 1717, 1517, 1457 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C29H21FNO 418.1602, found 418.1613; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 6.673 min (minor), tR = 7.683 min (major). 4-(2-(4-Methoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3ad). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 85% yield (43.1 mg); orange solid; mp 141−142 °C; [α]D20 −11.2 (c 0.72, acetone); 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.22−7.11 (m, 13H), 7.10−7.02 (m, 3H), 6.69 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.3 Hz, 2H), 4.71 (s, 1H), 3.93 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 153.2, 146.4, 146.4, 146.1, 141.3, 140.5, 140.4, 129.4, 129.2, 128.2, 128.1, 128.2, 128.1, 126.3, 126.2, 125.4, 124.5, 121.5, 120.1, 119.8, 114.5, 113.1, 111.9, 65.6, 57.1, 55.6, 55.2; IR (KBr) 3393, 1608, 1508, 1245, 1175, 1031 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C36H28NO2 506.2115, found 506.2119; Enantiomeric ratio = 97:3, determined by HPLC (Daicel Chiralpak OD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.777 min (minor), tR = 11.187 min (major). 4-(7-Chloro-2-(4-methoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3 cd). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 98% yield (53.0 mg); white solid; mp 118−119 °C; [α]D20 −10.8 (c 0.84, acetone); 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.26− 7.14 (m, 8H), 7.14−7.06 (m, 7H), 7.03 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.3 Hz, 2H), 4.71 (s, 1H), 3.91 (s, 2H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 153.3, 147.5, 146.2, 146.1, 140.1, 139.9, 139.5, 129.3, 129.1, 128.3, 128.2, 128.1, 128.0, 126.5, 126.4, 125.8, 125.4, 125.1, 121.7, 119.0, 114.6, 113.2, 112.8, 65.5, 57.1, 55.4, 55.2; IR (KBr) 3735, 2834, 2360, 1508, 1285, 1176 cm −1 ; HRMS (ESI-TOF) m/z [M − H] − calcd for C36H27ClNO2 540.1725, found 540.1728; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 10.660 min (major), tR = 14.490 min (minor). 4-(6-Bromo-2-(4-methoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3ed). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 98% yield (57.3 mg); yellow solid; mp 118−119 °C; [α]D20 −14.0 (c 0.39, acetone); 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.47 (s, 1H), 7.24−7.15 (m, 6H), 7.13 (d, J = 1.5 Hz, 2H), 7.12−7.05 (m, 6H), 7.02 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.3 Hz, 2H), 3.90 (s, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 153.4, 146.6, 146.1, 146.0, 141.9, 140.0, 139.9, 129.3, 129.0, 128.3, 128.2, 128.0, 127.9, 126.4, 126.3, 125.5, 123.4, 123.3, 120.7, 114.9, 114.8, 114.6, 113.1, 65.6, 58.5, 57.1, 55.4, 55.2; IR (KBr) 3710, 3689, 2359, 2341, 1716, 1507, 1457, 1030 cm−1; HRMS (ESITOF) m/z [M − H]− calcd for C36H27BrNO2 584.1220, found 584.1206; Enantiomeric ratio = 99:1, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 8.838 min (major), tR = 10.340 min (minor). 4-(2-(3,4-Dimethoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3ae). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 38% yield (20.5 mg); white solid; mp 101−102 °C; [α]D20 +7.5 (c 0.16, acetone); 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.25−7.14 (m, 8H), 7.14− 7.08 (m, 5H), 7.04 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 4.2 Hz, 2H), 6.63 (dd, J = 8.7, 3.1 Hz, 3H), 3.99 (d, J = 13.9 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.1, 147.1, 144.9, 141.8, 141.1, 132.7, 130.5, 129.6, 128.6, 128.0, 127.2, 126.7, 126.3, 123.1, 120.3, 117.7, 114.8, 114.3, 59.5, 58.5, 30.8, 29.7, 18.4; IR (KBr) 3735, 2961, 2360, 1490, 1261 cm−1; HRMS (ESITOF) m/z [M − H]− calcd for C37H30NO3 536.2220, found 536.2218; Enantiomeric ratio = 13:87, determined by HPLC (Daicel Chiralpak AD-H, hexane/isopropanol = 90:10, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 15.373 min (minor), tR = 20.533 min (major).

4-(2-(4-Methoxy-3-methylphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)phenol (3af). Preparative thin layer chromatography: petroleum ether/ethyl acetate = 5:1; reaction time = 12 h; 59% yield (30.7 mg); orange solid; mp 122−123 °C; [α]D20 −53 (c 0.33, acetone); 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.24−7.12 (m, 11H), 7.11−7.02 (m, 3H), 6.98 (d, J = 8.7 Hz, 1H), 6.89 (s, 1H), 6.59 (t, J = 7.5 Hz, 3H), 4.70 (s, 1H), 3.94 (d, J = 13.7 Hz, 1H), 3.87 (d, J = 13.8 Hz, 1H), 3.74 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.5, 153.2, 146.6, 146.5, 145.8, 141.3, 140.9, 139.9, 130.4, 129.3, 128.2, 128.2, 128.1, 126.4, 126.2, 126.2, 125.5, 124.5, 121.4, 120.0, 119.9, 114.5, 111.8, 109.1, 65.6, 57.1, 55.7, 55.2, 16.3; IR (KBr) 3853, 3676, 2359, 1749, 1507, 1245, 1132 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C37H30NO2 520.2271, found 520.2266; Enantiomeric ratio = 85:15, determined by HPLC (Daicel Chiralpak AD-H, hexane/ isopropanol = 70:30, flow rate 1.0 mL/min, T = 30 °C, 254 nm); tR = 3.480 min (major), tR = 3.887 min (minor).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01731. Characterization data, including 1H and 13C NMR and HPLC spectra, of products 3 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Feng Shi: 0000-0003-3922-0708 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from National Natural Science Foundation of China (21372002 and 21232007), PAPD, and Natural Science Foundation of Jiangsu Province (BK20160003).

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REFERENCES

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