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Article Cite This: J. Org. Chem. 2018, 83, 5931−5946

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Chemodivergent Tandem Cyclizations of 2‑Indolylmethanols with Tryptophols: C−N versus C−C Bond Formation Jing-Yi Wang,‡ Ping Wu,‡ Jia-Le Wu, Guang-Jian Mei,* and Feng Shi* School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China S Supporting Information *

ABSTRACT: A chemodivergent reaction of 2-indolylmethanols with tryptophols has been established via an interrupted Nazarov-type cyclization in the presence of Brønsted acid, leading to the efficient synthesis of two series of cyclopenta[b]indole derivatives in a broad substrate scope with high yields and excellent diastereoselectivities (42 examples, up to 99% yield, all >95:5 dr). It was found that the presence or absence of molecular sieves played an important role in controlling the chemoselectivity of the reaction. In the presence of 3 Å molecular sieves, tryptophol would utilize the nucleophilicity of its nitrogen atom to form a new C−N bond, while, in the absence of molecular sieves, tryptophol would utilize the nucleophilicity of its C2-position to generate a new C−C bond. Therefore, this reaction will provide a good example for additive-controlled chemoselectivity. In addition, this approach not only provides a useful strategy for the synthesis of structurally diversified cyclopenta[b]indoles but also demonstrates the practicability of 2-indolylmethanols in organic synthesis.

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INTRODUCTION

Moreover, synthetic compounds I−IV exhibit a broad scope of bioactivities such as antioxidant, being an antagonist of prostaglandin D2 receptor and being an agonist of progesterone receptor.3 As a result, continuous attention from the chemistry community has been paid to the synthesis of cyclopenta[b]indole derivatives.4 Chemodivergent reaction has proven to be one of the most important strategies for the generation of molecular diversity and complexity.5 From the same starting materials, chemodivergent reactions lead to different chemoselective processes.6 This chemodivergent strategy has not only been recognized as one of the most promising paradigms in drug discovery but has also become one of the main challenges in organic synthesis. In this regard, it is highly desired to develop chemodivergent reactions for the synthesis of cyclopenta[b]indole derivatives. Recently, indolylmethanols have emerged as versatile synthons in organic synthesis.7,8 Especially, 2-indolylmethanol-involved reactions have been widely employed in the synthesis of indole derivatives or indole-fused cyclic frameworks.9,10 However, the investigations on 2-indolymethannols are only limited to substitutions or cyclizations (Scheme 1). To the best of our knowledge, there is no report on the chemodivergent reactions of 2-indolymethannols.

Fused-polycyclic indoles represent one of the most important classes of heterocyclic compounds due to their versatile bioactivities.1 Among them, cyclopenta[b]indole frameworks are widely featured in biologically active natural products and synthetic compounds (Figure 1).2,3 For instance, the core structures of natural alkaloids Bruceolline J and Yeuhchukene are cyclopenta[b]indole frameworks. In addition, Yeuhchukene was reported to possess potent anti-implantation activity.2

Figure 1. Natural alkaloids and synthetic compounds containing the cyclopenta[b]indole scaffold. © 2018 American Chemical Society

Received: February 12, 2018 Published: May 7, 2018 5931

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry

occurred smoothly in toluene or chloroform, affording Nalkylation product 3aa through C−N bond formation in moderate yields (entries 5 and 6). It should be noted that the N-alkylation of indole derivatives has remained underdeveloped, possibly due to the low nucleophilicity of the N−H motif.18 Thus, inspired by this preliminary result, a series of Brønsted acids 5 were screened in chloroform (entries 6−11). The results revealed that Brønsted acids with strong acidity could successfully catalyze the reaction (entries 6−9) and Brønsted acid 5c was the best catalyst in terms of the yield (entry 8). However, Brønsted acids 5e and 5f with weak acidity failed to catalyze the reaction (entries 10 and 11). Therefore, 5c was selected as the optimal catalyst for subsequent condition optimization. It was found that additives had a significant effect on the reaction (entries 12−16). The reaction could not occur with 4 Å molecular sieves (entry 12). When employing 5 Å MS, MgSO4, and Na2SO4 as additives, a mixture of products 3aa (generated via C−N bond formation) and 4aa (generated via C−C bond formation) was observed (entries 13−15). Interestingly, in the absence of additives, 4aa was isolated as the sole product (entry 16). Therefore, this result provided a good opportunity for us to control the chemoselectivity of the reaction by adding 3 Å MS as additives or removing the additives. Subsequently, we were pleased to find that the yield of product 3aa or 4aa could be improved to an excellent or good level by increasing the equivalent ratio of substrate 1a (entries 17−19 and entries 20−22). In addition, the yield of 4aa could be further improved at a higher temperature or using a larger amount of catalyst 5c (entries 23 and 24), but further elevating the reaction temperature led to a slight decrease in the yield (entry 25). Finally, the optimal reaction conditions for this chemodivergent cyclization of 2-indolylmethanol 1a with tryptophol 2a were selected as those shown in entry 18 (for C− N bond formation) and entry 24 (for C−C bond formation), which afforded the corresponding products 3aa and 4aa in excellent yields of 97 and 83%, respectively. With the optimal reaction conditions in hand, we then carried out the investigation on the substrate scope of the interrupted Nazarov-type cyclization of 2-indolylmethanols 1 with tryptophols 2 through a C−N bond formation. As shown in Table 2, all reactions between various 2-indolylmethanols 1 and tryptophols 2 worked smoothly, providing tryptopholsubstituted cyclopenta[b]indoles 3 via C−N bond formation in moderate to excellent yields (57−99%). It seemed that the position and the electronic nature of the substituents (R/R1/ R2) of 2-indolylmethanols 1 had some delicate impacts on the yield. For instance, when R was a substituted phenyl group, a slight decrease in the yield was observed (entry 1 vs entries 2 and 3). Moreover, various substituted aryl groups (R1) at the terminal position of the alkenyl groups were tolerated (entries 4−10). It seemed that the electronic nature of the R2 group had some influence on the yield because 2-indolylmethanols 1m and 1n bearing electron-donating groups on the indole ring were superior to their counterpart 1l substituted with an electron-withdrawing group in terms of the yield (entry 11 vs entries 12 and 13). However, changing the position of the chloro group (entry 11 vs entry 14), the corresponding products 3la and 3oa were obtained in the same level of yield. Besides, a wide range of tryptophols 2 bearing various substituents on the benzene ring could be successfully employed in this reaction (entries 15−22). Among them, an excellent yield of 99% was obtained in the reaction of C5fluoro-substituted tryptophol 2d (entry 17). It should be noted

Scheme 1. Profile of 2-Indolymethanol-Involved Reactions

Recently, we established catalytic asymmetric interrupted Nazarov-type cyclizations of C3-alkenyl-substituted 2-indolymethanols with nucleophiles such as indoles (Scheme 2a).11,12 Scheme 2. Chemodivergent Reaction of C3-AlkenylSubstituted 2-Indolymethanols

When we utilize tryptophols as nucleophiles, we find a chemodivergent reaction of C3-alkenyl-substituted 2-indolylmethanols with tryptophols via an interrupted Nazarov-type cyclization process,13−16 leading to the synthesis of two series of cyclopenta[b]indole derivatives via carbon−nitrogen (C−N) or carbon−carbon (C−C) bond formation (Scheme 2b). Herein, we report the details on the chemodivergent reaction of 2-indolylmethanols with tryptophols in the presence of Brønsted acid, which led to the efficient synthesis of two series of cyclopenta[b]indole derivatives in a broad substrate scope with high yields and excellent diastereoselectivities (42 examples, up to 99% yield, all >95:5 dr). It should be noted that N-unprotected indole derivatives have two nucleophilic sites: one is indole C3 or C2-position; another is indole N1position. Therefore, how to control the chemoselectivity of the reaction is a great challenge. In this work, we find the chemoselectivity of the reaction between 2-indolylmethanols and tryptophols can be controlled by adding 3 Å molecular sieves.

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RESULTS AND DISCUSSION Our investigation was initiated by the model reaction between 2-indolylmethanol 1a and tryptophol 2a under Brønsted acid catalysis17 (Table 1). First, the solvent effect was examined by screening a series of solvents under the catalysis of phosphoric acid 5a at 30 °C in the presence of 3 Å molecular sieves (MS) because water would be generated during the reaction process (entries 1−6). To our delight, the interrupted Nazarov-type cyclization of 2-indolylmethanols 1a with tryptophols 2a 5932

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

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

entry

5

solvent

T (°C)

1a:2a

additives

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24c 25c

5a 5a 5a 5a 5a 5a 5b 5c 5d 5e 5f 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c

acetone CH3CN THF EtOAc toluene CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 40 40 50

1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1:1.2 1.2:1 1.5:1 1.8:1 1.2:1 1.5:1 1.8:1 1.8:1 1.8:1 1.8:1

3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 3 Å MS 4 Å MS 5 Å MS MgSO4 Na2SO4 3 Å MS 3 Å MS 3 Å MS

product

yieldb (%)

3aa 3aa 3aa 3aa 3aa

54 60 58 79 49

3aa/4aa 3aa/4aa 3aa/4aa 4aa 3aa 3aa 3aa 4aa 4aa 4aa 4aa 4aa 4aa

46/12 15/48 47/24 50 87 97 91 58 63 74 79 83 78

a

Unless indicated otherwise, the reaction was carried out at 0.05 mmol scale and catalyzed by 10 mol % 5 in a solvent (1 mL) for 8 h. bIsolated yield and only one diastereomer was observed in all cases. cCatalyzed by 20 mol % 5c.

that only one diastereomer of products 3 was observed in all cases (all >95:5 dr). Next, the generality of the interrupted Nazarov-type cyclization of 2-indolylmethanols 1 with tryptophols 2 through a C−C bond formation was examined (Table 3). First, this reaction was applicable to a variety of 2-indolylmethanols 1 with distinct R/R1/R2 substituents (entries 1−8). Among them, R groups could be various aryl groups bearing different substituents, which gave the corresponding products 4 in generally good yields (entries 2−4). Besides, excellent yields could be obtained when R1 substituents were electron-poor aryl groups (entries 5 and 6). The electronic nature of the R2 substituents might have a significant impact on the reactivity. For example, when the R2 substituent was a methyl group, an excellent yield could be observed (entry 7). However, there was a significant decrease in the yield when the R2 substituent was a strong electron-rich methoxy group (entry 8). Then, the applicability of tryptophols 2 was examined (entries 9−16). The results indicated that tryptophols 2 bearing electronwithdrawing substituents (2c, 2d, 2g, and 2j) were superior to their counterparts (2e, 2f, 2i, and 2k) substituted with electrondonating groups at the same position in terms of the yield

(entries 9 and 10 vs entries 11 and 12; entry 13 vs entry 14; entry 15 vs entry 16). Furthermore, all reactions proceeded with excellent diastereoselectivities (all >95:5 dr). It was worth noting that 3-(1H-indol-3-yl)propan-1-ol 2l could also be employed as a suitable substrate for this chemodivergent interrupted Nazarov-type cyclization of 2indolylmethanol. As shown in Scheme 3a, the reaction of 2indolylmethanol 1a with substrate 2l occurred smoothly under optimal reaction conditions, affording cyclopenta[b]indole products 3al and 4al in a chemodivergent manner with moderate to good yields and excellent diastereoselectivities. Moreover, N-methyl 2-indolylmethanol 1p could also be utilized for this reaction, which generated the corresponding products 3pa and 4pa in high yields and excellent diastereoselectivities (Scheme 3b). The structures of all products 3 and 4 were unambiguously assigned by 1H and 13C NMR, IR, and HRMS. Moreover, the relative configurations of products 3aa and 4aa were unambiguously determined to be trans by single crystal X-ray diffraction analysis (Figures S1 and S2 in the Supporting Information).19 The relative configurations of other products 3 and 4 were assigned by analogy. 5933

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry Table 2. Chemoselective Synthesis of Products 3 via C−N Bond Formationa

entry

3

R/R1/R2(1)

R3(2)

drb

yieldc (%)

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

3aa 3ba 3ca 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ak

Ph/Ph/H(1a) p-FC6H4/Ph/H(1b) p-MeC6H4/Ph/H(1c) Ph/p-ClC6H4/H(1e) Ph/p-FC6H4/H(1f) Ph/p-MeOC6H4/H(1g) Ph/m-ClC6H4/H(1h) Ph/m-MeC6H4/H(1i) Ph/o-FC6H4/H(1j) Ph/o-MeC6H4/H(1k) Ph/Ph/5-Cl(1l) Ph/Ph/5-Me(1m) Ph/Ph/5-MeO(1n) Ph/Ph/6-Cl(1o) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a)

H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) 5-Br(2b) 5-Cl(2c) 5-F(2d) 5-Me(2e) 5-MeO(2f) 6-Cl(2g) 6-F(2h) 7-MeO(2k)

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

97 78 81 94 67 91 85 69 74 78 62 99 95 70 80 88 99 84 77 57 63 61

a

Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale and catalyzed by 10 mol % 5c in CHCl3 (1 mL) with 3 Å MS (50 mg) at 30 °C for 3 h, and the molar ratio of 1:2 was 1.5:1. bDetermined by 1H NMR. cIsolated yield.

conditions, both of the two substrates 2p and 2q failed to participate in the reaction, and only the byproduct 8 was generated. These phenomena indicated that the existence of the OH group in the structure of substrates 2 played a crucial role in controlling the reactivity. On the basis of the experimental results and previous reports on the effect of molecular sieves,20 a possible reaction pathway was suggested to explain the observed chemoselectivity (Scheme 7). As exemplified by the formation of products 3aa and 4aa, under the catalysis of Brønsted acid 5c, the active carbocations A and B were generated from 2-indolylmethanol 1a via dehydration. Then, the sequential 4π electrocyclization of the carbocation intermediate resulted in a cyclopenta[b]indole carbocation intermediate C, which would be trapped by tryptophol 2a in a chemodivergent manner. In the presence of a 3 Å MS (path A), the water molecules generated from dehydration would be absorbed by the 3 Å MS, which would not affect the nucleophilicity of the nitrogen atom in the indole ring. In addition, the anion of catalyst 5c would act as a base to deprotonate the N−H group, thus increasing the nucleophilicity of the nitrogen atom. At the same time, the anion of catalyst 5c simultaneously generated a hydrogen bond with the OH group of tryptophol 2a and produced an ion pair interaction with the carbocation intermediate C, which facilitated a chemoselective nucleophilic attack of the nitrogen atom to carbocation C and led to the formation of product 3aa via C−N bond formation. On the contrary, in the absence of molecular sieves (path B), the water molecules generated from dehydration would form a hydrogen bond with the nitrogen

In addition, to further explore the scope and limitation of this chemodivergent reaction, 2-indolylmethanols 1q and 1r bearing a methyl group adjacent to the hydroxy functionality were employed as substrates to react with tryptophol 2a under the two standard conditions (Scheme 4). In the case of 2indolylmethanols 1q, tryptophol 2a failed to participate in the reaction and only a self-dimerization product 6 of substrate 1q was generated (Scheme 4a). In the case of 2-indolylmethanols 1r, only a self-cyclization product 7 of substrate 1q was observed (Scheme 4b), which might be formed via a dehydration/cyclization/oxidation sequence (Scheme 4c). These results implied that the two phenyl groups adjacent to the hydroxy functionality in the structures of 2-indolylmethanols 1 were necessary for perfoming the reaction between substrates 1 and 2. Moreover, other aromatic nucleophiles such as pyrrole 2m, benzofuran 2n, and benzothiophene 2o were utilized as substrates to react with 2-indolylmethanol 1a under the two standard conditions (Scheme 5). However, none of them could take part in the reaction, and only a byproduct 8 was generated by the Nazarov cyclization of substrate 1a. These outcomes demonstrated that the selection of a suitable aromatic nucleophile is very important for accomplishing the interrupted Nazarov-type cyclization. In order to gain some insights into the activation mode of the catalyst to substrates 2, we performed some control experiments (Scheme 6). When using tryptamine 2p and TBSprotected tryptophol 2q to replace tryptophol 2a as substrates to react with 2-indolylmethanol 1a under the two standard 5934

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

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The Journal of Organic Chemistry

reactions of 2-indolylmethanols with tryptophols were performed under the standard conditions, which generated the corresponding cyclopenta[b]indole products 3ad and 4ad in high yields and with excellent diastereoselectivities (Scheme 8). Finally, we carried out a preliminary investigation on the catalytic asymmetric version of this chemodivergent reaction. It was found that, either in the presence or in the absence of 3 Å MS, the reaction of 1a with 2a under the catalysis of chiral phosphoric acid (CPA) 9a could only generate product 3aa, and no product 4aa was observed. Therefore, we screened a series of CPAs 9 in the presence of a 3 Å MS. As shown in Table 4, most of CPAs 9 could catalyze the reaction apart from 9c and 9e (entries 3 and 5). Among them, CPA 9d bearing two 3,3′-(9-phenanthrenyl) groups displayed the highest capability in controlling the enantioselectivity of the reaction, which could afford product 3aa in a moderate enantioselectivity of 50% ee (entry 4). This result indicated that it is promising to develop a catalytic asymmetric version of this reaction after further optimization of reaction conditions.

Table 3. Chemoselective Synthesis of Products 4 via C−C Bond Formationa

entry

4

R/R1/R2(1)

R3(2)

drb

yieldc (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

4aa 4ba 4ca 4da 4fa 4ha 4ma 4na 4ac 4ad 4ae 4af 4ag 4ai 4aj 4ak

Ph/Ph/H(1a) p-FC6H4/Ph/H(1b) p-MeC6H4/Ph/H(1c) m-FC6H4/Ph/H(1d) Ph/p-FC6H4/H(1f) Ph/m-ClC6H4/H(1h) Ph/Ph/5-Me(1m) Ph/Ph/5-MeO(1n) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a) Ph/Ph/H(1a)

H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) H(2a) 5-Cl(2c) 5-F(2d) 5-Me(2e) 5-MeO(2f) 6-Cl(2g) 6-Me(2i) 7-Me(2j) 7-MeO(2k)

>95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5

83 92 80 95 99 99 99 47 79 97 77 67 99 75 91 66

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CONCLUSIONS

In summary, we have established a chemodivergent reaction of 2-indolylmethanols with tryptophols via an interrupted Nazarov-type cyclization in the presence of Brønsted acid, leading to the efficient synthesis of two series of cyclopenta[b]indole derivatives in a broad substrate scope with high yields and excellent diastereoselectivities (42 examples, up to 99% yield, all >95:5 dr). It was found that the presence or absence of molecular sieves played an important role in controlling the chemoselectivity of the reaction. In the presence of 3 Å molecular sieves, tryptophol would utilize the nucleophilicity of its nitrogen atom to form a new C−N bond, while, in the absence of molecular sieves, tryptophol would utilize the nucleophilicity of its C2-position to generate a new C−C bond. Therefore, this reaction will provide a good example for additive-controlled chemoselectivity. In addition, this approach not only provides a useful strategy for the synthesis of structurally diversified cyclopenta[b]indoles but also demonstrates the practicability of 2-indolylmethanols in organic synthesis, which will greatly enrich the chemistry of 2indolylmethanols.

a

Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale and catalyzed by 20 mol % 5c in CHCl3 (1 mL) at 40 °C for 8 h, and the molar ratio of 1:2 was 1.8:1. bDetermined by 1H NMR. c Isolated yield.

atom in the indole ring, thus greatly decreasing the nucleophilicity of the nitrogen atom. Therefore, in this case, tryptophol 2a would utilize its C2-nucleophilicity to attack carbocation C via a dual activation mode of the anion of catalyst 5c to substrate 2a and intermediate C, thus leading to the generation of product 4aa via C−C bond formation. The observed trans-configuration of products might be attributed to avoiding the steric hindrance between the indole ring and the adjacent phenyl group. Besides, to demonstrate the utility of this chemodivergent interrupted Nazarov-type cyclization, two 1 mmol scale Scheme 3. Further Substrate Expansion

5935

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry Scheme 4. Using 2-Indolylmethanols 1q and 1r as Substrates

available reagents were used as received. Substrates 1 were prepared according to the procedures in the literature.11 General Procedure for the Synthesis of Products 3. To the mixture of 2-indolylmethanols 1 (0.15 mmol), tryptophols 2 (0.1 mmol), catalyst 5c (0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction which was indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography to afford pure products 3. 2-(1-(2,3,3-Triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)1H-indol-3-yl)ethanol (3aa). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3aa (52.7 mg) in 97% yield as white solid. mp 94−95 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.21 (m, 1H), 7.18−7.12 (m, 2H), 7.11−6.98 (m, 9H), 6.90 (s, 1H), 6.79 (d, J = 7.2 Hz, 2H), 6.55 (d, J = 7.6 Hz, 2H), 6.29 (d, J = 5.4 Hz, 1H), 5.18 (d, J = 4.0 Hz, 1H), 3.80−3.74 (m, 2H), 2.91 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.3, 144.8, 142.7, 141.0, 136.6, 129.8, 129.7, 128.7, 127.7, 127.5, 127.0, 126.9, 126.7, 123.5, 122.4, 121.5, 120.7, 119.3, 118.9, 118.7, 116.5, 112.2, 110.7, 68.5, 62.6, 61.7, 28.7; IR (KBr): 3299, 3053, 2920, 1491, 1458, 1034, 742, 702 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H32N2ONa 567.2407, found 567.2425. 2-(1-(3,3-Bis(4-fluorophenyl)-2-phenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ba). Following the general procedure, to the mixture of (E)-bis(4fluorophenyl)(3-styryl-1H-indol-2-yl)methanol 1b (65.6 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ba (45.2 mg) in 78% yield as white solid. mp 98−99 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46−7.39 (m, 3H), 7.25−7.21 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.10−7.03 (m, 4H), 7.02 (d, J = 1.6 Hz, 2H), 7.00

Scheme 5. Using Other Aromatic Nucleophiles 2 as Substrates

Scheme 6. Control Experiments

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EXPERIMENTAL SECTION

1

H and 13C NMR spectra were measured at 400 and 100 MHz, respectively. The solvents used for NMR spectroscopy were acetone-d6 and CDCl3, using tetramethylsilane as the internal reference. HRMS (ESI) was determined by a HRMS/MS instrument. The X-ray source used for the single crystal X-ray diffraction analysis of compounds 3aa and 4aa was Mo Kα (λ = 0.71073), and the thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column chromatography were used after distillation, and commercially 5936

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry Scheme 7. Suggested Reaction Pathway

Table 4. Preliminary Investigation on the Catalytic Asymmetric Versiona

Scheme 8. One mmol Scale Synthesis

(s, 1H), 6.96 (t, J = 5.6 Hz, 2H), 6.86 (s, 1H), 6.79−6.67 (m, 4H), 6.50−6.37 (m, 2H), 6.24 (d, J = 5.6 Hz, 1H), 5.05 (s, 1H), 3.83−3.71 (m, 2H), 2.97−2.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.6 (J = 245 Hz), 141.1, 140.4, 138.2, 136.7, 131.2 (J = 8 Hz), 129.7, 129.3 (J = 8 Hz), 128.0, 127.2, 123.5, 122.7, 121.6, 121.0, 119.4, 119.0, 118.9, 116.6, 115.6 (J = 21 Hz), 114.3 (J = 21 Hz), 112.2, 110.9, 68.9, 62.6, 60.8, 54.7, 28.7; IR (KBr): 3256, 3058, 2916, 1601, 1506, 1458, 1225, 1161, 738 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H30F2N2ONa 603.2219, found 603.2232. 2-(1-(2-Phenyl-3,3-di-p-tolyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ca). Following the general procedure, to the mixture of (E)-(3-styryl-1H-indol-2-yl)di-p-tolylmethanol 1c (64.4 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ca (46.2 mg) in 81% yield as white solid. mp 83−84 °C; >95:5 dr; 1H NMR

entry

cat.

yieldb (%)

drc

eed (%)

1 2 3 4 5 6 7

9a 9b 9c 9d 9e 9f 9g

68 58 trace 58 trace 47 36

>95:5 >95:5

4 29

>95:5

50

>95:5 >95:5

20 33

a

Unless indicated otherwise, the reaction was carried out at 0.1 mmol scale and catalyzed by 20 mol % 9 in CHCl3 (1 mL) with 3 Å MS (50 mg) at 30 °C for 4 h, and the molar ratio of 1a:2a was 1.5:1. bIsolated yield. cDetermined by 1H NMR and HPLC. dDetermined by HPLC. (400 MHz, acetone-d6) δ 10.35 (s, 1H), 7.54 (d, J = 8.4 Hz, 3H), 7.45 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.14−7.09 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.05−6.92 (m, 7H), 6.91−6.83 (m, 5H), 6.45− 6.23 (m, 3H), 5.26 (d, J = 6.4 Hz, 1H), 3.73−3.63 (m, 2H), 3.43 (t, J = 5.4 Hz, 1H), 2.86−2.82 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 147.7, 142.3, 141.7, 140.4, 139.2, 136.7, 136.0, 135.8, 130.1, 129.5, 128.9, 128.0, 127.9, 127.4, 126.6, 123.4, 121.6, 120.8, 119.8, 118.7, 118.6, 118.5, 116.1, 112.4, 110.2, 68.8, 62.4, 5937

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry

707, 668 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2533. 2-(1-(2-(3-Chlorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ha). Following the general procedure, to the mixture of (E)-(3-(3chlorostyryl)-1H-indol-2-yl)diphenylmethanol 1h (65.3 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford >95:5 dr 3ha (49.4 mg) in 85% yield as white solid. mp 68−69 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.51−7.39 (m, 3H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.20 (m, 1H), 7.18−7.12 (m, 2H), 7.10−6.95 (m, 7H), 6.94−6.89 (m, 1H), 6.86 (s, 1H), 6.68 (d, J = 7.2 Hz, 2H), 6.54 (d, J = 7.6 Hz, 2H), 6.23 (d, J = 5.2 Hz, 1H), 5.09 (s, 1H), 3.83−3.71 (m, 2H), 2.91 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.0, 144.5, 142.4, 141.2, 136.6, 133.6, 129.8, 129.6, 128.9, 128.8, 128.5, 128.0, 127.7, 127.6, 127.5, 127.2, 127.0, 125.4, 123.5, 122.6, 121.7, 120.9, 119.3, 119.1, 118.9, 116.2, 112.2, 111.0, 110.5, 68.0, 62.7, 61.9, 55.1, 28.7; IR (KBr): 3407, 3236, 3055, 2922, 1458, 1036, 742, 706 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2014. 2-(1-(3,3-Diphenyl-2-(m-tolyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ia). Following the general procedure, to the mixture of (E)-(3-(3-methylstyryl)-1H-indol-2yl)diphenylmethanol 1i (62.2 mg, 0.15 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ia (38.4 mg) in 69% yield as white solid. mp 81−82 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.27 (s, 2H), 7.25 (s, 1H), 7.21−7.09 (m, 5H), 7.07−7.01 (m, 2H), 7.00−6.89 (m, 4H), 6.88−6.82 (m, 2H), 6.79 (s, 1H), 6.73 (d, J = 7.2 Hz, 2H), 6.67 (s, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.28 (d, J = 3.2 Hz, 1H), 3.79− 3.65 (m, 2H), 2.97−2.77 (m, 2H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.4, 145.6, 142.2, 141.5, 136.4, 129.8, 129.0, 128.4, 127.8, 127.2, 126.8, 126.5, 125.5, 124.7, 123.6, 122.5, 121.6, 120.9, 119.4, 119.1, 118.8, 115.9, 112.2, 110.4, 110.1, 64.6, 62.8, 62.4, 54.4, 28.6, 20.6; IR (KBr): 3546, 3285, 3057, 2920, 1700, 1487, 1451, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2555. 2-(1-(2-(2-Fluorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ja). Following the general procedure, to the mixture of (E)-(3-(2fluorostyryl)-1H-indol-2-yl)diphenylmethanol 1j (62.8 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ja (41.9 mg) in 74% yield as white solid. mp 88−89 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.47−7.41 (m, 3H), 7.31−7.27 (m, 2H), 7.23 (t, J = 7.2 Hz, 3H), 7.13−7.07 (m, 3H), 7.06−7.00 (m, 5H), 6.80 (t, J = 7.4 Hz, 1H), 6.78−6.70 (m, 3H), 6.67 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 4.4 Hz, 1H), 5.47 (d, J = 4.4 Hz, 1H), 3.78−3.68 (m, 2H), 2.95− 2.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.7 (J = 240 Hz), 148.1, 144.8, 142.5, 141.3, 136.6, 130.5, 129.6, 128.8, 128.6, 128.5, 127.7, 127.5, 127.0, 126.8, 124.6, 123.5, 123.4, 122.6, 120.8, 119.3, 119.0, 118.9, 116.2, 115.0 (J = 23 Hz), 112.2, 110.7, 110.2, 67.6, 62.7, 62.1, 54.1, 28.7; IR (KBr): 2917, 2849, 1511, 1459, 1254, 1178, 743, 704 cm −1 ; HRMS (ESI-TOF) m/z: [M + Na] + calcd for C39H31FN2ONa 585.2313, found 585.2335. 2-(1-(3,3-Diphenyl-2-(o-tolyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ka). Following the general

61.1, 54.6, 28.6, 20.1, 19.9; IR (KBr): 3252, 3053, 2924, 1579, 1452, 1256, 1009, 744, 708 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C41H36N2ONa 595.2721, found 595.2713. 2-(1-(2-(4-Chlorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ea). Following the general procedure, to the mixture of (E)-(3-(4chlorostyryl)-1H-indol-2-yl)diphenylmethanol 1e (65.3 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ea (54.4 mg) in 94% yield as white solid. mp 72−73 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49−7.40 (m, 3H), 7.33 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.24−7.20 (m, 1H), 7.17−7.11 (m, 2H), 7.09−7.03 (m, 4H), 7.02−6.91 (m, 4H), 6.87 (s, 1H), 6.68 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 7.6 Hz, 2H), 6.19 (d, J = 5.6 Hz, 1H), 5.10 (s, 1H), 3.83−3.73 (m, 2H), 2.91 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 144.5, 142.4, 141.1, 132.8, 131.1, 129.7, 128.8, 127.9, 127.7, 127.6, 127.2, 127.0, 123.5, 122.6, 121.6, 120.8, 119.3, 119.1, 118.9, 116.3, 112.2, 111.0, 110.4, 67.8, 62.7, 61.7, 55.6, 28.7; IR (KBr): 3278, 3056, 2923, 2852, 1706, 1458, 1288, 741, 701 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2033. 2-(1-(2-(4-Fluorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3fa). Following the general procedure, to the mixture of (E)-(3-(4fluorostyryl)-1H-indol-2-yl)diphenylmethanol 1f (62.8 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3fa (37.4 mg) in 67% yield as white solid. mp 98−99 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.20 (m, 1H), 7.17−7.11 (m, 2H), 7.09−7.03 (m, 4H), 7.02−6.92 (m, 2H), 6.89 (s, 1H), 6.74−6.65 (m, 4H), 6.51 (d, J = 7.6 Hz, 2H), 6.20 (d, J = 5.6 Hz, 1H), 5.12 (s, 1H), 3.82−3.72 (m, 2H), 2.92 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.8 (J = 240 Hz), 144.6, 142.6, 141.1, 136.7, 131.3 (J = 8 Hz), 129.7, 128.8, 127.7, 127.6, 127.1, 127.0, 123.5, 122.5, 121.6, 120.8, 119.3, 119.0, 118.9, 116.3, 114.6 (J = 21 Hz), 112.2, 110.9, 110.4, 67.7, 62.7, 61.6, 54.6, 28.7; IR (KBr): 3289, 3056, 2956, 1698, 1603, 1509, 1459, 1229, 833, 746, 701 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H32FN2O 563.2493, found 563.2487. 2-(1-(2-(4-Methoxyphenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ga). Following the general procedure, to the mixture of (E)-(3-(4methoxystyryl)-1H-indol-2-yl)diphenylmethanol 1g (64.6 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ga (52.5 mg) in 91% yield as white solid. mp 90−91 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.23−7.19 (m, 1H), 7.16−7.09 (m, 2H), 7.08−7.02 (m, 4H), 6.97 (d, J = 3.6 Hz, 2H), 6.91 (s, 1H), 6.62 (t, J = 9.4 Hz, 2H), 6.55−6.47 (m, 4H), 6.17 (d, J = 5.6 Hz, 1H), 5.10 (d, J = 4.8 Hz, 1H), 3.82−3.72 (m, 2H), 3.68 (s, 3H), 2.92 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 158.5, 144.8, 142.8, 141.0, 136.8, 136.5, 130.9, 129.7, 128.7, 128.5, 127.8, 127.6, 127.0, 126.8, 123.6, 122.5, 122.4, 122.2, 121.5, 120.7, 119.5, 119.3, 118.9, 118.8, 116.6, 113.1, 112.2, 111.2, 110.7, 67.8, 62.6, 61.5, 55.1, 54.9, 28.7; IR (KBr): 2359, 1245, 1035, 1005, 800, 744, 5938

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry procedure, to the mixture of (E)-(3-(2-methylstyryl)-1H-indol-2yl)diphenylmethanol 1k (62.2 mg, 0.15 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ka (43.3 mg) in 78% yield as white solid. mp 86−87 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.30−7.27 (m, 2H), 7.25 (s, 1H), 7.22−7.16 (m, 3H), 7.15−7.08 (m, 2H), 7.04 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 7.4 Hz, 2H), 6.91 (t, J = 8.6 Hz, 2H), 6.86−6.80 (m, 2H), 6.79−6.69 (m, 3H), 6.66 (s, 1H), 6.24 (d, J = 2.4 Hz, 1H), 5.27 (d, J = 3.2 Hz, 1H), 3.79−3.67 (m, 2H), 2.94−2.78 (m, 2H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.5, 145.6, 142.2, 141.5, 136.4, 129.8, 129.0, 128.4, 127.8, 127.2, 126.8, 126.5, 125.5, 123.6, 122.5, 121.6, 120.9, 119.4, 119.1, 118.8, 115.9, 112.2, 110.4, 110.1, 64.6, 62.8, 62.4, 55.3, 28.6, 20.6; IR (KBr): 3395, 3056, 2928, 1700, 1455, 1033, 740, 702, 657 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2572. 2-(1-(7-Chloro-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3la). Following the general procedure, to the mixture of (E)-(5-chloro-3-styryl-1H-indol-2-yl)diphenylmethanol 1l (65.3 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3la (36.0 mg) in 62% yield as white solid. mp 91−92 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.40−7.27 (m, 4H), 7.20−7.10 (m, 3H), 7.08−7.01 (m, 4H), 7.00−6.88 (m, 4H), 6.82 (s, 1H), 6.71 (d, J = 6.8 Hz, 2H), 6.46 (d, J = 7.6 Hz, 2H), 6.20 (s, 1H), 5.13 (s, 1H), 3.85− 3.67 (m, 2H), 2.91 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 144.5, 142.5, 139.3, 136.6, 129.8, 129.6, 128.8, 127.8, 127.7, 127.6, 127.2, 127.0, 126.9, 126.5, 124.6, 122.8, 121.6, 119.1, 118.9, 118.8, 116.3, 113.1, 111.1, 110.5, 68.1, 62.6, 61.6, 54.6, 28.7; IR (KBr): 3379, 3056, 2923, 1669, 1457, 1355, 1081, 742 cm−1; HRMS (ESI-TOF) m/ z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2014. 2-(1-(7-Methyl-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ma). Following the general procedure, to the mixture of (E)-(5-methyl-3-styryl-1H-indol-2yl)diphenylmethanol 1m (62.2 mg, 0.15 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ma (65.1 mg) in 99% yield as white solid. mp 62−63 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.36−7.30 (m, 3H), 7.27 (s, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.08−6.98 (m, 6H), 6.97−6.94 (m, 4H), 6.87 (s, 1H), 6.73 (d, J = 7.2 Hz, 2H), 6.51 (d, J = 7.6 Hz, 2H), 6.22 (d, J = 4.4 Hz, 1H), 5.09 (s, 1H), 3.81−3.71 (m, 2H), 2.96−2.87 (m, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.8, 139.4, 136.4, 135.7, 130.2, 129.9, 129.7, 128.7, 128.5, 127.7, 127.5, 126.9, 126.8, 126.7, 123.9, 123.8, 122.5, 122.2, 121.5, 119.5, 119.0, 118.9, 118.8, 118.7, 116.0, 111.8, 111.2, 66.3, 62.6, 61.7, 54.2, 28.7, 21.4; IR (KBr): 3381, 3059, 2924, 2854, 1713, 1620, 1453, 1186, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2558. 2-(1-(7-Methoxy-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3na). Following the general procedure, to the mixture of (E)-(5-methoxy-3-styryl-1H-indol-2yl)diphenylmethanol 1n (64.6 mg, 0.15 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by

preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3na (54.4 mg) in 95% yield as white solid. mp 80−81 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.30 (s, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.39−7.30 (m, 3H), 7.27− 7.23 (m, 1H), 7.12−7.08 (m, 1H), 7.06−6.93 (m, 8H), 6.92−6.84 (m, 3H), 6.82−6.77 (m, 1H), 6.52 (t, J = 5.0 Hz, 3H), 6.31 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 6.0 Hz, 1H), 3.73−3.64 (m, 2H), 3.58 (s, 3H), 3.41 (t, J = 5.2 Hz, 1H), 2.87 (s, 1H), 2.84 (s, 1H); 13C NMR (100 MHz, acetone-d6) δ 154.5, 148.1, 145.3, 143.6, 139.5, 136.7, 130.0, 129.6, 129.1, 128.3, 128.1, 127.5, 127.3, 126.6, 126.5, 126.4, 123.8, 120.8, 118.7, 118.5, 115.9, 113.0, 111.7, 111.6, 110.3, 100.9, 67.8, 62.4, 61.8, 54.9, 54.6, 31.1; IR (KBr): 3585, 2924, 2853, 1716, 1495, 1450, 1186, 1080, 996, 740 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2532. 2-(1-(6-Chloro-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3oa). Following the general procedure, to the mixture of (E)-(6-chloro-3-styryl-1H-indol-2-yl)diphenylmethanol 1o (65.3 mg, 0.15 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3oa (40.5 mg) in 70% yield as white solid. mp 106−107 °C; >95:5 dr; 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.38 (s, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.09−6.94 (m, 10H), 6.83 (s, 1H), 6.73 (d, J = 7.2 Hz, 2H), 6.48 (d, J = 7.6 Hz, 2H), 6.22 (d, J = 4.4 Hz, 1H), 5.15 (s, 1H), 3.82−3.67 (m, 2H), 2.90 (t, J = 6.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 144.5, 142.4, 141.3, 136.6, 129.8, 129.6, 128.8, 128.5, 128.3, 127.8, 127.7, 127.6, 127.2, 127.0, 126.9, 125.4, 122.1, 121.6, 121.5, 120.1, 119.1, 118.8, 116.6, 112.2, 110.9, 110.7, 70.5, 62.6, 61.7, 28.7; IR (KBr): 3380, 3050, 2920, 1669, 1457, 1360, 1080, 742 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2013. 2-(1-(4-Methyl-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3pa). Following the general procedure, to the mixture of (E)-(1-methyl-3-styryl-1H-indol-2yl)diphenylmethanol 1p (62.2 mg, 0.15 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3pa (43.6 mg) in 78% yield as white solid. mp 84−85 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 7.71−7.67 (m, 2H), 7.55−7.51 (m, 1H), 7.46−7.40 (m, 3H), 7.36−7.32 (m, 1H), 7.25 (s, 1H), 7.22−7.17 (m, 3H), 7.11−7.06 (m, 3H), 7.03−6.98 (m, 2H), 6.97−6.88 (m, 4H), 6.85−6.81 (m, 2H), 6.51−6.46 (m, 2H), 6.42 (d, J = 7.2 Hz, 1H), 5.19 (d, J = 7.6 Hz, 1H), 3.75−3.68 (m, 2H), 3.46 (t, J = 5.4 Hz, 1H), 3.20 (s, 3H), 2.91−2.87 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 148.0, 143.7, 141.9, 138.8, 138.4, 136.8, 130.2, 130.0, 129.1, 128.9, 128.4, 127.6, 127.3, 127.1, 127.0, 126.8, 123.0, 121.6, 120.4, 119.9, 118.8, 118.7, 118.5, 116.1, 112.2, 110.3, 110.2, 74.2, 62.4, 61.9, 54.6, 29.8, 29.2; IR (KBr): 3381, 3059, 2924, 2854, 1713, 1453, 1186, 970, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2578. 2-(5-Bromo-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ab). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(5-bromo-1H-indol-3-yl)ethanol 2b (24.0 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ab (49.7 mg) in 80% yield as white solid. mp 86−87 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.21 (m, 1H), 7.17−6.95 5939

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry (m, 9H), 6.88 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.2 Hz, 2H), 6.50 (d, J = 7.6 Hz, 2H), 6.19 (d, J = 5.6 Hz, 1H), 5.09 (s, 1H), 3.76−3.68 (m, 2H), 2.84 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.2, 144.6, 142.6, 141.0, 138.5, 135.2, 129.9, 129.7, 128.8, 127.8, 127.7, 127.6, 127.1, 126.9, 124.3, 123.4, 122.6, 121.4, 120.9, 119.2, 116.1, 112.4, 112.3, 110.6, 68.3, 62.5, 61.6, 28.5; IR (KBr): 3284, 3057, 2927, 1700, 1598, 1493, 1453, 1034, 861, 791, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31BrN2ONa 645.1512, found 645.1513. 2-(5-Chloro-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ac). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(5-chloro-1H-indol-3-yl)ethanol 2c (19.6 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 4 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ac (51.0 mg) in 88% yield as white solid. mp 103−104 °C; >95:5 dr; 1 H NMR (400 MHz, acetone-d6) δ 10.47 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39−7.34 (m, 2H), 7.30−7.25 (m, 1H), 7.17−7.08 (m, 3H), 7.06−7.01 (m, 4H), 7.00−6.95 (m, 4H), 6.90−6.87 (m, 2H), 6.86−6.81 (m, 1H), 6.48 (d, J = 7.6 Hz, 2H), 6.35 (d, J = 6.8 Hz, 1H), 5.27 (d, J = 6.4 Hz, 1H), 3.71−3.65 (m, 2H), 3.54 (t, J = 5.4 Hz, 1H), 2.86−2.80 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 147.4, 145.0, 143.3, 141.8, 138.9, 130.1, 129.6, 128.5, 128.1, 127.6, 127.4, 126.8, 126.7, 126.5, 123.8, 123.3, 121.9, 120.8, 120.0, 118.7, 118.3, 115.9, 112.5, 112.0, 111.6, 67.8, 62.4, 61.7, 28.7; IR (KBr): 3427, 3252, 3053, 2924, 1579, 1495, 1452, 1256, 708 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31ClN2ONa 601.2017, found 601.2018. 2-(5-Fluoro-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ad). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(5-fluoro-1H-indol-3-yl)ethanol 2d (17.9 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ad (64.9 mg) in 99% yield as white solid. mp 93−94 °C; >95:5 dr; 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.17 (m, 2H), 7.16−7.11 (m, 2H), 7.10−6.96 (m, 6H), 6.90 (s, 1H), 6.83−6.80 (m, 1H), 6.77−6.61 (m, 3H), 6.49 (d, J = 7.6 Hz, 2H), 6.18 (d, J = 6.0 Hz, 1H), 5.08 (s, 1H), 3.75−3.71(m, 2H), 2.84 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.6 (J = 224 Hz), 144.2, 142.6, 141.1, 138.7, 138.2, 129.9, 129.7, 128.8, 127.8, 127.7, 127.6, 127.1, 126.8, 123.5, 122.5, 120.8, 119.2, 116.2, 112.3, 111.3, 110.7, 109.8 (J = 26 Hz), 103.7 (J = 23 Hz), 68.2, 62.5, 61.6, 28.6; IR (KBr): 3292, 3056, 2975, 2929, 1692, 1455, 1170, 741, 702 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31FN2ONa 585.2313, found 585.2308. 2-(5-Methyl-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ae). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(5-methyl-1H-indol-3-yl)ethanol 2e (17.5 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ae (46.8 mg) in 84% yield as white solid. mp 115−116 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.43 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.39−7.31 (m, 3H), 7.29− 7.24 (m, 1H), 7.15−7.08 (m, 2H), 7.07−7.01 (m, 3H), 7.00−6.91 (m, 6H), 6.89 (d, J = 6.8 Hz, 2H), 6.72 (d, J = 7.6 Hz, 1H), 6.49 (d, J = 7.6 Hz, 2H), 6.31 (d, J = 6.4 Hz, 1H), 5.30 (d, J = 6.4 Hz, 1H), 3.75−3.60 (m, 2H), 3.44 (t, J = 5.4 Hz, 1H), 2.87−2.78 (m, 2H), 2.35 (s, 3H); 13 C NMR (100 MHz, acetone-d6) δ 147.2, 145.2, 143.4, 141.8, 139.2,

135.1, 130.0, 129.6, 128.4, 128.1, 127.5, 127.3, 127.2, 126.6, 126.4, 123.4, 122.4, 121.7, 119.8, 118.7, 118.5, 116.4, 112.4, 67.7, 62.4, 61.7, 54.1, 29.0, 20.6; IR (KBr): 3228, 3029, 2902, 1716, 1491, 1453, 1053, 862, 797, 744, 701 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2559. 2-(5-Methoxy-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3af). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(5-methoxy-1H-indol-3yl)ethanol 2f (19.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3af (44.3 mg) in 77% yield as white solid. mp 96−97 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.39−7.27 (m, 3H), 7.24−7.20 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.14−7.06 (m, 2H), 7.05−6.99 (m, 5H), 6.98−6.96 (m, 1H), 6.84 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 7.2 Hz, 2H), 6.64−6.58 (m, 1H), 6.51 (d, J = 7.6 Hz, 2H), 6.18 (d, J = 5.2 Hz, 1H), 5.11 (s, 1H), 3.83 (s, 3H), 3.78−3.69 (m, 2H), 2.92−2.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 153.7, 144.8, 142.7, 141.1, 131.9, 129.9, 129.7, 128.7, 127.7, 127.6, 127.5, 127.0, 126.9, 126.7, 123.6, 122.4, 121.7, 120.8, 119.4, 116.5, 112.2, 111.6, 100.6, 68.3, 62.6, 61.7, 55.8, 28.7; IR (KBr): 3027, 2921, 1611, 1509, 1457, 1357, 996, 698 cm −1 ; HRMS (ESI-TOF) m/z: [M + Na] + calcd for C40H34N2O2Na 597.2513, found 597.2512. 2-(6-Chloro-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ag). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(6-chloro-1H-indol-3-yl)ethanol 2g (19.6 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford >95:5 dr 3ag (32.9 mg) in 57% yield as white solid. mp 112−113 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 8.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.25−7.21 (m, 1H), 7.18−7.11 (m, 2H), 7.10−7.08 (m, 1H), 7.07−6.97 (m, 6H), 6.93 (s, 1H), 6.86 (s, 1H), 6.72 (d, J = 7.2 Hz, 2H), 6.49 (d, J = 7.6 Hz, 2H), 6.16 (d, J = 6.4 Hz, 1H), 5.07 (d, J = 6.0 Hz, 1H), 3.80−3.67 (m, 2H), 2.88 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.3, 144.7, 142.6, 141.0, 138.4, 137.1, 129.9, 129.7, 128.8, 127.8, 127.7, 127.6, 127.5, 127.2, 127.1, 126.9, 123.4, 122.6, 120.8, 119.7, 119.6, 119.2, 116.1, 112.3, 111.3, 110.6, 68.5, 62.7, 61.6, 28.6; IR (KBr): 3581, 3404, 3253, 2919, 2535, 1451, 1034, 803, 707 cm −1 ; HRMS (ESI-TOF) m/z: [M + Na] + calcd for C39H31ClN2ONa 601.2017, found 601.2018. 2-(6-Fluoro-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ah). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(6-fluoro-1H-indol-3-yl)ethanol 2h (17.9 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ah (35.2 mg) in 63% yield as white solid. mp 89−90 °C; >95:5 dr; 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.47−7.41 (m, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.25−7.20 (m, 1H), 7.16−7.12 (m, 2H), 7.10−6.98 (m, 6H), 6.90 (s, 1H), 6.82−6.77 (m, 1H), 6.73 (d, J = 7.4 Hz, 2H), 6.60 (d, J = 10.0 Hz, 1H), 6.50 (d, J = 7.2 Hz, 2H), 6.14 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 5.6 Hz, 1H), 3.81−3.70 (m, 2H), 2.88 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.7 (J = 236 Hz), 147.2, 144.7, 142.6, 141.0, 138.5, 136.6, 129.8 (J = 20 Hz), 128.8, 127.8, 127.7, 127.6, 127.2, 126.8, 125.1, 123.5, 122.5, 120.8, 119.5, 119.3 (J = 10 Hz), 116.2, 112.3, 107.7 (J = 24 Hz), 68.2, 62.6, 61.6, 28.7; IR (KBr): 3290, 3058, 2919, 2852, 2333, 1701, 1452, 1229, 1039, 701 cm−1; HRMS (ESI5940

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry TOF) m/z: [M + Na]+ calcd for C39H31FN2ONa 585.2313, found 585.2328. 2-(7-Methoxy-1-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (3ak). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 2-(7-methoxy-1H-indol-3yl)ethanol 2k (19.1 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 3 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3ak (35.2 mg) in 61% yield as white solid. mp 99−100 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.46−7.38 (m, 3H), 7.28 (d, J = 6.8 Hz, 1H), 7.25−7.20 (m, 4H), 7.16 (d, J = 7.6 Hz, 1H), 7.10−7.05 (m, 2H), 7.03−7.00 (m, 1H), 6.99−6.89 (m, 6H), 6.80−6.75 (m, 2H), 6.66 (s, 1H), 6.60−6.55 (m, 2H), 6.50 (d, J = 7.6 Hz, 1H), 5.06 (d, J = 4.0 Hz, 1H), 3.72−3.62 (m, 2H), 3.36 (s, 3H), 2.86−2.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 147.8, 147.5, 145.1, 143.0, 141.2, 140.1, 130.6, 129.8, 129.7, 128.4, 127.9, 127.3, 127.1, 126.8, 126.4, 126.3, 126.0, 124.9, 123.6, 122.3, 120.6, 119.4, 119.3, 118.1, 112.1, 111.5, 110.8, 102.2, 69.8, 62.6, 62.2, 61.9, 54.4, 28.8; IR (KBr): 3277, 3058, 2930, 1695, 1479, 1451, 1249, 1034, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2533. 3-(1-(2,3,3-Triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)1H-indol-3-yl)propan-1-ol (3al). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (60.2 mg, 0.15 mmol), 3-(1H-indol-3-yl)propan-1-ol 2l (17.5 mg, 0.1 mmol), catalyst 5c (1.8 mg, 0.01 mmol), and 3 Å MS (50 mg) was added chloroform (1 mL). Then, the reaction mixture was stirred at 30 °C for 4 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography (toluene/ethyl acetate = 10/1) to afford 3al (34.9 mg) in 63% yield as white solid. mp 105−106 °C; >95:5 dr; 1H NMR (400 MHz, acetoned6) δ 10.43 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.15−7.09 (m, 2H), 7.08−7.01 (m, 4H), 7.00−6.92 (m, 6H), 6.91−6.85 (m, 3H), 6.49 (d, J = 7.2 Hz, 2H), 6.36 (d, J = 6.4 Hz, 1H), 5.31 (d, J = 5.6 Hz, 1H), 3.57−3.49 (m, 2H), 3.43 (t, J = 5.2 Hz, 1H), 2.72 (t, J = 7.4 Hz, 2H), 1.82−1.74 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 147.2, 145.2, 143.4, 141.8, 139.2, 136.7, 130.0, 129.6, 128.9, 128.4, 128.1, 127.4, 127.1, 126.7, 126.4, 123.4, 121.8, 120.8, 119.9, 118.8, 118.6, 118.4, 116.4, 115.0, 112.4, 110.2, 67.8, 61.8, 61.2, 54.5, 33.4, 21.2; IR (KBr): 3269, 3058, 2923, 1704, 1452, 1185, 792, 744 cm −1 ; HRMS (ESI-TOF) m/z: [M + Na] + calcd for C40H34N2ONa 581.2564, found 581.2578. Typical Procedure for the Synthesis of Products 4. To the mixture of 2-indolymethanols 1 (0.18 mmol), tryptophols 2 (0.1 mmol), and catalyst 5c (0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by preparative thin layer chromatography to afford products 4. 2-(2-(2,3,3-Triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)1H-indol-3-yl)ethanol (4aa). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4aa (45.1 mg) in 83% yield as white solid. mp 94−95 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 11.6 Hz, 2H), 7.67−7.61 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.8 Hz, 3H), 7.33−7.28 (m, 1H), 7.22−7.14 (m, 3H), 7.13−6.97 (m, 9H), 6.72 (d, J = 7.2 Hz, 2H), 6.47−6.38 (m, 2H), 5.07 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 8.4 Hz, 1H), 3.50−3.39 (m, 1H), 2.99−2.88 (m, 1H), 2.77−2.66 (m, 1H), 2.59−2.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 147.0, 144.7, 142.7, 140.8, 138.3, 136.3, 135.7, 130.5, 129.8, 129.0, 128.8, 127.8, 127.6, 127.5, 127.0, 126.8, 122.1, 121.4, 120.5, 119.3, 119.2, 118.6, 117.6, 112.1, 110.8, 109.1, 68.4, 63.1, 62.1, 42.1,

27.9; IR (KBr): 3436, 3269, 2554, 1530, 1226, 1002, 834, 738, 699 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H32N2ONa 567.2408, found 567.2432. 2-(2-(3,3-Bis(4-fluorophenyl)-2-phenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ba). Following the general procedure, to the mixture of (E)-bis(4fluorophenyl)(3-styryl-1H-indol-2-yl)methanol 1b (78.7 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ba (53.4 mg) in 92% yield as white solid. mp 98−99 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.14 (s, 1H), 10.05 (s, 1H), 7.92−7.79 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24−7.16 (m, 3H), 7.10−7.02 (m, 4H), 7.01−6.92 (m, 3H), 6.91−6.84 (m, 5H), 6.44−6.22 (m, 2H), 5.35 (d, J = 9.2 Hz, 1H), 5.06 (d, J = 9.2 Hz, 1H), 3.65−3.53 (m, 1H), 3.45 (t, J = 5.4 Hz, 1H), 3.33−3.18 (m, 1H), 2.86−2.61 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 161.6 (J = 242 Hz), 161.5 (J = 242 Hz), 146.2, 141.3, 140.6, 138.8, 138.2, 136.5, 136.0, 131.4 (J = 8 Hz), 130.5 (J = 8 Hz), 130.2, 128.8, 127.5, 126.9, 124.0, 121.3, 120.6, 119.5, 118.7, 118.2 (J = 12 Hz), 114.9 (J = 21 Hz), 114.1 (J = 21 Hz), 112.2, 110.7, 109.2, 68.4, 62.6, 61.1, 40.9, 28.1; IR (KBr): 3287, 2921, 2882, 1457, 1026, 739, 702, 529 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H30F2N2ONa 603.2219, found 603.2226. 2-(2-(2-Phenyl-3,3-di-p-tolyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ca). Following the general procedure, to the mixture of (E)-(3-styryl-1H-indol-2-yl)di-p-tolylmethanol 1c (77.2 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ca (45.5 mg) in 80% yield as white solid. mp 77−78 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.02 (d, J = 4.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25−7.20 (m, 3H), 7.07−7.02 (m, 2H), 7.01−6.93 (m, 5H), 6.92−6.86 (m, 3H), 6.85−6.82 (m, 2H), 6.25 (d, J = 8.4 Hz, 2H), 5.30 (d, J = 9.2 Hz, 1H), 5.01 (d, J = 9.2 Hz, 1H), 3.63−3.54 (m, 1H), 3.52−3.34 (m, 1H), 3.31−3.22 (m, 1H), 2.84−2.72 (m, 2H), 2.34 (s, 3H), 2.27 (s, 3H); 13 C NMR (100 MHz, acetone-d6) δ 147.0, 142.0, 141.2, 140.0, 138.7, 136.5, 136.3, 135.9, 135.8, 130.4, 129.6, 128.9, 128.8, 128.5, 127.9, 127.2, 126.6, 124.0, 121.0, 120.5, 119.3, 118.5, 118.2, 118.0, 112.1, 110.7, 109.0, 68.1, 62.6, 61.4, 41.1, 28.2, 20.1, 20.0; IR (KBr): 3397, 3027, 2920, 1699, 1509, 1454, 1038, 821, 743, 702 cm−1; HRMS (ESITOF) m/z: [M + Na]+ calcd for C41H36N2ONa 595.2721, found 595.2731. 2-(2-(3,3-Bis(3-fluorophenyl)-2-phenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4da). Following the general procedure, to the mixture of (E)-bis(3fluorophenyl)(3-styryl-1H-indol-2-yl)methanol 1d (78.7 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4da (55.3 mg) in 95% yield as white solid. mp 113− 114 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.22 (s, 1H), 10.09 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.57−7.53 (m, 1H); 7.52−7.46 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.18−7.02 (m, 6H), 7.01−6.87 (m, 7H), 6.24−6.22 (m, 1H), 6.10−5.99 (m, 1H), 5.38 (d, J = 9.2 Hz, 1H), 5.13 (d, J = 9.2 Hz, 1H), 3.66−3.56 (m, 1H), 3.53−3.38 (m, 1H), 3.36−3.25 (m, 1H), 2.87−2.74 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 162.9 (J = 242 Hz), 162.3 (J = 242 Hz), 147.1 (J = 6 Hz), 145.6 (J = 6 Hz), 145.2, 141.3, 138.0, 136.5, 135.8, 130.2, 129.2 (J = 8 Hz), 128.8, 127.5, 127.0, 125.5, 125.4, 124.5, 124.4, 123.9, 121.5, 120.6, 119.6, 118.8, 118.3, 118.2, 116.5 (J = 22 Hz), 115.6 (J = 22 Hz), 113.6 (J = 14 Hz), 113.5 (J = 14 Hz), 112.2, 5941

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry

2-(2-(7-Methoxy-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4na). Following the general procedure, to the mixture of (E)-(5-methoxy-3-styryl-1H-indol-2yl)diphenylmethanol 1n (77.6 mg, 0.18 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4na (26.7 mg) in 47% yield as white solid. mp 84−84 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.82 (s, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.18−7.10 (m, 2H), 7.09−6.98 (m, 6H), 6.87−6.83 (m, 1H), 6.71 (d, J = 7.2 Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 6.44−6.35 (m, 2H), 5.03 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.46−3.39 (m, 1H), 2.91−2.83 (m, 1H), 2.75−2.66 (m, 1H), 2.54−2.47 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.9, 144.7, 142.8, 138.3, 136.3, 135.8, 135.6, 130.6, 129.7, 129.0, 128.8, 127.7, 127.5, 127.0, 126.8, 124.2, 121.4, 119.1, 118.6, 117.2, 112.7, 111.7, 110.8, 108.9, 101.5, 68.2, 63.0, 62.0, 56.1, 42.1, 28.0; IR (KBr): 3290, 3056, 2955, 1698, 1603, 1509, 1459, 1229, 833, 746, 701 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2508. 2-(2-(4-Methyl-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4pa). Following the general procedure, to the mixture of (E)-(1-methyl-3-styryl-1H-indol-2yl)diphenylmethanol 1p (74.7 mg, 0.18 mmol), 2-(1H-indol-3yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4pa (61.6 mg) in 99% yield as white solid. mp 67−68 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.40−7.27 (m, 5H), 7.25−7.11 (m, 5H), 7.10−7.00 (m, 6H), 6.68 (d, J = 7.2 Hz, 2H), 6.45 (d, J = 7.6 Hz, 2H), 5.04 (d, J = 8.8 Hz, 1H), 4.98 (d, J = 8.8 Hz, 1H), 3.55−3.45 (m, 1H), 3.14 (s, 3H), 3.04−2.96 (m, 1H), 2.85−2.76 (m, 1H), 2.64−2.55 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 148.6, 143.6, 141.6, 138.7, 138.4, 136.9, 135.6, 130.4, 129.2, 128.3, 127.5, 127.3, 127.2, 126.9, 126.8, 123.2, 121.5, 121.4, 119.9, 119.3, 119.2, 118.6, 116.6, 110.8, 109.8, 108.9, 75.2, 63.1, 62.6, 40.8, 30.2, 28.1; IR (KBr): 3387, 3057, 2924, 1697, 1451, 1034, 745, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2571. 2-(5-Chloro-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ac). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(5-chloro-1H-indol-3-yl)ethanol 2c (19.6 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ac (45.6 mg) in 79% yield as white solid. mp 105−106 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.96 (s, 1H), 7.64−7.60 (m, 2H), 7.45 (d, J = 2.0 Hz, 1H), 7.44−7.38 (m, 3H), 7.33−7.29 (m, 1H), 7.22− 7.14 (m, 2H), 7.12−6.99 (m, 9H), 6.71 (d, J = 7.2 Hz, 2H), 6.44−6.37 (m, 2H), 5.04 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 3.42−3.34 (m, 1H), 2.96−2.88 (m, 1H), 2.69−2.60 (m, 1H), 2.51−2.44 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 147.1, 144.6, 142.6, 140.7, 138.1, 137.9, 130.5, 130.1, 129.7, 128.9, 127.7, 127.6, 127.5, 127.1, 127.0, 126.9, 125.0, 123.7, 122.2, 121.6, 120.6, 119.1, 118.2, 117.3, 112.1, 111.7, 109.0, 68.3, 62.8, 62.1, 42.1, 27.7; IR (KBr): 3232, 3054, 2923, 1716, 1494, 1459, 1338, 1080, 799 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2011. 2-(5-Fluoro-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ad). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(5-fluoro-1H-indol-3-yl)ethanol 2d (17.9 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was

110.7, 109.3, 68.2, 62.5, 61.9, 40.9, 28.1; IR (KBr): 3399, 3025, 2919, 2342, 1509, 1452, 1039, 743 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H30F2N2ONa 603.2219, found 603.2213. 2-(2-(2-(4-Fluorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4fa). Following the general procedure, to the mixture of (E)-(3-(4fluorostyryl)-1H-indol-2-yl)diphenylmethanol 1f (75.4 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4fa (55.6 mg) in 99% yield as white solid. mp 95−96 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.10 (s, 1H), 10.03 (s, 1H), 7.84−7.77 (m, 2H), 7.48−7.38 (m, 4H), 7.34−7.29 (m, 1H), 7.25−7.18 (m, 2H), 7.15−7.09 (m, 2H), 7.08−7.04 (m, 1H), 7.01− 6.92 (m, 3H), 6.90−6.80 (m, 3H), 6.79−6.71 (m, 2H), 6.43−6.33 (m, 2H), 5.37 (d, J = 9.2 Hz, 1H), 4.99 (d, J = 9.6 Hz, 1H), 3.63−3.53 (m, 1H), 3.46 (t, J = 5.0 Hz, 1H), 3.30−3.18 (m, 1H), 2.82−2.71 (m, 2H); 13 C NMR (100 MHz, acetone-d6) δ 161.6 (J = 240 Hz), 146.3, 144.7, 143.2, 141.3, 136.5, 136.0, 134.8, 134.7, 132.0 (J = 8 Hz), 129.6, 128.8, 128.5, 128.4, 127.4, 126.6, 123.9, 121.1, 120.6, 119.4, 118.6, 118.3, 118.2, 118.1, 114.0 (J = 21 Hz), 112.1, 110.8, 109.1, 66.7, 62.6, 61.9, 41.6, 28.1; IR (KBr): 3834, 3735, 2466, 1698, 1490, 1472, 1450, 704 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31FN2ONa 585.2313, found 585.2301. 2-(2-(2-(3-Chlorophenyl)-3,3-diphenyl-1,2,3,4tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ha). Following the general procedure, to the mixture of (E)-(3-(3chlorostyryl)-1H-indol-2-yl)diphenylmethanol 1h (78.3 mg, 0.18 mmol), 2-(1H-indol-3-yl)ethanol 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ha (58.6) in 99% yield as white solid. mp 71−72 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.11 (s, 1H), 10.04 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.45−7.39 (m, 3H), 7.32 (t, J = 7.2 Hz, 1H), 7.26−7.19 (m, 2H), 7.16−7.04 (m, 4H), 7.03−6.92 (m, 4H), 6.91−6.77 (m, 3H), 6.40 (d, J = 7.6 Hz, 2H), 5.39 (d, J = 8.8 Hz, 1H), 5.02 (d, J = 9.2 Hz, 1H), 3.70−3.55 (m, 1H), 3.48 (s, 1H), 3.39−3.27 (d, 1H), 2.85−2.73 (m, 2H); 13C NMR (100 MHz, acetone-d6) δ 146.2, 144.5, 142.9, 141.3, 141.2, 136.5, 135.8, 132.8, 130.2, 129.6, 128.9, 128.8, 128.5, 128.4, 127.5, 126.8, 126.7, 123.9, 121.2, 120.6, 119.4, 118.6, 118.3, 118.2, 118.1, 112.2, 110.8, 109.2, 67.0, 62.6, 62.1, 41.4, 29.7; IR (KBr): 3397, 3027, 2920, 1699, 1509, 1454, 1304, 1038, 821, 743, 702 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C39H32ClN2O 579.2198, found 579.2193. 2-(2-(7-Methyl-2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ma). Following the general procedure, to the mixture of (E)-(5-methyl-3-styryl-1H-indol-2yl)diphenylmethanol 1m (74.7 mg, 0.18 mmol), 2a (16.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ ethyl acetate = 10/1) to afford 4ma (57.6 mg) in 99% yield as white solid. mp 102−103 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.32−7.28 (t, J = 7.4 Hz, 2H), 7.24−7.22 (d, J = 7.6 Hz, 1H), 7.17−7.09 (m, 3H), 7.08−6.93 (m, 6H), 6.92 (s, 1H), 6.70 (d, J = 7.2 Hz, 2H), 6.46−6.31 (m, 2H), 5.03 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 3.49−3.36 (m, 1H), 2.96−2.83 (m, 1H), 2.78−2.64 (m, 1H), 2.55−2.45 (m, 1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.2, 144.8, 142.8, 139.1, 138.3, 136.5, 135.6, 130.6, 130.0, 129.8, 129.1, 128.8, 127.8, 127.5, 127.0, 126.8, 124.0, 123.6, 121.3, 119.1, 118.9, 118.6, 117.0, 111.7, 110.9, 108.9, 68.3, 63.0, 62.0, 42.1, 27.9, 21.3; IR (KBr): 3261, 3057, 2961, 1702, 1611, 1095, 797, 702 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2588. 5942

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

Article

The Journal of Organic Chemistry

MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.44−7.36 (m, 4H), 7.31 (t, J = 7.2 Hz, 1H), 7.21−7.15 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 7.11−6.98 (m, 8H), 6.71 (d, J = 7.6 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 5.05 (d, J = 8.8 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H), 3.41−3.30 (m, 1H), 2.93−2.83 (m, 1H), 2.72−2.62 (m, 1H), 2.52− 2.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 147.1, 144.6, 142.7, 140.8, 138.2, 137.0, 136.0, 130.5, 129.8, 128.9, 127.7, 127.5, 127.4, 127.2, 127.0, 126.9, 123.7, 122.2, 120.6, 119.8, 119.5, 119.1, 117.3, 112.2, 110.7, 109.3, 68.2, 63.0, 62.1, 42.1, 27.8; IR (KBr): 3396, 3270, 2925, 1716, 1541, 1491, 1008, 743, 708 cm−1; HRMS (ESI-TOF) m/ z: [M + Na]+ calcd for C39H31ClN2ONa 601.2018, found 601.2035. 2-(6-Methyl-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ai). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(6-methyl-1H-indol-3-yl)ethanol 2i (17.5 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ai (42.0 mg) in 75% yield as white solid. mp 76−77 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 5.6 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.13−6.95 (m, 9H), 6.91 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.2 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 5.05 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H), 3.48−3.35 (m, 1H), 2.92 (s, 1H), 2.72−2.64 (m, 1H), 2.54−2.46 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.9, 144.8, 142.8, 140.7, 138.3, 136.1, 135.2, 131.2, 130.6, 129.8, 128.8, 127.8, 127.5, 127.4, 127.0, 126.9, 126.8, 123.8, 122.0, 120.8, 120.5, 119.3, 118.3, 117.7, 112.0, 110.8, 108.8, 68.3, 63.1, 62.0, 42.1, 28.0, 21.6; IR (KBr): 3285, 3056, 2923, 2853, 1709, 1458, 1033, 702 cm−1; HRMS (ESI-TOF) m/ z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2549. 2-(7-Methyl-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4aj). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(7-methyl-1H-indol-3-yl)ethanol 2j (17.5 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4aj (51.0 mg) in 91% yield as white solid. mp 98−99 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.46−7.39 (m, 3H), 7.38−7.30 (m, 2H), 7.22−7.15 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.10−6.98 (m, 7H), 6.93 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 7.6 Hz, 2H), 5.08 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 8.4 Hz, 1H), 3.49−3.40 (m, 1H), 2.97−2.87 (m, 1H), 2.73−2.65 (m, 1H), 2.55−2.47 (m, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.8, 144.9, 142.9, 140.8, 138.3, 135.8, 135.2, 130.6, 129.8, 128.9, 128.5, 127.8, 127.6, 127.5, 127.0, 126.9, 126.8, 123.8, 122.1, 122.0, 120.5, 120.1, 119.5, 119.2, 117.8, 116.4, 112.1, 109.7, 68.1, 63.1, 62.1, 42.3, 28.1, 16.8; IR (KBr): 3386, 3057, 2925, 1707, 1580, 1452, 1218, 1036, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2551. 2-(7-Methoxy-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ak). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(7-methoxy-1H-indol-3yl)ethanol 2k (19.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ak (37.9 mg) in 66% yield as white solid. mp 75−76 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.45−7.38 (m, 3H), 7.32 (t, J = 7.4 Hz, 1H), 7.22− 7.16 (m, 2H), 7.14−6.98 (m, 9H), 6.72 (d, J = 7.2 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 7.6 Hz, 2H), 5.09 (d, J = 8.8 Hz, 1H), 4.96 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 3.50−3.40 (m, 1H), 3.00−2.89 (m,

added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ad (54.7 mg) in 97% yield as white solid. mp 85−86 °C; >95:5 dr; 1H NMR (400 MHz, acetone-d6) δ 10.12 (d, J = 8.0 Hz, 2H), 7.82−7.78 (m, 2H), 7.44−7.38 (m, 3H), 7.33−7.29 (m, 1H), 7.22−7.14 (m, 3H), 7.11− 7.04 (m, 4H), 7.01−6.95 (m, 3H), 6.90−6.86 (m, 1H), 6.84−6.80 (m, 2H), 6.79−6.74 (m, 1H), 6.38−6.32 (m, 2H), 5.33 (d, J = 9.2 Hz, 1H), 5.01 (d, J = 9.2 Hz, 1H), 3.59−3.38 (m, 2H), 3.27−3.17 (m, 1H), 2.78−2.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.7 (J = 232 Hz), 147.1, 144.6, 142.7, 140.7, 138.4 (J = 19 Hz), 132.1, 130.5, 129.8, 129.3, 128.9, 127.7, 127.6 (J = 13 Hz) 127.1, 127.0, 126.9, 123.7, 122.1, 120.6, 119.1, 117.4, 112.1, 111.3 (J = 10 Hz), 109.5 (J = 22 Hz), 109.4, 103.8, 103.6, 68.3, 62.8, 62.1, 42.1, 27.9; IR (KBr): 3393, 3055, 2929, 1459, 1222, 836, 745, 705 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C39H31FN2ONa 585.2313, found 585.2320. 2-(5-Methyl-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ae). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(5-methyl-1H-indol-3-yl)ethanol 2e (17.5 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ae (42.8 mg) in 77% yield as white solid. mp 68−69 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 3H), 7.34−7.27 (m, 3H), 7.21−7.14 (m, 2H), 7.11−7.04 (m, 4H), 7.03−6.95 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 7.2 Hz, 2H), 6.41 (d, J = 7.6 Hz, 2H), 5.05 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H), 3.46−3.38 (m, 1H), 2.96−2.88 (m, 1H), 2.72−2.64 (m, 1H), 2.55−2.47 (m, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.9, 144.8, 142.8, 140.8, 138.3, 136.5, 134.0, 130.6, 129.8, 129.2, 128.8, 128.5, 127.8, 127.6, 127.5, 127.0, 126.8, 123.8, 122.9, 122.0, 120.5, 119.3, 118.4, 117.7, 112.0, 110.5, 108.6, 68.4, 63.1, 62.1, 42.1, 27.9, 21.5; IR (KBr): 2961, 1689, 1489, 1457, 1295, 1260, 1204, 800, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2578. 2-(5-Methoxy-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4af). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(5-methoxy-1H-indol-3yl)ethanol 2f (19.1 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4af (38.2 mg) in 67% yield as white solid. mp 95−96 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.42−7.36 (m, 3H), 7.30 (t, J = 7.4 Hz, 1H), 7.21− 6.94 (m, 11H), 6.80−6.68 (m, 3H), 6.45−6.37 (m, 2H), 5.06 (d, J = 8.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.45−3.36 (m, 1H), 2.93−2.85 (m, 1H), 2.73−2.64 (m, 1H), 2.54−2.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 153.9, 147.0 144.7, 142.7, 140.8, 138.3, 137.3, 130.7, 130.5, 129.8, 129.4, 128.8, 127.8, 127.5, 127.0, 126.8, 123.8, 122.1, 120.5, 119.2, 117.6, 112.1, 111.5, 111.3, 108.9, 100.8, 68.4, 63.0, 62.1, 56.0, 31.4, 30.2; IR (KBr): 2962, 1699, 1583, 1489, 1458, 1261, 1036, 802, 743, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2529. 2-(6-Chloro-2-(2,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)-1H-indol-3-yl)ethanol (4ag). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 2-(6-chloro-1H-indol-3-yl)ethanol 2g (19.6 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ethyl acetate = 10/1) to afford 4ag (58.1 mg) in 99% yield as white solid. mp 97−98 °C; >95:5 dr; 1H NMR (400 5943

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

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The Journal of Organic Chemistry 1H), 2.77−2.65 (m, 1H), 2.58−2.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 146.8, 145.9, 144.7, 142.8, 140.8, 138.2, 135.8, 130.6, 130.2, 129.8, 128.8, 127.8, 127.6, 127.5, 127.0, 126.8, 126.0, 123.8, 122.0, 120.4, 119.6, 119.3, 117.8, 112.1, 111.5, 109.7, 101.6, 68.2, 63.1, 62.0, 55.1, 42.1, 28.1; IR (KBr): 3472, 2339, 1640, 1112, 835, 647, 622, 602 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2O2Na 597.2513, found 597.2535. 3-(2-(2,3,3-Triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-1-yl)1H-indol-3-yl)propan-1-ol (4al). Following the general procedure, to the mixture of (E)-diphenyl(3-styryl-1H-indol-2-yl)methanol 1a (72.2 mg, 0.18 mmol), 3-(1H-indol-3-yl)propan-1-ol 2l (17.5 mg, 0.1 mmol), and catalyst 5c (3.6 mg, 0.02 mmol) was added chloroform (1 mL). Then, the reaction mixture was stirred at 40 °C for 8 h. After the completion of the reaction indicated by TLC, the reaction mixture was purified by flash column chromatography eluent (petroleum ether/ ethyl acetate = 10/1) to afford 4al (45.4 mg) in 81% yield as white solid. mp 71−72 °C; >95:5 dr; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.90 (s, 1H), 7.65−7.61 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.21−7.09 (m, 5H), 7.08− 7.01 (m, 5H), 7.00−6.96 (m, 2H), 6.72 (d, J = 7.2 Hz, 2H), 6.45−6.40 (m, 2H), 5.08 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 8.4 Hz, 1H), 3.45−3.34 (m, 2H), 2.49−2.41 (m, 1H), 2.39−2.32 (m, 1H), 1.70−1.63 (m, 1H), 0.92−0.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 147.0, 144.9, 142.9, 140.8, 138.7, 135.7, 135.2, 130.6, 129.8, 128.9, 128.8, 127.8, 127.5, 127.4, 127.0, 126.8, 126.7, 123.8, 122.0, 121.2, 120.5, 119.4, 118.9, 118.6, 117.8, 112.8, 112.0, 110.8, 68.4, 62.9, 62.2, 42.1, 33.6, 20.4; IR (KBr): 3390, 3059, 2933, 1717, 1493, 1451, 1304, 1033, 909, 743, 703 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C40H34N2ONa 581.2564, found 581.2575. Characteristic Data for Compounds 6−8. 3,3-Dimethyl-2phenyl-1-((Z)-2-(3-((E)-styryl)-1H-indol-2-yl)prop-1-en-1-yl)-1,2,3,4tetrahydrocyclopenta[b]indole (6). White solid; mp 108−109 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.87 (s, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.51−7.30 (m, 8H), 7.23−7.10 (m, 9H), 7.03−6.98 (m, 1H), 3.15 (d, J = 12.8 Hz, 1H), 2.86 (d, J = 12.8 Hz, 1H), 2.26 (s, 3H), 1.70 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 151.1, 139.9, 139.8, 139.2, 138.6, 135.9, 135.8, 131.2, 131.0, 128.6, 128.3, 127.8, 126.9, 126.2, 126.1, 125.6, 125.5, 124.6, 121.9, 121.4, 121.3, 121.0, 120.4, 120.3, 120.2, 111.6, 111.5, 110.7, 109.8, 104.8, 62.2, 61.6, 38.9, 29.7, 26.4; IR (KBr): 3429, 2968, 2926, 1449, 1310, 956, 740, 694, 544 cm−1; HRMS (ESITOF) m/z: [M + Na]+ calcd for C38H34N2Na 541.2615, found 541.2620. 1,3-Diphenyl-9H-carbazole (7). White solid; mp 97−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 6.4 Hz, 1H), 7.99 (s, 1H), 7.47−7.27 (m, 10H), 7.24−7.16 (m, 3H), 5.85 (s, 1H), 5.59 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 140.6, 139.8, 138.8, 136.9, 135.9, 128.7, 128.6, 128.5, 128.0, 126.6, 126.5, 126.3, 125.8, 123.1, 122.5, 120.9, 120.7, 118.9, 113.9, 111.1; IR (KBr): 3345, 3054, 1704, 1508, 919, 782, 727, 692 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H17NNa 342.1254, found 342.1241. 2,3,3-Triphenyl-3,4-dihydrocyclopenta[b]indole (8). White solid; mp 97−98 °C; 1H NMR (400 MHz, acetone-d6) δ 10.62 (s, 1H), 7.78−7.73 (m, 1H), 7.72 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.43−7.36 (m, 5H), 7.34−7.24 (m, 6H), 7.20 (t, J = 7.6 Hz, 2H), 7.16−7.07 (m, 3H); 13C NMR (100 MHz, acetone-d6) δ 157.6, 148.6, 141.0, 136.2, 128.6, 128.3, 127.9, 126.9, 126.1, 125.8, 124.0, 121.6, 121.0, 119.9, 119.2, 119.0, 112.3, 63.3; IR (KBr): 3407, 3029, 1593, 1490, 1249, 783, 761, 746 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H22N 384.1747, found 384.1760.

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Crystallographic information file for 3aa (CIF) Crystallographic information file for 4aa (CIF)

AUTHOR INFORMATION

Corresponding Authors

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

Feng Shi: 0000-0003-3922-0708 Author Contributions ‡

J.-Y.W., P.W.: These authors contributed equally to the work.

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 (21772069 and 21702077), Natural Science Foundation of Jiangsu Province (BK20160003 and BK20170227), Six Kinds of Talents Project of Jiangsu Province (SWYY-025), Natural Science Foundation of Xuzhou City (KH17021), and Undergraduate Students Project of Jiangsu Province.

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REFERENCES

(1) For selected reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles. Chem. Rev. 2006, 106, 2875−2911. (b) Bandini, M.; Eichholzer, A. Catalytic Functionalization of Indoles in a New Dimension. Angew. Chem., Int. Ed. 2009, 48, 9608−9644. (c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010, 110, 4489−4497. (d) Bartoli, G.; Dalpozzo, R.; Nardi, M. Applications of Bartoli Indole Synthesis. Chem. Soc. Rev. 2014, 43, 4728−4750. (2) (a) Kong, Y. C.; Cheng, K. F.; Cambie, R. C.; Waterman, P. G. Yuehchukene: A Novel Indole Alkaloid with Anti-implantation Activity. J. Chem. Soc., Chem. Commun. 1985, 47−48. (b) Kong, Y.C.; Ng, K. H.; But, P. P. H.; Li, Q.; Yu, S. X.; Zhang, H. T.; Cheng, K. F.; Soejarto, D. D.; Kan, W. S.; Waterman, P. G. Sources of the AntiImplantation Alkaloid Yuehchukene in the Genus Murraya. J. Ethnopharmacol. 1986, 15, 195−200. (c) Chen, H.; Bai, J.; Fang, Z.F.; Yu, S.-S.; Ma, S.-G.; Xu, S.; Li, Y.; Qu, J.; Ren, J.-H.; Li, L.; Si, Y.-K.; Chen, X.-G. Indole Alkaloids and Quassinoids From the Stems of Brucea Mollis. J. Nat. Prod. 2011, 74, 2438−2445. (3) (a) Qiao, M.-F.; Ji, N.-Y.; Liu, X.-H.; Li, K.; Zhu, Q.-M.; Xue, Q.Z. Indoloditerpenes From an Algicolous Isolate of Aspergillus Oryzae. Bioorg. Med. Chem. Lett. 2010, 20, 5677−5680. (b) Talaz, O.; Gulcin, I.; Goksu, S.; Saracoglu, N. Antioxidant Activity of 5, 10Dihydroindeno [1, 2-b] Indoles Containing Substituents on Dihydroindeno Part. Bioorg. Med. Chem. 2009, 17, 6583−6589. (c) Yi, P.; Rehmel, J.-F.; Cassidy, K.; Hadden, C.; Campanale, K.; Patel, N.; Johnson, J. Disposition and Metabolism of LY2452473, a Selective Androgen Receptor Modulator, in Humans. Drug Metab. Dispos. 2012, 40, 2354−2364. (d) Somei, M.; Kimura, J.; Takano, S. Jpn. Kokai Tokkyo Koho, JP 2004051503 A 20040219, 2004. (4) For selected examples, see: (a) Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X. Multistep One-Pot Synthesis of Enantioenriched Polysubstituted Cyclopenta [b] indoles. Angew. Chem., Int. Ed. 2012, 51, 1059−1062. (b) Yokosaka, T.; Nakayama, H.; Nemoto, T.; Hamada, Y. Acid-Promoted Cascade Cyclization to Produce Fused-Polycyclic Indole Derivatives. Org. Lett. 2013, 15, 2978−2981. (c) Zi, W.; Wu, H.; Toste, F. D. Gold (I)-Catalyzed Dearomative Rautenstrauch Rearrangement: Enantioselective Access to Cyclopenta[b] indoles. J. Am. Chem. Soc. 2015, 137, 3225−3228. (d) Santos, M. S.; Fernandes, D. C.; Rodrigues, M. T.; Regiani, T.; Andricopulo, A. D.; Ruiz, A. L. T. G.; Vendramini-Costa, D. B.; de

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00414. Characterization data (including 1H and 13C NMR spectra) of products 3, 4, and 6−8, HPLC copies of product 3aa, and single crystal data of products 3aa and 4aa (PDF) 5944

DOI: 10.1021/acs.joc.8b00414 J. Org. Chem. 2018, 83, 5931−5946

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