Weak Directing Group Steered Formal Oxidative [2+2+2]-Cyclization

Publication Date (Web): January 31, 2018. Copyright © 2018 American Chemical Society. *E-mail: [email protected]. Cite this:J. Org. Chem. 8...
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Article Cite This: J. Org. Chem. 2018, 83, 1810−1818

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Weak Directing Group Steered Formal Oxidative [2+2+2]-Cyclization for Selective Benzannulation of Indoles Kiran R. Bettadapur,‡ Raja Kapanaiah,‡ Veeranjaneyulu Lanke, and Kandikere Ramaiah Prabhu* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka India S Supporting Information *

ABSTRACT: A double C−H activation and double insertion process to achieve the synthesis benzo[e]indole frameworks has been disclosed. This type of benzannulation is directed by a trifluoromethylketone moiety, which is easy to install on the indole C3-position. Overall the reaction takes places as an oxidative cyclization of two alkynes with the C4−C5 position of indole.

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INTRODUCTION

(benzo[e]indole) is found in the natural product class of hasubanan alkaloids10 and several analogs of anticancer agents.

Alkynes have been used as useful synthons in traditional organic chemistry for more than a century. Several reviews and books have documented the theoretical, synthetic, and applied aspects of this area.1 Alkynes have been extensively used for the hydroarylation reaction for synthesizing trisubstituted alkenes. A related reaction is the benzannulation of arenes with alkynes. This reaction was originally reported by Heck (Scheme 1).2 The C−H activation3 version of the arene−alkyne benzannulation, catalyzed by Ir(III), was reported by Miura, with benzoic acids as the directing group and internal alkyne as a coupling partner.4a The same group has also reported the benzannulation of phenylpyrazoles using Rh(III) catalyst.4b Since these early reports, the benzannulation of arenes using a wide variety of transition metal catalysts and directing groups has been reported.5 Weak directing groups, however, have not been explored for such benzannulations. Our lab has been involved in the successful C4functionalization of indoles with a directing group located on the C3-position.6 We have observed that weak directing groups facilitate functionalization of the C4-position, while strong directing groups facilitate the functionalization at the C2position of indole (eq 1, Scheme 2). This differential functionalization strategy allows for a rapid access to C4substituted natural products, such as ergot alkaloid and indolactums.7 Therefore, methods to access C4-functionalization of indole are valuable. In continuation of our interest in indoles and hydroarylation reactions,8 we envisaged a hydroarylation of indole at the C4-position with alkynes, to obtain trisubstituted alkenes. However, when the reactions were carried out, the benzannulation was also observed. Thus, a C4−C5 oxidative annulation of indoles was achieved using a weak directing group at C3. This C4−C5 benzannulation provides the framework of polyaromatic hydrocarbons (PAHs) with an indole moiety. PAHs have been widely used as dyes and as photosensitizers in the fields of nonlinear optics, sensors, photovoltaic cells, etc.9 A C4−C5 annulated indole framework © 2018 American Chemical Society

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RESULTS AND DISCUSSION The preliminary reaction of 2,2,2-trifluoro-1-(1-methyl-1Hindol-3-yl)ethan-1-one (1a) with diphenyl acetylene (2a) in dichloroethane yielded the alkenylated product 4aa in 31% yield along with annulated product 3aa in 13% yield (entry 1, Table 1). Reducing the equivalents of the alkyne to 1 equiv reduced the yield of the alkenylated product (4aa) to 13%, and the annulated product (3aa) was not detected (entry 2). Changing the solvent to DMF, toluene, and THF did not result in the formation of products, and the starting materials were recovered intact (entries 3−5). However, by changing the solvent to hexafluoroisopropanol (HFIP), 55% of the annulated product, 3aa, was formed and the alkenylated product was not detected (entry 6). Using trifluoroethanol (TFE) as a solvent resulted in the formation of annulated product 3aa in 60% yield (entry 7). Further optimization studies were continued with TFE as the solvent. Increasing the amount of Cu(OAc)2·H2O to 2 equiv led to a marginal change in the yield of 3aa to 62% (entry 8). However, increasing the amounts of alkyne to 4 equiv increased the yield of 3aa to 75% (entry 9). With increasing the catalyst loading to 10 mol %, the yield of the product 3aa dropped to 67% (entry 10). With increasing the temperature to 120 °C, a slight drop in the yield was observed (70%, entry 11). By changing the amount of solvent from 3 to 1.5 mL, thereby doubling the concentration of the reactants, the yield of 3aa increased to 84% (entry 12). In all the control experiments, it took 24 h for the indole derivative (1a) to be completely consumed. Since the overall reaction was oxidative, the reaction vial was flushed with oxygen gas to see if any changes can be brought about. Surprisingly, the flushing with oxygen helped the reaction by reducing the reaction time to 12 h without changing the yield of 3aa (84%, entry 13). These Received: October 26, 2017 Published: January 31, 2018 1810

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry Scheme 1. Previous Reports

Scheme 2. Origin of the Work

However, the unprotected indole derivative was also found to furnish the corresponding annulated product 3ia in moderate yield (53%). Going back to N-methyl-substituted indoles, substitutions on the indole ring were explored. Unfortunately, the substituted indoles resulted in the formation of products in poor yields. When 6-chloro- and 6-bromoindole derivatives were subjected to the optimized conditions, the corresponding products, 3ja and 3ka, were furnished in low yields (27 and 12% yields, respectively), and we were unable to isolate the compounds in satisfactory purity. Surprisingly, when 2methylindole derivative was subjected to the reaction, the reaction did not progress and 3la was not detected. However, the 7-methylindole derivative furnished the corresponding product (3ma) in moderate yield (40% isolated yield). After exploring the reaction with diphenylacetylene, further investigations were carried out with aliphatic alkynes such as 1,4-dimethoxybut-2-yne, but-2-yn-1,4-diol, dimethyl acetylenedicarboxylate, and 3-hexyne. In none of the cases were either annulated or alkenylated products detected. Shifting to aliphatic−aromatic hybrid alkynes such as 1-phenylprop-1-yne was not helpful. Hence, the substrate scope has been explored only with symmetric aromatic alkyne derivatives (Scheme 4).

conditions were eventually decided upon as the best conditions developed for this reaction. Other variations in the reaction conditions did not result in the improvement of the yield (entries 14−25). The reaction of diphenyl acetylene with other directing groups, such as aldehyde, ketone, acid, ester, amide, and oxime under the reaction conditions, did not furnish the expected products (Table 1). The reaction of 1a with diphenyl acetylene under the optimal conditions furnished the product 3aa, in 74% isolated yield (Scheme 3). This reaction, when scaled up to 2 mmol furnished 3aa in 76% isolated yield. Using N-ethylindole derivative furnished a higher yield of the product 3ba (79%). Aromatic substitutions on the nitrogen led to lower yields of the corresponding products. Thus, N-phenyl indole derivative yielded 54% of the product (3ca), whereas the parachlorophenyl-substituted indole derivative yielded only 40% of the product (3da). Similar yields were obtained when N(meta-methoxyphenyl) indole derivative was used (3ea, 37%). When cleavable protecting groups such as N-benzyl and NPMB were used, the yields were found to be moderate (3fa and 3ga, 54 and 36%, respectively). When allyl-substituted indole derivative was used, the yields dropped to 42% (3ha). 1811

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry Table 1. Optimization Studiesa

Reaction conditions: 1a (0.1 mmol), argon flushed, [Rh] = [RhCp*Cl2]2, [Ag] = AgSbF6, [Cu] = Cu(OAc)2·H2O. trimethoxybenzene as internal standard. cO2 gas flushed instead of Ar. dAdded AcOH 5 equiv as an additive. a

Subjecting 1,2-bis(4-fluorophenyl)ethyne to the optimized conditions with 1a furnished the corresponding annulated product 3ab in 58% yield. However, Cl- and Br-substituted alkynes gave lower yields of the annulated products 3ac and 3ad (33 and 43%, respectively) along with 20% of nonannulated alkene products (4ac and 4ad). Ditolylacetylene resulted in a lower yield of the product 3ae (23%), probably due to the electron-rich nature of the alkyne. When dianisylacetylene was used, the annulated product was detected only in trace amounts. Alkynes with meta-substitution were found to be better substrates. When 1,2-bis(3-fluorophenyl)ethyne was subjected to the optimized reaction conditions with 1a, it formed the corresponding annulated product 3af in 70% yield. The m,m′-disubstituted Cl- and Br-phenylacetylenes also

b1

H NMR yields with 1,3,5-

furnished the annulated products 3ag and 3ah in good yields (66 and 70%, respectively). Even the m,m′-trifluoromethylphenyl acetylene underwent a facile reaction, furnishing the annulated product 3ai in good yield (60%). 1,2-Bis(3Nitrophenyl)ethyne underwent the reaction to furnish the alkenylated product 4aj in 24% yield. Unfortunately, electronrich alkyne m,m′-dianisylacetylene did not furnish the annulated product. With ortho-substituted alkynes, the annulated product was not observed, probably due to steric effects exerted by the ortho- substituents. However, in these reactions the corresponding alkenylated products were obtained. Surprisingly, 1,2-bis(2fluorophenyl)ethyne yielded only trace amounts of the alkenylated product, whereas 1,2-bis(2-chlorophenyl)ethyne yielded the alkenylated product (4ak) in a modest yield of 1812

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry Scheme 3. Substrate Scope with Different Indoles

form Int 1. The intermediate (Int 1) loses AcOH, and the site is replaced by diphenylacetylene. After the ligand exchange, the alkyne inserts into the Rh−C bond to form Int 2. This intermediate (Int 2) undergoes one more C−H activation to formInt 3 (Int 2 could also undergo quenching if the subsequent C−H activation is not feasible; in which case it forms the alkenylated product). Int 3 can then undergo a ligand exchange with diphenyl acetylene to form Int 4, which in turn undergoes insertion to form Int 5. The final C−C bond formation (in Int 5) between the alkenic moiety and the indole at the C5-position is brought about by the reductive elimination of Rh-species. The Rh(I) that is eliminated out in the last step of the process is reoxidized by Cu(OAc)2.H2O, thereby regenerating the active Rh(III) catalyst. In conclusion, a novel oxidative formal [2+2+2] cycloaddition to synthesize the benzannulated indoles has been disclosed. This method tolerates several para- and metasubstituted alkynes, furnishing the benzannulated products. The ortho-substituted alkynes, however, furnish only the alkenylated products in modest yields. Although, in many cases the yields are moderate to low, the current synthetic protocol is valuable due to the inherent difficulty in synthesizing annulated molecules with heterocyclic sections. Moreover, the benzannulated indole ring furnished in this

45%. 1,2-Bis(2,4-dichlorophenyl)ethyne yielded 30% of the alkenylated product (4al). The reactions of heterocyclic derivatives of symmetric alkynes were not successful and the corresponding starting materials were intact during the reaction. The observation in the oxidative [2+2+2]-benzannulation of indoles is that the yields are moderate to low in a few cases. However, the synthetic protocol is valuable due to the difficulties associated with synthesizing annulated molecules with heterocyclic sections. A few control experiments were carried out to shed light on the mechanism of the reaction (Scheme 5). When the reaction was carried out with 1,3-dimethylindole, i.e., without any directing group but with the C-3 position blocked, no reaction took place. This indicates that the COCF3 group is necessary for the reaction to take place. Subsequently, the same reaction was carried out with 1-methylindole, which does not have a directing group at the C-3-position, resulting in the formation of an interesting cyclic product 5aa in 33% yield. Starting with 4aa (the alkenylated product) as the substrate also did not yield the corresponding product 3aa. Based on the control reactions and the formation of 4aa during the optimization studies, the following brief mechanism has been proposed. The first step in the process is C−H activation at the C4position, which is assisted and guided by the COCF3 group to 1813

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry Scheme 4. Substrate Scope with Alkynes

[RhCp*Cl2]2 (5 mol %, 3.0 mg), AgSbF6 (20 mol %, 6.8 mg), alkyne derivative (4 equiv, 0.4 mmol) and Cu(OAc)2·H2O (1.2 equiv, 0.12 mmol, 24 mg). To this mixture was added trifluoroethanol (1.5 mL). The vial was capped under a stream of oxygen gas and placed in a preheated (100 °C) metal block. After the completion of the reaction (monitored by TLC) the reaction mixture was cooled to room temperature, and diluted with diethyl ether and passed through a short silica gel (100−200 mesh size) bed, and repeatedly washed with diethyl ether (20 mL × 3 times). The combined organic layers were concentrated under reduced pressure and the crude product was purified on a silica gel column using a DCM/pet. ether mixture.

reaction is a benzo[e]indole framework, which is found in several hasubanan alkaloids. Attempts were made to uninstall the directing group by hydrolysis, and unfortunately, none of the methods furnished the hydrolyzed products. Fluorescence studies on the benzannulated products indicated a weak solidstate fluorescence (λ em = 480 nm, λ ex = 390 nm).

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EXPERIMENTAL SECTION

Typical experimental procedures. Typical experimental procedure for 0.1 mmol scale reactions. To a predried 8 mL screw-cap vial was added indole derivative (0.1 mmol, 1 equiv), 1814

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry Scheme 5. Control Experiments and Proposed Mechanism

Typical experimental procedure for 2 mmol scale reaction of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (1a) with diphenylacetylene (2a). To a predried 50 mL sealed tube was added 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (1a, 454 mg, 2 mmol, 1 equiv), [RhCp*Cl2]2 (5 mol %, 60 mg), AgSbF6 (20 mol %, 136 mg), alkyne derivative (1424 mg, 4 equiv, 8 mmol) and Cu(OAc)2·H2O (480 mg, 1.2 equiv, 2.4 mmol). To this mixture was added trifluoroethanol (30 mL). The vial was capped under a stream of oxygen gas and placed in a preheated (100 °C) oil bath. After the completion of the reaction (24h, monitored by TLC) the reaction mixture was cooled to room temperature, and diluted with diethyl ether and passed through a short silica gel (100−200 mesh size) bed, and repeatedly washed with diethyl ether. The combined organic layers were concentrated under reduced pressure and the crude product was purified on a silica gel column using DCM/pet. ether mixture. Yield: 890 mg (76%) Characterization data for all isolated products. 2,2,2Trifluoro-1-(3-methyl-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)ethanone (3aa). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 74% (43 mg). Rf (30% DCM -Pet. ether) = 0.2. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1676. 1H NMR (CDCl3, 400 MHz): δ 7.55−7.51 (m, 2 H), 7.35 (d, J = 9.1 Hz, 1 H), 7.21−

7.16 (m, 5 H), 6.99−6.95 (m, 5 H), 6.88−6.82 (m, 6 H), 6.76 (br. s., 4 H), 3.92 (s, 3 H).13C{1H} NMR (CDCl3, 125 MHz): δ 173.4, 173.2, 172.9, 172.7, 140.91, 140.86, 140.49, 140.45, 140.33, 138.8, 138.5, 137.4, 136.8, 133.2, 133.1, 132.9, 131.7, 131.6, 131.3, 131.1, 127.6, 126.8, 126.6, 126.54, 126.49, 126.3, 126.1, 125.3, 120.5, 120.1, 117.8, 115.5, 115.3, 113.1, 110.2, 110.0, 34.2. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C39H26F3NONa 604.1864; Found 604.1863. 1-(3-Ethyl-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)-2,2,2-trifluoroethanone (3ba). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a white solid. Isolated yield: 79% (47 mg). Rf (30% DCM/Pet. ether) = 0.2. Melting point (°C): decomp. after 250. IR (KBr, cm−1): 1681. 1H NMR (CDCl3, 400 MHz): δ 7.56−7.52 (m, 2 H), 7.39 (d, J = 9.2 Hz, 1 H), 7.21−7.16 (m, 5 H), 7.01−6.89 (m, 5 H), 6.86−6.79 (m, 6 H), 6.76 (br. s., 4 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.60 (t, J = 7.3 Hz, 3 H). 13 C{1H} NMR (CDCl3, 125 MHz): δ 173.5, 173.3, 173.0, 172.7, 140.95, 140.88, 140.51, 140.47, 140.31, 138.8, 138.5, 137.4, 136.0, 132.9, 131.7, 131.6, 131.4, 131.2, 131.0, 127.6, 126.9, 126.6, 126.54, 126.49, 126.10, 126.06, 125.2, 120.6, 120.1, 117.8, 115.4, 113.2, 110.1, 42.4, 15.4. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C40H28F3NONa 618.2021; Found 618.2025. 2,2,2-Trifluoro-1-(3,6,7,8,9-pentaphenyl-3H-benzo[e]indol-1-yl)ethanone (3ca). Purified by flash chromatography on silica gel using DCM: Pet. ether (25:75) as eluent to obtain a yellow solid. Isolated 1815

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry

1-(3-Allyl-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)-2,2,2-trifluoroethanone (3ha). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 42% (25 mg). Rf (30% DCM/Pet. ether) = 0.2. Melting point (°C): 192−194. IR (neat, cm−1): 1642. 1H NMR (CDCl3, 400 MHz): δ 7.54−7.51 (m, 2 H), 7.34 (d, J = 9.1 Hz, 1 H), 7.24−7.18 (m, 5 H), 6.95 (br, s, 5 H), 6.86−6.82 (m, 6 H), 6.76−6.71 (m, 4 H), 6.07−6.00 (m, 1 H), 5.34 (d, J = 10.2 Hz, 1 H), 5.18 (d, J = 17.1 Hz, 1 H), 4.85 (d, J = 5.5 Hz, 2 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.7, 173.4, 173.1, 172.8, 140.93, 140.86, 140.49, 140.44, 140.37, 138.8, 138.6, 137.4, 136.3, 132.9, 132.2, 132.1, 131.6, 131.5, 131.3, 131.1, 127.6, 126.8, 126.6, 126.6, 126.5, 126.2, 126.1, 125.3, 120.6, 120.1, 119.3, 117.8, 115.6, 115.4, 113.0, 110.5, 50.0. HRMS (ESITOF) (m/z): [M + Na]+ Calcd for C41H28F3NONa 630.2021; Found 630.2020. 2,2,2-Trifluoro-1-(6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)ethanone (3ia). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 53% (30 mg). Rf (30% DCM/Pet. ether) = 0.1. Melting point (°C): 176−178. IR (KBr, cm−1): 3025, 1674. 1H NMR (CDCl3, 400 MHz): δ 9.24 (br. s., 1 H), 7.64 (br. s., 1 H), 7.53 (d, J = 9.1 Hz, 1 H), 7.36 (d, J = 9.2 Hz, 1 H), 7.25−7.17 (m, 5 H), 7.03−6.98 (m, 5 H), 6.92−6.85 (m, 6 H), 6.77−6.72 (m, 4 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 174.4, 174.1, 173.8, 173.5, 140.86, 140.81, 140.44, 140.40, 140.33, 139.0, 138.5, 137.2, 135.9, 131.6, 131.3, 131.1, 129.6, 129.4, 127.7, 127.6, 127.5, 126.7, 126.6, 126.6, 126.1, 125.3, 125.2, 120.1, 119.3, 117.8, 116.8, 115.4, 113.1, 112.2, 112.1, 112.0. HRMS (ESITOF) (m/z): [M + Na]+ Calcd for C38H24F3NONa 590.1708; Found 590.1707. 1-(3,4-dimethyl-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)-2,2,2trifluoroethanone (3ma). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 40% (24 mg). Rf (30% DCM -Pet. ether) = 0.2. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1689. 1H NMR (CDCl3, 400 MHz): δ 7.40 (s, 1 H), 7.18−7.16 (m, 6 H), 6.97−6.95 (m, 1 H), 6.91 (d, J = 2.8 Hz, 4 H), 6.86−6.81 (m, 6 H), 6.74 (br, s. Four H), 4.15 (s, 3 H), 2.71 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.6, 173.7, 173.1, 172.8, 141.00, 140.96, 140.49, 140.37, 139.5, 138.6, 137.7, 137.2, 136.3, 135.0, 134.9, 131.6, 131.3, 131.1, 127.5, 127.4, 126.5, 126.5, 126.4, 126.4, 125.9, 125.7, 125.2, 121.9, 121.6, 120.1, 117.8, 115.4, 114.9, 113.1, 38.6, 20.6. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C40H28F3NONa [M + Na]: 618.2021; Found: 618.2023. 2,2,2-Trifluoro-1-(6,7,8,9-tetrakis(4-fluorophenyl)-3-methyl-3Hbenzo[e]indol-1-yl)ethanone (3ab). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 58% (38 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 188−190. IR (neat, cm−1): 1685. 1H NMR (CDCl3, 400 MHz): δ 7.58 (br. s., 1 H), 7.50 (d, J = 8.6 Hz, 1 H), 7.40 (d, J = 9.2 Hz, 1 H), 7.11−7.08 (m, 2 H), 6.95−6.83 (m, 6 H), 6.69− 6.57 (m, 8 H), 3.9 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.8, 173.5, 173.2, 172.9, 163.5, 163.4, 162.6, 162.5, 161.9, 161.7, 160.8, 160.7, 160.5, 160.0, 159.8, 140.6, 139.3, 138.2, 137.8, 137.0, 136.9, 136.4, 136.3, 135.9, 133.7, 133.6, 132.9, 132.6, 132.5, 131.2, 130.8, 130.6, 128.8, 127.1, 127.0, 126.0, 125.9, 125.0, 120.4, 117.8, 115.4, 115.1, 114.7, 114.2, 114.1, 114.0, 113.9, 113.8, 113.6, 110.6, 110.5, 110.4, 97.0, 88.9, 34.3. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C39H22F7NONa: 676.1487; Found: 676.1487. 2,2,2-Trifluoro-1-(6,7,8,9-tetrakis(4-chlorophenyl)-3-methyl-3Hbenzo[e]indol-1-yl)ethanone (3ac). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 33% (24 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 123−125. IR (neat, cm−1): 1691. 1H NMR (CDCl3, 400 MHz): δ 7.60 (s, 1 H), 7.46 (d, J = 9.1 Hz, 1 H), 7.41 (d, J = 9.1 Hz, 1 H), 7.24 (d, J = 7.9 Hz, 2 H), 7.07 (d, J = 7.6 Hz, 2 H), 6.98−6.88 (m, 6 H), 6.85 (d, J = 8.5 Hz, 2 H), 6.66−6.62 (m, 4 H), 3.95 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.8, 173.5, 173.2, 173.0, 138.69, 138.66, 138.48, 138.29, 138.04, 137.9, 137.3, 137.1, 137.0, 136.7, 133.8, 133.8, 133.0, 132.6, 132.4, 132.3, 132.2, 131.9, 131.9, 131.1, 128.6, 128.4, 128.2, 127.6, 127.4, 127.4, 127.2,

yield: 54% (35 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1702. 1H NMR (CDCl3, 400 MHz): δ 7.77 (s, 1 H), 7.60−7.49 (m, 6 H), 7.39 (d, J = 9.2 Hz, 1 H), 7.19−7.16 (m, 5 H), 7.03−6.98 (m, 5 H), 6.88−6.83 (m, 6 H), 6.80−6.67 (m, 4 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 174.1, 173.8, 173.6, 173.3, 140.90, 140.81, 140.49, 140.44, 140.35, 138.8, 138.7, 137.7, 137.5, 136.6, 133.0, 131.9, 131.6, 131.5, 131.3, 130.1, 128.9, 127.7, 127.53, 127.46, 126.8, 126.6, 126.1, 125.6, 125.5, 125.4, 125.2, 120.5, 120.0, 117.7, 117.0, 115.4, 111.3, 111.2, 111.2, 111.1. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C44H28F3NONa 666.2021; Found 666.2020. 1-(3-(4-Chlorophenyl)-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1yl)-2,2,2-trifluoroethanone (3da). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 40% (27 mg). Rf (30% DCM/Pet. ether) = 0.2. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1696. 1H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1 H), 7.56 (d, J = 8.6 Hz, 2 H), 7.52−7.48(m, 3 H), 7.34 (d, J = 9.2 Hz, 1 H), 7.20−7.16 (m, 5 H), 7.00−6.99 (m, 5 H), 6.88−6.83 (m, 6 H), 6.77−6.72 (m, 4 H). 13 C{1H} NMR (CDCl3, 125 MHz): δ 173.8, 173.6, 173.1, 172.7, 140.79, 140.72, 140.63, 140.33, 140.26, 138.9, 137.5, 136.4, 136.2, 134.8, 131.6, 131.2, 130.3, 130.3, 130.2, 127.7, 127.6, 127.5, 126.8, 126.7, 126.6, 126.4, 125.4, 125.2, 120.8, 120.7, 120.6, 117.6, 117.3, 110.9, 110.8, 110.5. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C44H27ClF3NONa 700.1631; Found 700.1630. 2,2,2-Trifluoro-1-(3-(3-methoxyphenyl)-6,7,8,9-tetraphenyl-3Hbenzo[e]indol-1-yl)ethanone (3ea). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 37% (25 mg). Rf (30% DCM/Pet. ether) = 0.2. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1694. 1H NMR (CDCl3, 400 MHz): δ 7.7 (s, 1 H), 7.51−7.41 (m, 3 H), 7.18− 7.11 (m, 6 H), 7.06−7.01 (m, 7 H), 6.88−6.83 (m, 6 H), 6.77−6.73 (m, 4 H), 3.87 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 174.2, 173.8, 173.6, 173.2, 160.8, 140.89, 140.81, 140.47, 140.42, 140.35, 138.85, 138.78, 138.7, 137.5, 136.6, 133.0, 131.9, 131.7, 131.5, 131.2, 130.8, 127.6, 126.8, 126.7, 126.6, 126.6, 126.2, 125.3, 120.5, 117.6, 116.9, 115.3, 114.4, 111.4, 111.3, 55.7. HRMS (ESI-TOF) (m/z): [M + Na]+ Calculated for C45H30F3NO2Na [M + Na]: 696.2126, found [M + Na]: 696.2122. 1-(3-Benzyl-6,7,8,9-tetraphenyl-3H-benzo[e]indol-1-yl)-2,2,2-trifluoroethanone (3fa). Purified by flash chromatography on silica gel using DCM: Pet. ether (25:75) as eluent to obtain a yellow solid. Isolated yield: 54% (36 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): decomp. after 250. IR (neat, cm−1): 1679. 1H NMR (CDCl3, 400 MHz): δ 7.60 (s, 1 H), 7.48 (d, J = 9.2 Hz, 1 H), 7.34− 7.31 (m, 3 H), 7.29 (d, J = 9.2 Hz, 1 H), 7.18−7.11 (m, 7 H), 6.98− 6.97 (m, 5 H), 6.87−6.82 (m, 6 H), 6.75 (br. s., 4 H), 5.42 (s, 2 H). 13 C{1H} NMR (CDCl3, 125 MHz): δ 173.7, 173.4, 173.2, 173.0, 140.90, 140.82, 140.45, 140.42, 140.37, 138.8, 138.6, 137.4, 136.4, 135.3, 132.6, 132.5, 131.6, 131.3, 131.1, 129.3, 129.2, 128.6, 128.5, 128.4, 127.7, 127.4, 126.9, 126.8, 126.7, 126.6, 126.5, 126.3, 126.0, 125.3, 125.2, 120.7, 117.7, 115.8, 115.4, 110.6, 110.5, 51.5. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C45H30F3NONa [M + Na]: 680.2177; Found [M + Na]: 680.2175 2,2-Trifluoro-1-(3-(4-methoxybenzyl)-6,7,8,9-tetraphenyl-3Hbenzo[e]indol-1-yl)ethanone (3ga). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 36% (25 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 142−144. IR (neat, cm−1): 1687. 1H NMR (CDCl3, 400 MHz): δ 7.55 (s, 1 H), 7.47 (d, J = 9.1 Hz, 1 H), 7.30 (d, J = 9.1 Hz, 1 H), 7.18−7.15 (m, 5 H), 7.08 (d, J = 8.4 Hz, 2 H), 6.96 (br. s., 5 H), 6.87−6.81 (m, 8 H), 6.76 (br. s., 4 H), 5.34 (s, 2 H), 3.78 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.7, 173.4, 173.1, 172.9, 159.7, 140.91, 140.84, 140.47, 140.40, 138.8, 138.6, 137.9, 137.4, 136.4, 132.9, 132.4, 132.4, 131.7, 131.5, 131.3, 131.1, 129.3, 129.1, 128.7, 128.5, 127.8, 127.6, 127.5, 127.1, 126.6, 126.6, 126.5, 126.2, 126.1, 125.3, 124.1, 122.8, 120.7, 117.8, 115.6, 115.4, 114.6, 110.9, 110.7, 110.0, 55.4, 51.0. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C46H32F3NO2Na [M + Na]: 710.2283: Found [M + Na]: 710.2282. 1816

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry

(s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.4, 173.1, 172.8, 172.6, 142.2, 140.8, 139.78, 138.97, 138.94, 138.60, 137.83, 130.7, 129.6, 129.3, 129.1, 128.9, 128.5, 128.3, 128.0, 127.9, 127.0, 126.6, 125.9, 124.6, 124.4, 118.4, 116.1, 110.4, 109.1, 34.2. HRMS (ESITOF) (m/z): [M + Na]+ Calcd for C25H18F3NONa: 428.1238; Found: 428.1238. (E)-1-(4-(1,2-bis(3-Nitrophenyl)vinyl)-1-methyl-1H-indol-3-yl)2,2,2-trifluoroethanone (4aj). Purified by flash chromatography on silica gel using DCM: Pet. ether (50:50) as eluent to obtain a yellow solid. Isolated yield: 24% (12 mg). Rf (70% DCM/Pet. ether) = 0.3. Melting point (°C): 127−129. IR (neat, cm−1): 1677, 1527. 1H NMR (CDCl3, 400 MHz): δ 8.07−8.01 (m, 4 H), 7.96 (t, J = 2.0 Hz, 1 H), 7.60−7.57 (m, 2 H), 7.47−7.40 (m, 2 H), 7.34 (t, J = 8.1 Hz, 2 H), 7.18 (dd, J = 1.4, 6.9 Hz, 1 H), 6.62 (s, 1 H), 3.98 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.7, 173.5, 173.2, 172.9, 148.4, 148.3, 143.0, 141.6, 139.73, 139.70, 139.66, 138.70, 138.60, 137.1, 136.9, 135.5, 129.2, 128.9, 128.4, 126.0, 125.3, 124.7, 124.6, 124.3, 122.5, 122.1, 118.3, 110.4, 110.0, 34.4. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C25H16F3N3O5Na: 518.0940; Found 518.0938. (Z)-1-(4-(1,2-bis(2-Chlorophenyl)vinyl)-1-methyl-1H-indol-3-yl)2,2,2-trifluoroethanone (4ak). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 45% (22 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 187−189. IR (neat, cm−1): 1678. 1H NMR (CDCl3, 400 MHz): δ 7.99 (s, 1 H), 7.45 (br. s., 1 H), 7.29−7.26 (m, 1 H), 7.25−7.22 (m, 2 H), 7.19 (br, s, 1 H),7.17 (s, 1H), 7.11−7.09 (m, 2 H), 7.02−6.96 (m, 2 H), 6.87−6.83 (m, 1 H), 6.53 (s, 1 H), 3.87 (s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.3, 172.9, 172.6, 172.3, 140.02, 139.99, 139.58, 138.93, 138.29, 136.0, 134.00, 133.4, 132.7, 131.0, 130.3, 130.2, 129.8, 129.3, 128.8, 128.5, 128.1, 127.3, 126.7, 126.1, 125.4, 124.8, 124.4, 124.0, 119.8, 118.6, 116.2, 110.2, 109.5, 109.4, 34.3. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C25H16Cl2F3NONa: 496.0459; Found:496.0457. 1-Methyl-3-(2,3,4-triphenylnaphthalen-1-yl)-1H-indole (5aa). Purified by flash chromatography on silica gel using ethyl acetate: Pet. ether (2:98) as eluent to obtain a yellow solid. Isolated yield: 33% (65 mg). Rf (5% ethyl acetate -Pet. ether) = 0.5. Melting point (°C): 135− 137. IR (neat, cm−1):1651. 1H NMR (CDCl3, 400 MHz): δ 7.88 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.41−7.31 (m, 6 H), 7.27− 7.21 (m, 3 H), 7.17 (d, J = 3.7 Hz, 1 H), 7.09 (t, 7.3 Hz, 1 H), 6.98− 6.90 (m, 4 H), 6.87−6.75 (m, 6 H), 6.64 (s, 1 H), 3.66 (s, 3 H). 13 C{1H} NMR (CDCl3, 100 MHz): δ 141.5, 140.85, 140.65, 139.76, 138.98, 138.15, 136.2, 133.0, 132.1, 131.5, 131.4, 131.3, 131.20, 131.1, 130.2, 129.6, 129.5, 127.6, 127.2, 126.9, 126.7, 126.5, 126.4, 126.3, 126.1, 125.7, 125.6, 125.2, 125.1, 121.2, 120.6, 119.1, 113.2, 109.0, 32.6. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd C37H27NNa: 508.2041; Found: 508.2041.

127.0, 126.9, 125.9, 125.5, 120.3, 117.7, 115.4, 115.1, 111.2, 110.8, 34.4. HRMS (ESI-TOF) (m/z): [M + Na] + Cald for C39H22Cl4F3NONa: 740.0305; Found:740.0309. 2,2,2-Trifluoro-1-(6,7,8,9-tetrakis(3-fluorophenyl)-3-methyl-3Hbenzo[e]indol-1-yl)ethanone (3af). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 70% (46 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 127−129. IR (neat, cm−1): 1646. 1H NMR (CDCl3, 400 MHz): δ 7.61 (s, 1 H), 7.52 (d, J = 9.1 Hz, 1 H), 7.40 (d, J = 9.1 Hz, 1 H), 7.21 (d, J = 6.9 Hz, 1 H), 6.97−6.91 (m, 6 H), 6.77 (d, J = 6.7 Hz, 2 H), 6.69−6.49(m,7 H), 3.97 (s, 3 H). 13C{1H}NMR (CDCl3, 125 MHz): δ 173.7, 173.3, 173.1, 172.8, 163.3, 162.9, 162.7, 161.3, 161.0, 160.8, 160.8, 142.3, 142.3, 142.2, 142.2, 141.93, 141.87, 138.6, 138.00, 137.1, 136.8, 136.6, 133.8, 130.9, 129.4, 128.6, 128.5, 128.3, 128.1, 127.4, 127.2, 126.9, 126.7, 125.8, 120.2, 119.4, 118.3, 118.3, 118.2, 118.0, 117.9, 117.8, 115.4, 115.1, 114.1, 113.9, 113.4, 113.3, 113.0, 112.9, 110.9, 34.3. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C39H22F7NONa: 676.1487; Found: 676.1484. 2,2,2-Trifluoro-1-(6,7,8,9-tetrakis(3-chlorophenyl)-3-methyl-3Hbenzo[e]indol-1-yl)ethenone (3ag). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 66% (48 mg). Rf (30% DCM/Pet. ether) = 0.2. Melting point (°C): 168−170. IR (neat, cm−1):1687. 1 H NMR (CDCl3, 400 MHz): δ 7.61 (s., 1 H), 7.51−7.43 (m, 2 H), 7.20 (br. s., 3 H), 7.09−7.02 (m, 2 H), 6.94−6.85 (m, 8 H), 6.74−6.64 (m, 3 H), 3.97 (s, 3 H). 13C{1H}NMR (CDCl3, 125 MHz): δ 173.5, 173.4, 173.1, 172.8, 141.78, 141.62, 141.42, 138.51, 137.90, 137.1, 136.8, 136.6, 134.0, 133.1, 133.0, 132.7, 132.3, 131.9, 131.2, 131.0, 130.8, 129.6, 129.5, 129.3, 129.3, 129.2, 128.4, 128.3, 128.1, 128.0, 127.8, 127.3, 126.6, 126.6, 126.3, 125.8, 120.3, 117.1, 115.4, 115.1, 111.1, 109.9, 34.4. HRMS (ESI-TOF) (m/z): Calculated for C39H22Cl4F3NO[M + Na]: 740.0305, found [M + Na]: 740.0303. 2,2,2-Trifluoro-1-(6,7,8,9-tetrakis(3-bromophenyl)-3-methyl-3Hbenzo[e]indol-1-yl)ethanone (3ah). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 70% (63 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 147−149. IR (neat, cm−1): 1689. 1H NMR (CDCl3, 400 MHz): δ 7.62 (s, 1 H), 7.51 (d, J = 9.1 Hz, 1 H), 7.45 (d, J = 9.1 Hz, 1 H), 7.39−7.35 (m, 2 H), 7.19−7.01 (m, 7 H), 6.91−6.76 (m, 7 H), 3.97(s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.7, 173.5, 173.2, 172.9, 141.99, 141.84, 141.65, 138.48, 137.8, 137.1, 136.8, 136.5, 134.2, 134.1, 134.0, 133.8, 130.8, 130.2, 130.0, 129.9, 129.7, 129.5, 129.2, 129.1, 128.7, 128.6, 128.4, 128.3, 128.1, 126.6, 125.8, 122.0, 121.9, 121.3 121.2, 121.0, 120.8, 120.8, 120.3, 120.0, 117.7, 115.4, 115.0, 111.1, 34.4. HRMS (ESI-TOF) (m/z): [M + Na]+ Calcd for C39H22Br4F3NONa: 915.8285; Found: 915.8281. 2,2,2-Trifluoro-1-(3-methyl-6,7,8,9-tetrakis(3-(trifluoromethyl)phenyl)-3H-benzo[e]indol-1-yl)ethanone (3ai). Purified by flash chromatography on silica gel using DCM: Pet. ether (30:70) as eluent to obtain a yellow solid. Isolated yield: 60% (52 mg). Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 214−216. IR (neat, cm−1): 1691. 1H NMR (CDCl3, 400 MHz): δ 7.64 (s, 1 H), 7.55−7.52 (m, 2 H), 7.50−7.47 (m, 2 H), 7.42−7.37 (m, 3 H), 7.3 (d, J = 7.2 Hz, 1 H), 7.22−6.92 (m, 10 H),4.00(s, 3 H). 13C{1H} NMR (CDCl3, 125 MHz): δ 173.8, 173.5, 173.3, 173.0, 140.65, 140.58, 140.53, 140.49, 140.24, 138.7, 138.6, 138.5, 138.2, 138.2, 138.1, 137.2, 137.0, 137.0, 136.9, 134.3, 134.5, 134.3, 134.0, 134.0, 133.8, 130.9, 130.9, 130.6, 130.2, 129.8, 129.6, 128.6, 128.5, 128.4, 128.2, 128.0, 127.8, 127.8, 127.7, 127.6, 127.2, 127.1, 127.1, 126.8, 125.7, 125.1, 124.8, 123.9, 123.3, 122.8, 122.6, 120.4, 119.9, 117.6, 115.3, 115.0, 113.0, 111.5, 34.4. HRMS (ESI-TOF) (m/z): [M + Na] + Calcd for C43H22F15NONa: 876.1360; Found: 876.1367. (E)-1-(4-(1,2-Diphenylvinyl)-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethanone (4aa). Purified by flash chromatography on silica gel using DCM: Pet. ether (25:75) as eluent to obtain an off white solid. Isolated yield: 28% (23 mg). Note: Reaction performed in 0.2 mmol scale. Rf (30% DCM/Pet. ether) = 0.3. Melting point (°C): 130−132. IR (neat, cm−1): 1677. 1H NMR (CDCl3, 400 MHz): δ 7.91 (s, 1 H), 7.34−7.33 (m, 2 H), 7.25−7.21 (m, 4 H), 7.2−7.15 (m, 5 H), 7.13−7.10 (m, 2 H), 6.47 (s, 1 H), 3.88

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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.7b02719. 1 H and 13C spectra and spectral data for all compounds, and crystallographic information for 3fa (PDF) CIF file for 3fa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kandikere Ramaiah Prabhu: 0000-0002-8342-1534 Author Contributions ‡

These authors contributed equally.

Notes

The authors declare no competing financial interest. 1817

DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818

Article

The Journal of Organic Chemistry

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ACKNOWLEDGMENTS This work was supported by SERB (NO.SB/S1/OC-56/2013), New-Delhi, CSIR (No. 02(0226)15/EMR-II), New-Delhi, Indian Institute of Science, RL Fine Chem, Bangalore and Synovation Chemicals, and Sourcing Pvt Limited, Bangalore. We thank A. R. Ramesha (RL Fine Chem) and Sankar Iyer (Synovation Chemicals and Sourcing Pvt Limited) for useful discussions. KRB and VL thank CSIR, New-Delhi, for fellowships.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02719 J. Org. Chem. 2018, 83, 1810−1818