Synthesis of Polycyclic Benzo[b]indolo[3,2,1-de]acridines via

Oct 2, 2017 - ... Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China...
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Synthesis of Polycyclic Benzo[b]indolo[3,2,1-de]acridines via Sequential Allenylation, Diels−Alder Cyclization, and Hydrogen Migration Reaction Yulei Zhao, Yang Yuan, Xiaoyu Wang, and Yanzhong Li* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China S Supporting Information *

ABSTRACT: A novel methodology for stereoselective synthesis of benzo[b]indolo[3,2,1-de]acridines through the tandem reaction of propargylic compounds with organoboron is described, and only one diastereoisomer was obtained. The sequential procedure was triggered by Pd(0)-catalyzed allenylation of propargyl carbonate. Then, Diels−Alder cyclization and hydrogen migration processes proceeded successively to furnish the polycyclic target molecules. Control reactions suggested the base (Cs2CO3) was indispensable for the hydrogen migration.

T

Scheme 1. Construction of Polycyclic Structures from Propargylic Compounds with Allene Intermediates

he access to structurally complex polycyclic molecules via elegant and efficient sequential reactions with simple, readily available starting materials shows powerful developmental prospects,1 whereas the intramolecular Diels−Alder cycloaddition, as a very powerful synthetic tool, can generate molecular complexity in a single step.2 Therefore, the approaches involving tandem reactions in combination with a Diels−Alder process has attracted the attention of synthetic chemists. Propargylic compounds are useful building blocks. A variety of valuable compounds, such as alkynes, enynes, allenes, heterocycles, and carbocycles, were prepared through the transformation of propargylic substrates.3 In recent years, tandem reactions starting from propargylic substrates were also used to synthesize a complex polycyclic architecture.4 Bi and co-workers reported an excellent atom-economic route to benzo[f ]-1-indanone frameworks starting from the readily available gem-dialkylthio trienynes by intramolecular annulations (Scheme 1a).5 In their reactions, the electron-poor alkene moiety acted as the dienophile in the Diels−Alder process. Lai’s group developed an interesting sequential Sonogashira coupling/alkynyl imine−allenyl imine isomerization/azaDiels−Alder/elimination−aromatization reaction to provide a facile synthesis of substituted 2-azaanthracenes from 1,6-diynes and imidoyl chlorides (Scheme 1b).6 Baxendale and Baumann reported an efficient reaction sequence converting simple propargylic alcohols into tricyclic pyrrolo[1,2-a]quinolines in the presence of chlorophosphine and phosphite species (Scheme 1c).7 This tandem reaction included an allenylation and a nucleophilic addition process. In this procedure, the electron-rich pyrrole moiety was used as a nucleophile to attack the center carbon of allene. As part of our ongoing interest in developing a new methodology for the construction of carbo- and heterocyclic © 2017 American Chemical Society

compounds,8 we previously disclosed a tertiary amine selfcatalyzed intramolecular Csp3−H functionalization for the Received: June 29, 2017 Published: October 2, 2017 11198

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

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

formation of 3-alkenyl indolines.9 During this procedure, the Csp3−H functionalization was achieved by the nucleophilic attack of the allene generated in situ from propargyl carbonate. On this basis, we further designed substrates (1) bearing a propargyl carbonate and indole moiety. (Because of steric hindrance, atropisomerism might exist for the indolylsubstituted substrate 1. Therefore, the NMR spectra for the indole series display two distinct signals for the methoxy and C−H) We envision that it might be possible to prepare potentially useful complex ring-fused cyclic products via a Csp2−H functionalization of the C-2 site of indole. Interestingly, an unexpected Diels−Alder process was realized instead to afford a complex hexacyclic structure (Scheme 1d). In this process, the electron-rich pyrrole moiety acted as the dienophile, and only one diastereoisomer was observed. The thus formed polycyclic compounds contain the core pyrrolo[3,2,1-ij]quinoline skeletons that are key structural subunits and widely present in natural products (Figure 1).10−12 However,

entry catalyst (mol %) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 a

Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 − Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4

(5) (5) (5) (5) (5) (5) (5) (1) (2) (10) (2) (2) (2) (2) (2)

base (equiv)

temp (°C)

time (h)

yield (%)

Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) − Cs2CO3 (1) Cs2CO3 (3) Cs2CO3 (2) Cs2CO3 (2) Cs2CO3 (2) DBU DABCO Et3N DIPEA NaOH

rt 80 100 120 100 100 100 100 100 100 100 100 100 100 100 100

5 3 2 2 2 18 2 2 2 2 2 2 2 2 2 2

0 44 83 77 no reaction 39 70 78 72 89 84 25 88 56 49 18

The reaction was performed with 2.0 mL of 1,4-dioxane under N2.

catalyst and 2.0 equiv of Cs2CO3 as the additive at 100 °C in 1,4-dioxane under N2. With the optimized reaction conditions in hand (Table 1, entry 10), we next examined the substrate scope (Figure 2). First, we investigated the electronic effect of substituent R1 (3a−e). The substrates with electron-donating group gave yields (3c, R1 = p-OMePh, 91%) that were much better than the yields with the electron-withdrawing substituent (3d, R1 = p-ClPh, 74%; 3e, R1 = p-CNPh, 62%). Treatment of the substrate bearing a pyrrolyl group furnished oxidized 3f in 38% yield. Then, R2 substituents on the benzene ring of indoles were explored. Good to excellent yields of the corresponding benzo[b]indolo[3,2,1-de]acridines could be obtained irrespective of the presence of electron-donating or electron-withdrawing groups on the benzene ring (3g−l). Subsequently, we investigated the effect of different R3 substituents at the para position of the N-phenyl ring. It was found that a methyl- or chloro-substituted substrates also underwent the reaction smoothly to afford 3m and 3n in 96 and 92% yield, respectively. Notably, with a heterocyclic aryl substituent RM1 such as a 2thienyl group, the reaction was messy and no desired product 3o was detected. Finally, when R1 substituents were different from the aryl groups of organoborane reagents, good to excellent yields of target products (3q and 3r) could also be achieved with two isomers. In particular, when R1 = n-butyl, the desired 3p could be generated in 72% yield as a single isomer. In addition, it was found that 3a could be transformed to 5a in a moderate yield after a mild oxidation procedure in air (Scheme 2). It is noteworthy that the atropoisomerism of indolyl-substituted substrate 1 had no obvious effect on the yield or stereoselectivity of the reaction. To clarify the reaction mechanism, we performed several control experiments. First, the reaction of 1a with 2a was performed at room temperature to trap a possible intermediate in 1,4-dioxane (tetrahydrofuran was also suitable for the reaction). Luckily, allenylation compound 4a was obtained in

Figure 1. Natural products with a pyrrolo[3,2,1-ij]quinoline skeleton.

highly effective synthetic methods for producing this complex polycyclic structure are scarce. Therefore, the development of novel and efficient sequential reactions with readily available starting materials is highly desirable. Our preliminary studies focused on the reaction of 1-[2-(1Hindol-1-yl)phenyl]-3-phenylprop-2-yn-1-yl methyl carbonate (1a) with phenylboronic acid (2a) in the presence of 5 mol % Pd(PPh3)4 and 2.0 equiv of Cs2CO3 in 1,4-dioxane. When the reaction of 1a with 2a was performed at room temperature, an allenylation compound (4a) (see Scheme 3) was observed instead of benzo[b]indolo[3,2,1-de]acridine (3a) (Table 1, entry 1). When the temperature was increased to 100 °C, the desired product 3a was obtained with an encouraging yield of 83% (entry 3). It is worth noting that only one diastereoisomer was obtained under basic conditions at 100 °C. The structure of 3a was confirmed by X-ray crystallography.13 Without Pd(PPh3)4, no reaction occurred (enrty 5). 3a could be obtained in only 39% yield in the absence of Cs2CO3 (entry 6). Changing the amount of Cs2CO3 to 1.0 or 3.0 equiv did not produce better results (entries 7 and 8). The amount of Pd(PPh3)4 was further investigated (entries 9−11). It was found that 3a could be isolated in 89% yield in the presence of 2 mol % Pd(PPh3)4 within 2 h (entry 10). When the amount of Pd(PPh3)4 was decreased to 1 mol %, the yield of the desired 3a was reduced to 72% (entry 9 vs entry 10). Increasing the amount of Pd(PPh3)4 to 10 mol % resulted in only a lower yield (entry 11, 84%). Other bases such as 1,8diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diaza[2.2.2]bicyclooctane (DABCO), triethylamine (Et3N), ethyldiisopropylamine (DIPEA), and sodium hydroxide (NaOH) were also tested (entries 12−16, respectively). No better results were achieved, and using only BABCO gave a yield similar to that of Cs2CO3 (entry 13). Therefore, the optimal reaction conditions for the preparation of 3a included 2 mol % Pd(PPh3)4 as the 11199

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

The Journal of Organic Chemistry Table 2. Control Experiments

a

entry

catalyst (mol %)

base (equiv)

time (h)

yield (%)

1 2 3 4 5a

− − Pd(PPh3)4 (2) Pd(PPh3)4 (2) −

− Cs2CO3 (2) − Cs2CO3 (2) Cs2CO3 (2)

7 1 7 1 1

26 86 28 89 51

The reaction was performed under O2.

(entry 4). An oxygen atmosphere resulted in a lower yield of 3a because of a possible oxidation process (entry 5, 51%). These results implied that the allenylation compound was a possible intermediate, and Pd(Ph3P)4 was not effective for the subsequent cyclization step. In addition, Cs2 CO 3 was indispensable for the cyclization process. On the basis of these results and related precedents,14 we propose the following plausible mechanism for this reaction (Scheme 4). The reaction is initiated by SN2′ attack of Pd(0) Scheme 4. Possible Reaction Mechanism

Figure 2. Scope of the reaction. The reactions were performed under the optimized reaction conditions. Isolated yield. aThe reaction was messy, and no desired product was detected. bReacted with phenylboronic acid. cReacted with p-methylphenylboronic acid. d Reacted with p-chlorophenylboronic acid.

on propargylic carbonate 1a to form allenylpalladium intermediate 1a′. Then, 1a′ undergoes transmetalation with phenylboronic acid (2a) and reductive elimination of Pd(II) to generate allenylation intermediate 4a.14a−d Subsequently, the CC bond of the electron-rich indole group of intermediate 4a acts as the dienophile, whereas the benzene ring and CC bond of the allene moiety act as the diene components for Diels−Alder reaction to furnish intermediate 4a′. 4a′ was transformed to 4a″ by a 1,3-H shift process. Finally, the further hydrogen migration of 4a″ occurred under basic conditions, yielding target molecule 3a. In summary, we have developed a novel methodology for synthesizing benzo[b]indolo[3,2,1-de]acridines. This tandem reaction contains sequential Pd(0)-catalyzed allenylation, Diels−Alder cyclization, and hydrogen migration procedures. Mechanistic investigations suggested that allene was the key intermediate, and Cs2CO3 was indispensable for the subsequent hydrogen migration. Oxidation of benzo[b]indolo[3,2,1-de]acridine 3a could also be performed slowly in air to realize the aromatization.

Scheme 2. Oxidation Procedure

77% yield (Scheme 3). Without any catalyst or additive, 4a could be transformed to 3a smoothly in 26% yield (Table 2, entry 1), whereas 86% 3a could be obtained in the presence of Cs2CO3 only (entry 2). Using 2 mol % Pd(Ph3P)4 as the catalyst at 100 °C gave 3a in 28% yield (entry 3). Under the optimized reaction conditions, 3a could be formed in 89% yield Scheme 3. Intermediate Capture and Isolation

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EXPERIMENTAL SECTION

General Methods. All reactions were performed under N2 except noted. Anhydrous 1,4-dioxane, toluene, and tetrahydrofuran were distilled from sodium and benzophenone. Anhydrous acetonitrile was 11200

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

The Journal of Organic Chemistry prepared by distillation from CaSO4. Unless noted, all commercial reagents were used without further purification. Reactions were monitored by thin layer chromatography using ultraviolet light to visualize the course of the reaction. Purification of reaction products was performed by flash chromatography on silica gel (300−400 mesh). 1 H NMR spectra were recorded at 400 MHz and 13C NMR spectra at 100 MHz, in CDCl3 or (CD3)2SO (containing 0.03% TMS) solutions. 1 H NMR spectra were recorded with Me4Si (δ 0.00) as the internal reference, and 13C NMR spectra were recorded with CDCl3 (δ 77.00) or DMSO-d6 (δ 39.52) as the internal reference. High-resolution mass spectra were obtained using a Bruker Maxis Impact mass spectrometer with a TOF (for ESI) or FT-ICR (for MALDI) analyzer. Single-crystal X-ray diffraction data were collected in Bruker SMARTAPEX diffractometers with molybdenum cathodes. A Typical Procedure for the Synthesis of 1. Synthetic Route for the Synthesis of 1. Starting from o-iodobenzoic acid derivatives, we prepared intermediates B−D, and then protection of D gave 1. For the details, see Scheme S1. Intermediates B and C were prepared according to the literature methods.15,16 Synthesis of Intermediate D. To a solution of the corresponding terminal alkyne (1.3 equiv) in THF (40 mL) in a Schlenk tube was added n-BuLi (2.5 M, 3.2 mL, 1.3 equiv) at −78 °C, and then the mixture was stirred at −78 °C under nitrogen for 30 min. Then, a solution of C in THF (5 mL) was added dropwise and stirred at −78 °C for 1−2 h. After full conversion of C as monitored by thin layer chromatography, the resulting mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a petroleum ether/ethyl acetate (20:1 to 5:1) eluent afforded intermediate D in 71−93% yields. Synthesis of Substrate 1. To a solution of the corresponding intermediate D (1.5 mmol) in DCM (40 mL) in a Schlenk tube were added DMAP (17.0 mg, 0.1 equiv) and pyridine (1.2 mL, 10.0 equiv) at 0 °C. Then ClCO2Me (352 uL, 3.0 equiv) was added dropwise at 0 °C under N2. The mixture was slowly warmed to room temperature. Approximately 30 min later, after full conversion of D as determined by TLC analysis, the resulting mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (100 mL). The organic layers were washed with brine, dried over anhydrous Na 2SO4 , filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel with a petroleum ether/ethyl acetate/Et3N (100:10:1) eluent afforded substrate 1. Atropisomerism might exist for the indolyl-substituted substrate 1. 1-[2-(1H-Indol-1-yl)phenyl]-3-phenylprop-2-yn-1-yl Methyl Carbonate (1a). Yellow oil; 75% yield (429 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.03−7.91 (m, 1H), 7.74−7.60 (m, 1H), 7.55−7.42 (m, 2H), 7.37−7.20 (m, 7H), 7.16−7.07 (m, 3H), 6.71 (s, 1H), 6.30 (s, 1H), 3.69 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.19 (s, 1H), 3.50 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.4, 154.3, 138.1, 137.9, 137.8, 137.6, 135.1, 134.8, 132.0, 131.9, 130.4, 130.3, 129.5, 129.4, 129.4, 129.3, 129.2, 129.0, 129.0, 128.6, 128.6, 128.3, 122.5, 122.4, 121.9, 121.8, 121.1, 121.0, 120.4, 120.3, 110.6, 110.4, 103.5, 103.4, 88.1, 87.8, 84.5, 84.4, 65.8, 65.6, 54.9, 54.7; HRMS (ESI) calcd for C25H19NNaO3 [M + Na]+ 404.1257, found 404.1262. 1-[2-(1H-Indol-1-yl)phenyl]-3-(p-tolyl)prop-2-yn-1-yl Methyl Carbonate (1b). Yellow oil; 60% yield (356 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.04−7.92 (m, 1H), 7.73−7.65 (m, 1H), 7.59−7.45 (m, 2H), 7.40−7.05 (m, 9H), 6.72 (s, 1H), 6.28 (s, 1H), 3.73 (s, 3H), 2.32 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.16 (s, 1H), 3.53 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.3, 139.4, 138.2, 138.0, 137.9, 137.7, 135.3, 135.1, 132.1, 132.0, 130.4, 130.3, 129.6, 129.5, 129.3, 129.2, 129.1, 129.0, 128.7, 128.7, 122.5, 122.5, 121.0, 120.4, 120.3, 118.9, 118.8, 110.7, 110.6, 103.6,

103.4, 88.4, 88.1, 83.8, 65.9, 65.8, 54.9, 54.8, 21.2; HRMS (ESI) calcd for C26H21NNaO3 [M + Na]+ 418.1414, found 418.1418. 1-[2-(1H-Indol-1-yl)phenyl]-3-(4-methoxyphenyl)prop-2-yn-1-yl Methyl Carbonate (1c). Yellow oil; 62% yield (383 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.05−7.91 (m, 1H), 7.74−7.63 (m, 1H), 7.57−7.46 (m, 2H), 7.40−7.06 (m, 7H), 6.82− 6.66 (m, 3H), 6.28 (s, 1H), 3.77 (s, 3H), 3.72 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.16 (s, 1H), 3.53 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 160.4, 154.5, 154.4, 138.2, 138.0, 137.9, 137.7, 135.4, 135.1, 133.7, 133.6, 130.4, 130.3, 129.6, 129.6, 129.5, 129.3, 129.1, 129.0, 128.7, 128.7, 122.4, 121.1, 121.0, 120.4, 120.3, 114.0, 110.7, 110.6, 103.5, 103.4, 88.3, 87.9, 83.2, 66.1, 65.9, 55.1, 54.9, 54.8; HRMS (ESI) calcd for C26H21NNaO4 [M + Na]+ 434.1363, found 434.1374. 1-[2-(1H-Indol-1-yl)phenyl]-3-(4-chlorophenyl)prop-2-yn-1-yl Methyl Carbonate (1d). Yellow oil; 70% yield (437 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.00−7.88 (m, 1H), 7.72−7.65 (m, 1H), 7.59−7.49 (m, 2H), 7.42−7.34 (m, 1H), 7.30− 7.19 (m, 4H), 7.16−7.05 (m, 4H), 6.72 (d, J = 3.2 Hz, 1H), 6.29 (s, 1H), 3.75 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.17 (s, 1H), 3.58 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.4, 138.2, 138.0, 137.7, 135.2, 135.0, 134.6, 133.4, 133.3, 130.5, 129.8, 129.6, 129.3, 129.3, 129.2, 129.1, 128.8, 128.7, 122.5, 121.2, 121.1, 120.5, 120.4, 110.6, 110.5, 103.6, 86.9, 86.5, 85.5, 85.3, 66.0, 65.5, 55.0, 54.9; HRMS (ESI) calcd for C25H19ClNO3 [M + H]+ 416.1048, found 416.1056. 1-[2-(1H-Indol-1-yl)phenyl]-3-(4-cyanophenyl)prop-2-yn-1-yl Methyl Carbonate (1e). Yellow oil; 99% yield (604 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.01−7.82 (m, 1H), 7.74−7.62 (m, 1H), 7.60−7.47 (m, 4H), 7.45−7.35 (m, 1H), 7.34− 7.23 (m, 2H), 7.21−7.02 (m, 4H), 6.72 (s, 1H), 6.33 (s, 1H), 3.76 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.23 (s, 1H), 3.62 (s, 3H) (other peaks overlap with the signals of the first isomer); 13 C NMR (100 MHz, CDCl3) δ 154.4, 154.4, 138.1, 137.9, 137.6, 134.6, 134.1, 132.6, 132.5, 132.1, 132.0, 130.8, 130.7, 130.0, 129.7, 129.5, 129.4, 129.2, 129.1, 129.0, 128.9, 128.7, 128.7, 126.7, 126.6, 122.5, 121.2, 121.1, 120.5, 120.4, 118.4, 112.3, 112.3, 110.6, 110.4, 103.7, 103.5, 88.7, 88.4, 86.0, 85.5, 66.0, 65.2, 55.1, 55.0; HRMS (ESI) calcd for C26H19N2O3 [M + H]+ 407.1390, found 407.1389. 1-[2-(1H-Pyrrol-1-yl)phenyl]-3-phenylprop-2-yn-1-yl Methyl Carbonate (1f). Yellow oil; 57% yield (283 mg); 1H NMR (400 MHz, CDCl3) δ 7.94−7.86 (m, 1H), 7.50−7.39 (m, 4H), 7.35−7.26 (m, 4H), 6.92−6.85 (m, 2H), 6.40−6.35 (m, 2H), 6.34 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.6, 139.9, 133.3, 132.2, 130.1, 129.2, 129.2, 128.6, 128.5, 127.4, 123.0, 122.0, 109.8, 88.0, 84.9, 65.7, 55.0; HRMS (ESI) calcd for C21H17NNaO3 [M + Na]+ 354.1101, found 354.1102. 1-{2-[5-(Benzyloxy)-1H-indol-1-yl]phenyl}-3-phenylprop-2-yn-1-yl Methyl Carbonate (1g). Yellow oil; 87% yield (636 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.04−7.90 (m, 1H), 7.58−7.45 (m, 4H), 7.42−7.21 (m, 11H), 7.05−6.96 (m, 1H), 6.93− 6.85 (m, 1H), 6.63 (s, 1H), 6.29 (s, 1H), 5.12 (s, 2H), 3.74 (s, 3H); 1 H NMR (400 MHz, CDCl3), the other isomer, δ 6.18 (s, 1H), 3.57 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.2, 138.0, 135.2, 134.9, 133.8, 133.5, 132.1, 132.1, 130.5, 130.4, 130.2, 129.9, 129.6, 129.5, 129.3, 129.1, 129.1, 128.8, 128.4, 128.0, 127.8, 121.9, 113.4, 111.4, 111.3, 104.2, 104.1, 103.3, 103.2, 84.6, 70.8, 65.8, 65.7, 55.0, 54.9; HRMS (ESI) calcd for C32H26NO4 [M + H]+ 488.1856, found 488.1863. 1-[2-(5-Fluoro-1H-indol-1-yl)phenyl]-3-phenylprop-2-yn-1-yl Methyl Carbonate (1h). Yellow oil; 99% yield (593 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.06−7.90 (m, 1H), 7.62−7.46 (m, 2H), 7.41−7.21 (m, 8H), 7.05−6.95 (m, 1H), 6.94− 6.82 (m, 1H), 6.67 (s, 1H), 6.26 (s, 1H), 3.74 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.14 (s, 1H), 3.58 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 159.8, 157.5, 154.5, 154.4, 137.7, 137.5, 135.3, 135.0, 134.7, 132.1, 132.0, 131.1, 130.9, 130.5, 130.5, 129.7, 129.6, 129.4, 129.4, 129.2, 129.0, 128.5, 128.4, 121.9, 111.5, 111.4, 111.3, 111.2, 11201

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

The Journal of Organic Chemistry

(400 MHz, CDCl3), one atropisomeric product, δ 7.97−7.84 (m, 1H), 7.71−7.60 (m, 1H), 7.50−7.40 (m, 1H), 7.32−7.06 (m, 10H), 6.72 (s, 1H), 6.23 (s, 1H), 3.76 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.13 (s, 1H), 3.58 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.4, 154.2, 138.2, 137.9, 137.1, 136.8, 136.3, 136.2, 135.2, 135.0, 132.2, 132.1, 130.6, 130.5, 129.5, 129.3, 129.1, 128.8, 128.7, 128.5, 122.8, 121.7, 121.7, 121.3, 121.2, 120.7, 110.4, 104.1, 104.0, 96.1, 91.6, 88.6, 88.3, 83.9, 83.3, 65.3, 65.2, 55.1, 55.0; HRMS (ESI) calcd for C25H18ClNNaO3 [M + Na]+ 438.0867, found 438.0874. 1-[2-(1H-Indol-1-yl)phenyl]hept-2-yn-1-yl Methyl Carbonate (1o). Yellow oil; 81% yield (439 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 7.96−7.84 (m, 1H), 7.71− 7.42 (m, 1H), 7.56−7.45 (m, 2H), 7.40−7.27 (m, 1H), 7.25−7.20 (m, 1H), 7.16−7.11 (m, 2H), 7.10−7.02 (m, 1H), 6.69 (s, 1H), 6.03 (s, 1H), 3.71 (s, 3H), 2.20−2.00 (m, 2H), 1.48−1.27 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 5.94 (s, 1H), 3.50 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.3, 138.2, 138.0, 137.8, 137.7, 135.7, 135.5, 130.2, 130.1, 129.5, 129.4, 129.3, 129.7, 129.0, 128.9, 128.6, 122.4, 121.1, 120.9, 120.4, 120.3, 110.7, 110.5, 103.4, 103.3, 89.7, 89.5, 75.7, 65.7, 65.7, 54.8, 54.7, 30.0, 21.6, 18.1, 13.2; HRMS (ESI) calcd for C23H23NNaO3 [M + Na]+ 384.1570, found 384.1577. 1-[2-(1H-Indol-1-yl)phenyl]-3-(naphthalen-2-yl)prop-2-yn-1-yl Methyl Carbonate (1p). Yellow oil; 77% yield (498 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.10−7.94 (m, 1H), 7.88−7.65 (m, 5H), 7.61−7.26 (m, 7H), 7.21−7.10 (m, 3H), 6.74 (s, 1H), 6.36 (s, 1H), 3.76 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.24 (s, 1H), 3.58 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.4, 138.1, 138.0, 137.7, 135.2, 134.9, 133.3, 133.0, 132.4, 132.3, 130.5, 129.9, 129.7, 129.4, 129.3, 129.1, 128.8, 128.7, 128.5, 128.4, 128.0, 127.9, 127.2, 126.8, 122.6, 122.5, 121.2, 121.1, 120.5, 120.4, 119.2, 119.1, 110.7, 110.6, 103.6, 88.5, 88.1, 84.8, 84.6, 66.1, 65.8, 55.0, 54.9; HRMS (ESI) calcd for C29H22NO3 [M + H]+ 432.1594, found 432.1595. Synthesis and Characterization of 3. To a solution of 1 (0.2 mmol) in 1,4-dioxane (2 mL) in a Schlenk tube were added 2 (2.0 equiv), Cs2CO3 (2.0 equiv), and Pd(Ph3P)4 (4.6 mg, 0.02 equiv) at room temperature under nitrogen, and then the mixture was stirred at 100 °C. After the corresponding reaction time (see Figure 2 in the text), the solution was cooled to room temperature and concentrated under reduced pressure directly. The residue was purified by flash chromatography on silica gel with a petroleum ether/DCM (20:0 to 5:1) eluent to afford polycyclic product 3. (51S,15bR)-11-Phenyl-51,15b-dihydro-10H-benzo[b]indolo[3,2,1de]acridine (3a). Yellow solid; 89% yield (68 mg); mp 208−210 °C; 1 H NMR (400 MHz, CDCl3) δ 7.49−7.39 (m, 3H), 7.37−7.31 (m, 2H), 7.25−7.18 (m, 3H), 7.11−6.95 (m, 7H), 6.75−6.66 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.83 (d, J = 10.8 Hz, 1H), 3.57 (d, J = 21.6 Hz, 1H), 3.28 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 148.2, 140.1, 138.5, 134.4, 133.7, 133.2, 132.6, 129.8, 129.7, 129.7, 129.1, 128.7, 127.9, 127.6, 127.4, 127.3, 127.1, 126.7, 126.6, 126.4, 124.4, 123.3, 123.2, 119.3, 106.8, 62.6, 42.8, 31.3; HRMS (ESI) calcd for C29H22N [M + H]+ 384.1747, found 384.1743. (51S,15bR)-14-Methyl-11-(p-tolyl)-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3b). Yellow solid; 74% yield (61 mg); mp 212−214 °C; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.27−7.19 (m, 3H), 7.14 (d, J = 6.8 Hz, 1H), 7.10−7.94 (m, 6H), 6.90−6.81 (m, 2H), 6.75−6.67 (m, 1H), 6.50 (d, J = 7.6 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.76 (d, J = 10.4 Hz, 1H), 3.54 (d, J = 21.6 Hz, 1H), 3.28 (d, J = 21.6 Hz, 1H), 2.39 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 148.2, 140.2, 136.9, 136.8, 135.5, 133.4, 133.2, 132.5, 131.9, 129.9, 129.7, 129.6, 129.3, 127.8, 126.7, 126.3, 125.5, 124.4, 123.2, 123.1, 119.2, 106.7, 62.7, 42.8, 31.2, 21.0, 20.9; HRMS (ESI) calcd for C31H26N [M + H]+ 412.2060, found 412.2065. (51S,15bR)-14-Methoxy-11-(4-methoxyphenyl)-51,15b-dihydro10H-benzo[b]indolo[3,2,1-de]acridine (3c). Yellow solid; 91% yield

110.9, 110.9, 110.7, 110.6, 106.0, 105.8, 105.8, 105.6, 103.5, 103.5, 103.4, 88.3, 87.9, 84.4, 84.3, 65.8, 65.6, 55.0, 54.9; HRMS (ESI) calcd for C25H18FNNaO3 [M + Na]+ 422.1163, found 422.1165. Methyl {1-[2-(5-Nitro-1H-indol-1-yl)phenyl]-3-phenylprop-2-yn1-yl} Carbonate (1i). Yellow oil; 82% yield (524 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.80−8.50 (m, 1H), 8.13−7.86 (m, 2H), 7.70−7.51 (m, 2H), 7.50−7.33 (m, 2H), 7.33− 7.16 (m, 5H), 7.14−7.02 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.24 (s, 1H), 3.74 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.11 (s, 1H), 3.59 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.4, 142.5, 140.9, 140.8, 136.7, 16.3, 135.4, 135.0, 132.9, 132.6, 131.9, 130.8, 130.7, 130.3, 130.2, 129.4, 129.4, 129.3, 129.1, 128.9, 128.5, 128.4, 127.9, 121.5, 121.5, 118.4, 118.3, 118.1, 118.0, 110.8, 110.6, 105.6, 88.6, 88.1, 83.8, 83.6, 65.9, 65.3, 55.1, 55.0; HRMS (DART) calcd for C25H22N3O5 [M + NH4]+ 444.1554, found 444.1556. 1-[2-(5-Chloro-1H-indol-1-yl)phenyl]-3-(p-tolyl)prop-2-yn-1-yl Methyl Carbonate (1j). Yellow oil; 69% yield (445 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.02−7.90 (m, 1H), 7.68−7.60 (m, 1H), 7.60−7.46 (m, 2H), 7.39−7.26 (m, 2H), 7.25− 7.18 (m, 1H), 7.16−6.98 (m, 5H), 6.65 (s, 1H), 6.24 (s, 1H), 3.73 (s, 3H), 2.32 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.12 (s, 1H), 3.57 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 147.1, 139.8, 137.2, 137.0, 135.3, 133.7, 131.9, 131.7, 129.8, 129.6, 129.5, 129.3, 128.1, 127.9, 127.6, 126.9, 126.5, 125.1, 124.6, 123.7, 123.5, 123.2, 107.6, 63.1, 42.8, 31.1, 21.0, 20.9; HRMS (ESI) calcd for C26H20ClNNaO3 [M + Na]+ 452.1024, found 452.1033. 1-[2-(5-Chloro-1H-indol-1-yl)phenyl]-3-(4-methoxyphenyl)prop2-yn-1-yl Methyl Carbonate (1k). Yellow oil; 63% yield (421 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.03−7.90 (m, 1H), 7.68−7.62 (m, 1H), 7.61−7.48 (m, 2H), 7.39−7.23 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 7.11−7.04 (m, 1H), 7.04−6.95 (m, 1H), 6.84−6.74 (m, 2H), 6.65 (s, 1H), 6.24 (s, 1H), 3.79 (s, 3H), 3.73 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.12 (s, 1H), 3.58 (s, 3H) (other peaks overlap with the signals of the first isomer); 13 C NMR (100 MHz, CDCl3) δ 160.5, 154.5, 154.4, 137.5, 137.2, 136.7, 136.5, 135.2, 133.7, 133.6, 131.0, 130.6, 130.5, 129.9, 129.7, 129.7, 129.4, 129.4, 129.1, 129.0, 126.2, 126.1, 122.8, 122.7, 120.5, 120.4, 114.0, 114.0, 113.8, 113.7, 111.8, 111.6, 103.0, 88.4, 88.0, 83.0, 82.8, 66.1, 65.7, 55.2, 55.0, 54.8; HRMS (ESI) calcd for C26H20ClNNaO4 [M + Na]+ 468.0973, found 468.0990. 1-[2-(5-Chloro-1H-indol-1-yl)phenyl]-3-(4-chlorophenyl)prop-2yn-1-yl Methyl Carbonate (1l). Yellow oil; 89% yield (601 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 8.00−7.84 (m, 1H), 7.69−7.46 (m, 3H), 7.39−7.16 (m, 5H), 7.13−7.04 (m, 2H), 7.01−6.94 (m, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.25 (s, 1H), 3.74 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.13 (s, 1H), 3.60 (s, 3H) (other peaks overlap with the signals of the first isomer); 13 C NMR (100 MHz, CDCl3) δ 154.5, 154.4, 137.6, 137.2, 135.3, 135.1, 134.7, 133.3, 133.2, 131.0, 130.7, 130.6, 130.5, 130.0, 129.7, 129.5, 129.3, 129.2, 129.1, 128.8, 128.8, 126.3, 126.2, 122.8, 122.8, 120.6, 120.4, 111.8, 111.5, 103.1, 103.1, 87.0, 86.6, 85.2, 84.9, 66.0, 65.4, 55.1, 54.9; HRMS (ESI) calcd for C25H17Cl2NNaO3 [M + Na]+ 472.0478, found 472.0493. 1-[2-(1H-Indol-1-yl)-5-methylphenyl]-3-phenylprop-2-yn-1-yl Methyl Carbonate (1m). Yellow oil; 79% yield (469 mg); 1H NMR (400 MHz, CDCl3), one atropisomeric product, δ 7.80−7.72 (m, 1H), 7.71−7.65 (m, 1H), 7.35−7.23 (m, 8H), 7.16−7.09 (m, 3H), 6.71 (s, 1H), 6.23 (s, 1H), 3.74 (s, 3H), 2.49 (s, 3H); 1H NMR (400 MHz, CDCl3), the other isomer, δ 6.13 (s, 1H), 3.55 (s, 3H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.3, 139.5, 139.3, 138.3, 138.1, 135.2, 135.1, 134.8, 134.6, 132.1, 132.0, 131.2, 131.1, 129.9, 129.8, 129.7, 129.4, 129.1, 128.9, 128.8, 128.7, 128.6, 128.4, 122.4, 122.1, 122.0, 121.1, 121.0, 120.3, 120.3, 110.7, 110.6, 103.4, 103.3, 88.0, 87.7, 84.7, 84.6, 65.9, 65.7, 55.0, 54.8, 21.0; HRMS (ESI) calcd for C26H21NNaO3 [M + Na]+ 418.1414, found 418.1416. 1-[2-(1H-Indol-1-yl)-5-chlorophenyl]-3-phenylprop-2-yn-1-yl Methyl Carbonate (1n). Yellow oil; 94% yield (586 mg); 1H NMR 11202

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

The Journal of Organic Chemistry (81 mg); mp 188−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.0 Hz, 1H), 7.26−7.21 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.17− 6.94 (m, 7H), 6.91−6.84 (m, 2H), 6.75−6.69 (m, 1H), 6.65−6.50 (m, 2H), 5.16 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 10.4 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.55 (d, J = 21.6 Hz, 1H), 3.29 (d, J = 21.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.9, 158.8, 148.3, 140.2, 134.3, 132.9, 132.8, 131.0, 130.8, 129.7, 127.9, 127.9, 127.8, 124.3, 124.3, 123.2, 123.1, 119.2, 115.6, 114.3, 114.0, 111.2, 106.8, 62.6, 55.3, 55.1, 43.2, 31.2; HRMS (ESI) calcd for C31H26NO2 [M + H]+ 444.1958, found 444.1968. (51S,15bR)-14-Chloro-11-(4-chlorophenyl)-51,15b-dihydro-10Hbenzo[b]indolo[3,2,1-de]acridine (3d). Yellow solid; 74% yield (67 mg); mp 253−255 °C; 1H NMR (400 MHz, CDCl3) δ 7.50−7.36 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.25−7.22 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.08−6.94 (m, 6H), 6.89 (d, J = 7.6 Hz, 1H), 6.80−6.70 (m, 1H), 6.49 (d, J = 8.0 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 10.4 Hz, 1H), 3.53 (d, J = 21.6 Hz, 1H), 3.53 (d, J = 21.6 Hz, 1H), 3.24 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 148.0, 139.8, 136.3, 134.4, 133.6, 132.7, 132.6, 132.2, 131.8, 131.2, 131.1, 129.6, 129.5, 129.2, 129.0, 128.2, 127.7, 127.3, 127.1, 126.6, 124.3, 123.4, 123.3, 119.5, 107.0, 62.3, 42.6, 31.3; HRMS (ESI) calcd for C29H20Cl2N [M + H]+ 452.0967, found 452.0962. (51S,15bR)-11-(4-Cyanophenyl)-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine-14-carbonitrile (3e). Yellow solid; 62% yield (54 mg); mp 243−245 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.75 (m, 1H), 7.74−7.61 (m, 2H), 7.45−7.38 (m, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.32−7.26 (m, 1H), 7.17−6.95 (m, 5H), 6.92 (d, J = 7.2 Hz, 1H), 6.82−6.68 (m, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 4.87 (d, J = 10.4 Hz, 1H), 3.59 (d, J = 21.6 Hz, 1H), 3.20 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.7, 142.3, 139.4, 137.7, 133.8, 133.3, 133.0, 132.2, 131.6, 131.4, 130.7, 130.6, 129.5, 128.6, 127.0, 126.6, 126.2, 124.1, 123.7, 123.3, 119.8, 118.9, 118.6, 112.2, 110.6, 107.3, 62.0, 42.3, 31.5; HRMS (ESI) calcd for C31H20N3 [M + H]+ 434.1652, found 434.1660. 9-Phenyl-8H-benzo[b]pyrrolo[3,2,1-de]acridine (3f). Yellow solid; 38% yield (25 mg); mp 211−213 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.59−7.52 (m, 2H), 7.51−7.45 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.30−7.22 (m, 2H), 7.17−7.08 (m, 2H), 7.05−6.98 (m, 1H), 4.17 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 139.1, 135.3, 131.9, 130.9, 130.6, 130.5, 130.1, 129.0, 128.6, 127.6, 127.4, 127.1, 125.3, 124.6, 124.2, 123.9, 123.3, 121.8, 119.0, 119.0, 113.7, 104.2, 29.2; HRMS (ESI) calcd for C25H18N [M + H]+ 332.1434, found 332.1432. (51S,15bR)-2-(Benzyloxy)-11-phenyl-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3g). Yellow solid; 88% yield (86 mg); mp 139−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.47−7.43 (m, 1H), 7.42−7.30 (m, 8H), 7.30−7.27 (m, 1H), 7.25−7.17 (m, 3H), 7.11− 7.04 (m, 1H), 7.02−6.91 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 6.69−6.61 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.95− 4.87 (m, 2H), 4.77 (d, J = 10.4 Hz, 1H), 3.54 (d, J = 21.2 Hz, 1H), 3.26 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.1, 142.7, 140.6, 138.5, 137.7, 134.7, 134.4, 133.7, 132.3, 129.7, 129.7, 129.1, 129.0, 128.7, 128.0, 127.9, 127.4, 127.1, 126.4, 123.2, 122.9, 113.1, 112.9, 106.8, 70.8, 62.7, 43.0, 31.3; HRMS (ESI) calcd for C36H28NO [M + H]+ 490.2165, found 490.2176. (51S,15bR)-2-Fluoro-11-phenyl-51 ,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3h). Yellow solid; 91% yield (73 mg); mp 192−194 °C; 1H NMR (400 MHz, CDCl3) δ 7.49−7.42 (m, 1H), 7.40−7.31 (m, 4H), 7.29−7.17 (m, 3H), 7.13−7.06 (m, 1H), 7.04− 6.93 (m, 3H), 6.90−6.82 (m, 1H), 6.73−6.64 (m, 2H), 6.60 (d, J = 8.0 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.77 (d, J = 10.4 Hz, 1H), 3.55 (d, J = 21.6 Hz, 1H), 3.28 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.5 (d, JC−F = 236.0 Hz), 144.5, 140.2, 138.3, 134.9 (d, JC−F = 7.5 Hz), 134.4, 133.9, 131.9, 129.8, 129.7, 129.1, 128.9, 127.6, 127.4, 127.3, 126.9, 126.5, 123.3, 113.6 (d, JC−F = 23.1 Hz), 112.0 (d, JC−F = 24.6 Hz), 106.9 (d, JC−F = 8.0 Hz), 63.0, 42.9, 31.2; HRMS (ESI) calcd for C29H21FN [M + H]+ 402.1653, found 402.1660. (5 1 S,15bR)-2-Nitro-11-phenyl-5 1 ,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3i). Yellow solid; 62% yield (53 mg); mp 228−230 °C; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 1H),

7.84 (s, 1H), 7.47 (d, J = 6.8 Hz, 2H), 7.41−7.25 (m, 5H), 7.21 (d, J = 7.6 Hz, 1H), 7.15−7.02 (m, 3H), 7.01−6.85 (m, 2H), 6.62 (d, J = 8.0 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 22.0 Hz, 1H), 3.34 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.4, 140.4, 137.9, 137.7, 134.7, 134.3, 133.9, 130.9, 130.0, 129.6, 129.2, 129.1, 128.8, 128.2, 128.0, 127.9, 127.7, 127.2, 126.8, 126.6, 125.5, 124.8, 122.4, 121.0, 105.6, 63.9, 41.6, 31.2; HRMS (ESI) calcd for C29H21N2O2 [M + H]+ 429.1598, found 429.1612. (51S,15bR)-2-Chloro-14-methyl-11-(p-tolyl)-51,15b-dihydro-10Hbenzo[b]indolo[3,2,1-de]acridine (3j). Yellow solid; 72% yield (64 mg); mp 209−211 °C; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 1H), 7.28−7.23 (m, 2H), 7.22−7.19 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.05−6.95 (m, 3H), 6.93−6.83 (m, 4H), 6.52 (d, J = 7.6 Hz, 1H), 5.15 (d, J = 10.4 Hz, 1H), 4.73 (d, J = 10.4 Hz, 1H), 3.54 (d, J = 21.6 Hz, 1H), 3.29 (d, J = 21.6 Hz, 1H), 2.41 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.1, 139.8, 137.2, 137.0, 135.3, 133.7, 131.9, 131.7, 129.8, 129.6, 129.5, 129.3, 128.1, 127.9, 127.6, 126.9, 126.5, 125.1, 124.6, 123.7, 123.5, 123.2, 107.6, 63.1, 42.8, 31.1, 21.0, 20.9; HRMS (ESI) calcd for C31H25ClN [M + H]+ 446.1670, found 446.1672. (51S,15bR)-2-Chloro-14-methoxy-11-(4-methoxyphenyl)-51,15bdihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3k). Yellow solid; 87% yield (83 mg); mp 196−198 °C; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 1H), 7.25−7.20 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.05−6.93 (m, 5H), 6.93−6.83 (m, 4H), 6.62 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.72 (d, J = 10.4 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.53 (d, J = 21.6 Hz, 1H), 3.29 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 147.1, 139.8, 135.0, 133.5, 133.0, 130.9, 130.7, 130.5, 129.8, 128.1, 127.9, 127.7, 127.7, 126.4, 124.6, 123.9, 123.6, 123.5, 123.2, 115.6, 114.3, 114.0, 111.4, 107.6, 63.0, 55.3, 55.1, 43.0, 31.1; HRMS (ESI) calcd for C31H25ClNO2 [M + H]+ 478.1568, found 478.1580. (51S,15bR)-2,14-Dichloro-11-(4-chlorophenyl)-51,15b-dihydro10H-benzo[b]indolo[3,2,1-de]acridine (3l). Yellow solid; 90% yield (88 mg); mp 96−98 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.0, 2.0 Hz, 1H), 7.39−7.31 (m, 3H), 7.28−7.25 (m, 1H), 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.04 (s, 1H), 7.02− 6.97 (m, 2H), 6.91 (dd, J = 8.4, 2.0 Hz, 1H), 6.89−6.85 (m, 2H), 6.51 (d, J = 8.4 Hz, 1H), 5.14 (d, J = 10.4 Hz, 1H), 4.73 (d, J = 10.8 Hz, 1H), 3.53 (d, J = 22.0 Hz, 1H), 3.25 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 146.9, 139.5, 136.1, 134.2, 133.8, 133.6, 133.0, 132.6, 132.2, 131.2, 131.0, 129.7, 129.6, 129.2, 128.9, 128.0, 127.9, 127.7, 127.4, 127.2, 126.8, 124.5, 124.0, 123.8, 123.3, 107.9, 62.7, 42.5, 31.2; HRMS (ESI) calcd for C29H19Cl3N [M + H]+ 486.0578, found 486.0582. (51S,15bR)-8-Methyl-11-phenyl-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3m). Yellow solid; 96% yield (76 mg); mp 219−221 °C; 1H NMR (400 MHz, CDCl3) δ 7.48−7.40 (m, 2H), 7.35−7.27 (m, 3H), 7.24 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.10−7.00 (m, 3H), 6.98−6.90 (m, 3H), 6.85 (s, 1H), 6.73−6.66 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.80 (d, J = 10.4 Hz, 1H), 3.51 (d, J = 21.6 Hz, 1H), 3.23 (d, J = 21.6 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.5, 138.5, 137.5, 134.4, 133.7, 133.1, 132.7, 132.6, 130.1, 129.8, 129.7, 129.1, 128.6, 127.9, 127.4, 127.3, 127.3, 127.2, 127.0, 126.8, 126.7, 124.3, 123.2, 119.1, 106.8, 62.7, 42.9, 31.3, 20.6; HRMS (ESI) calcd for C30H24N [M + H]+ 398.1903, found 398.1905. (51S,15bR)-8-Chloro-11-phenyl-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3n). Yellow solid; 92% yield (77 mg); mp 243−245 °C; 1H NMR (400 MHz, CDCl3) δ 7.49−7.40 (m, 2H), 7.37−7.30 (m, 3H), 7.29−7.23 (m, 1H), 7.23−7.15 (m, 2H), 7.12− 6.90 (m, 6H), 6.78−6.70 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.15 (d, J = 10.8 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H), 3.52 (d, J = 22.0 Hz, 1H), 3.24 (d, J = 21.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 147.8, 138.7, 138.2, 134.2, 134.1, 133.1, 132.4, 129.7, 129.7, 129.4, 129.1, 129.1, 128.7, 128.1, 128.0, 127.5, 127.4, 127.2, 126.9, 126.6, 125.6, 124.5, 124.4, 119.6, 106.7, 62.5, 42.8, 31.2; HRMS (ESI) calcd for C29H21ClN [M + H]+ 418.1357, found 418.1366. 11-Butyl-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3p). Yellow solid; 72% yield (52 mg); mp 103−105 °C; 1H NMR 11203

DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

The Journal of Organic Chemistry (400 MHz, CDCl3) δ 7.45−7.21 (m, 7H), 7.12−6.85 (m, 4H), 6.75− 6.60 (m, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.67 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 21.2 Hz, 1H), 3.64 (d, J = 21.2 Hz, 1H), 2.54−2.25 (m, 2H), 1.50−1.25 (m, 4H), 1.00−0.70 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 148.2, 140.4, 133.4, 133.3, 132.9, 130.6, 129.7, 129.4, 128.0, 127.8, 127.5, 126.7, 126.5, 125.7, 124.2, 124.0, 123.5, 123.3, 119.2, 106.6, 62.7, 42.9, 30.0, 27.7, 22.8, 13.7; HRMS (ESI) calcd for C27H26N [M + H]+ 364.2060, found 364.2058. (5 1 S,15bR)-11-(p-Tolyl)-5 1 ,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3q) and (51S,15bR)-14-Methyl-11-phenyl-51,15bdihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3q′). Yellow solid; 82% yield (65 mg for 3q + 3q′); 1H NMR for one isomer (400 MHz, CDCl3) δ 7.48−7.36 (m, 2H), 7.35−7.30 (m, 1H), 7.28−7.13 (m, 4H), 7.10−6.95 (m, 6H), 6.90−6.82 (m, 1H), 6.76−6.68 (m, 1H), 6.47 (d, J = 7.6 Hz, 1H), 5.25−5.00 (m, 1H), 4.80−4.60 (m, 1H), 3.55 (d, J = 21.2 Hz, 1H), 3.40−3.20 (m, 1H), 2.40 (s, 3H); 1H NMR for the other isomer (400 MHz, CDCl3) δ 6.61 (d, J = 7.6 Hz, 1H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 148.2, 148.2, 140.2, 140.1, 138.6, 137.0, 136.9, 135.3, 134.5, 133.5, 133.2, 132.6, 132.5, 131.7, 129.9, 129.8, 129.8, 129.7, 129.6, 129.0, 128.6, 127.8, 127.7, 127.3, 127.0, 126.8, 126.7, 126.4, 125.5, 124.4, 123.3, 123.2, 123.1, 119.2, 106.8, 62.6, 62.6, 42.9, 42.8, 31.3, 31.2, 21.0, 20.9; HRMS (ESI) calcd for C30H24N [M + H]+ 398.1903, found 398.1908. (5 1 S,15bR)-14-Chloro-11-(4-methoxyphenyl)-51 ,15b-dihydro10H-benzo[b]indolo[3,2,1-de]acridine (3r) and (51S,15bR)-11-(4Chlorophenyl)-14-methoxy-51,15b-dihydro-10H-benzo[b]indolo[3,2,1-de]acridine (3r′). Yellow solid; 92% yield (82 mg for 3r + 3r′); 1 H NMR for the major isomer (400 MHz, CDCl3) δ 7.46−7.37 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.25−7.22 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.06−6.96 (m, 6H), 6.91 (d, J = 8.0 Hz, 1H), 6.77−6.68 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.14 (d, J = 10.8 Hz, 1H), 4.78 (d, J = 10.4 Hz, 1H), 3.86 (s, 3H), 3.53 (d, J = 21.2 Hz, 1H), 3.22 (d, J = 21.2 Hz, 1H); 1H NMR for the minor isomer (400 MHz, CDCl3) δ 3.83 (s, 3H), 3.30 (d, J = 22.0 Hz, 1H) (other peaks overlap with the signals of the major isomer); 13C NMR for the major isomer (100 MHz, CDCl3) δ 159.0, 148.2, 140.1, 137.0, 134.3, 133.3, 132.7, 132.2, 131.4, 131.1, 129.7, 129.3, 129.0, 128.0, 127.7, 127.4, 127.1, 126.5, 124.3, 123.3, 119.3, 115.7, 111.3, 106.8, 62.5, 55.3, 43.1, 31.1; HRMS (ESI) calcd for C30H23ClNO [M + H]+ 448.1463, found 448.1470. (51 S,17bR)-11-(Naphthalen-2-yl)-51 ,17b-dihydro-10H-indolo[3,2,1-de]naphtho[2,3-b]acridine (3s) and (4bR,4b1S)-11-(Naphthalen-2-yl)-4b,4b 1 -dihydro-12H-indolo[3,2,1-de]naphtho[2,1-b]acridine (3s′). Yellow solid; 85% yield (82 mg for 3s + 3s′); 1H NMR for one isomer (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 8.00− 7.68 (m, 5H), 7.60−7.38 (m, 7H), 7.30−7.25 (m, 1H), 7.07−6.96 (m, 4H), 6.84−6.71 (m, 2H), 6.65−6.57 (m, 1H), 5.63 (d, J = 10.8 Hz, 1H), 5.37 (d, J = 10.8 Hz, 1H), 3.72 (d, J = 21.2 Hz, 1H), 3.35 (d, J = 22.0 Hz, 1H); 1H NMR for the other isomer (400 MHz, CDCl3) δ 3.60 (d, J = 21.6 Hz, 1H), 3.34 (d, J = 22.0 Hz, 1H) (other peaks overlap with the signals of the first isomer); 13C NMR (100 MHz, CDCl3) δ 149.1, 140.2, 136.4, 136.3, 134.2, 134.1, 133.7, 133.3, 133.1, 132.8, 132.7, 132.3, 131.8, 131.6, 129.7, 128.8, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.9, 127.7, 127.6, 127.3, 127.2, 127.0, 126.5, 126.5, 126.4, 126.3, 125.7, 125.2, 125.1, 124.4, 124.1, 123.6, 119.3, 106.8, 63.6, 63.6, 39.3, 39.2, 31.2, 31.0; HRMS (ESI) calcd for C37H26N [M + H]+ 484.2060, found 484.2068. Synthesis and Characterization of 4a. To a solution of 1a (762.9 mg, 2.0 mmol) in 1,4-dioxane (20 mL; THF also worked well) in a Schlenk tube were added 2a (487.5 mg, 2.0 equiv), Cs2CO3 (2.0 equiv), and Pd(Ph3P)4 (115.5 mg, 0.05 equiv) at room temperature under nitrogen. Twelve hours later, the solution was concentrated under reduced pressure directly. The residue was purified by flash chromatography on silica gel with a 120:3:1 petroleum ether/ethyl acetate/Et3N eluent to afford allene 4a. 1-[2-(3,3-Diphenylpropa-1,2-dien-1-yl)phenyl]-1H-indole (4a). Yellow solid; 77% yield (590.1 mg); mp 135−137 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 7.6 Hz, 1H), 7.55−7.46 (m, 4H), 7.45−7.33 (m, 8H), 7.32−7.26 (m, 3H), 6.98 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.63 (s, br, 1H), 6.27 (s, 1H), 5.15 (s, 1H); 13C

NMR (100 MHz, DMSO-d6) δ 209.0, 153.6, 138.1, 136.7, 135.5, 132.7, 130.7, 129.1, 129.0, 129.0, 128.8, 128.4, 128.3, 128.1, 128.0, 127.9, 113.5, 113.1, 111.4, 104.3, 103.1, 93.0, 69.9; HRMS (ESI) calcd for C29H22N [M + H]+ 384.1747, found 384.1745. Synthesis and Characterization of 5a. A solution of 3a (76.6 mg, 0.2 mmol) in DCM (2 mL) in a Schlenk tube was stirred at room temperature under air. Three days later, the solution was concentrated under reduced pressure directly. The residue was purified by flash chromatography on silica gel with a 100:1 petroleum ether/ethyl acetate eluent to afford 5a. 11-Phenyl-10H-benzo[b]indolo[3,2,1-de]acridine (5a). Yellow solid; 42% yield (32 mg); mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.67−7.61 (m, 1H), 7.61− 7.51 (m, 5H), 7.50−7.45 (m, 1H), 7.40−7.30 (m, 4H), 7.24−719 (m, 1H), 7.10−7.03 (m, 1H), 4.16 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 138.9, 137.8, 137.2, 136.2, 136.0, 130.9, 130.5, 130.4, 128.9, 128.5, 127.8, 127.7, 127.7, 127.1, 126.4, 125.2, 125.0, 123.6, 123.6, 123.5, 122.8, 121.6, 119.4, 114.9, 114.2, 114.0, 30.1; HRMS (ESI) calcd for C29H20N [M + H]+ 382.1590, found 382.1595.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01614. 1 H and 13C NMR spectra for all new compounds (PDF) Crystallographic details for compound 3a (CIF)

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Corresponding Author

*E-mail: [email protected]. ORCID

Yulei Zhao: 0000-0002-8628-2680 Yanzhong Li: 0000-0002-2898-3075 Author Contributions

Y.Z. and Y.Y. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grant 21272074) and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) for financial support.

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REFERENCES

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DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205

Note

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DOI: 10.1021/acs.joc.7b01614 J. Org. Chem. 2017, 82, 11198−11205