General Approach To Construct Azepino[2,3-b:4,5-b′]diindoles

Jul 1, 2019 - General Approach To Construct Azepino[2,3-b:4,5-b′]diindoles, Azocino[2,3-b:4 .... X-ray crystallography of compound 3a (CIF). X-ray ...
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Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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General Approach To Construct Azepino[2,3‑b:4,5‑b′]diindoles, Azocino[2,3‑b:4,5‑b′]diindoles, and Azonino[2,3‑b:4,5‑b′]diindoles via Rh(II)-Catalyzed Reactions of 3‑Diazoindolin-2-imines with 3‑(Bromoalkyl)indoles Guorong Sheng,† Zhenmin Li,† Jianming Mao, Ping Lu,* and Yanguang Wang*

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Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China S Supporting Information *

ABSTRACT: Rh(II)-catalyzed reactions of 3-diazoindolin-2-imines with 3-(2-bromoethyl)indoles, 3-(3-bromopropyl)indoles, and 3-(4bromobutyl)indoles, followed by treatment with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) in a one-pot operation furnished azepino[2,3-b:4,5-b′]diindoles, azocino[2,3-b:4,5-b′]diindoles, and azonino[2,3-b:4,5-b′]diindoles, respectively. Structural uniqueness of the products, broad substrate scope, mild reaction conditions, and readily available starting materials are the merits of this approach.

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INTRODUCTION

RESULTS AND DISCUSSION In our previous work, we found that 2,3′-biindoles could be generated through the Rh2(oct)4-catalyzed reaction of 3diazoindolin-2-imines with 3-methylindole.6 Based on this result, the reaction between 3-diazoindolin-2-imine 1a and 3(2-bromoethyl)-1-methyl-1H-indole (2a) was employed as model reaction and Rh2(oct)4 was used as catalyst in our preliminary trial. When the reaction was conducted in 1,2dichloroethane (DCE) at 55 °C (oil bath) for 30 min and further treated with t-BuOK at the same temperature for 10 min, azepino[2,3-b:4,5-b′]diindole 3a was isolated in 12% yield (Table 1, entry 1). 3a was structurally characterized by 1H and 13 C NMR, HRMS, as well as X-ray single-crystal analyses.9 Several other Rh(II) and Cu(I) catalysts (Table 1, entries 2−5) as well as solvents (e.g., toluene, chloroform, dichloromethane (DCM), acetonitrile, and 1,4-dioxane) (Table 1, entries 6−10) were screened, but only trace of 3a could be observed in these cases. We then fixed Rh2(oct)4 as catalyst and DCE as solvent to screen the base. When the base was altered to DBU, a remarkable increment in yield of 3a (62%) was obtained (Table 1, entry 11). Triethylamine, 1,1,3,3-tetramethylguanidine (TMG), and 4-dimethylaminopyridine (DMAP) gave lower yields (Table 1, entries 12−14), whereas 1,4diazabicyclo[2.2.2]octane (DABCO) and inorganic bases (e.g., NaHCO3, Na2CO3, and K2CO3) did not promote the transformation efficiently (Table 1, entries 15−18). Further optimizations of reaction conditions were conducted by altering the reaction temperature and reaction time, but no improved

Indole derivatives are an important class of nitrogen heterocycles, which constitute a vast number of biologically active natural products and clinically valuable pharmaceuticals.1 Among all known indole derivatives, many compounds bearing a bisindole scaffold have been extensively evaluated or screened for their pharmaceutical activities and therapeutic potential.2−4 For example, birinapant is a bivalent antagonist of IAP proteins and has been selected for clinical trials for the treatment of solid tumors and hepatitis B virus infection (Figure 1).3 Several bisindole alkaloids, such as (−)-trigonoliimine C4a,b and iheyamines A and B,4c were found to exhibit anticancer and anti-HIV activities. Therefore, various methods have been developed for the synthesis of bisindoles.5 We continuously seek innovative and general approaches to construct this important class of scaffolds. In our previous reports, we developed practical approaches toward a class of indole-based diazo compounds (i.e., 3diazoindolin-2-imines)6 and applied them for the synthesis of indole derivatives, such as 3,3′-biindoles, triindoles, azepino[2,3-b]indoles, and tetrahydro-[1,4]diazepino[2,3-b]indoles, through transition-metal-catalyzed reactions.6,7 Recently, Novikov and co-workers have employed 3-diazoindolin-2-imines for the synthesis of 1,3′-biindoles.8 As a continuation of our research, we herein report a general approach to azepino[2,3b:4,5-b′]diindoles, azocino[2,3-b:4,5-b′]diindoles, and azonino[2,3-b:4,5-b′]diindoles via Rh(II)-catalyzed reactions of 3diazoindolin-2-imines with various 3-(bromoalkyl)indoles. The unique structure of these bisindoles consists of a central azepane, azocine, or azonine ring between two indole rings. © XXXX American Chemical Society

Received: April 30, 2019 Published: July 1, 2019 A

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Figure 1. Reprehensive drugs and bioactive compounds bearing a bisindole scaffold.

Table 1. Screening of Reaction Conditions for the Preparation of 3aa

entry

catalyst

solvent

base

temp (°C)

time (h)

yieldb (%)

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

Rh2(oct)4 Rh2(OAc)4 Rh2(S-DOSP)4 Rh2(S-PTAD)4 CuOTf·(benzene)0.5 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4 Rh2(oct)4

DCE DCE DCE DCE DCE PhCH3 CHCl3 DCM CH3CN 1,4-dioxane DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE

t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK DBU Et3N TMG DMAP DABCO NaHCO3 Na2CO3 K2CO3 DBU DBU DBU DBU

55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 45 65 50 50

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 1.0 0.25

12 trace trace trace trace trace trace trace trace trace 62 58 54 51 trace trace trace trace 43 51 53 38

a

Reaction conditions: (1) 1a (0.20 mmol), 2a (0.20 mmol), catalyst (2 mol %), solvent (2.0 mL); (2) base (0.20 mmol), 10 min. bIsolated yield.

yield was observed in these cases (Table 1, entries 19−22). Thus, the optimal reaction conditions were established (Table 1, entry 11). With the optimized reaction conditions, we investigated the substrate scope regarding both 3-diazoindolin-2-imine and 3-(2bromoethyl)indole components (Scheme 1). Diazo compounds 1 with different sulfonyl substituents (e.g., (4-chlorophenyl)sulfonyl, naphthalen-2-ylsulfonyl, and methylsulfonyl) were first examined for their reaction with 2a. The corresponding products 3b, 3c, and 3d were isolated in 59, 58, and 60% yields,

respectively. The substituent on the phenyl ring of diazo compounds 1 could be electron-donating group (5-OMe, product 3e) or electron-withdrawing group (5-Br, product 3f), while the substituent at 1 position of diazo compounds could be ethyl (product 3g). Thus, 3e, 3f, and 3g were obtained in yields of 58, 53, and 61%, respectively. The substituent at nitrogen atom of 3-(2-bromoethyl)indole 2 could be allyl (2b, product 3h), and the substituent at 6-position of 2 could be Br (2c, product 3i) and MeO (2d, product 3j). When 3-(2bromoethyl)-1H-indole (2e) was used, 3k was isolated in B

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 1. Preparation of Compounds 3a,b

Reaction conditions: (1)1 (0.20 mmol), 2 (0.20 mmol), Rh2(oct)4 (2 mol %), DCE (2 mL), 55 °C, 0.5 h. (2) DBU (0.20 mmol, 30 mg), 55 °C, 10 min. Product yields are given for compounds isolated after purification from a silica column. bThe reaction was conducted on 4 mmol scale.

a

tion and provided the desired products 5e−h with satisfactory yields (63−74%). 3-(3-Bromopropyl)-1H-indole (4b) without substituent at 1 position provides the desired product 5i in relatively lower yield. To construct nine-membered ring-fused biindole ring system, we tested 3-(4-bromobutyl)indoles 6 for their reactions with diazo compounds (Scheme 3). In these cases, the desired azonino[2,3-b:4,5-b′]diindoles 7a−j could be obtained, but the yields (27−59%) were relatively lower than those of the sevenand eight-membered ring-fused biindoles 3 and 5. The structure of 7g was unambiguously determined by its X-ray single-crystal analysis.9 A step-by-step experiment for the synthesis of 3j was conducted using 1a and 2d as starting materials. As shown in Scheme 4, the 2,3′-biindole intermediate 8 was isolated from the reaction mixture and was further converted to 3j by treatment with DBU under the standard condition.

yield of 33%. A poor yield was observed for 3l (7%) when 3-(1bromopropan-2-yl)-1-methylindole (2f) was used for this reaction. Finally, 7-ethyl- and 4-chloro-substituted 3-(2bromoethyl)indoles 2g and 2h were examined and the desired products 3m and 3n were isolated in 38 and 6% yields, respectively. To demonstrate the practical utility of this method, 3m was prepared on 4 mmol scale and 30% yield was obtained. Under the established reaction conditions, we next examined 3-(3-bromopropyl)indoles 4 for their reactions with diazo compounds to construct azocino[2,3-b:4,5-b′]diindoles 5 (Scheme 2). 3-(3-Bromopropyl)-1-methylindole (4a) reacted with different sulfonyl-substituted 3-diazoindolin-2-imines to give the corresponding products 5a−d in 68−80% yields. The yields are higher than those of azepino[2,3-b:4,5-b′]diindoles 3a−d (58−62%). The structure characterization of 5a was based on its X-ray analysis.9 5-Methoxy-, 5-bromo-, 1-ethyl-, and 1allyl-substituted 3-diazoindolin-2-imines underwent this reacC

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Scheme 2. Preparation of Compounds 5a

Reaction conditions: (1) 1 (0.20 mmol), 2 (0.20 mmol), Rh2(oct)4 (2 mol %), DCE (2.0 mL), 55 °C, 0.5 h. (2) DBU (0.20 mmol, 30 mg), 55 °C, 10 min. Isolated yield.

a

Scheme 3. Preparation of Compounds 7a

a Reaction conditions: (1) 1 (0.20 mmol), 2 (0.20 mmol), Rh2(oct)4 (2 mol %), DCE (2 mL), 55 °C, 0.5 h; (2) DBU (0.20 mmol, 30 mg), 55 °C, 10 min. Isolated yield.

the cyclopropanation of indole 2d with A leads to a spirointermediate B.10,11 B subsequently undergoes a rearrangement to form 2,3′-biindole 8, which can be isolated and converted to

Based on these observations, a possible mechanism for these transformations is proposed in Scheme 5. First, Rh carbene intermediate A is generated from diazo compound 1a.6,7 Then, D

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

acetate (EA), and dichloromethane (DCM) in a suitable ratio was used as eluent. Melting points were measured using an SGW X-4 melting point apparatus, and the values are uncorrected. Diazo compounds 1 were prepared according to our previous procedures.6 3-(Bromoalkyl)indoles 2, 4, and 6 were prepared through published methods.12 General Procedure for the Preparation of Compounds 3, 5, and 7. To a round-bottom flask equipped with a magnetic stirring bar were added sequentially 1 (0.20 mmol); Rh2(oct)4 (3 mg, 0.004 mmol); 2, 4, 6 (0.20 mmol, 1.0 equiv); and DCE (2.0 mL). The resulting mixture was stirred at 55 °C (oil bath) for 0.5 h. Then, DBU (0.20 mol, 1.0 equiv) was added and further reaction was allowed at 55 °C (oil bath) for 10 min. After cooled to room temperature, the reaction solution was concentrated in vacuo and the crude product was purified through silica gel column (PE/EA/DCM = 8:1:1.5, v/v/v). Procedure for 4 mmol Scale Preparation of Compound 3m. To a round-bottom flask equipped with a magnetic stirring bar were added sequentially 1a (1.304 g, 4 mmol), Rh2(oct)4 (2 mol%), 2g (1.060 g, 4 mmol), and DCE (40 mL). The resulting mixture was stirred at 55 °C (oil bath) for 0.5 h. Then, DBU (4 mmol, 1.0 equiv) was added and further reaction was allowed at 55 °C (oil bath) for 10 min. After cooled to room temperature, the reaction solution was concentrated in vacuo, and the crude product was purified through silica gel column (PE/EA/DCM = 8:1:1.5, v/v/v). Procedure for the Preparation of Compound 8. To a roundbottom flask equipped with a magnetic stirring bar were added sequentially 1a (0.20 mmol), Rh2(oct)4 (3 mg, 0.004 mmol), 2d (0.20 mmol, 1.0 equiv), and DCE (2.0 mL). The reaction solution was stirred at 55 °C (oil bath) for 30 min. After cooled to room temperature, the reaction solution was concentrated in vacuo and the crude product was purified through silica gel column (PE/EA = 3:1, v/v). Procedure for the Preparation of 3j from 8. To a round-bottom flask equipped with a magnetic stirring bar were added sequentially 8 (0.20 mmol, 1.0 equiv), DBU (0.20 mol, 1.0 equiv), and DCE (2.0 mL). The solution was stirred at 55 °C (oil bath) for 10 min. After cooled to room temperature, the reaction solution was concentrated in vacuo and the crude product was purified through silica gel column (PE/EA/ DCM = 8:1:1.5, v/v/v). 5,13-Dimethyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3-b:4,5b′]diindole (3a). Yellowish solid; yield: 62% (56.4 mg); mp 199−200 °C; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.41−7.34 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.24−7.18 (m, 1H), 7.16−7.02 (m, 5H), 6.51 (d, J = 8.0 Hz, 2H), 4.80−4.65 (m, 1H), 4.27−4.12 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 3.10−2.90 (m, 1H), 2.80−2.60 (m, 1H), 1.99 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.9, 137.2, 135.9, 135.6, 134.7, 133.2, 127.9, 127.2, 126.6, 123.6, 123.0, 121.0, 120.6, 120.4, 119.1, 117.1, 110.6, 109.7, 108.6, 104.1, 59.6, 32.0, 30.2, 22.2, 21.3; IR (neat, cm−1) 3050, 2917, 1596, 1536, 1471, 1347, 1249, 1162, 1091, 742; HRMS (EI-TOF): calcd for C27H25N3O2S [M]+: 455.1667, found: 455.1663. 6-((4-Chlorophenyl)sulfonyl)-5,13-dimethyl-6,7,8,13-tetrahydro5H-azepino[2,3-b:4,5-b′]diindole (3b). Yellowish solid; yield: 59% (56.1 mg); mp 232−233 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.45−7.30 (m, 2H), 7.24−7.16 (m, 3H), 7.15−7.07 (m, 3H), 6.65−6.57 (m, 2H), 4.90−4.70 (m, 1H), 4.34−4.20 (m, 1H), 3.94 (s, 3H), 3.50 (s, 3H), 3.10−2.90 (m, 1H), 2.80−2.60 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.4, 137.0, 136.6, 136.0, 134.0, 132.9, 127.9, 127.5, 126.9, 123.5, 123.2, 121.4, 120.8, 120.5, 119.5, 116.9, 110.6, 110.1, 109.1, 104.4, 60.7, 31.8, 30.1, 22.1; IR (neat, cm−1)3054, 2930, 1583, 1473, 1349, 1166, 1086, 743. 710; HRMS (EI-TOF): calcd for C26H22ClN3O2S [M]+: 475.1121, found: 475.1116. 5,13-Dimethyl-6-(naphthalen-2-ylsulfonyl)-6,7,8,13-tetrahydro5H-azepino[2,3-b:4,5-b′]diindole (3c). Yellowish solid; yield: 58% (57.0 mg); mp 107−108 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 1.7 Hz, 1H), 7.56−7.31 (m, 8H), 7.21−7.13 (m, 1H), 7.10 (dd, J = 8.7, 1.9 Hz, 1H), 7.06−6.97 (m, 2H), 6.76 (d, J = 8.7 Hz, 1H), 6.57 (dd, J = 6.9, 1.5 Hz, 1H), 5.16−4.90 (m, 1H), 4.38−4.26 (m, 1H), 3.99 (s, 3H), 3.10−2.90 (m, 1H), 2.75 (s, 3H), 2.76−2.60 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 136.5, 136.0, 134.9, 134.2, 132.9, 130.9, 128.9, 128.1, 127.8, 127.6, 127.5, 126.9, 126.8, 123.6, 123.0, 121.8,

Scheme 4. Step-by-Step Synthesis of 3j

Scheme 5. Proposed Reaction Mechanism

the seven-membered ring product 3j through a favored 7-exo-tet process in the presence of base. Eight-membered ring product 5 as well as nine-membered ring products 7 can be formed through a similar process.

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CONCLUSIONS In conclusion, we have demonstrated a general and efficient method for the construction of azepino[2,3-b:4,5-b′]diindoles, azocino[2,3-b:4,5-b′]diindoles, and azonino[2,3-b:4,5-b′]diindoles via Rh(II)-catalyzed reactions of 3-diazoindolin-2imines with 3-(2-bromoethyl)indoles, 3-(3-bromopropyl)indoles, and 3-(4-bromobutyl)indoles, respectively. This method provides unique product structures with broad substrate scope, mild reaction conditions, and readily available starting materials. Furthermore, since it is commonly difficult to construct eight- and nine-membered rings, our reactions provide a rapid and direct access to these types of aza-heterocyclic compounds.

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EXPERIMENTAL SECTION

General Information. 1H and 13C{1H} NMR spectra were recorded on 400, 500, or 600 MHz spectrometer at room temperature. Chemical shifts are reported in ppm referenced to the resonance of internal standard (0.0 ppm for TMS) or remaining proton of the deuterated solvent. The multiplicity of signal is described with an appropriate abbreviation [e.g., s (singlet), d (doublet), t (triplet), or m (multiplet)], and J values are reported in Hz. High-resolution mass spectroscopy (HRMS) images were recorded on an EI-TOF or ESITOF mass spectrometer. IR spectra were recorded on a Fourier transform infrared instrument, and νmax values are reported in cm−1. Preparative flash column chromatography was conducted with silica gel (300−400 mesh), and the mixture of petroleum ether (PE), ethyl E

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

(m, 1H), 7.25−7.17 (m, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 4.80−4.60 (m, 1H), 4.25−4.10 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 2.95−2.80 (m, 1H), 2.70−2.60 (m, 1H), 2.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.0, 135.9, 135.7, 135.0, 134.8, 128.8, 128.1, 126.7, 123.5, 123.3, 123.1, 120.8, 120.3, 119.7, 112.5, 110.7, 110.0, 109.2, 103.4, 59.2, 32.1, 30.2, 22.1, 21.4; IR (neat, cm−1) 3052, 2930, 1597, 1578, 1474, 1347, 1251, 1163, 1091, 910, 732; HRMS (EI-TOF): calcd for C27H24BrN3O2S [M]+: 533.0773, found: 533.0771. 10-Methoxy-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5Hazepino[2,3-b:4,5-b′]diindole (3j). Yellowish solid; yield: 61% (59.2 mg); mp 220−221 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.40−7.33 (m, 1H), 7.23−7.15 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.06−6.98 (m, 1H), 6.81−6.70 (m, 2H), 6.55 (d, J = 8.1 Hz, 2H), 4.80−4.60 (m, 1H), 4.30−4.10 (m, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.51 (s, 3H), 3.00−2.88 (m, 1H), 2.76−2.60 (m, 1H), 2.03 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.1, 142.9, 135.9, 135.6, 134.6, 133.9, 132.7, 128.0, 127.5, 126.7, 123.5, 122.9, 120.6, 120.4, 110.8, 110.5, 109.3, 109.3, 104.2, 99.4, 59.4, 56.1, 32.1, 30.2, 22.3, 21.4; IR (neat, cm−1) 3049, 2929, 1617, 1577, 1486, 1474, 1347, 1214, 1163, 1091, 911,733; HRMS (EI-TOF): calcd for C28H27N3O3S [M]+: 485.1773, found: 485.1781. 5-Methyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3-b:4,5-b′]diindole (3k). Yellowish solid; yield: 33% (29.1 mg); mp 218−219 °C; 1 H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.40−7.33 (m, 1H), 7.32−7.23 (m, 4H), 7.14 (d, J = 7.7 Hz, 1H), 7.09−7.04 (m, 1H), 7.04−6.99 (m, 1H), 6.54 (d, J = 8.0 Hz, 2H), 4.76−4.68 (m, 1H), 3.92 (s, 3H), 3.65−3.50 (m, 1H), 3.40−3.20 (m, 1H), 2.93 (dd, J = 17.4, 3.5 Hz, 1H), 1.72 (s, 3H); 13 C{1H} NMR (150 MHz, CDCl3) δ 144.0, 136.5, 135.7, 135.6, 135.1, 129.1, 128.9, 127.9, 126.9, 123.1, 122.6, 121.6, 120.8, 119.4, 119.0, 117.4, 110.8, 109.9, 108.5, 103.7, 51.5, 30.4, 24.3, 20.9; IR (neat, cm−1) 3405, 3054, 2947, 1595, 1549, 1468, 1400, 1344, 1161, 1088, 909, 748; HRMS (ESI-TOF): calcd for C26H23N3NaO2S+ [M + Na]+: 464.1403, found: 464.1414. 5,8,13-Trimethyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3b:4,5-b′]diindole (3l). Yellowish solid; yield: 7% (6.6 mg); mp 198− 199 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.43−7.29 (m, 2H), 7.26−7.18 (m, 1H), 7.13−7.02 (m, 5H), 6.50 (d, J = 8.2 Hz, 2H), 5.16−5.02 (m, 1H), 3.95 (s, 3H), 3.54 (s, 3H), 2.93 (dd, J = 14.9, 5.3 Hz, 1H), 2.34 (dd, J = 14.8, 12.5 Hz, 1H), 2.04 (s, 3H), 1.58 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.6, 136.9, 136.0, 135.7, 133.7, 133.6, 127.9, 126.7, 126.5, 123.4, 122.9, 120.7, 120.6, 120.3, 119.1, 117.1, 110.7, 109.9, 108.5, 104.3, 70.5, 31.6, 30.0, 29.9, 23.9, 21.4; IR (neat, cm−1) 3051, 2926, 1597, 1537, 1471, 1343, 1249, 1163, 1090, 909, 736; HRMS (EI-TOF): calcd for C28H27N3O2S [M]+: 469.1824, found: 469.1827. 12-Ethyl-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3-b:4,5-b′]diindole (3m). White solid; yield: 38% (36.7 mg); mp 218−219 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.39−7.39 (m, 1H), 7.25−7.17 (m, 3H), 7.13 (dd, J = 7.8, 1.0 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.1 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 4.66−4.76 (m, 1H), 4.16−4.08 (m, 1H), 3.94 (s, 3H), 3.73 (s, 3H), 3.26−3.15 (m, 1H), 3.05−2.91 (m, 2H), 2.76−2.60 (m, 1H), 1.97 (s, 3H), 1.39 (t, J = 7.5 Hz, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 142.9, 135.9, 135.84, 135.75, 134.8, 134.14, 128.7, 128.0, 127.2, 126.8, 123.7, 122.9, 122.2, 120.62, 120.55, 119.5, 115.1, 110.5, 110.0, 104.3, 58.7, 35.2, 30.1, 25.5, 22.4, 21.2, 16.5; IR (film, cm−1) 3047, 2967, 1597, 1541, 1472, 1446, 1343, 1243, 1163, 1090, 909, 810, 743; HRMS (ESI-TOF): calcd for C29H30N3O2S+ [M + H+]: 484.2053, found: 484.2049. 9-Chloro-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3-b:4,5-b′]diindole (3n). Yellowish solid; yield: 6% (5.9 mg); mp 234−235 °C; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.42−7.36 (m, 1H), 7.26−7.20 (m, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.05−6.95 (m, 3H), 6.58 (d, J = 8.0 Hz, 2H), 4.80− 4.70 (m, 1H), 4.35−4.26 (m, 1H), 3.96 (s, 3H), 3.67−3.59 (m, 1H), 3.57 (s, 3H), 2.64−2.53 (m, 1H), 2.00 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 142.8, 138.3, 136.0, 135.7, 135.5, 135.1, 127.9, 126.6, 124.9, 123.7, 123.4, 123.0, 121.0, 120.9, 120.13, 120.07, 110.7, 109.8,

120.8, 120.6, 120.4, 119.1, 116.9, 110.6, 110.0, 108.6, 104.5, 60.8, 31.0, 30.3, 22.2; IR (neat, cm−1) 3054, 2927, 1611, 1588, 1470, 1346, 1162, 1132, 739, 668; HRMS (ESI-TOF): calcd for C30H26N3O2S+ [M + H+]: 492.1740, found: 492.1749. 5,13-Dimethyl-6-(methylsulfonyl)-6,7,8,13-tetrahydro-5Hazepino[2,3-b:4,5-b′]diindole (3d). Yellowish solid; yield: 60% (45.5 mg); mp 283−284 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.43−7.35 (m, 2H), 7.30−7.23 (m, 2H), 7.22−7.16 (m, 1H), 4.65−4.50 (m, 1H), 4.30−4.10 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.22−3.10 (m, 1H), 2.92−2.76 (m, 1H), 2.18 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.6, 136.0, 134.4, 133.9, 127.3, 123.5, 123.2, 121.6, 121.0, 120.4, 119.8, 117.7, 110.7, 110.3, 109.6, 103.8, 59.7, 36.6, 32.2, 30.1, 22.4; IR (neat, cm−1) 3052, 2928, 1535, 1473, 1341, 1249, 1158, 962, 741; HRMS (EI-TOF): calcd for C21H21N3O2S [M]+: 379.1354, found: 379.1357. 2-Methoxy-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5Hazepino[2,3-b:4,5-b′]diindole (3e). Yellowish solid; yield: 58% (56.3 mg); mp 268−269 °C; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.17−6.96 (m, 7H), 6.51 (d, J = 8.0 Hz, 2H), 4.80−4.60 (m, 1H), 4.30−4.10 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.56 (s, 3H), 3.10−2.90 (m, 1H), 2.79−2.64 (m, 1H), 1.99 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.8, 142.9, 137.2, 135.6, 134.8, 133.3, 131.1, 127.9, 127.2, 126.6, 123.8, 120.9, 119.2, 117.1, 113.1, 111.4, 109.5, 108.6, 103.7, 102.2, 59.4, 55.9, 32.0, 30.3, 22.2, 21.3; IR (neat, cm−1) 3052, 2917, 1624, 1573, 1487, 1469, 1162, 1091, 870, 742; HRMS (EI-TOF): calcd for C28H27N3O3S [M]+: 485.1773, found: 485.1772. 2-Bromo-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3-b:4,5-b′]diindole (3f). Yellowish solid; yield: 53% (56.5 mg); mp 216−217 °C; 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.7, 1.8 Hz, 1H), 7.40−7.20 (m, 2H), 7.16−7.03 (m, 5H), 6.52 (d, J = 7.8 Hz, 2H), 4.80−4.60 (m, 1H), 4.30−4.10 (m, 1H), 3.93 (s, 3H), 3.55 (s, 3H), 3.10−2.90 (m, 1H), 2.80−2.60 (m, 1H), 2.00 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 143.1, 137.3, 135.6, 135.5, 134.5, 132.4, 128.0, 127.0, 126.6, 125.9, 125.0, 122.8, 121.3, 119.3, 117.2, 114.0, 112.1, 110.0, 108.7, 103.8, 59.6, 32.0, 30.4, 22.2, 21.3; IR (neat, cm−1) 3054, 2919, 1471, 1347, 1162, 1090, 794, 738; HRMS (ESI-TOF): calcd for C27H24BrN3NaO2S+ [M + Na+]: 556.0665, found: 556.0682. 5-Ethyl-13-methyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3b:4,5-b′]diindole (3g). Yellowish solid; yield: 61% (57.2 mg); mp 208− 209 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.39−7.33 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.23− 7.17 (m, 1H), 7.15−7.02 (m, 5H), 6.50 (d, J = 8.0 Hz, 2H), 4.80−4.70 (m, 1H), 4.70−4.60 (m, 1H), 4.50−4.33 (m, 1H), 4.20−4.10 (m, 1H), 3.55 (s, 3H), 3.10−2.90 (m, 1H), 2.80−2,60 (m, 1H), 1.98 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.8, 137.3, 135.6, 134.9, 134.1, 133.2, 127.9, 127.3, 126.7, 123.9, 122.9, 121.0, 120.54, 120.48, 119.1, 117.1, 110.9, 109.6, 108.6, 104.4, 59.3, 38.2, 32.0, 22.4, 21.3, 14.8; IR (neat, cm−1)3050, 2930, 1597, 1469, 1347, 1162, 1092, 744, 670; HRMS (EI-TOF): calcd for C28H27N3O2S [M]+: 469.1824, found: 469.1816. 13-Allyl-5-methyl-6-tosyl-6,7,8,13-tetrahydro-5H-azepino[2,3b:4,5-b′]diindole (3h). Yellowish solid; yield: 59% (56.8 mg); mp 202− 203 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.40−7.28 (m, 2H), 7.19−7.13 (m, 1H), 7.11−7.01 (m, 5H), 6.51 (d, J = 8.0 Hz, 2H), 6.29−6.10 (m, 1H), 5.37 (dd, J = 10.6, 0.9 Hz, 1H), 5.10 (dd, J = 17.3, 0.9 Hz, 1H), 4.77−4.64 (m, 2H), 4.29−4.20 (m, 1H), 4.20−4.11 (m, 1H), 3.94 (s, 3H), 3.00−2.90 (m, 1H), 2.80−2.60 (m, 1H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.8, 136.8, 135.7, 135.5, 134.7, 134.1, 133.2, 128.0, 127.3, 126.6, 124.0, 123.0, 121.0, 120.6, 120.2, 119.3, 117.1, 116.7, 110.42, 110.36, 110.1, 103.9, 59.9, 47.5, 30.3, 22.1, 21.4; IR (neat, cm−1) 3051, 2924, 1597, 1473, 1343, 1163, 1091, 743; HRMS (EI-TOF): calcd for C29H27N3O2S [M]+: 481.1824, found: 481.1827. 10-Bromo-5,13-dimethyl-6-tosyl-6,7,8,13-tetrahydro-5Hazepino[2,3-b:4,5-b′]diindole (3i). Yellowish solid; yield: 68% (72.5 mg); mp 150−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.40−7.34 F

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 107.3, 103.1, 61.4, 32.0, 30.2, 23.0, 21.4; IR (film, cm−1) 3058, 2925, 1596, 1532, 1474, 1355, 1249, 1163, 1090, 909, 735; HRMS (ESITOF): calcd for C27H25ClN3O2S+ [M + H]+: 490.1351, found: 490.1343. 5,14-Dimethyl-6-tosyl-5,6,7,8,9,14-hexahydroazocino[2,3-b:4,5b′]diindole (5a). Yellowish solid; yield: 74% (69.4 mg); mp 127−128 °C; 1H NMR (400 MHz, CDCl3) δ 7.51−7.43 (m, 2H), 7.41−7.33 (m, 2H), 7.25−7.16 (m, 3H), 7.11−7.00 (m, 3H), 6.42 (d, J = 8.0 Hz, 2H), 4.63 (d, J = 14.9 Hz, 1H), 3.90 (s, 3H), 3.49 (s, 3H), 3.15−3.00 (m, 2H), 2.19−2.00 (m, 1H), 1.96 (s, 3H), 1.84−1.73 (m, 1H), 1.68−1.50 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.9, 137.4, 136.9, 134.9, 130.5, 128.3, 127.7, 126.5, 124.8, 123.3, 121.2, 120.9, 120.6, 118.7, 117.8, 112.7, 110.4, 108.6, 105.1, 51.6, 31.2, 29.5, 27.0, 23.1, 21.2; IR (neat, cm−1) 3051, 2920, 1597, 1471, 1338, 1158, 1093, 740, 708; HRMS (ESI-TOF): calcd for C28H27N3NaO2S+ [M + Na+]: 492.1716, found: 492.1719. 6-((4-Chlorophenyl)sulfonyl)-5,14-dimethyl-5,6,7,8,9,14hexahydroazocino[2,3-b:4,5-b′]diindole (5b). Yellowish solid; yield: 80% (78.3 mg); mp 151−152 °C; 1H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.40−7.33 (m, 1H), 7.30− 7.25 (m, 2H), 7.24−7.15 (m, 1H), 7.17−7.11 (m, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 8.5 Hz, 2H), 4.65 (d, J = 14.8 Hz, 1H), 3.90 (s, 3H), 3.41 (s, 3H), 3.22−3.04 (m, 2H), 2.20−2.10 (m, 1H), 1.90−1.81 (m, 1H), 1.70−1.60 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 138.5, 137.9, 137.2, 135.1, 133.7, 130.2, 128.1, 128.0, 127.6, 124.8, 123.5, 121.8, 121.0, 120.7, 119.1, 117.7, 113.0, 110.4, 108.9, 105.3, 51.7, 31.2, 29.6, 27.2, 23.1; IR (neat, cm−1) 3055, 2939, 1585, 1472, 1349, 1339, 1161, 1089, 909, 737; HRMS (ESI-TOF): calcd for C27H24ClN3NaO2S+ [M + Na+]: 512.1170, found: 512.1166. 5,14-Dimethyl-6-(naphthalen-2-ylsulfonyl)-5,6,7,8,9,14hexahydroazocino[2,3-b:4,5-b′]diindole (5c). Yellowish solid; yield: 68% (68.7 mg); mp 136−137 °C; 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 1.1 Hz, 1H), 7.54−7.45 (m, 4H), 7.44−7.40 (m, 1H), 7.38−7.33 (m, 3H), 7.17−7.13 (m, 1H), 7.13−7.09 (m, 1H), 7.06−7.02 (m, 1H), 6.91 (dd, J = 8.6, 1.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 4.77 (d, J = 14.7 Hz, 1H), 3.95 (s, 3H), 3.20−3.10 (m, 2H), 2.85 (s, 3H), 2.22−2.08 (m, 1H), 1.93−1.86 (m, 1H), 1.85−1.77 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 136.8, 135.9, 135.1, 134.2, 133.7, 131.1, 130.2, 128.8, 128.4, 128.2, 128.0, 127.8, 127.6, 126.9, 124.8, 123.3, 121.3, 121.1, 120.9, 120.5, 118.7, 117.6, 113.1, 110.4, 108.7, 105.5, 51.7, 30.7, 29.7, 27.7, 23.1; IR (neat, cm−1) 3055, 2937, 1591, 1542, 1471, 1433, 1337, 1156, 1131, 1090, 909, 736; HRMS (EITOF): calcd for C31H27N3O2S [M]+: 505.1824, found: 505.1829. 5,14-Dimethyl-6-(methylsulfonyl)-5,6,7,8,9,14hexahydroazocino[2,3-b:4,5-b′]diindole (5d). Yellowish solid; yield: 76% (59.8 mg); mp 181−182 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.42−7.36 (m, 2H), 7.32−7.16 (m, 3H), 4.72−4.50 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.38 (dd, J = 14.9, 7.7 Hz, 1H), 3.13−2.99 (m, 1H), 2.30−2.20 (m, 1H), 2.06−1.95 (m, 4H), 1.92−1.78 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.5, 135.0, 134.3, 131.0, 127.6, 124.8, 123.6, 121.8, 120.9, 120.7, 119.4, 118.2, 113.9, 110.5, 109.3, 104.6, 51.9, 40.8, 31.3, 29.3, 28.0, 23.0; IR (neat, cm−1) 3052, 2930, 1569, 1542, 1471, 1434, 1347, 1336, 1151, 1090, 910, 736; HRMS (ESI-TOF): calcd for C22H23N3NaO2S+ [M + Na+]: 416.1403, found: 416.1417. 2-Methoxy-5,14-dimethyl-6-tosyl-5,6,7,8,9,14hexahydroazocino[2,3-b:4,5-b′]diindole (5e). Yellowish solid; yield: 74% (73.9 mg); mp 200−201 °C; 1H NMR (400 MHz, CDCl3) δ7.43− 7.30 (m, 2H), 7.25−7.15 (m, 2H), 7.13−6.99 (m, 4H), 6.88 (d, J = 2.3 Hz, 1H), 6.43 (d, J = 8.1 Hz, 2H), 4.62 (d, J = 14.9 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.51 (s, 3H), 3.18−3.02 (m, 2H), 2.24−2.11 (m, 1H), 1.97 (s, 3H), 1.85−1.74 (m, 1H), 1.68−1.59 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.8, 142.9, 137.3, 137.0, 134.5, 130.7, 130.1, 128.3, 127.7, 126.5, 125.1, 121.2, 118.8, 117.8, 113.8, 112.6, 111.3, 108.6, 104.7, 102.1, 55.8, 51.7, 31.3, 29.6, 27.1, 23.1, 21.2; IR (neat, cm−1) 3051, 2940, 1625, 1597, 1488, 1471, 1336, 1292, 1158, 1093, 910, 735; HRMS (ESI-TOF): calcd for C29H29N3NaO3S+ [M + Na+]: 522.1822, found: 522.1857. 2-Bromo-5,14-dimethyl-6-tosyl-5,6,7,8,9,14-hexahydroazocino[2,3-b:4,5-b′]diindole (5f). Yellowish solid; yield: 70% (76.6 mg); mp

186−187 °C; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.7 Hz, 1H), 7.45 (dd, J = 8.7, 1.8 Hz, 1H), 7.50−7.40 (m, 2H), 7.25−7.18 (m, 2H), 7.12−7.06 (m, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.43 (d, J = 8.1 Hz, 2H), 4.61 (d, J = 15.0 Hz, 1H), 3.88 (s, 3H), 3.51 (s, 3H), 3.16−3.03 (m, 2H), 2.18−2.06 (m, 1H), 1.97 (s, 3H), 1.85−1.74 (m, 1H), 1.65−1.50 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.2, 137.5, 136.8, 133.6, 129.7, 128.4, 127.6, 126.5, 126.4, 126.3, 123.2, 121.5, 118.9, 117.9, 113.9, 113.1, 112.0, 108.7, 104.8, 51.6, 31.3, 29.7, 26.9, 23.1, 21.2; IR (neat, cm−1) 3053, 2918, 1597, 1541, 1471, 1430, 1337, 1159, 1093, 735; HRMS (EI-TOF): calcd for C28H26BrN3O2S+ [M] + :547.0929, found: 547.0933. 5-Ethyl-14-methyl-6-tosyl-5,6,7,8,9,14-hexahydroazocino[2,3b:4,5-b′]diindole (5g). Yellowish solid; yield: 63% (60.9 mg); mp 146− 148 °C; 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 10.5, 8.2 Hz, 2H), 7.40−7.31 (m, 2H), 7.28−7.17 (m, 3H), 7.11−7.00 (m, 3H), 6.41 (d, J = 8.0 Hz, 2H), 4.65−4.46 (m, 1H), 4.40−4.25 (m, 1H), 3.55 (s, 3H), 3.20−3.02 (m, 2H), 2.20−2.11 (m, 1H), 1.96 (s, 3H), 1.83−1.72 (m, 1H), 1.66−1.51 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.0, 137.4, 137.0, 134.0, 130.7, 128.4, 127.8, 126.6, 125.2, 123.2, 121.2, 121.0, 120.5, 118.7, 117.8, 112.6, 110.8, 108.7, 105.0, 52.0, 37.9, 31.3, 29.7, 23.2, 21.2, 15.1; IR (neat, cm−1) 3051, 2921, 1597, 1470, 1340, 1161, 1093, 742, 670; HRMS (ESI-TOF): calcd for C29H30N3O2S+ [M + H+]: 484.2053, found: 484.2051. 5-Allyl-14-methyl-6-tosyl-5,6,7,8,9,14-hexahydroazocino[2,3b:4,5-b′]diindole (5h). Yellowish solid; yield: 71% (70.3 mg); mp 237− 238 °C; 1H NMR (400 MHz, CDCl3) δ7.52−7.40 (m, 2H), 7.37−7.30 (m, 2H), 7.25−7.16 (m, 3H), 7.12−7.06 (m, 1H), 7.03 (d, J = 8.3 Hz, 2H), 6.42 (d, J = 8.1 Hz, 2H), 6.20−6.00 m, 1H), 5.31−5.09 (m, 3H), 4.97−4.88 (m, 1H), 4.60−4.50 (m, 1H), 3.51 (s, 3H), 3.24−3.02 (m, 2H), 2.20−2.06 (m, 1H), 1.97 (s, 3H), 1.84−1.69 (m, 1H), 1.67−1.50 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.0, 137.5, 136.9, 134.5, 133.6, 130.5, 128.4, 127.7, 126.6, 125.0, 123.3, 121.3, 120.9, 120.6, 118.7, 117.8, 117.4, 112.8, 111.2, 108.7, 105.5, 51.9, 45.7, 31.3, 26.8, 23.2, 21.2; IR (neat, cm−1) 3052, 2918, 1597, 1542, 1470, 1462, 1339, 1291, 1159, 1094, 910, 737; HRMS (ESI-TOF): calcd for C30H29N3NaO2S+ [M + Na+]: 518.1873, found: 518.1873. 5-Methyl-6-tosyl-5,6,7,8,9,14-hexahydroazocino[2,3-b:4,5-b′]diindole (5i). Yellowish solid; yield: 40% (36.4 mg); mp 242−243 °C; 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.41−7.33 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.24−6.98 (m, 6H), 6.42 (d, J = 8.1 Hz, 2H), 4.49 (s, 1H), 3.88 (s, 3H), 3.31 (s, 1H), 2.76 (s, 1H), 2.43 (s, 1H), 1.89 (s, 4H), 1.76−1.62 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.2, 137.0, 136.3, 135.0, 128.9, 128.3, 126.7, 124.1, 123.5, 121.6, 120.6, 119.7, 119.1, 117.9, 110.4, 110.2, 106.4, 99.9, 51.9, 29.5, 23.6, 23.5, 21.2; HRMS (ESITOF): calcd for C27H25N3NaO2S+ [M + Na+]: 478.1560, found: 478.1557. 5,15-Dimethyl-6-tosyl-6,7,8,9,10,15-hexahydro-5H-azonino[2,3b:4,5-b′]diindole (7a). Yellowish solid; yield: 59% (57 mg); mp 117− 118 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 12.7, 5.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.38−7.25 (m, 4H), 7.18−7.08 (m, 4H), 6.67 (d, J = 8.0 Hz, 2H), 4.10−4.03 (m, 1H), 3.77 (s, 3H), 3.52 (s, 3H), 4.35−4.20 (m, 1H), 3.00−2.80 (m, 1H), 2.40−2.23 (m, 1H), 2.17 (s, 3H), 1.66−1.45 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 137.3, 136.7, 135.0, 134.6, 130.1, 129.0, 127.8, 127.4, 126.6, 123.2, 121.3, 120.6, 120.3, 118.6, 118.5, 114.2, 110.1, 108.9, 105.4, 50.1, 30.6, 29.7, 27.6, 26.0, 23.5, 21.3; IR (neat, cm−1) 3052, 2925, 1597, 1585, 1471, 1336, 1242, 1160, 1090, 741; HRMS (ESI-TOF): calcd for C29H29N3NaO2S+ [M + Na+]: 506.1873, found: 506.1865. 6-((4-Chlorophenyl)sulfonyl)-5,15-dimethyl-6,7,8,9,10,15-hexahydro-5H-azonino[2,3-b:4,5-b′]diindole (7b). Yellowish solid; yield: 53% (53.3 mg); mp 104−105 °C; 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.39−7.28 (m, 4H), 7.19− 7.13 (m, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.19− 2.90 (m, 1H), 3.79 (s, 3H), 3.48 (s, 3H), 3.60−3.20 (m, 1H), 3.00− 2.83 (m, 1H), 2.40−2.25 (m, 1H), 1.69−1.43 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 139.1, 138.1, 137.2, 135.2, 134.0, 129.8, 128.9, 128.7, 127.8, 126.5, 123.4, 121.7, 120.8, 120.4, 118.9, 118.6, 114.5, 110.1, 109.0, 105.8, 50.4, 30.5, 29.8, 27.8, 26.0, 23.8; IR (neat, cm−1) 3054, 2930, 1584, 1537, 1471, 1339, 1162, 1090, 907, 741; HRMS G

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (ESI-TOF): calcd for C28H26ClN3NaO2S+ [M + Na+]: 526.1326, found: 526.1335. 5,15-Dimethyl-6-(naphthalen-2-ylsulfonyl)-6,7,8,9,10,15-hexahydro-5H-azonino[2,3-b:4,5-b′]diindole (7c). Yellowish solid; yield: 41% (42.6 mg); mp 163−164 °C; 1H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.60−7.50 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.47−7.38 (m, 3H), 7.37−7.32 (m, 1H), 7.32−7.26 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 7.17−7.07 (m, 3H), 7.07−7.00 (m, 1H), 4.15−4.05 (m, 1H), 3.83 (s, 3H), 3.39−3.35 (m, 1H), 3.32 (s, 3H), 2.97−2.80 (m, 1H), 2.40−2.30 (m, 1H), 1.68−1.46 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 137.2, 136.2, 135.2, 134.7, 134.2, 131.7, 130.0, 129.2, 129.2, 128.7, 127.8, 127.7, 127.2, 126.6, 123.3, 122.4, 121.4, 120.6, 120.4, 118.7, 118.6, 114.5, 110.1, 109.1, 105.9, 50.3, 30.4, 29.9, 27.9, 26.1, 23.7; IR (neat, cm−1) 3053, 2918, 1590, 1538, 1470, 1334, 1158, 1131, 1075, 741; HRMS (ESI-TOF): calcd for C32H29N3NaO2S+ [M + Na+]: 542.1873, found: 542.1869. 5,15-Dimethyl-6-(methylsulfonyl)-6,7,8,9,10,15-hexahydro-5Hazonino[2,3-b:4,5-b′]diindole (7d). Yellowish solid; yield: 47% (38.3 mg); mp 176−177 °C; 1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.40−7.30 (m, 2H), 7.30−7.25 (m, 2H), 7.20−7.10 (m, 2H), 4.41−4.31 (m, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 3.26−3.16 (m, 1H), 3.03−2.94 (m, 1H), 2.50−2.40 (m, 1H), 2.41 (s, 3H), 2.06−1.88 (m, 2H), 1.76−1.63 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 137.5, 134.9, 134.9, 130.3, 127.7, 126.4, 123.4, 121.7, 120.8, 120.2, 119.1, 119.0, 114.0, 110.3, 109.3, 103.9, 50.0, 40.9, 30.6, 29.6, 27.0, 26.3, 22.8; IR (neat, cm−1) 3053, 2928, 1536, 1470, 1372, 1338, 1242, 1153, 960, 737; HRMS (ESI-TOF): calcd for C23H25N3NaO2S+ [M + Na+]: 430.1560, found: 430.1554. 5-Allyl-15-methyl-6-tosyl-6,7,8,9,10,15-hexahydro-5H-azonino[2,3-b:4,5-b′]diindole (7e). Yellowish solid; yield: 46% (46.8 mg); mp 184−185 °C;1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 1H), 7.43−7.26 (m, 5H), 7.18−7.11 (m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 6.15−6.00 (m, 1H), 5.24 (dd, J = 10.3, 1.0 Hz, 1H), 5.12 (d, J = 17.1 Hz, 1H), 4.96 (dd, J = 17.2, 5.6 Hz, 1H), 4.82−4.76 (m, 1H), 3.96−3.86 (m, 1H), 3.54 (s, 3H), 3.40−3.20 (m, 1H), 2.92−2.80 (m, 1H), 2.40−2.20 (m, 1H), 2.16 (s, 3H), 1.67−1.41 (m, 4H); 13 C{1H} NMR (150 MHz, CDCl3) δ 143.5, 137.3, 136.6, 134.7, 134.1, 133.4, 130.1, 129.0, 127.9, 127.5, 126.7, 123.3, 121.4, 120.7, 120.4, 118.6, 117.0, 114.4, 110.9, 109.0, 106.2, 50.4, 45.7, 30.6, 27.6, 26.1, 23.9, 21.3; IR (neat, cm−1) 3053, 2925, 1618, 1597, 1461, 1336, 1160, 1091, 910, 740; HRMS (ESI-TOF): calcd for C31H31N3NaO2S+ [M + Na+]: 532.2029, found: 532.2032. 5-Isopropyl-15-methyl-6-tosyl-6,7,8,9,10,15-hexahydro-5Hazonino[2,3-b:4,5-b′]diindole (7f). Yellowish solid; yield: 45% (46 mg); mp 153−154 °C; 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41−7.30 (m, 2H), 7.31−7.25 (m, 2H), 7.18−7.09 (m, 2H), 7.01 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 7.9 Hz, 2H), 4.98−4.88 (m, 1H), 7.96−7.80 (m, 1H), 3.53 (s, 3H), 3.35−3.20 (m, 1H), 2.90−2.80 (m, 1H), 2.38−2.26 (m, 1H), 2.14 (s, 3H), 1.79 (d, J = 6.9 Hz, 3H), 1.71 (d, J = 7.1 Hz, 3H), 1.69−1.58 (m, 1H), 1.53− 1.45 (m, 2H), 1.44−1.34 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 143.4, 137.1, 136.5, 133.8, 132.7, 130.2, 128.9, 128.0, 127.5, 122.5, 121.3, 120.7, 120.0, 118.5, 118.5, 114.4, 112.6, 109.0, 105.5, 50.6, 47.2, 30.6, 27.5, 26.1, 24.0, 21.9, 21.3, 20.9; IR (neat, cm−1) 3052, 2930, 1597, 1539, 1470, 1455, 1336, 1161, 1090, 909, 733; HRMS (ESITOF): calcd for C31H33N3NaO2S+ [M + Na+]: 534.2186, found: 534.2193. 15-Benzyl-5-methyl-6-tosyl-6,7,8,9,10,15-hexahydro-5Hazonino[2,3-b:4,5-b′]diindole (7g). Yellowish solid; yield: 40% (44.7 mg); mp 168−169 °C; 1H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.24−7.06 (m, 9H), 7.02 (d, J = 6.2 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.80−6.70 (m, 1H), 6.67 (d, J = 7.7 Hz, 2H), 5.15 (s, 2H), 3.97−3.85 (m, 1H), 3.74 (s, 3H), 3.34−3.25 (m, 1H), 3.01−2.89 (m, 1H), 2.38−2.27 (m, 1H), 2.21 (s, 3H), 1.70−1.43 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 143.6, 138.4, 137.3, 136.6, 135.0, 134.8, 130.3, 129.2, 128.3, 128.1, 127.6, 126.8, 126.6, 126.4, 122.9, 121.6, 120.6, 120.1, 118.9, 118.7, 115.4, 110.4, 109.6, 105.5, 50.3, 47.7, 29.7, 27.7, 26.3, 24.0, 21.4; IR (neat, cm−1) 3054, 2924, 1597, 1538, 1467, 1336, 1185, 1160, 1092, 908, 733; HRMS

(ESI-TOF): calcd for C35H33N3NaO2S+ [M + Na+]: 582.2186, found: 582.2179. 15-Allyl-5-methyl-6-tosyl-6,7,8,9,10,15-hexahydro-5H-azonino[2,3-b:4,5-b′]diindole (7h). Yellowish solid; yield: 39% (39.7 mg); mp 158−159 °C; 1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 1H), 7.44−7.37 (m, 3H), 7.35−7.30 (m, 1H), 7.27−7.23 (m, 1H), 7.17− 7.03 (m, 4H), 6.67 (d, J = 8.0 Hz, 2H), 6.07−5.90 (m, 1H), 5.21−5.10 (m, 2H), 4.64−4.48 (m, 2H), 3.95−3.85 (m, 1H), 3.73 (s, 3H), 3.30− 3.20 (m, 1H), 2.97−2.80 (m, 1H), 2.40−2.26 (m, 1H), 2.20 (s, 3H), 1.67−1.41 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 143.6, 137.0, 136.6, 135.1, 134.8, 134.4, 129.8, 129.1, 128.2, 127.6, 126.8, 123.2, 121.4, 120.9, 120.3, 118.8, 118.6, 116.6, 114.8, 110.4, 109.9, 105.5, 50.3, 47.2, 29.7, 27.7, 26.2, 23.9, 21.4; IR (neat, cm−1) 3052, 2923, 1619, 1597, 1467, 1336, 1160, 1092, 908, 741; HRMS (ESI-TOF): calcd for C31H31N3NaO2S+ [M + Na+]: 532.2029, found: 532.2038. 2-Methoxy-5,15-dimethyl-6-tosyl-6,7,8,9,10,15-hexahydro-5Hazonino[2,3-b:4,5-b′]diindole (7i). Yellowish solid; yield: 47% (48.2 mg); mp 99−100 °C; 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.32−7.26 (m, 2H), 7.16−7.08 (m, 3H), 6.99 (dd, J = 8.9, 2.4 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.67 (d, J = 8.0 Hz, 2H), 4.10−3.90 (m, 1H), 3.74 (s, 2H), 3.72 (s, 3H), 3.54 (s, 3H), 3.40−3.20 (m, 1H), 2.95−2.80 (m, 1H), 2.40−2.30 (m, 1H), 2.17 (s, 3H), 1.67−1.44 (m, 5H); 13C{1H} NMR (150 MHz, CDCl3) δ 154.9, 143.4, 137.2, 136.8, 134.7, 130.3, 130.2, 129.0, 127.8, 127.4, 126.9, 121.3, 118.59,118.58, 114.2, 113.9, 111.1, 109.0, 105.1, 101.3, 55.9, 50.2, 30.5, 29.8, 27.7, 26.0, 23.6, 21.3; IR (neat, cm−1) 3052, 2924, 1598, 1576, 1488, 1453, 1335, 1246, 1160, 1117, 738; HRMS (ESITOF): calcd for C30H31N3NaO3S+ [M + Na+]: 536.1978, found: 536.1984. 5-Methyl-6-tosyl-6,7,8,9,10,15-hexahydro-5H-azonino[2,3-b:4,5b′]diindole (7j). Yellowish solid; yield: 27% (25.3 mg); mp 123−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.47−7.40 (m, 2H), 7.38−7.31 (m, 2H), 7.24−7.15 (m, 5H), 7.14−7.05 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 4.10−4.25 (m, 1H), 3.85 (s, 3H), 3.40−3.30 (m, 1H), 2.87−2.70 (m, 1H), 2.47−2.30 (m, 1H), 2.29 (s, 3H), 1.81−1.51 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 143.5, 136.2, 136.1, 134.8, 133.6, 128.9, 127.9, 127.9, 127.2, 126.4, 123.3, 121.6, 120.3, 119.9, 118.9, 118.5, 114.3, 110.3, 110.1, 105.5, 49.8, 30.0, 27.2, 25.4, 22.6, 21.5; IR (neat, cm−1) 3370, 3054, 2842, 1597, 1546, 1467, 1434, 1326, 1157, 1091, 909, 743; IR (neat, cm−1) 3395, 3055, 2923, 1597, 1467, 1335, 1324, 1160, 1092, 908, 738; HRMS (ESI-TOF): calcd for C28H27N3NaO2S+ [M + Na+]: 492.1716, found: 492.1713. N-(3-(2-Bromoethyl)-5-methoxy-1,1′-dimethyl-1H,1′H-[2,3′-biindol]-2′-yl)-4-methylbenzenesulfonamide (8). Yellowish solid; yield: 81% (91.5 mg); mp 145−146 °C; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 1H), 7.37−7.30 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.18− 7.07 (m, 2H), 7.05−6.96 (m, 3H), 6.95−6.85 (m, 1H), 6.59 (d, J = 8.2 Hz, 2H), 3.95 (s, 3H), 3.94(s, 3H), 3.70−3.60 (m, 1H), 3.35−3.20 (m, 1H), 3.19−2.09 (m, 1H), 3.05−2.90 (m, 1H), 2.85 (s, 3H), 2.17 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 143.5, 136.1, 135.3, 132.7, 130.5, 128.9, 128.7, 127.1, 126.4, 126.4, 123.3, 120.9, 119.9, 111.6, 110.4, 110.3, 109.9, 102.1, 100.4, 56.1, 32.6, 30.2, 30.2, 29.8, 21.4; IR (neat, cm−1) 3254, 2940, 1618, 1597, 1486, 1325, 1160, 1091, 908, 735; HRMS (MALDI-TOF): calcd for: C28H29BrN3O3S+ [M + H+]: 566.1108, found: 566.1107.

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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.9b01169. 1

H NMR and 13C NMR spectra of all new compounds (PDF) X-ray crystallography of compound 3a (CIF)

X-ray crystallography of compound 5a (CIF) X-ray crystallography of compound 7g (CIF) H

DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

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Antonovich, R. S.; Cao, H.; Yan, J.; Cooper, A. J.; Rippin, S. R.; Alexander, M. D.; Kumar, P. T.; Hendi, M. S.; Lee, Y.-H.; Haimowitz, T.; Condon, S. M. Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate. Org. Process Res. Dev. 2016, 20, 242−252. (c) Ma, C.; Jiang, F.; Sheng, F. T.; Jiao, Y. C.; Mei, G. J.; Shi, F. Design and Catalytic Asymmetric Construction of Axially Chiral 3,3′-Bisindole Skeletons. Angew. Chem., Int. Ed. 2019, 58, 3014−3020 and references cited therein . (6) (a) Xing, Y. P.; Sheng, G. R.; Wang, J.; Lu, P.; Wang, Y. G. Preparation of Triazoloindoles via Tandem Copper Catalysis and Their Utility as α-Imino Rhodium Carbene Precursors. Org. Lett. 2014, 16, 1244−1247. (b) Sheng, G. R.; Huang, K.; Chi, Z. H.; Ding, H. L.; Xing, Y. P.; Lu, P.; Wang, Y. G. Preparation of 3-Diazoindolin-2-imines via Cascade Reaction between Indoles and Sulfonylazides and Their Extensions to 2,3-Diaminoindoles and Imidazo[4,5-b]indoles. Org. Lett. 2014, 16, 5096−5099. (7) (a) Du, Z.; Xing, Y. P.; Lu, P.; Wang, Y. G. Copper-Catalyzed Cascade Double C3-Indolations of 3-Diazoindolin-2-imines with Indoles: Convenient Access to 3,3-Diaryl-2-iminoindoles. Org. Lett. 2015, 17, 1192−1195. (b) Lang, B.; Zhu, H. T. Z.; Wang, C.; Lu, P.; Wang, Y. G. Rhodium-Catalyzed Cycloadditions between 3-Diazoindolin-2-imines and 1,3-Dienes. Org. Lett. 2017, 19, 1630−1633. (c) Sheng, G. R.; Huang, K.; Ma, S. C.; Qian, J.; Lu, P.; Wang, Y. G. Preparation of 3-aryl-2-aminoindoles, 3-allyl-3-amino-2-iminoindolines, and tetrahydro-[1,4]diazepino[2,3-b] indoles from 3-diazoindolin-2-imines. Chem. Commun. 2015, 51, 11056−11059. (8) Khaidarov, A. R.; Rostovskii, N. V.; Zolotarev, A. A.; Khlebnikov, A. F.; Novikov, M. S. Synthesis of 1-(2-Aminovinyl)indoles and 1,3′Biindoles by Reaction of 2,2-Diaryl-Substituted 2H-Azirines with αImino Rh(II) Carbenoids. J. Org. Chem. 2019, 84, 3743−3753. (9) CCDC 1857861 (3a), CCDC 1857867 (5a) and CCDC 1857866 (7g) contain supplementary crystallographic data for this paper. (10) For examples of cyclopropanations of metal carbenes with indoles, see: (a) Ö züduru, G.; Schubach, T.; Boysen, M. M. K. Enantioselective Cyclopropanation of Indoles: Construction of AllCarbon Quaternary Stereocenters. Org. Lett. 2012, 14, 4990−4993. (b) Song, H.; Yang, J.; Chen, W.; Qin, Y. Synthesis of Chiral 3Substituted Hexahydropyrroloindoline via Intermolecular Cyclopropanation. Org. Lett. 2006, 8, 6011−6014. (11) For a review on cyclopropanations of metal carbenes with alkenes, see: Davies, H. M. L.; Alford, J. S. Reactions of metallocarbenes derived from N-sulfonyl-1,2,3-triazoles. Chem. Soc. Rev. 2014, 43, 5151−5162. (12) (a) Han, L.; Liu, C.; Zhang, W.; Shi, X. X.; You, S. L. Dearomatization of tryptophols via a vanadium-catalyzed asymmetric epoxidation and ring-opening cascade. Chem. Commun. 2014, 50, 1231−1233. (b) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Biomimetic Approach to Perophoramidine and Communesin via an Intramolecular Cyclopropanation Reaction. Org. Lett. 2006, 8, 2187− 2190.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (P.L.). *E-mail: [email protected] (Y.W.). ORCID

Ping Lu: 0000-0002-3221-3647 Yanguang Wang: 0000-0002-5096-7450 Author Contributions †

G.R.S. and Z.M.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by NSFC (Nos. 21632003 and 21772169). REFERENCES

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DOI: 10.1021/acs.joc.9b01169 J. Org. Chem. XXXX, XXX, XXX−XXX