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Article

A Convenient Synthesis of 3,7′-Bisindole Derivatives

by
Teng Liu
1,
Hong-You Zhu
2,
Da-Yun Luo
1,
Sheng-Jiao Yan
1,* and
Jun Lin
1,*
1
Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
2
Guangdong Goodscend Pharm. Sci &Tech. Co., Ltd., Shantou 650091, China
*
Authors to whom correspondence should be addressed.
Molecules 2016, 21(5), 638; https://doi.org/10.3390/molecules21050638
Submission received: 15 March 2016 / Revised: 5 May 2016 / Accepted: 6 May 2016 / Published: 17 May 2016
(This article belongs to the Collection Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
An efficient and convenient method to synthesize highly functionalized 3,7′-bisindole derivatives has been developed via a Michael addition and cyclic condensation reaction of heterocyclic ketene aminals (HKAs) with 2-(1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione derivatives in ethanol-based solvents at room temperature. This strategy provides an efficient, environmentally friendly approach for easy access to various novel 3,7′-bisindole derivatives in moderate to good yields.

Graphical Abstract

1. Introduction

Bisindole-containing systems are prevalent molecular architectures that are widely found in natural products [1,2,3,4]. Furthermore, bisindole derivatives are especially important [5,6,7,8] due to their potent biological activities, including methicillin-resistant S. aureus (MRSA) pyruvate kinase inhibitors (cis-3,4-dihydrohamacanthin and spongotine A, Figure 1) [9,10,11], antitumor agents (Hydroxy CB1, Figure 1) [12,13,14], antihistamines and antimicrobials [15], anti-inflammatories [16], antibacterials and so on [17,18]. Because of their unique biological activities, more and more synthetic strategies to generate bisindole skeletons have been developed.
Generally, Lewis acids as well as Brønsted acids are employed as catalysts to form bisindole derivatives starting from indoles reacted with carbonyl compounds and their synthetic equivalents [19,20,21,22,23,24,25,26,27,28,29]. However, the synthetic pathways of highly functionalized bisindole derivatives usually suffer from common limitations, including harsh reaction conditions, multistep reactions, use of toxic solvents, and costly catalysts or enzymes [30]. Consequently, the development of more straightforward, eco-friendly and efficient strategies is highly desirable for the synthesis of bisindoles.
Heterocyclic ketene aminals (HKAs) are versatile building blocks used to construct a variety of fused heterocyclic compounds [31,32,33], such as quinolones [34,35], pyridines [36,37,38,39,40,41,42], pyrroles [43,44,45,46,47], spirooxindoles [48,49], etc. In recent years, we have developed some protocols to synthesize different substituted indole derivatives based on HKA building blocks [50,51,52] (Figure 2). Herein, we report an efficient and concise process to construct highly functionalized 3,7′-bisindole derivatives via an environmentally friendly and highly selective one-pot protocol.

2. Results and Discussion

Initially, the model reaction of 1a and 2a with different catalysts, solvents and temperatures was studied, and the results are summarized in Table 1. Results showed that alkaline catalysts are better than acid catalysts. Furthermore, different bases have remarkable effects on the reactions. The use of triethylamine as the catalyst in ethanol at room temperature made the reaction proceed smoothly and afforded the target product 3a in good yield (Table 1, entry 3). Carbonate catalysts, such as Na2CO3 and K2CO3, also gave product 3a with moderate yield (Table 1, entries 4–5). However, NaOEt provided product 3a with poor yield, which may be due to its strong basicity (Table 1, entry 6). Notably, trace product was detected when 1,8-diazabicyclo[5,4,0]undec-7ene (DBU) was employed as the catalyst (Table 1, entry 7). Next, solvent effects were examined. Most solvents had little influence and could facilitate good yield of the products, except H2O (Table 1, entries 8–13). Ultimately, EtOH was proved to be the best solvent (Table 1, entry 3). To gain further insight into the effects of reaction temperature, we examined 40 °C and reflux temperature. The results revealed that high temperature was adverse to the reaction (Table 1, entries 14–15). Therefore, it could be concluded that the optimum conditions for the synthesis of 3a were EtOH as the solvent and triethylamine as the catalyst at room temperature for 12 h (Table 1, entry 3).
With the optimized conditions in hand, the substrate scope was investigated (Table 2). The results showed that the reaction was tolerant to a variety of HKAs bearing an electron-donating or an electron-withdrawing group. Furthermore, the ring size of HKA 1 has a slight effect on the reaction yield. Six- and seven-membered HKAs as substrates usually afforded superior yields to that of the five-membered HKAs. Additionally, aryl-substituted substrate 2 (R4 = Ph) was also tolerant to the reaction. Notably, substrate 2, with or without a substituent group at N1 (R3 = Me, H), reacted smoothly with HKA 1 to provide the corresponding products 3 in moderate to good yields. Substrate 2 with a methoxy at C5 and no substituent at C2 reacted cleanly with HKA 1 to provide the corresponding product 3 in good yield. All new compounds were fully characterized using IR, HR-MS, 1H-NMR, 13C-NMR (Please see the Supplementary Materials).
A proposed mechanism of the base-catalyzed cyclocondensation of 1a with 2a is depicted in Scheme 1. Initially, HKA 1a reacted with 2a in the presence of Et3N to form intermediate 4a by a Michael addition reaction. Intermediate 4a was subsequently protonated to form compound 5a. Imine-enamine tautomerization of compound 5a then generates 6a, which cyclizes to 7a by intramolecular attack of the NH on the 2,4-cyclohexadienone. Loss of H2O from intermediate 7a then provides the final product 3a.

3. Experimental Section

3.1. General Information and Materials

All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker DRX400 and DRX500 (Fällanden, Zürich, Switzerland). Chemical shifts (δ) are expressed in ppm, J values are given in Hz, and deuterated DMSO-d6 and CDCl3 were used as solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 (Boston, MA, USA) using a KBr pellet. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254. The melting points were determined on a XT-4A melting point apparatus and are uncorrected. HRMs were performed on an Agilent LC/Msd TOF instrument (Palo Alto, CA, USA). All chemicals and solvents were used as received without further purification unless otherwise stated. Raw materials 1 and 2 were prepared according to the literature [53,54,55,56].

3.2. General Procedure for for the Preparation of the 3,7′-Bisindole Derivatives 3a–3w

Et3N (0.1 equiv) was added to a mixture of HKAs 1 (0.1 mmol) and compound 2 (0.11 mmol) in ethanol, and the mixture was stirred at room temperature until the HKAs 1 were completely consumed. Then, the solution was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether/EtOAc = 6/1) to afford the corresponding products 3a–3w with 65%–91% yield. The products were further identified by FT-IR, NMR, and HRMS, and were in good agreement with the assigned structures.
(8-Hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydro-pyrimido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone (3a). Yellow solid, yield 91%; Mp 221.5–222.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 8.51 (br, 1H, NH), 8.23 (s, 1H, ArH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.28–7.30 (m, 2H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH), 6.97–7.03 (m, 1H, ArH), 6.91–6.94 (m, 2H, ArH), 6.50 (br, 1H, OH), 3.91–3.95 (m, 2H, NCH2), 3.85 (s, 3H, OCH3), 3.46–3.50 (m, 2H, CH2N), 2.30 (s, 3H, CH3), 2.07–2.11 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 186.8, 160.7, 153.1, 150.3, 135.6, 135.5, 133.1, 129.4, 129.4, 128.9, 128.8, 125.3, 120.2, 118.9, 118.7, 114.7, 113.9, 113.9, 113.9, 110.6, 110.5, 105.4, 94.9, 55.6, 39.3, 38.1, 20.6, 13.0; IR (KBr) 3439, 3230, 2904, 2586, 1722, 1599, 1514, 1333, 1223, 752 cm−1; HRMS (ESI-TOF): m/z calcd for C28H26N3O3 [M + H]+, 452.1969; found, 452.1947.
(8-Hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydro-pyrimido[1,2-a]indol-10-yl)(p-tolyl)methanone (3b). Yellow solid, yield 88%; Mp 228–230 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.82 (br, 1H, NH), 8.44 (br, 1H, NH), 8.19 (s, 1H, ArH), 7.41 (d, J = 7.5 Hz, 2H, ArH), 7.23–7.32 (m, 3H, ArH), 7.21 (d, J = 7.5 Hz, 1H, ArH), 6.98 (t, J = 7.5 Hz, 1H, ArH), 6.85–6.92 (m, 2H, ArH), 6.32 (br, 1H, OH), 3.82–3.89 (m, 2H, NCH2), 3.42–3.46 (m, 2H, CH2N), 2.37 (s, 3H, CH3), 2.24 (s, 3H, ArCH3), 2.04–2.08 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 187.6, 153.3, 150.1, 139.8, 139.7, 135.5, 133.3, 129.3, 129.3, 129.0, 128.7, 127.3, 127.3, 125.1, 120.4, 118.9, 118.7, 115.1, 110.8, 110.5, 110.2, 105.4, 95.2, 39.5, 38.0, 21.4, 20.3, 12.7; IR (KBr) 3394, 3053, 2928, 2316, 1728, 1591, 1443, 1335, 1171, 750 cm−1; HRMS (ESI-TOF): m/z calcd for C28H26N3O2 [M + H]+, 436.2020; found, 436.2005.
(8-Hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydro-pyrimido[1,2-a]indol-10-yl)(phenyl)methanone (3c). Yellow solid, yield 82%; Mp 317–318.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.95 (br, 1H, NH), 8.60 (br, 1H, NH), 8.19 (s, 1H, ArH), 7.54–7.58 (m, 5H, ArH), 7.30 (t, J = 7.5 Hz, 2H, ArH), 6.98–7.04 (m, 1H, ArH), 6.90–6.98 (m, 2H, ArH), 6.34 (br, 1H, OH), 3.92–3.96 (m, 2H, NCH2), 3.47–3.51 (m, 2H, CH2N), 2.30 (s, 3H, CH3), 2.08–2.12 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 187.2, 153.2, 150.3, 143.2, 135.7, 133.2, 129.8, 128.9, 128.7, 128.7, 128.7, 127.3, 127.3, 125.2, 120.2, 118.9, 118.7, 114.9, 110.7, 110.6, 110.5, 105.4, 95.0, 39.3, 38.1, 20.6, 13.0; IR (KBr) 3323, 3055, 2972, 2866, 2314, 1726, 1614, 1529, 1319, 1174, 746 cm−1; HRMS (ESI-TOF): m/z calcd for C27H24N3O2 [M + H]+, 422.1863; found, 422.1871.
(4-Chlorophenyl)(8-hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)methanone (3d). Yellow solid, yield 89%; Mp 199.0–201.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.91 (br, 1H, NH), 8.55 (br, 1H, NH), 8.27–8.32 (m, 1H, ArH), 7.55–7.59 (m, 4H, ArH), 7.23–7.31 (m, 2H, ArH), 6.96–7.02 (m, 1H, ArH), 6.87–6.96 (m, 2H, ArH), 6.32 (br, 1H, OH), 3.91–3.95 (m, 2H, NCH2), 3.42–3.46 (m, 2H, CH2N), 2.27 (s, 3H, CH3), 2.08–2.12 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 185.6, 153.2, 150.5, 141.8, 135.6, 134.3, 133.1, 129.3, 129.3, 129.3, 128.9, 128.9, 128.9, 128.9, 124.9, 120.2, 118.9, 118.7, 115.0, 110.7, 110.5, 105.1, 95.0, 39.4, 38.1, 20.5, 13.0; IR (KBr) 3400, 3063, 2951, 2866, 2349, 1680, 1616, 1527, 1331, 750 cm−1; HRMS (ESI-TOF): m/z calcd for C27H23ClN3O2 [M + H]+, 456.1473; found, 456.1459.
(2-Chlorophenyl)(8-hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)methanone (3e). Yellow solid, yield 86%; Mp 301–303 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.94 (br, 1H, NH), 8.52 (br, 1H, NH), 8.07 (s, 1H, ArH), 7.61 (d, J = 1.0 Hz, 1H, ArH), 7.47–7.61 (m, 2H, ArH), 7.34–7.39 (m, 1H, ArH), 7.30 (d, J = 8.0 Hz, 1H, ArH), 7.26 (d, J = 7.5 Hz, 1H, ArH), 6.96–7.03 (m, 1H, ArH), 6.88–6.95 (m, 2H, ArH), 5.71 (br, 1H, OH), 3.90–3.94 (m, 2H, NCH2), 3.48–3.52 (m, 2H, CH2N), 2.26 (s, 3H, CH3), 2.08–2.12 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 183.7, 152.8, 150.5, 142.3, 135.7, 133.2, 130.4, 130.1, 129.6, 129.0, 128.9, 128.2, 128.1, 125.0, 120.3, 118.8, 118.7, 115.1, 110.7, 110.7, 110.4, 104.7, 95.7, 39.3, 38.1, 20.4, 13.0; IR KBr) 3342, 3061, 2966, 2868, 1726, 1618, 1531, 1429, 1329, 1176, 748 cm−1; HRMS (ESI-TOF): m/z calcd for C27H23ClN3O2 [M + H]+, 456.1473; found, 456.1462.
(4-Fluorophenyl)(8-hydroxy-6-(2-methyl-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)methanone (3f). Yellow solid, yield 89%; Mp 247–248.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.93 (br, 1H, NH), 8.54 (br, 1H, NH), 8.27 (s, 1H, ArH), 7.58–7.65 (m, 2H, ArH), 7.34 (t, J = 9.0 Hz, 2H, ArH), 7.28 (t, J = 9.0 Hz, 2H, ArH), 7.00 (t, J = 7.5 Hz, 1H, ArH), 6.87–6.97 (m, 2H, ArH), 6.31 (br, 1H, OH), 3.90–3.97 (m, 2H, NCH2), 3.47–3.51 (m, 2H, CH2N), 2.28 (s, 3H, CH3), 2.08–2.12 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 185.9, 164.0, 162.1, 153.1, 150.4, 139.6, 135.6, 133.1, 129.7, 129.7, 128.9, 125.1, 120.2, 118.9, 118.7, 115.7, 115.5, 114.9, 110.7, 110.7, 110.5, 105.1, 95.0, 39.4, 38.1, 20.5, 13.0; IR (KBr) 3394, 3053, 2928, 2860, 2316, 1720, 1591, 1441, 1335, 1170, 750 cm−1; HRMS (ESI-TOF): m/z calcd for C27H23FN3O2 [M + H]+, 440.1769; found, 440.1775.
(9-Hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)(4-methoxyphenyl)methan-one (3g). Yellow solid, yield 87%; Mp 179.5–182 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.93 (br, 1H, NH), 8.96 (br, 1H, NH), 8.32 (s, 1H, ArH), 7.59 (d, J = 7.6 Hz, 2H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.26 (d, J = 7.4 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 7.07 (d, J = 7.7 Hz, 2H, ArH), 7.00 (m, 1H, ArH), 6.91 (m, 1H, ArH), 6.45 (br, 1H, OH), 4.03–4.07 (m, 2H, NCH2), 3.86 (s, 3H, OCH3), 3.41–3.45 (m, 2H, CH2N), 2.29 (s, 3H, CH3), 1.87–1.97 (m, 4H, CH2CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 188.3, 161.0, 160.0, 150.5, 135.6, 135.0, 133.2, 129.7, 129.7, 129.5, 128.9, 125.7, 120.2, 118.9, 118.7, 115.7, 113.9, 113.9, 112.2, 110.6, 105.3, 97.7, 55.6, 45.5, 45.1, 29.3, 27.0, 13.0; IR (KBr) 3396, 3063, 2928, 2850, 2351, 1726, 1593, 1444, 1313, 1250, 1167, 1022, 744 cm−1; HRMS (ESI-TOF): m/z calcd for C29H28N3O3 [M + H]+, 466.2125; found, 466.2145.
(9-Hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)(p-tolyl)methanone (3h). Yellow solid, yield 84%; Mp 242–244 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 9.05 (br, 1H, NH), 8.23 (s, 1H, ArH), 7.49 (d, J = 7.7 Hz, 2H, ArH), 7.33 (d, J = 7.6 Hz, 2H, ArH), 7.29 (d, J = 7.9 Hz, 1H, ArH), 7.25 (d, J = 7.8 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 6.96–7.03 (m, 1H, ArH), 6.91 (t, J = 7.3 Hz, 1H, ArH), 6.34 (br, 1H, OH), 4.04–4.11 (m, 2H, NCH2), 3.39–3.43 (m, 2H, CH2N), 2.43 (s, 3H, ArCH3), 2.28 (s, 3H, CH3), 1.88–1.97 (m, 4H, CH2CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 188.8, 160.0, 150.5, 139.9, 139.8, 135.6, 133.2, 129.7, 129.2, 129.2, 128.9, 127.7, 127.7, 125.6, 120.2, 118.9, 118.7, 115.8, 112.2, 110.6, 110.5, 105.4, 97.6, 45.5, 45.0, 29.2, 26.9, 21.5, 13.0; IR (KBr) 3394, 3053, 2926, 2858, 2314, 1726, 1593, 1446, 1335, 1169, 748 cm−1; HRMS (ESI-TOF): m/z calcd for C29H28N3O2 [M + H]+, 450.2176; found, 450.2184.
(9-Hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)(phenyl)methanone (3i). Yellow solid, yield 83%; Mp 289–290 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 9.10 (br, 1H, NH), 8.21 (s, 1H, ArH), 7.53–7.57 (m, 5H, ArH), 7.29 (d, J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 7.5 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 6.96–7.03 (m, 1H, ArH), 6.87–6.94 (m, 1H, ArH), 6.23 (br, 1H, OH), 4.04–4.08 (m, 2H, NCH2), 3.45–3.49 (m, 2H, CH2N), 2.27 (s, 3H, CH3), 1.95–1.99 (m, 2H, CH2), 1.89–1.93 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 188.8, 160.1, 150.5, 142.8, 135.6, 133.2, 130.1, 129.7, 128.9, 128.8, 128.8, 127.4, 127.4, 125.6, 120.2, 118.9, 118.7, 115.9, 112.2, 110.7, 110.4, 105.4, 97.5, 45.5, 44.9, 29.1, 26.9, 12.9; IR (KBr) 3356, 3057, 2941, 2858, 2351, 1714, 1593, 1539, 1419, 1323, 1171, 748 cm−1; HRMS (ESI-TOF): m/z calcd for C28H26N3O2 [M + H]+, 436.2020; found, 436.2034.
(4-Chlorophenyl)(9-hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)methan-one (3j). Yellow solid, yield 87%; Mp 191–192.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 9.09 (br, 1H, NH), 8.37 (s, 1H, ArH), 7.56–7.60 (m, 4H, ArH), 7.28 (d, J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 7.5 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 6.99 (t, J = 7.5 Hz, 1H, ArH), 6.87–6.94 (m, 1H, ArH), 6.25 (br, 1H, OH), 4.05–4.09 (m, 2H, NCH2), 3.44–3.48 (m, 2H, CH2N), 2.27 (s, 3H, CH3), 1.95–1.99 (m, 2H, CH2), 1.88–1.92 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 187.1, 160.1, 150.7, 141.4, 135.6, 134.7, 133.2, 129.7, 129.4, 129.4, 128.9, 128.9, 128.9, 125.3, 120.2, 118.9, 118.7, 115.9, 112.3, 110.6, 110.5, 105.1, 97.4, 45.5, 44.9, 29.0, 26.8, 13.0; IR (KBr) 3394, 3057, 2926, 2854, 2353, 1687, 1599, 1539, 1417, 1169, 1092, 746 cm−1; HRMS (ESI-TOF): m/z calcd for C28H25ClN3O2 [M + H]+, 470.1630; found, 470.1637.
(2-Chlorophenyl)(9-hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)methan-one (3k). Yellow solid, yield 81%; Mp 240.5–241.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.94 (br, 1H, NH), 9.21 (br, 1H, NH), 8.15 (s, 1H, ArH), 7.61 (d, J = 7.5 Hz, 1H, ArH), 7.46–7.56 (m, 2H, ArH), 7.35–7.41 (m, 1H, ArH), 7.30 (d, J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 7.5 Hz, 1H, ArH), 7.09 (s, 1H, ArH), 7.00 (t, J = 7.5, 1H, ArH), 6.91 (t, J = 7.5 Hz, 1H, ArH), 5.69 (br, 1H, OH), 4.01–4.08 (m, 2H, NCH2), 3.51–3.55 (m, 2H, CH2N), 2.27 (s, 3H, CH3), 1.98–2.02 (m, 2H, CH2), 1.89–1.94 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 185.0, 159.8, 150.8, 142.0, 135.6, 133.3, 130.6, 130.1, 130.0, 129.5, 128.9, 128.1, 128.1, 125.4, 120.3, 118.9, 118.8, 116.0, 112.3, 110.7, 110.3, 104.6, 97.8, 45.5, 44.7, 28.8, 26.8, 13.0; IR (KBr) 3398, 3063, 2937, 2347, 1726, 1597, 1439, 1336, 1176, 750 cm−1; HRMS (ESI-TOF): m/z calcd for C28H25ClN3O2 [M + H]+, 470.1630; found, 470.1621.
(4-Fluorophenyl)(9-hydroxy-7-(2-methyl-1H-indol-3-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]indol-11-yl)methan-one (3l). Yellow solid, yield 83%; Mp 259–261 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.91 (br, 1H, NH), 9.06 (br, 1H, NH), 8.32 (s, 1H, ArH), 7.59–7.65 (m, 2H, ArH), 7.35 (t, J = 8.5 Hz, 2H, ArH), 7.29 (d, J = 7.5 Hz, 1H, ArH), 7.24 (d, J = 7.5 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 6.96–7.03 (m, 1H, ArH), 6.86–6.94 (m, 1H, ArH), 6.24 (br, 1H, OH), 4.04–4.08 (m, 2H, NCH2), 3.44–3.48 (m, 2H, CH2N), 2.28 (s, 3H, CH3), 1.95–1.99 (m, 2H, CH2), 1.89–1.93 (m, 2H, CH2); 13C-NMR (DMSO-d6, 125 MHz) δ 187.4, 164.2, 162.3, 160.0, 150.7, 139.2, 135.6, 133.2, 129.9, 129.7, 129.7, 128.9, 125.5, 120.2, 118.9, 118.7, 115.8, 115.6, 112.3, 110.6, 110.5, 105.1, 97.5, 45.5, 44.9, 29.1, 26.9, 13.0; IR (KBr) 3390, 3064, 2929, 2343, 1720,1595, 1535, 1428, 1222, 1167, 749 cm−1; HRMS (ESI-TOF): m/z calcd for C28H25FN3O2 [M + H]+, 454.1925; found, 454.1936.
(7-Hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)(4-methoxyphenyl)methanone (3m). Yellow solid, yield 82%; Mp 269–271 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.93 (br, 1H, NH), 8.40 (br, 1H, NH), 7.63–7.67 (m, 2H, ArH), 7.28–7.32 (m, 2H, ArH), 7.04–7.08 (m, 5H, ArH), 6.90–6.94 (m, 2H, ArH), 3.98–4.10 (m, 4H, CH2CH2), 3.85 (s, 3H, OCH3), 2.32 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 186.5, 161.2, 159.5, 150.4, 135.6, 134.8, 133.1, 130.7, 129.7, 129.7, 128.9, 126.0, 120.2, 118.9, 118.7, 115.0, 114.0, 114.0, 111.1, 110.7, 106.8, 93.4, 55.6, 49.5, 42.5, 13.0; IR (KBr) 3390, 3059, 2966, 2843, 2353, 1726, 1597, 1473, 1325, 1248, 1163, 744 cm−1; HRMS (ESI-TOF): m/z calcd for C27H24N3O3 [M + H]+, 438.1812; found, 438.1786.
(7-Hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)(p-tolyl)methanone (3n). Yellow solid, yield 75%; Mp 298.5–300 °C; 1H-NMR (DMSO-d6, 300 MHz) δ 10.91 (br, 1H, NH), 8.38 (br, 1H, NH), 7.53 (d, J = 6.5 Hz, 2H, ArH), 7.25–7.34 (m, 4H, ArH), 6.88–7.02 (m, 5H, ArH), 3.97–4.09 (m, 4H, CH2CH2), 2.40 (s, 3H, ArCH3), 2.29 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 187.2, 159.7, 150.4, 140.1, 139.6, 135.6, 133.1, 130.5, 129.3, 129.3, 128.9, 127.6, 127.6, 126.0, 120.3, 118.9, 118.7, 115.2, 111.1, 110.7, 110.5, 106.9, 93.5, 49.5, 42.5, 21.5, 13.0; IR (KBr) 3408, 2899, 2584, 2345, 1726, 1597, 1475, 1327, 1167, 752 cm−1; HRMS (ESI-TOF): m/z calcd for C27H24N3O2 [M + H]+, 422.1863; found, 422.1837.
(7-Hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)(phenyl)methanone (3o). Yellow solid, yield 73%; Mp 289.5–290.5 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 8.33 (br, 1H, NH), 7.61–7.65 (m, 2H, ArH), 7.52–7.56 (m, 3H, ArH), 7.28–7.32 (m, 2H, ArH), 6.91–7.02 (m, 5H, ArH), 3.99–4.11 (m, 4H, CH2CH2), 2.31 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 187.1, 159.7, 150.4, 142.6, 135.6, 133.1, 130.8, 130.4, 130.3, 128.8, 128.8, 127.5, 127.5, 126.1, 120.2, 118.9, 118.7, 115.2, 111.1, 110.7, 110.5, 106.8, 93.5, 49.5, 42.5, 13.0; IR (KBr): 3419, 3059, 2970, 2316, 1730, 1603, 1510, 1335, 1227, 744 cm−1; HRMS (ESI-TOF): m/z calcd for C26H22N3O2 [M + H]+, 408.1707; found, 408.1713.
(4-Chlorophenyl)(7-hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)methanone (3p). Yellow solid, yield 75%; Mp 204–206 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.95 (br, 1H, NH), 8.48 (br, 1H, NH), 7.60–7.66 (m, 2H, ArH), 7.54–7.60 (m, 2H, ArH), 7.25–7.32 (m, 3H, ArH), 7.00 (t, J = 7.0 Hz, 1H, ArH), 6.89–6.95 (m, 3H, ArH), 4.05–4.11 (m, 2H, NCH2), 3.98–4.03 (m, 2H, CH2N), 2.30 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 185.6, 159.7, 150.5, 141.2, 135.6, 134.9, 133.1, 130.3, 129.5, 129.5, 128.9, 128.9, 128.9, 126.0, 120.2, 118.9, 118.7, 115.3, 111.2, 110.7, 110.5, 106.7, 93.3, 49.5, 42.5, 13.0; IR (KBr) 3435, 3072, 2902, 2347, 1724, 1600, 1510, 1402, 1330, 1223, 752 cm−1; HRMS (ESI-TOF): m/z calcd for C26H21ClN3O2 [M + H]+, 442.1317; found, 442.1309.
(2-Chlorophenyl)(7-hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)methanone (3q). Yellow solid, yield 72%; mp 339–341 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 7.87–8.07 (m, 1H, ArH), 7.10–7.60 (m, 8H, ArH), 6.87–7.02 (m, 3H, ArH), 4.08– 4.12(m, 4H, CH2CH2), 2.26 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 184.0, 160.1, 150.1, 142.1, 135.6, 133.2, 130.6, 130.2, 129.5, 128.8, 128.1, 128.1, 128.1, 126.1, 120.3, 118.8, 118.8, 115.4, 111.2, 110.7, 110.3, 105.7, 94.1, 49.6, 42.4, 12.9; IR (KBr) 3429, 3346, 3059, 2918, 2580, 2318, 1728, 1520, 1464, 1327, 1225, 748 cm−1; HRMS (ESI-TOF): m/z calcd for C26H21ClN3O2 [M + H]+, 442.1317; found, 442.1302.
(4-Fluorophenyl)(7-hydroxy-5-(2-methyl-1H-indol-3-yl)-2,3-dihydro-1H-imidazo[1,2-a]indol-9-yl)methanone (3r). Yellow solid, yield 77%; Mp 268–270 °C; 1H-NMR (DMSO-d6, 500 MHz) δ 10.92 (br, 1H, NH), 8.39 (br, 1H, NH), 7.65–7.72 (m, 2H, ArH), 7.27–7.37 (m, 4H, ArH), 6.89–7.04 (m, 5H, ArH), 4.06–4.13 (m, 2H, NCH2), 3.98–4.04 (m, 2H, CH2N), 2.31 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125 MHz) δ 185.8, 164.4, 162.4, 159.7, 150.5, 139.0, 135.6, 133.1, 130.4, 130.0, 130.0, 128.9, 126.0, 120.2, 118.9, 118.7, 115.8, 115.6, 115.2, 111.2, 110.7, 106.7, 93.3, 49.5, 42.5, 13.0; IR (KBr) 3429, 3072, 2902, 2582, 2347, 1724, 1601, 1510, 1402, 1331, 1223, 1157, 752 cm−1; HRMS (ESI-TOF): m/z calcd for C26H21FN3O2 [M + H]+, 426.1612; found, 426.1622.
(6-(1,2-Dimethyl-1H-indol-3-yl)-8-hydroxy-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone (3s). Yellow solid, yield 87%; Mp 261–263 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.61 (br, 1H, NH), 7.69 (d, J = 8.8 Hz, 2H, ArH), 7.39 (d, J = 8.0 Hz, 1H, ArH), 7.34 (d, J = 8.0 Hz, 1H, ArH), 7.20–7.22 (m, 1H, ArH), 7.07–7.11 (m, 1H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 6.86 (s, 1H, ArH), 6.71 (s, 1H, ArH), 4.93 (br, 1H, OH), 3.90–3.93 (m, 2H, CH2N), 3.86 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 3.53–3.57 (m, 2H, CH2), 2.34 (s, 3H, CH3), 2.21–2.24 (m, 2H, CH2N); 13C-NMR (CDCl3, 100 MHz) δ 188.8, 161.0, 153.5, 149.3, 137.0, 135.4, 134.9, 129.4, 129.4, 129.3, 127.5, 126.6, 121.5, 119.9, 118.9, 113.6, 113.6, 113.2, 109.5, 108.9, 107.7, 104.7, 95.8, 55.3, 39.3, 38.1, 29.9, 20.8, 11.1; IR (KBr) 3439, 2926, 2853, 2347, 1728, 1616, 1510, 1471, 1350, 1324, 1168, 740 cm−1; HRMS (ESI-TOF): m/z calcd for C29H28N3O3 [M + H]+, 466.2125; found, 466.2120.
(6-(1,2-Dimethyl-1H-indol-3-yl)-8-hydroxy-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone(6-(1,2-dimethyl-1H-indol-3-yl)-8-hydroxy-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)(4-fluorophenyl)methanone (3t). Yellow solid, yield 70%; Mp 173–175 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.62 (br, 1H, NH), 7.67–7.71 (m, 2H, ArH), 7.34–7.39 (m, 2H, ArH), 7.11–7.26 (m, 3H, ArH), 7.08–7.11 (m, 1H, ArH), 6.87 (s, 1H, ArH), 6.53 (s, 1H, ArH), 4.88 (br, 1H, OH), 3.94 (t, J = 6.0 Hz, 2H, CH2N), 3.77 (s, 3H, NCH3), 3.57–3.63 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.23–2.29 (m, 2H, CH2N); 13C-NMR (CDCl3, 100 MHz) δ 188.0, 162.5, 153.6, 149.4, 138.5, 137.0, 135.4, 129.6, 129.5, 129.4, 127.4, 126.4, 121.6, 120.0, 118.8, 115.5, 115.3, 113.4, 109.6, 108.9, 107.6, 104.5, 95.9, 39.3, 38.1, 29.9, 20.7, 11.1; IR (KBr) 3437, 2925, 2582, 1721, 1617, 1534, 1470, 1325, 1221, 1173, 775 cm−1; HRMS (ESI-TOF): m/z calcd for C28H25N3O2 [M + H]+, 454.1925; found, 454.1931.
(8-Hydroxy-6-(2-phenyl-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone (3u). Yellow solid, yield 85%; Mp 179–181 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.92 (br, 1H, NH), 8.59 (br, 1H, NH), 7.69 (d, J = 8.8 Hz, 2H, ArH), 7.45–7.40 (m, 4H, ArH), 7.28–7.22 (m, 4H, ArH), 7.13–7.10 (m, 1H, ArH), 6.96 (d, J = 8.8 Hz, 2H, ArH), 6.85 (s, 1H, ArH), 6.72 (s, 1H, ArH), 4.94 (br, 1H, OH), 3.82–3.86 (m, 5H, CH2N, OCH3), 3.47–3.51 (m, 2H, NCH2), 2.19–2.16 (m, 2H, CH2); 13C-NMR (CDCl3, 100 MHz) δ 188.9, 161.1, 153.6, 149.3, 136.2, 135.2, 134.8, 131.9, 129.7, 129.5, 129.4, 129.4, 128.9, 128.9, 127.9, 127.0, 127.0, 123.1, 120.6, 119.8, 113.6, 113.6, 113.1, 113.0, 111.1, 109.5, 108.8, 105.2, 95.9, 55.3, 39.2, 38.0, 20.7; IR (KBr) 3438, 2925, 2854, 1728, 1616, 1577, 1532, 1445, 1326, 1253, 1168, 747 cm−1; HRMS (ESI-TOF): m/z calcd for C33H28N3O3 [M + H]+, 514.2125; found, 514.2121.
(4-Fluorophenyl)(8-hydroxy-6-(2-phenyl-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)methanone (3v). Yellow solid; yield 75%; Mp 264–266 °C; 1H-NMR (CDCl3, 400 MHz): δ 8.75 (br, 1H, NH), 8.61 (br, 1H, NH), 7.71–7.67 (m, 2H, ArH), 7.44–7.40 (m, 4H, ArH), 7.31–7.26 (m, 4H, ArH), 7.16–7.11 (m, 3H, ArH), 6.85 (s, 1H, ArH), 6.54 (s, 1H, ArH), 4.92 (br, 1H, OH), 3.86–3.83 (m, 2H, CH2N), 3.52–3.56 (m, 2H, NCH2), 2.22–2.19 (m, 2H, CH2); 13C-NMR (CDCl3, 100 MHz): δ 187.9, 165.0, 162.5, 153.7, 149.4, 138.4, 138.4, 136.1, 135.2, 131.9, 129.7, 129.6, 129.5, 128.9, 128.0, 126.9, 126.7, 123.2, 120.7, 119.8, 115.5, 115.3, 113.2, 111.1, 109.7, 108.7, 105.0, 104.9, 95.9, 39.2, 38.0, 20.4; IR (KBr) 3426, 2924, 1721, 1617, 1535, 1478, 1325, 1221, 1176, 774 cm−1; HRMS (ESI-TOF): m/z calcd for C32H25FN3O2 [M + H]+, 502.1925; found, 502.1933.
(8-Hydroxy-6-(5-methoxy-1H-indol-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]indol-10-yl)(4-methoxyphenyl)methanone (3w). Yellow solid; yield 65%; Mp 184–186 °C; 1H-NMR (CDCl3, 400 MHz) δ 8.60 (br, 1H, NH), 8.42 (br, 1H, NH), 7.70–7.68 (m, 1H, ArH), 7.64–7.61 (m, 2H, ArH), 7.35–7.33 (m, 1H, ArH), 7.01–6.94 (m, 5H, ArH), 6.70 (s, 1H, ArH), 5.08 (br, 1H, OH), 3.98–3.94 (m, 2H, CH2N), 3.88 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.58–3.56 (m, 2H, NCH2), 2.27–2.23 (m, 2H, CH2); 13C-NMR (CDCl3, 100 MHz) δ 188.8, 161.0, 154.8, 153.6, 148.9, 137.8, 134.7, 131.5, 129.4, 129.4, 126.5, 123.9, 118.8, 116.3, 113.6, 113.5, 112.3, 108.7, 107.6, 105.3, 105.1, 101.1, 95.8, 55.9, 55.3, 39.2, 38.0, 20.7; IR (KBr) 3430, 2921, 2852, 1724, 1612, 1557, 1528, 1450, 1340, 1250, 1170, 750 cm−1; HRMS (ESI-TOF): m/z calcd for C28H26N3O4 [M + H]+, 468.1918; found, 468.1922.

4. Conclusions

In summary, we have successfully developed a facile, economical, and environmentally friendly method for the construction of highly functionalized 3,7′-bisindole derivatives via a Michael addition/cyclocondensation reaction. This allowed for the rapid construction of a novel library of highly substituted 3,7′-bisindole derivatives through the simple and easy raw material HKAs 1 and 2-(1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione derivatives 2. Our further investigations into the in vitro biological activities of compounds 3 are currently ongoing.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/21/5/638/s1.

Acknowledgments

This work was supported by the Program for Changjiang Scholars and Innovative Research Team in University (IRT13095), the Program for the National Natural Science Foundation of China (Nos. U1202221, 21362042, 21262042, 21162037 and 21402070), the Talent Found in Yunnan Province (2012HB001), Excellent Young Talents, Yunnan University (XT412003), High-Level Talents Introduction Plan of Yunnan Province (CB143001), and Yang Fan Innovative & Entepreneurial Research Team Project (No. 201312S09).

Author Contributions

The list authors contributed to this work as follows: Sheng-Jiao Yan and Jun Lin conceived and designed the study. Teng Liu, Hong-You Zhu and Da-Yun Luo performed the experiments. Teng Liu wrote the paper. Sheng-Jiao Yan and Jun Lin edited and revised the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 3a–3w are available from the authors.
Molecules 21 00638 g001 550
Figure 1. Biologically active bisindole derivatives.
Figure 1. Biologically active bisindole derivatives.
Molecules 21 00638 g001
Molecules 21 00638 g002 550
Figure 2. Synthesis of 3,7′-bisindole derivatives based on the HKAs.
Figure 2. Synthesis of 3,7′-bisindole derivatives based on the HKAs.
Molecules 21 00638 g002
Molecules 21 00638 sch001 550
Scheme 1. A plausible mechanism for the synthesis of 3a.
Scheme 1. A plausible mechanism for the synthesis of 3a.
Molecules 21 00638 sch001
Table
Table 1. Optimization of reaction conditions a. Molecules 21 00638 i001
Table 1. Optimization of reaction conditions a. Molecules 21 00638 i001
EntrySolventCatalystt (°C)Time (h)Yield (%) b
1EtOH−rt12trace
2EtOHHOAcrt1245
3EtOHEt3Nrt1291
4EtOHNa2CO3rt1267
5EtOHK2CO3rt1266
6EtOHEtONart1225
7EtOHDBUrt12trace
8CH2Cl2Et3Nrt1278
9MeCNEt3Nrt1281
10tetrahydrofuranEt3Nrt1275
11tolueneEt3Nrt1268
12MeOHEt3Nrt1272
13H2OEt3Nrt1230
14EtOHEt3N401867
15EtOHEt3Nreflux2445
a The reaction was performed with 1a (0.1 mmol), 2a (0.11 mmol). b Isolated yields based on HKA 1a.
Table
Table 2. Preparation of the of 3,7′-bisindole derivatives a. Molecules 21 00638 i002
Table 2. Preparation of the of 3,7′-bisindole derivatives a. Molecules 21 00638 i002
EntrynR1R2R3R4R53Yield (%) b
12MeOHHMeH3a91
22MeHHMeH3b88
32HHHMeH3c82
42ClHHMeH3d89
52HClHMeH3e86
62FHHMeH3f89
73MeOHHMeH3g87
83MeHHMeH3h84
93HHHMeH3i83
103ClHHMeH3j87
113HClHMeH3k81
123FHHMeH3l83
131MeOHHMeH3m82
141MeHHMeH3n75
151HHHMeH3o73
161ClHHMeH3p75
171HClHMeH3q72
181FHHMeH3r77
192MeOHMeMeH3s87
202FHMeMeH3t70
212MeOHHPhH3u85
222FHHPhH3v75
232MeOHHHMeO3w65
a The reaction was performed with 1 (0.1 mmol), 2 (0.11 mmol). b Isolated yields based on HKA 1.

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Liu, T.; Zhu, H.-Y.; Luo, D.-Y.; Yan, S.-J.; Lin, J. A Convenient Synthesis of 3,7′-Bisindole Derivatives. Molecules 2016, 21, 638. https://doi.org/10.3390/molecules21050638

AMA Style

Liu T, Zhu H-Y, Luo D-Y, Yan S-J, Lin J. A Convenient Synthesis of 3,7′-Bisindole Derivatives. Molecules. 2016; 21(5):638. https://doi.org/10.3390/molecules21050638

Chicago/Turabian Style

Liu, Teng, Hong-You Zhu, Da-Yun Luo, Sheng-Jiao Yan, and Jun Lin. 2016. "A Convenient Synthesis of 3,7′-Bisindole Derivatives" Molecules 21, no. 5: 638. https://doi.org/10.3390/molecules21050638

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