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Article

Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-c]Quinoline Derivatives as Potential Antileukemia Agents

by
Ying Lin
1,
Dong Xing
1,
Wen-Biao Wu
2,3,
Gao-Ya Xu
2,3,
Li-Fang Yu
1,
Jie Tang
1,4,
Yu-Bo Zhou
2,3,
Jia Li
2,3,5,* and
Fan Yang
1,*
1
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
2
National Center for Drug Screening, Shanghai Institute of Material Medica, Chinese Academy of Science, Shanghai 201203, China
3
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
4
Shanghai Greenchem & Biotech Co. Ltd., Shanghai 200062, China
5
Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(1), 203; https://doi.org/10.3390/molecules25010203
Submission received: 14 December 2019 / Revised: 30 December 2019 / Accepted: 1 January 2020 / Published: 3 January 2020
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Abstract

:
Herein, we design and synthesize an array of benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-c]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.

Graphical Abstract

1. Introduction

Furo[3,2-c]pyridines belong to a novel class of heterocycles that exhibit a wide range of biological activities [1,2,3]. A large number of heterocyclic compounds bearing a furo[3,2-c]pyridine core have been reported as anticancer (Figure 1A, compounds A and B) [4,5] or antibacterial agents (Figure 1A, compound C) [6]. Among them, the tricyclic furo[3,2-c]quinoline skeleton possessing a fused aryl ring on the pyridine part has also shown unique pharmaceutical and biological activities. For example, compound D has been found to be a neuroprotective agent [7]. Compound E was reported to be a potent antiproliferative molecule against renal UO-31, melanoma UACC-257, and UACC-62 cell lines [8]. Agrawal et al. reported that compound F may be a potential topoisomerase-II inhibitor based on related computational studies [9]. In view of the diverse biological activities of such molecules, the design and synthesis of novel heterocyclic structures possessing the furo[3,2-c]pyridine skeleton would be highly valuable for biological studies. As our continuous research interest, herein we design and synthesize a new type of tetracyclic benzofuro[3,2-c]quinoline (Figure 1B, compound G) that contains the key furo[3,2-c]pyridine skeleton by introducing a fused aryl ring on the furan side. Although such types of tetracyclic heterocycles have been reported by several research groups, related biological studies are still very limited [10]. Based on our newly synthesized compounds, an in vitro biological evaluation was then conducted.
Recently, our group has developed an efficient route for the synthesis of 3-(2-methoxyphenyl)quinolin-4(1H)-ones 1 via an in situ Meinwald rearrangement/intramolecular reductive cyclization of chalcone epoxides (Figure 1B) [11,12]. This transformation was easily scaled up, showed a broad substrate scope, and tolerated a variety of functional groups. With this method developed, we envisioned that an efficient synthesis of benzofuro[3,2-c]quinoline G could be designed via demethylation followed by either one-pot or stepwise cyclization starting from 3-(2-methoxyphenyl)quinolin-4(1H)-ones 1 (Figure 1B). A batch of methods for the synthesis of such compounds have been reported, such as the palladium-catalyzed aromatization reaction [10], O-arylation/dehydrogenative cross-coupling reaction [13], C-O coupling reaction [14], demethyl-cyclization reaction [15], and many others [16,17,18]. The current method is featured due to it using a readily accessible starting material and involving the easy installation of different functional groups and the mild and metal-free reaction conditions to access a number of substituted benzofuro[3,2-c]quinoline derivatives for in vitro biological evaluations. Furthermore, it was found that this type of compound showed promising antileukemia activities.

2. Results and Discussion

2.1. Chemistry

Initially, 3-(2-methoxyphenyl)quinolin-4(1H)-one 1a, which was conveniently obtained from the corresponding chalcone epoxide, was chosen as the model substrate for the synthesis of benzofuro[3,2-c]quinoline 2a via a demethylation/cyclization cascade. However, upon a thorough condition screening, the formation of 2a could not be observed at all [Supplementary materials]. In order to access the desired product 2a from the readily available starting substrate 1a, a stepwise reaction was then developed (Scheme 1). First, by treating with suitable chlorination reagents, 1a was converted into the corresponding 4-chloroquinine 3a. Upon carefully investigating condition optimizations, SOCl2 was found to be the most effective, yielding 3a with a 93% yield using CH2Cl2 as the solvent. Treating 3a with 48% HBr under reflux gave the demethylation product 4a with a 98% yield. The chlorination and demethylation steps were conducted in a one-pot manner without the isolation of 3a, and the overall yield of 4a was maintained at a high level (96%). Finally, a simple intramolecular annulation of 4a with KOt-Bu led to the formation of the expected benzofuro[3,2-c]quinoline 2a with a high yield [Supplementary materials].
With the optimized reaction conditions identified, the scope of this stepwise chlorination/demethylation/cyclization transformation was investigated by preparing different substituted benzofuro[3,2-c]quinolines (Table 1). Several substrates bearing different functional groups on both the benzofuran and the quinoline were prepared and subjected to the standard reaction conditions. Halogen substituents at different positions on the benzofuran ring were all well tolerated, giving the corresponding tetracyclic products in high overall yields (2c, 2f–2i). A substrate bearing a trifluoromethoxyl substituent on the benzofuran ring also worked well (2k). With the methyl substituent at different positions on the benzofuran ring, this two-step transformation ran efficiently, providing the corresponding cyclization products in good overall yields (2b, 2d, and 2j). The substrate scope with different substituents on the quinoline moiety was then investigated. Both the electron-donating methyl substituent (2n, 2p, 2t, and 2v) and electron-withdrawing halogen substituents (2o and 2r–2s) at different positions all gave the corresponding cyclization products in good overall yields. A free hydroxyl substituent was introduced to different positions on both the benzofuran and quinoline rings, with the aim of increasing the potential biological activities of these molecules [19,20,21]. While the one-pot chlorination/demethylation step was still very efficient, the subsequent base-promoted cyclization for these hydroxyl-substituted substrates generally gave low yields of the corresponding cyclization products. The low yield of the second step may have come from the competitive reactions between the free hydroxyl groups with the base (2e, 2l, 2q, 2u, and 2w–2x), and we speculate that the low yields of the second steps may be improved via selective protection of the hydroxyl group, which is not involved in the cyclization reaction.

2.2. Benzofuro[3,2-c]Quinoline Inhibition Studies

With these newly synthesized benzofuro[3,2-c]quinoline derivatives available, their in vitro antileukemia activities were evaluated against the MV-4-11 cell line, which is one of the acute myelocytic leukemia (AML) cell lines (Table 2) [22,23]. As shown in Table 2, most of these compounds, except for 2h, 2k–2m, and 2v, exhibited good antileukemia activity against MV-4-11 cells. Among them, compound 2e, possessing a free hydroxyl group at the C5 position on the benzofuran ring, showed the highest antileukemia activity (IC50 = 0.12 μM). When the free hydroxyl group was replaced with Cl or CH3, the activities decreased 10-fold (2d and 2g). Compound 2q, bearing a free hydroxyl group at C8 on the quinoline ring, also showed promising antileukemia activity (IC50 = 0.24 μM). Similarly, when this hydroxyl substituent was replaced with Cl, the activity was reduce 10-fold (2o). On the other hand, replacing this hydroxyl group with methyl resulted in a slightly decreased activity (2p). Methyl, halogen, or hydroxyl substitutions at C3 showed only a slight difference on antileukemia activity (2r–2u). As concluded from these results, compounds with hydroxyl substitution (2e, 2q, and 2u) generally exhibited good activities; however, compounds bearing a free hydroxyl group at C4 of the benzofuran ring (2l and 2x) did not lead to increased activities.
It is vital to examine the cytotoxicity on normal cells during the development of an anticancer drug. Accordingly, four compounds that showed high antileukemia activities—2e, 2p, 2q, and 2u—were selected for the selectivity test on peripheral blood mononuclear cells (PBMCs) using an MTS assay (Table 3). The selectivity indexes (SIs) were counted by dividing the IC50 values in a PBMC by the IC50 values in MV-4-11 cell lines [25]. It was obvious that benzofuro[3,2-c]quinolines were less toxic on human peripheral blood mononuclear cell compared to human leukemia MV-4-11 cells. The most active compound, 2e (SI = 79.5), showed a 79.5 times higher selectivity toward cancer cells than toward normal cells.

3. Materials and Methods

3.1. Chemical Synthesis

3.1.1. General

All reagents were commercially available and used without purification. The progress of the reactions was monitored using silica gel thin-layer chromatography (TLC). Flash column chromatography was conducted using silica gel (Yantai Kangbinuo, ShanDong, Yantai, China, 200–300). 1H- and 13C-NMR spectra (Bruker Ascend, Bremen, Germany) were recorded at 400 and 100 MHz, respectively, using TMS (trimethyl chlorosilane) as the internal standard. Melting points were measured using a WRR-Y drug melting point measurement (Shanghai INESA Physico-Optical Instrument Co. Ltd, Shanghai, China). The high-resolution mass spectra were recorded on a Bruker micOTOF II spectrometer (Electrospray Ionization).

3.1.2. General Procedures for the Synthesis of 2-(4-Chloroquinolin-3-Yl)Phenol Substrates 4a–4x

A mixture of the substituted 3-phenylquinolin-4(1H)-one (1 equiv.), SOCl2 (4 equiv.), dichloromethane (5 mL) was refluxed until the reaction was completed (1 h), as evidenced using thin-layer chromatography (petroleum ether/ethyl acetate, 10:1). The cooled reaction mixture was concentrated in vacuo, diluted with water, then extracted with dichloromethane (3 × 20 mL). The combined organic layer were washed with water and brine, dried with anhydrous Na2SO4, and concentrated in vacuo. Then, the crude mixture was refluxed under 48% HBr without further purification until the reaction was completed. The mixture was poured into ice water and neutralized with saturated NaHCO3. The aqueous phase was extracted with ethyl acetate (3 × 20 mL), dried with anhydrous Na2SO4, and concentrated in vacuo. The crude mixture was purified using column chromatography over a silica gel using dichloromethane/methanol (80:1) as an eluent.
2-(4-Chloroquinolin-3-yl)phenol (4a): White solid (0.25 g, 96%), 1H-NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.78 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.89 (dd, J = 7.5, 4.1 Hz, 1H), 7.80 (dd, J = 7.8, 7.5 Hz, 1H), 7.34–7.28 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 7.4, 7.3 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 154.9, 152.2, 147.3, 139.6, 131.2, 130.9, 130.2, 130.0, 129.3, 128.2, 125.6, 124.0, 122.8, 119.0, 115.8.
2-(4-Chloroquinolin-3-yl)-6-methylphenol (4b): Orange solid (0.21 g, 78%), 1H-NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.47–8.44 (m, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.04–8.01 (m, 1H), 7.92–7.88 (m, 1H), 7.15 (d, J = 4.6 Hz, 1H), 7.01 (d, J = 5.7 Hz, 1H), 6.84–6.81 (m, 1H), 2.18 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.5, 156.3, 149.8, 140.7, 139.2, 137.2, 137.0, 135.3, 132.4, 131.8, 130.2, 130.0, 125.1, 124.3, 124.0, 20.2.
2-(4-Chloroquinolin-3-yl)-6-fluorophenol (4c): Yellow solid (0.24 g, 87%), 1H-NMR (400 MHz, DMSO-d6) δ 9.94 (br s, 1H), 8.91 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.97 (dd, J = 7.6, 7.1 Hz, 1H), 7.86 (dd, J = 7.5, 7.4 Hz, 1H), 7.35–7.30 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.97 (ddd, J = 8.0, 7.9, 5.0 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 151.7 (d, JC-F = 238.1 Hz), 150.9, 145.7, 142.7 (d, JC-F = 14.6 Hz), 141.8, 131.3, 129.8 (d, JC-F = 3.0 Hz), 128.9, 128.0, 126.6 (d, JC-F = 2.8 Hz), 125.7, 125.5 (d, JC-F = 3.3 Hz), 124.3, 119.3 (d, JC-F = 7.4 Hz), 116.5 (d, JC-F = 18.2 Hz).
2-(4-Chloroquinolin-3-yl)-5-methylphenol (4d): Yellow-green solid (0.22 g, 81%), 1H-NMR (400 MHz, DMSO-d6) δ 9.64 (br s, 1H), 8.76 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.88 (dd, J = 7.4, 7.2 Hz, 1H), 7.79 (dd J = 7.1, 7.0 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J = 7.5 Hz, 1H), 2.31 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ 154.7, 152.3, 147.1, 139.6 (2C), 130.9, 130.2, 129.2, 128.2, 125.6, 124.0 (2C), 119.9, 119.8, 116.3, 21.0.
4-(4-Chloroquinolin-3-yl)benzene-1,3-diol (4e): Black oil (0.24 g, 90%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 2/3) δ 8.89–8.88 (m, 1H), 8.38–8.36 (m, 2H), 7.96–7.92 (m, 1H), 7.87–7.81 (m, 1H), 7.02 (dd, J = 8.3, 6.8 Hz, 1H), 6.47–6.46 (m, 1H), 6.35 (dd, J = 6.8, 6.4 Hz, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 2/3) δ 157.4, 153.0, 148.7, 143.7, 134.1, 131.9, 129.9, 129.3, 128.4, 125.2, 123.2, 118.8, 108.2, 105.4, 100.4.
5-Bromo-2-(4-chloroquinolin-3-yl)phenol (4f): White solid (0.31g, 94%), 1H-NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.1, 7.2 Hz, 1H), 7.51 (dd, J = 8.0, 7.2 Hz, 1H), 7.30 (s, 1H), 7.19–7.16 (m, 1H), 7.08 (d, J = 8.2 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 154.2, 150.5, 145.9, 141.4, 131.4, 129.7, 128.2, 127.4, 127.2, 125.0, 123.5, 122.7, 122.5, 120.7, 119.5.
5-Chloro-2-(4-chloroquinolin-3-yl)phenol (4g): White solid (0.26 g, 88%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 2/3) δ 8.70 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 8.0, 7.1 Hz, 1H), 7.67 (dd, J = 8.1, 7.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.98–6.93 (m, 2H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 2/3) δ 154.8, 150.8, 146.3, 141.0, 134.4, 131.4, 129.5, 129.4, 127.6, 127.1, 125.8, 123.8, 120.8, 118.8, 115.2.
2-(4-Chloroquinolin-3-yl)-4-fluorophenol (4h): Yellow solid (0.22 g, 80%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 2/3) δ 8.73 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 7.9, 7.3 Hz, 1H), 7.68 (dd, J = 8.0, 7.2 Hz, 1H), 7.01–6.97 (m, 2H), 6.93–6.90 (m, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 2/3) δ 155.2 (d, JC-F = 235.9 Hz), 150.7, 150.1 (d, JC-F = 1.8 Hz), 146.4, 141.0, 129.6, 129.3, 127.7, 127.2, 125.8, 123.8, 122.8 (d, JC-F = 8.0 Hz), 116.6 (d, JC-F = 23.4 Hz), 115.8 (d, JC-F = 8.0 Hz), 115.6 (d, JC-F = 22.7 Hz).
4-Chloro-2-(4-chloroquinolin-3-yl)phenol (4i): Yellow solid (0.28 g, 95%), 1H-NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.25 (dd, J = 8.5, 6.9 Hz, 1H), 8.10 (dd, J = 8.2, 7.2 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.38 (dd, J = 8.8, 2.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H). 13C-NMR (100 MHz, CD3OD) δ 155.3, 153.9, 147.7, 138.8, 136.8, 132.8, 132.7, 132.6, 131.8, 129.0, 127.2, 125.5, 122.8, 122.2, 118.5.
2-(4-Chloroquinolin-3-yl)-4-methylphenol (4j): Brown solid (0.25 g, 92%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 1/4) δ 8.92 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.24 (s, 1H), 8.01–7.88 (m, 2H), 7.13–7.08 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 2.28 (s, 3H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 1/4) δ 152.3, 148.5, 148.2, 140.6, 133.4, 132.3, 131.8, 131.2, 130.1, 129.0, 127.4, 125.5, 123.8, 120.3, 115.8, 20.0.
2-(4-Chloroquinolin-3-yl)-4-(trifluoromethoxy)phenol (4k): Yellow solid (0.29 g, 85%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 1/4) δ 8.81 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.80 (dd, J = 8.0, 6.7 Hz, 1H), 7.69 (dd, J = 7.8, 7.3 Hz, 1H), 7.14–7.12 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 1/4) δ 150.9, 147.7, 142.3, 141.6, 138.9 (d, JC-F = 1.6 Hz), 129.1, 127.2, 126.2, 124.5, 124.3, 122.4, 121.8, 121.0, 120.2, 119.3, 116.7, 114.4.
2-(4-Chloroquinolin-3-yl)benzene-1,4-diol (4l): Brown solid (0.19 g, 68%), 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.01 (dd, J = 7.5, 7.1 Hz, 1H), 7.90 (dd, J = 7.5, 7.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.77–6.74 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 150.3, 149.7, 147.3, 143.5, 143.2, 131.9, 131.4, 129.3, 126.4, 126.0, 124.5, 122.0, 117.1, 117.0, 116.6.
3-Chloro-2-(4-chloroquinolin-3-yl)phenol (4m): Golden solid (0.27 g, 94%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 2/3) δ 8.62 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.80–7.76 (m, 1H), 7.68–7.64 (m, 1H), 7.22 (dd, J = 8.2, 8.1 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 2/3) δ 162.3, 155.4, 150.7, 146.5, 142.2, 133.7, 129.6, 127.9, 127.7, 127.0, 125.7, 123.8, 121.5, 119.4, 113.2.
2-(4-Chloro-5-methylquinolin-3-yl)phenol (4n): Yellow solid (0.26 g, 95%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 3/2) δ 8.65 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.63 (dd, J = 8.2, 7.4 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.31–7.27 (m, 1H), 7.21–7.19 (m, 1H), 6.98–6.94 (m, 2H), 3.06 (s, 3H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 3/2) δ 153.8, 148.9, 146.7, 143.3, 135.6, 132.1, 131.1, 130.2, 129.5, 129.4, 125.6 (2C), 122.5, 118.7, 115.0, 25.0.
2-(4,6-Dichloroquinolin-3-yl)phenol (4o): Orange solid (0.27 g, 94%), 1H-NMR (400 MHz, DMSO-d6) δ 9.83 (br s, 1H), 8.82 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 9.0, 2.3 Hz, 1H), 7.34–7.27 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.97–6.93 (m, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 154.8, 152.6, 145.5, 138.8, 133.0, 131.8, 131.5, 131.0, 130.9, 130.3, 126.5, 122.8, 122.3, 119.0, 115.8.
2-(4-Chloro-6-methylquinolin-3-yl)phenol (4p): Yellow solid (0.23 g, 86%), 1H-NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.61 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.24–7.18 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.8–6.84 (m, 1H), 2.42 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ 154.9, 151.2, 145.9, 138.8, 138.0, 132.2, 131.1, 130.8, 129.9, 129.1, 125.5, 122.9, 122.6, 119.0, 115.8, 21.4.
4-Chloro-3-(2-hydroxyphenyl)quinolin-6-ol (4q): Dark-red solid (0.25 g, 91%), 1H-NMR (400 MHz, DMSO-d6) δ 11.03 (br s, 1H), 9.93 (br s, 1H), 9.01 (s, 1H), 8.17–8.16 (m, 1H), 7.66–7.63 (m, 2H), 7.34 (s, 2H), 7.06–6.98 (m, 2H). 13C-NMR (100 MHz, DMSO-d6) δ 158.8, 154.8 (2C), 144.5, 135.2, 131.5, 131.1, 131.0, 130.7, 128.2, 121.2, 119.1, 115.9, 105.5, 99.5.
2-(4-Chloro-7-fluoroquinolin-3-yl)phenol (4r): Light yellow solid (0.25 g, 92%), 1H-NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.81 (s, 1H), 8.37 (dd, J = 9.3, 6.0 Hz, 1H), 7.91 (dd, J = 10.0, 2.5 Hz, 1H), 7.76–7.71 (m, 1H), 7.33–7.28 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.97–6.93 (m, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 162.6 (d, JC-F = 247.7 Hz), 154.9, 153.5, 148.2 (d, JC-F = 12.8 Hz), 139.8 (d, JC-F = 0.8 Hz), 131.1, 130.5 (d, JC-F = 2.4 Hz), 130.1, 127.0 (d, JC-F = 10.1 Hz), 122.9, 122.4, 119.0, 118.3 (d, JC-F = 25.1 Hz), 115.8, 112.9 (d, JC-F = 20.4 Hz).
2-(4,7-Dichloroquinolin-3-yl)phenol (4s): Orange solid (0.26 g, 90%), 1H-NMR (400 MHz, CD3OD/CDCl3 = 3/2) δ 8.76 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 9.0, 2.0 Hz, 1H), 7.32–7.28 (m, 1H), 7.24 (dd, J = 7.4, 1.0 Hz, 1H), 6.98–6.94 (m, 2H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 3/2) δ 156.1, 154.6, 148.8, 143.1, 137.6, 133.0, 132.6, 131.7, 130.1, 128.7, 127.6, 126.7, 123.9, 120.8, 117.1.
2-(4-Chloro-7-methylquinolin-3-yl)phenol (4t): Earthy solid (0.23 g, 86%), 1H-NMR (400 MHz, DMSO-d6) δ 9.79 (br s, 1H), 8.80 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.33–7.27 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.95 (dd, J = 7.4, 7.3 Hz, 1H), 2.58 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ 154.9, 151.5, 146.4, 140.9, 140.5, 131.2, 130.6, 130.2, 130.0, 127.3, 123.8 (2C), 122.5, 119.0, 115.8, 21.2.
4-Chloro-3-(2-hydroxyphenyl)quinolin-7-ol (4u): Brown solid (0.24 g, 89%), 1H-NMR (400 MHz, CD3OD) δ 8.96 (s, 1H), 8.51 (d, J = 9.3 Hz, 1H), 7.59 (dd, J = 9.4, 2.2 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.40–7.34 (m, 2H), 7.04–7.00 (m, 2H). 13C-NMR (100 MHz, CD3OD) δ 165.4, 156.4, 152.6, 146.7, 142.1, 132.4 (2C), 130.6, 129.2, 124.9, 123.5, 121.8, 120.8, 116.9, 103.5.
2-(4-Chloro-8-methylquinolin-3-yl)phenol (4v): Yellow solid (0.25 g, 91%), 1H-NMR (400 MHz, DMSO-d6) δ 9.74 (br s, 1H), 8.80 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.68–7.64 (m, 1H), 7.33–7.26 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 6.97–6.93 (m, 1H), 2.77 (s, 3H). 13C-NMR (100 MHz, DMSO-d6) δ 154.9, 150.9, 146.1, 140.0, 137.0, 131.1, 130.7, 130.2, 130.0, 127.8, 125.6, 122.9, 121.9, 119.0, 115.8, 17.9.
2-(7-Bromo-4-chloroquinolin-3-yl)benzene-1,4-diol (4w): Yellow solid (0.34 g, 97%), 1H-NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.26–8.24 (m, 2H), 7.82 (dd, J = 9.0, 1.9 Hz, 1H), 6.83–6.76 (m, 2H), 6.72 (d, J = 2.7 Hz, 1H). 13C-NMR (100 MHz, CD3OD) δ 154.6, 151.3, 149.0 (2C), 142.7, 133.2, 132.5, 131.9, 127.4, 126.7, 125.5, 124.4, 118.3, 118.2, 117.9.
2-(4,7-Dichloroquinolin-3-yl)benzene-1,4-diol (4x): Brick-red solid (0.28 g, 91%), 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.31 (d, J = 9.0 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 9.0, 1.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1H), 6.68 (d, J = 2.7 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 153.3, 149.7, 147.3, 147.0, 140.0, 135.0, 131.5, 128.9, 127.6, 126.3, 124.5, 122.5, 117.0, 116.9, 116.6.

3.1.3. General Procedures for the Synthesis of Benzofuro[3,2-c]Quionlines 2a–2x

To a solution of the 2-(4-chloroquinolin-3-yl)phenol (1 equiv.) in DMF (5 mL), KOt-Bu (2 equiv.) was added in one portion. The reaction mixture was first stirred at 25 °C for 0.5 h, then stirred at 60 °C for 2 h. The mixture was poured into ice water. The organic phase was separated and the water phase was extracted with ethyl acetate three times (3 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4. Removal of the solvent was done in vacuo, and the crude mixture was further purified using column chromatography over silica gel using petroleum ether/ethyl acetate (15:1) as eluent.
Benzofuro[3,2-c]quinoline (2a): White solid (0.19 g, 88%), m.p. 130–132 °C. 1H-NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.80–7.73 (m, 2H), 7.69 (dd, J = 7.6, 7.4 Hz, 1H), 7.54 (dd, J = 7.8, 7.4 Hz, 1H), 7.46 (dd, J = 7.4, 7.3 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 156.4, 154.9, 146.4, 143.4, 128.8, 128.2, 126.2, 126.0, 123.0, 121.6, 119.8, 119.6, 116.1, 115.3, 111.1; HRMS (ESI): calcd. for C15H10NO [M + H]+ 220.0757; found 220.0759.
6-Methylbenzofuro[3,2-c]quinoline (2b): White solid (0.15 g, 85%), m.p. 139–141 °C. 1H-NMR (400 MHz, CDCl3) δ 9.48–9.46 (m, 1H), 8.45 (dd, J = 7.8, 6.7 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.91 (dd, J = 8.6, 6.8 Hz, 1H), 7.80–7.76 (m, 1H), 7.69 (dd, J = 8.0, 6.9 Hz, 1H), 7.38–7.34 (m, 2H), 2.70 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.2, 153.9, 146.3, 143.6, 128.8, 128.1, 127.2, 125.8, 123.0, 121.4, 121.1, 119.8, 116.9, 116.2, 115.7, 14.2; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0906.
6-Fluorobenzofuro[3,2-c]quinoline (2c): White solid (0.17 g, 82%), m.p. 154–157 °C. 1H-NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.84–7.79 (m, 1H), 7.72 (dd, J = 7.4, 7.2 Hz, 1H), 7.40 (ddd, J = 8.0, 7.9, 4.3 Hz, 1H), 7.31–7.27 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ 156.8, 147.3 (d, JC-F = 249.5 Hz), 146.7, 143.3, 141.7 (d, JC-F = 11.3 Hz), 128.8, 128.7, 126.3, 125.2 (d, JC-F = 2.6 Hz), 123.8 (d, JC-F = 5.8 Hz), 119.8, 116.0, 115.1 (d, JC-F = 4.0 Hz), 115.0 (d, JC-F = 2.2 Hz), 112.7 (d, JC-F = 16.1 Hz); HRMS (ESI): calcd. for C15H9FNO [M + H]+ 238.0663; found 238.0667.
5-Methylbenzofuro[3,2-c]quinoline (2d): White solid (0.17 g, 92%), m.p. 146–149 °C. 1H-NMR (400 MHz,CDCl3) δ 9.40 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.74 (dd, J = 7.3, 7.0 Hz, 1H), 7.64 (dd, J = 7.8, 7.1 Hz, 1H), 7.48 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 2.53 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.2, 155.3, 146.0, 143.1, 136.8, 128.7, 127.9, 125.8, 124.2, 119.6, 119.0, 116.1, 115.3, 111.2, 20.9; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0907.
Benzofuro[3,2-c]quinolin-5-ol (2e): Earthy solid (0.03 g, 12%), m.p. >250 °C. 1H-NMR (400 MHz, CD3OD/CDCl3 = 3/2) δ 9.30 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.3, 7.0 Hz, 1H), 7.67 (dd, J = 7.4, 7.3 Hz, H), 7.17 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 3/2) δ 158.0, 157.6, 157.2, 145.7, 143.3, 128.9, 128.3, 127.0, 120.8, 120.4, 117.0, 116.9, 114.2, 113.1, 98.6; HRMS (ESI): calcd. for C15H10NO2 [M + H]+ 236.0706; found 236.0707.
5-Bromobenzofuro[3,2-c]quinoline (2f): White solid (0.24 g, 85%), m.p. 195–196 °C. 1H-NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.96–7.93 (m, 2H), 7.81 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.71 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 156.7, 155.1, 146.5, 143.1, 128.9, 128.6, 126.5, 126.3, 120.8, 120.5, 119.8, 119.4, 116.0, 114.7 (2C); HRMS (ESI): calcd. for C15H9BrNO [M + H]+ 297.9862; found 297.9869.
5-Chlorobenzofuro[3,2-c]quinoline (2g): White solid (0.17 g, 75%), m.p. 194–195 °C. 1H-NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.81 (ddd, J = 8.3, 7.0, 0.4 Hz, 1H), 7.76 (s, 1H), 7.71 (ddd, J = 8.0, 7.1, 0.7 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 156.8, 155.0, 146.4, 143.1, 131.9, 128.9, 128.6, 126.2, 123.8, 120.4, 120.1, 119.7, 116.0, 114.6, 111.8; HRMS (ESI): calcd. for C15H9ClNO [M + H]+ 254.0367; found 254.0362.
4-Fluorobenzofuro[3,2-c]quinoline (2h): White solid (0.17 g, 89 %), m.p. 187–188 °C. 1H-NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.2, 7.1 Hz,1H), 7.74–7.66 (m, 3H), 7.26–7.22 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ 158.7 (d, JC-F = 239.8 Hz), 157.6, 150.9, 146.5, 143.3, 128.9, 128.6, 126.2, 122.6 (d, JC-F = 10.6 Hz), 119.8, 116.0, 115.1 (d, JC-F = 3.7 Hz), 113.7 (d, JC-F = 25.8 Hz), 111.9 (d, JC-F = 9.4 Hz), 105.7 (d, JC-F = 25.5 Hz); HRMS (ESI): calcd. for C15H9FNO [M + H]+ 238.0663; found 238.0664.
4-Chlorobenzofuro[3,2-c]quinoline (2i): White solid (0.21 g, 86%), m.p. 181–182 °C. 1H-NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.2, 7.1 Hz, 1H), 7.70 (dd, J = 7.7, 7.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.8, 1.9 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 157.2, 153.2, 146.6, 143.2, 128.9, 128.7 (2C), 126.3, 126.2, 123.1, 119.8, 119.4, 116.0, 114.5, 112.1; HRMS (ESI): calcd. for C15H9ClNO [M + H]+ 254.0367; found 254.0361.
4-Methylbenzofuro[3,2-c]quinoline (2j): Yellow solid (0.20 g, 94%), m.p. 149–150 °C. 1H-NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.40–8.38 (m, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.79–7.75 (m, 1H), 7.70–7.66 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.34–7.32 (m, 1H), 2.55 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 157.7, 154.4, 147.3, 144.4, 133.8, 129.8, 129.2, 128.3, 126.9, 122.7, 120.8, 120.5, 117.3, 116.3, 111.6, 21.4; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0916.
4-(Trifluoromethoxy)benzofuro[3,2-c]quinoline (2k): White solid (0.16 g, 62%), m.p. 143–144 °C. 1H-NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.40–8.38 (m, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.84–7.79 (m, 1H), 7.75–7.69 (m, 2H), 7.40 (dd, J = 8.9,1.6 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 157.6, 152.8, 146.6, 144.7 (d, JC-F = 2.1 Hz), 143.2, 129.0, 128.8, 126.3, 122.7, 119.8, 119.7, 119.6 (q, JC-F = 255.5 Hz), 115.9, 114.8, 112.5, 112.0. 19F NMR (376 MHz, CDCl3): δ −58.1. HRMS (ESI): calcd. for C16H9F3NO2 [M + H]+ 304.0580; found 304.0584.
Benzofuro[3,2-c]quinolin-4-ol (2l): Light yellow solid (0.04 g, 23%), m.p. >250 °C. 1H-NMR (400 MHz, CD3OD/CDCl3 = 3/2) δ 9.30 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.4, 8.2 Hz, 1H), 7.68 (dd, J = 7.7, 7.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.03 (dd, J = 8.9, 2.5 Hz, 1H). 13C-NMR (100 MHz, CD3OD/CDCl3 = 3/2) δ 157.4, 153.3, 149.5, 145.5, 143.2, 128.8, 127.6, 126.4, 122.2, 120.0, 116.4, 115.9, 115.1, 111.6, 104.7; HRMS (ESI): calcd. for C15H10NO2 [M + H]+ 236.0706; found 236.0710.
3-Chlorobenzofuro[3,2-c]quinoline (2m): White solid (0.10 g, 42%), m.p. 160–162 °C. 1H-NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.40–8.38 (m, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.83–7.79 (m, 1H), 7.72–7.68 (m, 1H), 7.65 (dd, J = 6.7, 2.3 Hz, 1H), 7.48–7.43 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 156.5, 155.2, 146.4, 144.5, 128.9, 128.7, 127.0, 126.6, 126.1, 123.5, 120.7, 119.8, 115.7, 114.5, 109.4; HRMS (ESI): calcd. for C15H9ClNO [M + H]+ 254.0367; found 254.0348.
7-Methylbenzofuro[3,2-c]quinoline (2n): Light yellow solid (0.19 g, 85%), m.p. 146–147 °C. 1H-NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.11–8.09 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 8.0, 7.6 Hz, 1H), 7.54 (dd, J = 8.2, 7.1 Hz, 1H), 7.49–7.44 (m, 2H), 3.12 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 158.4, 155.8, 148.4, 144.1, 133.6, 128.9, 128.3, 127.6, 127.0, 124.0, 122.1, 120.4, 117.3, 116.6, 112.1, 22.4; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0914.
8-Chlorobenzofuro[3,2-c]quinoline (2o): White solid (0.22 g, 91%), m.p. 168–169 °C. 1H-NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.07–8.05 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (dd, J = 9.0, 2.4 Hz, 1H), 7.57–7.53 (m, 1H), 7.47 (ddd, J = 7.6, 7.5, 1.0 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 155.3, 155.0, 144.5, 143.5, 131.9, 130.4, 129.0, 126.6, 123.2, 121.3, 119.7, 118.8, 116.7, 115.9, 111.2; HRMS (ESI): calcd. for C15H9ClNO [M + H]+ 254.0367; found 254.0363.
8-Methylbenzofuro[3,2-c]quinoline (2p): White solid (0.17 g, 83%), m.p. 153–156 °C. 1H-NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.17 (br s, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.09–8.07 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.6, 1.9 Hz, 1H), 7.56–7.51 (m, 1H), 7.46 (ddd, J = 7.6, 7.4, 0.9 Hz, 1H), 2.63 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.1, 154.9, 145.0, 142.4, 136.1, 130.5, 128.5, 126.1, 122.9, 121.8, 119.6, 118.6, 116.0, 115.2, 111.0, 20.8. HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0919.
Benzofuro[3,2-c]quinolin-8-ol (2q): Yellow solid (0.03 g, 13%), m.p. >250 °C. 1H-NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.44 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 7.9, 7.5 Hz, 1H), 7.55–7.50 (m, 2H), 7.39 (dd, J = 9.1, 2.3 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 156.4, 155.5, 155.2, 142.0, 141.3, 131.3, 127.5, 124.2, 122.3, 121.6, 121.3, 117.5, 115.7, 112.1, 101.3; HRMS (ESI): calcd. for C15H10NO2 [M + H]+ 236.0706; found 236.0715.
9-Fluorobenzofuro[3,2-c]quinoline (2r): White solid (0.17 g, 77%), m.p. 150–151 °C. 1H-NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.39 (dd, J = 9.0, 6.0 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.89 (dd, J = 10.3, 2.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 7.7, 7.5 Hz, 1H), 7.50–7.46 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 161.9 (d, JC-F = 248.2 Hz), 156.5 (d, JC-F = 1.0 Hz), 154.8, 147.4 (d, JC-F = 12.4 Hz), 144.5, 126.3, 123.2, 121.9 (d, JC-F = 9.8 Hz), 121.4, 119.6, 116.3 (d, JC-F = 25.3 Hz), 115.0 (d, JC-F = 1.9 Hz), 113.1 (d, JC-F = 1.1 Hz), 112.9 (d, JC-F = 20.7 Hz), 111.1; HRMS (ESI): calcd. for C15H9FNO [M + H]+ 238.0663; found 238.0650.
9-Chlorobenzofuro[3,2-c]quinoline (2s): Light yellow solid (0.16 g, 69%), m.p. 155–157 °C. 1H-NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.58–7.53 (m, 1H), 7.50–7.46 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ 156.2, 154.9, 146.7, 144.4, 134.2, 128.0, 126.9, 126.5, 123.2, 121.4, 121.1, 119.7, 115.6, 114.5, 111.1; HRMS (ESI): calcd. for C15H9ClNO [M + H]+ 254.0367; found 254.0367.
9-Methylbenzofuro[3,2-c]quinoline (2t): Yellow-green solid (0.18 g, 92%), m.p. 159–161 °C. 1H-NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.1 Hz, 1H), 8.04 (br s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.54–7.50 (m, 2H), 7.48–7.44 (m, 1H), 2.62 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.6, 154.8, 146.7, 143.3, 138.7, 128.1, 128.0, 126.0, 122.9, 121.8, 119.5, 114.7, 114.0, 111.0, 21.0; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0909.
Benzofuro[3,2-c]quinolin-9-ol (2u): White solid (0.03 g, 15%), m.p. >250 °C. 1H-NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.53 (s, 1H), 8.28–8.25 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.58–7.54 (m, 1H), 7.50 (dd, J = 7.5, 6.8 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.9, 2.3 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 158.8, 157.0, 154.9, 149.0, 145.1, 126.9, 124.2, 122.4, 121.9, 120.8, 119.6, 113.7, 111.9, 111.3, 109.9; HRMS (ESI): calcd. for C15H10NO2 [M + H]+ 236.0706; found 236.0709.
10-Methylbenzofuro[3,2-c]quinoline (2v): Off-white solid (0.17 g, 79%), m.p. 203–204 °C. 1H-NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.60–7.52 (m, 2H), 7.48–7.45 (m, 1H), 2.91 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 156.8, 154.9, 145.4, 142.0, 136.7, 128.7, 126.1, 125.6, 122.9, 121.8, 119.6, 117.7, 116.0, 115.0, 111.0, 17.9; HRMS (ESI): calcd. for C16H12NO [M + H]+ 234.0913; found 234.0906.
9-Bromobenzofuro[3,2-c]quinolin-4-ol (2w): Light pink solid (0.05 g, 17%), m.p. >250 °C. 1H-NMR (400 MHz, DMSO-d6) δ 9.71–9.63 (m, 2H), 8.41 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 156.8, 154.6, 149.3, 147.2, 146.5, 131.5, 130.3, 122.6, 122.5 (2C), 116.8, 116.2, 115.3, 112.6, 106.1; HRMS (ESI): calcd. for C15H9BrNO2 [M + H]+ 314.9844; found 314.0560.
9-Chlorobenzofuro[3,2-c]quinolin-4-ol (2x): Pink solid (0.03 g, 12%), m.p. >250 °C. 1H-NMR (400 MHz, DMSO-d6) δ 9.86 (br s, 1H), 9.62 (s, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.9, 2.4 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 156.7, 154.7, 149.2, 147.0, 146.5, 133.8, 128.3, 127.7, 122.5, 116.7, 116.2, 115.1, 112.5, 106.1; HRMS (ESI): calcd. for C15H9ClNO2 [M + H]+ 270.0316; found 270.0318.

3.2. Cell Line and Culture Conditions

The cell lines used in this study were obtained from the American Type Culture Collection (ATCC). The MV-4-11 cell line and peripheral blood mononuclear cells (PBMCs) were cultured in RMPI 1640 medium (Shanghai Weike Biotechnology Co. Ltd, Shanghai, China) supplemented with 10% FBS (fatal bovine serum). All cells were grown at 37 °C in a 5% CO2 atmosphere.

3.3. Cell Viability Assay

The MV-4-11 cells and peripheral blood mononuclear cells (PBMCs) were seeded in 96-well plates at 10,000 cells per well and treated with compounds at the indicated concentrations and time intervals (3 days). The number of viable cells was assessed using CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay (Promega), according to the manufacturer’s protocol. The absorbance of the formazan at 490 nm was detected using SpectraMax® 340PC384 (Molecular Device).

4. Conclusions

In summary, we have developed an efficient sequential chlorination/demethylation, intramolecular annulation reaction for the synthesis of a variety of substituted benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones. This sequential transformation was metal-free and was conducted under mild reaction conditions. An in vitro biological evaluation indicated that these compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for further antileukemia studies.

Supplementary Materials

The following are available online. Table S1: Condition optimization for the dimethyl-cyclization (one-pot). Table S2: Condition optimization for the cyclization (stepwise). Table S3: Condition optimization for the cyclization from 4a to 2a.

Author Contributions

Conceptualization, J.T.; data curation, G.-Y.X.; investigation, Y.L. and W.-B.W.; methodology, Y.-B.Z.; supervision, L.-F.Y., J.T., Y.-B.Z., J.L., and F.Y.; writing—original draft, Y.L. and D.X.; Writing—review and editing, F.Y. All authors have read and agreed to the published version of the manuscript.

Funding

Financial support from the national Natural Science Foundation of China (21772043) is greatly acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Bennett, F.; Kezar, H.S., III; Girijavallabhan, V.; Huang, Y.H.; Huelgas, R.; Rossman, R.; Shih, N.Y.; Piwinski, J.J.; MacCoss, M.; Kwong, C.D.; et al. Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 5144–5149. [Google Scholar] [CrossRef]
  2. Ciustea, M.; Silverman, J.E.Y.; Druck Shudofsky, A.M.; Ricciardi, R.P. Identification of Non-Nucleoside DNA Synthesis Inhibitors of Vaccinia Virus by High-Throughput Screening. J. Med. Chem. 2008, 51, 6563–6570. [Google Scholar] [CrossRef] [Green Version]
  3. Martini, M.L.; Ray, C.; Yu, X.F.; Liu, J.; Pogorelov, V.M.; Wetsel, W.C.; Huang, X.P.; McCorvy, J.D.; Caron, M.G.; Jin, J. Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent In Vivo Antiparkinsonian Activity. ACS Chem. Neuro. 2019, 10, 4160–4182. [Google Scholar] [CrossRef]
  4. Zheng, X.Z.; Bauer, P.; Baumeister, T.; Buckmelter, A.J.; Caligiuri, M.; Clodfelter, K.H.; Han, B.S.; Ho, Y.C.; Kley, N.; Lin, J.; et al. Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors. J. Med. Chem. 2013, 56, 6413–6433. [Google Scholar] [CrossRef]
  5. Lv, Y.C.; Li, M.Y.; Liu, T.; Tong, L.J.; Peng, T.; Wei, L.X.; Ding, J.; Xie, H.; Duan, W.H. Discovery of a New Series of Naphthamides as Potent VEGFR-2 Kinase Inhibitors. ACS Med. Chem. Lett. 2014, 5, 592–597. [Google Scholar] [CrossRef] [Green Version]
  6. Sutherland, H.S.; Tong, A.S.T.; Choi, P.J.; Conole, D.; Blaser, A.; Franzblau, S.G.; Cooper, C.B.; Upton, A.M.; Lotlikar, M.U.; Denny, W.A.; et al. Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. Bioorg. Med. Chem. 2018, 26, 1797–1809. [Google Scholar] [CrossRef] [PubMed]
  7. Chen, Y.; Lin, H.Z.; Yang, H.Y.; Tan, R.X.; Bian, Y.Y.; Fu, T.M.; Li, W.; Wu, L.; Pei, Y.Q.; Sun, H.P. Discovery of new acetylcholinesterase and butyrylcholinesterase inhibitors through structure-based virtual screening. RSC Adv. 2017, 7, 3429–3438. [Google Scholar] [CrossRef] [Green Version]
  8. Wu, P.C.; Huang, Y.B.; Chang, C.K.; Chen, Y.L.; Tzeng, C.C.; Tsai, Y.H. Highly Sensitive Quantitative Analysis of 1-[3-(Furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone Oxime, a New Antitumor Agent, in Rat Plasma by LC with Electrochemical Detection. Chromatographia 2009, 70, 265–269. [Google Scholar] [CrossRef]
  9. Vaidya, A.; Jain, S.; Jain, A.K.; Prashanthakumar, B.R.; Kashaw, S.K.; Agrawal, R.K. Computational analysis of quinoline derivatives as potent topoisomerase-II inhibitors. Med. Chem. Res. 2015, 24, 383–393. [Google Scholar] [CrossRef]
  10. Shanahan, R.M.; Hickey, A.; Reen, F.J.; O’Gara, F.; McGlacken, G.P. Synthesis of Benzofuroquinolines via Phosphine-Free Direct Arylation of 4-Phenoxyquinolines in Air. Eur. J. Org. Chem. 2018, 2018, 6140–6149. [Google Scholar] [CrossRef]
  11. Luo, W.R.; Yu, Z.C.; Qiu, W.W.; Yang, F.; Liu, X.F.; Tang, J. One-pot production of chiral α,β-epoxy ketones from benzaldehydes and acetophenones by recyclable poly(amino acid) catalysis. Tetrahedron 2011, 67, 5289–5292. [Google Scholar] [CrossRef]
  12. Wang, S.; Zhao, C.; Liu, T.; Yu, L.F.; Yang, F.; Tang, J. Efficient construction of 3-arylquinolin-4(1 H )-ones via in situ Meinwald rearrangement/intramolecular reductive cyclization of 2′-nitrochalcone epoxides. Tetrahedron 2016, 72, 7025–7031. [Google Scholar] [CrossRef]
  13. Hong, F.L.; Chen, Y.W.; Lu, B.L.; Cheng, J.J. One-Pot Assembly of Fused Heterocycles via Oxidative Palladium-Catalyzed Cyclization of Arylols and Iodoarenes. Adv. Synth. Catal. 2016, 358, 353–357. [Google Scholar] [CrossRef]
  14. Ji, F.H.; Li, X.W.; Wu, W.Q.; Jiang, H.F. Palladium-Catalyzed Oxidative Carbonylation for the Synthesis of Polycyclic Aromatic Hydrocarbons (PAHs). J. Org. Chem. 2014, 79, 11246–11253. [Google Scholar] [CrossRef] [PubMed]
  15. Kawase, Y.; Yamaguchi, S.; Maeda, O.; Hayashi, A.; Hayashi, I.; Tabata, K.; Kondo, M. The Synthesis of Benzofuroquinolins. I. Some Benzofuro[2,3-b]quinoline and Benzofuro[3,2-c]quinoline Derivatives. J. Heterocyclic Chem. 1979, 16, 487–491. [Google Scholar] [CrossRef]
  16. Tummatorn, J.; Krajangsri, S.; Norseeda, K.; Thongsornkleeb, C.; Ruchirawat, S. A new synthetic approach to 6-unsubstituted phenanthridine and phenanthridine-like compounds under mild and metal-free conditions. Org. Biomol. Chem. 2014, 12, 5077–5081. [Google Scholar] [CrossRef]
  17. Mehra, M.K.; Tantak, M.P.; Kumar, I.; Kumar, D. Microwave-Assisted Metal- and Ligand-Free O-Arylation of Quino- lones Using Diaryliodonium Salts: An Easy and Rapid Synthesis of Aryloxyquinolines. Synlett 2016, 27, 604–610. [Google Scholar]
  18. Bao, Y.S.; Agula, B.; Zhaorigetu, B.; Jia, M.L.; Baiyin, M.H. One pot synthesis of diarylfurans from aryl esters and PhI(OAc)2 via palladium-associated iodonium ylides. Org. Biomol. Chem. 2015, 13, 4179–4182. [Google Scholar] [CrossRef]
  19. Zhang, W.; Lun, S.C.; Liu, L.L.; Xiao, S.Q.; Duan, G.F.; Gunosewoyo, H.; Yang, F.; Tang, J.; Bishai, W.R.; Yu, L.F. Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II. J. Med. Chem. 2019, 62, 3575–3589. [Google Scholar] [CrossRef]
  20. Yamada, T.; Saito, N.; Anraku, M.; Imai, T.; Otagiri, M. Physicochemical Characterization of a New Crystal Form and Improvements in the Pharmaceutical Properties of the Poorly Water-Soluble Antiosteoporosis Drug 3,9-bis(N,N-Dimethylcarbamoy-loxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) by Solid Dispersion with Hydroxypropylcellulose. Pharm. Dev. Technol. 2000, 5, 443–454. [Google Scholar]
  21. Zhang, W.; Lun, S.C.; Wang, S.H.; Jiang, X.W.; Yang, F.; Tang, J.; Manson, A.L.; Earl, A.M.; Gunosewoyo, H.; Bishai, W.R.; et al. Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. J. Med. Chem. 2018, 61, 791–803. [Google Scholar] [CrossRef] [PubMed]
  22. Quentmeier, H.; Reinhardt, J.; Zaborski, M.; Drexler, H.G. FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 2003, 17, 120–124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Han, S.Y.; Ahn, J.H.; Shin, C.Y.; Choi, S.U. Effects of indirubin derivatives on the FLT3 activity and growth of acute myeloid leukemia cell lines. Drug Develop. Res. 2010, 71, 221–227. [Google Scholar] [CrossRef]
  24. Nemes, Z.; Takács-Novák, K.; Völgyi, G.; Valko, K.; Béni, S.; Horváth, Z.; Szokol, B.; Breza, N.; Dobos, J.; Szántai-Kis, C.; et al. Synthesis and characterization of amino acid substituted sunitinib analogues for the treatment of AML. Bioorg. Med. Chem. Lett. 2018, 28, 2391–2398. [Google Scholar] [CrossRef]
  25. Chen, H.Q.; Xie, J.; Xing, D.; Wang, J.P.; Tang, J.; Yi, Z.F.; Xia, F.; Qiu, W.W.; Yang, F. Diastereoselective synthesis of 3,3-disubstituted 3-nitro-4-chromanone derivatives as potential antitumor agents. Org. Biomol. Chem. 2019, 17, 1062–1066. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
Molecules 25 00203 g001 550
Figure 1. (a) Representative biologically active heterocycles bearing a furo[3,2-c]pyridine skeleton and (b) the proposed synthesis method for tetracyclic benzofuro[3,2-c]quinolines.
Figure 1. (a) Representative biologically active heterocycles bearing a furo[3,2-c]pyridine skeleton and (b) the proposed synthesis method for tetracyclic benzofuro[3,2-c]quinolines.
Molecules 25 00203 g001
Molecules 25 00203 sch001 550
Scheme 1. Successful synthesis of benzofuro[3,2-c]quinoline 2a from 1a via a stepwise chlorination/demethylation/cyclization.
Scheme 1. Successful synthesis of benzofuro[3,2-c]quinoline 2a from 1a via a stepwise chlorination/demethylation/cyclization.
Molecules 25 00203 sch001
Table
Table 1. Substrate scope 1.
Table 1. Substrate scope 1.
Molecules 25 00203 i001
Entry2R1R2Yield of Step 1 (%)Yield of Step 2 (%)
12aHH9888
22bH6-Me9072
32cH6-F8782
42dH5-Me8192
52eH5-OH9012
62fH5-Br9485
72gH5-Cl8875
82hH4-F8089
92iH4-Cl9586
102jH4-Me9294
112kH4-OCF38562
122lH4-OH6823
132mH3-Cl9442
142n7-MeH9585
152o8-ClH9491
162p8-MeH8683
172q8-OHH9010
182r9-FH9277
192s9-ClH9069
202t9-MeH8692
212u9-OHH8714
222v10-MeH9179
232w9-Br4-OH9717
242x9-Cl4-OH9112
1 Reaction conditions: 1 (1 mmol), SOCl2 (4 equiv.), CH2Cl2 (5 mL), 48% HBr (5 mL), 4 (1 equiv.), KOt-Bu (2 equiv.), N,N-dimethylformamide (DMF) (5 mL).
Table
Table 2. In vitro antileukemia activity of benzofuro[3,2-c]quinoline derivatives against the growth of the MV-4-11 cell line.
Table 2. In vitro antileukemia activity of benzofuro[3,2-c]quinoline derivatives against the growth of the MV-4-11 cell line.
CompoundMV-4-11 1 IC50 (μM)CompoundMV-4-11 1 IC50 (μM)
2a2.40 ± 0.302p0.40 ± 0.068
2c2.27 ± 0.332q0.24 ± 0.10
2d4.34 ± 3.402r1.15 ± 0.35
2e0.12 ± 0.0442s1.91 ± 0.16
2g3.60 ± 1.302t1.22 ± 0.26
2h>20 22u0.80 ± 0.29
2k>202v>20
2l>202x16.39 ± 10.94
2m>20Cisplatin>20
2n9.21 ± 3.20Sunitinib<0.01 3
2o2.84 ± 0.33
From the MTS assay after 72 h of treatment. 1 IC50 data is an average of at least three independent experiments. 2 >IC50 value was above the highest concentration used in the assay. 3 From Nemes et al. [24].
Table
Table 3. Cytotoxic activity of benzofuro[3,2-c]quinoline derivatives against the growth of peripheral blood mononuclear cells (PBMCs).
Table 3. Cytotoxic activity of benzofuro[3,2-c]quinoline derivatives against the growth of peripheral blood mononuclear cells (PBMCs).
CompoundPBMC 1 IC50 (μM)MV-4-11 1 IC50 (μM)SI 2
2e9.54 ± 0.0630.12 ± 0.04479.5
2p>10 30.40 ± 0.068>25
2q>100.24 ± 0.10>42
2u>100.80 ± 0.29>12.5
From the MTS assay after 72 h of treatment 1 IC50 data is an average of at least three independent experiments. 2 SI: selectivity index. 3 >IC50 value was above the highest concentration used in the assay.

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MDPI and ACS Style

Lin, Y.; Xing, D.; Wu, W.-B.; Xu, G.-Y.; Yu, L.-F.; Tang, J.; Zhou, Y.-B.; Li, J.; Yang, F. Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-c]Quinoline Derivatives as Potential Antileukemia Agents. Molecules 2020, 25, 203. https://doi.org/10.3390/molecules25010203

AMA Style

Lin Y, Xing D, Wu W-B, Xu G-Y, Yu L-F, Tang J, Zhou Y-B, Li J, Yang F. Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-c]Quinoline Derivatives as Potential Antileukemia Agents. Molecules. 2020; 25(1):203. https://doi.org/10.3390/molecules25010203

Chicago/Turabian Style

Lin, Ying, Dong Xing, Wen-Biao Wu, Gao-Ya Xu, Li-Fang Yu, Jie Tang, Yu-Bo Zhou, Jia Li, and Fan Yang. 2020. "Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-c]Quinoline Derivatives as Potential Antileukemia Agents" Molecules 25, no. 1: 203. https://doi.org/10.3390/molecules25010203

APA Style

Lin, Y., Xing, D., Wu, W. -B., Xu, G. -Y., Yu, L. -F., Tang, J., Zhou, Y. -B., Li, J., & Yang, F. (2020). Design, Synthesis, and In Vitro Evaluation of Benzofuro[3,2-c]Quinoline Derivatives as Potential Antileukemia Agents. Molecules, 25(1), 203. https://doi.org/10.3390/molecules25010203

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