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Article

One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones

by
Jiaqi Yuan
1,2,
Qian He
1,
Shanshan Song
1,
Xiaofei Zhang
1,*,
Zehong Miao
1 and
Chunhao Yang
1,2,*
1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
2
School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(16), 3017; https://doi.org/10.3390/molecules24163017
Submission received: 25 July 2019 / Revised: 10 August 2019 / Accepted: 16 August 2019 / Published: 20 August 2019
(This article belongs to the Collection Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities.

Graphical Abstract

1. Introduction

Anthraquinone, as a classical pharmacophore, has been applied in drug discovery for many years, [1,2,3] and this scaffold contributes to a great number of important drugs, such as Mitoxantrone [4], Doxorubicin [5], and Daunorubicin [6]. Aza-anthraquinones are crucial analogues of anthraquinones, which have attracted considerable attention for their pronounced biological activities (Figure 1) [7,8,9]. For example, Marcanine A was first isolated from the stem bark of Goniothalamus marcanii in 1999 and was proved to have significant cytotoxicity against human tumor cell lines [10,11]. Kalasinamide was discovered in Polyalthia suberosa in 2000 and turned out to be a mild anti-HIV agent. [8,12]
As far as we know, there are some synthetic routes that have been elaborated to construct 1-aza-anthraquinones, such as Diels–Alder reactions [13,14,15,16], Friedel–Crafts reactions [17,18], Michael-type addition followed by ring expansion [19,20], and 6-exo-trig radical cyclization of N-(2-alkenylaryl)-substituted enamines [21]. Despite the great potential of these methods, the use of toxic metal agents, inconvenient availability of starting materials, as well as poor regioselectivity and low yields of these reactions limited their wide applications. Recently, Yao et al. developed a range of methods to assemble 1-aza-anthraquinone skeleton from N-propargylamino quinone through a 6-endo-dig electrophilic cyclization (Figure 2) [22,23,24]. Gogoi et al. reported a sequential Pd-catalyzed C-N bond formation, followed by intramolecular cyclization to synthesize 1-aza-anthraquinones [25]. These methods are efficient strategies to assemble 1-aza-anthraquinone scaffold with regioselectivity and good yields. Meanwhile, the preparation of N-propargylamino quinone and 2-Benzoyl-3-halonaphthalene-1,4-diones, which were catalyzed by expensive transition metal, limited the application of these methods in a sense [24,25]. Therefore, a new practical and convenient approach for 1-aza-anthraquinone is still highly desired.
Our lab has been focusing on the construction of nitrogen-containing heterocyclic frameworks derived from chromones for several years [26,27,28,29,30,31]. Previously, one synthetic compound YCH337 prepared from chromone was found to be a potent anti-proliferation agent against tumor cells with an averaged IC50 of 0.3 µM by targeting both microtubule and Topoisomerase 2 (Figure 1) [32]. Inspired by our previous works and great enthusiasm on the converged structure of YCH337 and potential bioactive 1-aza-anthraquinone scaffold, we designed and synthesized novel tricyclic 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives as YCH337 analogues.

2. Results and Discussion

3-Formylchromones are representative building blocks, which are usually employed to prepare varieties of heterocyclic systems with enamine-type compounds [33,34,35,36,37,38]. Accordingly, we chose 3-formylchromone (1a) and 2-amino-naphthalene-1,4-dione (2a) as the template substrates to optimize the reaction conditions (Table 1). Surprisingly, the initial attempt gave the targeting product 3a with 35% yield after stirring in acetic acid for 24 h at 80 °C (Table 1, entry 1). Based on this result, different reaction temperatures were examined (Table 1, entries 1 to 3). By the increasing reaction temperature, the yield was remarkably improved and the reaction time was shortened to 4 h under reflux. Then, a variety of solvents were screened for the reaction and the results showed that acetic acid was superior to other solvents (Table 1, entries 4 to 8). In addition, further investigations were conducted on the ratio of reactants, finding that 1.2 eq of 3-formylchromone gave a better yield (Table 1, entry 3, entries 9 to 12). Therefore, after the screening of the temperature, solvent, and reagents’ ratio, the optimized reaction conditions were established (Table 1, entry 10).
With the optimized reaction conditions in hand, we next explored the substrates’ scope and the generality of the reaction with different 3-formylchromones. To our delight, this protocol was applicable to a series of 3-formylchromones under the optimized reaction conditions, providing the corresponding products 3a–3t with moderate to excellent yields (Table 2, 40–95%). All substituted 3-formylchromones with electron-donating groups (methyl, methoxyl groups) or electron-withdrawing groups (chloro, bromo, fluoro, cyano, and nitro groups) could be transformed into the desired compounds (3a–3q, 40–90%). When there was an electron-donating group on C6-position of 3-formylchromones, the yield was decreased (3m, 3q vs. 3a). Meanwhile, the electron-donating mono-methoxyl group on 3-formylchromones were suitable substrates, affording the corresponding products in excellent yields (3j–3l, 82–85%). Then, several di-substituted 3-formylchromones were also investigated and gave good results (3g, 3n–3p, 40–75%). Interestingly, we found that two electron-donating groups on the benzene ring gave lower yields (3n, 3p vs. 3g, 3o). Notably, naphthyl-substituted 3-formylchromones were well-tolerated under the optimized reaction conditions, which afforded the desired products excellent yields up to 95% (3r, 3s). To further explore the substrate scope of this protocol, 2-amino-6,7-dimethoxynaphthalene-1,4-dione was also employed in this reaction, and successfully provided the corresponding product with a good yield (3t, 68%). The single crystal structure of 3t as trifluoroacetic acid salt hydrate was confirmed by X-ray crystallographic analysis (Figure 3).
Based on the isomerization of 2-amino-naphthalene-1,4-dione, we proposed two possible mechanisms (Scheme 1). In path A, the reaction initiates nucleophilic attack of 3-formylchromone by the nitrogen atom of 2a to give intermediate A. Then, intramolecular nucleophilic substitution of A generates intermediate B, which terminates by ring cleavage and aromatization to give the final product 3a. In path B, the C3-position of 2a becomes more nucleophilic than the nitrogen atom because of the conjugative effect. Subsequently, like path A, after intramolecular nucleophilic substitution, ring cleavage, and aromatization, the final product 3a was obtained.
Subsequently, some products were evaluated for anti-proliferative activity against human cervical cancer cell line Hela and colon cancer cell line HT-29 (Table 3). Some compounds displayed moderate to good anti-proliferation activity (such as 3j, 3l, 3n, 3p, 3q). Although these compounds were less potent than YCH337 and CA-4 to the Hela cells, compound 3q exhibited potent antiproliferative activity towards HT-29 cells.

3. Materials and Methods

3.1. General Information

All reagents were purchased from commercial suppliers and used without further purification. The progress of all of the reactions was monitored by thin layer chromatography with standard TLC silica gel plates, and the developed plates were visualized under UV light. All of the compounds were purified by column chromatography. Chromatography was performed on silica gel (100–200 mesh). Nuclear magnetic resonance spectra (1H, 13C NMR) were recorded on Varian Mercury-300/400 and Varian Mercury-400/500 spectrometers and TFA-d was used as the solvent. NMR peaks were calibrated by reference to standard peaks of TFA at 11.50 ppm for 1H and 116.60 and 164.20 ppm for 13C. For peak descriptions, the following abbreviations were used: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), pt (pseudo-triplet), ddd (double of doublets of doublets). EI-HRMS were recorded using a Thermo DFS mass spectrometer. The NMR spectra of the obtained compounds and some additional experimental details can be found in the Supplementary Materials.

3.2. Crystal Structure Determination of Compound 3t

CCDC 1921125 contains the supplementary crystallographic data for compound 3t. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk.
Crystal Data for C24H18F3NO9 (M = 521.39 g/mol): Orthorhombic, space group P212121 (no. 19), a = 4.8001(2) Å, b = 16.6714(8) Å, c = 27.6470(14) Å, V = 2212.43(18) Å3, Z = 4, T = 100.15 K, μ(MoKα) = 0.136 mm-1, Dcalc = 1.565 g/cm3, 23769 reflections measured (4.886° ≤ 2Θ ≤ 52.826°), 4503 unique (Rint = 0.0380, Rsigma = 0.0290), which were used in all calculations. The final R1 was 0.0393 (I > 2σ(I)) and wR2 was 0.1206 (all data).

3.3. General Procedure for the Synthesis of Compounds 1a–1t

To a cooled (0 °C) solution of 2’-hydroxyacetophenone (1 g, 1 eq) in DMF (30 mL), phosphorus oxychloride (5 eq) was added. The mixture was stirred at 64 °C for 4 h until the 2’-hydroxyacetophenone was consumed completely (TLC). The reaction was quenched with glacial water (100 mL), and the mixture was stirred for an additional 30 min. Then, the mixture was extracted three times with dichloromethane (100 mL). The solvent was evaporated in vacuo and the crude product was purified by column chromatography on silica gel.

3.4. General Procedure for 2-Amino-naphthalene-1,4-dione(2a)

To a cooled (0 °C) solution of hydroxylamine hydrochloride (1.8 g, 2 eq) in EtOH (100 mL), NEt3 was added (5.3 mL, 3 eq). To the well stirred mixture, an ethanol solution (20 mL) of 1,4-naphthoquinone (2.0 g, 1 eq) was added dropwise. The mixture was stirred at room temperature for an additional 2 h until 1,4-naphthoquinone was consumed (TLC). The mixture was diluted with water (100 mL), and extracted three times with dichloromethane (30 mL). The organic phase was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel.

3.5. General Procedure for the Synthesis of Compounds 3a–3t

To a solution of 2-amino-naphthalene-1,4-dione (0.5 mmol, 1 eq) in AcOH (6 mL), 3-formylchromone (0.6 mmol, 1.2 eq) was added. The resulting reaction mixture was heated to reflux for 4 h. Upon completion (determined by TLC), the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted three times with dichloromethane (10 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel. Several compounds were collected by filtration for poor solubility.
3-(2-Hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3a). Brown solid (136 mg, 83%). 1H NMR (500 MHz, TFA-d) δ 9.78 (d, J = 5.4 Hz, 1H), 9.71 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 6.6 Hz, 2H), 8.21–8.10 (m, 2H), 7.81 (t, J = 7.3 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.1 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 194.56, 179.95, 176.94, 163.62, 148.86, 147.38, 143.09, 142.88, 141.51, 139.48, 138.56, 133.88, 133.21, 132.90, 130.58, 130.43, 123.14, 120.58. HRMS (EI+): Calcd. for C20H11NO4 [M]+ 329.0688, found: 329.0685.
3-(5-Fluoro-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3b). Brown solid (139 mg, 80%). 1H NMR (500 MHz, TFA-d) δ 9.78 (d, J = 2.0 Hz, 1H), 9.72 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 6.9 Hz, 2H), 8.21–8.11 (m, 2H), 7.56–7.50 (m, 1H), 7.31–7.25 (m, 2H). 13C NMR (125 MHz, TFA-d) δ 194.00, 180.36, 177.39, 160.29, 158.43 (d, J = 243.2 Hz), 149.43, 147.66, 143.68, 142.90, 139.92, 139.00, 134.29, 133.67, 133.33, 131.01, 130.86, 129.27 (d, J = 24.3 Hz), 122.77 (d, J = 7.4 Hz), 119.84 (d, J = 6.7 Hz), 118.75 (d, J = 24.6 Hz). HRMS (EI+): Calcd. for C20H10FNO4 [M]+ 347.0594, found: 347.0579.
3-(5-Chloro-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3c). Brown solid (140 mg, 77%). 1H NMR (500 MHz, TFA-d) δ 9.78 (d, J = 3.8 Hz, 1H), 9.72 (d, J = 4.6 Hz, 1H), 8.57 (d, J = 7.2 Hz, 2H), 8.22–8.11 (m, 2H), 7.76–7.68 (m, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.27–7.21 (m, 1H). 13C NMR (125 MHz, TFA-d) δ 194.01, 180.40, 177.39, 162.61, 149.38, 147.66, 143.68, 142.92, 141.43, 139.92, 139.01, 134.29, 133.72, 133.33, 132.93, 131.02, 130.87, 128.80, 122.62, 120.84. HRMS (EI+): Calcd. for C20H10ClNO4 [M]+ 363.0298, found: 363.0282.
3-(5-Bromo-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3d). Brown solid (184 mg, 90%). 1H NMR (400 MHz, TFA-d) δ 9.78 (d, J = 2.0 Hz, 1H), 9.72 (d, J = 2.0 Hz, 1H), 8.61–8.54 (m, 2H), 8.22–8.10 (m, 2H), 7.86 (dt, J = 9.1, 2.0 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 193.95, 180.43, 177.39, 163.06, 149.37, 147.66, 144.29, 143.68, 142.93, 139.92, 139.02, 136.07, 134.29, 133.73, 133.34, 131.02, 130.88, 122.85, 121.46, 115.02. HRMS (EI+): Calcd. for C20H10BrNO4 [M]+ 406.9793, found: 406.9777.
3-(4-Fluoro-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3e). Brown solid (136 mg, 78%). 1H NMR (500 MHz, TFA-d) δ 9.73 (d, J = 3.8 Hz, 1H), 9.70 (d, J = 4.0 Hz, 1H), 8.57 (t, J = 4.3 Hz, 2H), 8.20–8.11 (m, 2H), 7.72–7.56 (m, 1H), 7.00–6.93 (m, 1H), 6.85 (d, J = 7.3 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 193.72, 180.39, 177.36, 172.19 (d, J = 264.0 Hz), 167.67 (d, J = 14.9 Hz), 149.25, 147.52, 143.56, 143.28, 139.91, 139.00, 137.13 (d, J = 12.8 Hz), 134.28, 133.66, 133.33, 131.01, 130.86, 117.11, 111.89 (d, J = 23.8 Hz), 107.99 (d, J = 24.9 Hz). HRMS (EI+): Calcd. for C20H10FNO4 [M]+ 347.0594, found: 347.0585.
3-(4-Bromo-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3f). Brown solid (145 mg, 71%). 1H NMR (600 MHz, TFA-d) δ 9.75 (d, J = 1.7 Hz, 1H), 9.69 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.20–8.12 (m, 2H), 7.49 (d, J = 1.7 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.30 (dd, J = 8.7, 1.7 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 194.28, 180.40, 177.37, 149.33, 147.59, 143.63, 143.11, 139.91, 139.01, 137.53, 134.82, 134.28, 133.66, 133.34, 131.01, 130.87, 127.06, 124.53, 118.87. HRMS (EI+): Calcd. for C20H10BrNO4 [M]+ 406.9793, found: 406.9792.
3-(3,5-Dichloro-2-hydroxybenzoyl)benzo[g]quinoline-5,10-dione (3g). Brown solid (129 mg, 65%). 1H NMR (500 MHz, TFA-d) δ 9.79 (d, J = 4.5 Hz, 1H), 9.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 7.3 Hz, 2H), 8.24–8.07 (m, 2H), 7.81 (d, J = 4.3 Hz, 1H), 7.56 (t, J = 3.3 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 192.96, 180.38, 177.39, 156.88, 149.50, 147.75, 143.84, 142.61, 139.92, 139.81, 139.01, 134.26, 133.72, 133.33, 131.69, 131.00, 130.86, 128.86, 126.91, 122.27. HRMS (EI+): Calcd. for C20H9Cl2NO4 [M]+ 396.9909, found: 396.9899.
3-(2-Hydroxy-5-nitrobenzoyl)benzo[g]quinoline-5,10-dione (3h). Brown solid (133 mg, 71%). 1H NMR (600 MHz, TFA-d) δ 9.81 (d, J = 1.8 Hz, 1H), 9.78 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.61 (dd, J = 9.5, 2.8 Hz, 1H), 8.60–8.56 (m, 2H), 8.20–8.13 (m, 2H), 7.42 (d, J = 9.3 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 193.87, 180.48, 177.45, 169.64, 149.64, 147.52, 144.06, 142.31, 142.26, 139.93, 139.06, 135.01, 134.29, 133.87, 133.37, 131.05, 130.89, 130.87, 122.58, 119.69. HRMS (EI+): Calcd. for C20H10N2O6 [M]+ 374.0539, found: 374.0534.
3-(5,10-Dioxo-5,10-dihydrobenzo[g]quinoline-3-carbonyl)-4-hydroxybenzonitrile (3i). Brown solid (120 mg, 68%). 1H NMR (600 MHz, TFA-d) δ 9.78 (d, J = 1.8 Hz, 1H), 9.76 (d, J = 1.8 Hz, 1H), 8.57 (td, J = 6.5, 5.7, 1.3 Hz, 2H), 8.16 (ddd, J = 9.4, 7.3, 1.5 Hz, 2H), 8.13 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 8.9, 2.0 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 193.47, 180.40, 177.43, 167.97, 149.72, 147.48, 143.95, 142.82, 142.31, 139.93, 139.78, 139.03, 134.27, 133.71, 133.34, 131.03, 130.87, 122.88, 121.05, 104.89. HRMS (EI+): Calcd. for C21H10N2O4 [M]+ 354.0641, found: 354.0636.
3-(2-Hydroxy-5-methoxybenzoyl)benzo[g]quinoline-5,10-dione (3j). Brown solid (153 mg, 85%). 1H NMR (600 MHz, TFA-d) δ 9.79 (d, J = 1.7 Hz, 1H), 9.73 (d, J = 1.8 Hz, 1H), 8.60–8.56 (m, 2H), 8.18 (td, J = 7.6, 1.6 Hz, 1H), 8.14 (td, J = 7.6, 1.6 Hz, 1H), 7.54 (dd, J = 9.3, 3.0 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 3.96 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 194.45, 180.40, 177.37, 158.75, 154.35, 149.35, 147.91, 143.43, 143.04, 139.93, 138.98, 134.30, 133.68, 133.30, 131.04, 130.85, 128.34, 122.32, 120.31, 119.65, 58.52. HRMS (EI+): Calcd. for C21H13NO5 [M]+ 359.0794, found: 359.0786.
3-(2-Hydroxy-4-methoxybenzoyl)benzo[g]quinoline-5,10-dione (3k). Brown solid (150 mg, 84%). 1H NMR (500 MHz, TFA-d) δ 9.72 (d, J = 1.7 Hz, 1H), 9.67 (d, J = 1.8 Hz, 1H), 8.59–8.55 (m, 2H), 8.15 (td, J = 7.1, 1.6 Hz, 2H), 7.47 (d, J = 9.1 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 9.1, 2.4 Hz, 1H), 4.03 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 192.61, 180.44, 177.36, 172.06, 168.41, 149.00, 147.55, 143.62, 143.32, 139.90, 138.99, 136.50, 134.30, 133.65, 133.32, 131.01, 130.86, 114.14, 112.71, 103.94, 57.51. HRMS (EI+): Calcd. for C21H13NO5 [M]+ 359.0794, found: 359.0780.
3-(2-Hydroxy-6-methoxybenzoyl)benzo[g]quinoline-5,10-dione (3l). Brown solid (148 mg, 82%). 1H NMR (500 MHz, TFA-d) δ 9.63 (s, 1H), 9.54 (s, 1H), 8.56 (d, J = 7.3 Hz, 2H), 8.19–8.09 (m, 2H), 7.76–7.67 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 3.68 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 193.46, 180.58, 177.39, 162.57, 148.24, 146.85, 146.57, 142.65, 142.54, 139.83, 138.92, 134.29, 133.38, 133.29, 130.96, 130.78, 115.89, 111.61, 105.59, 57.17. HRMS (EI+): Calcd. for C21H13NO5 [M]+ 359.0794, found: 359.0786.
3-(2-Hydroxy-5-methylbenzoyl)benzo[g]quinoline-5,10-dione (3m). Brown solid (127 mg, 74%). 1H NMR (400 MHz, TFA-d) δ 9.77 (s, 1H), 9.71 (s, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.22–8.09 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 7.21 (dd, J = 8.6, 2.0 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 194.98, 180.42, 177.36, 161.82, 149.24, 147.73, 143.45, 143.27, 139.91, 139.00, 134.41, 134.30, 133.68, 133.62, 133.33, 131.01, 130.86, 120.78, 119.86, 20.74. HRMS (EI+): Calcd. for C21H13NO4 [M]+ 343.0845, found: 343.0838.
3-(2-Hydroxy-4,5-dimethylbenzoyl)benzo[g]quinoline-5,10-dione (3n). Brown solid (97 mg, 54%). 1H NMR (400 MHz, TFA-d) δ 9.77 (d, J = 2.3 Hz, 1H), 9.70 (d, J = 2.3 Hz, 1H), 8.58 (dt, J = 7.3, 2.2 Hz, 2H), 8.22–8.11 (m, 2H), 7.28 (s, 1H), 7.12 (s, 1H), 2.45 (d, J = 2.8 Hz, 3H), 2.27 (d, J = 2.7 Hz, 3H). 13C NMR (125 MHz, TFA-d) δ 194.28, 180.43, 177.35, 162.50, 155.37, 149.11, 147.70, 143.60, 143.37, 139.90, 138.99, 134.30, 134.07, 133.67, 133.61, 133.32, 131.00, 130.85, 121.44, 118.02, 21.46, 19.28. HRMS (EI+): Calcd. for C22H15NO4 [M]+ 357.1001, found: 357.1001.
3-(5-Chloro-2-hydroxy-4-methylbenzoyl)benzo[g]quinoline-5,10-dione (3o). Brown solid (142 mg, 75%). 1H NMR (400 MHz, TFA-d) δ 9.78 (d, J = 1.9 Hz, 1H), 9.71 (d, J = 2.0 Hz, 1H), 8.60–8.54 (m, 2H), 8.21 − 8.11 (m, 2H), 7.52 (s, 1H), 7.20 (s, 1H), 2.53 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 193.58, 180.45, 177.38, 162.69, 153.15, 149.28, 147.63, 143.59, 143.10, 139.92, 139.02, 134.29, 133.71, 133.42, 133.33, 131.02, 130.87, 129.47, 122.92, 119.03, 21.72. HRMS (EI+): Calcd. for C21H12ClNO4 [M]+ 377.0455, found: 377.0447.
3-(2-Hydroxy-4,5-dimethoxybenzoyl)benzo[g]quinoline-5,10-dione (3p). Brown solid (78 mg, 40%). 1H NMR (600 MHz, TFA-d) δ 9.76 (s, 1H), 9.72 (s, 1H), 8.61–8.54 (m, 2H), 8.17 (t, J = 7.4 Hz, 1H), 8.14 (t, J = 7.4 Hz, 1H), 7.10 (s, 1H), 6.88 (s, 1H), 4.11 (s, 3H), 3.90 (s, 3H). 13C NMR (125 MHz, TFA-d) δ 192.10, 180.42, 177.39, 164.78, 162.56, 149.26, 147.37, 144.83, 143.67, 143.35, 139.87, 138.97, 134.27, 133.65, 133.34, 130.99, 130.84, 116.51, 112.44, 103.41, 59.17, 57.98. HRMS (EI+): Calcd. for C22H15NO6 [M]+ 389.0899, found: 389.0891.
3-(2-Hydroxy-5-morpholinobenzoyl)benzo[g]quinoline-5,10-dione (3q). Brown solid (142 mg, 69%). 1H NMR (400 MHz, TFA-d) δ 9.81 (s, 1H), 9.76 (s, 1H), 8.59 (d, J = 6.5 Hz, 2H), 8.22–8.12 (m, 3H), 8.05 (d, J = 9.4 Hz, 1H), 7.51 (d, J = 9.3 Hz, 1H), 4.42 (s, 4H), 4.00 (s, 4H). 13C NMR (125 MHz, TFA-d) δ 192.44, 180.52, 177.44, 149.90, 147.56, 143.92, 142.24, 139.97, 139.06, 134.91, 134.26, 133.64, 133.33, 131.33, 131.14, 130.89, 127.20, 124.13, 121.87, 66.56, 58.28. HRMS (EI+): Calcd. for C24H18N2O5 [M]+ 414.1216, found: 414.1212.
3-(2-Hydroxy-1-naphthoyl)benzo[g]quinoline-5,10-dione (3r). Brown solid (181 mg, 95%). 1H NMR (600 MHz, TFA-d) δ 9.75 (d, J = 1.8 Hz, 1H), 9.62 (d, J = 1.8 Hz, 1H), 8.53 (dd, J = 7.4, 1.6 Hz, 1H), 8.51 (dd, J = 7.4, 1.6 Hz, 1H), 8.16–8.09 (m, 3H), 7.90 (dd, J = 7.1, 2.2 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.46 (tt, J = 7.1, 5.4 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H). 13C NMR (150 MHz, TFA-d) δ 193.30, 180.41, 177.33, 161.62, 149.80, 148.43, 144.72, 143.24, 141.23, 139.88, 138.92, 134.23, 133.77, 133.41, 133.25, 131.67, 131.59, 131.52, 130.97, 130.78, 127.67, 125.92, 119.75, 115.50. HRMS (EI+): Calcd. for C24H13NO4 [M]+ 379.0845, found: 379.0812.
3-(1-Hydroxy-2-naphthoyl)benzo[g]quinoline-5,10-dione (3s). Brown solid (175 mg, 92%). 1H NMR (400 MHz, TFA-d) δ 9.81 (s, 1H), 9.74 (s, 1H), 8.57 (t, J = 6.6 Hz, 3H), 8.21– 8.09 (m, 2H), 7.83 (d, J = 6.3 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz, TFA-d) δ 193.82, 180.41, 177.37, 168.46, 149.07, 147.72, 143.85, 143.23, 141.06, 139.90, 138.98, 134.96, 134.29, 133.60, 133.32, 131.00, 130.85, 129.93, 129.52, 126.89, 126.77, 125.74, 123.05, 113.45. HRMS (EI+): Calcd. for C24H13NO4 [M]+ 379.0845, found: 379.0829.
3-(2-Hydroxybenzoyl)-7,8-dimethoxybenzo[g]quinoline-5,10-dione (3t). Brown solid (132 mg, 68%). 1H NMR (500 MHz, TFA-d ) δ 9.71 (s, 1H), 9.63 (s, 1H), 8.04 (s, 1H), 8.03 (s, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 4.25 (d, J = 3.3 Hz, 6H). 13C NMR (125 MHz, TFA-d) δ 195.04, 179.45, 175.96, 164.04, 158.82, 157.82, 148.49, 147.32, 143.89, 143.09, 141.92, 134.31, 133.64, 130.31, 128.93, 123.55, 121.00, 120.03, 112.03, 111.60, 58.36. HRMS (EI+): Calcd. for C22H15NO6 [M]+ 389.0899, found: 389.0885.

4. Conclusions

We have developed a facile, efficient, and mild synthetic strategy to assemble 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives from 3-formylchromones and 2-amino-naphthalene-1,4-dione. Most of the substrates bearing diverse substituents worked well with this procedure, and a great variety of 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives were successfully obtained in moderate to excellent yields, which are potentially useful skeletons in pharmaceutical discovery research. Moreover, this reaction could proceed without metal catalysis and be insensitive to air and moisture.

Supplementary Materials

The NMR spectra of the obtained compounds and some additional experimental details are available online.

Author Contributions

Conceptualization, C.Y.; methodology, J.Y. and X.Z.; chemical experiments, J.Y.; inspiration and discussions, J.Y., X.Z., and C.Y.; data curation, Q.H. and S.S.; writing—original draft preparation, J.Y.; writing—review and editing, X.Z., Z.M., and C.Y.

Funding

This study was funded by grants from the Science and Technology Commission of Shanghai Municipality (18431907100), Shanghai Sailing Program (17YF1423400), and SKLDR/SIMM (SIMM1903ZZ-03).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 1a–1t and 3a–3t are available from the authors.
Molecules 24 03017 g001 550
Figure 1. Biologically active aza-anthraquinone derivatives and YCH337.
Figure 1. Biologically active aza-anthraquinone derivatives and YCH337.
Molecules 24 03017 g001
Molecules 24 03017 g002 550
Figure 2. Different strategies to synthesize 1-aza-anthraquinone derivatives.
Figure 2. Different strategies to synthesize 1-aza-anthraquinone derivatives.
Molecules 24 03017 g002
Molecules 24 03017 g003 550
Figure 3. The single crystal structure of 3t.
Figure 3. The single crystal structure of 3t.
Molecules 24 03017 g003
Molecules 24 03017 sch001 550
Scheme 1. Proposed Mechanisms.
Scheme 1. Proposed Mechanisms.
Molecules 24 03017 sch001
Table
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 24 03017 i001
EntryRatio
(2a:1a)		SolventTemp
(°C)		Time
(h)		Yield b
(%)
11:1.1AcOH802435
21:1.1AcOH1001967
31:1.1AcOHReflux476
41:1.1DMF12024n.d. c
51:1.1DMSO1202432
61:1.1Propionic acid1201970
71:1.11,4-dioxaneReflux24n.d. c
81:1.1AcOH:Et3N
(1:1)		1002448
91:1AcOHReflux471
101:1.2AcOHReflux483
111:1.3AcOHReflux470
121:1.5AcOHReflux477
a Reaction conditions: 2 (0.50 mmol, 87 mg), solvent (6.0 mL). b Isolated yield. c n.d. = not detected.
Table
Table 2. Scope of the target compounds a, b.
Table 2. Scope of the target compounds a, b.
Molecules 24 03017 i002
Molecules 24 03017 i003
a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), and AcOH (6.0 mL) in air refluxed for 4 h. b Isolated yields. c 1a (0.6 mmol), 2-amino-6,7-dimethoxynaphthalene-1,4-dione (0.5 mmol) was used.
Table
Table 3. Anti-proliferation activity of selected compounds a.
Table 3. Anti-proliferation activity of selected compounds a.
CompdIC50 [μM] b,c
HelaHT-29
3q1.990.018
3p4.692.26
3j7.984.15
3n-4.41
3l12.811.27
CA-40.78 (nM)0.74
YCH3370.0280.063
a The experiments were assessed by SRB assay. b Exposure time: 72 h. c The average IC50 values were determined by at least three independent tests.

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MDPI and ACS Style

Yuan, J.; He, Q.; Song, S.; Zhang, X.; Miao, Z.; Yang, C. One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones. Molecules 2019, 24, 3017. https://doi.org/10.3390/molecules24163017

AMA Style

Yuan J, He Q, Song S, Zhang X, Miao Z, Yang C. One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones. Molecules. 2019; 24(16):3017. https://doi.org/10.3390/molecules24163017

Chicago/Turabian Style

Yuan, Jiaqi, Qian He, Shanshan Song, Xiaofei Zhang, Zehong Miao, and Chunhao Yang. 2019. "One Pot and Metal-Free Approach to 3-(2-Hydroxybenzoyl)-1-aza-anthraquinones" Molecules 24, no. 16: 3017. https://doi.org/10.3390/molecules24163017

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