An efficient synthesis of acridine-aza-anthraquinone hybrid compounds under microwave irradiation

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The efficient synthesis of 12-substituted-3,4,4a,5,12,12a-hexahydrobenzo[b]acridine-1,6,11(2H)-triones starting from 2-amino-1,4-naphthoquinone, 1,3-cyclohexanedione, and different (hetero)aromatic aldehydes was developed. These reactions were carried out in acetic acid under microwave irradiation in the presence of p-toluenesulfonic acid as catalyst. The structure of the newly synthesized compounds were confirmed employing spectroscopic data as well as elemental analysis. The plausible mechanism of these three-component domino reactions was also described.

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Nội dung Text: An efficient synthesis of acridine-aza-anthraquinone hybrid compounds under microwave irradiation

Cite this paper: Vietnam J. Chem., 2023, 61(2), 262-268 Research article DOI: 10.1002/vjch.202200164 An efficient synthesis of acridine-aza-anthraquinone hybrid compounds under microwave irradiation Dang Thi Tuyet Anh1,2, Le Nhat Thuy Giang1,2*, Nguyen Van Tuyen1,2, Nguyen Thi Quynh Giang1,2, Nguyen Ha Thanh1,2** 1 Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 10000, Viet Nam 2 Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 10000, Viet Nam Submitted August 29, 2022; Received September 29, 2022; Accepted November 8, 2022 Abstract The efficient synthesis of 12-substituted-3,4,4a,5,12,12a-hexahydrobenzo[b]acridine-1,6,11(2H)-triones starting from 2-amino-1,4-naphthoquinone, 1,3-cyclohexanedione, and different (hetero)aromatic aldehydes was developed. These reactions were carried out in acetic acid under microwave irradiation in the presence of p-toluenesulfonic acid as catalyst. The structure of the newly synthesized compounds were confirmed employing spectroscopic data as well as elemental analysis. The plausible mechanism of these three-component domino reactions was also described. Keywords. 2-Amino-1,4-naphthoquinone, benzo[b]acridine, multicomponent domino reaction. 1. INTRODUCTION well as cytotoxic effect.[6] Clestophiline, marcanine A, and pixantrone (figure 1) are representatives of The nitrogen heterocyclic compounds have attracted this class of compounds. the interest of scientists due to their remarkably On the other hand, acridine and its derivatives biological properties. Aza-anthraquinones, one of constitute well-known classes of bioactive the most abundant chemical classes of natural and compounds with biological properties, including synthesized nitrogen-containing heterocycles, which antitumor,[7,8] antibacterial,[9] and antileukemic have known as intercalating DNA binding agents in activities.[10] Several benzoacridine derivatives can cancer chemotherapy due to the planar structure.[1,2] be proved as tubulin polymerization inhibitiors.[11] Besides that, aza-anthraquinone derivatives have Aminacrine, euflavine, porflavine (figure 1) have also exhibited significant antibiotic[3], already approved as antibacterial drugs and have antimicrobial , anti-inflammatory activities[5] as [4] been available in the market for many years.[12] Figure 1: Some bioactive aza-anthraquinone and acridine derivatives 262 Wiley Online Library © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
25728288, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200164 by Readcube (Labtiva Inc.), Wiley Online Library on [02/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Le Nhat Thuy Giang et al. Although heterocycles having aza-anthraquinone the reaction mixture. The resulting mixture was and benzoacridine moieties are a great of interest, extracted with dichloromethane (3×20 mL), washed the hybridization of these two scaffolds into one with brine (3×10 mL), dried over Na2SO4, single molecules have rarely been studied.[13,14] In concentrated, and purified by column that respect, in our ongoing program for the chromatography using a CH2Cl2/EtOAc (95:5 v/v) to development of novel bioactive agents based on yield pure compounds 4a-k. nitrogen-containing heterocycles, herein we reported an efficient synthesis of novel 12-substituted- 12-Phenyl-3,4,4a,5,12,12a-hexahydro 3,4,4a,5,12,12a-hexahydrobenzo[b]acridine- benzo[b]acridine-1,6,11(2H)-trione (4a). Reaction 1,6,11(2H)-triones derivatives 4a-k via microwave- time 20 min. Yield 91 mg (76 %), purple solid, mp. assisted three-component reactions starting from 2- 307-308 °C. IR (KBr) 3334, 3069, 3032, 2936, amino-naphthoquinone, 1,3-cyclohexanedione and 1668, 1637, 1590, 1484, 1386, 1346, 1303, 1230, various (hetero)aromatic aldehydes. 1202, 1159, 1132, 998, 942, 773 cm-1. 1H NMR (DMSO-d6, 500 MHz): δ 9.91 (1H, s, NH), 8.02 2. MATERIALS AND METHODS (1H, dd, J = 1.2 Hz, J = 7.8 Hz), 7.91 (1H, dd, J = 1.2 Hz, J = 7.8 Hz), 7.81 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.77 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.25 (2H, 2.1. Method dd, J = 1.2 Hz, J = 7.8 Hz), 7.20 (2H, t, J = 7.8 Hz), 7.09 (1H, t, J = 7.2 Hz), 5.24 (1H, s, CH), 2.86 (dt, J Reactions were performed in an Anton Paar = 17.4 Hz, J = 4.8 Hz), 2.65-2.60 (1H, m), 2.33-2.24 Microwave Synthetic Reactor Monowave 400. All (2H, m), 1.99-1.93 (1H, m), 1.86-1.79 (1H, m). 13C reagents and solvents were purchased from Aldrich NMR (DMSO-d6, 150 MHz): δ 194.9 (C-1), 182.1 or Merck unless noted otherwise. Solvents for (C-11), 179.5 (C-6), 151.7, 145.7, 138.2, 134.7, reactions were dried and distilled by standard 133.2, 131.8, 130.2, 128.1 (2C), 127.8 (2C), 126.2, methods. Solvents for liquid chromatography and 125.8, 125.6, 119.0, 111.4, 36.8 (C-12), 33.2, 26.2, extraction were distilled prior to use. Silica gel 20.7. HRMS (ESI+) m/z [M+H]+ calcd. for: (60Å, particle size 40-60 µm) was used for column C23H18NO3: 356.1287, found: 356.1258. chromatography. Solvent systems were determined via initial TLC analysis on glass-backed silica plates 12-(p-Tolyl)-3,4,4a,5,12,12a- (Merck Kieselgel 60 with F254 indicator, precoated hexahydrobenzo[b]acridine-1,6,11(2H)-trione 0.25 mm). IR analysis was recorded on a Perkin (4b). Reaction time 30 min. Yield 96 mg (78 %), Elmer Spectrum Two spectrometer in KBr pellet. 1H purple solid, mp. 290-291 °C. IR (KBr) 3336, 2939, NMR and 13C NMR spectra were recorded on a 2889, 1666, 1605, 1637, 1589, 1482, 1385, 1350, Bruker Avance III spectrometer (600 and 150 MHz) 1302, 1232, 1203, 1134, 998, 937, 722 cm-1. 1H using deuterated solvents and tetramethylsilane NMR (DMSO-d6, 500 MHz): δ 9.87 (1H, s, NH), (TMS) as internal standard. HRMS was recorded on 8.02 (1H, dd, J = 1.2 Hz, J = 7.8 Hz), 7.91 (1H, dd, J SCIEX X500 QTOF system. Melting points were = 1.2 Hz, J = 7.8 Hz), 7.82 (1H, td, J = 7.2 Hz, J = measured using a Buchi Melting Point B-545. 1.2 Hz), 7.78 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.4 Hz), 5.19 2.2. Synthesis (1H, s, CH), 2.84 (dt, J = 17.4 Hz, J = 4.8 Hz), 2.63- 2.58 (1H, m), 2.28-2.25 (2H, m), 2.18 (3H, s, CH3), A vial containing a mixture of 2-amino-1,4- 1.97-1.93 (1H, m), 1.83-1.78 (1H, m). 13C NMR naphthoquinone 1 (52 mg, 0.3 mmol), 1,3- (DMSO-d6, 150 MHz): δ 194.9 (C-1), 182.1 (C-11), cyclohexanedione 2 (34 mg, 0.3 mmol), 179.5 (C-6), 151.5, 142.8, 138.1, 135.2, 134.7, (hetero)aromatic aldehyde 3a-k (0.3 mmol), p- 133.2, 131.9, 130.2, 128.7 (2C), 127.7 (2C), 125.8, toluenesulfonic acid monohydrate (12 mg, 20 mol%) 125.6, 119.2, 11.6, 36.8 (C-12), 32.8, 26.2, 20.7, in glacial acetic acid (5 ml) was sealed and placed in 20.5. HRMS (ESI+) m/z [M+H]+ calcd. for: an Anton Paar Microwave Synthetic Reactor. The C24H20NO3: 370.1443, found: 370.1420. vial was subjected to microwave (MW) irradiation, programmed at 110 oC and 150 W. After a period of 12-(3,4-Dimethoxyphenyl)-3,4,4a,5,12,12a- 30 second, the temperature reached a plauteau, hexahydrobenzo[b]acridine-1,6,11(2H)-trione 110oC, and remained constant. After completion of (4c). Reaction time 30 min. Yield 100 mg (81 %), the reaction (20-30 min), the vial was cooled to purple solid, mp. 266-267 °C. IR (KBr) 3389, 3072, room temperature, and water (20 ml) was added to 2941, 2836, 1671, 1639, 1605, 1514, 1465, 1390, © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 263
25728288, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200164 by Readcube (Labtiva Inc.), Wiley Online Library on [02/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry An efficient synthesis of acridine-aza… 1340, 1301, 1233, 1202, 1159, 1135, 1021, 1001, 134.7, 133.3, 131.8, 130.8, 130.3, 129.7 (2C), 128.0 924, 783, 720 cm-1. 1H NMR (DMSO-d6, 500 MHz, (2C), 125.9, 125.6, 118.4, 111.2, 36.7 (C-12), 33.0, 500 MHz): δ 9.86 (1H, s, NH), 8.02 (1H, dd, J = 1.2 26.2, 20.6. HRMS (ESI+) m/z [M+H]+ calcd. for: Hz, J = 7.2 Hz), 7.93 (1H, dd, J = 1.2 Hz, J = 7.2 C23H17ClNO3: 390.0897, found: 390.0860. Hz), 7.82 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.78 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 6.85 (1H, d, J = 1.8 Hz), 12-(4-Bromophenyl)-3,4,4a,5,12,12a- 6.76 (1H, d, J = 8.4 Hz), 6.69 (1H, dd, J = 1.8 Hz, J hexahydrobenzo[b]acridine-1,6,11(2H)-trione = 8.4 Hz), 5.16 (1H, s, CH), 3.68 (3H, s), 3.64 (3H, (4f). Reaction time 20 min. Yield 108 mg (83 %), s), 2.84 (1H, dt, J = 18.0 Hz, J = 4.8 Hz), 2.64-2.58 purple solid, mp. 260-261 °C. IR (KBr) 3244, 3059, (1H, m), 2.27 (2H, t, J = 4.8 Hz), 1.98-1.94 (1H, m), 2960, 1675, 1640, 1592, 1470, 1387, 1338, 1303, 1.86-1.82 (1H, m). 13C NMR (DMSO-d6, 500 MHz, 1232, 1201, 1133, 1070, 999, 938, 722 cm-1. 1H 150 MHz): δ 195.0 (C-1), 182.2 (C-11), 179.6 (C-6), NMR (DMSO-d6, 500 MHz, 500 MHz): δ 9.94 (1H, 151.5, 148.3, 147.4, 138.4, 137.9, 134.7, 133.2, s, NH), 8.02 (1H, dd, J = 1.2 Hz, J = 7.8 Hz), 7.90 131.9, 130.3, 125.8, 125.6, 119.7, 119.2, 112.1, (1H, dd, J = 1.2 Hz, J = 7.8 Hz, 7.82 (1H, td, J = 7.2 111.8, 111.5, 55.5, 55.4, 36.8 (C-12), 32.5, 26.2, Hz, J = 1.2 Hz), 7.78 (1H, td, J = 7.2 Hz, J = 1.2 20.8. HRMS (ESI+) m/z [M+H]+ calcd. for: Hz), 7.38 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 C25H22NO5: 416.1498, found: 416.1466. Hz), 5.19 (1H, s, CH), 2.84 (1H, dt, J = 17.4 Hz, J = 4.8 Hz), 2.64-2.58 (1H, m), 2.29-2.25 (2H, m), 1.96- 12-(4-Fluorophenyl)-3,4,4a,5,12,12a- 1.93 (1H, m), 1.84-1.79 (1H, m). 13C NMR (DMSO- hexahydrobenzo[b]acridine-1,6,11(2H)-trione d6, 500 MHz, 150 MHz): δ 194.95 (C-1), 182.0 (C- (4d). Reaction time 20 min. Yield 93 mg (83 %), 11), 179.4 (C-6), 151.9, 145.0, 138.4, 134.7, 133.3, purple solid, mp. 272-273 °C. IR (KBr) 3240, 3058, 131.8, 130.9 (2C), 130.3, 130.2 (2C), 125.9, 125.6, 2949, 1675, 1654, 1593, 1505, 1467, 1392, 1354, 119.3, 118.3, 111.1, 36.7 (C-12), 33.1, 26.2, 20.7. 1337, 1300, 1267, 1203, 1135, 997, 935, 839 cm-1. HRMS (ESI+) m/z [M+H]+ calcd. for: C23H17BrNO3: 1 H NMR (DMSO-d6, 500 MHz, 500 MHz): δ 9.93 434.0392 and 436.0371, found: 434.0379 and (1H, s, NH), 8.03 (1H, dd, J = 7.2 Hz, J = 1.2 Hz), 436.0382. 7.91 (1H, dd, J = 7.8 Hz, J = 1.2 Hz), 7.82 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.79 (1H, td, J = 7.2 Hz, J = 12-(3-Nitrophenyl)-3,4,4a,5,12,12a- 1.2 Hz), 7.28 (2H, dd, J = 5.4 Hz, J = 8.4 Hz), 7.02 hexahydrobenzo[b]acridine-1,6,11(2H)-trione (2H, t, J = 9.0 Hz), 5.23 (1H, s, CH), 2.85 (1H, dt, J (4g). Reaction time 30 min. Yield 90 mg (75 %), = 18.0 Hz, J = 4.8 Hz), 2.64-2.59 (1H, m), 2.29-2.24 purple solid, mp. 278-279 °C. IR (KBr) 3340, 3279, (2H, m), 1.99-1.94 (1H, m), 1.85-1.79 (1H, m). 13C 2923, 2854, 1674, 1641, 1590, 1524, 1467, 1390, NMR (DMSO-d6, 500 MHz, 150 MHz): δ 195.0 (C- 1349, 1300, 1229, 1202, 1133, 1085, 997, 810, 726 1), 182.1 (C-11), 179.5 (C-6), 160.7 (d, J = 140 Hz, cm-1. 1H NMR (DMSO-d6, 500 MHz, 500 MHz): δ CF), 151.8, 141.93, 141.91, 138.3, 134.8, 133.3, 10.11 (1H, s, NH), 8.15 (1H, t, J = 1.8 Hz), 8.10 131.9, 130.3, 129.7 (d, J = 7.5 Hz), 125.9, 125.6, (1H, dd, J = 7.2 Hz, J = 1.8 Hz), 8.04 (1H, dq, J = 118.8, 114.8 (d, J = 21.0 Hz), 36.7 (C-12), 32.7, 12 Hz, J = 1.2 Hz), 7.97 (1H, dd, J = 7.8 Hz, J = 1.2 26.2, 20.7. HRMS (ESI+) m/z [M+H]+ calcd. for: Hz), 7.89 (1H, td, J = 7.8 Hz, J = 1.8 Hz), 7.85 (1H, C23H17FNO3: 374.1192, found: 374.1161. td, J = 7.8 Hz, J = 1.8 Hz), 7.79 (1H, dt, J = 7.8 Hz, J = 1.2 Hz), 7.58 (1H, t, J = 7.8 Hz), 5.40 (1H, s), 12-(4-Chlorophenyl)-3,4,4a,5,12,12a- 2.93 (1H, dt, J = 18.0 Hz, J = 4.8 Hz), 2.75-2.67 hexahydrobenzo[b]acridine-1,6,11(2H)-trione (1H, m), 2.39-2.30 (2H, m), 2.04-1.93 (1H, m), 1.92- (4e). Reaction time 20 min. Yield 93 mg (80 %), 1.85 (1H, m). 13C NMR (DMSO-d6, 500 MHz, 150 purple solid, mp. 281-282 °C. IR (KBr) 3237, 3058, MHz): δ 195.1 (C-1), 182.1 (C-11), 179.4 (C-6), 2941, 1675, 1642. 1591, 1469, 1390, 1337, 1301, 165.5, 152.4, 147.7, 138.8, 134.8, 133.4, 131.8, 1231, 1202, 1136, 998, 722 cm-1. 1H NMR (DMSO- 130.4, 129.7, 126.0, 125.7, 122.6, 121.4, 117.8, d6, 500 MHz, 500 MHz): δ 9.95 (1H, s, NH), 8.03 114.5, 110.8, 36.7 (C-12), 34.0, 26.5, 20.7. HRMS (1H, dd, J = 1.2 Hz, J = 7.8 Hz), 7.91 (1H, dd, J = (ESI+) m/z [M+H]+ calcd. for: C23H17N2O5: 1.2 Hz, J = 7.8 Hz), 7.82 (1H, td, J = 7.2 Hz, J = 1.2 401.1137, found: 401.1146. Hz), 7.79 (1H, td, J = 7.2 Hz, J = 1.2 Hz), 7.28-7.24 (4H, m), 5.21 (1H, s, CH), 2.84 (1H, dt, J = 18.0 Hz, 12-(Naphthalen-2-yl)-3,4,5,12- J = 4.8 Hz), 2.65-2.59 (1H, m), 2.31-2.23 (2H, m), tetrahydrobenzo[b]acridine-1,6,11(2H)-trione 1.96-1.93 (1H, m), 1.85-1.78 (1H, m). 13C NMR (4h). Reaction time 30 min. Yield 96 mg (79 %), (DMSO-d6, 500 MHz, 150 MHz): δ 194.9 (C-1), purple solid, mp. 277-278 °C. IR (KBr) 3327, 3051, 182.0 (C-11), 179.4 (C-6), 151.8, 144.6, 138.4, 2946, 1667, 1637, 1592, 1481, 1386, 1348, 1305, © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 264
25728288, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200164 by Readcube (Labtiva Inc.), Wiley Online Library on [02/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Le Nhat Thuy Giang et al. 1228, 1200, 1133, 997, 939, 751, 723 cm-1. 1H NMR solid, mp. 271-272 °C. 1H NMR (DMSO-d6, 500 (DMSO-d6, 500 MHz, 500 MHz): δ 9.61 (1H, s MHz, 500 MHz): δ 10.07 (1H, s NH), 8.40 (1H, d, J NH), 8.04 (1H, dd, J = 7.2 Hz, J = 1.2 Hz), 7.89 = 8.4 Hz), 8.03 (1H, dd, J = 6.6 Hz, J = 2.4 Hz), (1H, dd, J = 7.8 Hz, J = 1.2 Hz), 7.82 (2H, td, J = 7.87-7.85 (2H, m), 7.80-7.75 (2H, m), 7.25-7.23 7.8 Hz, J = 1.8 Hz), 7.80-7.75 (3H, m), 7.70 (1H, s), (2H, m), 7.46 (1H, t, J = 7.2 Hz), 7.35 (1H, s), 7.33 7.49 (1H, dd, J = 8.4 Hz, J = 1.2 Hz), 7.43-7.40 (2H, (1H, t, J = 7.8 Hz), 5.58 (1H, s), 2.89 (1H, dt, J = m), 5.40 (1H, s), 2.89 (1H, dt, J = 17.4 Hz, J = 4.8 18.0 Hz, J = 4.8 Hz), 2.67-2.62 (1H, m), 2.28-2.22 Hz), 2.68-2.61 (1H, m), 2.30-2.23 (2H, m), 1.99- (2H, m), 1.96-1.93 (1H, m), 1.81-1.78 (1H, m). 13C 1.94 (1H, m), 1.85-1.81 (1H, m). 13C NMR (DMSO- NMR (DMSO-d6, 500 MHz, 150 MHz): δ 194.9 (C- d6, 500 MHz, 150 MHz): δ 195.1 (C-1), 182.2 (C- 1), 182.1 (C-11), 179.6 (C-6), 151.5, 142.4, 139.3, 11), 179.6 (C-6), 151.8, 143.3, 138.4, 134.7, 133.2, 138.1, 137.6, 134.7, 133.2, 131.9, 130.3, 125.9, 132.8, 131.9, 131.8, 130.3, 127.7, 127.6, 127.2, 125.6, 125.4, 124.1, 123.8, 123.4, 122.3, 119.1, 126.9, 126.0, 125.9, 125.8, 125.6, 125.5, 118.8, 112.0, 36.7 (C-12), 26.7, 26.3, 20.6. 111.5, 36.8 (C-12), 33.7, 26.3, 20.7. HRMS (ESI+) m/z [M+H]+ calcd. for: C27H20NO3: 406.1443, found: 3. RESULTS AND DISCUSSION 406.1421. Initially, the microwave-assisted three-component 12-(5-Methoxypyridin-3-yl)-3,4,5,12- sequential condensation reaction between 2-amino- tetrahydrobenzo[b]acridine-1,6,11(2H)-trione 1,4-naphthoquinone 1 (1 equivalent), 1,3- (4i). Reaction time 30 min. Yield 81 mg (70 %), red cyclohexanedione 2 (1 equivalent), benzaldehyde 3a solid, mp. 255-256 °C. 1H NMR (DMSO-d6, 500 (1 equivalent) was employed as a model reaction in MHz, 500 MHz): δ 10.00 (1H, s NH), 8.03 (1H, dd, order to develop the optimal reaction conditions. As J = 7.2 Hz, J = 1.2 Hz), 7.99 (1H, t, J = 5.4 Hz), shown in table 1, this reaction did not occur in 7.92 (1H, dd, J = 7.2 Hz, J = 1.2 Hz), 7.83 (1H, td, J ethanol without adding any catalyst (entry 1). In the = 7.8 Hz, J = 1.2 Hz), 7.79 (1H, td, J = 7.8 Hz, J = presence of Bronsted acid as catalyst including p- 1.2 Hz), 6.90 (1H, dd, J = 5.4 Hz, J = 1.8 Hz), 6.62 toluenesulfonic acid (p-TsOH), trifluoroacetic acid (1H, s), 5.20 (1H, s), 3.77 (3H, s), 2.87 (1H, dt, J = (TFA) or acetic acid (AcOH), compound 4a was 17.4 Hz, J = 4.8 Hz), 2.72-2.57 (1H, m), 2.31-2.29 achieved in 30-51 % yields (entries 2-4). These (2H, m), 1.99-1.94 (1H, m), 1.85-1.81 (1H, m). 13C results showed that p-TsOH was found to be NMR (DMSO-d6, 500 MHz, 150 MHz): δ 194.9 (C- appropriate catalyst for this transformation. 1), 181.9 (C-11), 179.3 (C-6), 163.7, 156.6, 152.4, The influence of the solvent on this product 146.6, 138.9, 134.7, 133.3, 131.8, 130.3, 125.9, yield was also screened. As shown in table 1 117.3, 117.0, 114.1, 110.2, 109.3, 52.9 (OCH3), 36.7 (entries 4-7), the highest yield of 4a was achieved by (C-12), 33.1, 26.2, 20.6. using acetic acid as the reaction media (entry 7). On the other hand, the yield of compound 4a 12-(Benzofuran-3-yl)-3,4,5,12- increased when using 20 mol% p-TsOH (entry 7). tetrahydrobenzo[b]acridine-1,6,11(2H)-trione However, when an excess amount of catalyst (30 (4j). Reaction time 30 min. Yield 89 mg (75 %), red mol%) was loaded the yield of compound 4a was solid, mp. 263-264 °C. 1H NMR (DMSO-d6, 500 not further improved (entry 9). According to these MHz, 500 MHz): δ 10.10 (1H, s NH), 8.04 (1H, dd, results, acetic acid as a solvent and p-TsOH (20 J = 7.8 Hz, J = 1.2 Hz), 7.93 (1H, dd, J = 7.8 Hz, J = mol%) as a catalyst at 110 oC under MW came out 1.2 Hz), 7.83-7.77 (3H, m), 7.72 (1H, s), 7.46-7.44 as the optimized conditions for the synthesis of (1H, m), 7.25-7.23 (2H, m), 5.43 (1H, s), 2.87 (1H, compound 4a. dt, J = 18.0 Hz, J = 4.8 Hz), 2.65-2.60 (1H, m), Based on the optimized reaction conditions, 2.30-2.28 (2H, m), 1.96-1.92 (1H, m), 1.83-1.78 different aromatic aldehydes 3a-h were applied to (1H, m). 13C NMR (DMSO-d6, 500 MHz, 150 this reaction to obtain a series of compounds 4a-h MHz): δ 195.0 (C-1), 182.1 (C-11), 179.4 (C-6), (scheme 1). After purification by means of column 154.7, 152.1, 143.9, 138.6, 134.7, 133.3, 131.9, chromatography, compounds 4a-h were obtained in 130.4, 126.3, 125.9, 125.6, 124.7, 124.0, 122.5, high yields (75-83 %). It is important to mention that 120.7, 117.5, 111.1, 110.3, 36.7 (C-12), 26.3, 23.1, the electronic nature of the substituents of aromatic 20.6. aldehydes has no significant effect on this microwave-assisted three-component reaction. The 12-(Benzo[b]thiophen-3-yl)-3,4,5,12- chemical structures of compounds 4a-h were tetrahydrobenzo[b]acridine-1,6,11(2H)-trione determined by IR, 1H NMR, 13C NMR, and HRMS, (4k). Reaction time 30 min. Yield 96 mg (78 %), red which were provided in the Experimental Section. © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 265
25728288, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200164 by Readcube (Labtiva Inc.), Wiley Online Library on [02/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry An efficient synthesis of acridine-aza… In order to broaden the reaction scope, aliphatic signals of four aromatic protons in the p-tolyl group aldehydes (propanal, isobutyraldehyde) or appeared as two doublets at 7.12 and 7.00 ppm, heteroaromatic aldehydes (5- three protons of methyl in the p-tolyl group were methoxynicotinaldehyde, benzofuran-3-carbaldehyde, observed as a singlet at 2.18 ppm. Signals benzo[b]thiophene-3-carbaldehyde) were employed corresponding to protons of dimedone moeity in the reaction with 2-amino-1,4-naphthoquinone (1), appeared as multiplets in the region from 2.84 to 1,3-cyclohexanedione (2) in the same conditions. In 1.78 ppm. Besides, carbonyl carbons C-1, C-6, and the case of aliphatic aldehydes, the reactions were C-11 assigned at 194.9, 179.5 and 182.1 ppm, checked via TLC analysis, however, only resulting in respectively. Meanwhile, the carbon C-12 assigned complex reaction mixtures. Meanwhile, three at 36.8 ppm. compounds 4i, 4j, 4k were obtained in 70-78 % yield A possible mechanistic interpretation of these when heteroaryl aldehydes 3i-k were used. three-component reactions began with the The 1H and 13C assignment of compounds 4a-h Knoevenagel condensation of 2-amino-1,4- were based on the NMR data of naphthoquinones naphthoquinone (1) with aromatic aldehydes 3, reported in the previous studies.[13-14] Taken followed by spontaneous dehydration to afford compound 4b as example, two doublets of doublets intermediates 8. The intermediates 8 underwent the at 8.02 and 7.91 ppm, two triplets of doublets at 7.82 Michael addition with enol form of cyclohexane-1,3- and 7.78 ppm, and one singlet 5.19 ppm were dione 2, intramolecular cyclization and dehydration assigned to protons H-10, H-7, H-8, H-9, and H-12 sequence of steps to furnish the final products 4 of the aza-anthraquinone ring, respectively. The (scheme 2). Ar = C6H5 (a), 4-MeC6H4 (b), 3,4-(MeO)2C6H3 (c), 4-FC6H4 (d), 4-ClC6H4 (e), 4-BrC6H4 (f), 3-NO2C6H4 (g), naphtalene-2-yl (h), 5-methoxypyridine-3-yl (i), benzofurane-3-yl (j), benzo[b]thiophene-3-yl (k) Scheme 1: Synthesis of 12-substituted-3,4,4a,5,12,12a-hexahydrobenzo[b]acridine-1,6,11(2H)-triones 4a-k Scheme 2: Possible mechanism for the formation of compounds 4 © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 266
25728288, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200164 by Readcube (Labtiva Inc.), Wiley Online Library on [02/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Le Nhat Thuy Giang et al. Table 1: Optimization of solvent and catalyst for the synthesis of compound 4a Entry Solvent Catalyst Temperature Time (min) Isolated yield (%)a 1 EtOH - reflux 20 0 2 EtOH TFA (10 mol%) reflux 20 30 3 EtOH AcOH (10 mol%) reflux 20 42 4 EtOH p-TsOH (10 mol%) reflux 20 51 5 CH3CN p-TsOH (10 mol%) reflux 20 59 6 DMF p-TsOH (10 mol%) reflux 20 68 o 7 AcOH p-TsOH (10 mol%) 110 C 20 73 8 AcOH p-TsOH (20 mol%) 110 oC 20 85 9 AcOH p-TsOH (30 mol%) 110 oC 20 85 a Reagents and conditions: 1 (0.3 mmol), 2 (0.3 mmol), 3a (0.3 mmol), solvent (5 ml), MW, 150 W. 4. CONCLUSION 151, 55-65. 3. T. Nguyen Van, G. Verniest, S. Claessens, N. De In this study, eleven 12-substituted-3,4,4a,5,12,12a- Kimpe. Total synthesis of four naturally occurring 2- hexahydrobenzo[b]acridine-1,6,11(2H)-trione azaanthraquinone antibiotics, 6-deoxy-8- methylbostrycoidin, 6-deoxybostrycoidin, 7-O- derivatives were successfully synthesized starting demethyl-6-deoxybostrycoidin and scorpinone, from 2-amino-1,4-naphthoquinone, 1,3- Tetrahedron, 2005, 61, 2295-2300. cyclohexanedione, and different (hetero)aromatic 4. N. Khan, F. Afroz, Mst. N. Begum, S. Roy Rony, S. aldehydes. These reactions were carried out in acetic Sharmin, F. Moni, C. Mahmood Hasan, K. Shaha, acid under microwave irradiation in the presence of Md. H. Sohrab. Endophytic Fusarium solani: A rich 20 mol% p-toluenesulfonic acid. The structure of the source of cytotoxic and antimicrobial newly syntheszied compounds were confirmed naphthoquinone and aza-anthraquinone derivatives, employing spectroscopic data as well as elemental Toxicol. Rep., 2018, 5, 970-976. analysis. 5. J. Wang, W. Li, J. Qin, L. Wang, S. Wei, H. Tang. Assessment of novel azaanthraquinone derivatives as potent multi-target inhibitors of inflammation and Acknowledgements. The authors are indebted to amyloid-β aggregation in Alzheimer’s disease, Vietnamese National Foundation for Science and Bioorganic Chemistry, 2019, 83, 477-486. Technology (NAFOSTED) (code: 104.01-2019.321) 6. P. Thanuphol, Y. Asami, K. Shiomi, A. for financial support. Wongnoppavich, P. Tuchinda, N. Soonthornchareonnon. Marcanine G, a new cytotoxic REFERENCES 1-azaanthraquinone from the stem bark of Goniothalamus marcanii Craib. Nat. Prod. Res., 1. G. Burckhardt, A. Walter, H. Triebel, K. Störl, H. 2018, 32, 1682-1689. Simon, J. Störl, A. Opitz, E. Roemer, C. Zimmer. 7. V. A. Bacherikov, T. C. Chou, H. J. Dong, C. H. Selective inhibition of DNA gyrase in vitro by a GC Chen, Y. W. Lin, T. J. Tsai, T. L. Su. Potent specific eight-ring hairpin polyamide at nanomolar antitumor N-mustard derivatives of 9-anilinoacridine, concentration, Biochemistry, 1998, 37, 4703-4711. synthesis and antitumor evaluation, Bioorg. Med. 2. G. Cavaletti, E. Cavaletti, L. Crippa, E. Di Luccio, N. Chem. Lett., 2004, 14, 4719-4722. Oggioni, B. Mazzanti, T. Biagioli, F. Sala, V. Sala, 8. I. Antonini, P. Polucci, A. Magnano, S. Martelli. M. Frigo, S. Rota, E. Tagliabue, L. Stanzani, S. Synthesis, antitumor cytotoxicity, and DNA-binding Galbiati, R. Rigolio, C. Zoia, G. Tredici, P. of novel N-5,2-di(ω-aminoalkyl)-2,6- Perseghin, M. Dassi, P. Riccio, F. Lolli. Pixantrone dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides, J. (BBR2778) reduces the severity of experimental Med. Chem., 2001, 44, 3329-3333. allergic encephalomyelitis, J. Neuroimmunol., 2004, 9. M. Wainwright, Acridine - a neglected antibacterial © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 267
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