Yun-Gang He,
Yong-Kang Huang,
Qi-Qi Fan,
Bo Zheng,
Yong-Qiang Luo,
Xing-Liang Zhu and
Xiao-Xin Shi*
Engineering Research Center of Pharmaceutical Process Chemistry of the Ministry of Education, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, People's Republic of China. E-mail: xxshi@ecust.edu.cn
First published on 6th September 2021
A mild, efficient and eco-friendly method for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs without concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs is very important for the syntheses of 1-Bz-DHIQ alkaloids and analogues. In this article, we developed a novel Cu(II)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp3)–H bonds adjacent to the C-1 positions of various 1-Bn-DHIQs. It was observed that when 0.2 equiv. of Cu(OAc)2·2H2O was used as the catalyst, 3.0 equiv. of AcOH was used as the additive and air (O2) was used as a clean oxidant, various 1-Bn-DHIQs could be efficiently oxidized to corresponding 1-Bz-DHIQs at 25 °C in DMSO. Especially, almost no concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs was observed during the above reaction. In addition, this method was successfully applied in the first total synthesis of the alkaloid canelillinoxine.
1-Benzoyl-3,4-dihydroisoquinolines (1-Bz-DHIQs) represent an important kind of isoquinoline alkaloids, which could be isolated from numerous plants.4 Since 1-Bz-DHIQ alkaloids and their synthetic analogues have exhibited various interesting biological activities,5 a mild, efficient and eco-friendly method for synthesis of 1-Bz-DHIQ alkaloids might be highly desirable for organic and medicinal chemists. 1-Bz-DHIQs usually can be synthesized via oxidation of 1-benzyl-3,4-dihydroisoquinolines (1-Bn-DHIQs), which could be readily prepared via the Bischler–Napieralski cyclization6 of corresponding amides. Some known methods for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs have been reported.7–14 However, these known methods usually suffered from some serious drawbacks: (a) use of poisonous and hazardous strong oxidants such as CrO3,7 SeO2,8 MnO2,9 CAN [Ce(NH4)2(NO3)6],10 Pb(OAc)4,11 and singlet oxygen (1O2);8,12 (b) concomitant excessive oxidation of 1-Bz-DHIQs could not be avoided, significant amount of undesired 1-benzoyl-isoquinolines (1-Bz-IQs) were formed as by-products during the reaction;7–13 (c) yields of 1-Bz-DHIQs as the desired products are only moderate in most instances; (d) use of precious palladium catalyst (Pd/C) in Andreu's method.14 In order to overcome the above-mentioned drawbacks, development of a mild, efficient and eco-friendly method for the oxidation of 1-Bn-DHIQs to 1-Bz-DHIQs without concomitant excessive oxidation of 1-Bz-DHIQs to 1-Bz-IQs remains a challenge to organic chemists. Herein, we want to disclose a very mild and efficient copper(II)-catalyzed and acid-promoted highly regioselective oxidation of tautomerizable C(sp3)–H bonds adjacent to the C-1 positions of various 1-Bn-DHIQs using air (O2) as a clean oxidant.
En. | Catalyst (equiv.) | Additive (equiv.) | Time (h) | Yield %b (2a/3a) |
---|---|---|---|---|
a Reaction conditions: 1a (2 mmol), catalyst, additive, DMSO (4.0 mL), stirred at 25 °C under an air atmosphere.b Isolated yields.c 70% of 1a was recovered.d Trace amount of 1-Bz-IQ 3a (<0.5%) was detected.e DBU = 1,8-Diazabicyclo[5,4,0]undec-7-ene. | ||||
1 | None | None | 72 | 25/1c |
2 | CuCl2·2H2O (0.2) | None | 24 | 76/16 |
3 | CuBr2·2H2O (0.2) | None | 24 | 75/17 |
4 | CuSO4·2H2O (0.2) | None | 24 | 71/21 |
5 | Cu(OAc)2·2H2O (0.1) | None | 25 | 79/15 |
6 | Cu(OAc)2·2H2O (0.2) | None | 16 | 82/13 |
7 | Cu(OAc)2·2H2O (0.5) | None | 12 | 81/14 |
8 | Cu(OAc)2·2H2O (1.0) | None | 10 | 80/14 |
9 | Cu(OAc)2·2H2O (0.2) | HCl (1.0) | 15 | 83/1 |
10 | Cu(OAc)2·2H2O (0.2) | H2SO4 (1.0) | 18 | 82/1 |
11 | Cu(OAc)2·2H2O (0.2) | H3PO4 (1.0) | 14 | 86/1 |
12 | Cu(OAc)2·2H2O (0.2) | CF3CO2H (1.0) | 12 | 87/1 |
13 | Cu(OAc)2·2H2O (0.2) | AcOH (1.0) | 10 | 90/1 |
14 | Cu(OAc)2·2H2O (0.2) | AcOH (2.0) | 9 | 92/1 |
15 | Cu(OAc)2·2H2O (0.2) | AcOH (3.0) | 8 | 95/<0.5d |
16 | Cu(OAc)2·2H2O (0.2) | AcOH (4.0) | 8 | 93/<0.5d |
17 | Cu(OAc)2·2H2O (0.2) | AcOH (5.0) | 9 | 91/1 |
18 | Cu(OAc)2·2H2O (0.2) | DBUe (1.0) | 15 | <0.5/89 |
19 | Cu(OAc)2·2H2O (0.2) | Py (1.0) | 15 | 20/72 |
20 | Cu(OAc)2·2H2O (0.2) | Et3N (1.0) | 15 | 25/68 |
21 | Cu(OAc)2·2H2O (0.2) | K2CO3 (1.0) | 15 | 23/65 |
22 | Cu(OAc)2·2H2O (0.2) | Na2CO3 (1.0) | 15 | 23/64 |
Subsequently, we tried effects of acid and base additives on the reaction, and found that acid and base additives dramatically changed the ratios of products 1-Bz-DHIQ 2a and 1-Bz-IQ 3a (entries 9–22). When acids were used as additives, 1-Bz-DHIQ 2a was formed as the major product (entries 9–17); when bases were used as additives, 1-Bz-IQ 3a was formed as the major product (entries 18–22).15 Especially, weak acid additive is better than strong acid (entry 13 versus entries 9–12), when 3.0 equiv. of acetic acid (AcOH) was used as the additive (entry 15), the desired product 1-Bz-DHIQ 2a was obtained in the best yield (95%), and only a trace amount (<0.5%) of undesired excessive oxidation product 1-Bz-IQ 3a was detected.
We have also tired the model reaction in different solvents, and found that the reaction is much faster in DMSO, and the yield of the desired product 2a is higher in DMSO than in several other solvents including N,N-dimethylforamide, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane, 1,2-dimethoxyethane, isopropanol and ethanol. Consequently, we concluded that the optimized reaction conditions for the above model reaction are as follows: DMSO is the solvent, cupric salt Cu(OAc)2·2H2O (0.2 equiv.) is the catalyst, acid AcOH (3.0 equiv.) is the additive, and the reaction were performed under an air (O2) atmosphere at room temperature (25 °C).
With the above optimized reaction conditions in hand, we then attempted Cu(OAc)2-catalyzed oxidation of variously substituted 1-Bn-DHIQs 1, which were prepared from corresponding amides according to the known method,15 under the above optimized conditions to prepare 1-Bz-DHIQs 2. As can be seen from Table 2, a total of twenty 1-Bn-DHIQs 1a–1t have been examined for the reaction, corresponding 1-BzDHIQs 2a–2t were thus obtained in high yields (85–96%). It is worth noting that the regioselectivity of oxidation of all tested substrates is extremely high, only tautomerizable C(sp3)–H bonds adjacent to the C-1 positions of 1-Bn-DHIQs were oxidized. Although C-4 is also a benzylic position, almost none of oxidation of C(sp3)–H bond at the C-4 position happened.
A possible mechanism for the above Cu(OAc)2-catalyzed and acid promoted aerobic oxidation of 1-Bn-DHIQs 1 was proposed in Scheme 1. 1-Bn-DHIQs 1 would first undergo acid-promoted tautomerization16 to form enamines 1′. Enamines 1′ would then coordinate with Cu(OAc)2 to produce Cu-complex I-A, which would further coordinate with molecule O2 (in air) to give more reactive Cu-complex I-B.17 Next, complex I-B would undergo intramolecular Jenkins-like oxidation18 to furnish an unstable perhydroxide compound I-C. Finally, decomposition19 of I-C would afford 1-Bz-DHIQs 2. Although acids can speed up tautomerization of imines 1 to enamines 1′, strong acids (HCl, H2SO4, etc.) would also react with imines 1 to form ammonium 1′-H+ reversibly, which could not coordinate with Cu(OAc)2 to form I-A, and that would retard the oxidation (Table 1, entries 9–12).
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Scheme 1 Possible mechanism for the Cu(OAc)2-catalyzed and acid-promoted aerobic oxidation of C(sp3)–H bonds adjacent to the C-1 positions of 1-Bn-DHIQs 1. |
To demonstrate the utility of above-described methodology, we have applied the protocol to an efficient total synthesis of 1-Bz-DHIQ canelillinoxine 4. The alkaloid canelillinoxine 4 was isolated from the stem bark of Aniba canelilla H.B.K. (Lauraceae) in 1993.20 Herein we would like to report the first total synthesis of canelillinoxine 4 starting from vanillin by using the above mild Cu(OAc)2-catalyzed and acid-promoted oxidation of as the key step. As depicted in the Scheme 2, EDA-catalyzed condensation of vanillin with nitromethane produced nitroalkene 5 in 92% yield.21 Compound 5 was then treated with 5.0 equiv. of LiAlH4, simultaneous reduction of the double bond and nitro group took place to give amine 6 in 82% yield. When compound 6 was exposed to 1.1 equiv. of freshly prepared 2-(3-acetoxy-phenyl) acetyl chloride and 3.0 equiv. of K2CO3, amide 7 was obtained in 80% yield. Treatment of compound 7 with 3.0 equiv. of Ac2O, 3.0 equiv. of Et3N and 0.1 equiv. of N,N-dimethylamino-pyridine (DMAP) gave compound 8 in 86% yield. Next, exposure of amide 8 to 3.0 equiv. of POCl3, Bischler–Napieralski cyclization6 took place smoothly to produce the tautomeric mixture of imine 9 and enamine 9′, which were then treated with 0.2 equiv. of Cu(OAc)2·2H2O and 3.0 equiv. of AcOH in DMSO under an air atmosphere at 25 °C to furnish compound 10 in 85% yield (over 2 steps from 8). Finally, when compound 10 was treated with excessive NH3·H2O, protecting groups (two Ac groups) were removed to afford 1-Bz-DHIQ canelillinoxine 4 in 89% yield.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone 2a: pale yellow crystals, m.p. 78–79 °C (lit.22 m.p. 78.8–79.4 °C). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (dd, J1 = 7.3 Hz, J2 = 7.4 Hz, 2H), 6.95 (s, 1H), 6.76 (s, 1H), 3.99–3.87 (m, 2H), 3.92 (s, 3H), 3.78 (s, 3H), 2.88–2.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.97, 164.39, 151.72, 147.62, 135.57, 133.85, 131.17, 130.43, 128.54, 119.30, 110.57, 109.59, 56.07, 56.02, 47.31, 25.37. IR (KBr film) ν 3080, 2936, 2907, 2844, 1656, 1586, 1516, 1485, 1265, 1239, 1146, 1024, 929, 865, 752 cm−1.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(3-methoxyphenyl)-methanone 2b: pale yellow crystals, m.p. 98–100 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.37 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.93 (s, 1H), 6.76 (s, 1H), 3.98–3.89 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 2.88–2.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.82, 164.54, 159.73, 151.77, 147.66, 136.85, 131.15, 129.58, 123.63, 120.63, 119.30, 113.96, 110.54, 109.58, 56.11, 56.05, 55.48, 47.21, 25.40. IR (KBr film) ν 3070, 2921, 2852, 1666, 1596, 1592, 1569, 1515, 1461, 1425, 1135, 1072, 1033, 935, 807, 754, 709 cm−1. HRMS (ESI) m/z calcd for C19H19NO4Na [M + Na]+: 348.1212, found: 348.1211.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(3,4-dimethoxy-phenyl)methanone 2c: pale yellow crystals, m.p. 188–189 °C (lit.23 m.p. 188–190 °C). 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 3.96 (s, 3H), 3.95–3.88 (m, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.79 (s, 3H), 2.89–2.76 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.76, 164.63, 154.16, 151.67, 149.16, 147.64, 131.08, 128.59, 126.61, 119.49, 111.21, 110.50, 110.02, 109.61, 56.16, 56.11, 56.04, 56.02, 47.25, 25.43. IR (KBr film) ν 3013, 2935, 2833, 2604, 1659, 1583, 1514, 1461, 1278, 1133, 1023, 866, 791, 755 cm−1.
(2-Bromophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)methanone 2d: pale yellow crystals, m.p. 159–161 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H),7.44 (dd, J1 = 7.8 Hz, J1 = 7.7 Hz, 1H), 7.36 (dd, J1 = 7.7 Hz, J2 = 7.7 Hz, 1H), 7.32 (s, 1H), 6.74 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.88–3.80 (m, 2H), 2.83–2.62 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 195.75, 163.67, 151.61, 147.54, 140.23, 133.14, 132.51, 131.68, 131.11, 127.51, 120.75, 119.16, 110.32, 110.28, 56.15, 56.02, 48.19, 25.12. IR (KBr film) ν 3054, 2942, 2899, 2844, 1681, 1587, 1499, 1478, 1460, 1381, 1315, 1266, 1032, 924, 868 cm−1. HRMS (ESI) m/z calcd for C18H16NO3Na [M + Na]+: 396.0211, found: 396.0215.
(4-Chlorophenyl)(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)methanone 2e: white crystals, m.p. 132–133 °C (lit.24 m.p. 130–131 °C). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 6.96 (s, 1H), 6.75 (s, 1H), 3.97–3.89 (m, 2H), 3.94 (s, 3H), 3.80 (s, 3H), 2.86–2.76 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.56, 163.93, 151.83, 147.69, 140.35, 134.01, 131.87, 131.22, 128.85, 119.17, 110.55, 109.61, 56.12, 56.06, 47.38, 25.38.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(4-methoxyphenyl)-methanone 2f: pale yellow crystals, m.p. 92–93 °C (lit.25 m.p. 91–92 °C). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 3.96–3.89 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.78 (s, 3H), 2.87–2.77 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.73, 164.67, 164.26, 151.61, 147.62, 132.91, 131.10, 128.50, 119.48, 113.87, 110.47, 109.61, 56.12, 55.56, 47.27, 29.72, 25.45.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(2-nitrophenyl)-methanone 2g: pale yellow crystals, m.p. 98–100 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.8 Hz, 1H), 7.78 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H), 7.71–7.61 (m, 3H), 6.70 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.74–3.62 (m, 2H), 2.70–2.56 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.66, 163.10, 151.69, 147.81, 147.56, 136.08, 134.17, 131.81, 131.04, 130.19, 123.57, 119.03, 110.97, 109.92, 56.17, 56.00, 47.84, 25.20. IR (KBr film) ν 3072, 2964, 2919, 2851, 1697, 1600, 1562, 1529, 1512, 1468, 1405, 1346, 1280, 1197, 1147, 1047, 906, 877, 800, 750, 707 cm−1. HRMS (ESI) m/z calcd for C18H17N2O5 [M + H]+: 341.1137, found: 341.1135.
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(4-nitrophenyl)-methanone 2h: white crystals, m.p. 160–161 °C. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.77 (s, 1H), 4.00–3.92 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 2.89–2.76 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 191.71, 163.27, 152.06, 150.42, 147.75, 140.75, 131.53, 131.43, 123.49, 118.87, 110.58, 109.68, 56.16, 56.12, 47.57, 25.32. IR (KBr film) ν 3003, 2924, 2853, 1674, 1637, 1606, 1564, 1519, 1458, 1347, 1200, 1043, 906, 859, 800, 781 cm−1. HRMS (ESI) m/z calcd for C18H17N2O5 [M + H]+: 341.1137, found: 341.1143.
(6-Methoxy-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone 2i: pale yellow crystals, m.p. 89–90 °C (lit.26 m.p. 88–90 °C). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (dd, J1 = 7.4 Hz, J2 = 7.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 6.76 (s, 1H), 6.73 (d, J = 8.5 Hz, 1H), 3.99–3.88 (m, 2H), 3.81 (s, 3H), 2.91–2.79 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 194.09, 164.86, 162.02, 139.57, 135.56, 133.86, 130.37, 128.56, 128.50, 120.16, 113.47, 112.13, 55.42, 47.13, 26.19.
(6-Methoxy-3,4-dihydroisoquinolin-1-yl)(4-methoxyphenyl)-methanone 2j: white crystals, m.p. 156–157 °C. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 6.76 (s, 1H), 6.72 (d, J = 8.5 Hz, 1H), 3.97–3.87 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.90–2.80 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.81, 165.11, 164.24, 161.93, 139.53, 132.77, 128.53, 128.50, 120.28, 113.87, 113.40, 112.09, 55.56, 55.38, 47.05, 26.20. HRMS (ESI) m/z calcd for C18H18NO3 [M + H]+: 296.1287, found: 296.1292.
(7-Methoxy-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone 2k: pale yellow crystals, m.p. 130–131 °C. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.48 (dd, J1 = 7.7 Hz, J2 = 7.8 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 4.03–3.89 (m, 2H), 3.73 (s, 3H), 2.87–2.76 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.80, 165.11, 158.55, 135.49, 133.94, 130.41, 129.19, 128.74, 128.60, 127.16, 117.68, 111.67, 55.49, 47.77, 24.78. IR (KBr film) ν 3058, 2973, 2946, 2836, 1664, 1598, 1575, 1498, 1475, 1448, 1353, 1311, 1259, 1222, 1199, 1112, 1031, 921, 879, 858, 740, 698 cm−1. HRMS (ESI) m/z calcd for C17H15NO2Na [M + Na]+: 288.1000, found: 288.1005.
(7-Methoxy-3,4-dihydroisoquinolin-1-yl)(4-methoxyphenyl)-methanone 2l: white crystals, m.p. 58–60 °C. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 6.90 (s, 1H), 3.98–3.91 (m, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.86–2.76 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.53, 165.38, 164.32, 158.54, 132.82, 129.17, 128.69, 128.42, 117.60, 113.91, 113.76, 111.69, 55.57, 55.48, 47.67, 24.80. IR (KBr film) ν 3037, 2947, 2924, 2833, 1652, 1603, 1572, 1499, 1468, 1422, 1357, 1317, 1259, 1222, 1209, 1169, 1126, 1040, 1019, 948, 926, 881, 819, 767 cm−1. HRMS (ESI) m/z calcd for C18H17NO3Na [M + Na]+: 318.1106, found: 318.1102.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(phenyl)-methanone 2m: pale yellow crystals, m.p. 76–77 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 8.1 Hz, 1H), 7.37 (dd, J1 = 8.0 Hz, J2 = 8.1 Hz, 2H), 6.76 (s, 1H), 6.62 (s, 1H), 5.85 (s, 2H), 3.88–3.74 (m, 2H), 2.74–2.63 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.80, 164.41, 149.91, 146.51, 135.42, 133.88, 132.99, 130.34, 128.55, 120.37, 108.29, 106.88, 101.48, 47.19, 25.85. IR (KBr film) ν 3054, 2921, 2846, 1664, 1621, 1581, 1502, 1483, 1461, 1058, 1037, 991, 931, 869, 730, 688 cm−1. HRMS (ESI) m/z calcd for C17H13NO3Na [M + Na]+: 302.0793, found: 302.0800.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(3-methoxy-phenyl)methanone 2n: pale yellow crystals, m.p. 70–72 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.36 (dd, J1 = 7.9 Hz, J2 = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.96 (s, 2H), 3.93–3.85 (m, 2H), 3.86 (s, 3H), 2.83–2.74 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.77, 164.53, 159.76, 149.94, 146.54, 136.71, 132.99, 129.59, 123.59, 120.71, 120.45, 113.82, 108.31, 106.98, 101.49, 55.51, 47.23, 25.92. IR (KBr film) ν 3077, 2941, 2903, 2837, 1677, 1592, 1568, 1481, 1459, 1429, 1375, 1318, 1264, 1191, 1104, 1038, 992, 935, 872, 751, 679 cm−1. HRMS (ESI) m/z calcd for C18H15NO4Na [M + Na]+: 332.0899, found: 332.0907.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(3,4-dimethoxy-phenyl)methanone 2o: pale yellow crystals, m.p. 154–155 °C (lit.5d m.p. 153–154 °C). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 6.64 (s, 1H), 5.88 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85–3.76 (m, 2H), 2.76–2.65 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.72, 164.68, 154.19, 149.87, 149.20, 146.52, 132.93, 128.47, 126.55, 120.64, 111.07, 110.01, 108.27, 107.04, 101.46, 56.18, 56.06, 47.18, 25.93.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(4-methoxy-phenyl)methanone 2p: pale yellow crystals, m.p. 131–132 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.83 (s, 1H), 6.71 (s, 1H), 5.95 (s, 2H), 3.94–3.82 (m, 2H), 3.86 (s, 3H), 2.84–2.73 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.60, 164.70, 164.27, 149.83, 146.49, 132.95, 132.80, 128.33, 120.57, 113.88, 108.26, 107.04, 101.45, 55.59, 47.17, 25.93. IR (KBr film) ν 3069, 2920, 2841, 1650, 1599, 1505, 1486, 1257, 1171, 1038, 932, 849, 768 cm−1. HRMS (ESI) m/z calcd for C18H16NO4 [M + H]+: 310.1079, found: 310.1073.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(2-nitrophenyl)-methanone 2q: pale yellow crystals, m.p. 180–181 °C (lit.7 m.p. 180–183 °C). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.8 Hz, 1H), 7.70 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H), 7.63–7.54 (m, 2H), 7.48 (s, 1H), 6.60 (s, 1H), 5.94 (s, 2H), 3.62–3.50 (m, 2H), 2.56–2.44 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.38, 163.19, 149.90, 147.77, 146.52, 136.00, 134.21, 133.78, 131.08, 130.26, 123.61, 120.01, 108.49, 107.70, 101.47, 47.78, 25.79.
(7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)(4-nitrophenyl)-methanone 2r: white crystals, m.p. 160–161 °C. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 2H), 8.18 (d, J = 8.9 Hz, 2H), 6.96 (s, 1H), 6.75 (s, 1H), 6.00 (s, 2H), 4.01–3.81 (m, 2H), 2.88–2.60 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 191.55, 163.31, 150.44, 150.25, 146.66, 140.56, 133.33, 131.46, 123.51, 119.95, 108.37, 106.99, 101.62, 47.47, 25.81. HRMS (ESI) m/z calcd for C17H13N2O5 [M + H]+: 325.0824, found: 325.0821.
(2-Bromophenyl)(7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)methanone 2s: pale yellow crystals, m.p. 147–148 °C. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.43 (dd, J1 = 7.7 Hz, J2 = 7.8 Hz, 1H), 7.35 (dd, J1 = 7.8 Hz, J2 = 7.9 Hz, 1H), 7.25 (s, 1H), 6.71 (s, 1H), 6.00 (s, 2H), 3.91–3.73 (m, 2H), 2.77–2.63 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 195.61, 163.63, 149.79, 146.43, 140.24, 133.04, 132.46, 131.05, 127.53, 120.66, 120.22, 108.02, 107.81, 101.46, 48.20, 25.70. HRMS (ESI) m/z calcd for C17H12BrNO3Na [M + Na]+: 379.9898, found: 379.9895.
(4-Chlorophenyl)(7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)methanone 2t: pale yellow crystals, m.p. 133–134 °C (lit.5d m.p. 132–133 °C). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 6.73 (s, 1H), 5.97 (s, 2H), 3.99–3.83 (m, 2H), 2.87–2.72 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 192.36, 164.05, 150.10, 146.60, 140.45, 133.82, 133.14, 131.79, 128.90, 120.24, 108.33, 107.01, 101.53, 47.20, 25.88. IR (KBr film) ν 3004, 2923, 2852, 1668, 1622, 1587, 1502, 1484, 1462, 1208, 1089, 1041, 936, 899, 821, 769 cm−1.
The above tautomeric mixture of 3,4-dihydroisoquinoline 9 and enamine 9′ were dissolved in DMSO (15 mL). Cu(OAc)2·2H2O (339.0 mg, 1.557 mmol) and CH3COOH (1.400 g, 23.31 mmol) were added. The resulting solution was then stirred at room temperature for 9 h under an atmosphere of air. After the reaction was completed (checked by TLC, EtOAc/hexane = 1:
1), a dilute ammonia aqueous solution (5% w/w, 60 mL) and EtOAc (60 mL) were added. After the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted again with EtOAc (50 mL). The organic extracts were combined, and dried over anhydrous MgSO4. Removal of solvent by vacuum distillation gave crude product, which was purified by flash chromatography (eluent: EtOAc/hexane = 1
:
3) to afford pure compound 10 (2.525 g, 6.621 mmol) as pale yellow crystals in 85% yield, m.p. 80–82 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.47 (dd, J1 = 8.0 Hz, J2 = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 4.01–3.94 (m, 2H), 3.88 (s, 3H), 2.92–2.79 (m, 2H), 2.31 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 192.12, 169.11, 168.90, 163.37, 153.78, 150.74, 138.18, 137.11, 136.82, 129.54, 128.14, 127.25, 123.21, 121.52, 119.38, 111.55, 56.10, 47.10, 25.71, 21.13, 20.54. IR (KBr film) ν 3072, 2923, 2849, 1763, 1673, 1608, 1585, 1563, 1512, 1438, 1367, 1282, 1200, 1127, 1068, 1045, 1008, 912, 886, 808, 756, 701 cm−1. HRMS (ESI) m/z calcd for C21H20NO6 [M + H]+: 382.1291, found: 382.1291.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra05671a |
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