3-Aryl-4-Isoquinolinone Derivatives An Efficient Oxidative Preparation

Abstract

A comparative study of the oxidation of 3-aryl-4-hydroxytetrahydroisoquinolines has been carried out. A modification of the Jones conditions turn out to be the best methodology for the regioselective preparation of target 4-isoquinolinone derivatives.

Notes

Selected data for new N-methyl derivatives 3:

(3R∗,4S∗)-6,7-Dimethoxy-3-(3,4-dimethoxyphenyl)-4-hydroxy-N-methyl-1,2,3,4-tetrahydroisoquinoline 3a., R_f (10% MeOH/CH₂Cl₂) 0.4; IR v_max 3490 (O-H); ¹H NMR (250 MHz, CDCl₃): δ 2.20 (3H, s, NMe), 2.28 (1H, bs, O-H), 3.32 (1H, d, J 6.6, H-3), 3.55 (1H, d, J 15.1, H-1_pseudo-eq), 3.72 (1H, d, J 15.1, H-1_pseudo-ax), 3.80 (3H, s, OMe), 3.87 (9H, s, OMe), 4.73 (1H, d, J 6.5, H-4), 6.55 (1H, s, H-8_arom), 6.76–6.81 (3H, m, H_arom), 7.01 (1H, s, H-5_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 43.2 (NMe), 55.8, 55.9 (OMe), 56.5 (C-1), 72.3, 72.9 (C-3, C-4), 108.1, 109.9, 110.8, 111.0, and 121.1 (C_arom-H), 126.5, 128.5, and 130.3(C _arom-C), 148.1, 148.5, 148.7, and 149.2 (C_arom-O); m/z 359 (M⁺, 2), 180 (100), 165 (10), 151 (8); (Found: C, 67.01; H, 7.03; N, 3.77. C₂₀H₂₅NO₅ requires C, 66.97; H, 7.01; N, 3.79%).

(1R∗,3R∗,4S∗)-6, 7-Dimethoxy-1, N-dimethyl-4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline 3c, R_f (5% MeOH/CH₂Cl₂) 0.5; IR v_max 3500–3020 (O-H); ¹H NMR (250 MHz, CDCl₃): δ 1.44 (3H, d, J 6.4, C₁Me), 2.32 (3H, s, NMe), 3.71 (1H, q, J 6.4, H-1), 3.89 (3H, s, OMe), 3.90 (3H, s, OMe), 3.96 (1H, d, J 5.0, H-3), 4.66 (1H, d, J 5.0, H-4), 6.64 (1H, s, H-8), 6.93 (1H, s, H-5), 7.11–7.28 (5H, m, H_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 18.9 (C₁ CH₃), 40.2 (NMe), 55.8, 55.9 (OMe), 56.6 (C-1), 68.6, 71.3 (C-3, C-4), 109.9, 110.7 and 127.7 (C_arom-H), 127.8 (C _arom-C), 128.3, 129.1 (C_arom-H), 132.5, and 137.8 (C _arom-C), 147.9 and 148.6 (C_arom-O); (Found: C, 72.82; H, 7.42; N, 4.46. C₁₉H₂₃NO₃ requires C, 72.80; H, 7.40; N, 4.47%);

(1S∗,3R∗,4S∗)-1, N-Dimethyl-4-hydroxy-3-phenyl-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline 3d, R_f (5% MeOH/CH₂Cl₂) 0.5; IR v_max 3600–3250 (O-H); ¹H NMR (250 MHz, CDCl₃: δ 1.39 (3H, d, J 6.3, C₁Me), 2.23 (3H, s, NMe), 3.20 (1H, d, J 8.8, H-3), 3.82 (1H, q, J 6.3, H-1), 3.87 (6H, s, OMe), 3.93 (3H, s, OMe), 4.67 (1H, d, J 8.8, H-4), 6.94 (1H, s, H-5), 7.34–7.46 (5H, m, H_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 23.6 (C₁ CH₃), 41.9 (NMe), 55.6, 56.5, 56.5 (OMe), 60.4 (C-1), 71.7 (C-3), 72.6 (C-4), 102.7 (C _arom-H), 124.4, (C _arom-C), 127.6, 128.4 and 128.7 (C_arom-H), 133.2, 140.7 (C_arom-C), 141.5, 149.5 and 151.8 (C_arom-O); (Found: C, 69.87; H, 7.30; N, 4.10. C₂₀H₂₅NO₄ requires C, 69.93; H, 7.34; N, 4.08%);

(1R∗, 3R∗, 4S∗)-1, N-Dimethyl-4-hydroxy-3-phenyl-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline 3e, R_f (5% MeOH/CH₂Cl₂) 0.5; IR v_max 3500–3200 (O-H); ¹H NMR (250 MHz, CDCl₃): δ 1.37 (3H, d, J 6.4, C₁Me), 2.18 (3H, s, NMe), 3.79 (1H, d, J 7.9, H-3), 3.83 (3H, s, OMe), 3.85 (3H, s, OMe), 3.93 (3H, s, OMe), 4.15 (1H, q, J 6.4, H-1), 4.76 (1H, d, J 7.9, H-4), 6.81 (1H, s, H-5), 7.33–7.36 (5H, m, H_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 14.7 (C₁CH₃), 39.6 (NMe), 54.7, 55.8 (OMe), 60.7 (C-1), 66.4, 72.4 (C-3, C-4), 105.6 (C _arom-H), 126.8, (C _arom-C), 127.9, 128.6 and 129.1 (C_arom-H), 131.1, 139.7 (C _arom-C), 141.2, 149.4 and 152.5 (C_arom-O); (Found: C, 69.90; H, 7.38; N, 4.11. C₂₀H₂₅NO₄ requires C, 69.93; H, 7.34; N, 4.08%);

(1S∗,3R∗4S∗)-1,N-Dimethyl-4-hydroxy-3-(2-methoxyphenyl)-6,7,8-t rimethoxy-1,2,3,4-tetrahydroisoquinoline 3f, R_f (5% MeOH/CH₂Cl₂) 0.5; IR v_max 3500–3200 (O-H); ¹H NMR (250 MHz, CDCl₃): δ 1.38 (3H, d, J 6.3, C₁Me), 2.22 (3H, s, NMe), 3.15 (1H, d, J 8.8, H-3), 3.83 (3H, s, OMe), 3.87 (6H, s, OMe), 3.88 (1H, q, J 6.3, H-1), 3.93 (3H, s, OMe), 4.64 (1H, d, J 8.8, H-4), 6.91–6.94 (3H, m, H_arom), 7.36–7.37 (2H, m, H_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 23.4 (C₁ CH₃), 41.8 (NMe), 55.1, 55.2, 55.7, 55.8 (OMe), 60.6 (C-1), 71.7, 72.0 (C-3, C-4), 102.8, 114.0, 124.4, 129.9 (C _arom-H), 132.5, 133.2 and 140.8 (C _arom-C), 149.7, 141.2, 152.0 and 159.2 (C_arom-O); (Found: C, 67.53; H, 7.20; N, 3.62. C₂₁H₂₇NO₅ requires C, 67.52; H, 7.29; N, 3.75%)

Selected data for new dehydration and aromatization products 4, 5, and 6: 4: (85%), oil, R_f (5% MeOH/CH₂Cl₂) 0.5; IR v_max 3700 (O-H), 1630 (C=N); ¹H NMR (250 MHz, CDCl₃): δ 2.12 (1H, bs, O-H), 3.93 (6H, s, OMe), 3.94 (6H, s, OMe), 4.55 (dd, 1H, J 10.1, 2.4, H-3), 4.72 (1H, d, J 10.2, H-4), 6.85–6.92 (4H, m, H_arom), 7.07 (1H, s, H-5_arom), 8.30 (1H, s, H-1); ¹³C NMR (62.83 MHz, CDCl₃): δ 55.8, 55.9, 56.1 and 56.2 (OMe), 68.4, 70.7 (C-3, C-4), 108.0, 110.1, 111.0, 111.1, and 120.1 (C_arom-H), 120.5, 131.4, and 133.0 (C _arom-C), 148.5, 148.8, 149.1, and 152.1 (C_arom-O), 159.5 (C-1); (Found: C, 66.40; H, 6.20; N, 4.02. C₁₉H₂₁NO₅ requires C, 66.44; H, 6.17; N, 4.08%).

6,7-Dimethoxy-1,2-dimethyl-4-hydroxy-3-phenylisoquinolinum salt 5: m.p. 74–75°C (diethyl ether), R_f (10% MeOH/CH₂Cl₂) 0.1; IR: v_max 3600–3300 (O-H); ¹H NMR (250 MHz, CDCl₃): δ 3.46 (3H, s, C₁CH₃), 4.09 (3H, s, OMe), 4.14 (3H, s, OMe), 4,31 (3H, s, NMe), 7.35 (1H, s, H-8_arom), 7.63–7.41 (5H, m, H_arom), 7.81 (1H, s, H-5_arom); (Found: C, 73.55; H, 6.47; N, 4.52. C₁₉H₂₀NO₃ requires C, 73.51; H, 6.49; N, 4.51%).

6.7-Dimethoxy-1,2-dimethyl-3-phenyl-1,2-dihydroisoquinoline 6: oil, R_f (5% MeOH/CH₂Cl₂ 0.7; IR v_max 1510 (C=C); ¹H NMR (250 MHz, CDCl₃): δ 1.28 (3H, d, J 6.7, C₁CH₃), 2.66 (1H, s, NMe), 3.89 (6H, s, OMe), 4.24 (1H, q, J 6.7, H-1), 5.94 (1H, s, H-4), 6.60 (1H, s, H-8_arom), 6.66 (1H, s, H-5_arom), 7.32–7.58 (5H, m, H_arom); ¹³C NMR (62.83 MHz, CDCl₃): δ 19.9 (C₁ CH₃), 39.4 (NMe), 55.8, 56.1 (OMe), 58.8 (C-1), 104.6, 107.0, and 109.1 (C_arom-H, C-4), 125.1, 125.4 (C _arom-C, C-3), 127.6, 127.8, and 128.(C_arom-H), 138.1, 144.6, 147.4, and 148.0 (C _arom-C, C_arom-O); (Found: C, 77.30; H, 7.17; N, 4.65. C₁₉H₂₁O₂N requires C, 77.25; H, 7.17; N, 4.65%).