New Synthetic Approach for the Preparation of 1-Aryl-3,4-dihydro­isoquinolines by Liebeskind–Srogl Reaction

Dedicated to Professor József Reiter on the occasion of his 75^th birthday

Abstract

An efficient synthetic methodology has been developed to construct 1-aryl-3,4-dihydroisoquinoline derivatives. The reaction was performed under neutral conditions by a palladium-catalyzed desulfitative carbon–carbon cross-coupling protocol.

Key words

isoquinolines - cross-coupling - Liebeskind–Srogl reaction - arylation - CuTC

• References and Notes

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• 20 General Procedure for the Synthesis of 1-Aryl-3,4-dihydroisoquinolines To the stirred solution of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1, 1.0 mmol, 0.18 g) in THF (10 mL) under argon atmosphere arylboronic acid (1.2 mmol), CuTC (3 equiv, 3.0 mmol, 0.57 g), and Pd(PPh₃)₄ (8 mol%, 0.08 mmol, 92 mg) were added. The reaction was followed by TLC and HPLC–MS. The mixture was refluxed until the starting material disappeared. After cooling, the solvent was evaporated and CHCl₃–MeOH (7:1) mixture (50 mL) was added. The crude reaction mixture was subsequently washed with 25% aq NH₃ (2 × 25 mL). The aqueous layer was extracted with CHCl₃–MeOH (7:1) mixture (2 × 25 mL). The combined organic phase was dried over Na₂SO₄ and the residue after evaporation purified by flash chromatography (silica gel 60 PF₂₅₄) using CH₂Cl₂–MeOH as the eluents. 1-[4-(Trifluoromethyl)phenyl]-3,4-dihydroisoquinoline (3c) Yield 0.21 g (76%), white crystals, mp 77–78 °C. IR (KBr): 2958, 1610, 1565, 1323, 1109, 846 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.73–7.68 (m, 4 H), 7.41–7.39 (m, 1 H), 7.30–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.90–3.67 (m, 2 H), 2.82 (t, J = 7.4 Hz, 2 H) ppm; lit.:^{22 1}H NMR (400 MHz, CDCl₃): δ = 7.70 (m, 4 H), 7.40 (m, 1 H), 7.26 (m, 2 H), 7.20 (m, 1 H), 3.88 (m, 2 H), 2.82 (m, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 142.5, 138.7, 131.2 (q, J = 33.0 Hz), 131.0, 129.2, 128.3, 127.6, 127.5, 126.7, 125.1 (q, J = 3.8 Hz), 124.1 (q, J = 272.0 Hz), 47.9, 26.2 ppm. HRMS: m/z calcd for C₁₆H₁₃NF₃ [M + H]⁺: 276.1000; found: 276.1002. 4-(3,4-Dihydroisoquinolin-1-yl)benzaldehyde (3d) Yield 0.21 g (89%), pale yellow crystals, mp 102–104 °C. IR (KBr): 2940, 1702, 1604, 1203 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 10.09 (s, 1 H), 7.96–7.94 (m, 2 H), 7.78–7.76 (m, 2 H), 7.41–7.40 (m, 1 H), 7.30–7.28 (m, 1 H), 7.27–7.25 (m, 1 H), 7.19–7.17 (m, 1 H), 3.90 (t, J = 7.3 Hz, 2 H), 2.83 (t, J = 7.3 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 191.8, 166.4, 144.8, 138.7, 136.8, 131.0, 129.5, 129.4, 128.3, 127.6, 127.4, 126.7, 47.9, 26.1 ppm. HRMS: m/z calcd for C₁₆H₁₄NO [M + H]⁺: 236.1075; found: 236.1081. Methyl 4-(3,4-Dihydroisoquinolin-1-yl)benzoate (3e) ²¹ Yield 0.23 g (85%), yellow oil. IR (film): 2950, 1724, 1610, 1279, 1104 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.11–8.09 (m, 2 H), 7.68–7.67 (m, 2 H), 7.42–7.38 (m, 1 H), 7.29–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.95 (s, 3 H), 3.90–3.87 (m, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 166.8, 166.6, 143.3, 138.7, 130.9, 130.8, 129.4, 128.8, 128.4, 127.6, 127.5, 126.7, 52.2, 47.8, 26.2 ppm. HRMS: m/z calcd for C₁₇H₁₆NO₂ [M + H]⁺: 266.1181; found: 266.1171. 4-(3,4-Dihydroisoquinolin-1-yl)-N,N-dimethylaniline (3f) Yield 0.08 g (32%), yellow crystals, mp 102–105 °C (MeCN). IR (KBr): 3444, 2888, 1608, 1525, 1346, 1195, 823 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.55–7.53 (m, 2 H), 7.40–7.36 (m, 2 H), 7.26–7.25 (m, 1 H), 6.74–6.73 (m, 2 H), 3.78 (t, J = 7.1 Hz, 2 H), 3.00 (s, 3 H), 2.76 (t, J = 7.1 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 166.7, 151.3 139.3, 130.2, 130.0, 129.1, 128.2, 127.2, 126.7, 126.3, 111.5, 65.5, 40.4, 26.6 ppm. HRMS: m/z calcd for C₁₇H₁₉N₂ [M + H]⁺: 251.1548; found: 251.1562. Benzyl [4-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3g) Yield 0.31 g (88%), white crystals, mp 194–195 °C (MeCN). IR (KBr): 3337, 2976, 1703, 1609, 1591, 1534, 1230, 1056, 744 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.57–7.55 (m, 2 H), 7.46–7.32 (m, 8 H), 7.31–7.21 (m, 3 H), 6.96 (s, 1 H), 5.22 (s, 2 H), 3.81 (t, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.6, 153.2, 138.9, 135.9, 134.0, 130.6, 129.7, 128.7, 128.6, 128.4, 127.8, 127.4, 126.5, 118.0, 67.1, 47.5, 26.3 ppm. HRMS: m/z calcd for C₂₃H₂₁N₂O₂ [M + H]⁺: 357.1603; found: 357.1598. 1-(1,3-Benzodioxol-5-yl)-3,4-dihydroisoquinoline (3j) ²² Yield 0.18 g (71%), yellow oil. IR (film): 2940, 1600, 1486, 1440, 1232, 1039, 936, 746 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.36 (m, 1 H), 7.33–7.31 (m, 1 H), 7.28–7.24 (m, 2 H), 7.14–7.09 (m, 2 H), 6.86–6.84 (m, 1 H), 6.00 (s, 2 H), 3.82–3.78 (m, 2 H), 2.78 (t, J = 7.3 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.4, 148.6, 147.5, 139.0, 133.1, 130.6, 128.7, 127.9, 127.3, 126.5, 123.1, 109.3, 107.8, 101.2, 47.5, 26.3 ppm. HRMS: m/z calcd for C₁₆H₁₃NO₂ [M+H]⁺: 251.0946; 251.0942. 1-(4-Fluorophenyl)-3,4-dihydroisoquinoline (3l) ²³ Yield 0.20 g (89%), yellow crystals, mp 37–38 °C (hexane). IR (KBr): 2941, 1604, 1506, 1152, 847 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.61–7.58 (m, 2 H), 7.41–7.37 (m, 1 H), 7.28–7.24 (m, 3 H), 7.12–7.09 (m, 2 H), 3.83 (t, J = 7.1 Hz, 2 H), 2.80 (t, J = 7.2 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 166.2, 163.5 (d, J = 249.0 Hz), 138.9, 135.1, 130.8, 130.7 (d, J = 8.3 Hz), 128.6, 127.7, 127.5, 126.6, 115.1 (d, J = 22.0 Hz), 47.6, 26.3 ppm. HRMS: m/z calcd for C₁₅H₁₃NF [M + H]⁺: 226.1032; found: 226.1033. 3-(3,4-Dihydroisoquinolin-yl)benzonitrile (3o) Yield 0.15 g (65%), pale yellow oil. IR (film): 2943, 2230, 1611, 1568, 1310, 708 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.93–7.92 (m, 1 H), 7.87–7.85 (m, 1 H), 7.74–7.72 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44–7.41 (m, 1 H), 7.31–7.26 (m, 2 H), 7.17–7.15 (m, 1 H), 3.87 (t, J = 7.2 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 165.4, 140.2, 138.7, 133.0, 132.7, 132.4, 131.2, 129.0, 127.9, 127.7, 127.2, 126.8, 118.4, 112.5, 47.8, 26.1 ppm. HRMS: m/z calcd for C₁₆H₁₃N₂ [M + H]⁺: 233.1079; found: 233.1069. tert-Butyl [3-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3p) Yield 0.25 g (76%), yellow oil. IR (KBr): 3232, 2975, 1723, 1609, 1549, 1240, 1159, 777 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 9.42 (s, 1 H), 7.74 (s, 1 H), 7.64–7.61 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.36–7.28 (m, 3 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 3.71 (t, J = 7.2 Hz, 2 H), 2.73 (t, J = 7.2 Hz, 2 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 165.8, 152.9, 139.5, 139.3, 138.6, 130.8, 128.9, 128.4, 127.6, 127.3, 126.8, 122.4, 119.0, 118.3, 79.2, 47.1, 28.3, 25.8 ppm. HRMS: m/z calcd for C₂₀H₂₃N₂O₂ [M + H]⁺: 323.1760; found: 323.1743. 1-(2-Fluorophenyl)-3,4-dihydroisoquinoline (3s) ²⁴ Yield 0.14 g (61%), yellow crystals, mp 79–80 °C (i-Pr₂O). IR (KBr): 3444, 2946, 1612, 1447, 1210, 768 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.53–7.50 (m, 1 H), 7.44–7.36 (m, 2 H), 7.26–7.21 (m, 3 H), 7.13–7.07 (m, 2 H), 3.90 (br s, 2 H), 2.87 (br s, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 163.9, 161.1, 160.0, 159.1, 137.2, 130.9, 130.8, 130.7, 127.4, 127.0 (d, J = 15.1 Hz), 124.3 (d, J = 3.4 Hz), 115.8 (d, J = 22.0 Hz), 94.8, 47.8, 26.0 ppm. HRMS: m/z calcd for C₁₅H₁₃NF [M + H]⁺: 226.1032; found: 226.1031. 1,1′-Benzene-1,4-diyldi-3,4-dihydroisoquinoline (3t) Yield 0.04 g (23%), white crystals, mp 198–199 °C (MeCN). IR (KBr): 3421, 2942, 1603, 1315 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.66–7.62 (m, 4 H), 7.48–7.45 (m, 2 H), 7.39–7.38 (m, 2 H), 7.36–7.32 (m, 2 H), 7.25–7.24 (m, 2 H), 3.76 (br s, 4 H), 2.77 (br s, 4 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 165.5, 139.4, 138.7, 130.9, 128.5, 127.8, 127.2, 126.9, 47.3, 25.8 ppm. HRMS: m/z calcd for C₂₄H₂₁N₂ [M + H]⁺: 337.1705; found: 337.1711.
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