Intramolecular Diels–Alder Furan-Mediated Synthesis of 8-Aryl-3,4-di-hydroisoquinolin-1(2H)-ones, Convenient Precursors of Indeno[1,2,3-ij]isoquinolines

Abstract

We describe herein preliminary studies on the intramolecular Diels–Alder furan-mediated synthesis of 8-aryl-3,4-dihydroisoquinolin-1(2H)-ones that constitutes a new, formal synthesis of indeno[1,2,3-ij]isoquinolines.

Key words

alkaloids - 8-arylisoquinolines - indeno[1,2,3-ij]isoquinolines - Bischler–Napieralski cyclization - intramolecular Diels–Alder furan reaction

• References and Notes

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Unsuccessful conditions to promote the IMDAF cyclization of 6a that resulted in the recovering of the starting material:
• 11a toluene, reflux, 5 d;
• 11b 145 °C, 21 h (no solvent);
• 11c MgBr₂, THF, MS, reflux, 21 h;
• 11d AlCl₃, THF, MS, reflux, 3 d;
• 11e 11·10³ bar, CH₂Cl₂, 20 °C, 1 d.
• 12 Synthesis of (4aR,7S,8aS)-2-Benzyl-8-phenyl-2,3,4,7,8,8a-hexahydro-1H-4a,7-epoxyisoquinolin-1-one (7a) A solution of amide 6a (60 mg, 0.181 mmol) in anhydrous CH₂Cl₂ (2 mL) was subjected to high pressure (19·10³ bar) at 27 ° C for 7 d. On depressurization, the solution was filtered through a plug of cotton wool to remove the solid matter, and the solvent was removed off under reduced pressure to afford 50 mg of crude material. Purification by column chromatography on silica (eluant: 1:1 light PE–Et₂O) furnished the cycloadduct 7a as a colorless oil (29 mg, 49% yield) and 15 mg (25% yield) of recovered starting 6a (64% yield of 7a on the basis of recovered starting material).
• 13 All new compounds gave satisfactory analytical and spectroscopic data. Selected Physical and Spectroscopic Data Compound 7a: ¹H NMR (CDCl₃, 250 MHz): δ = 2.23–2.29 (m, 2 H, CH₂CN), 2.60 (d, 1 H, J = 4.9 Hz, H_8a), 3.19–3.27 (m, 1 H, CH₂-N), 3.44–3.56 (m, 1 H, CH₂N), 3.72 (t, 1 H, J = 4.7 Hz, H₈), 4.34 (d, 1 H, J = 14.7 Hz, CH₂Ph), 4.84 (d, 1 H, J = 14.7 Hz, CH₂Ph), 5.13 (d, 1 H, J = 4.6 Hz, H₇), 6.27 (s, 2 H, HC=CH), 7.12–7.41 (m, 10 H, 10 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 26.0 (CH₂), 43.2 (CH₂), 50.3 (CH₂), 50.6 (CH), 50.7 (CH), 81.4 (CH), 87.5 (C), 126.5 (CH), 127.4 (CH), 128.0 (2 × CH), 128.1 (2 × CH), 128.3 (2 × CH), 128.6 (2 × CH), 136.5 (CH), 137.1 (CH + C), 139.8 (C), 171.2 (C=O) ppm. MS (CI): m/z (%) = 332 (53) [M + 1]⁺, 131 (100). HRMS: m/z calcd for C₂₂H₂₂NO₂: 331.1572; found: 331.1580. Compound 7b: ¹H NMR (CDCl₃, 250 MHz): δ = 2.21–2.27 (m, 2 H, CH₂CN), 2.56 (d, 1 H, J = 4.8 Hz, H_8a), 3.18–3.24 (m, 1 H, CH₂N), 3.40–3.48 (m, 1 H, CH₂N), 3.65 (t, 1 H, J = 4.7 Hz, H₈), 3.70 (s, 6 H, 2 × OCH₃), 4.39 (d, 1 H, J = 14.7 Hz, CH₂Ph), 4.77 (d, 1 H, J = 14.7 Hz, CH₂Ph), 5.07 (dd, 1 H, J = 4.6, 1.4 Hz, H₇), 6.23–6.30 (m, 3 H, 3 × ArH), 6.44–6.46 (m, 2 H, HC=CH), 7.20–7.26 (m, 5 H, 5 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 26.0 (CH₂), 43.2 (CH₂), 50.2 (CH₂), 50.6 (CH), 51.8 (CH), 55.2 (2 × OMe), 81.3 (CH), 87.4 (C), 98.3 (CH), 106.4 (2 × CH), 127.3 (CH), 127.9 (2 × CH), 128.6 (2 × CH), 136.5 (CH), 137.0 (CH + C), 142.2 (2 × C), 160.5 (2 × COMe), 171.1 (C=O). MS (CI): m/z (%) = 392 (100) [M + 1]⁺. HRMS: m/z calcd for C₂₄H₂₅NO₄: 391.1783; found: 391.1778. Compound 7c: mp 101–102 °C (MeOH). ¹H NMR (CDCl₃, 250 MHz): δ = 2.19–2.25 (m, 2 H, CH₂CN), 2.56 (d, 1 H, J = 4.9 Hz, H_8a), 3.14–3.23 (m, 1 H, CH₂N), 3.40–3.46 (m, 1 H, CH₂N), 3.67 (t, 1 H, J = 4.7 Hz, H₈), 3.69 (s, 3 H, OMe), 4.36 (d, 1 H, J = 14.7 Hz, CH₂Ph), 4.77 (d, 1 H, J = 14.7 Hz, CH₂Ph), 5.08 (1 H, dd, J = 4.8, 0.9 Hz, H₇), 6.22 (d, 1 H, d, J = 5.9 Hz, CH=CH), 6.25 (d, 1 H, J = 5.9 Hz, CH=CH), 6.64–6.67 (m, 1 H, m, ArH), 6.82–6.86 (m, 2 H, m, 2 × ArH), 7.07–7.24 (m, 6 H, 6 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 26.4 (CH₂), 43.7 (CH₂), 50.7 (CH₂), 51.1 (CH), 52.1 (CH), 55.6 (OMe), 81.8 (CH), 87.9 (C), 112.2 (CH), 114.6 (CH), 120.9 (CH), 127.9 (CH), 128.6 (2 × CH), 128.9 (2 × CH), 129.6 (CH), 137.0 (CH), 137.6 (CH + C), 142.0 (C), 159.9 (COMe), 171.6 (C=O) ppm. MS (CI): m/z (%) = 362 (100) [M + 1]⁺. Anal. Calcd for C₂₃H₂₃NO₃: C, 76.43; H, 6.41; N, 3.87. Found: C, 76.30; H, 6.37; N, 3.83. Compound 8a: mp 138–140 °C (MeOH). ¹H NMR (CDCl₃, 250 MHz): δ = 2.82 (t, 2 H, J = 6.3 Hz, CH₂CN), 3.45 (t, 2 H, J = 6.3 Hz, CH₂N), 4.63 (s, 2 H, CH₂Ph), 7.05–7.30 (m, 13 H, 13 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 29.6 (CH₂), 44.9 (CH₂), 50.1 (CH₂), 126.1 (CH), 126.6 (CH), 127.3 (CH), 127.6 (2xCH), 127.8 (C), 128.0 (2 × CH), 128.2 (2 × CH), 128.5 (2 × CH), 130.4 (CH), 130.6 (CH), 137.8 (C), 139.8 (C), 142.9 (C), 144.1 (C), 163.8 (C=O) ppm. MS (CI): m/z (%) = 314 (100) [M + 1]⁺. HRMS: m/z calcd for C₂₂H₁₉NO: 313.1467; found: 313.1466. Compound 8b: ¹H NMR (CDCl₃, 250 MHz): δ = 2.90 (t, 2 H, J = 6.2 Hz, CH₂CN), 3,52 (t, 2 H, J = 6.2 Hz, CH₂N), 3.80 (s, 6 H, 2 × OCH₃), 4.71 (s, 2 H, CH₂Ph), 6.45–6.48 (m, 3 H, 3 × ArH), 7.13–7.40 (m, 8 H, 8 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 29.6 (CH₂), 45.2 (CH₂), 50.3 (CH₂), 55.2 (2 × OMe), 98.9 (CH), 106.7 (2 × CH), 126.2 (CH), 127.3 (CH), 128.0 (2 × CH + C), 128.5 (2 × CH), 130.3 (CH), 130.4 (CH), 137.9 (C), 139.8 (C), 143.9 (C), 145.0 (C), 159.9 (2 × COMe), 163.6 (C=O) ppm. MS (CI): m/z (%): 374 (100) [M + 1]⁺. HRMS: m/z calcd for C₂₄H₂₃NO₃: 373.1678; found: 373.1677. Compound 8c: ¹H NMR (CDCl₃, 250 MHz): δ = 2.82 (t, 2 H, J = 6.4 Hz, CH₂CN), 3.45 (t, 2 H, J = 6.4 Hz, CH₂N), 3.75 (s, 3 H, OMe), 4.70 (s, 2 H, CH₂Ph), 6.70–6.82 (m, 3 H, 3 × ArH), 7.16–7.31 (m, 9 H, 9 × ArH) ppm. ¹³C NMR (CDCl₃, 62.5 MHz): δ = 30.1 (CH₂), 45.5 (CH₂), 50.6 (CH₂), 55.6 (OMe), 112.5 (CH), 114.5 (CH), 121.4 (CH), 126.7 (CH), 127.8 (CH), 128.4 (2 × CH), 128.5 (3 × CH), 130.9 (CH), 131.0 (CH), 138.4 (C), 140.3 (C), 144.4 (C), 144.8 (C), 159.4 (COMe), 164.1 (C=O) ppm. MS (CI): m/z (%) = 344 (100) [M + 1]⁺. HRMS: m/z calcd for C₂₂H₂₁NO₂: 343.1572; found: 343.1580.
• 14 Synthesis of 2-Benzyl-8-phenyl-3,4-dihydroisoquinolin-1(2H)-one (8a) Concentrated HCl (0.1 mL) was added to a solution of cycloadduct 7a (50 mg, 0.151 mmol) in MeOH (5 mL), and the mixture was refluxed for 4 h. The solution was neutralized with 2 M aq NaOH and extracted with CH₂Cl₂ (3 × 8 mL). The pooled organic extracts were washed with H₂O (15 mL) and dried (anhydrous sodium sulfate). Removal of the solvent under reduced pressure afforded a residue, which was purified by preparative TLC on silica (eluant: 1:1 light PE–Et₂O) to give 40 mg (85% yield) of isoquinoline 8a as a white solid.
• 15 The crystallographic data of compound 7c have been included in the Supporting Information.