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Synlett 2013; 24(17): 2221-2224
DOI: 10.1055/s-0033-1339693
letter
© Georg Thieme Verlag Stuttgart · New York

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

Mónica Treus
a   Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain   Fax: +34(981)591014   Email: ramon.estevez@usc.es
b   Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK   Fax: +44(118)3786121   Email: l.m.harwood@reading.ac.uk
,
Laurence M. Harwood*
b   Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK   Fax: +44(118)3786121   Email: l.m.harwood@reading.ac.uk
,
Juan C. Estévez
a   Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain   Fax: +34(981)591014   Email: ramon.estevez@usc.es
,
Cristian Salas
c   Departamento de Química Orgánica, Pontificia Universidad Católica de Chile, 702843 Santiago de Chile, Chile
,
Michael G. B. Drew
b   Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK   Fax: +44(118)3786121   Email: l.m.harwood@reading.ac.uk
,
Ramón J. Estévez*
a   Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain   Fax: +34(981)591014   Email: ramon.estevez@usc.es
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Further Information

Publication History

Received: 06 August 2013

Accepted after revision: 12 August 2013

Publication Date:
04 October 2013 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • 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, H8a), 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, H8a), 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, H8a), 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.