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Synlett 2004(13): 2347-2350  
DOI: 10.1055/s-2004-832850
LETTER
© Georg Thieme Verlag Stuttgart · New York

Photodecarboxylative Benzylation of N-Alkylphthalimides: A Concise Route to the Aristolactam Skeleton

Axel G. Griesbeck*a, Klaus-Dieter Warzechaa, Jörg M. Neudörfla, Helmut Görnerb
a University of Cologne, Institute of Organic Chemistry, Greinstr. 4, 50939 Köln, Germany
b Max-Planck-Institut für Bioanorganische Chemie, 45413 Mülheim an der Ruhr, Germany
Fax: +49(221)4705057; e-Mail: griesbeck@uni-koeln.de;
Further Information

Publication History

Received 15 July 2004
Publication Date:
24 September 2004 (online)

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Abstract

The photoinitiated metal-free benzylation of N-alkyl ­phthalimides with arylacetates in aqueous solution followed by acid-catalyzed dehydration serves as a convenient route to methoxy-substituted precursors to phenanthrene lactam alkaloids.

Key words

electron transfer - photochemistry - radical reactions - eliminations - aristolactam alkaloids

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Detailed report: Warzecha, K.-D.; Görner, H.; Griesbeck, A. G., manuscript in preparation.

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Typical Procedure: A solution of 10 mMol of N-alkyl-phthalimide 1, 12.5 mmol of arylacetic acid and 6 mmol of K2CO3 in 400 mL of a acetone-H2O (3:1) mixture is irradiated at λ = 300 nm in a Rayonet photoreactor under a gentle stream of nitrogen at r.t. The reaction progress is monitored by TLC and pH-control; complete conversion of the phthalimide is typically achieved after 4-6 h with a final pH of 9-10. Removal of the acetone from the reaction mixture on a rotary evaporator yields the white, semi-crystalline addition product, which is filtered off and dried. When using the conditions of excimer irradiation (cf. ref. [10] ), 20-30 g of crude product are obtained in 4-6 h of irradiation in a flow setup with a 308 nm XeCl excimer system with 3.0 kW electrical power and an approximate photon flux of 3.5 Einstein/h. The crude material was thoroughly washed with concd aq NaHCO3 and H2O and the solid material recrystallized from EtOH to give an average yield of 91 ± 5%.
3-(4-Methoxybenzyl)-3-hydroxy-2-methylisoindolin-1-one(3b):
Colorless needles, mp 148 °C (from EtOH). 1H NMR (300 MHz, acetone-d 6): δ = 7.55 (d, J = 1.18 Hz, 1.18 Hz, 1 H), 7.54 (d, J = 1.24 Hz, 1 H), 7.43 (dd, 1 H, J = 2.70 Hz, 1.40 Hz, 1 H), 7.41-7.37 (m, 1 H), 6.82 (approx. dt, J = 8.76 Hz, 2 H), 6.62 (approx. dt, J = 8.78 Hz, 2 H), 3,44 (d, J = 13.96 Hz, 1 H), 3.24 (d, J = 13.96 Hz, 1 H), 3.03 (s, 1 H).
13C NMR (300 MHz, acetone-d 6): δ = 166.6, 158.9, 147.7, 132.7, 131.7, 131.4, 129.4, 127.7, 123.4, 122.6, 113.5, 90.9, 54.1, 41.8, 23.7. HRMS: m/z calcd for C17H15NO2 [M+ - H2O]: 265.1103; found: 265.110. Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.98; H, 6.03; N, 4.92.
3-(3,4-Dimethoxybenzyl)-3-hydroxy-2-methylisoindolin-1-one(3c): Colorless needles, mp 145 °C (from EtOH). 1H NMR (300 MHz, acetone-d 6): δ = 7.64-7.62 (m, J = 7.42 Hz, 1.10 Hz, 1 H), 7.61-7.55 (m, 1 H), 7.47-7.39 (m, 1 H), 6.64 (d, J = 8.19 Hz, 1 H), 6.49 (dd, J = 8.19 Hz, 2.03 Hz, 1 H), 6.33 (d, J = 2.03 Hz, 1 H), 3.66 (s, 1 H), 3.48 (s, 3 H), 3.43 (d, J = 13.96 Hz, 1 H), 3.26 (d, J = 13.94 Hz, 1 H), 3.03 (s, 3 H). 13C NMR (300 MHz, acetone-d 6): δ = 167.7, 150.3, 150.0, 149.1, 133.0, 130.7, 124.7, 123.9, 115.4, 112.9, 92.3, 56.7, 56.7, 43.4, 24.9. HRMS: m/z calcd for C18H17NO3 [M+ - H2O]: 295.1208; found: 295.121. Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 68.94; H, 6.12; N, 4.41.

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X-ray structure analyses of compounds 3b (CCDC 244764) and E-4b (CCDC 244765) (from EtOH, colorless needles): The data were obtained from a Nonius Kappa CCD-diffractometer (MoKα irradiation) at 100 K. Structure was solved with direct methods and refinement against F 2 (SHELXL-97) with all independent reflexes.

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Typical Procedure: To a cooled solution (0 °C) of 3.5 mmol 3 in 100 mL CH2Cl2 5 drops of concd H2SO4 are added. When TLC monitoring reveals the complete disappearance of the starting material from the deep yellow reaction mixture (not later than after 15 min) solid Na2CO3 is added. After filtration and evaporation of the solvent deep yellow oil is obtained, from which the benzylidene isoindolinones are isolated in a total yield of 85% by column chromatography on silica using cyclohexane-EtOAc (7:3 → 1:1) as eluent.
( E )-3-(4-Methoxybenzylidene)-2-methylisoindolin-1-one ( E -4b):
Colorless needles, mp 144 °C (from benzene). 1H NMR (300 MHz, CDCl3): δ = 7.83 (dm, J = 7.15 Hz, 1.28 Hz, 1 H), 7.43-7.28 (m, 5 H), 6.96 (dm, J = 8.72 Hz, 2 H), 6.46 (s, 1 H), 3.88 (s, 3 H), 3.37 (s, 3 H). 13C NMR (300 MHz, CDCl3): δ = 166.4, 159.2, 136.8, 134.8, 131.3, 130.7, 130.5, 128.9, 127.3, 123.0, 122.8, 114.0, 110.1, 55.3, 26.0. HRMS: m/z calcd for C17H15NO2 [M+]: 265.1103; found: 265.110. Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.94; H, 5.58; N, 5.25.

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3-(3,4,5-Trimethoxybenzyl)-3-hydroxy-5,6-dimethoxy-2-methylisoindolin-1-one(5):
Colorless needles, mp 214 °C (from EtOH). 1H NMR (300 MHz, CDCl3): δ = 7.22 (s, 1 H), 6.78 (s, 1 H), 6.17 (s, 2 H), 3.76 (s, 3 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.65 (s, 6 H), 3.41 (d, J = 13.78 Hz, 1 H), 2.93 (s, 3 H), 2.77 (d, J = 13.82 Hz, 1 H). 13C NMR (300 MHz, CDCl3): δ = 167.1, 152.6, 152.0, 150.3, 139.4, 130.5, 123.6, 107.5, 105.5, 104.5, 89.7, 60.8, 56.1, 56.0, 43.2, 23.9. HRMS: m/z calcd for C21H23NO6 [M - H2O]+: 385.1525; found: 385.152.