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Synlett 2006(20): 3407-3410  
DOI: 10.1055/s-2006-956452
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel Chemoselective Desulfurization of γ-Phenylthio-Substituted Aromatic Lactams: Application to the Synthesis of Isoindolobenzazepine Alkaloid, Lennoxamine

Takamasa Suzuki, Kunihiko Takabe, Hidemi Yoda*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 4328561, Japan
Fax: +81(53)4781150; e-Mail: tchyoda@ipc.shizuoka.ac.jp;
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Publication History

Received 23 September 2006
Publication Date:
08 December 2006 (online)

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Abstract

Treatment of a variety of γ-phenylthio-substituted aromatic lactams with lithium aluminum hydride in the presence of cuprous iodide led to novel chemoselective desulfurization reactions to afford the corresponding substituted aromatic lactams without giving the carbonyl-reduced and/or ring-opened products in extremely high yields. This process was further applied to the total synthesis of an isoindolobenzazepine alkaloid, lennoxamine, by featuring the elaboration of the functionalized phthalimide derivative.

Key words

reductive desulfurization - lactams - LiAlH4-CuI - isoindolobenzazepine alkaloid - lennoxamine

4

Typical Experimental Procedure (Table 1, Entry 8):
Under N2 atmosphere, to a black solution of LiAlH4 (0.025 g, 0.664 mmol) and CuI (0.021 g, 0.111 mmol) in THF (0.5 mL) was added N-(p-methoxybenzyl)-3-benzyl-3-phenyl-thiophthalimidine (0.100 g, 0.221 mmol) in THF (1 mL) at -20 °C. After the mixture was stirred for 30 min at the same temperature, it was quenched with the addition of aq Et2O (1 mL) and filtered with celite pad, followed by extraction with EtOAc (3 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude was chromatographed and eluted with hexane-EtOAc (5:1) to give N-(p-methoxybenzyl)-3-benzylphthalimidine (0.071 g, 0.208 mmol) in 94% isolated yield. 1H NMR (CDCl3): δ = 2.81 (dd, J = 8.1, 13.4 Hz, 1 H), 3.37 (dd, J = 5.0, 13.6 Hz, 1 H), 3.79 (s, 3 H), 4.15 (d, J = 15 Hz, 1 H), 4.55 (dd, J = 4.8, 8.1 Hz, 1 H), 5.40 (d, J = 15 Hz, 1 H), 6.83-7.44 (m, 12 H), 7.81-7.84 (m, 1 H). IR (thin film): 747, 1032, 1250, 1514, 1690 cm-1.

7

Reduction of 7 with NaBH4 in MeOH afforded the reverse regioselective product predominantly (78:22, determined by 1H NMR). It is not clear at present which effect (stereoelectronic or steric effect) is more predominant on this regioselectivity.