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Synlett 2006(13): 2016-2020  
DOI: 10.1055/s-2006-947351
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Benz[c]benzothiopheno[2,3-e]azepines via Heck-Type Coupling and Pictet-Spengler Reaction

Emilie David, Claudine Rangheard, Stéphane Pellet-Rostaing, Marc Lemaire*
Université Claude Bernard Lyon 1, Laboratoire de Catalyse et Synthèse Organique, CPE Bât 308, UMR 5181, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72431408; e-Mail: marc.lemaire@univ-lyon1.fr;
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Publication History

Received 18 March 2006
Publication Date:
12 July 2006 (online)

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Abstract

New benz[c]benzothiopheno[2,3-e]azepine derivatives 1 of potential biological properties were synthesised in four steps from bromobenzo[b]thiophene. The synthetic pathway is based on ‘Heck-type’ and Pictet-Spengler reactions.

Key words

azepine - benzo[b]thiophene - fused-ring systems - Heck reaction - Pictet-Spengler reaction

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General Procedure for Preparation of Compounds 6. In a 1 M solution of 3-cyanobenzo[b]thiophene(5) in anhyd DMF were successively added under inert atmosphere DCH-18-C-6 (1 equiv), K2CO3 (3 equiv), 3-cyano-benzo[b]thiophene (5) and aryl bromide (1.1 equiv). The mixture was heated at 100 °C for 5 min and Pd(OAc)2 (0.05 equiv) was added. The resulting mixture was then heated at 130 °C overnight. After cooling to r.t., the mixture was filtered over Celite®, which was rinsed with CH2Cl2. The combined organic layers were successively washed with H2O and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of 3-Cyano-2-(3′,4′,5′-trimethoxy-phenyl)benzo[ b ]thiophene ( 6a).
Off-white solid obtained in 70% yield after flash chromatography (heptane-CH2Cl2 = 7:3) of the crude product; R f = 0.5 (CH2Cl2); mp 148-150 °C. 1H NMR (300 MHz, CDCl3): δ = 3.93 (s, 3 H), 3.96 (s, 6 H), 7.13 (s, 2 H), 7.42-7.55 (m, 2 H), 7.83 (d, 1 H, J = 7.9 Hz), 7.96 (d, 1 H, J = 7.9 Hz). 13C NMR (75 MHz, CDCl3): δ = 56.5 (2 CH3), 61.2 (CH3), 101.8 (C), 105.7 (2 CH), 115.5 (C), 122.4 (CH), 122.6 (CH), 126.2 (CH), 126.3 (CH), 126.9 (C), 137.2 (C), 139.3 (C), 140.2 (C), 153.8 (2 C), 155.2 (C). Anal. Calcd for C18H15NO3S: C, 66.44; H, 4.65; N, 4.30; S, 9.85. Found: C, 66.64; H, 4.63; N, 4.31; S, 9.20. MS (EI+): m/z = 325 [M+].

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General Procedure for the Preparation of Compounds 7. To a 0.3 M stirred solution of 2-aryl-3-cyanobenzo[b]thio-phene (6) in anhyd THF was added dropwise at 0 °C under inert atmosphere a 1 M borane solution in THF (2 equiv). The resulting mixture was allowed to warm at r.t. and then stirred at reflux until completion of the reaction. The reaction mixture was cooled to 0 °C, hydrolysed with a 6 M HCl aq solution, neutralised with a 2 M NaOH aq solution and then extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of C -[2-(3,4,5-Trimethoxyphen-yl)benzo[ b ]thiophen-3-yl]methylamine ( 7a).
Pale yellow oil obtained in 63% yield after flash chromatography (CH2Cl2-MeOH = 98:2) of the crude product; R f = 0.2 (CH2Cl2-MeOH = 98:2). 1H NMR (300 MHz, CDCl3): δ = 1.49 (br s, 2 H), 3.89 (s, 6 H), 3.91 (s, 3 H), 4.11 (s, 2 H), 6.88 (s, 2 H), 7.30-7.42 (m, 2 H), 7.80-7.83 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 37.8 (CH2), 56.2 (2 CH3), 60.9 (CH3), 121.2 (2 CH), 122.3 (CH), 124.4 (CH), 124.5 (CH), 129.5 (2 C), 138.1 (C), 139.0 (C), 139.9 (C), 140.5 (C), 153.2 (2 C). Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25; S, 9.73. Found: C, 65.39; H, 5.89; N, 4.13; S, 10.00. MS (EI+): m/z = 329 [M+].

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General Procedure for Preparation of Compounds 8-14. To a 0.2 M stirred solution of compound 7 in anhyd toluene was added the para-substituted benzaldehyde derivative (1.05 equiv). The reaction mixture was heated at reflux until total conversion of the amine into the imine intermediary (followed by 1H NMR). The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved in TFA to have a 1 M solution. The resulting reaction mixture was heated at r.t. until completion of the reaction. Residual TFA was neutralised with an aq sat. Na2CO3 solution. The reaction mixture was extracted with CH2Cl2. The combined organic layers were successively washed with H2O and brine, dried over MgSO4, filtered and solvents were removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of 5-( p -Chlorophenyl)-2,3,4-trimethoxy-5,6,7-trihydrobenz[ c ]benzothiopheno[2,3- e ]azepine ( 8b).
Pale yellow solid obtained in 57% yield after flash chromatography (CH2Cl2-MeOH = 99.5:0.5) of the crude product; R f = 0.2 (CH2Cl2-MeOH = 99:1). 1H NMR (300 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.92 (s, 3 H), 3.97 (d, 1 H, J = 17.3 Hz), 4.00 (s, 3 H), 4.25 (d, 1 H, J = 17.3 Hz), 6.05 (s, 1 H), 7.07-7.14 (m, 4 H), 7.24 (s, 1 H), 7.27-7.31 (m, 2 H), 7.42 (m, 1 H), 7.74 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 44.0 (CH2), 56.2 (CH3 + CH), 61.0 (CH3), 61.6 (CH3), 109.3 (CH), 121.5 (CH), 121.8 (CH), 124.3 (CH), 125.0 (CH), 128.5 (2 CH), 129.1 (C), 129.5 (C), 129.8 (2 CH), 132.6 (C), 133.7 (C), 137.5 (C), 137.9 (C), 138.6 (C), 139.8 (C), 141.8 (C), 151.4 (C), 152.5 (C). Anal. Calcd for C25H22ClNO3S: C, 66.44; H, 4.91; Cl, 7.84; N, 3.10; S, 7.09. Found: C, 66.55; H, 5.06; Cl, 7.61; N, 2.92; S, 7.24. MS (ESI+): m/z = 452 [MH+].