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Synlett 2005(2): 309-313  
DOI: 10.1055/s-2004-836031
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized 1,2,3,4-Tetrahydro-β-carboline Derived Enamines through Bischler-Napieralski Type Cyclization of Polarized Ketene N,S-Acetals

Sriparna Chakrabartia, Kausik Pandaa, Hiriyakkanavar Ila*a, Hiriyakkanavar Junjappa*b
a Department of Chemistry, Indian Institute of Technology, Kanpur - 208 016, India
Fax: +91(512)597436; Fax: +91(512)590260; e-Mail: hila@iitk.ac.in;
b BioOrganics and Applied Materials Pvt. Ltd., # B-64/1, III Stage, Peenya Industrial Area, Peenya, Bangalore-560 058, India
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Publication History

Received 7 October 2004
Publication Date:
29 November 2004 (online)

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Abstract

Synthesis of functionalized 1,2,3,4-tetrahydro-β-carboline derived enaminones, esters and nitriles has been developed via trifluoroacetic acid induced Bischler-Napieralski type cyclization of newly prepared polarized ketene N,S-acetals from tryptamine and polarized ketene dithioacetals.

Key words

enamines - esters - nitriles - natural products - β-carbolines - cyclization

17

General Procedure for the Bischler-Napieralski Type Intramolecular Cyclocondensation of N , S -Acetals 3a-j, 3l and Thioamide 6. Synthesis of 1-(Substituted)meth-ylene-1,2,3,4-tetrahydro-β-carbolines 4a-l: To a solution of the appropriate N,S-acetal or thioamide (3 mmol) in dry CH2Cl2 (15 mL), TFA (0.69 mL, 9 mmol) was added and the reaction mixture was stirred at r.t. or refluxed for 4-5 h (for 4e; monitored by TLC). The reaction mixture was poured into ice-cold water and extracted with CH2Cl2 (3 × 15 mL). The combined organic layer was washed with H2O (3 × 10 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure to afford the crude product which was purified by column chromatography over silica gel using hexane-EtOAc (8:2) as eluent.
Data for compound 4a: yield 66%; yellow solid (CHCl3-hexane); mp 170 °C (dec); R f = 0.42 (9:1 hexane-EtOAc). IR (KBr): 3333, 2960, 1603, 1284, 1200 cm-1. 1H NMR (400 MHz, CDCl3): δ = 2.89 (t, J = 7.1 Hz, 2 H, CH2), 3.43 (dt, J = 5.3, 7.1 Hz, 2 H, NCH2), 6.45 (s, 1 H, =CH), 7.07-7.28 (m, 6 H, ArH), 7.48-7.53 (m, 1 H, ArH), 7.97-7.99 (m, 2 H, ArH), 10.26 (br s, 1 H, NH), 10.81 (br s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 20.18, 40.04, 86.51, 112.07, 116.92, 119.54, 120.10, 124.80, 125.79, 127.01, 127.62, 128.16, 130.59, 137.93, 140.42, 153.23, 188.85. FAB-MS: m/z (%) = 289 (100) [M + 1]. Anal. Calcd for C19H16N2O (288.33): C, 79.14; H, 5.59; N, 9.72%. Found: C, 79.32; H, 5.42; N, 9.65%.
Data for compound 4f: yield 61%; orange solid (CHCl3-hexane); mp 234-235 °C; R f = 0.42 (9:1 hexane-EtOAc). IR (KBr): 3273, 2964, 1628, 1606, 1574 cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.11 (t, J = 7.1 Hz, 2 H, CH2), 3.37 (s, 3 H, NCH3), 3.75 (dt, J = 2.7, 7.1 Hz, 2 H, NCH2), 6.08 (br s, 1 H, NH), 6.91 (dd, J = 0.72, 7.6 Hz, 1 H, ArH), 7.07 (dt, J = 1.2, 7.6 Hz, 1 H, ArH), 7.11 (dt, J = 0.72, 7.6 Hz, 1 H, ArH), 7.16 (dt, J = 1.0, 7.8 Hz, 1 H, ArH), 7.29 (dt, J = 1.2, 7.8 Hz, 1 H, ArH), 7.44 (d, J = 7.6 Hz, 1 H, ArH), 7.52 (d, J = 8.3 Hz, 1 H, ArH), 7.59 (dd, J = 0.7 Hz, 8.3 Hz, 1 H, ArH), 14.22 (br s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 20.61, 26.15, 42.42, 95.39, 107.75, 112.99, 116.86, 118.15, 119.38, 119.78, 121.24, 123.74, 124.07, 124.87, 125.05, 127.33, 137.05, 138.49, 149.86, 167.95. FAB-MS: m/z (%) = 315 (100) [M+]. Anal. Calcd for C20H17N3O (315.36): C, 76.17; H, 5.43; N, 13.32%. Found: C, 76.32; H, 5.60; N, 13.14%.
Data for compound 4g: yield 65%; white solid (CHCl3-hexane); mp 152-153 °C; R f = 0.36 (9:1 hexane-EtOAc). IR (KBr): 3265, 2927, 2260, 1565, 1509 cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.08 (t, J = 7.1 Hz, 2 H, CH2), 3.66 (dt, J = 2.4, 7.1 Hz, 2 H, NCH2), 6.26 (br s, 1 H, NH), 7.15 (t, J = 7.0 Hz, 1 H, ArH), 7.35 (t, J = 7.1 Hz, 1 H, ArH), 7.41 (d, J = 8.3 Hz, 1 H, ArH), 7.56 (d, J = 8.3 Hz, 1 H, ArH), 9.31 (br s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 20.48, 41.37, 104.38, 112.67, 115.26, 117.91, 120.37, 120.84, 121.48, 123.15, 124.26, 127.45, 138.23, 168.37. FAB-MS: m/z (%) = 235 (50) [M + 1], 136 (100). Anal. Calcd for C14H10N4 (234.25): C, 71.78; H, 4.30; N, 23.92%. Found: C, 71.62; H, 4.46; N, 23.75%.
Data for compound 4h: yield 60%; yellow solid (DMF-EtOH); mp 220 °C (dec); R f = 0.40 (9:1 hexane-EtOAc). IR (KBr): 3334, 2985, 2192, 1665, 1595 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.37 (t, J = 7.1 Hz, 3 H, CH3), 3.11 (t, J = 7.3 Hz, 2 H, CH2), 3.69 (dt, J = 2.9, 7.3 Hz, 2 H, NCH2), 4.28 (q, J = 7.1 Hz, 2 H, CH2), 7.19 (t, J = 7.2 Hz, 1 H, ArH), 7.37 (t, J = 7.2 Hz, 1 H, ArH), 7.47 (d, J = 8.0 Hz, 1 H, ArH), 7.61 (d, J = 8.0 Hz, 1 H, ArH), 9.71 (br s, 1 H, NH), 9.87 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 14.39, 19.62, 40.12, 59.79, 113.44, 119.69, 120.03, 120.17, 120.33, 124.17, 124.23, 125.29, 125.56, 138.17, 155.49, 168.24. FAB-MS: m/z (%) = 282 (100) [M + 1]. Anal. Calcd for C16H15N3O2 (281.30): C, 68.31; H, 5.38; N, 14.94%. Found: C, 68.50; H, 5.46; N, 14.77%.
Data for compound 4k: yield 55%; white solid (CHCl3-hexane); mp 205-206 °C; R f = 0.27 (9:1 hexane-EtOAc). IR (KBr): 3216, 2931, 2235, 1640, 1511 cm-1. 1H NMR (400 MHz, CDCl3): δ = 3.02 (t, J = 6.6 Hz, 2 H, CH2), 3.44 (t, J = 6.6 Hz, 2 H, NCH2), 5.23 (br s, 1 H, NH), 7.15 (t, J = 7.8 Hz, 1 H, ArH), 7.28-7.33 (m, 2 H, ArH), 7.42-7.49 (m, 5 H, ArH), 7.57 (d, J = 8.0 Hz, 1 H, ArH), 9.68 (br s, 1 H, NH). 13C NMR (100 MHz, CDCl3): δ = 21.22, 41.46, 112.12, 117.39, 119.41, 120.39, 124.71, 125.08, 125.19, 125.66, 127.61, 128.93, 129.33, 129.52, 132.01, 136.93, 147.33. FAB-MS: m/z (%) = 285 (100) [M+]. Anal. Calcd for C19H15N3 (285.33): C, 79.97; H, 5.30; N, 14.73%. Found: C, 79.79; H, 5.51; N, 14.64%.
Data for compound 4l: yield 86%; yellow solid (CHCl3-hexane); mp 245-246 °C; R f = 0.35 (9:1 hexane-EtOAc). IR (KBr): 3220, 2936, 1602, 1550, 1511 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.99 (t, J = 6.6 Hz, 2 H, CH2), 3.67 (t, J = 6.6 Hz, 2 H, NCH2), 7.08 (t, J = 7.3 Hz, 1 H, ArH), 7.27 (t, J = 7.3 Hz, 1 H, ArH), 7.31 (s, 1 H, =CH), 7.42 (d, J = 7.8 Hz, 1 H, ArH), 7.61 (d, J = 7.8 Hz, 1 H, ArH), 9.85 (br s, 1 H, NH), 11.68 (br s, 1 H, NH). 13C NMR (100 MHz, DMSO-d 6): δ = 19.38, 40.41, 105.52, 112.36, 118.18, 120.06, 120.07, 124.71, 125.01, 125.42, 138.22, 146.89. FAB-MS: m/z (%) = 230 (100) [M + 1]. Anal. Calcd for C12H11N3O2 (229.23): C, 62.87; H, 4.84; N, 18.33%. Found: C, 62.68; H, 4.92; N, 18.46%.