Synthesis of Novel Pyrrolo[3,2-c]carbazole and Dipyrrolo[3,2-c:2′,3′-g]carbazole Derivatives

Abstract

Pyrrolocarbazole and dipyrrolocarbazoles have been synthesized via the Hemetsberger indole synthesis, starting from 9-ethyl carbazole-3-carbaldehyde and 9-ethylcarbazole-3,6-dicarbaldeyde, respectively. The pyrrolocarbazole structures were confirmed through ¹H NMR, ¹³C NMR, IR, mass spectrometry and single crystal X-ray diffraction techniques. The targeted compounds showed potent in vitro cytotoxicity against human colon cancer HT29 cells.

Key words

carbazole - pyrrolocarbazole - Hemetsberger indolization - HT29 cells - cyctotoxicity

• References and Notes

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• 18 A solution of sodium methoxide was prepared via the portionwise addition of metallic sodium (1.2 g, 52.17 mmol) to pre-cooled anhyd MeOH (40 mL) with stirring under nitrogen. The sodium methoxide solution was stirred and cooled to –15 °C in an ice-salt slurry before the dropwise addition of a solution containing the carbazole-3-carbaldehyde 2 (1.064 g, 4.77 mmol) and methyl azidoacetate (5.37 g, 46.5 mmol) in anhyd THF (6 mL) over 1 h. The mixture was stirred for a further 3 h with cooling and then poured onto crushed ice. The resulting precipitate was filtered and purified by flash column chromatograpy using CH₂Cl₂/hexane (5:5) as eluent to give the title compound 3 as a yellow solid (1.08 g, 71%); mp 107–109 °C. IR (KBr): 3071, 2983, 2950, 2120, 1708, 1592, 1497, 1471, 1430, 1371, 1336, 1250, 1228, 1155, 1078, 915, 807, 744 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.46 (m, 3 H, Me), 3.95 (s, 3 H, OMe), 4.40 (d, J = 7.0 Hz, 2 H, CH₂), 7.19–7.31 (m, 2 H, aryl H), 7.40–7.52 (m, 3 H, aryl H), 7.98 (m, 1 H, aryl H), 8.17 (d, J = 7.0 Hz, 1 H, alkyl H), 8.64 (s, 1 H, aryl H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8 (Me), 37.7 (CH₂), 52.7 (OMe), 108.8, 108.8, 119.5, 120.6, 122.2, 123.1, 123.4, 124.2, 126.1, 127.4, 128.8, 140.4 (aryl C), 168.8 (C=O). Maldi (TOF): m/z = 292 [M – 2 N].
• 19 The azidocinnamate 3 (1 g, 3.12 mmol) was dissolved in 1,2-dichlorobenzene (30 mL) and the resulting mixture was heated at reflux for 3 h. The solvent was then removed under reduced pressure and the residue was purified by flash column chromatograpy using CH₂Cl₂/hexane (8:2) as eluent to give the title compound 4 (0.76 g, 83%); mp 144–146 °C. IR (KBr): 3336, 1690, 1638, 1536, 1493, 1342, 1307, 1256, 1200, 1178, 1148 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.46 (t, J = 7.1 Hz, 3 H, Me), 3.97 (s, 3 H, OMe), 4.46 (q, 2 H, J = 7.1 Hz, CH₂), 7.27–7.51 (m, 5 H, aryl H), 7.74 (d, J = 8.7 Hz, 1 H, aryl H), 8.24 (d, J = 8.7 Hz, 1 H, aryl H), 9.54 (s, 1 H, pyrrolo NH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.1 (Me), 38.0 (CH₂), 51.8 (OMe), 104.9, 108.9, 110.6, 119.4, 120.6, 120.6, 121.2, 121.2, 124.2, 124.8, 132.1, 138.5, 138.8, 162.5 (aryl C). Maldi (TOF): m/z = 293 [M + H]⁺. HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₈H₁₆N₂O₂ : 293.1290; found: 293.1291.
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• 21 CCDC 1049555 (for 4) and 1400624 (for 9a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
• 22 A solution of sodium ethoxide was prepared via the portionwise addition of metallic sodium (0.6 g, 26.09 mmol) to pre-cooled anhyd EtOH (50 mL) with stirring under nitrogen. The sodium ethoxide solution was stirred and cooled to –5 °C in an ice-salt slurry before the addition of a solution containing the carbazole-3,6-dicarbaldehyde 6 (1.87 g, 7.42 mmol), methyl azidoacetate (9.83 g, 85.55 mmol) and ethyl trifluoroacetate (2.9 mL, 24.44 mmol) in anhyd THF (11 mL). The mixture was stirred for a further 3 h with cooling and then poured onto crushed ice. The resulting precipitate was filtered and purified (only for characterization) by flash column chromatograpy using CH₂Cl₂/hexane (5:5) as eluent to give the title compound 7b as a yellow solid (1.47 g, 42%); mp 131–133 °C. IR (KBr): 3382, 2981, 2108, 1699, 1590, 1483, 1365, 1304, 1228, 1196, 1157, 1129, 1078, 1018, 899, 801 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.43–1.49 (m, 9 H, 3 × Me), 4.37–4.43 (m, 6 H, 3 × CH₂), 7.17 (s, 2 H, alkyl H), 7.42 (d, J = 8.9 Hz, 2 H, aryl H), 8.03 (t, J = 7.5 Hz, 2 H, aryl H), 8.62 (s, 2 H, aryl H). Maldi (TOF): m/z = 418 [M – 4 N].
• 23 The azidocinnamate 7b (1.47 g, 3.11 mmol) was dissolved in 1,2-dichlorobenzene (30 mL) and the resulting mixture was heated at reflux for 3 h. The solvent was then removed under reduced pressure and the residue was purified by flash column chromatograpy using CH₂Cl₂/hexane (8:2) as eluent to give the title compound 9b (0.77 g, 60%); mp 227–229 °C. IR (KBr): 3477, 3361, 2975, 1698, 1670, 1633, 1532, 1499, 1388, 1345, 1300, 1257, 1198, 1154, 1017, 782, 743 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.63 (d, J = 5.7 Hz, 9 H, 3 × Me), 4.54–4.65 (m, 6 H, 3 × CH₂), 7.49 (s, 2 H, aryl H), 7.62 (s, 2 H, aryl H), 7.84 (d, 2 H, aryl H), 10.82 (s, 2 H, pyrrolo NH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.3, 14.4 (Me), 38.6, 61.0 (CH₂), 105.2, 119.5, 119.6, 121.7, 124.8, 132.0, 137.4, (aryl C), 163.3 (C=O). Maldi (TOF): m/z = 418 [M + H]⁺. HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₂₄H₂₃N₃O₄: 440.1586; found: 440.1577.
• 24 Walsh CT, Tsodikova SG, Howard-Jones AR. Nat. Prod. Rep. 2006; 23: 517
• 25 Pyrrolo carbazole 4 (1 g, 3.42 mmol) was heated to reflux in ethanolic (30 mL) potassium hydroxide (1.15 g, 20.55 mmol) for 3 h. After cooling, the solution was acidified with 5 M HCl and the resulting precipitate was filtered, washed with H₂O and dried to yield the carboxylic acid 11 as a green solid (0.73 g, 77%); mp 232–234 °C. IR (KBr): 3432, 2961, 1669, 1638, 1545, 1491, 1462, 1449, 1338, 1310, 1287, 1259 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.33 (t, J = 7.0 Hz, 3 H, Me), 4.51 (q, J = 7.5 Hz, 2 H, CH₂), 7.22 (t, J = 7.4 Hz, 1 H, aryl H), 7.34 (d, J = 1.9 Hz, 1 H, aryl H), 7.40–7.46 (m, 2 H, aryl H), 7.64 (d, J = 8.2 Hz, 1 H, aryl H), 7.74 (d, J = 8.7 Hz, 1 H, aryl H), 9.02 (d, J = 7.7 Hz, 1 H, aryl H), 12.04 (s, 1 H, carboxylic OH), 12.65 (s, 1 H, pyrrolo NH). ¹³C NMR (125 MHz, CDCl₃): δ = 14.4 (Me), 37.7 (CH₂), 105.2, 106.8, 109.2, 110.7, 119.2, 120.8, 121.3, 122.9, 124.4, 126.8, 132.2, 138.3, 138.6, 163.2 (aryl C). Maldi (TOF): m/z = 279 [M + H]⁺. HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₇H₁₄N₂O₂: 279.1134; found: 279.1129.