Extending the Utility of the Bartoli Indolization: Synthesis of Marinoquinolines C and E

Abstract

A short synthesis of marinoquinolines C and E has been achieved. The synthetic route involves an ipso nitration of an ­electron-deficient boronic acid, the first example of a Bartoli indolization on a nitroquinoline and Suzuki coupling between 2-chloropyrroloquinoline and two separate MIDA boronates.

Key words

marinoquinolines - ipso nitration - Bartoli indolization - Suzuki cross-coupling - pyrroloquinoline

• References and Notes

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• 26 General Procedure: Suzuki Coupling A sealed tube charged with toluene (1 mL), THF (1 mL), and deionized H₂O (0.3 mL) was degassed with nitrogen for 30 min. Pyrroloquinoline 9 (0.06–1 mmol) and tetrakis(triphenylphosphine) palladium(0) (10 mol%) were added. The mixture was stirred for a further 10 min at r.t. then the appropriate boronic acid MIDA ester (1.5–2 equiv) and Na₂CO₃ (4.5 equiv) were added. The tube was then sealed under a blanket of nitrogen and stirred for 24 h at reflux. The solution was cooled, H₂O was added (10 mL), and the mixture extracted with EtOAc (3 × 10 mL). The organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure. Purification of the crude oil by flash chromatography on silica gel eluting with hexanes–EtOAc (4:1) gave the title compound.
• 27 Marinoquinoline C (3)^3,11 According to the general procedure, using pyrroloquinoline 9 (19 mg, 0.094 mmol), tetrakis(triphenylphosphine) palladium(0) (11 mg, 0.009 mmol, 10 mol%), benzyl boronic acid MIDA ester (46 mg, 0.186 mmol), and Na₂CO₃ (44 mg, 0.415 mmol), the title compound (3 mg, 0.012 mmol, 13%) was obtained as a pale yellow solid, mp 155.4–161.2 °C [lit.¹¹ 187–188 °C]. IR: ν_max = 3445, 3086, 2917, 1589, 1477, 1363, 1125, 724 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 11.06 (1 H, br s, NH), 8.26–8.22 (1 H, m, CH), 8.08–8.05 (1 H, m, CH), 7.57–7.52 (3 H, m, 3 × CH), 7.44 (2 H, d, J = 7.6 Hz, 2 × CH), 7.24 (2 H, t, J = 7.5 Hz, 2 × CH), 7.15 (2 H, t, J = 7.5 Hz, 2 × CH), 4.57 (2 H, s, CH₂). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 148.9 (C), 143.7 (C), 139.9 (C), 130.2 (CH), 129.7 (2 × CH), 129.3 (C), 129.2 (2 × CH), 127.5 (CH), 127.1 (CH), 126.2 (CH), 126.0 (CH), 124.2 (C), 123.7 (CH), 102.1 (CH), 41.5 (CH₂), 1 × C not observed; ESI-MS: m/z (%) = 259 (100) [M + H]⁺, 213 (28), 181 (42), 113 (11). ESI-HRMS: m/z calcd for [C₁₈H₁₄N₂ + H]⁺: 259.1239 [M + H]⁺; found: 259.1230. Spectroscopic data are consistent with the literature.^3,11
• 28 N-Phenylsulfonyl Marinoquinoline E (12) According to the general procedure using pyrroloquinoline 9 (12 mg, 0.06 mmol), tetrakis(triphenylphosphine) palladium(0) (7 mg, 0.006 mmol, 10 mol%), 1-(phenylsulfonyl)-3-indolylboronic acid MIDA ester (37 mg, 0.09 mmol), and Na₂CO₃ (28 mg, 0.27 mmol), the title compound (20 mg, 0.050 mmol, 80%) was obtained as a light brown oil. IR (neat): ν_max = 3063, 2852, 2922, 1727, 1602, 1583, 1479, 1444, 1337, 1172, 1128, 1089 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO)]: δ = 11.26 (1 H, br s, NH), 8.67 (1 H, d, J = 7.6 Hz, CH), 8.50 (1 H, s, CH), 8.34–8.32 (1 H, m, CH), 8.15–8.08 (3 H, m, 3 × CH), 7.70–7.66 (2 H, m, 2 × CH), 7.60–7.57 (4 H, m, 4 × CH), 7.46–7.27 (4 H, m, 4 × CH). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 143.6 (C), 141.5 (C), 138.7 (C), 136.1 (C), 135.4 (CH), 130.9 (C), 130.6 (2 × CH), 130.4 (CH), 130.2 (C), 128.2 (CH), 128.0 (2 × CH), 127.6 (C), 127.1 (CH), 126.7 (CH), 126.6 (CH), 126.3 (CH), 124.8 (CH), 124.6 (CH), 124.1 (C), 123.8 (CH), 121.4 (C), 114.1 (CH), 102.4 (CH). ESI-MS: m/z (%) = 424 (100) [M + H⁺], 413 (4), 408 (5). ESI-HRMS: m/z calcd for [C₂₅H₁₇N₃O₂ + H]⁺: 424.1115 [M + H]⁺; found: 424.1114.
• 29 Marinoquinoline E (5)^3,11 A solution of N-(phenylsulfonyl marinoquinoline E (12, 10 mg, 0.02 mmol) and K₂CO₃ (39 mg, 0.3 mmol) in MeOH (1.5 mL) and H₂O (0.5 mL) was heated to reflux for 3 h. The solution was cooled, H₂O was added (5 mL), and the mixture extracted with EtOAc (3 × 5 mL). The organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Purification of the crude oil by flash chromatography on silica gel eluting with EtOAc gave the title compound (3 mg. 0.01 mmol, 45%) as a colorless solid; mp 258.7–263.5 °C [lit.¹¹ 264–266 °C]. IR (neat): ν_max = 3450, 3418, 2900, 1735, 1558, 1494 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 10.95 (1 H, br s, NH), 10.79 (1 H, br s, NH), 8.77 (1 H, d, J = 7.0 Hz, CH), 8.27 (2 H, d, J = 8.1 Hz, 2 × CH), 8.17 (1 H, d, J = 8.1 Hz, CH), 7.61–7.49 (4 H, m, 4 × CH), 7.27–7.19 (3 H, m, 3 × CH). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 144.5 (C), 144.1 (C), 138.0 (C), 130.1 (CH), 129.5 (C), 128.1 (C), 127.8 (C), 127.3 (CH), 126.8 (CH), 126.3 (CH), 125.4 (CH), 123.7 (CH), 123.6 (CH), 123.3 (CH), 121.0 (CH), 115.3 (C), 112.2 (CH), 102.2 (CH), 1 × C not observed. ESI-MS: m/z (%) = 284 (100) [M + H⁺], 214 (2), 127 (5). ESI-HRMS: m/z calcd for [C₁₉H₁₃N₃ + H]⁺: 284.1187 [M + H]⁺; found: 284.1182. Spectroscopic data are consistent with the literature.^3,11