Base-Free Synthesis of CF₃-Containing β-Tryptamine Derivatives from N-Nosyl-2-CF₃-Aziridine and Indoles

Abstract

Introduction of the Ns (o-nitrobenzenesulfonyl) group into 2-F₃C-aziridine enhanced the useful electrophilic character of the ring, which in turn enabled a base-free ring-opening reaction with indoles under thermal conditions. This method constitutes a practical synthetic route to a variety of CF₃-containing β-tryptamine derivatives, one of which could be transformed to the CF₃-containing melatonin analogue in high overall yields.

Key words

organofluorine - aziridine - ring-opening - base-free synthesis - tryptamine

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• 8 Experimental Procedure for 1 A 100 mL two-neck round-bottom flask equipped with a magnetic stir bar, a stopcock, and a three-way stopcock, was charged with 15 mL of hexane under argon. To this solution was added NaH (60% dispersion in mineral oil, 451.1 mg, 11.3 mmol, 1.2 equiv). After stirring for several minutes, the solvent was removed by syringe. To this flask was added 20 mL of THF. The flask was immersed in an ice bath. To this mixture was added NsNH₂ (1.98 g, 9.79 mmol, 1.0 equiv) and stirred for 10 min at 0 °C. To this mixture was added β-(trifluoromethyl)vinyl diphenyl sulfonium triflate (4.42 g, 10.3 mmol, 1.05 equiv),^3b and the resulting mixture was stirred at room temperature for 30 min. The reaction was carefully quenched with aq NH₄Cl solution (20 mL) and extracted with EtOAc. The extraction was repeated twice. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was initially purified by silica gel column chromatography (hexane–EtOAc = 30:1 then 2:1) to give yellow oil. Addition of hexane to this oily residue yielded a pale yellow precipitate, which was washed with Et₂O to afford a white solid (2.64 g, 91%); mp 67.9–68.1 °C. IR (KBr): 3102, 1547, 1428, 1365, 1283, 1232, 1175, 987, 940, 852, 755 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.27 (d, J = 7.7 Hz, 1 H), 7.95–7.70 (m, 3 H), 3.70–3.50 (1 H), 3.09 (d, J = 6.9 Hz, 1 H), 2.90–2.65 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 148.4, 135.4, 132.6, 131.5, 130.4, 124.6, 121.8 (q, J = 274.0 Hz), 37.4 (q, J = 42.1 Hz), 31.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –73.2 (d, J = 2.7 Hz). GC-MS (EI, 70 eV): m/z = 186 (100) [Ns], 110 (15) [M⁺ – Ns], 92 (6), 76 (8), 64 (6), 60 (8), 50 (8). Anal. Calcd for C₉H₇F₃N₂O₄S: C, 36.49; H, 2.38; N, 9.46. Found: C, 36.49; H, 2.27; N, 9.49.
• 9 Experimental Procedure for 3a (Table 1, Entry 6) To a round-bottom centrifuge tube with a screw cap was successively added aziridine 1 (60.1 mg, 0.203 mmol), indole 2a (34.4 mg, 0.294 mmol), and o-xylene (0.5 mL). The tube was immersed in a pre-heated oil bath (150 °C) and stirred at this temperature for 24 h. After cooling to room temperature, the mixture was directly purified by chromatography on a silica gel column (hexane–EtOAc = 20:1 then 1:1) to give 3a (70.4 mg, 84%) as a pale yellow solid; mp 192.0–193.0 °C. IR (KBr): 3412, 3340, 3119, 3095, 3072, 1541, 1426, 1343, 1272, 1185, 1125, 943, 855, 754 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.90–7.70 (m, 2 H), 7.30–7.05 (m, 5 H), 6.94 (s, 1 H), 5.80 (d, J = 8.3 Hz, 1 H), 4.50–4.75 (m, 1 H), 3.34 (d, J = 14.9 Hz, 1 H), 2.94 (dd, J = 14.9, 11.4 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃–CD₃OD = 4:1): δ = 145.7, 136.0, 133.1, 132.3, 132.0, 128.7, 126.0, 124.4 (q, J = 282.0 Hz), 124.3, 121.3, 119.0, 117.6, 111.5, 107.5, 107.0, 56.5 (q, J = 30.0 Hz), 24.1. ¹⁹F NMR (376 MHz, CDCl₃): δ = –77.4 (d, J = 5.6 Hz). GC-MS (EI, m/z, 70 eV): 413 (8) [M⁺], 186 (2), 130 (100), 103 (4), 77 (3). Anal. Calcd for C₁₇H₁₄F₃N₃O₄S: C, 49.39; H, 3.41; N, 10.17. Found: C, 49.11; H, 3.41; N, 10.06.
• 10 Experimental Procedure for 5b To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a stopcock, and a three-way stopcock, was successively added 3b (100.0 mg, 0.226 mmol), K₂CO₃ (62.6 mg, 0.453 mmol), thiophenol (46 μL, 0.390 mmol), and DMF (1.0 mL). The mixture was stirred at room temperature for 19 h. To the mixture was added a sat. aq NaCl (5 mL) and EtOAc (5 mL). After the organic layer was separated, an additional extraction with EtOAc was repeated two times. The combined organic solution was dried over Na₂SO₄, and concentrated in vacuo. The resulting oily residue was purified by chromatography on silica gel column (hexane–EtOAc–Et₃N = 80:20:1 then 50:50:1) to give 5b (54.4 mg, 93%) as a white solid; mp 98.0–99.6 °C. IR (ATR): 3387, 3367, 3186, 2923, 1585, 1486, 1214, 1171, 1090, 1030, 897, 776 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.04 (s, 1 H), 8.05 (s, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.10 (s, 1 H), 7.02 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 3.87 (s, 3 H), 3.65–3.50 (m, 1 H), 3.23 (d, J = 14.4 Hz, 1 H), 2.85–2.70 (m, 1 H), 1.38 (br s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.2, 131.5, 1275, 126.6 (q, J = 282.3 Hz), 123.9, 112.5, 112.1, 110.2, 100.3, 55.9, 53.8 (q, J = 28.2 Hz), 26.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –79.5 (d, J = 6.8 Hz). GC-MS (EI, 70 eV): m/z = 258 (22) [M⁺], 160 (100), 145 (17), 117 (10), 90 (3). Anal. Calcd for C₁₂H₁₃F₃N₂O: C, 55.81; H, 5.07; N, 10.85. Found: C, 55.91; H, 5.01; N, 10.75.
• 11 Experimental Procedure for 6b To a 25 mL two-neck round-bottom flask equipped with a magnetic stir bar, a stopcock ,and a three-way stopcock, was successively added 5b (45.3 mg, 0.175 mmol), Et₃N (76 μL, 0.524 mmol), Ac₂O (50 μL, 0.529 mmol), DMAP (4.2 mg, 20 mol%), and CH₂Cl₂ (1.0 mL). The mixture was stirred at room temperature for 3 h. To the mixture was added a sat. aq NaCl (5 mL). After the organic layer was separated, an additional extraction with EtOAc was repeated three times. The combined organic solution was dried over Na₂CO₄, and concentrated in vacuo. The resulting solid was recrystallized from acetone–pentane to give 6b (52.4 mg, 99%) as a white solid; mp 224.0–225.8 °C. IR (ATR): 3400, 3290, 1659, 1547, 1484, 1439, 1375, 1258, 1187, 1121, 1033 cm^–1. ¹H NMR (400 MHz, acetone-d ₆–MeOH-d ₄ = 2:3): δ = 7.76 (d, J = 8.6 Hz, 1 H), 7.11 (s, 2 H), 7.07 (s, 1 H), 7.23 (d, J = 8.6 Hz, 1 H), 4.95–4.80 (m, 1 H), 4.60–4.50 (m, 1 H), 3.82 (s, 3 H), 3.22 (d, J = 14.4 Hz, 1 H), 2.97 (dd, J = 14.4, 11.7 Hz, 1 H), 1.87 (s, 3 H). ¹³C NMR (101 MHz, acetone-d ₆–MeOH-d ₄ = 2:3): δ = 179.2, 155.2, 133.1, 128.9, 127.0 (q, J = 281.2 Hz), 125.0, 113.2, 112.9, 109.9, 101.0, 56.3, 52.3 (q, J = 29.6 Hz), 25.0, 22.6. ¹⁹F NMR (376 MHz, CDCl₃–acetone-d ₆–MeOH-d ₄ = 15:2:3): δ = –76.6 (d, J = 6.8 Hz). GC-MS (EI, 70 eV): m/z = 413 (8) [M⁺], 186 (2), 130 (100), 103 (4), 77 (3). Anal. Calcd for C₁₄H₁₅F₃N₃O₂: C, 56.00; H, 5.04; N, 9.33. Found: C, 55.72; H, 4.99; N, 9.13