Cycloaddition of Enamine and Iminium Ion Intermediates Formed in the Reaction of N-Arylpyrrolidines with T-HYDRO

Dedicated to Professor K. P. C. Vollhardt for his contributions to chemistry.

Abstract

The reaction of N-arylpyrrolidine derivatives with 70% aqueous tert-butyl hydroperoxide (T-HYDRO) in the presence of NaOAc·3H₂O gives tetracyclic amines in 59–78% yields via cycloaddition of the corresponding iminium ion and enamine intermediates formed in situ in cyclohexane solvent. The iminium ion intermediate reacts with t-BuOK in methanol to give the corresponding cyclic amides in 85–88% yields or undergoes alkylation to give the corresponding nitromethyl product in 74–79% yields using t-BuOK and nitromethane in methanol.

Key words

amine - amides - radical cation - iminium ion - enamine

• References and Notes

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• 14 General Experimental Procedure for the Preparation of N-Aryl-Substituted Pyrrolydines 1: To a stirred solution of K₂CO₃ (5.52 g, 40 mmol), KI (0.17 g, 5 mol%) in MeCN (30 mL) under nitrogen atmosphere, 1,4-dibromobutane (2.39 mL, 20 mmol) and aryl amines (25 mmol) were added. The reaction mixture was refluxed for 8 h. After completion of the reaction, the solvent was evaporated and EtOAc (50 mL) and H₂O (30 mL) were added. The organic layer was separated and extracted with EtOAc (20 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (100–200 mesh) using hexane as eluent to isolate the N-aryl-substituted pyrrolidines 1 in 82–89% yields. General Experimental Procedure for the Preparation of Tetracyclic Amines 2a–f: A mixture of 1 (1 mmol), T-HYDRO (0.55 mL, 4 mmol), NaOAc∙3H₂O (0.54 g, 4 mmol) in cyclohexane (2 mL) was stirred for 24 h at 70 °C. After completion of the reaction, the solvent was evaporated and EtOAc (10 mL) and H₂O (5 mL) were added. The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (100–200 mesh) using EtOAc–hexane (1:5) as eluent to get tetracyclic amines. 1-Phenyl-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2a): white solid; yield: 0.11 g, 72%; mp 154–156 °C. IR (KBr): 3047, 2970, 2838, 2805, 1611, 1501, 1479, 1358, 740 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.38 (m, 3 H), 7.13–7.16 (m, 1 H), 6.85–6.87 (m, 2 H), 6.72–6.77 (m, 1 H), 6.54–6.59 (m, 1 H), 6.43–6.46 (m, 1 H), 5.16 (d, J = 6.4 Hz, 1 H), 3.77–3.79 (m, 1 H), 3.51–3.55 (m, 1 H), 3.29–3.44 (m, 3 H), 2.52–2.59 (m, 1 H), 2.14–2.20 (m, 1 H), 1.95–2.13 (m, 3 H), 1.84–1.92 (m, 1 H), 1.69–1.79 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.9, 143.2, 129.4, 128.8, 128.1, 123.0, 115.8, 115.5, 111.3, 110.3, 57.5, 56.6, 47.4, 46.6, 40.1, 30.3, 23.4, 23.3. HRMS: m/z [M + H]⁺ calcd for C₂₀H₂₂N₂: 291.1862; found: 291.1860. 8-Methyl-1-(o-tolyl)-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2b): colorless oil; yield: 0.11 g, 69%. IR (neat): 3063, 3024, 2926, 2871, 1599, 1495, 1468, 1254, 1106, 761, 723 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.17–7.27 (m, 2 H), 6.95–7.01 (m, 3 H), 6.86 (d, J = 7.6 Hz, 1 H), 6.59 (t, J = 7.4 Hz, 1 H), 5.03 (d, J = 7.6 Hz, 1 H), 3.70–3.81 (m, 2 H), 3.42–3.55 (m, 2 H), 2.95–3.01 (m, 1 H), 2.70–2.77 (m, 1 H), 2.40 (s, 3 H), 2.39 (s, 3 H), 1.89–2.11 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.6, 145.7, 131.9, 131.2, 130.5, 127.0, 126.8, 126.5, 125.8, 121.8, 120.0, 118.5, 62.0, 58.9, 52.5, 51.5, 41.4, 29.6, 25.0, 24.1, 22.1, 19.6. HRMS: m/z [M + H]⁺ calcd for C₂₂H₂₆N₂: 319.2175; found: 319.2174. 10-Methyl-1-(p-tolyl)-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2c): colorless oil; yield: 0.10 g, 62%. IR (neat): 3063, 3014, 2964, 2866, 1600, 1496, 1430, 1293, 1096, 756, 712 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.09 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.99 (s, 1 H), 6.65 (d, J = 8.0 Hz, 3 H), 4.41 (d, J = 8.0 Hz, 1 H), 3.69 (t, J = 8.0 Hz, 1 H), 3.49 (t, J = 8.0 Hz, 1 H), 3.29–3.36 (m, 1 H), 2.72–2.87 (m, 2 H), 2.38–2.44 (m, 1 H), 2.32 (s, 3 H), 2.12–2.25 (m, 6 H), 1.98–2.04 (m, 1 H), 1.73–1.86 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.5, 145.0, 129.6, 128.8, 128.3, 127.6, 127.5, 125.6, 112.8, 112.0, 65.1, 60.1, 49.7, 48.3, 47.6, 31.9, 30.6, 22.3, 20.9, 20.3. HRMS: m/z [M + H]⁺ calcd for C₂₂H₂₆N₂: 319.2175; found: 319.2174. 1-(2,4-Dimethylphenyl)-8,10-dimethyl-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2d): colorless oil; yield: 0.10 g, 59%. IR (neat): 2953, 2915, 2866, 1605, 1496, 1474, 1342, 1288, 866, 816 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.06 (s, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.72 (s, 1 H), 4.85 (d, J = 7.6 Hz, 1 H), 3.75–3.79 (m, 1 H), 3.66–3.72 (m, 1 H), 3.40–3.44 (m, 2 H), 2.87–2.93 (m, 1 H), 2.64–2.69 (m, 1 H), 2.34 (s, 9 H), 2.17–2.23 (m, 1 H), 2.10 (s, 3 H), 1.95–2.06 (m, 3 H), 1.84–1.92 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.0, 143.1, 132.7, 131.8, 131.6, 131.2, 127.8, 127.7, 127.4, 127.1, 125.7, 120.6, 62.9, 58.8, 52.7, 52.5, 41.6, 29.7, 25.7, 24.1, 21.8, 20.7, 20.4, 19.2. HRMS: m/z [M + H]⁺ calcd for C₂₄H₃₀N₂: 347.2488; found: 347.2483. 3-(Naphthalen-1-yl)-2,3,3a,11,12,13,13a,13b-octahydro-1H-benzo[h]dipyrrolo[1,2-a:3′,2′-c]quinoline (2e): white solid; yield: 0.15 g, 78%; mp 203–205 °C. IR (KBr): 3036, 2953, 2926, 2855, 1556, 1512, 1463, 1397, 1277, 1107, 800, 778, 762 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.19 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.71–7.74 (m, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 2 H), 7.32–7.42 (m, 2 H), 7.27 (t, J = 7.6 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 4.46 (d, J = 5.6 Hz, 1 H), 4.16–4.21 (m, 1 H), 3.93–3.98 (m, 1 H), 3.53–3.59 (m, 1 H), 3.27–3.33 (m, 1 H), 3.13–3.18 (m, 1 H), 2.37–2.53 (m, 2 H), 2.20–2.26 (m, 1 H), 2.00–2.15 (m, 3 H), 1.87–1.94 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.6, 142.8, 134.4, 134.0, 132.9, 128.4, 127.9, 127.3, 125.7, 125.5, 125.2, 125.2, 124.8, 124.6, 124.5, 123.9, 121.6, 119.2, 118.9, 63.2, 59.4, 55.0, 53.8, 36.0, 29.2, 27.5, 23.7. HRMS: m/z [M + H]⁺ calcd for C₂₈H₂₆N₂: 391.2175; found: 391.2169. 8-Methoxy-1-(2-methoxyphenyl)-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2f): white solid; yield: 0.11 g, 64%; mp 120–122 °C. IR (KBr): 3058, 2964, 2960, 2855, 1600, 1507, 1458, 1227, 1036, 789, 734 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.85–6.90 (m, 3 H), 6.61–6.67 (m, 2 H), 6.44–6.49 (m, 2 H), 5.63–5.66 (m, 1 H), 3.92 (s, 3 H), 3.82–3.86 (m, 1 H), 3.78 (s, 3 H), 3.51–3.59 (m, 2 H), 3.13–3.20 (m, 2 H), 2.80–2.86 (m, 1 H), 1.88–2.06 (m, 5 H), 1.73–1.79 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.6, 148.2, 138.6, 137.4, 126.6, 121.8, 121.3, 119.9, 118.3, 117.6, 111.3, 110.9, 59.7, 59.6, 55.9, 55.5, 51.7, 47.8, 41.2, 28.8, 23.7, 23.4. HRMS: m/z [M + H]⁺ calcd for C₂₂H₂₆N₂O₂: 351.2073; found: 351.2072. General Experimental Procedure for the Preparation of Cyclic Amides 3: A mixture of the amine 1 (1 mmol), T-HYDRO (0.55 mL, 4 mmol), t-BuOK (0.45 g, 4 mmol) in MeOH (2 mL) was stirred for 24 h at 70 °C. After completion of the reaction, the solvent was evaporated and EtOAc (10 mL) and H₂O (5 mL) were added. The organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (100–200 mesh) using EtOAc–hexane (15:100) as eluent to isolate cyclic amides 3. 1-Phenylpyrrolidin-2-one (3a): white solid; yield: 0.14 g, 85%; mp 70–72 °C. IR (KBr): 3419, 3057, 2964, 2937, 1687, 1583, 1539, 1408, 1309 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.33–7.38 (m, 2 H), 7.11–7.15 (m, 1 H), 3.83 (t, J = 7.0 Hz, 2 H), 2.58 (t J = 8.0 Hz, 2 H), 2.09–2.16 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.1, 139.3, 128.6, 124.3, 119.8, 48.6, 32.6, 17.8. 1-(p-Tolyl)pyrrolidin-2-one (3b): white solid; yield: 0.15 g, 88%; mp 90–92 °C. IR (KBr): 2964, 2932, 2871, 1693, 1512, 1392, 1304, 1233, 833 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.50 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 3.84 (t, J = 7.0 Hz, 2 H), 2.60 (t, J = 8.2 Hz, 2 H), 2.34 (s, 3 H), 2.12–2.19 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.9, 136.8, 134.1, 129.2, 120.0, 48.8, 32.6, 20.8, 17.9. General Experimental Procedure for the Preparation of 2-(Nitromethyl)-1-phenylpyrrolidine 4: A mixture of the amine 1 (1 mmol), T-HYDRO (0.55 mL, 4 mmol), t-BuOK (0.45 g, 4 mmol), nitromethane (0.5 mL) in MeOH (2 mL) was stirred for 48 h at 70 °C. After completion of the reaction, the solvent was evaporated. EtOAc (10 mL) and H₂O (5 mL) were added and the organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (100–200 mesh) using EtOAc–hexane (5:100) as eluent to isolate 2-nitromethyl arylpyrrolidine products 4. 2-(Nitromethyl)-1-phenylpyrrolidine (4a): yellow oil; yield: 0.15 g, 74%. IR (neat): 2966, 2914, 2838, 1593, 1541, 1498, 1358, 1260, 1173, 990, 743 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.27–7.34 (m, 2 H), 6.79–6.83 (m, 1 H), 6.73 (d, J = 8.0 Hz, 2 H), 4.63–4.66 (m, 1 H), 4.42–4.46 (m, 1 H), 4.18–4.24 (m, 1 H), 3.49–3.54 (m, 1 H), 3.20–3.27 (m, 1 H), 2.07–2.17 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.8, 130.0, 117.4, 112.0, 111.7, 75.8, 57.4, 48.1, 29.3, 22.8. 2-(Nitromethyl)-1-(p-tolyl)pyrrolidine (4b): yellow oil; yield: 0.17 g, 79%. IR (neat): 2946, 2896, 2841, 1611, 1541, 1503, 1361, 1228, 1155, 807 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.07–7.19 (m, 2 H), 6.59–6.71 (m, 2 H), 4.58–4.72 (m, 1 H), 4.48–4.53 (m, 1 H), 4.13–4.29 (m, 1 H), 3.48–3.53 (m, 1 H), 3.19–3.25 (m, 1 H), 2.31 (s, 3 H), 2.07–2.19 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 130.2, 126.5, 112.0, 76.0, 57.6, 48.3, 29.3, 22.9, 20.2.