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Synlett 2015; 26(16): 2231-2236
DOI: 10.1055/s-0035-1560185
DOI: 10.1055/s-0035-1560185
letter
Cycloaddition of Enamine and Iminium Ion Intermediates Formed in the Reaction of N-Arylpyrrolidines with T-HYDRO
Weitere Informationen
Publikationsverlauf
Received: 11. Juni 2015
Accepted after revision: 30. Juli 2015
Publikationsdatum:
02. September 2015 (online)
![](https://www.thieme-connect.de/media/synlett/201516/lookinside/thumbnails/st-2015-b0195-l_10-1055_s-0035-1560185-1.jpg)
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560185.
- Supporting Information
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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.