General Procedure 3 (Synthesis of Amides)
In total, 1.0 mmol of the amine was dissolved in 20 mL toluene and 1.2 mmol of the acid chloride was added. After addition of 3.0 mL triethylamine, the mixture was stirred at room temperature for 6 h. The solvent was evaporated and the residue was dissolved in 20 mL 2 M aqueous sodium hydroxide solution and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash column chromatography (ethyl acetate:triethylamine 10:1).
1-Benzyl-N-(4-(tert-butyl)benzyl)piperidin-4-amine (2a): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 734 mg (4.5 mmol) 4-tert-butylbenzylamine, and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 707 mg (70%) of 2a as a colourless oil. 1H-NMR (400 MHz, dichloromethane-d2) δ 7.35–7.28 (m, 6 H, 6 arom. CH), 7.26–7.20 (m, 3 H, 3 arom. CH), 3.74 (s, 2 H; CH2), 3.46 (s, 2 H, CH2), 2.85–2.73 (m, 2 H, 2 CH2), 2.56–2.44 (m, 1 H, CH), 2.07–1.96 (m, 2 H, 2 CH2), 1.89–1.80 (m, 2 H, 2 CH2), 1.48–1.24 (m, 2 H, 2 CH2), 1.30 (s, 9 H, 3 CH3). 13C-NMR (100 MHz, dichloromethane-d2) δ 150.91 (quat. C), 140.47 (quat. C), 139.55 (quat. C), 130.27 (2 arom. CH), 129.36 (2 arom. CH), 128.97 (2 arom. CH), 128.05 (arom. CH), 126.44 (2 arom. CH), 64.31 (CH2), 55.68 (CH), 53.70 (CH2), 51.68 (2 CH2), 35.61 (quat. C), 34.18 (2 CH2), 32.44 (3 CH3). IR (KBr) ν (cm−1) = 2956, 2867, 2800, 1455, 1363, 1268, 1111, 819, 791, 737, 698. MS (EI): m/z: 336 (M+, 2), 245 (5), 189 (37), 173 (65), 91 (100). HRMS (EI) calcd. for C23H32N2: 336.2567. Found: 336.2561.
1-Benzyl-N-dodecylpiperidin-4-amine (2b): The compound was prepared according general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 834 mg (4.5 mmol) n-dodecylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 699 mg (65%) of 2b as a colourless oil. 1H-NMR (400 MHz, dichloromethane-d2) δ 7.34–7.14 (m, 5 H, 5 arom. CH), 3.45 (s, 2 H, CH2), 2.84–2.75 (m, 2 H, 2 CH2), 2.57 (t, J = 7.0 Hz, 2 H, CH2), 2.42 (tt, J = 10.5, 4.1 Hz, 1 H, CH), 1.99 (td, J = 11.7, 2.3 Hz, 2 H, CH2), 1.85–1.74 (m, 2 H, 2 CH2), 1.48–1.37 (m, 2 H, CH2), 1.34–1.20 (m, 20 H, 10 CH2), 0.87 (t, J = 6.9 Hz, 3 H, CH3). 13C-NMR (100 MHz, dichloromethane-d2) δ 140.41 (quat. C), 130.28 (2 arom. CH), 129.36 (2 arom. CH), 128.07 (arom. CH), 64.28 (CH2), 56.35 (CH), 53.77 (2 CH2), 48.00 (CH2), 33.95 (2 CH2), 33.24 (CH2), 31.55 (CH2), 30.99 (CH2), 30.96 (3 CH2), 30.90 (CH2), 30.67 (CH2), 28.73 (CH2), 24.01 (CH2), 15.20 (CH3). IR (KBr) ν (cm−1) = 2915, 2849, 2797, 1469, 1453, 1365, 1345, 1125, 1112, 792, 736, 727, 716, 694. MS (EI) m/z: 358 (M+, 2), 267 (22), 173 (100), 91 (70). HRMS (EI) calcd. for C24H42N2: 358.3348. Found: 358.3345.
1-Benzyl-N-octylpiperidin-4-amine (2c): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 581 mg (4.5 mmol) n-octylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 544 mg (60%) of 2c as a colourless oil. 1H-NMR (500 MHz, chloroform-d) δ 7.28–7.21 (m, 4 H, 4 arom. CH), 7.18–7.14 (m, 1 H, arom. CH), 3.42 (s, 2 H, CH2), 2.84–2.67 (m, 2 H, 2 CH2), 2.52 (t, J = 7.3 Hz, 2 H, CH2), 2.36 (dt, J = 10.6, 6.6 Hz, 1 H, CH), 1.99–1.85 (m, 2 H, 2 CH2), 1.83–1.69 (m, 2 H, 2 CH2), 1.44–1.35 (m, 2 H, 2 CH2), 1.35–1.26 (m, 2 H, CH2), 1.26–1.14 (m, 10 H, 5 CH2), 0.81 (t, J = 6.9 Hz, 3 H, CH3). MS (EI) m/z = 302 (M+, 3), 211 (20), 173 (100), 146 (16), 91 (88). 13C-NMR (100 MHz, chloroform-d) δ 138.67 (quat. C), 129.08 (2 arom. CH), 128.13 (2 arom. CH), 126.87 (arom. CH), 63.10 (CH2), 55.07 (CH), 52.57 (2 CH2), 46.92 (CH2), 32.90 (2 CH2), 31.84 (CH2), 30.51 (CH2), 29.54 (CH2), 29.28 (CH2), 27.46 (CH2), 22.67 (CH2), 14.11 (CH3). IR (KBr) ν (cm−1) = 2924, 2853, 2799, 1466, 1454, 1365, 1119, 792, 735, 697. MS (EI) m/z: 300 (M+, 0.2), 299 (1), 211 (13), 173 (100), 158 (26), 146 (14), 91 (72), 82 (20). HRMS (EI) calcd. for C20H32N2 (M+-2): 300.2566. Found: 300.2514.
1-Benzyl-N-isobutylpiperidin-4-amine (2d): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 329 mg (4.5 mmol) isobutylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 502 mg (68%) of 2d as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.29–7.06 (m, 5 H, 5 arom. CH), 3.42 (s, 2 H, CH2), 2.85–2.67 (m, 2 H, CH2),2.39–2.29 (m, 1 H, CH), 2.35 (d, J = 6.8 Hz, 2 H, CH2), 1.99–1.89 (m, 2 H, CH2), 1.82–1.72 (m, 2 H, CH2), 1.63 (hept, J = 6.7 Hz, 1 H, CH), 1.31 (qd, J = 11.4, 3.5 Hz, 2 H, CH2), 0.83 (d, J = 6.6 Hz, 6 H, 2 CH3). 13C-NMR (100 MHz, chloroform-d) δ 138.65 (quat. C), 129.10 (2 arom. CH), 128.14 (2 arom. CH), 126.89 (arom. CH), 63.10 (CH2), 55.03 (CH), 54.90 (2 CH2), 52.55 (CH2), 32.86 (2 CH2), 28.57 (CH), 20.76 (2 CH3). IR (KBr) ν (cm−1) = 2948, 2935, 2799, 1467, 1454, 1365, 1117, 979, 791. MS (EI) m/z: 246 (M+, 4), 173 (73), 146 (27), 91 (100), 82 (16). HRMS (EI) calcd. for C13H19N2 (M+-C3H7): 203.1548. Found: 203.1516.
1-Benzyl-N-hexylpiperidin-4-amine (2e): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 455 mg (4.5 mmol) n-hexylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 584 mg (71%) of 2e as a colourless oil. 1H-NMR (500 MHz, chloroform-d) δ 7.27–7.22 (m, 4 H, 4 arom. CH), 7.19–7.14 (m, 1 H, arom. CH), 3.42 (s, 2 H, CH2), 2.82–2.73 (m, 2 H, 2 CH2), 2.53 (t, J = 7.2 Hz, 2 H, CH2), 2.36 (tt, J = 10.5, 4.1 Hz, 1 H, CH), 1.94 (td, J = 11.7, 2.3 Hz, 2 H, 2 CH2), 1.83–1.69 (m, 2 H, 2 CH2), 1.43–1.36 (m, 2 H, CH2), 1.35–1.28 (m, 2 H, 2 CH2), 1.26–1.16 (m, 6 H, 3 CH2), 0.81 (t, J = 6.9 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 138.63 (quat. C), 129.10 (2 arom. CH), 128.14 (2 arom. CH), 126.89 (arom. CH), 63.10 (CH2), 55.06 (CH), 52.56 (2 CH2), 46.91 (CH2), 32.86 (2 CH2), 31.79 (CH2), 30.46 (CH2), 27.14 (CH2), 22.63 (CH2), 14.06 (CH3). IR (KBr) ν (cm−1) = 2924, 2853, 2797, 1466, 1454, 1365, 1342, 1117, 1072, 1029, 972, 792. MS (EI) m/z: 274 (M+, 4), 173 (99), 146 (17), 91 (100). HRMS (EI) calcd. for C18H30N2: 274.2409. Found: 274.2418.
1-Benzyl-N-cycloheptylpiperidin-4-amine (2f): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperi-done, 509 mg (4.5 mmol) cycloheptylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 860 mg (100%) of 2f as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.30 (d, J = 4.4 Hz, 4 H, 4 arom. CH), 7.26–7.21 (m, 1 H, 1 arom. CH), 3.49 (s, 2 H, CH2), 2.90–2.80 (m, 2 H, 2 CH2), 2.76 (tt, J = 8.1, 4.0 Hz, 1 H, CH), 2.51 (tt, J = 10.6, 4.0 Hz, 1 H, CH), 2.01 (td, J = 11.7, 2.3 Hz, 2 H, 2 CH2), 1.89–1.71 (m, 4 H, 3 CH2), 1.70–1.59 (m, 2 H, 2 CH2), 1.60–1.45 (m, 4 H, 2 CH2), 1.46–1.22 (m, 6 H, 3 CH2). 13C-NMR (100 MHz, chloroform-d) δ 138.63 (quat. C), 129.09 (2 arom. CH), 128.13 (2 arom. CH), 126.88 (arom. CH), 63.10 (CH2), 55.16 (CH), 52.77 (2 CH2), 51.71 (CH), 35.46 (2 CH2), 33.38 (2 CH2), 28.13 (2 CH2), 24.49 (2 CH2). MS (EI) m/z: 286 (M+, 4), 173 (98), 146 (6), 91 (100). HRMS (EI) calcd. for C19H30N2 (M+): 286.2409. Found: 286.2403.
(S)-1-Benzyl-N-(1-phenylethyl)piperidin-4-amine (2g): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 545 mg (4.5 mmol) (S)-α-methylbenzenemethanamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 730 mg (83%) of 2g as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.35–7.17 (m, 10 H, 10 arom. CH), 3.94 (q, J = 6.6 Hz, 1 H, CH), 3.44 (s, 2 H, CH2), 2.84–2.70 (m, 2 H, 2 CH2), 2.30 (tt, J = 10.5, 4.0 Hz, 1 H, CH), 1.99–1.83 (m, 3 H, 3 CH2), 1.72–1.62 (m, 1 H, CH2), 1.44–1.24 (m, 2 H, 2 CH2), 1.31 (d, J = 6.6 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 146.19 (quat. C), 138.60 (quat. C), 129.10 (2 arom. CH), 128.38 (2 arom. CH), 128.12 (2 arom. CH), 126.87 (arom. CH), 126.75 (arom. CH), 126.50 (2 arom. CH), 63.07 (CH2), 54.48 (CH), 52.59 (CH2), 52.41 (CH2), 51.95 (CH), 33.66 (CH2), 32.57 (CH2), 25.11 (CH3). IR (KBr) ν (cm−1) = 2924, 2799, 2759, 1493, 1467, 1451, 1366, 1343, 1117, 793, 761, 737, 698. MS (EI) m/z: 295 (M++H, 0.5), 189 (64), 175 (17), 172 (45), 158 (18), 146 (21), 105 (21), 91 (100). HRMS (EI) calcd. for C20H27N2 (M+ + H): 295.2174. Found: 295.2170. = −47.7° (1.525, CHCl3).
(S)-1-Benzyl-N-(1-cyclohexylethyl)piperidin-4-amine (2h): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 572 mg (4.5 mmol) (S)-(+)-1-cyclohexylethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 700 mg (78%) of 2h as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.33–7.27 (m, 4 H, 4 arom. CH), 7.27–7.17 (m, 1 H, arom. CH), 3.49 (s, 2 H, CH2), 2.88–2.77 (m, 2 H, 2 CH2), 2.57–2.42 (m, 2 H, 2 CH), 2.01 (qd, J = 11.5, 2.6 Hz, 2 H, 2 CH2), 1.89–1.59 (m, 7 H, 6 CH2, CH), 1.45–1.05 (m, 6 H, 6 CH2), 1.06–0.87 (m, 2 H, 2 CH2), 0.95 (d, J = 6.4 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 138.72 (quat. C), 129.09 (2 arom. CH), 128.13 (2 arom. CH), 126.86 (arom. CH), 63.13 (CH2), 53.93 (CH), 52.73 (CH2), 52.61 (CH2), 51.99 (CH), 43.28 (CH), 33.80 (CH2), 32.96 (CH2), 30.01 (CH2), 28.17 (CH2), 26.79 (CH2), 26.65 (CH2), 26.51 (CH2), 17.70 (CH3). IR (KBr) ν (cm−1) = 2921, 2849, 1449, 1366, 1264, 1109, 1072, 890, 792, 735, 697. MS (EI) m/z: 301 (M+ + H, 0.1), 217 (16), 172 (56), 146 (37), 91 (100). HRMS (EI) calcd. for C20H33N2 (M+ + H): 301.2644. Found: 301.2638. = 14.4° (c = 2.33, CHCl3).
1-Benzyl-N-(4-chlorophenethyl)piperidin-4-amine (2i): The compound was prepared according to general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 700 mg (4.5 mmol) 4-chlorophenylethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 738 mg (75%) of 2i as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.32–7.28 (m, 4 H, 4 arom. CH), 7.27–7.21 (m, 3 H, 3 arom. CH), 7.13 (d, J = 8.5 Hz, 2 H, 2 arom. CH), 3.48 (s, 2 H, CH2), 2.90–2.79 (m, 4 H, 3 CH2), 2.75 (t, J = 7.0 Hz, 2 H, CH2), 2.50–2.40 (m, 1 H, CH), 2.00 (td, J = 11.2, 1.9 Hz, 2 H, 2 CH2), 1.86–1.77 (m, 2 H, 2 CH2), 1.35 (qd, J = 12.2, 11.7, 3.8 Hz, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d) δ 138.62 (quat. C), 138.57 (quat. C), 131.89 (quat. C), 130.01 (2 arom. CH), 129.06 (2 arom. CH), 128.54 (2 arom. CH), 128.15 (2 arom. CH), 126.90 (arom. CH), 63.07 (CH2), 54.88 (CH), 52.45 (2 CH2), 47.93 (CH2), 36.06 (CH2), 32.80 (2 CH2). IR (KBr) ν (cm−1) = 2942, 2883, 2800, 1492, 1363, 1091, 1015, 972, 808, 738, 698. MS (EI) m/z: 330 (M+, 38), 328 (M+, 96), 299 (20), 289 (100), 271 (28). HRMS (EI) calcd. for C20H26ClN2 (M+ + H): 329.1785. Found: 329.1779.
1-Benzyl-N-(4-methoxybenzyl)piperidin-4-amine (2j): The compound was prepared according to general procedure 1 from 379 mg (2.0 mmol) 1-benzyl-4-piperidone, 412 mg (3.0 mmol) 4-methoxybenzylamine and 892 mg (4.0 mmol) sodium triacetoxyborohydride to give 610 mg (98%) of 2j as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.33–7.29 (m, 4 H, 4 arom. CH), 7.25–7.20 (m, 1 H, arom. CH), 7.23 (d, J = 8.7 Hz, 2 H, 2 arom. CH), 6.85 (d, J = 8.7 Hz, 2 H, 2 arom. CH), 3.79 (s, 3 H, OCH3), 3.74 (s, 2 H, CH2), 3.49 (s, 2 H, CH2), 2.84 (dt, J = 11.6, 2.8 Hz, 2 H, 2 CH2), 2.50 (tt, J = 10.5, 4.1 Hz, 1 H, CH), 2.01 (td, J = 11.6, 2.3 Hz, 2 H, 2 CH2), 1.91–1.82 (m, 2 H, 2 CH2), 1.49–1.35 (m, 2 H, CH2). 13C-NMR (100 MHz, chloroform-d) δ 158.54 (quat. C), 138.63 (quat. C), 132.94 (quat. C), 129.20 (2 arom. CH), 129.10 (2 arom. CH), 128.14 (2 arom. CH), 126.89 (arom. CH), 113.80 (2 arom. CH), 63.12 (CH2), 55.28 (OCH3), 54.15 (CH), 52.42 (2 CH2), 50.23 (CH2), 32.78 (2 CH2). IR (KBr) ν (cm−1) = 2936, 2828, 2092, 1510, 1447, 1300, 1239, 1027, 993, 908, 740. MS (EI) m/z: 311 (M+, 0.3), 219 (1), 189 (24), 172 (43), 146 (20), 136 (14), 121 (74), 91 (100). HRMS (EI) calcd. for C20H27N2O (M+ + H): 311.2123. Found: 311.2117.
N-Isobutyl-1-phenethylpiperidin-4-amine (3a): The compound was prepared according to general procedure 1 from 915 mg (4.5 mmol) 1-(2-phenylethyl)-4-piperidone, 4.67 mg (6.4 mmol) isobutylamine and 1.50 g (6.8 mmol) sodium triacetoxyborohydride to give 696 mg (59%) of 3a as a colourless oil. 1H-NMR (500 MHz, chloroform-d) δ 7.30–7.26 (m, 2 H, 2 arom. CH), 7.22–7.17 (m, 3 H, 3 arom. CH), 3.00–2.93 (m, 2 H, CH2), 2.83–2.77 (m, 2 H, CH2), 2.60–2.54 (m, 2 H, CH2), 2.48–2.39 (m, 1 H, CH), 2.43 (d, J = 6.8 Hz, 2 H, CH2), 2.11–2.02 (m, 2 H, CH2), 1.93–1.86 (m, 2 H, CH2), 1.71 (dp, J = 13.3, 6.7 Hz, 1 H, CH), 1.46 (m, 2 H, CH2), 0.91 (d, J = 6.6 Hz, 6 H, 2 CH3). 13C-NMR (101 MHz, chloroform-d) δ 140.57 (quat. C), 128.71 (2 arom. CH), 128.35 (2 arom. CH), 125.97 (arom. CH), 60.68 (CH2), 54.99 (CH), 54.91 (2 CH2), 52.64 (CH2), 33.90 (CH2), 32.91 (2 CH2), 28.58 (CH), 20.76 (2 CH3). IR (KBr) ν (cm−1) = 2947, 2804, 1497, 1468, 1373, 1244, 1120, 1031, 978, 771, 744. MS (EI) m/z: 260 (M+, 0.2), 169 (100), 126 (48), 70 (93). HRMS (EI) calcd. for C17H28N2 (M+): 260.2253. Found: 260.2231.
N-Dodecyl-1-phenethylpiperidin-4-amine (3b): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 872 mg (4.5 mmol) n-dodecylamine and 1.339 g (6.0 mmol) sodium triacetoxyborohydride to give 677 mg (61%) of 3b as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.31–7.26 (m, 2 H, 2 arom. CH), 7.23–7.16 (m, 3 H, 3 arom. CH), 3.01–2.91 (m, 2 H, 2 CH2), 2.87–2.74 (m, 2 H, CH2), 2.66–2.54 (m, 4 H, 2 CH2), 2.46 (tt, J = 10.4, 3.9 Hz, 1 H, CH), 2.07 (td, J = 11.6, 2.3 Hz, 2 H, 2 CH2), 1.95–1.84 (m, 2 H, 2 CH2), 1.55–1.43 (m, 2 H, 2 CH2), 1.42–1.34 (m, 2 H, CH2), 1.34–1.20 (m, 18 H, 9 CH2), 0.87 (t, J = 6.7 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 140.59 (quat. C), 128.71 (2 arom. CH), 128.35 (2 arom. CH), 125.96 (arom. CH), 60.70 (CH2), 55.06 (CH), 52.69 (2 CH2), 46.95 (CH2), 33.92 (CH2), 32.97 (CH2), 31.93 (2 CH2), 30.54 (CH2), 29.68 (CH2), 29.65 (CH2), 29.63 (2 CH2), 29.59 (CH2), 29.36 (CH2), 27.47 (CH2), 22.70 (CH2), 14.13 (CH3). IR (KBr) ν (cm−1) = 2921, 2849, 2805, 1466, 1454, 1371, 1122, 746, 697. MS (EI) m/z: 351 (M+ + H, 30), 259 (67), 216 (45), 147 (97), 117 (33), 96 (100), HRMS: calcd. for C25H43N2 (M+-H): 371.3426. Found: 371.3418.
N-(4-(tert-Butyl)benzyl)-1-phenethylpiperidin-4-amine (3c): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 734 mg (4.5 mmol) 4-tert-butylbenzylamine and 1.339 g (6.0 mmol) sodium triacetoxyborohydride to give 609 mg (58%) of 3c as a pale yellow oil. 1H-NMR (400 MHz, dichloromethane-d2) δ 7.33 (d, J = 8.4 Hz, 2 H, 2 arom. CH), 7.30–7.14 (m, 7 H, 7 arom. CH)), 3.75 (s, 2 H, CH2), 2.92 (dd, J = 11.8, 4.4 Hz, 2 H, 2 CH2), 2.76 (dd, J = 9.4, 6.4 Hz, 2 H, 2 CH2), 2.58–2.45 (m, 3 H, CH2, CH), 2.05 (td, J = 11.5, 2.2 Hz, 2 H, CH2), 1.94–1.83 (m, 2 H, 2 CH2), 1.44–1.33 (m, 2 H, 2 CH2), 1.30 (s, 9 H, 3 CH3). 13C-NMR (101 MHz, dichloromethane-d2) δ 150.92 (quat. C), 142.28 (quat. C), 139.53 (quat. C), 130.01 (2 arom. CH), 129.52 (2 arom. CH), 128.98 (2 arom. CH), 127.09 (arom. CH), 126.45 (2 arom. CH), 61.78 (CH2), 55.71 (CH), 53.72 (CH2), 51.67 (2 CH2), 35.61 (quat. C), 35.03 (CH2), 34.16 (2 CH2), 32.44 (3 CH3). MS (EI) m/z: 351 (M++H, 30), 259 (67), 216 (45), 202 (12), 147 (97), 119 (27), 117 (27), 105 (36), 96 (100). HRMS (EI) calcd. for C24H35N2 (M+ + H): 351.2795. Found: 351.2793
(S)-1-Phenethyl-N-(1-phenethyl)piperidin-4-amine (3d): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 610 (4.5 mmol) (S)-1-phenylethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 748 mg (81%) of 3d as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.36–7.11 (m, 10 H, 10 arom. CH), 3.96 (q, J = 6.6 Hz, 1 H, CH), 2.96–2.85 (m, 2 H, 2 CH2), 2.81–2.73 (m, 2 H, CH2), 2.56–2.48 (m, 2 H, CH2), 2.38–2.27 (m, 1 H, CH), 2.02–1.89 (m, 3 H, 3 CH2), 1.78–1.68 (m, 1 H, CH2), 1.46–1.35 (m, 2 H, 2 CH2), 1.33 (d, J = 6.6 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 146.18 (quat. C), 140.56 (quat. C), 128.69 (2 arom. CH), 128.40 (2 arom. CH), 128.34 (2 arom. CH), 126.78 (arom. CH), 126.52 (2 arom. CH), 125.96 (arom. CH), 60.66 (CH2), 54.52 (CH), 52.72 (CH2), 52.54 (CH2), 51.94 (CH), 33.89 (CH2), 33.69 (CH2), 32.62 (CH2), 25.12 (CH3). IR (KBr) ν (cm−1) = 2931, 2820, 1602, 1493, 1450, 1369, 1122, 1111, 762, 750. HRMS (EI) calcd. for C21H29N2 (M+ + 1): 309.2331. Found: 309.2323. = −52.2° (c = 2.745, CHCl3).
(S)-N-(1-Cyclohexylethyl)-1-phenethylpiperidin-4-amine (3e): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 610 mg (4.5 mmol) 1-(S)-cyclohexylethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 797 mg (85%) of 3e as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.33–7.15 (m, 5 H, arom. CH), 3.00–2.89 (m, 2 H, 2 CH2), 2.85–2.76 (m, 2 H, CH2), 2.62–2.45 (m, 4 H, 2 CH, 2 CH2), 2.07 (qd, J = 11.6, 11.1, 2.1 Hz, 2 H, 2 CH2), 1.93–1.80 (m, 2 H, 2 CH2), 1.79–1.57 (m, 5 H, CH, 4 CH2), 1.47–1.29 (m, 2 H, 2 CH2), 1.30–1.05 (m, 6 H, 6 CH2), 1.05–0.96 (m, 2 H, 2 CH2), 0.96 (d, J = 6.4 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 140.60 (quat. C), 128.71 (2 arom. CH), 128.34 (2 arom. CH), 125.96 (arom. CH), 60.72 (CH2), 53.98 (CH), 52.83 (CH2), 52.71 (CH2), 51.96 (CH), 43.30 (CH2), 33.93 (CH2), 33.83 (CH2), 32.97 (CH2), 30.02 (CH2), 28.19 (CH2), 26.80 (CH2), 26.65 (CH2), 26.52 (CH2), 17.70 (CH3). IR (KBr) ν (cm−1) = 2922, 2849, 2800, 1496, 1449, 1372, 1241, 1116, 1030, 979, 746, 698. MS (EI) m/z: 315 (M+, 0.3), 223 (69), 186 (20), 180 (85), 166 (19), 160 (45), 105 (38), 98 (48), 96 (100), 70 (82). HRMS (EI) calcd. for C21H35N2 (M+ + 1): 315.2800. Found: 315.2792.
N-(4-Chlorophenethyl)-1-phenethylpiperidin-4-amine (3f): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 700 mg (4.5 mmol) 4-chlorophenylethylamine and 1.339 g (6.0 mmol) sodium triacetoxyborohydride to give 686 mg (67%) of 3f as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.36–7.08 (m, 9 H, 9 arom. CH), 3.00–2.91 (m, 2 H, 2 CH2), 2.88 (t, J = 7.2 Hz, 2 H, CH2), 2.83–2.71 (m, 4 H, 3 CH2), 2.62–2.54 (m, 2 H, CH2), 2.53–2.44 (m, 1 H, CH), 2.12–2.03 (m, 2 H, CH2), 1.93–1.82 (m, 2 H, 2 CH2), 1.46–1.32 (m, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d) δ 140.53 (quat. C), 138.56 (quat. C), 131.90 (quat. C), 130.02 (2 arom. CH), 128.70 (2 arom. CH), 128.55 (2 arom. CH), 128.36 (2 arom. CH), 125.98 (arom. CH), 60.64 (CH), 54.89 (CH), 52.55 (2 CH2), 47.95 (CH2), 36.07 (CH2), 33.90 (2 CH2), 32.82 (CH2). IR (KBr) ν (cm−1) = 2938, 2797, 1492, 1451, 1358, 1143, 1120, 1043, 1014, 812, 739, 699. MS (EI) m/z: 343 (M++H, 0.2), 208 (72), 194 (12), 160 (22), 139 (60), 125 (31), 103 (39), 96 (100), 91 (22), 70 (38). HRMS (EI) calcd. for C21H28N2Cl (M+ + H): 343.1941. Found: 343.1936.
N-Hexyl-1-phenethylpiperidin-4-amine (3g): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 455 mg (4.5 mmol) n-hexylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 553 mg (64%) of 3g as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.24–7.19 (m, 2 H, 2 arom. CH), 7.15–7.09 (m, 3 H, 2 arom. CH), 2.94–2.85 (m, 2 H, CH2), 2.77–2.69 (m, 2 H, CH2), 2.57- 2.47 (m, 4 H, CH2), 2.39 (tt, J = 10.5, 4.1 Hz, 1 H, CH), 2.00 (td, J = 11.6, 2.4 Hz, 2 H, CH2), 1.87–1.79 (m, 2 H, CH2), 1.45–1.16 (m, 10 H, 5 CH2), 0.82 (t, J = 6.6 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 140.56 (quat. C), 128.71 (2 arom. CH), 128.35 (2 arom. CH), 125.97 (arom. CH), 60.68 (CH2), 55.05 (CH), 52.68 (2 CH2), 46.93 (CH2), 33.90 (CH2), 32.92 (2 CH2), 31.80 (CH2), 30.48 (CH2), 27.15 (CH2), 22.64 (CH2), 14.07 (CH3). IR (KBr) ν (cm−1) = 2926, 2853, 2802, 1467, 1455, 1120, 745.
tert-Butyl 4-((4-(tert-butyl)benzyl)amino)piperidine-1-carboxylate (4a): The compound was prepared according to general procedure 1 from 450 mg (2.3 mmol) 1-Boc-4-piperidone, 553 mg (3.4 mmol) 4-tert-butylbenzylamine and 1.0 g (4.52 mmol) sodium triacetoxyborohydride to give 783 mg (100%) of 4a as a white solid. Mp: 73–75 °C. 1H-NMR (400 MHz, chloroform-d, 323 K) δ 7.33 (d, J = 8.4 Hz, 2 H, 2 arom. CH), 7.23 (d, J = 8.4 Hz, 2 H, 2 arom. CH), 4.04–3.91 (m, 2 H, 2 CH2), 3.78 (s, 2 H, CH2N), 2.83 (ddd, J = 13.8, 11.3, 2.9 Hz, 2 H, 2 CH2), 2.69 (tt, J = 9.9, 3.9 Hz, 1 H, CH), 1.92–1.80 (m, 2 H, 2 CH2), 1.45 (s, 9 H, 3 CH3), 1.32 (s, 9 H, 3 CH3), 1.35–1.28 (m, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d, 323 K) δ 154.93 (CO), 149.97 (quat. C), 137.69 (quat. C), 127.76 (2 arom. CH), 125.38 (2 arom. CH), 79.36 (quat. C), 54.33 (CH), 50.59 (CH2), 42.60 (2 CH2), 34.50 (quat. C), 32.61 (2 CH2), 31.43 (3 CH3), 28.53 (3 CH3). MS (EI) m/z: 346 (M+, 2), 289 (45), 162 (100), 147 (80), 57 (56). HRMS (EI) calcd. for C21H34N2O2: 346.2620. Found: 346.2620.
tert-Butyl 4-(dodecylamino)piperidine-1-carboxylate (4b): The compound was prepared according to general procedure 1 from 598 mg (3.0 mmol) 1-Boc-4-piperidone, 834 mg (4.5 mmol) n-dodecylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 1.0 g (90%) of 4b as a colourless oil. 1H-NMR (400 MHz, chloroform-d, 323 K) δ 4.13–3.76 (m, 2 H, 2 CH2), 2.80 (ddd, J = 13.9, 12.9, 2.8 Hz, 2 H, CH2), 2.61 (t, J = 7.1 Hz, 2 H, CH2), 2.60–2.54 (m, 1 H, CH), 1.85–1.76 (m, 2 H, 2 CH2), 1.50–1.44 (m, 2 H, 2 CH2), 1.45 (s, 9 H, 3 CH3), 1.36–1.19 (m, 20 H, 10 CH2), 0.87 (t, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 154.83 (CO), 79.24 (quat. C) 54.99 (CH), 46.88 (CH2), 42.51 (2 CH2), 32.69 (CH2), 31.85 (2 CH2), 30.51 (CH2), 29.59 (CH2), 29.56 (CH2) 29.54 (2 CH2), 29.51 (CH2), 29.26 (CH2), 28.43 (3 CH3), 27.39 (CH2), 22.59 (CH2), 13.95 (CH3). IR (ATR, HCl of 4b) ν (cm−1) = 2920, 2851, 2714, 1683, 1471, 1425, 1365, 1242, 1166, 1141, 866, 772, 720. MS (EI) m/z: 368 (M+, 8), 311 (100), 127 (50), 57 (86). HRMS (EI) calcd. for C22H44O2N2 (M+): 368.3403. Found: 368.3394.
tert-Butyl 4-(octylamino)piperidine-1-carboxylate (4c): The compound was prepared according to general procedure 1 from 897 mg (4.5 mmol) 1-Boc-4-piperidone, 872 mg (6.75 mmol) n-octylamine and 2.0 g (9.0 mmol) sodium triacetoxyborohydride to give 1.1 g (78%) of 4c as a colourless oil. 1H-NMR (400 MHz, chloroform-d, 323 K) δ 4.08–3.91 (m, 2 H, 2 CH2), 2.87–2.73 (m, 2 H, 2 CH2), 2.60 (t, J = 7.3 Hz, 2 H, CH2), 2.61–2.52 (m, 1 H, CH), 1.86–1.74 (m, 2 H, 2 CH2), 1.52–1.42 (m, 2 H, 2 CH2). 1.45 (s, 9 H, 3 CH3), 1.35–1.22 (m, 12 H, 6 CH2), 0.87 (t, J = 7.2 Hz, 3 H, CH3). 13C-NMR (101 MHz, chloroform-d, 323 K) δ 154.86 (CO), 79.35 (quat. C), 55.12 (CH), 46.92 (CH2), 42.73 (2 CH2), 32.66 (2 CH2), 31.83 (CH2), 30.47 (CH2), 29.53 (CH2), 29.27 (CH2), 28.45 (3 CH3), 27.44 (CH2), 22.66 (CH2), 14.16 (CH3). MS (EI) m/z: 312 (M+, 0.8), 255 (6), 143 (2), 127 (4), 113 (3), 83 (13), 41 (100). HRMS (EI) calcd. for C18H36N2O2: 312.2777. Found: 312.2771.
tert-Butyl 4-(cycloheptylamino)piperidine-1-carboxylate (4d): The compound was prepared according to general procedure 1 from 598 mg (3.0 mmol) 1-Boc-4-piperidone, 509 mg (4.5 mmol) cycloheptylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 870 mg (98%) of 4d as a colourless oil. 1H-NMR (400 MHz, chloroform-d, 323 K) δ 4.08–3.93 (m, 2 H, 2 CH2), 2.87–2.71 (m, 3 H, CH, 2 CH2), 2.72–2.60 (m, 1 H, CH), 1.87–1.73 (m, 4 H, 4 CH2), 1.72–1.08 (m, 12 H, 6 CH2), 1.45 (s, 9 H, 3 CH3). 13C-NMR (100 MHz, chloroform-d) δ 154.92 (CO), 79.35 (quat. C), 55.22 (CH), 51.95 (CH), 42.97 (2 CH2), 35.71 (2 CH2), 33.35 (2 CH2), 28.54 (3 CH3), 28.28 (2 CH2), 24.50 (2 CH2). IR (ATR) ν (cm−1) = 2980, 2921, 2852, 1688, 1419, 1364, 1234, 1169, 869, 769. MS (EI) m/z: 296 (M+, 20), 239 (6), 183 (100), 143 (54), 127 (44), 57 (54). HRMS (EI) calcd. for C17H32N2O2 (M+): 296.2464. Found: 296.2457.
tert-Butyl 4-((pyridin-3-ylmethyl)amino)piperidine-1-carboxylate (4e): The compound was prepared according to general procedure 1 from 1.1 g (6.2 mmol) 1-Boc-4-piperidone, 977 mg (9.03 mmol) 3-picolylamine and 2.67 g (12.0 mmol) sodium triacetoxyborohydride to give 1.75 g (100%) of 4e as a colourless oil. 1H-NMR (400 MHz, chloroform-d, 323 K) δ 8.56 (d, J = 1.7 Hz, 1 H, arom. CH), 8.49 (dd, J = 4.8, 1.6 Hz, 1 H, arom. CH), 7.67 (dt, J = 7.8, 1.7 Hz, 1 H, arom. CH), 7.24 (ddd, J = 7.8, 4.8, 0.7 Hz, 1 H, arom. CH), 4.07–3.91 (m, 2 H, 2 CH2), 3.84 (s, 2 H, CH2N), 2.92–2.75 (m, 2 H, 2 CH2), 2.67 (ddd, J = 10.0, 6.0, 4.0 Hz, 1 H, CH), 1.92–1.78 (m, 2 H, 2 CH2), 1.64–1.47 (m, 2 H, 2 CH2), 1.45 (s, 9 H, 3 CH3). 13C-NMR (100 MHz, chloroform-d, 323 K) δ 154.88 (quat. C), 149.70 (arom. CH), 148.59 (arom. CH), 136.04 (quat. C), 135.66 (arom. CH), 123.39 (arom. CH), 79.48 (quat. C), 54.44 (CH), 48.27 (CH2), 42.55 (2 CH2), 32.60 (2 CH2), 28.53 (3 CH3). IR (KBr) ν (cm−1) = 2937, 2796, 1683, 1452, 1421, 1360, 1172, 1121, 1043, 843, 738, 697. MS (EI) m/z: 291 (M+, 26), 218 (18), 107 (23), 94 (40), 92 (47), 57 (100). HRMS: calcd. for C16H25N3O2: 291.1947. Found: 291.1942.
tert-Butyl 4-((2-(pyrrolidin-1-yl)ethyl)amino)piperidine-1-carboxylate (4f): The compound was prepared according to general procedure 1 from 598 mg (3.0 mmol) 1-Boc-4-piperidone, 977 mg (9.03 mmol) 1-pyrrolidineethanamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 580 mg (65%) of 4f as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 4.08–3.93 (m, 2 H, 2 CH2), 2.89–2.73 (m, 4 H, 2 CH2), 2.67–2.55 (m, 7 H, CH, 3 CH2), 1.88–1.72 (m, 6 H, 3 CH2), 1.45 (s, 9 H, 3 CH3), 1.37–1.20 (m, 2 H, CH2). 13C-NMR (100 MHz, chloroform-d) δ 154.92 (CO), 79.39 (quat. C), 56.23 (2 CH2), 55.24 (CH), 54.23 (CH2), 45.30 (CH2), 42.68 (2 CH2), 32.61 (2 CH2), 28.53 (3 CH3), 23.59 (2 CH2). IR (KBr) ν (cm−1) = 3266, 2791, 1683, 1419, 1364, 1240, 1168, 1139, 873. MS (EI) m/z: 291 (M+, 2), 224 (6), 84 (100). HRMS: calcd. for C16H31N3O2: 297.2416. Found: 297.2411.
N-(4-(tert-Butyl)benzyl)piperidin-4-amine (5a): The compound was prepared according to general procedure 2 from 200 mg (0.58 mmol) of 4a to give 120 mg (84%) of 5a as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.35 (d, J = 8.4 Hz, 2 H, 2 arom. CH), 7.25 (d, J = 8.4 Hz, 2 H, 2 arom. CH), 3.78 (s, 2 H, CH2), 3.15 (dt, J = 12.7, 3.7 Hz, 2 H, 2 CH2), 2.77–2.53 (m, 3 H, 2 CH2, CH), 2.00–1.87 (m, 2 H, 2 CH2), 1.42–1.23 (m, 2 H, 2 CH2), 1.31 (s, 9 H, 3 CH3). 13C-NMR (100 MHz, chloroform-d) δ 149.89 (quat. C), 137.38 (quat. C), 127.78 (2 arom. CH), 125.38 (2 arom. CH), 53.83 (CH), 50.26 (CH2), 44.66 (2 CH2), 34.47 (quat. C), 33.11 (2 CH2), 31.39 (3 CH3). IR (ATR) ν (cm−1) = 2954, 2863, 1461, 1363, 1269, 1201, 1128, 830, 800, 720.
N-Dodecylpiperidin-4-amine (5b): The compound was prepared according to general procedure 2, from 200 mg (0.54 mmol) of 4b to give 120 mg (83%) of 5b as a colourless oil. 1H-NMR (400 MHz, methanol-d4) δ 4.03–3.89 (m, 2 H, 2 CH2), 3.07–2.97 (m, 1 H, CH), 2.77–2.42 (m, 6 H, 3 CH2), 1.87–1.69 (m, 2 H, 2 CH2), 1.47–1.37 (m, 2 H, 2 CH2), 1.31–1.07 (m, 20 H, 10 CH2), 0.79 (t, J = 6.8 Hz, 3 H, CH3). 13C-NMR (100 MHz, methanol-d4) δ 54.81 (CH2), 46.03 (2 CH2), 45.67 (CH), 31.67 (CH2), 31.19 (CH2), 29.36 (CH2), 29.34 (CH2), 29.30 (CH2), 29.27 (CH2), 29.24 (CH2), 29.08 (CH2), 27.26 (CH2), 27.04 (CH2), 26.98 (CH2), 22.33 (CH2), 13.03 (CH3). IR (ATR, HCl) ν (cm−1) = 2920, 2851, 2721, 1471, 1426, 1243, 1167, 1142, 866, 772, 720. HRMS (EI) calcd. for C17H35N2 (M+-H): 267.8000. Found: 267.2795.
N-Octylpiperidin-4-amine (5c): The compound was prepared according to general procedure 2 from 200 mg (0.64 mmol) of 4c to give 120 mg (88%) of 5c as a colourless oil. 1H-NMR (400 MHz, methanol-d4) δ 3.58–3.39 (m, 3 H, 2 CH2, CH), 3.11 (td, J = 13.2, 2.7 Hz, 2 H, 2 CH2), 3.05–2.96 (m, 2 H, CH2), 2.40–2.28 (m, 2 H, 2 CH2), 2.07 (ddt, J = 22.3, 13.8, 7.1 Hz, 2 H, 2 CH2), 1.80–1.67 (m, 2 H, CH2), 1.47–1.24 (m, 10 H, 5 CH2), 0.89 (t, J = 6.8 Hz, 3 H, CH3). 13C-NMR (100 MHz, methanol-d4) δ 52.14 (CH), 44.94 (CH2), 42.18 (2 CH2), 31.55 (2 CH2), 28.87 (2 CH2), 26.38 (CH2), 26.10 (CH2), 24.91 (CH2), 22.39 (CH2), 13.34 (CH3). IR (KBr) ν (cm−1) = 2928, 1431, 1200, 1174, 1130, 836, 797, 721. MS (EI) m/z: 211 (M+-1, 46), 168 (46), 157 (38), 84 (74), 57 (100). HRMS (EI) calcd. for C13H27N2 (M+-H): 211.2180. Found: 211.2169.
N-(Pyridin-3-ylmethyl)piperidin-4-amine (5e): The compound was prepared according to general procedure 2 from 670 mg (2.3 mmol) of 4e to give 100 mg (20%) of 5e as a brown oil. 1H-NMR (400 MHz, methanol-d4) δ 8.55 (s, 1 H, NH), 8.51–8.40 (m, 2 H, NH, arom. CH), 7.91–7.84 (m, 1 H, arom. CH), 7.83–7.73 (m, 1 H, arom. CH), 7.45–7.38 (m, 1 H, arom. CH), 3.86 (s, 2 H, CH2), 3.45–3.36 (m, 2 H, 2 CH2), 3.05–2.95 (m, 2 H, 2 CH2), 2.91–2.80 (m, 1 H, CH), 1.71–1.55 (m, 2 H, 2 CH2), 1.38–1.24 (m, 2 H, 2 CH2).
N-(2-(Pyrrolidin-1-yl)ethyl)piperidin-4-amine (5f): The compound was prepared according to general procedure 2 from 200 mg (0.67 mmol) of 4e to give 100 mg (76%) of 5e as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 3.25–3.11 (m, 4 H, 2 CH2), 2.76 (t, J = 6.3 Hz, 2 H, CH2), 2.72–2.64 (m, 1 H, CH), 2.61 (t, J = 6.3 Hz, 2 H, CH2), 2.55–2.47 (m, 4 H, 2 CH2), 2.02–1.87 (m, 2 H, 2 CH2), 1.82–1.72 (m, 4 H, 2 CH2), 1.43–1.25 (m, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d) δ 55.99 (2 CH2), 54.68 (CH), 54.13 (CH2), 45.18 (CH2), 44.65 (2 CH2), 32.97 (2 CH2), 23.43 (2 CH2). IR (KBr) ν (cm−1) = 2955, 2912, 2827, 1448, 1410, 1200, 1173, 1128, 799. MS (EI) m/z: 194 (2, M+-3), 113 (14), 97 (10), 84 (100). HRMS (EI) calcd. for C11H21N3 (M+-2H): 195.1736. Found: 195.1729.
N-Dodecyl-N-(1-phenethylpiperidin-4-yl)acetamide (6a): The compound was prepared according to general procedure 3 from 261 mg (0.7 mmol) of 3b and 110 mg (2.0 mmol) acetyl chloride to give 280 mg (97%) of 6a as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.33–7.25 (m, 2 H, 2 arom. CH), 7.23–7.14 (m, 3 H, 3 arom. CH), 4.47–4.35 (m, 1 H, CH), 3.25–3.11 (m, 2 H, CH2), 3.10–2.98 (m, 2 H, CH2), 2.84–2.75 (m, 2 H, CH2), 2.65–2.56 (m, 2 H, CH2), 2.09 (s, 3 H, CH3), 1.76–1.63 (m, 3 H, 2 CH2), 1.61–1.47 (m, 3 H, 2 CH2), 1.37–1.18 (m, 20 H, 10 CH2), 0.88 (t, J = 6.8 Hz, 3 H, CH3). 13C-NMR (100 MHz, DMSO-d6) δ 169.67 (CO), 140.77 (quart. C), 128.99 (2 arom.), 128.63 (2 arom. CH), 126.23 (arom. CH), 60.09 (CH2), 56.05 (CH), 53.25 (2 CH2), 44.64 (CH2), 33.49 (CH2), 31.78 (CH2), 31.27 (CH2), 30.77 (CH2), 29.81 (CH2), 29.49 (CH2), 29.42 (2 CH2), 29.19 (CH2), 27.20 (CH2), 26.91 (2 CH2), 22.58 (CH2), 22.31 (CH3), 14.40 (CH3). IR (KBr) ν (cm−1) = 2923, 2852, 2804, 1644, 1455, 1420, 1369, 1287, 1122, 1041, 747, 699. MS (EI) m/z: 413 (M+-H, 0.1), 0.323 (100), 280 (14), 238 (15). HRMS (EI) calcd. for C27H45N2O (M+-H): 413.3532. Found: 413.3521.
N-(4-(tert-Butyl)benzyl)-N-(1-phenethylpiperidin-4-yl)undec-10-enamide (6b): The compound was prepared according to general procedure 3 from 501 mg (1.43 mmol) of 3c and 580 mg (2.9 mmol) 10-undecenoyl chloride to give 575 mg (78%) of 6b as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.39–7.00 (m, 9 H, 9 arom. CH), 5.80 (ddt, J = 16.9, 10.1, 6.6 Hz, 1 H, -CH=), 5.04–4.87 (m, 2 H, CH2), 4.69–4.58 (m, 1 H, CH), 4.50 (s, 2 H, CH2), 3.09–2.95 (m, 2 H, 2 CH2), 2.80–2.71 (m, 2 H, CH2), 2.61–2.50 (m, 2 H, CH2), 2,24 (t, J = 7.4 Hz, 2 H, CH2), 2.16–1.98 (m, 4 H, 3 CH2), 1.71–1.53 (m, 6 H, 3 CH2), 1.43–1.18 (m, 10 H, 5 CH2), 1.31 (s, 9 H, 3 CH3). 13C-NMR (100 MHz, chloroform-d) δ 174.22 (CO), 150.02 (quat. C), 140.27 (quat. C), 139.20 (-CH=), 135.49 (quat. C), 128.64 (2 arom. CH), 128.38 (2 arom. CH), 126.03 (arom. CH), 125.51 (2 arom. CH), 125.35 (2 arom. CH), 114.11 (=CH2), 60.45 (CH2), 53.29 (2 CH2), 53.13 (CH2), 51.69 (CH), 46.20 (CH2), 33.85 (quat. C), 33.79 (2 CH2), 31.37 (3 CH3), 29.74 (CH2), 29.40 (CH2), 29.34 (CH2), 29.32 (CH2), 29.08 (CH2), 28.90 (CH2), 25.49 (CH2). IR (KBr) ν (cm−1) = 2925, 2853, 2802, 1643, 1457, 1412, 1373, 1194, 1120, 1031, 993, 908, 820, 747, 699. MS (EI) m/z: 516 (M+, 2), 425 (100), 147 (90). HRMS (EI) calcd. for C35H52N2O: 516.4080. Found: 516.3837.
N-Dodecyl-N-(1-phenethylpiperidin-4-yl)butyramide (6c): The compound was prepared according to general procedure 3 from 373 mg (1.0 mmol) of 3b and 160 mg (1.5 mmol) butanoyl chloride to give 427 mg (96%) of 6c as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.33–7.27 (m, 2 H, arom. CH), 7.24–7.15 (m, 3 H, 3 arom. CH), 4.53–3.50 (m, 1 H, CH), 3.24–3.00 (m, 4 H, 3 CH2), 2.86–2.74 (m, 2 H, CH2), 2.66–2.53 (m, 2 H, CH2), 2.35–2.23 (m, 2 H, 2 CH2), 2.20–2.02 (m, 2 H, CH2), 1.96–1.79 (m, 1 H, CH2), 1.78–1.45 (m, 9 H, 5 CH2), 1.35–1.22 (m, 16 H, 8 CH2), 1.00–0.94 (m, 3 H, CH3), 0.91–0.85 (m, 3 H, CH3). IR (KBr) ν (cm−1) = 2924, 2853, 1642, 1456, 1420, 1372, 1288, 1241, 1122, 1032, 747, 699. MS (EI) m/z: 441 (M+-H, 0.2), 351 (100), 238 (14), 105 (12). HRMS (EI) calcd. for C22H43N2O (M+-C7H7 (Bn)): 351.3375. Found: 351.3387.
N-Dodecyl-N-(1-phenethylpiperidin-4-yl)cinnamamide (6d): The compound was prepared according to general procedure 3 from 373 mg (1.0 mmol) of 3b and 250 mg (1.5 mmol) cinnamoyl chloride to give 440 mg (88%) of 6d as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 15.3 Hz, 1 H, -CH=), 7.52 (dd, J = 7.6, 1.6 Hz, 2 H, 2 arom. CH), 7.44–7.34 (m, 3 H, 3 arom. CH), 7.33–7.27 (m, 2 H, 2 arom. CH), 7.25–7.16 (m, 3 H, 3 arom. CH), 6.80 (d, J = 15.3 Hz, 1 H, -CH=), 4.69–4.52 (m, 1 H, CH), 3.38–3.27 (m, 2 H, CH2), 3.15–3.04 (m, 2 H, CH2), 2.87–2.79 (m, 2 H, CH2), 2.65–2.58 (m, 2 H, CH2), 2.24–2.15 (m, 1 H, CH2), 1.84–1.69 (m, 3 H, 2 CH2), 1.38–1.23 (m, 22 H, 11 CH2), 0.87 (t, J = 6.8 Hz, 3 H, CH3). MS (EI) m/z: 502 (M+, 0.3), 501 (0.4), 411 (96), 281 (24), 131 (100), 103 (18). HRMS (EI) calcd. for C34H49N2O (M+-H): 501.3845. Found: 501.3824.
N-(1-Benzylpiperidin-4-yl)-N-dodecyl-[1,1′-biphenyl]-2-carboxamide (6e): The compound was prepared according to general procedure 3 from 717 mg (2.0 mmol) of 3b and 648 mg (3 mmol) 2-phenylbenzoyl chloride (prepared from 607 mg (3.0 mmol) biphenyl-2-carboxylic acid and 595 mg (5.0 mmol) thionyl chloride) to give 900 mg (78%) of 6e as a pale yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 11.25–10.65 (m, 1 H, NH), 7.68–7.23 (m, 14 H, 14 arom. CH), 4.35–3.93 (m, 2 H, CH2), 3.38–2.85 (m, 7 H, CH, 3 CH2), 2.81–2.58 (m, 2 H, CH2), 2.37–1.82 (m, 2 H, CH2), 1.57–1.44 (m, 2 H, CH2), 1.38–1.02 (m, 18 H, 9 CH2), 0.88 (t, J = 6.9 Hz, 3 H, CH3). IR (KBr) ν (cm−1) = 2922, 2852, 1623, 1455, 1437, 1419, 1302, 1047, 777, 744, 700. MS (ESI) m/z: 539 (100, M+ + H). HRMS (ESI) calcd. for C37H51N2O+ (M++H)+: 539.3996. Found: 539.3999.
N-Dodecyl-N-(1-phenethylpiperidin-4-yl)propionamide (6f): The compound was prepared according to general procedure 3 from 373 mg (1.0 mmol) of 3b and 139 mg (1.5 mmol) propionyl chloride to give 420 mg (98%) of 6f as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.34–7.27 (m, 2 H, 2 arom. CH), 7.25–7.16 (m, 3 H, 3 arom. CH), 4.53–4.41 and 3.62–3.49 (m, 1 H, CH), 3.27–3.01 (m, 4 H, 3 CH2), 2.87–2.75 (m, 2 H, CH2), 2.66–2.52 (m, 2 H, CH2), 2.42–2.25 (m, 2 H, 2 CH2), 2.22–2.01 (m, 2 H, CH2), 1.88 (qd, J = 13.9, 4.8 Hz, 1 H, CH2), 1.79–1.63 (m, 3 H, 2 CH2), 1.59–1.46 (m, 2 H, CH2), 1.34–1.20 (m, 20 H, 10 CH2), 1.19–1.10 (m, 3 H, CH3), 0.88 (t, J = 6.3 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 173.78 (CO), 140.12 (quat. C), 128.67 (2 arom. CH), 128.41 (2 arom. CH), 126.08 (arom. CH), 60.49 (CH2), 55.33 (CH), 53.32 (CH2), 53.23 (2 CH2), 43.53 (CH2), 33.87 (CH2), 33.80 (CH2), 31.92 (CH2), 31.68 (CH2), 30.89 (CH2), 29.96 (CH2), 29.63 (CH2), 27.43 (2 CH2), 27.22 (CH2), 26.94 (CH2), 26.74 (CH2), 22.70 (CH2), 14.13 (CH3), 9.84 (CH3). IR (KBr) ν (cm−1) = 2918, 2851, 2814, 1611, 1456, 1378, 1253, 1145, 1117, 857, 808, 748, 699. MS (EI) m/z: 411 (M+, 2), 337 (100), 238 (16), 100 (56). HRMS (EI) calcd. for C28H48N2O: 428.3767. Found: 428.3674.
N,1-Dibenzyl-N-methylpiperidin-4-amine (7a): The compound was prepared according general procedure 1 from 568 mg (3.0 mmol) 1-benzyl-4-piperidone, 556 mg (4.5 mmol) N-benzylmethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 701 mg (79%) of 7a as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.34–7.28 (m, 8 H, 8 arom. CH), 7.27–7.20 (m, 2 H, 2 arom. CH), 3.57 (s, 2 H, CH2), 3.49 (s, 2 H, CH2), 3.04–2.86 (m, 2 H, 2 CH2), 2.44 (tt, J = 11.6, 3.9 Hz, 1 H, CH), 2.19 (s, 3 H, CH3), 1.96 (td, J = 11.7, 2.3 Hz, 2 H, 2 CH2), 1.84–1.74 (m, 2 H, 2 CH2), 1.68 (td, J = 11.7, 3.5 Hz, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d) δ 140.16 (quat. C), 138.54 (quat. C), 129.16 (2 arom. CH), 128.76 (2 arom. CH), 128.19 (2 arom. CH), 128.16 (2 arom. CH), 126.93 (arom. CH), 126.73 (arom. CH), 63.15 (CH2), 60.98 (CH), 57.98 (CH2), 53.38 (2 CH2), 37.79 (CH3), 27.91 (2 CH2). IR (KBr) ν (cm−1) = 2940, 2793, 1658, 1452, 1363, 1254, 1147, 1122, 1044, 1017, 970, 906, 880, 789, 735, 697. MS (EI) m/z: 203 (M+, 11), 173 (44), 172 (30), 146 (24), 91 (100). HRMS (EI) calcd. for C20H27N2 (M+ + H): 295.2174. Found: 295.2167.
N-Benzyl-N-methyl-1-phenethylpiperidin-4-amine (7b): The compound was prepared according to general procedure 1 from 610 mg (3.0 mmol) 1-(2-phenylethyl)-4-piperidone, 556 mg (4.5 mmol) N-benzylmethylamine and 1.34 g (6.0 mmol) sodium triacetoxyborohydride to give 711 mg (77%) of 7b as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.41–7.13 (m, 10 H, 10 arom. CH), 3.59 (s, 2 H, CH2), 3.17–3.04 (m, 2 H, 2 CH2), 2.86–2.75 (m, 2 H, CH2), 2.64–2.54 (m, 2 H, CH2), 2.50–2.41 (m, 1 H, CH), 2.21 (s, 3 H, CH3), 2.02 (td, J = 11.8, 2.4 Hz, 2 H, 2 CH2), 1.89–1.80 (m, 2 H, 2 CH2), 1.71 (qd, J = 12.3, 3.8 Hz, 2 H, 2 CH2). 13C-NMR (100 MHz, chloroform-d) δ 140.50 (quat. C), 140.12 (quat. C), 128.70 (2 arom. CH), 128.38 (2 arom. CH), 128.22 (2 arom. CH), 126.76 (arom. CH), 126.00 (arom. CH), 60.91 (CH), 60.69 (CH2), 57.94 (CH2), 53.49 (2 CH2), 37.79 (CH3), 33.97 (CH2), 27.89 (2 CH2). IR (KBr) ν (cm−1) = 2937, 2800, 1495, 1453, 1359, 1313, 1263, 1196, 1120, 1043, 843, 738, 697. MS (EI) m/z: 308 (M+, 3), 217 (100), 160 (33), 174 (22), 187 (12), 146 (11), 120 (12), 105 (31), 96 (90), 91 (69), 70 (74), 42 (30). HRMS (EI) calcd. for C21H28N2: 308.2252. Found: 308.2246.
N-Dodecyl-1-phenethyl-N-(3-phenylpropyl)piperidin-4-amine (8d): 503 mg (1.0 mmol) of 6d was dissolved in 20 mL dry THF and 380 mg (10.0 mmol) LiAlH4 was added at 20 °C. The suspension was stirred for 1 h and then refluxed for 4 h. After careful addition of 20 mL ice water, the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The crude residue was purified by flash column chromatography (ethyl acetate:triethylamine 10:1) to give 185 mg (38%) of 8d as a pale yellow oil. 1H-NMR (400 MHz, chloroform-d) δ 7.30–7.23 (m, 4 H, arom. CH), 7.22–7.13 (m, 6 H, 6 arom. CH), 3.11–2.96 (m, 2 H, CH2), 2.84–2.71 (m, 2 H, CH2), 2.66–2.39 (m, 7 H, CH, 4 CH2), 1.96 (dd, J = 11.5 Hz, J = 2.0 Hz, 2 H, 2 CH2), 1.80–1.66 (m, 3 H, 3 CH2), 1.64–1.51 (m, 2 H, CH2), 1.48–1.33 (m, 3 H, 2 CH2), 1.35–1.09 (m, 20 H, 10 CH2), 0.88 (t, J = 6.8 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 142.65 (quat. C), 140.54 (quat. C), 128.71 (2 arom. CH), 128.39 (4 arom. CH), 128.28 (2 arom. CH), 126.00 (arom. CH), 125.63 (arom. CH), 60.78 (CH2), 58.70 (CH), 53.82 (2 CH2), 50.78 (CH2), 50.37 (CH2), 34.00 (CH2), 33.81 (CH2), 31.97 (CH2), 30.92 (CH2), 29.75 (CH2), 29.74 (CH2), 29.70 (CH2), 29.68 (CH2), 29.41 (CH2), 29.29 (CH2), 28.27 (2 CH2), 27.57 (CH2), 22.74 (CH2), 14.18 (CH3). IR (KBr) ν (cm−1) = 2920, 2852, 1680, 1539, 1455, 1199, 1139, 800, 724, 700. MS (EI) m/z: 489 (M+-1, 4), 399 (22), 187 (30), 160 (42), 96 (100). HRMS: calcd. for C34H54N2 (M+): 490.4287. Found: 490.4277.
N-([1,1′-Biphenyl]-2-ylmethyl)-1-benzyl-N-dodecylpiperidin-4-amine (8e): 349 mg (0.6 mmol) of 6e as hydrochloride was dissolved in 20 mL dry THF and 224 mg (5.9 mmol) LiAlH4 was added at 20 °C. The suspension was stirred for 1 h and then refluxed for 4 h. After careful addition of 20 mL ice water, the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The crude residue was purified by flash column chromatography (ethyl acetate/trimethylamine 10:1) to give 310 mg (100%) of 8e as a colourless oil. 1H-NMR (400 MHz, chloroform-d) δ 7.68 (d, J = 8.2 Hz, 1 H, arom. CH), 7.40–7.20 (m, 12 H, 12 arom CH), 7.17 (dd, J = 7.5, 1.3 Hz, 1 H, arom. CH), 3.53 (s, 2 H, CH2), 3.44 (s, 2 H, CH2), 2.90–2.79 (m, 2 H, 2 CH2), 2.39–2.32 (m, 1 H, CH), 2.33 (t, J = 7.0 Hz, 2 H, CH2), 1.82 (td, J = 11.0, 4.0 Hz, 2 H, 2 CH2), 1.52–1.48 (m, 4 H, 3 CH2), 1.35–1.11 (m, 20 H, 10 CH2), 0.87 (t, J = 6.7 Hz, 3 H, CH3). 13C-NMR (100 MHz, chloroform-d) δ 141.88 (quat. C), 141.63 (quat. C), 138.75 (quat. C), 138.47 (quat. C), 129.62 (arom. CH), 129.33 (2 arom. CH), 129.25 (arom. CH), 129.18 (2 arom. CH), 128.12 (2 arom. CH), 127.86 (2 arom. CH), 127.14 (arom. CH), 126.89 (arom. CH), 126.71 (arom. CH), 125.99 (arom. CH), 63.18 (CH2), 57.56 (CH), 53.60 (2 CH2), 51.71 (CH2), 49.97 (CH2), 31.94 (CH2), 29.70 (CH2), 29.69 (2 CH2), 29.67 (2 CH2), 29.56 (CH2), 29.38 (CH2), 28.62 (CH2), 27.88 (CH2), 27.36 (CH2), 22.71 (CH2), 14.14 (CH3). IR (KBr) ν (cm−1) = 2922, 2851, 2799, 1454, 1365, 1147, 1072, 750, 699. MS (EI) m/z: 524 (M+, 1), 425 (23), 350 (64), 173 (89), 167 (100). HRMS: calcd. for C37H52N2 (M+): 524.4130. Found: 524.4127.