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S. D. Banister et al. / Bioorg. Med. Chem. 21 (2013) 6038–6052
2
gave 9e (465 mg, 88%) as a colourless oil: mp (HCl salt) 260 °C
(dec); Rf 0.72 (silica gel, CH2Cl2–MeOH-28% aq NH4OH; 90:9:1);
IR (thin film); 3342 (br), 2919, 2861, 2799, 1603, 1453, 1351,
1136, 747, 697; 1H NMR (400 MHz, CDCl3); d 7.31–7.27 (2H, m),
7.22–7.18 (3H, m), 2.89–2.73 (5H, m), 2.66–2.62 (1H, m), 2.60–
2.53 (2H, m), 2.49–2.44 (1H, m), 2.31–2.28 (1H, m), 2.23–2.16
(4H, m), 1.67 (1H, d, J = 10.3 Hz), 1.18 (1H, br s, NH), 1.16 (1H, d,
J = 10.3 Hz), 0.96 (1H, dt, J = 11.9, 3.7 Hz); 13C NMR (100 MHz,
CDCl3); d 140.6 (quat.), 128.8, 128.5, 126.1, 61.8, 50.7 (CH2), 47.4,
44.8, 44.3, 42.1, 42.0, 40.9, 37.9, 37.0 (CH2), 36.4, 34.9 (CH2), 28.8
(CH2); m/z (+ESI) 265.87 ([M+H]+, 100); Anal. (C19H23NÁHCl): calcd
C 75.60, H 8.01, N 4.64; found, C 75.73, H 7.94, N 4.63.
112.6 (d, JCF = 21.0 Hz), 62.2, 48.8 (CH2), 47.4, 44.8, 44.4, 42.1,
42.0, 41.0, 38.0, 36.5, 34.9 (CH2), 33.6 (CH2), 32.2 (CH2), 28.9
(CH2); m/z (+ESI) 298.07 ([M + H]+, 100); Anal. (C20H24NFÁHCl):
calcd C 71.95, H 7.55, N 4.20; found, C 72.14, H 7.55, N 4.25.
4.1.2.9. N-(3,4,5-Trimethoxybenzyl)-8-aminopentacyclo[5.4.0.
02,6.03,10.05,9]undecane (9i).
Treating 22 (320 mg, 2.00 mmol)
with 3,4,5-trimethoxybenzylamine (342 L, 2.00 mmol, 1.0 equiv)
l
as described above gave 9i (652 mg, 95%) as a colourless oil: mp
(HCl salt) 252 °C (dec); Rf 0.65 (silica gel, CHCl3–MeOH-28% aq NH4-
OH; 95:4.5:0.5); IR (thin film); 3394, 2952, 2782, 1588, 1421, 1329,
1243, 1123, 997, 780, 690; 1H NMR (400 MHz, CDCl3); d 6.58 (2H, s),
3.86 (6H, s, 2 Â OCH3), 3.83 (3H, s, OCH3), 3.72 (2H, s), 2.78 (1H, t,
J = 3.3 Hz), 2.70–2.64 (1H, m), 2.59–2.53 (3H, m), 2.48–2.43 (1H,
m), 2.33 (1H, d, J = 8.0 Hz), 2.24–2.18 (3H, m), 1.67 (1H, d,
J = 10.3 Hz), 1.43 (1H, br s, NH), 1.17 (1H, d, J = 10.3 Hz), 1.02 (1H,
dt, J = 11.6, 3.8 Hz); 13C NMR (100 MHz, CDCl3); d 153.2 (2 Â quat.),
137.5 (quat.), 136.8 (quat.), 104.8, 62.0, 61.0 (CH3), 56.2 (2 Â CH3),
54.0 (CH2), 47.4, 44.8, 44.4, 42.147, 42.072, 41.0, 38.0, 36.5, 34.8
(CH2), 28.9 (CH2); m/z (+ESI) 341.93 ([M+H]+, 100), 181.00 ([ArCH2]+,
57); Anal. (C21H27NO3ÁHCl): calcd C 66.74, H 7.47, N 3.71; found, C
66.55, H 7.59, N 3.70.
4.1.2.6. N-(2-(3-Fluorophenyl)ethyl)-8-aminopentacyclo[5.4.0.
02,6.03,10.05,9]undecane (9f).
Treating 22 (320 mg, 2.00 mmol)
with 2-(3-fluorophenyl)ethylamine (261 L, 2.00 mmol, 1.0 equiv)
l
as described above gave 9f (521 mg, 92%) as a colourless oil: mp
(HCl salt) 272 °C (dec); Rf 0.65 (silica gel, CHCl3–MeOH-28% aq NH4-
OH; 90:9:1); IR (thin film); 3329 (br), 2950, 2861, 2799, 1615, 1588,
1487, 1449, 1352, 1248, 1139, 781, 692; 1H NMR (400 MHz, CDCl3);
d 7.26–7.21 (1H, m), 6.98 (1H, d, J = 7.7 Hz), 6.93–6.86 (2H, m), 2.88–
2.72 (5H, m), 2.66–2.62 (1H, m), 2.58–2.53 (2H, m), 2.49–2.44 (1H,
m), 2.29 (1H, d, J = 9.5 Hz), 2.22–2.18 (3H, m), 1.67 (1H, d,
J = 10.4 Hz), 1.18 (1H, br s, NH, obscured), 1.16 (1H, d, J = 10.4 Hz),
0.96 (1H, dt, J = 11.9, 3.8 Hz); 13C NMR (100 MHz, CDCl3); d 163.1
4.1.2.10.
[5.4.0.02,6.03,10.05,9]undecane (9j).
mmol) with piperonylamine (249
N-(3,4-Methylenedioxybenzyl)-8-aminopentacyclo
Treating 22 (320 mg, 2.00
1
3
(d, JCF = 245.3 Hz, quat.), 143.2 (d, JCF = 7.2 Hz, quat.), 129.9 (d,
lL, 2.00 mmol, 1.0 equiv) as de-
3JCF = 8.4 Hz), 124.5 (d, JCF = 2.6 Hz), 115.6 (d, JCF = 20.8 Hz), 113.0
scribed above gave 9j (520 mg, 88%) as a colourless oil: mp (HCl
salt) 232 °C (dec); Rf 0.47 (silica gel, CHCl3–MeOH-28% aq NH4OH;
95:4.5:0.5); IR (thin film); 3382, 2952, 2866, 2777, 1585, 1481,
1437, 1252, 1106, 1040, 937, 895, 809, 777, 707; 1H NMR
(400 MHz, CDCl3); d 6.86 (1H, d, J = 1.3 Hz), 6.76 (1H, dd, J = 7.9,
1.3 Hz), 6.73 (1H, d, J = 7.9 Hz), 5.92 (2H, s, OCH2O), 3.67 (2H, s),
2.76 (1H, t, J = 3.4 Hz), 2.69–2.64 (1H, m), 2.59–2.50 (3H, m),
2.48–2.43 (1H, m), 2.32 (1H, d, J = 8.4 Hz), 2.23–2.17 (3H, m),
1.67 (1H, d, J = 10.3 Hz), 1.44 (1H, br s, NH), 1.16 (1H, d,
J = 10.3 Hz), 1.01 (1H, dt, J = 11.7, 3.8 Hz); 13C NMR (100 MHz,
CDCl3); d 147.7 (quat.), 146.4 (quat.), 135.7 (quat.), 121.0, 108.7,
108.1, 100.9 (CH2), 61.6, 53.4 (CH2), 47.4, 44.8, 44.4, 42.2, 42.1,
41.1, 37.9, 36.5, 34.8 (CH2), 28.9 (CH2); m/z (+ESI) 296.20 ([M +
H]+, 100), 135.07 ([ArCH2]+, 11); Anal. (C19H21NO2ÁHCl): calcd C
68.77, H 6.68, N 4.22; found, C 68.63, H 6.78, N 4.25.
4
2
2
(d, JCF = 20.9 Hz), 61.8, 50.3 (CH2), 47.4, 44.8, 44.3, 42.1, 42.0, 41.0,
37.9, 36.8 (CH2), 36.4, 34.8 (CH2), 28.8 (CH2); m/z (+ESI) 283.80
([M+H]+, 100); Anal. (C19H22NFÁHCl): calcd C 71.35, H 7.25, N 4.38;
found, C 71.64, H 7.05, N 4.39.
4.1.2.7.
N-(2-(2-Pyridyl)ethyl)-8-aminopentacyclo[5.4.0.02,6
.
03,10.05,9]undecane (9g).
Treating 22 (320 mg, 2.00 mmol)
with 2-(2-pyridyl)ethylamine (262 lL, 2.20 mmol, 1.10 equiv) as
described above gave 9g (463 mg, 87%) as a colourless oil: mp
(2HCl salt) 172 °C (dec); Rf 0.30 (silica gel, CHCl3–MeOH-28% aq
NH4OH; 90:9:1); IR (thin film); 3302, 2963, 1633, 1563, 1478,
1432, 1373, 1337, 1269, 1230, 1035, 999, 831, 773, 687, 627; 1H
NMR (400 MHz, CDCl3); d 8.52 (1H, dd, J = 5.0, 1.8 Hz), 7.58 (1H,
td, J = 7.6, 1.8 Hz), 7.17 (1H, d, J = 7.6 Hz), 7.10 (1H, dd, J = 7.6,
5.0 Hz), 3.01–2.93 (4H, m), 2.74 (1H, t, J = 3.5 Hz), 2.66–2.61 (1H,
m), 2.60–2.52 (1H, m), 2.48–2.43 (1H, m), 2.29 (1H, d, J = 9.5 Hz),
2.24–2.16 (4H, m), 1.66 (1H, d, J = 10.3 Hz), 1.62 (1H, br s, NH),
1.15 (1H, d, J = 10.3 Hz), 0.95 (1H, dt, J = 11.9, 3.6 Hz); 13C NMR
(100 MHz, CDCl3); d 160.8 (quat.), 149.4, 136.4, 123.4, 121.2,
61.8, 49.0 (CH2), 47.4, 44.8, 44.2, 42.1, 42.0, 40.9, 39.2 (CH2),
37.8, 36.4, 34.8 (CH2), 28.8 (CH2); m/z (+ESI) 267.07 ([M+H]+,
100); Anal. (C18H22N2Á2HCl): calcd C 71.35, H 7.25, N 4.38; found:
C, 71.64; H, 7.35; N, 4.39.
4.1.2.11.
03,10.05,9]undecane (9k).
N-(Cyclohexyl)methyl-8-aminopentacyclo[5.4.0.02,6
Treating 22 (641 mg, 4.00 mmol)
.
with (cyclohexyl)methylamine (453 mg, 4.00 mmol, 1.0 equiv) as
described above gave 9k (967 mg, 94%) as a glass/microcrystalline
solid: mp (HCl salt) 265 °C (dec); Rf 0.45 (silica gel, CHCl3–MeOH-
28% aq NH4OH; 96:3.6:0.4); IR (thin film); 3427, 2964, 2925, 2852,
2808, 1595, 1453, 1415, 1268, 1231, 1112, 1029, 985, 890, 777,
706, 595; 1H NMR (400 MHz, CDCl3); d 2.68–2.63 (2H, m), 2.57–
2.53 (2H, m), 2.48–2.43 (1H, m), 2.42–2.37 (2H, m), 2.35–2.30
(2H, m), 2.22–2.16 (3H, m), 1.75–1.63 (6H, m), 1.43–1.33 (1H,
m), 1.28–1.09 (5H, m), 0.98 (1H, dt, J = 12.0, 3.7 Hz), 0.93–0.83
(2H, m); 13C NMR (100 MHz, CDCl3); d 62.1, 56.4 (CH2), 47.4,
44.8, 44.3, 42.1, 42.0, 41.0, 38.5, 37.9, 36.5, 34.9 (CH2), 31.7
(CH2), 28.9 (CH2) 26.9 (CH2), 26.3 (CH2); m/z (+ESI) 258.27
([M+H]+, 100); Anal. (C18H27NÁHCl): calcd C 73.57, H 9.60, N 4.77;
found: C 73.47, H 9.75, N 4.81.
4.1.2.8. N-(3-(3-Fluorophenyl)propyl)-8-aminopentacyclo[5.4.0.
0
2,6.03,10.05,9]undecane
(9h).
Treating
22
(320 mg,
(306 mg,
2.00 mmol)
with
3-(3-fluorophenyl)propylamine
2.00 mmol, 1.0 equiv) as described above gave 9h (475 mg, 80%)
as a colourless oil: mp (HCl salt) 236 °C (dec); Rf 0.70 (silica gel,
CHCl3–MeOH-28% aq NH4OH; 94:5.4:0.6); IR (thin film); 2952,
2867, 2673, 1613, 1583, 1485, 1444, 1416, 1260, 1143, 1038,
896, 782, 745, 694; 1H NMR (400 MHz, CDCl3); d 7.25–7.19 (1H,
m), 6.96 (1H, d, J = 7.6 Hz), 6.90–6.84 (2H, m), 2.68–2.64 (4H, m),
2.63–2.52 (4H, m), 2.49–2.44 (1H, m), 2.37–2.31 (2H, m), 2.30–
2.18 (3H, m), 1.80–1.73 (2H, m), 1.68 (1H, d, J = 10.4 Hz), 1.17
(1H, d, J = 10.4 Hz), 1.17 (1H, br s, NH, obscured), 1.01 (1H, dt,
4.1.2.12.
05,9]undecane (9l).
N-(Cubyl)methyl-8-aminopentacyclo[5.4.0.02,6.03,10
Treating 22 (160 mg, 1.00 mmol) with
.
(cubyl)methylamine (133 mg, 1.00 mmol, 1.0 equiv) as described
above gave 9l (249 mg, 91%) as a colourless oil: mp (HCl salt)
281 °C (dec); Rf 0.24 (silica gel, CHCl3–MeOH-28% aq NH4OH;
90:9:1); IR (thin film); 3407, 2957, 2863, 2758, 2664, 1575, 1444,
1373, 1326, 1300, 1268, 1230, 1039, 838, 811, 775, 682; 1H NMR
J = 12.0, 3.8 Hz); 13C NMR (100 MHz, CDCl3);
d 163.1 (d,
3
1JCF = 245.0 Hz, quat.), 145.2 (d, JCF = 7.2 Hz, quat.), 129.7 (d,
4
2
3JCF = 8.3 Hz), 124.2 (d, JCF = 2.5 Hz), 115.4 (d, JCF = 20.7 Hz),