1276
C.-Y. Kuo, M.-J. Wu / European Journal of Medicinal Chemistry 44 (2009) 1271–1277
This mixture was then heated at 55 ꢂC for 4 h. DMF was
evaporated in vacuo and the residue partitioned between
H2O and CH2C12. The organic layer was separated, dried
(Na2SO4) and evaporated in vacuo. The crude product was
purified by column chromatography using silica gel (EtOAc/
n-hexane, 1:5).
4.7.5. 7-Methoxy-N-phenoxyethyl-1-(2-N-
phenoxyethylaminophenyl)-1,2,3,4-tetrahydroisoquinoline (5g0)
1H NMR (400 MHz, CDCl3)
d
7.20–7.33 (5H, m, H-60, 2PhO-m),
7.11–7.16 (2H, m, H-30,40), 7.05 (1H, ddd, J ¼ 7.2, 7.2, 2.4 Hz, H-50),
6.92–6.96 (2H, m, 2PhO-p), 6.81–6.83 (4H, m, 2PhO-o), 6.71 (1H,
dd, J ¼ 8.4, 2.8 Hz, H-6), 6.65 (1H, d, J ¼ 2.8 Hz, H-5), 6.55 (1H, d,
J ¼ 8.4 Hz, H-8), 6.27 (1H, s, H-5), 4.68 (1H, s, H-1), 4.08 (2H, m),
3.76 (3H, s, OCH3), 3.54–3.57 (1H, m, H–), 3.40–3.43 (1H, m, H–),
3.04–3.19 (2H, m, H–), 2.75–2.92 (4H, m, H–); 13C NMR
4.7.2. N-Phenoxyethyl-1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (5f)
IR (neat, cmꢁ1) 3400, 3300 (NH2), 3018 (aromatic CH), 2956,
(100 MHz, CDCl3) d 158.6 (C-7), 151.7 (NCH2CH2OPh–C1), 139.6
2838 (aliphatic CH), 1595, 1500 (aromatic C]C), 1240 (C–O); 1H
(C–NH2), 136.2 (C-4a), 134.4 (C-8a), 129.4 (C-10), 129.3 (CH), 128.7
(CH), 128.3 (CH), 128.0 (CH), 127.6 (CH), 126.4 (OPh-m), 126.0
(OPh-m), 120.7 (NCH2CH2OPh-p), 118.2 (NHCH2CH2 OPh-p), 117.6
(OPh-o), 114.4 (OPh-o), 114.3 (C-6), 113.0 (C-8), 68.8 (OCH2CH2N),
65.7 (C-1), 55.6 (OCH3), 53.0 (OCH2CH2NH), 48.6 (C-3), 40.8
(OCH2CH2N), 35.4 (OCH2CH2NH), 28.1 (C-4). EI-MS m/z (%) ¼ 494
(12.9) [Mþ], 373 (100) [Mþ ꢁ PhOCH2CH2]. Anal. Calcd for
C32H34N2O3: C, 77.70; H, 6.93; N, 5.66. Found: C, 77.34; H, 7.01;
N, 5.54.
NMR (400 MHz, CDCl3)
d 7.26–7.31, (2H, m, H-6,7), 7.11–7.18 (3H,
m, H-5,8,400), 7.03–7.08 (2H, m, H-300,500), 6.96 (1H, d, J ¼ 7.2 Hz, H-
60), 6.82–6.87 (3H, m, H-40,200,600), 6.72–6.75 (1H, m, H-50), 6.60
(1H, J ¼ 8.0, 1.2 Hz, H-30), 4.73 (1H, s, H-1), 4.08–4.11 (2H, m,
CH2–O), 3.50 (1H, J ¼ 5.2, 4.0 Hz, H-3a), 3.08–3.21 (2H, m,
CH2CH2O), 2.78–2.94 (3H, m, H-3e,4); 13C NMR (100 MHz, CDCl3)
d
158.7 (C-100), 145.9 (C–NH2), 136.5 (C-4a), 134.5 (C-8a), 131.8 (C-
10), 129.5 (C-40), 128.5 (C-60), 128.3 (C-300,500), 127.6 (C-5), 126.3 (C-
6), 126.3 (C-7), 125.9 (C-8), 120.7 (C-400), 117.2 (C-50), 116.7 (C-30),
114.4 (C-200,600), 69.0 (OCH2CH2N), 65.8 (C-1), 53.1 (OCH2CH2N),
48.9 (C-3), 28.4 (C-4). EI-MS m/z (%) ¼ 344 (44.3) [Mþ], 343 (9.3)
[Mþ ꢁ H], 252 (100) [Mþ ꢁ H–PhOCH2CH2]. Anal. Calcd for
C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C, 80.68; H, 6.92; N,
7.92.
4.7.6. 6,7-Dimethoxy-N-phenoxyethyl-1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (5h)
1H NMR (400 MHz, CDCl3) 7.24–7.30 (2H, m, H-300,500), 7.10 (1H,
d
ddd, J ¼ 8.4, 7.6, 1.6 Hz, H-400), 6.92–6.97 (2H, m, H-200,600), 6.83–6.87
(2H, m, H-40,60), 6.67–6.71 (1H, m, H-50), 6.60 (1H, s, H-8), 6.60–6.62
(1H, m, H-30), 6.29 (1H, s, H-5), 4.73 (1H, s), 4.08–4.13 (2H, m), 3.85
(3H, OCH3), 3.62 (3H, OCH3), 3.29–3.39 (1H, m), 3.08–3.20 (1H, m),
4.7.3. N-Phenoxyethyl-1-(2-N-phenoxyethylaminophenyl)-1,2,3,4-
tetrahydroisoquinoline (5f0)
2.77–2.97 (4H, m); 13C NMR (100 MHz, CDCl3)
d 158.63, 158.56,
IR (neat, cmꢁ1) 3300 (NH), 3018 (aromatic CH), 2956, 2838
147.90, 147.68, 147.33, 146.05, 145.26, 133.48, 131.48, 131.00, 129.48,
129.43, 128.73, 128.41, 127.91, 126.95, 126.70, 126.50, 120.84, 120.75,
118.10, 117.27, 116.74, 114.69, 114.38, 110.91, 110.76, 110.66, 108.85,
68.00, 67.30, 65.76, 65.62, 55.83, 55.72, 55.69, 52.83, 52.76, 48.16,
47.63, 29.65, 27.12, 26.74, EI-MS m/z (%) ¼ 404 (3.0) [Mþ], 283 (100)
[Mþ ꢁ PhOCH2CH2]. Anal. Calcd for C25H28N2O3: C, 74.23; H, 6.98;
N, 6.93. Found: C, 74.39; H, 6.86; N, 7.06.
(aliphatic CH), 1595, 1500 (aromatic C]C), 1250, 1230 (C–O); 1H
NMR (400 MHz, CDCl3)
d 7.31–7.34 (1H, m, H-7), 7.21–7.30 (4H,
m, H-5,6,8,50), 7.02–7.13 (2H, m, 2PhO-p), 6.90–6.99 (4H, m,
2PhO-m), 6.78–6.83 (4H, m, 2PhO-o), 6.70–6.75 (2H, m, H-40,60),
6.65 (1H, d, J ¼ 8.0 Hz, H-30), 4.70 (1H, s, H-1), 4.01–4.10 (2H, m,
CH2O), 3.96–4.00 (1H, m, NHCH2CH2O-a), 3.40–3.45 (1H, m,
NHCH2CH2O-
NHCH2- ), 3.00–3.04 (1H, m, NHCH2-
3e,4); 13C NMR (100 MHz, CDCl3)
158.67 (2PhO–C-1), 147.09 (C-
b
), 3.31–3.38 (3H, m, H-3a, NCH2), 3.12–3.19 (1H, m,
a
b
), 2.73–2.84 (3H, m, H-
4.7.7. 6,7-Dimethoxy-N-phenoxyethyl-1-(2-N-
d
phenoxyethylaminophenyl)-1,2,3,4-tetrahydroisoquinoline (5h0)
20), 136.93 (C-4a), 134.73 (C-8a), 131.95 (C-10), 129.58 (CH), 129.48
(CH), 129.40 (CH), 128.71 (PhO-m), 128.02 (PhO-m), 127.25 (CH),
126.15 (CH), 126.02 (CH), 125.79 (CH), 120.77 (PhO-p), 120.61
(PhO-p), 115.92 (C-30), 114.43 (PhO-o), 111.20 (NHCH2CH2OPh-o),
69.74 (OCH2CH2N), 66.58 (OCH2CH2NH), 66.21 (C-1), 53.05
(OCH2CH2N), 49.62 (C-3), 42.08 (NHCH2), 28.90 (C-4). EI-MS m/z
(%) ¼ 464 (2.4) [Mþ], 343 (9.3) [Mþ ꢁ PhOCH2CH2]. Anal. Calcd for
C31H32N2O2: C, 80.14; H, 6.94; N, 6.93. Found: C, 80.35; H, 6.89;
N, 6.84.
1H NMR (400 MHz, CDCl3) 7.19–7.27 (5H, m, H-50, 2PhO-m),
d
7.03 (1H, d, J ¼ 6.4 Hz, H-40), 6.90–6.96 (2H, m, 2PhO-p), 6.78–6.83
(4H, m, 2PhO-o), 6.69 (2H, dd, J ¼ 7.2, 7.2 Hz, H-30,60), 6.49 (1H, s, H-
8), 6.27 (1H, s, H-5), 4.64 (1H, s), 3.85–4.07 (3H, m), 3.81 (3H, s),
3.80 (1H, m), 3.60 (3H, s), 3.32–3.42 (3H, m), 3.12–3.19 (1H, m),
2.65–2.91 (4H, m); 13C NMR (100 MHz, CDCl3)
d 158.6 (C-6,7), 150.9
(NCH2CH2OPh–C1), 147.4 (NHCH2CH2OPh–C1), 145.9 (C-20), 138.8
(C-4a), 131.8 (C-8a), 131.6 (C-10), 129.3 (C-40), 127.9 (OPh-m), 127.1
(OPh-m), 125.9 (C-60), 123.3 (C-60), 121.9 (C-30), 120.6
(NCH2CH2OPh-p), 120.1 (NHCH2CH2OPh-p), 114.4 (C-8), 111.5 (C-5),
111.2 (2OPh-o), 66.1 (OCH2CH2N), 61.9 (OCH2CH2NH), 55.8 (C-7),
55.8 (C-6), 52.7 (C-1), 47.8 (C-3), 46.2 (2CH2N), 29.7 (C-4). EI-MS m/z
(%) ¼ 524 (0.3) [Mþ], 403 (100) [Mþ ꢁ PhOCH2CH2]. Anal. Calcd for
C33H36N2O4: C, 75.55; H, 6.92; N, 5.34. Found: C, 75.26; H, 7.04; N,
5.23.
4.7.4. 7-Methoxy-N-phenoxyethyl-1-(2-aminophenyl)-1,2,3,4-
tetrahydroisoquinoline (5g)
1H NMR (400 MHz, CDCl3)
d 7.23–7.29 (H, m, PhO-m), 7.09 (1H,
ddd, J ¼ 8.0, 2.0, 2.0 Hz, H-50), 7.04 (1H, d, J ¼ 8.4 Hz, H-30), 6.92–
6.97 (2H, m, H-40, PhO-p), 6.83–6.85 (2H, m, PhO-o), 6.71–6.74
(1H, m, H-60), 6.68 (1H, d, J ¼ 7.6, 2.8 Hz, H-6), 6.59 (1H, dd,
J ¼ 8.0, 1.2 Hz, H-5), 6.35 (1H, d, J ¼ 2.8 Hz, H-8), 4.71 (1H, s, H-1),
4.09 (2H, t, J ¼ 6.4 Hz, H–CH2–O), 3.63 (3H, s, OCH3), 3.35–3.40
(1H, m, H–H-3a), 3.13–3.19 (1H, m, H–CH2CH2O), 2.96–2.99 (1H,
m, H–CH2CH2O), 2.78–2.86 (3H, m, H–H-3e,4); 13C NMR
4.7.8. 6,7-Dimethoxy-N-phenoxyethyl-1-(5-methoxy-2-
aminophenyl)-1,2,3,4-tetrahydroisoquinoline (5i)
1H NMR (400 MHz, CDCl3)
d
7.25–7.32 (2H, m, H-300,500),
6.93–6.97 (2H, m, H-200,600), 6.91 (1H, dd, J ¼ 2.8, 0.8 Hz, H-400),
6.84–6.87 (2H, m, H-40,60), 6.69 (1H, dd, J ¼ 8.8, 2.8 Hz, H-30),
6.60 (1H, s, H-8), 6.56 (1H, d, J ¼ 8.8 Hz, H-40), 6.33 (1H, s, H-5),
4.66 (1H, s), 4.08–4.10 (2H, m, CH2O), 3.85 (3H, OCH3), 3.73 (3H,
OCH3), 3.67 (3H, OCH3), 3.29–3.34 (1H, m, H-3a), 3.10–3.17 (1H,
m, H-3e), 2.77–2.90 (4H, m, CH2CH2O, H-4). EI-MS m/z (%) ¼ 434
(0.5) [Mþ], 313 (100) [Mþ ꢁ PhOCH2CH2]. Anal. Calcd for
C26H30N2O4: C, 71.85; H, 6.96; N, 6.45. Found: C, 71.57; H, 6.87;
N, 6.66.
(100 MHz, CDCl3)
d
158.6 (C-100), 157.7 (C-7), 145.9 (C-NH2), 137.3
(C-4a), 131.4 (C-8a), 129.4 (C-10), 129.2 (C-40), 128.5 (C-60), 126.6
(C-300,500), 126.2 (C-5), 120.7 (C-6), 117.4 (C-400), 116.8 (C-30), 114.3
(C-50), 112.7 (C-200,600), 112.6 (C-8), 68.7 (OCH2CH2N), 65.7 (C-1),
55.0 (OCH3), 52.9 (OCH2CH2N), 48.8 (C-3), 27.0 (C-4). EI-MS m/z
(%) ¼ 374 (2.5) [Mþ], 253 (100) [Mþ ꢁ PhOCH2CH2]. Anal. Calcd for
C24H26N2O2: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.39; H, 6.96; N,
7.57.