G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5381
5J ¼ 1.9 Hz, 3H, CNCH3), 2.24 (dd, 2J ¼ 16.0 Hz, 3J ¼ 13.3 Hz, 1H, CH2),
3J ¼ 6.8 Hz, 3H, CH3). 13C NMR (CDCl3)
d
164.0, 156.9, 139.7, 138.4,
1.31 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d
173.4, 164.5, 158.7,
133.7, 133.4, 132.4, 131.2, 128.4, 127.8, 127.6, 127.0, 126.2, 125.9,
125.4, 119.4, 55.5, 51.6, 32.3, 27.7, 21.8. EI-MS (70 eV) m/z (%): 317
(39), 316 (31), 315 [M]þ (78), 314 (58), 313 (100), 304 (36), 303 (46),
302 (30), 300 (41), 288 (36), 286 (29), 257 (30), 215 (32), 202 (32),
189 (18) 57 (31). MS (ESI) exact mass calcd for C19H22NO: 316.16959
[M þ H]þ; found: 316.16961 [M þ H]þ.
156.6, 138.3, 132.4, 132.7, 130.4, 119.7, 113.6, 109.8, 55.5, 55.3, 51.8,
32.7, 27.4, 21.9. EI-MS (70 eV) m/z (%): 296 (26), 295 [M]þ (100), 294
(58), 293 (73), 282 (15), 281 (16), 280 (46), 279 (14), 237 (21), 165
(20), 152 (13), 97 (14), 83 (16), 69 (18). MS (ESI) exact mass calcd for
C22H22NO: 296.16451 [M þ H]þ; found: 296.16454 [M þ H]þ.
4.4.4. (R)-5-(40-Chlorophenyl)-8-methoxy-1,3-dimethyl-3,4-
4.4.8. (R)-8-Methoxy-1,3-dimethyl-5-(naphthalen-2-yl)-3,4-
dihydroisoquinoline (42a)
dihydroisoquinoline (46a)
White solid (29.0 mg, 96.7
m
mol, 83%); mp 114 ꢂC (CH2Cl2/
Bright yellow solid (25.8 mg, 82.0 m
mol, 72%); mp 119 ꢂC (ethyl
MeOH). ½a 2D5
ꢃ
¼ ꢀ123ꢂ (c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
)
n
acetate). ½a 2D5
ꢃ
¼ ꢀ129ꢂ (c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n
2925, 2852, 1620, 1475. 1H NMR (CDCl3)
d
7.39 (d, 3J ¼ 8.6 Hz, 2H,
2924, 2852, 1620, 1028, 938, 865. 1H NMR (CDCl3)
d 7.90e7.85 (m,
Ar-H), 7.29 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 7.21 (d, 3J ¼ 8.6 Hz, 2H, Ar-H),
6.92 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.91 (s, 3H, OeCH3), 3.19 (m, 1H, CH),
2.53 (d, 5J ¼ 1.9 Hz, 3H, CNCH3), 2.52 (dd, 2J ¼ 15.8 Hz, 3J ¼ 4.2 Hz,
1H, CH2), 2.23 (dd, 2J ¼ 15.8 Hz, 3J ¼ 13.1 Hz, 1H, CH2), 1.32 (d,
3H, Ar-H), 7.74 (s, 1H, Ar-H), 7.52 (m, 2H, Ar-H), 7.43 (m, 2H, Ar-H),
6.96 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OeCH3), 3.18 (m, 1H, CH),
2.62 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.2 Hz, 1H, CH2), 2.55 (d, 5J ¼ 1.9 Hz, 3H,
CH3), 2.31 (dd, 2J ¼ 16.0 Hz, 3J ¼ 13.3 Hz, 1H, CH2), 1.30 (d,
3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d
157.7, 139.3, 138.8, 133.7,
3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d 164.3, 156.8, 138.5, 137.8,
133.3, 132.2, 131.4, 129.1, 110.6, 56.2, 52.3, 33.3, 28.1, 22.5. EI-MS
(70 eV) m/z (%): 301 (35), 300 (38), 299 [M]þ (100), 298 (49), 286
(18), 285 (13), 284 (52), 270 (14), 269 (14), 256 (13), 178 (18), 165
(13). MS (ESI) exact mass calcd for C17H18NO: 300.11497 [M þ H]þ;
found: 300.11408 [M þ H]þ.
133.2, 132.8, 132.7, 132.2, 128.0, 127.9, 127.7, 126.3, 126.0, 119.7,
109.8, 55.5, 51.7, 32.7, 27.5, 21.9. EI-MS (70 eV) m/z (%): 315 [M]þ (4),
314 (27), 313 (100), 270 (7), 257 (22), 239 (7), 229 (13), 228 (17), 226
(8), 156 (4), 113 (4). MS (ESI) exact mass calcd for C22H22NO:
316.16959 [M þ H]þ; found: 316.16972 [M þ H]þ.
4.4.5. (R)-8-Methoxy-1,3-dimethyl-5-(40-(trifluoromethyl)phenyl)-
3,4-dihydroisoquinoline (43a)
White solid (105 mg, 0.31 mmol, 84%); mp 123 ꢂC (CH2Cl2/
4.5. General procedure of O-demethylation of 39ae46a using BBr3
MeOH). ½a 2D5
ꢃ
¼ ꢀ127ꢂ (c ¼ 0.01 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n
2952, 2896, 2845, 1735, 1616, 1585, 1565, 1523, 1478, 1442, 1420,
1399, 1368, 1323, 1286, 1270, 1196, 1170, 1153, 1113, 1095, 1068,
1043,1017, 964, 942, 924, 905, 876, 857, 812, 766, 748, 710, 683, 664,
BBr3 (0.25 mL, 1 M solution in n-hexane, 5 equiv.) was added to
a solution of the isoquinoline in CH2Cl2 (6 mL) at 0 ꢂC. After stirring
at 0 ꢂC for 5 h the mixtures were warmed to room temperature and
stirred for additional 24 h. Then MeOH (5 mL) was added and the
solvent removed under reduced pressure. The residue was
submitted to column chromatography on deactivated silica (7.5%
NH3, CH2Cl2/MeOH 15:1 to 12:1).
621. 1H NMR (CDCl3)
d
7.66 (d, 3J ¼ 8.0 Hz, 2H, Ar-H), 7.38 (d, 3J ¼ 7.9,
2H, Ar-H), 7.28 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 6.92 (d, 3J ¼ 8.6 Hz, 1H, Ar-
H), 3.90 (s, 3H, OeCH3), 3.13 (m, 1H, CH), 2.49 (d, 5J ¼ 2.0 Hz, 3H,
CNCH3), 2.49 (dd, 2J ¼ 15.9 Hz, 3J ¼ 4.2, 1H, CH2), 2.22 (dd,
2J ¼ 13.2 Hz, 3J ¼ 2.7 Hz, 1H, CH2), 1.29 (d, 3J ¼ 6.8 Hz, 3H, CH3). 13
C
NMR (CDCl3)
d
157.4, 144.2, 138.5, 132.6, 131.6, 129.9, 129.5, 129.2,
4.5.1. (R)-1,3-Dimethyl-5-phenyl-3,4-dihydroisoquinolin-8-ol
125.4, 120.1, 110.2, 55.7, 51.9, 32.8, 27.7, 22.2. EI-MS (70 eV) m/z (%):
334 (23), 333 [M]þ (100), 332 (41), 331 (12), 320 (33), 319 (14), 318
(70), 304 (14), 303 (11), 290 (15), 275 (10). MS (ESI) exact mass calcd
for C19H19F3NO: 334.14133 [M þ H]þ; found: 334.14118 [M þ H]þ.
(39b)
Yellowish oil (27 mg, 0.11 mmol, 73%);
½
a 2D5
ꢃ
¼ 99:8ꢂ
(c ¼ 0.02 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2974, 2927, 2363, 2160,
2001, 1716, 1610, 1528, 1472, 1451, 1426, 1364, 1340, 1303, 1279,
1229, 1206, 1180, 1161, 1076, 1046, 1023, 877, 829, 773, 756, 735,
4.4.6. (R)-5-(3-Chlorophenyl)-8-methoxy-1,3-dimethyl-3,4-
703, 674, 622, 611. 1H NMR (CDCl3)
d 7.39e7.18 (m, 6H, Ar-H), 6.78
dihydroisoquinoline (44a)
(d, 3J ¼ 8.8 Hz, 1H, Ar-H), 3.54e3.48 (m, 1H, CH), 2.83 (d, 4J ¼ 1.4 Hz,
3H, CNCH3), 2.75 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.5 Hz, 1H, CH2), 2.48 (dd,
2J ¼ 16.0 Hz, 3J ¼ 11.4 Hz, 1H, CH2), 1.33 (d, 3J ¼ 6.7, 3H, CH3). 13C
Yellowish oil (53 mg, 0.18 mmol, 64%);
½
a 2D5
ꢃ
¼ 104ꢂ
(c ¼ 0.1 mol/l). IR (KBr, cmꢀ1
) n 2927, 1614, 1453, 1398, 1323, 1267,
1234,1197,1133,1109,1075, 973, 838, 803, 764, 697. 1H NMR (CDCl3)
NMR (CDCl3) d 171.5, 168.2, 140.9, 137.3, 135.1, 129.7, 128.4, 127.1,
d
7.38e7.29 (m, 3H, Ar-H), 7.25 (m, 1H, Ar-H), 7.12 (m, 1H, Ar-H),
126.7, 120.6, 115.7, 49.5, 33.2, 25.3, 19.9. EI-MS (70 eV) m/z (%): 251
[M]þ (4), 91 (16), 83 (10), 70 (12), 69 (15), 67 (10), 57 (17), 44 (90),
43 (20), 41 (31). MS (ESI) exact mass calcd for C17H18NO: 252.13829
[M þ H]þ; found: 252.13829 [M þ H]þ.
6.91 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.89 (s, 3H, OeCH3), 3.17 (m, 1H, CH),
2.57 (s, 3H, CNCH3), 2.56 (m, 1H, CH2), 2.27 (dd, 2J ¼ 15.5 Hz,
3J ¼ 12.5 Hz, 1H, CH2), 13C NMR (CDCl3)
d 142.2, 138.3, 134.4, 133.2,
131.8, 129.7, 129.6, 129.6, 129.5, 127.8, 127.5, 127.4, 119.7, 110.2, 109.0,
55.8, 51.6, 32.7, 27.4, 21.7. EI-MS (70 eV) m/z (%): 302 (7), 301 (35),
300 (36), 299 [M]þ (100), 298 (50), 286 (18), 285 (11), 284 (47), 270
(12), 269 (12), 256 (12), 243 (6). MS (ESI) exact mass calcd for
C18H19NO: 300.11497 [M þ H]þ; found: 300.11497 [M þ H]þ.
4.5.2. (R)-1,3-Dimethyl-5-p-tolyl-3,4-dihydroisoquinolin-8-ol
(40b)
a 2D5
Yellowish oil (10 mg, 37.7
m
mol, 72%);
½
ꢃ
¼ 43:2ꢂ
(c ¼ 0.02 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2923, 2363,1611,1440,1301,
1203, 1019, 816, 698, 643, 632, 612. 1H NMR (CDCl3)
d 7.18e7.10 (m,
4.4.7. (R)-8-Methoxy-1,3-dimethyl-5-(naphthalen-1-yl)-3,4-
dihydroisoquinoline (45a)
5H, Ar-H), 6.77 (d, 3J ¼ 8.8 Hz,1H, Ar-H), 3.47 (m,1H, CH), 2.80 (s, 3H,
CH3), 2.74 (dd, 2J ¼ 16.1 Hz, 3J ¼ 4.6 Hz, 1H, CH2), 2.45 (dd,
2J ¼ 16.0 Hz, 3J ¼ 11.6 Hz, 1H, CH2), 2.37 (s, 3H, CH3), 1.31 (d,
Yellowish oil (28.7 mg, 91.0
m
mol, 78%);
½
a 2D5
ꢃ
¼ ꢀ129ꢂ
(c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
)
n
2925, 2853, 1618, 1277,
3J ¼ 4.8 Hz, 3H, CH3). 13C NMR (CDCl3)
¼ 171.3, 168.1, 138.0, 137.4,
d
1022, 938. 1H NMR (CDCl3)
d
7.93e7.88 (m, 2H, Ar-H), 7.55e7.46 (m,
136.4,135.1,129.6,129.1,127.2,120.7,115.6, 49.6, 33.2, 25.4, 21.3, 20.0.
EI-MS (70 eV) m/z (%): 266 (21), 265 [M]þ (100), 264 (37), 250 (21),
237 (21), 236 (10), 178 (10), 165 (8). MS (ESI) exact mass calcd for
C18H20NO: 266.15394 [M þ H]þ; found: 266.15394 [M þ H]þ.
3H, Ar-H), 7.43e7.28 (m, 3H, Ar-H), 6.89 (d, 3J ¼ 8.5 Hz, 1H, Ar-H),
3.96 (s, 3H, OeCH3), 3.28e3.15 (m, 1H, CH), 2.58 (d, 5J ¼ 1.9 Hz, 3H,
CNCH3), 2.26e2.15 (m, 1H, CH2), 2.07e1.93 (m, 1H, CH2), 1.20 (d,