Sep-Oct 2003
New trans/cis Tetrahydroisoquinolines. 2
801
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-tri-
fluoromethyl-phenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydro-
isoquinolin-1-one (10d).
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(2,6-
dimethyl-morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-
1-one (10h).
This compound was obtained from 9 and 3-(trifluoromethyl)-
N-phenylpiperazine as white crystals (from ethyl acetate), 1.56 g
(47 %), mp 169-172 °C; H nmr: δ 2.46 (dd, 1H, 15-H, J = 12.8,
4.0 Hz), 2.62-2.66 (m, 2H, 16-H), 2.82 (t, 1H, 15-H, J = 12.8 Hz),
2.91-2.95 (m, 2H, 16-H), 3.04-3.15 (m, 3H, 10-, 9-H), 3.18 (dd,
1H, 4-H, J = 12.0, 3.6 Hz), 3.33-3.40 (m, 4H, 17-H), 3.71 (s, 3H,
14-H), 4.41-4.48 (m, 1H, 9-H), 5.4 (s, 1H, 3-H), 5.62-5.63 (m,
1H, 11-H), 5.92-5.94 (m, 1H, 12-H), 6.56-6.57 (m, 1H, 13-H),
7.11-7.58 (m, 12H, phenyl protons), 8.25 (dd, 1H, 8-H, J = 7.0,
2.0 Hz); ms: m/z 572 (molecular ion).
This compound was obtained from 9 and 2,6-dimethylmorpho-
line as amorphous compound, 1.85 g (70 %), mp 46-48 °C; H
1
1
nmr: δ 0.98-1.05 (m, 6H, 18-H), 1.67 (t, 1H, 16-H, J = 10.7 Hz),
1.79 (t, 1H, 16-H, J = 10.7 Hz), 2.10 (dd, 1H, 15-H, J = 12.8, 3.9
Hz), 2.33 (d, 1H, 15-H, J = 12.8 Hz), 2.43-2.49 (m, 2H, 16-H),
2.76-2.93 (m, 4H, 10-, 4-, 9-H), 3.44 (s, 3H, 14-H), 3.47-3.55 (m,
2H, 17-H), 4.13-4.22 (m, 1H, 9-H), 5.10 (s, 1H, 3-H), 5.36-5.38
(m, 1H, 11-H), 5.67-5.69 (m, 1H, 12-H), 6.30-6.32 (m, 1H, 13-
H), 6.84-7.25 (m, 8H, phenyl protons), 8.00 (dd, 1H, 8-H, J = 7.1,
2.0); ms: m/z 457 (molecular ion).
Anal. Calcd. for C
H
F N O: C, 71.30; H, 6.16; N, 9.78.
Anal. Calcd. for C H N O : C, 76.11, H, 7.71. Found: C,
34 35
3
4
29 35 3 2
Found: C, 71.29; H, 5.90; N, 9.75
75.91; H, 7.82.
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-
chlorophenyl)piperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinolin-1-one (10e).
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(thiomor-
pholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one (10i).
This compound was obtained from 9 and thiomorpholine as
This compound was obtained from 9 and 1-(3-chlorophenyl)-
colourless prisms (from ethyl acetate), 1.6 g (62 %), mp 149-
150 °C; H nmr: δ 2.53 (dd, 1H, 15-H, J = 13.0, 4.0 Hz), 2.70 (t,
1
piperazine as white crystals (from ethyl acetate), 1.62 g (52 %),
1
mp 188-191 °C; H nmr: δ 2.20 (dd, 1H, 15-H, J = 12.8, 3.9 Hz),
1H, 15-H, J = 13.0 Hz), 2.78-2.91 (m, 6H, 16-, 17-H), 3.04-3.20
(m, 6H, 16-, 10-, 4-H), 3.75 (s, 3H, 14-H), 4.43-4.50 (m, 1H, 9-
H), 5.37 (s, 1H, 3-H), 5.66-5.67 (m, 1H, 11-H), 5.97-5.98 (m,
1H, 12-H), 6.60-6.61 (m, 1H, 13-H), 7.12-7.53 (m, 8H, phenyl
protons), 8.29 (m, 1H, 8-H, J = 7.1, 2.0 Hz); ms: m/z 445 (mol-
ecular ion).
2.35-2.38 (m, 2H, 16-H), 2.58 (t, 1H, 15-H, J = 12.8 Hz) 2.63-
2.67 (m, 2H, 16-H), 2.78-2.84 (m, 3H, 10-, 9-H), 2.92 (dd, 1H, 4-
H, J = 11.8, 3.8 Hz), 2.98-3.11 (m, 4H, 17-H), 3.45 (s, 3H, 14-H),
4.16-4.23 (m, 1H, 9-H), 5.15 (s, 1H, 3-H), 5.36-5.38 (m, 1H, 11-
H), 5.67-6.68 (m, 1H, 12-H), 6.30-6.31 (m, 1H, 13-H), 6.61-6.72
(m, 3H, phenyl protons), 6.87-7.22 (m, 9H, phenyl protons), 8.00
(dd, 1H, 8-H, J = 7.0, 2.0 Hz); ms: m/z 538 (molecular ion).
Anal. Calcd. for C
H N OS: C, 72.77; H, 7.01. Found: C,
27 31 3
72.74; H, 6.99.
Anal. Calcd. for C
Found: C, 75.99; H, 6.40; N, 9.68.
H ClN O: C, 75.71; H, 6.69; N, 9.38.
33 35 4
General Procedure for the Preparation of (±)-trans-2-Benzyl-3-
(1-methyl-1H-pyrrol-2-yl)-4-(N,N-disubstituted-aminomethyl)-
1,2,3,4-tetrahydroisoquinolines (11).
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-fluo-
rophenyl)-piperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-
1-one (10f).
Lithium aluminium hydride (2.4 mmoles) was added in por-
tions to a solution of 10 (2 mmoles) in 10 mL dry tetrahydrofuran
and the reaction mixture was refluxed 1-2 hours. After cooling,
water (9.6 mmoles) was added. The reaction mixture was stirred
for 30 min and dried (magnesium sulfate). The inorganic precipi-
tate was filtered and washed with dichloromethane. The solvent
was removed from the filtrate and the product was purified by
chromatographic filtration or recrystallisation.
This compound was obtained from 9 and 1-(4-fluorophenyl)-
piperazine as colourless prisms (from hexane-ethyl acetate), 2.18 g
(72 %), mp 114-116 °C; H nmr: δ 2.17 (dd, 1H, 15-H, J = 12.8, 3.9
Hz), 2.33-2.36 (m, 2H, 16-H), 2.55 (t, 1H, 15-H, J = 12.8 Hz), 2.62-
2.65 (m, 2H, 16-H), 2.74-2.81 (m, 3H, 10-, 9-H), 2.89 (dd, 1H, 4-H,
J = 12.0, 3.9 Hz), 2.92-3.01 (m, 4H, 17-H), 3.41 (s, 3H, 14-H), 4.12-
4.19 (m, 1H, 9-H), 5.12 (s, 1H, 3-H), 5.33-5.34 (m, 1H, 11-H), 5.63-
5.65 (m, 1H, 12-H), 6.26-6.27 (m, 1H, 13-H), 6.67-6.98 (m, 5H,
phenyl protons), 7.02-7.19 (m, 7H, phenyl protons), 7.96 (m, 1H, 8-
H, J = 7.0, 2.1 Hz); ms: m/z 522 (molecular ion).
1
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-
[(piperidin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (11a).
This compound was obtained from 10a as white crystals (from
1
hexane), 0.47 g (57 %), mp 92.5-94 °C; H nmr: δ 1.34-1.42 (m,
Anal. Calcd. for C
H FN O: C, 75.83; H, 6.75. Found: C,
33 35 4
6H, 17-H), 2.05 (dd, 1H, 15-H, J = 12.0, 3.6 Hz), 2.08 (broad s,
2H, 16-H), 2.35 (broad s, 2H, 16-H), 2.41-2.48 (m, 1H, 9-H),
2.57-2.63 (m, 1H, 9-H), 2.66-2.78 (m, 4H, 10-, 4-, 15-H), 3.51 (s,
3H, 14-H), 3.60 (d, 1H, 1-H, J = 15.5 Hz), 3.73 (d, 1H, 1-H, J =
15.5 Hz), 4.53 (s, 1H, 3-H), 5.25-5.29 (m, 1H, 11-H), 5.75-5.77
(m, 1H, 12-H), 6.34 (s, 1H, 13-H), 6.80-7.09 (m, 9H, phenyl pro-
tons); ms: m/z 413 (molecular ion).
75.75; H, 6.83.
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(mor-
pholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one (10g).
This compound was obtained from 9 and morpholine as white
crystals (from hexane-ethyl acetate), 1.57 g (63 %), mp 127-129
1
°C; H nmr: δ 2.34-2.43 (m, 3H, 16- 15-H), 2.65-2.71 (m, 3H,
16-, 15-H), 2.93-3.11 (m, 4H, 10-, 4-, 9-H), 3.65 (s, 3H, 14-H),
3.73-3.93 (m, 4H, 17-H), 4.35-4.42 (m, 1H, 9-H), 5.31 (s, 1H, 3-
H), 5.57-5.58 (m, 1H, 11-H), 5.87-5.89 (m, 1H, 12-H), 6.50-6.51
(m, 1H, 13-H), 7.02-7.05 (m, 1H, phenyl proton), 7.21-7.47 (m,
7H, phenyl protons), 8.20 (d, 1H, 8-H, J = 7.3 Hz); ms: m/z 429
(molecular ion).
Anal. Calcd. for C
81.31; H, 8.59.
H N : C, 81.31; H, 8.53. Found: C,
28 35 3
(±)-trans-2-Phenethyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-
phenyl-pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinoline(11b).
This compound was obtained from 10b as white crystals (from
ethyl acetate), 0.45 g (46 %), mp 137-139 °C; H nmr: δ 2.16 (d,
Anal. Calcd. for C
H N O : C, 75.50; H, 7.27. Found: C,
27 31 3 2
1
75.51; H, 7.40.