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M. F. Dalence-Guzman et al. / Bioorg. Med. Chem. 16 (2008) 2499–2512
2509
5.2.2.23. N-[2-(4-Chlorophenyl)ethyl]-6,7-dihydroxy-3-
methyl-3,4-dihydroisoquinoline-2(1H)-carbothioamide (36).
Compound 36 was prepared from 32 as described in the
general procedure for coupling and purified by flash col-
umn chromatography (silica, Pet. Ether/EtOAc
procedure for coupling and purified by flash column
chromatography (silica, gradient elution 0–3% MeOH
in CH2Cl2) (65%). H NMR (CD3OD 400 MHz) d 2.81
1
(t, J = 6.0 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H), 3.83 (t,
J = 7.4 Hz, 2H), 3.96 (t, J = 6.0 Hz, 2H), 4.84 (s, 2H),
6.62 (d, J = 7.8 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 7.01
(t, J = 7.8 Hz, 1H), 7.23 (m, 4H). 13C NMR (CD3OD
100 MHz) d 23.6, 35.7, 46.6, 47.9, 50.7, 113.8, 118.3,
123.1, 128.0, 129.4, 129.4, 131.5, 131.5, 133.0, 135.8,
139.6, 155.8, 182.0. HR-MS (ESI) calculated for
C18H20ClN2OS (M+H) 347.0985, found 347.0980.
1
1:1 + 1% AcOH) (91%). H NMR (CD3OD 400 MHz)
d 1.02 (d, J = 6.6 Hz, 3H) 2.50 (dd, J = 15.6 Hz,
J = 2.2 Hz, 1H), 2.95 (m, 3H), 3.85 (m, 2H), 4.32 (d,
J = 15.3 Hz, 1H), 4.73 (d, J = 15.3 Hz, 1H), 5.39 (br s,
1H), 6.58 (s, 1H), 6.59 (s, 1H), 7.22 (d, J = 8.5 Hz,
2H), 7.27 (t, J = 8.5 Hz, 2H). 13C NMR (CD3OD
100 MHz) d 17.5, 35.1, 35.7, 47.1, 47.9, 51.1, 113.7,
116.6, 123.8, 125.2, 129.4, 129.4, 131.6, 131.6, 133.0,
139.6, 145.1, 145.6, 181.4. HR-MS (ESI) calculated for
C19H22ClN2O2S (M+H) 377.1091, found 377.1084.
5.2.2.28. 1,2,3,4-tert-Butyl 8-methoxy-3,4-dihydroiso-
quinoline-2(1H)-carboxylate (43) and tert-butyl 6-meth-
oxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
(44).
These compounds were prepared from 2-(3-methoxy-
phenyl)ethylamine, 42, by the procedure described for
39, affording 43 and 44 in a 1:5 ratio. Purification was
done by flash column chromatography (silica, gradient
elution, 10–30% EtOAc in Pet. Ether) (47%).
5.2.2.24. 1-Benzyl-N-[2-(4-chlorophenyl)ethyl]-6,7-dihy-
droxy-3,4-dihydroisoquinoline-2(1H)-carbothioamide (37).
Compound 37 was prepared from 33 as described in the
general procedure for coupling and purified by flash col-
umn chromatography (silica, Pet. Ether/EtOAc 4:1 + 1%
AcOH) (97%). 1H NMR (CD3OD 400 MHz) d 2.75 (br s,
4H), 2.97 (m, 1H), 3.26 (br s, 1H), 3.49 (m, 1H), 3.87 (br
s, 3H), 5.90 (br s, 1H), 6.22 (br s, 1H), 6.58 (s, 1H), 7.15
(m, 9H). 13C NMR (CD3OD 100 MHz) d 28.1, 35.6, 43.0,
44.4, 47.8, 62.1, 115.5, 115.6, 126.9, 127.4, 128.8, 129.2,
129.2, 129.4, 129.4, 130.8, 130.8, 131.4, 131.4, 132.9,
139.5, 139.7, 144.4, 145.4, 181.6. HR-MS (ESI) calculated
for C25H26ClN2O2S (M+H) 453.1404, found 453.1394.
1
Compound 43: H NMR (CDCl3 400 MHz) d 1.50 (s,
9H), 2.82 (br s, 2H), 3.64 (br s, 2H), 3.83 (s, 3H), 4.49
(s, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz,
1H), 7.14 (t, J = 8.0 Hz, 1H).
1
Compound 44: H NMR (CDCl3 400 MHz) d 1.49 (s,
9H), 2.81 (br s, 2H), 3.62 (br s, 2H), 3.78 (s, 3H), 4.50
(s, 2H), 6.67 (s, 1H), 6.75 (d, J = 8.3 Hz, 1H), 7.02 (d,
J = 8.3 Hz, 1H).
5.2.2.25. tert-Butyl 5-methoxy-3,4-dihydroisoquino-
line-2(1H)-carboxylate (39). 2-(2-Methoxyphenyl)ethyla-
mine, 38 (1.0 equiv), paraformaldehyde (5.0 equiv) and
MgSO4 (3.0 equiv) were suspended in anhydrous
CH2Cl2. After stirring for 2 h the solid was filtered off.
The filtrate was concentrated. The residue was dissolved
in anhydrous trifluoroacetic acid and refluxed under
nitrogen overnight. The mixture was poured into a mix-
ture of ice and water. The water phase was made basic
with NaOH (6 M) and extracted with CH2Cl2. The or-
ganic phase was dried (MgSO4) and concentrated. The
remaining oil was dissolved in THF. To this solution
were added di-tert-butyl dicarbonate (1.2 equiv) and tri-
ethylamine (3.0 equiv). The mixture was stirred for 3 h
and then concentrated. The residue was dissolved in
EtOAc and washed with a saturated solution of
Na2CO3. The organic phase was dried (MgSO4) and
concentrated. Purification was done by flash column
chromatography (silica, Pet. Ether/EtOAc 6:1) (26%).
1H NMR (CDCl3 400 MHz) d 1.47 (s, 9H), 2.74 (br s,
2H), 3.62 (br s, 2H), 3.81 (s, 3H), 4.55 (s, 2H), 6.70
(m, 2H), 7.14 (t, J = 8.0 Hz, 1H).
5.2.2.29. 1,2,3,4-Tetrahydroisoquinolin-8-ol hydrobro-
mide (45). This compound was prepared from 43 using
the general procedure for demethylation (quantitative),
1H NMR (CD3OD 300 MHz) d 3.08 (t, J = 6.3 Hz,
2H), 3.47 (t, J = 6.3 Hz, 2H), 4.25 (s, 2H), 6.72 (m,
2H), 7.12 (t, J = 7.9 Hz, 1H).
5.2.2.30. N-[2-(4-Chlorophenyl)ethyl]-8-hydroxy-3,4-
dihydroisoquinoline-2(1H)-carbothioamide (46). This
compound was prepared from 45 as described in the
general procedure for coupling and purified by flash col-
umn chromatography (silica, Pet. Ether/EtOAc/AcOH
70:30:1) (55%). 1H NMR (CD3OD 400 MHz) d 2.74
(t, J = 5.7 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 3.75 (t,
J = 7.4 Hz, 2H), 3.94 (t, J = 5.7 Hz, 2H), 4.63 (s, 2H),
6.55 (d, J = 7.8 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.92
(t, J = 7.8 Hz, 1H), 7.14 (m, 4H). 13C NMR (CD3OD
100 MHz) d 29.7, 35.8, 46.1, 47.0, 48.0, 113.2, 120.2,
120.9, 128.3, 129.4, 129.4, 131.6, 131.6, 133.0, 137.6,
139.7, 154.9, 182.3. HR-MS (ESI) calculated for
C18H20ClN2OS (M+H) 347.0985, found 347.0993.
5.2.2.26. 1,2,3,4-Tetrahydroisoquinolin-5-ol hydrobro-
mide (40). This compound was prepared from 39 using
the general procedure for demethylation (quantitative).
1H NMR (CD3OD 300 MHz) d 2.98 (t, J = 6.5 Hz, 2H),
3.50 (t, J = 6.5 Hz, 2H), 4.31 (s, 2H), 6.70 (d, J = 7.7 Hz,
1H), 6.75 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H).
5.2.2.31. 1,2,3,4-Tetrahydroisoquinolin-6-ol hydrobro-
mide (47). This compound was prepared from 44 using
the general procedure for demethylation (quantitative).
1H NMR (CD3OD 300 MHz) d 3.06 (t, J = 6.4 Hz,
2H), 3.47 (t, J = 6.4 Hz, 2H), 4.26 (s, 2H), 6.67 (s,
2H), 6.71 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H).
5.2.2.27.
N-[2-(4-Chlorophenyl)ethyl]-5-hydroxy-3,4-
5.2.2.32. N-[2-(4-Chlorophenyl)ethyl]-6-hydroxy-3,4-
dihydroisoquinoline-2(1H)-carbothioamide (48). This
compound was prepared from 47 as described in the
dihydroisoquinoline-2(1H)-carbothioamide (41). This com-
pound was prepared from 40 as described in the general