656
Y. M. Al-Hiari, S. J. Bennett, B. Cox, R. J. Davies, A. I. Khalaf, R. D. Waigh and A. J. Worsley
Vol. 42
6.07 (t, J = 6.8 Hz, 1H, CH-N), 6.68 (d, J = 7.2 Hz, 1H, Ar-H),
6.92 (d, J =7.5 Hz, 1H, Ar-H), 7.11-7.37 (m, 12H, Ar-H). hrms:
tallized from ether/hexane to give the title compound as white
crystals (85 mg, 54%), R = 0.34 (chloroform/ether 3/1), mp 227-
F
-1
1
found 328.16983, calculated for C
H
NO; 328.17014. This
229 °C; ir: 3291, br (OH), 1604s (C=O) cm ; H nmr: δ
(400MHz) 1.23 (s, 9H, t-Bu), 3.06 (d, J = 6.4 Hz, 2H, Ph-CH ),
23 22
compound has been reported to be an oil, from an alternative
synthesis [24].
2
2.73-2.77 (m, 1H, Ar-CH -CH -N), 2.94-3.01 (m, 1H, Ar-CH -
2
2
2
CH -N), 3.44-3.51 (m, 1H, Ar-CH -CH -N), 4.21 (br s, 1H, Ar-
2
2
2
1-Benzyl-2-pivaloyl-1,2,3,4-tetrahydroisoquinoline (32).
Amide: N-pivaloyl-1,2,3,4-tetrahydroisoquinoline, (31, 1.74 g,
CH -CH -N), 5.84 (br s, 1H, CH-N), 5.97 (br s, 1H, OH, D O
2
2
2
exch.), 6.98 (d, J = 8.4 Hz, 2H, Ar-H), 6.96 (d, J = 7.0 Hz, 1H,
Ar-H), 7.03 (d, J = 8.4 Hz, 2H, Ar-H), 7.10-7.18 (m, 3H, Ar-H);
3
8.00 mmol); tetramethylethylenediamine (1.2 cm , 8.00 mmol,
3
0.929 g); t-butyllithium (4.94 cm , 8.40 mmol); benzyl chloride
hrms: found 323.18864, calculated for C
H NO ; 323.18853.
21 25 2
3
(1.012 g, 8.00 mmol, in 5 cm tetrahydrofuran) stirred for 2 h at -
Removal of the N-Pivaloyl Group from 1-Benzyl-2-pivaloyl-
1,2,3,4-tetrahydroisoquinoline (32) to Give 1-Benzyl-1,2,3,4-
tetrahydroisoquinoline (34).
78 °C. A deep red colour persisted for 20 min. After work-up as
above, the crude yellow semi-solid (2.722 g) was recrystallized
from ether/hexane to give 32 as a white solid, mp 98-100 °C, [lit.
-1
1
[14] 101 °C] (1.69 g, 69%); ir: 1614s (C=O) cm ; H nmr: δ
(250MHz) 1.20 (s, 9H, t-Bu), 2.68-2.76 (dt, J = 3.3H z, 1H, Ar-
CH -CH -N), 2.88-3.01 (m, 1H, Ar-CH -CH -N), 3.11 (d, J =
A solution of 1-benzyl-2-pivaloyl-1,2,3,4-tetrahydroisoquino-
line (32, 3.28 g, 10.68 mmol) in hydrochloric acid (2.0 M, 30
3
cm ) was heated under reflux for 24 h. The mixture was cooled in
2
2
2
2
3
6.7 Hz, 2H, Ph-CH ), 3.33-3.54 (m, 1H, Ar-CH -CH -N), 4.17
an ice bath, ether (200 cm ) was added and the solution was
2
2
2
(br s,1H, Ar-CH -CH -N), 5.85 (t, J =6.7 Hz, 1H, CH-N), 6.91-
made alkaline with potassium hydroxide pellets (pH 11). The
mixture was extracted with ether (3 x 100 cm ), dried (magne-
2
2
3
6.94 (d, J = 7.2 Hz, 1H, Ar-H), 7.10-7.29 (m, 8H, Ar-H); hrms:
found 308.20137, calculated for C NO; 308.20144.
H
sium sulfate), filtered and evaporated under reduced pressure to
give an oil (1.92 g). The oil was poured into ethereal hydrogen
chloride solution, and the salt was collected by filtration and
21 26
Anal. Calcd. for C
H NO: C, 82.04; H, 8.20; N, 4.56.
21 25
Found: C, 81.77; H, 7.92; N, 4.88.
3
washed with ether (40 cm ). The solid was basified and extracted
1-(4-Benzyloxybenzyl)-2-pivaloyl-1,2,3,4-tetrahydroisoquino-
line (33).
with chloroform to give the 1-benzyl tetrahydroisoquinoline (34,
0.852 g, 36%) as a yellow oil, identical with the compound
described above.
Amide: N-pivaloyl-1,2,3,4-tetrahydroisoquinoline (31, 1.74 g,
3
8.00 mmol); tetramethylethylenediamine (1.2 cm , 8.00 mmol,
1-(4-Benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinoline (36).
To a solution of N-pivaloyl-1-(4-benzyloxybenzyl)-1,2,3,4-
3
0.93 g); t-butyllithium (5.0 cm , 8.40 mmol, 1.07 M excess); ben-
3
zyloxybenzyl chloride (1.86 g, 8.00 mmol, in 10 cm tetrahydro-
3
furan); stirred for 2 h at -78 °C. A deep red colour persisted for 15
min. Work-up as above gave a yellow oil (2.99 g) which was
crystallised from ether/hexane to give 33 as fine white crystals
(3.15 g, 95%) mp 121-122 °C (Lit. [25] 121-122°C); ir: 1611s
tetrahydroisoquinoline (33, 300 mg, 0.725 mmol, in 20 cm of
dry tetrahydrofuran) stirred at 0 °C was added a solution of
sodium aluminium hydride (78 mg, 1.450 mmol, 2.5 M excess, in
3
25 cm of dry tetrahydrofuran). The mixture was allowed to
-1
1
(C=O) cm ; H nmr: δ (250MHz; 20°C) 1.21 (s, 9H, t-Bu), 3.11
(d, J =6.9 Hz, 2H, Ph-CH ), 2.68-3.51 (m, 2H, Ar-CH -CH -N
warm slowly to room temperature, and then heated under reflux
for 90 h under nitrogen. The reaction mixture was left for two
2
2
2
3
and m, 1H, Ar-CH -CH -N), 4.14 (br s,1H, Ar-CH -CH -N),
more days at room temperature; water (20 cm ) was added fol-
2
2
2
2
3
5.05 (s, 2H, OCH ), 5.83 (br s, 1H, CH-N), 6.85-7.46 (m, 13H,
lowed by ether (100 cm ). The basic products were extracted
2
1
3
Ar-H); H nmr: δ (400MHz; 57 °C) 1.23 (s, 9H, t-Bu), 2.69-2.73
with dilute hydrochloric acid (2 M, 100 cm ), separated, rebasi-
(ddd, J = 3.3, 3.9, 16.1 Hz, 1H, Ar-CH -CH -N), 2.90-2.98 (ddd,
fied with potassium hydroxide solution (10%, w/v) and extracted
with chloroform (3 x 150 cm ). After drying (magnesium sulfate)
2
2
3
J = 5.6, 13.7, 16.1 Hz, 1H, Ar-CH -CH -N), 3.11 (d, J = 6.7 Hz,
2
2
2H, Ph-CH ), 3.34-3.42 (ddd, J = 3.9, 13.7, 15.6 Hz, 1H, Ar-
and removal of the solvents under reduced pressure, the benzy-
loxybenzylisoquinoline was obtained as a pale yellow oil (105
2
CH -CH -N), 4.18 (br d, J = 14.3 Hz,1H, Ar-CH -CH -N), 5.06
2
2
2
2
(s, 2H, OCH ), 5.81 (t, J = 6.7 Hz, 1H, CH-N), 6.85 (dd, J = 2.8,
mg, 44%), R = 0.61 (ethyl acetate/n-hexane, 1:1); ir: 3332w
2
F
-1
1
8.6 Hz, 2H, Ar-H), 6.94 (dd, J = 2.2, 7.6 Hz, 1H, Ar-H), 7.05 (dd,
J = 2.2, 8.5 Hz, 2H, Ar-H), 7.10-7.18 (m, 3H, Ar-H), 7.31-7.45
(m, 5H, Ar-H).
(NH) cm ; H nmr: δ (250MHz; CDCl ) 1.87 (1H, br, NH,
H
3
D O exch.), 2.81-2.98 (4H, m, CH ), 3.21-3.25 (2H, m, CH ),
2
2
2
4.16 (1H, dd, J 3.3, 9.8Hz, CH-N), 5.07 (2H, s, OCH ), 6.94 (2H,
2
Anal. Calcd for C
H
NO : C, 81.33; H, 7.56; N, 3.39.
d, J 7.6Hz, Ar-H), 7.11-7.47 (11H, m, Ar-H); hrms: found
28 31
2
Found: C, 81.06; H, 7.42; N, 3.32.
329.17705, calculated for C H NO; 329.17796. This com-
23 23
pound oxidised very rapidly when exposed to air.
1-(4-Hydroxybenzyl)-2-pivaloyl-1,2,3,4-tetrahydroisoquinoline
(35).
1,2,3,4,8,9,10,11-Octahydro-13-oxa-6-thia-2,10-diazapentacene
(23),
A mixture of 1-benzyloxybenzyl-2-pivaloyl-tetrahydroiso-
quinoline (33, 0.200 g, 4.84 mmol), concentrated hydrochloric
acid solution (20 cm ), and absolute ethanol (30 cm ) was heated
3,4,8,9-Tetrahydro-13-oxa-6-thia-2,10-diazapentacene (14), in
a mixture with 17 (ca 20%) and a possible trace of 18 (see above),
(0.570 g, 1.86 mmol) was dissolved in absolute ethanol (50 cm ).
3
3
3
at 80 °C overnight. The mixture was kept stirring overnight under
3
a nitrogen atmosphere. Water (20 cm ) was added and ethanol
An excess of sodium borohydride (0.211 g, 5.58 mmol) was
added very carefully. The reaction mixture was heated under
reflux for 1 h and left stirring overnight at 80 °C. The solvent was
evaporated under reduced pressure and the solid material was dis-
was evaporated under reduced pressure. The residue was taken
up in chloroform, then dried (MgSO ), filtered and the solvent
4
was removed under reduced pressure to give the crude hydroxy-
benzylisoquinoline as a yellow gum (0.236 g), which was crys-
3
solved in chloroform (100 cm ) and washed with water. The water