1270
V.M. Mastranzo et al. / Tetrahedron 68 (2012) 1266e1271
1.67 M in hexanes of n-BuLi (1.29 mL, 2.15 mmol, 1.2 equiv) was
added. After 30 min, a solution of (S)-6 (0.52 g, 1.79 mmol, 1 equiv)
in THF (8 mL) was added via cannula. After 1 h at ꢀ78 ꢁC, a solution
of sulfinylimine (S)-10 (0.653 g, 1.79 mmol, 1 equiv) in THF (10 mL)
was added. The resulting solution was stirred at room temperature
for 12 h. The reaction mixture was hydrolyzed with saturated
aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2
(3ꢂ20 mL), washed with brine (2ꢂ20 mL), dried (Na2SO4), and
evaporated. The 300 MHz 1H NMR spectrum of the crude product
revealed a diastereomeric excess >96%. The residue was purified
by flash column chromatography using hexane/EtOAc 1:1 as eluent
(82% yield); ½a 2D0
ꢃ
ꢀ52.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
2.33 (s, 3H), 2.75e2.86 (m, 1H), 2.88e3.08 (m, 2H), 3.24e3.42 (m,
3H), 3.84 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.40e4.47
(m, 1H), 5.40e5.90 (br s, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 7.08 (d, 1H, J
8.7 Hz), 7.20 (d, 1H, J 8.3 Hz), 7.20 and 7.45 (AA0BB0 system, 4H); 13C
NMR (CDCl3, 100 MHz)
d 21.3, 27.6, 36.8, 40.8, 55.9, 56.1, 56.2, 56.3,
61.5, 109.6, 111.6, 116.1, 124.4, 126.1, 127.3, 129.0, 129.9, 130.0, 136.0,
140.6, 141.0, 147.8, 147.9, 148.0, 152.0; EIMS m/z 482 (1, Mþþ1), 464
(8), 192 (100); HRMS-FAB m/z [Mþ1]þ calcd for C27H32NO5S
482.2001, found 482.1999.
to give 0.79 g (71% yield) of 12 as a white foam; ½a D20
ꢃ
þ11.9 (c 1.0,
4.9.2. (1S)-1-[3,4-Dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-
methylenedioxy-1,2,3,4-tetrahydroisoquinoline (15). Colorless oil,
CHCl3); 1H NMR (CDCl3, 400 MHz)
d 2.31 (s, 3H), 2.37 (s, 3H),
2.46e2.51 (m, 1H), 3.06e3.39 (m, 4H), 3.70 (dd, 1H, J 4.8 and
14.5 Hz), 3.83 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.86
(dd, 1H, J 4.8 and 10.5 Hz), 6.52 (s, 1H), 6.77 (s, 1H), 6.86 (d, 1H, J
8.4 Hz), 6.99 (d, 1H, J 8.4 Hz), 7.01e7.12 (AA0BB0 system, 4H),
0.437 g (94% yield); ½a D20
ꢃ
ꢀ71.9 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz)
d 1.60e2.00 (br, 1H), 2.34 (s, 3H), 2.58e2.83 (m, 3H),
3.09e3.20 (m, 2H), 3.54 (dd, 1H, J 3.4 and 14.0 Hz), 3.78 (s, 3H), 3.86
(s, 3H), 4.04 (dd, 1H, J 3.4 and 10.5 Hz), 5.89 (s, 2H), 6.54 (s, 1H), 6.76
(s, 1H), 7.01 (d, 1H, J 8.6 Hz), 7.07 (d, 1H, J 8.6 Hz), 7.21 and 7.52
7.17e7.52 (AA0BB0 system, 4H); 13C NMR (CDCl3, 100 MHz)
d 21.3,
21.4, 29.3, 37.7, 38.0, 55.9, 56.0, 56.2, 61.3, 62.3, 110.1, 111.8, 114.9,
124.6, 126.1, 126.4, 128.9, 129.2 (2C), 129.9, 132.6, 136.7, 140.5,
140.8, 141.4, 142.0, 147.2, 147.7, 148.0, 151.7; MS-FAB m/z 620 (3,
Mþþ1), 480 (92), 330 (55), 289 (18), 257 (19), 191 (62), 136 (60), 89
(81), 77 (100); HRMS-FAB m/z [Mþ1]þ calcd for C34H38NO6S2
620.2141, found 620.2137.
(AA0BB0 system, 4H); 13C NMR (CDCl3, 100 MHz)
d 21.3, 30.0, 37.7,
40.5, 56.0, 57.2, 61.1, 100.6, 106.6, 108.8, 115.7, 124.5, 127.5, 128.3,
129.6, 131.8, 133.0, 136.7, 140.0, 142.1, 145.8, 145.9, 148.1, 151.7; EIMS
m/z 466 (2, Mþþ1), 448 (19), 176 (100); HRMS-FAB m/z [Mþ1]þ
calcd for C26H28NO5S 466.1688, found 466.1695.
4.8. (1S)-1-[3,4-Dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-
methylenedioxy-2-(S)-p-tolylsulfinyl-1,2,3,4-
tetrahydroisoquinoline 13
4.10. General procedure for the microwave assisted
PicteteSpengler synthesis of 2 and 4
To a stirred solution of diisopropylamine (0.166 g, 0.23 mL,
1.65 mmol, 1.6 equiv) in THF (5 mL) cooled at ꢀ78 ꢁC a solution
1.8 M in hexanes of n-BuLi (0.69 mL, 1.24 mmol, 1.2 equiv) was
added. After 30 min, a solution of (S)-6 (0.30 g, 1.03 mmol, 1 equiv)
in THF (5 mL) was added via cannula. After 1 h at ꢀ78 ꢁC, a solution
of sulfinylimine (S)-11 (0.395 g, 1.13 mmol, 1.1 equiv) in THF (5 mL)
was added. The resulting solution was stirred at room temperature
for 12 h. The reaction mixture was hydrolyzed with saturated
aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2
(3ꢂ20 mL), washed with brine (2ꢂ20 mL), dried (Na2SO4), and
evaporated. The 300 MHz 1H NMR spectrum of the crude product
revealed a diastereomeric excess >96%. The residue was purified by
flash column chromatography using hexane/EtOAc 1:1 as eluent to
A solution of the amine 14 or 15 (1 mmol), paraformaldehyde
(1.2 mmol 1.2 equiv), TFA (8 mmol, 8 equiv) in toluene (1 mL) was
placed in a microwave vial, which was then capped and irradiated
in a Monowave 300 microwave equipment at 140 ꢁC for 0.5 h. The
volatiles were removed under reduced pressure and the crude re-
action mixture was suspended in cold water (3 mL), treated with
2 M aqueous NaOH to pH 8 and extracted with CH2Cl2 (3ꢂ5 mL).
The combined organic extracts were dried (Na2SO4) and concen-
trated. The residue was purified by flash column chromatography
using hexane/EtOAc 1:1 as eluent.
4.10.1. (S)-(ꢀ)-5,8,13,13a-Tetrahydro-2,3,9,10-tetramethoxy-6H-di-
benzo[a,g]quinolizine [(S)-(ꢀ)-tetrahydropalmatine (2)]. Light yel-
low solid, 0.199 g (56% yield); mp 142e144 ꢁC (lit.18 141e142 ꢁC);
give 0.42 g (68% yield) of 13 as a white solid; mp 182e184 ꢁC; ½a D20
ꢃ
þ12.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
d
2.31 (s, 3H), 2.37
½
a 2D0
ꢃ
ꢀ269.1 (c 1.0, CHCl3) [lit.19
½
a 2D0
ꢃ
ꢀ269.0 (c 0.8, CHCl3)]; 1H NMR
(s, 3H), 2.42e2.54 (m, 1H), 3.30e3.26 (m, 3H), 3.29 (dd, 1H, J 10.8
and 14.3 Hz), 3.71 (dd, 1H, J 4.5 and 14.3 Hz), 3.91 (s, 3H), 3.95 (s,
3H), 4.82 (dd, 1H, J 4.5 and 10.8 Hz), 5.89 (AB system, 2H), 6.49 (s,
1H), 6.78 (s, 1H), 6.89 (d, 1H, J 8.5 Hz), 6.92e7.10 (AA0BB0 system,
4H), 7.01 (d, 1H, J 8.5 Hz), 7.16e7.51 (AA0BB0 system, 4H); 13C NMR
(CDCl3, 400 MHz) d 2.61e2.71 (m, 2H), 2.83 (dd, 1H, J 11.6 and
15.6 Hz), 3.10e3.24 (m, 2H), 3.27 (dd, 1H, J 3.6 and 16.0 Hz),
3.51e3.58 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H),
4.24 (d, 1H, J 16.0 Hz), 6.62 (s, 1H), 6.73 (s, 1H), 6.79 (d, 1H, J 8.4 Hz),
6.88 (d, 1H, J 8.4 Hz); 13C NMR (CDCl3, 100 MHz)
d 29.1, 36.3, 51.5,
(CDCl3, 100 MHz)
d
21.2, 21.3, 29.7, 37.3, 37.8, 56.1, 61.2, 62.6, 100.7,
54.0, 55.8 (2C), 56.0, 59.3, 60.1, 108.6, 110.9, 111.3, 123.8, 126.7, 127.7,
128.7, 129.7, 145.0, 147.4 (2C), 150.2. These analytical data are in
accordance with the values reported in the literature.11a
107.0, 108.9, 114.9, 124.5, 126.2, 127.2, 128.6, 129.1, 129.8, 130.3,
132.5, 136.7, 140.4, 140.7, 141.3, 141.9, 145.8, 146.5, 147.6, 151.6; MS-
FAB m/z 604 (6, Mþþ1), 464 (100), 314 (64), 289 (19), 176 (38), 154
(65), 136 (47), 77 (23); HRMS-FAB m/z [Mþ1]þ calcd for
C33H34NO6S2 604.1828, found 604.1833.
4.10.2. (S)-(ꢀ)-5,8,13,13a-Tetrahydro-9,10-dimethoxy-6H-benzo[g]-
1,3-benzodioxolo[5,6-a]quinolizine [(S)-(ꢀ)-canadine (4)]. Light
yellow solid, 0.180 g (53% yield); mp 129e131 ꢁC (lit.20 134 ꢁC); ½a 2D0
ꢃ
4.9. General procedure for the preparation of 14 and 15
ꢀ292.0 (c 1.0, CHCl3) [lit.20
½
a 2D0
ꢃ
ꢀ291.0 (c 0.93, CHCl3)]; 1H NMR
(CDCl3, 400 MHz)
d 2.56e2.72 (m, 2H), 2.82 (dd, 1H, J 11.5 and
To a stirred solution of 12 or 13 (1 mmol, 1 equiv) in MeOH
(10 mL) cooled at 0 ꢁC trifluoroacetic acid (3 mmol, 3 equiv) was
added. The resulting solution was stirred at 0 ꢁC for 3 h. The vola-
tiles were evaporated and the residue was chromatographed in an
SCX column affording the corresponding amine.
15.8 Hz), 3.05e3.22 (m, 2H), 3.22 (dd,1H, J 3.5 and 15.8 Hz), 3.52 (m,
1H), 3.54 (d, 1H, J 15.2 Hz), 3.84 (s, 6H), 4.24 (d, 1H, J 15.8 Hz), 5.90
(s, 2H), 6.59 (s, 1H), 6.72 (s, 1H), 6.77 (d, 1H, J 8.4 Hz), 6.86 (d, 1H, J
8.4 Hz); 13C NMR (CDCl3,100 MHz)
d 29.6, 36.5, 51.4, 54.0, 56.0, 59.7,
60.2, 100.8, 105.6, 108.4, 111.1, 123.9, 127.7, 127.8, 128.6, 130.8, 145.2,
146.0, 146.2, 150.4; EIMS m/z 339 (96, Mþ), 338 (51), 308 (14), 205
(13), 174 (19), 164 (100), 149 (65), 105 (35), 77 (8). Analytical data
were in agreement with literature values.11b
4.9.1. (1S)-1-[3,4-Dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (14). Colorless oil, 0.394 g