2870
R. Worayuthakarn et al. / Tetrahedron 68 (2012) 2864e2875
(9), 530 (42), 529 (100), 515 (11), 514 (30); HRMS-FAB m/z [MþH]þ
2.89 (dt, J¼15.2, 4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 167.6,
calcd for C33H37N2O8: 589.2550, found 589.2552.
165.8, 149.0, 148.8, 148.2, 146.5, 136.5, 134.1, 132.3, 131.8, 131.4,
130.0, 128.8 (2C), 128.7 (2C), 128.2 (2C), 127.4, 127.0 (2C), 122.5 (2C),
118.0, 113.2, 113.0, 111.3, 109.7, 55.9 (2C), 55.8 (2C), 55.3, 50.4, 40.8,
28.8; EIMS: m/z 590 (M þ, 0.91), 470 (32), 469 (100), 454 (35);
HRMS-FAB m/z [MþH]þ calcd for C36H35N2O6: 591.2495, found
591.2492; Anal. Calcd for C36H34N2O6: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.04; H, 5.97; N, 4.45.
4.2.11. N-[9,10-Dimethoxy-1-(30,40-dimethoxyphenyl)-2-(300,400-
methylenedioxyphenyl)-4-oxo-3,4,6,7-tetrahydro-2H-pyrido[2,1-a]
isoquinolin-3-yl]acetamide (9k). The general procedure was used
with azlactone 8e (231 mg, 1.00 mmol) and 1-(30,40-dimethox-
ybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline 7d (512 mg,
1.50 mmol) to give tetrahydro-2H-pyrido[2,1-a]isoquinoline 9k cis/
trans (15:85) (225 mg, 39%): 9k-cis as a pale yellow oil. Rf (70%
EtOAc/hexane; developed twice) 0.20; IR (cmꢀ1): 3326, 1660, 1608,
4.2.13. N-[1,2-Bis-(30,40-dimethoxyphenyl)-9,10-dimethoxy-4-oxo-
3,4,6,7-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3-yl]benzamide
(9m). The general procedure was used with azlactone 8d (309 mg,
1.00 mmol) and 1-(30,40-dimethoxybenzyl)-6,7-dimethoxy-3,4-
dihydroisoquinoline 7d (512 mg, 1.50 mmol) to give tetrahydro-
2H-pyrido[2,1-a]isoquinoline 9m cis/trans (32:68) (553 mg, 85%):
9m-cis as a pale brown oil. Rf (70% EtOAc/hexane) 0.49; IR (cmꢀ1):
1580, 1509; 1H NMR (300 MHz, CDCl3)
d 6.73e6.63 (m, 5H), 6.59 (d,
J¼1.5 Hz, 1H), 6.55 (dd, J¼8.0, 1.5 Hz, 1H), 6.41 (s, 1H), 6.35 (d,
J¼6.1 Hz,1H), 5.89 (d, J¼5.6 Hz, 1H), 5.88 (d, J¼5.6 Hz, 1H), 5.11 (br t,
J¼6.1 Hz, 1H), 4.53e4.43 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.71 (s,
3H), 3.36 (ddd, J¼12.4, 12.1, 3.9 Hz, 1H), 3.29 (s, 3H), 3.05 (ddd,
J¼13.4, 12.1, 4.7 Hz, 1H), 2.97e2.87 (m, 1H), 2.07 (s, 3H); 13C NMR
1652, 1604, 1509; 1H NMR (300 MHz, CDCl3)
d 7.82e7.74 (m, 2H),
(75 MHz, CDCl3)
d
170.3,166.1,148.9,148.8,148.3,147.8,146.9, 146.6,
7.56e7.48 (m, 1H), 7.48e7.39 (m, 2H), 7.05 (d, J¼5.2 Hz, 1H),
6.82e6.65 (m, 6H), 6.60 (s, 1H), 6.46 (s, 1H), 5.30 (br t, J¼6.5 Hz, 1H),
4.73 (d, J¼6.5 Hz, 1H), 4.55e4.45 (m, 1H), 3.89 (s, 3H), 3.80 (s, 3H),
3.79 (s, 3H), 3.74 (s, 3H), 3.58 (s, 3H), 3.42 (ddd, J¼12.1, 11.9, 4.0 Hz,
1H), 3.31 (s, 3H), 3.06 (ddd, J¼13.4, 11.9, 4.8 Hz, 1H), 3.01e2.91 (m,
131.7, 131.0, 129.4, 128.3, 122.9 (2C), 122.2, 121.0, 113.3, 113.0, 111.1,
109.5, 108.6, 108.3, 100.9, 56.0, 55.8, 55.7, 55.2, 54.1, 46.4, 40.6, 28.5,
23.2; EIMS: m/z 572 (Mþ, 8), 515 (6), 514 (34), 513 (100), 498 (39);
HRMS-FAB m/z [MþH]þ calcd for C32H33N2O8: 573.2237, found
573.2242: 9k-trans as a white solid. Rf (70% EtOAc/hexane; de-
veloped twice) 0.09; Mp: 167e169 ꢁC; IR (cmꢀ1): 3384, 1664, 1578,
1H); 13C NMR (75 MHz, CDCl3)
d 167.4, 166.2, 149.1, 148.9, 148.7,
148.5, 148.4, 146.8, 134.0, 132.0, 131.8, 131.1, 129.2, 128.6 (2C), 127.0
(2C), 126.9, 123.1, 123.0, 121.2, 120.3, 113.6, 113.2, 112.3, 111.4, 111.3,
109.7, 56.1, 55.9 (2C), 55.7, 55.4, 55.3, 54.7, 46.3, 40.7, 28.6; EIMS: m/
z 650 (Mþ, 6), 531 (7), 530 (33), 529 (100), 515 (9), 514 (25), 470
(30), 469 (88), 455 (12), 454 (27); HRMS-FAB m/z [MþH]þ calcd for
C38H39N2O8: 651.2706, found 651.2709: 9m-trans as a pale brown
oil. Rf (70% EtOAc/hexane) 0.40; IR (cmꢀ1): 3336, 1668, 1604, 1579,
1509; 1H NMR (300 MHz, CDCl3)
d 6.80e6.62 (m, 5H), 6.62e6.55
(m, 1H), 6.49 (br s, 1H), 6.40 (s, 1H), 6.21 (d, J¼8.0 Hz, 1H), 5.88 (s,
2H), 4.92 (dd, J¼8.0, 3.9 Hz,1H), 4.28e4.18 (m,1H), 4.14 (d, J¼3.9 Hz,
1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.46e3.36 (m,1H), 3.27 (s,
3H), 3.03e2.89 (m, 1H), 2.89e2.78 (m, 1H), 2.09 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 170.0,165.7,149.0,148.8,148.3,147.9,146.8,146.5,
132.3, 131.2, 130.3, 130.0, 122.6, 122.3, 121.4, 117.8, 113.4, 113.2, 111.4,
109.7, 108.5, 108.4, 100.9, 56.0, 55.9 (2C), 55.5, 55.3, 50.3, 40.6, 28.7,
23.4; EIMS: m/z 572 (Mþ, 7), 529 (2), 515 (7), 514 (36), 513 (100),
498 (11); HRMS-FAB m/z [MþH]þ calcd for C32H33N2O8: 573.2237,
found 573.2236.
1513; 1H NMR (300 MHz, CDCl3)
d 7.81e7.74 (m, 2H), 7.55e7.46 (m,
1H), 7.46e7.36 (m, 2H), 7.02e6.83 (m, 3H), 6.74 (d, J¼8.2 Hz, 1H),
6.66 (s, 1H), 6.65 (d, J¼7.5 Hz, 1H), 6.56 (dd, J¼8.2, 1.5 Hz, 1H), 6.48
(br s, 1H), 6.41 (s, 1H), 5.16 (dd, J¼7.4, 4.7 Hz, 1H), 4.39 (d, J¼4.7 Hz,
1H), 4.25e4.14 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.76 (s,
3H), 3.54 (s, 3H), 3.50e3.37 (m, 1H), 3.24 (s, 3H), 3.01e2.79 (m, 2H);
4.2.12. N-[1-(30,40-Dimethoxyphenyl)-9,10-dimethoxy-4-oxo-2-
phenyl-3,4,6,7-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3-yl]benza-
mide (9l). The general procedure was used with azlactone 8b
(249 mg, 1.00 mmol) and 1-(30,40-dimethoxybenzyl)-6,7-
dimethoxy-3,4-dihydroisoquinoline 7d (512 mg, 1.50 mmol) to
give tetrahydro-2H-pyrido[2,1-a]isoquinoline 9l cis/trans (35:65)
(513 mg, 86%): 9l-cis as a white solid. Rf (60% EtOAc/hexane) 0.26;
Mp: 146e148 ꢁC; IR (cmꢀ1): 3371, 1645, 1603, 1579, 1515; 1H NMR
13C NMR (75 MHz, CDCl3)
d 167.6, 166.1, 149.0, 148.9, 148.7, 148.1
(2C), 146.5, 134.0, 132.3, 131.7, 131.1, 129.7, 128.7, 128.5 (2C), 127.0
(2C), 122.5 (2C), 120.0, 118.5, 113.2, 113.0, 111.4, 111.1, 111.2, 109.7,
55.8 (2C), 55.7 (4C), 55.3, 49.7, 40.7, 28.7; EIMS: m/z 650 (Mþ, 11),
531 (7), 530 (35), 529 (100), 514 (25), 105 (2), 77 (3); HRMS-FAB m/z
[MþH]þ calcd for C38H39N2O8: 651.2706, found 651.2712.
4.2.14. N-[9,10-Dimethoxy-1-(30,40-dimethoxyphenyl)-2-(300,400-
methylenedioxyphenyl)-4-oxo-3,4,6,7-tetrahydro-2H-pyrido[2,1-a]
isoquinolin-3-yl]-benzamide (9n). The general procedure was used
with azlactone 8f (293 mg, 1.00 mmol) and 1-(30,40-dimethox-
ybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline 7d (512 mg,
1.50 mmol) to give tetrahydro-2H-pyrido[2,1-a]isoquinoline 9n cis/
trans (38:62) (532 mg, 84%): 9n-cis as a white solid. Rf (60% EtOAc/
hexane) 0.23; Mp: 134e135 ꢁC; IR (cmꢀ1): 3392, 1677, 1651, 1607,
(400 MHz, CDCl3) d 7.86e7.82 (m, 2H), 7.63e7.57 (m, 1H), 7.55e7.49
(m, 2H), 7.33e7.20 (m, 5H), 7.07 (d, J¼5.6 Hz, 1H), 6.86 (s, 1H), 6.82
(d, J¼8.4 Hz, 1H), 6.79 (s, 1H), 6.75 (d, J¼8.4 Hz, 1H), 6.56 (s, 1H),
5.44 (dd, J¼7.0, 5.6 Hz, 1H), 4.83 (d, J¼7.0 Hz, 1H), 4.60 (ddd, J¼12.4,
4.6, 3.5 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 3.50 (ddd,
J¼12.4, 12.0, 3.5 Hz, 1H), 3.40 (s, 3H), 3.20 (ddd, J¼15.2, 12.0, 4.6 Hz,
1H), 3.04 (dt, J¼15.2, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 167.6,
166.2,149.0, 148.8, 148.3,146.7, 134.6, 134.1, 131.9, 131.7, 131.3, 129.4,
128.8 (2C), 128.6 (4C), 127.5, 127.1 (2C), 122.9 (2C), 120.9, 113.3,
113.0, 111.2, 109.6, 56.1, 55.9, 55.8, 55.3, 54.4, 46.7, 40.7, 28.6; EIMS:
m/z 590 (Mþ, 17), 513 (8), 470 (33), 469 (100), 454 (26), 105 (1), 77
(1); HRMS-FAB m/z [MþH]þ calcd for C36H35N2O6: 591.2495, found
591.2496; Anal. Calcd for C36H34N2O6: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.31; H, 5.80; N, 4.68: 9l-trans as a white solid. Rf (60%
EtOAc/hexane) 0.20; Mp: 183 ꢁC; IR (cmꢀ1): 3285, 1667, 1634, 1601,
1580, 1515; 1H NMR (400 MHz, CDCl3)
d 7.80e7.72 (m, 2H),
7.55e7.50 (m, 1H), 7.47e7.42 (m, 2H), 7.03 (d, J¼5.3 Hz, 1H), 6.76 (br
s, 1H), 6.73 (br d J¼8.5 Hz, 1H), 6.69 (s, 1H), 6.68 (d, J¼8.5 Hz, 1H),
6.65 (d, J¼1.6 Hz, 1H), 6.63 (dd, J¼8.0 Hz, 1H), 6.57 (dd, J¼8.0, 1.6 Hz,
1H), 6.45 (s, 1H), 5.88 (d, J¼4.2 Hz, 1H), 5.87 (d, J¼4.2 Hz, 1H), 5.28
(br t, J¼6.8 Hz, 1H), 4.68 (d, J¼6.8 Hz, 1H), 4.52 (ddd, J¼12.5, 4.7,
3.5 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.40 (ddd, J¼12.5,
12.3, 3.5 Hz, 1H), 3.31 (s, 3H), 3.14e3.04 (m, 1H), 2.94 (dt, J¼15.0,
1579, 1532, 1513; 1H NMR (400 MHz, CDCl3)
d
7.82e7.77 (m, 2H),
3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 167.6, 166.2, 149.0, 148.9,
7.56e7.51 (m, 1H), 7.47e7.42 (m, 2H), 7.39e7.34 (m, 2H), 7.25e7.31
(m, 2H), 7.23e7.17 (m, 1H), 6.76 (d, J¼7.8 Hz, 1H), 6.69 (s, 1H), 6.66
(d, J¼8.3 Hz, 1H), 6.59 (dd, J¼8.3, 1.8 Hz, 1H), 6.48 (d, J¼1.8 Hz, 1H),
6.44 (s, 1H), 5.19 (dd, J¼7.8, 4.5 Hz, 1H), 4.43 (d, J¼4.5 Hz, 1H), 4.25
(ddd, J¼12.8, 4.6, 4.5 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.55 (s, 3H),
3.58e3.48 (m, 1H), 3.26 (s, 3H), 3.01 (ddd, J¼15.2, 10.6, 4.6 Hz, 1H),
148.3, 147.9, 147.0, 146.7, 134.1, 131.8, 131.7, 131.2, 129.4, 128.6 (2C),
128.2, 127.1 (2C), 123.0, 122.9, 122.5, 121.0, 113.3, 113.0, 111.2, 109.6,
108.5, 108.3, 100.9, 56.1, 55.9, 55.8, 55.3, 54.6, 46.4, 40.7, 28.6; EIMS:
m/z 634 (Mþ, 20), 515 (8), 514 (28), 513 (100), 498 (17), 77 (6);
HRMS-FAB m/z [MþH]þ calcd for C37H35N2O8: 635.2393, found
635.2405; Anal. Calcd for C37H34N2O8: C, 70.02; H, 5.40; N, 4.41.