S.-Y. Sit et al. / Bioorg. Med. Chem. 12 (2004) 715–734
727
5.9. (ꢂ)-7-Alkyl-8,9-methylenedioxy-2,3,7,11b-tetrahydro-
1H-dibenz[de,h]isoquinoline and (ꢂ)-7-alkyldinapsoline
(28a–28f)
5.9.4. (ꢂ)-7,70-Diethyl-8,9-methylenedioxy-2,3,7,11b-tet-
rahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7,70-die-
thyldinapsoline hydrobromide (28d). This compound
was obtained as a pale gray dry foam (8% yield): MS m/
1
Products from alkylation were reduced as described
previously using sodium cyanoborohydride in acidified
THF. Products from the reduction step were depro-
tected using BBr3 in CH2Cl2 at ꢀ78 ꢁC. The desired
products were isolated in accordance with the proce-
dures described previously. Some of the 7-substituted
intermediates (27d, 27f) could not withstand the BBr3
deprotection conditions; only four compounds from this
series survived to the end.
z 352.11 (MH+). H NMR (DMSO-d6) d 1.14 (t, 3H),
2.6 (m, 2H), 3.08 (t, 1H), 4.11 (m, 6H), 4.58 (t, 1H), 6.01
(s, 1H), 6.08 (s, 1H), 6.77 (d, J=8.0, 1H), 6.85 (d,
J=8.0, 1H), 7.1 (t, 1H), 7.21 (d, J=4.3, 2H). Attempted
BBr3 deprotection led to extensive decomposition of the
starting material.
5.9.5. (ꢂ)-7-Ethoxycarbonylmethyl-8,9-methylenedioxy-
2,3,7,11b-tetrahydro-1H-dibenz[de,h]isoquinoline
and
(ꢂ)-7-methoxycarbonylmethyldinapsoline (28e). The
5.9.1. (ꢂ)-7-Methyl-8,9-methylenedioxy-2,3,7,11b-tetra-
hydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-methyldi-
napsoline hydrobromide (28a). The reduction product
was obtained as a dry yellow foam (57% yield): MS m/z
reduced compound was obtained as a brown gum (24%
1
yield): MS m/z 284.15 (MH+). H NMR (DMSO-d6) d
2.87 (t, 1H), 3.47 (dd, J=17.8, 3.5, 1H), 3.7 (bt, 1H), 3.9
(d, J=11.4, 3H), 4.2 (d, J=17.9, 1H), 6.01 (s, 1H), 6.07
(s, 1H), 6.82 (q, 2H), 7.01 (d, J=7.6, 2H). Evidently the
ethyl ester group was also trans-esterified into the methyl
ester upon methanol workup. This compound was
obtained as a pale gray dry foam (8% yield): MS m/z
1
280.2 (MH+). H NMR (DMSO-d6) d 1.31 (d, J=7.2,
3H), 3.09 (t, 1H), 4.28 (m, 5H), 6.02 (s, 1H), 6.1 (s, 1H),
6.87 (m, 2H), 7.06 (d, J=6.7, 1H), 7.24 (t, 1H), 7.30 (d,
J=7.4, 1H). The deprotected final product was obtained
as a yellow foam (57% yield): MS m/z 268.18 (MH+). 1H
NMR (DMSO-d6) d 1.24 (d, J=7.1, 3H), 3.33 (m, 5H),
6.56 (d, J=8.3, 1H), 6.70 (d, J=8.2, 1H), 7.12 (d, J=7.1,
1H), 7.33 (m, 2H), 8.5 (s, 1H), 9.31 (s, 1H).
1
326.19 (MH+). 324.14 (MꢀH). H NMR (DMSO-d6) d
2.482 (m, 2H), 2.62 (dd, J=13. 9, 4.7, 1H), 3.53 (s, 3H),
4.31 (m, 2H), 4.37 (s, 2H), 4.83 (q, 1H), 6.57 (d, J=8.2,
1H), 6.73 (d, J=8.2, 1H), 7.15 (t, 1H), 7.27 (m, 2H),
8.67 (s, 1H), 9.42 (s, 1H). 13C NMR (DMSO-d6) d
14.08, 20.70, 31.88, 35.11, 43.73, 44.18, 51.32, 59.75,
113.38, 114.1, 124.69, 125.71, 126.67, 126.73, 127.06,
127.99, 131.95, 138.45, 142.10, 143.88, 171.17. Anal.
5.9.2. (ꢂ)-7,70-Dimethyl-8,9-methylenedioxy-2,3,7,11b-
tetrahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7,70-di-
methyldinapsoline hydrobromide (28b). The reduction
product was obtained as a yellow foam (65% yield): MS
m/z 294.2 (MH+). 1H NMR (DMSO-d6) d 1.43 (d,
J=18.0, 3H), 1.98 (d, J=21.4, 3H), 2.94 (t, 1H), 4.19
(m, 4H), 6.10 (t, 2H), 6.82 (m, 2H), 7.17 (m, 1H), 7.22
(m, 1H), 7.5 (m, 1H). The deprotected final product was
obtained as a yellow foam (65% yield): MS m/z 282.2
.
calcd for C19H19NO4 1.0HBr: C, 54.12; H, 5.60; N,
3.32. Found: C, 54.06; H, 5.51; N, 3.29.
5.9.6. (ꢂ)-7-Cyanomethyl-8,9-methylenedioxy-2,3,7,11b-
tetrahydro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-cyano-
methyldinapsoline (28f). This compound was obtained
as a yellow solid (19% yield): MS m/z 292.08 (MH+).
1H NMR (DMSO-d6) d 0.71 (m, 1H), 1.01 (m, 1H), 1.98
(m, 1H), 2.29 (m, 1H), 4.22 (m, 4H), 5.94 (s, 1H), 5.98
(s, 1H), 6.73 (d, J=8.2, 1H), 6.80 (d, J=8.0, 1H), 7.22
(m, 3H). Attempted deprotection with BBr3 in methyl-
ene chloride at ꢀ78 ꢁC caused extensive decomposition
of the starting material.
1
(MH+). H NMR (DMSO-d6) d 1.69 (s, 3H), 1.81 (s,
3H), 4.31 (m, 5H), 6.70 (d, J=8.4, 1H), 6.81 (d, J=8.4,
1H), 7.25 (d, J=7.4, 1H), 7.39 (t, 1H), 7.66 (d, J=7.8,
1H), 8.34 (s, 1H), 9.55 (s, 1H). 13C NMR (DMSO-d6) d
29.22, 29.62, 31.81, 37.35, 43.31, 45.82, 113.48,
116.66, 122.30, 124.39, 126.37, 127.02, 128.90, 129.02,
129.66, 143.71, 144.38, 144.72. Anal. calcd for
.
.
C18H19NO2 1.6HBr 0.6H2O: C, 51.28; H, 5.21; N, 3.33;
Br, 30.32. Found: C, 50.89; H, 5.11; N, 3.94; Br, 29.44.
5.9.7. 5-Chloro-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-
quinoline (29a). To a solution of starting material 10
(0.36 g, 1.38 mmol) in CH2Cl2 (15 mL) was slowly
added SO2Cl2 (0.276 mL) at 0 ꢁC. The mixture was stir-
red at 0 ꢁC for 3 h, and was then quenched with satu-
rated NaHCO3 solution. The product was extracted
with CH2Cl2, dried over Na2SO4, and purified by chro-
matography (silica gel, EtOAc in hexanes). This com-
pound was obtained as a yellow dry foam (57% yield):
1H NMR (DMSO-d6) d 4.35 (s, 2H), 6.21 (s, 2H), 7.18
(s, 1H), 7.66 (t, 1H), 7.73 (d, J=7.6, 1H), 7.98 (d,
J=7.8, 1H), 9.19 (s, 1H), 9.72 (s, 1H).
5.9.3. (ꢂ)-7-Ethyl-8,9-methylenedioxy-2,3,7,11b-tetrahy-
dro-1H-dibenz[de,h]isoquinoline and (ꢂ)-7-ethyldinapso-
line hydrobromide (28c). The reduction product was
obtained as a dry pale yellow foam (57% yield): MS m/z
294.2 (MH+). 1H NMR (DMSO-d6) d 0.90 (t, 3H), 1.61
(m, 2H), 2.79 (t, 1H), 3.9 (m, 4H), 5.96 (s, 1H), 6.05 (s,
1H), 6.79 (m, 2H), 6.96 (m, 1H), 7.14 (m, 2H). This final
compound was obtained as a pale yellow dry foam
1
(57% yield): MS m/z 282.4 (MH+); 280.3 (MꢀH). H
NMR (DMSO-d6) d 0.868 (t, 3H), 1.17 (m, 2H), 4.37
(m, 5H), 6.55 (d, J=8.2, 1H), 6.7 (d, J=8.2, 1H), 7.17
(t, 1H), 7.27 (t, 2H), 8.45 (s, 1H), 9.3 (s, 1H). 13C NMR
(DMSO-d6) d 12.33, 27.25, 31.97, 40.85, 43.86, 44.21,
112.82, 114.04, 124.09, 126.38, 126.49, 127.56, 127.70,
131.66, 140.15, 142.21, 143.80. Anal. calcd for
5.9.8. 5-Nitro-12H-benzo[de]-1,3-benzodioxol[4,5-h]iso-
quinoline (29b). To a solution of starting material 10
(0.10 g, 0.38 mmol) in acetic acid (4 mL) was added
HNO3 (70%, 0.4 mL). The mixture was stirred at 45 ꢁC
until starting material disappeared (about 35 min) and
was then poured into ice-water. The resulting mixture
.
C18H19NO2 1.0HBr: C, 53.25; H, 5.67; N, 3.45. Found:
C, 53.26; H, 5.58; N, 3.44.