6904
M. Schulze et al. / Bioorg. Med. Chem. 17 (2009) 6898–6907
lization from methanol/diethyl ether yielded 23% brown powder.
Mp: 245 °C, 1H NMR: 250 MHz (DMSO-d6): d 2.97–3.91 (m, 6H);
4.52–4.74 (m, 2H); 4.76–4.92 (m, 1H, 13a); 6.63–6.64 (d, J = 2,1 Hz,
1H, 4); 6.74–6.78 (dd, J = 1.9, 8.2 Hz, 1H, 2); 7.25–7.32 (m, 5H, 1, 9,
10, 11, 12); 10.52 (s, 1H, OH); 13C NMR, dept: 250 MHz (DMSO-d6):
d 23.97; 33.21; 50.45; 54.88; 59.56 (13a); 115.05; 115.19; 122.86;
126.51; 127.26; 127.35; 128.27; 128.84; 129.24; 132.15; 133.23;
157.22. Anal. (C17H18BrNO ꢁ 1/8 HBr): C, H, N.
up from the lithium aluminum hydride reduction was accom-
plished as free base. Either strongly alkaline or acidic conditions
should be avoided. This isoindole-derivative is very instable and at-
tempts to convert it into an HCl-salt failed due the immediate for-
mation of a dark green solution and no solids. The free base forms
yellow oil which solidifies to a brick red solid upon storage in the
refrigerator. Mp: 68–70 °C. Due to the instability, the pure com-
pound shows three decomposition compounds in the GC–MS.
The fragmentation of the amine is characteristic for quinolizine-
like compounds and has a mꢀ1 peak as the most stable fragment:
m/z: 265 (34%); 264 (100%); 248 (32%); 236 (9%); 220 (8%); 204
(5%); 191 (6%); 156 (6%); 144 (13%); 131 (14%). 1H NMR
250 MHz (CDCl3): d1.75–1.98 (m, 2H, 6); 2.74–3.40 (m, split in four
separate signals, each matching 1H, 4H, 5, and 6); 3.83 (s, 3H, O–
Me); 3.79–3.88 (d, J = 13 Hz, 1H, 8); 4.39–4.44 (d, J = 13 Hz, 1H,
8); 5.70 (s,1H, 13b); 6.62–6.67 (dd, J = 2.6, 8.5 Hz, 1H, 2); 6.77–
6.78 (d, J = 2.6, 1H, 4); 7.17–7.20 (d, J = 8.5 Hz, 1H, 1); 7.25–7.30
(m, 4H, 9, 10, 11, 12). Anal. (C18H19NO ꢁ H2O): C, H, N.
5.1.6. 10-Methoxy-6-methyl-5,6,7,8,13,14-hexahydrodibenzo[c,g]
azecine hydrochloride (7)
The synthesis was performed according to the general proce-
dures in the manuscript using 0.7 g of 13. Flash chromatography
on silica gel with methanol/chloroform (1:4) as eluent, gave a yel-
low oil. Addition of two drops of ethereal HCl and recrystallization
from 2-propanol/diethyl ether yielded 9.7% of white crystals. Mp:
214 °C, 1H NMR: 250 MHz (methanol-d4): d 2.80–2.94 (m, 1H, 4);
3.08–3.51 (m, 8H, 7, 8, 13, 14); 3.85–3.97 (m, 1H, 5); 4.42–4.48
(dd, J = 4.4, 10.7 Hz, 1H, 5); 5.95–5.99 (d, J = 8.4 Hz, 1H, 9); 6.35–
6.39 (dd, J = 2.5, 8.4 Hz, 1H, 11); 6.68–6.69 (d, J = 2.3 Hz, 1H, 12);
7.10–7.22 (m, 4H, 1, 2, 3, 4). HRMS m/z calcd for C19H24NO
282.1852 found 282.1850; EI-MS m/z: 281 (100%); 266 (12%);
250 (23%); 235 (13%); 223 (51%); 208 (17%); 192 (7%); 176
(56%); 165 (9%); 159 (7%); 146 (35%); 134 (23%); 115 (11%); 104
(18%); 91 (19%); 78 (10%); 65 (5%); 57 (9%); 44 (29%); 36 (17%);
GC–MS: (base) m/z: 281 (3%); 266 (3%); 250 (5%); 235 (3%); 219
(2%); 176 (10%); 162 (8%); 144 (30%); 130 (11%); 118 (20%); 104
(100%); 91 (40%); 78 (80%); 65 (20%). Anal. (C19H24ClNO ꢁ 1/9
HCl) C, N; for H calcd 7.55, found 6.92.
5.1.9. 11-Methoxy-6-methyl-5,6,7,8,9,14-hexahydrodibenzo[c,f]
azecine (10)
According the general procedure in the manuscript, 1.7 mmol
(700 mg) of the mossy green crude quaternary salt 16 were ring
opened with sodium in liq. ammonia. The amber colored oily res-
idue was dissolved in 1 mL of 2-propanol and converted into an
HCl-salt by the addition of three drops concd HCl acid. The green-
ish precipitation was recrystallized from acetone/2-propanol to
give 300 mg of white needles with mp 208–210 °C. Yield: 55% after
recrystallization. 1H NMR 250 MHz (methanol-d4): (HCl-salt) d
1.9–2.2 (m, 1H, 5, 6 or 7); 2.4–3.0 (m, 4H, 5, 6 or 7); 3.09 (s, 3H,
N-Me); 3.09–3.28 (m, 1H, 5, 6 or 7); 3.74 (s, 3H, O-Me); 3.91–
3.97 (d, J = 15 Hz, 1H, 14); 4.21–4.27 (d, J = 15 Hz, 1H, 14); 4.41–
4.46 (d, J = 13 Hz, 1H, 9); 4.76–4.80 (d, J = 13 Hz, 1H, 9); 6.72 (d,
J = 2.5 Hz, 1H, 4); 6.79–6.81 (dd, J = 2.5, 8.5 Hz 1H, 2); 7.29–7.51
(m, 4H, 10, 11, 12, 1); 7.51–7.77 (dd, J = 8.0/1.0 Hz, 1H, 13). GC–
MS: (base) m/z: 281 (37%); 266 (5%); 249 (10%); 235 (7%); 223
(19%); 209 (100%); 190 (84%); 177 (35%); 165 (32%); 152 (9%);
145 (21%); 115 (14%). Anal. (C19H23NO ꢁ HCl): C, H, N.
5.1.7. 6-Methyl-5,6,7,8,13,14-hexahydrodibenzo[c,g]azecin-10-
ol hydrochloride (8)
The synthesis was performed according to the general proce-
dures in the manuscript from 0.05 g of the methyl-ether 7. The
crude product was dissolved in a small amount of acetone. After
adding two drops of ethereal HCl and some drops of ether, brown
oil separates, which could be dried in vacuo to a brown powder.
Mp: 198 °C. Yield 14.1%. 1H NMR: 250 MHz (methanol-d4): d
2.78–2.91 (m, 1H,7); 2.99–3.09 (m, 7H, 13, 14, N–Me); 3.30–3.34
(m, 2H, 8); 3.50–3.60 (m, 1H, 7); 4.43–4.58 (q, J = 14.0 Hz, 2H, 5);
6.53–6.60 (m, 2H, 9, 11); 7.01–7.04 (d, J = 8.2 Hz, 1H, 12); 7.20–
7.26 (m, 3H, 1,2,3,); 7.42–7.49 (d, J = 8.1 Hz, 4) 13C NMR, dept:
250 MHz (methanol-d4): d 25.14; 31.74; 32.13; 42.82 (N–Me);
54.42; 55.66; 114.31; 115.46; 126.65; 127.74; 128.47; 128.66;
129.79; 130.55; 131.52; 132.29; 136.19; 142.02; 155.89. GC–MS:
(base) m/z: 267 (2%); 252 (2%); 236 (2%); 223 (1%); 210 (2%); 146
(14%); 132 (2%); 120 (20%); 104 (30%); 91 (28%); 78 (33%); 65
(15%); 52 (18%); 44 (100%). Anal. (C18H22ClNO ꢁ 4/5H2O ꢁ 1/
5HCl) C, H, N.
5.1.10. 6-Methyl-5,6,7,8,9,14-hexahydrodibenzo[c,f]azecin-11-
ol (11)
An aqueous solution of 317 mg 10 HCl (1 mmol) was alkalized
with some NaOH and extracted with CHCl3. After drying over
MgSO4, the solvent was evaporated to approximately 50 mL. With
an external cooling bath and under nitrogen atmosphere, 450 lL of
BBr3 (ꢂ5 mmol) were added through a septum. The cooling bath
was removed and the reaction mixture was brought to reflux for
1 h. When the mixture returned to room temperature, it was
poured onto chipped ice and the pH was brought to 9 with 2 N
NaOH. Extraction with CH2Cl2, drying over MgSO4 and evaporation
yielded 151 mg of white foam. Yield 56%. Mp: 139–140 °C, 1H
NMR: 250 MHz (CDCl3): (base): d 1.48–1.51 (mc, 4H, 6, 10);
2.03–2.07 (mc, 4H, 7, 9); 2.17 (s, 3H, N–Me); 2.65–2.75 (mc, 4H,
5, 11); 4.06, (s, 2H, 16); 6.47–6.52 (dd, J = 2.6, 8.2, 1H, 2); 6.61 (d,
J = 2.6, 1H, 4); 6.86–6.90 (d, J = 8.2, 1H, 1); 7.01–7.14 (m, 4H, 12,
13, 14, 15). GC–MS: (base) m/z: 267 (3%); 252 (2%); 236 (5%);
221 (3%); 209 (12%); 195 (39%); 176 (18%); 165 (45%); 152
(30%); 146 (30%); 132 (35%); 120 (46%); 115 (52%); 107 (48%);
104 (72%); 102 (71%); 91 (100%); 70 (100%); 57 (92%). Anal.
(C18H21NO ꢁ 1/5 H2O): C, H, N.
5.1.8. 3-Methoxy-6,7,9,13b-tetrahydro-5H-isoindolo[1,2-
a][2]benzazepine (9)
To a suspension of 5.0 g (0.13 mol) lithium aluminum hydride
in 150 mL of dry THF there was added slowly under nitrogen and
with cooling a solution of 5.0 g (0.18 mol) of the lactam 13 in
50 mL of dry THF. The mixture was refluxed for 1 h and stirred
overnight. With cooling, the residual lithium aluminum hydride
was decomposed by the careful addition of a saturated aqueous
solution of potassium-sodium tartrate. After filtration of inorganic
solids and washing of the filter cake with 50 mL of THF, the layers
were separated and the aqueous layer was extracted with dichloro-
methane. After evaporation of the pooled organic extracts, the res-
idue was dissolved in 50 mL of dichloromethane and dried over
Na2SO4. Evaporation of the solvent yielded 2.2 g of 9 as yellow
oil that slowly solidified after storage in the refrigerator. Work
5.1.11. 3-Methoxy-7-methyl-5,8,13,13a-tetrahydro-6H-
isoquino[3,2-a]isoquinolinium iodide (13)
The synthesis was performed according to the general proce-
dures in the manuscript using 2 g of 5. The precipitate was filtered
and washed with little ether to yield 96% of white crystals. Mp: