G. Nadler et al./Bioorg. Med. Chem. 6 (1998) 1993±2011
2007
A sample was sali®ed to aord the hydrochloride as
yellow crystals (mp 204 ꢁC). 1H NMR (hydrochloride)
(DMSO-d6) d 10.18 (broad s, 1H), 8.06 (d, 2H), 7.57 (d,
2H), 6.94 (s, 1H), 6.87±6.57 (m, 4H), 5.00±4.75 (m, 1H),
3.73 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.81±
3.32 (m, 3H), 3.23±2.51 (m, 6H), 2.43±1.56 (m, 6H).
2.22 (s, 3H), 1.56 (m, 2H). Note: This reaction can also
be performed, in the same solvent and temperature
conditions, by replacing KF on Celite1 by NEt3. Yields
are usually slightly lower.
Step 2: N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-3-(4-
nitrophenoxy)-propanamine (59). A suspension of NaH
at 60% in oil (0.11 g, 2.7 mmol) was added to a solution
of 15 (0.69 g, 2.7 mmol) in DMSO (5 mL) and the mix-
ture was stirred for 2 h at rt. 1-Fluoro-4-nitrobenzene
(0.43 g, 3 mmol) was added and the mixture was stirred
for 1 h at rt then poured onto ice water (50 mL). The
aqueous mixture was extracted with AcOEt, washed
with water, dried over MgSO4 and concentrated in
vacuo. The residue was puri®ed by chromatography
(SiO2, CH2Cl2:CH3OH, 95:5) to aord 59 (0.77 g, 76%).
A sample was sali®ed as usual, aording 59.HCl as an
amorphous solid. 1H NMR (hydrochloride) (DMSO-d6)
10.82 (broad s, 1H), 8.23 (d, 2H), 7.16 (d, 2H), 6.92±6.78
(m, 3H), 4.24 (t, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.30 (m,
4H), 2.98 (t, 2H), 2.82 (s, 3H), 2.24 (m, 2H).
()-trans-N-(3,4-Dimethoxyphenyl)-N-(8,9-dimethoxy-
1,3,4,6,11,11a-hexahydro-2H-benzo[b]-quinolizin-2-yl)-4-
nitrobenzamide (49). This compound was synthesized by
the same procedure starting from 2 and 8,9-dimethoxy-
3,4,11,11a-tetrahydro-1H-benzo[b]quinolizin-2-6H-on.20
The reductive amination gave predominantly the trans
form.
Step 1: ()-trans-N-(3,4-Dimethoxyphenyl)-8,9-dimeth-
oxy-1,3,4,6,11,11a-hexahydro-2H-benzo[b]-quinolizine-2-
amine. 1H NMR (DMSO-d6) d 6.70 (d, 1H), 6.62 (s,
2H), 6.29 (d, 1H), 6.08 (dd, 1H), 5.04 (d, 1H), 4.04±3.62
(m, 13H), 3.19±3.12 (m, 2H), 3.03±2.98 (m, 1H), 2.70±
2.62 (m, 1H), 2.41±1.95 (m, 4H), 1.45±1.29 (m, 1H),
1.19±1.02 (m, 1H).
The following compounds have been obtained by this
method:
Step 2: ()-trans-N-(3,4-Dimethoxyphenyl)-N-(8,9-di-
methoxy-1,3,4,6,11,11a-hexahydro-2H-benzo[b]-quino-
lizine-2-yl)-4-nitrobenzamide (49). Melting point 175 ꢁC.
1H NMR (DMSO-d6) d 8.05 (d, 2H), 7.56 (d, 2H), 6.88
(d, 1H), 6.75 (m, 2H), 6.61 (s, 2H), 4.62 (m, 1H), 3.85±
3.66 (m, 13H), 3.44±3.33 (m, 2H), 3.20±3.02 (m, 1H),
2.73±2.65 (1H), 2.51±2.09 (m, 4H), 1.57±1.40 (m, 1H),
1.32±1.21 (m, 1H).
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-N0-(4-nitro-
phenyl)-1,3-propanediamine (58). Starting from N-[2-
(3,4-dimethoxyphenyl)ethyl]-N-methyl-1,3-propanedia-
mine22 and using K2CO3 instead of NaH, this method
aorded 58.HCl as an orange amorphous solid (mp
80±85 ꢁC). Elemental analysis was consistent with the
hemihydrate. 1H NMR (hydrochloride) (DMSO-d6)
10.63 (broad s, 1H), 8.00 (d, 2H), 7.52 (t, 1H), 6.91±6.67
(m, 5H), 3.75 (s, 3H), 3.72 (s, 3H), 3.28±3.15 (m, 6H),
3.01 (t, 2H), 2.80 (s, 3H), 2.03 (m, 2H).
General method D (Scheme 4)
This method can be illustrated by the synthesis of com-
pound 59.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-1,3-prop-
anediamine was obtained by reduction of N-[[2-(3,4-
dimethoxyphenyl)ethyl]methylamino]propanamide as
described in method A. H NMR (CDCl3) d 6.82±6.71
(m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.79±2.53 (m, 6H), 2.47
(t, 2H), 2.30 (s, 3H), 2.15 (broad s, 2H), 1.65 (m, 2H).
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methyl-3-(4-nitro-
phenoxy)propanamine (59)
1
Step 1: N-(3-Hydroxypropyl)-N-methyl-3,4-dimethoxy-
benzeneethanamine (15). A solution of 4 (1.0 g, 5 mmol),
and 3-chloro-1-propranol (1.89 g, 20 mmol) was treated
with potassium ¯uoride on Celite121 (2.75 g) in dry
acetonitrile (30 mL) and the mixture was heated at 85 ꢁC
for 20 h under argon. After cooling, the mixture was ®l-
tered and the solid was washed with CH2Cl2 (150 mL).
The organic solutions were combined, concentrated in
vacuo and the residue was taken up in CH2Cl2 (50 mL),
washed with water (50 mL), with 5% aqueous NaHCO3
(50 mL) and again with water, then dried over MgSO4
and concentrated in vacuo. The residue was puri®ed by
chromatography (SiO2, CH2Cl2:CH3OH, 95:5) aord-
N-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]prop-
anamide was obtained by reaction of 4 on 3-chloro-
propanamide as described in method A. 1H NMR
(CDCl3) d 7.71 (broad s, 2H), 6.78±6.70 (m, 3H), 3.87 (s,
3H), 3.85 (s, 3H), 2.79±2.74 (m, 6H), 2.46 (t, 2H), 2.40
(s, 3H).
N-[4-[3-[2-[(3,4-Dimethoxyphenyl)ethyl]methylamino]-
propyl]oxyphenyl] methanesulfonamide (62)
1
ing 15 (0.71 g, 56%) as a yellow oil. H NMR (DMSO-
d6) d 6.86±6.69 (m, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 3.43
(t, 2H), 3.37 (s, 1H), 2.69±2.52 (m, 4H), 2.43 (t, 2H),
Step 1: 3-(4-Aminophenoxy)-N-[2-(3,4-dimethoxyphenyl)-
ethyl]-N-methylpropanamine. A mixture of 59 (2.78 g,
7.4 mmol) and SnCl2.2H2O (10.05 g, 44.5 mmol) in