1092 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Tercel et al.
3.56-3.50 (m, 2 H, CH2), 3.36 (t, J ) 6.0 Hz, 2 H, CH2); 13C
NMR δ 147.1 (C-8), 134.9, 124.1 (C-9,10), 134.7, 128.3, 123.3
(C-5,6,7), 57.1, 55.4, 50.5, 47.3 (C-1,3 and NCH2CH2OH), 24.9
(C-4). Anal. (C11H14N2O3‚HCl) C, H, N, Cl.
J ) 8.5 Hz, 1 H, H-8), 5.65 (t, J ) 5.1 Hz, 1 H, OH), 4.90 (AB
quartet, J ) 16.2 Hz, 2 H, ArCH2N), 3.95-3.90 (m, 2 H, CH2),
3.87 (t, J ) 6.5 Hz, 2 H, CH2), 3.55-3.50 (m, 2 H, CH2), 3.38-
3.32 (m, 2 H, CH2), 3.22 (s, 3 H, NCH3); 13C NMR δ 147.0 (C-
6), 134.7, 132.2 (C-9,10), 128.7, 123.7, 121.6 (C-5,7,8), 64.0,
61.3, 56.9, 54.5 (C-1,3 and NCH2CH2OH), 48.2 (NCH3), 23.2
(C-4). Anal. (C12H17ClN2O3‚0.25H2O) C, H, N, Cl.
Chlorination of 23b with SOCl2 as described above gave
N-(2-chloroethyl)-N-methyl-6-nitro-1,2,3,4-tetrahydroisoquino-
linium chloride (23a ) as a foam that could not be induced to
crystallize. The product was purified by repeatedly dissolving
in a polar solvent (CH3CN or EtOH) and separating the salt
by slow addition of a less polar solvent (Et2O or Me2CO).
Decanting the supernatant at each cycle, and drying, gave a
yellow-brown gum (87%): 1H NMR [(CD3)2SO] δ 8.24 (d, J )
2.3 Hz, 1 H, H-5), 8.16 (dd, J ) 8.5, 2.3 Hz, 1 H, H-7), 7.49 (t,
J ) 8.5 Hz, 1 H, H-8), 4.91 (AB quartet, J ) 16.2 Hz, 2 H,
ArCH2N), 4.23 (t, J ) 6.8 Hz, 2 H, CH2), 3.98-3.80 (m, 4 H, 2
x CH2), 3.36-3.30 (m, 2 H, CH2), 3.19 (s, 3 H, NCH3); 13C NMR
δ 147.1 (C-6), 134.3, 132.1 (C-9,10), 128.8, 123.8, 121.8 (C-
5,7,8), 62.9, 60.8, 56.7 (C-1,3 and NCH2CH2Cl), 47.2 (NCH3),
35.9 (CH2Cl), 23.1 (C-4). Anal. (C12H16Cl2N2O2‚H2O) C, H, N,
Cl.
N -(2-C h lo r o e t h y l)-N -m e t h y l-7-n it r o -1,2,3,4-t e t r a -
h yd r oisoqu in olin iu m Ch lor id e (22a ). Alkylation of 7-ni-
tro-1,2,3,4-tetrahydroisoquinoline hydrochloride31 (39) with
bromoethanol as above gave N-(2-hydroxyethyl)-7-nitro-1,2,3,4-
tetrahydroisoquinoline (40) as a brown oil (80%): 1H NMR
(CDCl3) δ 7.99 (dd, J ) 8, 2 Hz, 1 H, H-6), 7.92 (d, J ) 2 Hz,
1 H, H-8), 7.26 (d, J ) 8 Hz, 1 H, H-5), 3.78 (s, 2 H, ArCH2N),
3.74 (t, J ) 5.3 Hz, 2 H, CH2OH), 3.00 (t, J ) 5.8 Hz, 2 H,
ArCH2CH2N), 2.86 (t, J ) 5.8 Hz, 2 H, ArCH2CH2N), 2.76 (t,
J ) 5.3 Hz, 2 H, NCH2CH2OH), 2.35 (br s, 1 H, OH); 13C NMR
δ 146.1, 142.2, 136.1 (C-7,9,10), 129.6, 121.7, 121.3 (C-5,6,8),
59.0, 58.2, 55.4, 49.9 (C-1,3 and NCH2CH2OH), 29.4 (C-4).
Hydrochloride salt: mp (MeOH) 218-219 °C dec; Anal.
(C11H14N2O3‚HCl) C, H, N, Cl.
A solution of 35 (0.50 g, 2.3 mmol) and dimethyl sulfate (0.23
mL, 2.5 mmol) in CH3CN (15 mL) was stirred at 20 °C for 16
h, then diluted with Et2O, and stirred until the separated oil
solidified completely. The solid was filtered off and dried to
give N-(2-hydroxyethyl)-N-methyl-8-nitro-1,2,3,4-tetrahydroiso-
quinolinium methosulfate (21b) (0.57 g, 73%): mp (i-PrOH)
103.5-107 °C; 1H NMR [(CD3)2SO] δ 8.06 (d, J ) 8.0 Hz, 1 H,
H-5 or 7), 7.75 (d, J ) 7.7 Hz, 1 H, H-5 or 7), 7.64 (t, J ) 7.9
Hz, 1 H, H-6), 5.34 (t, J ) 5 Hz, 1 H, OH), 4.97 (AB quartet,
J ) 18 Hz, 2 H, ArCH2N), 3.95-3.86 (m, 2 H, CH2), 3.81 (t, J
) 6.5 Hz, 2 H, CH2), 3.49 (t, J ) 4.8 Hz, 2 H, CH2), 3.37 (s, 3
H, CH3OSO3), 3.36-3.30 (m, 2 H, CH2), 3.18 (s, 3 H, NCH3);
13C NMR δ 147.6 (C-8), 132.9, 122.6 (C-9,10), 134.9, 128.6,
123.7 (C-5,6,7), 64.1, 59.6, 55.8, 54.6 (C-1,3 and NCH2CH2OH),
52.7 (CH3OSO3), 48.4 (NCH3), 23.2 (C-4). Anal. (C12H17N2-
O3.CH3O4S) C, H, N, S.
The methosulfate salt of 21b (0.51 g, 1.5 mmol) was
chromatographed on Dowex 50 WX8 ion exchange resin (7
mL), eluting with 6 N HCl (35 mL). The aqueous phase was
evaporated, and the residue was extracted with hot i-PrOH,
filtered, and evaporated to give the chloride salt of 21b as a
yellow solid. This was reacted with SOCl2 as above to give
N-(2-chloroethyl)-N-methyl-8-nitro-1,2,3,4-tetrahydroisoquino-
linium chloride (21a ) (60%): mp (iPrOH) 225-226 °C; 1H NMR
[(CD3)2SO] δ 8.07 (d, J ) 8.1 Hz, 1 H, H-5 or 7), 7.75 (d, J )
7.2 Hz, 1 H, H-5 or 7), 7.65 (t, J ) 7.9 Hz, 1 H, H-6), 5.05 (AB
quartet, J ) 16.6 Hz, 2 H, ArCH2N), 4.28-4.17 (m, 2 H, CH2),
3.96-3.80 (m, 4 H, 2 × CH2), 3.35-3.29 (m, 2 H, CH2), 3.21
(s, 3 H, NCH3); 13C NMR δ 147.3 (C-8), 134.7, 128.5, 123.6
(C-5,6,7), 132.5, 122.0 (C-9, 10), 62.5, 58.8, 55.2 (C-1,3 and
NCH2CH2Cl), 47.5 (NCH3), 35.7 (CH2Cl), 22.8 (C-4). Anal.
(C12H16Cl2N2O2) C, H, N, Cl.
N -(2-C h lo r o e t h y l)-N -m e t h y l-6-n it r o -1,2,3,4-t e t r a -
h yd r oisoqu in olin iu m Ch lor id e (23a ). Deamination of 32
as described above gave N-acetyl-6-nitro-1,2,3,4-tetrahydroiso-
quinoline (36) (69%): mp (EtOAc) 117-118 °C; 1H NMR
(CDCl3), a 2:1 mixture of amide conformers doubling most
signals, δ 8.10-8.00 (m, 2 H, H-5,7), 7.36-7.25 (m, 1 H, H-8),
4.83 (s, 0.7 H, ArCH2N), 4.72 (s, 0.3 H, ArCH2N), 3.87 (t, J )
5.9 Hz, 0.7 H, ArCH2CH2N), 3.74 (t, J ) 5.9 Hz, 1.3 H, ArCH2-
CH2N), 3.02 (t, J ) 5.9 Hz, 1.3 H, ArCH2CH2N), 2.96 (t, J )
5.9 Hz, 0.7 H, ArCH2CH2N), 2.21 (s, 3 H, COCH3); 13C NMR δ
169.5 and 169.3 (COCH3), 147.4 and 146.5, 140.9 and 139.7,
136.8 and 135.5 (C-6,9,10), 127.7 and 127.0, 124.0 and 123.5,
121.7 and 121.4 (C-5,7,8), 47.9, 44.0, 43.4, 38.8 (C-1,3), 29.4
and 28.5 (C-4), 21.8 and 21.5 (COCH3). Anal. (C11H12N2O3)
C, H, N.
Hydrolysis of 36 as described above gave 6-nitro-1,2,3,4-
tetrahydroisoquinoline hydrochloride (37) (87%): mp (MeOH)
256-257 °C dec; 1H NMR [(CD3)2SO] δ 10.00 (br s, 2 H, NH2),
8.16 (d, J ) 2.3 Hz, 1 H, H-5), 8.09 (dd, J ) 8.5, 2.3 Hz, 1 H,
H-7), 7.54 (d, J ) 8.5 Hz, 1 H, H-8), 4.38 (s, 2 H, ArCH2N),
3.38 (t, J ) 6.2 Hz, 2 H, ArCH2CH2N), 3.17 (t, J ) 6.2 Hz, 2
H, ArCH2CH2N); 13C NMR δ 146.4 (C-6), 136.9, 134.3 (C-9,-
10), 128.3, 123.5, 121.1 (C-5,7,8), 43.2, 39.7 (C-1,3), 24.6 (C-
4). Anal. (C9H10N2O2‚HCl) C, H, N.
Methylation of 40 with dimethyl sulfate as above gave N-(2-
hydroxyethyl)-N-methyl-7-nitro-1,2,3,4-tetrahydroisoquinolin-
ium methosulfate (22b) as a tan solid (3.84 g, 90%): mp (i-
1
PrOH) 122-124.5 °C; H NMR [(CD3)2SO] δ 8.22-8.15 (m, 2
H, H-6,8), 7.62 (d, J ) 8.4 Hz, 1 H, H-5), 5.37 (t, J ) 4.9 Hz,
1 H, OH), 4.83 (AB quartet, J ) 15.8 Hz, 2 H, ArCH2N), 3.97-
3.91 (m, 2 H, CH2), 3.84 (t, J ) 6.5 Hz, 2 H, CH2), 3.53-3.47
(m, 2 H, CH2), 3.38 (s, 3 H, CH3OSO3), 3.37-3.31 (m, 2 H,
CH2), 3.19 (s, 3 H, NCH3); 13C NMR δ 146.2, 138.1, 129.0 (C-
7,9,10), 130.4, 122.7, 122.4 (C-5,6,8), 63.9, 61.1, 57.1, 54.7 (C-
1,3 and NCH2CH2OH), 52.8 (CH3OSO3), 48.3 (NCH3), 23.4 (C-
4). Anal. (C12H17N2O3‚CH3O4S) C, H, N, S.
Conversion of 22b to the chloride form by ion exchange
chromatography on Dowex 50 WX8 resin and reaction of this
with SOCl2 as above gave N-(2-chloroethyl)-N-methyl-7-nitro-
1,2,3,4-tetrahydroisoquinolinium chloride (22a ) (42%): mp
(MeCN) 202-203 °C; 1H NMR [(CD3)2SO] δ 8.20 (dd, J ) 8.5,
2.3 Hz, 1 H, H-6), 8.15 (d, J ) 2.3 Hz, 1 H, H-8), 7.63 (d, J )
8.5 Hz, 1 H, H-5), 4.97 (AB quartet, J ) 15.7 Hz, 2 H, ArCH2N),
4.30-4.19 (m, 2 H, CH2), 4.02-3.87 (m, 4 H, 2 × CH2), 3.41-
3.33 (m, 2 H, CH2), 3.23 (s, 3 H, NCH3); 13C NMR δ 146.2,
138.0, 128.6 (C-7,9,10), 130.5, 122.7, 122.4 (C-5,6,8), 62.6, 60.5,
56.8 (C-1,3 and NCH2CH2Cl), 47.2 (NCH3), 35.8 (CH2Cl), 23.3
(C-4). Anal. (C12H16Cl2N2O2‚0.25H2O) C, H, N, Cl.
Alkylation of 37 with 2-bromoethanol as described above
gave N-(2-hydroxyethyl)-6-nitro-1,2,3,4-tetrahydroisoquinoline
Red u ction of 22a a n d 23a w ith Nick el Bor id e.
A
1
(38) (76%). Hydrochloride salt: mp (EtOH) 181-182 °C; H
solution of 22a (39 mg, 0.13 mmol) in MeOH (3 mL) was
treated successively with Ni2B46 (0.10 g) and aqueous HCl (2
N, 1.5 mL). The suspension was stirred under reflux for 4.5
h, during which time most of the Ni2B was consumed, giving
a green solution. The mixture was evaporated, and the residue
was dissolved in MeOH and filtered to remove the last of the
Ni2B. Ion exchange chromatography on Dowex 50 WX8 resin
(1 mL), eluting first with 2 N HCl (5 mL) to remove other salts
and then with 6 N HCl (5 mL), gave 7-ammonio-N-(2-
chloroethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium dihy-
drochloride (41) as a pale green oil (14 mg, 35%): 1H NMR
[(CD3)2SO) δ 7.38 (d, J ) 8.2 Hz, 1 H, H-5 or H-6), 7.31 (d, J
) 8.2 Hz, 1 H, H-5 or H-6), 7.17 (s, 1 H, H-8), 4.79 (AB quartet,
J ) 15.6 Hz, 2 H, ArCH2N), 4.22 (t, J ) 6.7 Hz, 2 H, CH2),
NMR (D2O) δ 8.19 (d, J ) 2.0 Hz, 1 H, H-5), 8.13 (dd, J ) 8.6,
2.0 Hz, 1 H, H-7), 7.46 (t, J ) 8.6 Hz, 1 H, H-8), 4.68 (br s, 2
H, ArCH2N), 4.06 (t, J ) 5.2 Hz, 2 H, CH2), 3.90-3.65 (br m,
2 H, CH2), 3.54 (t, J ) 5.2 Hz, 2 H, CH2), 3.36 (t, J ) 5.9 Hz,
2 H, CH2); 13C NMR δ 150.0 (C-6), 137.4, 135.4 (C-9,10), 130.8,
126.6, 124.7 (C-5,7,8), 60.0, 57.8, 55.5, 51.9 (C-1,3 and NCH2-
CH2OH), 27.4 (C-4). Anal. (C11H14N2O3‚HCl) C, H, N, Cl.
Quaternization of 38 with dimethyl sulfate, followed by ion
exchange chromatography as described above, gave N-(2-
hydroxyethyl)-N-methyl-6-nitro-1,2,3,4-tetrahydroisoquinolin-
ium chloride (23b) (48%): mp (from MeCN by ultrasound
1
induction) 156-157.5 °C; H NMR [(CD3)2SO] δ 8.24 (d, J )
2.2 Hz, 1 H, H-5), 8.15 (dd, J ) 8.5, 2.2 Hz, 1 H, H-7), 7.51 (t,