S. Graßmann et al. / Bioorg. Med. Chem. 11 (2003) 2163–2174
2171
General procedure for the preparation of imidazole
derivatives 11–13
mmol) were stirred at 140 ꢀC for 12 h. After cooling
aqueous NaOH (c=6 mol/L) and EtOAc were added
and the mixture was stirred for 1 h at rt The organic
layer was isolated, washed (aqueous NaOH), and the
solvent was removed in vacuo. The residue was dis-
solved in THF (15 mL) and aqueous HCl (c=2 mol/L,
15 mL) was added. After being heated under reflux for
2 h the organic solvent was removed under reduced
pressure. The aqueous layer was filtrated, washed
(CH2Cl2), basified, and extracted with CH2Cl2. After
removal of the solvent in vacuo the crude product was
purified by flash chromatography (eluent: EtOAc/
Histamine (11a, 0.33 g, 3 mmol) or N-methyl-2-(1H-
imidazol-4-yl)ethanamine (13a, 0.35 g, 2.8 mmol),32 the
corresponding aryl chloride (2.5 mmol) and phenol (3 g,
31.9 mmol) were stirred at 140 ꢀC for 12 h. After cooling
aqueous NaOH (c=6 mol/L) and EtOAc were added
and the mixture was stirred for 1 h at rt The organic
layer was separated, washed (aqueous NaOH), and the
solvent was removed in vacuo. The residue was purified
by column chromatography (eluent: EtOAc/MeOH/
triethylamine; 95:5:5).
1
MeOH/triethylamine; 95:10:5). Yield: 55%; H NMR
(CF3COOD) d 2.36 (m, 2H, ImCH2CH2), 3.07 (t,
J=7.8 Hz, 2H, ImCH2), 3.82 (t, J=7.1 Hz, 2H,
CH2NHQuin), 6.85 (d, J=7.1 Hz, 1H, Quin-3H), 7.33
(s, 1H, Im-5H), 7.79 (m, 1H, Quin-6H), 7.88 (d,
J=8.5 Hz, 1H, Quin-5H), 8.01 (m, 1H, Quin-7H), 8.20
(d, J=8.5 Hz, 1H, Quin-8H), 8.32 (d, J=7.1 Hz, 1H,
Quin-2H), 8.60 (s, 1H, Im-2H); EI–MS m/z (%) 252
N-Quinolin-4-yl-2-(1H-imidazol-4-yl)ethanamine dihy-
drochloride (11). From 11a and 4-chloroquinoline.
Yield: 42%; 1H NMR d 3.10 (t, J=6.7 Hz, 2H, ImCH2),
3.90 (s, 2H, NCH2), 7.00 (m, J=7.3 Hz, 1H, Quin-3H),
7.57 (s, 1H, Im-4H), 7.70–8.00 (m, 3H, Quin-6H, Quin-
7H, Quin-5H), 8.56 (t, J=7.8, 1H, Quin-2H), 8.64 (m,
1H, Quin-8H), 9.07 (s, 1H, Im-2H); APCI-MS m/z (%)
ꢂ
(M+ , 22).
ꢂ
239.2 ([M+H]+ , 100).
N-(1,2,3,4-Tetrahydroacridin-9-yl)-3-(1H-imidazol-4-yl)-
propanamine dihydrogen oxalate (15). NaH (suspended
in mineral oil, o=60%, 0.3 g, 7.5 mmol) was added to a
solution of 1,2,3,4-tetrahydroacridin-9-amine (0.99 g,
5 mmol) in dry DMF (20 mL). After stirring for 1 h at
60 ꢀC and subsequent cooling to rt compound 14a
(0.92 g, 2.5 mmol)33 and a catalytic amount of tetra-n-
butylammonium iodide were added. The mixture was
stirred for 12 h at 140 ꢀC. After removal of the solvent in
vacuo and addition of EtOAc and H2O the organic
layer was washed with an aqueous solution of K2CO3.
The organic solvent was removed under reduced pres-
sure, THF (15 mL) and aqueous HCl (c=2 mol/L,
15 mL) were added, and the mixture was stirred and
heated for 2 h under reflux. The organic solvent was
removed under reduced pressure and the aqueous layer
was filtrated, washed (CH2Cl2), basified, and extracted
with CH2Cl2. The organic extracts were combined and
after removal of the solvent in vacuo the crude product
was purified by flash chromatography (eluent: EtOAc/
MeOH/triethylamine; 95:5:5). Yield: 8%; 1H NMR
(CF3COOD) d 2.08 (m, 4H, 2Acr-2,3H), 2.38 (m, 2H,
ImCH2CH2), 2.72 (m, 2H, 2Acr-1H), 3.07 (m, 4H,
ImCH2, 2Acr-4H), 4.21 (t, J=7.2 Hz, 2H, CH2NHAcr),
7.32 (s, 1H, Im-5H), 7.65 (m, 1H, Acr-6H), 7.77 (d,
J=8.5 Hz, 1H, Acr-8H), 7.90 (m, 1H, Acr-7H), 8.35 (d,
J=8.7 Hz, 1H, Acr-5H), 8.61 (s, 1H, Im-2H); EI–MS m/
N-(1,2,3,4-Tetrahydroacridin-9-yl)-2-(1H-imidazol-4-
yl)ethanamine dihydrogen oxalate (12). From 11a and
9-chloro-1,2,3,4-tetrahydroacridine. Yield: 44%; 1H
NMR d 1.84 (m, 4H, 2Acr-2,3H), 2.63 (m, 2H, 2Acr-4H),
2.97 (m, 2H, 2Acr-1H), 3.06 (t, J=6.7 Hz, 2H, ImCH2),
4.15 (t, J=6.3 Hz, 2H, CH2NAcr), 7.16 (s, 1H, Im-5H),
7.59 (m, 1H, Acr-6H), 7.88 (m, 1H, Acr-8H), 7.82 (m,
1H, Acr-7H), 8.37 (s, 1H, Im-2H), 8.54 (d, J=8.8 Hz,
ꢂ
1H, Acr-5H); EI–MS m/z (%) 292 (M+ , 18).
N-Methyl-N-quinolin-4-yl-2-(1H-imidazol-4-yl)ethana-
mine dihydrogen oxalate (13). From 13a and 4-chloro-
1
quinoline. Yield: 35%; H NMR d 3.48 (t, J=7.5 Hz,
2H, ImCH2); 3.68 (s, 3H, CH3), 4.27 (t, J=7.4 Hz, 2H,
CH2NQuin), 7.07 (d, J=7.3 Hz, 1H, Quin-3H), 7.45 (s,
1H, Im-5H), 7.76 (m, 1H, Quin-6H), 7.92 (d, J=8.5 Hz,
1H, Quin-5H), 8.01 (m, 1H, Quin-7H), 8.32 (d,
J=7.2 Hz, 1H, Quin-2H), 8.34 (d, J=9.2 Hz, 1H, Quin-
ꢂ
8H), 8.67 (s, 1H, Im-2H); EI–MS m/z (%) 252 (M+ , 9).
3 - (1 - Triphenylmethyl - 1H - imidazol - 4 - yl)propanamine
(14b). In an autoclave 4-(3-chloropropyl)-1-(triphe-
nylmethyl)-1H-imidazole hydrochloride (14a, 1.01 g,
2.4 mmol),33 catalytic amounts of tetra-n-butylammo-
nium chloride and NH4Cl, and EtOH (50 mL) were
cooled to 0 ꢀC. Liquid ammonia (150 mL) was added
and the mixture was stirred for 12 h at rt and then for
24 h at 60 ꢀC (p=20-25 bar). After cooling, ablation of
the ammonia and removal of the solvent under reduced
pressure the residue was purified by flash chromato-
graphy (eluent: CH2Cl2/MeOH, NH3-satd.; 95:5).
Yield: 67%; 1H NMR d 1.66 (m, 2H, ImCH2CH2),
2.45 (t, J=7.0 Hz, 2H, CH2N), 2.60 (t, J=7.4 Hz, 2H,
ImCH2), 6.60 (s, 1H, Im-5H), 7.08 (m, 6H, 6Ph), 7.25
(s, 1H, Im-2H), 7.39 (m, 9H, 9Ph); EI–MS m/z (%) 367
(M+., 1).
ꢂ
z (%) 306 (M+ , 18).
N - Methyl - 3 - (1H - imidazol - 4 - yl)propanamine (16a).
Methanamine (solution in EtOH, o=33%, 15 mL,
150 mmol), KOH (2.8 g, 50 mmol), 14a (0.5 g,
7.5 mmol),33 and KI (catalytic amount) were dissolved
in H2O (15 mL) and stirred under reflux for 12 h. After
removal of the solvent in vacuo and addition of EtOAc
and H2O the organic layer was separated and washed
(H2O). After removal of the solvent in vacuo the crude
product was purified by flash chromatography (eluent:
EtOAc!CH2Cl2/MeOH, NH3-satd.; 95:5). Yield: 34%;
1H NMR (CF3COOD) d 2.34 (m, 2H, ImCH2CH2), 3.00
(m, 5H, CH2NHCH3), 3.38 (m, 2H, ImCH2), 7.35 (s, 1H,
N-Quinolin-4-yl-3-(1H-imidazol-4-yl)propanamine dihy-
drogen oxalate (14). 4-Chloroquinoline (0.41 g, 2.5
mmol), 14b (0.94 g, 2.5 mmol) and phenol (3 g, 31.9