3976 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ohmori et al.
(1.04 g, 33%). This orange-colored intermediate was added to
a solution of imidazole (3.76 g, 55.2 mmol) and KOH (85%,
0.54 g, 83.1 mmol) in DMSO (10 mL). The mixture was heated
at 120 °C for 2 h and then poured onto ice-water (60 g). The
resulting precipitate was collected and washed with water to
give 4a (1.11 g, 93%): 1H NMR δ 8.48 (s, 1H), 8.33 (br m, 1H),
8.19 (d, 1H), 7.94 (t, 1H), 7.15 (t, 1H), 7.08 (dd, 1H), 6.95 (d,
1H), 3.05 (d, 3H); MS (EI) m/ z 218 (M).
mL). The resulting precipitate was collected and washed with
water to give 4a (2.09 g, 97%): 1H NMR δ 8.31 (d, 1H), 8.14
(br m, 1H), 7.94 (t, 1H), 7.25-7.35 (m, 2H), 6.78 (d, 1H), 6.68
(dd, 1H), 3.39 (m, 2H), 1.42 (t, 3H); MS (EI) m/ z 232 (M).
Gen er a l Meth od for P r ep a r a tion of 1-Su bstitu ted -7-
im id a zolyl-6-n it r oq u in oxa lin ed ion es 6a -k . The com-
pounds were prepared by hydrogenation of the appropriate
o-nitroanilines 4a -k under atmospheric pressure using Pd-
C, followed by reaction with oxalic acid in 4 N HCl at reflux
temperature and then nitration by fuming HNO3 (6a -c,e-k )
or nitronium tetrafluoroborate (6d ).
5-(1H-Im idazol-1-yl)-2-n itr o-N-pr opylan ilin e (4c): 3 equiv
of n-propylamine was used in a place of aqueous methylamine;
1
90% from 3a (two steps); H NMR δ 8.48 (s, 1H), 8.32 (br s,
1H), 8.19 (d, 1H), 7.94 (s, 1H), 7.16 (s, 2H), 7.01 (dd, 1H), 3.44
(q, 2H), 1.69 (se, 2H), 0.98 (t, 3H); MS (EI) m/ z 246 (M).
N-Decyl-5-(1H-im idazol-1-yl)-2-n itr oan ilin e (4d): 3 equiv
of n-decylamine was used in a place of aqueous methylamine;
7-(1H-Im idazol-1-yl)-1-m eth yl-2,3(1H,4H)-qu in oxalin edi-
on e Hyd r och lor id e (5a ‚HCl). Imidazolylaniline 4a (1.08 g,
4.95 mmol) was hydrogenated in a solution of methanol (50
mL) and concentrated HCl (1.5 mL) under atmospheric pres-
sure using 10% palladium on carbon (0.11 g), filtered, and
evaporated to give suitably substituted phenylenediamine,
which was treated with oxalic acid (0.45 g, 4.95 mmol) in 4 N
HCl (15 mL) at reflux overnight. The resulting precipitate was
collected and washed with water to give 5a ‚HCl (1.20 g,
1
89% from 3a (two steps); H NMR δ 8.48 (s, 1H), 8.26 (br d,
1H), 8.19 (d, 1h), 7.93 (t, 1H), 7.17 (s, 1H), 7.15 (s, 1H), 7.01
(dd, 1H), 3.45 (q, 2H), 1.24-1.74 (m, 16H), 0.85 (t, 3H); MS
(EI) m/ z 344 (M).
5-(1H-Im id a zol-1-yl)-N-isop en tyl-2-n itr oa n ilin e (4e): 5
equiv of isopentylamine was used in a place of aqueous
methylamine; 99% from 3a (two steps); 1H NMR δ 8.48 (s, 1H),
8.19 (d, 1H), 8.19 (br s, 1H), 7.93 (t, 1H), 7.17 (m, 2H), 7.01
(dd, 1H), 3.46 (dd, 2H), 1.43-1.90 (m, 3H), 0.96 (d, 6H); MS
(EI) m/ z 274 (M).
1
87%): mp >300 °C; H NMR δ 12.26 (br s, 1H), 9.64 (s, 1H),
8.29 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.59 (d, 1H), 7.34 (d,
1H), 3.58 (s, 3H); MS (FAB) m/ z 243 (M + 1).
1-Eth yl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in oxa lin ed i-
on e h yd r och lor id e (5b‚HCl): 89% from 4b; 1H NMR δ 12.40
(br s, 1H), 9.87 (s, 1H), 8.35 (d, 1H), 7.94 (d, 1H), 7.83 (d, 1H),
7.61 (dd, 1H), 7.44 (d, 1H), 4.24 (q, 2H), 1.26 (t, 3H); MS (FAB)
m/ z 257 (M + 1).
N-Cycloh exyl-5-(1H-im id a zol-1-yl)-2-n itr oa n ilin e (4f):
3 equiv of cyclohexylamine at 60 °C was used in a place of
aqueous methylamine at ambient temperature; 91% from 3a
1
(two steps); H NMR δ 8.48 (t, 1H), 8.19 (d, 2H), 7.93 (t, 1H),
7-(1H-Im idazol-1-yl)-1-pr opyl-2,3(1H,4H)-qu in oxalin edi-
on e h yd r och lor id e (5c‚HCl): 93% from 4c; mp > 300 °C
7.16-7.22 (m, 2H), 7.00 (dd, 1H), 3.92 (m, 1H), 1.37-2.00 (m,
10H); MS (EI) m/ z 286 (M).
1
(H2O); H NMR δ 12.35 (br s, 1H), 9.79 (s, 1H), 8.31 (s, 1H),
N -(Cycloh e xylm e t h yl)-5-(1H -im id a zol-1-yl)-2-n it r o-
a n ilin e (4g): 3 equiv of cyclohexylmethylamine was used in
a place of aqueous methylamine; 85% from 3a (two steps); 1H
NMR δ 8.48 (s, 1H), 8.19 (d, 1H) 8.19 (br s, 1H), 7.93 (t, 1H),
7.17 (m, 2H), 7.01 (dd, 1H), 3.32 (t, 2H), 0.97-1.83 (m, 11H);
MS (EI) m/ z 300 (M).
7.92 (s, 1H), 7.78 (d, 1H), 7.59 (dd, 1H), 7.40 (d, 1H), 4.15 (t,
2H), 1.70 (se, 2H), 0.96 (t, 3H); MS (FAB) m/ z 271 (M + 1).
1-Decyl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in oxa lin ed i-
on e h yd r och lor id e (5d ‚HCl): 78% from 4d ; mp 183-186 °C
1
(H2O-HCl); H NMR δ 12.37 (br s, 1H), 9.82 (s, 1H), 8.32 (t,
1H), 7.93 (t, 1H), 7.71 (dd, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 4.19
(t, 2H), 1.24-1.64 (m, 16H), 0.85 (t, 3H); MS (FAB) m/ z 369
(M + 1).
N-[2-(Dim eth yla m in o)eth yl]-5-(1H-im id a zol-1-yl)-2-n i-
tr oa n ilin e (4h ): 3 equiv of N,N-dimethylethylenediamine was
used in a place of aqueous methylamine; 84% from 3a (two
7-(1H -Im id a zol-1-yl)-1-isop en t yl-2,3(1H ,4H )-q u in ox-
a lin ed ion e h yd r och lor id e (5e‚HCl): 50% from 4e; mp >300
°C; 1H NMR δ 12.39 (br s, 1H), 9.83 (s, 1H), 8.33 (s, 1H), 7.94
(s, 1H), 7.56-7.69 (m, 2H), 7.42 (d, 1H), 4.20 (m, 2H), 1.57
(m, 3H), 0.96 (d, 6H); MS (FAB) m/ z 299 (M + 1).
1-Cycloh exyl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in ox-
a lin ed ion e h yd r och lor id e (5f‚HCl): 30% from 4f; mp >300
°C; 1H NMR δ 12.31 (br s, 1H), 9.81 (s, 1H), 8.28 (s, 1H), 7.92
(s, 1H), 7.90 (d, 1H), 7.56 (dd, 1H), 7.39 (d, 1H), 4.50 (m, 1H),
2.32-2.44 (br m, 2H), 1.36-1.77 (br m, 8H); MS (FAB) m/ z
311 (M + 1).
1
steps); H NMR δ 8.49 (s, 1H), 8.45 (t, 1H), 8.19 (d, 1H), 7.95
(s, 1H), 7.17 (d, 1H), 7.16 (s, 1H), 7.03 (dd, 1H), 3.50 (dd, 2H),
3.33 (d, 1H), 2.53 (d, 1H), 2.24 (s, 6H); MS (EI) m/ z 275 (M).
5-(1H -Im id a zol-1-yl)-2-n it r o-N -(1-b e n zyl-3-p yr r oli-
d in yl)a n ilin e (4i): 2 equiv of 1-benzyl-3-aminopyrrolidine was
used in a place of aqueous methylamine; 97% from 3a (two
steps). Spectral data for 3-chloro-2-nitroaniline intermedi-
ate: 1H NMR δ 8.25 (br d, 1H), 8.14 (d, 1H), 7.27-7.48 (m,
5H), 7.18 (d, 1H), 6.79 (dd, 1H), 4.33 (m, 1H), 3.72 (s, 2H),
2.30-2.92 (m, 6H); MS (EI) m/ z 331 (M).
5-(1H -Im id a zol-1-yl)-2-n it r o-N-(3-q u in u clid in yl)a n i-
lin e (4j): 2 equiv of 3-aminoquinuclidine dihydrochloride with
10 equiv of triethylamine was used in a place of aqueous
methylamine; 65% from 3a (two steps); 1H NMR δ 8.52 (br d,
1H), 8.48 (s, 1H), 8.21 (dd, 1H), 7.93 (t, 1H), 7.16 (t, 1H), 6.97-
7.09 (m, 2H), 4.02 (m, 1H), 3.41-3.56 (m, 2H), 2.41-2.77 (m,
4H), 1.96-2.06 (m, 1H), 1.44-2.06 (m, 4H); MS (EI) m/ z 313
(M).
N-(2-H yd r oxylet h yl)-5-(1H -im id a zol-1-yl)-2-n it r oa n i-
lin e (4k ): 2 equiv of ethanolamine was used in a place of
aqueous methylamine; 91% from 3a (two steps); 1H NMR δ
8.48 (s, 1H), 8.36 (br d, 1H), 8.18 (d, 1H), 7.93 (t, 1H), 7.16 (m,
2H), 7.00 (dd, 1H), 5.02 (t, 1H), 3.50-3.73 (m, 4H); MS (FAB)
m/ z 249 (M + 1).
N-Eth yl-5-(1H-im id a zol-1-yl)-2-n itr oa n ilin e (4b). To an
ice-cold solution of ethanol (10 mL) and aqueous ethylamine
(70%, 10 mL, excess equivalent) was added portionwise 2,4-
difluoronitrobenzene (3b) (3.00 g, 18.9 mmol). The reaction
mixture was stirred at same temperature for 30 min, allowed
to warm to room temperature, and then poured into water (100
mL). The resulting precipitate was collected and washed with
a small amount of chilled ethanol-water solution to give
N-ethyl-5-fluoro-2-nitroaniline (3.32 g, 96%). (Note: The
aniline was sublimed under reduced pressure.) This inter-
mediate (1.70 g, 9.23 mmol) was dissolved in a solution of
imidazole (6.28 g, 92.2 mmol) in DMF (20 mL). The mixture
was heated at 140 °C for 3 h and then poured into water (100
1-(Cycloh exylm eth yl)-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-
qu in oxa lin ed ion e h yd r och lor id e (5g‚HCl): 87% from 4g;
1
mp >300 °C (H2O-HCl); H NMR δ 12.34 (br s, 1H), 9.72 (s,
1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.75 (d, 1H), 7.57 (dd, 1H), 7.39
(d, 1H), 4.10 (d, 2H), 1.59-1.86 (m, 6H), 1.01-1.14 (m, 5H);
MS (FAB) m/ z 325 (M + 1).
1-[2-(Dim et h yla m in o)et h yl]-7-(1H -im id a zol-1-yl)-2,3-
(1H,4H)-qu in oxa lin ed ion e Dih yd r och lor id e (5h ‚2HCl):
86% from 4h ; mp 249-252 °C (H2O-HCl-iPrOH); 1H NMR δ
12.43 (s, 1H), 10.86 (br s, 1H), 10.04 (s, 1H), 8.48 (s, 1H), 8.05
(d, 1H), 7.94 (s, 1H), 7.67 (dd, 1H), 7.46 (d, 1H), 4.65 (t, 2H),
3.46 (s, 2H), 2.90 (s, 6H); MS (FAB) m/ z 300 (M + 1).
7-(1H-Im id a zol-1-yl)-1-(3-p yr r olid in yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e d ih yd r och lor id e (5i‚2HCl): 97% from 4i
(the deprotection of benzyl group occurred simultaneously in
1
the reduction step); H NMR δ 12.38 (br s, 1H), 9.95 (s, 1H),
8.43 (s, 1H), 7.92 (s, 1H), 7.37-7.69 (m, 3H), 5.71 (m, 1H), 4.55
(br m, 2H), 3.64 (br m, 4H); MS (FAB) m/ z 297 (M + 1).
7-(1H-Im idazol-1-yl)-1-(3-qu in u clidin yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e d ih yd r och lor id e (5j‚2HCl): 36% from 4j; 1H
NMR δ 12.23 (br s, 1H), 9.00 (s, 1H), 8.05 (s, 1H), 7.31-7.53
(m, 4H), 5.15-5.30 (m, 2H), 4.27-4.42 (m, 1H), 3.28-3.77 (s,
5H), 1.68-2.31 (s, 4H); MS (FAB) m/ z 338 (M + 1).
1-(2-Hydr oxyeth yl)-7-(1H-im idazol-1-yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e h yd r och lor id e (5k ‚HCl): 49% from 4k ; mp
>300 °C (H2O-HCl); 1H NMR δ 12.31 (br s, 1H), 9.87 (s, 1H),