6306 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Kemnitzer et al.
mmol) in ethanol (20 mL) was added piperidine (1.2 mL, 11
mmol). The mixture was stirred at room temperature over-
night and then the solvent was evaporated. The resulting solid
was collected by filtration and washed with diethyl ether.
Recrystallization of the black solid (1:1, DMSO:water) yielded
(1.5 g, 74%) of compound 1a as a light brown solid: mp 168-
171 °C; 1H NMR (DMSO-d6) 6.85 (s, 1H), 6.82 (s, 2H), 6.52 (d,
J ) 1.5, 1H), 6.49-6.45 (m, 1H), 6.29 (d, J ) 1.5, 1H), 6.21 (d,
J ) 2.7, 1H), 5.94 (d, J ) 6.3, 2H), 4.54 (s, 1H), 3.81 (s, 3H),
2.86 (s, 6H).
The following compounds were prepared from the corre-
sponding substituted benzaldehyde, 3-(dimethylamino)phenol,
and malononitrile by a procedure similar to that described for
the preparation of compound 1a.
8.7, 1H), 6.45-6.42 (m, 1H), 6.30 (d, J ) 2.7, 1H), 4.64 (s, 1H),
4.63 (s, 2H), 2.94 (s, 6H). Anal. (C17H16N4O) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-phenyl-4H-
chromene (3l). To a mixture of 3-dimethylaminophenol (0.129
g, 0.940 mmol), malononitrile (0.062 g, 0.94 mmol), and
benzaldehyde (96 µL, 0.94 mmol) in ethanol (5 mL) was added
piperidine (0.20 mL, 2.0 mmol). The white suspension was
stirred at room temperature for 2 h and the resulting precipi-
tate was collected by filtration, washed with methanol, and
then dried in vacuo to yield compound 3l as a white solid (0.202
g, 74%): mp 206-207 °C; 1H NMR (DMSO-d6) 7.32-7.27 (m,
2H), 7.22-7.14 (m, 3H), 6.82 (s, 2H), 6.78 (d, J ) 8.7, 1H),
6.45 (dd, J ) 8.7 and 2.4, 1H), 6.23 (d, J ) 2.4, 1H), 4.59 (s,
1H), 2.86 (s, 6H). Anal. (C18H17N3O) C, H, N.
The following compounds were prepared from the corre-
sponding substituted benzaldehyde, 3-(dimethylamino)phenol,
and malononitrile by a procedure similar to that described for
the preparation of compound 3l.
2-Amino-3-cyano-7-(dimethylamino)-4-(3,4,5-trimethoxy-
phenyl)-4H-chromene (1b): white solid (78%); mp 179-181
°C; 1H NMR (DMSO-d6) 6.90-6.84 (m, 3H), 6.48-6.46 (m, 3H),
6.23 (s, 1H), 4.57 (s, 1H), 3.72 (s, 6H), 3.62 (s, 3H), 2.87 (s,
6H). Anal. (C21H23N3O4) C, H. N.
2-Amino-3-cyano-7-(dimethylamino)-4-(3-iodo-4,5-
dimethoxyphenyl)-4H-chromene (1e): white solid (18%);
mp 176-177 °C; 1H NMR (DMSO-d6) 7.02 (d, J ) 1.8, 1H),
6.96 (s, 1H), 6.88 (s, 2H), 6.86 (d, J ) 8.7, 1H), 6.49-6.46 (m,
1H), 6.22 (d, J ) 2.4, 1H), 4.59 (s, 1H), 3.78 (s, 3H), 3.66 (s,
3H), 2.87 (s, 6H). Anal. (C20H20IN3O3) C, H, N.
2-Amino-4-(3-bromo-4,5-methylenedioxyphenyl)-3-cy-
ano-7-(dimethylamino)-4H-chromene (1f): brown solid
(56%); mp 232-234 °C (dec); 1H NMR (DMSO-d6) 6.87 (s, 2H),
6.84-6.80 (m, 2H), 6.67 (d, J ) 1.2, 1H), 6.50-6.46 (m, 1H),
6.22 (d, J ) 2.4, 1H), 6.08 (d, J ) 6.9, 2H), 4.58 (s, 1H), 2.87
(s, 6H). Anal. (C19H16BrN3O3) C, H, N.
2-Amino-3-cyano-4-(3,5-dimethoxyphenyl)-7-(dimethyl-
amino)-4H-chromene (2a): white solid (38%); mp 169-170
°C; 1H NMR (DMSO-d6) 6.85 (d, J ) 8.7, 1H), 6.81 (s, 2H),
6.46 (dd, J ) 8.7 and 2.7, 1H), 6.36-6.34 (m, 1H), 6.31 (d, J )
2.1, 2H), 6.22 (d, J ) 2.4, 1H), 4.52 (s, 1H), 3.70 (s, 6H), 2.86
(s, 6H). Anal. (C20H21N3O3) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(3-methylphe-
nyl)-4H-chromene (3f): white solid (24%); mp 174-175 °C;
1H NMR (DMSO-d6) 7.18 (t, J ) 7.5, 1H), 7.00 (d, J ) 7.2,
1H), 6.95 (d, J ) 2.1, 2H), 6.80 (s, 2H), 6.78 (d, J ) 8.7, 1H),
6.46-6.43 (m, 1H), 6.22 (d, J ) 2.4, 1H), 4.54 (s, 1H), 2.86 (s,
6H), 2.26 (s, 3H). Anal. (C19H19N3O) C, H, N.
2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-
(dimethylamino)-4H-chromene (1c): white solid (24%);
1
recrystallized from 5:1, hexanes:EtOAc; mp 200-202 °C; H
NMR (CDCl3) 6.89 (d, J ) 1.8, 1H), 6.79 (d, J ) 8.7, 1H), 6.72
(d, J ) 1.8, 1H), 6.46-6.43 (m, 1H), 6.28 (d, J ) 2.7, 1H), 4.58
(s, 1H), 4.57 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.94 (s, 6H).
Anal. (C20H20BrN3O3) C, H, N.
2-Amino-4-(3-chloro-4,5-dimethoxyphenyl)-3-cyano-7-
(dimethylamino)-4H-chromene (1d): tan solid (57%); re-
crystallized from 5:1, hexanes:EtOAc; mp 190-192 °C; 1H
NMR (CDCl3) 6.82-6.69 (m, 3H), 6.48-6.44 (m, 1H), 6.30 (d,
J ) 2.7, 1H), 4.59 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 2.85 (s,
6H). Anal. (C20H20ClN3O3) C, H, N.
2-Amino-4-(3-bromo-5-methoxyphenyl)-3-cyano-7-(di-
methylamino)-4H-chromene (2b): white solid (50%); re-
crystallized from 5:1, hexanes:EtOAc; mp 210-212 °C; 1H
NMR (DMSO-d6) 6.99 (s, 1H), 6.91 (s, 2H), 6.85 (s, 1H), 6.84
(d, J ) 8.7, 1H), 6.77 (s, 1H), 6.49-6.46 (m, 1H), 6.24 (d, J )
3.0, 1H), 4.61 (s, 1H), 3.75 (s, 3H), 2.87 (s, 6H). Anal. (C19H18-
BrN3O2) C, H, N.
2-Amino-3-cyano-4-(3,5-dichlorophenyl)-7-(dimethyl-
amino)-4H-chromene (2c): yellow solid (24%); recrystallized
from 1:1, hexanes:dichloromethane; mp 212-214 °C; 1H NMR
(DMSO-d6) 7.47 (t, J ) 1.8, 1H), 7.20 (d, J ) 2.1, 2H), 6.98 (s,
2H), 6.83 (d, J ) 8.7, 1H), 6.49 (dd, J ) 8.9 and 2.6, 1H), 6.24
(d, J ) 2.4, 1H), 4.73 (s, 1H), 2.88 (s, 6H). Anal. (C18H15Cl2N3O)
C, H, N.
2-Amino-3-cyano-4-(3,4-dimethoxyphenyl)-7-(dimethyl-
amino)-4H-chromene (2d): white solid (23%); recrystallized
1
from 5:1, hexanes:EtOAc; mp 158-160 °C; H NMR (CDCl3)
6.81 (s, 1H), 6.79 (s, 1H), 6.75 (d, J ) 1.8, 1H), 6.69 (d, J )
1.8, 1H), 6.45-6.41 (m, 1H), 6.29 (d, J ) 3.0, 1H), 4.60 (s, 1H),
4.54 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.93 (s, 6H). Anal.
(C20H21N3O3*0.6H2O) C, H, N.
2-Amino-4-(3-benzyloxyphenyl)-3-cyano-7-(dimethyl-
amino)-4H-chromene (3j): white solid (76%); mp 197-198
1
2-Amino-4-(3-carboxyphenyl)-3-cyano-7-(dimethylami-
no)-4H-chromene (3h): yellow solid (80%); recrystallized
from 1:1:0.1, hexanes:EtOAc:MeOH; mp 204-206 °C; 1H NMR
(DMSO-d6) 7.72-7.68 (m, 1H), 7.64 (s, 1H), 7.29-7.25 (m, 2H),
6.84 (s, 2H), 6.76 (d, J ) 9.0, 1H), 6.45 (dd, J ) 8.9 and 2.6,
1H), 6.23 (d, J ) 2.7, 1H), 4.62 (s, 1H), 2.86 (s, 6H). Anal.
(C19H17N3O3) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(3-pyridyl)-4H-
chromene (4a): brown solid (93%); recrystallized from
1:1:0.1, hexanes:EtOAc:MeOH; mp 210-214 °C (dec); 1H NMR
(CDCl3) 8.49-8.47 (m, 2H), 7.52-7.49 (m, 1H), 7.26-7.22
(m, 1H), 6.75 (d, J ) 8.7, 1H), 6.45-6.41 (m, 1H), 6.30 (d, J )
2.4, 1H), 4.69 (s, 1H), 4.62 (s, 2H), 2.93 (s, 6H). Anal.
(C17H16N4O*0.3H2O) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(2-pyridyl)-4H-
chromene (4b): brown solid (35%); recrystallized from 1:1,
hexanes:dichloromethane; mp 206-208 °C; 1H NMR (DMSO-
d6) 8.46 (dd, J ) 5.7 and 1.8, 1H), 7.73 (td, J ) 7.7 and 1.8,
1H), 7.23-7.20 (m, 2H), 6.88 (s, 2H), 6.85 (d, J ) 9.0, 1H),
6.44 (dd, J ) 8.9 and 2.6, 1H), 6.23 (d, J ) 3.0, 1H), 4.70 (s,
1H), 2.85 (s, 6H). Anal. (C17H16N4O) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(4-pyridinyl)-
4H-chromene (4c): brown solid (47%); recrystallized from
1:1, hexanes:dichloromethane; mp 202-204 °C; 1H NMR
(CDCl3) 8.54-8.52 (m, 2H), 7.13-7.11 (m, 2H), 6.75 (d, J )
°C; H NMR (DMSO-d6) 7.46-7.33 (m, 5H), 7.22 (t, J ) 7.8,
1H), 6.87-6.79 (m, 5H), 6.75 (d, J ) 7.2, 1H), 6.45 (dd, J )
8.9 and 2.6, 1H), 6.22 (d, J ) 2.1, 1H), 5.04 (s, 2H), 4.56 (s,
1H), 2.86 (s, 6H). Anal. (C25H23N3O2) C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(3-dodecyloxy-
phenyl)-4H-chromene (3k): white solid (54%); mp 94 °C;
1H NMR (DMSO-d6) 7.19 (t, J ) 7.8, 1H), 6.83-6.69 (m, 6H),
6.45 (dd, J ) 8.6 and 2.6, 1H), 6.22 (d, J ) 2.7, 1H), 4.55 (s,
1H), 3.90 (t, J ) 6.3, 2H), 2.86 (s, 6H), 1.70-1.65 (m, 2H),
1.38-1.24 (m, 18H), 0.85 (t, J ) 6.6, 3H). Anal. (C30H41N3O2)
C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(4-methoxyphe-
nyl)-4H-chromene (3m): yellow solid (80%); mp 174-176 °C;
1H NMR (CDCl3) 7.12-7.10 (m, 2H), 6.85-6.76 (m, 3H), 6.42
(dd, J ) 8.4 and 2.4, 1H), 6.28 (d, J ) 2.4, 1H), 4.60 (s, 1H),
4.51 (br s, 2H), 3.77 (s, 3H), 2.92 (s, 6H). Anal. (C19H19N3O2)
C, H, N.
2-Amino-3-cyano-7-(dimethylamino)-4-(2-methoxyphe-
nyl)-4H-chromene (3n): yellow solid (30%); mp 152-153 °C
1
(dec); H NMR (CDCl3) 7.20-7.14 (m, 1H), 7.00 (dd, J ) 7.5
and 1.8, 1H), 6.91-6.84 (m, 3H), 6.41 (dd, J ) 8.7 and 2.7,
1H), 6.28 (d, J ) 2.4, 1 H), 5.17 (s, 1H), 4.50 (br s, 2H), 3.85
(s, 3H), 2.91(s, 6H). Anal. (C19H19N3O2) C, H, N.
2-Amino-4-(5-bromo-3-pyridyl)-3-cyano-7-(dimethylami-
no)-4H-chromene (4d): brown solid (8%); mp 230-232 °C