Journal of Medicinal Chemistry
ARTICLE
(
E)-2-(4-(2-Fluorostyryl)phenyl)-1-methyl-1H-imidazole
(E)-4-(2,6-Difluorostyryl)-N,N-dimethylaniline (4r). Procedure
1
(
4l). Procedure B was used. Yield 47%. Colorless crystals from hexane.
B was used. Yield 94%. Colorless crystals from hexane. Mp 112-113 °C. H
1
Mp 60-61 °C. H NMR: δ 7.82-7.78 (m, 1H), 7.65 (d, 1H, J =
6.0 Hz), 7.35-7.29 (m, 1H), 7.26 (d, 1H, J = 16.0 Hz), 7.22-7.13
m, 2H), 7.08 (d, 1H, J = 1.2 Hz), 6.96 (d, 1H, J = 0.8 Hz), 3.81 (s, 3H).
C NMR: δ 160.65 (d, J = 246.7 Hz), 145.39, 129.53 (d, J = 8.3 Hz),
28.89, 127.66 (d, J = 3.0 Hz), 124.98 (d, J = 11.4 Hz), 124.71 (d, J =
.8 Hz), 122.73 (d, J = 3.8 Hz), 122.18, 116.99 (d, J = 5.3 Hz), 115.83
NMR: δ 7.45 (d, 2H, J = 8.4 Hz), 7.35 (d, 1H, J = 16.8 Hz), 7.27-7.20 (m,
1H), 7.01 (dd, 2H, J = 8.4 and 8.8 Hz), 6.91 (1H, d, J = 16.8 Hz), 6.75 (d,
1
13
(
2H, J = 9.2 Hz), 2.98 (s, 6H). C NMR: δ 160.86 (d, J = 247.4 Hz), 160.78
(d, J = 248.3 Hz), 151.10, 135.99 (t, J = 8.3 Hz), 127.97, 127.57 (t, J = 11.3
Hz), 125.41, 115.50 (t, J = 16.0 Hz), 112.40, 111.82 (d, J = 19.0 Hz), 111.76
(d, J = 19.0 Hz), 109.73, 39.65. MS: m/z (%) 259 (100), 258 (71), 243
1
3
1
3
(
(
d, J = 22.0 Hz), 32.04. MS: m/z (%) 202 (17), 201 (59), 186 (20), 183
2
100), 168 (25), 146 (16), 128 (17). Anal. Calcd for C12 11FN :
(25), 195 (11). Anal. Calcd for C16
74.08; H, 5.79.
H F N: C, 74.11; H, 5.83. Found: C,
15 2
H
C, 71.27; H, 5.48. Found: C, 71.24; H, 5.61.
E)-4-(2,3-Difluorostyryl)-N,N-dimethylaniline (4m). Procedure
(E)-4-(2,6-Difluorostyryl)-N,N-diethylaniline (4s). Procedure
B was used. Yield 57%. Yellow crystals from hexane. Mp 70-71 °C.
(
1
1
A was used. Yield 88%. Yellow crystals. Mp 132-133 °C. H NMR: δ
.50-7.47 (m, 1H), 7.45 (d, 2H, J = 9.2 Hz), 7.24 (d, 1H, J = 16.4
Hz), 7.16-7.06 (m, 2H), 7.03 (d, 1H, J = 16.4 Hz), 6.73 (d, 2H, J =
H NMR: δ 7.43 (d, 2H, J = 8.4 Hz), 7.34 (d, 1H, J = 16.8 Hz),
7
7.27-7.20 (m, 1H), 7.01 (dd, 2H, J = 8.4 Hz), 6.89 (d, 1H, J = 16.8
Hz), 6.72 (d, 2H, J = 8.8 Hz), 3.43 (q, 4H, J = 7.2 Hz), 1.16 (t, 6H, J =
1
3
13
8
(
1
(
3
(
.8 Hz), 2.96 (s, 6H). C NMR: δ 151.01 (dd, J = 243.6 Hz), 147.87
dd, J = 246.3 Hz), 133.18 (d, J = 5.3 Hz), 128.69 (d, J = 9.1 Hz),
28.19, 124.95, 124.57 (d, J = 7.6 Hz), 124.53 (d, J = 7.6 Hz), 121.78
t, J = 3.0 Hz), 114.65 (d, J = 17.4 Hz), 114.24 (t, J = 3.8 Hz), 112.37,
9.64. MS: m/z (%) 259 (100), 258 (78), 243 (25), 214 (16), 195
16). Anal. Calcd for C16 N: C, 74.11; H, 5.83. Found: C, 74.01;
7.2 Hz). C NMR: δ 160.83 (d, J = 246.7 Hz), 160.75 (d, J = 247.4
Hz), 148.30, 136.07 (t, J = 8.3 Hz), 128.29, 127.37 (t, J = 10.6 Hz),
124.45, 115.62 (t, J = 16.0 Hz), 111.81 (d, J = 19.0 Hz), 111.74 (d, J =
19.8 Hz), 111.73, 109.07, 44.20, 12.20. MS: m/z (%) 287 (44), 272
(100), 244 (21), 243 (15). Anal. Calcd for C18
6.66. Found: C, 75.12; H, 6.79.
19 2
H F N: C, 75.24; H,
15 2
H F
H, 5.71.
(E)-4-(3,4-Difluorostyryl)-N,N-dimethylaniline (4t). Procedure
A was used. Yield 59%. Yellow crystals from hexane. Mp 159-160 °C.
(
E)-4-(2,4-Difluorostyryl)-N,N-dimethylaniline (4n). Procedure
1
B was used. Yield 58%. Yellow crystals from acetonitrile. Mp
H NMR: δ 7.50-7.44 (m, 1H), 7.41 (d, 2H, J = 8.8 Hz), 7.32-7.28
1
1
39-140 °C. H NMR: δ 7.77-7.71 (m, 1H), 7.44 (d, 2H, J = 8.4
(m, 1H), 7.27-7.20 (m, 1H), 7.11 (d, 1H, J = 16.0 Hz), 6.92 (d, 1H,
1
3
Hz), 7.17 (d, 1H, J = 16.4 Hz), 7.01 (d, 1H, J = 16.4 Hz), 7.02-6.97
J = 16.4 Hz), 6.71 (d, 2H, J = 8.8 Hz), 2.95 (s, 6H). C NMR: δ
150.82, 150.56 (dd, J = 243.9 Hz), 150.50, 148.98 (dd, J = 244.3 Hz),
136.59, 130.55 (d, J = 3.0 Hz), 127.91, 125.16, 122.71 (d, J = 6.1 Hz),
122.68 (d, J = 6.1 Hz), 121.68 (d, J = 2.3 Hz), 117.49 (d, J = 17.4 Hz),
113.96 (d, J = 17.5 Hz), 112.43, 39.68. MS: m/z (%) 259 (100), 258
1
3
(
(
m, 2H), 6.75 (d, 2H, J = 9.2 Hz), 2.98 (s, 6H). C NMR: δ 161.64
dd, J = 245.2 Hz), 159.99 (dd, J = 248.9 Hz, 248.2 Hz), 150.87,
1
1
2
31.54 (dd, J = 4.5 Hz), 127.89, 125.34, 122.84 (dd, J = 12.1 Hz),
14.56 (t, J = 1.6 Hz), 112.43, 111.73 (dd, J = 21.3 Hz), 103.85 (t, J =
6.5 Hz, J = 25.8 Hz), 39.68. MS: m/z (%) 259 (100), 258 (71), 243
(82), 243 (36), 215 (22), 195 (16). Anal. Calcd for C16
74.11; H, 5.83. Found: C, 74.24; H, 5.79.
H F N: C,
15 2
(
30), 215 (15), 195 (14). Anal. Calcd for C H F N: C, 74.11; H,
16 15 2
5
.83. Found: C, 74.25; H, 5.77.
E)-4-(2,5-Difluorostyryl)-N,N-dimethylaniline (4o). Procedure
(E)-4-(3,5-Difluorostyryl)-N,N-dimethylaniline (4u). Procedure
36
(
A was used. Yield 51%. Yellow crystals. Mp 136-137 °C (lit. 139-
1
A was used. Yield 77%. Yellow crystals. Mp 146-147 °C. H NMR: δ
.51-7.46 (m, 3H), 7.28 (d, 1H, J = 16.4 Hz), 7.18-7.12 (m, 1H), 7.03
d, 1H, J = 16.4 Hz), 7.00-6.95 (m, 1H), 6.76 (d, 2H, J = 8.8 Hz), 2.99
15 2
141 °C). Anal. Calcd for C16H F N: C, 74.11; H, 5.83. Found: C, 74.38; H,
7
5.70.
(
(
(E)-N,N-Dimethyl-4-(2,3,6-trifluorostyryl)aniline (4v). Procedure
13
1
s, 6H). C NMR: δ 159.28 (dd, J = 236.0 Hz), 156.22 (dd, J = 241.4
B was used. Yield 45%. Light yellow crystals from hexane. Mp 91-92 °C. H
Hz), 151.09, 133.04 (d, J = 3.8 Hz), 128.21, 124.94, 117.01 (d, J = 25.8
Hz), 116.92 (d, J = 25.1 Hz), 114.12 (d, J = 25.1 Hz), 114.03 (d, J = 24.3
Hz), 112.37, 112.12 (d, J = 4.5 Hz), 39.64. MS: m/z (%) 259 (100), 258
NMR: δ 7.48 (d, 2H, J = 9.2 Hz), 7.39 (d, 1H, J = 16.8 Hz), 7.22-7.14 (m,
1H), 7.06-7.00 (m, 1H), 6.89 (d, 1H, J = 16.8 Hz), 6.76 (d, 2H, J = 8.0 Hz),
13
3.00 (s, 6H). C NMR: δ 157.35-154.83 (m, 1C), 151.31, 149.49-146.37
(m, 2C), 137.17 (t, J = 8.4 Hz), 128.23, 124.89, 117.43 (dd, J = 17.4 Hz, J =
16.7 Hz), 114.01 (dd, J = 18.9 Hz, J = 19.8 Hz), 112.33, 111.39-111.02 (m,
1C), 108.99, 39.59. MS: m/z (%) 277 (100), 276 (83), 261 (24), 214 (16),
213 (12). Anal. Calcd for C H F N: C, 69.30; H, 5.09. Found: C, 69.50; H,
(
84), 243 (29), 215 (18), 195 (17). Anal. Calcd for C H F N: C,
16 15 2
74.11; H, 5.83. Found: C, 74.63; H, 5.90.
(
E)-2-(2,6-Difluorostyryl)-N,N-dimethylaniline (4p). Procedure
1
B was used. Yield 92%. Yellow oil. H NMR: δ 7.78 (d, 1H, J = 16.8 Hz),
.65 (dd, 1H, J = 1.6 Hz), 7.36-7.26 (m, 2H), 7.12-7.03 (m, 4H), 7.09
d, 1H, J = 17.2 Hz), 2.74 (s, 6H). C NMR: δ 161.10 (d, J = 248.2 Hz),
16 14 3
7
(
4.97.
13
(E)-N,N-Dimethyl-4-(2,4,6-trifluorostyryl)aniline (4w). Pro-
1
1
1
61.02 (d, J = 248.2 Hz), 152.77, 133.80 (t, J = 8.3 Hz, J = 7.6 Hz),
31.25, 129.19, 128.59 (t, J = 11.4 Hz, J = 10.6 Hz), 126.72, 122.65,
18.46, 115.31 (t, J = 15.2 Hz, J = 15.9 Hz), 113.84, 111.95 (d, J = 19.7
cedure B was used. Yield 63%. Light yellow crystals from hexane. Mp
1
127-128 °C. H NMR: δ 7.45 (d, 2H, J = 8.8 Hz), 7.29 (d, 1H, J =
16.8 Hz), 6.91 (t, 2H, J = 9.2 Hz, J = 8.8 Hz), 6.83 (d, 1H, J = 16.8
1
3
Hz), 111.89 (d, J = 19.0 Hz), 44.31. MS: m/z (%) 259 (100), 258 (14),
Hz), 6.75 (d, 2H, J = 8.8 Hz), 2.99 (s, 6H). C NMR: δ 160.87 (dd,
J = 249.1 Hz, J = 248.9 Hz), 160.72 (dd, J = 249.0 Hz), 151.09, 135.59
(t, J = 7.7 Hz, J = 8.3 Hz), 127.94, 125.24, 112.38, 108.80, 100.65 (dd,
J = 25.8 Hz), 39.64. MS: m/z (%) 277 (100), 276 (75), 261 (29).
Anal. Calcd for C H F N: C, 69.30; H, 5.09. Found: C, 69.49; H,
132 (8). Anal. Calcd for C H F N: C, 74.11; H, 5.83. Found: C, 74.38;
16 15 2
H, 5.79.
(
E)-3-(2,6-Difluorostyryl)-N,N-dimethylaniline (4q). Procedure
1
B was used. Yield 53%. Colorless crystals from hexane. Mp 69-71 °C. H
NMR: δ 7.38 (d, 1H, J = 16.8 Hz), 7.33-7.26 (m, 1H), 7.19 (t, 1H, J = 8.4
Hz, J = 8.0 Hz), 7.11 (d, 1H, J = 17.2 Hz), 7.03 (dd, 2H, J = 8.4 and 8.8 Hz),
1
6
14 3
4.99.
4-(2,6-Difluorophenethyl)-N,N-dimethylaniline (5r). To 150 mg
(0.58 mmol) of 4r in 10 mL of THF was added 50 mg of 10% Pd-C.
The mixture was hydrogenated at 40 psi on a Parr shaker for 5 h. The mix-
ture was filtered through Celite and chromatographed using 1:10 EtOAc/
hexane to afford 110 mg (76%) of 5r: colorless crystals from hexane. Mp
13
6.93-6.91 (m, 2H), 6.72-6.69 (m, 1H), 2.96 (s, 6H). C NMR: δ 161.06
(d, J = 248.2 Hz), 160.98 (d, J = 248.2 Hz), 151.38, 138.03, 136.83 (t, J = 7.6
Hz, J = 8.3 Hz), 129.46, 128.70 (t, J = 10.6 Hz, J = 11.4 Hz), 114.87 (t, J = 16
Hz), 114.81, 114.09, 112.98, 111.94 (d, J= 19.7 Hz), 111.88 (d, J= 19.0 Hz),
1
111.21, 39.93. MS: m/z (%) 259 (100), 258 (52), 239 (31), 238 (33), 223
42-43 °C. H NMR: δ 7.31-7.23 (m, 1H), 7.02 (d, 2H, J = 8.4 Hz), 6.94
(16), 222 (37). Anal. Calcd for C H F N: C, 74.11; H, 5.83. Found: C,
(t, 2H, J = 8.4 Hz, J = 8.0 Hz), 6.66 (d, 2H, J = 8.4 Hz), 2.90-2.89 (m, 2H),
16 15 2
13
74.30; H, 5.78.
2.85 (s, 6H), 2.77-2.73 (m, 2H). C NMR: δ 161.72 (d, J = 243.7 Hz),
1
295
dx.doi.org/10.1021/jm101248v |J. Med. Chem. 2011, 54, 1288–1297