Journal of Medicinal Chemistry
ARTICLE
J = 9.6, 3.2 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H). MS
(ESI) m/z: 417.9 [M + H]+.
3,5-Dichloro-2-hydroxy-N-(4-(naphthalen-2-yloxy)phenyl)benzamide
3,5-Dichloro-N-(2-chlorophenyl)-2-hydroxybenzamide (8b). Yield
1
2
60%; Rf = 0.75 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ 12.82 (br
s, 1H), 10.92 (s, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H),
7.82 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H),
7.33 (t, J = 7.6 Hz, 1H). MS (ESI) m/z: 314.2 [M ꢀ H]ꢀ.
1
2
(6h). Yield 47%; Rf = 0.60 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ
12.82 (br s, 1H), 10.74 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.98 (d, J =
8.9 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.82
(d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.47 (m, 2H), 7.39 (d, J = 2.2
Hz, 1H), 7.32 (dd, J = 8.9, 2.3 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H). MS
(ESI) m/z: 422.4 [M ꢀ H]ꢀ.
3,5-Dichloro-N-(3-chlorophenyl)-2-hydroxybenzamide (8c). Yield
1
2
62%; Rf = 0.70 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ 12.39
(br s, 1H), 10.74 (s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 7.87 (t, J = 2.0 Hz,
1H), 7.82 (d, J = 2.5 Hz, 1H), 7.63 (ddd, J = 8.2, 1.9, 0.9 Hz, 1H), 7.44 (t,
J = 8.1 Hz, 1H), 7.26 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H). MS (ESI) m/z: 314.2
[M ꢀ H]ꢀ.
3,5-Dichloro-N-(3-fluoro-4-(naphthalen-2-yloxy)phenyl)-2-hydro-
1
2
xybenzamide (6i). Yield 57%; Rf = 0.72 (CH Cl2); H NMR (300 MHz,
DMSO-d6) δ 12.45 (br s, 1H), 10.92 (s, 1H), 8.05 (d, J = 0.9 Hz, 1H),
7.98 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H),
7.82 (d, J = 4.5 Hz, 1H), 7.55 (dd, J = 9.3, 1.7 Hz, 1H), 7.46 (m, 2H), 7.36
(dd, J = 2.5, 1.2 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 1.0 Hz,
1H). MS (ESI) m/z: 440.3 [M ꢀ H]ꢀ.
3,5-Dichloro-N-(4-chlorophenyl)-2-hydroxybenzamide (8d). Yield
1
2
73%; Rf = 0.70 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ 12.53
(s, 1H), 10.72 (s, 1H), 8.11 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H),
7.73 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.9 Hz, 2H). MS (ESI) m/z: 314.2
[M ꢀ H]ꢀ.
3,5-Dichloro-2-hydroxy-N-o-tolylbenzamide (8e). Yield 57%; Rf =
3,5-Dichloro-2-hydroxy-N-(4-(naphthalen-2-yloxy)-3-(trifluoromethyl)
1
1
2
0.69 (CH2Cl2); H NMR (300 MHz, DMSO-d6) δ 13.10 (br s, 1H),
phenyl)benzamide (6j). Yield 63%; Rf = 0.67 (CH Cl2); H NMR (300
MHz, DMSO-d6) δ12.40 (br s, 1H), 10.90 (s, 1H), 8.22 (d, J=2.2Hz, 1H),
8.08 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.97 (dd, J = 2.3, 9.1 Hz,
1H), 7.95 (d, J = 7.1 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 2.4 Hz,
1H), 7.50 (td, J = 13.0, 6.0 Hz, 2H), 7.47 (d, J = 1.5 Hz, 1H), 7.33 (dd, J =
8.9, 2.5 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H). MS (ESI) m/z: 490.3 [M ꢀ H]ꢀ.
3,5-Dichloro-2-hydroxy-N-(3-methyl-4-(naphthalen-2-yloxy)phenyl)
10.57 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.38 (d,
J = 6.6 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H), 7.25 (m, 2H), 2.24 (s, 3H). MS
(ESI) m/z: 294.3 [M ꢀ H]ꢀ.
3,5-Dichloro-2-hydroxy-N-m-tolylbenzamide (8f). Yield 71%; Rf =
1
0.74 (CH2Cl2); H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H),
10.59 (s, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.53 (s,
1H), 7.49 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.1 Hz,
1H), 2.33 (s, 3H). MS (ESI) m/z: 294.2 [M ꢀ H]ꢀ.
1
2
benzamide (6k). Yield 64%; Rf = 0.64 (CH Cl2); H NMR (300 MHz,
DMSO-d6) δ 12.80 (br s, 1H), 10.70 (s, 1H), 8.14 (d, J = 1.9 Hz, 1H),
7.96 (d, J = 9.1 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H),
7.78 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.8, 2.3 Hz,
1H), 7.44 (dt, J = 15.9, 6.9 Hz, 2H), 7.29 (dd, J = 8.9, 2.4 Hz, 1H), 7.15
(d, J = 1.7 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 2.22 (s, 3H). MS (ESI) m/z:
436.2 [M ꢀ H]ꢀ.
3,5-Dichloro-2-hydroxy-N-p-tolylbenzamide (8g). Yield 66%; Rf =
1
0.69 (CH2Cl2); H NMR (300 MHz, DMSO-d6) δ 12.88 (br s, 1H),
10.56 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.38 (d,
J = 6.6 Hz, 1H), 7.31 (d, J = 2.9 Hz, 1H), 7.25 (dd, J = 6.4, 3.4 Hz, 2H),
2.24 (s, 3H). MS (ESI) m/z: 294.3 [M ꢀ 1]ꢀ.
3,5-Dichloro-2-hydroxy-N-benzamide (8h). Yield 66%; Rf = 0.69
(CH2Cl2); 1H NMR (300 MHz, DMSO-d6) δ 12.78 (br s, 1H), 10.70
(s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.68 (d, J =
8.4 Hz, 2H), 7.41 (t, J = 7.8 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H). MS (ESI)
m/z: 280.2 [M ꢀ 1]ꢀ.
3,5-Dichloro-N-(3-chloro-4-(p-tolyloxy)phenyl)-2-hydroxybenzamide
1
2
(6l). Yield 51%; Rf = 0.71 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ
12.53 (br s, 1H), 10.69 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 2.6
Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.62 (dd, J = 8.9, 2.6 Hz, 1H), 7.18 (d,
J = 8.5 Hz, 2H), 7.08 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 2.27
(s, 3H). MS (ESI) m/z: 422.1 [M + H]+.
2,4-Dichloro-6-((3-chloro-4-(naphthalen-2-yloxy)phenylimino)methyl)
phenol (9). To a stirred solution of 100 mg (0.37 mmol) of 3a in 10 mL
of ethanol was added 140 mg (0.74 mmol, 2 equiv) of 3,5-dichlorohy-
droxybenzaldehyde dissolved in 2 mL of methanol, and the reaction
mixture was left stirring until a bright orange precipitate formed. The
reaction was monitored by TLC (CH2Cl2), and once completed, the
mixture was chilled to 4 °C. The precipitate was filtered and washed
twice with 10 mL of ethanol to obtain 9 as an orange solid. Yield 90%;
3,5-Dichloro-N-(3-chloro-4-phenoxyphenyl)-2-hydroxybenzamide
1
2
(6m). Yield 54%; Rf = 0.56 (CH Cl2); H NMR (300 MHz, DMSO-d6)
δ 12.42 (br s, 1H), 10.79 (s, 1H), 8.06 (d, J = 2.9 Hz, 1H), 8.02 (d, J = 2.8
Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.65 (dd, J = 8.9, 2.8 Hz, 1H), 7.39 (t,
J = 7.7 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.0 Hz, 1H), 6.96 (d,
J = 8.1 Hz, 2H). MS (ESI) m/z: 408.2 [M ꢀ H]ꢀ.
3,5-Dichloro-2-hydroxybenzamide (7). To a stirred solution of
ammonium hydroxide (2 mmol, 5 equiv) in 5 mL of CH2Cl2 was added
salicylic acid chloride (0.4 mmol, 1 equiv), and the reaction mixture was
stirred at room temperature for 30 min. The reaction was monitored by
TLC (CH2Cl2), and once completed, the mixture was concentrated in
vacuo and purified by column chromatography (CH2Cl2) to obtain 7 as
1
2
Rf = 0.83 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ 13.98 (s, 1H),
9.09 (s, 1H), 8.01 (d, J = 9.7 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.90 (d, J =
2.5 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.74 (d, J =
2.6 Hz, 1H), 7.55 (dd, J = 8.7, 2.5 Hz, 1H), 7.48 (m, 2H), 7.36
(dd, J = 6.6, 2.8 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.31 (d, J =
8.7 Hz, 1H). MS (ESI) m/z: 440.3 [M ꢀ H]ꢀ.
1
3
a white solid. Yield 23%; Rf = 0.60 (10% MeOH/CHCl ); H NMR (300
MHz, DMSO-d6) δ 14.15 (s, 1H), 8.70 (s, 1H), 8.33 (s, 1H), 8.00 (d, J =
1.4 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H). MS (ESI) m/z: 204.1 [M ꢀ H]ꢀ.
General Procedure for the Synthesis of Compounds
8aꢀh. To a stirred solution of selected anilines (0.3 mmol) in 5 mL
of CH2Cl2 was added salicylic acid chloride (0.3 mmol, 1 equiv), and the
reaction mixture was stirred at room temperature for 30 min. The
reaction was monitored by TLC (CH2Cl2), and once completed, the
mixture was concentrated in vacuo and purified by column chromatog-
raphy (CH2Cl2) to obtain compounds 8aꢀh as off-white solids.
3,5-Dichloro-N-(3-chloro-4-hydroxyphenyl)-2-hydroxybenzamide
2,4-Dichloro-6-((3-chloro-4-(naphthalen-2-yloxy)phenylamino)methyl)
phenol (10). To a stirred solution of 50 mg (0.113 mmol) of 9 in 5 mL
of methanol was added 113 μL of 5 M sodium cyanoborohydride
(0.565 mmol, 5 equiv), and the mixture was left stirring for 24 h at 70 °C.
The reaction was monitored by TLC (CH2Cl2), and once completed,
routine aqueous workup was performed. The organic phase was con-
centrated and purified by column chromatography (CH2Cl2) to obtain
1
2
10 as an orange solid. Yield 40%; Rf = 0.76 (CH Cl2); H NMR (300
MHz, DMSO-d6) δ 9.78 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 8.0
Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.41 (m, 2H),
7.25 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 6.3, 2.6 Hz, 1H), 7.07 (d, J = 8.6 Hz,
1H), 7.02 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 8.9,
2.7 Hz, 1H), 6.49 (t, J = 5.8 Hz, 1H), 4.29 (d, J = 5.6 Hz, 2H). MS (ESI)
m/z: 442.1 [M ꢀ H]ꢀ.
1
2
(8a). Yield 58%; Rf = 0.13 (CH Cl2); H NMR (300 MHz, DMSO-d6) δ
12.91 (br s, 1H), 10.59 (s, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.81 (d, J = 2.4
Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.8, 2.5 Hz, 1H), 7.01 (d,
J = 8.8 Hz, 1H), 4.11 (s, 1H). MS (ESI): m/z 330.3 [M ꢀ H]ꢀ.
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dx.doi.org/10.1021/jm200325s |J. Med. Chem. 2011, 54, 5403–5413