2-Bromo-3-hydroxy-4-methoxy-N-methylbenzamide (6a). To a suspension of 5 (3.71 g, 15 mmol) in CH Cl
2
2
(50 mL) was added thionyl chloride (4.37 mL, 60 mmol) and a catalytic amount of DMF. The mixture was stirred at room
temperature for 2 h. The solvent was removed by evaporation in vacuo to give 3.98 g (100%) of the acid chloride of 5. To a
solution of 30% aqueous methylamine (10.31 mL, 90 mmol) in THF (20 mL) was added a solution of the acid chloride
obtained above in CH Cl (15 mL) dropwise with cooling by an ice-water bath. The mixture was stirred at room temperature
2
2
for 2 h. The reaction mixture was diluted with EtOAc, washed with aqueous saturated NaHCO , water, and brine, and dried
3
over Na SO . Filtration and concentration in vacuo and purification by silica gel flash chromatography (CHCl –MeOH 30:1)
2
4
3
gave 3.16 g (84%) of 6a as a white solid.
Compounds 6b and 6c were prepared by using the general procedure described above.
2-Bromo-3-{2-[(3,4-dichlorophenyl)amino]-2-oxoethoxy}-4-methoxy-N-methylbenzamide (T9). To a suspension
of 6a (1.53 g, 5.90 mmol) in dehydrated ethanol (70 mL) was added anhydrous potassium carbonate (2.45 g, 17.70 mmol). The
mixture was stirred at room temperature for 30 min and then 2-chloro-N-(3,4-dichlorophenyl)acetamide (1.54 g, 6.49 mmol)
was added. The reaction mixture was refluxed for 10 h. Filtration and evaporation of alcohol was done in vacuum. The residue
was extracted with EtOAc (3 ꢃ 20 mL). The combined organic layers were washed with H O (3 ꢃ 10 mL), 2 M NaOH (3 ꢃ 10 mL),
2
2 M HCl (3 ꢃ 10 mL), and brine (2 ꢃ 10 mL), dried over Na SO , and the solvent was removed. The crude product was purified
2
4
by silica gel column chromatography to give T9 (2.13 g, 78%) as a white crystalline powder, mp 190–191ꢂC. EI-MS,
+
1
m/z 462.9 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.89 (1H, s), 7.85 (1H, s), 7.51 (1H, s), 7.47–7.40 (2H, m), 6.99
3
(1H, d, J = 8.5), 6.12 (1H, s), 4.69 (2H, s), 4.01 (3H, s), 3.03 (3H, d, J = 4.6).
Compounds T1–T13 were prepared in the same way.
3-{2-[(3-Chloro-4-fluorophenyl)amino]-2-oxoethoxy}-4-methoxy-N-methylbenzamide (T1), mp 197–198ꢂC.
+
1
EI-MS, m/z 366.1 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.88 (1H, s), 7.80 (1H, d, J = 4.7), 7.51 (1H, s), 7.46 (2H,
3
d, J = 8.4), 7.17–7.12 (1H, m), 6.97 (1H, d, J = 8.4), 6.27 (1H, s), 4.69 (2H, s), 4.00 (3H, s), 3.03 (3H, s).
4-Methoxy-3-{2-[(4-methoxyphenyl)amino]-2-oxoethoxy}-N-methylbenzamide (T2), mp 187–188ꢂC. EI-MS,
+
1
m/z 344.1 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.83 (1H, s), 7.54 (2H, d, J = 8.5), 7.51–7.41 (2H, m), 6.92 (3H,
3
d, J = 8.5), 6.48 (2H, s), 4.71 (2H, s), 3.98 (3H, s), 3.83 (3H, s), 3.03 (3H, s).
3-{2-[(4-Bromophenyl)amino]-2-oxoethoxy}-4-methoxy-N-methylbenzamide (T3), mp 225–226ꢂC. EI-MS,
+
1
m/z 392.9 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.89 (1H, s), 7.68–7.46 (6H, m), 6.97 (1H, d, J = 8.5), 4.70 (2H,
3
s), 4.00 (3H, s), 3.04 (3H, s).
3-{2-[(3-Fluorophenyl)amino]-2-oxoethoxy}-4-methoxy-N-methylbenzamide (T4), mp 178–179ꢂC. EI-MS,
+
1
m/z 332.0 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.96 (1H, s), 7.57 (1H, d, J = 10.8), 7.51 (1H, s), 7.47 (1H, d, J = 7.9),
3
7.42–7.21 (2H, m), 6.97 (1H, d, J = 7.9), 6.87 (1H, t, J = 25.6, 7.9), 6.30 (1H, s), 4.69 (2H, s), 4.00 (3H, s), 3.02 (3H, s).
3-{2-[(4-Bromophenyl)amino]-2-oxoethoxy}-N-isopropyl-4-methoxybenzamide (T5), mp 174–175ꢂC. EI-MS,
+
1
m/z 422.1 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.88 (1H, s), 7.48 (6H, dd, J = 21.8, 9.0), 6.94 (1H, d, J = 8.4), 6.07
3
(1H, d, J = 7.0), 4.65 (2H, s), 4.27 (1H, dt, J = 13.9, 7.0), 3.97 (3H, s), 1.27 (6H, d, J = 6.4).
3-{2-[(3-Fluorophenyl)amino]-2-oxoethoxy}-N-isopropyl-4-methoxybenzamide (T6), mp 167–168ꢂC. EI-MS,
+
1
m/z 360.1 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.95 (1H, s), 7.57 (1H, d, J = 10.8), 7.50 (1H, s), 7.38–7.24 (2H,
3
m), 6.96 (1H, d, J = 8.4), 6.86 (1H, t, J = 8.1), 6.02 (1H, d, J = 5.4), 4.68 (2H, s), 4.29 (1H, dt, J = 13.4, 6.7), 3.99 (3H, s), 1.28
(6H, d, J = 6.5).
N,N-Diethyl-4-methoxy-3-{2-[(4-methoxyphenyl)amino]-2-oxoethoxy}benzamide (T7), mp 110–111ꢂC. EI-MS,
+
1
m/z 386.3 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 8.74 (1H, s), 7.51 (2H, d, J = 8.3), 7.11 (1H, d, J = 8.4), 7.06 (1H, s),
3
6.96 (1H, d, J = 8.4), 6.90 (1H, d, J = 8.4), 4.66 (2H, s), 3.96 (3H, s), 3.81 (3H, s), 3.42 (4H, m), 1.26 (6H, m).
N,N-Diethyl-3-{2-[(3-fluorophenyl)amino]-2-oxoethoxy}-4-methoxybenzamide (T8), mp 94–95ꢂC. EI-MS,
+
1
m/z 374.1 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 9.15 (1H, s), 8.40 (1H, t, J = 7.9), 7.40–7.02 (5H, m), 6.95 (1H,
3
d, J = 8.2), 4.69 (2H, s), 4.52 (3H, s), 3.95 (3H, s), 3.42 (4H, m), 1.20 (6H, m).
2-Bromo-3-{2-[(3-fluorophenyl)amino]-2-oxoethoxy}-4-methoxy-N-methylbenzamide (T10), mp 171–172ꢂC.
+
1
EI-MS, m/z 412.0 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 9.09 (1H, s), 7.63 (1H, d, J = 8.5), 7.57 (1H, d, J = 8.5),
3
7.51 (1H, s), 7.47 (1H, d, J = 8.5), 7.31 (1H, d, J = 8.5), 6.96–6.95 (1H, m), 6.14 (1H, s), 4.67 (2H, s), 3.93 (3H, s), 3.03 (3H,
d, J = 4.0).
2-Bromo-3-{2-[(4-bromophenyl)amino]-2-oxoethoxy}-N-isopropyl-4-methoxybenzamide (T11), mp 157–158ꢂC.
+
1
EI-MS, m/z 500.8 (M ). H NMR (400 MHz, CDCl , ꢄ, ppm, J/Hz): 9.04 (1H, s), 7.56 (2H, d, J = 8.3), 7.47 (2H, d, J = 8.3),
3
7.32 (1H, d, J = 8.5), 6.93 (1H, d, J = 8.5), 5.94 (1H, d, J = 7.7), 4.59 (2H, s), 4.28 (12H, dt, J = 13.5, 6.7), 3.91 (3H, s), 1.28
(6H, d, J = 6.5).
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