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T. Fukaya et al. / Bioorg. Med. Chem. 20 (2012) 5568–5582
5.1.50. N-Methyl-2-{2-oxo-5-[3-(trifluoromethyl)phenyl]-1,3-
benzoxazol-3(2H)-yl}-N-phenylacetamide (70)
that described for compound 61 as a pale brown solid (1.44 g,
80%): mp 163–165 °C (iPrOH); 1H NMR (400 MHz, CDCl3) d: 8.80
(1H, d, J = 2.0 Hz), 8.61 (1H, dd, J = 5.0, 2.0 Hz), 7.86–7.82 (1H, m),
7.53 (2H, dd, J = 7.6, 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.40–7.33
(3H, m), 7.30–7.26 (2H, m), 7.04 (1H, s), 4.37 (2H, s), 3.33 (3H, s);
IR (ATR) 1780, 1657, 1483, 1425, 1385 cmꢁ1; HRMS (ESI) m/z calcd
for C21H18N3O3 [M+H]+ 360.1343; found 360.1341; Anal. Calcd for
Compound 70 was prepared from 67 (90.3 mg, 0.250 mmol) and
3-(trifluoromethyl)phenylboronic acid (61.7 mg, 0.325 mmol) in a
manner similar to that described for compound 61 as a yellow so-
lid (77.7 mg, 73%): mp 193–195 °C (iPrOH); 1H NMR (400 MHz,
CDCl3) d 7.77 (1H, s), 7.71 (1H, d, J = 7.6 Hz), 7.62 (1H, d,
J = 7.6 Hz), 7.59–7.49 (3H, m), 7.45 (1H, t, J = 7.3 Hz), 7.36 (2H, d,
J = 7.3 Hz), 7.33–7.27 (2H, m), 7.04 (1H, s), 4.37 (2H, s), 3.33 (3H,
s); IR (ATR) 1788, 1651, 1489, 1381, 1329 cmꢁ1; HRMS (ESI) m/z
calcd for C23H18F3N2O3 [M+H]+ 427.1264; found 427.1252; Anal.
Calcd for C23H17F3N2O3ꢀ0.50H2O: C, 63.45; H, 4.17; N, 6.43; F,
13.09. Found: C, 63.47; H, 4.04; N, 6.29; F, 13.21.
C
21H17N3O3ꢀ0.25H2O: C, 69.32; H, 4.85; N, 11.55. Found: C, 68.97;
H, 4.75; N, 11.18.
5.1.55. N-Methyl-2-[2-oxo-5-(pyridin-4-yl)-1,3-benzoxazol-
3(2H)-yl]-N-phenylacetamide (75)
Compound 75 was prepared from 67 (2.00 g, 5.54 mmol) and 4-
pyridineboronic acid (0.817 g, 6.64 mmol) in a manner similar to
that described for compound 61 as a grey solid (1.35 g, 68%): mp
213–214 °C (MeOH); 1H NMR (400 MHz, CDCl3) d 8.67 (2H, d,
J = 4.9 Hz), 7.53 (2H, dd, J = 7.4, 7.4 Hz), 7.49–7.43 (3H, m), 7.39–
7.34 (3H, m), 7.29 (1H, d, J = 8.3 Hz), 7.10 (1H, d, J = 1.5 Hz), 4.38
5.1.51. N-Methyl-2-{2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3-
benzoxazol-3(2H)-yl}-N-phenylacetamide (71)
Compound 71 was prepared from 67 (500 mg, 1.38 mmol) and
4-(trifluoromethyl)phenylboronic acid (316 mg, 1.66 mmol) in a
manner similar to that described for compound 61 as a white solid
(342 mg, 58%): mp 218–220 °C (iPrOH); 1H NMR (400 MHz, CDCl3)
d 7.70 (2H, d, J = 8.3 Hz), 7.64 (2H, d, J = 8.3 Hz), 7.53 (2H, dd, J = 7.4,
7.4 Hz), 7.45 (1H, t, J = 7.4 Hz), 7.35 (2H, d, J = 7.4 Hz), 7.33–7.27
(2H, m), 7.05 (1H, d, J = 1.5 Hz), 4.37 (2H, s), 3.33 (3H, s); IR
(ATR) 1784, 1772, 1684, 1676, 1489 cmꢁ1; HRMS (ESI) m/z calcd
for C23H18F3N2O3 [M+H]+ 427.1264; found 427.1251; Anal. Calcd
for C23H17F3N2O3ꢀ0.75H2O: C, 62.80; H, 4.24; N, 6.37; F, 12.96.
Found: C, 62.47; H, 4.02; N, 6.35; F, 12.60.
(2H, s), 3.33 (3H, s); IR (ATR) 1780, 1770, 1668, 1597, 1485 cmꢁ1
;
HRMS (ESI) m/z calcd for C21H18N3O3 [M+H]+ 360.1343; found
360.1340; Anal. Calcd for C21H17N3O3ꢀ0.25H2O: C, 69.32; H, 4.85;
N, 11.55. Found: C, 69.58; H, 4.74; N, 11.69.
5.1.56. N-Methyl-2-(2-oxo-1,3-benzoxazol-3(2H)-yl)-N-
phenylacetamide (76)
To a solution of 67 (542 mg, 1.50 mmol) in MeOH (50 mL) was
added 10% Pd/C (50% wet, 271 mg), and stirred at room tempera-
ture for 2.5 h under hydrogen atmosphere. The reaction mixture
was filtered through Celite, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography
using CHCl3 as eluent to give 76 (407 mg, 96%) as a white solid:
mp 141–143 °C (iPrOH); 1H NMR (400 MHz, CDCl3) d 7.51 (2H,
dd, J = 7.6, 7.6 Hz), 7.44 (1H, t, J = 7.6 Hz), 7.33 (2H, d, J = 7.6 Hz),
7.20–7.06 (3H, m), 6.88 (1H, d, J = 7.1 Hz), 4.32 (2H, s), 3.32 (3H,
s); IR (ATR) 1767, 1670, 1489, 1369, 1240 cmꢁ1; HRMS (ESI) m/z
calcd for C16H15N2O3 [M+H]+ 283.1077; found 283.1071; Anal.
Calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.13;
H, 4.99; N, 10.04.
5.1.52. N-Methyl-2-{2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-
benzoxazol-3(2H)-yl}-N-phenylacetamide (72)
Compound 72 was prepared from 67 (50.0 mg, 0.138 mmol) and
4-(trifluoromethoxy)phenylboronic acid (34.2 mg, 0.166 mmol) in
a manner similar to that described for compound 61 as an orange
solid (40.0 mg, 66%): mp 164–166 °C (iPrOH); 1H NMR (400 MHz,
CDCl3) d 7.56–7.49 (4H, m), 7.45 (1H, t, J = 7.3 Hz), 7.35 (2H, d,
J = 7.6 Hz), 7.29 (2H, d, J = 8.5 Hz), 7.26–7.24 (2H, m), 7.01 (1H, s),
4.35 (2H, s), 3.32 (3H, s); IR (ATR) 1786, 1774, 1662, 1489,
;
1385 cmꢁ1 HRMS (ESI) m/z calcd for C23H18F3N2O4 [M+H]+
443.1213; found 443.1199; Anal. Calcd for C23H17F3N2O4: C,
62.44; H, 3.87; N, 6.33; F, 12.88. Found: C, 62.32; H, 3.93; N,
6.45; F, 12.84.
5.1.57. N-Methyl-2-(2-oxo-5-phenoxy-1,3-benzoxazol-3(2H)-
yl)-N-phenylacetamide (77)
A
mixture of 67 (722 mg, 2.00 mmol), phenol (753 mg,
5.1.53. N-Methyl-2-[2-oxo-5-(pyridin-2-yl)-1,3-benzoxazol-
3(2H)-yl]-N-phenylacetamide (73)
8.00 mmol), CuO (796 mg, 10.0 mmol) and K2CO3 (1.66 g,
12.0 mmol) in pyridine (10 mL) was heated at reflux for 18 h and
cooled to room temperature. The reaction mixture was filtered
through Celite, and the filtrate was diluted with CHCl3 and 2 M
HCl solution. The organic layer was separated, washed with brine,
and dried over anhydrous sodium sulfate. After filtration, the sol-
vent was removed in vacuo, and the residue was purified by silica
gel column chromatography using hexane/EtOAc (3:1, v/v) as elu-
ent. The solvent was removed in vacuo, and the resulting solid was
triturated with Et2O to give 77 (269 mg, 36%) as a white solid: mp
133–135 °C (iPrOH); 1H NMR (400 MHz, CDCl3) d 7.48 (2H, dd,
J = 7.3, 7.3 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.35 (2H, dd, J = 7.8,
7.8 Hz), 7.28 (2H, d, J = 7.3 Hz), 7.14–7.10 (2H, m), 6.99 (2H, d,
J = 7.8 Hz), 6.72 (1H, dd, J = 8.5, 2.2 Hz), 6.58 (1H, d, J = 2.2 Hz),
4.25 (2H, s), 3.29 (3H, s); IR (ATR) 1778, 1664, 1487, 1387,
To a solution of 67 (181 mg, 500
nyl)pyridine (0.192 mL, 600 mol) in toluene (3.0 mL) was added
Pd(PPh3)4 (28.9 mg, 25.0 mol) in room temperature. The reaction
lmol) and 2-(tributylstan-
l
l
mixture was stirred at reflux for 7 h and cooled to room tempera-
ture. Water was then added, and the mixture was extracted with
EtOAc. The organic layer was washed with brine, and dried over
anhydrous sodium sulfate. After filtration, the solvent was re-
moved in vacuo, and the residue was purified by silica gel column
chromatography using hexane/EtOAc (1:3, v/v) as eluent to give 73
(131 mg, 73%) as a beige solid: mp 166–168 °C (iPrOH); 1H NMR
(400 MHz, CDCl3) d 8.68 (1H, d, J = 4.9 Hz), 7.79–7.73 (1H, m),
7.70 (1H, d, J = 7.8 Hz), 7.68–7.62 (2H, m), 7.53 (2H, dd, J = 7.3,
7.3 Hz), 7.45 (1H, t, J = 7.3 Hz), 7.37 (2H, d, J = 7.3 Hz), 7.29–7.23
(2H, m), 4.39 (2H, s), 3.31 (3H, s); IR (ATR) 1786, 1660, 1587,
1471, 1464 cmꢁ1; HRMS (ESI) m/z calcd for C21H18N3O3 [M+H]+
360.1343; found 360.1341; Anal. Calcd for C21H17N3O3: C, 70.18;
H, 4.77; N, 11.69. Found: C, 70.05; H, 4.83; N, 11.67.
1217 cmꢁ1
;
HRMS (ESI) m/z calcd for C22H19N2O4 [M+H]+
375.1339; found 375.1337; Anal. Calcd for C22H18N2O4: C, 70.58;
H, 4.85; N, 7.48. Found: C, 70.32; H, 4.98; N, 7.44.
5.1.58. N-Methyl-2-{5-[methyl(phenyl)amino]-2-oxo-1,3-
benzoxazol-3(2H)-yl}-N-phenylacetamide (78)
5.1.54. N-Methyl-2-[2-oxo-5-(pyridin-3-yl)-1,3-benzoxazol-
3(2H)-yl]-N-phenylacetamide (74)
Compound 74 was prepared from 67 (1.81 g, 5.00 mmol) and 3-
pyridineboronic acid (0.738 g, 6.00 mmol) in a manner similar to
A
(81.3
mixture of 67 (181 mg, 0.500 mmol), N-methylaniline
L, 0.750 mmol), Pd2(dba)3 (22.9 mg, 0.0250 mmol), Xant-
l
phos (43.4 mg, 0.0750 mmol) and Cs2CO3 (228 mg, 0.700 mmol)