E. Najahi et al. / European Journal of Medicinal Chemistry 76 (2014) 369e375
371
Scheme 1. General synthetic route for the indolone-N-oxide derivatives. Reagents and conditions: (i) (CH3)3SieC^CH, Pd(PPh3)2Cl2, CuI, Et3N, N2, rt.; (ii) CH3OH, CH2Cl2, K2CO3; (iii)
AcOH, HNO3 fuming; (iv) Pd(PPh3)2Cl2, CuI, NEt3, N2, rt.; and (v) Pd(CH3CN)2Cl2, CH3CN, N2, reflux 86 ꢂC.
plates. Compounds 18 and 19 were obtained from MDPI (Postfach
4005 Basel, Switzerland).
1178, 1046, 1030, 757. HRMS (DCI, CH4) m/z calcd for C19H21N2O3
[MþH]þ 325.1552. Found 325.1541.
4.1.2. Synthesis of compounds f: general procedure for the
Sonogashira coupling
4.1.3.4. 5-Methoxy-2-(4-morpholin-4-yl-phenyl)-1-oxy-indol-3-one
(9). Violet solid, yield 62%, mp: 224e226 ꢂC. 1H RMN (300 MHz,
See Supporting information.
CDCl3)
d
: 3.33 (t, J ¼ 6 Hz, 4H, 2 CH2), 3.89 (t, J ¼ 6 Hz, 2H, 2 CH2),
3.91 (s, 3H, CH3), 6.98 (d, J ¼ 9 Hz, 2H), 7.07 (d, J ¼ 6 Hz, 1H), 7.14 (s,
1H), 7.54 (d, J ¼ 9 Hz, 1H), 8.68 (d, J ¼ 9 Hz, 2H). 13C RMN (75 MHz,
4.1.3. General procedure for the cycloisomerization
Pd(CH3CN)2Cl2 (0.025 mmol, 6.5 mg, 5 mol-%) was added to a
solution of o-alkynylnitrobenzene f (0.5 mmol) in CH3CN (15 mL),
and the mixture was refluxed for 1 h in an argon atmosphere. The
reaction mixture was concentrated, and the residue obtained was
purified by column chromatography (ethyl acetate in petroleum
ether) to give the indolone-N-oxide.
CDCl3)
d: 47.6 (CH2), 56.2 (CH3), 66.6 (CH2), 107.9, 114.0 (ꢃ2), 114.9,
117.1, 118.2, 124.6, 129.0 (ꢃ2), 131.7, 141.1, 151.9, 161.9, 187.4 (C]O).
IR (KBr) cmꢀ1: 3054, 2981,1701, 1602, 1540, 1480, 1420, 1381, 1265,
1183, 1087, 875, 756. HRMS (DCI, CH4) m/z calcd for C19H19N2O4
[MþH]þ 339.1345. Found 339.1332.
4.1.3.5. 5-Methoxy-1-oxy-2-pyridin-3-yl-indol-3-one
(10). Red
: 3.92
4.1.3.1. 2-(4-Amino-phenyl)-1-oxy-indol-3-one (3). Violet solid,
solid, yield 47%, mp: 157e157 ꢂC. 1H RMN (300 MHz, CDCl3)
d
yield: 55%, mp: 161e163 ꢂC. 1H RMN (300 MHz, DMSO-d6):
d: 6.09
(s, 3H, CH3), 7.09e7.18 (m, 2H), 7.40e7.44 (m,1H), 7.61 (d, J ¼ 8.7 Hz,
(br, 2H, NH2), 6.68 (d, J ¼ 9 Hz, 2H), 7.50e7.60 (m, 3H), 7.71e7.77 (m,
1H), 8.66 (d, J ¼ 4.2 Hz, 1H), 8.91 (d, J ¼ 8.4 Hz, 1H), 9.80 (s, 1H). 13
C
1H), 8.47 (d, J ¼ 9 Hz, 2H). 13C RMN (75 MHz, DMSO-d6)
d: 113.1
RMN (75 MHz, CDCl3) d: 55.9 (CH3), 114.1, 116.7, 121.7, 122.2, 124.3,
(ꢃ2), 113.2, 121.2, 122.6, 129.0 (ꢃ2), 129.3, 130.2, 131.6, 135.2, 147.7,
151.5, 187.6 (C]O). IR (KBr, cmꢀ1): 3473, 3377, 1703, 1621, 1598,
1534, 1492, 1459, 1379, 1301, 1281, 1178, 1139, 1073, 875, 835, 785.
HRMS (DCI, CH4) m/z calcd for C14H11N2O2 [MþH]þ 239.0821.
Found 239.0826.
126.6, 128.5, 133.2, 136.4, 137.8, 151.3, 162.1, 187.6 (C]O). IR (KBr)
cmꢀ1: 3084, 3030, 1708, 1598, 1520, 1485, 1451, 1376, 1274, 1187,
1090, 871, 753. HRMS (DCI, CH4) m/z calcd for C14H11N2O3 [MþH]þ
255.0770. Found 255.0781.
4.1.3.6. 6-amino-2-(4-diméthyaminophényl)-1-oxy-indol-3-one (13).
Yellow solid, yield 85%, mp: 197e199 ꢂC. 1H RMN (300 MHz, DMSO-
4.1.3.2. 2-(4-Dimethylamino-3-methyl-phenyl)-5-methoxy-1-oxy-
indol-3-one (7). Purple solid, yield 62%, mp: 161e163 ꢂC. 1H RMN
d6)
6.82e6.88 (m, 3H), 7.72 (dd, J ¼ 9 Hz, J ¼ 1 Hz, 1H), 8.07 (d, J ¼ 9 Hz,
2H). 13C RMN (75 MHz, DMSO-d6)
d: 3.09 (s, 6H, 2 CH3), 6.12 (br, 2H, NH2), 6.32 (d, J ¼ 3 Hz, 1H),
(CDCl3, 300 MHz) d: 2.38 (s, 3H, CH3), 2.80 (s, 6H, 2 CH3), 3.89 (s, 3H,
CH3), 7.05 (d, J ¼ 9 Hz, 2H), 7.13 (s, 1H), 7.54 (d, J ¼ 8.4 Hz, 1H), 8.45
(d, J ¼ 6.9 Hz, 2H). 13C RMN (75 MHz, CDCl3)
d: 13.3 (CH3), 40 (2
d
: 40.1 (2 CH3), 85.6, 111.5 (ꢃ2),
116.8, 122.0, 123.3, 125.4, 132.6 (ꢃ2), 150.8, 154.3, 159.0, 160.0, 187.6
(C]O). IR (KBr) cmꢀ1: 3434, 3343, 1702, 1644, 1583, 1378, 1287,
1195, 1141, 1064, 820, 740. HRMS (DCI, CH4) m/z calcd for
CH3), 56.1 (CH3), 108.1, 111.4, 112.1, 114.2, 115.7, 118.2, 125.1, 128.9,
129, 133.2, 139.9, 151.1, 161.9, 187.4 (C]O). IR (KBr, cmꢀ1): 3054,
2980, 1690, 1602, 1540, 1480, 1420, 1383, 1265, 1194. HRMS (DCI,
CH4) m/z calcd for C18H19N2O3 [MþH]þ 311.1396. Found 311.1387.
C
16H16N3O2 [MþH]þ 282.1243. Found 282.1242.
4.1.3.3. 2-(4-Butylamino-phenyl)-5-methoxy-1-oxy-indol-3-one (8).
Purple solid, yield 53%, mp: 187e189 ꢂC. 1H RMN (300 MHz, CDCl3)
4.1.3.7. 6-Amino-2-(4-chloro-phenyl)-1-oxy-indol-3-one
(14).
Brown solid, yield 81%, mp: 169e171 ꢂC. 1H RMN (300 MHz, DMSO-
d
: 1.00 (t, J ¼ 7.2 Hz, 3H, CH3), 1.26e1.32 (m, 2H, CH2), 1.37e1.50 (m,
d6)
d
: 6.56 (dd, J ¼ 9 Hz, J ¼ 3 Hz, 1H, AreH), 6.92 (br, 2H, NH2), 7.35
2H, CH2), 3.19 (t, 2H, CH2), 3.87 (s, 3H, OCH3), 4.15 (br, 1H, NH), 6.65
(d, J ¼ 9 Hz, 1H), 7.58e7.74 (m, 3H), 8.60 (d, J ¼ 9 Hz, 2H). 13C RMN
(d, J ¼ 9 Hz, 2H), 7.01e7.09 (m, 2H), 7.49 (d, J ¼ 8.1 Hz, 1H), 8.61 (d,
(75 MHz, DMSO-d6)
d: 100.1, 108.7, 112.9, 124.9, 125.7, 129.1 (ꢃ2),
J ¼ 9 Hz, 2H). 13C RMN (75 MHz, CDCl3)
d: 13.1 (CH3), 19.8 (CH2),
129.4 (ꢃ2), 135.1, 151.4, 154.5, 156.8, 184.3 (C]O). IR (KBr) cmꢀ1
:
32.4 (CH2), 43.1 (CH2), 56 (CH3), 107.8, 110.3 (ꢃ2), 114.7, 115.1, 117.9,
124.7, 128.6 (ꢃ2), 131.9, 141.5, 151.1, 162.1, 187.8 (C]O). IR (KBr)
cmꢀ1: 3360, 3052, 2986, 1711, 1608, 1532, 1467, 1420, 1374, 1265,
3423, 3349, 1706, 1649, 1584, 1521, 1474, 1375, 1300, 1268, 1011, 818,
729. HRMS (DCI, CH4) m/z calcd for C14H10ClN2O2 [MþH]þ 273.0431.
Found 273.0443.