B. Chen et al.
MED
7.54 (m, 1H), 7.34–7.28 (m, 2H), 6.91 (d, J=3.0 Hz, 1H), 6.60 ppm
(dd, J=2.0 Hz, 3.5 Hz, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
106.1, 112.8, 113.0, 113.6, 121.4, 122.1, 123.6, 124.5, 124.8, 127.1,
127.2, 137.3, 138.2, 139.5, 143.5, 153.8, 163.2, 182.7 ppm; IR (solid):
n˜ =3282, 1669, 1605, 1588, 1573, 1495, 1440, 1412, 1240, 1114,
1007, 829, 783, 712, 687, 659 cmꢁ1; MS (ES): m/z (%): 331 (100)
[M+H]+; HRMS-ES: m/z [M+H]+ calcd for C20H15N2O3: 331.1083,
found: 331.1067.
8.94 (s, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.36–8.32 (m, 1H), 8.02 (d, J=
9.0 Hz, 2H), 7.87 (d, J=9.0 Hz, 2H), 7.77–7.71 (m, 2H), 7.39–7.33
(m, 2H), 6.55 (dd, J=1.8 Hz, 2.2 Hz, 1H), 4.23 (d, J=7.5 Hz, 2H),
1.41–1.30 (m, 1H), 0.59–0.54 (m, 2H), 0.49–0.43 ppm (m, 2H);
13C NMR (100 MHz, [D6]DMSO): d=3.8, 11.1, 50.5, 107.7, 111.0,
111.4, 118.7, 121.0, 121.4, 123.1, 123.6, 126.8, 127.5, 135.9, 136.2,
136.5, 140.70, 140.74, 162.2, 181.2 ppm; IR (solid): n˜ =3342, 3126,
3001, 1678, 1616, 1595, 1522, 1502, 1486, 1393, 1376, 1220, 1175,
1050, 934, 829, 745, 674, 655, 613 cmꢁ1; MS (ES): m/z (%): 385 (100)
[M+H]+; HRMS-ES: m/z [M+H]+ calcd for C23H21N4O2: 385.1665,
found: 385.1656.
2-(1H-Indol-3-yl)-2-oxo-N-(4-(thiophen-2-yl)phenyl)acetamide
(1p): Golden yellow solid (64 mg, 9%): 1H NMR (400 MHz,
[D6]DMSO): d=12.38 (s, 1H), 10.38 (s, 1H), 8.80 (d, J=2.5 Hz, 1H),
8.33–8.28 (m, 1H), 7.94 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H),
7.60–7.55 (m, 1H), 7.54–7.48 (m, 2H), 7.34–7.28 (m, 2H), 7.14 ppm
(dd, J=3.5 Hz, 5.0 Hz, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
111.9, 112.7, 120.7, 121.2, 122.7, 123.2, 123.6, 125.2, 125.8, 126.2,
128.4, 129.7, 136.4, 137.5, 138.6, 143.1, 162.3, 181.7 ppm; IR (solid):
n˜ =3278, 1669, 1606, 1575, 1506, 1441, 1408, 1238, 1123, 814, 781,
716, 688, 661, 598 cmꢁ1; MS (ES): m/z (%): 347 (100) [M+H]+;
HRMS-ES: m/z [M+H]+ calcd for C20H15N2O2S: 347.0854, found:
347.0862.
N-(4-(1H-Pyrazol-1-yl)phenyl)-2-(1-cyclopropyl-1H-indol-3-yl)-2-
oxoacetamide (7e): Bright yellow powder (83 mg, 15%): 1H NMR
(400 MHz, [D6]DMSO): d=10.87 (s, 1H), 8.72 (s, 1H), 8.49 (d, J=
2.5 Hz, 1H), 8.34–8.29 (m, 1H), 8.01 (d, J=9.0 Hz, 2H), 7.86 (d, J=
9.0 Hz, 2H), 7.77–7.72 (m, 2H), 7.43–7.35 (m, 2H), 6.55 (t, J=2.0 Hz,
1H), 3.71–3.63 (m, 1H), 1.20–1.12 (m, 2H), 1.11–1.06 ppm (m, 2H);
13C NMR (100 MHz, [D6]DMSO): d=5.9, 28.1, 107.7, 111.0, 111.6,
118.7, 121.1, 121.5, 123.5, 123.9, 126.8, 127.5, 136.0, 136.1, 137.6,
140.4, 140.7, 162.0, 181.3 ppm; IR (solid): n˜ =3342, 3154, 3010,
1684, 1622, 1534, 1495, 1482, 1465, 1359, 1313, 1224, 1168, 1024,
934, 870, 831, 785, 759, 738, 726, 674, 651, 609 cmꢁ1; MS (ES): m/z
(%): 371 (100) [M+H]+; HRMS-ES: m/z [M+H]+ calcd for
C22H19N4O2: 371.1508, found: 371.1508.
N-(4-(1H-Pyrazol-1-yl)phenyl)-2-(1-methyl-1H-indol-3-yl)-2-oxo-
acetamide (7a): Crystalline, pale orange solid (151 mg, 29%):
1H NMR (400 MHz, [D6]DMSO): d=10.87 (s, 1H), 8.86 (s, 1H), 8.49
(d, J=2.5 Hz, 1H), 8.35–8.30 (m, 1H), 8.02 (d, J=9.0 Hz, 2H), 7.87
(d, J=9.0 Hz, 2H), 7.75 (d, J=1.5 Hz, 1H), 7.66–7.62 (m, 1H), 7.41–
7.33 (m, 2H), 6.55 (dd, J=2.0 Hz, 2.5 Hz), 3.95 ppm (s, 3H); 13C NMR
(100 MHz, [D6]DMSO): d=33.4, 107.7, 110.8, 111.2, 118.7, 121.0,
121.3, 123.1, 123.6, 126.7, 127.5, 135.9, 136.2, 137.1, 140.7, 142.0,
162.2, 181.2 ppm; IR (solid): n˜ =3343, 3096, 1683, 1622, 1524, 1502,
1463, 1369, 1123, 1083, 838, 788, 748, 652 cmꢁ1; MS (ES): m/z (%):
345 (100) [M+H]+; HRMS-ES: m/z [M+H]+ calcd for C20H17N4O2:
345.1352, found: 345.1358.
2-Chloro-1-(1H-indol-3-yl)ethanone (8): Pyridine (8.1 mL, 0.1 mol)
was added to a suspension of indole (11.7 g, 0.1 mol) in dry diox-
ane (100 mL) under N2. The resultant mixture was warmed to 608C
then chloroacetyl chloride (8.0 mL, 11.3 g, 0.1 mol) was added
dropwise over 10 min. The reaction mixture was maintained at
608C for 1 h then poured over water (200 mL) and extracted into
EtOAc. The organic layer was washed with brine, dried (MgSO4), fil-
tered and concentrated in vacuo. The oily residue was crystallised
from MeOH, then the solids triturated with MeCN to afford the title
N-(4-(1H-Pyrazol-1-yl)phenyl)-2-(1-ethyl-1H-indol-3-yl)-2-oxoacet-
amide (7b): Yellow to orange powder (126 mg, 23%): 1H NMR
(400 MHz, [D6]DMSO): d=10.88 (s, 1H), 8.89 (s, 1H), 8.49 (d, J=
2.5 Hz, 1H), 8.36–8.31 (m, 1H), 8.02 (d, J=9.0 Hz, 2H), 7.87 (d, J=
9.0 Hz, 2H), 7.75 (d, J=1.5 Hz, 1H), 7.72–7.67 (m, 1H), 7.40–7.33
(m, 2H), 6.55 (t, J=2.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.44 ppm (t,
J=7.0 Hz, 3H); 13C NMR (100 MHz, [D6]DMSO): d=16.0, 42.4, 108.6,
111.9, 112.1, 119.6, 121.9, 122.4, 124.0, 124.5, 127.8, 128.4, 136.8,
137.0, 137.1, 141.5, 141.6, 163.1, 182.1 ppm; IR (solid): n˜ =3350,
3127, 1682, 1617, 1593, 1532, 1502, 1484, 1388, 1311, 1220, 1169,
1129, 1050, 934, 872, 823, 788 cmꢁ1; MS (ES): m/z (%): 359 (100)
[M+H]+; HRMS-ES: m/z [M+H]+ calcd for C21H19N4O2: 359.1508,
found: 359.1518.
compound as
a
pale brown powder (2.4 g, 13%): 1H NMR
(400 MHz, [D6]DMSO): d=12.16 (s, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.18
(d, J=7.1 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.29–7.20 (m, 2H),
4.90 ppm (s, 2H); 13C NMR (100 MHz, [D6]DMSO): d=46.4, 112.3,
113.6, 121.1, 122.1, 123.2, 125.4, 134.7, 136.6, 186.1 ppm; IR (solid):
n˜ =3179, 2944, 1639, 1579, 1516, 1490, 1457, 1427, 1398, 1338,
1315, 1278, 1236, 1152, 1138, 1096, 1007, 952, 919, 792, 759 cmꢁ1
;
MS (ES): m/z (%): 193 (100) [M]+; HRMS-ES: m/z [M]+ calcd for
C10H9ClNO: 193.0294, found: 193.0292.
General synthesis of indole-3-(2-aminoacetyl) derivatives (2a–d):
N,N-Diisopropylethylamine (DIPEA; 0.45 mL, 0.33 g, 2.6 mmol) and
KI (45 mg, 0.3 mmol) were added to a suspension of 8 (388 mg,
2.0 mmol) in dry MeCN (8 mL) under N2. The respective amine
(2.2 mmol) was added, and the mixture heated at reflux for 18 h.
After thorough mixing with water (8 mL) and concentration in
vacuo, the resultant solids were washed with water then triturated
in hot MeCN to afford the product.
N-(4-(1H-Pyrazol-1-yl)phenyl)-2-(1-isopropyl-1H-indol-3-yl)-2-oxo-
acetamide (7c): Pale orange powder (124 mg, 22%): 1H NMR
(400 MHz, [D6]DMSO): d=10.88 (s, 1H), 8.88 (s, 1H), 8.49 (d, J=
2.0 Hz, 1H), 8.37–8.33 (m, 1H), 8.02 (d, J=8.5 Hz, 2H), 7.87 (d, J=
8.5 Hz, 2H), 7.78–7.72 (m, 2H), 7.39–7.33 (m, 2H), 6.55 (t, J=2.0 Hz,
1H), 4.91 (septet, J=6.5 Hz, 1H), 1.56 ppm (d, J=6.5 Hz, 6H);
13C NMR (100 MHz, [D6]DMSO): d=22.9, 49.0, 108.6, 112.1, 112.4,
119.6, 122.0, 122.4, 124.1, 124.5, 127.8, 128.4, 136.8, 137.0, 138.2,
141.6, 163.1, 182.0 ppm; IR (solid): n˜ =3351, 3129, 2976, 1685,
1625, 1596, 1532, 1497, 1412, 1402, 1382, 1305, 1218, 1170, 827,
787, 755, 734, 665, 650 cmꢁ1; MS (ES): m/z (%): 373 (100) [M+H]+;
HRMS-ES: m/z [M+H]+ calcd for C22H21N4O2: 373.1665, found:
373.1676.
2-Anilino-1-(1H-indol-3-yl)ethanone (2a): Cream coloured solid
1
(33 mg, 7%): H NMR (400 MHz, [D6]DMSO): d=12.07 (s, 1H), 8.58
(d, J=3.0 Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 7.51 (dd, J=1.6 Hz,
6.7 Hz, 1H), 7.23 (dq, J=3.6 Hz, 7.1 Hz, 2H), 7.09 (t, J=7.8 Hz, 2H),
6.70 (d, J=7.8 Hz, 2H), 6.56 (t, J=7.2 Hz, 1H), 5.89 (t, J=5.4 Hz,
1H), 4.48 ppm (d, J=5.5 Hz, 2H); 13C NMR (100 MHz, [D6]DMSO):
d=49.8, 112.2, 112.4, 114.2, 115.9, 121.2, 121.8, 122.8, 125.4, 128.8,
133.7, 136.4, 148.4, 191.8 ppm; IR (solid): n˜ =3326, 1644, 1602,
1528, 1496, 1429, 1413, 1340, 1311, 1246, 1179, 1158, 1106, 1094,
1010, 986, 947, 883 cmꢁ1; MS (ES): m/z (%): 251 (100) [M+H]+;
N-(4-(1H-Pyrazol-1-yl)phenyl)-2-(1-(cyclopropylmethyl)-1H-indol-
3-yl)-2-oxoacetamide (7d): Microcrystalline, bright yellow solid
(337 mg, 59%): 1H NMR (400 MHz, [D6]DMSO): d=10.89 (s, 1H),
126
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ChemMedChem 2011, 6, 115 – 130