J.-P. Wan et al. / Tetrahedron 64 (2008) 11115–11123
11119
NMR (DMSO-d6, 125 MHz):
d
169.3, 158.2, 153.1, 143.3, 137.9, 134.4,
(d, 2H, J¼8.0 Hz), 6.77 (d, 1H, J¼8.0 Hz), 6.10 (t, 1H, J¼5.0 Hz), 5.88–
5.80 (m, 2H), 5.57 (d, 1H, J¼8.0 Hz), 3.34–3.30 (m, 2H), 2.93–2.90
(m, 2H), 1.14 (t, 3H, J¼7.0 Hz), 0.91 (t, 3H, J¼7.0 Hz); 13C NMR
132.3, 130.2, 128.8, 128.7, 128.1, 125.7, 125.0, 62.7, 55.1, 35.4, 35.3,
16.8, 16.3; IR (KBr, cmꢂ1) 3383, 3301, 3051, 2967, 2925, 2871, 1717,
1668,1552,1471,1447,1362,1299,1253,1140,1104, 746, 698; HRMS:
Calcd for C21H24N4O3Na [MþNa]þ, 403.1741. Found, 403.1734.
(DMSO-d6, 125 MHz): d 169.4, 158.1, 153.1, 142.7, 140.2, 134.6, 132.2,
130.2, 129.4, 125.2, 124.5, 121.2, 64.6, 54.1, 35.2, 35.0, 16.3, 15.9; IR
(KBr, cmꢂ1) 3383, 3310, 2979, 2931, 2877, 1717, 1668, 1552, 1487,
1361,1252,1142,1104, 762, 737, 698; HRMS: Calcd for C21H23BrN4O3
[MþNa]þ, 481.0846. Found, 481.0842.
4.2.2. N-Ethyl-1-((3-ethylureido) (p-tolyl) methyl)-3-
oxoisoindoline-2-carboxamide (8ab)
White solid, mp 200–202 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
8.38 (t, 1H, J¼5.5 Hz), 7.82–7.77 (m, 2H), 7.59–7.54 (m, 2H), 6.85–
4.2.7. N-Ethyl-1-((3-ethylureido)(4-hydroxyphenyl)methyl)-3-
oxoisoindoline-2-carboxamide (8ag)
6.83 (m, 2H), 6.45–6.41 (m, 3H), 6.21 (t, 1H, J¼5.5 Hz), 5.85 (t, 1H,
J¼5.5 Hz), 5.53 (d, 1H, J¼5.5 Hz), 3.38–3.27 (m, 2H), 3.12–3.07 (m,
2H), 2.13 (s, 3H), 1.16 (t, 3H, J¼7.0 Hz), 1.04 (t, 3H, J¼7.0 Hz); 13C
White solid, mp 247–249 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
9.39 (s, 1H), 8.44 (t, 1H, J¼5.5 Hz), 7.76 (d, 1H, J¼7.0 Hz), 7.61–7.50
NMR (DMSO-d6, 125 MHz):
d
169.3, 158.2, 153.1, 143.4, 137.9, 134.8,
(m, 2H), 6.95 (d, 2H, J¼8.0 Hz), 6.74 (d, 3H, J¼8.0 Hz), 6.04 (t, 1H,
J¼5.0 Hz), 5.85 (d,1H, J¼10.0 Hz), 5.63 (d,1H, J¼8.0 Hz), 5.48 (s,1H),
3.32–3.29 (m, 2H), 2.93–2.88 (m, 2H), 1.14 (t, 3H, J¼7.0 Hz), 0.91 (t,
134.5, 132.4, 130.3, 130.1, 129.3, 128.0, 127.3, 125.7, 125.3, 125.0,
124.9, 124.7, 62.7, 54.8, 35.4, 21.8, 16.8, 16.2; IR (KBr, cmꢂ1) 3309,
2968, 2925, 2873, 1716, 1685, 1626, 1542, 1468, 1371, 1252, 1167,
1041, 1020, 760, 727, 706; HRMS: Calcd for C22H26N4O3Na [MþNa]þ,
417.1897. Found, 417.1901.
3H, J¼7.0 Hz); 13C NMR (DMSO-d6, 125 MHz):
d 169.5, 158.2, 157.3,
153.1, 143.0, 134.2, 132.2, 130.6, 130.0, 128.2, 125.0, 124.6, 116.0, 65.1,
53.7, 35.2, 35.0, 16.3, 16.0; IR (KBr, cmꢂ1) 3395, 3361, 3309, 2972,
2935, 1716, 1656, 1615, 1560, 1465, 1364, 1253, 1101, 761, 731, 702;
HRMS: Calcd for C21H24N4O4Na [MþNa]þ, 419.1690. Found,
419.1692.
4.2.3. N-Ethyl-1-((3-ethylureido) (4-methoxyphenyl)methyl)-3-
oxoisoindoline-2-carboxamide (8ac)
White solid, mp 219–222 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
8.43 (t,1H, J¼5.5 Hz), 7.78 (d,1H, J¼7.5 Hz), 7.63–7.55 (m, 2H), 7.08
4.2.8. N-Ethyl-1-(((3-ethylureido)-4-(dimethylamino)phenyl)-
methyl)-3-oxoisoindoline-2-carboxamide (8ah)
(d, 2H, J¼8 Hz), 6.94 (d, 2H, J¼8.0 Hz), 6.73 (d, 1H, J¼7.0 Hz), 6.05 (t,
1H, J¼5.0 Hz), 5.89 (d, 1H, J¼10.0 Hz), 5.69 (d, 1H, J¼9.5 Hz), 5.52 (s,
1H), 3.76 (s, 3H), 3.36–3.31 (m, 2H), 2.94–2.89 (m, 2H), 1.47 (t, 3H,
J¼7.0 Hz), 0.92 (t, 3H, J¼7.0 Hz); 13C NMR (DMSO-d6, 125 MHz):
Deep brown solid, mp 229–232 ꢀC; 1H NMR (DMSO-d6,
500 MHz):
d
8.43 (t, 1H, J¼5.5 Hz), 7.77 (d, 1H, J¼7.5 Hz), 7.62–7.53
(m, 2H), 6.98 (d, 2H, J¼8.5 Hz), 6.73 (t, 3H, J¼8.5 Hz), 6.02 (t, 1H,
J¼5.0 Hz), 5.85 (d, 1H, J¼10.0 Hz), 5.57 (d, 1H, J¼10.0 Hz), 5.47 (d,
1H, 2.5 Hz), 3.32–3.29 (m, 2H), 2.92–2.89 (m, 8.0H), 1.15 (t, 3H,
J¼7.0 Hz), 0.91 (t, 3H, J¼7.0 Hz); 13C NMR (DMSO-d6, 125 MHz):
d
169.6, 159.5, 158.4, 153.3, 143.1, 134.5, 132.6, 132.4, 130.3, 128.4,
125.3, 124.8, 114.9, 65.2, 56.2, 53.9, 35.4, 35.2, 16.6, 16.2; IR (KBr,
cmꢂ1) 3387, 3302, 2968, 2933, 2864, 2837, 1716, 1666, 1591, 1551,
1470, 1362, 1249, 1137, 1101, 760, 701; HRMS: Calcd for
C22H26N4O4Na [MþNa]þ, 433.1846. Found, 433.1846.
d
169.5, 158.3, 153.1, 150.4, 143.0, 134.2, 132.2, 130.0, 127.8, 125.0,
124.6, 113.1, 65.1, 53.5, 35.2, 34.9, 16.4, 16.0; IR (KBr, cmꢂ1) 3395,
3311, 3076, 2971, 2932, 2873, 2808, 1716, 1671, 1616, 1545, 1525,
1467, 1367, 1250, 1143, 1102, 762, 730, 701; HRMS: Calcd for
C23H29N5O3Na [MþNa]þ, 446.2163. Found, 446.2155.
4.2.4. N-Ethyl-1-((3-ethylureido)(4-fluorophenyl)methyl)-3-
oxoisoindoline-2-carboxamide (8ad, mixed diastereoisomers)
Pale yellow solid, mp 206–207 ꢀC; 1H NMR (DMSO-d6,
500 MHz):
d
8.37 (t, 1H, J¼5.5 Hz), 7.81–7.78 (m, 2H), 7.60–7.54 (m,
4.2.9. N-Ethyl-1-((3-ethylureido)(4-(trifluoromethyl)-
2H), 7.21–7.16 (m, 1H), 6.90 (t, 2H, J¼8.5 Hz), 6.58–6.51 (m, 3H), 6.18
(t, 1H, J¼5.0 Hz), 5.86 (dd, 1H, J1¼5.0 Hz, J2¼3.0 Hz), 5.53 (d, 1H,
J¼5.0 Hz), 3.38–3.27 (m, 4H, mixed isomers and water signal), 3.10–
3.07 (m, 2H), 1.17–1.13 (m, 4H, mixed isomers), 1.04 (t, 3H,
phenyl)methyl)-3-oxoisoindoline-2-carboxamide (8ai, racemate)
White solid, mp 189–192 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
8.44 (t, 1H, J¼5.5 Hz), 8.38 (t, 1H, J¼5.5 Hz), 7.89–7.75 (m, 5H),
7.66–7.53 (m, 4H), 7.44 (d, 2H, J¼8.0 Hz), 7.39 (d, 2H, J¼7.5 Hz),
6.81 (d, 2H, J¼7.5 Hz), 6.75 (d, 1H, J¼7.0 Hz), 6.66 (d, 1H,
J¼8.0 Hz), 6.22 (t, 1H, J¼5.5 Hz), 6.15 (t, 1H, J¼5.5 Hz), 6.01 (d,
1H, J¼9.5 Hz), 5.93 (s, 2H), 5.64 (s, 1H), 5.56 (d, 1H, J¼5.5 Hz),
3.36–3.28 (m, 4H), 3.09–3.03 (m, 2H), 2.95–2.90 (m, 2H), 1.17–
1.13 (m, 6H), 1.03 (t, 3H, J¼7.0 Hz), 0.92 (t, 3H, J¼7.0 Hz); 13C
J¼7.0 Hz); 13C NMR (DMSO-d6, 125 MHz):
d 169.3, 163.4, 161.5, 158,
153.0, 143.1, 134.7, 134.5, 134.3, 132.3, 130.4, 129.9, 129.3, 125.7,
125.0, 124.7, 116.4, 115.7, 115.5, 62.7, 54.5, 35.4, 35.2, 16.8, 16.2; IR
(KBr, cmꢂ1) 3358, 3307, 3057, 2974, 2933, 2875, 1717, 1686, 1663,
1627, 1546, 1510, 1379, 1251, 1164, 1104, 761, 734, 704; HRMS: Calcd
for C21H23FN4O3 [MþNa]þ, 421.1646. Found, 421.1651.
NMR (DMSO-d6, 125 MHz):
d 169.6, 169.3, 158.3, 158.1, 153.3,
153.0, 145.9, 143.2, 143.0, 142.7, 134.8, 134.6, 132.3, 132.0, 130.5,
130.4, 129.2, 128.9, 128.8, 128.3, 126.5, 125.7, 125.6, 125.5, 125.0,
124.6, 64.7, 62.7, 55.0, 54.6, 35.4, 35.2, 16.7, 16.4, 16.2, 16.1; IR
(KBr, cmꢂ1) 3385, 3351, 3316, 2991, 2931, 2871, 1721, 1667, 1618,
1552, 1469, 1360, 1327, 1252, 1166, 1124, 1070, 761, 742, 705;
HRMS: Calcd for C22H23F3N4O3Na [MþNa]þ, 471.1614. Found,
471.1620.
4.2.5. N-Ethyl-1-((3-ethylureido)(4-chlorophenyl)methyl)-3-
oxoisoindoline-2-carboxamide (8ae)
White solid, mp 209–210 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
8.38 (t, 1H, 5.5 Hz), 7.84–7.78 (m, 2H), 7.61–7.54 (m, 2H), 7.13 (d,
2H, J¼8.0 Hz), 6.57–6.53 (m, 3H), 6.19 (t, 1H, J¼5.5 Hz), 5.85 (dd, 1H,
J1¼5.5 Hz, J2¼2 Hz), 5.54 (d, 1H, J¼5.5 Hz), 3.37–3.28 (m, 2H), 3.09–
3.06 (m, 2H), 1.16 (t, 3H, J¼7.0 Hz), 1.03 (t, 3H, J¼7.0 Hz); 13C NMR
(DMSO-d6, 125 MHz):
d
169.3, 158.1, 153.0, 143.1, 137.2, 134.5, 133.2,
4.2.10. N-Ethyl-1-((3-ethylureido)(2-fluorophenyl)methyl)-3-
oxoisoindoline-2-carboxamide (8aj)
132.1, 130.3, 129.8, 128.8, 125.7, 125.0, 62.6, 54.6, 35.4, 35.3, 16.7,
16.2; IR (KBr, cmꢂ1) 3306, 3049, 2972, 2931, 2875, 1716, 1685, 1625,
1564, 1540, 1492, 1376,1318, 1252, 1164, 1092, 762, 734, 704; HRMS:
Calcd for C21H23ClN4O3 [MþNa]þ, 437.1351. Found, 437.1343.
White solid, mp 214–216 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
d
8.28 (t, 1H, J¼5.5 Hz), 7.84 (d, 1H, J¼7.5 Hz), 7.79–7.76 (m, 1H),
7.58–7.52 (m, 2H), 7.14–7.10 (m, 1H), 6.99 (t, 1H, J¼9.0 Hz), 6.77 (t,
1H, 7.5 Hz), 6.55 (d, 1H, J¼8.5 Hz), 6.41 (t, 1H, J¼7.5 Hz), 6.26 (t, 1H,
J¼5.5 Hz), 6.13 (dd, 1H, J1¼4.5 Hz, J2¼3.5 Hz), 5.55 (d, 1H, J¼4.0 Hz),
3.35–3.24 (m, 2H), 3.09–3.01 (m, 2H), 1.14 (t, 3H, J¼7.0 Hz), 1.02 (t,
4.2.6. N-Ethyl-1-((3-ethylureido)(4-bromophenyl) methyl)-3-
oxoisoindoline-2-carboxamide (8af)
White solid, mp 229–232 ꢀC; 1H NMR (DMSO-d6, 500 MHz):
3H, J¼7.0 Hz); 13C NMR (DMSO-d6, 125 MHz):
d 169.2, 162.0, 160.1,
d
8.43 (t, 1H, J¼5.5 Hz), 7.79 (d, 1H, J¼7.0 Hz), 7.65–7.56 (m, 4H), 7.10
158.0, 152.8, 143.5, 134.4, 132.0, 130.5, 130.4, 130.3, 129.6, 125.6,