10.1002/cmdc.201900054
ChemMedChem
FULL PAPER
2JAB = 14.8 Hz), 6.62 (s, 1H), 6.99–7.08 (m, 2H), 7.26–7.32 (m,
2H), 11.11 (s, 1H), 11.31 (s, 1H); 13C-NMR (DMSO-d6) = 11.0,
27.8, 28.2, 34.9, 35.2, 35.8, 47.6, 51.9, 99.7, 110.4, 113.1, 116.0,
117.9, 120.8, 124.8, 126.5, 128.2, 128.5, 135.8, 141.0, 166.8,
= 1.00 (s, 3H), 1.02 (s, 3H), 2.11 (s, 3H), 2.15 (s, 2H), 2.28 (s,
3H), 2.64 (s, 2H), 2.75 (s, 3H), 4.45 (AB, 1H, 2JAB = 15.6 Hz), 4.71
(AB, 1H), 7.20 (d, 1H, 3J = 4.4 Hz), 7.37 (d, 1H, 3J = 4.4 Hz), 11.46
(s, 1H); 13C-NMR (DMSO-d6) = interpretation wasn’t feasible
due to low signal intensity; HRMS (ESI, m/z) [M+H]+: calcd for
C20H25N4O2S+: 385.1693, found: 385.1683.
1
191.2; isomer 2: H-NMR (DMSO-d6): = 1.04 (s, 6H), 2.12 (s,
3H), 2.23 (s, 2H), 2.59 (s, 2H), 2.81 (s, 3H), 4.34 (AB, 1H, 2JAB
=
15.6 Hz), 4.86 (AB,1H, 2JAB = 15.6 Hz), 6.22 (s, 1H), 6.72 (d, 1H,
3J = 6.8 Hz), 6.99–7.08 (m, 1H), 7.26–7.32 (m, 2H), 11.11 (s, 1H),
11.31 (s, 1H); 13C-NMR (DMSO-d6) = 11.0, 27.8, 28.2, 32.1,
35.2, 35.8, 51.7, 52.0, 98.7, 110.5, 112.9, 115.9, 117.3, 120.8,
125.2, 126.0, 127.2, 128.5, 135.8, 140.9, 167.0, 191.3; HRMS
N,2,6,6-Tetramethyl-4-oxo-N-(quinolin-3-ylmethyl)-4,5,6,7-
tetrahydro-1H-indole-3-carboxamide (16n). By method A, 21 h
at 40 °C, product was additionally purified via prepHPLC
1. (ACN/H2O, 75:25) and 2. (ACN/H2O, 50:50), yield = 0.03 g
(15%) colorless solid, mp: 119–121 °C. IR: ṽ (cm-1) = 2956 (w);
1651 (s); 1602 (s). isomer 1: 1H-NMR (DMSO-d6): = 1.04 (s, 6H),
2.13 (s, 3H), 2.24 (s, 2H), 2.63 (s, 2H), 2.78 (s, 3H), 4.61 (AB, 1H,
2JAB = 15.2 Hz), 5.12 (AB, 1H, 2JAB = 15.2 Hz), 7.60–7.64 (m, 1H),
7.72–7.76 (m, 1H), 7.90–8.05 (m, 2H), 8.48 (s, 1H), 8.95 (s, 1H),
11.39 (s, 1H); 13C-NMR (DMSO-d6) = 10.9, 27.9, 28.2, 35.2,
+
(ESI, m/z) [M+H]+: calcd for C22H26N3O2 : 364.2020, found:
364.2006.
N,2,6,6-Tetramethyl-N-[(2-methylisoindolin-5-yl)methyl]-4-
oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (16k). By
method A, 16 h at 40 °C, product was additionally purified via
prepHPLC (ACN/H2O, 50:50). yield = 0.03 g (22%) colorless solid, 35.4, 35.8, 47.5, 51.9, 112.5, 116.0, 126.7, 127.6, 127.8, 128.6,
mp: 158–159 °C. IR: ṽ (cm-1) = 2952 (w); 1652 (s); 1600 (s).
isomer 1: 1H-NMR (DMSO-d6): = 1.03 (s, 6H), 2.09 (s, 3H), 2.20
(s, 2H), 2.47 (s, 3H), 2.61 (s, 2H), 2.65 (s, 3H), 3.73 (s, 2H), 3.78
(s, 2H), 4.56 (AB, 1H, 2JAB = 14.8 Hz), 4.65 (AB, 1H, 2JAB = 14.8
Hz), 7.17 (d, 1H, J = 7.6 Hz), 7.22 (d, 1H, J = 8.0 Hz), 7.28 (s,
1H), 11.36 (s, 1H); 13C-NMR (DMSO-d6) = 10.9, 27.9, 28.2, 35.0, 13C-NMR (DMSO-d6) = 11.2, 27.9, 28.2, 32.5, 35.3, 35.8, 51.3,
128.7, 129.0, 130.8, 133.8, 141.2, 146.8, 150.9, 167.4, 191.5;
isomer 2: 1H-NMR (DMSO-d6): = 1.21 (s, 6H), 2.03 (s, 3H), 2.24
2
(s, 2H), 2.60 (s, 2H), 2.93 (s, 3H), 4.47 (AB, 1H, JAB = 16.0 Hz),
4.69 (AB, 1H, 2JAB = 16.0 Hz), 7.60–7.64 (m, 1H), 7.72–7.76 (m,
1H), 7.90–8.05 (m, 2H), 8.44 (s, 1H), 8.56 (s, 1H), 11.32 (s, 1H);
3
3
35.2, 35.8, 41.9, 49.3, 51.9, 60.1, 60.3, 112.8, 115.9, 121.3, 121.8, 51.9, 112.5, 116.0, 126.8, 127.7, 127.8, 128.6, 128.7, 129.0,
125.9, 127.4, 136.2, 139.3, 140.9, 141.0, 167.1, 191.2; isomer 2:
1H-NMR (DMSO-d6): = 1.03 (s, 6H), 2.06 (s, 3H), 2.20 (s, 2H),
2.44 (s, 3H), 2.59 (s, 2H), 2.80 (s, 3H), 3.73 (s, 2H), 3.79 (s, 2H),
4.13 (AB, 1H, 2JAB = 15.2 Hz), 4.49 (AB, 1H, 2JAB = 15.6 Hz), 6.88
(d, 1H, 3J = 7.6 Hz), 6.91 (s, 1H), 7.12 (d, 1H, 3J = 7.6 Hz), 11.33
130.9, 133.6, 141.2, 146.9, 150.9, 167.4, 191.5; HRMS (ESI, m/z)
+
[M+H]+: calcd for C23H26N3O2 : 376.2020, found: 376.2023.
N-[(2,5-Dimethylthiophen-3-yl)methyl]-N,2,6,6-tetramethyl-4-
oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (16o). By
method A, 3 d at 20 °C, product was additionally purified via
(s, 1H); 13C-NMR (DMSO-d6) = 11.0, 27.8, 28.2, 32.0, 35.2, 35.7, prepHPLC (ACN/H2O, 60:40), yield = 0.10 g (62%) colorless solid,
41.9, 51.9, 53.3, 60.0, 60.1, 112.7, 115.8, 120.7, 122.0, 125.4,
mp: 91–93 °C. IR: ṽ (cm-1) = 2957 (w); 1659 (s); 1600 (s). isomer
1: 1H-NMR (DMSO-d6): = 1.03 (s, 6H), 2.07 (s, 3H), 2.19 (s, 2H),
2.33 (s, 3H), 2.34 (s, 3H), 2.60 (s, 2H), 2.61 (s, 3H), 4.37 (AB, 1H,
2JAB = 14.4 Hz), 4.51 (AB, 1H, 2JAB = 14.4 Hz), 6.74 (s, 1H), 11.31
(s, 1H); 13C-NMR (DMSO-d6) = 10.9,12.0, 14.9, 27.9, 28.2, 34.6,
35.2, 35.8, 42.6, 51.9, 112.9, 115.9, 126.1, 127.3, 132.3, 133.5,
134.4, 140.9, 166.6, 191.1; isomer 2: 1H-NMR (DMSO-d6):
= 1.03 (s, 6H), 2.05 (s, 3H), 2.10 (s, 3H), 2.21 (s, 2H), 2.29 (s,
3H), 2.60 (s, 2H), 2.78 (s, 3H), 3.97 (AB, 1H, 2JAB = 15.2 Hz), 4.31
127.6, 136.1, 139.7, 141.0, 141.1, 167.0, 191.2; HRMS (ESI, m/z)
+
[M+H]+: calcd for C23H30N3O2 : 380.2333, found: 380.2329.
N-(2-Chloro-4,5-dimethoxybenzyl)-N,2,6,6-tetramethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide (16l). By method
A, 17 h at 40 °C, yield = 0.11 g (85%) colorless, waxy solid, mp:
1
224 °C. IR: ṽ (cm-1) = 2847 (w); 1652 (s); 1509 (s). isomer 1: H-
NMR (DMSO-d6): = 1.04 (s, 6H), 2.12 (s, 3H), 2.22 (s, 2H), 2.62
(s, 2H), 2.73 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 4.41 (AB, 1H, 2JAB
2
2
= 15.2 Hz), 4.88 (AB, 1H, JAB = 15.6 Hz), 7.02 (s, 1H), 7.21 (s,
(AB, 1H, JAB = 15.2 Hz), 6.35 (s, 1H), 11.31 (s, 1H); 13C-NMR
1H), 11.39 (s, 1H); 13C-NMR (DMSO-d6) = 10.9, 27.8, 28.2, 35.2, (DMSO-d6) = 10.9,12.5, 14.7, 27.8, 28.2, 31.8, 35.2, 35.8, 46.6,
35.5, 35.8, 47.0, 51.9, 55.9, 111.6, 112.5, 112.6, 115.9, 123.0,
126.5, 127.9, 141.2, 148.2, 148.3, 167.3, 191.4; isomer 2: 1H-
NMR (DMSO-d6): = 1.04 (s, 6H), 2.07 (s, 3H), 2.22 (s, 2H), 2.60
(s, 2H), 2.82 (s, 3H), 3.74 (s, 6H), 4.22 (AB, 1H, 2JAB = 15.6 Hz),
4.54 (AB, 1H, 2JAB = 15.6 Hz), 6.70 (s, 1H), 6.95 (s, 1H), 11.32 (s,
1H); 13C-NMR (DMSO-d6) = 11.0, 27.6, 28.3, 32.0, 35.2, 35.8,
50.6, 51.9, 55.7, 55.9, 111.9, 112.5, 112.7, 116.0, 122.8, 126.2,
127.8, 141.2, 147.9, 148.6, 167.2, 191.3; HRMS (ESI, m/z)
[M+H]+: calcd for C22H28N2O4Cl+: 419.1732, found: 419.1722.
N,2,6,6-Tetramethyl-N-[(6-methylimidazo[2,1-b]thiazol-5-
yl)methyl]-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide
(16m). By method A, 16 h at 40 °C, yield = 0.09 g (77%) pale
orange, waxy solid, mp: 229–230 °C. IR: ṽ (cm-1) = 2957 (w);
52.0, 112.8, 115.9, 127.2, 127.9, 132.1, 133.2, 135.0, 141.0,
166.6, 191.2; HRMS (ESI, m/z) [M+H]+: calcd for C20H27N2O2S+:
359.1788, found: 359.1785.
N-[(1,1′-Biphenyl)-4-ylmethyl]-N,2,6,6-tetramethyl-4-oxo-
4,5,6,7-tetrahydro-1H-indole-3-carboxamide (16p). By method
A, 3 d at 20 °C, product was additionally purified via prepHPLC
(ACN/H2O, 75:25), yield = 0.16 g (65%) colorless solid, mp: 133–
1
135 °C. IR: ṽ (cm-1) = 3026 (w); 1652 (s); 1593 (s). isomer 1: H-
NMR (DMSO-d6): = 1.04 (s, 6H), 2.13 (s, 3H), 2.22 (s, 2H), 2.63
(s, 2H), 2.72 (s, 3H), 4.61 (AB, 1H, 2JAB = 14.8 Hz), 4.77 (AB, 1H,
2JAB = 15.2 Hz), 7.33–7.38 (m, 1H), 7.43–7.53 (m, 2H), 7.59 (d,
2H, 3J = 8.0 Hz), 7.62–7.69 (m, 4H), 11.35 (s, 1H); 13C-NMR
(DMSO-d6) = 11.0, 27.8, 28.2, 35.2, 35.2, 35.8, 49.1, 51.9,
1659 (s); 1600 (s). isomer 1: 1H-NMR (DMSO-d6): = 1.00 (s, 3H), 112.8, 115.9, 126.6, 127.3, 127.8, 128.0, 128.9, 137.1, 138.7,
1.02 (s, 3H), 2.04 (s, 3H), 2.15 (s, 2H), 2.28 (s, 3H), 2.59 (s, 2H),
140.0, 141.0, 167.2, 191.3; isomer 2: 1H-NMR (DMSO-d6):
= 1.04 (s, 6H), 2.10 (s, 3H), 2.22 (s, 2H), 2.60 (s, 2H), 2.85 (s,
2
2.61 (s, 3H), 4.76 (AB, 1H, JAB = 15.2 Hz), 4.88 (AB, 1H, 2JAB
=
15.2 Hz), 7.18 (d, 1H, 3J = 4.4 Hz), 7.86 (d, 1H, 3J = 4.4 Hz), 11.34
3H), ).4.21 (AB, 1H, JAB = 16.0 Hz), 4.54 (AB, 1H), 7.17 (d, 2H,
2
(s, 1H); 13C-NMR (DMSO-d6) = 10.9, 13.1, 27.8, 28.2, 34.1, 35.2, 3J = 8.0 Hz), 7.33–7.38 (m, 1H), 7.43–7.53 (m, 2H), 7.62–7.69 (m,
35.7, 38.3, 51.8, 111.5, 112.3, 115.9, 118.0, 119.6, 127.6, 141.0,
142.2, 147.3, 167.2, 191.1; isomer 2: 1H-NMR (DMSO-d6):
4H), 11.35 (s, 1H); 13C-NMR (DMSO-d6) = 11.0, 27.9, 28.2, 32.2,
35.2, 35.8, 51.9, 53.1. 112.7, 115.8, 126.6, 126.8, 127.4, 127.6,
10
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