F.A.M. Mohamed et al.
Bioorganic Chemistry 112 (2021) 104960
4.1.7.1. 5-Chloro-3-(hydroxymethyl)-N-phenethyl-1H-indole-2-carbox-
amide 9. This compound was prepared using 7 (0.27 g, 1.20 mmol),
phenethylamine (0.18 mL, 1.44 mmol), BOP (0.8 g, 1.79 mmol), and
DIPEA (0.39 mL, 2.39 mmol). The precipitate formed after stirring
overnight at rt was filtered and dried to afford 9 (0.28 g, 71%) as a white
solid; mp 179–180 ◦C. ν max (KBr disc)/cmꢀ 1 3229 (OH and NH), 3085,
calcd for [M]+ C22H24ClN3O2: 397.1552, found: 397.1553.
4.1.7.5. 5-Chloro-3-(hydroxymethyl)-N-(4-(2-methylpyrrolidin-1-yl)phe-
nethyl)-1H-indole-2-carboxamide 13. This compound was prepared using
7 (0.25 g, 1.11 mmol), 2-(4-(2-Methylpyrrolidin-1-yl)phenyl)ethan-
amine (0.27 g, 1.33 mmol), BOP (0.74 g, 1.66 mmol), and DIPEA (0.37
mL, 2.22 mmol). The precipitate formed after stirring overnight at rt was
filtered and dried to afford 13 (0.37 g, 81%) as a white solid; mp
–
2933, 2879, 1615 (C O), 1526, 1445, 1333, 1280, 1034, 800, 750, 698,
–
640. 1H NMR (400 MHz, DMSO): δ 11.70 (1H, s, indole NH); 8.86 (1H, t,
J = 5.6 Hz, amide NH); 7.77 (1H, d, J = 2.0 Hz); 7.40 (1H, d, J = 9.6 Hz);
7.30–7.15 (6H, m); 5.83 (1H, t, J = 5.2 Hz, OH); 4.65 (2H, d, J = 5.6 Hz);
3.50 (2H, q, J = 7.2 Hz); 2.85 (2H, t, J = 7.0 Hz). 13C NMR (100 MHz,
DMSO): δ 161.6; 139.0; 133.8; 131.7; 129.1; 128.8; 128.2; 126.7; 124.5;
123.9; 119.5; 116.1; 114.2; 53.9; 41.1; 35.5. HRESI-MS m/z calcd for
[M+H]+ C18H18ClN2O2: 329.1051, found: 329.1057.
212–214 ◦C.
ν
(KBr disc)/cmꢀ 1 3258 (NH and OH), 3089, 2963,
max
–
2826, 1614 (C O), 1517, 1440, 1361, 1267, 1198, 995, 801, 781, 697.
–
1H NMR (400 MHz, DMSO): δ 11.68 (1H, s, indole NH); 8.82 (1H, t, J =
5.6 Hz, amide NH); 7.75 (1H, d, J = 2.0 Hz); 7.39 (1H, d, J = 8.8 Hz);
7.16 (1H, dd, J = 2.0, 8.4 Hz); 7.03 (2H, d, J = 8.4 Hz); 6.45 (2H, d, J =
8.4 Hz); 5.77 (1H, t, J = 5.2 Hz, OH); 4.76 (2H, d, J = 5.2 Hz); 3.77 (1H,
m); 3.48 (2H, q, J = 6.8 Hz); 3.28 (1H, m); 3.01 (1H, q, J = 8.0 Hz); 2.71
(2H, t, J = 7.2 Hz); 2.06–1.87 (3H, m); 1.62–1.60 (1H, m); 1.05 (3H, d, J
= 6.0 Hz). 13C NMR (100 MHz, DMSO): δ 161.5; 145.9; 133.7; 131.9;
129.7; 128.2; 125.7; 124.5; 123.9; 119.5; 116.0; 114.2; 112.2; 53.9;
53.5; 48.2; 41.7; 34.7; 32.0; 23.2; 19.5. HREI-MS m/z calcd for [M]+
C23H26ClN3O2: 411.1708, found: 411.1714.
4.1.7.2. 5-Chloro-N-(4-(dimethylamino)phenethyl)-3-(hydroxymethyl)-
1H-indole-2-carboxamide 10. This compound was prepared using 7
(0.33 g, 1.46 mmol), 4-(2-Aminoethyl)-phenyl] dimethylamine (0.29 g,
1.76 mmol), BOP (0.9 g, 2.19 mmol), and DIPEA (0.48 mL, 2.93 mmol).
The precipitate formed after stirring overnight at rt was filtered and
dried to afford 10 (0.45 g, 83%) as a white solid; mp 198–200 ◦C. ν max
(KBr disc)/cmꢀ 1 3279 (OH and NH), 3086, 2929, 2883, 1614 (C O),
–
–
1526, 1444, 1361,1276, 1002, 798, 691. 1H NMR (400 MHz, DMSO): δ
11.68 (1H, s, indole NH); 8.83 (1H, t, J = 5.2 Hz, amide NH); 7.75 (1H,
d, J = 2.0 Hz); 7.39 (1H, d, J = 8.8 Hz); 7.16 (1H, dd, J = 2.0, 8.8 Hz);
7.07 (2H, d, J = 8.4 Hz); 6.65 (2H, d, J = 8.4 Hz); 5.78 (1H, t, J = 5.2 Hz,
OH); 4.75 (2H, d, J = 4.8 Hz); 3.50 (2H, q, J = 7.2 Hz); 2.82 (6H, s); 2.75
(2H, t, J = 7.2 Hz). 13C NMR (100 MHz, DMSO): δ 161.5; 149.5; 133.8;
131.8; 129.6; 128.2; 127.1; 124.5; 123.9; 119.5; 116.0; 114.2; 113.1;
53.9; 41.6; 39.3; 34.6. HRESI-MS m/z calcd for [M+H]+ C20H23ClN3O2:
372.1473, found: 372.1474.
4.1.7.6. 5-Chloro-3-(hydroxymethyl)-N-(3-(2-methylpyrrolidin-1-yl)phe-
nethyl)-1H-indole-2-carboxamide 14. This compound was prepared using
7 (0.17 g, 0.75 mmol), 2-(3-(2-Methylpyrrolidin-1-yl)phenyl)ethan-
amine (0.19 g, 0.9 mmol), BOP (0.5 g, 1.13 mmol), and DIPEA (0.25 mL,
1.5 mmol) to yield 14 (0.23 g, 74%) as a white solid after purification by
flash chromatography on silica gel using a mixture of EtOAc, hexanes
◦
(1:2) as eluent; mp 182–183 C.
ν
(KBr disc)/cmꢀ 1 3274 (NH and
max
–
–
OH), 3090, 2961, 1605 (C O), 1500, 1449, 1367, 1281, 988, 797, 769,
698. 1H NMR (400 MHz, DMSO): δ 11.68 (1H, s, indole NH); 8.82 (1H, t,
J = 5.6 Hz, amide NH); 7.75 (1H, d, J = 2.0 Hz); 7.38 (1H, d, J = 8.4 Hz);
7.16 (1H, dd, J = 2.0, 8.4 Hz); 7.04 (1H, t, J = 8.0 Hz); 6.47 (1H, d, J =
7.6 Hz); 6.41 (1H, s); 6.36 (1H, d, J = 7.6 Hz); 5.76 (1H, t, J = 5.2 Hz,
OH); 4.75 (2H, d, J = 5.2 Hz); 3.82–3.78 (1H, m); 3.55 (2H, q, J = 7.2
Hz); 3.28 (1H, m); 3.03 (1H, q, J = 7.6 Hz); 2.76 (2H, t, J = 7.2 Hz);
2.47–1.86 (3H, m); 1.61–1.53 (1H, m); 1.04 (3H, d, J = 6.0 Hz). 13C
NMR (100 MHz, DMSO): δ 161.5; 147.4; 140.3; 133.8; 131.8; 129.4;
128.2; 124.5; 123.9; 119.5; 116.1; 115.8; 114.2; 112.4; 110.2; 53.9;
53.4; 48.9; 41.3; 36.1; 32.8; 23.2; 19.4. HRESI-MS m/z calcd for
[M+H]+ C23H27ClN3O2: 412.1786, found: 412.1785.
4.1.7.3. 5-Chloro-3-(hydroxymethyl)-N-(4-(pyrrolidin-1-yl)phenethyl)-
1H-indole-2-carboxamide 11. This compound was prepared using 7 (0.2
g, 0.89 mmol), 2-(4-(Pyrrolidin-1-yl)phenyl)ethanamine (0.22 g, 1.06
mmol), BOP (0.59 g, 1.33 mmol), and DIPEA (0.3 mL, 1.77 mmol). The
precipitate formed after stirring overnight at rt was filtered and dried to
afford 11 (0.27 g, 77%) as a white solid; mp 225–227 ◦C. νmax (KBr
disc)/cmꢀ 1 3277 (OH and NH), 3090, 2960, 2848, 1614 (C O), 1525,
–
–
1448, 1376, 1333, 1276, 799, 689. 1H NMR (400 MHz, DMSO): δ 11.69
(1H, s, indole NH); 8.82 (1H, t, J = 5.2 Hz, amide NH); 7.75 (1H, d, J =
1.6 Hz); 7.39 (1H, d, J = 8.8 Hz); 7.17 (1H, dd, J = 2.0, 8.4 Hz); 7.05
(2H, d, J = 8.8 Hz); 6.44 (2H, d, J = 8.8 Hz); 5.78 (1H, t, J = 5.2 Hz, OH);
4.75 (2H, d, J = 4.8 Hz); 3.49 (2H, q, J = 7.2 Hz); 3.16 (4H, t, J = 6.4
Hz); 2.72 (2H, t, J = 7.2 Hz); 1.19–1.88 (4H, m). 13C NMR (100 MHz,
DMSO): δ 161.5; 146.8; 133.7; 131.9; 129.6; 128.2; 125.9; 124.5; 123.9;
119.5; 116.0; 114.2; 112.1; 53.9; 47.8; 41.7; 34.8; 25.4. HRESI-MS m/z
calcd for [M+H]+ C22H25ClN3O2: 398.1630, found: 398.1626.
4.1.7.7. 5-Chloro-3-(hydroxymethyl)-N-(4-(piperidin-1-yl)phenethyl)-1H-
indole-2-carboxamide 15. This compound was prepared using 7 (0.17 g,
0.75 mmol), 2-(4-(Piperidin-1-yl)phenyl)ethylamine (0.18 g, 0.9 mmol),
BOP (0.5 g, 1.13 mmol), and DIPEA (0.25 mL, 1.5 mmol). The precipi-
tate formed after stirring overnight at rt was filtered and dried to afford
15 (0.25 g, 80%) as a white solid; mp 218–220 ◦C. ν max (KBr disc)/cmꢀ 1
–
3267 (OH and NH), 2932, 2850, 1617 (C O), 1516, 1445, 1330, 1277,
–
1239, 1128, 991, 802, 782. 1H NMR (400 MHz, DMSO): δ 11.71 (1H, s,
indole NH); 8.85 (1H, t, J = 5.2 Hz, amide NH); 7.77 (1H, d, J = 2.0 Hz);
7.42 (1H, d, J = 8.4 Hz); 7.18 (1H, dd, J = 2.0, 8.8 Hz); 7.10 (2H, d, J =
8.5 Hz); 6.84 (2H, d, J = 8.5 Hz); 5.75 (1H, t, J = 5.2 Hz, OH); 4.77 (2H,
d, J = 5.2 Hz); 3.53 (2H, q, J = 7.2 Hz); 3.06 (4H, t, J = 5.2 Hz); 2.76
(2H, t, J = 7.6 Hz); 1.62–1.50 (6H, m). 13C NMR (100 MHz, DMSO): δ
161.3; 150.7; 133.8; 131.8; 129.5; 128.2; 124.5; 123.9; 119.5; 116.5;
116.1; 114.2; 53.9; 50.3; 41.4; 34.7; 25.8; 24.4. HRESI-MS m/z calcd for
[M+H]+ C23H27ClN3O2: 412.1786, found: 412.1780.
4.1.7.4. 5-Chloro-3-(hydroxymethyl)-N-(3-(pyrrolidin-1-yl)phenethyl)-
1H-indole-2-carboxamide 12. This compound was prepared using 7
(0.23 g, 1.02 mmol), 2-(3-(Pyrrolidin-1-yl)phenyl)ethanamine (0.26 g,
1.22 mmol), BOP (0.68 g, 1.53 mmol), and DIPEA (0.35 mL, 2.04 mmol).
The precipitate formed after stirring overnight at rt was filtered and
dried to afford 12 (0.32 g, 79%) as a white solid; mp 208–209 ◦C. ν max
(KBr disc)/cmꢀ 1 3296 (NH and OH), 3079, 2964, 2868, 1612 (C O),
–
–
1501, 1455, 1379, 1287, 1008, 802, 766, 701. 1H NMR (400 MHz,
DMSO): δ 11.7 (1H, s, indole NH); 8.84 (1H, t, J = 5.2 Hz, amide NH);
7.76 (1H, d, J = 2.0 Hz); 7.40 (1H, d, J = 8.8 Hz); 7.13 (1H, dd, J = 2.0,
8.8 Hz); 7.06 (1H, t, J = 7.6 Hz); 6.49 (1H, d, J = 7.6 Hz); 6.42 (1H, s);
6.36 (1H, d, J = 7.6 Hz); 5.78 (1H, t, J = 5.2 Hz, OH); 4.76 (2H, d, J =
4.8 Hz); 3.56 (2H, q, J = 7.2 Hz); 3.12 (4H, t, J = 6.4 Hz); 2.78 (2H, t, J
= 6.8 Hz); 1.92–1.88 (4H, m). 13C NMR (100 MHz, DMSO): δ 161.5;
148.3; 140.3; 133.8; 131.8; 129.4; 128.2; 124.5; 123.9; 119.5; 116.1;
116.0; 114.2; 112.4; 110.2; 53.9; 47.7; 41.3; 36.1; 25.4. HREI-MS m/z
4.1.7.8. 5-chloro-3-(hydroxymethyl)-N-(3-(piperidin-1-yl)phenethyl)-1H-
indole-2-carboxamide 16. This compound was prepared using 7 (0.21 g,
0.93 mmol), 2-(3-(Piperidin-1-yl)phenyl)ethylamine (0.23 g, 1.12
mmol), BOP (0.62 g, 1.40 mmol), and DIPEA (0.31 mL, 1.86 mmol) to
yield 16 (0.28 g, 73%) as a white solid after purification by flash
chromatography on silica gel using a mixture of EtOAc, hexanes (1:2) as
eluent; mp 182–184 ◦C. ν max (KBr disc)/cmꢀ 1 3283 (OH and NH), 3096,
11