F.-X. Toublet, J. Lalut, B. Hatat et al.
European Journal of Medicinal Chemistry 210 (2021) 113059
equiv) was added to a solution of 3-hydroxybenzaldehyde (2.17 g,
17.74 mmol, 1.0 equiv) in acetone (89 mL) with at 0 ꢀC. After 5 min,
the benzyl bromide (3.34 g, 19.51 mmol, 1.1 equiv) was added in the
mixture. The solution was stirred for 1 night at rt. After concen-
trating the mixture in vacuo, the crude was dissolved with EtOAc,
then the organic layer was washed with brine, dried over MgSO4
and concentrated in vacuo. The crude was purified by chromatog-
raphy on silica gel column (CHX/EtOAc, gradient 100:0 to 90:10)
and concentrated under reduced pressure to afford the compound
14 as a white powder (2.48 g, 66% isolated yield). M. p. 60 ꢀC; 1H
3.14 (t, 2H, J ¼ 7.5 Hz); 13C NMR (MeOD, 100 MHz, 295 K)
d 161.3 (d,
J ¼ 235.6 Hz), 160.6, 138.3, 138.2 (d, J ¼ 12.6 Hz), 134.4, 131.4, 129.5
(2C), 129.0, 128.6 (2C), 124.9, 124.7 (d, J ¼ 3.4 Hz), 123.1, 119.9 (d, J ¼
10.3 Hz), 117.3, 116.9, 110.7, 108.5 (d, J ¼ 24.9 Hz), 98.4 (d, J ¼
26.0 Hz), 71.0, 52.2, 48.7, 23.4; 19F NMR (MeOD, 374 MHz, 295 K)
d
ꢁ121.0 (td, J ¼ 9.6, 5.3 Hz); MS: m/z [MþH]þ 375.51; HRMS/ESI: m/
z calcd. For C24H24FN2O [MþH]þ 375.1873, found 375.1873; IR (neat,
cmꢁ1
) nmax 3432.
3-[[2-(6-fluoro-1H-indol-3-yl)ethylamino]methyl]phenyl N-ethyl-
N-methylcarbamate 7. Following procedure A with 11 (491 mg,
2.76 mmol) and 15, we obtained 7 as a brown oil (211 mg, 21%
NMR (CDCl3, 400 MHz, 295 K)
d
9.98 (s, 1H), 7.50e7.33 (m, 8H), 7.26
192.2,
(m, 1H), 5.13 (s, 2H); 13C NMR (CDCl3, 100 MHz, 295 K)
d
isolated yield). 1H NMR (DMSO, 400 MHz, 363 K)
d 10.60 (s, 1H),
159.4, 137.9, 136.4, 130.2, 128.8 (2C), 128.3, 127.7 (2C), 123.8, 122.3,
113.3, 70.3.
7.48 (dd, 1H, J ¼ 8.7, 5.4 Hz), 7.28 (t, 1H, J ¼ 7.7 Hz), 7.14 (d, 1H, J ¼
7.7 Hz), 7.11e7.05 (m, 3H), 6.96 (dd, 1H, J ¼ 7.7, 2.4 Hz), 6.79 (dd, 1H,
J ¼ 10.0, 8.7, 2.4 Hz), 3.78 (s, 2H), 3.39 (q, 2H, J ¼ 7.1 Hz), 2.97 (s, 3H),
2.86 (m, 4H), 1.17 (t, 3H, J ¼ 7.1 Hz); 13C NMR (DMSO, 100 MHz,
(3-formylphenyl) N-ethyl-N-methylcarbamate 15 [31]. K2CO3
(6.79 g, 49.13 mmol, 3.0 equiv) was added to a solution of 3-
hydroxybenzaldehyde (2.0 g, 16.38 mmol, 1.0 eq) in DMF (70 mL)
at 0 ꢀC. After 5 min, the ethylmethylcarbamic chloride (2.7 mL,
24.57 mmol, 1.5 equiv) was added to the mixture. The solution was
then stirred for 2 h at 70 ꢀC. After concentrating the mixture in
vacuo, the crude product was dissolved with EtOAc, then the
organic layer was washed with brine, dried over MgSO4 and
concentrated in vacuo. The crude product was purified by chro-
matography on silica gel column (CHX/EtOAc, gradient 100:0 to
70:30) and concentrated under reduced pressure to afford the
compound 15 as a yellowish oil (2.96 g, 87% isolated yield). 1H NMR
363 K)
d
158.5 (d, J ¼ 232.9 Hz), 153.2, 151.1, 142.1, 135.8 (d, J ¼
12.6 Hz), 128.2, 123.9, 123.8, 122.5 (d, J ¼ 2.1 Hz), 120.4, 119.2, 118.7
(d, J ¼ 10.6 Hz), 122.7, 106.0 (d, J ¼ 24.7 Hz), 96.7 (d, J ¼ 24.9 Hz),
52.0, 49.0, 43.0, 33.2, 25.0, 12.1; 19F NMR (DMSO, 374 MHz, 295 K)
d
ꢁ124.5 (td, J ¼ 9.9 Hz, J ¼ 5.4 Hz); MS: m/z [MþH]þ 370.53; HRMS/
ESI: m/z calcd. For C21H25FN3O2 [MþH]þ 370.1931, found 370.1929;
IR (neat, cmꢁ1
) nmax 3425, 1706, 1168.
5.1.4. Synthesis of compound 6
3-[[2-(6-fluoro-1H-indol-3-yl)ethylamino]methyl]phenol 6. To a
stirred solution of 16 (527 mg, 1.41 mmol, 1.0 equiv) in MeOH
(120 mL) was charged Pd/C 10% (150 mg, 10 mol%) and the mixture
was stirred for 60 h under H2 at room temperature. The mixture
was filtered through a pad of Celite and evaporated. The crude was
purified by flash chromatography on silica gel column (DCM/MeOH,
gradient 100:0 to 95:5) and to afford the compound 6 as a brown
powder (149 mg, 37% isolated yield). M. p. 70e80 ꢀC; 1H NMR
(DMSO, 400 MHz, 363 K)
d
10.02 (s, 1H), 7.76 (td, 1H, J ¼ 7.8, 1.2 Hz),
7.65 (dd, 1H, J ¼ 2.4, 1.2, 0.4 Hz), 7.61 (dd, 1H, J ¼ 7.8, 0.4 Hz), 7.46
(dd, 1H, J ¼ 7.8, 2.4, 1.2 Hz), 3.41 (q, 2H, J ¼ 7.1 Hz), 3.00 (s, 3H), 1.19
(t, 3H, J ¼ 7.1 Hz); 13C NMR (DMSO, 100 MHz, 363 K)
d 191.6, 152.8,
151.6, 137.2, 129.6, 127.2, 125.6, 121.4, 43.2, 33.3, 12.0.
5.1.3. General procedure for the synthesis of compounds (2, 7, 16)
Procedure A. To a stirred solution of amine (1.0 equiv) in MeOH,
was added aldehyde (1.1 equiv) with few drops of acetic acid was
stirred at rt for 1 night. NaBH4 (3.0 equiv) was added and the so-
lution was stirred at rt for 5 h. The solvent was removed in vacuo.
The crude was purified by flash chromatography on silica gel col-
umn (DCM/MeOH, gradient 100:0 to 80:20), and concentrated
under reduced pressure to afford amine compound.
(MeOD, 400 MHz, 295 K)
d
7.49 (dd, 1H, J ¼ 8.7, 5.2 Hz), 7.21 (t, 1H,
J ¼ 8.0 Hz), 7.12 (s, 1H), 7.06 (dd, 1H, J ¼ 10.0, 2.3 Hz), 6.89e6.85 (m,
2H), 6.84e6.78 (m, 2H), 4.00 (s, 2H), 3.17 (t, 2H, J ¼ 6.8 Hz), 3.09 (t,
2H, J ¼ 6.8 Hz); 13C NMR (MeOD, 100 MHz, 295 K)
d
161.2 (d, J ¼
235.3 Hz),159.1,138.1 (d, J ¼ 12.5 Hz),136.0,131.1,125.0,124.4 (d, J ¼
3.3 Hz), 121.4, 120.0 (d, J ¼ 10.3 Hz), 117.3, 116.8, 111.4, 108.4 (d, J ¼
24.9 Hz), 98.3 (d, J ¼ 26.0 Hz), 52.7, 49.0, 23.9; 19F NMR (MeOD,
2-(6-fluoro-1H-indol-3-yl)-N-[[3-(2,2,3,3-tetrafluoropropoxy)
374 MHz, 295 K)
d
ꢁ124.1 (td, J ¼ 9.8, 5.2 Hz); MS: m/z [MþH]þ
phenyl]methyl]ethanamine 2. Following procedure
(185 mg, 1.04 mmol) and 13, we obtained 2 as a brown oil (21 mg,
5% isolated yield). 1H NMR (MeOD, 400 MHz, 295 K)
7.43 (dd, 1H,
A
from 11
285.48; HRMS/ESI: m/z calcd. For C17H18FN2O [MþH]þ 285.1403,
found 285.1405. IR (neat, cmꢁ1
) nmax 3427.
d
J ¼ 8.7, 5.4 Hz), 7.24 (t, 1H, J ¼ 8.0 Hz), 7.03 (s, 1H), 7.02 (dd, 1H, J ¼
10.0, 2.4 Hz), 6.93 (m, 1H, H8), 6.92 (d, 1H, J ¼ 1.6 Hz), 6.88 (m, 1H),
6.76 (dd, 1H, J ¼ 9.8, 8.7, 2.4 Hz), 6.31 (tt, 1H, J ¼ 52.8, 5.4 Hz), 4.38
(tt, 2H, J ¼ 12.4, 1.6 Hz), 3.75 (s, 2H), 2.98e2.92 (m, 2H), 2.91e2.85
5.1.5. General procedure for the preparation of fumarate salts
(17e18)
Procedure B. To a stirred solution of basic compound (1.0 equiv)
in iPrOH was added fumaric acid (0.95 equiv). The solution was
refluxed for 1 h. The mixture was then concentrated in vacuo. The
residue was triturated in Et2O and then filtrated to yield the
fumarate salt.
3-[[2-(6-fluoro-1H-indol-3-yl)ethylamino]methyl]phenol fumaric
acid salt 17. Following procedure B with compound 6 (240 mg,
0.84 mmol), we obtained compound 17, as a brown yellow powder
(212 mg, 63 yield). M. p. > 250 ꢀC; 1H NMR (MeOD, 400 MHz, 295 K)
(m, 2H); 13C NMR (MeOD, 101 MHz, 295 K)
d
161.2 (d, J ¼ 253.2 Hz),
159.2, 142.4, 138.1 (d, J ¼ 12.1 Hz), 130.7, 125.4, 123.9 (d, J ¼ 3.0 Hz),
123.3,120.1 (d, J ¼ 10.1 Hz), 116.2 (tt, J ¼ 248.0, 26.6 Hz), 115.6, 114.6,
113.6, 110.0 (tt, J ¼ 247.5, 33.1 Hz), 108.0 (d, J ¼ 24.7 Hz), 98.2 (d, J ¼
25.8 Hz), 66.3 (t, J ¼ 29.4 Hz), 53.9, 50.1, 26.0; 19F NMR (MeOH,
376 MHz, 295 K)
d
ꢁ124.6 (td, 1F, J ¼ 9.9, 5.4 Hz), ꢁ127.4e127.5 (m,
2F), ꢁ141.6 (dt, 2F, J ¼ 52.8, 4.8 Hz); MS m/z [MþH]þ 399.52; HRMS/
ESI m/z calcd. For C20H20F5N2O [MþH]þ 399.1496, found 399.1502;
d
7.48 (dd,1H, J ¼ 8.7, 5.4 Hz), 7.25 (t,1H, J ¼ 8.1 Hz), 7.15 (s, 1H), 7.06
IR (neat, cmꢁ1
)
nmax 3425, 1104.
(dd, 1H, J ¼ 9.9, 2.3 Hz), 6.93e6.89 (m, 2H), 6.88e6.79 (m, 2H), 6.70
N-[(3-benzyloxyphenyl)methyl]-2-(6-fluoro-1H-indol-3-yl)ethan-
amine 16. Following procedure A with 11 (458 mg, 2.57 mmol) and
14, we obtained 16 as a brown powder (265 mg, 24% isolated yield).
(s, 2H), 4.13 (s, 2H), 3.28 (t, 2H, J ¼ 6.6 Hz), 3.14 (t, 2H, J ¼ 6.6 Hz); 13
C
NMR (MeOD, 101 MHz, 295 K)
d
171.3 (2C), 161.3 (d, J ¼ 235.6 Hz),
159.4, 138.2 (d, J ¼ 12.6 Hz), 136.2 (2C), 133.9, 131.4, 124.8, 124.7 (d,
J ¼ 3.6 Hz),121.6,119.9 (d, J ¼ 10.3 Hz),117.7,117.5,110.6,108.5 (d, J ¼
24.9 Hz), 98.5 (d, J ¼ 26.0 Hz), 52.1, 48.7, 23.2; 19F NMR (MeOD,
M. p. 128 ꢀC; 1H NMR (MeOD, 400 MHz, 295 K)
d
7.49 (dd, 1H, J ¼
8.6, 5.3 Hz), 7.42 (d, 2H, J ¼ 7.5 Hz), 7.34 (t, 2H, J ¼ 7.5 Hz), 7.33 (d,
1H, J ¼ 8.0 Hz), 7.28 (t, 1H, J ¼ 7.5 Hz), 7.15 (s, 1H), 7.13 (t, 1H, J ¼
2.0 Hz), 7.07 (dd,1H, J ¼ 9.6, 2.4 Hz), 7.05e7.02 (m, 2H), 6.82 (dd,1H,
J ¼ 9.6, 8.6, 2.4 Hz), 5.09 (s, 2H), 4.14 (s, 2H), 3.25 (t, 2H, J ¼ 7.5 Hz),
376 MHz, 295 K)
d
ꢁ124.0 (td, J ¼ 9.9, 5.4 Hz); MS m/z
[M þ HeC4H4O4]þ 285.50; HRMS/ESI m/z calcd. For C17H18FN2O
[MþH]þ 285.1403, found 285.1404; IR (neat, cmꢁ1
) nmax 3358, 3047,
9