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by preparative HPLC (20–100% CH3CN/MeOH (1:1) in H2O (0.01%
TFA)) which provided after lyophilization 32 mg (52%) of the title
compound 35 as a colorless solid; 1H NMR (400 MHz, CDCl3): d=
8.10 (s, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.66–
7.58 (m, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.21
(d, J=7.0 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H),
6.68 (dd, J=2.4, 8.3 Hz, 1H), 5.23 (s, 2H), 3.98 (t, J=8.4 Hz, 2H),
2.88 (t, J=8.4 Hz, 2H), 2.48 ppm (s, 3H).
6-((3,5-dichloropyridin-4-yl)methoxy)-1-((3-(trifluoromethyl)phe-
nyl)sulfonyl)indoline 40: The title compound was prepared ac-
cording to General Procedure C from 1-((3-(trifluoromethyl)phenyl)-
sulfonyl)indolin-6-ol 26 (30 mg, 0.09 mmol) and 4-(bromomethyl)-
3,5-dichloropyridine (32 mg, 0.13 mmol). The crude product was
purified by preparative HPLC (20–100% CH3CN/MeOH (1:1) in H2O
(0.01% TFA)) which provided after lyophilization 33 mg (61%) of
the title compound 40 as a colorless solid as TFA salt; 1H NMR
(400 MHz, CDCl3): d=8.58 (s, 2H), 8.09 (s, 1H), 7.99 (d, J=7.8 Hz,
1H), 7.84 (d, J=7.8 Hz, 1H), 7.68–7.58 (m, 1H), 7.36 (d, J=2.3 Hz,
1H), 7.02 (d, J=8.1 Hz, 1H), 6.66 (dd, J=2.4, 8.2 Hz, 1H), 5.27 (s,
2H), 3.97 (t, J=8.3 Hz, 2H), 2.88 ppm (t, J=8.3 Hz, 2H); MS (ESI+)
m/z: 502.73 [M+H+].
6-((2,6-dimethylbenzyl)oxy)-1-((3-(trifluoromethyl)phenyl)sulfo-
nyl)indoline 36: The title compound was prepared according to
General Procedure B from 1-((3-(trifluoromethyl)phenyl)sulfonyl)in-
dolin-6-ol 26 (40 mg, 0.12 mmol) and (2,6-dimethylphenyl)metha-
nol (17 mg, 0.12 mmol). The crude product was purified by prepa-
rative HPLC (20–100% CH3CN/MeOH (1:1) in H2O (0.01% TFA))
which provided after lyophilization 28 mg (52%) of the title com-
6-((3-chloro-5-fluoropyridin-4-yl)methoxy)-1-((3-(trifluorome-
thyl)phenyl)sulfonyl)indoline 41: The title compound was pre-
pared according to General Procedure C from 1-((3-(trifluorome-
thyl)phenyl)sulfonyl)indolin-6-ol 26 (20 mg, 0.06 mmol) and 4-(bro-
momethyl)-3-chloro-5-fluoropyridine (16 mg, 0.07 mmol). The
crude product was purified by preparative HPLC (20–100% CH3CN/
MeOH (1:1) in H2O (0.01% TFA)) which provided after lyophilization
24 mg (69%) of the title compound 41 as a colorless solid as TFA
1
pound 36 as a colorless solid; H NMR (400 MHz, CDCl3): d=8.10 (s,
1H), 7.98 (d, J=7.8 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.64–7.58 (m,
1H), 7.37 (d, J=2.3 Hz, 1H), 7.23–7.17 (m, 1H), 7.11 (d, J=7.6 Hz,
2H), 7.02 (d, J=8.1 Hz, 1H), 6.67 (dd, J=2.4, 8.2 Hz, 1H), 5.07 (s,
2H), 3.98 (t, J=8.3 Hz, 2H), 2.88 (t, J=8.3 Hz, 2H), 2.43 ppm (s,
6H).
1
salt; H NMR (400 MHz, CDCl3): d=8.53 (s, 1H), 8.47 (s, 1H), 8.08 (s,
6-((2-chloro-6-(trifluoromethyl)benzyl)oxy)-1-((3-(trifluorome-
thyl)phenyl)sulfonyl)indoline 37: The title compound was pre-
pared according to General Procedure B from 1-((3-(trifluorome-
thyl)phenyl)sulfonyl)indolin-6-ol 26 (40 mg, 0.12 mmol) and (2-
chloro-6-(trifluoromethyl)phenyl)methanol (26 mg, 0.12 mmol). The
crude product was purified by preparative HPLC (20–100% CH3CN/
MeOH (1:1) in H2O (0.01% TFA)) which provided after lyophilization
1H), 7.97 (d, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.66–7.57 (m,
1H), 7.34 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.64 (dd, J=
2.4, 8.1 Hz, 1H), 5.22 (d, J=1.5 Hz, 2H), 3.97 (t, J=8.3 Hz, 2H),
2.87 ppm (t, J=8.3 Hz, 2H); MS (ESI+) m/z: 486.90 [M+H+].
6-((3-chloro-5-(trifluoromethyl)pyridin-4-yl)methoxy)-1-((3-(tri-
fluoromethyl)phenyl)sulfonyl)indoline 42: The title compound
was prepared according to General Procedure C from 1-((3-(trifluor-
omethyl)phenyl)sulfonyl)indolin-6-ol 26 (20 mg, 0.06 mmol) and 4-
1
35 mg (56%) of the title compound 37 as a colorless solid; H NMR
(400 MHz, CDCl3): d=8.10 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.83 (d,
J=7.8 Hz, 1H), 7.72–7.68 (m, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.52–7.42
(m, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.66 (dd,
J=2.4, 8.2 Hz, 1H), 5.26 (s, 2H), 3.98 (t, J=8.5 Hz, 2H), 2.88 ppm (t,
J=8.3 Hz, 2H).
(bromomethyl)-3-chloro-5-(trifluoromethyl)pyridine
(18 mg,
0.07 mmol, obtained by the same synthetic pathway than 4-(bro-
momethyl)-3-chloro-5-fluoropyridine). The crude product was puri-
fied by preparative HPLC (20–100% CH3CN/MeOH (1:1) in H2O
(0.01% TFA)) which provided after lyophilization 22 mg (65%) of
the title compound 42 as a colorless solid as TFA salt; 1H NMR
(400 MHz, CDCl3): d=8.91 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 8.00 (d,
J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.69–7.59 (m, 1H), 7.33 (d,
J=2.5 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.64 (dd, J=2.3, 8.3 Hz, 1H),
5.24 (s, 2H), 3.98 (t, J=8.3 Hz, 2H), 2.89 ppm (t, J=8.1 Hz, 2H); MS
(ESI+) m/z: 536.81 [M+H+].
6-((3-methoxypyridin-2-yl)methoxy)-1-((3-(trifluoromethyl)phe-
nyl)sulfonyl)indoline 38: The title compound was prepared ac-
cording to General Procedure C from 1-((3-(trifluoromethyl)phenyl)-
sulfonyl)indolin-6-ol 26 (30 mg, 0.09 mmol) and 2-(bromomethyl)-
3-methoxypyridine (26 mg, 0.13 mmol). The crude product was pu-
rified by preparative HPLC (20–100% CH3CN/MeOH (1:1) in H2O
(0.01% TFA)) which provided after lyophilization 43 mg (85%) of
the title compound 38 as a colorless solid as TFA salt; 1H NMR
(400 MHz, CDCl3): d=8.52 (d, J=4.4 Hz, 1H), 8.05 (s, 1H), 7.88 (d,
J=7.9 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.77–7.66 (m, 2H), 7.64–7.57
(m, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.76 (dd,
J=2.2, 8.3 Hz, 1H), 5.38 (s, 2H), 4.07 (s, 3H), 3.92 (t, J=8.3 Hz, 2H),
2.82 ppm (t, J=8.3 Hz, 2H); MS (ESI+) m/z: 464.88 [M+H+].
6-((2-chloro-6-fluorobenzyl)oxy)-1H-indole 27: The title com-
pound was prepared according to General Procedure C from 6-hy-
droxyindole 24 (400 mg, 3.00 mmol) and 2-(bromomethyl)-1-
chloro-3-fluorobenzene (738 mg, 3.11 mmol). The crude product
was purified by Combiflash silica gel chromatography (0–20% of
EtOAc in hexane), which provided 565 mg (68%) of the title com-
1
pound 27 as a colorless solid; H NMR (400 MHz, CDCl3): d=8.09 (s,
6-((2,4-dichloropyridin-3-yl)methoxy)-1-((3-(trifluoromethyl)phe-
nyl)sulfonyl)indoline 39: The title compound was prepared ac-
cording to General Procedure C from 1-((3-(trifluoromethyl)phenyl)-
sulfonyl)indolin-6-ol 26 (25 mg, 0.07 mmol) and 3-(bromomethyl)-
2,4-dichloropyridine (35 mg, 0.15 mmol). The crude product was
purified by preparative HPLC (20–100% CH3CN/MeOH (1:1) in H2O
(0.01% TFA)) which provided after lyophilization 25 mg (56%) of
the title compound 39 as a colorless solid as TFA salt; 1H NMR
(400 MHz, CDCl3): d=8.35 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 8.00 (d,
J=8.1 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.66–7.60 (m, 1H), 7.41 (d,
J=5.3 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.67
(dd, J=2.4, 8.2 Hz, 1H), 5.29 (s, 2H), 3.98 (t, J=8.5 Hz, 2H),
2.88 ppm (t, J=8.5 Hz, 2H); MS (ESI+) m/z: 502.79 [M+H+].
1H), 7.55 (d, J=8.6 Hz, 1H), 7.35–7.23 (m, 1H), 7.15 (dd, J=2.4,
3.3 Hz, 1H), 7.10–7.03 (m, 2H), 6.92 (dd, J=2.2, 8.8 Hz, 1H), 6.54–
6.51 (m, 1H), 5.24 ppm (d, J=2.0 Hz, 2H); MS (ESI+) m/z: 276.07
[M+H+].
Synthesis of 6-((2-chloro-6-fluorobenzyl)oxy)indoline 28: The
title compound was prepared according to General Procedure A
from 6-((2-chloro-6-fluorobenzyl)oxy)-1H-indole 27 (200 mg,
0.72 mmol). The extraction provided 200 mg (100%) of the title
compound 28 as a colorless solid which was used without further
1
purification; H NMR (400 MHz, CDCl3): d=7.33–7.17 (m, 3H), 7.08–
7.00 (m, 2H), 6.37 (dd, J=2.2, 8.3 Hz, 1H), 5.12 (d, J=2.0 Hz, 2H),
3.58 (t, J=8.3 Hz, 2H), 2.98 ppm (t, J=8.3 Hz, 2H); MS (ESI+) m/z:
278.11 [M+H+].
ChemMedChem 2016, 11, 1 – 15
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