Journal of Medicinal Chemistry
Article
1
3
1
1
.64 (s, 6H), 3.76 (s, 3H), 3.92 (m, 4H), 6.33 (s, 2H), 7.15 (t, J = 7.1 Hz,
H), 7.32 (t, J = 7.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.1 Hz,
188−191 °C (from ethanol). H NMR (CDCl ): δ 3.65 (s, 6H), 3.76
3
(s, 3H), 6.33 (s, 2H), 7.22 (m, 1H), 7.31 (m, 1H), 7.37−7.41 (m 1H),
7.48 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 8.16−8.17 (m, 1H),
8.62 (m, 1H), 9.02 (m, 1H), 9.26 ppm (broad s, disappeared on
treatment with D O, 1H). C NMR (DMSO-d ): δ 56.28, 60.48, 98.8,
103.33, 112.63, 119.31, 121.21, 123.66, 124.12, 127.75, 130.72, 133.85,
135.99, 136.82, 139.7, 149.19, 149.68, 153.77 ppm. IR: ν 2923, 3674
cm . Anal. (C H N O S (392.47)) C, H, N.
2-(Pyridin-4-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
(57). 57 was synthesized similarly to 17, starting from 94. Yield 60% as a
H), 8.31 (broad s, disappeared on treatment with D O, 1H), 12.10
2
ppm (broad s, disappeared on treatment with D O, 1H). IR: ν 2852,
2
2
−1
13
921 cm . Anal. (C H N O S (383.46)) C, H, N, S.
20
21
3
3
2
6
2-Phenyl-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (34). 34
was synthesized similarly to 17, starting from 84. Yield 3%, mp 158−160
1
−1
°
C (from ethanol). H NMR (CDCl ): δ 3.64 (s, 6H), 3.78 (s, 3H), 6.37
3
22 20
2
3
(
s, 2H), 7.18−7.22 (m, 1H), 7.27−7.30 (m, 2H), 7.41−7.50 (m, 3H),
7
.69 (d, J = 7.9 Hz, 1H), 7.80−7.82 (m, 2H), 8.56 ppm (broad s,
−1
1
disappeared on treatment with D O, 1H). IR: ν 3329 cm . Anal.
yellow solid, mp 215−218 °C (from ethanol). H NMR (DMSO-d ): δ
2
6
(
C H NO S (391.48)) C, H, N, S.
3.53 (s, 6H), 3.57 (s, 3H), 6.32 (s, 2H), 7.14−7.18 (m, 1H), 7.27−7.31
(m, 1H), 7.53−7.57 (m, 2H), 7.92 (dd, J = 1.7 and 4.5 Hz, 2H), 8.71 (dd,
J = 1.6 and 4.5 Hz, 2H), 12.36 ppm (broad s, disappeared on treatment
23
21
3
2
-(4-Chlorophenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-in-
dole (38). 38 was synthesized similarly to 17, starting from 85. Yield
1
13
1
6
7
1%, mp 190−195 °C (from ethanol). H NMR (CDCl ): δ 3.64 (s,
3
with D O, 1H). C NMR (DMSO-d ): δ 56.27, 60.47, 100.49, 103.60,
2
6
H), 3.78 (s, 3H), 6.34 (s, 2H), 7.19−7.23 (m, 1H), 7.29−7.31 (m, 1H),
.43−7.46 (m, 3H), 7.68−7.70 (m, 1H), 7.72−7.75 (m, 2H), 8.59 ppm
1
1
12.82, 119.63, 121.38, 122.5, 124.25, 130.89, 133.39, 135.99, 136.92,
38.76, 139.02, 150.52, 153.8 ppm. IR: ν 3320 cm− . Anal.
1
−1
(
broad s, disappeared on treatment with D O, 1H). IR: ν 3335 cm .
2
(C H N O S (392.47)) C, H, N.
2-Cyclobutyl-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
(73). 73 was synthesized similarly to 17, starting from 95. Yield 56%, mp
22 20 2 3
Anal. (C H ClNO S (425.93)) C, H, N, Cl, S.
23
20
3
2
-(2-Fluorophenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-in-
dole (39). 39 was synthesized similarly to 17, starting from 86. Yield
1
1
49−153 °C (from ethanol). H NMR (DMSO-d ): δ 1.85−1.92
6
1
3
9% mp 175−180 °C (from toluene). H NMR (DMSO-d ): δ 3.54
6
(m, 1H), 1.98−2.10 (m, 1H), 2.23−2.28 (m, 2H), 2.28−2.30 (m, 2H),
(
s, 6H), 3.56 (s, 3H), 6.26 (s, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.24 (t, J =
2
7
.57 (s, 9H), 3.94−4.03 (m, 1H), 6.27 (s, 2H), 7.01−7.05 (m, 1H),
.11−7.15 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H),
7
1
.8 Hz, 1H), 7.33−7.42 (m, 2H), 7.49−7.54 (m, 3H), 7.65 (t, J = 7.5 Hz,
H), 12.07 ppm (broad s, disappeared on treatment with D O, 1H). IR:
2
11.74 ppm (broad s, disappeared on treatment with D O, 1H). IR: ν
2
−1
ν 3342 cm . Anal. (C H FNO S (409.47)) C, H, N, F, S.
−1
23
20
3
3361 cm . Anal. (C H NO S (369.48)) C, H, N, S.
21
23
3
2
-(3-Fluorophenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-in-
2
-Cyclopentyl-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
dole (41). 41 was synthesized similarly to 17, starting from 87. Yield
(
75). 75 was synthesized similarly to 17, starting from 96. Yield 56%, mp
1
6
3
7
5%, mp 180−185 °C (from toluene). H NMR (DMSO-d ): δ 3.59 (s,
1
6
178−183 °C (from ethanol). H NMR (DMSO-d ): δ 1.66−1.68 (m,
6
H), 3.64 (s, 6H), 6.79 (s, 2H), 7.07−7.35 (m, 5H), 7.45−7.48 (m, 1H),
.52 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 12.27 (broad s,
2
H), 1.17−1.85 (m, 4H), 1.95−1.98 (m, 2H), 3.52−3.54 (m, 1H), 3.56
(
(
s, 6H), 3.57 (s, 3H), 6.28 (s, 2H), 7.0−7.04 (m, 1H), 7.09−7.13
−1
disappeared on treatment with D O, 1H). IR: ν 1571, 3187 cm . Anal.
2
m, 1H), 7.36−7.41 (m, 2H), 11.51 ppm (broad s, disappeared on treat-
(
C H FNO (405.42)) C, H, N, F, S.
−1
24
20
4
ment with D O, 1H). IR: ν 3331 cm . Anal. (C H NO S (383.50)) C,
2
22 25
3
2
-(4-Fluorophenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-in-
H, N, S.
-Cyclohexyl-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
77). 77 was synthesized similarly to 17, starting from 97. Yield 48%, mp
dole (43). 43 was synthesized similarly to 17, starting from 88. Yield
2
1
3
7%, mp 170−175 °C (from toluene). H NMR (DMSO-d ): δ 3.53
6
(
(
s, 6H), 3.57 (s, 3H), 6.30 (s, 2H), 7.12 (t, J = 7.0 Hz, 1H), 7.23 (t, J =
.4 Hz, 1H), 7.38 (t, J = 8.9 Hz, 2H), 7.49 (t, J = 7.2 Hz, 2H), 7.90−7.93
m, 2H), 12.09 (broad s, disappeared on treatment with D O, 1H). IR:
1
2
14−219 °C (from ethanol). H NMR (DMSO-d ): δ 1.24−1.42
6
7
(
(
(
(
m, 3H), 1.66−1.83 (m, 7H), 3.09−3.17 (m, 1H), 3.56 (s, 6H), 3.57
2
s, 3H), 6.28 (s, 2H), 7.0−7.02 (m, 1H), 7.09−7.13 (m, 1H), 7.35−7.41
−1
ν 3318 cm . Anal. (C H FNO S (409.47)) C, H, N, F, S.
23
20
3
m, 2H), 11.52 ppm (broad s, disappeared on treatment with D O, 1H).
2
2
-(2-Methoxyphenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-
−1
IR: ν 3327 cm . Anal. (C H NO S (397.53)) C, H, N, S.
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27
3
indole (45). 45 was synthesized similarly to 17, starting from 89. Yield
1
General Procedure for the Preparation of Compounds 14, 16,
7, 48, 59, 62, and 72. Example: 2-(1H-Pyrazol-4-yl)-3-((3,4,5-
5
3
%, mp 160−165 °C (from ethanol). H NMR (CDCl ): δ 3.64 (s, 6H),
3
3
.77 (s, 3H), 3.92 (s, 3H), 6.35 (s, 2H), 7.04−7.08 (m, 2H), 7.15−7.19
trimethoxyphenyl)thio)-1H-indole (14). 2-(1H-Pyrazol-4-yl)-1H-
indole (98) (0.08 g, 0.000 44 mol) was added to an ice-cooled sus-
pension of NaH (0.058 g, 0.001 45 mol, 60% dispersion in mineral oil)
in anhydrous DMF (3 mL) under an Ar stream. After 15 min, bis(3,4,5-
trimethoxyphenyl)disulfide (0.21 g, 0.000 53 mol) was added, and the
reaction mixture was heated at 60 °C for 12 h under an Ar stream. After
cooling, the reaction mixture was quenched on crushed ice and extracted
with ethyl acetate. The organic layer was washed with brine, dried, and
filtered. Removal of the solvent gave a residue that was purified by
column chromatography (silica gel, ethyl acetate/n-hexane = 7:3) to
(
m, 1H), 7.25−7.29 (m, 1H), 7.36−7.40 (m, 1H), 7.45−7.47 (m, 1H),
.67−7.69 (m, 1H), 7.97−7.99 (m, 1H), 9.40 ppm (broad s, disappeared
7
−1
on treatment with D O, 1H). IR: ν 3338 cm . Anal. (C H NO S
2
24 23
4
(
421.51)) C, H, N, S.
-(3-Methoxyphenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-
indole (46). 46 was synthesized similarly to 17, starting from 90. Yield
2
1
4
3
%, mp 192−194 °C (from ethanol). H NMR (CDCl ): δ 3.63 (s, 6H),
3
.75 (s, 3H), 3.76 (s, 3H), 6.36 (s, 2H), 6.93−6.96 (m, 1H), 7.18−7.21
(
m, 1H), 7.25−7.40 (m, 4H), 7.44−7.46 (m, 1H), 7.69−7.71 (m, 1H),
.57 ppm (broad s, disappeared on treatment with D O, 1H). IR: ν 3333
8
2
1
−1
furnish 14 (0.1 g, 59%), mp 178−182 °C (from ethanol). H NMR
cm . Anal. (C H NO S (421.51)) C, H, N, S.
24
23
4
(
(
DMSO-d ): δ 3.53 (s, 6H), 3.57 (s, 3H), 6.33 (s, 2H), 7.06−7.10
6
2
-(4-Methoxyphenyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-
m, 1H), 7.15−7.19 (m, 1H), 7.44−7.46 (m, 2H), 8.23 (m, 2H), 11.88
indole (47). 47 was synthesized similarly to 17, starting from 91. Yield
1
(broad s, disappeared on treatment with D O, 1H), 13.17 ppm (broad s,
8
3
%, mp 165−170 °C (from ethanol). H NMR (CDCl ): δ 3.63 (s, 6H),
2
3
−1
disappeared on treatment with D O, 1H). IR: ν 3158, 3291 cm . Anal.
C H N O S (381.45)) C, H, N, S.
.78 (s, 3H), 3.85 (s, 3H), 6.37 (s, 2H), 6.97−6.99 (m, 2H), 7.17−7.23
2
(
(
m, 2H), 7.41−7.43 (m, 1H), 7.66−7.74 (m, 3H), 8.68 ppm (broad s,
20 19 3 3
−1
2-(1H-Pyrazol-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-in-
22
disappeared on treatment with D O, 1H). IR: ν 3324 cm . Anal.
2
dole (16). 16 was synthesized similarly to 14, starting from 99. Yield
(
C H NO S (421.51)) C, H, N, S.
24 23 4
1
3
5%, mp 194−197 °C (from ethanol). H NMR (DMSO-d ): δ 3.51
2
-(Pyridin-2-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
6
(
s, 6H), 3.55 (s, 3H), 6.35 (s, 2H), 6.97−6.98 (m, 1H), 7.07 (t, J =
(
53). 53 was synthesized similarly to 17, starting from 92. Yield 26% as
1
7
1
.6 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.46−7.49 (m, 2H), 7.83 (s, 1H),
an oil. H NMR (CDCl ): δ 3.63 (s, 6H), 3.76 (s, 3H), 6.39 (s, 2H), 7.18
3
1.97 (broad s, disappeared on treatment with D O, 1H), 13.23 ppm
(
7
(
t, J = 7.1 Hz, 1H), 7.24−7.27 (m, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.70−
.77 (m, 2H), 8.63−8.64 (m, 1H), 8.73 (d, J = 8.1 Hz, 1H), 10.23 ppm
broad s, disappeared on treatment with D O, 1H). IR: ν 2828, 2933,
2
(broad s, disappeared on treatment with D O, 1H). IR: ν 2936, 3348
cm . Anal. (C20H N O S (381.45)) C, H, N, S.
19 3 3
2-(p-Tolyl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (37).
37 was synthesized similarly to 14, starting from 100. Yield 72%, mp
2
−
1
2
−1
3
003, 3056 cm . Anal. (C H N O S (392.47)) C, H, N, S.
22
20
2
3
2
-(Pyridin-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
1
(55). 55 was synthesized similarly to 17, starting from 93. Yield 20%, mp
168−171 °C (from ethanol). H NMR (DMSO-d ): δ 2.36 (s, 3H), 3.52
6
P
dx.doi.org/10.1021/jm3013097 | J. Med. Chem. XXXX, XXX, XXX−XXX