Journal of Medicinal Chemistry
Article
(s), 127.36 (s), 123.48 (s), 121.30 (s), 114.71 (s), 112.37 (s), 102.68
(s).
Synthesis of Alk-1-en-1-yl-1H-indoles. Compounds 13, 22
([alk-1-en-1-yl] derivatives at C-2), 31 (5-Cl analogue), and 38 (6-Cl
analogue) were synthesized as shown for 22:
177.9, 170.6, 140.6, 136.0, 128.2, 124.6, 123.9, 120.4, 116.3, 109.3,
36.5, 34.5, 32.6, 32.1, 31.7, 29.0, 22.6, 19.5, 14.1.
5-(6-Hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (18). Yield: 66%.
HRMS (ESI) m/z calcd for [C19H25NO3 + H]+: 316.1913, found
1
316.1909. H NMR (CDCl3): δ 8.24 (s, 1H), 7.38 (d, J = 8.08 Hz,
2-Hex-1-enyl-1H-indole (22). To a stirred suspension of
phosphonium salt 21 (973 mg, 2.36 mmol) in anhydrous THF (4
mL) was added LiHMDS (1.0 M in THF, 2.12 mL, 2.12 mmol) at
−40οC under argon. The mixture was stirred for 20 min, cooled to
−78οC, and a solution of aldehyde 11 (114 mg, 0.785 mmol) in 0.5
mL of dry THF was added. The reaction mixture was stirred at −78
°C for 1 h, warmed to 25 °C, stirred for 3 h, quenched with saturated
NH4Cl solution, and extracted with EtOAc. The organic layers were
combined and dried over Na2SO4. The solvent was evaporated under
reduced pressure, and the crude residue was purified by silica gel
chromatography using (15:85) EtOAc/Hex as eluent to afford 22 as
pale-yellow solid (142 mg, 85.0%). HRMS (ESI) m/z calcd for
1H), 7.32 (d, J = 3.54 Hz, 1H), 7.04 (d, J = 8.08 Hz, 1H), 6.52 (d, J =
3.54 Hz, 1H), 2.95 (t, J = 6.95 Hz, 2H), 2.65 (t, J = 7.71 Hz, 2H), 2.52
(t, J = 6.82 Hz, 2H), 2.05−2.17 (m, 2H), 1.59 (qt, J = 7.33 Hz, 2H),
1.15−1.33 (m, 6H), 0.80 (t, J = 6.44 Hz, 3H). 13C NMR (CDCl3): δ
177.9, 170.6 140.7, 136.0, 128.2, 124.6, 123.9, 116.3, 109.3, 36.5, 34.5,
32.6, 32.1, 31.7, 29.0, 22.6, 19.4, 14.1.
5-(7-Hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (19). Yield: 74%.
HRMS (ESI) m/z calcd for [C19H25NO3 + H]+: 316.1913, found
316.1917. 1H NMR (CDCl3): δ 7.47 (d, J = 3.79 Hz, 1H), 7.42 (d, J =
7.33 Hz, 1H), 7.19−7.27 (m, 2H), 6.66 (d, J = 3.79 Hz, 1H), 3.01−
3.12 (m, 4H), 2.61 (t, J = 6.95 Hz, 2H), 2.18−2.27 (m, 2H), 2.01−
2.09 (m, 2H), 1.46−1.55 (m, 2H), 1.24−1.37 (m, 4H), 0.88 (t, 3H).
13C NMR (CDCl3): δ 177.6, 169.9, 134.3, 132.3, 131.7, 127.3, 126.0,
124.1, 118.7, 109.3, 35.7, 35.4, 31.8, 30.2, 29.7, 29.3, 22.6, 20.2, 14.1.
5-(2-Butyl-1H-indol-1-yl)-5-oxo-valeric Acid (24). Yield: 68.0%.
HRMS (ESI) m/z calcd for [C17H21NO3 + H]+: 288.1600, found
1
[C14H17N + H]+: 200.1439, found 200.1443. H NMR (CDCl3): δ
7.98 (s, 1H), 7.45−7.47 (d, 1H), 7.21−7.23 (d, 1H), 7.06 (t, 1H), 6.98
(t, 1H), 6.32−6.44 (m, 2H), 5.95−6.02 (m, J = 16.04 Hz, 1H), 2.15−
2.20 (q, 2H), 1.29−1.44 (m, 4H), 0.86 (t, 3H).
Synthesis of alkyl-1H-indoles. Compounds 14, 23, 32 (5-Cl
analogue), and 38 (6-Cl analogue) were synthesized as shown for 2-
hex-1-enyl-1H-indole (23):
1
288.1596. H NMR (CDCl3): δ 7.72 (d, J = 7.83 Hz, 1H), 7.37−7.42
(m, 1H), 7.09−7.19 (m, 2H), 6.33 (s, 1H), 3.05 (t, J = 6.95 Hz, 2H),
2.92 (t, J = 7.58 Hz, 2H), 2.50 (t, J = 7.07 Hz, 2H), 2.12 (qt, J = 7.01
Hz, 2H), 1.61 (qt, J = 7.52 Hz, 2H), 1.37 (m, 2H), 0.89 (t, J = 7.20 Hz,
3H). 13C NMR (CDCl3): δ 178.5, 172.7, 143.1, 136.0, 130.1, 123.4,
123.0, 120.2, 114.7, 108.3, 37.9, 32.8, 31.1, 30.4, 22.5, 19.9, 13.9.
5-(2-Pentyl-1H-indol-1-yl)-5-oxo-valeric Acid (25). Yield: 40%.
HRMS (ESI) m/z calcd for [C18H23NO3 + H]+: 302.1756, found
2-Hexyl-1H-indole (23). To a stirred solution of 22 (35 mg, 0.16
mmol) in anhydrous EtOH (1 mL) was added 10% PD/C (10% wt) at
rt under H2 atmosphere and stirred for 6 h. The reaction mixture was
filtered through Celite/florisil. The filtrate was concentrated under
reduced pressure and the crude residue purified by silica gel
chromatography using (1:9) Et2O/Hex solvent as eluent to afford
23 as white solid (32 mg, 90%). HRMS (ESI) m/z calcd for [C14H19N
1
302.1756. H NMR (CDCl3): δ 7.69 (d, J = 6.93 Hz, 1H), 7.32−7.39
(m, 1H), 6.98−7.12 (m, 2H), 6.27 (s, 1H), 3.18 (t, J = 7.23 Hz, 2H),
2.98 (t, J = 7.68 Hz, 2H), 2.50 (t, J = 7.16 Hz, 2H), 2.21 (m 2H), 1.58
(qt, J = 7.52 Hz, 2H), 1.04 (m, 4H), 0.92 (t, J = 6.97 Hz, 3H). 13C
NMR (CDCl3): δ 179.1, 173.2, 144.7, 135.6, 129.8, 122.7, 121.9,
119.5, 113.8, 109.1, 38.2, 32.7, 31.5, 30.8, 23.1, 22.5, 19.7, 13.9.
5-(2-Heptyl-1H-indol-1-yl)-5-oxo-valeric Acid (27). Yield: 46%.
HRMS (ESI) m/z calcd for [C20H27NO3 + H]+: 330.2069, found
1
+ H]+: 202.1596, found 202.1596. H NMR (CDCl3): δ 7.8 (s, 1H),
7.45 (d, 1H), 7.22 (d, 1H), 6.93−7.08 (m, 2H), 6.14 (s, 1H), 2.68 (t,
2H), 1.59−1.60 (m, 2H), 1.15−1.38 (m, 6H), 0.82 (t, 3H).
Synthesis of Alkyl-(5-oxo-valeric acid)indoles. Compounds
16−19 (hexyl at C-3, 5, 6, and 7), 24−29 (alkyl at C-2 = butyl 24,
pentyl 25, hexyl 26, heptyl 27, octyl 28, and undecyl 29), 33 (5-Cl
analogue), and 39 (6-Cl analogue) were synthesized using the general
procedure for 24 as follows:
1
330.2058. H NMR (CDCl3): δ 7.72 (d, J = 7.83 Hz, 1H), 7.37−7.43
(m, 1H), 7.10−7.20 (m, 2H), 6.34 (s, 1H), 3.06 (t, J = 7.07 Hz, 2H),
2.92 (t, J = 7.58 Hz, 2H), 2.51 (t, J = 7.07 Hz, 2H), 2.12 (qt, J = 7.07
Hz, 2H), 1.62 (qt, J = 7.45 Hz, 2H), 1.15−1.39 (m, 8H), 0.77−0.85 (t,
3H). 13C NMR (CDCl3): δ 172.7, 143.1, 136.0, 130.0, 123.4, 122.9,
120.0, 114.7, 108.3, 37.9, 32.8, 31.8, 30.7, 29.4, 29.2, 29.0, 22.6, 20.0,
14.1.
5-(2-Hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (26). To a solution of
23 (32 mg, 0.16 mmol) in anhydrous DMSO was added crushed KOH
(44.5 mg, 0.795 mmol) at rt under nitrogen. The reaction mixture was
stirred for 30 min, followed by addition of glutaric anhydride 15 (90.6
mg, 0.795 mmol). The stirring was continued for 3 h. The reaction
mixture was quenched with saturated NH4Cl solution and extracted
with EtOAc, and the organic layers combined and dried over Na2SO4.
The solvent was evaporated under reduced pressure, and the crude
residue was purified by silica gel chromatography using 50% EtOAc/
Hex as eluent to afford 26 as a white solid (30.1 mg, 60%). HRMS
(ESI) m/z calcd for [C19H25NO3 + H]+: 316.1913, found 316.1913.
1H NMR (CDCl3): δ 7.82 (1H, d), 7.49−7.51 (1H, m), 7.21−7.28
(2H, m), 6.43 (1H, s), 3.15 (2H, t), 3.02 (2H, t), 2.6 (2H, t), 2.18−
2.25 (2H, m), 1.68−1.76 (2H, m), 1.28−1.47 (6H, m), 0.93 (3H, t).
13C NMR (CDCl3): δ 179.1, 172.7, 143.1, 136.0, 130.1, 123.4, 123.0,
120.2, 114.8, 108.3, 37.9, 32.9, 31.7, 30.7, 29.2, 28.9, 22.6, 19.8, 14.1.
5-(3-Hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (16). Yield: 72%.
HRMS (ESI) m/z calcd for [C19H25NO3 + H]+: 316.1913, found
316.1904. 1H NMR (CDCl3): δ 8.46 (1H, s), 7.55 (1H, d), 7.37 (1H,
t), 7.28−7.32 (2H, m), 7.24 (1H, s), 3.03 (2H, t), 2.67−2.72 (2H, m),
2.62 (2H, t), 2.16−2.23 (2H, m), 1.69−1.77 (2H, m), 1.28−1.45 (6H,
m), 0.92 (3H, t). 13C NMR (CDCl3): δ 178.1, 170.3, 136.1, 130.8,
125.2, 123.8, 123.4, 120.7, 119.0, 116.7, 34.6, 32.7, 31.7, 29.3, 29.1,
25.0, 22.6, 19.4, 14.1.
5-(2-Octyl-1H-indol-1-yl)-5-oxo-valeric Acid (28). Yield: 65.5%.
HRMS (ESI) m/z calcd for [C21H29NO3 + H]+: 344.2226, found
1
344.2222. H NMR (CDCl3): δ 7.71 (d, J = 7.58 Hz, 1H), 7.36−7.43
(m, 1H), 7.10−7.20 (m, 2H), 6.33 (s, 1H), 3.03−3.12 (m, 1H), 2.87−
2.96 (m, 3H), 2.71 (qd, J = 6.68, 13.29 Hz, 1H), 2.52 (dd, J = 6.32,
15.66 Hz, 1H), 2.34 (dd, J = 7.20, 15.54 Hz, 1H), 1.62 (qt, J = 7.52
Hz, 2H), 1.28−1.39 (m, 3H), 1.14−1.28 (m, 8H), 1.08 (d, J = 6.82
Hz, 3H), 0.76−0.85 (t, 3H). 13C NMR (CDCl3): δ 177.6, 172.3,
143.0, 136.0, 130.0, 123.3, 122.9, 120.2, 114.7, 108.2, 45.2, 40.4, 31.8,
30.6, 29.5, 29.2, 29.0, 27.2, 22.6, 19.9, 14.1.
5-(2-Undecyl-1H-indol-1-yl)-5-oxo-valeric Acid (29). Yield: 46%.
HRMS (ESI) m/z calcd for [C24H35NO3 + H]+: 386.2695, found
386.2674. 1H NMR (CDCl3): δ 7.80 (d, J = 7.6 Hz, 1H), 7.48 (d, J =
6.8 Hz, 1H), 7.22 (dd, J = 12.1, 7.1 Hz, 2H), 6.41 (s, 1H), 3.13 (t, J =
6.4 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.58 (t, J = 6.5 Hz, 2H), 2.26−
2.14 (m, 2H), 1.77−1.62 (m, 2H), 1.49−1.18 (m, 18H), 0.89 (t, J =
5.8 Hz, 3H). 13C NMR (CDCl3): δ 178.72 (s), 172.70 (s), 143.16 (s),
135.99 (s), 130.06 (s), 123.42 (s), 122.96 (s), 120.25 (s), 114.78 (s),
108.27 (s), 37.91 (s), 32.84 (s), 31.93 (s), 30.72 (s), 29.77−29.59 (m),
29.52 (d, J = 5.4 Hz), 29.36 (s), 28.95 (s), 22.70 (s), 19.85 (s), 14.14
(s).
5-(5-Hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (17). Yield: 54%.
HRMS (ESI) m/z calcd for [C19H25NO3 + H]+: 316.1913, found
1
316.1921. H NMR (CDCl3): δ 8.24 (s, 1H), 7.38 (d, J = 8.08 Hz,
5-(5-Chloro-2-hexyl-1H-indol-1-yl)-5-oxo-valeric Acid (33). Yield:
1H), 7.32 (d, J = 3.54 Hz, 1H), 7.04 (d, J = 8.08 Hz, 1H), 6.52 (d, J =
3.54 Hz, 1H), 2.95 (t, J = 6.95 Hz, 2H), 2.65 (t, J = 7.71 Hz, 2H), 2.52
(t, J = 6.82 Hz, 2H), 2.05−2.16 (m, 2H), 1.59 (qt, J = 7.33 Hz, 2H),
1.16−1.33 (m, 6H), 0.80 (t, J = 6.44 Hz, 3H). 13C NMR (CDCl3): δ
64%. HRMS (ESI) m/z calcd for [C19H24ClNO3 + H]+: 350.1523 and
1
352.1493, found 350.1523 and 352.1567. H NMR (CDCl3): δ 7.72
(d, J = 7.58 Hz, 1H), 7.38−7.42 (m, 1H), 7.12−7.18 (m, 1H), 6.34 (s,
1H), 3.06 (t, J = 7.07 Hz, 2H), 2.92 (t, J = 7.71 Hz, 2H), 2.51 (t, J =
3730
dx.doi.org/10.1021/jm400480j | J. Med. Chem. 2013, 56, 3725−3732