N. Lebegue et al.
MED
over MgSO4, filtered off, evaporated under reduced pressure, and
the resulting residue was purified by flash column chromatography
(toluene/EtOAc 97:3) to afford the corresponding oxime ether as
a racemic mixture of E and Z isomers.
3J=5.7 Hz), 6.60 (d, 1H, 3J=2.6 Hz), 6.74 (d, 2H, 3J=8.5 Hz), 7.09
3
3
3
(d, 2H, J=8.5 Hz), 7.46 (d, 1H, J=8.2 Hz), 7.56 (t, 2H, J=7.3 Hz),
7.62–7.80 (m, 5H), 8.07 ppm (s, 1H); LC–MS: tR =4.12 min (96%),
m/z 458.0 [M+H]+; Anal. calcd for C28H27NO5: C 73.51, H 5.95, N
3.06, found: C 73.35, H 6.10, N 3.02.
Ethyl 2-ethoxy-3-{4-[2-(5-{[Z/E]-methoxyimino]phenylmethyl}in-
dol-1-yl)ethoxy]phenyl}propionate 17a: Colorless oil (0.97 g,
3-{4-[2-(5-Benzoyl-3-methylindol-1-yl)ethoxy]phenyl}-2-ethoxy-
propionic acid 16c: White solid (0.79 g, 84%); mp: 54–588C;
1H NMR (CDCl3): d=1.13 (t, 3H, 3J=7.3 Hz), 2.31 (s, 3H), 2.98 (m,
1
76%); H NMR (CDCl3): d=1.16 (m, 3H), 1.24 (m, 3H), 2.93 (m, 2H),
3.33 (m, 1H), 3.60 (m, 1H), 3.96 (m, 4H), 4.18 (m, 2H), 4.27 (m, 2H),
4.52 (m, 2H), 6.50 (m, 1H), 6.75 (m, 2H), 7.10–7.21 (m, 4H), 7.24–
7.45 (m, 4H), 7.51–7.67 ppm (m, 3H); MS m/z 515.1 [M+H]+; Anal.
calcd for C31H34N2O5: C 72.35, H 6.66, N 5.44, found: C 72.46, H
6.57, N 5.50.
3
2H), 3.43 (m, 1H), 3.57 (m, 1H), 4.02 (t, 1H, J=5.7 Hz), 4.21 (t, 2H,
3
3
3J=6.9 Hz), 4.47 (t, 2H, J=6.9 Hz), 6.75 (d, 2H, J=8.1 Hz), 7.05 (s,
3
1H), 7.11 (d, 2H, J=8.1 Hz), 7.39–7.62 (m, 4H), 7.72–7.82 (m, 3H),
8.09 ppm (d, 1H, 4J=1.5 Hz); LC–MS: tR =4.15 min (99%), m/z
472.2 [M+H]+; Anal. calcd for C29H29NO5: C 73.87, H 6.20, N 2.97,
found: C 73.76, H 6.24, N 3.01.
Ethyl 2-ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}in-
dol-1-yl)ethoxy]phenyl}propionate 17b: Colorless oil (1.01 g,
1
79%); H NMR (CDCl3): d=1.18 (m, 3H), 1.23 (m, 3H), 2.96 (m, 2H),
3-{4-[2-(5-Cyclopropanoylindol-1-yl)ethoxy]phenyl}-2-ethoxypro-
pionic acid 16d: Pasty solid (0.66 g, 79%); 1H NMR (CDCl3): d=
1.04 (m, 2H), 1.17 (t, 3H, 3J=6.7 Hz), 1.27 (m, 2H), 2.82 (m, 1H),
2.93 (dd, 1H, 3J=14.0 Hz, 3J=7.6 Hz), 3.06 (dd, 1H, 3J=14.0 Hz,
3.35 (m, 1H), 3.61 (m, 1H), 3.96 (m, 1H), 4.03 (s, 3H), 4.21 (m, 4H),
4.50 (m, 2H), 6.54 (m, 1H), 6.75 (m, 2H), 7.10–7.21 (m, 4H), 7.23–
7.50 (m, 4H), 7.52–7.72 ppm (m, 3H); MS m/z 515.1 [M+H]+; Anal.
calcd for C31H34N2O5: C 72.35, H 6.66, N 5.44, found: C 72.42, H
6.60, N 5.49.
3
3J=7.6 Hz), 3.41 (m, 1H), 3.62 (m, 1H), 4.02 (t, 1H, J=5.8 Hz), 4.28
3
3
3
(t, 2H, J=5.9 Hz), 4.55 (t, 2H, J=5.9 Hz), 6.67 (d, 1H, J=3.2 Hz),
3
3
3
6.77 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 7.30 (d, 1H, J=
3.2 Hz), 7.46 (d, 1H, 3J=8.8 Hz), 7.97 (dd, 1H, 3J=8.8 Hz, 4J=
1.8 Hz), 8.42 ppm (d, 1H, 4J=1.8 Hz); LC–MS: tR =3.84 min (95%),
m/z 422.3 [M+H]+; Anal. calcd for C25H27NO5: C 71.24, H 6.46, N
3.32, found: C 71.31, H 6.40, N 3.38.
Ethyl 2-ethoxy-3-{4-[2-(5-{cyclopropyl-[Z/E]-methoxyimino]me-
thyl}indol-1-yl)ethoxy]phenyl}propionate 17c: Colorless oil
(0.97 g, 81%); H NMR (CDCl3): d=0.62–0.96 (m, 4H), 1.16 (m, 3H),
1.22 (m, 3H), 2.35 (m, 1H), 2.94 (m, 2H), 3.34 (m, 1H), 3.61 (m, 1H),
3.96 (m, 1H), 4.02 (s, 3H), 4.18 (m, 2H), 4.25 (m, 2H), 4.52 (m, 2H),
6.53 (m, 1H), 6.78 (m, 2H), 7.17 (m, 2H), 7.21–7.42 (m, 3H),
7.68 ppm (m, 1H); MS m/z 479.4 [M+H]+; Anal. calcd for
C28H34N2O5: C 70.27, H 7.16, N 5.85, found: C 70.35, H 7.08, N 5.92.
1
3-{4-[2-(5-Cyclohexanoylindol-1-yl)ethoxy]phenyl}-2-ethoxypro-
1
pionic acid 16e: White solid (0.78 g, 85%); mp: 72–768C; H NMR
(CDCl3): d=1.16 (t, 3H, 3J=7.0 Hz), 1.20–1.62 (m, 6H), 1.72–1.98
(m, 4H), 2.92 (m, 1H), 3.08 (m, 1H), 3.42 (m, 2H), 3.58 (m, 1H), 4.01
(t, 1H, J=5.9 Hz), 4.26 (t, 2H, J=6.2 Hz), 4.52 (t, 2H, J=6.2 Hz),
Ethyl 2-ethoxy-3-{4-[2-(5-{cyclohexyl-[Z/E]-methoxyimino]methy-
l}indol-1-yl)ethoxy]phenyl}propionate 17d: Colorless oil (0.97 g,
75%); 1H NMR (CDCl3): d=1.15 (m, 3H), 1.22–1.38 (m, 7H), 1.43–
1.92 (m, 6H), 2.95 (m, 2H), 3.34 (m, 2H), 3.60 (m, 1H), 3.80–3.95 (m,
4H), 4.18 (m, 2H), 4.24 (m, 2H), 4.52 (m, 2H), 6.57 (m, 1H), 6.73 (m,
2H), 7.13 (m, 2H), 7.26 (m, 2H), 7.39 (m, 2H), 7.48 (s, 0.5H),
7.63 ppm (s, 0.5H); MS m/z 521.2 [M+H]+; Anal. calcd for
C31H40N2O5: C 71.51, H 7.74, N 5.38, found: C 71.64, H 7.67, N 5.42.
3
3
3
3
3
3
6.64 (d, 1H, J=2.9 Hz), 6.74 (d, 2H, J=7.9 Hz), 7.12 (d, 2H, J=
7.9 Hz), 7.27 (d, 1H, 3J=2.9 Hz), 7.43 (d, 1H, 3J=8.8 Hz), 7.92 (d,
3
1H, J=8.8 Hz), 8.31 ppm (s, 1H); LC–MS: tR =4.33 min (94%), m/z
464.2 [M+H]+; Anal. calcd for C28H33NO5: C 72.55, H 7.18, N 3.02,
found: C 72.46, H 7.25, N 2.94.
2-Ethoxy-3-{4-[2-(5-{[Z/E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 18a: White solid (0.79 g, 82%);
General procedure for the synthesis of carboxylic acids 16a–e,
18a–d: LiOH (0.15 g, 6.0 mmol, 3.0 equiv) was added to a solution
of ester 15a–e or 17a–d (2.0 mmol, 1.0 equiv) dissolved in a 2:1
mixture of THF (20 mL) and H2O (10 mL), and the mixture was then
stirred at room temperature for 12 h. Thereafter, the whole was
concentrated in vacuo, and the concentrate was hydrolyzed with
1m HCl(aq), then extracted twice with CH2Cl2. The combined organic
extracts were dried over MgSO4, filtered off, evaporated under re-
duced pressure, and the resulting residue was purified by flash
column chromatography (CH2Cl2/MeOH 95:5) to afford the corre-
sponding carboxylic acids.
1
mp: 47–508C; H NMR (CDCl3): d=1.18 (m, 3H), 2.95 (m, 1H), 3.08
(m, 1H), 3.44 (m, 1H), 3.60 (m, 1H), 4.01 (m, 4H), 4.28 (m, 2H), 4.52
(m, 2H), 6.50 (m, 1H), 6.78 (m, 2H), 7.10–7.69 ppm (m, 11H); LC–
MS: tR =4.22 and 4.27 min (52 and 45%), m/z 487.1 [M+H]+; Anal.
calcd for C29H30N2O5: C 71.59, H 6.21, N 5.76, found: C 71.64, H
6.32, N 5.81.
2-Ethoxy-3-{4-[2-(6-{[Z/E]-methoxyimino]phenylmethyl}indol-1-
yl)ethoxy]phenyl}propionic acid 18b: White solid (0.81 g, 83%);
mp: 104–1058C; 1H NMR (DMSO): d=1.02 (m, 3H), 2.81 (m, 2H),
3.28 (m, 1H), 3.49 (m, 1H), 3.90 (m, 4H), 4.21 (m, 2H), 4.51 (m, 2H),
6.59 (m, 1H), 6.71 (m, 2H), 6.92 (m, 0.5H), 7.09 (m, 2.5H), 7.28–
7.63 ppm (m, 8H); LC–MS: tR =4.44 and 4.46 min (50 and 48%), MS
m/z 487.2 [M+H]+; Anal. calcd for C29H30N2O5: C 71.59, H 6.21, N
5.76, found: C 71.50, H 6.30, N 5.58.
3-{4-[2-(5-Benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropionic
acid 16a: White solid (0.77 g, 84%); mp: 49–528C; 1H NMR
3
(DMSO): d=1.03 (t, 3H, J=6.8 Hz), 2.82 (m, 2H), 3.27 (m, 1H), 3.48
3
3
(m, 1H), 3.91 (t, 1H, J=6.3 Hz), 4.30 (t, 2H, J=5.9 Hz), 4.66 (t, 2H,
3J=5.9 Hz), 6.66 (d, 1H, 3J=3.1 Hz), 6.80 (d, 2H, 3J=8.6 Hz), 7.12
(d, 2H, 3J=8.6 Hz), 7.57 (m, 3H), 7.67 (m, 2H), 7.73 (m, 3H),
7.99 ppm (s, 1H); LC–MS: tR =4.19 min (98%), m/z 458.1 [M+H]+;
Anal. calcd for C28H27NO5: C 73.51, H 5.95, N 3.06, found: C 73.59, H
5.88, N 3.10.
2-Ethoxy-3-{4-[2-(5-{cyclopropyl-[Z/E]-methoxyimino]methyl}in-
dol-1-yl)ethoxy]phenyl}propionic acid 18c: Colorless oil (0.73 g,
1
81%); H NMR (CDCl3): d=0.62–0.96 (m, 4H), 1.18 (m, 3H), 1.82 (m,
0.5H), 2.36 (m, 0.5H), 2.92 (m, 1H), 3.07 (m, 1H), 3.47 (m, 1H), 3.58
(m, 1H), 3.82 (s, 1.5H), 4.01 (m, 2.5H), 4.25 (m, 2H), 4.51 (m, 2H),
6.52 (m, 1H), 6.73 (m, 2H), 7.05–7.44 (m, 5H), 7.60 (m, 0.5H),
7.62 ppm (m, 0.5H); LC–MS: tR =4.83 and 4.09 min (30 and 67%),
m/z 451.2 [M+H]+; Anal. calcd for C26H30N2O5: C 69.31, H 6.71, N
6.22, found: C 69.42, H 6.65, N 6.27.
3-{4-[2-(6-Benzoylindol-1-yl)ethoxy]phenyl}-2-ethoxypropionic
acid 16b: White solid (0.74 g, 81%); mp: 131–1328C; 1H NMR
3
(DMSO): d=1.01 (t, 3H, J=6.7 Hz), 2.80 (m, 2H), 3.28 (m, 1H), 3.49
3
3
(m, 1H), 3.90 (t, 1H, J=6.1 Hz), 4.27 (t, 2H, J=5.7 Hz), 4.65 (t, 2H,
2188
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2012, 7, 2179 – 2193