Journal of Medicinal Chemistry
Article
for 50 min. To the mixture was cannulated a solution of iodoacetic
acid benzyl ester (2.19 mmol, 605 mg) in tetrahydrofuran (3.0 mL)
and the whole was stirred for further 18 h. To the mixture was added
sat. aq NH4Cl. The solvent was partially removed by evaporation, and
the organic compounds were extracted with AcOEt. Organic layers
were washed with brine and dried over Na2SO4. The solvents were
filtered and evaporated under reduced pressure. The obtained residue
was subjected to column chromatography (NH2 silica gel, hexane to
hexane/AcOEt = 30:1) to give 4c (0.22 mmol, 64 mg, 30%) as a
yellow oil.
3 h. The pH of the solution was changed to 12 with 20% KOH at 0
°C, and organic compounds were extracted with Et2O. Organic layers
were washed with water and brine and dried over Na2SO4. After
filtration, solvents were evaporated under reduced pressure. To a
solution of the obtained residue in toluene (30 mL) was added
iodomethane (5.22 mmol, 325 μL), and the mixture was stirred for 12
h. After evaporation, to a solution of the obtained solid in water (21
mL) and MeCN (7 mL) was added KCN (3.13 mmol, 204 mg), and
the mixture was refluxed for 5 h. After cooling, organic compounds
were extracted with AcOEt. Organic layers were washed with water
and brine and dried over Na2SO4. The solvents were filtered and
evaporated under reduced pressure. The obtained residue was
subjected to column chromatography (neutral silica gel, hexane/
AcOEt = 3:1) to give 2-phenyl-1H-indol-3-ylacetonitrile30 (2.24 mmol,
521 mg, three steps 86%) as colorless plates.
1H NMR (500 MHz, CDCl3) d 7.91 (br, 1 H), 7.53 (d, 1 H, J = 8.0
Hz), 7.33−7.26 (m, 5 H), 7.20 (d, 1 H, J = 8.0 Hz), 7.12−7.06 (m, 2
H), 5.08 (s, 2 H), 3.73 (s, 2 H), 2.70 (q, 2 H, J = 7.4 Hz), 1.20 (t, 3 H,
J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 171.89, 138.43, 135.90,
134.98, 128.38, 128.02, 121.14, 119.41, 118.19, 110.36, 103.30, 66.39,
30.30, 19.29, 13.89; LRMS (EI) m/z 293.16 (M+); HRMS (EI) calcd
for C19H19NO2 (M+); 293.1416, found 293.1404.
To a solution of 4c (0.13 mmol, 38 mg) in tetrahydrofuran (1.0
mL) was added dropwise a solution of tBuOK in tetrahydrofuran (1.0
M, 0.17 mmol, 170 μL) at −40 °C, and the mixture was stirred for 1 h.
To the mixture was cannulated a solution of p-chlorobenzoyl chloride
(0.21 mmol, 27 μL) in tetrahydrofuran (0.1 mL), and the whole was
stirred for 2 h. To the mixture was added sat. aq NH4Cl. The solvent
was partially removed by evaporation, and organic compounds were
extracted with AcOEt. Organic layers were washed with brine and
dried over Na2SO4. The solvents were filtered and evaporated under
reduced pressure. The obtained residue was subjected to column
chromatography (neutral silica gel, hexane/AcOEt = 19:1) to give 5c
(90 μmol, 39 mg, 69%) as a yellow oil.
1
Mp 130 °C (CH2Cl2); H NMR (CDCl3, 400 MHz) δ 8.26 (br, 1
H, NH), 7.70 (d, 1 H, J = 7.7 Hz, aromatic), 7.53−7.51 (m, 3 H,
aromatic), 7.46−7.40 (m, 2 H, aromatic), 7.29−7.19 (m, 3 H,
aromatic), 3.88 (s, 2 H, CH2); 13C NMR (CDCl3, 100 MHz) δ 136.07,
135.41, 131.07, 128.89, 128.26, 127.87, 127.39, 122.71, 120.21, 118.37,
117.98, 111.17, 100.17, 13.43; LRMS (EI) m/z 232.15 (M+).
To a solution of 2-phenyl-1H-indol-3-ylacetonitrile (851 mg, 3.36
mmol) in dioxane (18 mL) was added 12 N HCl (10 mL), and the
mixture was refluxed for 2 h. After cooling, organic compounds were
extracted with AcOEt. Organic layers were washed with water and
brine and dried over Na2SO4. The solvents were filtered and
evaporated under reduced pressure. The obtained residue was
subjected to column chromatography (hexane/AcOEt = 2:1) to give
4d31 (3.57 mmol, 898 mg, 98%) as a colorless needle.
1H NMR (500 MHz, CDCl3) δ 7.68 (d, 2 H, J = 8.3 Hz), 7.51 (d, 1
H, J = 7.4 Hz), 7.46 (d, 2 H, J = 8.3 Hz), 7.35−7.29 (m, 5 H), 7.15
(dd, 1 H, J = 7.1, 7.4 Hz), 7.00 (dd, 1 H, J = 7.1, 8.6 Hz), 6.72 (d, 1 H,
J = 8.6 Hz), 5.14 (s, 2 H), 3.77 (s, 2 H), 2.95 (q, 2 H, J = 7.4 Hz), 1.14
(t, 3 H, J = 7.4 Hz); 13C NMR (125 MHz, CDCl3) δ 170.77, 168.51,
141.62, 139.65, 136.24, 135.70, 133.48, 131.39, 129.49, 129.19, 128.50,
128.23, 128.15, 123.02, 122.49, 118.69, 113.78, 111.61, 66.75, 30.24,
19.13, 14.43; LRMS (EI) 431.15 (M+); HRMS (EI) calcd for
C26H22ClNO3 (M+); 431.1288, found 431.1275
1
Mp 174−175 °C (CH2Cl2); H NMR (CDCl3, 400 MHz) δ 8.15
(br, 1 H), 7.66 (d, 1 H, J = 8.2 Hz), 7.62 (d, 2 H, J = 8.6 Hz), 7.49 (dd,
2 H, J = 7.2, 7.2 Hz), 7.42−7.38 (m, 2 H), 7.26−7.22 (m, 1 H), 7.17
(dd, 1 H, J = 7.2. 7.2 Hz), 3.87 (s, 2 H); 13C NMR (CDCl3, 125 MHz)
δ 177.64, 136.43, 135.66, 132.15, 129.01, 128.82, 128.24, 128.20,
122.73, 120.23, 119.21, 110.92, 104.83, 30.69; LRMS (EI) m/z 251.15
(M+).
To a solution of 5c (0.10 mmol, 44 mg) in AcOEt (1.0 mL) was
added 10% Pd on carbon (15 mg) under H2 atmosphere (1 atm), and
the mixture was stirred for 4 h. After Celite545 pad filtration, the crude
was subjected to column chromatography (acidic silica gel, hexane/
AcOEt = 5:1) to give 1c (90 μmol, 30 mg, 90%) as yellow needles.
To a solution of 4d (4.06 mmol, 1.02 g) in N,N-dimethylformamide
(30 mL) were added CsCO3 (2.23 mmol, 728 mg) and BnBr (4.47
mmol, 530 μL) at 0 °C, and the mixture was stirred at rt for 5 h. To
the mixture was added sat. aq NH4Cl. Organic compounds were
extracted with AcOEt. Organic layers were washed with brine and
dried over Na2SO4. The solvents were filtered and evaporated under
reduced pressure. The obtained residue was subjected to column
chromatography (silica gel, hexane to hexane/AcOEt = 10:1) to give
benzyl 2-phenyl-3-indoleacetate (3.66 mmol, 918 mg, 90%) as yellow
statues.
1
Mp 112−113 °C (50% aq EtOH); H NMR (CDCl3, 500 MHz) δ
7.70 (d, 1 H, J = 8.6 Hz), 7.52 (d, 1 H, J = 8.0 Hz), 7.47 (d, 1 H, J =
8.6 Hz), 7.17 (dd, 1 H, J = 7.4, 8.0 Hz), 7.01 (dd, 1 H, J = 7.4, 7.4 Hz),
6.70 (d, 1 H, J = 7.4 Hz), 3.76 (s, 2 H), 2.97 (q, 2 H, J = 7.4 Hz), 1.18
(t, 3 H, J = 7.4 Hz); 13C NMR (125 MHz, CDCl3) δ 176.90, 168.53,
141.88, 139.74, 136.21, 133.39, 131.43, 129.35, 123.13, 122.56, 118.56,
113.86, 110.97, 29.89, 19.13, 14.42; LRMS (EI) m/z 341.12 (M+);
HRMS (EI) calcd for C19H16ClNO3 (M+); 341.0819, found 341.0819.
2-[1-(4-Chlorobenzoyl)-2-phenylindole-3-yl]acetic Acid (1d). To a
solution of 2d (0.15 mmol, 53 mg) in MeOH (1.5 mL) was added
KOH (1.53 mmol, 86 mg), and the mixture was refluxed for 4 h. To
the mixture was added 1 N HCl, and the organic compounds were
extracted with AcOEt. Organic layers were washed with brine and
dried over Na2SO4. The solvents were filtered and evaporated under
reduced pressure. The obtained residue was subjected to column
chromatography (NH2 silica gel, hexane/AcOEt = 6:1) to give 3d29
(0.12 mmol, 23 mg, 78%) as colorless needles.
1
Mp 110 °C (AcOEt); H NMR (CDCl3, 500 MHz) δ 8.15 (br, 1
H), 7.65 (d, 1 H, J = 8.0 Hz), 7.58 (dd, 2 H, J = 7.4, 7.4 Hz), 7.39 (t, 2
H, J = 7.4 Hz), 7.35−7.28 (m, 7 H), 7.18 (dd, 1 H, J = 6.9, 7.4 Hz),
7.12 (dd, 1 H, J = 6.9, 8.0 Hz), 5.13 (s, 2 H), 3.87 (s, 2 H); 13C NMR
(CDCl3, 100 MHz) δ 172.11, 136.10, 135.70, 135.60, 132.12, 128.76,
128.69, 128.35, 128.07, 128.01, 127.79, 122.32, 119.80, 119.05, 110.90,
105.02, 66.52, 30.96; LRMS (EI) m/z 341.22 (M+); Anal. Calcd for
C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 81.13; H, 5.65; N,
4.09.
Mp 89 °C (CH2Cl2, ref 85−86 °C); 1H NMR (400 MHz, CDCl3) δ
8.33 (br, 1 H), 7.68−7.65 (m, 2 H), 7.63 (d, 1H, J = 8.0 Hz), 7.46−
7.42 (m, 2 H), 7.40 (d, 1 H, J = 8.0 Hz), 7.33 (t, 1 H, J = 7.7 Hz), 7.20
(ddd, 1 H, J = 0.9, 1.4, 8.0 Hz), 7.12 (ddd, 1 H, J = 0.9, 1.4, 8.0 Hz),
6.83 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 137.83, 136.73, 132.28,
129.19, 128.98, 127.68, 125.10, 122.31, 120.63, 120.24, 110.89, 99.92;
LRMS (EI) m/z 193 (M+).
To a solution mixture of 50% Me2NH (3.39 mmol, 305 μL), acetic
acid (0.7 mL), and 36−38% formic acid (3.13 mmol, 254 μL) was
added 3c (2.61 mmol, 504 mg) at 0 °C, and the mixture was stirred for
To a solution of benzyl 2-phenyl-3-indoleacetate (3.26 mmol, 1.11
g) in tetrahydrofuran (20 mL) was added dropwise a solution of
tBuOK in tetrahydrofuran (1.0 M, 3.91 mmol, 170 μL) at −40 °C, and
the mixture was stirred for 1 h. To the mixture was cannulated a
solution of p-chlorobenzoyl chloride (4.89 mmol, 627 μL) in
8158
dx.doi.org/10.1021/jm301084z | J. Med. Chem. 2012, 55, 8152−8163