D. Heimann et al. / European Journal of Medicinal Chemistry 146 (2018) 409e422
419
d
(ppm) ¼ 4.66 (dt, J ¼ 25.3/4.9 Hz, 2H, CH2CH2F), 4.85 (dt, J ¼ 46.7/
C-2carb), 114.6 (1C, C-8carb), 115.4 (d, J ¼ 21.6 Hz, 1C, C-5phenyl), 117.9
(1C, C-6carb), 120.0 (1C, C-5carb), 121.3 (d, J ¼ 25.1 Hz, 1C, C-3phenyl),
122.1 (1C, C-4bcarb), 122.2 (d, J ¼ 10.2 Hz, 1C, C-2phenyl), 122.9 (1C, C-
4acarb), 124.6 (d, J ¼ 3.5 Hz, 1C, C-1phenyl), 125.1 (1C, C-7carb), 133.4
(1C, C-9acarb), 133.6 (d, J ¼ 9.4 Hz, 1C, C-6phenyl), 140.4 (1C, C-8acarb),
142.3 (1C, C-3carb), 162.9 (d, J ¼ 253.3 Hz, 1C, C-4phenyl), 166.7 (1C, C-
5.0 Hz, 2H, CH2F), 7.34e7.43 (m, 1H, 6-H), 7.42e7.51 (m, 2H, 1-H, 8-
H), 7.58 (ddd, J ¼ 8.3/7.1/1.1 Hz, 1H, 7-H), 8.17 (dd, J ¼ 7.8/1.0 Hz, 1H,
5-H), 8.39 (dd, J ¼ 9.1/2.2 Hz, 1H, 2-H), 9.01 (d, J ¼ 2.2 Hz, 1H, 4-H).
13C NMR (151 MHz, CDCl3):
d
(ppm) ¼ 44.1 (d, J ¼ 22.1 Hz, 1C,
CH2CH2F), 81.8 (d, J ¼ 173.4 Hz, 1C, CH2F), 108.6 (d, J ¼ 2.1 Hz, 1C, C-
1), 109.6 (d, J ¼ 1.0 Hz, 1C, C-8), 117.4 (1C, C-4), 121.2 (1C, C-5), 121.4
(1C, C-6), 121.9 (1C, C-2), 123.0 (1C, C-4a), 123.2 (1C, C-4b), 127.8
(1C, C-7), 141.2 (1C, C-3), 141.7 (1C, C-8a), 143.9 (1C, C-9a). FTIR
(neat): ṽ (cmꢁ1) ¼ 3055 (w, C-H, arom), 2920, 2850 (w, C-H, aliph),
1307 (s, NO2).
3
oxadiazole), 180.0 (1C, C-5oxadiazole). FTIR (neat): ṽ (cmꢁ1) ¼ 3379 (w,
N-H), 3055 (w, C-H, arom), 2935 (w, C-H, aliph), 1593 (m, C-C,
arom), 1573 (m, C-C, arom).
7.3.7. N-{3-[3-(2-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]
propyl}-9-(2-fluoroethyl)-N-methylcarbazol-3-amine (24a)
7.3.5. 9-(2-Fluoroethyl)carbazol-3-ammonium chloride (22·HCl)
Under N2 atmosphere, nitrocarbazole 20 (2.50 g, 9.7 mmol, 1
eq.) was dissolved in dry THF (260 mL). Pd/C 10% (0.375 g) was
added and the mixture was stirred for 23 h under H2 atmosphere
(balloon). After filtration through Celite®, the solvent was removed
under reduced pressure and the residue was dissolved in Et2O
(300 mL). A solution of HCl in Et2O (2 M, 5.0 mL, 10 mmol, 1.03 eq.)
was added dropwise until the salt 22$HCl precipitated completely.
The precipitate was filtered off, washed with cold Et2O and dried
under reduced pressure. Rf ¼ 0.61 (cyclohexane/ethyl acetate 3:7).
Grey solid, mp 230e253 ꢀC (decomposition), yield 2.41 g (94%).
Purity (HPLC): 95.9% (tR ¼ 15.2 min). C14H14ClFN2 (264.7 g/mol).
Exact mass (APCI): m/z ¼ 229.1135 (calcd. 229.1136 for C14H14ClFN2
Under N2 atmosphere, triethylamine (0.16 mL, 1.1 mmol, 3 eq.)
and iodomethane (0.24 mL, 3.8 mmol, 10 eq.) were added to a so-
lution of secondary amine 23a (195 mg, 0.38 mmol, 1 eq.) in dry
CH3CN (20 mL). After the reaction mixture was heated at reflux for
2.75 h, the cold mixture was filtered and all volatiles were removed
in vacuo. The residue was dissolved in ethyl acetate (20 mL) and the
mixture was washed with HCl solution (1 M, 10 mL) and water
(3 ꢂ 10 mL). Afterwards, the organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by fc (∅ ¼ 2 cm,
l ¼ 20 cm, v ¼ 10 mL, cyclohexane/ethyl acetate/dimethylethyl-
amine 92:8:3, Rf ¼ 0.73 (cyclohexane/ethyl acetate 6:4)). Brown
resin, yield 73 mg (37%). Purity (HPLC): 95.8% (tR ¼ 21.2 min).
C26H23BrF2N4O (525.4 g/mol). Exact mass (APCI): m/z ¼ 525.1082
79
[M þ Hþ]). 1H NMR (400 MHz, DMSO-D6):
d
(ppm) ¼ 4.72e4.87 (m,
(calcd. 525.1096 for C
H
26 24
BrF2N4O [M þ Hþ]). 1H NMR (400 MHz,
4H, CH2CH2F), 7.23e7.28 (m, 1H, 6-H), 7.48e7.54 (m, 2H, 2-H, 7-H),
7.68 (d, J ¼ 8.3 Hz, 1H, 8-H), 7.75 (d, J ¼ 8.7 Hz, 1H, 1-H), 8.16 (d, J ¼
CDCl3):
d
(ppm) ¼ 2.23 (quint, J ¼ 7.2 Hz, 2H, NCH2CH2CH2), 3.01 (s,
3H, NCH3), 3.08 (t, J ¼ 7.3 Hz, 2H, NCH2CH2CH2), 3.51 (t, J ¼ 6.3 Hz,
2H, NCH2CH2CH2), 4.55 (dt, J ¼ 23.7/4.7 Hz, 2H, CH2CH2F), 4.77 (dt,
J ¼ 46.8/5.2 Hz, 2H, CH2F), 7.05e7.13 (m, 2H, 5-Hphenyl, 2-Hcarb), 7.17
(t, J ¼ 7.4 Hz, 1H, 6-Hcarb), 7.30 (d, J ¼ 8.8 Hz, 1H, 1-Hcarb), 7.35 (d, J ¼
8.1 Hz, 1H, 8-Hcarb), 7.40e7.45 (m, 1H, 7-Hcarb), 7.47 (dd, J ¼ 8.2/
2.6 Hz, 1H, 3-Hphenyl), 7.50e7.56 (m, 1H, 4-Hcarb), 7.80 (dd, J ¼ 8.7/
6.0 Hz, 1H, 6-Hphenyl), 8.01 (d, J ¼ 7.8 Hz, 1H, 5-Hcarb). 13C NMR
2.1 Hz, 1H, 4-H), 8.19 (d, J ¼ 7.8 Hz, 1H, 5-H), 10.52 (s, 3H, -NHþ3 ). 13
C
NMR (101 MHz, DMSO-D6):
d
(ppm) ¼ 43.5 (d, J ¼ 20.0 Hz, 1C,
CH2CH2F), 83.0 (d, J ¼ 167.7 Hz, 1C, CH2F), 110.4 (1C, C-8), 110.9 (1C,
C-1), 115.2 (1C, C-4), 120.0 (1C, C-6), 121.0 (1C, C-5), 121.2 (1C, C-2),
121.9 (1C, C-4b), 122.8 (1C, C-4a), 123.6 (1C, C-3), 127.07 (1C, C-7),
139.8 (1C, C-9a),141.3 (1C, C-8a). FTIR (neat): ṽ (cmꢁ1) ¼ 3051 (w, C-
H, arom), 2843 (m, C-H, aliph).
(101 MHz, CDCl3):
NCH2CH2CH2), 40.6 (1C, NCH3), 43.6 (d, J ¼ 22.8 Hz, 1C, CH2CH2F),
54.2 (1C, NCH2CH2CH2), 82.1 (d, J ¼ 172.6 Hz,1C, CH2F),106.3 (1C, C-
d
(ppm) ¼ 24.0 (1C, NCH2CH2CH2), 24.3 (1C,
7.3.6. N-{3-[3-(2-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5-yl]
propyl}-9-(2-fluoroethyl)carbazol-3-amine (23a)
4
carb), 108.6 (1C, C-8carb), 109.3 (1C, C-1carb), 115.0 (d, J ¼ 21.4 Hz, 1C,
Under N2 atmosphere, triethylamine (0.20 mL, 1.5 mmol, 3 eq.),
chloroalkane 14 (156 mg, 0.49 mmol, 1 eq.) and tetrabutylammo-
nium iodide (181 mg, 0.49 mmol, 1 eq.) were sequentially added to
a suspension of carbazolamine hydrochloride 22$HCl (144 mg,
0.54 mmol, 1.1 eq.) in dry toluene (20 mL). After the reaction
mixture was heated at reflux for 68 h, the cold mixture was filtered
and all volatiles were removed under reduced pressure. The residue
was dissolved in ethyl acetate (40 mL). Afterwards, the organic
layer was washed with HCl solution (1 M, 15 mL) and water
(2 ꢂ 15 mL), dried (Na2SO4) and concentrated in vacuo. The residue
was purified by fc (∅ ¼ 2 cm, l ¼ 17 cm, v ¼ 10 mL, cyclohexane/
ethyl acetate/dimethylethylamine 85:15:3, Rf ¼ 0.64 (cyclohexane/
ethyl acetate 6:4)). Brown solid, mp 103 ꢀC, yield 137 mg (55%).
Purity (HPLC): 96.2% (tR ¼ 20.9 min). C25H21BrF2N4O (511.4 g/mol).
C-5phenyl), 115.9 (1C, C-2carb), 118.9 (1C, C-6carb), 120.5 (1C, C-5carb),
121.7 (d, J ¼ 24.7 Hz, 1C, C-3phenyl), 122.9 (d, J ¼ 9.7 Hz,1C, C-2phenyl),
123.0 (1C, C-4bcarb), 123.9 (1C, C-4acarb), 124.8 (d, J ¼ 3.6 Hz, 1C, C-
1
phenyl), 125.9 (1C, C-7carb), 133.4 (d, J ¼ 9.1 Hz, 1C, C-6phenyl), 134.9
(1C, C-9acarb), 141.1 (1C, C-8acarb), 144.1 (1C, C-3carb), 163.4 (d, J ¼
255.5 Hz, 1C, C-4phenyl), 167.3 (1C, C-3oxadiazole), 179.4 (1C, C-5oxa-
diazole). FTIR (neat): ṽ (cmꢁ1) ¼ 3051 (w, C-H, arom), 2947 (w, C-H,
aliph), 1600 (m, C-C, arom), 1573 (m, C-C, arom).
7.3.8. 5-[9-(2-Fluoroethyl)carbazol-3-yl]-5-oxopentanoic acid (25)
Under N2 atmosphere, BF3·Et2O (78.5 mL, 620 mmol, 33 eq.) was
added to a mixture of 4-(methoxycarbonyl)butanoyl chloride
(3.9 mL, 28 mmol, 1.5 eq.) and fluoroethylcarbazole 18 (4.00 g,
19 mmol, 1 eq.). The mixture was heated at 50 ꢀC. After 2 h, addi-
tional acid chloride (1.3 mL, 9.4 mmol, 0.5 eq.) was added at room
temperature and the reaction mixture was heated at 50 ꢀC for
another 19 h. At 0 ꢀC NaOH solution (20%, 320 mL) was slowly
added to the reaction mixture (violent reaction). The organic sol-
vent was evaporated in vacuo and methanol (250 mL) was added
dropwise at 0 ꢀC. Stirring was continued at room temperature for
74 h. Afterwards, methanol was removed in vacuo and the pH value
was adjusted to 1 with HCl 37%. The resulting suspension was
filtered and washed with 50 ꢀC warm ethyl acetate (200 mL). The
aqueous layer was extracted with ethyl acetate (2 ꢂ 200 mL). The
combined organic layers were washed with brine (100 mL), dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue was
purified by fc with a gradient (∅ ¼ 6 cm, l ¼ 18 cm, v ¼ 60 mL,
Exact mass (APCI): m/z ¼ 511.0915 (calcd. 511.0940 for
79
C
d
H
25 22
BrF2N4O [M
þ
Hþ]). 1H NMR (400 MHz, DMSO-D6):
(ppm) ¼ 2.15 (quint, J ¼ 7.1 Hz, 2H, NCH2CH2CH2), 3.19 (t, J ¼
7.4 Hz, 2H, NCH2CH2CH2), 3.27 (t, J ¼ 6.8 Hz, 2H, NCH2CH2CH2), 4.61
(dt, J ¼ 27.3/4.6 Hz, 2H, CH2CH2F), 4.74 (dt, J ¼ 47.4/4.6 Hz, 2H,
CH2F), 5.45 (s, 1H, NH), 6.86 (dd, J ¼ 8.7/2.2 Hz, 1H, 8-Hcarb), 7.06 (t,
J ¼ 7.4 Hz,1H, 6-Hcarb), 7.28 (d, J ¼ 2.1 Hz,1H, 4-Hcarb), 7.32e7.38 (m,
2H, 2-Hcarb, 7-Hcarb), 7.43 (td, J ¼ 8.4/2.6 Hz, 1H, 5-Hphenyl), 7.49 (d,
J ¼ 8.2 Hz, 1H, 1-Hcarb), 7.82e7.89 (m, 2H, 3-Hphenyl, 6-Hphenyl), 7.96
(d,
J
¼
7.7 Hz, 1H, 5-Hcarb). 13C NMR (101 MHz, DMSO-D6):
d
(ppm) ¼ 23.6 (1C, NCH2CH2CH2), 25.5 (1C, NCH2CH2CH2), 42.9 (d,
J ¼ 20.4 Hz, 1C, CH2CH2F), 43.1 (1C, NCH2CH2CH2), 82.6 (d, J ¼
167.9 Hz, 1C, CH2F), 101.5 (1C, C-4carb), 109.2 (1C, C-1carb), 110.0 (1C,