F. Lafzi, D. Kilic, M. Yildiz et al.
Journal of Molecular Structure 1241 (2021) 130566
g, 80%) (Mp: 165-166 °C). 1H-NMR (400 MHz, Aceton-d6): δ 9.96
(bs, 1H), 8.54 (bs, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.61 (bs, 1H), 7.50-
7.32 (m, 6H), 7.13 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.21 (s,
2H). 13C-NMR (100 MHz, Aceton-d6): δ 154.3, 137.6, 134.8, 128.6,
128.2, 128.1, 122.2, 121.4, 118.6, 117.8, 115.8, 114.6, 111.5, 66.2.
(400 MHz, CDCl3): δ 8.99 (bs, 1H), 7.75-7.73 (m, 1H), 7.55-7.54 (m,
1H), 7.44-7.43 (m, 2H), 7.20 (m, 1H). 13C-NMR (100 MHz, CDCl3): δ
160.0, 138.5, 129.4, 127.9, 127.0, 123.5, 121.8, 116.2, 112.3.
4.2.22. 1H-Indole-2-carbonyl azide (33)
To a solution of 1H-indole-2-carbonyl chloride (1.05 g, 5.85
mmol) in THF (15 mL) a solution of NaN3 (2.28 g, 35.08 mmol) in
H2O (3 mL) was added. Upon completion of the addition, the re-
sulting mixture was stirred for 48 at room temperature. Water (20
mL) was added and extracted with EtOAc (3 × 20 mL). The com-
bined organic layer was dried over Na2SO4. Removal of the sol-
vent under reduced pressure gave 33, which was used without fur-
ther purification in the next step (1.0 g, 91%). 1H-NMR (400 MHz,
CDCl3): δ 8.99 (bs, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.9 Hz,
1H), 7.37 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.17 (t, J = 7.9 Hz, 1H).
13C-NMR (100 MHz, CDCl3): 166.3, 138.1, 128.1, 127.3, 126.7, 123.1,
121.3, 112.1, 111.0.
4.2.17. 1H-Indol-3-amine (27)
N-(1H-Indol-3-yl)-2-phenylacetamide (1.0 g, 3.76 mmol) was
dissolved in MeOH (30 mL) and 10% Pd/C (100 mg) was added.
The mixture was stirred in an H2 atmosphere for 4 h. The Pd/C
was removed by filtration and concentrated under reduced pres-
sure to afford 1H-indol-3-amine which was used in the next step
without further purification.
4.2.18. (S)-1-(1H-Indol-3-yl)-3-(1-phenylethyl)urea (21)
To a stirred solution of 1H-indol-3-amine (400 mg, 3.03 mmol)
in CH2Cl2 (10 mL) Et3N (0.42 mL, 3.03 mmol) was added to the
solution, followed by (S)-(1-isocyanatoethyl)benzene (445 mg, 3.03
mmol). The reaction was stirred for 12 h at room temperature. The
mixture was washed with water and brine, combined organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography respec-
tively (hexane/ EtOAc = 8:2) and (MeOH, 150 mL) to obtain pure
product (21) as a light-green oil (600 mg, 71%).1H-NMR (400 MHz,
CDCl3): δ 8.53 (bs, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.29-7.12 (m, 7H),
7.09-7.05 (m, 2H), 6.45 (bs, 1H), 5.31 (bs, 1H), 5.01 (p, J = 7.0 Hz,
1H), 1.33 (d, J = 7.0 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 157.1,
144.1, 134.8, 128.6, 127.1, 125.9 (2C), 123.5, 122.8, 120.1, 117.7, 114.1,
111.7, 49.7, 22.7. HPLC (OJ column; hexane/2-propanol = 80/20; flow
rate 1.0 mL/ min; T=25 °C; 254 nm): tR-(-) = 19.1 min. Enan-
tiomeric rate: (+) = 0.0 and (-) = 100.0.
4.2.23. (R)-N-(1-Phenylethyl)-1H-indole-2-carboxamide (35)
To a stirred solution of 1H-indole-2-carbonyl chloride (500 mg,
2.78 mmol) in CH2Cl2 (10 mL) was added (R)-1-phenylethan-1-
amine (337 mg, 2.78 mmol) and stirred at room temperature
for 12 h. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (hexane/
EtOAc = 7:3) to give compound 35 (660 mg, 90%) as a light-yellow
solid (Mp: 167-168 °C). 1H NMR (400 MHz, CDCl3): δ 9.85 (bs, 1H),
7.62 (d, J = 8.0 Hz, 1H), 7.44-7.34 (m, 4H), 7.33-7.26 (m, 2H), 7.26-
7.20 (m, 1H), 7.14-7.07 (m, 1H), 6.86 (s, 1H), 6.45 (d, J = 7.1 Hz, 1H),
5.39 (p, J = 7.1 Hz, 1H), 1.64 (d, J = 7.1 Hz, 3H). 13C-NMR (100 MHz,
CDCl3): δ 161.0, 143.0, 136.5, 130.6, 128.8, 127.6, 127.5, 126.2, 124.5,
121.8, 120.6, 112.12, 102.0, 49.1, 22.0. HPLC (OJ column; hexane/2-
propanol = 90/10; flow rate 1.0 mL/ min; T=25 °C; 254 nm): tR-(-
) = 52.4 min. Enantiomeric rate: (+) = 0.0 and (-) = 100.0.
4.2.19. (S)-1-(1H-Indol-3-yl)-3-(1-phenylethyl)thiourea (22)
Prepared according to the synthesis procedure of 21 using 1H-
indol-3-amine (400 mg, 3.03 mmol), Et3N (0.42 mL, 3.03 mmol)
and (S)-(1-isothiocyanatoethyl)benzene (494 mg, 3.03 mmol). Pu-
rification was carried out by column chromatography using respec-
tively (hexane/ EtOAc = 8:2) and (MeOH, 150 mL) to obtain pure
product (26) as a light-green oil (620 mg, 73%). 1H-NMR (400
MHz, CDCl3): δ 8.52 (bs, 1H), 7.64 (bs, 1H), 7.44 (d, J = 7.8 Hz,
1H), 7.38 (d, J = 7.8 Hz, 1H), 7.28-7.07 (m, 8H), 6.22 (d, J = 5.5 Hz,
1H), 5.73-5.70 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H). 13C-NMR (100 MHz,
CDCl3): δ 181.1, 142.5, 135.0, 128.6, 127.4, 126.2, 123.5, 123.3, 121.3,
121.0, 118.0, 112.4, 112.0, 54.1, 21.5. HPLC (OJ column; hexane/2-
propanol = 80/20; flow rate 1.0 mL/ min; T=25 °C; 254 nm): tR-(-
) = 30.3 min. Enantiomeric rate: (+) = 0.0 and (-) = 100.0.
4.2.24. 2,2,2-Trifluoro-N-(2-iodophenyl)acetamide (37)
To a solution of 2-iodoaniline (1.0 g, 4.30 mmol) and triethy-
lamine (0.7 mL, 4.55 mmol) in THF (10 mL) at -15 °C was slowly
added trifluoroacetic anhydride (0.65 mL, 4.30 mmol) in 5 mL of
THF. The resulting mixture was stirred for 1 h and then allowed
to warm to room temperature and stirred for 16 h. The reaction
mixture was then poured into a separatory funnel containing wa-
ter (100 mL) and extracted with ethyl acetate (3 × 30 mL). The or-
ganic layers were dried over anhydrous Na2SO4. The solvent was
removed under vacuum to give desired product 37 (1.3 g, 90%) as
a white solid (Mp: 105-106 °C). 1H-NMR (400 MHz, CDCl3): δ 8.29
(s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6
Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H) [34].
4.2.20. Benzyl (1H-indol-2-yl)carbamate (29)
Prepared according to the synthesis procedure of 26 using
diphenylphosphoryl azide (3.21 mL, 14.89 mmol), Et3N (2.08 mL,
12.89 mmol) and 1H-indole-2-carboxylic acid (2.0 g, 12.41 mmol).
Purification was carried out by column chromatography using sil-
ica gel (hexane/ EtOAc = 9:1) to afford the title compound 29 (2.4
g, 72%) as an off-white solid (Mp: 141-142 °C). 1H-NMR (400 MHz,
CDCl3): δ 9.80 (bs, 1H), 7.47-7.33 (m, 6H), 7.31-7.27 (m, 1H), 7.15
(bs, 1H), 7.12-7.05 (m, 2H), 5.82 (s, 1H), 5.24 (s, 2H). 13C-NMR (100
MHz, CDCl3): δ 153.4, 135.4, 134.0, 132.5, 128.7, 128.6, 128.3, 127.2,
120.5, 120.2, 119.0, 110.6, 85.1, 67.7.
4.2.25. 2-Amino-1H-indole-3-carbonitrile (38)
To
a
stirred
solution
of
2,2,2-trifluoro-N-(2-
iodophenyl)acetamide (1.3 g, 0.5 mmol) in DMSO (15) was
added malononitrile (1.3 g, 0.5 mmol), L-proline (95 mg, 0.1
mmol) and K2CO3 (1.14 g, 1.0 mmol). After stirring the mixture for
15 min under nitrogen atmosphere CuI (78 mg, 0.05 mmol) was
added to the flask. The mixture was stirred at 60 °C for 12 h. The
resulting mixture was cooled to room temperature and filtered.
The solid was washed with methanol two times (2 × 3 mL), and
the combined filtrate was concentrated on the rotary evaporator,
and the residue was purified by column chromatography on silica
gel using petroleum ether/ethyl acetate (1:2) as eluent to give
the desired product 38 (1.1 g, 85%) as a light yellow solid (Mp:
191-192 °C). 1H-NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 7.13
(d, J = 8.3 Hz, 2H), 6.30 (m, 2H), 6.70 (s, 2H). 13C-NMR (100 MHz,
DMSO-d6): δ 154.3, 132.6, 128.8, 121.2, 120.1, 118.4, 115.6, 110.7,
4.2.21. 1H-Indole-2-carbonyl chloride (32)
To a stirred solution of indoline-2-carboxylic acid (1.0 g, 6.21
mmol) in CH2Cl2 (15 mL) was slowly added SOCl2 (1 mL, 14.2
mmol). The reaction mixture was then refluxed at 70 °C for 2h.
The solvent was removed on a rotary evaporator. The crude prod-
uct was purified by column chromatography (hexane/ EtOAc = 9:1)
to give compound 32 as a light-yellow solid (1.05 g, 95%). 1H-NMR
12