3
952
S. Roy et al.
PAPER
1
H NMR (500 MHz, DMSO-d ): d = 8.51 (s, 1 H), 8.21 (d, J = 7.6
N-{2-[1-(3-Cyanopropyl)-1H-indol-3-yl]-2-oxoethyl}-1-methyl-
1H-indole-3-acetamide (22)
To a mixture of amine trifluoroacetate 19 (0.87 g, 2.45 mmol), 1-
6
Hz, 1 H), 7.71 (d, J = 8.2 Hz, 1 H), 7.39 (t, J = 8.2 Hz, 1 H), 7.32 (t,
J = 7.6 Hz, 1 H), 7.08 (t, J = 5.8 Hz, 1 H), 5.65 (s, 2 H), 4.29 (d,
J = 5.8 Hz, 2 H), 1.41 (s, 9 H).
methylindole-3-acetic acid (1.40 g, 7.35 mmol), EDC·H O (1.41 g,
2
1
3
7.35 mmol), HOBt·H
2
O (0.99 g, 7.35 mmol) and NaHCO (3.09 g,
3
C NMR (125 MHz, DMSO-d ): d = 190.9, 156.0, 135.9, 135.8,
6
3
6.75 mmol) at r.t. was added DMF (25 mL). The mixture was
1
2
25.8, 123.8, 123.0, 121.7, 115.9, 114.5, 110.6, 78.0, 46.9, 34.5,
8.2;
stirred at r.t. for 24 h. It was then poured into sat. aq NaHCO solu-
tion (100 mL) and extracted with EtOAc (2 × 100 mL). The organic
phase was washed with HCl (1N, 100 mL), H O (100 mL), brine
3
+
MS (EI): m/z (%) = 313 [M ], 257, 240, 213, 183 (100), 169, 143,
9
2
1.
(100 mL) and dried over MgSO . The solvent was evaporated and
4
the residue was purified by column chromatography on silica gel
CH Cl –MeOH, 95:5) to yield the desired product (0.64 g, 63% )
as a yellowish-white solid.
HRMS (EI): m/z calcd for C H N O : 313.1427; found: 313.1423.
1
7
19
3
3
(
2
2
A large amount of unreacted starting material (0.89 g, 67%) was re-
covered from the reaction mixture after column chromatography.
Mp 73–75 °C.
3
-[3-(2-Aminoacetyl)indol-1-yl]propionitrile Trifluoroacetate
IR (thin film): 3392, 3053, 2935, 2247, 1646, 1527, 1467, 1394,
(
18)
–1
1
215, 1161, 1073, 919, 744 cm .
Compound 14 (0.17 g, 0.5 mmol) was dissolved in neat TFA (8 mL)
at r.t. and stirred for 15 min. The solvent was evaporated by rotary
evaporation. The residual TFA was removed by co-evaporation
with benzene (3 × 10 mL). It was then extensively dried in vacuo
and the white solid (0.17 g, 100%) was used in the next reaction
without any further purification.
1
H NMR (500 MHz, DMSO-d ): d = 8.48 (s, 1 H), 8.18–8.21 (m, 2
6
H), 7.62 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.24–7.31
(
J = 5.5 Hz, 2 H), 4.29 (t, J = 7.0 Hz, 2 H), 3.76 (s, 3 H), 3.65 (s, 2
H), 2.51 (t, J = 7.0 Hz, 2 H), 2.12 (quin, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, DMSO-d
m, 3 H), 7.15 (t, J = 8.2 Hz, 1 H), 7.02 (t, J = 7.0 Hz, 1 H), 4.48 (d,
1
6
): d = 189.9, 170.9, 136.5, 136.3,
28.3, 127.6, 125.9, 123.1, 122.3, 121.5, 121.1, 120.0, 119.0, 118.4,
H NMR (500 MHz, DMSO-d ): d = 8.63 (s, 1 H), 8.26 (br s, 3 H),
6
1
1
8
.19 (d, J = 7.9 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.30–7.37 (m, 2
13.3, 110.6, 109.5, 108.1, 45.9, 44.9, 32.3, 25.3, 13.9.
H), 4.62 (t, J = 6.4 Hz, 2 H), 4.36 (s, 2 H), 3.17 (t, J = 6.4 Hz, 2 H).
+
MS (EI): m/z (%) = 412 [M ], 394, 285, 228, 211 (100), 197, 171,
4
-[3-(2-Aminoacetyl)indol-1-yl]butyronitrile Trifluoroacetate
144, 129, 77.
(
19)
HRMS (EI): m/z calcd for C H N O : 412.1899; found: 412.1892.
2
5
24
4
2
Compound 15 (0.84 g, 2.45 mmol) was dissolved in neat TFA (30
mL) at r.t. and stirred for 25 min. The solvent was evaporated by ro-
tary evaporation. The residual TFA was removed by co-evaporation
with benzene (4 × 10 mL). The residue was then extensively dried
in vacuo to yield the desired product (0.87 g, 100%) as a white solid
which was used in the next reaction without any further purification.
1
3
-{3-[2-(1-Methyl-1H-indol-3-ylmethyl)oxazol-5-yl]indol-1-
yl}propionitrile (8)
To a stirred solution of PPh (53 mg, 0.2 mmol), I (52 mg, 0.2
3
2
mmol) and Et N (41 mg, 0.4 mmol) in CH Cl (2 mL) at r.t. was
3
2
2
added a solution of ketoamide 21 (40 mg, 0.1 mmol) in CH Cl (5
2
2
H NMR (300 MHz, DMSO-d ): d = 8.58 (s, 1 H), 8.27 (br s, 2 H),
8
4
mL). The mixture was stirred for 24 h and then diluted with CH Cl
6
2 2
.18–8.20 (m, 1 H), 7.68 (d, J = 7.3 Hz, 1 H), 7.28–7.36 (m, 2 H),
.33–4.38 (m, 4 H), 2.58 (t, J = 7.3 Hz, 2 H), 2.16 (quin, J = 6.96
(15 mL). The organic phase was treated with 5% aq Na S O solu-
2 2 3
tion (25 mL). Et O (100 mL) was added and the combined organic
2
Hz, 2 H).
phase was washed with sat. aq NaHCO (25 mL). The bicarbonate
3
solution was extracted with CH Cl (15 mL). The combined organic
2
2
N-[2-[1-(2-Cyanoethyl)-1H-indol-3-yl]-2-oxoethyl]-1-methyl-
phases were dried over Na SO . The solvent was evaporated and the
2 4
1
H-indole-3-acetamide (21)
To a mixture of amine trifluoroacetate 18 (0.17 g, 0.5 mmol), 1-
residue was purified by column chromatography on silica gel
(CH Cl –MeOH, 95:5) to yield the desired product (16 mg, 42%) as
2
2
methylindole-3-acetic acid (0.11 g, 0.6 mmol), EDC·H O (0.29 g,
a yellowish-brown oil.
2
1
.5 mmol), HOBt·H O (0.20 g, 1.5 mmol) and NaHCO (0.63 g, 7.5
IR (thin film): 1690, 1611, 1467, 990, 745 cm–1.
2
3
mmol) at r.t. was added DMF (5 mL). The mixture was stirred at r.t.
for 20 h. It was then poured into sat. aq NaHCO solution (50 mL)
and extracted with EtOAc (3 × 50 mL). The organic phase was
washed with HCl (1 N, 50 mL), H O (50 mL), brine (50 mL) and
dried over MgSO . The solvent was evaporated and the residue was
purified by column chromatography on silica gel (CH Cl –MeOH,
9
1
H NMR (500 MHz, DMSO-d ): d = 7.80 (d, J = 7.9 Hz, 1 H), 7.74
d, J = 7.9 Hz, 1 H), 7.43 (s, 1 H), 7.32–7.34 (m, 3 H), 7.25–7.28
m, 2 H), 7.17–7.20 (m, 2 H), 7.12 (s, 1 H), 4.47 (t, J = 6.7 Hz, 2 H),
6
3
(
(
2
4
.37 (s, 2 H), 3.79 (s, 3 H), 2.85 (t, J = 6.7 Hz, 2 H).
4
13
2
2
C NMR (125 MHz, DMSO-d ): d = 160.8, 146.7, 135.9, 127.9,
6
:1) to yield the desired product (0.14 g, 70%) as a yellowish solid.
1
1
27.2, 125.8, 123.9, 122.5, 121.3, 120.6, 119.9, 119.7, 118.8, 118.7,
18.6, 110.6, 109.7, 107.9, 104.0, 41.3, 32.3, 24.2, 18.5.
Mp 155–157 °C.
+
MS (EI): m/z (%) = 380 (100) [M ], 214, 197, 174, 144, 129.
HRMS (EI): m/z calcd for C H N O: 380.1641; found: 380.1637.
IR (thin film): 3392, 3053, 2928, 2251, 1644, 1527, 1392, 1185,
1
–1
064, 746 cm .
2
4
20
4
1
H NMR (300 MHz, DMSO-d ): d = 8.53 (s, 1 H), 8.17–8.22 (m, 2
6
4
-{3-[2-(1-Methyl-1H-indol-3-ylmethyl)oxazol-5-yl]indol-1-
yl}butyronitrile (9)
To a stirred solution of PPh (106 mg, 0.4 mmol ), I (103 mg, 0.4
H), 7.70–7.33(m, 1 H), 7.62 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 8.4 Hz,
1
H), 7.25–7.33 (m, 3 H), 7.15 (t, J = 7.2 Hz, 1 H), 7.00–7.05 (m, 1
H), 4.56 (t, J = 6.6 Hz, 2 H), 4.47 (d, J = 5.5 Hz, 2 H), 3.76 (s, 3 H),
3
3
2
mmol), Et N (0.12 mL, 0.8 mmol) in CH Cl (3 mL) at r.t. was add-
.65 (s, 2 H), 3.13 (t, J = 6.6 Hz, 2 H).
3
2
2
ed a solution of 22 (83 mg, 0.2 mmol) in CH Cl (1.5 mL). The re-
1
3
2
2
C NMR (75 MHz, DMSO-d ): d = 189.9, 170.9, 136.5, 136.2,
6
action mixture was stirred at r.t. for 22 h and then diluted with
1
1
36.1, 128.2, 127.6, 125.8, 123.2, 122.5, 121.4, 121.1, 119.0, 118.5,
CH Cl (10 mL) and washed with 5% aq Na S O (25 mL). Et O
2
2
2
2
3
2
18.4, 113.7, 110.9, 109.5, 108.1, 45.9, 41.8, 32.3, 18.3.
(
100 mL) was added and the combined organic phase was washed
+
MS (EI): m/z (%) = 398 [M ], 323, 271, 197 (100), 144, 129, 102.
HRMS (EI): m/z calcd for C H N O : 398.1743; found: 398.1745.
with sat. aq NaHCO solution (25 mL) and then dried over Na SO .
3
2
4
The solvent was evaporated and the residue was purified by column
2
4
22
4
2
Synthesis 2006, No. 23, 3948–3954 © Thieme Stuttgart · New York