PAPER
Synthesis of 2-Substituted Melatonin Derivatives
275
H, CH, major isomer), 6.80 (m, 5 H, ArH), 7.07 (s, 1 H, ArH), 10.42
reduced pressure and the residue was washed with aq K CO . The
2
3
(s, 1 H, NH, major isomer), 10.51 (s, 1 H, NH, minor isomer).
product was extracted with EtOAc (2 × 10 mL), and the organic lay-
er was dried (Na SO ) and concentrated under reduced pressure;
2
4
(
5-Methoxy-2-oxoindolin-3-yl)acetonitrile (4)
yield: 0.177 g (68%).
A soln of cyano(5-methoxy-2-oxoindolin-3-yl)acetic acid (3; 2 g,
0
2
reduced pressure and the dark oil was dissolved in warm EtOAc.
The solution was passed through a silica gel column, which gave a
light-orange solid after evaporation of the EtOAc; yield: 1.09 g
1
H NMR (400.13 MHz, CDCl ): d = 1.26 (t, 3 H), 2.04–2.08 (m, 3
3
.008 mol) in 2-ethoxyethanol (10 mL) was heated under reflux for
.5 h with stirring. Afterwards, the mixture was concentrated under
H), 2.18–2.28 (m, 2 H), 3.20–3.27 (m, 1 H), 3.73 (s, 3 H), 6.68 (m,
2
H), 6.93 (s, 1 H).
(
2-Chloro-5-methoxy-1H-indol-3-yl)acetonitrile (6)
A mixture of (5-methoxy-2-oxoindolin-3-yl)acetonitrile (4; 0.1 g,
.5 mmol) and pure POCl (5 mL) was heated under reflux for 4 h
6
b
(
66%); mp 155–160 °C (Lit. 180–181 °C).
0
3
IR (vaseline oil): 2315–2340 (NH), 2280 (CN), 1700 (br, CONHR),
1
with stirring. After the reaction was complete, the excess POCl was
evaporated under reduced pressure. The residue was washed with
3
620 cm–1 (C=C).
1
aq K
2 3 2 2
CO and extracted with CH Cl (2 × 10 mL). The organic layer
H NMR (400.13 MHz, CDCl ): d = 2.77 (dd, J = 17.0, 9.1 Hz, 1 H,
3
was dried (Na SO ) and concentrated to give a beige solid; yield:
2
4
CH ), 3.10 (dd, J = 17.0, 4.8 Hz, 1 H, CH ), 3.70 (dd, J = 8.6, 4.8
Hz, 1 H, CH), 3.81 (s, 3 H, OCH ), 6.89 (dd, J = 8.6, 8.6 Hz, 1 H,
ArH), 7.02 (s, 1 H, ArH), 7.20 (d, J = 8.6 Hz, 1 H, ArH), 8.45 (s, 1
2
2
0
.09 g (82%); mp 135–136 °C.
3
IR (film): 2650–2800 (NH), 2270 (CN), 1700, 1600 cm–1 (C=C).
H, NH).
1
H NMR (400.13 MHz, CDCl ): d = 3.77 (s, 2 H), 3.88 (s, 3 H), 6.89
3
MS (EI, 70 eV): m/z (%) = 202 (25), 175 (2), 162 (100), 147 (14),
(dd, J = 8.8, 2.3 Hz, 1 H), 7.02 (s, 1 H), 7.19 (d, J = 8.9 Hz, 1 H),
1
31 (13), 119 (18), 104 (11), 91 (9), 77 (14).
8.45 (s, 1 H, NH).
1
3
C NMR (100.6 MHz, CDCl ): d = 12.96, 22.69, 29.70, 55.85,
3
N-[2-(5-Methoxy-2-oxoindolin-3-yl)ethyl]acetamide (2-Oxo-
,3-dihydromelatonin, 5)
Method A (Scheme 2)
5-Methoxy-2-oxoindolin-3-yl)acetonitrile (4; 1 g, 0.005 mol) was
9
9.72, 111.83, 113.22, 115.00, 126.64, 129.19, 154.95.
2
+
MS (EI, 70 eV): m/z (%) = 220 (100) [M ], 205 (75), 194 (7), 185
(
(
35), 177 (85), 170 (7), 162 (10), 148 (35), 142 (32), 134 (7), 120
15).
(
hydrogenated over Adams’ catalyst (50 mg, 0.22 mmol) in the pres-
ence of Ac O (0.5 mL) in glacial AcOH (15 mL) at atmospheric
2
N-[2-(2-Chloro-5-methoxy-1H-indol-3-yl)ethyl]acetamide (2-
Chloromelatonin; Table 1, Entry 5)
pressure and r.t. Hydrogenation was continued until 0.222 L of H2
was absorbed (nearly 4 h). The catalyst was filtered off and the so-
lution was concentrated under reduced pressure. The residue was
dissolved in CH Cl (30 mL), which was then washed with dilute aq
(2-Chloro-5-methoxy-1H-indol-3-yl)acetonitrile (6; 0.150 g, 0.68
mmol), MeOH (3.58 mL), Ac O (0.13 mL, 1.4 mmol) and anhyd
2
2
2
NiCl (0.018 g, 0.138 mmol) were placed into a 30-mL flask.
NaHCO (10 mL) and concentrated; yield: 1 g (80%); mp 138–
2
3
NaBH (0.18 g, 4.7 mmol) was added at 0 °C. The mixture was
1
46 °C (dec).
4
stirred at 25 °C for 4 d, and NaBH (0.15 g) was added once per day.
4
When the reaction was complete, the MeOH was evaporated under
Method B (Table 1, Entry 2)
5-Methoxy-2-oxoindolin-3-yl)acetonitrile (4; 0.436 g, 2.2 mmol),
MeOH (10 mL), Ac O (0.63 mL, 6.7 mmol) and anhyd NiCl (0.018
reduced pressure and the residue was washed with aq K CO . The
(
2
3
product was extracted with EtOAc (2 × 5 mL), and the organic layer
was dried (Na SO ) and concentrated under reduced pressure; yield:
2
2
g, 0.14 mmol) were placed into a 30-mL flask. NaBH (0.18 g, 4.7
2
4
4
4
0
.1 g (55%); mp 120–130 °C (dec) (Lit. 124 °C).
mmol) was added at 0 °C. The mixture was stirred at 25 °C for 4 d,
and NaBH (0.04 g) was added once per day. When the reaction was
1
4
H NMR (400.13 MHz, CDCl ): d = 1.93 (s, 3 H, CH ), 2.92 (t,
3 3
complete, the MeOH was evaporated under reduced pressure and
J = 6.6 Hz, 2 H), 3.53 (dd, J = 6.3, 6.4 Hz, 2 H), 3.84 (s, 3 H,
the residue was washed with aq K CO . The product was extracted
2
3
OCH ), 5.60 (s, 1 H), 6.84 (dd, J = 2.3, 8.8 Hz, 1 H), 6.96 (d, J = 2.3
3
with EtOAc (2 × 10 mL), and the organic layer was dried (Na SO )
2
4
Hz, 1 H), 7.18 (d, J = 8.8 Hz, 1 H), 8.50 (s, 1 H, NH).
and concentrated under reduced pressure; yield: 0.2 g (37%).
MS (EI, 70 eV): m/z (%) = 266 (20), 207 (100), 194 (80), 185 (27),
177 (33), 170 (7), 162 (10), 151 (33), 142 (17), 114 (50), 89 (20).
1
H NMR (400.13 MHz, CDCl ): d = 1.95 (s, 3 H, CH ), 1.98–2.09
3
3
(
m, 1 H), 2.17–2.24 (m, 1 H), 3.41–3.51 (m, 3 H), 3.77 (s, 3 H,
Anal. Calcd for C H ClN O : C, 58.54; H, 5.67; N, 10.50. Found:
1
3
15
2
2
OCH ), 6.58 (br s, 1 H, NH), 6.72–6.75 (dd, J = 10.6, 6.4 Hz, 1 H),
3
C, 58.30; H, 5.84; N, 9.35.
6
.79–6.81 (d, J = 8.4 Hz, 1 H), 6.90 (s, 1 H), 9.04 (s, 1 H, NH).
1
3
C NMR (100.6 MHz, CDCl ): d = 23.04, 29.94, 36.96, 44.75,
3
N-[2-(2-Chloro-5-methoxy-1H-indol-3-yl)ethyl]propanamide
5
1
5.76, 110.38, 111.09, 112.75, 130.59, 135.01, 155.76, 170.82,
80.47.
(
Table 1, Entry 6)
(2-Chloro-5-methoxy-1H-indol-3-yl)acetonitrile (6; 0.109 g, 0.495
+
mmol), MeOH (10 mL), propionic anhydride (0.14 mL, 1.1 mmol)
MS (EI, 70 eV): m/z (%) = 248 (35), 205 (7) [M – CH CO], 189
(
3
+
and anhyd NiCl (0.016 g, 0.12 mmol) were placed into a 30-mL
45), 176 (100) [M – CH CONHCH ], 163 (17), 117 (23), 83 (38).
2
3
2
flask. NaBH (0.18 g, 4.7 mmol) was added at 0 °C. The mixture
4
Anal. Calcd for C H N O : C, 62.89; H, 6.50; N, 11.28. Found: C,
6
1
3
16
2
3
was stirred at 25 °C for 4 d, and NaBH (0.1 g) was added once per
4
2.70; H, 6.31; N, 11.12.
day. When the reaction was complete, the MeOH was evaporated
under reduced pressure and the residue was washed with aq K CO .
2
3
N-[2-(5-Methoxy-2-oxoindolin-3-yl)ethyl]propanamide (Table
, Entry 3)
5-Methoxy-2-oxoindolin-3-yl)acetonitrile (4; 0.211 g, 0.001 mol),
The product was extracted with EtOAc (2 × 5 mL), and the organic
layer was dried (Na SO ) and concentrated under reduced pressure;
1
(
2
4
yield: 0.017 g (12%).
MeOH (10 mL), propionic anhydride (0.3 mL, 0.0023 mol) and an-
hyd NiCl (0.027 g, 0.21 mmol) were placed into a 30-mL flask.
NaBH (0.2 g, 5.3 mmol) was added at 0 °C. The mixture was
stirred at 25 °C for 4 d, and NaBH (0.1 g) was added twice per day.
1
H NMR (400.13 MHz, CDCl ): d = 1.27 (t, 3 H), 2.12–2.18 (m, 2
3
2
H), 3.04 (m, 2 H), 3.68–3.73 (m, 2 H), 3.84 (s, 3 H), 6.83 (d, J = 7.1
Hz, 1 H), 6.99 (d, J = 7.1 Hz, 1 H), 7.15 (s, 1 H).
4
4
When the reaction was complete, the MeOH was evaporated under
Synthesis 2011, No. 2, 273–276 © Thieme Stuttgart · New York