January 2001
93
HR-MS m/z: Calcd for C15H20N2O2: 260.1525. Found: 260.1518.
br s), 7.03 (1H, dd, Jϭ2.4, 8.8 Hz), 7.24 (1H, d, Jϭ2.4 Hz), 7.31 (1H, t,
Jϭ7.7 Hz), 7.38 (2H, t, Jϭ7.7 Hz), 7.47 (2H, d, Jϭ7.7 Hz), 7.55 (1H, s),
8.04 (1H, br d, Jϭ8.8 Hz), 9.24 (1H, br s). HR-MS m/z: Calcd for
C20H20N2O4: 352.1423. Found: 352.1421.
1-Formyl-5-methoxy-N,N-dimethyltryptamine (11b) from 2e A solu-
tion of 2e (40.4 mg, 0.18 mmol) in 85% HCOOH (4.0 ml) was heated at
80 °C for 86 h with stirring. After evaporation of the solvent under reduced
pressure, the residue was subjected to p-TLC on SiO2 with CHCl3–MeOH–
28% aq. NH3 (46 : 5 : 0.5, v/v). Under UV light, two bands were detected.
Extraction from the upper band with CHCl3–MeOH–28% aq. NH3 (46 : 5 :
0.5, v/v) afforded 11b (22.5 mg, 50%). Extraction from the lower band with
the same solvent as above afforded unreacted 2e (13.0 mg, 32%). 11b: Col-
5-Benzyloxytryptamine (12b) from 12a 40% aq. NaOH (2.0 ml) was
added to a solution of 12a (174.9 mg, 0.50 mmol) in MeOH (6.0 ml) and the
mixture was refluxed for 4 h with stirring. After addition of H2O, the whole
was extracted with CHCl3–MeOH (95 : 5, v/v). The extract was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave an
oil, which was column-chromatographed on SiO2 with CHCl3–MeOH–28%
aq. NH3 (46 : 2 : 0.2, v/v) to give 12b (126.5 mg, 96%). 12b: mp 97.5—
99.5 °C (colorless powder, recrystallized from CHCl3–hexane). IR (KBr):
1
orless viscous oil. IR (film): 1708, 1602 cmϪ1. H-NMR (DMSO-d6, 60 °C)
d: 2.37 (6H, s), 2.76 (2H, t, Jϭ7.5 Hz), 2.86 (2H, t, Jϭ7.5 Hz), 3.83 (3H, s),
6.96 (1H, dd, Jϭ8, 2.7 Hz), 7.15 (1H, d, Jϭ2.7 Hz), 7.60 (1H, s), 8.06 (1H,
br s), 9.20 (1H, br s). HR-MS m/z: Calcd for C14H18N2O2: 246.1367. Found:
246.1368.
1585, 1490, 1465, 1205, 1010 cmϪ1 1H-NMR (CDCl3) d: 1.51 (2H, br s,
.
disappeared on addition of D2O), 2.86 (2H, t, Jϭ6.6 Hz), 3.01 (2H, t, Jϭ
6.6 Hz), 5.11 (2H, s), 6.94 (1H, dd, Jϭ2.5, 8.8 Hz), 7.02 (1H, d, Jϭ2.5 Hz),
7.14 (1H, d, Jϭ2.5 Hz), 7.25 (1H, d, Jϭ8.8 Hz), 7.31 (1H, br t, Jϭ7.7 Hz),
7.38 (2H, br t, Jϭ7.7 Hz), 7.48 (2H, br d, Jϭ7.7 Hz), 7.94 (1H, br s, disap-
peared on addition of D2O). MS m/z: 266 (Mϩ). Anal. Calcd for
C17H18N2O·1/8H2O: C, 76.02; H, 6.85; N, 10.43. Found: C, 76.10; H, 6.81;
N, 10.49.
N-Methylserotonin (1b) from 9b LiAlH4 (59.9 mg, 1.58 mmol) was
added to a solution of 9b (31.2 mg, 0.13 mmol) in anhydrous Et2O–THF
(1 : 1, v/v, 4.0 ml) and the mixture was refluxed for 26 h with stirring. After
cooling, MeOH was added to the reaction mixture to destroy excess LiAlH4.
After evaporation of the solvent under reduced pressure, the residual oil was
column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (5 : 1 :
1, v/v) to give 1b (16.4 mg, 65%). 1b: Colorless viscous oil.3) IR (film):
N-[2-(5-Benzyloxyindol-3-yl)ethyl]succinamic Acid (3b) from 12b
Succinic anhydride (22.6 mg, 0.22 mmol) was added to a solution of 12b
(49.0 mg, 0.18 mmol) in anhydrous THF (4.0 ml) and the mixture was stirred
at room temperature for 20 min. The solvent was evaporated under reduced
pressure to leave an oil, which was column-chromatographed on SiO2 with
CHCl3–MeOH–AcOH (46 : 5 : 0.5, v/v) to give 3b (64.6 mg, 96%). 3b: mp
145—147 °C (colorless plates, recrystallized from MeOH–CHCl3). IR
3380, 3280, 1618, 1578, 1460 cmϪ1 1H-NMR (CD3OD) d: 2.38 (3H, s),
.
2.82—2.90 (4H, m, A2B2), 6.66 (1H, dd, Jϭ8.5, 2.4 Hz), 6.92 (1H, dd,
Jϭ2.4, 0.5 Hz), 7.00 (1H, s), 7.15 (1H, dd, Jϭ8.5, 0.5 Hz). HR-MS m/z:
Calcd for C11H14N2O: 190.1106. Found: 190.1106.
5-Hydroxy-N,N-dimethyltryptamine (1c, Bufotenine) from 8e c-
H2SO4 (1.0 ml) was added to a solution of 8e (31.2 mg, 0.15 mmol) in H2O
(19.0 ml) and the mixture was refluxed for 6 h with stirring. After cooling,
the reaction mixture was made neutral by adding sat. aq. NaHCO3 and the
whole was extracted with CHCl3–MeOH (95 : 5, v/v). The extract was dried
over Na2SO4, and evaporated under reduced pressure to leave an oil, which
was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3
(46 : 5 : 0.5, v/v) to give 6e (4.5 mg, 16%) and 1c (14.7 mg, 47%) in the order
of elution. 1c: mp 146—147 °C (colorless prisms, recrystallized from
EtOAc, lit.,3) mp 146—147 °C). IR spectrum was identical with that of the
reported chart.3) 1H-NMR (CD3OD) d: 2.41 (6H, s), 2.73 (2H, t, Jϭ8.1 Hz),
2.90 (2H, t, Jϭ8.1 Hz), 6.66 (1H, dd, Jϭ8.6, 2.4 Hz), 6.90 (1H, dd, Jϭ2.4,
0.5 Hz), 7.00 (1H, s), 7.15 (1H, dd, Jϭ8.6, 0.5 Hz). MS m/z: 204 (Mϩ). Anal.
Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.72. Found: C, 70.48; H, 8.17;
N, 13.58. Iodomethylate: mp 218—219 °C (colorless prisms, recrystallized
from MeOH, lit.,3) mp 214—215 °C). IR (KBr): 1620, 1584, 1475 cmϪ1. 1H-
NMR (CD3OD) d: 3.19—3.26 (2H, m), 3.24 (9H, s), 3.57—3.62 (2H, m),
6.71 (1H, dd, Jϭ8.5, 2.4 Hz), 6.94 (1H, dd, Jϭ2.4, 0.5 Hz), 7.15 (1H, s),
7.19 (1H, dd, Jϭ8.5, 0.5 Hz). Anal. Calcd for C13H19N2OI: C, 45.10; H,
5.53; N, 8.09. Found: C, 44.98; H, 5.66; N, 7.80. Monopicrate: mp 185—
186 °C (orange prisms, recrystallized from MeOH, lit.,3) mp 179—180 °C).
(KBr): 3400, 1710, 1610, 1545, 1195 cmϪ1 1H-NMR (CDCl3) d: 2.41—
.
2.44 (2H, m), 2.63—2.66 (2H, m), 2.95 (2H, t, Jϭ6.6 Hz), 3.61 (2H, q,
Jϭ6.6 Hz), 5.11 (2H, s), 5.75 (1H, br t, Jϭ6.6 Hz), 6.96 (1H, dd, Jϭ8.8,
2.2 Hz), 7.02 (1H, d, Jϭ2.2 Hz), 7.11 (1H, d, Jϭ2.2 Hz), 7.28 (1H, t,
Jϭ8.8 Hz), 7.32 (1H, t, Jϭ7.7 Hz), 7.39 (2H, br t, Jϭ7.7 Hz), 7.48 (2H, d,
Jϭ7.7 Hz), 8.02 (1H, br s, disappeared on addition of D2O). Anal. Calcd for
C21H22N2O4: C, 68.83; H, 6.05; N, 7.65. Found: C, 68.73; H, 6.02; N, 7.57.
Methyl N-[2-(5-Benzyloxyindol-3-yl)ethyl]succinamate (3d) and N-[2-
(5-Benzyloxyindol-3-yl)ethyl]succinimide (13a) from 3b An excess
amount of ethereal CH2N2 was added to a solution of 3b (166.0 mg,
0.45 mmol) in MeOH (5.0 ml) at room temperature and stirring was contin-
ued for 10 min. After evaporation of the solvent under reduced pressure, the
residual oil was column-chromatographed with CHCl3–MeOH (99 : 1, v/v)
to give 13a (47.5 mg, 30%) and 3d (98.7 mg, 57%) in the order of elution.
3d: mp 108—110 °C (colorless needles, recrystallized from CHCl3–hexane).
IR (KBr): 3390, 1725, 1658 cmϪ1 1H-NMR (CDCl3) d: 2.40 (2H, t,
.
Jϭ6.8 Hz), 2.65 (2H, t, Jϭ6.8 Hz), 2.92 (2H, t, Jϭ6.6 Hz), 3.58 (2H, q,
Jϭ6.6 Hz), 3.65 (3H, s), 5.11 (2H, s), 5.67 (1H, br t, Jϭ6.6 Hz), 6.95 (1H,
dd, Jϭ8.6, 2.4 Hz), 7.04 (1H, d, Jϭ2.2 Hz), 7.13 (1H, d, Jϭ2.4 Hz), 7.27
(1H, d, Jϭ8.6 Hz), 7.32 (1H, t, Jϭ7.4 Hz), 7.39 (2H, t, Jϭ7.4 Hz), 7.48 (2H,
d, Jϭ7.4 Hz), 7.98 (1H, br s). Anal. Calcd for C22H24N2O4: C, 69.45; H,
6.36; N, 7.36. Found: C, 69.43; H, 6.34; N, 7.31. 13a: mp 172—174 °C (col-
orless powder, recrystallized from CHCl3–hexane). IR (KBr): 3380, 1767,
1
IR (KBr): 1626, 1609, 1561, 1333 cmϪ1. H-NMR (DMSO-d6) d: 2.85 (6H,
s), 2.98 (2H, t, Jϭ8.1 Hz), 3.29 (2H, t, Jϭ8.1 Hz), 6.64 (1H, dd, Jϭ8.5,
2.4 Hz), 6.87 (1H, d, Jϭ2.4 Hz), 7.13 (1H, d, Jϭ2.4 Hz, collapsed to s on ad-
dition of D2O), 7.16 (1H, d, Jϭ8.5 Hz), 8.59 (2H, s), 8.64 (1H, s, disap-
peared on addition of D2O), 9.15 (1H, br s, disappeared on addition of D2O),
10.63 (1H, br s, disappeared on addition of D2O). Anal. Calcd for
C12H16N2O·C6H3N3O7: C, 49.88; H, 4.42; N, 16.16. Found: C, 49.84; H,
4.38; N, 15.90.
1
1690 cmϪ1. H-NMR (CDCl3) d: 2.62 (4H, s), 3.01 (2H, t, Jϭ7.6 Hz), 3.81
(2H, t, Jϭ7.6 Hz), 5.12 (2H, s), 6.93 (1H, dd, Jϭ8.8, 2.4 Hz), 7.06 (1H, d,
Jϭ2.4 Hz), 7.23 (1H, s), 7.24 (1H, d, Jϭ8.8 Hz), 7.31 (1H, br t, Jϭ7.6 Hz),
7.38 (2H, t, Jϭ7.6 Hz), 7.51 (2H, d, Jϭ7.6 Hz), 7.90 (1H, br s). Anal. Calcd
for C21H20N2O3: C, 72.39; H, 5.79; N, 8.04. Found: C, 72.15; H, 5.72; N,
7.98.
Compound 1c from 2e 1 M solution of BBr3 in toluene (5.7 ml,
5.7 mmol) was added to a solution of 2e (245.4 mg, 1.13 mmol) in CH2Cl2
(12.0 ml) at Ϫ15 °C and the mixture was stirred at Ϫ15 °C for an additional
4 h. After addition of ice and H2O, the mixture was made basic (pH 8—9) by
adding 30% aq. NaOH. The whole was extracted with CHCl3–MeOH (9 : 1,
v/v). The extract was washed with brine, dried over Na2SO4, and evaporated
under reduced pressure to leave an oil, which was column-chromatographed
on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 5 : 0.5, v/v) to give unre-
acted 2e (58.5 mg, 24%) and 1c (145.4 mg, 63%) in the order of elution.
5-Benzyloxy-1-formyl-N-methoxycarbonyltryptamine (12a) from 9a
A solution of benzyl bromide (217.7 mg, 1.27 mmol) in anhydrous DMF
(1.0 ml) was added to a mixture of K2CO3 (165.3 mg, 1.20 mmol) and 9a
(104.3 mg, 0.39 mmol) in anhydrous DMF (2.0 ml), and the whole was
stirred at room temperature for 2.5 h. After addition of H2O, the whole was
extracted with CHCl3–MeOH (95 : 5, v/v). The extract was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave an
oil, which was column-chromatographed on SiO2 with EtOAc–hexane (1 : 4,
v/v) to give 12a (132.1 mg, 94%). 12a: pale yellow oil. IR (film): 3300,
Compound 3d from 3b An excess amount of ethereal CH2N2 was
added to a solution of 3b (99.6 mg, 0.27 mmol) in MeOH (3.0 ml) at 0 °C
and stirring was continued for 10 min at 0 °C. After evaporation of the sol-
vent under reduced pressure, the residual oil was column-chromatographed
with CHCl3–MeOH (99 : 1, v/v) to give 3d (101.0 mg, 97%).
Bufobutanoic Acid (3a) from 3b
A solution of 3b (54.2 mg,
0.15 mmol) in MeOH (3.0 ml) was hydrogenated in the presence of 10%
Pd/C (53.4 mg) at room temperature and 1 atm for 1 h. Catalyst was filtered
off and the filtrate was evaporated under reduced pressure to leave an oil,
which was column-chromatographed on SiO2 with CHCl3–MeOH–AcOH
(46 : 5 : 0.5, v/v) to give 3a (40.4 mg, 99%). 3a: Pale brown oil. IR (film):
1
3390, 1710, 1620, 1580, 1540, 1485, 1460, 1365, 1185, 938, 800 cmϪ1. H-
NMR (DMSO-d6) d: 2.32 (2H, t, Jϭ7.2 Hz), 2.43 (2H, t, Jϭ7.2 Hz), 2.70
(2H, t, Jϭ7.6 Hz), 3.28 (2H, q, Jϭ7.6 Hz), 6.58 (1H, dd, Jϭ8.6, 2.2 Hz),
6.81 (1H, d, Jϭ2.2 Hz), 7.02 (1H, d, Jϭ2.2 Hz), 7.11 (1H, d, Jϭ8.6 Hz),
7.94 (1H, t, Jϭ7.6 Hz), 8.60 (1H, br s, disappeared on addition of D2O),
10.45 (1H, s). HR-MS m/z: Calcd for C14H16N2O4: 276.1110. Found:
276.1109. Spectral data are identical with the reported values.8)
1700, 1600, 1478 cmϪ1
Jϭ7.2 Hz), 3.32 (2H, q, Jϭ7.2 Hz), 3.54 (3H, s), 5.16 (2H, s), 6.84 (1H,
.
1H-NMR (DMSO-d6, 90 °C) d: 2.81 (2H, t,