The chemistry of indoles. CVII. A synthesis of 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles and a new finding on pictet-spengler reaction

Article abstract of DOI:10.1248/cpb.49.1159

Serotonins were found to produce 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles by simple heating with amines under an oxygen atmosphere. Serotonins also reacted with various aldehydes to provide 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]

Full text of DOI:10.1248/cpb.49.1159

September 2001
Chem. Pharm. Bull. 49(9) 1159—1165 (2001)
1159
The Chemistry of Indoles. CVII.1) A Novel Synthesis of 3,4,5,6-
Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles and a New Finding on
Pictet–Spengler Reaction
Masanori SOMEI,* Sakiko TERANISHI, Koji YAMADA, and Fumio YAMADA
Faculty of Pharmaceutical Sciences, Kanazawa University, 13–1 Takara-machi, Kanazawa 920–0934, Japan.
Received April 27, 2001; accepted June 4, 2001
Serotonins were found to produce 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles by simple heat-
ing with amines under an oxygen atmosphere. Serotonins also reacted with various aldehydes to provide 3,4,5,6-
tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indoles rather than b-carbolines under basic conditions. In these
novel reactions, the presence of the 5-hydroxy group on the indole nucleus was suggested to be essential. Possible
mechanisms are discussed.
Key words 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole; serotonin
Aurantioclabine (1a) and clavicipitic acid (1b) are mem- cess Et3N under an oxygen atmosphere. The results of this
bers of ergot alkaloids (Fig. 1).2) Na,Nb-Dimethylserotonin novel reaction are summarized in Table 1. The desired 5a and
(2a), serotonin (2b), and Nb-methylserotonin (2c) are well an unreacted 2a were obtained in 26 and 74% yields, respec-
known biologically active amines.3) Combination of the for- tively, after refluxing for 20 h (entry 1). As can be seen from
mer compounds with the latter ones results in a chimera entries 1—3, the longer the reaction time, the better the yield
skeleton such as 7-substituted 3,4,5,6-tetrahydro-1H-azepino- of 5a. It should be noted that the reaction was clean, and no
[5,4,3-cd]indole, as shown in a general formula (3). In our at- tar formation was observed; thus, even after 68 h refluxing,
tempt to develop biologically active substances, we have only 5a and 2a were obtained in 49 and 50% yields, respec-
identified 3 and its various derivatives to be possible promis- tively (entry 3). Interestingly, the introduction of bubbling
ing compounds.
oxygen into the reaction medium did not improve the rate of
In 1988, we reported the preparation of 3,4,5,6-tetrahydro- formation or the yield of 5a.
1H-azepino[5,4,3-cd]indole derivatives (4) starting from 4-
The compound (5a) was found to be identical by direct
cyanoindoles.4) However, the synthetic route is not applicable comparison with the sample prepared in 91% yield, alterna-
for the preparation of 3, because suitably functionalized 4- tively, by reacting 2a with acetaldehyde under similar reac-
cyanoindole derivatives are not readily available.5) On the
other hand, we have established a simple method for sero-
tonin congeners6a) (2a—c) utilizing our 1-hydroxyindole
chemistry.7) Making use of 2a—c as starting materials, we
now wish to report our success in developing a novel syn-
thetic method for 3,4,5,6-tetrahydro-7-hydroxy-1H-azepino-
[5,4,3-cd]indoles (5) as one of our targets (3).
Table 1.
Et3N, MeOH, O2 balloon, reflux
2a
→5a + recovery
Yield (%) of
Additive
(mol eq)
Entry
Reaction time (h)
5a
Recovery
I. A Novel Reaction for Preparing 3,4,5,6-Tetrahydro-
7-hydroxy-1H-azepino[5,4,3-cd]indoles Synthesis of 3,4,
5,6-tetrahydro-7-hydroxy-1,5,6-trimethyl-1H-azepino[5,4,3-
cd]indole (5a) was easily attained by refluxing the MeOH so-
lution of Na,Nb-dimethylserotonin (2a) in the presence of ex-
1
2
3
4
—
—
—
20
43
68
26
36
49
91
74
52
50
0
MeCHO (1.7)
2/3
Fig. 1
To whom correspondence should be addressed. e-mail: somei@dbs.p.kanazawa-u.ac.jp
© 2001 Pharmaceutical Society of Japan

1160
Vol. 49, No. 9
Chart 1
Table 2.
Et3N, MeOH
2b HCl
→5c + recovery (2b)
Reaction conditions
Yield (%) of
Recovery
Additive
(mol eq)
Entry
Atmosphere
Note
Temp. (°C)
Time (h)
5c
1
2
3
4
O2
O2
O2
Ar
—
Reflux
21.5
21.5
24
20
4
24
4
20
0
0
59
51
18
44
Clean
Tar
Tar
MeCHO (3)
MeCHO (6)
MeCHO (3)
8
Tar
Chart 2

September 2001
Table 3.
1161
MeOH, MeCHO Open, reflux
2b HCl
→5c +
14
Yield (%) of
MeCHO
(mol eq)
Concentration of
Entry
pH
Time (h)
Note
2b·HCl (10Ϫ2 mol/l)
5c
14
Recovery (2b)
1
2
3
4
4
4
5
5
50
50
50
10
11.9
2.4
2.5
2.4
1
20
20
20
0
0
27
28
26
13
53
30
0
0
0
Tar
Tar
Clean
Clean
40
tion conditions (entry 4). With an aim to prove its structure, 94% yield. Although comparison of the spectroscopic data of
the acetylation of 5a was carried out with Ac2O–pyridine to 5f and 11 suggested their structures to be as shown, further
give 6 in 82% yield (Chart 1). Further treatment of 6 with re- proof was obtained by direct comparison with authentic 5f.
fluxing Ac2O cleaved the seven-membered ring to afford 7 Thus, it was prepared by the reaction of 2b·HCl with ben-
1
and 8 in 29 and 34% yields, respectively. In the H-NMR zaldehyde in MeOH at reflux in 57% yield, in addition to un-
spectra of these compounds (5a, 6—8), two ortho-coupled reacted 2b and 1,2,3,4-tetrahydro-6-hydroxy-1-phenyl-b-car-
protons and a singlet proton were observed in the aromatic boline (12) in the respective yields of 15 and 2%.
region, suggesting that 5a and 6 have a 1H-azepino[5,4,3-
The attempt to obtain an authentic sample of 5e resulted in
cd]indole skeleton. To obtain further proof, the reaction of 2a poor yields. Thus, the reaction of 2b·HCl directly with
with p-methoxybenzaldehyde in refluxing tetrahydrofuran formaldehyde in methanolic Et3N formed a lot of tar, to-
(THF) was carried out. In this case, luckily, a set of isomers, gether with the desired 5e in only 3% yield. A better yield of
5b and 9, were produced in 88 and 11% yields, respectively. 5e was attained by employing the following two-step route.
Although the pattern of proton signals of 5b is quite similar Thus, 2b was converted to compound (13) by Mannich reac-
to those of 5a, 6—8, the spectrum of 9 is different and it tion with HCHO in the presence of dimethylamine in 78%
clearly exhibits meta-coupled signals assignable to the 5- and yield. Subsequent heating of its methanol solution at reflux
7-positions of the b-carboline nucleus.
afforded a 35% yield of 5e.
II. Pictet–Spengler Type Reaction for Serotonin Con-
The above results suggested that Et3N worked as an ac-
etaldehyde equivalent. To confirm this view, the reaction was geners under Basic Conditions The reaction of trypta-
applied to serotonin (2b). Using serotonin hydrochloride mines with aldehydes under acidic or neutral conditions is
(2b·HCl), the reaction with excess Et3N for 20 h under an well known as the Pictet–Spengler reaction for preparing b-
oxygen atmosphere was expectedly successful and clean, and carbolines.8) Under basic reaction conditions, as described in
the corresponding 5c and unreacted 2b were obtained in 20 the section I, our results upon reactions of serotonins (2a—c)
and 59% yields, respectively (Table 2, entry 1). In order to with amines or aldehydes are quite different from the Pictet–
confirm the structure of 5c, an attempt was made to react 2b Spengler reaction, giving 3,4,5,6-tetrahydro-7-hydroxy-1H-
with acetaldehyde, but the reaction afforded tar matter, even azepino[5,4,3-cd]indoles rather than b-carbolines.
at room temperature, and the desired 5c was not formed
Therefore, under careful pH control, we next examined the
under the reaction conditions described in entries 2 and 3. reaction of 2b·HCl with acetaldehyde. A summary of typical
Considering the intrinsically sensitive nature of 2b to oxy- results is shown in Table 3. Adjusting the pH of the reaction
gen, the reaction was next examined under Ar atmosphere. media to 4 by adding aq. HCl, the reactions of 2b·HCl with
Monitoring with thin layer chromatography, the reaction time an excess amount (50 mol eq) of acetaldehyde provided b-
for maximizing 5c was found to be 4 h, at which an 8% yield carboline (14) as the sole product in 26% yield, together with
of 5c was obtained, together with a significant amount of tar tar matter (entry 1). When the concentration of 2b·HCl was
(entry 4).
diluted with an aim to reduce the formation of tar, the yield
As in the cases of 2a,b, the reaction of 2c with excess of 14 dropped to 13% (entry 2). Interestingly, under similar
Et3N under an oxygen atmosphere was also clean giving 5d reaction conditions, except for pH 5, the more basic condi-
in 23% yield after 20 h refluxing (Chart 2). The authentic tions, 7-hydroxy-5-methyl-1H-azepino[5,4,3-cd]indole (5c)
sample of 5d was prepared in 80% yield by reacting 2c with was obtained in 27% yield, together with 53% yield of 14
acetaldehyde.
(entry 3). Use of less acetaldehyde (10 mol eq) decreased the
Since Et3N was found to function as a good substitute for yield of 5c and 14 into 28 and 30% yields, respectively, in
acetaldehyde, we next tried to extend this novel reaction to addition to unreacted 2b (entry 4).
other amines such as N,N-dimethylbenzylamine. A methanol
Since pH was suggested to be an important factor in deter-
solution of 2b·HCl and an excess amount of N,N-dimethyl- mining products, further trials were carried out to confirm
benzylamine was refluxed for 6 h under an oxygen atmo- this. The reaction of Na,Nb-dimethylserotonin (2a) with ac-
sphere. The reaction was again clear, and 3,4,5,6-tetrahydro- etaldehyde at pH 5 produced 15 and 5a in 27 and 58%
7-hydroxy-1H-azepino[5,4,3-cd]indole (5e), its 6-phenyl de- yields, respectively (Chart 3). In the same reaction, except
rivative (5f), and 1,2,3,4-tetrahydro-6-hydroxy-b-carboline for the presence of excess Et3N (the more basic conditions),
(10) were obtained in 14, 9, and 6% yields, respectively, in the formation of 15 was completely excluded and 5a was ob-
addition to a 29% yield of unreacted 2b. Treatment of 5f tained in 91% yield. In contrary, when the reaction of 16,6)
with Ac2O and pyridine afforded a diacetyl compound (11) in prepared in 94% yield by a LiAlH4 reduction of 5-methoxy-

1162
Vol. 49, No. 9
Chart 3
Chart 4. Possible Mechanism
Nb-methoxycarbonylindole9) (17), with acetaldehyde was
carried out at pH 5, b-carboline (18) was obtained in 82%
yield as a sole product, while the formation of 19 was not de-
tected at all.
These results clearly suggest that the 5-hydroxy group is
essential for the formation of 1H-azepino[5,4,3-cd]indole.
Under basic conditions, the 5-hydroxy group loses a proton
to give a phenoxide ion which is responsible for activating

September 2001
1163
the nucleophilic reactivity of the 4-position of the indole nu- Jϭ7.0 Hz), 2.61 (3H, s), 2.91 (1H, ddd, Jϭ16.4, 3.4, 2.4 Hz), 3.08 (1H, ddd,
Jϭ14.3, 4.9, 2.4 Hz), 3.25 (1H, dddd, Jϭ16.4, 13.1, 4.9, 1.2 Hz), 3.65 (1H,
ddd, Jϭ14.3, 13.1, 3.4 Hz), 3.68 (3H, s), 4.67 (1H, q, Jϭ7.0 Hz), 6.69 (1H,
d, Jϭ8.5 Hz), 6.79 (1H, s), 6.97 (1H, d, Jϭ8.5 Hz). High-resolution MS
m/z: Calcd for C14H18N2O: 230.1419. Found: 230.1417. Anal. Calcd for
cleus toward aldehydes.
III. Possible Mechanism for the Reaction of Amines
with Serotonins In section I, we found a novel reaction in
which Et3N and N,N-dimethylbenzylamine worked as ac-
etaldehyde, benzaldehyde, and formaldehyde equivalents in
reactions with serotonins (2). A possible reaction mechanism
is shown in Chart 4, employing Et3N as a representative.
Initially, an oxygen molecule interacts with both triethy-
lamine and 2 generating a phenoxyl radical (A) and diethyl-
aminoethyl radical (B). The radical (A) tautomerizes to radi-
cal (C) and it combines with B to produce D. Liberation of
diethylamine from D affords o-quinomethane (E). Subse-
quent intramolecular cyclization of Nb-nitrogen to the b-car-
bon of the a,b-unsaturated carbonyl part in E completes the
process to 5 through the intermediate ketone (F).
C14H18N2O·1/4H2O: C, 71.61; H, 7.94; N, 11.93. Found: C, 71.58; H, 7.78;
N, 11.88.
[Entry 2] Et3N (3 ml) was added to a solution of 2a (22.5 mg,
0.11 mmol) in MeOH (3 ml) at 0 °C and the mixture was refluxed for 43 h
with stirring under O2 atmosphere (O2 balloon). After the same work-up
and separation described in entry 1, 5a (9.2 mg, 36%) and unreacted 2a
(11.7 mg, 52%) were obtained.
[Entry 3] Et3N (4 ml) was added to a solution of 2a (22.1 mg,
0.11 mmol) in MeOH (4 ml) at 0 °C, and the mixture was refluxed for 68 h
with stirring under O2 atmosphere (O2 balloon). After the same work-up and
separation described in entry 1, 5a (12.3 mg, 49%) and unreacted 2a
(11.0 mg, 50%) were obtained.
Method 2: Acetaldehyde (0.04 ml, 0.72 mmol) was added to a solution of
2a (84.5 mg, 0.41 mmol) in MeOH (4 ml) and Et3N (4 ml) at 0 °C and the
mixture was refluxed for 40 min with stirring under O2 atmosphere (O2 bal-
loon). After evaporation of the solvent, H2O was added to the residue. The
whole was extracted with CHCl3. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure to leave an oil, which
The other possibility is the interaction of molecular oxy-
gen with 2, culminating in phenoxyl (A) and hydropeoxy
radicals. Their recombination to hydroperoxide (G), followed
by elimination of the hydroperoxide anion from G generates was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3
(46 : 3 : 0.3, v/v) to give 5a (87.9 mg, 91%).
3,4,5,6-Tetrahydro-7-hydroxy-6-(4-methoxyphenyl)-1,5-dimethyl-1H-
azepino[5,4,3-cd]indole (5b) and 1,2,3,4-Tetrahydro-6-hydroxy-1-(4-me-
thoxyphenyl)-2,9-dimethyl-b-carboline (9) from 2a p-Methoxybenzalde-
hyde (0.062 ml, 0.51 mmol) in anhydrous THF (0.5 ml) was added to a solu-
a p-quinoneimine type cation (H). Subsequent single electron
tranfer from Et3N to H produces a radical (I) and cation radi-
cal (J). J is then converted to imminium species (K) by the
abstraction of a-hydrogen by I, as it transforms to L. L then
enolizes to the starting phenol (2), and it can react with K to
provide D.
The interaction of amine with molecular oxygen, as shown
in M providing radical (B) and a hydroperoxide radical, is
another possible pathway for the formation of K. Subsequent
recombination of the radicals generates hydroperoxide (N).
Elimination of the hydroperoxide anion from N affords K. If
this mechanism is working, substrates would not be limited
to serotonin congeners. Therefore, we examined the reaction
using N-methyltryptamine (20, Chart 3). Refluxing of a
MeOH solution of 20 with excess Et3N for 20 h under an
oxygen atmosphere resulted in the complete recovery of un-
reacted 20 without a trace amount of b-carboline or 1H-
azepino[5,4,3-cd]indoles.
tion of 2a (21.6 mg, 0.11 mmol) in anhydrous THF (2.5 ml) at 0 °C, and the
mixture was refluxed for 22 h with stirring. The solvent was evaporated
under reduced pressure to leave an oil, which was column-chromatographed
repeatedly on SiO2, successively, with CHCl3, CHCl3–MeOH (97 : 3, v/v),
and CHCl3–MeOH (95 : 5, v/v) to give 9 (3.8 mg, 11%) and 5b (30.1 mg,
88%) in the order of elution. 5b: Colorless oil. IR (film): 2914, 1510, 1456,
1246, 756 cmϪ1 1H-NMR (CDCl3) d: 2.72 (3H, s), 2.81—2.88 (2H, m),
.
3.21—3.28 (2H, m), 3.73 (6H, s), 5.70 (1H, s), 6.75 (2H, d, Jϭ8.8 Hz), 6.77
(1H, d, Jϭ8.6 Hz), 6.83 (1H, s), 7.05 (2H, d, Jϭ8.5 Hz), 7.08 (1H, d,
Jϭ8.6 Hz). High-resolution MS m/z: Calcd for C20H22N2O2: 322.1681.
Found: 322.1694. 9: mp 177—181 °C (colorless needles, recrystallized from
CHCl3–hexane). IR (KBr): 2920, 1603, 1508, 1224, 1032, 755 cmϪ1 1H-
.
NMR (CDCl3) d: 2.43 (3H, s), 2.74 (1H, dt, Jϭ11.8, 5.4 Hz), 2.79—2.89
(2H, m), 2.98—3.04 (1H, m), 3.16 (3H, s), 3.79 (3H, s), 4.59 (1H, s), 6.73
(1H, dd, Jϭ8.6, 2.4 Hz), 6.83 (2H, d, Jϭ8.8 Hz), 6.94 (1H, d, Jϭ2.4 Hz),
7.04 (1H, d, Jϭ8.6 Hz), 7.08 (2H, d, Jϭ8.8 Hz). MS m/z: 322 (Mϩ). Anal.
Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.35; H, 6.87;
To determine the reaction mechanism and extend the N, 8.65.
3,4,5,6-Tetrahydro-7-acetoxy-1,5,6-trimethyl-1H-azepino[5,4,3-cd]in-
scope of the present novel reaction, we are now examining
various amines in their reactions with serotonins, considering
that any amines can become substitutes for aldehydes or ke-
tones. We belive that this type of reaction would be working
in our living body and associated with the function of sero-
tonins.
dole (6) from 5a Ac2O (2.5 ml) was added to a solution of 5a (55.8 mg,
0.24 mmol) in pyridine (5 ml) under ice cooling and the mixture was stirred
at room temperature for 2 h. The solvent was evaporated under reduced pres-
sure to leave an oil, which was column-chromatographed on SiO2 with
CHCl3–MeOH (97 : 3, v/v) to give 6 (53.9 mg, 82%). 6: Colorless oil. IR
(film): 1755, 1365, 1215, 1193 cmϪ1 1H-NMR (CDCl3) d: 1.50 (3H, d,
.
Jϭ7.0 Hz), 2.35 (3H, s), 2.61 (3H, s), 3.01 (1H, br d, Jϭ15.4 Hz), 3.18—
3.30 (2H, m), 3.68 (1H, dt, Jϭ3.6, 13.7 Hz), 3.73 (3H, s), 4.51 (1H, br q,
Jϭ7.0 Hz), 6.87 (1H, d, Jϭ8.8 Hz), 6.88 (1H, s), 7.15 (1H, d, Jϭ8.8
Hz). High-resolution MS m/z: Calcd for C16H20N2O2: 272.1525. Found:
272.1526.
Experimental
Melting points were determined on a Yanagimoto micro melting point ap-
paratus and are uncorrected. IR spectra were determined with a Shimadzu
IR-420 spectrophotometer, and 1H-NMR spectra with a JEOL GSX-500
spectrometer, with tetramethylsilane as an internal standard. MS spectra
were recorded on a JEOL SX-102 A spectrometer. Column chromatography
was performed on silica gel (SiO2, 100—200 mesh, from Kanto Chemical
Co., Inc.). Preparative thin layer chromatography (p-TLC) was performed on
Merck Kiesel-gel GF254 (type 60) (SiO2).
5-Acetoxy-4-(1؅-acetoxyethyl)-Nb-acetyl-Na,Nb-dimethyltryptamine
(7) and 5-Acetoxy-Nb-acetyl-Na,Nb-dimethyl-4-vinyltryptamine (8) from
6
A solution of 6 (53.9 mg, 0.20 mmol) in Ac2O (8 ml) was heated for 4 h
at 105 °C with stirring. The solvent was evaporated under reduced pressure
to leave an oil, which was column-chromatographed on SiO2 with AcOEt
and CHCl3 to give 8 (21.3 mg, 34%) and 7 (21.8 mg, 29%) in the order of
elution. 7: Colorless oil. IR (film): 1758, 1738, 1635, 1568, 1245,
3,4,5,6-Tetrahydro-7-hydroxy-1,5,6-trimethyl-1H-azepino[5,4,3-cd]in-
dole (5a) from Na,Nb-Dimethylserotonin (2a) Method 1: [Entry 1] Et3N
(2 ml) was added to a solution of 2a (20.3 mg, 0.10 mmol) in MeOH (2 ml)
at 0 °C, and the mixture was refluxed for 20 h with stirring under O2 atmo-
sphere (O2 balloon). The solvent was evaporated under reduced pressure to
leave an oil, which was column-chromatographed on SiO2 with CHCl3–
MeOH–28% aq. NH3 (46 : 3 : 0.3, then 46 : 5 : 0.5, v/v) to give 5a (6.0 mg,
26%) and unreacted 2a (15.0 mg, 74%) in the order of elution. 5a: mp
162.0—163.5 °C (pale yellow powder, recrystallized from CHCl3–hexane).
1
1200 cmϪ1. H-NMR (DMSO-d6, 110 °C) d: 1.63 (3H, d, Jϭ6.7 Hz), 1.91
(6H, s), 2.27 (3H, s), 2.92 (3H, br s), 2.98—3.17 (2H, m), 3.60 (2H, t,
Jϭ7.6 Hz), 3.70 (3H, s), 6.54 (1H, br q, Jϭ6.7 Hz), 6.81 (1H, d, Jϭ8.7 Hz),
7.14 (1H, s), 7.28 (1H, d, Jϭ8.7 Hz). High-resolution MS m/z: Calcd for
C20H26N2O5: 374.1841. Found: 374.1830. 8: mp 118—119 °C (colorless nee-
dles). IR (film): 1759, 1644, 1206 cmϪ1 1H-NMR (DMSO-d6, 120 °C) d:
.
1.89 (3H, br s), 2.19 (3H, s), 2.81—2.92 (3H, s), 2.96 (2H, br t, Jϭ7.3 Hz),
3.45 (2H, br t, Jϭ7.3 Hz), 3.71 (3H, s), 5.45 (1H, d, Jϭ18.3 Hz), 5.55 (1H,
1
IR (KBr): 1577, 1457, 1242, 787 cmϪ1. H-NMR (CDCl3) d: 1.49 (3H, d,

1164
Vol. 49, No. 9
d, Jϭ12.0 Hz), 6.84 (1H, d, Jϭ8.7 Hz), 7.04 (1H, dd, Jϭ18.3, 12.0 Hz), 7.12 Jϭ8.5 Hz). High-resolution MS m/z: Calcd for C11H12N2O: 188.0950.
(1H, s), 7.26 (1H, d, Jϭ8.7 Hz). High-resolution MS m/z: Calcd for Found: 188.0946.
C18H22N2O3: 314.1630. Found: 314.1630.
3,4,5,6-Tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole
(5c) from Serotonin Hydrochloride (2b·HCl) [Entry 1] Et3N (2 ml) was
3,4,5,6-Tetrahydro-7-hydroxy-6-phenyl-1H-azepino[5,4,3-cd]indole
(5f) and 1,2,3,4-Tetrahydro-6-hydroxy-1-phenyl-b-carboline (12) from
2b·HCl Benzaldehyde (0.48 ml, 4.72 mmol) was added to a solution of
added to a solution of 2b·HCl (20.9 mg, 0.10 mmol) in MeOH (2 ml) at 2b·HCl (201.4 mg, 0.95 mmol) in MeOH (5 ml) and Et3N (5 ml) at 0 °C, and
0 °C, and the mixture was refluxed for 20 h with stirring under O2 atmo- the mixture was refluxed for 20 h with stirring. The solvent was evaporated
sphere (O2 balloon). The solvent was evaporated under reduced pressure to under reduced pressure to leave an oil, which was column-chromatographed
leave an oil, which was column-chromatographed on SiO2 with CHCl3–
repeatedly on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 3 : 0.3, 46 : 5 :
MeOH–28% aq. NH3 (46 : 5 : 0.5, then 46 : 10 : 1, v/v) to give 5c (4.0 mg, 0.5, then 46 : 10 : 1, v/v) to give 12 (3.9 mg, 2%), 5f (141.8 mg, 57%), and
20%) and unreacted 2b (10.2 mg, 59%) in the order of elution. 5c: Pale yel- unreacted 2b (25.5 mg, 15%) in the order of elution. 12: Pale yellow viscous
low oil. IR (KBr): 3400, 3300, 1579, 1417, 794 cmϪ1. 1H-NMR (CD3OD) d: oil. IR (KBr): 3400, 3290, 1625, 1593, 1454, 1201, 702 cmϪ1 1H-NMR
.
1.49 (3H, d, Jϭ6.8 Hz), 2.93—3.01 (1H, m), 3.10—3.15 (2H, m), 3.35—
3.41 (1H, m), 4.91 (1H, q, Jϭ6.8 Hz), 6.63 (1H, d, Jϭ8.6 Hz), 6.95 (1H, s), Jϭ12.5, 7.8, 5.1 Hz), 3.25 (1H, dt, Jϭ12.5, 5.1 Hz), 5.13 (1H, s), 6.60 (1H,
7.03 (1H, d, Jϭ8.6 Hz). High-resolution MS m/z: Calcd for C12H14N2O: dd, Jϭ8.5, 2.2 Hz), 6.84 (1H, d, Jϭ2.2 Hz), 7.03 (1H, d, Jϭ8.5 Hz), 7.27—
(CD3OD) d: 2.71—2.77 (1H, m), 2.82—2.88 (1H, m), 3.03 (1H, ddd,
202.1107. Found: 202.1110.
7.36 (5H, m). High-resolution MS m/z: Calcd for C17H16N2O: 264.1263.
[Entry 2] Acetaldehyde (0.016 ml, 0.29 mmol) was added to a solution of Found: 264.1259.
2b·HCl (20.5 mg, 0.10 mmol) in MeOH (2 ml) and Et3N (2 ml) at 0 °C, and
7-Acetoxy-5-acetyl-3,4,5,6-tetrahydro-6-phenyl-1H-azepino[5,4,3-
the mixture was stirred at room temperature for 4 h under O2 atmosphere (O2 cd]indole (11) from 5f Ac2O (1 ml) was added to a solution of 5f (4.7 mg,
balloon). After the same work-up and separation as described in entry 1, un-
reacted 2b (8.6 mg, 51%) was obtained.
0.02 mmol) in pyridine (2 ml) under ice cooling, and the mixture was stirred
for 3 h at room temperature. The solvent was evaporated under reduced pres-
sure to leave a solid, which was column-chromatographed on SiO2 with
CHCl3–MeOH (99 : 1, v/v) to give 11 (18.7 mg, 94%). 11: Colorless oil. IR
[Entry 3] Acetaldehyde (0.16 ml, 2.86 mmol) was added to a solution of
2b·HCl (98.1 mg, 0.46 mmol) in MeOH (4 ml) and Et3N (4 ml) at 0 °C, and
the mixture was stirred at room temperature for 24 h under O2 atmosphere (film): 3276, 1757, 1628, 1423, 1198, 750 cmϪ1 1H-NMR (DMSO-d6,
.
(O2 balloon). After the same work-up and separation as described in entry 1, 140 °C) d: 1.85 (3H, br s), 2.17 (3H, s), 2.79—4.02 (4H, m), 6.55 (1/3H, br
an unidentified product (10.1 mg) and unreacted 2b (14.9 mg, 18%) were ob- s), 6.82 (1H, d, Jϭ8.6 Hz), 6.92—6.97 (2H, m), 7.11 (1H, br s), 7.17—7.23
tained.
(3H, m), 7.31 (1H, br d, Jϭ8.6 Hz), 7.60 (2/3H, br s), 10.65 (1H, br s, disap-
[Entry 4] Acetaldehyde (0.016 ml, 0.29 mmol) was added to a solution of peared on addition of D2O). High-resolution MS m/z: Calcd for C21H20N2O3:
2b·HCl (20.5 mg, 0.10 mmol) in MeOH (2 ml) and Et3N (2 ml) at 0 °C, and
348.1474. Found: 348.1474.
the mixture was stirred at room temperature for 4 h under Ar atmosphere.
5-Hydroxy-4-(N,N-dimethylaminomethyl)tryptamine (13) from 2b·
After the same work-up and separation as described in entry 1, 5c (1.5 mg, HCl 50% Me2NH (2 ml) and HCHO (35%, 0.20 ml, 2.46 mmol) were
8%) and unreacted 2b (7.5 mg, 44%) were obtained.
added to a solution of 2b·HCl (104.5 mg, 0.49 mmol) in MeOH (2 ml) at
3,4,5,6-Tetrahydro-7-hydroxy-5,6-dimethyl-1H-azepino[5,4,3-cd]in-
0 °C. The mixture was stirred at room temperature for 4 h. After the addition
dole (5d) from Nb-Methylserotonin (2c) Method 1: Et3N (2 ml) was of H2O under ice cooling, the whole was extracted with CHCl3–MeOH
added to a solution of 2c (21.4 mg, 0.11 mmol) in MeOH (2 ml) at 0 °C, and (95 : 5, v/v). The extract was washed with brine, dried over Na2SO4, and
the mixture was refluxed for 20 h with stirring under O2 atmosphere (O2 bal- evaporated under reduced pressure to leave an oil, which was column-chro-
loon). The solvent was evaporated under reduced pressure to leave an oil, matographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 3 : 0.3, v/v) to
which was column-chromatographed on SiO2, successively, with CHCl3–
give 13 (89.5 mg, 78%). 13: mp 127—128 °C (dec., unstable colorless
1
MeOH–28% aq. NH3 (46 : 5 : 0.5, then 46 : 10 : 1, v/v) to give 5d (5.6 mg, solid). IR (KBr): 3342, 1583, 1469, 1417, 1232, 991, 796 cmϪ1. H-NMR
23%) and unreacted 2c (13.4 mg, 63%) in the order of elution. 5d: Pale yel- (CD3OD) d: 2.38 (6H, s), 2.90 (2H, t, Jϭ6.6 Hz), 2.97 (2H, t, Jϭ6.6 Hz),
1
low oil. IR (KBr): 3400, 1579, 1435, 790 cmϪ1. H-NMR (CD3OD) d: 1.44 4.05 (2H, s), 6.61 (1H, d, Jϭ8.5 Hz), 6.99 (1H, s), 7.12 (1H, d, Jϭ8.5 Hz).
(3H, d, Jϭ6.8 Hz), 2.59 (3H, s), 2.97—3.04 (2H, m), 3.19—3.27 (1H, m), High-resolution MS m/z: Calcd for C13H19N3O: 233.1528. Found: 233.1525.
3.60—3.68 (1H, m), 4.73 (1H, q, Jϭ6.8 Hz), 6.65 (1H, d, Jϭ8.6 Hz), 6.95
3,4,5,6-Tetrahydro-7-hydroxy-1H-azepino[5,4,3-cd]indole (5e) from 13
(1H, s), 7.03 (1H, d, Jϭ8.6 Hz). High-resolution MS m/z: Calcd for A solution of 13 (10.5 mg, 0.05 mmol) in MeOH (2 ml) was refluxed for 9 h
C13H16N2O: 216.1262. Found: 216.1266.
with stirring. The solvent was evaporated under reduced pressure to leave an
oil, which was column-chromatographed on SiO2 with CHCl3–MeOH–28%
aq. NH3 (46 : 3 : 0.3, v/v) to give 5e (3.0 mg, 35%).
Method 2: Acetaldehyde (0.018 ml, 0.32 mmol) was added to a solution of
2c (20.3 mg, 0.11 mmol) in MeOH (2 ml) and Et3N (2 ml) at 0 °C, and the
mixture was stirred at room temperature for 4 h under O2 atmosphere (O2
5-Methoxy-Nb-methyltryptamine6) (16) from 5-Methoxy-Nb-methoxy-
balloon). The solvent was evaporated under reduced pressure to leave an oil, carbonyltryptamine9) (17) LiAlH4 (184.7 mg, 4.87 mmol) was added to a
which was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. solution of 175) (120.6 mg, 0.49 mmol) in anhydrous THF (20 ml) at 0 °C,
NH3 (46 : 5 : 0.5, v/v) to give 5d (18.5 mg, 80%).
and the mixture was refluxed for 1 h with stirring. After the addition of
3,4,5,6-Tetrahydro-7-hydroxy- (5e), -6-Phenyl-1H-azepino[5,4,3-cd]in- MeOH and saturated Rochelle salt under ice cooling, the whole was ex-
dole (5f), and 1,2,3,4-Tetrahydro-6-hydroxy-b-carboline (10) from 2b· tracted with CHCl3. The extract was washed with brine, dried over Na2SO4,
HCl N,N-Dimethylbenzylamine (2 ml) was added to a solution of 2b·HCl and evaporated under reduced pressure to leave an oil, which was column-
(20.5 mg, 0.10 mmol) in MeOH (2 ml) at 0 °C, and the mixture was refluxed
chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46 : 3 : 0.3,
for 6 h with stirring under O2 atmosphere (O2 balloon). The solvent was v/v) to give 166a) (93.0 mg, 94%).
evaporated under reduced pressure to leave an oil, which was column-chro-
1,2,3,4-Tetrahydro-6-methoxy-1,2-dimethyl-b-carboline (18) from 16
matographed on SiO2 successively with CHCl3–MeOH–28% aq. NH3 A solution of 16 (49.4 mg, 0.24 mmol) in MeOH (3.5 ml) was made acidic
(46 : 3 : 0.3, then 46 : 5 : 0.5, v/v) to give 5f (2.3 mg, 9%), 5e (2.5 mg, 14%), (pH 5.0) by adding 1% HCl in MeOH (v/v). Acetaldehyde (0.67 ml,
10 (1.0 mg, 6%), and unreacted 2b (4.9 mg, 29%) in the order of elution. 5e: 12.0 mmol) in MeOH (0.5 ml) was added to the solution at 0 °C, and the
Pale beige viscous oil. IR (KBr): 3305, 1581, 1433, 795 cmϪ1 1H-NMR mixture was refluxed for 20 h with stirring. The solvent was evaporated
.
(CD3OD) d: 3.08 (2H, t, Jϭ5.4 Hz), 3.20 (2H, t, Jϭ5.4 Hz), 4.31 (2H, s), under reduced pressure to leave a solid, which was subjected to p-TLC on
6.65 (1H, d, Jϭ8.5 Hz), 6.99 (1H, s), 7.05 (1H, d, Jϭ8.5 Hz). High-resolu- SiO2, developed twice with CHCl3–MeOH–28% aq. NH3 (46 : 3 : 0.3, v/v).
tion MS m/z: Calcd for C11H12N2O: 188.0950. Found: 188.0949. 5f: mp
Extraction of the band having an Rf value of 0.43—0.27 with CHCl3–
122.5—124.0 °C (colorless prisms, recrystallized from CHCl3–MeOH). IR MeOH–28% aq. NH3 (46 : 3 : 0.3, v/v) gave 18 (45.9 mg, 82%). 18: mp
1
(KBr): 3290, 1577, 1425, 1298, 1242, 1011, 796, 756, 704 cmϪ1. H-NMR 155—157 °C (colorless powder, recrystallized from CHCl3–hexane). IR
1
(CD3OD) d: 2.79 (1H, ddd, Jϭ13.4, 4.6, 3.7 Hz), 2.87 (1H, ddd, Jϭ13.4, (KBr): 1629, 1602, 1489, 1217, 1157, 820 cmϪ1. H-NMR (CDCl3) d: 1.44
11.0, 4.2 Hz), 2.94—3.04 (2H, m), 5.92 (1H, s), 6.63 (1H, d, Jϭ8.6 Hz), (3H, d, Jϭ6.6 Hz), 2.51 (3H, s), 2.70—2.75 (2H, m), 2.78—2.85 (1H, m),
6.98 (1H, s), 7.03 (2H, br d, Jϭ7.3 Hz), 7.13 (1H, d, Jϭ8.6 Hz), 7.11—7.20 3.11—3.15 (1H, m), 3.56 (1H, q, Jϭ6.6 Hz), 3.85 (3H, s), 6.79 (1H, dd,
(3H, m). MS m/z: 264 (Mϩ). Anal. Calcd for C17H16N2O·MeOH: C, 72.95; Jϭ8.8, 2.4 Hz), 6.94 (1H, d, Jϭ2.4 Hz), 7.19 (1H, d, Jϭ8.8 Hz), 7.56 (1H,
H, 6.80; N, 9.45. Found: C, 73.19; H, 6.78; N, 9.40. 10: mp 285 °C (dec., br s, disappeared on addition of D2O). MS m/z: 230 (Mϩ). Anal. Calcd for
colorless powder). IR (KBr): 3398, 3265, 1589, 1565, 1454, 1200 cmϪ1. 1H- C14H18N2O·1/4H2O: C, 71.61; H, 7.94; N, 11.93. Found: C, 71.37; H, 7.75;
NMR (CD3OD) d: 2.71 (2H, t, Jϭ5.9 Hz), 3.13 (2H, t, Jϭ5.9 Hz), 3.96 (2H, N, 11.88.
s), 6.60 (1H, dd, Jϭ8.5, 2.3 Hz), 6.77 (1H, d, Jϭ2.3 Hz), 7.08 (1H, d,
Reaction of Nb-Methyltryptamine (20) with Et3N Et3N (2 ml) was

September 2001
1165
added to a solution of 20 (20.4 mg, 0.12 mmol) in MeOH (2 ml) at 0 °C, and 0 °C, and the mixture was refluxed for 20 h with stirring. The solvent was
the mixture was refluxed for 20 h with stirring under O2 atmosphere (O2 bal- evaporated under reduced pressure to leave an oil, which was column-
loon). The solvent was evaporated under reduced pressure to leave an oil, chromatographed repeatedly on SiO2 with CHCl3–MeOH–28% aq. NH3
which was column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. (46 : 1 : 0.1, 46 : 3 : 0.3, then 46 : 5 : 0.5, v/v) to give 15 (7.5 mg, 27%), 5a
NH3 (46 : 5 : 0.5, v/v) to give unreacted 20 (20.2 mg, 99%).
(16.3 mg, 58%), and unreacted 2a (2.3 mg, 9%) in the order of elution. 15:
1,2,3,4-Tetrahydro-6-hydroxy-1-methyl-b-carboline (14) and 3,4,5,6- mp 201—202 °C (colorless powder, recrystallized from CHCl3–hexane). IR
1
Tetrahydro-7-hydroxy-6-methyl-1H-azepino[5,4,3-cd]indole (5c) from (KBr): 1627, 1583, 1471, 1419, 1163 cmϪ1. H-NMR (CDCl3) d: 1.40 (3H,
2b·HCl [Entry 1] A solution of 2b·HCl (100.8 mg, 0.47 mmol) in MeOH d, Jϭ6.7 Hz), 1.60 (1H, br s, disappeared on addition of D2O), 2.52 (3H, s),
(4 ml) was made acidic (pH 4) by adding 2 N HCl under ice cooling, then ac-
etaldehyde (1.32 ml, 23.6 mmol) was added to the solution at 0 °C. The mix- 3.83 (1H, q, Jϭ6.7 Hz), 6.73 (1H, dd, Jϭ8.8, 2.4 Hz), 6.88 (1H, d,
ture was refluxed for 1 h with stirring. The whole was made basic (pH 8) by
Jϭ2.4 Hz), 7.11 (1H, d, Jϭ8.8 Hz). MS m/z: 230 (Mϩ). Anal. Calcd for
2.53—2.57 (1H, m), 2.80—2.90 (2H, m), 3.11—3.17 (1H, m), 3.58 (3H, s),
adding 14% aq. NH3 under ice cooling, and was then extracted with CHCl3. C14H18N2O·1/2H2O: C, 70.26; H, 8.00; N, 11.70. Found: C, 70.46; H, 7.70;
The extract was washed with brine, dried over Na2SO4, and evaporated N, 11.38.
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 14
(24.7 mg, 26%). 14: mp 257—258 °C (dec., colorless prisms, recrystallized
References and Notes
1) Part 106: Somei M., Noguchi K., Yamada F., Heterocycles, 55, 1237—
1240 (2001).
1
from MeOH). IR (KBr): 3383, 3273, 1589, 1454, 852, 798 cmϪ1. H-NMR
(CD3OD) d: 1.45 (3H, d, Jϭ6.6 Hz), 2.61 (1H, dddd, Jϭ15.3, 4.9, 3.3,
1.5 Hz), 2.73 (1H, dddd, Jϭ15.3, 9.6, 5.5, 2.0 Hz), 2.95 (1H, ddd, Jϭ12.7,
9.6, 4.9 Hz), 3.26—3.30 (1H, m), 4.09 (1H, q, Jϭ6.6 Hz), 6.60 (1H, dd,
Jϭ8.6, 2.4 Hz), 6.76 (1H, d, Jϭ2.4 Hz), 7.09 (1H, d, Jϭ8.6 Hz). MS m/z:
202 (Mϩ). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found:
C, 70.89; H, 7.01; N, 13.62.
[Entry 2] A solution of 2b·HCl (20.2 mg, 0.10 mmol) in MeOH (3.5 ml)
was made acidic (pH 4) by adding 2 N HCl under ice cooling. Then, ac-
etaldehyde (0.27 ml, 4.83 mmol) in MeOH (0.5 ml) was added to the solu-
tion at 0 °C. The mixture was refluxed for 20 h with stirring. After the same
work-up and separation as described in entry 1, 14 (2.4 mg, 13%) was ob-
tained.
[Entry 3] Acetaldehyde (0.28 ml, 5.01 mmol) in MeOH (0.5 ml) was
added to a solution of 2b·HCl (21.2 mg, 0.100 mmol) in MeOH (3.5 ml) at
0 °C. The pH of the resulting solution was 5. Then, the mixture was refluxed
for 20 h with stirring. The solvent was 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 14 (10.7 mg, 53%) and 5c
(5.4 mg, 27%).
[Entry 4] Acetaldehyde (0.054 ml, 0.97 mmol) was added to a solution of
2b·HCl (20.7 mg, 0.10 mmol) in MeOH (4 ml) at 0 °C.The pH of the result-
ing solution was 5. Then, the mixture was refluxed for 20 h with stirring.
After the same work-up and separation as described in entry 3, 14 (5.8 mg,
30%), 5c (5.6 mg, 28%) and unreacted 2b (6.8 mg, 40%) were obtained in
the order of elution.
2) Somei M., Yokoyama Y., Murakami Y., Ninomiya I., Kiguchi T., Naito
T., “The Alkaloids,” Vol. 54, ed. by Cordell G. A., Academic Press,
2000, pp. 191—257 and references cited therein.
3) Rapport M. M., Green A. A., Page I. H., Science, 108, 329—330
(1948); Idem, J. Biol. Chem., 176, 1237—1241 (1948); Rapport M.
M., Ibid., 180, 961—969 (1949); Stoll A., Troxler F., Peyer J., Hof-
mann A., Helv. Chim. Acta, 38, 1452—1472 (1955) and references
cited therein.
4) Somei M., Wakida M., Ohta T., Chem. Pharm. Bull., 36, 1162—1168
(1988) and references cited therein.
5) Review on 4-substituted indoles: Somei M., Yuki Gosei Kagaku Kyokai
Shi, 40, 387—400 (1982); Idem, Yakugaku Zasshi, 108, 361—380
(1988). See also ref. 2.
6) a) Somei M., Yamada F., Kurauchi T., Nagahama Y., Hasegawa M.,
Yamada K., Teranishi S., Sato H., Kaneko C., Chem. Pharm. Bull., 49,
87—96 (2001); b) Wilkinson S., J. Chem. Soc., 1958, 2079—2081;
Glennon R. A., Dukat M., El-Bermawy M., Law H., Angeles J. D. L.,
Teitler M., King A., Herrick-Davis K., J. Med. Chem., 37, 1929—1935
(1994); Bascop S.-I., Sapi J., Laronze J.-Y., Levy J., Heterocycles, 38,
725—732 (1994); Somei M., Yamada F., Morikawa H., ibid., 46, 91—
94 (1997).
7) Somei M., Kawasaki T., Heterocycles, 29, 1251—1254 (1989); Re-
view: Somei M., Yuki Gosei Kagaku Kyokai Shi, 49, 205—217 (1991);
Idem, Heterocycles, 50, 1157—1211 (1999) and references cited
therein.
3,4,5,6-Tetrahydro-7-hydroxy-1,5,6-trimethyl-1H-azepino[5,4,3-cd]in-
dole (5a) and 1,2,3,4-Tetrahydro-6-hydroxy-1,2,9-trimethyl-b-carboline
(15) from 2a A solution of 2a (24.9 mg, 0.12 mmol) in MeOH (3.5 ml)
was made acidic (pH 5) by adding 1% HCl in MeOH (v/v). Acetaldehyde
(0.34 ml, 6.08 mmol) in MeOH (0.5 ml) was added to the solution at
8) Review on Pictet–Spengler reaction: Cox E. D., Cook J. M., Chem.
Rev., 95, 1797—1842 (1995) and references cited therein.
9) Somei M., Fukui Y., Hasegawa M., Oshikiri N., Hayashi T., Heterocy-
cles, 53, 1725—1736 (2000). See also ref. 6a.