Investigations into the mechanism of lactamization of lactones yielding in a novel route to biologically active tryptamine derivatives

Article abstract of DOI:10.1016/j.tet.2004.03.073

The mechanism of lactamization of corresponding lactones was investigated by means of gas chromatography and synthesis of possible intermediates as references. Lactones react with amines via the amino acid with subsequent elimination of water to the corresponding lactams. In the first step, also hydroxyamides are in equilibrium with the lactones and amines, respectively, which are not able to form the amide though. This mechanism opens a new approach for the synthesis of N^β-disubstituted tryptamines.

Full text of DOI:10.1016/j.tet.2004.03.073

Tetrahedron 60 (2004) 4567–4578
Investigations into the mechanism of lactamization of
lactones yielding in a novel route to biologically active
tryptamine derivatives
*
Michael Decker, Thi Thanh Huyen Nguyen and Jochen Lehmann
¨ ¨ ¨
Lehrstuhl fur Pharmazeutische/Medizinische Chemie, Institut fur Pharmazie, Friedrich-Schiller-Universitat Jena, Philosophenweg 14,
D-07743 Jena, Germany
Received 3 February 2004; revised 12 March 2004; accepted 26 March 2004
Abstract—The mechanism of lactamization of corresponding lactones was investigated by means of gas chromatography and synthesis of
possible intermediates as references. Lactones react with amines via the amino acid with subsequent elimination of water to the
corresponding lactams. In the first step, also hydroxyamides are in equilibrium with the lactones and amines, respectively, which are not able
to form the amide though. This mechanism opens a new approach for the synthesis of N b-disubstituted tryptamines.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
temperatures below 180 8C mainly N-alkyl-4-hydroxy-
butanamide is formed.5
The reaction of lactones to lactams is of general importance
in organic chemistry. Especially in the field of medicinal
chemistry, where this reaction is relevant for the synthesis of
versatile intermediates like tetrahydro-9H-pyrido[3,4-
b]indolones (1) out of 4,9-dihydropyrano[3,4-b]indol-
1(3H)-ones (2) (Scheme 1), for preparation of b-carbolines,
serotonin derivatives, and other substances, that are lead
substances for drugs for the treatment of diseases of the
central nervous system, like psychosis, or are made
responsible for causing Parkinson’s disease, respectively.1–3
The formation of either hydroxy acid amides or lactams is
dependent on the applied conditions: N-methyl-phthal-
imidine can be synthesized under high pressure (3) out of
(2-hydroxymethyl)-N-methylbenzamide (4). Under normal
pressure, the lactone (5) and methylamine are formed
(Scheme 2).6 The more basic the amine, the higher are the
temperatures to be applied for lactam formation.4 Also the
ring size of the corresponding lactone strongly influences
the course of the reaction. Aniline reacts with d-valero-
lactone (tetrahydro-2H-pyran-2-one) to the hydroxyamide,
whereas g-butyrolactone (dihydrofuran-3(2H)-one) gives
the lactam.7 An important hint concerning the mechanism
gives the reaction of lactones with secondary amines, in
which no cyclization to a lactam is possible. Depending on
temperature and reaction time, apart from the hydroxy
amide an amino amide is formed, the formation of which
could be explained by reaction of an amino acid as
intermediate with excess amine.5,8 Also other experimental
data, for example the facts that neither 4-hydroxy-N-
phenylbutanamide nor compound 6 do form a lactam,
leads to the assumption of an amino acid as an intermediate
(Scheme 3).9,10
Scheme 1. Lactamization of 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2)
with primary amines yielding tetrahydro-9H-pyrido[3,4-b]indolones (1).
Different relevant experimental data has been found for the
¨
course of this reaction: first, Spath and Lintner found that in
general lactams are formed with primary amines out of the
corresponding lactones at temperatures above 250 8C.4
Later, this could be proved by the preparation of
pyrrolidin-2-ones out of g-butyrolactones, in which case at
The following scheme (Scheme 4) gives an illustration
which ways can lead from the lactone (7) to the lactam (8).
For our purposes, we decided to use g-butyrolactone (7) as
the reacting lactone and benzylamine (9) as the respective
amine. Path a would mean, that in the first step the hydroxy-
amide is formed, which could eliminate water to form the
Keywords: Lactamization; Lactones; Amino acids; Hydroxyamides;
Tryptamines; Hallocinogens.
*
Corresponding author. Tel.: þ49-3641-949803; fax: þ49-3641-949802;
e-mail address: j.lehmann@uni-jena.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.073

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M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
Scheme 2. Dependence of N-methyl-phthalimidine (3) formation out of (2-hydroxymethyl)-N-methylbenzamide (4) on the applied pressure.
Scheme 3. 5-Hydroxy-N-[2-(1H-indol-3-yl)ethyl]pentanamide does not cyclize to the corresponding lactam at elevated temperatures.
Scheme 4. Different mechanistic routes to the formation of 1-benzylpyrrolidin-2-one (8) out of benzylamine (9) and g-butyrolactone (7).
lactam. In path b addition of the amine leads to an amino
acid that cyclizes to the lactam. Both hydroxyamide and
amino acid could add a second molecule amine to form the
amino amide, that might in turn eliminate amine to give
the lactam (path c). An interesting possibility to evaluate the
mechanism lies in the use of secondary amines to react with
the lactone, because the intermediates cannot further react to
the lactam.
temperatures necessary for lactamization (and also for gas
chromatography) they might directly eliminate water to
form the lactam. This should be circumvented by using
N-benzyl-N-methylamine as the amine component, so that
no lactams can be formed. Corresponding hydroxyamide
(13), amino acid (14) and amino amide (15) should be
synthesized as references (Scheme 5).
If indeed the reaction proceeds through the amino acid, it
should also be possible to make use of this fact for the
synthesis of compounds which are used in medicinal
chemistry concerned with drugs for the central nervous
system. 4,9-Dihydropyrano[3,4-b]indol-1(3H)-ones (2)
could then react to an indole-2-carboxylic acid (16),
which easily decarboxylates to an N b-disubstituted
All possible intermediates and products, that is, hydroxy-
amide (10), amino acid (11), amino amide (12), and the
lactam (8) were synthesized, in order to get references to
investigate the reaction using gas chromatography. One
major problem is of course, that amino acids have never
been identified as intermediates, because at the high

M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
4569
Table 1. Gas chromatographic retention times of the compounds specified
in Scheme 4 and their silylated derivatives
tR (min) (silylated compound)
Compound
0.78
1.25 (2.84)
6.45
6.45a (7.54)
8.15 (8.65)
12.5
g-Butyrolactone 7
Benzylamine 9
Lactam 8
Amino acid 11
Hydroxyamide 10
Amino amide 12
a
The lactam 8, which is formed under the applied conditions.
Scheme 5. Possible intermediates for the reaction of N-benzyl-N-
methylamine with g-butyrolactone (7).
Scheme 6. Formation of N b-disubstituted tryptamines (17) from 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2) and secondary amines.
tryptamine (17) (Scheme 6). Also the toxic bufotenin
(5-hydroxy-N,N-dimethyltrytamine) from Bufo sp. and the
hallucinogenic compound psilocine (4-hydroxy-N,N-
yielded 90% lactam, and after heating to 200 8C no amino
acid was detectable any more.
dimethyltryptamine)
from
Psilocybe
mexicana
For studying the reaction, two equimolar mixtures of
g-butyrolactone and benzylamine were heated for 20 h;
one at 150 8C, the other one at 200 8C. After 15 min, 1, 4,
20 h, respectively, samples were taken and chromato-
graphed. It was proved in advance, that the amino acid
directly lactamizes, therefore no derivatization was necess-
ary. The changes in the amounts of starting materials and
products are given in Figure 1. For estimating the
quantitative amounts, the peak area was used. For our
qualitative investigation this was precise enough, using
naphthalene as an internal standard for determining a
correction factor did not improve accuracy, because
different reference substances, that are closely related to
the respective compounds would have been necessary.
(Agaricaceae) belong to this class of compounds, which
are derivatives of the neurotransmitter serotonin
(5-hydroxy-tryptamine).
2. Results and discussion
The hydroxyamide 10 was synthesized by reaction of
g-butyrolactone with benzylamine at room temperature, the
amino acid 11 by hydrolysis of lactam 8 with barium
hydroxide solution. The lactam 8 was formed by reaction of
g-butyrolactone with benzylamine at 220 8C. The amino
amide 12 was prepared in a two-step synthesis out of
4-chlorobutanoyl chloride: aminolysis with benzylamine (9)
at room temperature yielded N-benzyl-4-chlorobutanamide,
which gave the amino amide (12) by refluxing with excess
benzylamine.
As can be seen from Figure 1, in the 150 8C batch only very
low amounts of lactam 8 are formed. The hydroxyamide 10
is rapidly formed. After 1 h the maximum amount is
reached, after this time, its amount significantly decreases,
while the lactone and the amine peaks, respectively,
increase. These results indicate that there might be an
equilibrium between the hydroxyamide on the one hand,
and lactone and amine on the other hand. In the 200 8C
batch, the lactam peak rapidly increases, while the amine
and lactone peaks, respectively, decrease. In analogy to the
150 8C batch, the amount of hydroxyamide rapidly
increases within the first 15 min, but decreases to almost
zero shortly after. This might be either due to the fact, that
the hydroxyamide is a direct intermediate, or it exists in
equilibrium with the lactone, which can in turn react to
Retention times of the above mentioned compounds were
determined with a gas chromatograph (Table 1). Through
derivatization with MSTFA (N-methyl-trimethylsilyl-
trifluoroacetamide) benzylamine 9, amino acid 11 and
hydroxyamide 10 were silylated, so that their retention
times changed (Table 1). Silylation was necessary to
determine the amino acid, because cyclisation occurs at
the temperatures necessary for gas chromatography yielding
the lactam 8. This could be easily proved by heating the
amino acid, followed by silylation and gas chromatography.
Heating to the melting point (142 8C) and direct cooling

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M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
Figure 1. Product formation during the course of reaction of g-butyrolactone (7) and benzylamine (9) at different reaction temperatures (150 and 200 8C,
respectively) measured by gas chromatography.
another intermediate (the amino acid). It could be easily
proved, that hydroxyamide 10 is not a direct intermediate,
by heating the hydroxyamide at 200 8C and determine the
accruing products. As can be seen from Table 2, small
amounts of lactone and amine, respectively, are formed, but
even after 20 h only negligible amounts of lactam 8. Heating
the amino amide 12 at 200 8C for 1 h gave the lactam, but
large amounts of starting material could be isolated (data not
shown). Taking into account this thermal stability of 12, and
the fact, that it could not be determined during the
lactamization process, makes it an improbable intermediate.
obtained in two steps out of ethyl 4-bromobutanoate. In the
first step the bromine atom was replaced by the N-benzyl-N-
methylamine group, in the second step the ester was
hydrolyzed with hydrochloric acid. The corresponding
amino amide 15 was also prepared in two steps with
N-benzyl-N-methylamine out of 4-chlorobutanoyl chloride
(16) via N-benzyl-4-bromo-N-methylbutanamide (17).
Retention times of the respective compounds and their
silylated derivatives are given in Table 3. An equimolar
mixture of N-benzyl-N-methylamine and g-butyrolactone
was heated at 200 8C for 7h. Samples were taken after
15 min, 30 min, 2 h, 4 h and 7 h. As can be seen from
Figure 2, the starting materials are consumed quite fast; the
hydroxyamide 18 is readily formed (it is the kinetically
formed product), but disappears rapidly, while the amino
Table 2. Amounts of products/starting material during the course of
pyrolysis of hydroxyamide 10
tR (min)
Compound
Area at 200 8C after (%)
15 min
1 h
20 h
0.79
1.25
6.46
8.15
g-Butyrolactone 7
Benzylamine 9
Lactam 8
2.2
0
0
83.17
3.82
0
0
88.27
3.16
4.19
1.83
71.33
Table 3. Gas chromatographic retention times of the compounds specified
in Scheme 5 (reaction of g-butyrolactone 7 with N-benzyl-methylamine)
and their silylated derivatives
Hydroxyamide 10
tR (min) (silylated compound)
Compound
We also investigated the reaction of g-butyrolactone with
N-benzyl-N-methylamine. The reference substances
(Scheme 5) were synthesized as follows. Heating g-butyro-
lactone with N-benzyl-N-methylamine for 18 h at 100 8C
yielded the hydroxyamide 13. The amino acid 14 was
0.79
g-Butyrolactone 7
N-Benzyl-N-methylamine
Amino acid 14
Hydroxyamide 13
Amino amide 15
1.47 (3.13)
5.85 (7.31)
6.86 (8.75)
10.0

M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
4571
Figure 2. Product formation during the course of reaction of g-butyrolactone (7) and N-benzyl-N-methylamine at 200 8C measured by gas chromatography.
amide 20 is formed. The formation of an amino amide out of
the hydroxyamide does not take place, because heating the
hydroxyamide 18 with N-benzyl-N-methylamine for 3 h at
200 8C gave only low amounts of amino amide, probably
via g-butyrolactone formation, which in turn reacted with
N-benzyl-N-methylamine to the amino amide. Therefore,
the amino amide 20 has to be formed via the amino acid 19,
which accrues out of lactone and amine and subsequent
reaction with a second amine molecule. The hydroxyamide
exists in equilibrium with the starting materials, which are
consumed to form the amino amide. In order to prove this
assumption, the amino acid 19 was heated with N-benzyl-N-
methylamine at 200 8C. After 30 min, no starting material
was found anymore because of complete amino amide
formation.
the kinetic product, that exists in an equilibrium with the
starting materials. This information could be used for the
preparation of tryptamines, which can be regarded as
the amino acid intermediate after decarboxylation.
3. Experimental
3.1. General
Melting points were measured on ‘Melting Point Apparatus’
by Gallenkamp and are uncorrected. IR spectra were
recorded on a Perkin–Elmer ‘1420’. Elemental analyses
were determined with ‘CHNO-Analyser Rapid’ by
1
Heraeus. H NMR spectra were recorded with ‘WH-90’
(90 MHz, Bruker) and ‘AC-200’ (200 MHz, Bruker).
Chemical shifts (d) are given in parts per million relative
to tetramethylsilane (d¼0.00) as internal standard. Coupling
constants (J) are given in Hz. EI mass spectra were
measured with MS-30 and MS-50, respectively, A.E.I.,
Manchester, UK. Analytical thin-layer chromatography
(tlc) was conducted on precoated aluminium plates: silica
gel 60 F254 (Merck Darmstadt, Germany), layer thickness
0.2 mm. For detection iodine vapour or UV light (254 nm),
respectively, was used. Silica gel column chromatography
utilized silica gel 60 63–200 mm (Baker).
We also examined the reaction of 4,9-dihydropyrano[3,4-
b]indol-1(3H)-ones (2) with secondary amines. In this case,
hydroxyamide 21, amino acid 16, amino amide 22 and
trytamines 17 are possible products (Scheme 6). Taking into
account the results we obtained with g-butyrolactone,
suppression of formation of the kinetic product 21 is
possible by using long reaction times and high temperatures.
Decarboxylation occurs faster than reaction with excess
amine to the amino amide 22, therefore reaction of lactones
with secondary amines opens a new way for the preparation
of the pharmacologically relevant Nb-disubstituted
tryptamines (17), for example, reaction of lactone 2 with
N-methylaniline leads to N-[2-(1H-indol-2-yl)ethyl]-N-
methyl-N-phenylamine in 44% yield (Table 4). The
formation of tryptamines is of course a further prove for
the reaction mechanism previously described. Other
different Nb-disubstituted tryptamines (17a–p) were pre-
pared using this reaction, which are listed in Table 4.
Compounds 17i and 17k, respectively, incorporate a
2-piperidin-4-yl-1H-isoindole-1,3(2H)-dione moiety,
which is a structural feature of the dopaminergic anti-
psychotic pimocid. They were screened for their affinity to
different receptors (Table 5), including the dopamine
receptor. Some of these compounds showed high,
nanomolar affinities to D2, a1 and various serotonin
(5-HT) receptors (Table 6).
Gas chromatography was performed with Hewlett–Packard
model 5890 series II in connection with HP 3396 series II
integrator. A capillary column DB-5 (fused silica,
30 m£0.32 mm, film thickness 0.25 mm) by J & W
Scientific Inc., California, was applied. Gas supply was
adjusted in the following manner: carrier gas hydrogen
(15 mL/min); make-up-gas nitrogen (15 mL/min); FID
detector: hydrogen (30 mL/min), air (400 mL/min); pre-
pressure: 23 psi; split ratio: 1/20. Injection volume was
1 mL of a 0.1% sample solution. Temperature programme:
injector: 200 8C; FID detector: 270 8C; initial temperature:
80 8C (1 min); rate: 15 8C/min; final temperature: 270 8C
(2 min). For the reaction of g-butyrolactone with N-benzyl-
methylamine, conditions were the same, apart from the final
temperature [300 8C (2 min)] and the rate (20 8C/min).
Silylation was conducted by adding 100 mL MSTFA
(N-methyl-trimethylsilyl-trifluoroacetamide) and after-
wards 200 mL acetonitrile to 1 mg of the respective sample.
In summary, the formation of lactams out of lactones goes
via the amino acid, but not via the hydroxyamide, which is

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M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
Table 4. Nb-Disubstituted tryptamines (17a–p) formed by reaction of 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2) with secondary amines
Compound
Compound number
Reaction temperature (8C)
Reaction time (h)
12
Yield (%)
44
17a
200
17ba
200
200
200
150
12
12
12
12
38
41
18
16
17c
17da
17e
17fa
200
12
33
17ga
200
12
47
17ha
200
12
37

M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
4573
Table 4 (continued)
Compound
Compound number
Reaction temperature (8C)
200
Reaction time (h)
2
Yield (%)
46
17i
17k
200
2
49
17l
200
2
20
17m
200
2
21
17n
180
12
33
17oa
180
12
39
(continued on next page)

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M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
Table 4 (continued)
Compound
Compound number
Reaction temperature (8C)
180
Reaction time (h)
9
Yield (%)
39
17pa
a
As the hydrochloride.
This mixture was heated for 15 min at 70 8C. The solution
obtained was injected.
Compound 10. White, glittering flat crystals (4.35 g, 56%
yield). Mp 74–75 8C (lit.4 mp 74–75 8C). 1H NMR
(90 MHz, DMSO-d6) d 1.62 (2H, qi, J¼8 Hz, C(O)CH2),
2.16 (2H, t, J¼8 Hz, HOCH2), 3.36 (2H, tt, J¼5, 8 Hz,
CH2CH2CH2), 4.2–4.3 (2H, d, J¼6 Hz, benzyl), 4.46 (1H, t,
J¼5 Hz, OH), 7.22 (5H, m, arom.) ppm. IR (KBr ):
1649 cm21 (CvO-valence).
3.1.1. N-Benzyl-4-hydroxybutanamide (10). To 3.1 mL
(40 mmol) of g-butyrolactone were added 4.4 mL
(40 mmol) of benzylamine. The mixture was allowed to
stand for 24 h at room temperature. The white precipitate
was filtered off and recrystallized from ethanol/diethylether
(1/1).
3.1.2. N-Benzyl-pyrrolidin-2-one (8). A mixture of 6.2 mL
Table 5. Pharmacological screening results of compounds 17g, 17i, 17k, 17n, 17o (N b-disubstituted tryptamines) at different receptors
Receptor/ligand
Decrease in receptor-bound radioactivity (%)
Concentration of test solution (M)
17g
17i
17k
17n
17o
Adenosine receptors
3H-CPDPX (A1)
3H-NBTI
19
9
21
262
14
250
22
10
26
10
1026
1025
Adrenoceptors
3H-Prazosin (a1)
298
2100
296
292
244
1026
Peptide receptors
3H-Angiotensin-II
3H-Bradykinin
3
0
2
3
27
23
1
29
3
21
5
21
9
2
0
1025
1025
1025
3H-Sarafot (ET)
Dopamine receptors
3H-Spiperone
291
25
276
214
272
211
238
217
229
219
1025
1025
GABA receptor
3H-Muscimol (GABA-A)
Glutamate receptors
3H-MK801
3H-AMPA
220
3
222
29
216
10
230
29
226
214
1025
1025
ACh receptors
3H-Cytisin (Nic)
3H-Pirenzipin (M1)
7
25
29
229
211
229
24
29
21
211
1025
1026
Serotonin receptors
3H-8OH-DPAT (5-HT1A
3H-Ketanserin (5-HT2)
)
292
292
295
271
2100
293
294
2100
271
232
248
233
287
249
233
1026
1026
1026
3H-Paroxetin (5-HTcar
3H-PDBU (Phorbol)
)
23
7
213
22
24
24
211
0
24
0
1025
1025
3H-Glibenclamide (Kþ)
Bold numbers mark high affinities (i.e. more than 275% decrease).
Table 6. Inhibition constants of compounds 17g, 17i, 17k, 17n, 17o (N b-disubstituted tryptamines) at a1, 5-HT1A, 5-HT2, and 5-HTcar receptors, respectively
Compound
3H-Prazosin (a1)
3H-8OH-DPAT (5-HT1A
)
3H-Ketanserin (5-HT2)
3H-Paroxetin (5-HTcar
)
3H-Spiperone (D2)
17g
17i
17k
17n
17o
KI¼11 nM
KI¼79.1 nM
KI¼504 nM
KI¼40.6 nM
Low affinity
KI¼12.5 nM
KI¼17.2 nM
KI¼146 nM
KI¼362 nM
KI¼101 nM
Low affinity
Low affinity
KI¼101 nM
KI¼3.3 nM
KI¼6.7 nM
KI¼28 nM
KI¼17.9 nM
Not determined
Not determined
Not determined
Not determined
KI¼19.1 nM
Moderate affinity
Moderate affinity
Moderate affinity

M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
4575
(80 mmol) of g-butyrolactone and 8.8 mL (80 mmol) of
benzylamine was heated for 24 h in a metal bath (bath
temperature 220 8C) under reflux and afterwards distilled to
yield 11 g of colourless oil (79% yield).
at 100 8C (inner temperature) for 18 h. After cooling, the
product was purified by column chromatography with
dichloromethane as eluent to give 4.5 g (43.5% yield) of a
viscous, colourless oil consisting of two conformers.
1
Compound 8. Bp 124–125 8C/0.8 mm (lit.4 bp 130–140 8C/
Compound 13. H NMR (90 MHz, DMSO-d6) d 1.7 (2H,
1
1 mm). n2D0¼1.5527 (lit.4 n2D0¼1.5520) H NMR (90 MHz,
qui, J¼7 Hz, CH2CH2CH2), 2.38 (2H, t, J¼7 Hz, CH2CO)
and 2.41 (t, J¼7 Hz, CH2CO, second conformer), 2.8 (3H, s,
CH3) and 2.85 (s, CH3, second conformer), 4.4–4.5 (1H, brd
s, OH), 4.5 (2H, s, benzyl) and 4.58 (s, benzyl, second
conformer), 3.3–3.5 (2H, m, CH2OH), 7.12–7.42 (5H, m,
arom.) ppm. IR (KBr): 1630 cm21 (CvO-valence).
DMSO-d6) d 1.89 (2H, qui, J¼8 Hz, CH2CH2CH2), 2.29
(2H, t, J¼8 Hz, C(O)CH2), 3.20 (2H, tt, J¼8 Hz, CH2N),
4.37 (2H, s, benzyl), 7.29 (5H, m, arom.) ppm. IR (KBr):
1680 cm21 (CvO-valence).
3.1.3. 4-(Benzylamino)butanoic acid (11). To a solution of
200 mL of 10% aqueous barium hydroxide were added
17.5 g (100 mmol) of N-benzyl-pyrrolidin-2-one (8). The
mixture was heated for 24 h under reflux. After cooling dry
ice was added in small pieces until pH¼7 was reached.
Barium carbonate was filtered off, and the solvent was
evaporated to give a solid, which was recrystallized from
ethanol/diethylether (1/1) to yield 12 g (62% yield) of white
crystals.
3.1.6. 4-[Benzyl(methyl)amino]butanoic acid (14) and
143HCl, respectively. A solution of 11.75 g (50 mmol) of
ethyl 4-[benzyl(methyl)amino]butanoate in 50 mL of 2 M
hydrochloric acid was heated for 12 h under reflux. The
water was removed under reduced pressure and the residue
was recrystallized from acetone to give 11.2 g (92% yield)
of the hydrochloride of 14.
Compound 14£HCl. Mp 173 8C. 1H NMR (90 MHz,
DMSO-d6) d 1.8–2.0 (2H, m, CH2CH2CH2), 2.24 (2H, t,
J¼8 Hz, CH2N), 2.55 (3H, s, NCH3), 2.98 (2H, t, J¼8 Hz,
CH2COOH), 4.22 (2H, s, benzyl),7.2–7.4 (5H, m,
arom.) ppm. IR (KBr): 1720 cm21 (CvO-valence). Anal.
calcd for C12H17NO2: C, 59.14; H, 7.44; N, 5.75. Found: C,
58.65; H, 7.33; N, 5.80.
Compound 11. Mp 142 8C (decomp., lit.11 mp 139 8C).
1
n2D0¼1.5527 (lit.4 n2D0¼1.5520) H NMR (90 MHz, metha-
nol-d4) d 1.87 (2H, qui, J¼6 Hz, CH2CH2CH2), 2.38 (2H, t,
J¼6 Hz, CH2COOH), 3.05 (2H, t, J¼6 Hz, CH2N), 4.13
(2H, s, benzyl), 7.44 (5H, m, arom.) ppm. IR (KBr):
1640 cm21 (CvO-valence).
3.1.4. N-Benzyl-4-(benzylamino)butanamide (12). To a
solution of 20 mL (183 mmol) of benzylamine in 250 mL of
diethylether were added under stirring and ice cooling
10 mL (89 mmol) of 4-chlorobutanoyl chloride. Stirring
was continued for 1 h at room temperature. The precipitated
amine hydrochloride was filtered off, and the filtrate
concentrated under reduced pressure. A white solid
(N-benzyl-4-chlorobutanamide) was formed (14.8 g, 79%
yield), that was recrystallized from acetone/petrolether
(40/60) (1/1). Mp 66 8C (lit.12 mp 68 8C), no further
spectroscopic characterization.
The hydrochloride 14£HCl (10 g, 41 mmol) was dissolved
in 10 mL of water, alkalized with saturated NaHCO3-
solution to pH¼7–8, and the water removed under reduced
pressure. The residue is suspended three times with 50 mL
of acetone and filtered off. Removal of the solvent yielded
8.1 g (i.e., 95% yield related to the hydrochloride) of a
colourless, viscous oil, which did not crystallize.
1
Compound 14. H NMR (90 MHz, DMSO-d6) d 1.4–1.9
(2H, m, CH2CH2CH2), 2.09 (2H, s, NCH3), 2.1–2.4 (4H, m,
2£CH2), 3.47 (2H, s, benzyl),7.31 (5H, m, arom.) ppm. IR
(KBr): 1550 cm21 (CvO-valence).
A
solution of N-benzyl-4-chlorobutanamide (11 g,
50 mmol), 11 mL (100 mmol) of benzylamine, and 0.1 g
of sodium iodide in 100 mL of ethanol was heated under
reflux for 12 h. After cooling, 200 mL of diethylether were
added, the precipitated hydrochloride filtered and dried. The
hydrochloride was dissolved in 100 mL of water, alkalized
with saturated NaHCO3-solution and extracted three times
with dichloromethane. Dichloromethane is removed under
reduced pressure, and the white solid is recrystallized from
diethylether to give 7.2 g (63% yield) of 12 as a white solid.
3.1.7. N-Benzyl-4-[benzyl(methyl)amino]-N-methyl-
butanamide (15). To a solution of 23.2 mL (180 mmol)
of N-benzyl-methylamine in 250 mL of diethylether were
added under stirring and ice cooling 10 mL (89 mmol) of
4-chlorobutanoyl chloride. Stirring was continued for 1 h at
room temperature. The precipitated amine hydrochloride
was filtered off, and the filtrate concentrated under reduced
pressure. A white solid (N-benzyl-4-chloro-N-methyl-
butanamide) was formed (16 g, 80% yield), that was
recrystallized from acetone/petrolether (40/60) (1/1) with-
out any further characterization.
1
Compound 12. Mp 62–63 8C. H NMR (90 MHz, DMSO-
d6) d 1.67 (2H, qui, J¼7.5 Hz, CH2CH2CH2), 2.18 (2H, t,
J¼7.5 Hz, CH2CO), 2.47 (2H, t, J¼7.5 Hz, CH2N), 3.1–3.4
(1H, brd amine-NH), 3.64 (2H, s, amine-benzyl), 4.24 (2H,
d, J¼6 Hz, amide-benzyl), 7.2–7.3 (10H, m, arom.),
8.1–8.4 (1H, brd t, J¼6 Hz, amide-NH) ppm. IR (KBr):
1640 cm21 (CvO-valence).
A solution of N-benzyl-4-chloro-N-methylbutanamide
(11.3 g, 50 mmol), 13 mL (100 mmol) of N-benzyl-methyl-
amine, and 0.1 g of sodium iodide in 100 mL of ethanol was
heated under reflux for 12 h. After cooling, the solvent was
removed under reduced pressure, the solid dissolved in
100 mL of water. The hydrochloride was dissolved in
100 mL of water, alkalized with saturated NaHCO3-solution
and extracted three times with dichloromethane. Dichloro-
methane is removed under reduced pressure, and the residue
3.1.5. N-Benzyl-4-hydroxy-N-methylbutanamide (13). A
mixture of 3.8 mL (50 mmol) of g-butyrolactone and
6.5 mL (50 mmol) of N-benzyl-methylamine were heated

4576
M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
was purified by column chromatography with MeOH/
CH2Cl2 (1/20) to give a colourless oil (11.6 g, 74% yield
related to N-benzyl-4-chloro-N-methylbutanamide), con-
sisting of two conformation isomers.
off. The resulting product was purified by recrystallization
from methanol/diethylether (1/1).
3.1.9. N-[2-(1H-Indol-3-yl)ethyl]-N-methyl-N-phenyl-
amine (17a). N-Methylaniline and 4,9-dihydropyrano[3,4-
b]indol-1(3H)-one as starting materials. Method a. Beige
powder. Mp 140 8C. 1H NMR (200 MHz, CDCl3) d 3.0 (3H,
s, NCH3), 3.08 (2H, t, J¼7.7 Hz, CH2CH2N), 3.72 (2H, t,
J¼7.7 Hz, CH2CH2N), 6.7–6.9 (3H, m, 2Ho, Hp), 7.0 (1H,
s, H-2), 7.2–7.5 (5H, m, H-5, H-6, H-7, 2Hm) ppm. IR
(KBr): 3400, 1600, 1500, 1450, 805, 740, 690 cm21. EI-MS
m/z 250 (Mþ). Anal. calcd for C17H18N2: C, 81.56; H, 7.25;
N, 11.19. Found: C, 81.20; H, 7.12; N, 11.01.
1
Compound 15. Mp 62–63 8C. H NMR (90 MHz, DMSO-
d6) d 1.5–2.0 (2H, m, CH2CH2CH2), 2.07 (3H, s, amine-
CH3) and 2.13 (s, amine-CH3, second conformer), 2.2–2.6
(4H, m, CH2CH2CH2), 2.82 (3H, s, amide-CH3) and 2.91 (s,
amide-CH3, second conformer), 3.44 (2H, s, amine-benzyl)
and 3.49 (s, amine-benzyl, second conformer), 4.5 (2H, s,
amide-benzyl) and 4.58 (s, amide-benzyl, second confor-
mer),7.0–7.4 (10H, m, arom.) ppm. IR (KBr): 1640 cm21
(CvO-valence).
3.1.10. N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]-N-methyl-
N-phenylamine (17b). N-Methylaniline and 4,9-dihydro-6-
methoxy-pyrano[3,4-b]indol-1(3H)-one as starting materials.
The 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2)
necessary for the following reactions can be either obtained
out of d-valerolactone by reaction with oxalyl ester,
followed by reaction with diazotized aniline (Japp–
Klingemann-reaction),13 or out of g-butyrolactone and
oxalyl esters, respectively, following hydrolysis and reac-
tion with phenylhydrazones, as described previously.14
1
Method a. Brown hygroscopic crystals. Mp 88–92 8C. H
NMR (200 MHz, DMSO-d6) d 2.8 (2H, m, CH2CH2N), 3.1
(3H, s, NCH3), 3.5–3.8 (5H, m, CH2CH2N, OCH3), 6.7 (1H,
dd, J¼10.7, 1.8 Hz, H-6), 7.0 (1H, d, J¼1.8 Hz, H-4), 7.1 (1H,
d, J¼1.8 Hz, H-2), 7.24 (1H, d, J¼10.7 Hz, H-7), 7.3–7.6
(5H, m, arom.), 7.6–7.8 (1H, brd, NþH), 10.77 (1H, brd,
indole-NH) ppm. IR (KBr): 3420, 3250, 2500, 1600, 1480,
1215, 690 cm21. Anal. calcd for C18H21N2OCl£1.1H2O: C,
64.22; H, 6.95; N, 8.32. Found: C, 64.02; H, 6.94; N, 8.46.
3.1.8. General procedure for the preparation of N b-
disubstituted tryptamines (17a–p) out of 4,9-dihydro-
pyrano[3,4-b]indol-1(3H)-ones (2). A mixture of 10 mmol
pyrano-indolone (2) and 10–40 mmol of the secondary
amine were either heated in an autoclave at 200 8C (as
indicated in Table 4, in some cases lower temperatures
should be applied to avoid by-product formation). After the
respective reaction time (see Table 4), the mixture was
allowed to cool to room temperature and the excess amine
was removed by distillation under reduced pressure. The
resulting brown, viscous residue was dissolved in 250 mL of
methanol under warming. The insoluble solids were filtered
off, the filtrate was concentrated under reduced pressure,
and the residue heated for 10 min with refluxing
diethylether. Again, the solids were filtered off. Depending
on the water solubility of the remaining amine, the filtrate
was either treated according to method a) (hardly and non-
water-soluble amines) or method b) (water-soluble amines).
3.1.11. N-Ethyl-N-[2-(1H-indol-3-yl)ethyl]-N-phenyl-
amine (17c). N-Ethylaniline and 4,9-dihydropyrano[3,4-
b]indol-1(3H)-one as starting materials. Method a. Beige
powder. Mp 99–100 8C. 1H NMR (200 MHz, DMSO-d6) d
1.07 (3H, t, J¼7.0 Hz, NCH2CH3), 2.94 (2H, t, J¼7.8 Hz,
CH2CH2N), 3.34 (2H, q, J¼7.0 Hz, NCH2CH3), 3.52 (2H, t,
J¼7.8 Hz, CH2CH2N), 6.57 (1H, t, J¼7.2 Hz, Hp), 6.7 (2H,
d, J¼8.0 Hz, 2Ho), 6.95–7.28 (5H, m, H-5, H-6, H-2, 2Hm),
7.39 (1H, d, J¼7.5 Hz, H-7), 7.57 (1H, d, J¼7.5 Hz, H-4),
10.9 (1H, brd, indole-NH) ppm. 13C NMR (200 MHz,
DMSO-d6) d 12.25, 22.9, 44.3, 50.83, 111.48, 111.87,
115.01, 118.22, 118.39, 120.99, 122.81, 127.33, 129.26,
136.36, 147.46 ppm. IR (KBr): 3380, 1580, 1500, 1450,
1350, 740, 690 cm21. Anal. calcd for C18H20N2: C, 81.78;
H, 7.62; N, 10.60. Found: C, 81.59; H, 7.56; N, 10.33.
(a) The filtrate was extracted two times with 2 N
hydrochloric acid, once with water, and dried over
Na2SO4. The organic phase was treated with 2% hydro-
chloric acid in ether until the hydrochloride completely
precipitated. The suspension was allowed to stand for
30 min, the ether decanted and the residue dried under
reduced pressure at 40 8C. To isolate the free base, the
hygroscopic hydrochloride was dissolved in 500 mL of
boiling water and the hot solution was filtrated. The filtrate
is alkalized with 2 N NaOH aqueous solution and extracted
three times with diethylether. The organic phase was
washed with water, dried over Na2SO4, and the ether
evaporated. The solid residue was purified by recrystalliza-
tion from petrolether (40/60)/diethylether (1/1).
3.1.12. N-Benzyl-N-[2-(1H-indol-3-yl)ethyl]-N-methyl-
amine (17d). N-Benzyl-methylamine and 4,9-dihydro-
pyrano[3,4-b]indol-1(3H)-one as starting materials.
Method b. The free base was purified by column
chromatography with diethylether as eluent, and the product
was treated with 2% hydrochloric acid in ether until the
hydrochloride completely precipitated. The suspension was
allowed to stand for 30 min, the ether decanted and the
residue dried under reduced pressure at 40 8C. Brown
1
crystals. Mp 92–95 8C. H NMR (200 MHz, DMSO-d6) d
2.7 (3H, d, J¼5.0 Hz, NCH3), 3.1–3.3 (4H, m, CH2CH2),
4.2–4.5 (2H, m, benzyl), 6.9–7.1 (2H, m, H-5, H-6), 7.2
(1H, d, J¼2.5 Hz, H-2), 7.3–7.7 (7H, m, H-7, H-4, arom.),
10.98 (1H, brd, indole-NH), 11.17 (1H, brd, NþH) ppm. IR
(KBr): 3200, 2550, 1620, 1450, 740, 700 cm21. Anal. calcd
for C18H21N2Cl£0.5H2O: C, 69.78; H, 7.10; N, 9.04. Found:
C, 69.89; H, 7.36; N, 8.92.
(b) The filtrate was extracted three times with water, and
dried over Na2SO4. The ether was removed under reduced
pressure. The product was purified by recrystallization from
petrolether/diethylether (1/1). The respective hydrochloride
was obtained by adding 2% HCl solution in diethylether to
the above filtrate, and filtering the resulting hydrochloride
3.1.13. 3-[2-(2,3-Dihydro-1H-indol-1-yl)ethyl]-1H-indole
(17e). Indoline and 4,9-dihydropyrano[3,4-b]indol-1(3H)-one

M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
4577
as starting materials. Method a. Brown powder. Mp 126–
1
128 8C. H NMR (90 MHz, DMSO-d6) d 2.7–3.1 (4H, m,
4.16 (1H, m, piperidine-CH), 6.9–7.1 (5H, m, H-5, 4Harom.),
7.1–7.26 (2H, m, H-6, H-2), 7.34 (1H, d, J¼7 Hz, H-7),
7.52 (1H, d, J¼8.5 Hz, H-4), 10.78 (1H, brd, indole-NH),
10.86 (1H, brd, amide-NH) ppm. IR (KBr): 1690, 1470,
CH2CH2NCH2CH2), 3.2–3.6 (4H, m, CH2NCH2), 6.4–6.7
(2H0, t, J¼0 7 Hz, H-50, H-60), 6.9–7.3 (5H, m, H-5, H-6, H-2,
H-4 , H-7 ), 7.38 (1H, dd, J¼5.6, 2.6 Hz, H-7), 7.53 (1H, dd,
J¼5.6, 2.6 Hz, H-4), 10.85 (1H, brd, indole-NH) ppm. IR
(KBr): 3400, 1605, 1485, 1450, 740 cm21. Anal. calcd for
C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.25; H,
6.95; N, 10.62.
1370, 1100, 730, 690 cm21
.
Anal. calcd for
C22H24N4O£0.5H2O: C, 71.52; H, 6.82; N, 15.17. Found:
C, 71.73; H, 6.88; N, 14.88.
3.1.18. 1-({1-[2-(5-Methoxy-1H-indol-3-yl)ethyl]piper-
idin-4-yl}methyl)-1,3-dihydro-2H-benzimidazol-2-one
3.1.14. 1-[2-(1H-Indol-3-yl)ethyl]-1,2,3,4-tetrahydro-
quinoline (17f). 1,2,3,4-Tetrahydroquinoline and 4,9-
dihydropyrano[3,4-b]indol-1(3H)-one as starting materials.
Method a. Peachy powder. Mp 148–149 8C. 1H NMR
(200 MHz, DMSO-d6) d 1.81 (2H, qui, J¼6 Hz, CH2CH2-
CH2N), 2.65 (2H, t, J¼6 Hz, CH2CH2CH2), 2.9 (2H, dd,
J¼10, 5.5 Hz, CH2CH2N), 3.25 (2H, t, J¼6 Hz, CH2CH2-
CH2N), 3.49 (2H, dd, J¼10, 5.5 Hz, CH2CH2N), 6.45 (1H,
t, J¼7.5 Hz, H-60), 6.65 (1H, d, J¼8 Hz, H-80), 6.85 (1H, d,
J¼7.5 Hz, H-50), 6.9–7.13 (3H, m, H-5, H-6, H-70), 7.2 (1H,
d, J¼2.4 Hz, H-2), 7.34 (1H, d, J¼7.5 Hz, H-7), (1H, d,
J¼7.5 Hz, H-4), 10.85 (1H, brd, indole-NH) ppm. IR (KBr):
3400, 1600, 1490, 1450, 740 cm21. Anal. calcd for
C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.83;
H, 7.30; N, 10.01.
(17k).
1-Piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-
one and 4,9-dihydro-6-methoxy-pyrano[3,4-b]indol-1(3H)-
one as starting materials. Method a. White powder. Mp
249–220 8C. H NMR (200 MHz, CD2Cl2) d 1.85 (2H, d,
1
J¼12 Hz, piperidine-CH2CH2N), 2.25 (2H, t, J¼12 Hz,
piperidine-CH2CH2N), 2.50 (2H, q, J¼12 Hz, piperidine-
CH2CH2N), 2.72 (2H, m, NCH2CH2), 2.93 (2H, m,
NCH2CH2), 3.20 (2H, d, J¼12 Hz, piperidine-CH2CH2N),
3.86 (3H, s, OCH3), 4.30 (1H, m, piperidine-CH), 6.8 (1H,
dd, J¼9, 3 Hz, H-6), 7.0–7.18 (5H, m, H-4, 4Harom.), 7.2–
7.3 (2H, s, d, J¼9 Hz, H-2, H-7), 8.08 (1H, brd, indole-NH),
9.02 (1H, brd, amide-NH) ppm. IR (KBr): 1690, 1480,
1370, 1210, 690 cm21. Anal. calcd for C23H26N4O2: C,
70.75; H, 6.71; N, 14.35. Found: C, 70.26; H, 6.97; N, 14.10.
3.1.19. 4-Anilino-1-[2-(1H-indol-3-yl)ethyl]piperidine-4-
carboxamide (17l). 4-Anilinopiperidine-4-carboxamide
and 4,9-dihydropyrano[3,4-b]indol-1(3H)-one as starting
materials. Method a. Yellow powder. Mp 127 8C. 1H NMR
(200 MHz, CDCl3) d 1.98 (2H, d, J¼13 Hz, 2£1H-
piperidine-CH2CH2N), 2.1–2.5 (4H, m, 2H-piperidine-
CH2CH2N, 2£1H-piperidine-CH2CH2N), 2.65 (2H, t,
J¼8.5 Hz, CH2CH2N), 2.8–3.0 (4H, m, CH2N, 2£1H-
piperidine-NCH2CH2), 4.05 (1H, brd, NH), 5.42 (2H, brd,
CO–NH2), 6.64 (2H, d, J¼7.8 Hz, 2Ho), 6.75–6.95 (2H, m,
H-5, Hp), 7.0–7.25 (4H, m, H-6, H-2, 2Hm), 7.35 (1H, d,
J¼8.3 Hz, H-7), 7.58 (1H, d, J¼8.3 Hz, H-4), 8.02 (1H, brd,
indole-NH) ppm. IR (KBr): 1670, 1600, 1500, 740,
3.1.15. 3-[2-(4-Methylpiperazin-1-yl)ethyl]-1H-indole
(17g). 1-Phenylpiperazine and 4,9-dihydropyrano[3,4-
b]indol-1(3H)-one as starting materials. Method a. White-
1
beige powder. Mp 130–132 8C (lit.15 mp 132–134 8C). H
NMR (200 MHz, DMSO-d6)
d
3.0–3.5 [8H, m,
N(CH2CH2)2N], 3.6–3.7 (2H, m, NCH2CH2), 3.7–3.9
(2H, m, CH2N), 6.85 (1H, t, J¼6.5 Hz, H-5), 6.95–7.05
(3H, m, 2Ho, Hp), 7.1 (1H, t, J¼6.5 Hz, H-6), 7.2–7.3 (3H,
m, H-2, 2Hm), 7.35 (1H, t, J¼6.5 Hz, H-7), 7.55 (1H, t,
J¼6.5 Hz, H-4), 11 (1H, brd, indole-NH), 11.4 (1H, brd,
NþH) ppm. IR (KBr): 3400, 1600, 1490, 1450, 740 cm21
.
3.1.16. N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-[2-(1H-
indol-3-yl)ethyl]-N-methylamine (17h). N-[2-(3,4-
690 cm21
.
Dimethoxyphenyl)ethyl]-N-methylamine and 4,9-dihydro-
pyrano[3,4-b]indol-1(3H)-one as starting materials. Method
a. Brown, hygroscopic crystals. Mp 88–90 8C. H NMR
3.1.20. 4-Anilino-1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-
piperidine-4-carboxamide (17m). 4-Anilinopiperidine-4-
carboxamide and 9-dihydro-6-methoxy-pyrano[3,4-b]indol-
1(3H)-one as starting materials. Method b. White powder.
1
(200 MHz, DMSO-d6/D2O) d 2.7–2.96 (2H, m, dimethoxy-
phenyl-CH2CH2N), 2.88 (3H, s, NCH3), 3.05 (2H, m,
indole-CH2CH2N), 3.15–3.45 (4H, m, CH2N(CH3)CH2),
3.6–3.8 (9H, s, s, s, 3£CH3), 6.55–6.9 (4H, m, H-6,
3Harom.), 7.04 (1H, d, J¼2 Hz, H-4), 7.16 (1H, s H-2), 7.26
(1H, d, J¼9 Hz, H-7), 10.65 (1H, brd, indole-NH) ppm. IR
1
Mp 159 8C. H NMR (200 MHz, CDCl3) d 1.98 (2H, d,
J¼13 Hz, 2£1H-piperidine-CH2CH2N), 2.1–2.5 (4H, m,
2H-piperidine-CH2CH2N,
2£1H-piperidine-CH2CH2N),
2.65 (2H, t, J¼8.5 Hz, CH2CH2N), 2.8–3.0 (4H, m,
CH2N, 2£1H-piperidine-NCH2CH2), 3.84 (3H, s, OCH3),
4.05 (1H, brd, NH), 5.42 (2H, brd, CO–NH2), 6.64 (2H, d,
J¼7.8 Hz, 2Ho), 6.75–6.95 (2H, m, H-6, Hp), 7.0–7.05 (2H,
s, s, H-2, H-4), 7.1–7.25 (3H, m, H-7, 2Hm), 8.02 (1H, brd,
indole-NH) ppm. IR (KBr): 3400, 1670, 1600, 800,
690 cm21. EI-MS m/z 392 (Mþ).
(KBr): 1620, 1580, 1510, 1480, 1210, 1020, 800 cm21
.
Anal. calcd for C22H29N2O3Cl£0.5H2O: C, 63.83; H, 7.31;
N, 6.77. Found: C, 63.53; H, 7.46; N, 7.05.
3.1.17. 1-({1-[2-(1H-Indol-3-yl)ethyl]piperidin-4-
yl}methyl)-1,3-dihydro-2H-benzimidazol-2-one
1-Piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one and
4,9-dihydropyrano[3,4-b]indol-1(3H)-one as starting
materials. Method a. White powder. Mp 249–250 8C. H
NMR (200 MHz, DMSO-d6) d 1.65 (2H, d, J¼12 Hz,
piperidine-CH2CH2N), 2.13 (2H, t, J¼12 Hz, piperidine-
CH2CH2N), 2.35 (2H, t, J¼12 Hz, piperidine-CH2CH2N),
2.64 (2H, t, J¼8 Hz, NCH2CH2), 2.88 (2H, t, J¼8 Hz,
NCH2CH2), 3.12 (2H, d, J¼12 Hz, piperidine-CH2CH2N),
(17i).
3.1.21. 3-[2-(4-Methylpiperidin-1-yl)ethyl]-1H-indole
(17n). 4-Methylpiperidine and 9-dihydropyrano[3,4-
b]indol-1(3H)-one as starting materials. Method b. White
1
1
powder. Mp 108 8C (lit.16 Mp 110 8C). H NMR (90 MHz,
DMSO-d6) d 0.9 (3H, s, CH3), 1.0–2.7 (9H, m, piperidine-
H), 2.8–3.0 (4H, m, CH2CH2N), 6.9–7.1 (2H, m, H-5, H-6),
7.2 (1H, d, J¼1.8 Hz, H-2), 7.35 (1H, dd, J¼7.2, 2 Hz, H-
7), 7.62 (1H, dd, J¼7.2, 2 Hz, H-4), 11.0 (1H, brd,

4578
M. Decker et al. / Tetrahedron 60 (2004) 4567–4578
indole-NH) ppm. IR (KBr): 3400, 3120, 2920, 1625, 1450,
740 cm21. All the other spectroscopic data were identical
with reported data in Ref. 16.
References and notes
1. Witt, T.; Hock, F. J.; Lehmann, J. J. Med. Chem. 2000, 43,
2079–2081.
3.1.22. 5-Methoxy-3-[2-(4-methylpiperidin-1-yl)ethyl]-
1H-indole (17o). 4-Methylpiperidine and 9-dihydro-6-
methoxy-pyrano[3,4-b]indol-1(3H)-one as starting materials.
Method b. Yellow, hygroscopic crystals. Mp 207–209 8C. 1H
NMR(200 MHz,D2O)d0.96(3H,d,J¼7 Hz,CH3),1.39(2H,
t, J¼12 Hz, CHCH2), 1.62 (1H, m, CH), 1.9 (2H, d, J¼14 Hz,
CHCH2), 2.86 (2H, t, J¼14 Hz, piperidine-N–CH2), 3.1 (2H,
m, CH2CH2N), 3.25 (2H, m, CH2CH2N), 3.52 (2H, d,
J¼12 Hz, piperidine-N–CH2), 3.86 (3H, s, OCH3), 6.9 (1H,
dd, J¼9.5, 2.4 Hz, H-6), 7.12 (1H, d, J¼2.4 Hz, H-4), 7.22
(1H, s, H-2), 7.43 (1H, d, J¼9.5 Hz, H-7) ppm. IR (KBr):
3250, 2930, 2650, 1485, 1450, 1220, 800, 640 cm21. Anal.
calcd for C17H25N2OCl£0.3H2O: C, 64.97; H, 8.21; N, 8.92.
Found: C, 64.84; H, 8.39; N, 8.79.
2. Neafsey, E. J.; Albores, R.; Gearhart, D.; Kindel, G.; Raikoff,
K.; Tamayo, F.; Collins, M. A. Brain Res. 1995, 675,
279–288.
¨
3. Abadi, A. H.; Lankow, S.; Hofgen, B.; Decker, M.; Kasssack,
M. U.; Lehmann, J. Arch. Pharm. Pharm. Med. Chem. 2002, 8,
367–373.
¨
4. Spath, E.; Lintner, J. Ber. 1936, 69, 2727–2729.
5. Reppe, W. Ann. 1955, 596, 171–176.
6. Theilacker, W.; Kalenda, K. Ann. 1953, 584, 87–91.
7. Knobler, Y.; Bonni, E.; Sheradsky, T. J. Org. Chem. 1964, 29,
1229–1236.
8. Lunsford, C. D.; Murphey, R. S.; Rose, E. R. J. Org. Chem.
1957, 22, 1225–1228.
9. Nakagawa, M.; Kiuchi, M.; Obi, M.; Tonozuka, M.;
Kobayashi, K.; Hino, T.; Ban, Y. Chem. Pharm. Bull. 1975,
23, 304–312.
3.1.23. N,N-Diethyl-N-[2-(1H-indol-3-yl)ethyl]amine
(17p). Diethylamine and 9-dihydropyrano[3,4-b]indol-
1(3H)-one as starting materials. Method b. White powder.
Mp 171 8C (lit.17 mp 168–169 8C). 1H NMR (90 MHz,
D2O) d 1.28 (6H, t, J¼7.3 Hz, 2£CH3), 3.0–3.5 (8H, m,
CH2CH2, 2£NCH2), 7.1–7.4 (3H, m, H-5, H-6, H-2), 7.5–
7.8 (2H, m, H-7, H-4) ppm. IR (KBr): 3200, 2640, 1450,
1430, 745, 700 cm21. All the other spectroscopic data were
identical with reported data in Ref. 17.
10. Strojny, R. A.; White, H. C.; Strojny, E. J. J. Org. Chem. 1962,
27, 1241–1247.
11. Morosawa, S.; Yokoo, A. Bull. Chem. Soc. Jpn 1963, 36,
179–183.
12. Hanford, W. E.; Adams, R. J. Am. Chem. Soc. 1935, 57,
921–924.
13. Lehmann, J.; Pohl, U. Arch. Pharm. Pharm. Med. Chem. 1987,
320, 1202–1209.
14. Lehmann, J.; El-Gendy, A. A. Arch. Pharm. Pharm. Med.
Chem. 1987, 320, 698–704.
Acknowledgements
15. Archer, S. US Patent 3,135,794, 1964.
16. Lounasmaa, M.; Jokela, R. Tetrahedron 1989, 12, 3975–3992.
We would like to thank Aventis Pharma, Germany, for
performing the pharmacological screening.
´
17. Nogradi, T. Monatsh. Chem. 1957, 88, 768–777.
´