A new strategy for 2-substituted indolylalkylamines: Synthesis of 2-aryldihomotryptamines

Article abstract of DOI:10.1016/S0040-4039(02)02105-6

Substituted homologues of tryptamines were synthesized in one step in high yields under mild conditions. The key intermediates are arylhydrazones of 6-aminohexanones, which undergo Fischer rearrangement readily in glacial acetic acid. An easy and ready for scale-up procedure is developed and formerly unknown 2-substituted dihomotryptamines are obtained.

Full text of DOI:10.1016/S0040-4039(02)02105-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8449–8451
A new strategy for 2-substituted indolylalkylamines:
synthesis of 2-aryldihomotryptamines
Valentine G. Nenajdenko,* Eugene P. Zakurdaev and Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, 119899 Moscow, Russia
Received 16 July 2002; revised 19 September 2002; accepted 25 September 2002
Abstract—Substituted homologues of tryptamines were synthesized in one step in high yields under mild conditions. The key
intermediates are arylhydrazones of 6-aminohexanones, which undergo Fischer rearrangement readily in glacial acetic acid. An
easy and ready for scale-up procedure is developed and formerly unknown 2-substituted dihomotryptamines are obtained. © 2002
Published by Elsevier Science Ltd.
Indolylalkylamines have importance as a main struc-
tural unit of indole alkaloids, many biologically active
substances and remedies. Recently, derivatives of 2-
low yield using the reaction of 4-chlorobutyrophenone
with phenyl hydrazines. The Fischer reaction has often
been applied to the synthesis of 2-unsubstituted indolyl-
alkylamines from aminoaldehydes, which are very
labile compounds and need to be protected before
being used. This drawback increases the total expense
and time of this method.
1
12
substituted tryptamines attracted a lot of attention
2
because of their high selectivity for serotonin,4
3
melatonin and gonadotropin releasing hormone
receptors.
Three general approaches exist to 2-substituted
tryptamines. The first consists of attaching the alkyl-
amine fragment to the indole core. The second
In this investigation we propose and elaborate a new
general method for the synthesis of homologues of
tryptamine, substituted in 2-position. The starting com-
pounds are various aminoketones and arylhydrazines.
5
involves multi-step modification of the 3-indole sub-
6,7
stituent into the alkylamine chain. The third lies in
the synchronous creation of the selected alkylamine
fragment and the indole core and is the method of
choice because it should provide a shortened and sim-
plified procedure.
Our approach is the first example of the Fischer’s
reaction of aminocarbonyl compounds containing an
unprotected amino group.
The synthesis of various arylhydrazines is well-known,
therefore we aimed at developing a convenient synthesis
of 6-aminohexanones from readily available and inex-
pensive substances. We chose a-acyllactams as the
starting materials for synthesis of the aminoketones on
the basis of literature analysis: they can be easily
To fulfil such an approach there are Fischer, Grand-
berg or Japp–Klingemann reactions. The last one limits
8
the range of products to 2-carboxyindolylalkylamines.
9,10
It has been shown
that 2-arylindolylalkylamines can-
not be obtained by the Grandberg approach, but the
1
1
authors were able to obtain 2-aryltryptamines in a
Scheme 1.
Keywords: Fischer reaction; amino ketones; indolisation; biologically active compounds.
*
Corresponding author. Fax: +7-(095)-932-88-46; e-mail: nen@acylium.chem.msu.ru
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02105-6

8
450
V. G. Nenajdenko et al. / Tetrahedron Letters 43 (2002) 8449–8451
Table 1. Aminohexanones obtained via Scheme 1
Entry
Aminohexanone, R
C H
Isolated yield (%)
Entry
Aminohexanone, R
4-ClC H
Isolated yield (%)
1a
1b
1c
66
86
70
1d
1e
1f
81
85
78
6
5
6
4
3-MeC H
4-BrC H
6
4
6 4
3-MeOC H
3,4-Cl C H
2 6 3
6
4
Table 2. 2-Aryldihomotryptamine 2a–j produced via
ous arylhydrazines with donor and acceptor groups
15
Scheme 2
were synthesized. It was found that in all cases diho-
16
motryptamines were isolated in good to high yields.
Entry
R
R%
Isolated yield (%)
The experimental data obtained allow the anticipation
that development of this work can make this approach
a new general method for the synthesis of substituted
indolylalkylamines ( tryptamines, homotryptamines and
isotryptamines) from other aminoketones.
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
C H
H
85
78
80
84
85
65
57
72
62
6
5
5
5
5
5
C H
5-Br
5-MeO
4,6-Me2
5-n-Bu
H
H
H
H
H
6
C H
6
C H
6
C H
6
a
3-MeC H4
3-MeOC H
4-ClC H4
4-BrC H4
In conclusion, we propose a new general method for
synthesis of various dihomotryptamines with desired
substituents in all positions of the indole core. This
work is in progress in our laboratory and the results
will be reported in due course.
6
a
6
4
a
6
a
6
a
j
3,4-Cl C H
3
77
2
6
a
Glacial acetic acid, saturated by HCl, was used.
Acknowledgements
obtained by Claisen condensation of an N-protected
1
3
lactam and ester. We used a N-vinylcaprolactam,
which is commercially available, and methyl esters of
substituted benzoic acids. It is known that the N-vinyl
protecting group is stable for the condensation (and
isolation of a-acyllactams) and can be easily removed
during subsequent acidic hydrolysis and decarboxyla-
tion. We modified this method to obtain the 6-amino-
hexanones 1a–f as hydrochloride salts (Scheme 1, Table
The research described in this publication was sup-
ported by Russian Fundamental Investigation Founda-
tion (Grants N 03-03-32187).
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1
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1
4
(
Scheme 2).
6
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substituents on the yield of the Fischer reaction, vari-
Scheme 2.

V. G. Nenajdenko et al. / Tetrahedron Letters 43 (2002) 8449–8451
8451
7
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2
3
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8
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2
4
1
0. Sannicolo, F.; Benincori, T.; Brenna, E. J. Chem. Soc.,
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2 2
1
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1
13
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3
(
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microanalysis data. Selected data: compound 2a, 4-(2-
phenyl-1H-indol-3-yl)-1-butylamine hydrochloride): Yield
1
85%. R
0.25. Mp 236°C. H NMR (400 MHz, (CD
)
2
SO)
f
3
5
l 1.60–1.71 (m, 4H), 2.75 (t, 2H, J=6.95 Hz), 2.85 (t, 2H,
J=7.11 Hz), 6.95–7.65 (m, 9H), 7.94 (bs, 3H), 11.21 (s,
1
1
3. Deur, C.; Hegedus, L. S. Org. Synth. 1997, 75, 215.
4. General procedure: A mixture of 6 mmol arylhydrazine
hydrochloride and 5 mmol aminoketone was refluxed in
glacial acetic acid. The progress of the reaction was
monitored by TLC (MeCN:EtOH:NH3 (aq)=80:12:8).
After the reaction was finished, the mixture was concen-
trated in vacuo and recrystalized from water. If the
13
1H). C NMR (100 MHz, (CD SO) l 23.94 (CH
27.29 (CH ), 27.60 (CH ), 38.71 (CH ), 111.16 (C), 111.45
2
)
),
3
2
2
2
2
(CH), 118.57 (CH), 118.67 (CH), 121.42 (CH), 127.21
(C), 127.74 (CH), 128.60 (CH), 128.72 (CH), 133.03 (C),
133.93 (C), 135.99 (C). Anal. calcd for C18
71.87; H, 7.04. Found: C, 72.04; H, 6.91%.
H21ClN : C,
2