Convenient synthesis of melatonin analogues: 2- and 3-substituted -N-acetylindolylalkylamines

Article abstract of DOI:10.1016/j.tet.2004.10.006

A new method for the synthesis of 2- and 3-substituted indolylalkylamides, derivatives of melatonin, from arylhydrazines and amidoketones by the Fischer reaction was elaborated. The amidoketones can be easily prepared from cyclic imines by reaction with acylpyridinium chloride. This method is a one-step synchronous creation of the selected alkylamide fragment and the indole core. Variation of the arylhydrazines create the desired substituents in the carbocycle of indolylalkylamides and suitable choice of amidoketone can direct the amidoalkyl chain to the 2- or 3-position of the indole. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.10.006

Tetrahedron 60 (2004) 11719–11724
Convenient synthesis of melatonin analogues:
2- and 3-substituted -N-acetylindolylalkylamines
*
Valentine G. Nenajdenko, Eugene P. Zakurdaev, Eugene V. Prusov and Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, Leninskie Gory, 119992 Moscow, Russian Federation
Received 1 July 2004; revised 9 September 2004; accepted 1 October 2004
Available online 18 October 2004
Abstract—A new method for the synthesis of 2- and 3-substituted indolylalkylamides, derivatives of melatonin, from arylhydrazines and
amidoketones by the Fischer reaction was elaborated. The amidoketones can be easily prepared from cyclic imines by reaction with
acylpyridinium chloride. This method is a one-step synchronous creation of the selected alkylamide fragment and the indole core. Variation
of the arylhydrazines create the desired substituents in the carbocycle of indolylalkylamides and suitable choice of amidoketone can direct
the amidoalkyl chain to the 2- or 3-position of the indole.
q 2004 Published by Elsevier Ltd.
1. Introduction
an agonist and N-acetyltryptamine, a partial agonist
(Scheme 1).5
Melatonin I (5-methoxy-N-acetyltryptamine) is a hormone
which regulates a number of neuroendocrine and physio-
logical processes. Seasonal changes in various aspects of
physiology in photoperiodic species, such as sheep and
hamsters, are controlled by actions of melatonin. Melatonin
administration can also entrain the circadian clock by a
direct action on the CNS. Many studies have also indicated
an influence on immune function and antioxidant actions.
Scheme 1.
Melatonin is a derivative of indolylalkylamines, which have
importance as a main structural unit of indole alkaloids
which contain many biologically active substances and
remedies.1 Recently, derivatives of 2-substituted trypta-
mines have attracted a lot of attention because of their high
selectivity for serotonin,2 melatonin3 and gonadotropin
releasing hormone4 receptors. Substitution at the 2-position
of the indole ring of melatonin also increases affinity and
potency; in part because steric effects restrict the flexible
C-3 side-chain allowing easier docking at the active site of
the receptor. For example, 2-position substitution improves
affinity at both melatonin receptor subtypes ML1 and ML2;
2-iodomelatonin II and 2-phenylmelatonin III show a
w10-fold improvement in affinity (Kiw60 pM) over
melatonin itself. Other analogues which have been used to
characterise melatonin binding sites are 6-chloromelatonin,
Four general approaches exist to N-acylindolylalkylamines.
The first is an acylation of a previously synthesized
indolylalkylamines.6 The second consists in attaching the
acylamine fragment to the indole core.7 The third involves
multi-step modification of the 3-indole substituent into the
acylamine chain.8 The forth lies in the synchronous creation
of the selected acylamine fragment and the indole core and
is the method of choice because it should provide a
shortened and simplified procedure.
To fulfil such an approach there is the Fischer reaction. It
has been applied to the synthesis of 2-unsubstituted
indolylalkylamides from amidoaldehydes (with the
aminogroup protected by Phth-,9 Boc-10 or Cbz11-group).
Reaction of cyclic amidoketones (with Phth-,12 carbamoyl-,13
benzoyl-14 or acetyl-15 protective group) with arylhydra-
zines leads to indoles condensed with saturated cycle (with
nitrogen atom in cycle or attached to it). It should be noted
that in most cases protective groups remained intact during
the Fischer reaction so it is the main way for the direct
synthesis of melatonin derivatives.
Keywords: Melatonin; Cyclic imines; Amidoketones; Arylhydrazines;
Fischer reaction; Indoles.
* Corresponding author. Tel.: C70959392276; fax: C70959328846;
e-mail: nen@acylium.chem.msu.ru
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.10.006

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V. G. Nenajdenko et al. / Tetrahedron 60 (2004) 11719–11724
Recently,16 we elaborated an easy and scaleable procedure
for the synthesis of previously unknown 2-arylindolylalkyl-
amines from arylhydrazones of 6-aminohexanones, which
readily undergo Fischer rearrangement in glacial acetic
acid. On the basis of this work we developed a new and
effective synthesis of melatonin analogues from derivatives
of aminoketones.
Table 1. Synthesis of 2-substituted cyclic imines 1a–c (from 3-
acyllactams), imines 1d–h (by reaction of N-vinyllpirrolidone with RLi)
and synthesis of amidoketones 2a–h
R
Imine, yield, %
Amidoketone, yield, %
C6H5
C6H5CH2
Me
4-Me–C6H4
2,4-MeO–C6H3
2-Thienyl
2-Furyl
1a, 89
1b, 85
1c, 70
1d, 65
1e, 60
1f, 65
1g, 65
1h, 50
2a, 91
2b, 86
2c, 75
2d, 95
2e, 70
2f, 87
2g, 80
2h, 85
n-Bu
2. Results and discussion
We proposed that arylketones with a N-acyl group should
give rise to 2-aryl substituted indolylalkylamides in the
Fischer reaction (Scheme 2).
We introduced amidoketones 2 in the Fischer reaction and
the corresponding indolylalkylamides 3 and 4 were obtained
in good to near quantitative yields using acetic acid
saturated with gaseous HCl as catalyst (Scheme 4 and
Table 2).
Scheme 2.
Scheme 4.
At the first step we aimed at developing a convenient
synthesis of arylketones with a N-acyl group from
aminoketones. We chose a-acyllactams as the starting
materials for synthesis of the aminocarbonyl compounds on
the basis of literature analysis: they can be obtained by
Claisen condensation of an N-protected lactam and ester.
Recently we thoroughly investigated this condensation of
the 5-, 6- and 7-membered lactams with various esters.17 On
the basis of NMR spectra we have found out that in the case
of 5-membered 3-acyllactams, acidic hydrolysis and
decarboxylation18 leads to mixture of cyclic imines and
aminoketones. Thus, the reaction mixture was basified by
50% KOH and pure cyclic imines were obtained. In the case
of readily available organolithium derivatives or acidic-
sensitive substituents reaction of organolithium reagents
with N-vinylpyrrolidone was used,19–24 and it was also
basified to give the cyclic imines.
Table 2. Synthesis of 2-substituted N-acetyltryptamines 3a, d–g, i–m
R0
N-Acetyl-tryptamine
R
Yield, %
3a
3d
3e
3f
3g
3i
3j
3k
3l
C6H5
H
H
H
H
93
95
65
66
43a
64
87
80
85b
84
4-Me–C6H4
2,4-MeO–C6H3
2-Thienyl
2-Furyl
C6H5
C6H5
C6H5
C6H5
C6H5
H
5-F
5-Cl
5-Br
5-MeO
7-Et
3m
a Ethyl ester of polyphosphoric acid (PPE, 3 equiv), 1 h, 85 8C.
b Glacial AcOH, reflux, 10 min.
To investigate the scope of the method and the effect of
substituents on the yield of the Fischer reaction, various
arylhydrazines with donor and acceptor groups were
synthesized.27 It was found that in all cases N-acetyltrypta-
mines were isolated in good to high yields. Generally no
restriction of hydrazine or ketone structure for this approach
was found. Yields are quite good except in the case of
amidoketone 2g with a furyl substituent, when this
conditions of Fischer rearragement lead to tar formation.
Thus, we selected a more soft catalyst, namely ethyl ester of
polyphosphoric acid28 (PPE, 3 equiv), to give 2-furyl-N-
acetyltryptamine 3g. 2-Phenylmelatonin was obtained in
high yield from 4-methoxyphenylhydrazone of amidoke-
tone 2a by refluxing it for 10 min in pure acetic acid.
There are rare examples of acylation of cyclic imines to
amidoketones,20,25,26 but none lead to satisfactory results.
So we developed a new method of acylation using
N-acetylpyridinium chloride IV. The results are shown in
Scheme 3 and Table 1.
Amidoketones with two CH2 units at carbonyl group has
two ways for Fischer indolyzation. Thus, it opens
possibilities to synthesize two different classes of
Scheme 3.

V. G. Nenajdenko et al. / Tetrahedron 60 (2004) 11719–11724
11721
indolylalkylamides, containing an amidoalkyl chain in the
2- or 3-position of the indole core. To investigate the effect
of substituents on the regioselectivity of the Fischer
rearrangement, we synthesized compounds 2b, 2c and 2h.
reaction. The amidoketones can be easily prepared from
cyclic imines by reaction with acylpyridinium chloride. It
should be noted especially, that our method is a one-step
synchronous creation of the selected acylamine fragment
and the indole core. Variation of the arylhydrazines creates
the desired substituents in the carbocycle of indolylalkyl-
amides and suitable choice of amidoketone directs the
amidoalkyl chain to the 2- or 3-position of the indole.
Reaction of 2b with phenylhydrazine gives rises only to
N-acetylizohomotryptamine 4b with a Ph group in the
3-position of the indole core. We explain that regioselec-
tivity due to stabilization of enehydrazine by mesomeric
conjugation of ene-bond with the aromatic core. In the case
of amidoketone 2c also only 3c was obtained, because one
enehydrazine is more stable thermodynamically in com-
parison with the other terminal enhydrazine, so this factor is
decisive for direction of the reaction to proceed.
4. Experimental
4.1. General
TLC was performed with ‘Silufol UV-254’ plates, and flash
chromatography was carried out with silica gel (63–200
4-Oxooctyl-N-acetamide 2h reacted with phenylhydrazine
giving a mixture of 3h (2-butyl-N-acetyltryptamine) and 4h
(3-propyl-N-acetylizohomotryptamine) in 1:2 ratio, both of
which can be easily separated by flash chromatography
(Scheme 5 and Table 3).
mesh), using EtOAc/CH2Cl2 in 1:2 proportions. 1H and 13
C
NMR spectra of CDCl3 solutions (if not mentioned
otherwise) were respectively recorded at 400 and
100 MHz, TMS was used as internal standard. IR spectra
were recorded in thin layer for liquid and in nujol for solid
substances.
4.2. General procedure for the synthesis of N-(4-oxo-4-
substituted butyl)-acetamides
To a well stirred solution of 1.6 mL (20 mmol) pyridine in
20 mL abs. CH2Cl2 solution of 0.71 mL (0.8 g, 10 mol)
AcCl in 10 mL abs. CH2Cl2 was slowly added and mixture
was stirred an additional 15 min.
To a suspension of N-acetylpyridinium chloride obtained
solution of 10 mmol cyclic imine 1a–h in 25 mL abs.
CH2Cl2 was added dropwise with stirring. After addition
reaction mixture was stirred until N-acetylpyridinium salt
was dissolved totally and then an additional 10 min.
To a clear solution obtained 20 mL 5% HCl was added with
intensive stirring and after 15 min of it organic layer was
separated, washed with water (2!20 mL), dried with
Na2SO4 and evaporated. The residue was triturated with
hexanes giving amidoketones 2a–h.
Scheme 5.
Table 3. Direction of indolyzation of amidoketones 2b, 2c and 2h
4.2.1. N-(4-Oxo-4-phenylbutyl)acetamide (2a). White
crystal solid, 1.87 g, yield 91%, mp 95 8C. IR, (n, cmK1):
1640 (O]CNH), 1680 (PhC]O). 1H NMR d 1.93 (s, 3H),
1.96 (tt, JZ6.7, 5.9 Hz, 2H), 3.03 (t, JZ6.7 Hz, 2H), 3.32
(dt, JZ6.7, 5.9 Hz, 2H), 5.93 (bs, 1H), 7.44 (t, JZ7.6 Hz,
2H), 7.55 (t, JZ7.6 Hz, 1H), 7.93 (d, JZ7.6 Hz, 2H). 13C
NMR d 23.3, 23.7, 36.0, 39.3, 128.0 (2C), 128.6 (2C), 133.2,
136.6, 169.0, 200.0. Calcd for C12H15NO2, C 70.40, H 7.28;
found C 70.22, H 7.37.
N-Acetylindolylalkylamine
R
Yield, %
4b
3c
3h/4h
Ph
H
Pr
93
77
90 (1/2)
The reaction of amidoketones with two alkyl substituents at
the carbonyl group allows preparation of previously
unknown 3-subsituted N-acetylizohomotryptamines and
shows that preferable direction of indolyzation depends on
the stability of the intermediate enehydrazines.
4.2.2. N-(4-Oxo-5-phenylpentyl)acetamide (2b). Brown
crystal solid, 1.89 g, yield 86%, mp 43–44 8C. IR, (n, cmK1):
1640 (O]CNH), 1700 (PhCH2C]O). 1H NMR d 1.72 (tt,
JZ6.7 Hz, 2H), 1.87 (s, 3H), 2.5 (t, JZ6.7 Hz, 2H), 3.14
(dt, JZ6.7 Hz, 2H), 3.67 (s, 2H), 5.8 (bs, 1H), 7.18 (d, JZ
7.0 Hz, 2H), 7.25 (tt, JZ7.3, 7.0 Hz, 1H), 7.31 (t, JZ
7.3 Hz, 2H). 13C NMR d 23.1, 23.2, 38.9, 39.2, 50.1, 127.0,
128.7 (2C), 129.3 (2C), 134.0, 170.2, 208.2. Calcd for
C13H17NO2 C 72.21, H 7.81; found C 72.29, H 7.81.
3. Conclusion
We have described a new method for the synthesis of 2- and
3-substituted indolylalkylamides, derivatives of melatonin,
from arylhydrazines and amidoketones by the Fischer

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V. G. Nenajdenko et al. / Tetrahedron 60 (2004) 11719–11724
4.2.3. N-(4-Oxopentyl)acetamide (2c). Red crystal solid,
1.07 g, yield 75%, mp 48–50 8C. IR, (n, cmK1): 1630
(O]CN), 1700 (CH3C]O). H NMR d 1.71 (tt, JZ7.0,
6.7 Hz, 2H), 1.9 (s, 3H), 2.1 (s, 3H), 2.45 (t, JZ7.0 Hz, 2H),
3.16 (dt, JZ6.7, 5.9 Hz, 2H), 6.2 (bs, 1H). 13C NMR d 23.0,
23.3, 30.0, 39.9, 40.9, 170.4, 208.7. Calcd for C7H13NO2, C
58.72, H 9.15; found C 58.31, H 8.91.
acetic acid, saturated with gaseous HCl at 20 8C, was
quickly warmed to boiling. When all solids were dissolved
refluxing was continued for 5 min. Then reaction mixture
was evaporated and distributed between water and CH2Cl2.
Organic phase was washed with water (2!20 mL) and
evaporated. The flash chromatography of the residue
afforded the products.
1
4.2.4. N-(4-Oxo-4-(4-methylphenyl)-butyl)acetamide
(2d). Yellowish crystal solid, 2.08 g, yield 95%, mp 118–
120 8C. IR, (n, cmK1): 1630 (O]CNH), 1665 (ArC]O).
1H NMR d 1.92 (s, 3H), 1.93 (tt, JZ7.0, 6.7 Hz, 2H), 2.38
(s, 3H), 3.0 (t, JZ7.0 Hz, 2H), 3.35 (dt, JZ6.7, 5.9 Hz, 2H),
6.00 (bs, 1H), 7.23 (d, JZ8.1 Hz, 2H), 7.82 (d, JZ8.1 Hz,
2H). 13C d NMR 21.5, 23.3, 23.7, 36.0, 39.3, 128.0 (2C),
129.3 (2C), 134.2, 144.0, 170.0, 200.0. Calcd for
C13H17NO2, C 72.21, H 7.81; found C 72.41, H 7.95.
4.3.1. N-[2-(2-Phenyl-1H-indol-3-yl)ethyl]acetamide
(3a). Cream crystal solid, 2.59 g, yield 93%, mp 114–
116 8C. Rf (EtOAc)Z0.45. IR, (n, cmK1): 1620 (O]CNH).
1H NMR d 1.73 (s, 3H), 3.11 (t, JZ6.7 Hz, 2H), 3.52 (dt,
JZ6.7, 6.2 Hz, 2H), 5.53 (bs, 1H), 7.14 (t, JZ7.0 Hz, 1H),
7.21 (t, JZ7.0 Hz, 1H), 7.35 (t, JZ7.3 Hz, 1H), 7.38 (d, JZ
8.1 Hz, 1H), 7.45 (t, JZ7.3 Hz, 2H), 7.56 (d, JZ7.3 Hz,
2H), 7.62 (d, JZ8.1 Hz, 1H), 8.48 (bs, 1H). 13C NMR d
23.1, 24.4, 40.1, 109.6, 111.0, 118.8, 119.8, 122.3, 127.7,
127.9 (2C), 128.9 (2C), 132.9, 133.2, 135.3, 135.9, 170.1.
Calcd for C18H18N2O, C 77.67, H 6.52; found C 77.67, H
6.50.
4.2.5. N-(4-Oxo-4-(2,4-dimethoxyphenyl)butyl)aceta-
mide (2e). Brown crystal solid, 1.86 g, yield 70%, mp 78–
80 8C. IR, (n, cmK1): 1640 (O]CNH), 1680 (ArC]O). 1H
NMR d 1.87 (tt, JZ7.0, 6.7 Hz, 2H), 1.92 (s, 3H), 2.98 (t,
JZ7.0 Hz, 2H), 3.26 (dt, JZ6.7, 5.6 Hz, 2H), 3.82 (s, 3H),
3.86 (s, 3H), 6.07 (bs, 1H), 6.42 (d, JZ2.3 Hz, 1H), 6.49
(dd, JZ8.8, 2.3 Hz, 1H), 7.76 (d, JZ8.8 Hz, 1H). 13C NMR
d 23.3, 23.7, 39.7, 41.3, 55.4, 55.5, 98.3, 105.2, 120.7,
132.5, 160.7, 164.5, 170.3, 200.0. Calcd for C14H19NO4 C
63.38, H 7.22; found C 62.84, H 7.25.
4.3.2. N-[3-(3-Phenyl-1H-indol-2-yl)propyl]acetamide
(4b). Grey crystal solid, 2.75 g, yield 93%, mp 123 8C. Rf
(EtOAc)Z0.6. IR, (n, cmK1): 1620 (O]CNH). 1H NMR d
1.72 (tt, JZ6.5, 6.2 Hz, 2H), 1.84 (s, 3H), 2.76 (t, JZ
6.5 Hz, 2H), 3.19 (dt, JZ6.5, 6.2 Hz, 2H), 5.63 (bs, 1H),
7.01 (t, JZ7.0 Hz, 1H), 7.09 (t, JZ7.0 Hz, 1H), 7.23 (t, JZ
7.0 Hz, 1H), 7.37 (m, 5H), 7.55 (d, JZ7.9 Hz, 1H), 9.70 (bs,
1H). 13C NMR d 22.3, 23.0, 30.2, 38.3, 111.0, 114.0, 118.6,
116.6, 121.4, 125.8, 127.6, 128.6 (2C), 129.6 (2C), 135.1,
135.4, 135.6, 171.5. Calcd for C19H20N2O, C 78.05, H 6.89;
found C 77.93, H 6.86.
4.2.6. N-(4-Oxo-4-thien-2-ylbutyl)acetamide (2f). White
crystal solid, 1.84 g, yield 87%, mp 72 8C. IR, (n, cmK1):
1640 (O]CNH), 1660 (thienyl-CO). H NMR d 1.67 (tt,
1
JZ7.0, 6.7 Hz, 2H), 1.82 (s, 3H), 2.45 (t, JZ6.7 Hz, 2H),
3.09 (dt, JZ6.7, 5.9 Hz, 2H), 5.75 (bs, 1H), 7.08–7.27 (m,
3H). 13C NMR d 23.3, 23.7, 36.0, 39.3, 128.0, 131.8, 133.5,
143.8, 170.0, 192.0. Calcd for C10H13NO2S, C 56.85, H
6.20; found C 56.65, H 6.07.
4.3.3. N-[2-(2-Methyl-1H-indol-3-yl)ethyl]acetamide
(3c). Yellowish solid, 1.67 g, yield 77%, mp 83–85 8C. Rf
(EtOAc)Z0.4. IR, (n, cmK1): 1620 (O]CNH). 1H NMR d
1.88 (s, 3H), 2.36 (s, 3H), 2.90 (t, JZ6.7 Hz, 2H), 3.48 (dt,
JZ6.7, 6.2 Hz, 2H), 5.57 (bs, 1H), 7.06 (t, JZ7.3 Hz, 1H),
7.11 (t, JZ7.3 Hz, 1H), 7.26 (d, JZ7.3 Hz, 1H), 7.47 (d,
JZ7.3 Hz, 1H), 8.14 (bs, 1H). 13C NMR d 11.5, 23.3, 24.1,
40.0, 108.4, 110.3, 117.7, 119.3, 121.1, 128.6, 131.9, 135.3,
170.0. Calcd for C13H16N2O, C 72.19, H 7.46; found C
72.09, 7.13 H.
4.2.7. N-[4-(2-Furyl)-4-oxobutyl]acetamide (2g). Grey
crystal solid, 1.56 g, yield 80%, mp 66–68 8C. IR, (n, cmK1):
1640 (O]CNH), 1655 (furyl-C]O). H NMR d 1.91 (tt,
1
JZ7.0, 6.7 Hz, 2H), 1.92 (s, 3H), 2.87 (t, JZ7.0 Hz, 2H),
3.29 (dt, JZ6.7, 5.9 Hz, 2H), 6.07 (bs, 1H), 6.50 (dd, JZ
3.5, 1.8 Hz, 1H), 7.17 (dd, JZ3.5, 0.6 Hz, 1H), 7.55 (dd,
JZ1.8, 0.6 Hz, 1H). 13C NMR d 23.3, 23.7, 36.0, 39.3,
112.0, 146.5, 117.3, 152.5, 170.0, 189.0. Calcd for
C10H13NO3, C 61.53, H 6.71; found C 61.36, H 6.62.
4.3.4. N-{2-[2-(4-Methylphenyl)-1H-indol-3-yl]ethyl}
acetamide (3d). White crystal solid, 2.78 g, yield 95%,
mp 165–166 8C. Rf (EtOAc)Z0.5. IR, (n, cmK1): 1620
1
(O]CNH). IR, (n, cmK1): 1620 (O]CNH). H NMR d
4.2.8. N-(4-Oxooctyl)acetamide (2h). Brownish crystal
solid, 1.57 g, yield 85%, mp 65–67 8C. IR, (n, cmK1): 1640
(O]CN), 1695 (CH2C]O). 1H NMR d 0.84 (t, JZ7.3 Hz,
3H), 1.24 (dt, JZ7.6, 7.3 Hz, 2H), 1.48 (tt, JZ7.6, 7.3 Hz,
2H), 1.72 (tt, JZ7.0, 6.7 Hz, 2H), 1.91 (s, 3H), 2.35 (t, JZ
7.3 Hz, 2H), 2.42 (t, JZ7.0 Hz, 2H), 3.17 (dt, JZ6.7,
5.9 Hz, 2H), 6.16 (bs, 1H). 13C NMR d 13.7, 22.2, 23.1,
23.2, 25.8, 39.2, 40.0, 42.5, 170.3, 211.2. Calcd for
C10H19NO2, C 64.83, H 10.34; found C 64.56, H 10.20.
1.76 (s, 3H), 2.4 (s, 3H), 3.11 (t, JZ6.7 Hz, 2H), 3.54 (dt,
JZ6.7, 6.2 Hz, 2H), 5.44 (bs, 1H), 7.14 (t, JZ7.0 Hz, 1H),
7.21 (t, JZ7.0 Hz, 1H), 7.28 (d, JZ8.1 Hz, 2H), 7.38 (d,
JZ8.1 Hz, 1H), 7.44 (d, JZ8.1 Hz, 2H), 7.62 (d, JZ
8.1 Hz, 1H), 8.16 (bs, 1H). 13C NMR d 21.2, 23.2, 24.4,
40.2, 109.5, 110.9, 118.8, 119.8, 122.3, 127.8 (2C), 129.1,
129.7 (2C), 130.0, 135.4, 135.8, 137.9, 170.0. Calcd for
C19H20N2O, C 78.05, H 6.89; found C 78.01, H 6.89.
4.3.5.
N-{2-[2-(2,4-Dimethoxyphenyl)-1H-indol-3-
4.3. General procedure for the synthesis of N-acetyl-
indolylalkylamines
yl]ethyl}acetamide (3e). Yellowish crystal solid, 2.2 g,
yield 65%, mp 161–163 8C. Rf (EtOAc)Z0.5. IR, (n, cmK1):
1620 (O]CNH). 1H NMR d 1.76 (s, 3H), 3.0 (t, JZ6.4 Hz,
2H), 3.50 (dt, JZ6.4, 6.2 Hz, 2H), 3.82 (s, 3H), 3.85 (s, 3H),
5.52 (bs, 1H), 6.58–6.61 (m, 2H), 7.11 (t, JZ7.5 Hz, 1H),
Mixture of 11 mmol arylhydrazine (salt or free base),
10 mmol N-(4-oxo-4-substituted butyl)acetamide in 20 mL

V. G. Nenajdenko et al. / Tetrahedron 60 (2004) 11719–11724
11723
7.18 (t, JZ7.5 Hz, 1H), 7.37 (dd, JZ8.0, 5.0 Hz, 2H) 7.61
(d, JZ7.5 Hz, 1H), 8.47 (bs, 1H). 13C NMR d 23.1, 24.5,
39.7, 55.5, 55.6, 99.2, 104.9, 109.9, 110.7, 113.9, 118.5,
119.3, 121.9, 128.2, 132.0, 132.5, 135.6, 158.1, 161.0,
169.9. Calcd for C20H22N2O3, C 70.99, H 6.55; found C
70.81, H 6.57.
7.5 Hz, 2H), 7.52 (m, 1H), 7.57 (dd, JZ7.5, 1.5 Hz, 1H),
8.48 (bs, 1H). 13C NMR d 23.1, 24.4, 40.2, 109.6, 112.0,
118.3, 122.6, 125.5, 128.0 (2C), 128.2, 129.1 (2C), 130.2,
132.4, 134.2, 136.7, 170.1. Calcd for C18H17N2OCl, C
69.12, H 5.48; found C 68.82, H 5.35.
4.3.11. N-[2-(5-Bromo-2-phenyl-1H-indol-3-yl)ethyl]
acetamide (3k). Reddish crystal solid, 2.86 g, yield 80%,
mp 113–115 8C. Rf (EtOAc)Z0.4. IR, (n, cmK1): 1620
(O]CNH). 1H NMR d 1.76 (s, 3H), 3.03 (t, JZ6.7 Hz, 2H),
3.47 (dt, JZ6.7, 6.2 Hz, 2H), 5.55 (bs, 1H), 7.25 (m, 2H),
7.35 (d, JZ7.3 Hz, 1H), 7.43 (t, JZ7.3 Hz, 2H), 7.53 (d,
JZ7.3 Hz, 2H), 7.71 (s, 1H), 8.66 (bs, 1H). 13C NMR d
23.1, 24.4, 40.2, 109.4, 112.5, 112.9, 121.4, 125.1, 128.0
(2CH), 128.15, 129.0 (2CH), 130.8, 132.4, 135.4, 136.6,
170.3. Calcd for C18H17BrN2O, C 60.52, H 4.80; found C
61.07, H 4.76.
4.3.6. N-{2-[2-(2-Thienyl)-1H-indol-3-yl]ethyl}acetamide
(3f). Cream crystal solid, 1.88 g, yield 66%, mp 113–
116 8C. Rf (EtOAc)Z0.55. IR, (n, cmK1): 1620 (O]CNH).
1H NMR d 1.81 (s, 3H), 3.17 (t, JZ6.5 Hz, 2H), 3.51 (q, JZ
6.5 Hz, 2H), 5.57 (bs, 1H), 7.12 (m, 2H), 7.21 (t, JZ7.0 Hz,
1H), 7.29 (d, JZ4.3 Hz, 1H), 7.33 (d, JZ4.3 Hz, 1H), 7.36
(d, JZ8.1 Hz, 1H), 7.58 (d, JZ8.1 Hz, 1H), 8.45 (bs, 1H).
13C NMR d 23.2, 24.7, 39.9, 110.5, 110.9, 118.8, 120.0,
122.9, 124.9, 125.3, 127.8, 129.1, 129.2, 134.4, 135.9 170.3.
Calcd for C16H16N2OS, C 67.58, H 5.67; found C 67.71, H
5.71.
4.3.12. N-[2-(7-Ethyl-2-phenyl-1H-indol-3-yl)ethyl]acet-
amide (3m). Brown crystal solid, 2.57 g, yield 84%, mp
147–149 8C. Rf (EtOAc)Z0.5. IR, (n, cmK1): 1620
4.3.7. N-[2-(2-Butyl-1H-indol-3-yl)ethyl]acetamide (3h).
Yellowish oil, 0.78 g, yield 30%. Rf (EtOAc)Z0.7. IR, (n,
1
1
cmK1): 1620 (O]CNH). H NMR d 0.94 (t, JZ7.3 Hz,
(O]CNH). H NMR d 1.39 (t, JZ7.6 Hz, 3H), 1.74 (s,
3H), 1.39 (m, 2H), 1.64 (m, 2H), 1.89 (s, 3H), 2.72 (t, JZ
7.6 Hz, 2H), 2.91 (t, JZ6.7 Hz, 2H), 3.51 (dt, JZ6.7,
6.2 Hz, 2H), 5.54 (bs, 1H), 7.07 (td, JZ7.0, 1.2 Hz, 1H),
7.13 (td, JZ7.0, 1.2 Hz, 1H), 7.28 (dd, JZ7.0, 1.2 Hz, 1H),
7.5 (dd, JZ7.0, 1.2 Hz, 1H), 8.02 (bs, 1H). 13C NMR d 14.3,
22.3, 23.2, 24.2, 26.3, 30.4, 38.6, 110.6, 111.5, 118.2, 118.5,
120.6, 128.5, 134.5, 135.3, 171.2. Calcd for C16H22N2O, C
74.38, H 8.58; found C 74.28, H 8.47.
3H), 2.91 (q, JZ7.6 Hz, 2H), 3.10 (t, JZ6.7 Hz, 2H), 3.53
(dt, JZ6.7, 6.2 Hz, 2H), 5.52 (bs, 1H), 7.08–7.14 (m, 2H),
7.37 (m, 1H), 7.44–4.51 (m, 3H), 7.58 (m, 2H), 8.27 (bs,
1H). 13C NMR d 13.8, 23.1, 24.0, 24.5, 40.1, 110.3, 116.6,
120.2, 121.0, 126.5, 127.8, 128.1 (2C), 128.7, 129.0 (2C),
133.1, 134.7, 135.1, 170.0. Calcd for C20H22N2O, C 78.40,
H 7.24; found C 78.23, H 7.12.
4.4. Synthesis of N-[2-(5-methoxy-2-phenyl-1H-indol-3-
yl)ethyl]acetamide (3l)
4.3.8. N-[3-(3-Propyl-1H-indol-2-yl)propyl]acetamide
(4h). White solid, 1.55 g, yield 60%, mp 120 8C. Rf
1
(EtOAc)Z0.4. IR, (n, cmK1): 1620 (O]CNH). H NMR
Mixture of 502 mg of 4-methoxyphenylhydrazine oxalate
(2.2 mmol) and 411 mg of N-(4-oxo-4-phenylbutyl)aceta-
mide (2a) (2 mmol) was refluxed in 20 mL of EtOH for
20 min. After evaporation the residue was refluxed in 15 mL
of glacial AcOH for 10 min. Then reaction mixture was
evaporated and distributed between water and CH2Cl2.
Organic phase was washed with water (2!20 mL) and
evaporated. The flash chromatography of the residue
afforded the product as amorphous solid, 0.52 g, yield
85%. Rf (EtOAc)Z0.4. All spectral data of the compound is
identical to the literature.29
d 0.96 (t, JZ7 Hz, 3H), 1.64 (m, 2H), 1.78 (m, 2H), 1.98 (s,
3H), 2.66 (t, JZ6.5 Hz, 2H), 2.72 (m, 2H), 3.32 (dt, JZ6.5,
6.2 Hz, 2H), 5.95 (bs, 1H), 7.02–7.15 (m, 2H), 7.32 (d, JZ
7.9 Hz, 1H), 7.51 (d, JZ7.9 Hz, 1H), 9.35 (bs, 1H). 13C
NMR d 14.2, 19.5, 23.0, 23.5, 27.6.2, 30.3, 41.2, 111.5,
114.4, 118.7, 119.2, 120.6, 130.8, 132.6, 135.2, 171.5. Calcd
for C16H22N2O, C 74.38, H 8.58; found C 74.33, H 8.45.
4.3.9. N-[2-(5-Fluoro-2-phenyl-1H-indol-3-yl)ethyl]acet-
amide (3i). Yellow crystals, 1.90 g, yield 64%, mp 147–
149 8C. Rf (EtOAc)Z0.62. IR, (n, cmK1): 1620 (O]CNH).
1H NMR d 1.71 (s, 3H), 3.06 (t, JZ6.7 Hz, 2H), 3.49 (dt,
JZ6.7 Hz, 2H), 5.48 (bs, 1H), 6.94 (td, JZ8.7, 2.5 Hz, 1H),
7.24–7.30 (m, 2H), 7.37 (t, JZ7.3 Hz, 1H), 7.46 (t, JZ
7.3 Hz, 2H), 7.55 (d, JZ7.3 Hz, 2H), 8.22 (bs, 1H). 13C
NMR (DMSO-d6) d 22.6, 25.0, 40.1, 103.2 (d, JZ23.4 Hz),
109.3 (d, JZ4.4 Hz), 109.6 (d, JZ26.4 Hz), 112.12 (d, JZ
10.2 Hz), 127.6, 127.8 (2C), 128.7 (2C), 129.1 (d, JZ
10.3 Hz), 132.5, 132.6, 136.6, 156.9 (d, JZ231.3 Hz),
169.2. Calcd for C18H17N2OF, C 72.95, H 5.78; found C
72.79, H 5.73.
4.5. Synthesis of N-{2-[2-(2-furyl)-1H-indol-3-yl]ethyl}
acetamide (3g)
Mixture of 380 mg 4-oxo-4-furylbutyl-N-acetamide (2g)
(2 mmol), 216 mg (2 mmol) phenylhydrazine and 2.4 g
(6 mmol) ethyl ester of polyphosphoric acid was warmed on
the water bath at 85 8C for 1 h. Then reaction mixture was
evaporated and distributed between water and CH2Cl2.
Organic phase was washed with water (2!20 mL) and
evaporated. The flash chromatography of the residue
afforded the product as yellowish oil, 0.23 g, yield 43%.
Rf (EtOAc)Z0.55. IR, (n, cmK1): 1620 (O]CNH). 1H
NMR d 1.82 (s, 3H), 3.17 (t, JZ6.7 Hz, 2H), 3.55 (dt, JZ
6.7, 6.5 Hz, 2H), 5.80 (bs, 1H), 6.48 (dd, JZ3.2, 1.8 Hz,
1H), 6.75 (d, JZ3.2 Hz 1H), 7.09 (t, JZ7.0 Hz, 1H), 7.18 (t,
JZ7.0 Hz, 1H), 7.35 (d, JZ8.1 Hz, 1H), 7.44 (d, JZ
1.8 Hz, 1H), 7.55 (d, JZ8.1 Hz, 1H), 9.0 (bs, 1H). 13C NMR
d 23.2, 24.5, 39.7, 106.5, 109.4, 110.9, 111.9, 118.5, 119.7,
4.3.10. N-[2-(5-Chloro-2-phenyl-1H-indol-3-yl)ethyl]
acetamide (3j). Brownish cubic crystals, 2.72 g, yield
87%, mp 147–149 8C. Rf (EtOAc)Z0.4. IR, (n, cmK1):
1
1620 (O]CNH). H NMR d 1.76 (s, 3H), 3.05 (t, JZ
6.7 Hz, 2H), 3.48 (dt, JZ6.7, 6.2 Hz, 2H), 5.50 (bs, 1H),
7.14 (dd, JZ8.5, 1.5 Hz, 1H), 7.28 (d, JZ8.5 Hz, 1H), 7.36
(t, JZ7.5 Hz, 1H), 7.44 (t, JZ7.5 Hz, 2H), 7.35 (t, JZ

11724
V. G. Nenajdenko et al. / Tetrahedron 60 (2004) 11719–11724
10. Gorohovsky, S.; Meir, S.; Shkoulev, V.; Byk, G.; Gellerman,
G. Synlett 2003, 10, 1411.
122.6, 126.2, 128.8, 137.8, 141.5, 147.4, 170.4. Calcd for
C16H16N2O2, C 71.62, H 6.01; found C 71.35, H 6.07.
11. Jandu, K. S.; Barret, V.; Brockwell, M.; Cambridge, D.;
Farrant, D. R.; Foster, C.; Giles, H.; Glen, R.; Hill, A. P.;
Hobbs, H.; Honey, A.; Martin, G. R.; Salmon, J.; Smith, D.;
Woolard, P.; Sekwood, D. L. J. Med. Chem. 2001, 44, 681.
12. (a) Brennan, J. P.; Saxton, J. E. Tetrahedron 1987, 43(1), 191.
(b) Glennon, R. A.; Hong, S. S.; Bondarev, M.; Law, H.;
Dukat, M.; Rakhit, S.; Power, P.; Fan, E.; Kinneau, D.;
Kamboj, R.; Teiler, M.; Herrick-Davis, K.; Smith, C. J. Med.
Chem. 1996, 39, 314. (c) Barf, T.; Wikstrom, H.; Pauwels,
P. J.; Palmier, C.; Tardif, S.; Lundmark, M.; Sundell, S.
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