Mild and regioselective straightforward synthesis of isomelatonin analogues

Article abstract of DOI:10.1070/MC2006v016n04ABEH002280

A mild and regioselective strategy for 3-arylisomelatonins, compounds with prominent potential use as ligands for melatonin receptors, is developed.

Full text of DOI:10.1070/MC2006v016n04ABEH002280

Mendeleev Commun., 2006, 16(4), 213–215
Mild and regioselective straightforward synthesis of isomelatonin analogues
Eugene P. Zakurdaev, Elizabeth S. Balenkova and Valentine G. Nenajdenko*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
DOI: 10.1070/MC2006v016n04ABEH002280
A mild and regioselective strategy for 3-arylisomelatonins, compounds with prominent potential use as ligands for melatonin
receptors, is developed.
Melatonin I (N-acetyl-5-methoxytryptamine, Scheme 1) is secreted
i, Py/CH Cl ,
2
2
by the pineal gland in brain and is important in the regulation of
many hormonal processes in the body. In addition to its hormone
actions, melatonin also possesses strong antioxidant properties;
preliminary evidence that it may strengthen the immune system
room temperature
ii, H3O+
n
R
N
+
Cl–
N
O
1
1a–i
is obtained. The pharmacological effects of melatonin in humans
O
have also been investigated in psychiatric disorders and in the
a R = Ph
b R = 2-MeC H
2
cardiovascular system. The molecular mechanisms underlying
R
n
N
6
4
3
4
5
H
the reported antioxidant, neuroprotective, anticarcinogenic and
c R = 2-MeOC H
6
4
O
6
d R = 3-MeC H
immunostimulatory properties of melatonin are under thorough
6
4
e R = 4-FC H
2a n = 1, 84% 2f n = 1, 79%
2b n = 1, 89% 2g n = 2, 78%
2c n = 2, 75% 2h n = 2, 86%
investigation.
6 4
f R = 4-ClC H
6
4
Melatonin is a derivative of indolylalkylamines (tryptamines),
which have importance as the main structural unit of indole
alkaloids, many biologically active substances and remedies.7
Recently, derivatives of tryptamines have attracted a lot of
g R = 4-MeC H
6
4
h R = 4-MeOC H
i R = cyclohexyl
2d n = 2, 91%
2e n = 2, 81%
2i n = 2, 75%
6
4
Scheme 3
8
attention because of their high selectivity for serotonin, mela-
9
10
tonin and gonadotropin releasing hormone receptors.
Here, we describe an effective and facile straightforward route
to isomelatonin derivatives. We proposed that benzyl (ω-amido-
alkyl) ketones should give rise regioselectively to 3-aryl-2-
NHAc
(
ω-amidoalkyl)indoles during the Fischer reaction with aryl-
MeO
MeO
NHAc
hydrazines, due to the more favourable conjugation of the ene
bond of an intermediate enehydrazine with the aromatic core
n
(
Scheme 2).
N
N
n = 1–3
Recently, we developed a new general method13 for the syn-
H
H
thesis of amidoketones from cyclic imines such as 1a–i using
N-acetylpyridinium chloride. Amidoketones 2a–i were obtained
in high yields (Scheme 3).†
I
II
Scheme 1
Derivatives of relative 2-indolylalkylamides II are investigated
more feebly, mainly due to the absence of facile methods for
their preparation.
The known procedures for the preparation of 3-arylindoles
1
4
from benzylketones involve various catalysts such as AcOH,
1
5
16
17
18
19
HCl in H O or EtOH, H SO , ZnCl , TsOH in AcOH,
2
2
4
2
2
0
21
A new series of partial agonists and antagonists of melatonin I
were discovered by transposing the amidoalkyl side chain from
C to C of the indole nucleus (Scheme 1, structures II, deriva-
montmorillonite clay, PCl /benzene, mordenite or zeolite Y
3
2
2
23
24
in xylene, CCl COOH, polyphosphoric acid and BF ·Et O
3
3
2
in AcOH.25 However, to the best of our knowledge, examples of
3
2
11
tives of isomelatonin). Only two approaches to N-acyl-2-indolyl-
alkylamines are described, i.e., the acylation of preliminary
prepared isotryptamines and the decarboxylation of α-acetyl-
aminoindol-2-yl acetic acid.12 Both methods are lacking of
structural diversity of the target molecules.
†
1H and 13C NMR spectra were recorded at 400 and 100 MHz, respec-
11
tively; TMS was used as an internal standard. IR spectra were recorded
in Nujol. TLC was performed with Silufol UV-254 plates, and flash
chromatography was carried out with silica gel (63–200 mesh) using
EtOAc as an eluent.
The two-component Fischer reaction seems to be satisfactory
of diversity requirements. Note that acylamino groups remain
intact during this reaction.
General procedure for the synthesis of amidoketones 2a–i. To a well
stirred solution of 1.6 ml (20 mmol) of pyridine in 20 ml of abs. CH Cl
2
2
2
a solution of 0.71 ml (0.8 g, 10 mmol) of AcCl in 10 ml of abs. CH Cl
2
was added for 30 min, and the mixture was stirred for additional 15 min.
To a suspension of N-acetylpyridinium chloride an obtained solution
of 10 mmol of cyclic imine 1a–i in 25 ml of abs. CH Cl was added
dropwise with stirring. After addition, the reaction mixture was stirred
until N-acetylpyridinium salt was dissolved totally and then for 3 h.
To a clear solution obtained 20 ml of 5% HCl was added and stirred
overnight; then, the organic layer was separated, washed with water
R
Ar
NHAc
2
2
+
NH2
N
H
O
n
n = 1, 2
(
2×10 ml), dried with Na SO and evaporated. Amidoketone 2a was
2 4
R
R
subjected to flash chromatography (hexane–EtOAc, 1:1), and amido-
ketones 2b–i were used in the next step without isolation.
NHAc
Ar
NHAc
n
All compounds obtained were reliably characterised by their 1H,
C NMR and IR spectra and satisfactory elemental analyses.
Ar
1
3
N
N
N
N
n
H
H
H
H
N-(4-Oxo-5-phenylpentyl)acetamide 2a: yellowish crystal solid, yield
–
1
8
6%, mp 43–44 °C. IR (n/cm ): 1640 (O=CNH), 1700 (PhCH C=O).
2
NHAc
1
H NMR (CDCl ) d: 1.72 (q, 2H, CH CH CH NHCOMe, J 6.7 Hz),
3
2
2
2
Ar
R
1.87 (s, 3H, COMe), 2.50 (t, 2H, CH CH CH NHCOMe, J 6.7 Hz),
2 2 2
3
.14 (q, 2H, CH CH CH NHCOMe, J 6.7 Hz), 3.67 (s, 2H, PhCH ),
2 2 2 2
n
5.80 (br. s, 1H, NHCOMe), 7.18 (d, 2H, J 7.0 Hz), 7.25 (tt, 1H, J 7.3 and
1
3
N
7.0 Hz), 7.31 (t, 2H, J 7.3 Hz). C NMR (CDCl3) d: 23.1, 23.2, 38.9,
9.2, 50.1, 127.0, 128.7 (2C), 129.3 (2C), 134.0, 170.2, 208.2. Found
(%): C, 71.29; H, 7.81. Calc. for C H NO (%): C, 71.21; H, 7.81.
3
H
Scheme 2
1
3
17
2
Mendeleev Commun. 2006 213

Mendeleev Commun., 2006, 16(4), 213–215
NHAc
Ar
NHAc
+
R
n
NH2
HCl /AcOH
reflux
N
O
n
+
R
H · HCl
NH2
2
a–h
NHAc
N
H
O
R'
Ar
2
a R' = H, n = 1
b R' = Me, n = 2
R = H, Me
2
n
EtOH
reflux
NHAc
R'
N
R
NHAc
+
n
R'
H
R
R
3a Ar = Ph, R = H, n = 1, 77%
n
3
3
3
3
3
3
3
3
3
3
3
b Ar = 2-MeC H , R = H, n = 1, 78%
6 4
N
N
c Ar = 2-MeOC H , R = H, n = 2, 68%
6
4
d Ar = 3-MeC H , R = H, n = 2, 49% (in HCl/AcOH)
H
H
6 4
e Ar = 4-FC H , R = H, n = 2, 66%
Ar = 4-ClC H , R = H, n = 1, 77%
6
4
3
d,m
4a,b
f
6 4
g Ar = 4-MeC H , R = H, n = 2, 81%
3
3
m + 4a R = Me, R' = H, n = 1, 17:1
d + 4b R = H, R' = Me, n = 2, 10:1
6 4
h Ar = 4-MeOC H , R = H, n = 2, 71%
6 4
i
j
Ar = Ph, R = 5-F, n = 1, 87%
Scheme 4
Ar = Ph, R = 5-Cl, n = 1, 83%
k Ar = Ph, R = 5-Br, n = 1, 90%
regioselective synthesis of 3-arylindoles from ArCH COCH R
2
2
n = 1, 87%
l
Ar = Ph, R = 5-I,
ketones are missing.
3
m Ar = Ph, R = 5-Me, n = 1, 84% (68% in HCl/AcOH)
In our experiments, we tested a solution of dry HCl in AcOH13
as the catalyst of the Fischer reaction; however, a mixture of
regioisomers 3 (3-arylisomelatonins, ~50–70%) and 4 (2-benzyl-
3n Ar = Ph, R = 5-MeO, n = 1, 93% (in arylhydrazine oxalate)
3o Ar = Ph, R = 5-CN, n = 1, 32%
3
3
p Ar = Ph, R = 4-Br and 6-Br (1:1), n = 1, 72%
q Ar = Ph, R = 7-CF , n = 1, 55%
3
melatonins, ~5%) was obtained especially in the case of amido-
ketones with donor substituents (Scheme 4).‡
Scheme 5
We found that the yields of 2-arylmethylmelatonins increased
with the acidity of catalysts used. Therefore, we reasoned that
milder conditions of the reaction may improve its regioselectivity.
Ph NHAc
+
H2N
NH2
N
N
O
In fact, target isomelatonin analogues 3a–q were prepared regio-
H · HCl
H · HCl
selectively in high yields (Scheme 5).§
2a
Thus, conjugation of the ene bond of enehydrazine with the
aromatic core is an effective decisive factor for regioselective
indolization.
AcHN
NHAc
Ph
Ph
EtOH
reflux
To investigate the scope of the method and the effect of
substituents on the yield of the Fischer reaction, various aryl-
hydrazines with electron donor and acceptor groups were syn-
N
N
H
H
26
thesised. In all cases, N-acetylindolylalkylamines were isolated
3
r
in good to high yields, only arylhydrazines with strong electron-
Scheme 6
withdrawing substituents (4-CN and 2-CF ) furnish indoles in
3
moderate yields. Generally, no serious restriction in the struc-
tures of hydrazine or ketone components was found. Bis(4,4'-
arylhydrazine) gave a 5,5'-methylene-linked derivative of iso-
melatonin 3r in 73% yield (Scheme 6).
To compare the influence of steric and electronic factors on
the regioselectivity of this method, we tested amidoketone 2i,
which mimics the structure of 2a except aromaticity. This
experiment gave 3-(ω-amidoalkyl)substituted melatonin deriva-
tive 4c, that is replacement of the phenyl ring by cyclohexyl
§
General procedure for the synthesis of N-acetylindolylalkylamines
3
a–c,e–r and 4c. A mixture of 1.2 mmol of arylhydrazine hydrochloride
and 1 mmol of amidoketones 2a–h [2 mmol of amidoketone 2a in the
case of bis(4,4'-arylhydrazine)] in 15 ml of EtOH were refluxed until
the end of the reaction (10–24 h; TLC control; eluent, EtOAc). Then, the
reaction mixture was evaporated and distributed between water (10 ml)
and EtOAc (20 ml). The organic phase was washed with water (2×5 ml)
and evaporated. The flash chromatography of the residue afforded the
products.
‡
General procedure for the synthesis of N-acetylindolylalkylamines
4
a,b and 3m,d. A mixture of 1.1 mmol of arylhydrazine hydrochloride,
1.0 mmol of corresponding amidoketones in 15 ml of acetic acid, saturated
preliminarily with gaseous HCl at 20 °C, was quickly warmed to boiling.
When all solids were dissolved refluxing was continued for 15 min. Then,
the reaction mixture was evaporated and distributed between water
and CH Cl . The organic phase was washed with water (2×10 ml) and
N-[3-(5-Methoxy-3-phenyl-1H-indol-2-yl)propyl]acetamide 3n: cream
2
2
–
1
evaporated. The flash chromatography of the residue afforded the products.
crystals, 299 mg, yield 93%, mp 144–145 °C. R (EtOAc) 0.22. IR (n/cm ):
f
1
N-[3-(2-Benzyl-5-methyl-1H-indol-3-yl)ethyl]acetamide 4a: reddish
1100–1150 (C–O–C), 1655 (O=C), 3405 (NHAc). H NMR (CDCl ) d:
3
–
1
amorphous solid, 13 mg, yield 4%. R (EtOAc) 0.58. IR (n/cm ): 1660
1.76–1.82 (m, 2H, CH CH CH NHCOMe), 1.93 (s, 3H, NHCOMe),
f
2
2
2
1
(
O=C), 3400 (NHAc). H NMR (CDCl ) d: 1.76 (s, 3H, COMe), 2.44 (s,
2.83 (t, 2H, CH CH CH NHCOMe, J 6.5 Hz), 3.26–3.30 (m, 2H,
3
2 2 2
3
H, 5-Me), 2.95 (t, 2H, CH CH NHCOMe, J 6.6 Hz), 3.50 (dt, 2H,
CH CH CH NHCOMe), 3.84 (s, 3H, 5-MeO), 5.68 (br. s, 1H, NHCOMe),
2 2 2
2
2
CH CH NHCOMe, J 6.6 and 6.2 Hz), 4.08 (s, 2H, PhCH ), 5.48 (br. s,
1
1
1
6.87 (dd, 1H, J 8.8 and 2.4 Hz), 7.14 (d, 1H, J 2.4 Hz), 7.28–7.52 (m,
2
2
2
1
3
H, NHCOMe), 6.96 (d, 1H, J 7.6 Hz), 7.12–7.45 (m, 7H), 7.84 (br. s,
6H), 9.75 (br. s, 1H). C NMR (CDCl ) d: 21.2, 23.1, 30.0, 38.4, 56.1,
3
1
3
H). C NMR (CDCl ) d: 21.45, 23.1, 24.1, 32.1, 40.0, 108.8, 110.3,
101.4, 111.4, 111.8, 114.1, 126.0, 128.2, 128.8 (2C), 129.5 (2C), 130.8,
135.8, 136.4, 154.3, 171.4. Found (%): C, 74.41; H, 6.93. Calc. for
C H N O (%): C, 74.51; H, 6.88.
3
17.9, 123.0, 126.7, 128.4 (2C), 128.5, 128.7, 128.8 (2C), 133.9, 134.3,
38.8, 170.1. Found (%): C, 78.57; H, 7.40. Calc. for C H N O (%):
1
20
22
2
20 22
2
2
C, 78.40; H, 7.24.
N-[3-(5-Methyl-3-phenyl-1H-indol-2-yl)propyl]acetamide 3m: brownish
N-{4-[2-(Cyclohexylmethyl)-1H-indol-3-yl]propyl}acetamide 4c: brownish
–1
yellow amorphous solid, 147 mg, yield 47%. R (EtOAc) 0.49. IR (n/cm ):
f
–1
1
crystals, 257 mg, yield 84%, mp 136–137 °C. R (EtOAc) 0.20. IR (n/cm ):
1660 (O=C), 3400 (NHAc). H NMR (CDCl ) d: 0.96–1.93 (m, 16H,
f
3
1
660 (O=C), 3405 (NHAc). 1H NMR (CDCl ) d: 1.76–1.82 (m, 2H,
cyclohexyl, NHCOMe, CH CH CH NHCOMe), 2.59 (d, 2H, cyclo-
3
2
2
2
CH CH CH NHCOMe), 1.92 (s, 3H, NHCOMe), 2.47 (s, 3H, 5-Me),
hexyl-CH , J 7.2 Hz), 2.75 (t, 2H, CH CH CH NHCOMe, J 7.4 Hz),
3.29 (m, 2H, CH CH CH NHCOMe), 5.62 (br. s, 1H, NHCOMe), 7.07–
2 2 2
2
2
2
2 2 2 2
2
.84 (t, 2H, CH CH CH NHCOMe, J 6.5 Hz), 3.24–3.29 (m, 2H,
2
2
2
CH CH CH NHCOMe), 5.62 (br. s, 1H, NHCOMe), 7.04 (d, 1H, J 8.2 Hz),
7.14 (m, 2H), 7.29 (d, 1H, J 7.6 Hz), 7.51 (d, 1H, J 7.4 Hz), 8.04 (br. s,
2
2
2
13
13
7
2
1
.28–7.54 (m, 7H), 9.70 (br. s, 1H). C NMR (CDCl ) d: 21.6, 22.4,
3.2, 30.1, 38.3, 110.7, 113.9, 118.4, 123.1, 125.9, 128.0, 128.7 (2C),
28.9, 129.7 (2C), 133.8, 135.3, 135.9, 171.3. Found (%): C, 78.31;
1H). C NMR (CDCl ) d: 21.8, 23.2, 26.2 (2C), 26.3, 30.4, 33.4 (2C),
3
3
34.0, 38.8, 39.8, 110.4, 111.3, 118.0, 119.0, 120.9, 128.3, 134.6, 135.4,
170.2. Found (%): C, 76.75; H, 9.09. Calc. for C H N O (%): C, 76.88;
2
0
28
2
H, 7.13. Calc. for C H N O (%): C, 78.40; H, 7.24.
H, 9.03.
2
0
22
2
2
14 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(4), 213–215
6
7
8
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D. K. H. Lee, J. Med. Chem., 2000, 43, 1011.
N
N
H
NHAc
H
NHAc
9
M. Mor, G. Spadoni, B. D. Giacomo, G. Diamantini, A. Bedini, G. Tarzia,
P. V. Plazzi, S. Rivara, R. Nonno, V. Lucini, M. Pannacci, F. Fraschini
and B. M. Stankov, Bioorg. Med. Chem., 2001, 9, 1045.
N
H
N
H
EtOH
reflux
NHAc
10 T. F. Walsh, R. B. Toupence, F. Ujjainwalla, J. R. Young and M. T.
NHAc
Goulet, Tetrahedron, 2001, 57, 5233.
1
1 G. Spadoni, C. Balsamini, A. Bedini, G. Diamantini, B. Di Giacomo,
A. Tontini, G. Tarzia, M. Mor, P. V. Plazzi, S. Rivara, R. Nonno,
M. Pannacci, V. Lucini, F. Fraschini and B. Stankov, J. Med. Chem.,
n
+
NH2
1
998, 41, 3624.
N
O
N
H · HCl
12 V. I. Shvedov, G. N. Kurilo, A. A. Cherkasova and A. N. Grinev, Khim.
Geterotsikl. Soedin., 1973, 1040 [Chem. Heterocycl. Compd. (Engl.
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28, 321.
2
i
H
4
c, 47%
Scheme 7
proved that the above mentioned conjugation is crucial for the
direction of reaction (Scheme 7).
Due to mild reaction conditions, only the enehydrazine with
less steric hindrance around the ene bond undergoes hetero-
cyclisation. The formation of alternative regioisomer was not
detected.
In summary, we have developed a new general strategy for
the synthesis of 3-arylisomelatonins, compounds with prominent
potential use as ligands for melatonin receptors. The method
developed is a mild and regioselective and allows us to easily
vary both ketone and arylhydrazine components.
1
1
1
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Received: 21st November 2005; Com. 05/2622
Mendeleev Commun. 2006 215