Synthesis of ethyl 3-amino-5-arylthiophene-2-carboxylates based on α-chlorocinnamonitriles

Article abstract of DOI:10.1134/S1070428002120138

A new procedure was developed for preparation of ethyl 3-amino-5- arylthiophene-2-carboxylates by the reaction of α-chlorocinnamonitriles and their analogs with ethyl mercaptoacetate for a wide range of substrates. The reaction products form in high yield

Full text of DOI:10.1134/S1070428002120138

ISSN 1070-4280 Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 2, pp. 238-240. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó A.V. Shastin, I.V. Golubinskii, O.N. Lenkova, E.S. Balenkova, V.G. Nenaidenko, 2006, published in Zhurnal Organicheskoi
Khimii, 2006, Vol. 42, no. 2, pp. 254-256.
Synthesis of Ethyl 3-Amino-5-arylthiophene-2-carboxylates
Based on a-Chlorocinnamonitriles
1
2
2
A.V. Shastin , I.V. Golubinskii , O.N. Lenkova ,
2
2
E.S. Balenkova , and V.G. Nenaidenko
1
Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, Russia
2
Moscow State University, Moscow, 119992 Russia
e-mail: nen@acylium.chem.msu.ru
Received October 18, 2004
Abstract—A new procedure was developed for preparation of ethyl 3-amino-5-arylthiophene-2-carboxylates by
the reaction of a-chlorocinnamonitriles and their analogs with ethyl mercaptoacetate for a wide range of substrates.
The reaction products form in high yields.
DOI: 10.1134/S1070428002120138
A combination of carboxy and amino groups at the
thiophene ring of the 3-amino-5-arylthiophenecarboxylic
acids opens wide synthetic opportunities for further
modification. Based on their derivatives quite a number
of biologically active substances were obtained [1–4].
We investigated the possibility to obtain ethyl 3-amino-
5-arylthiophene-2-carboxylates with various aryl sub-
stituents by a reaction of a-chlorocinnamonitriles with
ethyl mercaptoacetate.
We formerly demonstrated that the initial nitriles were
easily prepared by catalytic olefination of aromatic
aldehydes hydrazones with trichloroacetonitrile in the
presence of catalytic quantity of copper(I) chloride [8].
These compounds were formerly synthesized by reac-
tions of b-chlorocinnamonitriles and also of b-aroylacrylo-
nitriles with esters of the mercaptoacetic acid [5, 6].
Besides a single example was published of a reaction
between a-chlorocinnamonitrile with ethyl mercapto-
acetate in the presence of sodium ethylate resulting
in the corresponding thiophene derivative in a 75%
yield [7].
We followed the known preparation method of esters
of aminothiophenecarboxylic acids [7]. In the published
procedure the reaction with ethyl mercaptoacetate was
carried out in the presence of a triple excess of sodium
ethylate. We showed that at the use of a freshly prepared
sodium ethylate in a 20% excess the reaction occurred
within 10 min and furnished the target product in a high
yield. The reaction of the ethyl mercaptoacetate with
nitriles under study proceeded regioselectively and
afforded a single isomer of the corresponding ethyl
aminothiophenecarboxylate (see the scheme) as proved
by NMR, IR spectra, and comparison with the published
data.
Scheme.
ꢀ
ꢁꢂꢃ1 + ꢃꢃ+ 2
ꢀꢄꢂꢃ&&O &1ꢅꢃ&X&O
&1
$U
2
$U
&
ꢀꢀꢀ,K
O
B
,
&
22(W
ꢃ
(
+
6&+ &22(Wꢅ
Hence we prepared a series of ethyl 3-amino-5-aryl-
thiophene-2-carboxylates and demonstrated that the reac-
tion of a-chlorocinnamonitriles with the ethyl mercapto-
acetate is of a general character, and it was easy to obtain
the corresponding substituted thiophenes from substrates
containing both donor and acceptor substituents, and also
heterocyclic and polyaromatic fragments.
W21D (W2+
6
1+
$U
B
,
, ꢀꢀꢀ,,K
Ar = 4-ClC H (a), 4-MeOC H (b), 4-NMe C H (c),
6
4
6
4
2
6
4
4
-NO C H (d), 2-naphthyl (e), 1-naphthyl (f), 2-thienyl
2 6 4
(
g), 4-MeC H (h).
6 4
238

SYNTHESIS OF ETHYL 3-AMINO-5-ARYLTHIOPHENE-2-CARBOXYLATES
239
EXPERIMENTAL
Ethyl 3-amino-5-(2-naphthyl)thiophene-2-
carboxylate (IIe). Yield 58%, yellow crystals, mp 90–
IR spectra were recorded on a spectrophotometer
UR-20 from mulls in mineral oil. H and C NMR spectra
were registered on a spectrometer Varian VXR-400
–
1
9
2°C. IR spectrum, n, cm : 3430, 3340 (NH ), 1660
2
1
13
1
(
CO). H NMR spectrum, d, ppm: 1.26 t (3H, J 7.2 Hz),
4
.23 q (2H, J 7.2 Hz), 6.63 br.s (2H, NH ), 6.85 s
2
(
operating frequencies 400 and 100 MHz respectively)
(
8
1Hthiophene), 7.62–7.53 m (4Harom), 8.02–7.98 m (2Harom),
from solutions in DMSO-d , internal reference TMS.
6
13
.18–8.14 m (1Harom).
C NMR spectrum, d, ppm:
TLC was performed on Merck 60 F254 plates.
1
1
5
63.56, 154.85, 145.74, 133.40, 131.06, 130.39, 129.21,
28.50, 127.46, 127.00, 126.33, 125.38, 124.62, 120.74,
9.42, 14.45. Found, %: C 68.33; H 5.22. C H N O S.
Ethyl 3-amino-5-arylthiophene-2-carboxylates
IIa–IIh. In 3 ml of ethanol was dissolved 0.083 g
3.6 mmol) of Na. To the obtained solution of sodium
1
7
15
2
2
(
Calculated, %: C 68.66; H 5.08.
ethylate was added at stirring 0.43 g (3.6 mmol) of ethyl
mercaptoacetate. Then at stirring to this mixture was
added dropwise within 2 min a solution of 2.8 mmol of
a-chlorocinnamonitrile in 2 ml of ethanol. The mixture
was stirred for another 30 min where the precipitate
formation was observed. The reaction mixture was
quenched with 30 ml of water, the reaction product was
filtered off and recrystallized from ethanol.
Ethyl 3-amino-5-(1-naphthyl)thiophene-2-
carboxylate (IIf). Yield 56%, yellow crystals, mp 124–
–
1
1
(
4
(
27°C. IR spectrum, n, cm : 3420, 3330 (NH ), 1670
2
1
CO). H NMR spectrum, d, ppm: 1.27 t (3H, J 7.2 Hz),
.22 q (2H, J 7.2 Hz), 6.60 br.s (2H, NH ), 7.12 s
2
1Hthiophene), 7.56–7.51 m (2Harom), 7.77–7.74 m (1Harom),
1
3
8
.01–7.91 m (3Harom), 8.22 s (1Harom).
C NMR
spectrum, d, ppm: 163.58, 155.49, 147.37, 132.95, 132.91,
30.18, 128.71, 128.23, 127.55, 126.81, 126.72, 124.36,
23.40, 116.53, 59.44, 14.44. Found, %: C 68.95; H 5.16.
Ethyl 3-amino-5-(4-chlorophenyl)thiophene-2-
1
1
carboxylate (IIa). Yield 72%, yellow crystals, mp 106–
1
07°C [5]. 1H NMR spectrum, d, ppm: 1.25 t (3H,
C H N O S. Calculated, %: C 68.66; H 5.08.
1
7
15
2
2
J 7.2 Hz), 4.20 q (2H, J 7.2 Hz), 6.57 br.s (2H, NH2),
.98 s (1Hthiophene), 7.48 d (2Harom, J 8.7 Hz), 7.64 d
Ethyl
3-amino-5-(2-thienyl)thiophene-2-
6
carboxylate (IIg). Yield 68%, yellowish crystals, mp
(2Harom, J 8.7 Hz).
–1
1
(
4
2
07°C. IR spectrum, n, cm : 3415, 3300 (NH ), 1640
2
Ethyl 3-amino-5-(4-methoxyphenyl)-thiophene-
1
CO). H NMR spectrum, d, ppm: 1.25 t (3H, J 7.0 Hz),
2
1
-carboxylate (IIb). Yield 64%, greenish crystals, mp
18–120°C (publ.: mp 119–120°C [5]). H NMR
.18 q (2H, J 7.0 Hz), 6.55 br.s (2H, NH ), 6.78 s (1H,
2
1
,3,5-substituted thiophene.), 7.11 d.d (1Harom, J 3.6 Hz,
spectrum, d, ppm: 1.25 t (3H, J 7.2 Hz), 3.78 s (3H, OMe),
.19 q (2H, J 7.2 Hz), 6.53 br.s (2H, NH ), 6.85 s
J 5.1 Hz), 7.39 d (1Harom, J 3.6 Hz), 7.60 d (1Harom
J 5.1 Hz). C NMR spectrum, d, ppm: 163.44, 155.13,
,
4
2
13
(
1Hthiophene), 6.98 d (2Harom, J 8.5 Hz), 7.56 d (2Harom,
1
5
40.68, 135.77, 128.51, 127.13, 125.64, 115.98, 96.01,
J 8.5 Hz).
9.45, 14.44. Found, %: C 51.85; H 4.24. C H NO S .
1
1
11
2 2
Ethyl 3-amino-5-(4-N,N-dimethylaminophenyl)-
thiophene-2-carboxylate (IIc). Yield 64%, greenish
Calculated, %: C 52.15; H 4.38.
Ethyl 3-amino-5-(4-methylphenyl)thiophene-2-
–1
crystals, mp 167–168°C. IR spectrum, n, cm : 3420, 3310
carboxylate (IIh). Yield 63%, light-green crystals,
1
(
NH ), 1630 (CO). H NMR spectrum, d, ppm: 1.24 t
2
–
1
mp 110–111°C. IR spectrum,n, cm : 3450, 3350 (NH ),
2
(
3H, J 7.2 Hz), 2.94 s (6H, NMe ), 4.17 q (2H, J 7.2 Hz),
2
1
1
670 (CO). H NMR spectrum, d, ppm: 1.25 t (3H,
6
.48 br.s (2H, NH ), 6.72 d (2Harom, J 9.1 Hz), 6.75
2
J 7.2 Hz), 2.31 s (3H, Me), 4.19 q (2H, J 7.2 Hz),
C (1Hthiophene.), 7.43 d (2Harom, J 9.1 Hz). 13
spectrum, d, ppm: 163.64, 155.86, 150.70, 148.90, 126.43,
20.27,113.04,112.04,94.85,59.12,39.70(NMe ), 14.51.
C NMR
6
.54 br.s (2H, NH ), 6.92 s (1H
J 8.1 Hz), 7.51 d (2Harom, J 8.1 Hz). C NMR spectrum
thiophene
), 7.23 d (2Harom
,
,
2
1
3
1
2
d, ppm: 163.60, 155.51, 147.63, 138.74, 130.05, 129.65,
25.38, 115.56, 115.32, 59.34, 20.74, 14.44. Found, %:
C 64.13; H 5.83. C H NO S. Calculated, %: C 64.34;
Found, %: C 61.88; H 5.93. C H N O S. Calculated,
1
5
18
2
2
1
%
: C 62.04; H 6.25.
Ethyl 3-amino-5-(4-nitrophenyl)thiophene-2-
carboxylate (IId). Yield 69%, red crystals, mp 139–
1
4
15
2
H 5.79.
1
The authors are grateful to the Russian Foundation
for Basic Research for the financial support (grant no.
03-03-32052a) and to the Foundation for Assistance to
the Domestic Science.
1
41°C (publ.: mp 140–147°C [5]). H NMR spectrum, d,
ppm: 1.26 t (3H, J 7.2 Hz), 4.21 q (2H, J 7.2 Hz),
.67 br.s (2H, NH ), 7.20 s (1Hthiophene), 7.88 d (2Harom
6
,
2
J 8.5 Hz), 8.24 d (2Harom, J 8.5 Hz).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 2 2006

240
SHASTIN et al.
Marc, Courchesne, M., Proulx, M., Siddiqui, A., Yanno-
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