Chemistry of iminofurans 3.*Synthesis and intramolecular cyclization of (Z)-4-aryl- 2-[3-(ethoxycarbonyl)-4,5,6,7-tetra- hydrobenzo[b]thiophen-2- ylamino]- 4-oxobuten-2-oic acids

Article abstract of DOI:10.1007/s10593-009-0334-3

(Z)-4-Aryl-2-[3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b] thiophen-2-ylamino]-4-oxobuten-2-oic acids, which exist in the enamino keto form in solutions, were synthesized by the action of ethyl 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate o

Full text of DOI:10.1007/s10593-009-0334-3

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
CHEMISTRY OF IMINOFURANS
3.* SYNTHESIS AND INTRAMOLECULAR
CYCLIZATION OF (Z)-4-ARYL-
2-[3-(ETHOXYCARBONYL)-4,5,6,7-TETRA-
HYDROBENZO[b]THIOPHEN-2-YLAMINO]-
4-OXOBUTEN-2-OIC ACIDS
S. A. Shipilovskikh1, A. E. Rubtsov1**, and V. V. Zalesov1
(Z)-4-Aryl-2-[3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino]-4-oxobuten-2-oic acids,
which exist in the enamino keto form in solutions, were synthesized by the action of ethyl 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate on 4-aryl-2-hydroxy-4-oxobuten-2-oic acids. Under
the influence of acetic anhydride the obtained acids undergo cyclization to ethyl 2-(5-aryl-2-oxofuran-
3(2H)-ylideneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylates.
Keywords: amino acids, 4-aryl-2-hydroxy-4-oxobuten-2-oic acids, 3-imino-3H-furan-2-ones, Gewald
thiophene, cyclization.
Compounds containing 3-imino-3H-furan-2-one in their structure are represented in the literature by a
few examples of their preparation [2]. Earlier we proposed a simple method for the production of a series of
N-substituted 5-aryl-3-imino-3H-furan-2-ones by the intramolecular cyclization of N-substituted 2-amino-
4-aryl-4-oxobuten-2-oic acids by the action of acetic anhydride [3]. At the same time, the rare type of
2-furanone derivatives seemed extremely promising from the standpoint of high reactivity and the possible
presence of biologically active compounds in a series of furan derivatives, while the introduction of a thiophene
substituent [4] into the structure at the imine nitrogen atom increases the prospects of the compounds even
further. The aim of the present work was the synthesis of N-substituted 5-aryl-3-imino-3H-furan-2-ones
combining two different heterocycles in their structure.
Initially, 4-aryl-2-[3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino]-4-oxobuten-2-oic
acids 3a-h were synthesized by the reaction of 4-aryl-2-hydroxy-4-oxobuten-2-oic acids 1a-h with ethyl
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 2 (Table 1).
_______
* For Communication 2, see [1].
** To whom correspondence should be addressed, e-mail: Alekhsandr.Rubtsov@psu.ru.
1Perm State University, Perm 614990, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 832-835, June, 2009. Original
article submitted March 6, 2008.
658
0009-3122/09/4506-0658©2009 Springer Science+Business Media, Inc.

OEt
H
O
O
O
+
OH
–H2O
Ar
S
NH2
2
1a–h
O
OEt
OEt
O
O
Ac2O
S
NH
O
S
N
–2AcOH
Ar
HO
Ar
O
4a–h
3a–h
O
O
1, 3, 4 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-MeOC6H4, d Ar = 4-EtOC6H4,
e Ar = 4-FC6H4, f Ar = 4-ClC6H4, g Ar = 4-BrC6H4, h Ar = 2,4-(MeO)2C6H3
The IR spectra of the acids 3a-h contain a broad band for the stretching vibrations of the NH group
(3410-3380) and absorption bands for the stretching vibrations of the ester and carboxy groups (1715-1701 and
1668-1665 cm−1).
TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Decomp.
Yield, %
points, °С
C
N
S
3a
3b
3с
3d
3e
3f
C21H21NO5S
C22H23NO5S
C22H23NO6S
C23H25NO6S
C21H20FNO5S
C21H20ClNO5S
C21H20BrNO5S
C23H25NO7S
C21H19NO4S
C22H21NO4S
C22H21NO5S
C23H23NO5S
C21H18FNO4S
C21H18ClNO4S
C21H18BrNO4S
C23H23NO6S
63.12
63.14
3.52
3.51
8.03
8.03
189-190
188-189
186-187
172-173
181-182
176-177
172-173
183-184
190-192
154-156
144-145
177-180
186-187
155-157
165-167
161-164
88
72
85
90
85
83
82
93
86
63
68
41
48
40
45
74
64.04
63.90
3.41
3.39
7.79
7.75
61.68
61.52
3.24
3.26
7.42
7.47
62.32
62.29
3.15
3.16
7.22
7.23
60.45
60.42
3.34
3.36
7.65
7.68
58.15
58.13
3.19
3.23
7.41
7.39
3g
3h
4a
4b
4c
4d
4e
4f
52.70
52.73
2.95
2.93
6.72
6.70
60.09
60.12
2.99
3.05
6.95
6.98
66.13
66.12
3.63
3.67
8.45
8.41
66.83
66.82
3.59
3.54
8.09
8.11
64.22
64.22
3.37
3.40
7.76
7.79
64.95
64.92
3.29
3.29
7.58
7.54
63.18
63.15
3.47
3.51
7.99
8.03
60.64
60.65
3.33
3.37
7.73
7.71
4g
4h
54.75
54.79
3.03
3.04
6.98
6.97
62.53
62.57
3.13
3.17
7.25
7.26
659

The 1H NMR spectra of compounds 3a-h (Table 2) contain signals for the protons of both fragments of
the initial molecules. A characteristic feature is the presence of a singlet signal at 12.7-12.8 ppm for the proton
of the NH group involved in a hydrogen bond.
We studied the intramolecular cyclization of the acids 3a-h in boiling acetic anhydride and established
that ethyl 2-(5-aryl-2-oxofuran-3(2H)-ylideneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylates 4a-h
are formed in the reaction (Tables 1 and 2).
TABLE 2. The Spectral Characteristics of Compounds 3a and 4a-h
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
3a
3b
3с
3d
3131 (br., NH), 12.78 (1Н, s, NH); 7.76 (5Н, m, arom.); 6.52 (1H, s, C=CH);
1708 (COO)
4.32 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1.33 (3H, t, J = 6.9, OCH2CH3)
3442 (br., NH), 12.75 (1Н, s, NH); 7.61 (4Н, m, arom.); 6.51 (1H, s, C=CH);
1715 (COO)
4.32 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
2.38 (3Н, s, СН3); 1.33 (3H, t, J = 6.9, OCH2CH3)
3412 (br., NH), 12.75 (1Н, s, NH); 7.5 (4Н, m, arom.); 6.51 (1H, s, C=CH);
1712 (COO)
4.31 (2Н, q, J = 6.9, OCH2CH3,); 3.85 (3Н, s, OСН3);
3.0-1.5 (8H, m, (СН2)4); 1.33 (3H, t, J = 6.9, OCH2CH3)
3416 (br., NH), 12.70 (1Н, s, NH); 7.50 (4Н, m, arom.); 6.51 (1H, s, C=CH);
1701 (COO)
4.32 (2Н, q, J = 6.9, OCH2CH3); 4.18 (2Н, q, J = 6.8, OCH2CH3);
3.0-1.5 (8H, m, (СН2)4); 1.33 (3H, t, J = 6.9, OCH2CH3);
1.35 (3H, t, J = 6.8, OCH2CH3)
3e
3f
3412 (br., NH), 12.79 (1Н, s, NH); 7.75 (4Н, m, arom.); 6.52 (1H, s, C=CH);
1707 (COO)
4.31 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1.33 (3H, t, J = 6.9, OCH2CH3)
3412 (br., NH), 12.79 (1Н, s, NH); 7.78 (4Н, m, arom.); 6.50 (1H, s, C=CH);
1701 (COO)
4.32 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1.33 (3H, t, J = 6.9, OCH2CH3)
3g
3h
4a
4b
4c
4d
3402 (br., NH), 12.79 (1Н, s, NH); 7.81 (4Н, m, arom.); 6.49 (1H, s, C=CH);
1701 (COO)
4.32 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1.33 (3H, t, J = 6.9, OCH2CH3)
3392 (br., NH), 12.58 (1Н, s, NH); 7.3 (4Н, m, arom.); 6.57 (1H, s, C=CH);
1670 (br.)
4.31 (2Н, q, J = 6.9, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1.32 (3H, t, J = 6.9, OCH2CH3)
1796 (COlact),
7.5 (5Н, m, arom.); 7.31 (1H, s, C=CH);
1715 (COOEt), 4.3 (2Н, q, J = 6.8, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1607 (С=N)
1.39 (3H, t, J = 6.8, OCH2CH3)
1794 (COlact),
7.8 (4Н, m, arom.); 7.19 (1H, s, C=CH);
1716 (COOEt), 4.28 (2Н, q, J = 6.8, OCH2CH3); 2.4 (3Н, s, СН3);
1607 (С=N)
3.0-1.5 (8H, m, (СН2)4); 1.31 (3H, t, J = 6.8, OCH2CH3)
1796 (COlact),
7.6 (4Н, m, arom.); 7.12 (1H, s, C=CH);
1697 (COOEt), 4.3 (2Н, q, J = 6.8, OCH2CH3); 3.85 (3Н, s, OСН3);
1610 (С=N)
3.0-1.5 (8H, m, (СН2)4); 1.31 (3H, t, J = 6.8, OCH2CH3)
1800 (COlact),
7.4 (3Н, m, arom.); 7.02 (1H, s, C=CH);
1694 (COOEt), 4.27 (2Н, q, J = 6.8, OCH2CH3); 4.17 (2Н, q, J = 6.8, OCH2CH3);
1609 (С=N)
3.0-1.5 (8H, m, (СН2)4); 1.35 (3H, t, J = 6.8, OCH2CH3);
1.29 (3H, t, J = 6.8, OCH2CH3)
4e
4f
1804 (COlact),
7.75 (4Н, m, arom.); 7.26 (1H, s, C=CH);
1707 (COOEt), 4.3 (2Н, q, J = 6.8, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1610 (С=N)
1.3 (3H, t, J = 6.8, OCH2CH3)
1793 (COlact),
7.9 (4Н, m, arom.); 7.32 (1H, s, C=CH);
1711 (COOEt), 4.3 (2Н, q, J = 6.8, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1607 (С=N)
1.28 (3H, t, J = 6.8, OCH2CH3)
4g
4h
1796 (COlact),
7.9 (4Н, m, arom.); 7.31 (1H, s, C=CH);
1711 (COOEt), 4.3 (2Н, q, J = 6.8, OCH2CH3); 3.0-1.5 (8H, m, (СН2)4);
1611 (С=N)
1.28 (3H, t, J = 6.8, OCH2CH3)
1785 (COlact),
7.4 (3Н, m, arom.); 7.02 (1H, s, C=CH);
1719 (COOEt), 4.2 (2Н, q, J = 6.8, OCH2CH3); 4.03(3Н, s, OСН3);
1609 (С=N)
3.89 (3Н, s, OСН3); 3.0-1.5 (8H, m, (СН2)4);
1.28 (3H, t, J = 6.8, OCH2CH3)
660

The IR spectra of compounds 4a-h contain a band for the stretching vibrations of the lactone carbonyl of
the furan ring (1793-1804), a band for the absorption of the ester carbonyl (1694-1715), and a band for the
absorption of the C=N bond (1607-1611 cm−1). The 1H NMR spectra of compounds 4a-h do not contain signals
for the proton of the amino group, but a singlet for the methine proton (H-4) of the heterocycle is observed in the
more downfield region (7.02-7.32 ppm) compared with the singlet of the methine proton of the initial acids. The
downfield position of the singlet for the methine proton of the furan ring of compounds 4 may be due to its
screening by the bulky heterocyclic substituent at the imine nitrogen atom.
EXPERIMENTAL
1
The IR spectra were obtained in vaseline oil on an FSM-1201 instrument. The H NMR spectra were
recorded in DMSO-d6 on a Varian-Mercury +300 instrument (300 MHz) with TMS as internal standard. The
chemical purity of the compounds and the end of the reaction were monitored by TLC on Silufol UV-254 plates
in the 10:9:1 ether–benzene–acetone system. The decomposition points were determined on a PTP-2 instrument.
(Z)-4-Aryl-2-[3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino]-4-oxo-buten-2-oic
Acids (3). To a solution of the respective 4-aryl-2-hydroxy-4-oxobuten-2-oic acid (0.5 g, 0.01 mol) in ethanol
(10 ml) we added a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 2 (0.01 mol)
in ethanol (10 ml). The mixture was left at room temperature for 24 h. The precipitate was filtered off and
recrystallized from acetonitrile.
Ethyl 2-(5-Aryl-2-oxofuran-3(2H)-ylideneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxy-
lates 4a-h. A solution of the respective acid 3a-h (0.01 mol) in acetic anhydride (8 ml) was boiled for 1 h. The
precipitate that separated after cooling was filtered off, washed with anhydrous ether, and recrystallized from
anhydrous toluene.
The work was carried out with support from the Russian Fundamental Research Fund (08-03-00488-a).
REFERENCES
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2.
V. V. Zalesov, A. E. Rubtsov, and O. A. Bystritskaya, Zh. Org. Khim., 43, 739 (2007).
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40, 133 (2004)].
3.
4.
R. W. Sabnis, D. W. Rangnekar, and N. D. Sonawane, J. Heterocycl. Chem., 36, 333 (1999).
A. E. Rubtsov and V. V. Zalesov, Zh. Org. Khim., 39, 918 (2003).
661