Utility of 2-aminothiophene-3-carboxamide in the synthesis of biologically active, fused heterocyclic derivatives

Article abstract of DOI:10.1080/104265090508028

2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1) reacted with 3-iminobutyronitrile (2) to give the imino product 3. The latter product was used in synthesis of a series of annulated products which have pharmaceutical interest. The in vitro an

Full text of DOI:10.1080/104265090508028

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Utility of 2-Aminothiophene-3-
carboxamide in the Synthesis
of Biologically Active, Fused
Heterocyclic Derivatives
Wagnat W. Wardakhan a , Gamal A. Elmegeed b &
Fatima M. Manhi c
a National Organization for Drug Control & Research
P.O. 29, Cairo, A. R., Egypt
b National Research Center, Hormones Department,
Dokki, Giza, A. R., Egypt
c National Organization for Drug Control & Research
P.O. 29, Cairo, A. R., Egypt
Published online: 01 Feb 2007.
To cite this article: Wagnat W. Wardakhan , Gamal A. Elmegeed & Fatima M. Manhi
(2005) Utility of 2-Aminothiophene-3-carboxamide in the Synthesis of Biologically
Active, Fused Heterocyclic Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:1, 125-140, DOI: 10.1080/104265090508028
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Phosphorus, Sulfur, and Silicon, 180:125–140, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508028
Utility of 2-Aminothiophene-3-carboxamide
in the Synthesis of Biologically Active,
Fused Heterocyclic Derivatives
Wagnat W. Wardakhan
National Organization for Drug Control & Research P.O. 29,
Cairo, A. R. Egypt
Gamal A. Elmegeed
National Research Center, Hormones Department, Dokki,
Giza, A. R. Egypt
Fatima M. Manhi
National Organization for Drug Control & Research P.O. 29,
Cairo, A. R. Egypt
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1) reacted with 3-
iminobutyronitrile (2) to give the imino product 3. The latter product was used
in synthesis of a series of annulated products which have pharmaceutical interest.
The in vitro antimicrobial activity of some newly synthesized compounds against
bacteria was studied.
Keywords Antimicrobial; benzo[b]thiophene; pyridazine; pyridine; triazine
INTRODUCTION
Over recent years there has been an increasing interest in the chem-
istry of thiophenes because of their biological significance. Many of
them have been widely investigated for therapeutic uses especially
as antifungal,1,2 antibacterial,3 antinflammatory,4 anticonvulsant,5
antiasthmatic,6 and analgesic7 agents. They also were known to show
anti-HIV,8 antiproliferative,9 germicidal,10 and D2 dopaminergic11 ac-
tivities. Moreover, they were reported to act as selective type 4 phospho-
diesterase inhibitors,12 of the response to oxytocin,13 and high-affinity
retinoic acid receptor antagonists.14 As a continuation of our system-
atic investigations dealing with application of 2-aminothiophenes in
Received April 18, 2004; accepted June 16, 2004.
Address correspondence to Wagnat W. Wardakhan, National Organization for Drug
Control & Research P.O. 29, Cairo, A. R. Egypt. E-mail: wagnatward@hotmail.com
125

126
W. W. Wardakhan et al.
the synthesis of polyfunctionally substituted heterocycles,15−17 we de-
cided to synthesize a series of novel annulated heterocyclic derivatives
with a potential spectrum of bio-responses. The antimicrobial activities
of the new synthesized compounds against gram-positive and gram-
negative bacteria were studied.
RESULTS AND DISCUSSION
Chemistry
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1)18 re-
acted with 3-iminobutyronitrile via heating in an oil bath to give the
imino product 3. The structure of 3 was based on analytical and spec-
1
tral data. The H NMR spectrum of the product showed, besides the
expected signal for the cyclohexenyl moiety, a singlet at δ 2.89 for a
CH3 group, a singlet at δ 5.40 for an NH2 group and a singlet at δ 5.21
for a CH2 group. Moreover, the 13C NMR (ppm) data showed signals at
26.73 (CH3), δ 36.8, 44.2, 46.8 (4 CH2), 60.7 (CH2), 117.2, 118.8, 119.4,
119.9 (thiophene C), 120.3 (CN), 160.7 (C N), and 180.4 (C O).
Compound 3 is the key starting material used for the synthesis of a
variety of heterocyclic and fused compounds with pharmaceutical im-
portance. Thus, the reaction of 3 with benzenediazonium chloride 4
at 0–5◦C, gave the phenyl hydrazone derivative 5. The latter product
reacted with phenyl isothiocyanate 6 to give the 1,2,4-triazine deriva-
tive 7. The structure of the latter product was based on the analytical
and spectral data. Thus the 1H NMR spectrum showed, besides the ex-
pected cyclohexene protons, a singlet at δ 2.91 for CH3 group, a singlet
at δ 5.42 (D2O exchangeable) characteristic for the NH2 group, a muti-
plet at δ 7.26–7.35 for the two phenyl protons, and a singlet at δ 8.65
(D2O exchangeable) characteristic for NH group.
The reaction of compound 3 with benzaldehyde in a boiling 1,4-
dioxane solution containing a catalytic amount of piperidine gave the
benzal derivative 9. The reaction of the latter product with malonon-
itrile 10 gave a single product with molecular formula C23H20N5O.
The cyclohexadiene structure 11 was assigned for the reaction prod-
uct. Confirmation for this structure was based on analytical and spec-
tral data. Thus, the 13C NMR (ppm) spectrum of 11 showed signals
at 36.4, 44.3, 46.6 (4 CH2), 117.0, 118.5, 118.7, 119.0, 119.7, 120.0,
120.2, 139.3, 140.0 (thiophene, benzene, cyclohexadiene), 120.6, 120.8
(2 CN), 160.4 (C N), and 180.2 (C O). Compound 11 underwent cy-
clization when heated in sodium ethoxide solution to give the 4,5,6,7-
tetrahydrobenzo[b]thieno[4,5:2,3]cyclohexadieno[e]pyridine derivative
12, via ammonia elimination.

2-Aminothiophene-3-Carboxamide
127
SCHEME 1
The behavior of 3 toward thiophene formation via Gewald’s thio-
phene synthesis18 was also examined. Thus, 3 reacted with sulfur and
the cyanomethylene reagents, namely malononitrile (13a) and ethyl
cyanoacetate (13b), to give the thiophene derivatives 14a and 14b re-
spectively. Both elemental and spectral data of the latter products were
consistent with the assigned structure.

128
W. W. Wardakhan et al.
SCHEME 2
As an extension of this synthetic route, the behavior of 3 toward
some 1,3-dicarbonyl compounds was investigated. Thus, 3 reacted with
acetylacetone (15) to give the benzene derivative 16; its structure be-
1
ing based on analytical and spectral data. Thus, the H NMR spec-
trum of 16 showed, besides the expected signals, a singlet at δ 3.24
characteristic for a CH3 group, a singlet at δ 5.38 for an NH2 group,
two singlets at δ 7.32, 7.38 for benzene H-2, H-4, and a broad singlet

2-Aminothiophene-3-Carboxamide
129
SCHEME 3
(D2O exchangeable) for an OH group. In a similar way, the reaction of
3 with acetoacetanilide 17 afforded the 2-iminopyridine derivative 18.
The C-3 position in 18 showed interesting reactivity towards coupling
with diazonium salts. Thus, compound 18 reacted with benzene diazo-
nium chloride to give the phenylazo derivative 19. Both elemental and

130
W. W. Wardakhan et al.
spectral data of 18 and 19 were consistent with the assigned structures
(cf. experimental data).
Compound 3 underwent ready cyclization when heated in sodium
ethoxide solution using a boiling water bath to give the 4,5,6,7-
tetrahydrobenzo[b]thieno[5,4:2,3]pyridine derivative 20, via ammonia
elimination. Compound 20, with its methyl group in ortho position to
the electronegative cyano group, showed interesting reactivity towards
electrophilic reagents. Thus it is coupled with benzene diazonium chlo-
ride to give the phenylhydrazone derivative 21. The latter product un-
derwent ready cyclization when heated in a boiling sodium ethoxide
solution to give the pyridazine derivative 22. Moreover, the o-hydroxy
nitrile moiety present in compound 20 showed interesting reactiv-
ity toward nucleophilic reagents. Thus, with either hydrazine hydrate
(23a) or phenyl hydrazine (23b) it gave the 4,5,6,7-tetrahydrobenzo[b]-
thieno[5,4:2,3]pyrido[5,4:4,5]pyrazole derivatives 24a and 24b, respec-
tively. In a similar manner, the reaction of 20 with hydroxylamine
hydrochloride (25) gave the 4,5,6,7-tetrahydrobenzo[b]thieno[5,4:2,3]-
pyrido[5,4:4,5]isoxazole derivative 26. Structures of 24a,b and 26 were
established on the basis of elemental and spectral data (cf. experimental
section).
The reactivity of compound 20 toward cyanomethylene reagents
was studied in the aim to form annulated products with potential
pharmaceutical interest. Thus, compound 20 reacts with either mal-
ononitrile (13a) or ethyl cyanoacetate (13b) in refluxing 1,4-dioxane
containing a catalytic amount of triethylamine to afford the annu-
lated products 27a and 27b, respectively. Moreover, the reaction of 20
with phenyl isothiocyanate gave the 4,5,6,7-tetrahydrobenzo[b]thieno-
[5,4:2,3]pyrido[5,6:3,4]pyridine derivative 29. Structures of 27a,b and
29 were based on analytical and spectral data, which are consistent
with the assigned structures (Scheme 4).
ANTIMICROBIAL ACTIVITY
The diverse biological activities of thiophene and fused derivatives
prompted us to test and study the biological activities of some of the
newly synthesized products. Many antimicrobial agents have been in-
troduced into therapy; however the field still needs extensive efforts for
the development of new antimicrobial agents to overcome the highly re-
sistant strains of microorganisms. The bactericidal activity of the newly
synthesized products against two groups of microorganisms, including
two strains of gram-positive bacteria and two strains of gram-negative
bacteria, was investigated in vitro by the hole plate and filter paper disc

2-Aminothiophene-3-Carboxamide
131
SCHEME 4
methods19,20 (Table I). A disc of blotting paper was impregnated with
a known volume and appropriate concentration of a compound to be
tested. This paper was then placed on a sensitivity testing agar plate
that was inoculated with the test organism. The compound diffused
from the disc into the medium. The culture was examined for areas of
no growth around the disc (zones of inhibition) after overnight incuba-
tion. Growth of bacterial strains sensitive to a compound is inhibited at
certain distances from the center of the disc whereas resistant stains
grow up to the edge of the disc. In conclusion, the data of the suscep-
tibility tests for the compounds clearly showed significant and potent
antibacterial activity (bactericidal) against all gram-positive and gram-
negative tested bacteria. Further studies should be done to elucidate the

132
W. W. Wardakhan et al.
TABLE I In Vitro Bactericidal Activity of Some of the Newly
Synthesized Compoundsa
Compound
no.
Bacillus cereus
Staph. Aureus
E. Coli
K. Pneumonia
(Gram-positive) (Gram-positive) (Gram-negative) (Gram-negative)
3
5
7
6b
9
++
+++
++
++
+
+++
++
+++
+++
+
++
+++
++
+++
++
+
++
+++
++
++
+++
+
11
14a
14b
16
18
19
20
21
22
24a
26
27a
27b
29
++
+
+++
+++
+
+++
++
++
+++
+
+++
+++
++
++
+++
+
+++
+++
+
++
+
+++
++
+++
+
+++
+
+++
++
+++
+
++
++
++
+++
−
−
+
+++
++
++
++
+++
++
++
+
++
++
+++
+
+
+
++
+++
ano inhibition (−); Slight inhibition (+); moderate inhibition (++); Strong inhibition
(+++); Rating percent control: no inhibition, 0; slight inhibition, 10, 20, 30%; moderate
inhibition, 40, 50, 60%; strong inhibition, 70, 80, 90%; complete inhibition, 100%.
mechanism of action of the tested novel compounds and to determine
whether their activity is lethal or merely inhibitory to the microorgan-
isms. In addition, the bioactivity of the promising compounds and their
structure–activity relationships will be studied.
Experimental
All melting points are uncorrected. IR spectra were recorded (KBr) on a
Pye Unicam SP-1000 spectrophotometer. 1H NMR and 13C NMR spec-
tra were obtained on a Varian EM-390 90 MHz spectrophotometer in
DMSO-d6 as the solvent and TMS as internal reference. Chemical shifts
are expressed in δ or ppm. Antibacterial results were recorded by Profes-
sor S. A. Aouf, Botany Department, Faculty of Science, Cairo University,
Giza, Egypt
2-Imino(butyronitrilo-β-ylidino)-4,5,6,7-
tetrahydrobenzo[ b]thiophene-3-carboxamide (3)
To a dry mixture of 1 (1.96 g, 0.01 mol) and β-iminobutyronitrile
(2) (0.82 g, 0.01 mol) was added ammonium acetate (1.44 g, 0.02 mol).

2-Aminothiophene-3-Carboxamide
133
The reaction mixture was heated in an oil bath (120◦C) for 8 h and
then left to cool. The solid product, obtained upon triturating the fused
product with ethanol followed by pouring onto ice water, was collected
by filtration.
Orange crystals of 3 from 1,4-dioxane, yield 2.08 g (80%), m.p. 282–
5◦C. C13H15N3SO (261.35). Calcd: C, 59.74; H, 5.78; N, 16.07; S, 12.26.
Found: C, 59.61; H, 5.56; N, 16.22; S, 12.44. IR (υ/cm−1): 3465, 3387
(NH2), 2987, 2886 (CH3, CH2), 2220 (CN), 1687 (C O), 1665 (C N),
1
1643 (C C); H NMR (δ): 2.23–2.26 (m, 4H, 2CH2), 2.35–2.38 (m, 4H,
2CH2), 2.89 (s, 3H, CH3), 5.21 (s, 2H, CH2), 5.40 (s, 2H, NH2, D2O
exchangeable). 13C NMR (ppm): 26.73 (CH3), 36.8, 44.2, 46.8 (4 CH2),
60.7 (CH2), 117.2, 118.8, 119.4, 119.9 (thiophene C), 120.3 (CN), 160.7
(C N), 180.4 (C O).
2-Imino(α-phenylhydrazonobutyronitrilo-β-ylidino)-4,5,6,7-
tetrahydrobenzo[ b]thiophene-3-carboxamide (5),
2-Iminoacetylideno(2-imino-6-hydroxy-4-methyl-5-
phenylazo-1-phenylpyridin-3-yl)-4,5,6,7-tetrahydro-benzo-
[ b]thiophene-3-carboxamide (19), 3-Cyano-4-hydroxy-2-
phenyl-hydrazomethino-4,5,6,7-tetrahydrobenzo-
[b]thieno[5,4:2,3]pyridine (21)
General procedure. To a cold solution (0–5◦C) of either 3 (2.61 g,
0.01 mol), 18 (3.90 g, 0.01 mol), or 20 (2.44 g, 0.01 mol) in ethanol (50 ml)
containing sodium hydroxide (10 ml, 40%), was added with continuous
stirring benzenediazonium chloride (0.01 mol) [prepared by adding a
cold solution of sodium nitrite (0.7 g, 0.01 mol) to a cold solution (0–5◦C)
of aniline (0.93 g, 0.01 mol) in concentrated hydrochloric (3 ml)]. The
reaction mixture, in each case, was left at room temperature for 3 h
after which was formed a solid product which was collected by filtration.
Compound 5. Orange crystals from acetic acid, yield 4.37 g (72%),
m.p. 166–70◦C. C19H19N5SO (365.46). Calcd: C, 62.44; H, 5.24; N, 19.16;
S, 8.77. Found: C, 62.60; H, 5.46; N, 19.28; S, 8.54. IR (υ/cm−1): 3455–
3330 (NH2, NH), 3055 (CH aromatic), 2984, 2883 (CH3, CH2), 2222
(CN), 1681 (C O), 1659 (C N), 1638 (C C); 1H NMR (δ): 2.22–2.24 (m,
4H, 2CH2), 2.32–2.36 (m, 4H, 2CH2), 2.92 (s, 3H, CH3), 5.19 (s, 2H,
CH2), 5.42 (s, 2H, NH2, D2O exchangeable), 7.30–7.36 (m, 5H, C6H5),
8.87 (s, 1H, NH).
Compound 19. Red crystals from acetic acid, yield 3.36 g (66%), m.p.
222–25◦C. C29H28N6SO2 (524.65). Calcd: C, 66.39; H, 5.37; N, 16.01;
S, 6.11. Found: C, 66.61; H, 5.49; N, 16.32; S, 6.34. IR (υ/cm−1): 3434–
3320 (NH2, NH, OH), 3050 (CH aromatic), 2982, 2890 (CH3, CH2), 1685
(C O), 1660 (C N), 1634 (C C); 1H NMR (δ): 2.20–2.25 (m, 4H, 2CH2),

134
W. W. Wardakhan et al.
2.34–2.38 (m, 4H, 2CH2), 2.91, 3.24 (2s, 6H, 2CH3), 5.40 (s, 2H, NH2,
D2O exchangeable), 7.31–7.37 (m, 10H, 2C6H5), 8.90 (s, 1H, NH), 9.85
(s, br, 1H, OH).
Compound 21. Reddish brown crystals from 1,4-dioxane, yield
2.02 g (58%), m.p. >300◦C. C19H16N4SO (348.43). Calcd: C, 65.49; H,
4.63; N, 16.07; S, 9.20. Found: C, 65.14; H, 4.60; N, 16.37; S, 9.51. IR
(υ/cm−1): 3487–3305 (OH, NH), 3045 (CH aromatic), 2980, 2885 (CH3,
CH2), 1665 (C N), 1639 (C C); 1H NMR (δ): 2.22–2.26 (m, 4H, 2CH2),
2.32–2.37 (m, 4H, 2CH2), 7.28–7.34 (m, 6H, C6H5, pyridazine H-3), 9.21
(s, 1H, NH), 10.37 (s, br, 1H, OH).
2-Iminoacetylideno(6-imino-1,3-diphenyl-2-thioxo-1,3,4-
triazine-5-yl)-4,5,6,7-tetrahydrobenzo[ b]thiophene-3-
carboxamide (7)
To a solution of compound 5 (3.64 g, 0.01 mol) in 1,4-dioxane (50 ml)
containing triethylamine (0.5 ml) was added phenylisothiocyanate (6)
(1.3 g, 0.01 mol). The reaction mixture was heated under reflux for 3 h
and then poured onto ice/water containing a few drops of hydrochloric
acid. The solid product was collected by filtration.
Yellow crystals of 7 from ethanol, yield 3.45 g (69%), m.p. 154–6◦C.
C26H24N6S2O (500.65). Calcd: C, 62.37; H, 4.83; N, 16.78; S, 12.81.
Found: C, 62.53; H, 4.62; N, 16.67; S, 12.56. IR (υ/cm−1): 3474, 3325
(NH, NH2), 2985, 2882 (CH3, CH2), 2222 (CN), 1677 (C O), 1660
(C N), 1636 (C C), 1210, 1190 (C S); 1H NMR (δ): 2.22–2.26 (m,
4H, 2CH2), 2.34–2.35 (m, 4H, 2CH2), 2.91 (s, 3H, CH3), 5.42 (s, 2H,
NH2, D2O exchangeable), 7.26–7.35 (m, 10H, 2C6H5), 8.65 (s, br, 1H,
NH).
2-Imino(α-benzalbutyronitrilo-β-ylidino)-4,5,6,7-
tetrahydrobenzo[ b]-thiophene-3-carboxamide (9)
Equimolecular amounts of compound 3 (1.96 g, 0.01 mol) and ben-
zaldehyde (1.08, 0.01 mol) in dimethylformamide (30 ml) containing
piperidine (0.5 ml) was heated under reflux for 5 h and then was evap-
orated in vacuum. The remaining product was triturated with diethyl
ether, and the solid product was collected by filtration.
Yellow crystals of 9 from ethanol, yield 2.44 g (70%), m.p. 246–8◦C.
C20H19N3SO (349.46). Calcd: C, 68.74; H, 5.48; N, 12.02; S, 9.17. Found:
C, 68.50; H, 5.22; N, 12.37; S, 8.96. IR (υ/cm−1): 3490–3330 (NH2), 3040
(CH aromatic), 2988, 2891 (CH3, CH2), 2225 (CN), 1665 (C N), 1639
(C C); 1H NMR (δ): 2.22–2.28 (m, 4H, 2CH2), 2.30–2.37 (m, 4H, 2CH2),
5.23 (s, 2H, NH2), 6.87 (s, 1H, CH C), 7.29–7.36 (m, 5H, C6H5).

2-Aminothiophene-3-Carboxamide
135
2-Imino(5-benzal-4-cyano-3,5-diamino-1-ylideno)-4,5,6,7-
tetrahydrobenzo[ b]thiophene-3-carboxamide (11)
To a solution of compound 9 (3.49 g, 0.01 mol) in 1,4-dioxane (40 ml)
containing triethylamine (0.5 ml) was added malononitrile (10) (0.66 g,
0.01 mol). The reaction mixture was heated under reflux for 3 h and
then was evaporated in vacuum. The remaining product was triturated
with diethyl ether, and the solid product was collected by filtration.
Yellow crystals of 11 from DMF, yield 2.48 g (60%), m.p. 144–
6◦C. C23H21N5SO (415.52). Calcd: C, 66.48; H, 5.09; N, 16.85; S, 7.71.
Found: C, 66.63; H, 4.92; N, 16.53; S, 7.50. UV (CHCl3) (λmax/nm, log ε):
216, 4.47; 229, 5.53; 284, 4.30. IR (υ/cm−1): 3446–3312 (3NH2), 3060
(CH aromatic), 2980, 2875 (CH3, CH2), 2220 (CN), 1655 (C N), 1630
(C C); 1H NMR (δ): 2.22–2.26 (m, 4H, 2CH2), 2.32–2.37 (m, 4H, 2CH2),
4.45, 4.48, 5.31 (3s, 6H, 3NH2), 6.89 (s, 1H, CH C), 7.28–7.34 (m,
6H, C6H5, benzene H-2); 13C NMR (ppm): 36.4, 44.3, 46.6 (4 CH2),
117.0, 118.5, 118.7, 119.0, 119.7, 120.0, 120.2, 139.3, 140.0 (thiophene,
benzene, cyclohexadiene), 120.6, 120.8 (2 CN), 160.4 (C N), 180.2
(C O).
2-Imino[acetyl-α-(4-cyano-3,5-diaminothiopheno-2-yl)]-
4,5,6,7-tetrahydrobenzo[ b]thiophene-3-carboxamide (14a)
and 2-Imino[acetyl-α-(ethyl-3,5-diaminothiopheno-
2-yl-4-carboxylato)]-4,5,6,7-tetrahydrobenzo[ b]thiophene-
3-carboxamide (14b)
General procedure. To a solution of 3 (2.61 g, 0.01 mol) in absolute
ethanol (40 ml) containing triethylamine (0.5 ml) was added either mal-
ononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol). To
each reaction mixture was added elemental sulfur (0.23 g, 0.01 mol)
and the whole reaction mixture was heated under reflux for 1 h and
then left to cool. The solid product formed in each case was collected by
filtration.
Compound 14a. Orange crystals from acetic acid, yield 2.70 g (60%),
m.p. 232–5◦C. C16H17N5S2O (359.48). Calcd: C, 53.46; H, 4.76; N, 19.48;
S, 17.84. Found: C, 53.39; H, 4.56; N, 19.32; S, 17.52. IR (υ/cm−1): 3541–
3323 (3NH2), 2987, 2870 (CH3, CH2), 2218 (CN), 1688 (C O), 1662
1
(C N), 1637 (C C); H NMR (δ): 2.24–2.28 (m, 4H, 2CH2), 2.31–2.38
(m, 4H, 2CH2), 2.88 (s, 3H, CH3), 4,46, 4.47, 5.30 (3s, 6H, 3NH2).
Compound 14b. Pale brown crystals from acetic acid, yield 2.88 g
(71%), m.p. 176–9◦C. C18H22N4S2O3 (406.53) Calcd: C, 53.18; H, 5.45; N,
13.78; S, 15.77. Found: C, 53.37; H, 5.76; N, 13.47; S, 15.48. IR (υ/cm−1):
3532–3347 (3NH2), 2982, 2889 (CH3, CH2), 1660 (C N), 1643 (C C);

136
W. W. Wardakhan et al.
1H NMR (δ): 1.35 (t, 3H, CH3), 2.23–2.26 (m, 4H, 2CH2), 2.32–2.36 (m,
4H, 2CH2), 2.92 (s, 3H, CH3), 4.22 (q, 2H, CH2), 4,44, 4.49, 5.34 (3s, 6H,
3NH2).
2-Imino[acetyl-α-(3-amino-5ꢀ-methylphenol-4-yl)]-4,5,6,7-
tetrahydrobenzo[ b]thiophene-3-carboxamide (16) and
2-Imino[acetyl-α-(6-hydroxy -2-Imino-4-methyl-1-
phenylpyridino-3-yl]-4,5,6,7-tetrahydrobenzo[ b]thiophene-
3-carboxamide (18)
General procedure. To a solution of compound 3 (2.61 g, 0.01 mol)
in 1,4-dioxane (40 ml) containing triethylamine (0.5 ml), was added ei-
ther acetylacetone (15) (1.0 g, 0.01 mol) or acetoacetanilide (17) (1.78 g,
0.01 mol). The whole reaction mixture in each case was heated under
reflux for 45 min and then left to cool. A solid product formed upon
pouring onto ice/water containing few drops of hydrochloric acid and
was collected by filtration.
Compound 16. Yellow crystals from 1,4-dioxane, yield 2.05 g (66%),
m.p. 222–5◦C. C18H21N3SO2 (343.45). Calcd: C, 62.94; H, 6.16; N, 12.23;
S, 9.33. Found: C, 62.67; H, 5.96; N, 12.40; S, 9.58.IR (υ/cm−1): 3577–
3321 (OH, 2NH2), 2980, 2873 (CH3, CH2), 1684 (C O), 1662 (C N),
1
1639 (C C); H NMR (δ): 2.22–2.25 (m, 4H, 2CH2), 2.34–2.38 (m, 4H,
2CH2), 2.90, 3.24 (2s, 6H, 2CH3), 4.56, 5.38 (2s, 4H, 2NH2), 7.32, 7.38
(2s, 2H, C6H2), 8.97 (s, br, 1H, OH).
Compound 18. Yellowish brown crystals from 1,4-dioxane, yield
3.06 g (73%), m.p. 180–3◦C. C23H24N4SO2 (420.54). Calcd: C, 65.69;
H, 5.75; N, 13.32; S, 7.62. Found: C, 65.75; H, 6.03; N, 13.59; S, 7.40.
IR (υ/cm−1): 3567–3342 (OH, NH, NH2), 2986, 2893 (CH3, CH2), 1688
1
(C O), 1667 (C N), 1641 (C C); H NMR (δ ppm): 2.21–2.25 (m, 4H,
CH2), 2.32–2.36 (m, 4H, 2CH2), 2.87, 3.09 (2s, 6H, 2CH3), 7.28–7.34 (m,
6H, C6H5, benzene H-5), 9.24 (s, br, 1H, OH).
3-Cyano-4-hydroxy-2-methyl-4,5,6,7-tetrahydrobenzo-
[ b]thieno[5,4:2,3]pyridine (20)
A solution of compound 3 (0.01 mol) in dimethylformamide contain-
ing piperidine (0.5 ml) was heated under reflux for 8 h and then poured
onto ice/water. The formed solid product was collected by filtration.
Pale yellow crystals of 20 from methanol, yield 1.36 g (56%), m.p.
>300◦C. C13H12N2SO (244.32). Calcd: C, 63.91; H, 4.95; N, 11.46; S,
13.12. Found: C, 63.72; H, 4.66; N, 11.74; S, 13.48. IR (υ/cm−1): 3543–
3387 (OH), 2990, 2872 (CH3, CH2), 2220 (CN), 1658 (C N), 1636 (C C).
1H NMR (δ): 2.22–2.27 (m, 4H,CH2), 2.30–2.35 (m, 4H, 2CH2), 3.09 (s,
3H, CH3), 9.11 (s, br, 1H, OH).

2-Aminothiophene-3-Carboxamide
137
1-Benzal-3-cyano-2,4-diamino-4,5,6,7-tetrahydrobenzo-
[ b]thieno[5,4:2ꢀ,3ꢀ]pyridine[e]1,3-cyclohexadiene (12) and
4-Imino-5-hydroxy-3-phenyl-4,5,6,7-tetrahydrobenzo[ b]-
thieno[5,4:2,3]pyridine[6,5:4,5]pyridazine (22)
General procedure. A solution of either compound 11 (4.41 g,
0.01 mol) or 21 (3.48 g, 0.01 mol) in sodium ethoxide solution (0.02 mol)
[prepared by dissolving sodium metal (0.46 g, 0.02 mol) in absolute
ethanol (50 ml)] was heated in a boiling water bath for 8 h and then
was poured onto ice/water containing hydrochloric acid (to pH 6). The
formed solid product was collected by filtration.
Compound 12. Yellow crystals from DMF, yield 2.62 g (66%), m.p.
>300◦C. C23H18N4SO (398.49). Calcd: C, 69.32; H, 4.55; N, 14.05; S,
8.04. Found: C, 69.62; H, 4.86; N, 14.38; S, 7.88. UV (CHCl3) (λ max/nm,
log ε): 220, 4.24; 227, 4.26; 277, 4.13; 284, 4.15. IR (υ/cm−1): 3466–3332
(2NH2), 3055 (CH aromatic), 2875 (CH2), 2222 (CN), 1683 (C O), 1652
1
(C N), 1638 (C C); H NMR (δ): 2.22–2.25 (m, 4H, 2CH2), 2.32–2.36
(m, 4H, 2CH2), 4,47, 4.49 (2s, 4H, 2NH2), 6.88 (s, 1H, CH C), 7.29–7.32
(m, 5H, C6H5).
Compound 22. Orange crystals from acetone, yield 2.15 g (62%),
m.p. >284–7◦C. C19H16N4SO (348.43). Calcd: C, 65.49; H, 4.62; N, 16.07;
S, 9.20. Found: C, 65.77; H, 4.90; N, 16.40; S, 9.54. IR (υ/cm−1): 3552–
3314 (OH, NH), 2982, 2878 (CH3, CH2), 1693–1680 (3 C O), 1663
1
(C N), 1633 (C C); H NMR (δ): 2.20–2.25 (m, 4H, CH2), 2.32–2.35
(m, 4H, 2CH2), 7.28–7.32 (m, 5H, C6H5, pyridazine H-3), 9.26 (s, br,
1H, OH).
3-Amino-5[H]-2-methyl-4,5,6,7-tetrahydrobenzo[ b]thieno-
[5,4:2,3]pyrido[5,4:4,5]pyrazole (24a) and 3-Amino-
5-phenyl-2-methyl-4,5,6,7-tetrahydrobenzo[ b]thieno-
[5,4:2,3]pyrido[5,4:4,5]pyrazole (24b)
General procedure. To a solution of compound 20 (2.44 g, 0.01 mol)
in 1,4-dioxane (40 ml) was added either hydrazine hydrate (0.5 g,
0.01 mol) or phenyl hydrazine (1.08 g, 0.01 mol). The reaction mixture
was heated under reflux for 2 h and then poured onto water contain-
ing few drops of hydrochloric acid. The solid product was collected by
filtration.
Compound 24a. Brown crystals from 1,4-dioxane, yield 1.80 g (70%),
m.p. 222–5◦C. C13H14N4S (258.35). Calcd: C, 60.43; H, 5.46; N, 21.68; S,
12.41. Found: C, 60.64; H, 5.80; N, 21.41; S, 12.59. IR (υ/cm−1): 3446–
3315 (NH, NH2), 2986, 2881 (CH3, CH2), 1687, 1682 (2 C O), 1652
(C N), 1640 (C C); 1H NMR (δ): 2.23–2.26 (m, 4H,CH2), 2.32–2.36 (m,
4H, 2CH2), 3.13 (s, 3H, CH3), 4.67 (s, 2H, NH2), 8.08 (s, br, 1H, NH).

138
W. W. Wardakhan et al.
Compound 24b. Orange crystals from 1,4-dioxane, yield 2.20 g
(66%), m.p. 145–7◦C. C19H18N4S (334.44). Calcd: C, 68.23; H, 5.42; N,
16.75; S, 9.58. Found: C, 67.97; H, 5.56; N, 16.48; S, 9.81. IR (υ/cm−1):
3439, 3356 (NH2), 2984, 2880 (CH3, CH2), 1655 (C N), 1637 (C C). 1H
NMR (δ): 2.22–2.26 (m, 4H, CH2), 2.32–2.38 (m, 4H, 2CH2), 3.17 (s, 3H,
CH3), 4.88 (s, 2H NH2), 7.32–7.38 (m, 5H, C6H5).
3-Amino-5[ H]-2-methyl-4,5,6,7-tetrahydrobenzo[ b]thieno-
[5,4:2,3]pyrido[5,4:4,5]isoxazole (26)
Equimolecular amounts of compounds 20 (2.44 g, 0.01 mol) and hy-
droxylamine hydrochloride (0.69 g, 0.01 mol) in absolute ethanol (50 ml)
containing sodium acetate (1.0 g) was heated under reflux for 7 h and
then poured onto water. The solid product formed upon stirring at room
temperature overnight was collected by filtration.
Yellow crystals of 26 from diethyl ether, yield 1.55 g (60%), m.p. 170–
3◦C. Found: C, 60.57; H, 4.92; N, 15.94; S, 12.68. C13H13N3SO (259.33).
Calcd: C, 60.21; H, 5.05; N, 16.20; S, 12.36. IR (υ/cm−1): 3444, 3349
1
(NH2), 2990, 2876 (CH3, CH2), 1650 (C N), 1640 (C C). H NMR (δ):
2.20–2.24 (m, 4H,CH2), 2.31–2.36 (m, 4H, 2CH2), 3.20 (s, 3H, CH3), 4.49
(s, 2H, NH2).
3-Cyano-2,4-diamino-5-hydroxy-4,5,6,7-tetrahydrobenzo-
[ b]thieno[5,4:2,3]pyrido[e]benzene (27a) and
2,4-Diamino-3-ethoxycarbonyl-5-hydroxy-4,5,6,7-
tetrahydrobenzo[ b]thieno[5,4:2,3]pyrido[e]benzene (27b)
General procedure. To a solution of compound 20 (2.44 g, 0.01 mol)
in 1,4-dioxane (40 ml) containing triethylamine (0.5 ml) was added
either malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g,
0.01 mol). The reaction mixture, in each case, was heated under reflux
for 2 h and then evaporated in vacuum. The remaining product was
triturated with ethanol, and the formed solid product was collected by
filtration.
Compound 27a. Orange crystals from 1,4-dioxane, yield 2.23 g
(72%), m.p. 256–7◦C. C16H14N4SO (310.38). Calcd: C, 61.91; H, 4.54;
N, 18.05; S, 10.33. Found: C, 62.07; H, 4.76; N, 18.36; S, 10.60. IR
(υ/cm−1): 3562–3315 (OH, 2NH2), 2880 (CH2), 2225 (CN), 1660 (C N),
1
1633 (C C); H NMR (δ): 2.20–2.25 (m, 4H,CH2), 2.32–2.35 (m, 4H,
2CH2), 4.88, 5.34 (2s, 4H, 2NH2), 7.44 (s, 1H, benzene CH), 9.11 (s, br,
1H, OH).
Compound 27b. Pale brown crystals from 1,4-dioxane, yield 2.14 g
(60%), m.p. 190–3◦C. C18H19N3SO3 (357.43). Calcd: C, 60.48; H, 5.35;
N, 11.75; S, 8.97. Found: C, 60.72; H, 5.63; N, 11.66; S, 9.17. IR

2-Aminothiophene-3-Carboxamide
139
(υ/cm−1): 3555–3323 (OH, 2NH2), 2887 (CH2), 1689 (C O), 1656 (C N),
1
1640 (C C); H NMR (δ): 1.37 (t, 3H, CH3), 2.22–2.26 (m, 4H,CH2),
2.33–2.38 (m, 4H, 2CH2), 4.23 (q, 2H, CH2), 4.92, 5.30 (2s, 4H, 2NH2),
9.08 (s, br, 1H, OH).
5-Hydroxy-4-imino-3-phenyl-2-thiolo-4,5,6,7-
tetrahydrobenzo[ b]thieno[5,4:2,3]pyrido-
[5,6:3,4]pyridine (29)
To a solution of compound 20 (2.44 g, 0.01 mol) in 1,4-dioxane (40 ml)
containing triethylamine (1.0 ml) was added phenyl isothiocyanate
(1.30 g, 0.01 mol). The reaction mixture was heated under reflux for
2 h and then was poured onto ice/water. The solid product formed was
collected by filtration.
Orange crystals of 29 from acetic acid, yield 2.05 g (55%), m.p. 130–
2◦C. Found: C, 61.99; H, 4.46; N, 11.34; S, 16.68. C20H17N3S2O (379.51).
Calcd: C, 63.29; H, 4.51; N, 11.07; S, 16.89. IR (υ/cm−1): 3547–3323 (OH,
NH), 3056 (CH aromatic), 2876 (CH2), 2240 (SH), 1668 (exocyclic C N),
1642 (C C); 1H NMR (δ ppm): 2.21–2.24 (m, 4H,CH2), 2.32–2.34 (m, 4H,
2CH2), 4.66 (s, br, 1H, SH), 7.25–7.33 (m, 5H, C6H5), 8.79 (s, 1H, NH),
9.11 (s, br, 1H, OH).
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