Synthesis of new heterocycles festooned with thiophene and evaluating their antioxidant activity

Article abstract of DOI:10.1002/jhet.4122

The chemical performance of 5-bromo-2-(bromoacetyl)-thiophene (1) was tested toward the reaction with numerous bi-nucleophilic reagents (namely; 2-aminobenzothiazoles, 2-aminothiazole, 2-aminotetrazole, 2-aminotriazole, 2-aminopyridines, 2-aminobenzimidaz

Full text of DOI:10.1002/jhet.4122

Synthesis of new heterocycles festooned with thiophene and evaluating their
antioxidant activity
Nader A. Abed  Mohamed M. Hammouda  Mohamed A. Ismail  Ehab Abdel-Latif
Correspondence
Ehab Abdel-Latif, Chemistry Department, Faculty of Science, Mansoura University, 35516
Mansoura, Egypt.
Email: ehabattia00@gmx.net
Abstract
The chemical performance of 5-bromo-2-(bromoacetyl)-thiophene (1) was tested towards the
reaction with numerous bi-nucleophilic reagents (namely; 2-aminobenzothiazoles, 2-
aminothiazole, 2-aminotetrazole, 2-aminotriazole, 2-aminopyridines, 2-aminobenzimidazole
and o-phenylenediamine). Therefore, a series of bridged nitrogen heterocycles bearing
thiophene moiety 3, 5, 7, 9, 11, 13 and 15, respectively was synthesized. In addition, the
reaction of 5-bromo-2-(bromoacetyl)-thiophene with the thiocarbamoyl compounds 17, 19
and/or 24 afforded the corresponding thienyl-thiazoles 18 or dithien-2-yl ketones 20 and 25,
based on the reaction conditions. Treatment of 1 with 2-mercapto-4,6-dimethylnicotinonitrile
was achieved to obtain the target dithien-2-yl ketone 28. The new synthesized scaffolds were
examined for their antioxidant activity by means of ABTS antioxidant assay. The thienyl-
thiazole scaffold 18c and 2-((2-(thiophen-2-yl)-2-oxoethyl)thio)nicotinonitrile derivative 27
displayed a reasonable radical scavenging activity.
1  INTRODUCTION
As problems of world’s health growth and population increases discovering novel
therapeutics will be even more substantial. The drug design scaffolds conceivable shows
approximately the greatest prospect aimed at achievement in current and the future period.
The study for novel scaffolds owing properties of antioxidant is very important area of the
research, so they able to protect human body from attacking by free radical and hinder the
development of several long-lasting diseases for example cancer, vascular and the oxidative
stress diseases responsible for protein, DNA and also membrane destruction behaviors.[1,2]
The heterocyclic scaffolds are broadly spread in nature and necessary for the life, there are
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massive many pharmacologically active heterocyclic moieties numerous of that are in
consistent clinical use.
Substituted thiophenes are considered as a one of the more significant aromatic
heterocyclic derivatives. They concerned the attention of biologists and chemists because of
their extensive range of biological activities and its application as a synthetic intermediate.
Numerous molecules including thiophene moiety displayed significant pharmacological
interests particularly antioxidant activity.[3–6] 3-Cyano-2,4-diaminothiophenes were identified
as maternal embryonic leucine zipper kinase (MELK) inhibitors.[7] Moreover, thiophene
derivatives find large application in coordination chemistry,[8,9] material science[10–20] and as
potential intermediate in organic synthesis.[21,22] In addition, the imidazole ring is commonly
existing in many synthetic and natural products. One of the structural advantages of imidazole
moiety is that it readily binds to various receptors and enzymes in biological systems. Thus,
fused imidazole heterocycles displaying broad bioactivities like anticonvulsant[23] anti-
inflammatory,[24] sodium channel blocking,[25] antimicrobial,[26] anticancer,[27-29] CB1 receptor
and antihypertensive properties.[30] For example, imidazo[2,1-b]thiazole-guanylhydrazone
derivative (III) (Figure 1) is considered as promising drug compound which displayed
effective antiproliferative activity against many cancer cell lines. Substituted 7,8-dihydro-
imidazo[2,1-b]benzothiazol-5-one derivatives were screened for their virus-inhibiting activity
against influenza A virus.[31]
Depending on the significant pharmacological interests mainly antioxidant activity of
substituted thiophenes, there is a strong inspiration for the continuous synthesis of new
heterocyclic systems incorporating substituted thiophene moiety. Therefore, further
continuation of our previous work,[32-36] we are informing here the synthesis of some more
analogues of various heterocyclic systems (namely; imidazo-thiazole, imidazo-tetrazole,
imidazo-triazole, imidazo-pyridine, imidazo-imidazole, thiazole and/or thiophene)
incorporating 2-thienyl moiety and evaluating their in vitro anti-oxidant activity.
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FIGURE 1 Examples of biologically active thiophene and imidazole compounds
2  RESULTS AND DISCUSSION
2.1  CHEMISTRY
The highly versatile α-bromocarbonyl reagent, 5-bromo-2-(bromoacetyl)-thiophene (1), has
been prepared by the reported conditions through the free radical bromination of 2-
acetylthiophene substrate.[37] The chemical behavior of 5-bromo-2-(bromoacetyl)-thiophene
(1) was verified towards the reaction with several bi-nucleophilic reagents in order to prepare
several bridge nitrogen compounds. Thus, 5-bromo-2-(bromoacetyl)-thiophene (1) was heated
with 2-aminobenzothiazole derivatives 2, 2-aminothiazole (4), 2-aminotetrazole (6), 2-
aminotriazole (8), 2-aminopyridine derivatives 10, 2-aminobenzimidazole (12) and/or o-
phenylenediamine (14) in absolute ethanol in a non-catalyzed reaction. The reaction afforded
a series of the corresponding nitrogen containing heterocycles bearing thiophene moiety,
namely; imidazo-thiazoles 3 and 5, imidazo-tetrazole 7, imidazo-triazole 9, imidazo-pyridines
11, imidazo-imidazole 13 and quinoxaline 15, respectively (Scheme 1). The chemical
structures of the synthesized scaffolds were demonstrated by standard spectroscopic data such
as IR, 1H NMR, 13C NMR and mass analyses.
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SCHEME 1 Synthesis of thienyl-fused heterocyclic compounds 3, 5, 7, 9, 11, 13 and 15
In the course of our investigation, a synthetic route was established to the synthesis of
thiazoles, which consider a privileged structure for its antioxidant activity[38] and the
thiophene moiety. The treatment of activated nitriles 16 (namely; malononitrile, ethyl
cyanoacetate and cyanoacetamide) with phenyl isothiocyanate was carried out by stirring in
dimethylformamide in the presence of potassium hydroxide to afford the highly activated
potassium sulfide intermediates 17. In situ treatment of 17 with 5-bromo-2-(bromoacetyl)-
thiophene (1) promoted heterocyclization to obtain a series of thiazole bearing thiophene
scaffolds 18a, 18b and 18c in good yields (Scheme 2). On the other hand, acidification of
potassium sulfide intermediates 17 with dilute HCl furnished their corresponding
thiocarbamoyl derivatives 19. The reaction of 19 with 5-bromo-2-(bromoacetyl)-thiophene (1)
was achieved in boiling ethanol and triethylamine to present different cyclization behavior
and afforded the di-thien-2-yl ketones 20a, 20b and 20c in good yields (Scheme 2).
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SCHEME 2 Synthesis of thienyl-thiazole and dithienyl-ketone compounds 18 and 20
The reaction mechanism illustrating the establishment of compounds 18a, 18b and 18c
hypothesized by the authors is depicted in (Scheme 3). In a first step, the sulfide nucleophile
can be readily attacking the α-carbon carrying the bromide atom in a bimolecular nucleophilic
substitution reaction to give the intermediate 21, which is not stable and undergo
intramolecular heterocyclization through the nucleophilic nitrogen-affording compound 22.
Dehydration of 22 results in the formation of the scaffolds 18a, 18b and 18c.
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SCHEME 3 Reaction mechanism for the formation of thienyl-thiazole compounds 18a-c
The open-chain precursor 21 is also the intermediate for treatment of 5-bromo-2-
(bromoacetyl)-thiophene (1) with the thiocarbamoyl nucleophiles 19 under reflux in absolute
ethanol and triethylamine. The authors described the synthesis of the di-thien-2-yl ketones
scaffolds 20a, 20b and 20c depending on the tendency of the open-chain precursors 21 to
undergo in situ heterocyclization through nucleophilic addition of methylene group to the
carbonyl group and elimination of water molecule (Scheme 4).
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SCHEME 4 Reaction mechanism for the formation of dithien-2-yl ketones 20a-c
In line with our research plan, the highly functionalized dithien-2-yl ketones 25a, 25b
and 25c were obtained as the main products, on treating thiocarbamoyl derivatives 24 with 5-
bromo-2-(bromoacetyl)-thiophene (1) in the presence of ethanol and triethylamine as a
catalyst (Scheme 5). In view of the extensive and increasing interest in the pharmaceutical
activities of pyridine containing scaffolds, we investigated the reaction of 1 with 2-mercapto-
4,6-dimethylnicotinonitrile (26) by heating in acetone and potassium carbonate to furnish the
corresponding sulfide 27. The formation dithien-2-yl ketone of the type 28 was achieved via
boiling the open-chain precursor 27 in ethanolic sodium ethoxide solution.
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SCHEME 5 Synthesis dithien-2-yl ketones 25a-c and 28
2.2.  Assessment of antioxidant activity
Reactive oxygen species (ROS) and Free radicals are extremely responsive and can be
produced by regular cellular processes. Cell components respond with ROS inspire mutilation
of proteins, lipids, DNA and carbohydrates are involved with several diseases, including
diabetes, cancer and atherosclerosis. In current years, researchers in the area of medicinal
chemistry motived to the synthesis of numerous thiophene derivative due to their extensive
range of applications as anticancer and antioxidants agents. Depending on the numerous
biological reputations of these scaffolds, we explored the newly synthesized thiophene
derivatives as a privileged structure for their antioxidant activity and ABTS antioxidant assay
is used for this assessment.[39] The ABTS (2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic
acid)) examine is a typical method to assessment the overall antioxidant capacity of tissue,
biological fluids, cell, natural and synthetic scaffolds. The estimate measures ABTS•+ radical
cation consistence stimulated by MnO2 which has green color and the resulted absorbance can
be estimated at 734 nm. Antioxidants have the ability to reduce radical cation to ABTS by
electron donation radical scavenging, so prevent the development of the green ABTS radical.
ABTS antioxidant assay is fast and precise. However, the authors must conscious that
chemical antioxidant assay may be disagreement with in vivo actions. The obtained results of
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the ABTS antioxidant assay (Table 1) indicated that clubbing between thiophene and thiazole
in compound 18c promoted the antioxidant activity to the 84.26% percent inhibition that is
very close to the reference antioxidant L-Ascorbic acid (88.44%). The combination between
nicotinonitrile and thiophene moieties in the sulfide compound 27 promoted acceptable
antioxidant activity with percent inhibition = 79.08%. The dithien-2-yl ketone compounds
20a and 20c displayed acceptable antioxidant activity with percent inhibition ranged 65.54%
and 69.92%, respectively. Furthermore, compounds 5, 13, 18a, 18b, 25a and 25c exhibited a
reasonable radical scavenging action with percent inhibition higher than 50%. .
TABLE 1 ABTS radical scavenging activity of the synthesized thien-2-yl heterocycles.
Compounds
Absorbance of samples
0.502
% Inhibition
0
Control of ABTS
0.058
88.44%
46.41%
39.84%
51.00%
46.81%
38.25%
26.89%
35.66%
60.96%
31.67%
55.98%
52.99%
84.26%
65.54%
41.83%
69.92%
58.57%
49.60%
56.37%
79.08%
32.67%
Ascorbic-acid
0.269
3a
3b
0.302
0.246
5
0.267
7
0.31
9
0.367
11a
11b
13
0.323
0.196
0.343
15
0.221
18a
18b
18c
20a
20b
20c
25a
25b
25c
27
0.236
0.079
0.173
0.292
0.151
0.208
0.253
0.219
0.105
0.338
28
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3  CONCLUSION
The present study proposals fast and effective method to the annulated heterocyclization using
bi-nucleophiles. The precursor 5-bromo-2-(bromoacetyl)-thiophene was utilized as a vital
intermediate in the synthetic tactic of novel annulated heterocycles via the reaction of with bi-
nucleophiles as a route to higher heterocyclic systems substituted with 2-thienyl moiety, such
as imidazo-thiazole, imidazo-tetrazole, imidazo-triazole, imidazo-pyridine, imidazo-
imidazole, and quinoxaline. Moreover, the reaction of 5-bromo-2-(bromoacetyl)-thiophene
with various thiocarbamoyl derivatives furnished a new series of thienyl-thiazoles and
dithien-2-yl ketones based on the reaction conditions. All the synthesized compounds were
1
characterized by IR, H NMR, 13C NMR and mass analyses and were investigated for their
antioxidant activity in vitro using ABTS assay. Among the tested thiophene-based
compounds, compounds 18c and 27 displayed the best antioxidant potentiality.
4  EXPERIMENTAL
All melting points were determined on a Gallenkamp electric melting point apparatus.
1
Infrared spectra were measured Thermo Scientific Nicolet iS10 FTIR spectrometer. H NMR
13
(500 MHz) and C NMR (125 MHz) data were obtained in DMSO-d6 solution on JEOL’s
NMR spectrometer using TMS as internal reference. Mass spectra were recorded on a GC–
MS QP-1000 EX Shimadzu instrument by electron ionization technique at 70 eV. Elemental
analyses (C, H and N) were determined on Perkin-Elmer 2400 analyzer.
4.1  General procedure of the synthesis of nitrogen containing heterocycles bearing
thiophene moiety 3, 5, 7, 9, 11, 13 and 15:
A mixture of 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (1) (0.85 g, 0.003 mol) and 2-
aminobenzothiazole derivatives 2, 2-aminothiazole (4), 2-aminotetrazole (6), 2-aminotriazole
(8), 2-aminopyridine derivatives 10, 2-aminobenzimidazole (15) and/or o-phenylenediamine
(17) (0.003 mol) was refluxed in absolute ethanol (25 mL) for 12 hours, the mixture was
cooled. The formed products were collected and then recrystallized from ethanol/DMF
mixture (5:1) to give compounds 3, 5, 7, 9, 11, 13 and 15 respectively.
3-(5-Bromothiophen-2-yl)benzo[d]imidazo[2,1-b]thiazole (3a): Yield = 54% (gray
crystals); m.p. = 220-221°C. IR (KBr): 1604 (C=N), 1518 (C=C), 1273 (C-N), 635 cm-1 (C-
1
Br). H NMR (DMSO-d6):  = 8.69 (s, 1H, imidazole-H), 8.03 (d, J = 8.00 Hz, 1H, Ar-H),
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7.96 (d, J = 8.00 Hz, 1H, Ar-H), 7.55 (t, J = 7.25 Hz, 1H, Ar-H), 7.42 (t, J = 7.25 Hz, 1H, Ar-
13
H), 7.21-7.24 ppm (2d, J = 3.75 Hz, 2H, thiophene-H3 and -H4). C NMR (DMSO-d6): δ =
147.09, 140.27, 139.26, 131.29, 129.22, 126.80, 125.41, 125.10, 122.85, 113.47, 113.11,
109.66, 108.63 ppm. MS: m/z (%) = 336 (M+, 81Br, 19.24), 334 (M+, 79Br, 21.37), 290
(42.57), 258 (100), 217 (43.47), 152 (31.96), 126 (53.03), 105 (32.07). Analysis of
C13H7BrN2S2 (335.24): Calculated: C, 46.58; H, 2.10; N, 8.36%. Found: C, 46.76; H, 2.04; N,
8.26%.
3-(5-Bromothiophen-2-yl)-7-methoxybenzo[d]imidazo[2,1-b]thiazole (3b): Yield = 48%
(brown crystals); m.p. = 152-153°C. IR (KBr): 3434 (N-H), 2832 (CH3), 1599 (C=N), 1524
1
(C=C), 1027 (C-O), 737 cm-1 (C-Br). H NMR (DMSO-d6):  = 8.60 (s, 1H, imidazole-H),
7.88 (d, J = 9.00 Hz, 1H, Ar-H), 7.67 (d, J = 2.50 Hz, 1H, Ar-H), 7.18-7.20 (2d, J = 4.00 Hz,
2H, thiophene-H3 and -H4), 7.12, 7.14 (dd, J = 9.00, 2.50 Hz, 1H, Ar-H), 3.81 ppm (s, 3H,
OCH3). 13C NMR (DMSO-d6): 55.72, 108.62, 109.42, 113.97, 114.12, 122.70, 125.66,
81
130.57, 131.25, 137.36, 139.15, 139.55, 146.48, 157.11 ppm. MS: m/z (%) = 366 (M+, Br,
7.85), 348 (55.46), 248 (53.20), 160 (21.04), 113 (70.93), 69 (93.04), 43 (100). Analysis of
C14H9BrN2OS2 (365.26): Calculated: C, 46.04; H, 2.48; N, 7.67%. Found: C, 46.25; H, 2.55;
N, 7.56%.
5-(5-Bromothiophen-2-yl)imidazo[2,1-b]thiazole (5): Yield = 60% (brown crystals); m.p. =
1
181-182°C. IR (KBr): 1667 (C=N), 1634 (C=C), 1235 (C-N), 714 cm-1 (C-Br). H NMR
(DMSO-d6):  = 9.54 (s, 1H, imidazole-H), 7.95 (d, J = 4.00 Hz, 1H), 7.53 (d, J = 4.00 Hz,
13
1H), 7.33 (d, J = 4.00 Hz, 1H), 7.04 ppm (d, J = 4.00 Hz, 1H). C NMR (DMSO-d6): δ =
183.04, 169.10, 141.42, 135.48, 132.71, 130.55, 123.01, 107.38, 54.19 ppm. MS: m/z (%) =
81
79
286 (M+, Br, 36.12), 284 (M+, Br, 38.33), 279 (59.01), 233 (82.58), 186 (76.06), 128
(100), 120 (65.07), 56 (61.12). Analysis of C9H5BrN2S2 (285.18): Calculated: C, 37.91; H,
1.77; N, 9.82%. Found: C, 37.80; H, 1.83; N, 9.91%.
6-(5-Bromothiophen-2-yl)-4H-imidazo[1,2-d]tetrazole (7): Yield = 50% (light brown
crystals); m.p. = 212-213°C. IR (KBr): 3325 (N-H), 1663 (C=N), 1590 (C=C), 1340 (C-N),
687 cm-1 (C-Br). 1H NMR (DMSO-d6):  = 7.98 (d, J = 4.00 Hz, 1H, thiophene-H), 7.51 (d, J
13
= 4.00 Hz, 1H, thiophene-H), 6.76 (s, 1H, NH), 5.78 ppm (s, 1H, imidazole-H). C NMR
(DMSO-d6): δ = 156.51, 141.81, 135.36 (2C), 132.70 (2C), 122.96 ppm. MS: m/z (%) = 271
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(M+, 81Br, 13.37), 269 (M+, 79Br, 16.56), 219 (48.16), 206 (62.33), 154 (51.37), 98 (57.90), 84
(77.80), 43 (100). Analysis of C7H4BrN5S (270.11): Calculated: C, 31.13; H, 1.49; N,
25.93%. Found: C, 30.96; H, 1.43; N, 25.81%.
6-(5-Bromothiophen-2-yl)-4H-imidazo[1,2-b][1,2,4]triazole (9): Yield = 37% (pale brown
crystals); m.p. = 262-263°C. IR (KBr): 3213 (N-H), 1665 (C=N), 1575 (C=C), 747 cm-1 (C-
1
Br). H NMR (DMSO-d6):  = 8.46 (s, 1H, triazole-H), 8.01 (d, J = 4.00 Hz, 1H, thiophene-
H), 7.55 (d, J = 4.00 Hz, 1H, thiophene-H), 5.81 (s, 1H, imidazole-H), 5.68 ppm (s, 1H, NH).
13C NMR (DMSO-d6): δ = 150.75, 141.22, 140.87, 135.83, 135.55, 132.83 (2C), 123.34 ppm.
81
79
MS: m/z (%) = 270 (M+, Br, 10.88,), 268 (M+, Br, 12.36), 152 (44.33), 141 (60.96), 119
(28.75), 84 (49.24), 77 (100), 42 (44.49). Analysis of C8H5BrN4S (269.12): Calculated: C,
35.70; H, 1.87; N, 20.82%. Found: C, 35.51; H, 1.95; N, 20.90%.
2-(5-Bromothiophen-2-yl)-6-chloroimidazo[1,2-a]pyridine (11a): Yield = 39% (gray
crystals); m.p. = 240-241°C. IR (KBr): 1646 (C=N), 1594 (C=C), 1251 (C-N), 800 (C-Cl),
1
706 cm-1 (C-Br). H NMR (DMSO-d6):  = 9.06 (s, 1H, pyridine-H), 8.52 (s, 1H, imidazole-
H), 7.81 (d, J = 9.00 Hz, 1H, pyridine-H), 7.74 (d, J = 9.00 Hz, 1H, pyridine-H), 7.54 (d, J =
13
4.00 Hz, 1H, thiophene-H), 7.33 ppm (d, J = 4.00 Hz, 1H, thiophene-H). C NMR (DMSO-
d6): δ = 143.24, 137.10, 131.68, 131.46, 127.46, 125.85, 125.67, 122.70, 121.02, 117.58,
81
79
109.82 ppm. MS: m/z (%) = 314 (M+, Br, 90.88), 312 (M+, Br, 100), 311 (84.23), 309
(42.68), 77 (2.19), 43 (29.45). Analysis of C11H6BrClN2S (313.60): Calculated: C, 42.13; H,
1.93; N, 8.93%. Found: C, 42.35; H, 2.05; N, 8.79%.
2-(5-Bromothiophen-2-yl)imidazo[1,2-a]pyridine (11b): Yield = 46% (white crystals); m.p.
1
= 213-214oC. IR (KBr): 1651 (C=N), 1607 (C=C), 1361 (C-N), 620 cm-1 (C-Br). H NMR
(DMSO-d6):  = 8.78 (d, J = 6.50 Hz, 1H, pyridine-H), 8.64 (s, 1H, imidazole-H), 7.87-7.80
(m, 2H, pyridine-H), 7.57 (d, J = 4.00 Hz, 1H, thiophene-H), 7.40 (d, J = 4.00 Hz, 1H,
thiophene-H), 7.37 ppm (d, J = 6.50 Hz, 1H, pyridine-H). 13C NMR (DMSO-d6): δ = 140.45,
132.92, 131.98, 130.84, 130.18, 128.85, 128.48, 116.95, 114.95, 112.48, 110.77 ppm. MS:
m/z (%) = 280 (23.04, M+ + 2), 278 (26.04, M+), 167 (68.96), 82 (100), 90 (85.88), 92 (96.02),
139 (82.95), 178 (95.22). Analysis of C11H7BrN2S (279.16): Calculated: C, 47.33; H, 2.53; N,
10.04%. Found: C, 47.44; H, 2.55; N, 10.11%.
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3-(5-Bromothiophen-2-yl)-1H-benzo[d]imidazo[1,2-a]imidazole (13): Yield = 55% (gray
crystals); m.p. = 242-243oC. IR (KBr): 3237 (N-H), 1676 (C=N), 1524 (C=C), 1200 (C-N),
671 cm-1 (C-Br). 1H NMR (DMSO-d6):  = 8.17 (d, J = 4.00 Hz, 1H, thiophene-H), 7.81 (d, J
= 7.50 Hz, 1H, Ar-H), 7.57 (d, J = 4.00 Hz, 1H, thiophene-H), 7.56 (s, 1H, NH), 7.32 (t, J =
7.50 Hz, 1H, Ar-H), 7.26 (t, J = 7.50 Hz, 1H, Ar-H), 7.19-7.17 (m, 1H, Ar-H), 5.88 ppm (s,
1H, imidazole-H). 13C NMR (DMSO-d6): δ = 142.01, 135.85, 135.74, 132.81, 131.19, 123.90,
81
123.21, 122.69, 121.11, 111.66, 110.99, 109.17, 103.45 ppm. MS: m/z (%) = 319 (M+, Br,
79
33.23), 317 (M+, Br, 29.91), 219 (54.68), 119 (45.68), 75 (6.38). Analysis of C13H8BrN3S
(318.19): Calculated: C, 49.07; H, 2.53; N, 13.21%. Found: C, 49.28; H, 2.41; N, 13.07%.
2-(5-Bromothiophen-2-yl)quinoxaline (15): Yield = 68% (brown crystals); m.p. = 168-
169°C. IR (KBr): 1639 (C=N), 1546 (C=C), 1309 (C-N), 610 cm-1 (C-Br). 1H NMR (DMSO-
d6):  = 9.52 (s, 1H, pyrazine-H), 8.06 (d, J = 3.50 Hz, 1H, thiophene-H), 8.04 (d, J = 1.50
Hz, 1H, Ar-H), 7.99-7.97 (dd, J = 8.25, 1.50 Hz, 1H, Ar-H), 7.84-7.76 (m, 2H, Ar-H), 7.40
13
ppm (d, J = 3.50 Hz, 1H, thiophene-H). C NMR (DMSO-d6): δ = 146.20, 143.55, 142.21,
140.99, 140.84, 132.36, 130.95, 129.75, 129.38, 12.96, 128.48, 117.01 ppm. MS: m/z (%) =
81
79
292 (M+, Br, 9.76), 290 (M+, Br, 13.35), 266 (30.99), 127 (41.74), 105 (55.15), 91 (100),
77 (70.39), 62 (57.38). Analysis of C12H7BrN2S (291.17): Calculated: C, 49.50; H, 2.42; N,
9.62%. Found: C, 49.38; H, 2.45; N, 9.70%.
4.2  Synthesis of 4-(5-bromothiophen-2-yl)-3-phenylthiazol-2(3H)-ylidene derivatives
18a-c:
A mixture of each activated nitrile derivative 16a, 16b or 16c (0.002 mol), phenyl
isothiocyanate (0.24 mL, 0.002 mol) and potassium hydroxide (0.12 g, 0.002 mol) was stirred
in 15 mL DMF for overnight. Then 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (1) (0.57
g, 0.002 mol) was added with continuous stirring for additional 4 hours. The suspension was
poured into ice water and the solid product that obtained was collected by filtration and
recrystallized from ethanol to give 18a, 18b and 18c, respectively.
2-(4-(5-Bromothiophen-2-yl)-3-phenylthiazol-2(3H)-ylidene)-malononitrile (18a): Yield =
52% (yellow powder); m.p. = 216-217°C. IR (KBr): 2214, 2198 (C≡N), 1598 (C=C), 696 cm-
1
1
(C-Br). H NMR (DMSO-d6):  = 7.44-7.43 (m, 5H, Ar-H), 7.38 (s, J = 4.00 Hz, 1H,
thiophene-H), 7.25 ppm (d, J = 4.00 Hz, 2H, thiophene-H and thiazole-H). 13C NMR (DMSO-
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d6): δ = 173.17, 164.71, 158.8,4 147.21, 139.52, 131.72, 129.66 (2C), 129.34, 125.96, 122.18
(2C), 118.01, 113.27, 91.56, 79.86 ppm. MS: m/z (%) = 387 (M+, 81Br, 49.16), 385 (M+, 79Br,
53.57), 322 (97.24), 320 (100), 271 (80.08), 137 (80.75), 108 (56.65), 63 (93.65). Analysis of
C16H8BrN3S2 (386.29): Calculated: C, 49.75; H, 2.09; N, 10.88%. Found: C, 49.61; H, 2.16;
N, 10.76%.
Ethyl 2-(4-(5-bromothiophen-2-yl)-3-phenylthiazol-2(3H)-ylidene)-2-cyanoacetate (18b):
Yield = 82% (yellowish white powder); m.p. = 177-178°C. IR (KBr): 2981 (C-H), 2205
1
(C≡N), 1692 (C=O), 693 cm-1 (C-Br). H NMR (CDCl3):  = 7.64-7.59 (m, 1H, Ar-H), 7.51
(t, J = 8.50 Hz, 2H, Ar-H), 7.33 (d, J = 9.50 Hz, 2H, Ar-H), 6.82 (s, 1H, thiazole-H), 6.81 (d,
J = 4.00 Hz, 1H, thiophene-H), 6.46 (d, J = 4.00 Hz, 1H, thiophene-H), 4.24 (q, J = 7.25 Hz,
13
2H, CH2), 1.26 ppm (t, J = 7.25 Hz, 3H, CH3). C NMR (CDCl3): δ = 168.01, 167.58,
135.74, 133.58, 131.91 (2C), 130.06, 129.83 (2C), 129.27, 126.28, 125.81, 115.48, 114.78,
109.57, 97.07, 61.12, 14.31 ppm. MS: m/z (%) = 434 (M+, 81Br, 15.36), 432 (M+, 79Br, 17.38),
200 (53.27), 189 (73.00), 133 (89.79), 91 (100), 78 (86.49), 64 (63.55). Analysis of
C18H13BrN2O2S2 (433.34): Calculated: C, 49.89; H, 3.02; N, 6.46%. Found: C, 49.70; H, 3.11;
N, 6.31%.
2-(4-(5-Bromothiophen-2-yl)-3-phenylthiazol-2(3H)-ylidene)-2-cyanoacetamide
(18c):
Yield 57 % (orang crystal); m.p. = 182-183°C; IR (KBr): 3396, 3314 (NH2), 2184 (C≡N),
1641 (C=O), 696 cm-1 (C-Br). 1H NMR (DMSO-d6):  = 7.57 (s, 2H, NH2), 7.52-7.47 (m, 5H,
Ar-H), 7.35 (s, 1H, thiazole-H), 7.07 (d, J = 3.50 Hz, 1H, thiophene-H), 6.80 ppm (d, J = 3.50
13
Hz, 1H, thiophene-H). C NMR (DMSO-d6): δ = 167.69, 165.57, 136.00 133.94, 131.55,
131.30, 130.37 (2C), 130.27, 129.95, 129.48 (2C), 116.29, 113.92, 110.83, 66.45 ppm. MS:
m/z (%) = 405 (M+, 81Br, 6.33), 158 (51.27), 117 (86.89), 86 (53.83), 80 (97.52), 77 (100), 51
(20.85). Analysis of C16H10BrN3OS2 (404.30): Calculated: C, 47.53; H, 2.49; N, 10.39%.
Found: C, 47.38; H, 2.56; N, 10.48%.
4.3  Synthesis of 4-amino-5-(5-bromothiophene-2-carbonyl)-2-(phenylamino)thiophene
derivatives 20a-c:
A mixture of 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (1) (0.28 g, 0.001 mol) and each
derivative of cyano-3-mercapto-3-(phenylamino)acrylates 19 (0.001 mol) was refluxed in
absolute ethanol (15 mL) and triethylamine (0.5 mL) for 2 hours. The reaction mixture was
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permitted to cool and then the formed solid product was collected and recrystallized from
EtOH/DMF mixture (5:1) to give the corresponding 4-aminothiophene derivatives 20a, 20b
and 20c.
4-Amino-5-(5-bromothiophene-2-carbonyl)-2-(phenylamino)thiophene-3-carbonitrile
(20a): Yield = 43% (brown powder); m.p. = 122-123°C. IR (KBr): (NH2), 4357, 3380, 3234
(NH2 and NH), 2216 (C≡N), 1609 (conjugated C=O), 690 cm-1 (C-Br). 1H NMR (DMSO-d6):
 = 10.72 (s, 1H, NH), 8.15 (s, 2H, NH2), 7.45-7.43 (m, 4H, Ar-H), 7.38 (d, J = 4.00 Hz, 1H,
13
thiophene-H), 7.26-7-22 ppm (m, 2H, Ar-H and thiophene-H). C NMR (DMSO-d6): δ =
173.18, 164.74, 158.86, 147.21, 139.52, 131.76, 129.68 (2C), 129.38, 125.99, 122.20 (2C),
81
79
118.03, 113.28, 91.55, 79.84 ppm. MS: m/z (%) = 405 (M+, Br, 18.76), 403 (M+, Br,
20.94), 371 (39.59), 272 (43.39), 115 (11.94), 81 (46.74), 41 (100). Analysis of
C16H10BrN3OS2 (404.30): Calculated: C, 47.53; H, 2.49; N, 10.39%. Found: C, 47.44; H,
2.46; N, 10.45%.
Ethyl-4-amino-5-(5-bromothiophene-2-carbonyl)-2-(phenylamino)thiophene-3-
carboxylate (20b): Yield = 70% (orang crystal); m.p. = 162-163°C. IR (KBr): 3473, 3272
1
(NH2 and NH), 1659 (C=O), 742 cm-1 (C-Br). H NMR (DMSO-d6):  = 10.27 (s, 2H, NH2),
9.09 (s, 12H, NH2), 7.50-7.44 (m, 4H, Ar-H), 7.33 (d, J = 4.0 Hz, 1H, thiophene-H), 7.31-
7.27 (m, 1H, Ar-H), 7.22 (d, J = 4.00 Hz, 1H, thiophene-H), 4.36 (q, J = 7.25 Hz, 2H, CH2)
13
1.34 ppm (t, J = 7.25 Hz, 3H, CH3). C NMR (DMSO-d6): δ = 172.79, 164.91, 163.99,
158.57, 147.74, 138.86, 131.30, 129.50 (2C), 128.57, 126.07, 122.49 (2C), 117.15, 96.34,
81
91.26, 60.36, 14.09 ppm. MS: m/z (%) = 452 (M+, Br, 19.35), 450 (M+, 79Br, 22.40), 320
(100), 297 (52.95), 127 (61.12), 104 (80.14), 75 (57.78). Analysis of C18H15BrN2O3S2
(451.35): Calculated: C, 47.90; H, 3.35; N, 6.21%. Found: C, 47.74; H, 3.42; N, 6.33%.
4-Amino-5-(5-bromothiophene-2-carbonyl)-2-(phenylamino)thiophene-3-carboxamide
(20c): Yield = 49% (Light brown powder); m.p. = 280-281°C. IR (KBr): 3454, 3404, 3330,
1
3256 (NH2 and NH), 1653 (C=O), 691 cm-1 (C-Br). H NMR (DMSO-d6):  = 10.26 (s, 1H,
NH), 8.08 (s, 2H, NH2), 7.49 (s, 2H, NH2), 7.42-7.37 (m, 5H, Ar-H and thiophene-H), 7.26 (d,
13
J = 4.50 Hz, 1H, thiophene-H), 7.17-7.14 ppm (m, 1H, Ar-H). C NMR (DMSO-d6): δ =
173.08, 165.97, 160.55, 158.48, 148.05, 140.23, 131.62, 129.54 (2C), 128.98, 124.56, 120.72
(2C), 117.44, 103.66, 92.89 ppm. MS: m/z (%) = 423 (M+, 81Br, 42.27), 421 (M+, 79Br, 45.49),
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407 (50.61), 387 (59.38), 368 (54.19), 271 (59.15), 255 (100), 95 (52.03). Analysis of
C16H12BrN3O2S2 (422.32): Calculated: C, 45.51; H, 2.86; N, 9.95%. Found: C, 45.67; H, 2.78;
N, 9.86%.
4.4  Synthesis of 4-amino-5-(5-bromothiophene-2-carbonyl)-N-phenyl-2-(phenylamino)-
thiophene-3-carboxamide derivatives 25a-c:
A suspension of 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (1) (0.28 g, 0.001 mol) and
each N-aryl-2-cyano-3-mercapto-3-(phenylamino)-acrylamide derivative 24a, 24b or 24c
(0.001 mol) was refluxed for 45 minutes in absolute ethanol (15 mL) and triethylamine (0.5
mL), then allowed to cool. The formed solid product was collected and recrystallized from
ethanol/DMF mixture (5:1) to give 25a, 25b and 25c.
4-Amino-5-(5-bromothiophene-2-carbonyl)-N-phenyl-2-(phenylamino)thiophene-3-
carboxamide (25a): Yield = 47% (yellow crystals); m.p. = 225-226°C. IR (KBr): 3369,
3339, 3274 (NH2 and NH), 1637 (C=O), 681 cm-1 (C-Br). 1H NMR (DMSO-d6):  = 9.98 (s,
1H, NH), 9.97 (s, 1H, NH), 7.99 (s, 2H, NH2), 7.43 (d, J = 4.00 Hz, 1H, thiophene-H), 7.41-
7.29 (m, 8H, Ar-H), 7.27 (d, 1H, J = 4.00 Hz, 1H, thiophene-H), 7.16-7.14 (m, 1H, Ar-H),
13
7.07-7.05 ppm (m, 1H, Ar-H). C NMR (DMSO-d6): δ = 173.01, 162.09, 159.47, 158.31,
148.05, 140.47, 138.87, 131.62, 129.44 (2C), 128.97, 128.39 (2C), 124.54, 123.47, 120.90
81
(2C), 120.33 (2C), 117.89, 105.11, 92.84 ppm. MS: m/z (%) = 499 (M+, Br, 15.69), 497
79
(M+, Br, 14.93), 437 (67.68), 394 (64.20), 352 (63.71), 162 (66.06), 153 (100). Analysis of
C22H16BrN3O2S2 (498.41): Calculated: C, 53.02; H, 3.24; N, 8.43%. Found: C, 53.11; H, 3.10;
N, 8.51%.
4-Amino-5-(5-bromothiophene-2-carbonyl)-2-(phenylamino)-N-(p-tolyl)thiophene-3-
carboxamide (25b): Yield = 70% (yellow crystals); m.p. = 220-221°C; IR (KBr): 3383,
3330, 3289 (NH2 and NH), 2916 (C-H), 1632 (C=O), 679 cm-1 (C-Br). 1H NMR (DMSO-d6):
 = 9.98 (s, 1H, NH), 9.81 (s, 1H, NH), 8.04 (s, 2H, NH2), 7.42 (d, J = 4.00 Hz, 1H,
thiophene-H), 7.39-7.37 (m, 6H, Ar-H), 7.32 (d, J = 9.00 Hz, 2H, Ar-H), 7.25 (d, J = 4.00 Hz,
1H, thiophene-H), 7.15-7.12 (m, 1H, Ar-H), 2.34 ppm (s, 3H, CH3). 13C NMR (DMSO-d6): δ
173.00, 161.92, 159.32, 158.34, 148.07, 140.53, 136.33, 132.45, 131.76, 129.46 (2C), 129.00,
128.80 (2C), 124.49, 120.84 (2C), 120.36 (2C), 117.50, 97.06, 104.73, 20.51 ppm. MS: m/z
(%) = 513 (M+, 81Br, 9.94), 511 (M+, 79Br, 11.11), 422 (42.52), 347 (66.78), 297 (52.49), 112
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(54.59), 71 (75.55), 57 (100). Analysis of C23H18BrN3O2S2 (512.44): Calculated: C, 53.91; H,
3.54; N, 8.20%. Found: C, 53.75; H, 3.62; N, 8.06%.
4-Amino-5-(5-bromothiophene-2-carbonyl)-N-(4-methoxyphenyl)-2-(phenylamino)-
thiophene-3-carboxamide (25c): Yield = 51% (yellow crystals); m.p. = 205-206°C. IR
1
(KBr): 3384, 3326 (NH2 and NH), 1629 (C=O), 682 cm-1 (C-Br). H NMR (DMSO-d6):  =
9.97 (s, 1H, NH), 9.83 (s, 1H, NH), 7.98 (s, 2H, NH2), 7.54 (d, J = 9.00 Hz, 2H, Ar-H), 7.42
(d, J = 4.00 Hz, 1H, thiophene-H), 7.40-7.39 (m, 4H, Ar-H), 7.26 (d, J = 4.00 Hz, 1H,
thiophene-H), 7.15-7.12 (m, 1H, Ar-H), 6.89 (d, J = 9.00 Hz, 2H, Ar-H), 3.71 ppm (s, 3H,
13
OCH3). C NMR (DMSO-d6): δ = 173.02, 161.77, 159.17, 158.35, 155.54, 148.11, 140.54,
131.89, 131.69, 129.49 (2C), 129.03, 124.48, 122.01 (2C), 120.80 (2C), 117.52, 113.58 (2C),
81
79
105.25, 92.89, 55.22 ppm. MS: m/z (%) = 529 (M+, Br, 16.34), 527 (M+, Br, 19.67), 493
(53.71), 335 (74.43), 248 (72.89), 112 (59.48), 76 (60.87), 55 (100). Analysis of
C23H18BrN3O3S2 (528.44): Calculated: C, 52.28; H, 3.43; N, 7.95%. Found: C, 52.21; H, 3.47;
N, 8.01%.
4.5

Synthesis of 2-((2-(5-bromothiophen-2-yl)-2-oxoethyl)thio)-4,6-dimethyl-
nicotinonitrile (27):
To a mixture of 2-bromo-1-(5-bromothiophen-2-yl)ethan-1-one (1) (1.13 g, 0.004 mol) and 2-
mercapto-4,6-dimethylbenzonitrile (26) (0.59 g, 0.004 mol) in 20 mL acetone, potassium
carbonate (0.55 g, 0.004 mol) was added and then refluxed for 3 hours. The reaction mixture
was decanted onto crushed ice and when the precipitated product was formed, it was collected
by the filtration and then washed with water. The obtained solid was recrystallized from
ethanol to give the corresponding sulfide 27.
Yield = 68% (yellow crystals); m.p. = 142-143°C. IR (KBr): 2914 (C-H), 2214 (C≡N), 1658
1
(C=O), 707 cm-1 (C-Br). H NMR (CDCl3):  = 7.66 (d, J = 4.00 Hz, 1H, thiophene-H), 7.14
(d, J = 4.00 Hz, 1H, thiophene-H), 6.77 (s, 1H, pyridine-H), 4.45 (s, 2H, CH2), 2.43 (s, 3H,
CH3), 2.28 ppm (s, 3H, CH3). 13C NMR (CDCl3): δ = 185.56, 161.18, 159.85, 152.22, 144.47,
132.55, 131.22, 123.09, 120.37, 114.74, 104.61, 36.49, 24.17, 20.06 ppm. MS: m/z (%) = 368
81
79
(M+, Br, 48.24), 366 (M+, Br, 44.37), 355 (96.42), 206 (64.76), 160 (42.14), 132 (65.53),
125 (100), 47 (72.14). Analysis of C14H11BrN2OS2 (367.28): Calculated: C, 45.78; H, 3.02; N,
7.63%. Found: C, 45.91; H, 3.07; N, 7.71%.
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4.6  Synthesis of (3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)(5-bromothiophen-2-
yl)methanone (28):
A solution of sulfide compound 27 (0.36 g, 0.001 mol) was refluxed for 2 hours in
sodium ethoxide, which prepared from 0.11 g Na and 20 mL absolute ethanol. The mixture
was permitted to be cool and then poured onto ice-water. The obtained product was dried out
and recrystallized from ethanol to give 28.
Yield = 56% (orange crystals); m.p. = 188-189°C. IR (KBr): 3491 3276 (NH2), 1590
1
(conjugated C=O), 736 cm-1 (C-Br). H NMR (CDCl3):  = 7.73 (d, J = 4.00 Hz, 1H,
thiophene-H), 7.41 (broad s, 2H, NH2), 7.12 (d, J = 4.00 Hz, 1H, thiophene-H), 6.92 (s, 1H,
13
pyridine-H), 2.77 (s, 3H, CH3), 2.63 ppm (s, 3H, CH3). C NMR (CDCl3/DMSO-d6): δ =
177.14, 159.28, 152.64, 146.44, 145.71, 130.21, 129.61, 121.49, 121.10, 119.12, 100.67,
22.78, 19.65 ppm. MS: m/z (%) = 368 (84.88, M+ + 2), 366 (85.98 M+) 328 (44.85), 191
(67.24), 118 (100), 112 (81.74), 42 (90.80). Analysis of C14H11BrN2OS2 (367.28): Calculated:
C, 45.78; H, 3.02; N, 7.63%. Found: C, 45.66; H, 3.08; N, 7.71%.
4.7  ABTS antioxidant assay:
The radical cation derived from ABTS was prepared by addition of 2 mL ABTS solution (60
µM) to 3 mL MnO2 (25 mg/mL) in 5 mL aqueous buffer solution (pH = 7). The produced
suspension was shaken for a few minutes, centrifuged and then filtered. The absorbance (A
control) of the green-blue solution that obtained (ABTS radical solution) was determined at
λmax 734 nm. The absorbance (A test) of each tested compound was measured upon the
addition of (20 μL of 1 mg/mL) solution in spectroscopic grade MeOH/phosphate buffer (1:1)
to the ABTS solution. The decrease in the absorbance is expressed as % inhibition, which is
calculated from the equation: %Inhibition = [A(control) – A(test) / A(control)] × 100
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