A one-pot synthesis of thiophenes and their annulated derivatives with potential pharmaceutical interest

Article abstract of DOI:10.1080/10426500600605749

The reaction of 2-cyanomethylene benzo[d]imidazole (1) with carbon disulphide in basic DMF solution gave the di-potassium disulphide salt (3). The reaction of the latter with the α-halocarbonyl compounds 4 and 13 afforded the thiophene derivatives 5 and 1

Full text of DOI:10.1080/10426500600605749

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A One-Pot Synthesis of
Thiophenes and Their
Annulated Derivatives With
Potential Pharmaceutical
Interest
Wagnat Wahba Wardakhan a
a National Organization for Drug Control & Research,
Cairo, Arab Republic of Egypt
Published online: 21 Sep 2006.
To cite this article: Wagnat Wahba Wardakhan (2006): A One-Pot Synthesis of
Thiophenes and Their Annulated Derivatives With Potential Pharmaceutical Interest,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:9, 2051-2061
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Phosphorus, Sulfur, and Silicon, 181:2051–2061, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600605749
A One-Pot Synthesis of Thiophenes and Their Annulated
Derivatives With Potential Pharmaceutical Interest
Wagnat Wahba Wardakhan
National Organization for Drug Control & Research, Cairo,
Arab Republic of Egypt
The reaction of 2-cyanomethylene benzo[d]imidazole (1) with carbon disulphide in
basic DMF solution gave the di-potassium disulphide salt (3). The reaction of the
latter with the α-halocarbonyl compounds 4 and 13 afforded the thiophene deriva-
tives 5 and 14, respectively. The latter products were used to synthesize annulated
products with potential pharmaceutical interest.
Keywords Benzo[d]imidazole; carbon disulphide; thieno[3,2-b]pyridine; thiophene
INTRODUCTION
Our long-term continuing interest in the chemistry of thiophenes1−4
forms a part of our systematic efforts to obtain pyridines, pyrimidines,
pyridazines, thiophenes, and their analogous. The importance of such
compounds is due to their diverse pharmaceutical activities, including
antibacterial,5,6 anti-diabetic,7 anti-HIV,8 antiviral,9,10 and analgesic11
activities.
RESULTS AND DISCUSSION
Chemistry
Recently we have reported on the uses of thiophenes to form annulated
systems.12,13 In continuation to our previous work, we report herein
the reaction of 2-cyanomethylenobenzo[d]imidazole with carbon disul-
phide in basic dimethylformamide. The reaction lead to the formation
Received November 14, 2005; accepted December 9, 2005.
The screening antimicrobial tests were recorded by Professor S. A. Ouf and his re-
search group, Department of Botany, Faculty of Science, Botany Department; his efforts
were greatly appreciated.
Address correspondence to Wagnat Wahba Wardakhan, National Organization for
Drug Control & Research, PO Box 29, Cairo, A. R. Egypt. E-mail: wagnatward@hotmail.
com
2051

2052
W. W. Wardakhan
of the intermediate di-potassium disulphide salt 3. The reaction of 3
with α-haloesters was studied. Thus, ethyl α-chloroacetate (4) gave the
thiophene derivative 5. The structure of compound 5 was based on ana-
lytical and spectral data. Thus, the IR spectrum of the reaction product
showed NH and NH2 stretchings at υ− 3480–3328 cm−1, and two C O
stretchings at υ− 1694 and 1685 cm−1. Moreover, the 1H NMR spectrum
showed two triplets at δ 1.13, and 1.18 for two esters CH3 groups, two
quartets at δ 4.24 and 4.26 for two esters CH2 groups, a singlet at δ
4.88 for a CH2 group, a singlet (D2O exchangeable) at δ 5.32 for a NH2
group, a multiplet at δ 7.28–7.34 for a C6H4 group, and a singlet at δ
8.88 (D2O exchangeable) for a NH group. The reaction of compound 5
with benzaldehyde (6) afforded the benzal derivative 7. However, with
salicylaldehyde (8), the coumarin derivative 9 was formed14 (Scheme
1). The analytical and spectral data for compounds 8 and 9 were in-
consistent with the assigned structures (see the Experimental section).
The reaction of compound 5 with hydrazine hydrate gave the 5-
hydrazino thiophene derivative 11. The latter product underwent
ready cyclization when heated in dimethylformamide solution contain-
ing triethylamine to give the benzo[d]imidazo[3,2:2,3]pyrazolo[5,4:2,3]-
thiophene derivative 12 through ammonia elemination. The structure
of the latter product was based on 1H NMR spectrum, which showed a
triplet at δ 1.16 for ester CH3, a quartet at δ 4.23 for the ester CH2 group,
a singlet (D2O exchangeable) at δ 4.89 for a NH2 group, a multiplet at δ
7.30–7.37 for C6H4 protons, and a singlet at δ 9.03 (D2O exchangeable)
for NH a group.
Next, we moved toward studying the reactivity of the intermediate
di-potassium disulphide salts 4 toward α-haloketones. Thus, the reac-
tion of 3 with ω-bromoacetophenone (13) gave the thiophene deriva-
tive 14. Analytical and spectral data were in agreement with the
proposed structure (see the Experimental section). The reaction of 14
with hydrazine hydrate (10) gave the 4-hydrazinothieno[3,2-c]pyrazole
15 (Scheme 2).
The reactivity of 14 toward cyanomethylene derivatives was stud-
ied in aim to form fused thiophene derivatives with potential phar-
maceutical uses. Thus, the reaction of 14 with either malononitrile
(16a) or ethyl cyanoacetate (16b) gave the theino[3,2:b]pyridine deriva-
tives 17a and 17b, respectively. The structures of 17a,b were assigned
on the basis of their elemental analyses and spectral data. Thus, the
IR spectrum of 17a indicated the presence of NH2 and NH groups
stretching at υ− 3487–3345 cm−1, CN groups stretching at υ− 2225
cm−1, and one C O group stretching at υ− 1668 cm−1. The reac-
tion of either 17a or 17b with hydrazine hydrate in refluxing 1,4-
dioxan solution gave the 5-hydrazinothieno[3,2:b]pyridine derivatives

Thiophenes and Their Annulated Derivatives
2053
SCHEME 1
18a and 18b, respectively. Compounds 18a,b underwent ready cy-
clization when heated in an oil bath at 140◦C to give the annu-
lated products 19a and 19b, respectively, through ammonia libera-
tion. The analytical and spectral data of the reaction products were

2054
W. W. Wardakhan
SCHEME 2
in accordance with the proposed structures (see the Experimental sec-
tion). The latter reaction constituted a facile and convenient one-pot
reaction leading to fused heterocyclic derivatives, which are difficult to
access (Scheme 3).

Thiophenes and Their Annulated Derivatives
2055
SCHEME 3
SCREENING FOR ANTIMICROBIAL ACTIVITY
Twelve compounds were screened in vitro for their antimicrobial ac-
tivity against two bacterial isolates 1 sapro (Escherichia coli), para-
sitic (Xanthomonas citi), 3 fungal isolates, 1 saprophytic (Aspergillus
fumigatus), 2 phytopathogenic (Rhizoctonia solani and Fusarium

2056
W. W. Wardakhan
TABLE I Inhibition Zones in mm for Some of the Synthesized
Compounds at a Concentration Level of 25 µg/mL
Compound
E. coli
X. citri
A. fumigatus
R. solani
F. oxysporum
5
7
9
11
12
15
17a
17b
18a
18b
19a
19b
7
10
19
15
29
22
35
19
35
20
36
19
7
12
14
19
21
18
32
22
19
14
14
10
10
7
6
15
8
17
17
12
15
6
8
7
6
0
0
0
5
0
16
18
16
16
18
10
14
8
18
18
16
8
20
12
16
5
18
10
oxysporum). The culture medium was the nutrient agar for bacteria
and Czapek’s Dox agar medium for fungi. The sterile medium was in-
oculated with the test organism so that each 100 mL of the medium
received 1 mL of a 24-h culture of the bacterium or a 7-day-old culture
of a spore suspension of the fungus. Solutions of the tested compounds
at 25 µg/mL in dimethylformamide (DMF) were placed separately in
the cup (8-mm diameter). The plates were incubated at 28◦C, and the
resulting inhibition zones were measured. DMF as a blank exhibited
no antimicrobial activity against any of the tested organisms used.
The recorded inhibition zones are summarized in Table I. The results
indicated that most of the prepared compounds were active against the
test organisms. The most toxic compounds against bacterial and fungal
isolates were 12, 15, 17a, 18a, and 19a followed by 17b, 18b, and 19b.
Compounds 5, 7, 9, and 11 were less toxic to the test organisms. The
bacterial isolates were more susceptible to the synthesized compounds
than fungal isolates. The biological investigation was recorded by Pro-
fessor S. O. Abou Elyazeed, whose efforts are greatly appreciated.
CONCLUSION
The work described in this article showed an easy way for the synthesis
of thiophenes and their fused derivatives. Most of the newly synthesized
products revealed either high or moderate toxicity.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded (KBr)
1
on a Pye Unicam Sp-1000 spectrophotometer. H NMR spectra were

Thiophenes and Their Annulated Derivatives
2057
obtained on a Varian EM-390 90 MHz spectrometer in DMSO-d6 as a
solvent and TMS as an internal reference. Chemical shifts δ are ex-
pressed in ppm.
Ethyl 3-Amino-4-(benzo[d]imidazolo-2-yl)-5-
ethoxycarbonylmethyl-sulfanylthiophen-2-carboxylate (5)
and 3-Amino-2-benzoyl-4-(benzo[d]imidazolo-2-yl)-5-
benzoylmethylsulfanylthiophene (14)
General Procedure
To a solution of the 2-cyanomethylbenzo[d]imidazole (1) in dimethyl-
formamide (1.57 g, 0.01 mol) containing potassium hydroxide (0.56 g,
0.01 mol), carbon disulphide (0.76 g, 0.01 mol) was added. The reac-
tion mixture was stirred at r.t. overnight, and then either ethyl α-
chloroacetate (4) or ω-bromoacetophenone (13) was added; the whole
mixture was left at r.t. for another night with continuous stirring. The
reaction mixture was poured onto ice/water containing hydrochloric
acid (until pH 5–6), and the formed solid product, in each case, was
collected by filtration.
5: Orange crystals (from ethanol), yield 67% (2.71 g), m.p. 88◦C. IR υ
(cm−1
)
3480–3328 (NH2, NH), 3057 (CH aromatic), 2987, 2880 (CH3,
CH2), 1694, 1685 (2 C O), 1660 (C N), 1642 (C C). 1H NMR δ = 1.13,
1.18 (2t, 6H, J = 4.56, 6.72 Hz, 2CH3), 4.24, 4.26 (2q, 4H, J = 4.56, 6.72
Hz 2CH2), 4.88 (s, 2H, CH2), 5.32 (s, 2H, NH2), 7.28–7.34 (m, 4H, C6H4),
8.88 (s, 1H, NH). C18H19N3O4S2 (405.49): Calcd.: C, 53.32; H, 4.72; N,
10.36; S, 15.82. Found: C, 53.06; H, 5.18; N, 10.07; S, 15.65.
14: Yellow crystals (from ethanol), yield 72% (3.37 g), m.p. 111◦C.
IR υ (cm−1) = 3480–3321 (NH2, NH), 3060 (CH aromatic), 2890 (CH2),
1688, 1683 (2 C O), 1657 (C N), 1634 (C C). 1H NMR δ = 5.21 (s, 2H,
CH2), 5.38 (s, 2H, NH2), 7.30–7.38 (m, 14H, 2C6H5, C6H4), 8.92 (s, 1H,
NH). C26H19N3O2S2 (469.09): Calcd.: C, 66.50; H, 4.08; N, 8.95; S, 13.66;
Found: C, 66.26; H, 4.18; N, 9.31; S, 13.83.
Ethyl 3-Amino-4-(benzo[d]imidazolo-2-yl)-5-
ethoxycarbonybenzallmeth-yidinosulfanylthiophen-2-
carboxylate (7) and Ethyl 3-Amino-4-(benzo[d]-
imidazolo-2-yl)-5-coumarin-3-yl-sulfanylthiophen-2-
carboxylate (9)
General Procedure
To a solution of compound 5 (4.05 g, 0.01 mol) in 1,4-dioxan (40 mL)
containing piperidine (0.5 g), either benzaldehyde (1.06 g, 0.01 mol)
or salicyaldehyde (1.22 g, 0.01 mol) was added. The reaction mixture,

2058
W. W. Wardakhan
in each case, was heated under reflux for 4 h and then poured onto
ice/water containing a few drops of hydrochloric acid. The solid product,
formed in each case, was collected by filtration.
7: Orange crystals (from ethanol), yield 78% (3.84 g), m.p. 180◦C.
IR υ (cm−1) = 3472–3318 (NH2, NH), 3045 (CH aromatic), 2980, 2894
1
(CH3, CH2), 1692, 1687 (2 C O), 1655 (C N), 1640 (C C). H NMR
δ = 1.13, 1.16 (2t, 6H, J = 6.43, 6.77 Hz, 2CH3), 4.23, 4.27 (2q, J = 6.43,
6.77 Hz, 4H, 2CH2), 5.36 (s, 2H, NH2), 6.89 (s, 1H, CH C), 7.31–7.37
(m, 9H, C6H5, C6H4), 9.02 (s, 1H, NH). C25H23N3O4S2 (493.60): Calcd.:
C, 60.83; H, 4.70; N, 8.51; S, 12.99. Found: C, 60.62; H, 5.03; N, 8.89; S,
13.34.
9: Orange crystals (from ethanol), yield 86% (3.30 g), m.p. 222–225◦C.
IR υ (cm−1) = 3469–3331 (NH2, NH), 3052 (CH aromatic), 2983, 2877
(CH3, CH2), 1689, 1683 (2 C O), 1658 (C N), 1639(C C). 1H NMR δ =
1.15 (t, 3H, J = 7.03 Hz, CH3), 4.25 (q, H, J = 7.03 Hz, CH2), 5.32 (s,
2H, NH2), 6.99 (s, 1H, coumarin H-4), 7.26–7.34 (m, 8H, 2C6H4), 8.92
(s, 1H, NH). C23H17N3O4S2 (463.53): Calcd.: C, 59.60; H, 3.70; N, 9.07;
S, 13.84. Found: C, 60.02; H, 4.09; N, 9.45; S, 13.32.
Ethyl 3-Amino-4-(benzo[d]imidazolo-2-yl)-5-
hydrazinothiophen-2-carboxylate (11) and
4-Hydrazino-5-(benzo[d]imidazolo-2-yl)-3-phenylthieno[3,2-
c]pyrazole (15)
General Procedure
To a solution of either 5 (4.05 g, 0.01 mol) or 14 (4.69 g, 0.01 mol)
in ethanol (40 mL), hydrazine hydrate (0.50 mL, 0.01 mol) was added.
The reaction mixture was heated under reflux for 4 h and then poured
onto ice/water. The solid product, formed in each case, was collected by
filtration.
11: Pale yellow crystals (from 1,4-dioxan), yield 78% (3.84 g), m.p.
180◦C. IR υ (cm−1) = 3466–3323 (2NH2, 2NH), 3060 (CH aromatic),
2983, 2890 (CH3, CH2), 1677 (C O), 1654 (C N), 1633 (C C). 1H NMR
δ = 1.15 (t, 3H, J = 6.89 Hz, CH3), 4.26 (q, 2H, J = 6.89 Hz, CH2), 4.88,
5.33 (2s, 4H, 2NH2), 7.32–7.40 (m, 4H, C6H4), 8.23, 8.93 (2s, 2H, 2NH).
C14H15N5O2S (317.37): Calcd.: C, 52.98; H, 4.76; N, 22.07; S, 10.10.
Found: C, 52.59; H, 4.56; N, 22.07; S, 9.78.
15: Pale yellow crystals (from ethanol), yield 70% (2.33 g), m.p. 189–
192◦C. IR υ (cm−1) = 3468–3313 (2NH2, NH), 3055 (CH aromatic), 2894
1
(CH2), 1682 (C O) 1660 (C N), 1630 (C C). H NMR δ 5.66 (s, 2H,
NH2), 7.32–7.35 (m, 9H, C6H5, C6H4), 8.67, 9.21–9.26 (3s, 3H, 3NH).
C18H14N6S (346.10): Calcd.: C, 62.41; H, 4.07; N, 24.26; S, 9.26. Found:
C, 62.46; H, 4.34; N, 24.85; S, 10.02.

Thiophenes and Their Annulated Derivatives
2059
Ethyl 3-Aminobenzo[d]imidazo[3,2:2,3]pyrazolo[5,4:2,3]-
thiophen-2-carboxylate (12)
A solution of 11 (3.17 g, 0.01 mol) in dimethylformamide (40 mL) con-
taining triethylamine (0.5 mL) was heated under reflux for 8 h and then
evaporated in vacuum. The remaining product was triturated in diethyl
ether, and the solidified product was collected by filtration.
12: Pale yellow crystals (from AcOH), yield 80% (2.40 g), m.p. 112◦C.
IR υ (cm−1) = 3445–3312 (NH2, NH), 3056 (CH aromatic), 2980,
2893 (CH3, CH2), 1682 (C O), 1651 (C N), 1636 (C C). 1H NMR
δ = 1.16 (t, 3H, J = 7.02 Hz, CH3), 4.23 (q, 2H, J = 7.02 Hz, CH2), 4.89
(s, 2H, NH2), 7.30–7.37 (m, 4H, C6H4), 9.03 (s, 1H, NH). C14H12N4O2S
(300.34): Calcd.: C, 55.99; H, 4.03; N, 18.65; S, 10.68. Found: C, 56.31;
H, 4.40; N, 18.31; S, 11.09.
2-Amino-5-benzoylmethylsulfanyl-3-cyano-6-
benzo[d]imidazo-2-ylthieno-[3,2-c]pyridine (17a) and Ethyl
2-Amino-5-benzoylmethyl-sulfanyl-6-benzo[d]imidazo-2-
ylthieno-[3,2-c]pyridine-3-carboxylate (17b)
General Procedure
To a solution of 14 (4.69 g, 0.01 mol) in 1,4-dioxan (40 mL) contain-
ing triethylamine (0.5 mL), either malononitrile (0.66 g, 0.01 mol) or
ethyl cyanoacetate (1.13 g, 0.01 mol) was added. The reaction mixture
was heated under reflux for 6 h and then evaporated under vacuum.
The remaining product was triturated with toluene, and the solidified
product was collected by filtration.
17a: Pale yellow crystals (from 1,4-dioxan), yield 77% (3.98 g), m.p.
267–270◦C. IR υ (cm−1) = 3487–3345 (NH2, NH), 3062 (CH aromatic),
2886 (CH2), 2225 (CN), 1668 (C O), 1656 (C N), 1641 (C C). 1H
NMR δ = 5.21 (s, 2H, CH2), 5.59 (s, 2H, NH2), 7.32–7.40 (m, 14H,
2C6H5, C6H4), 8.87 (s, 1H, NH). C29H19N5OS2 (517.63): Calcd.: C,
67.29; H, 3.70; N, 13.53; S, 12.39. Found: C, 67.06; H, 4.16; N, 13.31;
S, 11.96.
17b: Pale brown crystals (from 1,4-dioxan), yield 63% (3.55g), m.p.
147–149◦C. IR υ (cm−1) = 3480–3323 (NH2, NH), 3056 (CH aromatic),
2987, 2886 (CH3, CH2), 1702, 1680 (2 C O), 1661 (C N), 1633 (C C).
1H NMR δ = 1.14 (t, 3H, J = 4.66 Hz, CH3), 4.25 (q, 2H, J = 4.66
Hz, CH2), 5.23 (s, 2H, CH2), 5.49 (s, 2H, NH2), 7.31–7.36 (m, 14H,
2C6H5, C6H4), 8.89 (s, 1H, NH). C31H24N4O3S2 (564.68): Calcd.: C,
65.94; H, 4.28; N, 9.92; S, 11.36. Found: C, 65.76; H, 4.26; N, 10.25;
S, 11.65.

2060
W. W. Wardakhan
2-Amino-5-hydrazino-3-cyano-6-benzo[d]imidazo-2-ylthieno-
[3,2-c]pyridine (18a) and Ethyl 2-Amino-5-hydrazino-6-
benzo[d]imidazo-2-ylthieno-[3,2-c]pyridine-3-
carboxylate (18b)
General Procedure
Equimolar amounts of either 17a (5.17 g, 0.01 mol) or 17b (5.64 g,
0.01 mol) and hydrazine hydrate (0.5 g, 0.01 mol) in 1,4-dioxan (50 mL)
was heated under reflux for 5 h. The solid product formed, in each case,
upon pouring onto ice/water containing few drops of hydrochloric acid
was collected by filtration.
18a: Yellow crystals (from 1,4-dioxan), yield 70% (2.77 g), m.p. 203–
206◦C. IR υ (cm−1) = 3460–3321 (2NH2, 2NH), 3052 (CH aromatic),
2221 (CN), 1648 (C N), 1633 (C C). 1H NMR δ =s 4.78, 5.53 (2s,
4H, 2NH2), 7.28–7.35 (m, 9H, C6H5, C6H4), 8.69, 9.03 (2s, 2H, 2NH).
C21H15N7S (397.11): Calcd.: C, 63.46; H, 3.80; N, 24.67; S, 8.07. Found:
C, 63.25; H, 4.22; N, 24.43; S, 7.89.
18b: Pale brown crystals (ethanol), yield 83% (3.68 g), m.p. 188–
190◦C. IR υ (cm−1) = 3497–3334 (2NH2, 2NH), 3055(CH aromatic),
2992, 2880 (CH3, CH2), 1684 (C O), 1666 (C N), 1639 (C C). 1H NMR
δ = 1.16 (t, 3H, J = 5.89 Hz, CH3), 4.24 (q, 2H, J = 5.89 Hz, CH2), 4.92,
5.49 (2s, 4H, 2NH2), 7.33–7.38 (m, 9H, C6H5, C6H4), 8.78, 9.21 (2s, 2H,
2NH). C23H20N6O2S (444.51): Calcd.: C, 62.15; H, 4.54; N, 18.91; S, 7.21.
Found: C, 62.45; H, 4.87; N, 18.22; S, 7.07.
2-Amino-3-cyano-4-phenylbenzo[d]imidazolo[3,2:2,3]-
thieno[4,5:2,3]-pyrazole (19a) and Ethyl 2-Amino-3-cyano-
phenylbenzo[d]imidazolo-[3,2:2,3]thieno-[4,5:2,3]-
pyrazol-3-carboxylate (19b)
General Procedure
A dry solid of either 18a (3.97 g, 0.01 mol) or 18b (4.44 g, 0.01 mol)
was heated in an oil bath at 140◦C for 1 h and then left to cool. The
remaining product was triturated with diethyl ether, and the formed
solid product was collected by filtration.
19a: Pale yellow crystals (from 1,4-dioxan), yield 66% (2.50 g), m.p.
> 300◦C. IR υ (cm−1) = 3442–3321 (NH2, NH), 3059 (CH aromatic),
1
2218 (CN), 1658 (C N), 1640 (C C). H NMR δ = 5.33 (s, 2H, NH2),
7.25–7.33 (m, 9H, C6H5, C6H4), 9.04 (s, 1H, NH). C21H12N6S (380.43):
Calcd.: C, 66.30; H, 3.18; N, 22.09; S, 8.43; Found: C, 66.81; H, 2.87; N,
21.85; S, 8.02.
19b: Buff crystals (ethanol), yield 56% (2.39 g), m.p. 240–243◦C. IR υ
(cm−1) = 3477–3341 (NH2, 2NH), 3052 (CH aromatic), 2988, 2887 (CH3,

Thiophenes and Their Annulated Derivatives
2061
1
CH2), 1688 (C O), 1660 (C N), 1630 (C C). H NMR δ = 1.14 (t, 3H,
J = 7.22 Hz, CH3), 4.22 (q, 2H, J = 7.22 Hz, CH2), 5.39 (s, 2H, NH2),
7.30–7.33(m, 9H, C6H5, C6H4), 9.09 (s, H, NH). C23H17N5O2S (427.48):
Calcd.: C, 64.62; H, 4.01; N, 16.38; S, 7.50. Found: C, 64.45; H, 3.88; N,
16.05; S, 7.33.
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