Synthesis of some new thieno[2,3-b]pyridines, pyrimidino[4′,5′: 4,5]thieno[2,3-b]-pyridines, and 2,3-dihydro-1,3,4-thiadiazoles

Article abstract of DOI:10.1080/10426500802077630

Thieno[2,3-b]pyridines were synthesized from 6-benzofuran-2-yl-4-phenyl-2- sulfanylpyridine-3-carbonitrile and each of chloro acetone, ethyl chloroacetate, -bromoacetophenone, and chloroacetonitrile. These compounds were conveniently converted into novel

Full text of DOI:10.1080/10426500802077630

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Synthesis of Some New
Thieno[2,3-b]pyridines,
Pyrimidino[4′,5′:4,5]thieno[2,3-
b]-pyridines, and 2,3-
Dihydro-1,3,4-thiadiazoles
Abdou O. Abdelhamid a , Zeineb H. Ismail b , Soad
M. Abdel-Gawad b , Moustafa M. Ghorab c & Anhar
Abdel-Aziem b
a Department of Chemistry, Faculty of Science, Cairo
University, Giza, Egypt
b Department of Chemistry, Faculty of Science (Girls
Branch), Al-Azhar University, Cairo, Egypt
c Department of Drug Radiation Research, National
Center of Radiation Research and Technology, Naser
City, Cairo, Egypt
Version of record first published: 19 Dec 2008
To cite this article: Abdou O. Abdelhamid, Zeineb H. Ismail, Soad M. Abdel-Gawad,
Moustafa M. Ghorab & Anhar Abdel-Aziem (2008): Synthesis of Some New Thieno[2,3-
b]pyridines, Pyrimidino[4′,5′:4,5]thieno[2,3-b]-pyridines, and 2,3-Dihydro-1,3,4-
thiadiazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:1, 58-75
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Phosphorus, Sulfur, and Silicon, 184:58–75, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802077630
Synthesis of Some New Thieno[2,3-b]pyridines,
Pyrimidino[4ꢀ,5ꢀ:4,5]thieno[2,3-b]-pyridines, and
2,3-Dihydro-1,3,4-thiadiazoles
Abdou O. Abdelhamid,1 Zeineb H. Ismail,2 Soad M.
Abdel-Gawad,2 Moustafa M. Ghorab,3 and Anhar
Abdel-Aziem2
1Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
2Department of Chemistry, Faculty of Science (Girls Branch),
Al-Azhar University, Cairo, Egypt
3Department of Drug Radiation Research, National Center of Radiation
Research and Technology, Naser City, Cairo, Egypt
Thieno[2,3-b]pyridines were synthesized from 6-benzofuran-2-yl-4-phenyl-2-
sulfanylpyridine-3-carbonitrile and each of chloro acetone, ethyl chloroacetate, ω-
bromoacetophenone, and chloroacetonitrile. These compounds were conveniently
converted into novel pyrido[4ꢀ,5ꢀ:4,5]thieno[3,2-d]pyrimidines. Also, 2,3-dihydro-
1,3,4-thiadiazole was synthesized from hydrazonoyl halides and 2-benzofuran-
2-yl-3-(phenylamino)-3-thioxopropanenitrile. The structures of the products have
been elucidated by elemental analyses, spectral data studies, and alternative syn-
theses whenever possible. The newly synthesized compounds were tested towards
microorganisms.
Keywords 2,3-Dihydro-1,3,4-thiadiazole; hydrazonoyl halides; pyrimidino[4ꢀ,5ꢀ:4,
5]thieno[2,3-b]pyridine; thieno[2,3-b]pyrimidine
INTRODUCTION
Thienopyrimidine derivatives are characterized by a very broad spec-
trum of biological activities, such as antiallergic,1 antiatherosclerotic,2
antibacterial,3−5 anticancer,6 antiviral,7,8 antihypertensive,9,10 anti-
depressant,11 antihistaminic,12 antimicrobial,13−16 and neurotropic17
activities. We report herein the reaction of 6-benzofuran-2-yl-4-
phenyl-2-sulfanylpyridine-3-carbonitrile with each of chloro acetone,
Received 15 November 2007; accepted 11 February 2008.
Address correspondence to Department of Chemistry, Faculty of Science, Cairo
University, Giza 12613, Egypt. E-mail: abdelhamid45@gmail.com
58

Some New Thieno[2,3-B]pyridines
59
ethyl chloroacetate, ω-bromoacetophenone, and chloroacetonitrile.
Also, the reaction of hydrazonoyl halides with 2-benzofuran-2-yl-3-
(phenylamino)-3-thioxopropanenitrile was studied.
RESULTS AND DISCUSSION
Treatment of 1-benzofuran-2-yl-3-phenylprop-2-en-1-one18 (1) with
cyanothioacetamide (2) in sodium methoxide afforded 6-benzofuran-
2-yl-4-phenyl-2-sulfanylpyridine-3-carbonitrile (3). Structure 3 was
confirmed by elemental analysis, spectral data, and chemical trans-
formation. Thus, compound 3 reacted with each of methyl io-
dide and chloroacetone in ethanoilc triethylamine (or ethanolic
potassium hydroxide) to give 4a and 4b, respectively (Scheme 1),
as evidenced from its elemental analysis and spectral data. The
latter was cyclized in boiling ethanol containing few drops of
piperidine to afford 1-(3-amino-6-benzofuran-2-yl-4-phenylthieno[2,3-
b]pyridin-2-yl)ethan-1-one (5a). In contrast, compound 3 reacted
with ethyl chloroacetate, ω-bromoacetophenone, or chloroacetonitrile
to give ethyl 3-amino-6-benzofuran-2-yl-4-phenylthieno[2,3-b]pyridine-
2-carboxylate (5b), (3-amino-6-benzofuran-2-yl-4-phenylthieno[2,3-
b]pyridin-2-yl)phenylmethanone (5c), and 3-amino-6-benzofuran-2-yl-
4-phenylthieno[2,3-b]pyridine-2-carbonitrile (5d), respectively. The IR
spectra of compounds 5b–d revealed amino groups with two bands
appearing at 3496–3249 cm−1 in the form of two bands due to in-
tramolecular association between the 3-NH2 and 2-COOC2H5, CO or
2-C≡N group of compounds 5b–d, as observed in other cyclo enamino
esters.19 1H NMR spectra of compounds 5b–d showed a broad singlet at
δ 6.21–6.57 (b, 2H) assigned for the NH2 group and a singlet at δ 7.84–
8.31 (s, 1H) assigned for the pyridine-5H of the thieno[2,3-b]pyridine
ring. The 1H NMR spectrum of 5b showed signals at δ = 1.29 (t, J= 7Hz,
3H, CH2CH3), 4.24 (q, J= 7Hz, 2H, CH2CH3), 6.21 (s, br., 2H, NH2)
and 7.12–7.87 (m, 10H, aromatic protons) and 7.99 (s, 1H, 5-H of the
thienopyridine ring).
Compound 5b reacted with hydrazine hydrate in refluxing ethanol
to
give
N-amino-(3-amino-6-benzofuran-2-yl-4-phenylthieno[2,3-
b]pyridine-2-yl)carboxamide (6) (Scheme 1). The structure of 6 was
1
confirmed by spectral data and elemental analyses. Its H NMR spec-
trum revealed the absence of ethyl ester protons signals, indicating
the elimination of ethanol and all other spectral data (IR and mass
spectra) are in agreement with the proposed structure. Compound 6,
reacted with the arylazoacetylacetone derivatives 7a–c in ethanolic
triethylamine, yielded 8a–c (Scheme 1).

60
A. O. Abdelhamid et al.
SCHEME 1 Synthesis of compounds 3–6, 8, 9, 12, 13, and 14.
Alternatively, compound 6 reacted with the appropriate 7a–c in
glacial acetic acid to give the N-acetyl derivative 9. Structure 9 was
confirmed by elemental analyses, spectral data, and alternate syn-
thetic route. Thus, compound 6 reacted with acetyl chloride to give
the N-acetyl derivative to afford the product identical in all aspects
(mp., mixed mp., and spectra) with 9.
Also, treatment of 6 with the appropriate arylazo of each of ethyl ace-
toacetate or malononitrile 10a, 10b, 11a–c in ethanolic triethylamine
gave pyrazoles 12a, 12b, and 13a–c, respectively. Compound 6d re-
acted with nitrous acid to give 14. The IR spectrum of 14 revealed a
band at 2119 cm−1 representative of the azido group. Compound 5d
reacted with the appropriate formic acid, formamide, or triethyl ortho-
formate to give 15–17, respectively (Scheme 2). Structures 15–17 were

Some New Thieno[2,3-B]pyridines
61
SCHEME 2 Synthesis of compounds 15–20.
confirmed by elemental analysis, spectral data, and chemical transfor-
mation. Thus, compound 17 reacted with formamide to give product
identical in all aspects (mp., mixed mp., and spectra) with 16.
Treatment of 15 with phosphorus oxychloride afforded the chloro-
derivative 18; the latter reacted with the appropriate hydrazine hy-
drate, aniline, 4-methylaniline, and sodium thiophenolate or sodium
benzenesulfinate to give 19a–e, respectively. Structures 19 were elu-
cidated by elemental analysis, spectral data, and chemical reactions.
Thus, treatment of 19d with hydrogen peroxide in acetic acid at room
temperature gave product identical in all aspects (mp., mixed mp., and
spectra) with 19e. Also, compound 19a reacted with nitrous acid to give
teterazole 20.
3-Benzofuran-2-yl-3-oxopropanenitrile20 (21) reacted with phenyl
isothiocyanate in N,N-dimethylformamide containing potassium

62
A. O. Abdelhamid et al.
SCHEME 3 Synthesis of compounds 22, 27, and 28.
hydroxide to give non-isolable product, which was converted to 22 by
hydrochloric acid. Structure 22 was elucidated by microanalytical, spec-
tral data, and chemical transformation (Scheme 3). IR (cm−1) spectrum
of 22 revealed characteristic bands at 3386 (NH) and 2198 (CN). Its 1H
NMR showed signals at δ = 7.31–8.10 (m, 11H, aromatic protons) and
12, 53 (s, br., 1H).
Treatment of the appropriate hydrazonoyl halides 23a–e with 22 in
ethanolic triethylamine at room temperature gave 2,3-dihydro-1,3,4-
thiadiazole derivatives 27a–e, respectively (Scheme 3). IR spectra
of 27a–e revealed bands near 2190 (CN) and 1720–1680 (CO). 1H
NMR spectrum of 27a showed signals at δ = 1.36 (t, 3H, J= 7.5 Hz,
CH2CH3), 4.2 (q, 2H, J= 7.5 Hz, CH2CH3), 7.10–7.92 (m, 10H) ppm.
Its 13C NMR spectrum showed signals at δ = 13.8 (CH3CH2O), 60.7
(CH3CH2O), 87.2, 111.6, 115.9, 116.3, 116.7, 118.8, 121.0, 123.3, 124.7,
129.6, 131.4, 146.4, 154, 155.2, 195.2, 161.0, 161.7, 175 (CO) ppm.
Also, treatment of C-ethoxycarbonyl-N-phenylhydrazonoyl chloride

Some New Thieno[2,3-B]pyridines
63
23a with 2-(benzo[d]furan-2-ylcarbonyl)-3-methylthio-3-sulfanylprop-
2-enenitrile (28), which was prepared from 21 and carbon disulfide
in potassium hydroxide followed by iodomethane, in ethanolic triethy-
lamine to give a product identical in all aspects (mp., mixed mp., and
spectra) with 27a .
In light of these results, the mechanism outlined in Scheme 3 seems
to be the most plausible pathway for the formation of 27 from the reac-
tion of the 22 with 23 (or nirile imine 26), which was prepared in situ
by treatment of 23 with triethylamine. The reaction involves the ini-
tial formation of thiohydrazonate 24, which undergoes intermolecular
cyclization as soon as it is formed to yield the intermediate 26 or via
1,3-dipolar cycloaddition of nitrilimine 26 to C=S double bond of 22 to
give final product 27 via elimination of aniline.
Biological Activity
The tested microorganisms were Gram-positive bacteria [Staphylococ-
cus aureus (ATCC25923) and Streptococcus pyrogenes (ATCC19615)],
Gram-negative bacteria [Pseudomonas Phaseolicola (GSPB 2828) and
Pseudomonas fluorescens (S 97)], and some fungal pathogens (Fusar-
ium oxysporum and Aspergillus funigatus).
The tested compounds were dissolved in N,N-dimethylformamide,
which has no inhibition activity, to obtained concentrations of 2 mg/mL
and 1 mg/1 mL. The test was performed on medium potato dextrose
agar (PDA), which contains infusion 200 g potato, 6g dextrose, and
15g agar. Uniform size filter paper disks (3 disks per compound) were
impregnated by equal volume (10 µL) from the specific concentration
of dissolved tested compounds and carefully placed on inoculated agar
surface. After incubation for 36 h at 27◦C in the case of bacteria and
48 h at 24◦C in the case of fungi, inhibition of the organisms, which is
evidenced by a clear zone surround each disk, was measured and used
to calculate mean inhibition zones.21 See Table I.
In general (for high concentration), compounds 6e, 11, and 31a were
capable of a high inhibition, compounds 6b,c, 12, 17b,d, 23b, 31b,e,
33b,c, and 38a,b were capable of intermediate to inhibition, and com-
pounds 17e, 22, 26b, 31c, and 33a were capable of low to inhibition of
the growth of Gram-positive and Gram-negative.
EXPERIMENTAL
All melting points were determined on an electrothermal appara-
tus and are uncorrected. IR spectra were recorded (KBr discs) on a

64
A. O. Abdelhamid et al.
TABLE I Response of Various Microorganisms to Some Synthesized
Compounds in Vitro (Culture)
Mean * of zone diameter, nearest whole mm
Gram-positive
Gram-negative bacteria
Fungi**
Staphyl
Strepto
coccus
Pseud
omonas
ococcus
aureus
(ATCC
25923)
Pseud
pyogenes phaseolicola omonas
(ATCC
19615)
(GSPB
2828)
fluorescens Fusarium Aspergillus
(S 97) oxysporum fumigatus
Organisms
Conc.
1
2
1
2
1
2
1
2
1
1
1
2
Sample
2mg/ 1mg/ 2mg/ 1mg/ 2mg/ 1mg/ 2mg/ 1mg/ 2mg/ 1mg/ 2mg/ 1mg/
ml
ml
ml
ml
ml
ml
ml
ml
ml
ml
ml
ml
3
5a
5b
5d
6
7a
7b
10c
11a
11c
15
16
17
19a
19e
27b
27c
27d
27e
Control #
H
I
I
H
L
H
I
H
I
L
L
–
l
I
H
l
I
L
–
L
L
I
I
I
I
–
–
I
L
L
L
–
–
L
L
L
H
–
–
–
–
–
I
I
I
–
I
–
I
I
L
L
–
L
–
L
L
L
–
–
–
–
–
L
L
–
–
I
I
–
–
–
I
–
L
–
–
L
–
L
–
–
–
–
–
–
–
–
L
–
L
–
H
–
–
–
I
–
–
–
I
–
–
–
–
–
L
L
–
–
–
–
H
–
–
–
–
–
–
–
L
–
–
–
–
–
–
–
–
–
–
–
H
–
L
L
I
–
–
–
–
–
–
–
–
–
–
L
L
–
–
–
–
H
I
L
I
I
I
I
L
–
–
–
–
–
–
–
–
I
L
L
–
I
L
L
–
–
–
L
I
L
–
L
I
–
L
L
H
I
I
I
I
–
L
–
–
–
I
L
L
–
H
L
H
–
I
–
L
L
L
I
L
L
L
L
H
L
L
L
L
L
L
L
H
L
I
H
H
H
L
I
–
I
–
H
–
H
H
H
* = Calculate from 3 values.
** = Identified depending on morphological and microscopically characters = No
effect.
L = Low activity = Mean of zone diameter ≤1/3 of mean zone diameter of control.
I = Intermediate activity = Mean of zone diameter ≤2/3 of mean zone diameter of
control.
H = High activity = Mean of zone diameter ≥2/3 of mean zone diameter of control.
# = Chloramphencol in the case of Gram-negative bacteria, Cephalothin in the case of
Gram-positive bacteria and Cicloheximide in the case of fungi.
1
Shimadzu FT-IR 8201 PC spectrophotometer. H NMR and 13C NMR
spectra were recorded in CDCl3 and (CD3)2 SO solutions on a Varian
Gemini 300 MHz spectrometer, and chemical shifts are expressed in
δ units using TMS as an internal reference. Elemental analyses and

Some New Thieno[2,3-B]pyridines
65
microorganism tests were carried out at the Microanalytical Center
of Cairo University. Hydrazonoyl halides22−26 23a-e were obtained as
previously reported.
Synthesis of 6-Benzofuran-2-yl-4-phenyl-2-sulfanylpyridine-
3-carbonitrile (3)
A mixture of 1 (3.61 g, 10 mmoles) and cyanothioacetamide 2 (1.0 g,
0.1 mol) was heated under reflux in methoxide solution [sodium metal
(0.23g) in methanol (25 mL)] for 7 h. The reaction mixture was cooled
and stirred at room temperature overnight. The precipitate was fil-
tered, washed with water, and recrystallized from ethanol to give 3
(Tables II and III).
Synthesis of 6-Benzofuran-2-yl-2-methylthio-4-phenylpyridine-
3-carbonitrile (4a) and 2-Acetyl-6-benzofuran-2-yl-4-
phenylpyridine-3-carbonitrile (4b)
A mixture of 3 (1.6 g, 10 mmol) and potassium hydroxide (0.6 g,
10 mmol) in N,N-dimethylformamide (20 mL) was stirred for 2 h at
room temperature. Each of methyl iodide and chloroacetone (10 mmol
each) was added, and stirring was continued for 2 h. The resulting solid
was collected and recrystallized from the proper solvent to give 4a and
4b, respectively (Tables II and III).
Synthesis of 1-(3-Amino-6-benzofuran-2-yl-4-
phenylthieno[2,3-b]pyridin-2-yl)ethan-1-one (5a)
A solution of 4b (1.71 g, 5 mmol) in ethanol (20 mL) containing
piperidine (0.3 mL) was heated under reflux for 2 h. After cooling,
the resulting solid was collected by filtration and recrystallized from
dioxin/ethanol to give 5a (Tables II and III).
Synthesis of Ethyl 3-amino-6-benzofuran-2-yl-4-
phenylthieno[2,3-b]pyridine-2-carboxylate (5b), (3-Amino-6-
benzofuran-2-yl-4-phenylthieno[2,3-b]pyridin-2-
yl)phenylmethanone (5c), and 3-Amino-6-benzofuran-2-yl-4-
phenylthieno[2,3-b]pyridine-2-carbonitrile (5d)
A mixture of 3 (1.6 g, 10 mmol) and potassium hydroxide (0.6 g,
10 mmol) in N,N-dimethylformamide (20 mL) was stirred for 2 h at
room temperature. Each of ethyl chloroacetate, ω-bromoacetophenone,

66
A. O. Abdelhamid et al.
TABLE II Characterization Data of the Newly Synthesized
Compounds
% Analyses, Calcd./Found
Compd.
no.
Mp., ◦
Solvent
C
Yield %
Colour
Mol. Formula
Mol. Wt.
C
H
N
S
3
>300
EtOH
>300
90
Yellow
80
Yellow
80
Yellow
75
Yellow
80
Yellow
80
Orange
85
Yellow
90
White
80
Yellow
80
Yellow
75
Yellow
90
White
80
Yellow
80
White
80
Yellow
90
Yellow
85
C20H12N2OS
328.39
73.15
73.24
73.66
73.54
71.86
71.58
71.86
71.68
69.55
69.64
75.32
75.23
71.92
72.12
65.99
66.21
69.70
69.51
70.09
70.24
67.56
67.34
65.13
65.23
67.36
67.23
67.79
67.57
65.25
65.12
65.74
65.85
63.26
63.41
64.22
64.42
69.86
69.75
70.03
70.25
70.91
70.85
3.68
3.86
4.11
4.12
4.19
4.18
4.19
4.28
4.38
4.50
4.06
4.18
3.57
3.75
4.03
3.88
4.25
4.32
4.50
4.23
3.95
4.13
4.10
3.89
3.89
3.98
4.14
4.00
3.89
4.11
4.14
2.24
3.60
3.65
3.18
3.20
3.31
3.42
3.58
3.75
4.05
4.21
8.53
8.35
8.18
18.23
7.28
7.15
7.28
7.46
6.76
6.80
9.76
10.23
9.36
9.57
8.34
8.43
8.34
8.43
7.74
7.85
7.18
8.32
8.73
8.64
8.01
7.75
5.64
5.46
5.50
5.74
5.47
5.70
7.25
7.42
5.62
5.72
5.48
5.64
5.62
5.45
5.48
5.62
5.45
5.54
7.80
7.62
8.11
8.53
8.13
7.95
7.57
7.73
4a
4b
5a
5b
5c
5d
6
C
21H14N2OS
342.41
Dioxan
260–62
Dioxan
270–71
Dioxan
260–62
Dioxan
>300
Dioxan
>300
Dioxan
290
Dioxan
270
Dioxan
160
EtOH
200
EtOH
>300
Dioxan
>300
Dioxan
240
EtOH
290
Dioxan
170
Dioxan
190
Dioxan
> 300
EtOH
>300
Dioxan
>300
Dioxan
220-21
EtOH
C
C
C
C
23H16N2O2S
384.46
23H16N2O2S
384.46
24H18N2O3S
414.49
28H18N2O2S
446.53
6.27
6.42
C
22H13N3OS
367.43
11.44
11.21
13.99
14.12
14.78
14.87
14.42
14.34
14.33
14.20
12.66
12.43
14.73
14.85
14.37
14.31
19.64
19.52
19.17
19.329
19.04
28.88
17.02
16.91
10.63
10.45
14.20
14.37
9.92
C
C
C
22H16N4O2S
400.64
33H24N6O2S
568.66
34H26N6O2S
582.69
8a
8b
8c
9
C
33H23N6O2SF
586.65
C
24H18N4O3S
442.62
12a
12b
13a
13b
13c
14
15
16
17
C
32H22N6O3S
570.63
C
C
C
33H24N6O3S
584.66
31H22N8O2S
570.64
32H24N8O2S
584.66
C
31H21N8O2FS
588.63
Yellow
Colorless
90
90
Yellow
80
Yellow
90
White
C
22H13N5O2S
411.44
C
23H13N3O2S
395.44
C
23H14N4OS
394.46
C
25H17N3O2S
423.50
10.24

Some New Thieno[2,3-B]pyridines
67
TABLE II Characterization Data of the Newly Synthesized
Compounds (Continued)
% Analyses, Calcd./Found
Compd.
no.
Mp., ◦
Solvent
C
Yield %
Colour
Mol. Formula
Mol. Wt.
C
H
N
S
18
>300
Dioxan
280
EtOH
240-43
AcOH
260
90
Black
80
Brown
80
Brown
80
Brown
80
Brown
80
Brown
80
Brown
70
Brown
70
Yellow
70
Yellow
70
Red
80
Red
70
C23H12N3OSCl
413.89
66.75
66.65
67.47
67.65
74.02
74.18
74.36
74.53
71.44
7.24
67.04
67.21
65.70
65.60
67.48
67.65
63.30
63.15
67.23
67.42
65.11
65.00
69.48
69.51
68.70
68.64
56.71
65.84
2.92
2.84
3.69
3.81
3.86
3.68
4.16
4.28
3.51
3.62
3.30
3.51
2.88
3.00
3.78
3.87
3.62
3.52
3.47
3.37
3.38
3.41
3.36
3.27
3.09
2.95
3.29
3.40
10.15
10.34
17.10
17.23
11.91
12.26
11.56
11.35
8.62
8.75
8.09
7.85
19.99
20.12
8.74
7.75
7.91
7.83
7.85
6.81
6.64
6.61
6.42
13.15
13.00
12.34
12.42
7.63
7.85
10.01
9.89
7.68
7.86
6.90
6.81
8.28
8.41
7.13
7.25
6.55
6.72
23.29
23.42
19a
19b
19c
19d
19e
20
C
C
C
23H15N5OS
409.47
29H18N4OS
470.56
30H20N4OS
484.58
EtOH
> 300
EtOH
> 300
EtOH
> 300
EtOH
140-41
EtOH
210-12
EtOH
190-91
EtOH
200-202
EtOH
180-81
EtOH
220-22
EtOH
160-61
EtOH
C
29H17N3OS2
487.61
C
29H17N3O3S2
519.61
C
23H12N6OS
420.46
22
C18H12N2O2S
320.37
8.65
27a
27b
27c
27d
27e
28
C
C
C
C
C
22H15N3O4S
417.45
26H16N4O3S
464.51
21H13N3O3S
387.42
26H15N3O3S
449.49
10.07
40.21
12.06
11.89
10.85
10.99
9.35
9.53
8.58
8.74
5.09
28H15N3O4S
489.51
Red
70
Brown
C
13H9NO2S2
275.35
5.18
and chloroacetonitrile (10 mmol each) was added, and stirring was con-
tinued for 2 h. The resulting solid was collected and recrystallized from
the proper solvent to give 5b–d, respectively (Tables II and III).
Synthesis of N-Amino(3-amino-6-benzofuran-2-yl-4-
phenylthieno[2,3-b]pyridine-2-yl)carboxamide (6)
A mixture of compound 5b (1.8 g, 10 mmol) and hydrazine hydrate
(4 mL, 85% solution, 4 mmol) in absolute ethanol (20 mL) for 2 h was
heated under reflux. The reaction mixture was cooled, and the resulting

68
A. O. Abdelhamid et al.
TABLE III Spectral Data of Some Newly Synthesized Compounds
Compound
No.
Spectral data
3
IR: 3342 (NH), 2217 (CN)
1H NMR: 6.67–7.42 (m, 10H, aromatic proton), 8.21 (s, 1H, 5-H of the
pyridinethione ring), 14.10 (b, 1H, SH).
4a
4b
5a
IR: 2198 (CN)
1H NMR: 2.47 (s, 3H, CH3), 6.67–8.02 (m, 10H, aromatic proton),
8.21 (s, 1H, 5-H of the pyridinethione ring).
IR: 2190 (CN), 1655 (CO)
1H NMR: 2.33 (s, 3H, CH3CO), 4.15 (s, 2H, SCH2), 7.25–7.75 (m,
10H, aromatic proton), 8.17 (s, 1H, 5-H of the pyridinethione ring).
IR: 3316, 3124 (NH2), 1596 (CO)
1H NMR: 2.38 (s, 3H, CH3CO), 6.45 (br, 2H, NH2), 7.16–7.73 (m,
10H, aromatic protons), 7.82 (s, 1H, 5-H of the thienopyridine ring).
MS: 386 (8), 385 (28), 384 (100), 340 (29), 279 (4), 191 (10), 170 (4), 89
(8), 77 (11)
5b
IR: 3481, 3351 (NH2), 1731 (CO)
1H NMR: 1.29 (t, 3H, J= 7 Hz, CH3), 4.24 (q, 2H, J= 7 Hz, CH2),
6.21 (br, 2H, NH2), 7.12–7.87 (m, 10H, aromatic protons), 7.99 (s, 1H,
5-H of the thienopyridine ring).
5c
5d
6
IR: 3408, 3300 (NH2), 1685 (CO).
1H NMR: 16.21 (br, 2H, NH2), 7.52–7.87 (m, 15H, aromatic protons),
7.99 (s, 1H, 5-H of the thienopyridine ring).
IR: 3496, 3300 (NH2), 2198 (CN)
1H NMR: 6.57 (br, 2H, NH2), 7.12 (m, 10H, aromatic protons), 8.31(s,
1H, 5-H of the thienopyridine ring).
IR: 3414, 3199 (NH2, NH), 1650 (CO)
1H NMR: 4.38 (br, 2H, N-NH2), 6.70 (br, 2H, NH2), 7.15–7.78 (m,
10H, aromatic protons), 8.29 (s, 1H, 5-H of the thienopyridine ring),
9.39 (br, 1H, NH).
8a
8b
8c
9
IR: 3445, 3257 (NH2), 1640 (CO)
1H NMR: 2.80 (s, 6H, 3-,5-CH3 of pyrazole), 6.81 (br, 2H, NH2),
7.12–7.84 (m, 15H, aromatic protons), 8.31 (s, 1H, 5-H of the
thienopyridine ring).
IR: 3445, 3257 (NH2), 1640 (CO)
1H NMR: 2.34 (s, 3H, CH3), 2.80 (s, 6H, 3-,5-CH3 of pyrazole), 6.81
(br, 2H, NH2), 7.12–7.84 (m, 14H, aromatic protons), 8.31 (s, 1H, 5-H
of the thienopyridine ring).
IR: 3445, 3257 (NH2), 1640 (CO)
1H NMR: 2.80 (s, 6H, 3-,5-CH3 of pyrazole), 6.81 (br, 2H, NH2),
7.12–7.84 (m, 14H, aromatic protons), 8.31 (s, 1H, 5-H of the
thienopyridine ring).
IR: 3414, 3199 (NH2, NH), 1650 (CO)
MS: 442 (12%), 341 (100%), 240 (16%).

Some New Thieno[2,3-B]pyridines
69
TABLE III Spectral Data of Some Newly Synthesized Compounds
(Continued)
Compound
No.
Spectral data
12a
IR: 3445, 3257 (NH2), 1720, 1640 (CO’s)
1H NMR: 1.24 (s, 3H, 3-CH3 of pyrazole), 6.81 (br, 2H, NH2),
7.12–7.84 (m, 15H, aromatic protons), 8.31 (s, 1H, 5-H of the
thienopyridine ring), 11.23 (s, 1H, br., NH).
12b
IR: 3445, 3257 (NH2), 1717, 1640 (CO’s)
1H NMR: 1.24 (s, 3H, 3-CH3 of pyrazole), 2.41 (s, 3H, CH3), 6.81 (br,
2H, NH2), 7.12–7.84 (m, 14H, aromatic protons), 8.31 (s, 1H, 5-H of
the thienopyridine ring), 11.23 (s, 1H, br., NH).
IR: 3458, 3216 (NH2), 1651 (CO)
13a
13b
1H NMR: 6.79 (br, 2H, NH2), 6.98 (br, 4H, 2 NH2), 7.14–7.93 (m,
15H, aromatic protons), 8.01 (s, 1H, 5-H of the thienopyridine ring).
IR: 3458, 3216 (NH2), 1651 (CO)
1H NMR: 2.41 (s, 3H, CH3), 6.79 (br, 2H, NH2), 6.98 (br, 4H, 2 NH2),
7.14–7.93 (m, 14H, aromatic protons), 8.01 (s, 1H, 5-H of the
thienopyridine ring).
13c
IR: 3458, 3216 (NH2), 1651 (CO)
1H NMR: 6.79 (br, 2H, NH2), 6.98 (br, 4H, 2 NH2), 7.14–7.93 (m,
14H, aromatic protons), 8.01 (s, 1H, 5-H of the thienopyridine ring).
IR: 3458, 3216 (NH2), 2119 (azido group), 1692 (CO).
1H NMR: 6.79 (br, 2H, NH2), 7.14–8.21 (m, 11H, aromatic protons).
IR: 3423 (NH), 1660 (CO)
14
15
1H NMR: 7.02–7.99 (m, 10H, aromatic protons), 8.25 (s, 1H, 5-H of
the thienopyridine ring), 8.57 (s, 1H, Proton on C-2 of pyrimidine
ring), 12.56 (s, 1H, NH of pyrimidine ring).
16
17
IR: 3458, 3216 (NH2)
1H NMR: 6.79 (br, 2H, NH2), 7.14–7.93 (m, 11H, aromatic protons),
8.01 (s, 1H, 5-H of the thienopyridine ring).
IR: 2248 (CN)
1H NMR: 1.22 (t, 3H, J= 7.5 Hz, CH3), 4.33 (q, 2H, J= 7.5 Hz, CH2),
6.73–7.98 (m, 10H, aromatic protons), 8.11 (s, 1H, 5-H of the
thienopyridine ring), 8.66 (s, 1H, CH N).
18
1H NMR: 7.05–7.89 (m, 10H, aromatic protons), 8.17 (s, 1H, 5-H of the
thienopyridine ring), 9.66 (s, 1H, Proton on C-2 of pyrimidine ring).
IR: 3414, 3199 (NH2, NH)
19a
1H NMR: 4.38 (br, 2H, N-NH2), 7.15–7.78 (m, 11H, aromatic protons),
8.29 (s, 1H, 5-H of the thienopyridine ring), 9.39 (br, 1H, NH).
IR: 3340 (NH)
19b
1H NMR: 7.15–7.78 (m, 15H, aromatic protons), 8.29 (s, 1H, 5-H of
the thienopyridine ring), 8.69 (s, 1H, Proton on C-2 of pyrimidine
ring), 9.39 (br, 1H, NH).
MS: 408 (31), 407 (52), 361 (47), 307 (47), 250 (57), 225 (50), 174 (65),
110 (39), 77 (55).
(Continued on next page)

70
A. O. Abdelhamid et al.
TABLE III Spectral Data of Some Newly Synthesized Compounds
(Continued)
Compound
No.
Spectral data
19c
IR: 3340 (NH)
1H NMR: 2.42 (s, 3H, CH3), 7.15–7.78 (m, 14H, aromatic protons),
8.29 (s, 1H, 5-H of the thienopyridine ring), 8.69 (s, 1H, Proton on
C-2 of pyrimidine ring), 9.39 (br, 1H, NH).
20
IR: 3072 (CH), 1640 (C N)
1H NMR: 7.14–7.93 (m, 11H, aromatic protons), 9.26 (s, 1H, 2-H of
the pyrimidine ring).
22
IR: 3386 (NH) and 2198 (CN).
1H NMR: 7.31–8.10 (m, 11H) and 12. 53 (s, br., 1H).
IR: 2190 (CN) and 1720–1680 (CO).
27a
1H NMR: 1.36 (t, 3H, J= 7.5 Hz, CH2CH3), 4.2 (q, 2H, J= 7.5 Hz,
CH2CH3), 7.10–7.92 (m, 10H).
13C NMR: 13.8 (CH3CH2O), 60.7 (CH3CH2O), 87.2, 111.6, 115.9,
116.3, 116.7, 118.8, 121.0, 123.3, 124.7, 129.6, 131.4, 146.4, 154,
155.2, 195.2, 161.0, 161.7, 175 (CO).
27b
27c
27d
27e
28
IR: 3220 (NH), 2190 (CN) and 1680, 1665 (CO).
1H NMR: 7.10–7.92 (m, 15H, aromatic protons), 9.31 (s, br., 1H, NH)
IR: 2190 (CN) and 1665, 1655 (CO).
1H NMR: 2.11 (s, 3H, CH3), 7.10–7.92 (m, 10H, aromatic protons).
IR: 2190 (CN) and 1665, 1660 (CO).
1H NMR: 7.10–7.92 (m, aromatic protons).
IR: 2364 (CS), 2190 (CN) and 1665, 1655 (CO).
1H NMR: 7.10–8.24 (m, aromatic protons).
IR: 2190 (CN) and 1665 (CO).
1H NMR: 2.47 (s, 3H, SCH3), 6.65–7.59 (m,5H, aromatic protons),
12.10 (s, 1H, SH).
solid was collected and washed with ethanol/water and recrystallized
from dioxan to give 6 (Tables II and III).
Synthesis of N-[2-(N-amino(3-aminocarbamoyl)-6-benzofuran-
2-yl-4-phenylthieno[2,3-b]pyridine-2-yl]acetamide (9)
Method A
A mixture of compound 6 (0.9 g, 5 mmol) and the appropriate of
arylazoacetylacetone 7a–c (5 mmol) was heated under reflux in acetic
acid (10 mL) with stirring for 10 h. The reaction mixture was cooled
to room temperature, and the separated solid was filtered, washed
with water, dried, and recrystallized from the proper solvent to give
9 (Tables II and III).

Some New Thieno[2,3-B]pyridines
71
Method B
A mixture of compound 6 (0.9 g, 5 mmol), acetic anhydride (5 mL),
and acetic acid (10 mL) was heated under reflux for 1 h. The reaction
mixture was cooled to room temperature and poured onto ice (50 g),
and the separated solid was filtered, washed with water, dried, and
recrystallized from the proper solvent to give product identical in all
aspects (mp., mixed mp. and spectra) with 9 (Tables II and III).
Synthesis of 3-Amino-6-benzofuran-2-yl-4-phenylthieno[2,3-
b]-2-pyridyl-4-arylazo-3,5-disubstituted-1-pyrazolylmethanone
(8, 12 , 13a–c)
A mixture of compound 6 (0.9 g, 5 mmol) and the appropriate amounts
of arylazoacetylacetone 7a–c, ethyl arylazoacetoacetate 10a,b, and ary-
lazomalononitrile 11a–c (5 mmol) was heated under reflux in ethanol
(10 mL) containing triethylamine (0.75 g, 5 mmol) with stirring for
10 h. The reaction mixture was cooled to room temperature, and the
separated solid was filtered, washed with water, dried, and recrystal-
lized from the proper solvent to give (8, 12, and 13a–c) (Tables II and
III).
Synthesis of 3-Amino-6-benzofuran-2-yl-4-phenylthieno[2,3-
b]pyridine-2-carbonylazide (14)
A saturated solution of sodium nitrite was added to a stirred solution
of 6 (0.9 g, 5 mmol) in acetic acid (10 mL) at room temperature for
20 min. The resulting solution was collected, washed with water, and
recrystallized from ethanol to give 14 (Tables II and III).
Synthesis of 7-Benzofuran-2-yl-9-phenyl-3-
hydropyrimidino[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine-4-one (15)
A mixture of 5d (1.8 g, 10 mmol) and formic acid (99%, 20 mL) was
heated under reflux for 7 h. After cooling, the reaction mixture was
poured over ice (100 g), and the resulting solid was collected and re-
crystallized from N,N-dimethylformamide to give 15 (Tables II and III).
Synthesis of 4-Amino-7-benzofuran-2-yl-9-phenyl-3-
hydropyrimidino[4ꢀ,5ꢀ:4,5]-thieno[2,3-b]pyridine (16)
Compound 5d (1.8 g, 10 mmol) was heated with formamide (20 mL) at
180◦C for 2 h. After cooling, the reaction mixture was poured over ice,

72
A. O. Abdelhamid et al.
and the formed solid was collected by filtration and recrystallized from
N,N-dimethylformamide to give 16 (Tables II and III).
Synthesis of 7-Benzofuran-2-yl-4-chloro-9-phenyl-3-
hydropyrimidino[4ꢀ,5ꢀ:4,5]-thieno[2,3-b]pyridine (18)
Compound 15 (0.9 g, 5 mmol) reacted with POCl3 (20 mL) under reflux
for 5 h. The reaction mixture was poured over ice (100 g), and the re-
sulting solid was collected by filtration and recrystallized from ethanol
to give 18 (Tables II and III).
Synthesis of 3-(1-Aza-2-ethoxyvinyl)-6-benzofuran-2-yl-4-
phenylthieno[2,3-b]-pyridin-2-carbonitrile (17)
A mixture of 5d (1.8 g, 10 mmol) and triethylorthoformate (20 mL)
with a catalytic amount of acetic acid were heated under reflux at
140◦C for 6 h. The resulting dark brown solution was allowed to cool to
room temperature and was evaporated under vacuum. N-Hexane was
added to the residue, and the separated solid was filtered, washed with
n-hexane, and recrystallized from ethanol to give 17 (Tables II and III).
Synthesis of 7-Benzofuran-2-yl-9-
phenylpyrimidino[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine-4-ylhydrazine
(19a), (7-Benzofuran-2-yl-9-phenylpyrimidino[4ꢀ,5ꢀ:4,5]thieno-
[2,3-b]pyridine-4-yl)phenylamine (19b), (7-Benzofuran-2-yl-9-
phenylpyrimidino-[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine-4-yl)(4-
methylphenyl)amine (19c), 7-Benzofuran-2-yl-9-phenyl-4-
phenylthiopyrimidino[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine (19d), and
7-Benzofuran-2-yl-9-phenyl-4-(phenylsulfonyl)pyrimidino[4ꢀ,
5ꢀ:4,5]thieno[2,3-b]-pyridine (19e)
Compound 18 (1.7 g, 5 mmol) was dissolved in ethanol (10 mL) con-
taining the appropriate amounts of hydrazine hydrate, aniline, p-
toluidine, sodium thiophenolate, or sodium benzenesulfinate (10 mmol)
was heated under reflux for 4 h. Ethanol was removed under vacuum.
The crude product residue was tritrated with hexane and recrystallized
from the proper solvent to give 19a–e, respectively (Tables II and III).
Alternative Method for 19d
Hydrogen peroxide (5 mL, 30%) was added to a solution of 19d (0.5 g)
in acetic acid (15 mL) while stirring at room temperature. Stirring was

Some New Thieno[2,3-B]pyridines
73
continued for 24 h and then poured over water (50 mL). The crude
product was collected and recrystallized from ethanol to give 19d.
Synthesis of 8-Benzofuran-2-yl-10-phenyl-2a-hydro-12,3,4-
tetrazolo[1",5":6ꢀ,1ꢀ]-pyrimidino[4ꢀ,5ꢀ:4,5]thieno[2,3-b]pyridine
(20)
A saturated solution of sodium nitrite was added to a stirred solution
of 6 (0.9 g, 5 mmol) in acetic acid (10 mL) at room temperature for
20 min. The resulting solution was collected, washed with water, and
recrystallized from ethanol to give 20 (Tables II and III).
Synthesis of 2-Benzofuran-2-yl-3-(phenylamino)-3-
thioxopropanenitrile (22)
Phenyl isothiocyanate (0.65 g [0.6 mL], 5 mmol) was added to a mixture
of 21 (0.9 g, 5 mmol) and potassium hydroxide (0.28 g, 5 mmol) in N,N-
dimethylformamide (15 mL) while stirring at room temperature until
the potassium hydroxide dissolved completely, and then the reaction
mixture was stirred for a further 1 h. The reaction mixture was poured
onto water (30 mL) and acidified with dilute hydrochloric acid. The
resulting solid was collected and recrystallized from dioxan to give
thioanilide 22 (Tables II and III).
Synthesis of 2,3-Dihydro-1,3,4-thiadiazoles 27a–e
Method A
Phenyl isothiocyanate (0.65 g [0.6 mL], 5 mmol) was added to a mix-
ture of benzofuran-2-oylacetonitrile (0.9 g, 5 mmol) 21 and potassium
hydroxide (0.28 g, 5 mmol) in N,N-dimethylformamide (15 mL) while
stirring at room temperature until the potassium hydroxide dissolve
completely, and the reaction mixture was continued stirring for further
30 min. The appropriate hydrazonoyl halides 23a–e (5 mmol) were
added, and stirring was continued for 3 h. The resulting solid was col-
lected and recrystallized from the appropriate solvent to afford 27a–e
(Tables II and III).
Method B
Triethylamine (0.5 g, [0.75 mL], 5 mmol) was added dropwise to a
mixture of the appropriate hydrazonoyl halides 23a–e and 28 (5 mmol)
in ethanol (20 mL) while stirring. Stirring was continued for 1 h, and the
resulting solid was collected and recrystallized. The product is identical

74
A. O. Abdelhamid et al.
in all aspects (mp., mixed mp. and spectra) with those obtained in
method A.
Synthesis of 2-(Benzofuran-2-ylcarbonyl)-3-mercapto-3-
methylsulfanylacrelonitrile (28)
A mixture of 21 (0.9 g, 5 mmol), potassium hydroxide (0.28 g (5 mmol),
and carbon disulfide (0.47 g, 5 mmol) in N,N,-dimethylformamide
(15 mL) was stirred for 6h at room temperature. Iodometane (0.71 g,
5 mmol) was added dropwise to the above mixture and stirred for 1 hr.
The resulting solid was collected and crystallized from ethanol to give
28 (Tables II and III).
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Some New Thieno[2,3-B]pyridines
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