Synthesis and characterization of 6-(aryl)-2-thioxo-1,2-dihydropyridine-3- carbonitriles

Article abstract of DOI:10.1080/17415993.2012.661734

In the present study, 3-aminothieno[2,3-b]pyridines, pyrido[3′, 2′:4,5]thieno[3,2-d]pyrimidinones, and pyrido[3′,2′:4,5] thieno[3,2-d][1,3]oxazinones were prepared via the reaction of 6-(aryl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles with active-halog

Full text of DOI:10.1080/17415993.2012.661734

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Synthesis and characterization of 6-
(aryl)-2-thioxo-1,2-dihydropyridine-3-
carbonitriles
Fawzy A. Attaby a , Ahmed H. El-Ghandour b , Abdelwahed R.
Sayed b , Ashraf A. El Bassuony c & Ahmed A.M. El-Reedy d
a Chemistry Department, Faculty of Science, Cairo University,
12613, Giza, Egypt
b Chemistry Department, Faculty of Science, Beni-Suef University,
Beni-Suef, Egypt
c Spinning-Weaving Department, Faculty of Industrial Education,
Beni-Suef University, Beni-Suef, Egypt
d Basic-Applied Science Department, Faculty of Oral and Dental
Medicine, Nahda University, Beni-Suef, Egypt
Version of record first published: 21 Mar 2012.
To cite this article: Fawzy A. Attaby, Ahmed H. El-Ghandour, Abdelwahed R. Sayed, Ashraf A. El
Bassuony & Ahmed A.M. El-Reedy (2012): Synthesis and characterization of 6-(aryl)-2-thioxo-1,2-
dihydropyridine-3-carbonitriles, Journal of Sulfur Chemistry, 33:2, 197-221
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Journal of Sulfur Chemistry
Vol. 33, No. 2, April 2012, 197–221
Synthesis and characterization of
6-(aryl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles
Fawzy A. Attabya*, Ahmed H. El-Ghandourb, Abdelwahed R. Sayedb, Ashraf A. El Bassuonyc
and Ahmed A.M. El-Reedyd
aChemistry Department, Faculty of Science, Cairo University, 12613 Giza, Egypt; bChemistry Department,
Faculty of Science, Beni-Suef University, Beni-Suef, Egypt; cSpinning-Weaving Department, Faculty of
Industrial Education, Beni-Suef University, Beni-Suef, Egypt; dBasic-Applied Science Department, Faculty
of Oral and Dental Medicine, Nahda University, Beni-Suef, Egypt
(Received 21 December 2011; final version received 25 January 2012)
In the present study, 3-aminothieno[2,3-b]pyridines, pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidinones, and
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]oxazinones were prepared via the reaction of 6-(aryl)-2-thioxo-1,2-
dihydropyridine-3-carbonitriles with active-halogen-containing compounds. The structures of all the newly
synthesized heterocyclic compounds were established by considering elemental analysis and spectral data.
CN
N
S
N
H
N
S
Y
R
X
R'
NH2
Y
M
z
N
S
N
S
O
Y = CN, CONH2, COCH3 , COOH, COAr; X = M = Z = Nitrogen;
M = Nitrogen or CarbonR = R' = H, CH3, Cl
Keywords: thienopyridines; pyridinethiones; pyridothienopyrimidinones; pyridothienotriazines;
pyridothienooxazinones
Introduction
In the present study, several new heterocyclic derivatives with a range of biological activities have
been obtained. The pyridine nucleus constitutes the major part of these derivatives. Pyridines have
been reported earlier to exhibit diverse biological activities as antioxidants and biocides (1–3) and
*Corresponding author. Emails: fattaby@hotmail.com; fattaby@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.661734
http://www.tandfonline.com

198 F.A. Attaby et al.
function as valuable anticancer (4) and antimicrobial (5) substances. For example, a wide range of
antimicrobial (6–9), anticancer (10), and anti-inflammatory (11) biological activities have been
attributed specifically to thieno[2,3-b]pyridines. In addition, pyrimidines were reported to exhibit
antitumor (12), anticancer (13), and anti-inflammatory (14) activities and were used as new drugs
for treatment of insomnia (15). In light of all these considerations and in continuation of our
long-term interest in the chemistry of pyridines (16–23), we were motivated to synthesize and
characterize sulfur-containing derivatives of these compounds.
Results and discussion
We were interested in exploring the synthetic potential of 6-(aryl)-2-thioxo-1,2-dihydropyridine-
3-carbonitriles 1a–1c (24–26) (R = H, CH3, and Cl, respectively) as substrates in reactions with
active-halogen-containing compounds such as chloroacetamide and chloroacetonitrile (2a and
2b). Thus, we were delighted to find that 1a reacted with chloroacetamide (2a) and chloroace-
tonitrile (2b) in methanolic sodium methoxide under stirring at room temperature for 30 min to
give 3a and 3d. The IR (cm−1) spectra of these reaction products showed an absorption band for
1
− −
−
the CN group and exhibited H NMR spectra that revealed the signals for S CH2 , pyridine,
and aromatic protons. Moreover, their mass spectra gave molecular ion peaks (M+) at m/z = 269
and 251, which correspond to the molecular weights of the assigned structures 3a and 3d, respec-
tively.A further verification of the structures of 3a and 3d was obtained by the detection of peaks at
m/z corresponding to the loss of the CONH2, CH2CONH2, SCH2CONH2, CH2CN, and SCH2CN
fragments (cf. Scheme 1). Similarly, analogs 1b and 1c reacted with 2a and 2b under the same
experimental conditions as 1a to afford the corresponding products 3b, 3c, 3e, and 3f, respectively,
1
whose structures were established by the examination of their IR, H NMR, and mass spectra
and confirmed by elemental analyses (cf. Scheme 1). Further confirmation of the 3a–3f structures
arose from their cyclization in methanolic sodium methoxide under reflux for 5 h to give 4a–4f,
respectively. A CN absorption band was absent in the IR spectra of the cyclization products and
instead a band for the newly formed NH2 was detected.
The work was extended to explore the synthetic potential of 4a–4f to synthesize a variety of
heterocyclic compounds required for several chemical transformations to produce compounds for
our medicinal chemistry program. Thus, it has been found that 4a–4c reacted with formic acid
(5) to afford the corresponding pyridothienopyrimidinones 6a–6c whose structures were verified
by IR and elemental analyses. In addition, the mass spectra of 6a–6c gave the parent peaks (M+)
at m/z = 279, 293, and 313, which correspond to their molecular weights (cf. Scheme 1).
In a further investigation, compounds 4a–4c reacted with acetic anhydride (7) under reflux for
3–5 h to afford unexpectedly the reaction products 8a–8c. The IR (cm−1) spectra of these reaction
products showed bands corresponding to NH and CO groups. Moreover, the mass spectra of 8a–8c
gave m/z = 293, 307, and 327, which correspond to their respective molecular weights. On the
other hand, pyridothienotriazines 10a–10c were obtained in good yields and in a very pure state
through the reaction of 4a–4c with nitrous acid (9). The structures of 10a–10c were elucidated by
the examination of their IR (cm−1) spectra, which exhibited absorption bands for both CO and
NH groups, and by the examination of their mass spectra, which exhibited the parent peaks at
m/z = 280, 294, and 314, which correspond to their molecular weights.
The reactivity of both neighboring NH2 and CONH2 groups in 4a–4c and NH2 and CN in 4d–4f
with both phenyl isothiocyanate (11) and carbon disulfide (13) was examined. Thus, compounds
4d–4f reacted with phenyl isothiocyanate (11) in pyridine (15 ml) under reflux for 6 h to give
the reaction products 12a–12c, respectively. The IR spectra of these reaction products showed no
absorption bands for the CN group, and the NH2 group was not detected in either the IR or 1H
NMR spectra. Moreover, their mass spectra gave the parent peaks (M+) at m/z = 386, 400, and

Journal of Sulfur Chemistry 199
Scheme 1. Synthetic route of compounds 3, 4, 6.
420, which correspond to their molecular weights. Other peaks corresponding to fragment ions
at m/z = 309, 385, and 325 in the case of compound 12a; at m/z = 323, 399, and 341 in the case
+
+
of 12b; and at m/z = 343 (M+ Ph), 342 (M H), and 361 (M HNCS) in the case of 12c
also provide verification of the product structures. Compounds 4a–4c were reacted with carbon
disulfide (13) in pyridine to give the reaction products 14a–14c whose structures were established
by consideration of their IR and 1H NMR data and their elemental analysis. Moreover, their mass
spectra gave the parent ions at m/z = 311, 325, and 345, which correspond to their molecular
weights (cf. Scheme 2).
−
−
−
Inafurtherinvestigation, 1a–1creactedwith1-bromo-2-phenylethan-2-one(15a)inmethanolic
sodium methoxide under stirring at room temperature for 15 min to give the corresponding 2-
alkylthio derivatives 16a–16c whose structures were elucidated by considering their IR (cm−1
)
and 1H NMR spectra and their elemental analyses.
The mass spectra of 16a–16c gave the parent peaks (M+) at m/z = 302, 316, and 336, which
correspond to their molecular weights (cf. Experimental). In addition, 16a–16c were cyclized in
ethanolic sodium ethoxide under reflux for 30 min to give the corresponding thieno[2,3-b]pyridine
derivatives 17a–17c, respectively, which were also obtained via refluxing of 1a–1c with 15a

200 F.A. Attaby et al.
Scheme 2. Synthetic route of compounds 8, 10, 12, 14.
in ethanolic sodium ethoxide for 2 h. In similar reactions, 1a–1c were reacted with 15b and
15c in methanolic sodium methoxide under the above-mentioned experimental conditions to
give the corresponding 2-alkylthiopyridine derivatives 16d–16i, respectively, whose structures
1
were established by considering their IR, H NMR, and mass spectral data and their elemental
analyses. Compounds 16d–16i cyclized in ethanolic sodium ethoxide under reflux for 30 min to
afford the corresponding thieno[2,3-b]pyridines 17d–17i whose structures were established by
the examination of their IR, 1H NMR, and mass spectral data and their elemental analyses. On
the other hand, authentic samples of 17d–17i were obtained directly via the reactions of 1a–1c
with 15b and 15c in ethanolic sodium ethoxide under reflux for 30 min. It is important to point
out here that samples of 17a–17i obtained by the two pathways were identical in all physical and
chemical properties (cf. Scheme 3).
Compounds 1a–1c also reacted with chloroacetone (18a) in methanolic sodium methoxide
under stirring for 15 min at room temperature to give the corresponding 2-acetonylthiopyridines
19a–19c. The IR (cm−1) spectra of these reaction products showed bands for the CN groups, while
1
−
−
their H NMR spectra revealed the signals for the SCH2 protons. Moreover, their mass spectra
gave the parent peaks (M+) at m/z = 268, 282, and 302, which correspond to their molecular
weights in addition to other peaks at m/z = M+ CH3, M COCH3, M CH2COCH3, and
SCH2COCH3, which gave further confirmation of their structures. Similarly, compounds 1a–1c
reacted with 3-chloro-2,4-pentandione (18b) under the above-mentioned experimental conditions
to give the same reaction products 19a–19c which were obtained from the reactions of 1a–1c with
chloroacetone (18a) (Scheme 4).
+
+
−
−
−
Compounds 1a–1c also reacted with ethyl 2-chloro-3-oxobutanoate (18c) to give the corre-
sponding thieno[2,3-b]pyridine derivatives 21a–21c via the non-isolable intermediates 19d–19i.

Journal of Sulfur Chemistry 201
Scheme 3. Synthetic route of compounds 16, 17.
The structures of 21a–21c were confirmed by their IR, 1H NMR, and mass spectral data as well
as by their elemental analyses (cf. Experimental). Compounds 1a–1c reacted with chloroacetic
acid (22) in methanolic sodium methoxide under stirring at room temperature to give the reaction
products 23a–23c.
The IR spectra of these reaction products showed absorption bands corresponding to carboxylic
1
−
−
CO, OH, and CN groups and their H NMR spectra revealed signals for COOH, CH2 , aro-
matic, and pyridine protons. Moreover, the mass spectra of 23a–23c gave the parent peaks at
m/z = 270, 284, and 304, which correspond to their molecular weights. The appearance of peaks
corresponding to M+ COOH, M CH2COOH, and M SCH2COOH fragments also provides
further confirmation of the structures of 23a–23c. Compounds 23a–23c underwent intramolec-
ular cyclization by refluxing in ethanolic sodium ethoxide for 4 h to afford the corresponding
thieno[2,3-b]pyridines 24a–24c. The structures of 24a–24c were established by considering the
IR and 1H NMR data and by elemental analyses and mass spectrometry.
+
+
−
−
−
The synthetic potential of 24a–24c was investigated by examining their reactions with acetic
anhydride with the goal of generating a fused oxazine ring on the thieno[2,3-b]pyridine system.
The success of the reaction was firmly established by showing that compounds 24a–24c reacted
with acetic anhydride to give reaction products in which the absence of COOH and NH2 is
1
clearly demonstrated by the IR and H NMR spectral data. Moreover, their mass spectra gave

202 F.A. Attaby et al.
Scheme 4. Synthetic route of compounds 19, 20, 21.
the parent peaks at m/z = 294, 308, and 328 corresponding to the molecular weights of 25a–
25c. Compounds 25a–25c reacted with aromatic amines 26a and 26b and hydrazine to give the
pyrimidinones 27a–27f and 28a–28c, respectively, whose structures were elucidated by their IR,
1H NMR, and elemental analysis data. Moreover, their mass spectra gave the parent peaks at 369,
383, 403, 383, 397, 417, 308, 322, and 342 corresponding to the molecular weights of 27a–27f
and 28a–28c (cf. Scheme 5).
Conclusion
−
−
Both the CH2 and CN groups in compounds 3a–3f were involved in the cyclization step to
give the imino derivatives Ia–If as intermediates, which tautomerized to afford the final isolable
products 4a–4f, respectively, as illustrated by Scheme 1. During the preparation of compounds
6a–6c, 8a–8c, and 10a–10c, each of formic acid, acetic anhydride, and nitrous acid caused partial
hydrolysis of the CN groups at the 2-position of 4d–4f and the products subsequently underwent
intramolecular cyclization to give the final isolated reaction products 6a–6c, 8a–8c, and 10a–10c,
respectively.

Journal of Sulfur Chemistry 203
Scheme 5. Synthetic route of compounds 23, 24, 25, 27, 28.
Biological activity
The antimicrobial and antifungal properties of all the newly synthesized heterocyclic compounds
were tested. Some of these compounds exhibited high activities and, on the other hand, other
compounds exhibited low, medium, or no activities (cf. Table 1).
Experimental
All melting points are uncorrected. IR spectra (KBr discs) were recorded on Shimadzu FTIR-
8201PC spectrophotometer. 1H NMR spectra were recorded on Varian Mercury 300 MHz
spectrometers using TMS as an internal standard and DMSO-d6 as a solvent, and chemical
shifts, δ, are expressed in ppm. Mass spectra were recorded on a GCMS-QP1000EX spectrometer

204 F.A. Attaby et al.
Table 1. Response of various microorganisms to some synthesized compounds in vitro.
Inhibition zone diameter (mm/mg sample)
Escherichia
Staphylococcus
Aspergillus
flavus (fungus)
Candida albicans
Compound
coli (G−)
aureus (G+)
(fungus)
Tetracycline (antibacterial agent)
Amphotericin B (antifungal agent)
4a
33
–
30
–
–
19
9
–
20
9
13
13
12
14
12
11
16
15
14
12
20
16
12
13
14
14
13
15
11
15
14
15
13
16
14
15
13
14
11
14
13
15
11
10
13
11
12
15
14
15
14
13
11
25
15
12
12
13
12
15
11
15
13
16
14
15
12
13
13
12
13
15
12
11
14
15
4b
4c
4d
4e
4f
8a
8b
8c
7
11
9
5
8
0
11
9
0
9
10
7
11
0
9
10
10
14
9
0
0
0
9
11
8
11
10
11
10
11
10
9
11
7
9
11
10
10
11
10
12a
12b
12c
14a
14b
14c
16a
16b
16c
16d
16e
16f
16g
16h
16i
23a
23b
23c
27a
27b
27c
28a
28b
28c
8
11
11
0
11
9
10
12
7
9
11
9
8
8
9
12
9
11
11
10
9
9
12
9
using inlet type at 70 eV. Microanalyses were performed at the Micro-analytical Center of Cairo
University.
Compounds 1a–1c were prepared according to the literature procedure (24–26).
Synthesis of 3a–3f, 16a–16i, 19a–19c, and 23a–23c (general method)
A solution of each of 1a–1c (0.63, 0.67, and 0.73 g, 3 mmol) and 2-chloroacetamide (2a, 0.28 g,
3 mmol), chloroacetonitrile (2b, 0.22 g, 3 mmol), 2-bromo-1-phenylethanone (15a, 0.59 g), 2-
bromo-1-(4-chlorophenyl)ethanone (15b, 0.69 g), 2-bromo-1-(4-methylphenyl)ethanone (15c,
0.63 g) (3 mmol from each), 1-chloroacetone (18a, 0.27 g, 3 mmol), 3-chloropentane-2,4-dione
(18b, 0.40 g, 3 mmol), 2-chloro-3-oxobutanoate (18c, 0.49 g, 3 mmol), and chloroacetic acid (22,
0.28 g, 3 mmol) in sodium methoxide (prepared from 0.07 g of sodium metal and 25 ml methanol)
was stirred at room temperature for 15 min. The precipitates that were formed were collected by
filtration, washed with water, and crystallized from the proper solvent to afford 3a–3f, 16a–16i,
19a–19c, and 23a–23c, respectively.

Journal of Sulfur Chemistry 205
2-[(3-Cyano-6-phenylpyridin-2-yl)sulfanyl]acetamide (3a)
Yellow crystals (67%), crystallized from dioxane, mp. 255◦C, IR (ν, cm−1): 2976, 2877
−
−
(C H stretching of aliphatic), 3422, 3299 (NH2), 3067 (C H aromatic), 2219 (CN), 1669
(amide CO); MS (m/z) = 269 (M+, 100%, which corresponds to its molecular weight), 268
(M+ H, 13.8%), 267 (M 2H, 9.4%), 253 (M NH2, 32.8%), 225 (M CONH2, 17.2%),
+
+
+
−
−
−
−
211 (M+ CH2CONH2, 22.1%), 179 (M SCH2CONH2, 52.2%); H NMR (DMSO-d6) (δ,
+
1
−
−
−
−
−
ppm): 4.52 (s, 2H, SCH2 ), 5.58 (br., s, 2H, NH2), 7.02–8.44 (m, 5H, Ar, pyridinyl C4H),
9.57 (s, 2H, pyridinyl C5H). Anal. for C14H11N3OS (269), calcd./found (%): C (62.43/62.45), H
(4.12/4.15), N (15.60/15.58), and S (11.91/11.88).
2-{[3-Cyano-6-(4-methylphenyl)pyridin-2-yl]sulfanyl}acetamide (3b)
Brown crystals (58%), crystallized from dioxane, mp. 230◦C, IR (ν, cm−1): 2977, 2873 (C H
−
−
stretching of aliphatic), 3417, 3276 (NH2), 3086 (C H aromatic), 2222 (CN), 1673 (amide
CO); MS (m/z) = 283 (M+, 100%, which corresponds to its molecular weight), 382 (M+ H,
−
+
+
22.3%), 281 (M+ 2H, 13.2%), 267 (M NH2, 17.3%), 239 (M CONH2, 33.8%), 225
−
−
−
+
(M+ CH2CONH2, 15.9%), 193 (M SCH2CONH2, 57.9%); H NMR (DMSO-d6) (δ, ppm):
1
−
−
−
−
−
0.89 (s, 3H, CH3), 4.24 (s, 2H, SCH2 ), 5.56 (br., s, 2H, NH2), 7.15–8.53 (m, 5H, Ar,
pyridinyl C4H), 9.68 (s, 1H, pyridinyl C5H). Anal. for C15H13N3OS (283), calcd./found (%): C
(63.58/63.61), H (4.62/4.59), N (14.83/14.80), and S (11.32/11.29).
2-{[6-(4-Chlorophenyl)-3-cyanopyridin-2-yl]sulfanyl}acetamide (3c)
Yellow crystals (60%), crystallized from dioxane, mp. 235◦C, IR (ν, cm−1): 2977, 2873 (C H
−
−
stretching of aliphatic), 3417, 3276 (NH2), 3086 (C H aromatic), 2222 (CN), 1673 (amide
CO); MS (m/z) = 303 (M+, 100%, which corresponds to its molecular weight), 302 (M+ H,
−
+
+
17.3%), 301 (M+ 2H, 22.6%), 287 (M NH2, 31.2%), 259 (M CONH2, 23.5%), 245
−
−
−
(M+ CH2CONH2, 52.3%), 213 (M SCH2CONH2, 22.3%); H NMR (DMSO-d6) (δ, ppm):
+
1
−
−
−
−
−
4.35 (s, 2H, SCH2 ), 5.67 (br., s, 2H, NH2), 7.13–8.42 (m, 5H, Ar, pyridinyl C4H), 9.56
(s, 1H, pyridinyl C5H). Anal. for C14H10ClN3OS (303), calcd./found (%): C (55.35/55.32), H
(3.32/3.29), Cl (11.67/11.69), N (13.83/13.85), and S (10.56/10.58).
2-[(Cyanomethyl)sulfanyl]-6-phenylpyridine-3-carbonitrile (3d)
Brown crystals (80%), crystallized from dioxane, mp. 265◦C, IR (ν, cm−1): 2985, 2873 (C H
−
+
−
stretching of aliphatic), 3076 (C H, aromatic), 2219 (CN); MS (m/z) = 251 (M , 100%, which
+
corresponds to its molecular weight), 225 (M+ CN, 21.7%), 211 (M CH2CN, 37.6%), 179
−
−
(M+ SCH2CN, 57.9%); H NMR (DMSO-d6) (δ, ppm): 4.55 (s, 2H, SCH2 ), 7.11–8.70 (m,
6H, Ar, pyridinyl C5H), 9.51 (s, 1H, pyridinyl C4H). Anal. for C14H9N3S (251), calcd./found
(%): C (66.91/66.89), H (3.61/3.58), N (16.72/16.75), and S (12.76/12.78).
1
−
−
−
2-[(Cyanomethyl)sulfanyl]-6-(4-methylphenyl)pyridine-3-carbonitrile (3e)
Yellow crystals (70%), crystallized from ethanol, mp. 220◦C, IR (ν, cm−1): 2987, 28+79 (C H
−
−
stretching of aliphatic), 3083 (C H, aromatic), 2220 (CN); MS (m/z) = 265 (M , 100%,
which corresponds to its molecular weight), 239 (M+ CN, 14.5%), 225 (M CH2CN, 19.3%),
+
−
−
193 (M+ SCH2CN, 44.3%); 1H NMR (DMSO-d6) (δ, ppm): 1.00 (s, 3H, CH3), 4.38 (s,
−
−
−
2H, SCH2 ), 7.22–8.51 (m, 5H, Ar, pyridinyl C5H), 9.50 (s, 1H, pyridinyl C4H). Anal. for

206 F.A. Attaby et al.
C15H11N3S (265), calcd./found (%): C (67.90/67.92), H (4.18/4.15), N (15.84/15.81), and S
(12.08/12.11).
6-(4-Chlorophenyl)-2-[(cyanomethyl)sulfanyl]pyridine-3-carbonitrile (3f)
Brown crystals (60%), crystallized from ethanol, mp. 185◦C, IR (ν, cm−1): 2979, 28+95 (C H
−
−
stretching of aliphatic), 3068 (C H, aromatic), 2217 (CN); MS (m/z) = 285 (M , 100%,
which corresponds to its molec+ular weight), 284 (M+ H, 13.9%), 283 (M 2H, 23.7%),
+
−
−
+
269 (M+ NH2, 17.2%), 255 (M CH2NH2, 44.3%), 223 (M SCH2NH2, 27.1%); H NMR
1
−
−
−
−
−
(DMSO-d6) (δ, ppm): 4.63 (s, 2H, SCH2 ), 7.14–8.52 (m, 5H, Ar, pyridinyl C5H), 9.62 (s, 1H,
pyridinyl C4H). Anal. for C14H8ClN3S (285), calcd./found (%): C (58.84/58.87), H (2.82/2.85),
Cl (12.41/12.39), N (14.71/14.69), and S (11.22/11.25).
2-[(2-Oxo-2-phenylethyl)thio]-6-phenylpyridine-3-carbonitrile (16a)
Brown crystals (56%), crystallized from ethanol, mp. 225◦C, IR (ν, cm−1): 2985, 2879 (C H
−
−
stretching of aliphatic), 3087 (C H, aromatic), 2219 (CN), 1704 (CO); MS (m/z) = 330
(M+, 65.3%, which corresponds+to its molecular weight), 225 (M+ COPh, 37.5%), 211
−
(M+ CH2COPh, 75.2%), 179 (M SCH2COPh, 100%); H NMR (DMSO-d6) (δ, ppm): 4.29
1
−
−
−
−
(s, 2H, SCH2 ), 7.15–8.83 (m, 11H, Ar, pyridinyl C5H), 9.53 (s, 1H, pyridinyl C4H). Anal.
for C20H14N2OS (330), calcd./found (%): C (72.70/72.67), H (4.27/4.29), N (8.48/8.51), and S
(9.71/9.74).
2-[(2-Oxo-2-phenylethyl)thio]-6-(4-methylphenyl)pyridine-3-carbonitrile (16b)
Yellow crystals (77%), crystallized from ethanol, mp. 199◦C, IR (ν, cm−1): 2979, 2885 (C H
−
−
stretching of aliphatic), 3067 (C H, aromatic), 2220 (CN), 1701 (CO); MS (m/z) = 344
(M+, 53.8%, which corresponds+to its molecular weight), 253 (M+ COPh, 32.8%), 239
−
(M+ CH2COPh, 88.5%), 207 (M SCH2CO Ph, 100%); H NMR (DMSO-d6) (δ, ppm): 1.13
1
−
−
−
−
(s, 3H, CH3), 4.16 (s, 2H, SCH2 ), 7.28–8.91 (m, 10H, Ar, pyridinyl C5H), 9.48 (s, 1H,
pyridinyl C4H). Anal. for C21H16N2OS (344), calcd./found (%): C (73.23/73.25), H (4.68/4.71),
N (8.13/8.16), and S (9.31/9.34).
2-[(2-Oxo-2-phenylethyl)thio]-6-(4-chlorophenyl)pyridine-3-carbonitrile (16c)
Yellow crystals (70%), crystallized from dioxane, mp. 259◦C, IR (ν, cm−1): 2973, 2889 (C H
−
−
stretching of aliphatic), 3085 (C H, aromatic), 2216 (CN), 1700 (CO); MS (m/z) = 364
(M+, 47.3%, which corresponds+to its molecular weight), 293 (M+ COPh, 17.3%), 279
−
(M+ CH2COPh, 75.9%), 247 (M SCH2COPh, 100%); H NMR (DMSO-d6) (δ, ppm): 4.24
1
−
−
−
−
(s, 2H, SCH2 ), 7.16–8.78 (m, 10H, Ar, pyridinyl C5H), 9.63 (s, 1H, pyridinyl C4H). Anal.
for C20H13ClN2OS (364), calcd./found (%): C (65.84/65.87), H (3.59/3.61), Cl (9.72/9.69), N
(7.68/7.66), and S (8.79/8.81).
2-{[2-(4-Chlorophenyl)-2-oxoethyl]thio}-6-phenylpyridine-3-carbonitrile (16d)
Yellow crystals (55%), crystallized from ethanol, mp. 165◦C, IR (ν, cm−1): 2955, 2869 (C H
−
−
stretching of aliphatic), 3069 (C H, aromatic), 2217 (CN), 1705 (CO); MS (m/z) = 364
(M+, 64.1%, which corresponds to the molecular weight), 259 (M+ COPh, 28.3%), 245
−

Journal of Sulfur Chemistry 207
+
(M+ CH2COPh, 66.9%), 213 (M SCH2COPh, 100%); H NMR (DMSO-d6) (δ, ppm): 4.23
1
−
−
−
−
(s, 2H, SCH2 ), 7.15–8.85 (m, 10H, Ar, pyridinyl C5H), 9.56 (s, 1H, pyridinyl C4H). Anal.
for C20H13ClN2OS (364), calcd./found (%): C (65.84/65.87), H (3.59/3.61), Cl (9.72/9.69), N
(7.68/7.66), and S (8.79/8.81).
2-{[2-(4-Chlorophenyl)-2-oxoethyl]thio}-6-(4-methylphenyl)pyridine-3-carbonitrile (16e)
Brown crystals (82%), crystallized from ethanol, mp. 180◦C, IR (ν, cm−1): 2959, 2872
−
−
(C H stretching of aliphatic), 3074 (C H, aromatic), 2222 (CN), 1700 (CO); MS (m/z) =
378 (M+, 44.3%, which corresponds to its molecular weight), 273 (M+ COC6H4 p-CH3,
−
−
21.8%), 259 (M+ CH2COC6H4 p-CH3, 67.2%), 227 (M SCH2COC6H4 p-CH3, 100%);
+
−
−
−
−
1H NMR (DMSO-d6) (δ, ppm): 1.02 (s, 3H, CH3), 4.16 (s, 2H, SCH2 ), 7.13–8.83
(m, 9H, Ar, pyridinyl C5H), 9.56 (s, 1H, pyridinyl C4H). Anal. for C21H15ClN2OS (378),
calcd./found (%): C (66.57/66.59), H (3.99/4.02), Cl (9.36/9.33), N (7.39/7.41), and S
(8.46/8.48).
−
−
2-{[2-(4-Chlorophenyl)-2-oxoethyl]thio}-6-(4-chlorophenyl)pyridine-3-carbonitrile (16f)
Brown crystals (50%), crystallized from ethanol, mp. 188◦C, IR (ν, cm−1): 2967, 2869 (C H
−
+
−
stretching of aliphatic), 3076 (C H, aromatic), 2221 (CN), 1702 (CO); MS (m/z) = 399 (M ,
53.8%, which corresponds to its molecula+r weight), 260 (M+ COC6H4 p-Cl, 18.3%), 246
−
−
(M+ CH2COC6H4 p-Cl, 55.9%), 214 (M SCH2COC6H4 p-Cl, 100%); H NMR (DMSO-
1
−
−
−
−
−
−
d6) (δ, ppm): 4.26 (s, 2H, SCH2 ), 7.10–8.84 (m, 9H, Ar, pyridinyl C5H), 9.44 (s, 1H, pyridinyl
C4H). Anal. for C20H12Cl2N2OS (399), calcd./found (%): C (60.16/60.18), H (3.03/3.05), Cl
(17.76/17.74), N (7.02/6.99), and S (8.03/8.00).
2-{[2-(4-Methylphenyl)-2-oxoethyl]thio}-6-phenylpyridine-3-carbonitrile (16g)
Yellow crystals (83%), crystallized from ethanol, mp. 215◦C, IR (ν, cm−1): 2971, 2892 (C H
−
−
stretching of aliphatic), 3076 (C H, aromatic), 2218 (CN), 1700 (CO); MS (m/z) = 344
(M+, 53.8%, which corresponds to the molecular weight), 239 (M+ COC6H4 p-CH3, 32.8%),
−
−
+
225 (M+ CH2COC6H4 p-CH3, 88.5%), 193 (M SCH2CO C6H4 p-CH3, 100%); H NMR
1
−
−
−
−
−
−
(DMSO-d6) (δ, ppm): 1.13 (s, 3H, CH3), 4.16 (s, 2H, SCH2 ), 7.28–8.91 (m, 10H, Ar,
pyridinyl C5H), 9.48 (s, 1H, pyridinyl C4H). Anal. for C21H16N2OS (344), calcd./found (%):
C (73.23/73.25), H (4.68/4.71), N (8.13/8.16), and S (9.31/9.34).
2-{[2-(4-Methylphenyl)-2-oxoethyl]thio}-6-(4-methylphenyl)pyridine-3-carbonitrile (16h)
Yellow crystals (59%), crystallized from ethanol, mp. 126◦C, IR (ν, cm−1): 2979, 2898 (C H
−
−
stretching of aliphatic), 3088 (C H, aromatic), 2216 (CN), 1705 (CO); MS (m/z) = 358
(M+, 43.6%, which corresponds to the molecular weight), 253 (M+ COC6H4 p-CH3, 18.5%),
−
−
+
239 (M+ CH2COC6H4 p-CH3, 75.8%), 207 (M SCH2CO C6H4 p-CH3, 100%); H NMR
1
−
−
−
−
−
−
(DMSO-d6) (δ, ppm): 1.13 (s, 6H, two CH3), 4.26 (s, 2H, SCH2 ), 7.13–8.84 (m, 9H, Ar,
pyridinyl C5H), 9.57 (s, 1H, pyridinyl C4H). Anal. for C22H18N2OS (358), calcd./found (%): C
(73.71/73.69), H (5.06/5.09), N (7.82/7.85), and S (8.95/8.97).

208 F.A. Attaby et al.
2-{[2-(4-Methylphenyl)-2-oxoethyl]thio}-6-(4-chlorophenyl)pyridine-3-carbonitrile (16i)
Brown crystals (68%), crystallized from ethanol, mp. 150◦C, IR (ν, cm−1): 2968, 2877 (C H
−
−
stretching of aliphatic), 3085 (C H, aromatic), 2217 (CN), 1700 (CO); MS (m/z) = 378
(M+, 54.8%, which corresponds to the molecular weight), 273 (M+ COC6H4 p-CH3, 33.6%),
−
−
259 (M+ CH2COC6H4 p-CH3, 73.4%), 227 (M SCH2CO C6H4 p-CH3, 100%); H NMR
+
1
−
−
−
−
−
−
(DMSO-d6) (δ, ppm): 1.11 (s, 3H, CH3), 4.35 (s, 2H, SCH2 ), 7.11–8.81 (m, 9H, Ar,
pyridinyl C5H), 9.63 (s, 1H, pyridinyl C4H). Anal. for C21H15ClN2OS (378), calcd./found (%):
C (66.57/66.59), H (3.99/4.02), Cl (9.36/9.33), N (7.39/7.41), and S (8.46/8.48).
2-[(2-Oxopropyl)sulfanyl]-6-phenylpyridine-3-carbonitrile (19a)
Yellow crystals (58%), mp. 195◦C, crystallized from ethanol, IR (ν, cm−1): 2960, 2879 (C H
−
−
stretching of aliphatic), 3082 (C H, aromatic), 2218 (CN), 1700 (CO); MS (m/z) = 268
(M+, 48.5%, which corresponds to+its molecular weight), 225 (M+ COCH3, 58.2%), 211
−
(M+ CH2COCH3, 52.1%), 179 (M SCH2COCH3, 100%); H NMR (DMSO-d6) (δ, ppm):
1
−
−
−
−
2.67 (s, 3H, CH3CO), 4.26 (s, 2H, SCH2 ), 7.15–8.83 (m, 6H, Ar, pyridinyl C5H), 9.66 (s, 1H,
pyridinyl C4H). Anal. for C15H12N2OS (268), calcd./found (%): C (67.14/67.16), H (4.51/4.53),
N (10.44/10.47), and S (11.95/11.98).
6-(4-Methylphenyl)-2-[(2-oxopropyl)sulfanyl]pyridine-3-carbonitrile (19b)
Yellow crystals (65%), 225◦C, crystallized from ethanol, IR (ν, cm−1): 2978, 2898 (C H stretch-
−
+
−
ing of aliphatic), 3076 (C H, aromatic), 2222 (CN), 1708 (CO); MS (m/z) = 282 (M , 65.2%,
which corresponds to its molecular weight), 239 (M+ COCH3, 55.8%), 225 (M CH2COCH3,
+
−
−
52.1%), 193 (M+ SCH2COCH3, 100%); H NMR (DMSO-d6) (δ, ppm): 1.35 (s, 3H, CH3),
1
−
−
−
2.67 (s, 3H, CH3CO), 4.26 (s, 2H, SCH2 ), 7.16–8.88 (m, 5H, Ar, pyridinyl C5H), 9.68 (s, 1H,
pyridinyl C4H). Anal. for C16H14N2OS (282), calcd./found (%): C (68.06/68.03), H (5.00/4.97),
N (9.92/9.95), and S (11.36/11.34).
6-(4-Chlorophenyl)-2-[(2-oxopropyl)sulfanyl]pyridine-3-carbonitrile (19c)
Yellow crystals (75%), 263◦C, crystallized from ethanol, IR (ν, cm−1): 2973, 2891 (C H stretch-
−
+
−
ing of aliphatic), 3066 (C H, aromatic), 2218 (CN), 1705 (CO); MS (m/z) = 302 (M , 66.3%,
+
which corresponds to its molecular weight), 259 (M+ COCH3, 58.2%), 245 (M CH2COCH3,
−
−
52.1%), 213 (M+ SCH2COCH3, 100%); H NMR (DMSO-d6) (δ, ppm): 2.53 (s, 3H, CH3CO),
1
−
−
−
4.17 (s, 2H, SCH2 ), 7.10–8.90 (m, 5H, Ar, pyridinyl C5H), 9.66 (s, 1H, pyridinyl C4H). Anal.
for C15H11ClN2OS (302), calcd./found (%): C (59.50/59.52), H (3.66/3.68), Cl (11.71/11.74),
N (9.25/9.27), and S (10.59/10.61).
[(3-Cyano-6-phenylpyridin-2-yl)sulfanyl]acetic acid (23a)
Yellow crystals (52%), crystallized from ethanol, mp. 173◦C, IR (ν, cm−1): 2976, 2889
−
−
(C H stretching of aliphatic), 3325–3543 (broad band for acidic OH), 3064 (C H aromatic),
2215 (CN), 1710 (CO); MS (m/z) = 270 (M+, 100%, which corresponds to its molecular
weight), 253 (M+ OH, 13.8%), 225 (M COOH, 33.6%), 211 (M CH2COOH, 17.3%), 179
+
+
−
−
−
(M+ SCH2COOH, 56.8%); H NMR (DMSO-d6) (δ, ppm): 2.53 (s, 2H, SCH2 ), 7.12–8.51
1
−
−
−
(m, 6H, Ar, pyridinyl C5H), 9.33 (s, 1H, pyridine C4H), and 13.82 (s, br., 1H, COOH). Anal. for

Journal of Sulfur Chemistry 209
C14H10N2O2S (270), calcd./found (%): C (62.21/62.18), H (3.73/3.71), N (10.36/10.39), and S
(11.86/11.84).
{[3-Cyano-6-(4-methylphenyl)pyridin-2-yl]sulfanyl}acetic acid (23b)
Brown crystals (59%), crystallized from ethanol, mp. 185◦C, IR (ν, cm−1): 2966, 2896
−
−
(C H stretching of aliphatic), 3318–3522 (broad band for acidic OH), 3069 (C H aromatic),
2219 (CN), 1708 (CO); MS (m/z) = 284 (M+, 100%, which corresponds to its molecular
weight), 267 (M+ OH, 23.8%), 239 (M COOH, 39.6%), 225 (M CH2COOH, 27.8%),
+
+
−
−
−
193 (M+ SCH2COOH, 53.2%); H NMR (DMSO-d6) (δ, ppm): 1.10 (s, 3H, CH3), 2.54 (s, 2H,
1
−
−
−
SCH2 ), 7.13–8.52 (m, 5H, Ar, pyridinyl C5H), 9.34 (s, 1H, pyridine C4H), and 13.57 (s, br.,
1H, COOH). Anal. for C15H12N2O2S (284), calcd./found (%): C (63.36/63.38), H (4.25/4.28),
N (9.85/9.82), and S (11.28/11.31).
{[6-(4-Chlorophenyl)-3-cyanopyridin-2-yl]sulfanyl}acetic acid (23c)
Yellow crystals (66%), crystallized from ethanol, mp. 216◦C, IR (ν, cm−1): 2976, 2898
−
−
(C H stretching of aliphatic), 3322–3538 (broad band for acidic OH), 3077 (C H aromatic),
2222 (CN), 1710 (CO); MS (m/z) = 304 (M+, 100%, which corresponds to its molecular
weight), 287 (M+ OH, 33.2%), 259 (M COOH, 17.6%), 245 (M CH2COOH, 38.8%), 213
+
+
−
−
−
(M+ SCH2COOH, 57.8%); H NMR (DMSO-d6) (δ, ppm): 2.54 (s, 2H, SCH2 ), 7.15–8.57
(m, 5H, Ar, pyridinyl C5H), 9.53 (s, 1H, pyridine C4H), and 13.62 (s, br., 1H, COOH). Anal. for
C14H9ClN2O2S (304), calcd./found (%): C (55.18/55.16), H (2.98/3.01), Cl (11.63/11.65), N
(9.19/9.22), and S (10.52/10.55).
1
−
−
−
Synthesis of 4a–4f, 17a–17i, 20a–20c, and 24a–24c (general method)
A solution of each of 3a–3f (0.80, 0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol), 16a–16i (0.99, 1.03,
1.09, 1.03, 1.07, 1.13, 1.09, 1.13, and 1.19 g, 3 mmol), 19a–19c (0.80, 0.85, and 0.91 g, 3 mmol),
or 23a–23c (0.81, 0.85, and 0.91 g, 3 mmol) in sodium ethoxide solution (prepared from 0.07 g of
3 mmol sodium and 25 ml ethanol) was heated under reflux for 3 h. The solids that formed after
cooling were collected by filtration and washed with water and ethanol and then crystallized from
dioxane to give 4a–4c, 17a–17i, 20a–20c, and 24a–24c, respectively.
3-Amino-6-phenylthieno[2,3-b]pyridine-2-carbonitrile (4a)
Gray crystals (83%), crystallized from ethanol, mp. 220◦C, IR (ν, cm−1): 3412, 3387, 3255, 3165
(NH2 and amidic NH2), 1669 (amide CO); MS (m/z) = 251 (M+, 100%, which corresponds to
+
+
the molecular weight),+235 (M+ NH2, 23.8%), 234 (M NH2, H, 18.3%), 233 (M NH2,
−
−
−
−
−
−
−
2H, 22.7%), 205 (M CONH2, 2H, 30.9%). Anal. for C14H9N3S (251), calcd./found (%):
C (66.91/66.89), H (3.61/3.58), N (16.72/16.75), and S (12.76/12.78).
3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridine-2-carbonitrile (4b)
Yellow crystals (55%), crystallized from dioxane, mp. 248◦C, IR (ν, cm−1): 2977, 2876 (C H
−
stretching of aliphatic), 3412, 3345, 3222, 3172 (NH2 and amidic NH2), 1672 (amide CO); MS
(m/z) = 265 (M+, 100%, which corresponds to the molecular weight), 249 (M+ NH2, 9.9%),
−
+
+
248 (M+ NH2, H, 22.1%), 247 (M NH2, 2H, 17.5%), 219 (M CONH2, 2H, 18.1%).
−
−
−
−
−
−

210 F.A. Attaby et al.
Anal. for C15H11N3S (265), calcd./found (%): C (67.90/67.92), H (4.18/4.15), N (15.84/15.81),
and S (12.08/12.11).
3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carbonitrile (4c)
Yellow crystals (74%), crystallized from dioxane, mp. 244◦C, IR (ν, cm−1): 3401, 3385, 3208,
3185 (NH2 and amidic NH2), 1669 (amide CO); MS (m/z) = 285 (M+, 100%, which corresponds
+
+
to the molecular weight), 269 (M+ NH2, 15.4%), 268 (M NH2, H, 23.9%), 267 (M NH2,
−
−
−
−
+
−
−
−
2H, 14.6%), 239 (M CONH2, 2H, 22.6%). Anal. for C14H8ClN3S (285), calcd./found (%):
C (58.84/58.87), H (2.82/2.85), Cl (12.41/12.39), N (14.71/14.69), and S (11.22/11.25).
3-Amino-6-phenylthieno[2,3-b]pyridine-2-carboxamide (4d)
Yellow crystals (90%), crystallized from dioxane, mp. 269◦C, IR (ν, cm−1): 3464, 3421, 3298,
3158 (NH2 and amidic NH2), 1667 (amide CO); MS (m/z) = 269 (M+, 100%, which corre-
+
sponds to the molecular weight), 2+53 (M+ NH2, 17.3%), 252 (M NH2, H, 44.2%), 251
−
−
−
(M+ NH2, 2H, 13.6%), 225 (M CONH2, 2H, 72.3%), 166 (M PhCN NH2, 7.3%).
Anal. for C14H11N3OS (269), calcd./found (%): C (62.43/62.45), H (4.12/4.15), N (15.60/15.58),
and S (11.91/11.88).
+
−
−
−
−
−
−
3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridine-2-carboxamide (4e)
Yellow crystals (60%), crystallized from dioxane, mp. 232◦C, IR (ν, cm−1): 2987, 2874 (C H
−
stretching of aliphatic), 3455, 3414, 3277, 3147 (NH2 and amidic NH2), 1675 (amide CO); MS
(m/z) = 283 (M+, 100%, which corresponds to the molecular weight), 267 (M+ NH2, 23.8%),
−
266 (M+ NH2, H, 36.3%), 265 (M NH2, 2H, 21.7%), 237 (M CONH2, 2H, 56.9%).
Anal. for C15H13N3OS (283), calcd./found (%): C (63.58/63.61), H (4.62/4.59), N (14.83/14.80),
and S (11.32/11.29).
+
+
−
−
−
−
−
−
3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxamide (4f)
Yellow crystals (80%), crystallized from dioxane, mp. 240◦C, IR (ν, cm−1): 3438, 3402, 3253,
3153 (NH2 and amidic NH2), 1669 (amide CO); MS (m/z) = 303 (M+, 100%, which corresponds
+
+
to the molecular weigh+t), 287 (M+ NH2, 33.1%), 286 (M NH2, H, 21.8%), 285 (M NH2,
−
−
−
−
−
−
−
2H, 13.3%), 257 (M CONH2, 2H, 34.1%). Anal. for C14H10ClN3OS (303), calcd./found
(%): C (55.35/55.32), H (3.32/3.29), Cl (11.67/11.69), N (13.83/13.85), and S (10.56/10.58).
(3-Amino-6-phenylthieno[2,3-b]pyridin-2-yl)(phenyl)methanone (17a)
Yellow crystals (80%), crystallized from ethanol, mp. 183◦+C, IR (ν, cm−1): 3466, 3376 (NH2),
−
3076 (C H aromatic), 1678 (CO); MS (m/z) = 330 (M , 53.8%, which corresponds to the
+
+
molecular weight), 329 (M+ H, 29.7%), 314 (M NH2, 17.9%), 225 (M COPh, 100%); H
NMR (DMSO-d6) (δ, ppm): 5.99 (s, 2H, NH2), 7.11–8.54 (m, 11H, Ar, and pyridinyl C4H), and
9.68 (m, 1H, pyridinyl C4H). Anal. for C20H14N2OS (330), calcd./found (%): C (72.70/72.67),
H (4.27/4.29), N (8.48/8.51), and S (9.71/9.74).
1
−
−
−
[3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridin-2-yl](phenyl)methanone (17b)
Yellow crystals (55%), crystallized from ethanol, mp. 195◦C, IR (ν, cm−1): 2987, 2867 (C H
−
−
stretching of aliphatic), 3458, 3373 (NH2), 3066 (C H aromatic), 1669 (CO); MS (m/z) = 344

Journal of Sulfur Chemistry 211
+
(M+, 58.2%, which corresponds to the molecular weight), 343 (M+ H, 33.3%), 328 (M NH2,
−
−
32.7%), 238 (M+ COPh, 100%); H NMR (DMSO-d6) (δ, ppm): 0.96 (s, 3H, CH3), 5.98 (s,
1
−
2H, NH2), 7.24–8.69 (m, 10H, Ar, and pyridinyl C4H), and 9.583 (m, 1H, pyridinyl C4H). Anal.
for C21H16N2OS (344), calcd./found (%): C (73.23/73.25), H (4.68/4.71), N (8.13/8.16), and S
(9.31/9.34).
[3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridin-2-yl](phenyl)methanone (17c)
Yellow crystals (72%), crystallized from ethanol, mp. 213◦+C, IR (ν, cm−1): 3463, 3377 (NH2),
−
3068 (C H aromatic), 1677 (CO); MS (m/z) = 364 (M , 55.9%, which corresponds to the
+
+
molecular weight), 363 (M+ H, 21.9%), 348 (M NH2, 33.2%), 258 (M COPh, 100%); H
NMR (DMSO-d6) (δ, ppm): 6.04 (s, 2H, NH2), 7.11–8.58 (m, 10H, Ar, and pyridinyl C4H), and
9.65 (m, 1H, pyridinyl C4H). Anal. for C20H13ClN2OS (364), calcd./found (%): C (65.84/65.87),
H (3.59/3.61), Cl (9.72/9.69), N (7.68/7.66), and S (8.79/8.81).
1
−
−
−
(3-Amino-6-phenylthieno[2,3-b]pyridin-2-yl)(4-chlorophenyl)methanone (17d)
Yellow crystals (70%), crystallized from ethanol, mp. 206◦+C, IR (ν, cm−1): 3422, 3319 (NH2),
−
3072 (C H aromatic), 1677 (CO); MS (m/z) = 364 (M , 55.2%, which corresponds to the
+
+
molecular weight), 363 (M+ H, 32.8%), 348 (M NH2, 23.7%), 225 (M COC6H4 p-Cl,
100%); 1H NMR (DMSO-d6) (δ, ppm): 5.83 (s, 2H, NH2), 7.11–8.62 (m, 10H, Ar, and pyridinyl
C4H), and 9.50 (m, 1H, pyridinyl C4H). Anal. for C20H13ClN2OS (364), calcd./found (%): C
(65.84/65.87), H (3.59/3.61), Cl (9.72/9.69), N (7.68/7.66), and S (8.79/8.81).
−
−
−
−
[3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridin-2-yl](4-chlorophenyl)methanone (17e)
Yellow crystals (55%), crystallized from ethanol, mp. 166◦C, IR (ν, cm−1): 2973, 2889 (C H
−
−
stretching of aliphatic), 3412, 3338 (NH2), 3056 (C H aromatic), 1679 (CO); MS (m/z) = 378
+
(M+, 64.3%, which corresponds to the molecular weight), 377 (M+ H, 33.1%), 362 (M NH2,
−
−
9.7%), 239 (M+ COC6H4 p-Cl, 100%); H NMR (DMSO-d6) (δ, ppm): 1.11 (s, 3H, CH3), 6.15
(s, 2H, NH2), 7.14–8.86 (m, 9H, Ar, and pyridinyl C4H), and 9.67 (m, 1H, pyridinyl C4H). Anal.
for C21H15ClN2OS (378), calcd./found (%): C (66.57/66.59), H (3.99/4.02), Cl (9.36/9.33), N
(7.39/7.41), and S (8.46/8.48).
1
−
−
[3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridin-2-yl](4-chlorophenyl)methanone (17f)
Yellow crystals (65%), crystallized from dioxane, mp. 237◦+C, IR (ν, cm−1): 3422, 3344 (NH2),
−
3076 (C H aromatic), 1677 (CO); MS (m/z) = 399 (M , 44.8%, which corresponds to the
+
+
molecular weight), 398 (M+ H, 23.9%), 383 (M NH2, 27.3%), 260 (M COC6H4 p-Cl,
100%);1H NMR (DMSO-d6) (δ, ppm): 6.17 (s, 2H, NH2), 7.13–8.91 (m, 9H, Ar, and pyridinyl
C4H), and 9.58 (m, 1H, pyridinyl C4H). Anal. for C20H12Cl2N2OS (399), calcd./found (%): C
(60.16/60.18), H (3.03/3.05), Cl (17.76/17.74), N (7.02/6.99), and S (8.03/8.00).
−
−
−
−
(3-Amino-6-phenylthieno[2,3-b]pyridin-2-yl)(4-methylphenyl)methanone (17g)
Yellow crystals (76%), crystallized from ethanol, mp. 226◦C, IR (ν, cm−1): 2965, 2884 (C H
−
−
stretching of aliphatic), 3437, 3322 (NH2), 3066 (C H aromatic), 1688 (CO); MS (m/z) = 344
+
(M+, 63.4%, which corresponds to the molecular weight), 343 (M+ H, 18.9%), 328 (M NH2,
−
−
44.7%), 278 (M+ COPh, 100%); H NMR (DMSO-d6) (δ, ppm): 1.11 (s, 3H, CH3), 5.93 (s,
1
−
2H, NH2), 7.12–8.68 (m, 10H, Ar, and pyridinyl C4H), and 9.582 (m, 1H, pyridinyl C4H). Anal.
for C21H16N2OS (344), calcd./found (%): C (73.23/73.25), H (4.68/4.71), N (8.13/8.16), and S
(9.31/9.34).

212 F.A. Attaby et al.
[3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridin-2-yl](4-methylphenyl)methanone (17h)
Brown crystals (65%), crystallized from ethanol, mp. 215◦C, IR (ν, cm−1): 2958, 2877 (C H
−
−
stretching of aliphatic), 3421, 3317 (NH2), 3082 (C H aromatic), 1672 (CO); MS (m/z) = 358
+
(M+, 55.7%, which corresponds to the molecular weight), 357 (M+ H, 23.7%), 342 (M NH2,
−
−
31.9%), 278 (M+ COC6H4 p-CH3, 100%); H NMR (DMSO-d6) (δ, ppm): 1.20 (s, 6H,
two CH3), 5.96 (s, 2H, NH2), 7.15–8.69 (m, 9H, Ar, and pyridinyl C4H), and 9.63 (m, 1H,
pyridinyl C4H). Anal. for C22H18N2OS (358), calcd./found (%): C (73.71/73.69), H (5.06/5.09),
N (7.82/7.85), and S (8.95/8.97).
1
−
−
[3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridin-2-yl](4-methylphenyl)methanone (17i)
Red crystals (69%), crystallized from ethanol, mp. 220◦C, IR (ν, cm−1): 2964, 2896 (C H
−
−
stretching of aliphatic), 3417, 3322 (NH2), 3076 (C H aromatic), 1669 (CO); MS (m/z) = 378
+
(M+, 34.9%, which corresponds to the molecular weight), 377 (M+ H, 18.6%), 362 (M NH2,
−
−
11.8%), 298 (M+ COC6H4 p-CH3, 100%); H NMR (DMSO-d6) (δ, ppm): 1.15 (s, 3H, CH3),
6.10 (s, 2H, NH2), 7.14–8.73 (m, 9H, Ar, and pyridinyl C4H), and 9.59 (m, 1H, pyridinyl
C4H). Anal. for C21H15ClN2OS (378), calcd./found (%): C (66.57/66.59), H (3.99/4.02), Cl
(9.36/9.33), N (7.39/7.41), and S (8.46/8.48).
1
−
−
1-(3-Amino-6-phenylthieno[2,3-b]pyridin-2-yl)ethanone (20a)
Yellow crystals (68%), crystallized from ethanol, mp. 218◦C, IR (ν, cm−1): 2976, 2856
−
−
(C H stretching of aliphatic), 3069 (C H, aromatic), 2209 (CN), 1715 (CO); MS (m/z) =
268 (M+, 100%, which corres+ponds to the molecular weight), 367 (M+ H, 32.4%),
−
266 (M+ 2H, 17.3%), 225 (M COCH3, 22.8%), 211 (M CH2COCH3, 53.7%), 179
+
−
−
−
(M+ SCH2COCH3, 62.8%); H NMR (DMSO-d6) (δ, ppm): 2.36 (s, 3H, COCH3), 4.28 (s,
1
−
−
−
−
2H, SCH2 ), 7.11–8.59 (m, 6H, Ar, pyridinyl C5H), 9.56 (s, 1H, pyridinyl C4H). Anal. for
C15H12N2OS (268), calcd./found (%): C (67.14/67.16), H (4.51/4.53), N (10.44/10.47), and S
(11.95/11.98).
1-[3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridin-2-yl]ethanone (20b)
Yellow crystals (77%), crystallized from ethanol, mp. 228◦C, IR (ν, cm−1): 2959, 2877 (C H
−
+
−
stretching of aliphatic), 3077 (C H, aromatic), 2215 (CN), 1711 (CO); MS (m/z) = 282 (M ,
+
100%, which corresponds to the molecular weight+), 267 (M+ CH3, 37.8%), 239 (M CH3CO,
−
−
52.1%), 225 (M+ CH2COCH3, 44.3%), 193 (M SCH2COCH3, 66.3%); H NMR (DMSO-
1
−
−
−
−
−
d6) (δ, ppm): 1.11 (s, 3H, CH3), 2.56 (s, 3H, COCH3), 4.30 (s, 2H, SCH2 ), 7.14–8.58 (m,
5H, Ar, pyridinyl C5H), 9.53 (s, 1H, pyridinyl C4H). Anal. for C16H14N2OS (282), calcd./found
(%): C (68.06/68.03), H (5.00/4.97), N (9.92/9.89), and S (11.36/11.33).
1-[3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridin-2-yl]ethanone (20c)
Yellow crystals (66%), crystallized from ethanol, mp. 215◦C, IR (ν, cm−1): 2967, 2869 (C H
−
+
−
stretching of aliphatic), 3069 (C H, aromatic), 2219 (CN), 1709 (CO); MS (m/z) = 302 (M ,
+
100%, which corresponds to the molecular weight), 287 (M+ CH3, 19.6%), 259 (M CH3CO,
−
−
+
43.7%), 245 (M+ CH2COCH3, 32.8%), 213 (M SCH2COCH3, 56.8%); H NMR (DMSO-d6)
1
−
−
−
−
−
(δ, ppm): 2.42 (s, 3H, COCH3), 4.22 (s, 2H, SCH2 ), 7.10–8.55 (m, 5H, Ar, pyridinyl C5H),

Journal of Sulfur Chemistry 213
9.58 (s, 1H, pyridinyl C4H). Anal. for C15H11ClN2OS (302), calcd./found (%): C (59.50/59.53),
H (3.66/3.68), Cl (11.71/11.74), N (9.25/9.28), and S (10.59/10.56).
3-Amino-6-phenylthieno[2,3-b]pyridine-2-carboxylic acid (24a)
Brown crystals (55%), crystallized from ethanol, mp. 199◦C, IR (ν, cm−1): 3084 (C H aromatic),
−
3473 (NH2), 3275–3472 (acidic OH); MS (m/z):+270 (M+, 100%, which corresponds to the
molecular weight), 253 (M+ OH, 53.2%), 225 (M COOH, 28.9%); H NMR (DMSO-d6) (δ,
ppm): 5.35 (s, 2H, NH2), 7.13–8.25 (m, 6H, Ar, pyridinyl C5H), 9.54 (s, 1H, pyridinyl C4H), and
14.52 (s, br., 1H, COOH). Anal. for C14H10N2O2S (270), calcd./found (%): C (62.21/62.18), H
(3.73/3.71), N (10.36/10.39), and S (11.86/11.84).
1
−
−
3-Amino-6-(4-methylphenyl)thieno[2,3-b]pyridine-2-carboxylic acid (24b)
Brown crystals (75%), crystallized from ethanol, mp. 212◦C, IR (ν, cm−1): 2985, 2879 (C H
−
−
stretching of aliphatic), 3088 (C H aromatic), 3477 (NH2), 3235–3479 (acidic OH); MS (m/z):
284 (M+, 100%, which corresponds to the molecular weight), 267 (M+ OH, 53.2%), 239
−
(M+ COOH, 33.7%); H NMR (DMSO-d6) (δ, ppm): 1.13 (s, 3H, CH3), 5.32 (s, 2H, NH2),
1
−
7.16–8.58 (m, 5H, Ar, pyridinyl C5H), 9.59 (s, 1H, pyridinyl C4H), and 14.12 (s, br., 1H, COOH).
Anal. for C15H12N2O2S (284), calcd./found (%): C (63.36/63.38), H (4.25/4.28), N (9.85/9.82),
and S (11.28/11.31).
3-Amino-6-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxylic acid (24c)
Yellow crystals (69%), crystallized from ethanol, mp. 200◦C, IR (ν, cm−1): 3076 (C H aromatic),
−
3474 (NH2), 3235–3479 (acidic OH); MS (m/z):+304 (M+, 100%, which corresponds to the
molecular weight), 287 (M+ OH, 43.8%), 259 (M COOH, 13.3%); H NMR (DMSO-d6) (δ,
ppm): 5.53 (s, 2H, NH2), 7.13–8.55 (m, 5H, Ar, pyridinyl C5H), 9.38 (s, 1H, pyridinyl C4H), and
14.33 (s, br., 1H, COOH). Anal. for C14H9ClN2O2S (304), calcd./found (%): C (55.18/55.16),
H (2.98/3.01), Cl (11.63/11.65), N (9.19/9.22), and S (10.52/10.55).
1
−
−
Synthesis of 6a–6c (general method)
A solution of each of 4a–4f (0.80, 0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol) and formic acid
(20 ml) was heated under reflux for 6 h. The excess solvent was evaporated. The solids that
were formed were collected by filtration, dried, and crystallized from dioxane to give 6a–6c,
respectively.
7-Phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6a)
White crystals (80%), crystallized from ethanol, mp. 183◦C, IR (ν, cm−1): 3173 (NH), 3088 (C H
−
aromatic), 1676 (CO); MS (m/z): 279 (M+, 86.3%, wh+ich corresponds to the molecular weight),
278 (M+ H, 100%), 277 (M 2H, 22.7%), 252 (M NCH, 8.7%), 251 (M CO, 21.3%),
+
+
−
−
−
−
223 (M+ CONHCH, 32.7%). Anal. for C15H9N3OS (279), calcd./found (%): C (64.50/64.53),
−
H (3.25/3.23), N (15.04/15.06), and S (11.48/11.50).
7-(4-Methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6b)
White crystals (78%), crystallized from DMF, mp. > 300◦C, IR (ν, cm−1): 2967, 2873 (C H
−
+
−
stretching of aliphatic), 3168 (NH), 3075 (C H aromatic), 1670 (CO); MS (m/z): 293 (M ,

214 F.A. Attaby et al.
+
55.7%, which corresponds to the molecular weight), 292 (M+ H, 100%), 291 (M 2H,
−
−
17.9%), 266 (M+ NCH, 22.3%), 265 (M CO, 9.9%), 237 (M CONHCH, 19.1%). Anal.
for C16H11N3OS (293), calcd./found (%): C (65.51/65.53), H (3.78/3.81), N (14.32/14.29), and
S (10.93/10.90).
+
+
−
−
−
7-(4-Chlorophenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (6c)
Yellow crystals (70%), crystallized from DMF, mp. > 300◦C, IR (ν, cm−1): 3166 (NH), 3053
+
−
(C H aromatic), 1669 (CO); MS (m/z): 313 (M , 69.1%, which corresponds to the molecular
+
+
+
weight), 312 (M+ H, 100%), 313 (M 2H, 19.3%), 286 (M NCH, 15.1%), 285 (M CO,
−
−
−
−
33.8%), 257 (M+ CONHCH, 17.1%). Anal. for C15H8ClN3OS (313), calcd./found (%): C
(57.42/57.45), H (2.57/2.60), Cl (11.30/11.33), N (13.39/13.37), and S (10.22/10.25).
−
Synthesis of 8a–8c (general method)
A solution of each of 4a–4f (0.80, 0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol) in acetic anhydride
(20 ml) was heated under reflux for 6 h; the excess solvents were evaporated. The solids that were
so formed were collected by filtration and crystallized from dioxane to give 8a–8c, respectively.
2-Methyl-7-phenylpyrido[3ꢀ,2ꢀ:4, 5]thieno[3,2-d]pyrimidin-4(3H)-one (8a)
Green crystals (67%), crystallized from DMF, mp. > 300◦C, IR (ν, cm−1): 2982, 2872 (C H
−
+
−
stretching of aliphatic), 3138 (NH), 3064 (C H aromatic), 1669 (CO); MS (m/z): 293 (M , 100%,
+
which corresponds to the molecul+ar weight), 292 (M+ H, 44.9%), 278 (M CH3, 31.8%), 251
−
−
(M+ NHCCH3, 33.7%), 223 (M CONHCCH3, 37.1%); H NMR (DMSO-d6) (δ, ppm): 2.25
(s, 3H, CH3); 7.10–8.65 (m, 6H, Ar, pyridinyl C9H), 9.24 (s, 1H, pyridinyl C8H); 12.63 (s,
1H, NH). Anal. for C16H11N3OS (293), calcd./found (%): C (65.51/65.53), H (3.78/3.81), N
(14.32/14.29), and S (10.93/10.90).
1
−
−
2-Methyl-7-(4-methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8b)
Yellow crystals (57%), crystallized from DMF, mp. >300◦C, IR (ν, cm−1): 2988, 2879 (C H
−
+
−
stretching of aliphatic), 3155 (NH), 3077 (C H aromatic), 1673 (CO); MS (m/z): 307 (M , 100%,
+
which corresponds to the molecul+ar weight), 306 (M+ H, 32.5%), 292 (M CH3, 45.1%), 265
−
−
(M+ NHCCH3, 22.3%), 237 (M CONHCCH3, 19.1%); H NMR (DMSO-d6) (δ, ppm): 0.89
(s, 3H, CH3), 2.41 (s, 3H, CH3); 7.04–8.73 (m, 5H, Ar, pyridinyl C9H), 9.51 (s, 1H, pyridinyl
C8H); 12.55 (s, 1H, NH). Anal. for C17H13N3OS (307), calcd./found (%): C (66.43/66.45), H
(4.26/4.29), N (13.67/13.69), and S (10.43/10.45).
1
−
−
7-(4-Chlorophenyl)-2-methylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (8c)
Yellow crystals (63%), crystallized from dioxane, mp. 295◦C, IR (ν, cm−1): 2981, 2893 (C H
−
+
−
stretching of aliphatic), 3165 (NH), 3078 (C H aromatic), 1671 (CO); MS (m/z): 327 (M , 100%,
which corresponds to the molecul+ar weight), 326 (M+ H, 22.3%), 312 (M CH3, 33.7%), 285
+
−
−
(M+ NHCCH3, 16.8%), 257 (M CONHCCH3, 22.7%); H NMR (DMSO-d6) (δ, ppm): 2.52
(s, 3H, CH3); 7.09–8.75 (m, 5H, Ar, pyridinyl C9H), 9.62 (s, 1H, pyridinyl C8H); 12.49 (s, 1H,
NH). Anal. for C16H10ClN3OS (327), calcd./found (%): C (58.63/58.65), H (3.07/3.10), Cl
(10.82/10.85), N (12.82/12.79), and S (9.78/9.81).
1
−
−

Journal of Sulfur Chemistry 215
−
Synthesis of 10a 10c (general method)
Sodium nitrite solution (2.0 g in 10 ml water) was added to a solution of compounds 4a–4f (0.80,
0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol) in concentrated hydrochloric acid (5 ml) and glacial
acetic acid (10 ml) at 0◦C and stirred for 5 min. The mixture was allowed to stand at room
temperature for 30 min. The solids that precipitated on dilution with water were collected and
crystallized from dioxane to give 10a–10c, respectively.
7-Phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]triazin-4(3H)-one (10a)
Yellow crystals (86%), crystallized from dioxane,+mp. 233◦C, IR (ν, cm−1): 3423 (NH), 3073
−
(C H aromatic), 1666 (CO); MS (m/z): 280 (M , 100%, which +corresponds to the molecu-
+
lar weight), 279 (M+ H, 85.4%), 278 (M 2H, 58.7%), 251 (M NHN, 33.7%). Anal. for
C14H8N4OS (280), calcd./found (%): C (59.99/60.01), H (2.88/2.85), N (19.99/20.02), and S
(11.44/11.47).
−
−
−
7-(4-Methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]triazin-4(3H)-one (10b)
Yellow crystals (85%), crystallized from dioxane,+mp. 238◦C, IR (ν, cm−1): 3452 (NH), 3085
−
(C H aromatic), 1677 (CO); MS (m/z): 294 (M , 100%, which +corresponds to the molecu-
lar weight), 293 (M+ H, 79.6%), 292 (M 2H, 55.3%), 265 (M NHN, 17.5%). Anal. for
C15H10N4OS (294), calcd./found (%): C (61.21/61.19), H (3.42/3.45), N (19.04/19.06), and S
(10.89/10.92).
+
−
−
−
7-(4-Chlorophenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]triazin-4(3H)-one (10c)
Yellowcrystals(83%), crystallizedfromethanol, mp. 202◦C, IR(ν, cm−1):3445(NH), 3068(C H
−
aromatic), 1673 (CO); MS (m+/z): 314 (M+, 100%, w+hich corresponds to the molecular weight),
313 (M+ H, 76.4%), 312 (M 2H, 52.3%), 285 (M NHN, 31.1%). Anal. for C14H7ClN4OS
(314), calcd./found (%): C (53.42/53.45), H (2.24/2.27), Cl (11.26/11.23), N (17.80/17.77),
and S (10.19/10.21).
−
−
−
−
Synthesis of 12a 12c (general method)
A solution of each of 4a–4f (0.80, 0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol) and phenyl isoth-
iocyanate (0.40 g, 3 mmol) in pyridine (20 ml) was heated under reflux for 48 h. The reaction
mixture was then cooled, poured into ice-cold water, and neutralized with a few drops of acetic
acid and the solid was collected by filtration and crystallized from dioxane to give 12a–12c,
respectively.
4-Imino-3,7-diphenyl-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyramidine-2(1H)-thione
(12a)
Yellow crystals (73%), crystallized from dioxane, mp. 284◦+C, IR (ν, cm−1): 3358, 3222 (2NH),
−
=
3067 (C H aromatic), 1555 (C S); MS (m/z): 386 (M , 100%, whi+ch corresponds to the
+
molecular weight), 385 (M+ H, 58.7%), 384 (M 2H, 46.9%), 309 (M C6H5, 37.3%), 306
−
−
−
(M+ 2H, C6H5, 44.1%); H NMR (DMSO-d6) (δ, ppm): 5.55 (s, 1H, NH at 1-position); 7.24–
8.97 (m, 11H, Ar, pyridinyl C9H), 9.54 (s, 1H, pyridinyl C8H); 13.23 (s, 1H, NH at 4-position).
1
−

216 F.A. Attaby et al.
Anal. for C21H14N4S2 (386), calcd./found (%): C (65.26/65.29), H (3.65/3.62), N (14.50/14.53),
and S (16.59/16.61).
4-Imino-7-(4-methylphenyl)-3-phenyl-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-pyrimidine
-2(1H)-thione (12b)
Yellow crystals (91%), crystallized from DMF, mp. >300◦C, IR (ν, cm−1): 2988, 2874 (C H
−
−
=
stretching of aliphatic), 3355, 3216 (2NH), 3076 (C H aromatic), 1547 (C S); MS (m/+z): 400
(M+, 100%, which corresponds to the molecular weight), 399 (M+ H, 36.9%), 398 (M 2H,
−
−
+
44.1%), 323 (M+ C6H5, 24.1%), 321 (M 2H, C6H5, 31.7%); H NMR (DMSO-d6) (δ, ppm):
1.02 (s, 3H, CH3), 5.27 (s, 1H, NH at 1-position); 7.17–8.96 (m, 10H, Ar, pyridinyl C9H), 9.70 (s,
1H, pyridinyl C8H); 13.54 (s, 1H, NH at 4-position). Anal. for C22H16N4S2 (400), calcd./found
(%): C (65.97/66.00), H (4.03/4.05), N (13.99/14.01), and S (16.01/15.98).
1
−
−
7-(4-Chlorophenyl)-4-imino-3-phenyl-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-pyrimidine
-2(1H)-thione (12c)
Yellow crystals (78%), crystallized from DMF, mp. > 300◦+C, IR (ν, cm−1): 3357, 3214 (2NH),
−
=
3072 (C H aromatic), 1558 (C S); MS (m/z): 420 (M , 100%, whi+ch corresponds to the
+
molecular weight), 419 (M+ H, 48.3%), 418 (M 2H, 38.3%), 343 (M C6H5, 55.8%), 341
−
−
−
(M+ 2H, C6H5, 31.8%); H NMR (DMSO-d6) (δ, ppm): 5.27 (s, 1H, NH at 1-position); 7.18–
8.910 (m, 10H, Ar, pyridinyl C9H), 9.69 (s, 1H, pyridinyl C8H); 13.45 (s, 1H, NH at 4-position).
Anal. for C21H13ClN4S2 (420), calcd./found (%): C (59.92/59.89), H (3.11/3.14), Cl (8.42/8.45),
N (13.31/13.33), and S (15.24/15.26).
1
−
−
Synthesis of 14a 14c (general method)
A solution of each of 4a–4f (0.80, 0.84, 0.90, 0.75, 0.79, and 0.85 g, 3 mmol) and carbon disulfide
(5 ml) in pyridine (20 ml) was heated under reflux for 48 h. The reaction mixture was then cooled,
poured into ice-cold water, and neutralized with a few drops of acetic acids; the solids that were
so formed were collected by filtration, dried, and crystallized from ethanol to give 14a–14c,
respectively.
7-Phenyl-2-thioxo-2,3-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(1H)-one (14a)
Yellow crystals (79%), crystallized from DMF, m+p. > 300◦C, IR (ν, cm−1): 3344 (NH), 3069
−
=
(C H aromatic), 1552 (C S); MS (m/+z): 311 (M , 100%, which corresponds to the molecular
+
+
weight), 310 (M+ H, 55.3%), 297 (M N, 33.9%), 295 (M H, NH, 30.8%), 279 (M S,
−
−
−
−
14.8%), 253 (M+ CSN, 22.3%); H NMR (DMSO-d6) (δ, ppm): 7.10–8.73 (m, 6H,Ar, pyridinyl
C9H), 9.52 (s, 1H, pyridinyl C8H), 12.55 (s, 1H, NH at 3-position); 13.78 (s, 1H, NH at 3-position).
Anal. forC15H9N3OS2 (311), calcd./found(%):C(57.86/57.89), H(2.91/2.88), N(13.49/13.51),
and S (20.60/20.62).
1
−
7-(4-Methylphenyl)-2-thioxo-2,3-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(1H)-one
(14b)
Yellow crystals (90%), crystallized from dioxane, mp. 296◦C, IR (ν, cm−1): 2978, 2876 (C H
−
+
−
=
stretching of aliphatic), 3338 (NH), 3077 (C H aromatic), 1555 (C S); MS (m+/z): 325 (M ,
100%, which corresponds to the molecular weight), 324 (M+ H, 34.8%), 311 (M N, 26.3%),
−
−

Journal of Sulfur Chemistry 217
+
+
309 (M+ H, NH, 22.1%), 293 (M S, 32.1%), 267 (M CSN, 12.9%); H NMR (DMSO-d6)
(δ, ppm): 1.21 (s, 3H, CH3), 7.21–8.82 (m, 5H, Ar, pyridinyl C9H), 9.62 (s, 1H, pyridinyl C8H),
12.44 (s, 1H, NH at 3-position); 13.20 (s, 1H, NH at 3-position). Anal. for C16H11N3OS2 (325),
calcd./found (%): C (59.06/59.09), H (3.41/3.39), N (12.91/12.88), and S (19.71/19.68).
1
−
−
−
7-(4-Chlorophenyl)-2-thioxo-2,3-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(1H)-one
(14c)
Yellowcrystals(83%), crystallizedfromDMF, mp. >300◦C, IR(ν, cm−1):3348(NH), 3088(C H
−
+
=
aromatic), 1550 (C S); MS (m/z): 345 (M , 100%, which corresponds to the molecular weight),
+
+
+
344 (M+ H, 32.8%), 331 (M N, 48.2%), 329 (M H, NH, 21.7%), 313 (M S, 24.7%), 287
−
−
−
−
(M+ CSN, 17.9%); H NMR (DMSO-d6) (δ, ppm): 7.18–8.35 (m, 5H, Ar, pyridinyl C9H), 9.64
1
−
(s, 1H, pyridinyl C8H), 12.63 (s, 1H, NH at 3-position); 13.55 (s, 1H, NH at 3-position). Anal.
for C15H8ClN3OS2 (345), calcd./found (%): C (52.10/52.13), H (2.33/2.36), Cl (10.25/10.28),
N (12.15/12.13), and S (18.54/18.57).
−
Synthesis of 25a 25c (general method)
A solution of each of 24a–24c (0.81, 0.84, and 0.90 g, 1 mmol) and acetic anhydride (20 ml)
was heated under reflux for 4 h. The excess solvent was evaporated and then cooled. The solids
that were so formed were collected by filtration and crystallized from dioxane to give 25a–25c,
respectively.
2-Methyl-7-phenyl-4H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]oxazin-4-one (25a)
Gray crystals (67%), crystallized from dioxane, mp. 278◦C, IR (ν, cm−1): 29+87, 2873 (C H
−
−
stretching of aliphatic), 3077 (C H aromatic), 1731 (CO); MS (m/z):+294 (M , 100%, which
corresponds to the molecular weight), 279 (M+ CH3, 33.12%), 253 (M NCCH3, 23.7%), 251
−
−
+
(M+ 2H, NCCH3, 15.7%), 250 (M CO2, 38.9%); H NMR (DMSO-d6) (δ, ppm): 2.36 (s, 3H,
CH3); 7.11–8.51 (m, 6H,Ar, pyridinyl C9H), 9.52 (s, 1H, pyridinyl C8H).Anal. for C16H10N2O2S
(294), calcd./found (%): C (65.29/65.31), H (3.42/3.45), N (9.52/9.49), and S (10.89/10.87).
1
−
−
2-Methyl-7-(4-methylphenyl)-4H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]oxazin-4-one (25b)
Brown crystals (66%), crystallized from DMF, mp. > 300◦C, IR (ν, cm−1): 29+84, 2879 (C H
−
−
stretching of aliphatic), 3072 (C H aromatic), 1727 (CO); MS (m/z):+308 (M , 100%, which
corresponds to the molecular weight), 293 (M+ CH3, 22.59%), 267 (M NCCH3, 53.2%), 265
−
−
+
(M+ 2H, NCCH3, 9.18%), 264 (M CO2, 75.3%); H NMR (DMSO-d6) (δ, ppm): 0.98 (s,
3H, CH3), 2.53 (s, 3H, CH3); 7.13–8.58 (m, 5H, Ar, pyridinyl C9H), 9.58 (s, 1H, pyridinyl C8H).
Anal. for C17H12N2O2S (308), calcd./found (%): C (66.22/66.24), H (3.92/3.95), N (9.08/9.11),
and S (10.40/10.43).
1
−
−
7-(4-Chlorophenyl)-2-methyl-4H-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,3]oxazin-4-one (25c)
Brown crystals (65%), crystallized from DMF, mp. >300◦C, IR (ν, cm−1): 29+75, 2868 (C H
−
−
stretching of aliphatic), 3063 (C H aromatic), 1729 (CO); MS (m/z): 328 (M , 100%, which
corresponds to the molecular weight), 313 (M+ CH3, 17.33%), 287 (M NCCH3, 33.9%),
+
−
−
+
285 (M+ 2H, NCCH3, 14.22%), 284 (M CO2, 62.8%); H NMR (DMSO-d6) (δ, ppm): 2.56
1
−
−
(s, 3H, CH3); 7.10–8.54 (m, 5H, Ar, pyridinyl C9H), 9.53 (s, 1H, pyridinyl C8H). Anal. for

218 F.A. Attaby et al.
C16H9ClN2O2S (328), calcd./found (%): C (58.45/58.48), H (2.76/2.79), Cl (10.78/10.76), N
(8.52/8.55), and S (9.75/9.73).
−
Synthesis of 27a 27f (general method)
A solution of each of 26a–26c (0.88, 0.92, and 0.98 g, 3 mmol) and aniline or p-toluidine (0.27
and 0.36g, 3 mmol) in acetic acid (20 ml) was heated under reflux for 3 h. The excess solvent was
evaporated and then cooled. The solids that were so formed were collected by filtration, dried,
and crystallized from acetic acid to give 28a–28f, respectively.
2-Methyl-3,7-diphenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (27a)
Yellow crystals (77%), crystallized from dioxane, mp. 285◦C, IR (ν, cm−1): 29+76, 2865 (C H
−
−
stretching of aliphatic), 3045 (C H aromatic), 1676 (CO); MS (m/z); 3+69 (M , 100%, which
corresponds to the molecular weight), 368 (M+ H, 42.9%), 354 (M CH3, 33.5%), 341
−
−
(M+ CO, 26.12%), 250 (M CONC6H5, 17.22%); H NMR (DMSO-d6) (δ, ppm): 2.53 (s,
3H, CH3); 7.22–8.55 (m, 11H, Ar, pyridinyl C9H), 9.56 (s, 1H, pyridinyl C8H). Anal. for
C22H15N3OS (369), calcd./found (%): C (71.52/71.55), H (4.09/4.12), N (11.37/11.39), and S
(8.68/8.65).
+
1
−
−
2-Methyl-3-(4-methylphenyl)-7-phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-(3H)-one
(27b)
Yellow crystals (65%), crystallized from dioxane, mp. 244◦C, IR (ν, cm−1)+: 2956, 2887 (C H
−
−
stretching of aliphatic), 3086 (C H aromatic), 1678 (CO); MS (m/z); 383 (M , 100%, wh+ich cor-
responds to the molecular weight), 382 (M+ H, 22.3%), 368 (M CH3, 33.5%), 355 (M CO,
+
−
−
−
16.33%), 250 (M+ CONC6H4 p-CH3, 33.32%); H NMR (DMSO-d6) (δ, ppm): 0.98 (s, 3H,
CH3), 2.56 (s, 3H, CH3); 7.26–8.57 (m, 10H,Ar, pyridinyl C9H), 9.58 (s, 1H, pyridinyl C8H).Anal.
for C23H17N3OS (383), calcd./found (%): C (72.04/72.06), H (4.47/4.50), N (10.96/10.98), and
S (8.36/8.33).
1
−
−
2-Methyl-7-(4-methylphenyl)-3-phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-(3H)-one
(27c)
Yellow crystals (58%), crystallized from ethanol, mp. 228◦C, IR (ν, cm−1): 29+53, 2896 (C H
−
−
stretching of aliphatic), 3065 (C H aromatic), 1672 (CO); MS (m/z); 3+83 (M , 100%, which
corresponds to the molecular weight), 382 (M+ H, 22.4%), 368 (M CH3, 63.1%), 355
−
−
+
(M+ CO, 42.33%), 264 (M CONC6H5, 27.34%); H NMR (DMSO-d6) (δ, ppm): 2.55 (s,
6H, two CH3); 7.23–8.54 (m, 10H, Ar, pyridinyl C9H), 9.55 (s, 1H, pyridinyl C8H). Anal. for
C23H17N3OS (383), calcd./found (%): C (72.04/72.06), H (4.47/4.50), N (10.96/10.98), and S
(8.36/8.33).
1
−
−
2-Methyl-3,7-bis(4-methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (27d)
Yellow crystals (54%), crystallized from dioxane, mp. 266◦C, IR (ν, cm−1)+: 2966, 2897 (C H
−
−
stretching of aliphatic), 3077 (C H aromatic), 1669 (CO); MS (m/z); 397 (M , 100%, wh+ich cor-
responds to the molecular weight), 396 (M+ H, 9.18%), 382 (M CH3, 13.7%), 369 (M CO,
+
−
−
−
42.03%), 264 (M+ CONC6H4 p-CH3, 30.31%); H NMR (DMSO-d6) (δ, ppm): 0.98 (s, 6H,
two CH3), 2.62 (s, 3H, CH3); 7.20–8.36 (m, 9H, Ar, pyridinyl C9H), 9.58 (s, 1H, pyridinyl C8H).
1
−
−

Journal of Sulfur Chemistry 219
Anal. for C24H19N3OS (397), calcd./found (%): C (72.52/72.49), H (4.82/4.85), N (10.57/10.60),
and S (8.07/8.09).
7-(4-Chlorophenyl)-2-methyl-3-phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-(3H)-one
(27e)
Brown crystals (77%), crystallized from dioxane, mp. 255◦C, IR (ν, cm−1): 3046 (C H aro-
−
matic), 1672 (CO); MS (m/z); 403 (M+, 100%, which corresponds to the molecular weight), 402
+
+
+
(M+ H, 12.8%), 388 (M CH3, 42.2%), 275 (M CO, 23.52%), 284 (M CONPh, 27.19%);
1H NMR (DMSO-d6) (δ, ppm): 2.63 (s, 3H, CH3); 7.16–8.47 (m, 10H, Ar, pyridinyl C9H), 9.49
(s, 1H, pyridinyl C8H). Anal. for C22H14ClN3OS (403), calcd./found (%): C (65.42/65.39), H
(3.49/3.51), Cl (8.78/8.76), N (10.40/10.38), and S (7.94/7.92).
−
−
−
−
7-(4-Chlorophenyl)-2-methyl-3-(4-methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-pyrimidin-
4(3H)-one
(27f)
Yellow crystals (77%), crystallized from ethanol, mp. 199◦C, IR (ν, cm−1): 2954, 2889 (C H
−
+
−
stretching of aliphatic), 3065 (C H aromatic), 1674 (CO); MS (m/z); 417 (M , 100%, wh+ich cor-
+
respondstothemolecularweight), 416(M+ H, 13.76%), 402(M CH3, 32.6%), 389(M CO,
−
−
−
32.53%), 298 (M+ CONC6H4 p-CH3, 17.17%); H NMR (DMSO-d6) (δ, ppm): 0.98 (s, 3H,
CH3), 2.54 (s, 3H, CH3); 7.14–8.55 (m, 9H,Ar, pyridinyl C9H), 9.59 (s, 1H, pyridinyl C8H).Anal.
for C23H16ClN3OS (417), calcd./found (%): C (66.10/66.13), H (3.86/3.83), Cl (8.48/8.51), N
(10.05/10.02), and S (7.67/7.64).
1
−
−
Synthesis of 29a–29c (general method)
A solution of each of 26a–26c (0.88, 0.92, and 0.98 g, 3 mmol) in hydrazine hydrate (5 ml) and
ethanol (20 ml) was heated under reflux for 2 h; the excess solvents were evaporated and then
cooled. The solids that were so formed were collected by filtration, dried, and crystallized from
acetic acid to give 29a–29c, respectively.
3-Amino-2-methyl-7-phenylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (28a)
Brown crystals (55%), crystallized from dioxane, mp. 244◦C, IR (ν, cm−1): 2987, 2867 (C H
−
−
stretching of aliphatic), 3455, 3228 (NH2), 3054 (C H aromatic), 1667 (CO); MS (m+/z): 308
(M+, 100%, which corresponds to the molecul+ar weight), 307 (M+ H, 34.28%), 293 (M CH3,
−
−
39.31%), 292 (M+ NH2, 54.22%), 279 (M 2H, CCH3, 56.7%); H NMR (DMSO-d6) (δ,
ppm): 2.56 (s, 3H, CH3); 6.20 (br., 2H, NH2); 7.13–8.53 (m, 6H, Ar, pyridinyl C9H), 9.58 (s, 1H,
pyridinyl C9H). Anal. for C16H12N4OS (308), calcd./found (%): C (62.32/62.35), H (3.92/3.89),
N (18.17/18.15), and S (10.40/10.38).
1
−
−
3-Amino-2-methyl-7-(4-methylphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-(3H)-one
(28b)
Yellow crystals (64%), crystallized from ethanol, mp. 195◦C, IR (ν, cm−1): 2977, 2898 (C H
−
−
stretching of aliphatic), 3439, 3233 (NH2), 3060 (C H aromatic), 1677 (CO); MS (m+/z): 322
(M+, 100%, which corresponds to the mol+ecular weight), 321 (M+ H, 13.58%), 317 (M CH3,
−
−
9.23%), 316(M+ NH2, 55.34%), 293(M 2H, CCH3, 28.13%); HNMR(DMSO-d6)(δ, ppm):
0.89 (s, 3H, CH3), 2.56 (s, 3H, CH3); 6.24 (br., 2H, NH2); 7.13–8.56 (m, 5H, Ar, pyridinyl C9H),
1
−
−

220 F.A. Attaby et al.
9.54 (s, 1H, pyridinyl C9H). Anal. for C17H14N4OS (322), calcd./found (%): C (63.33/63.31), H
(4.38/4.35), N (17.38/17.40), and S (9.95/9.97).
3-Amino-7-(4-chlorophenyl)-2-methylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-(3H)-
one (28c)
Brown crystals (66%), crystallized from dioxane, mp. 278◦C, IR (ν, cm−1): 2987, 2867 (C H
−
−
stretching of aliphatic), 3451, 3233 (NH2), 3064 (C H aromatic), 1669 (CO); MS (m+/z): 342
(M+, 100%, which corresponds to the mole+cular weight), 341 (M+ H, 18.22%), 327 (M CH3,
−
−
19.72%), 326(M+ NH2, 17.13%), 313(M 2H, CCH3, 36.3%); HNMR(DMSO-d6)(δ, ppm):
2.58(s, 3H, CH3);6.24(br., 2H, NH2);7.14–8.54(m, 5H,Ar, pyridinylC9H), 9.59(s, 1H, pyridinyl
C9H). Anal. for C16H11ClN4OS (342), calcd./found (%): C (56.06/56.03), H (3.23/3.21), Cl
(10.34/10.37), N (16.34/16.32), and S (9.35/9.33).
1
−
−
Materials and methods
Detection of biological activity (sensitivity tests) using the Kirby-Bauer method
Antimicrobial activity of the tested samples was determined using a modified Kirby-Bauer disc
diffusion method (27). Briefly, 100 μl of the test bacteria/fungi was grown in 10 ml of fresh
media until a count of approximately 108 cells/ml was reached for bacteria or of 105 cells/ml was
reached for fungi (28); 100 μl of microbial suspension was spread onto agar plates corresponding
to the broth in which the organisms were maintained. Isolated colonies of each organism that
might be playing a pathogenic role should be selected from the primary agar plates and tested for
susceptibility by the disc diffusion method; of the many media available, National Committee for
Clinical Laboratory Standard (NCCLS) recommends Mueller-Hinton agar due to its good batch-
to-batch reproducibility. For filamentous fungi, the disc diffusion method was performed by using
the approved standard method (M38-A) for evaluating the susceptibilities of filamentous fungi
to antifungal agents. For yeasts, the disc diffusion method was developed by using the approved
standard method (M44-P). The plates were inoculated with filamentous fungi such as Aspergillus
flavus at 25◦C for 48 h; Gram (+) bacteria such as Staphylococcus aureus and Bacillus subtilis
and Gram (-) bacteria such as Escherichia coli and Pseudomonas aeurginosa were incubated at
35–37◦C for 24–48 h and yeasts such as Candida albicans were incubated at 30◦C for 24–48 h
and then the diameters of the inhibition zones were measured in millimeters (27). Standard discs
of Tetracycline (antibacterial agent) and Amphotericin B (antifungal agent) served as positive
controls for antimicrobial activity, but filter discs impregnated with 10 μl of a solvent (distilled
water, chloroform, or DMSO) were used as a negative control. The agar that was used was the
Mueller-Hinton agar that was rigorously tested for composition and pH. Furthermore, the depth
of the agar in the plate is a factor to be considered in the disc diffusion method. This method
is well documented and standard zones of inhibition have been determined for susceptible and
resistant values. Blank paper disks (Schleicher & Schuell, Spain) with a diameter of 8.0 mm were
impregnated with 10 μ of the tested concentration of the stock solution. When a filter paper disc
impregnated with a tested chemical is placed on agar, the chemical diffuses from the disc into the
agar. This diffusion will place the chemical in the agar only around the disc. The solubility of the
chemical and its molecular size will determine the size of the area of chemical infiltration around
the disc. If an organism is placed on the agar, it will not grow in the area around the disc if it is
susceptible to the chemical. This area growth around the disc is known as the “zone of inhibition”
or “clear zone”. In the disc diffusion method, the zone diameters were measured with slipping
calipers of the NCCLS. Agar-based methods such as the E-test and disk diffusion can be good
alternatives because they are simpler and faster than the broth-based methods (29, 30).

Journal of Sulfur Chemistry 221
Acknowledgements
Authors want to thank Cairo University and Faculty of Science for their financial support.
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