Synthesis and antibacterial activity of some new ethyl thionicotinates, thieno[2,3-b]pyridines, pyrido[3′,2′:4,5] thieno[3,2-d]pyrimidines, and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazines containing sulfonamide moieties

Article abstract of DOI:10.1080/10426500902800253

Ethyl 5-cyano-6-mercaptonicotinate derivatives 1a,b reacted with the N-[4-(aminosulfonyl) phenyl]-2-chloroacetamide derivatives 2a,b to give the ethyl 6-[(2-{[4-(aminosulfonyl) phenyl]amino}-2-oxoethyl)thio]nicotinate derivatives 3a-d. Cyclization of 3a-d

Full text of DOI:10.1080/10426500902800253

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Phosphorus, Sulfur, and Silicon and the
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Synthesis and Antibacterial
Activity of Some New Ethyl
Thionicotinates, Thieno[2,3-
b]pyridines, Pyrido[3′,2′:4,5]
thieno[3,2-d]pyrimidines, and
Pyrido[3′,2′:4,5]thieno[3,2-d]
[1,2,3]triazines Containing Sulfonamide
Moieties
Mohamed A. M. Gad-Elkareem a & Abu-Bakr A. A. M. El-Adasy a
a Chemistry Department, Faculty of Science, Al-Azhar University,
Assiut, Egypt
Published online: 03 Feb 2010.
To cite this article: Mohamed A. M. Gad-Elkareem & Abu-Bakr A. A. M. El-Adasy (2010) Synthesis and
Antibacterial Activity of Some New Ethyl Thionicotinates, Thieno[2,3-b]pyridines, Pyrido[3′,2′:4,5]
thieno[3,2-d]pyrimidines, and Pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazines Containing Sulfonamide
Moieties, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:2, 411-421
To link to this article: http://dx.doi.org/10.1080/10426500902800253
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Phosphorus, Sulfur, and Silicon, 185:411–421, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902800253
SYNTHESIS AND ANTIBACTERIAL ACTIVITY
OF SOME NEW ETHYL THIONICOTINATES,
THIENO[2,3-b]PYRIDINES, PYRIDO[3ꢀ,2ꢀ:4,5]
THIENO[3,2-d]PYRIMIDINES, AND
PYRIDO[3ꢀ,2ꢀ:4,5]THIENO[3,2-d][1,2,3]TRIAZINES
CONTAINING SULFONAMIDE MOIETIES
Mohamed A. M. Gad-Elkareem and Abu-Bakr
A. A. M. El-Adasy
Chemistry Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
Ethyl 5-cyano-6-mercaptonicotinate derivatives 1a,b reacted with the N-[4-(aminosulfonyl)
phenyl]-2-chloroacetamide derivatives 2a,b to give the ethyl 6-[(2-{[4-(aminosulfonyl)
phenyl]amino}-2-oxoethyl)thio]nicotinate derivatives 3a–d. Cyclization of 3a–d afforded the
corresponding ethyl 3-amino-2-({[4-(aminosulfonyl)phenyl]amino}carbonylthieno[2,3-b]
pyridine-5-carboxylate derivatives 4a–d. Ethyl 3-[4-(amino-sulfonyl)phenyl]-4-oxopyrido
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxylate derivatives 5a–d and ethyl 3-[4-(amino-
sulfonyl)phenyl]-4-oxopyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]-triazine-8-carboxylate derivat-
ives 6a–d were prepared from 4a–d. Reaction of 1a,b with chloroacetonitrile (7) and
condensation of the thus formed 3-aminothienopyridines 8a,b with dimethylformamide-
dimethylacetal (DMF-DMA) yielded the corresponding ethyl 2-cyano-3-{[(N,N-
dimethylamino)methylene]amino}thieno[2,3-b]pyridine-5-carboxylate derivatives 9a,b.
Reaction of compounds 9a,b with the sulfadiazine (10) gave ethyl 4-{[4-(amino-
sulfonyl)phenyl]amino}pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxylate derivatives
12a,b. Antibacterial activity was screened for some of the newly synthesized compounds.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Antibacterial; ethyl thionicotinates; pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]pyrimidines;
pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d][1,2,3]triazines; sulfonamides; thieno[2,3-b]pyridines
INTRODUCTION
Aromatic sulfonamide derivatives exhibit a wide range of bioactivities, includ-
ing antiangiogenic,1 antitumor,2,3 anti-inflammatory,4,5 antianalgesic,4,5 antidiabetic,6
antitubercular,7 antiglaucoma,8 anti–HIV-19, anti–HIV-2,10 cytotoxic,11 antihypertensive,12
Received 28 December 2008; accepted 5 February 2009.
The authors thank Al-Azhar University for financial support. Also, the authors are grateful to the Botany and
Microbiology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt for performing the antibacterial
activities tests.
Address correspondence to Mohamed A. M. Gad-Elkareem, Chemistry Department, Faculty of Science,
Al-Azhar University, Assiut 71524, Egypt. E-mail: m65gad@yahoo.com
411

412
M. A. M. GAD-ELKAREEM AND A.-B. A. A. M. EL-ADASY
antimicrobial,13 and antimalarial14 agents and cyclin-dependent kinase inhibitors.15
Furthermore, S-substituted thiopyridines possess neurotropic,16 cardiovascular,17 and an-
timicrobial18 activities and are used as adenosine receptor ligands.19 Also, ethyl nicotinate
derivatives have been reported to be used as agrochemical fungicides20 and anticancer21
agents. Moreover, thieno[2,3-b]pyridines possess a wide range of biological activities
such as antiviral,22,23 antidiabetic,24 antimicrobial,18,25,26 anti-inflammatory,27 antitumor,28
antiparasitic,29 and neurotropic16 activities. Furthermore, pyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-d]-
pyrimidines have been reported to have antiallergic,30 antiprotozoal,31 antianaphylactic,32
and antimicrobial18,25,26 activities. On the other hand, pyridothienotriazines have been used
as antiprotozoal,31,33 antitumor,34 antiangiogenic,35 and antimicrobial18 agents and have
been reported to inhibit NO and eicosanoid biosynthesis.36 The above findings, and in
continuation of our research in the chemistry of sulfonamides37–39 and fused pyridines,40–46
have stimulated interest for the synthesis of new derivatives that are required in medicinal
chemistry programs.
RESULTS AND DISCUSSION
Ethyl 5-cyano-6-mercapto-2-methyl-4-(4-methylphenyl)nicotinate (1a)47 reacted
with N-[4-(aminosulfonyl)phenyl]-2-chloroacetamide (2a)48 in DMF/AcONa solution
under stirring at room temperature to give the ethyl 5-cyano-6-[(2-{[4-(aminosulfonyl)-
phenyl]amino}-2-oxoethyl)thio]nicotinate derivative 3a in good yield. The IR spectrum of
3a indicated the presence of CN, NH2, and two CO groups, and its 1H NMR spectrum re-
vealed SCH2 protons at δ = 4.21 ppm. Similarly 1a reacted with 2-chloro-N-{4-[(pyrimidin-
2-yl amino)sulfonyl]phenyl}acetamide (2b)48 to yield the corresponding ethyl 5-cyano-6-
{[2-oxo-2-({4-[(pyrimidin-2-ylamino)sulfonyl]phenyl}amino)ethyl]thio}nicotinate deri-
1
vative 3b in good yield. The IR and H NMR spectra of 3b were found to be in
good agreement with the assigned structure. In the same way, 1b49 reacted with 2a,b
to afford the corresponding ethyl 5-cyano-6-[(2-{[4-(aminosulfonyl)phenyl]amino}-2-
oxoethyl)thio]nicotinate derivatives 3c,d in good yield. The IR spectra of 3c,d indicated
1
the presence of CN, NH2, and two CO groups, while its H NMR spectra revealed the
signals of SCH2 at δ = 4.28 and 4.23 ppm, in addition to the other signals.
The structures of 3a–d were further elucidated via elemental analysis and their
cyclization into the corresponding ethyl 3-amino-2-({[4-(aminosulfonyl)phenyl]amino}-
carbonylthieno[2,3-b]pyridine-5-carboxylate derivatives 4a–d upon treatment with ethano-
lic potassium hydroxide under reflux. The structures of 4a–d were confirmed based on
elemental analysis and spectral data. The IR spectra of 4a–d indicated the absence of CN
1
group instead of the newly born NH2 group was detected, while its H NMR spectra re-
vealed the protons of the newly NH2 and absence of any signals that might be attributed to
SCH2 protons (see Scheme 1 and the Experimental section).
Unequivocal support for the structure of 4a–d was achieved via its synthesis through
an alternate route via the reaction between 1a,b and 2a,b in ethanolic sodium ethoxide
solution under reflux (see Scheme 1 and the Experimental section).
Compound 4a reacted with acetic anhydride in glacial acetic acid under reflux to
afford a reaction product that corresponded to equimolecular addition of the reagent to 4a
followed by loss of one molecule of acetic acid. The IR spectrum of the reaction product
showed the absorption bands of two carbonyl groups at 1731 and 1628 cm−1 and NH2 at
3487, 3326 cm−1, while its 1H NMR spectrum revealed the disappearance of NH2 and NH

ETHYL THIONICOTINATES CONTAINING SULFONAMIDE MOIETIES
413
O
Ar
O
CN
SH
O
S
EtO
+
Cl
NHR
NH
H3C
N
O
1a, Ar = 4-Me-C6H4
b, Ar = 4-Cl-C6H4
2a, R = H
b, R = pyrimidin-2-yl
EtONa/EtOH/ reflux
AcONa/DMF/ r. t.
O
Ar
N
NH2
O
O
Ar
N
EtO
H3C
CN
S
KOH/EtOH
reflux
H
EtO
H3C
N
S
O
O
O
S
NHR
N
S
NHR
4a-d
3a-d
O
H
O
3,4a, Ar = 4-Me-C6H4, R = H
b, Ar = 4-Me-C6H4, R = pyrimidin-2-yl
c, Ar = 4-Cl-C6H4, R = H
d, Ar = 4-Cl-C6H4, R = pyrimidin-2-yl
Scheme 1
protons, and instead of the protons of CH3 group, on position 2 of the pyrimidine ring was
detected at δ = 2.65 ppm. Based on the above data and the elemental analysis, the reaction
product could be formulated as the ethyl 3-[4-(aminosulfonyl)phenyl]-2,7-dimethyl-9-(4-
methylphenyl)-4-oxo-3,4-dihydropyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-b]pyrimidine-8-carboxylate
(5a). Similarly, 4b–d reacted with acetic anhydride in glacial acetic acid to give the
corresponding ethyl 3-[4-(aminosulfonyl)phenyl]-2,7-dimethyl-4-oxo-3,4-dihydropyrido-
[3ꢁ,2ꢁ:4,5]thieno[3,2-d]pyrimidine-8-carboxylate derivatives 5c–d. The structure of 5a–d
was elucidated via elemental analysis and spectral studies (see Scheme 2 and the
Experimental section).
Diazotization and self coupling of compounds 4a–d afforded the corresponding ethyl
3-[4-(aminosulfonyl)phenyl]-7-methyl-4-oxo-3,4-dihydropyrido[3ꢁ,2ꢁ:4,5]thieno[3,2-b]-
1
[1,2,3]triazine-8-carboxylate derivatives 6a–d. H NMR spectra of 6a–d revealed the
absence of the signals corresponding to NH and NH2 protons (see Scheme 2 and the
Experimental section).
The reaction of 1a, b with chloroacetonitrile (7) in sodium ethoxide solution under re-
flux afforded the corresponding ethyl 3-amino-2-cyanothieno[2,3-b]pyridine-5-carboxylate
derivatives 8a,b. The IR spectra of 8a,b indicated the presence of the absorption band
1
of NH2 and CN group in addition to the ester carbonyl group. The H NMR spec-
trum of 8a revealed the NH2 protons at δ = 5.46 pm. Condensation of 8a,b with
DMF-DMA in dry dioxane under reflux yielded the ethyl 2-cyano-3-{[(N,N-dimethyl-
amino)methylene]amino}thieno[2,3-b]pyridine-5-carboxylate derivatives 9a,b. The struc-
ture of 9a,b was inferred via elemental analysis, spectral data, and chemical transformations
(see Scheme 3 and the Experimental section).
The reaction of 9a,b with sulfadiazine (10) in acetic acid under reflux gave the cor-
responding ethyl 4-{[4-(aminosulfonyl)phenyl]amino]-7-methyl-9-arylpyrido[3ꢁ,2ꢁ:4,5]-
thieno[3,2-d]-pyrimidine-8-carboxylate derivatives 12a,b. The structures of 12a,b were
established based on elemental analysis and spectral studies (see Scheme 3 and the

414
M. A. M. GAD-ELKAREEM AND A.-B. A. A. M. EL-ADASY
O
Ar
N
N
O
CH3
EtO
Ac2O
AcOH
/
N
H3C
S
O
S
5a-d
O
NHR
4a-d
O
Ar
N
EtO
H3C
N
NaNO2/AcOH
N
N
S
O
S
NHR
O
6a-d
O
5 and 6a; Ar = 4-Me-Ph, R = H
b; Ar = 4-Me-Ph, R = pyrimidin-2-yl
c; Ar = 4-Cl-Ph, R = H
d; Ar = 4-Cl-Ph, R = pyrmidin-2-yl
Scheme 2
Experimental section). The IR spectra of 12a,b showed the absorption bands of two NH
1
groups, and their H NMR spectra revealed the signals of two NH, pyrimidine protons,
and absence of the signals of N(CH3)2 protons. The formation of 12a,b in this reaction
proceed via the addition of compound 10 to 9a,b followed by cyclization with elimination
N(CH3)2
O
Ar
O
Ar
N
NH2
CN
N
ClCH CN
(7)
DMF-DMA
2
EtO
H3C
EtO
H3C
1a,b
EtONa/EtOH
N
S
S
CN
9a,b
8a,b
O
S
N
N
NH2
N
H
O
10
O
Ar
O
Ar
N
AcOH
N
EtO
H3C
EtO
H3C
N
N
N
S
- NH(CH3)2
N
S
Dimroth
NH
O
NH
S
rearrang.
NH
11a,b
O
N
N
O
N
S
O
N
NH
1,8,9,11and12a,Ar = 4-CH3-C6H4
b, Ar = 4-Cl-C6H4
Scheme 3
12a,b
Scheme 3

ETHYL THIONICOTINATES CONTAINING SULFONAMIDE MOIETIES
415
of dimethylamine, yielding the non-isolable intermediate imino compounds 11a,b, which
underwent Dimroth rearrangement41,43,50 under the applied reaction condition to give the
final reaction products 12a,b.
BIOLOGICAL ACTIVITY
Ten of the synthesized compounds were screened in vitro for their biological activities
against four strains of bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli,
and Pseudomonas aeruginosa) by the agar diffusion technique.51 (see Table I S in the
Supplemental Materials online).
EXPERIMENTAL
Melting points were measured with a Gallenkamp apparatus and are uncorrected.
IR spectra in KBr discs were recorded on BRUKER Vector 22 FT-IR spectrophotometer.
1H NMR spectra were determined in DMSO-d6 at 300 MHz on Varian Mercury VX
spectrometer using TMS as an internal standard. Chemical shifts are expressed as δ ppm
and J as Hz units. Elemental analyses were carried out at the Microanalytical Center of Cairo
University. Compounds 1a,47 1b,49 and 2a,b48 were prepared according to the procedures
in the literature.
Synthesis of Ethyl 6-[(2-{[4-(Aminosulfonyl)phenyl]amino}-2-
oxoethylthio]-4-aryl-5-cyanonicotinate Derivatives 3a–d
A solution of 1a,b (0.01 mol) in DMF (20 mL) containing 0.03 mol of sodium acetate
was treated with 2a,b (0.01 mol). The reaction mixtures were stirred at room temperature
for 2 h then poured onto ice-cold water. The precipitates that formed were collected by
filtration and crystallized from the proper solvent to yield the reaction products 3a–d,
respectively (see Tables I and II).
Synthesis of Ethyl 3-Amino-2-({[4-(aminosulfonyl)phenyl]amino}-
carbonyl)-4-aryl-6-methylthieno[2,3-b]pyridine-5-carboxylate Derivatives
4a–d
Method A (cyclization of 3a–d). A solution of 3a–d (0.01 mol) in ethanol
(30 mL), containing 0.02 mol of potassium hydroxide, was heated under reflux for 3 h. The
reaction mixture was then cooled, poured onto ice-cold water, and neutralized with dilute
HCl (10%), and then the precipitated solid products were filtered off, washed with water,
and crystallized from the proper solvent to yield the reaction products 4a–d (see Tables I
and II).
Method B (reaction of 1a,b with 2a,b). A solution of 1a,b (0.01 mol) in
ethanolic sodium ethoxide, prepared from 0.02 atom of sodium metal in 30 mL of ethanol,
was treated with 2a,b (0.01 mol) and then heated under reflux for 3 h. The reaction mixture
was then cooled, poured onto ice-cold water, and neutralized with dilute HCl (10%). The
solid products thus formed were filtered off and crystallized from the proper solvent to
yield the reaction products 4a–d (see Tables I and II).

416
M. A. M. GAD-ELKAREEM AND A.-B. A. A. M. EL-ADASY
Table I Characterization data of the newly synthesized compounds
Elemental analysis Calcd./Found %
Compound
No.
Mp ◦C,
Solvent
Yield %
Color
Mol. Formula/
M. Wt.
C
H
N
S
Cl
3a
3b
3c
138–140
EtOH
140–142
EtOH
170–172
DMF
160–162
EtOH
260–262
Dioxane
269–271
Dioxane
296–298
DMF
254–256
Dioxane
313–315
DMF
328–330
DMF
230–232
EtOH
270–272
AcOH
286–288
DMF
282–284
AcOH
246–248
EtOH
280–282
AcOH
164–166
EtOH
75
Yellow
72
Yellow
68
Yellow
67
Yellow
71
Yellow
65
Yellow
70
Yellow
61
Yellow
65
White
68
White
67
White
58
White
64
Yellow
53
Yellow
62
Yellow
60
Yellow
70
C25H24N4 O5S2
(524.62)
57.24
57.50
57.79
57.99
52.89
52.60
53.97
53.60
57.24
57.53
57.79
57.50
52.89
52.64
53.97
53.70
59.11
59.40
59.41
59.60
54.88
54.60
55.68
55.88
56.06
56.30
56.76
56.56
51.84
51.99
53.04
53.30
64.94
64.70
58.14
58.30
65.00
65.26
59.08
59.23
58.91
58.70
55.10
55.30
4.61
4.40
4.35
4.08
3.88
3.60
3.72
3.98
4.61
4.37
4.35
4.68
3.88
3.60
3.72
3.45
4.41
4.20
4.18
4.48
3.72
3.98
3.68
3.40
3.95
3.70
3.78
3.50
3.26
3.40
3.18
3.50
4.88
4.61
3.79
3.74
5.46
5.70
4.48
4.70
4.12
4.40
3.51
3.30
10.68
10.91
13.94
13.68
10.28
10.56
13.49
13.76
10.68
10.92
13.94
13.68
10.28
11.50
13.49
13.73
10.21
10.45
13.41
13.19
9.85
12.22
12.48
10.64
10.35
11.77
11.51
10.29
10.55
10.22
10.40
10.64
10.86
11.77
11.98
10.29
10.05
11.69
11.46
10.23
10.49
11.27
11.01
9.91
—
—
—
C
29H26N6O5S2
(602.70)
—
C
C
24H21N4O4S2Cl
(545.04)
28H23N6O5S2Cl
(623.11)
6.50
6.30
5.69
5.40
—
—
—
—
6.50
6.78
5.69
5.45
—
—
—
—
6.23
6.47
5.48
5.75
—
—
—
—
6.38
6.60
5.59
5.81
—
3d
4a
4b
4c
C
25H24N4O5S2
(524.62)
C
29H26N6O5S2
(602.70)
C
C
24H21N4O5S2Cl
(545.04)
28H23N6O5S2Cl
(623.11)
4d
5a
5b
5c
C
27H24N4 O5S2
(548.64)
C
31H26N6O5S2
(626.72)
C
C
26H21N4O5S2Cl
(569.06)
30H23N6O5S2Cl
(647.14)
9.57
5d
6a
6b
6c
12.99
12.75
13.08
13.29
15.98
15.77
12.26
12.50
15.46
15.70
11.96
11.72
11.30
11.55
13.78
13.90
13.12
13.51
16.03
16.31
15.51
15.80
9.70
C
25H21N5O5S2
(535.60)
11.97
11.72
10.45
10.74
11.53
11.40
10.11
10.33
9.12
9.34
8.62
8.42
7.89
7.61
7.51
7.74
10.48
10.68
10.14
10.38
C29H23N7O5S2
(613.68)
C
24H18N5O5S2Cl
(556.02)
6d
8a
8b
9a
9b
12a
12b
C
28H20N7O5S2Cl
(634.01)
C19H17N3O2S
Yellow
65
Yellow
75
Yellow
58
Yellow
66
(351.43)
—
172–174
EtOH
146–148
Dioxane
134–136
EtOH
272–274
Dioxane
278–280
Dioxane
C
18H14N3O2S Cl
3.79
3.53
—
(371.85)
22H22N4O2S
(406.51)
C
—
C21H19N4O2SCl
8.30
8.58
—
—
5.61
5.35
(426.93)
C
30H25N7O4S2
(611.71)
Yellow
60
Yellow
C
29H22N7O4S2Cl
(632.12)
Synthesis of Ethyl 3-[4-(aminosulfonyl)phenyl]-9-aryl-2,7-dimethyl-4-
oxo-3,4-dihydropyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine-8-carboxylate
Derivatives 5a–d
A solution of the 4a–d (0.01 mol) in glacial acetic acid (30 mL) was treated with
acetic anhydride (5 mL) and then heated under reflux for 3 h. The reaction mixture was then

ETHYL THIONICOTINATES CONTAINING SULFONAMIDE MOIETIES
417
Table II Spectral data of the newly synthesized compounds
Compound
No.
Spectral data, IR: ν (cm−1) and 1H NMR δ ppm
3a
IR: ν 3331, 3240 (NH2), 3120 (NH), 3030 (CH arom.), 2983 (CH aliph.), 2224 (CN), 1721, 1679
(2C O). 1H NMR (DMSO-d6) δ 0.93 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.56
(s, 3H, CH3), 4.09 (q, J = 7.2 Hz, 2H, CH2), 4.21 (s, 2H, SCH2), 7.13 (s, 2H, SO2NH2),
7.33–7.79 (m, 8H, Ar H) and 9.71 (s, 1H, NH).
3b
IR: ν 3343, 3105 (2NH), 30340 (CH arom.), 2980 (CH aliph.), 2223 (CN), 1722, 1690 (2C O).
1H NMR (DMSO-d6) δ 0.98 (t, J = 7.2 Hz, 3H, CH3), 2.45 (s, 3H, CH3), 2.64 (s, 3H, CH3)
4.10 (q, J = 7.2 Hz, 2H, CH2), 4.26 (s, 2H, SCH2), 7.09 (t, J = 4.8 Hz, 1H, 5H-pyrimidine),
7.52–7.87 (m, 8H, Ar H), 8.53 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidine), 9.95 (s, 1H, NH),
11.53 (br., 1H, NH).
3c
IR: ν 3270, 3226 (NH2), 3123 (NH), 3027 (CH aliph.), 2225 (CN), 1701, 1693 (2C O).1H
NMR (DMSO-d6) δ 0.87 (t, J = 7.2 Hz, 3H, CH3), 2.49 (s, 3H, CH3), 3.97 (q, J = 7.2 Hz, 2H,
CH2), 4.28 (s, 2H, SCH2), 7.24 (s, 2H, NH2), 7.42–7.77 (m, 8H, Ar H), 10.69 (s, 1H, NH).
IR: ν 3259, 3115 (2NH), 3045 (CH arom.), 2976 (CH aliph.), 2221 (CN), 1728, 1677 (2C O).
1H NMR (DMSO-d6) δ 0.98 (t, J = 7.2 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 4.0 (q, J = 7.2 Hz,
2H, CH2), 4.23 (s, 2H, SCH2), 7.08 (t, J = 4.8 Hz, 1H, 5H-pyrimidine), 7.32–7.84 (m, 8H,
Ar H), 8.59 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidine), 9.97 (s, 1H, NH) and 11.52 (br., 1H,
NH).
3d
4a
4b
IR: ν 3474, 3362, 3329, 3225 (2NH2), 3110 (NH), 3048 (CH arom.), 2982 (CH aliph.), 1734,
1628 (2C O). 1H NMR (DMSO-d6) δ 0.89 (t, J = 7.2 Hz, 3H, CH3), 2.41 (s, 3H, CH3), 2.60
(s, 3H, CH3), 3.97 (q, J = 7.2 Hz, 2H, CH2), 5.89 (s, 2H, NH2), 7.23 (s, 2H, SO2NH2),
7.27–7.86 (m, 8H, Ar H) and 9.81 (s, 1H, NH).
IR: ν 3474, 3326 (NH2), 3220, 3104 (2NH), 3040 (CH arom.), 2958 (CH aliph), 1720, 1638
(2C O). 1H NMR (DMSO-d6) δ 0.89 (t, J = 7.2 Hz, 3H, CH3), 2.40 (s, 3H, CH3), 2.59
(s, 3H, CH3) 3.99 (q, J = 7.2 Hz, 2H, CH2), 5.89 (s, 2H, NH2), 7.03 (t, J = 4.8 Hz, 1H,
5H-pyrimidine), 7.42–7.77 (m, 8H, Ar H), 8.49 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidine),
9.85 (s, 1H, NH), 11.60 (br., 1H, NH).
4c
IR: ν 3489, 3366, 3336, 3237 (2NH2), 3109 (NH), 3030 (CH arom.), 2982 (CH aliph.), 1740,
1626 (2C O). 1H NMR (DMSO-d6) δ 0.1.02 (t, J = 7.2 Hz, 3H, CH3), 2.60 (s, 3H, CH3),
4.08 (q, J = 7.2 Hz, 2H, CH2), 5.56 (s, 2H, NH2), 7.15 (s, 2H, SO2NH2), 7.37–7.76 (m, 8H,
Ar H) and 9.61 (s, 1H, NH).
4d
IR: ν 3478, 3313 (NH2), 3116 (NH), 3042 (CH arom.), 2958 (CH aliph.), 1722, 1636 (2C O). 1H
NMR (DMSO-d6) δ 0.91 (t, J = 7.4 Hz, 3H, CH3), 2.49 (s, 3H, CH3), 4.04 (q, J = 7.4 Hz, 2H,
CH2), 5.89 (s, 2H, NH2), 7.02 (t, J = 4.8 Hz, 1H, 5H-pyrimidine), 7.42–7.94 (m, 8H, Ar H),
8.49 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidine), 9.88 (s, 1H, NH) and 11.62 (br., 1H, NH).
IR: ν 3487, 3326 (NH2), 3032 (CH arom.), 2978 (CH aliph.), 1731, 1682 (2C O). 1H NMR
(DMSO-d6) δ 0.99 (t, J = 7.2 Hz, 3H, CH3), 2.28 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.65 (s, 3H,
CH3), 4.02 (q, J = 7.2 Hz, 2H, CH2), 7.13 (s, 2H, SO2NH2), 7.37–7.84 (m, 8H, Ar H).
IR: ν 3361 (NH), 3035 (CH arom.), 2983 (CH aliph.), 1721, 1671 (2C O). 1H NMR
(DMSO-d6) δ 0.96 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.69 (s, 3H,
CH3), 4.05 (q, J = 7.2 Hz, 2H, CH2), 7.10 (t, J = 4.8 Hz, 1H, 5H-pyrimidinyl), 7.42–7.76 (m,
8H, Ar H), 8.50 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidinyl) and 11.28 (br., 1H, NH).
IR: ν 3449, 3345 (NH2), 3041 (CH arom.), 2979 (CH aliph.)1726, 1678 (2C O). 1H NMR
(DMSO-d6) δ = 0.97 (t, J = 7.4 Hz, 3H, CH3), 1.86 (s, 3H, CH3), 2.69 (s, 3H, CH3), 4.01 (q,
J = 7.4 Hz, 2H, CH2), 7.37 (s, 2H, SO2NH2), 7.41–8.09 (m, 8H, Ar H).
5a
5b
5c
5d
IR: ν 3374 (NH), 3025 (CH arom.), 2977 (CH aliph.), 1733, 1691 (2C O). 1H NMR
(DMSO-d6) δ 0.98 (t, J = 7.2 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 2.61 (s, 3H, CH3), 4.09
(q, J = 7.2 Hz, 2H, CH2), 7.09 (t, J = 4.8 Hz, 1H, 5H-pyrimidinyl), 7.35–7.89 (m, 8H,
Ar H), 8.58 (d, J = 4.8 Hz, 2H, 4H- & 6H-pyrimidinyl) and 11.48 (br., 1H, NH).
IR: ν 3313, 3223 (NH2) 3015 (CH arom.), 2972 (CH aliph.), 1728, 1659 (2C O). 1H NMR
(DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 2.37 (s, 3H, CH3), 2.46 (s, 3H, CH3), 4.12
(q, J = 7.2 Hz, 2H, CH2), 7.20 (s, 2H, SO2NH2), 7.45–7.94 (m, 8H, Ar H).
(Continued on next page)
6a

418
M. A. M. GAD-ELKAREEM AND A.-B. A. A. M. EL-ADASY
Table III Spectral data of the newly synthesized compounds (Continued)
Compound
No.
Spectral data, IR: ν (cm−1) and 1H NMR δ ppm
6b
IR: ν 3110 (NH), 3040 (CH arom.), 2940 (CH aliph.), 1720, 1680 (2 C O).1H NMR
(DMSO-d6) δ 0.93 (t, J = 7.2 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.04
(q, J = 7.2 Hz, 2H, CH2), 7.04 (t, J = 4.8 Hz, 1H, 5H-pyrimidine), 7.31–8.17 (m, 8H, Ar H),
8.51 (d, J = 4.8 Hz, 2H, 4H- & 5H-pyrimidine), 12.10 (br., 1H, NH).
6c
IR: ν 3310, 3223 (NH2), 3015 (CH arom.), 2976 (CH aliph.), 1728, 1675 (2C O). 1H NMR
(DMSO-d6) δ 1.05 (t, J = 7.2 Hz, 3H, CH3), 2.41 (s, 3H, CH3), 4.10 (q, J = 7.2 Hz, 2H,
CH2), 7.19 (s, 2H, SO2NH2), 7.53–7.88 (m, 8H, Ar H).
6d
IR: ν 3364 (NH), 3031 (CH arom.), 2983 (CH aliph.), 1725, 1675 (2 C O). 1H NMR
(DMSO-d6) δ 0.97 (t, J = 7.2 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 4.09 (q, J = 7.2 Hz, 2H,
CH2), 7.14 (t, J = 4.8 Hz, 1H, 5H-pyrimidine), 7.40–8.09 (m, 8H, Ar H), 8.58 (d, J = 4.8
Hz, 2H, 4H- & 5H-pyrimidine), 11.91 (br., 1H, NH).
8a
IR: ν 3463, 3335 (NH2), 3040 (CH arom.), 2979 (CH aliph.), 2198 (CN), 1727 (C O). 1H NMR
(DMSO-d6) δ 0.88 (t, J = 7.2 Hz, 3H, CH3), 2.41(s, 3H, CH3), 2.58 (s, 3H, CH3), 3.97 (q, J =
7.2 Hz, 2H, CH2), 5.46 (s, 2H, NH2), 7.27 (d, J = 8.4 Hz, 2H, Ar H) and 7.37 (d, J = 8.1 Hz,
2H, Ar H).
8b
9a
IR: ν 3483, 3342 (NH2), 3035 (CH arom.), 2977 (CH alip.), 2198 (CN), 1728 (C O). 1H NMR
(DMSO-d6) δ 0.94 (t, J = 7.2 Hz, 3H, CH3), 2.67 (s, 3H, CH3), 4.04 (q, J = 7.2 Hz, 2H, CH2),
5.33 (s, 2H, NH2), 7.36 (d, J = 8.4 Hz, 2H, Ar H) and 7.45 (d, J = 8.1 Hz, 2H, Ar H).
IR: ν 3035 (CH arom.), 2972 (CH aliph.), 2202 (CN), 1729 (C O).1H NMR (DMSO-d6) δ 0.86
(t, J = 7.2 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.79 (s, 3H,
CH3), 3.98 (q, J = 7.2 Hz, 2H, CH2), 7.01 (d, J = 8.1 Hz, 2H, Ar H), 7.17 (d, J = 8.1 Hz,
2H, Ar H) and 7.49 (s, 1H, N = CH).
9b
IR: ν 3483, 3342 (NH2), 3035 (CH arom.), 2977 (CH aliph.), 2198 (CN), 1728 (C O). 1H NMR
(DMSO-d6) δ 0.90 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.76 (s, 3H, CH3), 2.86 (s, 3H,
CH3), 4.01 (q, J = 7.2 Hz, 2H, CH2), 7.18 (d, J = 8.1 Hz, 2H, Ar H), 7.44 (d, J = 8.1 Hz,
2H, Ar H) and 7.59 (s, 1H, N = CH).
12a
IR: ν 3307, 3121(2NH), 3051 (CH arom), 2975 (CH aliph.), 1725 (C O).1H NMR (DMSO-d6)
δ = 0.97 (t, J = 7.2 Hz, 3H, CH3), 2.45 (s, 3H, CH3), 2.76 (s, 3H, CH3), 4.00 (q, J = 7.2 Hz,
2H, CH2), 7.10 (t, J = 4.8 Hz, 1H, 5H-pyrimidinyl), 7.22–7.82 (m, 8H, Ar H), 8.55 (s, 1H,
C2-H-pyrimidine) 8.48 (d, J = 4.8 Hz, 2H, 4H- and 6H-pyrimidinyl), 9.82 (s, 1H, NH) and
11.25 (br., 1H, NH).
12b
IR: ν 3321, 3112 (NH), 3045 (CH-arom), 2987(CH aliph.), 1717 (CO). 1H NMR (DMSO-d6)
δ = 1.06 (t, J = 7.2 Hz, 3H, CH3), 2.66 (s, 3H, CH3), 4.11 (q, J = 7.2 Hz, 2H, CH2), 7.14
(t, J = 4.8 Hz, 1H, 5H-pyrimidinyl), 7.31–7.88 (m, 8H, Ar H), 8.49 (s, 1H, C2-H-pyrimidine)
8.55 (d, J = 4.8 Hz, 2H, 4H- and 6H-pyrimidinyl), 9.72 (s, 1H, NH) and 11.31 (br., 1H, NH).
cooled. The solid products thus formed were filtered off and crystallized from the proper
solvent to yield the reaction products 5a–d (see Tables I and II).
Synthesis of Ethyl 3-[4-(aminosulfonyl)phenyl]-9-aryl-7-methyl-4-oxo-
3,4-dihydropyrido[3’,2’:4,5]thieno[3,2-d][1,2,3]triazine-8-carboxylate
Derivatives 6a–d
A solution of 4a–d (0.01 mol) in glacial acetic acid (30 mL) was treated with cold
solution of sodium nitrite (0.02 mol in 3 mL of water), and the reaction mixture was stirred
in an ice chest for 2 h. The solid products thus formed were filtered off and crystallized
from the proper solvent to yield the reaction products 6a–d (see Tables I and II).

ETHYL THIONICOTINATES CONTAINING SULFONAMIDE MOIETIES
419
Synthesis of Ethyl 3-Amino-2-cyano-6-methyl-4-arylthieno[2,3-b]-
pyridine-5-carboxylate Derivatives 8a,b
A solution of 1a,b (0.01 mol) in ethanolic sodium ethoxide, prepared from 0.02 atom
of sodium metal in 30 mL of ethanol, was treated with chloroacetonitrile (7) (0.01 mol)
and then heated under reflux for 3 h. The reaction mixture was then cooled, poured onto
ice-cold water, and neutralized with dilute HCl (10%). The solid products thus formed were
filtered off and crystallized from ethanol to yield the reaction products 8a,b (see Tables I
and II).
Synthesis of Ethyl 2-Cyano-3-{[(N,N-dimethylamino)-
methylene]amino}thieno[2,3-b]pyridine-5-carboxylate Derivatives 9a,b
A solution of the appropriate 8a,b (0.01 mol) in dry xylene (30 mL) and DMF-DMA
(0.015 mol) was heated under reflux for 4 h. The reaction mixture was then cooled. The
solid products thus formed were filtered off and crystallized from the proper solvent to
yield the reaction products 9a,b (see Tables I and II).
Synthesis of Ethyl 4-{[4-(Aminosulfonyl)phenyl]amino}-7-methyl-9-
arylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-carboxylate Derivatives
12a,b
A solution of the appropriate formamidine derivatives 9a,b (0.01 mol) and sulfadi-
azine (10) (0.01 mol) in glacial acetic acid (30 mL) was heated under reflux for 3–5 h.
The reaction mixture was then cooled. The solid products thus formed were filtered off and
crystallized from dioxane to yield the products 12a,b (see Tables I and II).
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