Synthesis and antimicrobial evaluation of some new thienopyridine, pyrazolopyridine and pyridothienopyrimidine derivatives

Article abstract of DOI:10.1080/17415993.2011.593635

Thieno[2,3-b]pyridines 7, 8, 9 were obtained via the S-alkylation of 3 with a variety of alkylating agents followed by cyclization in a basic medium. On the other hand, compound 3 reacted with methyl iodide to give compound 10 which was converted to pyrazolo[3,4-b]pyridine derivative 13 by reaction with hydrazine hydrate. Pyrido[3′, 2′:4,5]thieno[3,2-d]pyrimidines derivatives 14, 16 were obtained by reaction of 7 with each of formic acid and formic/formamide, respectively. Furthermore, compound 14 was obtained by the reaction of 8 with formamide. Structures of the newly synthesized products were determined by elemental analysis and spectral data.

Full text of DOI:10.1080/17415993.2011.593635

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Synthesis and antimicrobial
evaluation of some new
thienopyridine, pyrazolopyridine and
pyridothienopyrimidine derivatives
Nora M. Rateb a , Shaimaa H. Abdelaziz a & Hussein F. Zohdi a
a Department of Chemistry, Faculty of Science, Cairo University,
Giza, 12613, Egypt
Version of record first published: 22 Jun 2011.
To cite this article: Nora M. Rateb, Shaimaa H. Abdelaziz & Hussein F. Zohdi (2011): Synthesis and
antimicrobial evaluation of some new thienopyridine, pyrazolopyridine and pyridothienopyrimidine
derivatives, Journal of Sulfur Chemistry, 32:4, 345-354
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Journal of Sulfur Chemistry
Vol. 32, No. 4, August 2011, 345–354
Synthesis and antimicrobial evaluation of some new
thienopyridine, pyrazolopyridine and pyridothienopyrimidine
derivatives
Nora M. Rateb, Shaimaa H. Abdelaziz and Hussein F. Zohdi*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
(Received 18 April 2011; final version received 31 May 2011)
Thieno[2,3-b]pyridines 7, 8, 9 were obtained via the S-alkylation of 3 with a variety of alkylating agents
followed by cyclization in a basic medium. On the other hand, compound 3 reacted with methyl iodide to
give compound 10 which was converted to pyrazolo[3,4-b]pyridine derivative 13 by reaction with hydrazine
hydrate. Pyrido[3ꢀ, 2ꢀ:4,5]thieno[3,2-d]pyrimidines derivatives 14, 16 were obtained by reaction of 7 with
each of formic acid and formic/formamide, respectively. Furthermore, compound 14 was obtained by the
reaction of 8 with formamide. Structures of the newly synthesized products were determined by elemental
analysis and spectral data.
R
R
NH2
CN
XCH2Y
Y
Ar
N
H
S
S
Ar
N
MeI/NH2NH2
HCOOH/HCONH2
R
NH2
N
R
N
N
N
Ar
N
z
S
N
Ar
H
Keywords: cyanopyridinethiones; thienopyridine; polycyclic pyridines; cyanothioacetamide; pyridoth-
ienopyrimidine; enaminonitrile
*Corresponding author. Email: zohdi@cu.edu.eg
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2011.593635
http://www.informaworld.com

346 N.M. Rateb et al.
1. Introduction
3-Cyano-2(1H)-pyridinethiones are of interest because of their use as intermediates for the
synthesis of biologically active polycyclic compounds (1, 2). Numerous thieno[2,3-b]pyridines
have been investigated in relation to their biological and pharmacological activities and some of
them proved to possess antibacterial (3, 4), antiviral (5), antihypertensive (6) and immunostimu-
lating (7) activities. Others are characterized by a broad spectrum of biological activities such as
anticancer (8), antidepressant (9) and neurotropic activities (10). Also, the biological activities of
condensed pyridines and pyrimidines as antimicrobial (11–13), sedative and antimalarial agents
are well documented (14, 15). On the other hand, pyridothienopyrimidine derivatives have found
applications as analgesics (16), antipyretics (17), anti-inflammatories (18) and selective Cdc7
kinase inhibitors (19). In view of the above facts, it was of interest to synthesize the ring system
combining both the pyrimidine and the thienopyridine moieties which might have good biological
and medicinal applications.
2. Results and discussion
2.1. Chemistry
Treatment of (2E)-1-(4-chlorophenyl)-3-(2-furyl)prop-2-en-1-one (1) with 2-cyanothioacetamide
(2) in ethanolic sodium ethoxide solution afforded 6-(4-chlorophenyl)-4-(2-furyl)-2-
thioxopyridine-1,2-dihydro-3-carbonitrile (3) in moderate yield. The structure of the product was
supported by its elemental analysis and spectral data. Compound 3 was alkylated with chloroace-
tonitrile, ethyl bromoacetate and chloroacetone in dimethylformamide (DMF)/KOH to give 4, 5
and 6 derivatives, respectively (Scheme 1).
The IR spectrum of compound 4 revealed the presence of two absorption bands at 2193 and
1
2215 cm−1 for the two cyano groups. H NMR spectrum showed a signal at δ 4.48 (s, 2H,
CH2), signal at δ 6.80 (s, 1H, 5-H of the pyridinethione ring) and a broad signal at δ 7.60–8.35
(m, 7H, Ar-H).
The IR spectrum of compound 5 revealed the presence of absorption bands at 2210 and
1
1736 cm−1 for the cyano group and the CO ester group, respectively. Its H NMR spectrum
showed signal at δ 1.55 (t, 3H, CH3), δ 4.08 (s, 2H, CH2), δ 4.23 (q, 2H, CH2), δ 6.68 (s, 1H, 5-H
of the pyridinethione ring) and a broad signal at δ 7.27–8.06 (m, 7H, Ar-H).
Both structures 4 and 5 were confirmed by their mass spectra which showed peaks corre-
sponding to their molecular ion at m/z 351 and m/z 398, respectively. Similarly, the structure of
compound 6 was confirmed based on elemental analysis and spectral data. Compounds 4, 5 and 6
were converted to the corresponding thienopyridine derivatives by refluxing in sodium ethoxide
solution for 3–6 h to give 7, 8 and 9, respectively (Scheme 1). The reaction seemed to proceed via
intramolecular cyclocondensation to give the substituted thieno[2,3-b]pyridine derivatives in good
yield.TheabsenceofcyanogroupabsorptionintheIRspectrumofcompound 9andtheappearance
of absorption bands at 3421 and 3301 cm−1 for the amino group confirmed the proposed structure.
Furthermore, 1H NMR spectrum showed signals at δ 2.50 (s, 3H, CH3), δ 6.81 (s, 1H, 5-H of the
pyridinethione ring), broad signal at δ 6.90–8.10 (m, 7H, Ar-H) and δ 13.90 (s, 2H, NH2) and the
disappearance of the signal at δ 4.2 (s, 2H, CH2). Based on these facts, the structure of compound 9
was assigned as 1-(3-amino-6-(4-chlorophenyl)-4-(2-furyl)thieno[2,3-b]pyridine-2-yl)ethanone.
On the other hand, reaction of 3 with methyl iodide gave the methyl sulfide derivative 10,
as evident from its elemental analysis and spectral data, in a very good yield. Treatment of 10
with hydrazine hydrate under reflux for 12 h gave compound 11 in almost a quantitative yield
(Scheme 2).

Journal of Sulfur Chemistry 347
O
NCCH2CSNH2
+
Ar
R
1
2
Ar = C6H4-pCl
R = 2-C4H3O
R
CN
Ar
N
H
S
3
ClCH2COCH3
ClCH2CN
BrCH2COOC2H5
R
R
R
CN
CN
CN
CH3
O
CH3
Ar
N
S
Ar
N
S
Ar
N
S
CN
O
O
4
6
5
NaOC2H5
NH2
NaOC2H5
NH2
NaOC2H5
R
R
N
R
N
NH2
CH3
CH3
O
CN
S
S
O
S
Ar
N
Ar
O
Ar
7
8
9
Scheme 1. Reactions of pyridinethione with chloroacetonitrile, ethyl bromoacetate and
chloroacetone.
The IR spectrum of compound 11 revealed an absorption bands at 2210 cm−1 for the cyano
group, 3436 and 3339 cm−1 for NHNH2 group and its mass spectra showed the molecular ion
peak at m/z 310. Based on the above data, structure 11 was assigned as 6-(4-chlorophenyl)-4-(2-
furyl)-2-hydrazinylpyridine-3-carbonitrile. Meanwhile, treatment of 10 with hydrazine hydrate
under reflux for 24 h gave compound 13 which can also be prepared by the reaction of 12 with
hydrazine hydrate under the same conditions (Scheme 2). The IR spectrum of compound 13
revealed absorption bands at 3190 and 3100 cm−1 for the amino group and no absorption was
detected for the cyano group.
Compound 7 as a typical enaminonitrile derivative reacted with formic acid upon heating for
several hours to yield 7-(4-chlorophenyl)-9-(2-furyl) pyrido[3ꢀ, 2ꢀ:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (14) (Scheme 3). The absence of cyano absorption and the appearance of the NH and
carbonyl absorption bands at 3434 and 1650 cm−1 in the IR spectrum confirmed the proposed
structure 14. Its mass spectrum showed a peak at m/z 379 (M+). Compound 14 was alternatively
obtained by heating compound 8 in formamide under reflux for 12 h (Scheme 3).
4-Chloro-7-(4-chlorophenyl)-9-(2-furyl)pyrido[3ꢀ,2ꢀ:4,5]thieno-[3,2-d]pyrimidine (15) was
obtained by the reaction of 14 with POCl3 under reflux for 1 h. Compound 7 reacted with

348 N.M. Rateb et al.
R
R
R
CN
S
CN
S
CN
CH3I
H2O2
CH3
CH3
Ar
N
H
3
CH3COOH
Ar
N
Ar
N
SO2
10
12
R
R
NH2
N
NH2NH2
24 hrs
CN
NH2NH2
12hrs
NH2NH2
24hrs
N
Ar
N
NHNH2
Ar
N
H
11
13
Scheme 2. Conversion of S-methyl derivative 10 to pyrazolopyridine derivative 13.
R
R
NH2
N
H
N
NH2
N
Ar
N
S
S
O
Ar
N
NH2
16
17
NH2NH2
NH2
HCOOH/HCONH2
NH2
R
N
R
N
CN
S
COOC2H5
S
Ar
Ar
7
8
R
N
HCONH2
HCOOH
NH
Ar
N
S
O
14
POCl3
N
R
N
Ar
N
S
Cl
15
Scheme 3. Reactions of thienopyridines (7, 8) with formic acid, formamide and hydrazine.
a mixture of HCOOH/HCONH2 under reflux for several hours to give 7-(4-chlorophenyl)-
9-(2-furyl)-pyrido[3ꢀ,2ꢀ: 4,5]thieno[3,2-d]pyrimidin-4-amine (16). Finally, compound 8 reacted
with hydrazine hydrate under reflux for 24 h to give the corresponding hydrazide derivative 17
(Scheme 3). Structures of compounds 16 and 17 have been determined by elemental analyses and
spectral data studies. The IR spectrum of 16 revealed absorption bands at 3421 and 3301 cm−1
for the amino group, while its mass spectrum showed a peak at m/z 378 (M+). On the other hand,

Journal of Sulfur Chemistry 349
the IR spectrum of 17 revealed absorption bands at 3468 and 3373 cm−1 for the amino group and
its mass spectrum showed a peak at m/z 384 (M+).
2.2. Antimicrobial activity
The antibacterial and antifungal activities were carried out in the Microbiology Division of the
Microanalytical Center at Cairo University, using the diffusion plate method (20–22). A bot-
tomless cylinder containing a measured quantity (1 ml, 20 mg/ml) of the sample is placed on
a plate (7 scm diameter) containing a solid bacterial medium (nutrient agar broth) or a fungal
medium (Dox’s medium) which has been heavily seeded with the spore suspension of the test
organism. After incubation (24 h for bacteria and 5 days for fungi), the diameter of the clear zone
of inhibition surrounding the sample is taken as a measure of the inhibitory power of the sample
against the particular test organism (% inhibition = sample inhibition zone (cm)/plate diameter
× 100). All measurements were done in DMSO as a solvent which has zero inhibition activity.
The obtained results were compared with some reference antibiotics that were purchased from
Egyptian markets. As shown in Table 1, all the tested compounds were found to exhibit moderate
to high activity against both Escherichia coli and Staphylococcus aureus microorganisms with
respect to the used reference tetracycline. The antifungal activity of compounds 7, 8 and 12 were
found to be much higher than the used reference Amphotericin B.
2.3. Minimum inhibitory concentration determination (by serial dilution method)
Stationary-phase cultures of bacteria were prepared at 37◦C and used to inoculate fresh 5.0 ml
culture to an OD600 of 0.05. The 5.0 ml cultures were then incubated at 37◦C until an OD600 of 0.10
was achieved from which standardized bacterial suspensions were prepared to a final cell density
of 6 × 10−5 colony forming units (CFUs)/ml. Serial dilutions from the treatments (0–320 μg/ml)
were prepared and mixed with 5.0 ml of the standardized bacteria suspension and then added to
the plates and incubated for 24 h at 37◦C. The CFUs were counted for each dilution (23).
Table 1. Antibacterial and antifungal activities of some of the synthesized compounds.
E. coli
S. aureus
Candida albicans
Sample
inhibition (%)
inhibition (%)
inhibition (%)
Control: DMSO
3
4
7
8
9
12
13
14
15
16
17
0.0
42.4
36.4
36.4
36.4
30.3
30.3
36.4
36.4
33.3
30.3
30.3
33.0
–
0.0
50.0
46.7
43.3
50.0
43.3
33.3
40.0
36.7
36.7
40.0
33.3
30.0
–
0.0
0.0
0.0
52.6
63.2
0.0
47.4
0.0
0.0
0.0
0.0
0.0
Tetracycline
Amphotericin B
–
19.0
Minimum inhibitory concentration (MIC) determination
MIC (μg/ml)
Sample
E. coli (G−)
S. aureus (G+)
3
214
86
198
116
Standard: tetracycline antibacterial agent

350 N.M. Rateb et al.
3. Experimental
Melting points were measured on an Electrothermal Melting PointApparatus and are uncorrected.
IR spectra were recorded on Shimadzu FT-IR 8101 PC infrared spectrophotometer. The 1H NMR
spectra were determined in DMSO-d6 at 300 MHz on a Varian mercury VX 300 NMR spec-
trometer using TMS as an internal standard. 13C spectra were run at 75.46 MHz in DMSO-d6.
Chemical shifts are quoted in δ and were related to that of the solvent. Mass spectra were mea-
sured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the
Microanalytical Center of Cairo University.
3.1. Synthesis of 3
A mixture of 1 (11.6 g, 50 mmol) and cyanothioacetamide 2 (5 g, 50 mmol) was heated under
reflux in ethoxide solution (1.15 g of Na in 50 ml ethanol) for 4 h. The reaction mixture was
cooled; the so-formed solid was filtered and recrystallized from methanol/DMF.
3.1.1. 6-(4-Chlorophenyl)-4-(2-furyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (3)
Deep red crystals, m.p. = 228–232◦C; yield: 23%. IR (KBr): 2217 and 3143 cm−1 (CN, NH); 1H
NMR (δ ppm): 6.88 (s, 1H, 5-H of pyridinethione ring), 7.33–8.15 (m, 7H, Ar-H), 14.10 (b, 1H,
NH). 13C NMR: δ = 102.6 (CH), 110.2 (C), 111.4 (CH), 112.7 (CH), 115.9 (C), 127.8 (2CH),
=
128.8 (CH), 128.8 (2CH), 132.4 (C), 133.5 (C), 149.9 (C), 162.8 (C), 169.3 (C), 170.6 (C S).
MS (m/z): 312 (M+). Anal. Calcd. for C16H9ClN2OS (312.78): C, 61.44; H, 2.90; N, 8.96; S,
10.25%; found: C, 61.50; H, 3.00; N, 8.99; S, 10.00%.
3.2. General procedure for the synthesis of 4, 5, 6 and 10
A mixture of 3 (3.1 g, 10 mmol) and potassium hydroxide (0.62 g, 11 mmol) in DMF (10 ml) was
stirredfor2 hatroomtemperature. Eachofchloroacetonitrile, ethylbromoacetateorchloroacetone
and methyl iodide (10 mmol each) was added and stirring was continued for 2 h. The resulting
solid was collected and recrystallized from the proper solvent to give 4, 5, 6 and 10, respectively.
3.2.1. 6-(4-Chlorophenyl)-2-(cyanomethylthio)-4-(2-furyl)nicotinonitrile (4)
Pink crystals, m.p. = 260–263◦C; yield: 99% (DMF). IR (KBr): 2193 and 2215 cm−1, 2(CN).
1H NMR (δ ppm): 4.48 (s, 2H, CH2), 6.80 (s, 1H, 5-H of the pyridinethione ring), 7.60–8.35 (m,
7H, Ar-H). MS (m/z): 351 (M+). Anal. Calcd for C18H10ClN3OS (351.82): C, 61.54; H, 2.87; N,
11.94; S, 9.11%; found: C, 61.65; H, 2.90; N, 12.00; S, 9.35%.
3.2.2. Ethy{[6-(4-chlorophenyl)-3-cyano-4-(2-furyl)pyridine-2-yl]-thio}acetate (5)
Brown crystals, m.p. = 172–175◦C; yield: 90% (EtOH/DMF). IR (KBr): 2210 and 1736 cm−1
(CN, CO ester). 1H NMR (δ ppm): 1.55 (t, 3H, CH3), 4.08 (s, 2H, CH2), 4.23 (q, 2H, CH2), 6.68
(s, 1H, 5-H of the pyridinethione ring), 7.27–8.06 (m, 7H, Ar-H); MS (m/z): 398 (M+). Anal.
Calcd. for C20H15ClN2O3S (398.87): C, 60.22; H, 3.79; N, 7.02; S, 8.04%; found: C, 60.00; H,
3.89; N, 7.15; S, 8.00%.

Journal of Sulfur Chemistry 351
3.2.3. 6-(4-Chlorophenyl)-4-(2-furyl)-2-[(2-oxopropylthio)]nicotinonitrile (6)
Brown crystals, m.p. = 192–194◦C; yield: 88% (ETOH/DMF). IR (KBr): 2218 and 1710 cm−1
(CN, CO). 1H NMR (δ ppm): 2.28 (s, 3H, CH3), 4.37 (s, 2H, CH2), 6.80 (s, 2H, CH2), 6.80 (s, 1H,
5-H of pyridinethione ring), 7.60–8.20 (m, 7H, Ar-H). 13C NMR: δ = 29.8 (CH3), 47.7 (CH2),
103.1 (C), 105.0 (C), 107.2 (CH), 117.7 (CH), 129.0 (CH), 129.4 (2CH), 132.9 (C), 134.4 (C),
+
=
142.9 (CH), 149.3 (CH), 154.0 (C), 158.9 (C), 164.2 (C), 200.4 (C O). MS (m/z): 368 (M ).
Anal. Calcd. for C19H13ClN2O2S (368.84): C, 61.87; H, 3.55; N, 7.60; S, 8.69%; found: C, 61.90;
H, 3.65; N, 7.85; S, 8.70%.
3.2.4. 6-(4-Chlorophenyl)-4-(2-furyl)-2-(methylthio)nicotinonitrile (10)
White crystals, m.p. = 158–160◦C; yield: 98% (ETOH/DMF). IR (KBr): 2210 cm−1 (CN). 1H
NMR (δ ppm): 2.70 (s, 3H, CH3), 6.62 (s, 1H, 5-H of pyridinethione ring), 7.20–8.11 (m, 7H,
Ar-H). MS (m/z): 326 (M+). Anal. Calcd. for C17H11ClN2OS (326.81): C, 62.48; H, 3.39; N,
8.57; S, 9.81%; found: C, 62.50; H, 3.45; N, 8.55; S, 9.71%.
3.3. General procedure for the synthesis of 7, 8 and 9
Each of 4 (3.5 g, 10 mmol), 5 (4.0 g, 10 mmol) and 6 (3.7 g, 10 mmol) was refluxed in sodium
ethoxide solution (0.23 g, 10 ml) for 6 h. The so-formed solid was collected by filtration and
recrystallized from the proper solvent to give 7, 8 and 9, respectively.
3.3.1. 3-Amino-6-(4-chlorophenyl)-4-(furyl)thieno[2,3-b]pyridine-2-carbonitrile (7)
Orange crystals, m.p. = 259–262◦C, yield: 43% (DMF). IR (KBr): 2193, 3450 and 3379 cm−1
(CN, NH2). 1H NMR (δ ppm): 6.80 (s, 1H, 5-H of the pyridinethione ring), 7.33–8.20 (m, 7H,
Ar-H), 10.50 (s, 2H, NH2). 13C NMR: δ = 82.9 (C), 105.0 (C), 107.0 (CH), 111.2 (C), 121.1 (C),
121.7 (CH), 129.0 (CH), 129.4 (2CH), 132.9 (C), 134.4 (C), 142.9 (CH), 144.9 (C), 148.1 (C),
154.0 (C), 155.2 (C), 157.1 (C). MS (m/z): 351 (M+). Anal. Calcd. for C18H10ClN3OS (351.82):
C, 61.45; H, 2.87; N, 11.94; S, 9.11%; found: C, 61.55; H, 2.85; N, 11.75; S, 9.00%.
3.3.2. [3-Amino-6-(4-chlorophenyl)-4-(2-furyl)thieno[2,3-b]pyridine-2yl](ethoxy)
methanol (8)
Green crystals, m.p. = 117–120◦C; yield: 96% (ETOH/DMF). IR (KBr): 1751, 3448 and 3348
cm−1, (CO, NH2). H NMR (δ ppm): 1.43 (t, 3H, CH3), 4.41 (q, 2H, CH2), 6.80 (s, 1H, 5-H
1
of the pyridinethione ring), 6.96–8.08 (m, 7H, Ar-H), 14.01 (s, 2H, NH2). 13C NMR: δ = 14.1
(CH3), 60.9 (CH2), 105.0 (CH), 107.2 (CH), 118.6 (C), 121.2 (C), 121.7 (CH), 129.0 (2CH),
129.4 (2CH), 132.9 (C), 134 (C), 134.4 (C), 142.9 (CH), 144.9 (C), 154.0 (C), 155.2 (C), 156.5
+
=
(C), 160.6 (C O ester). MS (m/z): 398 (M ). Anal. Calcd. for C20H15ClN2O3S (398.87): C,
60.22; H, 3.79; N, 7.02; S, 8.04%; found: C, 60.10; H, 3.57; N, 7.00; S, 8.20%.
3.3.3. 1-(3-Amino-6-(4-chlorophenyl)-4-(2-furyl)thieno[2,3-b]pyridine-2-yl)ethanone (9)
Orange crystals, m.p. = 208–210◦C; yield: 97% (ETOH/DMF). IR (KBr): 1616, 3421 and
3301 cm−1 (CO, NH2); 1H NMR (δ ppm): 2.50 (s, 3H, CH3), 6.81 (s, 1H, 5-H of the pyridinethione
ring), 6.90–8.10 (m, 7H,Ar-H), 13.90 (s, 2H, NH2). 13C NMR: δ = 27.8 (CH3), 105.0 (CH), 107.2
(CH), 121.3 (C), 121.7 (CH), 129.0 (2CH), 129.4 (2CH), 133 (C), 134 (C), 134.4 (C), 142.9 (CH),

352 N.M. Rateb et al.
+
=
144.9 (C), 146 (C), 154.0 (C), 155.2 (C), 157.3 (C), 190.5 (C O). MS (m/z): 368 (M ). Anal.
Calcd. for C19H13ClN2O2S (368.84): C, 61.87; H, 3.55; N, 7.60; S, 8.69%; found: C, 62.00; H,
3.35; N, 7.80; S, 8.56%.
3.4. Synthesis of 11
A mixture of 10 (1 g, 3 mmol) and excess of hydrazine hydrate was refluxed for 12 h. The reaction
mixture was cooled, and the so-formed solid was filtered, dried and recrystallized from ethanol
to give 11.
3.4.1. 6-(4-Chlorophenyl)-4-(2-furyl)-2-hydrazinylpyridine-3-carbonitrile (11)
Yellow crystals, m.p. = 245–247◦C; yield: 99%. IR (KBr): 2210, 3421, 3301 and 3143 cm−1 (CN,
NH2, NH). 1H NMR (δ ppm): 6.80 (s, 1H, 5-H of the pyridinethione ring), 7.00–7.93 (m, 7H, Ar-
H), 10.45 (b, 1H, NH), 13.90 (s, 2H, NH2). MS (m/z): 310 (M+). Anal. Calcd. for C16H11ClN4O
(310.75): C, 61.84; H, 3.57; N, 18.03%; found: C, 61.75; H, 3.50; N, 18.00%.
3.5. Synthesis of 12
To a stirred mixture of 10 (1.6 g, 5 mmol) in glacial acetic acid (10 ml) was added 30% H2O2
solution (15 ml) and the mixture was heated under reflux for 3 h. After cooling, the so-formed
solid was collected and recrystallized from DMF.
3.5.1. 6-(4-Chlorophenyl)-4-(2-furyl)-2-(methylsulfonyl)thieno[2,3-b]pyridine-3-carbonitrile
(12)
Brown crystals, m.p. = 263–266◦C; yield: 66%. IR (KBr): 2209 cm−1 (CN). 1H NMR (δ ppm):
3.40 (s, 3H, CH3), 6.88 (s, 1H, 5-H of the pyridinethione ring), 6.99–8.20 (m, 7H, Ar-H). MS
(m/z): 358 (M+).Anal. Calcd. for C17H11ClN2O3S (358.81): C, 56.91; H, 3.09; N, 7.81, S, 8.94%;
found: C, 57.00; H, 3.10; N, 7.99; S, 9.00%.
3.6. Synthesis of 13
A mixture of 10 or 12 (1 g, 3 mmol) and excess of hydrazine hydrate was refluxed for 24 h. The
reaction mixture was cooled; the so-formed solid was filtered, dried and recrystallized from acetic
acid to give 13.
3.6.1. 6-(4-Chlorophenyl)-4-(furyl)-1H-pyrazolo[3,4-b]pyridine-3-amine (13)
Yellow crystals, m.p. = 285–288◦C; yield: 95%. IR (KBr): 3462, 3378 and 3100 cm−1 (NH2,
NH). 1H NMR (δ ppm): 6.80 (s, 1H, 5-H of the pyridinethione ring), 7.00–8.20 (m, 7H, Ar-H),
13.90 (s, 1H, NH), 14.20 (s, 2H, NH2). MS (m/z): 310 (M+). Anal. Calcd. for C16H11ClN4O
(310.75): C, 61.84; H, 3.57; N, 18.03%; found: C, 61.90; H, 3.75; N, 18.20%.
3.7. Synthesis of 14
A mixture of 7 (1.8 g, 5 mmol) and formic acid (20 ml) or a mixture of compound 8 (2 g, 5 mmol)
and formamide (20 ml) was heated under reflux for 12 h. After cooling, the reaction mixture was
poured on ice and the formed solid was collected and recrystallized from DMF to give 14.

Journal of Sulfur Chemistry 353
3.7.1. 7-(4-Chlorophenyl)-9-(2-furyl) pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (14)
Orange crystals, m.p. > 300◦C; yield: (80%). IR (KBr):1650 and 3110 cm−1 (CO, NH); 1H NMR
(δ ppm): 6.86 (s, 1H, 5-H of the pyridinethione ring), 7.00–8.10 (m, 7H, Ar-H), 8.90 (s, 1H, NH).
13C NMR: δ = 105.0 (CH), 107.2 (CH), 121.7 (CH), 125.6 (C), 129.0 (CH), 129.4 (2CH), 132.9
(C), 134.4 (C), 137 (C), 144.9 (C),+145.6 (CH), 146 (C), 154.0 (C), 155.2 (C), 158.9 (C), 160.1
=
(C O amide). MS (m/z): 379 (M ). Anal. Calcd. for C19H10ClN3O2S (379.83): C, 60.08; H,
2.65; N, 11.06; S, 8.44%; found: C, 60.10; H, 2.50; N, 11.00; S, 8.22%.
3.8. Synthesis of 15
Compound 14 (1.1 g, 3 mmol) reacted with POCl3 (20 ml) under reflux for 1 h. The reaction
mixture was poured over ice, and the resulting solid was collected by filtration and recrystallization
from DMF to give 15.
3.8.1. 4-Chloro-7-(4-chlorophenyl)-9-(2-furyl)pyrido[3ꢀ,2ꢀ:4,5]thieno-[3,2-d]pyrimidine (15)
1
Brown crystals, m.p. = 260–263◦C; yield: (88%). H NMR (δ ppm): 6.80 (s, 1H, 5-H of the
pyridinethione ring), 7.00–8.12 (m, 7H, Ar-H), 9.46 (s, 1H, 2-H of the pyrimidine ring). MS
(m/z): 412 (M+). Anal. Calcd. for C19H9Cl2N3S2 (412.96): C, 55.08; H, 2.19; N, 10.14; S,
15.48%; found: C, 55.00; H, 2.10; N, 10.00; S, 15.45%.
3.9. Synthesis of 16
A mixture of 7 (1.8 g, 5 mmol), formamide (0.5 ml) and formic acid (20 ml) was heated under
reflux for 11 h. After cooling, the reaction mixture was poured on ice and the formed solid was
collected and recrystallized from DMF to give 16.
3.9.1. 7-(4-Chlorophenyl)-9-(2-furyl)-pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4-amine (16)
Orange crystals, m.p. > 300◦C; yield: (82%). IR (KBr): 3421 and 3301 cm−1 (NH2). MS (m/z):
378 (M+). Anal. Calcd. for C19H11ClN4S (378.84): C, 60.24; H, 2.93; N, 14.79; S, 8.46%; found:
C, 60.00; H, 3.00; N, 14.90; S, 8.66%.
3.10. Synthesis of 17
A mixture of 8 (4.0 g, 10 mmol) and hydrazine hydrates (4 ml, 85% solution, 4 mmol) in absolute
ethanol(20 ml)for24 hwasheatedunderreflux.Thereactionmixturewascooled, andtheresulting
solid was collected and washed with ethanol/water and recrystallized from acetic acid to give 17.
3.10.1. 3-Amino-6-(4-chlorophenyl)-4-(2-furyl)thieno[2,3-b]pyridine-2-carbohydrazide (17)
Orange crystals, m.p. = 230–233◦C; (96%); IR (KBr): 3468 and 3373 cm−1 (NH2). 13C NMR:
δ = 105.0 (CH), 107.2 (CH), 121.7 (CH), 121.6 (C), 129.0 (CH), 129.4 (2CH), 134.4 (C), 137
=
(C), 142.9 (CH), 144.9 (C), (CH), 155.2 (C), 158.9 (C), 160.7 (C O amide). MS (m/z): 384
(M+). Anal. Calcd. for C18H13ClN4O2S (384.85): C, 56.18; H, 3.40; N, 14.56; S, 8.33%; found:
C, 56.20; H, 3.50; N, 14.75; S, 8.20%.

354 N.M. Rateb et al.
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