Convenient synthesis and antimicrobial evaluation of multicyclic thienopyridines

Article abstract of DOI:10.1080/10426500701501276

Thieno[2,3-b]pyridines 7, 8, and 10 could be obtained via the S-alkylation of 3-cyano-4,6-di-2-furyl-2(1H)pyridinethione (3) with a variety of alkylating agents. These compounds were conveniently converted into novel pyrido[3',2':4,5]thieno[3,2-d]pyrimidines 12-15 and 17-20 and thieno[2,3-b;4,5-b']dipyridine 11 derivatives. Structures of the products have been determined by elemental analyses and spectral data studies. All the tested compounds were found to exhibit moderate antimicrobial activity.

Full text of DOI:10.1080/10426500701501276

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Convenient Synthesis and
Antimicrobial Evaluation of
Multicyclic Thienopyridines
Nora M. Rateb a
a Department of Chemistry, Faculty of Science, Cairo
University, Giza, Egypt
Version of record first published: 23 Aug 2007.
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Evaluation of Multicyclic Thienopyridines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 182:10, 2393-2407
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Phosphorus, Sulfur, and Silicon, 182:2393–2407, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701501276
Convenient Synthesis and Antimicrobial Evaluation of
Multicyclic Thienopyridines
Nora M. Rateb
Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
Thieno[2,3-b]pyridines 7, 8, and 10 could be obtained via the S-alkylation of 3-
cyano-4,6-di-2-furyl-2(1H)pyridinethione (3) with a variety of alkylating agents.
These compounds were conveniently converted into novel pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
d]pyrimidines 12–15 and 17–20 and thieno[2,3-b;4,5-bꢀ]dipyridine 11 derivatives.
Structures of the products have been determined by elemental analyses and spectral
data studies. All the tested compounds were found to exhibit moderate antimicrobial
activity.
Keywords Multicyclic pyridines; pyridothienopyrimidine; thienodipyridine; thienopy-
ridine
INTRODUCTION
3-Cyano-2(1H)-pyridinethiones are of interest because of their
use as intermediates for the synthesis of the biologically ac-
tive deazafolic acid and for deazaaminopterin ring synthesis.1,2
On the other hand, fused pyrimidines continue to attract con-
siderable attention because of their great practical usefulness,
primarily, due to a very wide spectrum of biological activities.
Thienopyrimidine derivatives are characterized by a very broad
spectrum of biological activities, which includes several activities such
as antiallergic,3 antiatherosclerotic,4 antibacterial,5−7 anticancer,8
antiviral,9,10 antihypertensive,11,12 antidepressant,13 antihistaminic,14
antimicrobial,15−19 and neurotropic20 activities. Various thieno[2,3-
d]pyrimidine and thieno[3,2-d]pyrimidine derivatives show pronounced
antitumor21,22 and radioprotective23 activities. Thus, it was of inter-
est to synthesize ring systems combining both the pyridine and the
thienopyrimidine moieties for testing their antimicrobial activities.
Received May 5, 2007; accepted May 17, 2007.
Address correspondence to Nora Rateb, Chemistry Department, Faculty of Science,
Cairo University, Giza 12613, Egypt. E-mail: noraratb@hotmail.com
2393

2394
N. M. Rateb
RESULTS AND DISCUSSION
Treatment of 1,3-di-2-furylpropenone (1) with 2-cyanothioacetamide
(2)
in
methoxide
solution
afforded
3-cyano-4,6-di-2-furyl-
2(1H)pyridinethione (3) in moderate yield after crystallization from
methanol. The structure of the product was supported by its elemental
analysis and spectral data. Compound 3 was alkylated with methyl
iodide, chloroacetonitrile, ethyl bromoacetate, and chloroacetone in
DMF-KOH to give different product in each case (Scheme 1).
SCHEME 1

Multicyclic Thienopyridines
2395
Thus, the reaction of 3 with methyl iodide gave the methyl sulfide 4,
as evident from its elemental analysis and spectral data, in good yield.
Attempts to affect direct displacement of the methyl sulfide group of 4
with hydrazine were unsatisfactory, giving only intractable mixtures.
Moreover, the corresponding sulfone (5), prepared by oxidation of 4 with
hydrogen peroxide in acetic acid also failed to give any recognizable
product upon reaction with hydrazine hydrate.
On the other hand, 3 was cyclized with the appropriate alkylating
agents such as chloroacetonitrile and ethyl bromoacetate in DMF in the
presence of potassium hydroxide at room temperature to form the non-
isolable S-alkylated intermediate 6, which via nucleophilic substitution
and intramolecular cyclocondensation gave the corresponding polyfunc-
tionally substituted 3-amino-4,6-di-(2-furyl)-2-substituted-thieno[2,3-
b]pyridines 7, 8 in good yields (Scheme 1). The IR spectra of compounds
7, 8 revealed the absence of NH and C S bands, and the amino group
appears at 3496–3249 cm−1 in the form of two bands due to intramolec-
ular association between the 3-NH2 and 2-C≡N or 2-COOC2H5 group
of compounds 7, 8, as observed in other cyclicenamino ester24. 1H NMR
spectra (DMSO-d6) of compounds 7, 8 showed a broad singlet at δ 6.21–
6.57 (b, 2H) assigned for the NH2 group and a singlet at δ 7.84–8.31 (s,
1H) assigned for the 5-H of the thieno[2,3-b]pyridine ring. Furthermore,
the IR spectrum of compound 8 revealed the absence of cyano group and
the characteristic absorption band of the carbonyl group at 1684 cm−1
.
The 1H NMR spectrum (DMSO-d6) of compound 8 showed a triplet at δ
1.30 (t, 3H, J = 3.7 Hz) and a quartet at δ 4.31 (q, 2H, J = 2.5 Hz) as-
signed for the ethyl group (-CH2CH3). Moreover, compounds 7, 8 showed
signals at δ 6.76 (dd, 1H, J = 4.0, 4.0 Hz), 7.52 (d, 1H, J = 3.8 Hz), and
7.99 (d, 1H, J = 3.8 Hz), which were assigned to the protons 4-H, 3-H,
and 5-H of the two furyl moieties of the thieno[2,3-b]pyridine ring. As-
signment of structures 7, 8 was also confirmed by their mass spectra,
which showed peaks corresponding to their molecular ions at m/z 307
(M+) and 354 (M+), respectively.
Whereas, compound 3 was found to react smoothly with chloroace-
tone in DMF in the presence of potassium hydroxide at room tempera-
ture to give the corresponding 2-oxopropylthionicotinonitrile derivative
9 (Scheme 1) in good yield. Elemental analyses and the spectral char-
acteristics of compound 9 are in agreement with the proposed struc-
ture. Thus, in IR spectrum, the strong absorption band of the cyano
1
group was observed at 2218 cm−1. The H NMR spectrum (DMSO-d6)
showed, beside the signals due to the furyl and thienopyridine moi-
eties, two singlets at δ 2.32 (3H, CH3CO) and 4.22 (2H, SCH2). Mass
spectrum showed a peak at m/z 324 (M+). Upon refluxing in ethanol
containing catalytic amount of piperidine, compound 9 underwent self

2396
N. M. Rateb
condensation with the formation of 1-(3-amino-4,6-di-2-furylthieno[2,3-
b]pyridin-2-yl)ethanone (10) in good yield. Structure 10 was evident
from the spectral data. Thus, IR spectrum of compound 10 revealed ab-
sorption bands at 3480 cm−1 and 3289 cm−1 corresponding to NH2 and
the characteristic absorption band of the carbonyl group at 1596 cm−1
,
and the absence of cyano group absorption. Its1H NMR spectrum
(DMSO-d6) showed, beside the signals due to the furyl and thienopy-
ridine moieties, signals at δ 2.38 (s, 3H, CH3) and at δ 7.25 (br, 2H,
NH2) along with the disappearance of the signal at 4.22 because of the
methylene group.
Treatment of 1-(3-amino-4,6-di-2-furylthieno[2,3-b]pyridin-2-yl)eth-
anone (10) with the malononitrile in refluxing ethanolic sodium
ethoxide, afforded 2-amino-7,9-di-2-furyl-4-methylpyrido[2ꢀ,3ꢀ:4,5]-
thieno[2,3-b]pyridine-3-carbonitrile (11).
The structure of compound 11 was established on the basis of its
elemental analyses and spectral data. The IR spectrum of compound
11 showed absorption bands 3374 cm−1 and 3198 cm−1 corresponding
to NH2, and the characteristic absorption band of the cyano group at
2213 cm−1, and the absence of carbonyl group absorption at 1596 cm−1
.
Its 1H NMR spectrum revealed signals at δ 2.01 (s, 3H, CH3) and δ 6.43
(br, 2H, NH2) and its mass spectrum showed a peak at m/z 372 (M+).
Compound 7, as a typical enaminonitrile derivative,25 reacted
with formic acid upon heating for several hours to yield 7,9-di-2-
furylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)-one (12) (Scheme 1).
IR spectrum of compound 12 revealed NH and carbonyl absorption
bands at 3423 and 1662 cm−1, respectively, as well as the absence of
the cyano absorption at 2197 cm−1. Its1H NMR spectrum (DMSO-d6)
revealed, beside the signals due to the furyl and thienopyridine moi-
eties, signals at δ 8.57 (s, 1H, proton on C-2 of pyrimidine ring) and
δ 12.56 (s, 1H, NH, of pyrimidine ring). Compound 12 was also ob-
tained by heating 8 in formamide at 180◦C for 2 h. 4-chloro-7,9-di-2-
furylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine (13) was obtained by the
reaction of 12 with POCl3 under reflux for 1 h.
Next, Compound 7 was fused with each of urea and thiourea to af-
ford the corresponding pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine deriva-
tives 14 and 15, respectively (Scheme 2). The spectral characteristics
of compounds 14 and 15 are in agreement with the proposed structure.
In the IR spectra of compounds 14 and 15, the absence of the cyano
absorption indicates that cyclization was completed. Their 1H NMR
showed signals at δ 7.32–7.41 corresponding to the NH2 peaks and at δ
12.89–12.97 corresponding to the NH pyrimidine ring and all other sig-
nals are exactly matching their structures. Compound 7 reacted with
triethylorthoformate in presence of acetic acid at 140◦C to give ethyl

Multicyclic Thienopyridines
2397
SCHEME 2
(2-cyano-4,6-di-2-furylthieno[2,3-b]-pyridin-3-yl)imidoformate (16) in a
moderate yield. The structure of compound 16 was established on the
basis of its elemental analyses and spectral data. The IR spectrum of
compound 16 revealed cyano absorption band at 2248 cm−1, and the
1
absence of amino absorption bands at 3400–3100 cm−1. Its H NMR
spectrum (DMSO-d6) revealed signals at δ 1.22 (t, 3H, J = 8.2 Hz, CH3),
4.33 (q, 2H, J = 9.6 Hz, CH2), and δ 8.66 (s, 1H, CH O) and its mass
spectrum showed a peak at m/z 363 (M+). Compound 16 was further
reacted with aniline to afford 4-phenylaminopyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
d]pyrimidine derivative, 17. The IR spectrum of compound 17 revealed
absorption band at 3452 cm−1 (NH) and the absence of cyano absorption
band at 2248 cm−1. Its 1H NMR spectrum (DMSO-d6) revealed signals
at δ 6.21 (1H, br, s, NH), 8.82 (s, 1H, proton on C-2 of pyrimidine ring)
along with the furyl and phenyl signals and its mass spectrum showed
a peak at m/z 410 (M+).
Compound 8 also reacted with each of urea, thiourea, and phenyl
isothiocyanate to afford the corresponding pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-
d]pyrimidine derivatives 18–20, respectively. Structures 18–20 were
established on the basis of their elemental analyses and spectral data.
IR and Mass spectra of compounds 18–20 are in agreement with the
1
proposed structures. Their H NMR spectra (DMSO-d6) revealed the
absence of ethyl ester protons signals, indicating complete cyclization.
Finally, compound 8 reacted with 85% excess of hydrazine hydrate
in refluxing ethanol to give 3-amino-4,6-di-2-furylthieno[2,3-b]pyridine-
2-carbohydrazide (21) (Scheme 3). The structure of compound
21 was confirmed by spectral data and elemental analyses. Its
1H NMR spectrum (DMSO-d6) revealed the absence of ethyl es-
ter protons signals, and its IR data are in agreement with

2398
N. M. Rateb
SCHEME 3
the proposed structure. Compound 21, reacted with the azoben-
zeneacetylacetone derivatives 22a, b in glacial acetic acid to
yield the (3-amino-4,6-di-2-furylthieno[2,3-b]pyridin-2-yl)-[4-arylazo-
3,5-dimethyl-1-pyrazolylmethanone 23a, b (Scheme 3). The reaction
proceeds in two stages, viz., the initially formed hydroxypyrazoline sub-
sequently loses water by an acid-catalysed reaction.26−28 Compound
21 when reacted with azobenzenemalononitrile derivatives 22c,d in a
similar manner gave (3-amino-4,6-di-2-furylthieno[2,3-b]pyridin-2-yl)-
4-arylazo-3,5-diamino-1-pyrazolylmethanone 23c, d. Characterization
and spectral data of compounds 23a–d are shown in Tables II and III.
Antimicrobial Activity
The antibacterial and antifungal activities were carried out in the Mi-
crobiology Division of the Microanalytical Center at Cairo University,
using the diffusion plate method.29−31 A bottomless cylinder contain-
ing a measured quantity (1 mL, 20 mg/mL) of the sample is placed
on a plate (7 cm diameter) containing a solid bacterial medium (nutri-
ent agar broth) or a fungal medium (Dox’s medium), which has been

Multicyclic Thienopyridines
2399
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 mea-
sure 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 I, all the tested compounds were found to exhibit
moderate activity against both Escherichia coli and Staphylococcus au-
reus microorganisms with respect to the used reference tetracyclin. The
antifungal activity of all the tested compounds was found to be similar
or higher than the used reference Amfoterisin B.
EXPERIMENTAL
Melting points were measured on an Electrothermal melting point ap-
paratus and are uncorrected. IR spectra were recorded on Shimadzu
FT-IR 8101 PC infrared spectrophotometer. The 1H NMR spectra were
TABLE I Antibacterial and Antifungal Activities of Some of the
Synthesized Compounds
Escherichia coli Staphylococcus aureus
Candida albicans
Inhibition (%)b
Samplea
Inhibition (%)b
Inhibition (%)b
Control: DMSO
3
4
7
8
10
14
15
18
19
20
21
23a
23b
23d
Tetracyclin
Amfoterisin B
0.0
17.2
17.2
15.8
17.2
17.2
18.6
18.6
17.2
17.2
17.2
17.2
17.2
15.8
15.8
34.0
—
0.0
18.6
20.0
15.8
17.2
15.7
17.2
20.0
18.6
15.8
17.2
15.8
15.8
15.8
17.2
32.0
—
0.0
15.8
18.6
15.8
17.2
15.7
18.6
17.2
17.2
15.8
17.2
17.2
17.2
15.8
15.8
—
16.0
aCompound 15 is the only one that exhibited inhibition (15.8%) against
Aspergillus flavus among the tested compounds;
b100% inhibition means no growth of either bacteria or fungi allover the plate.

2400
N. M. Rateb
determined in DMSO-d6 at 300 MHz on a Varian mercury VX 300 NMR
spectrometer using TMS as an internal standard. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental
analyses were carried out at the Microanalytical Center of Cairo Uni-
versity.
4,6-di-(2-Fury)l-2-sulfanylpyridine-3-carbonitrile (3)
A mixture of 1 (20.7 g, 110 mmoles) and cyanothioacetamide 2 (10 g,
100 mmoles) was heated under reflux in methoxide solution (2.3 g of
Na in 100 mL methanol) for 7 h. The reaction mixture was cooled and
stirred at room temperature over night. The precipitate was filtered,
washed with water, and recrystallized from methanol (Tables II and III).
4,6-Di-2-Furyl-2-(methylthio)nicotinenitrile (4),
3-Amino-4,6-di-2- furylthieno[2,3-b]pyridine-2-carbonitrile (7),
Ethyl 3-Amino-4,6-di-2-furylthieno[2,3-b]pyridine-2-
carboxylate (8) and 4,6-Di-2-furyl-2-[(2-oxopropyl)thio]
nicotinenitrile (9). General Procedure
A mixture of 3 (2.68 g, 10 mmol) and potassium hydroxide (0.62 g, 11
mmol) in N,N-dimethylformamide (20 mL) was stirred for 2 h at room
temperature. Each of methyl iodide, chloroacetonitrile, ethyl bromoac-
etate, and chloroacetone (10 mmol each) was added and stirring was
continued for 2 h. The resulting solid was collected and recrystallized
from the proper solvent (Tables II and III).
4,6-Di-2-Furyl-2-(methylsulfonyl)nicotinenitrile (5)
To a stirred mixture of 4 (0.85 g, 3 mmol) in glacial acetic acid (10
mL) was added 30% H2O2 solution (10 mL), and the mixture was heated
under reflux for 30 min. After cooling, H2O was added; the resulting
solid was collected and recrystallized from ethanol (Tables II and III).
1-(3-Amino-4,6-di-2-furylthieno[2,3-b]pyridin-2-yl)-
ethanone (10)
A solution of 9 (3.24 g, 10 mmol) in ethanol (30 mL) containing 0.5 mL
piperidine was heated under reflux for 2 h. After cooling, the resulting
solid was collected by filtration and recrystallized from ethanol/dioxin
(Tables II and III).
2-Amino-7,9-di-2-furyl-4-methylpyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-
b]pyridine-3-carbonitrile (11)
A mixture of 10 (3.24 g, 10 mmol) and malononitrile (0.73 g, 11 mmol)
was heated under reflux in ethoxide solution (0.23 g of Na in 30 mL
ethanol) for 7 h. The reaction mixture was cooled and stirred at room

Multicyclic Thienopyridines
2401
TABLE II Physical and Analytical Data of the Newly Synthesized
Compounds
Elemental Analysis
(%) Calcd/Found
m.p. (◦C)
Solvent
Yield Mol. Formula
Compound Color
(%)
(Mol. Wt)
C
H
N
S
3
Red
233-4
MeOH
168-9
48
C14H8N2O2S 62.68 3.01 10.44 11.95
(268.30) 62.57 3.11 10.53 11.77
C15H10N2O2S 63.82 3.57 9.92 11.36
(282.32) 63.67 3.68 10.0 11.19
15H10N2O4S 57.32 3.21 8.91 10.20
(314.32) 57.55 3.22 8.89 10.36
16H9N3O2S 62.53 2.95 13.67 10.43
(307.33) 62.28 3.11 13.82 10.51
18H14N2O4S 61.01 3.98 7.90 9.05
(354.39) 60.89 4.08 8.05 8.88
17H12N2O3S 62.95 3.73 8.64 9.89
(324.36) 63.11 3.66 8.77 9.78
C17H12N2O3S 62.95 3.73 8.64 9.89
(324.36) 62.88 3.88 8.61 10.02
20H12N4O2S 64.51 3.25 15.04 8.61
(372.41) 64.67 3.17 14.89 8.73
17H9N3O3S 60.89 2.71 12.53 9.56
(335.34) 61.02 2.63 12.59 9.33
38 C17H8ClN3O2S 57.72 2.28 11.88 9.06
(353.79) 57.86 2.19 11.69 9.21
C17H10N4O3S 58.28 2.88 15.99 9.15
350.36 58.11 3.01 16.12 9.01
33 C17H10N4O2S2 55.73 2.75 15.29 17.50
(366.42) 55.89 2.82 15.41 17.39
C19H13N3O3S 62.80 3.61 11.56 8.82
(363.40) 63.01 3.47 11.71 8.68
C23H14N4O2S 67.30 3.44 13.65 7.81
(410.46) 67.44 3.57 13.49 7.99
C17H9N3O4S 58.12 2.58 11.96 9.13
(351.34) 57.97 2.71 11.77 9.29
C17H9N3O3S2 55.58 2.47 11.44 17.45
(367.41) 55.41 2.61 11.31 17.61
64 C23H13N3O3S2 62.29 2.95 9.47 14.46
(443.51) 62.11 2.78 9.33 14.30
C16H12N4O3S 56.46 3.55 16.46 9.42
(340.36) 56.66 3.67 16.31 9.55
46 C27H19FN6O3S 61.59 3.64 15.96 6.09
(526.55) 61.78 3.51 15.77 6.21
33 C28H19F3N6O3S 58.33 3.32 14.58 5.56
(576.56) 58.19 3.22 14.71 5.39
39 C25H17FN8O3S 56.81 3.24 21.20 6.07
(528.53) 56.66 3.36 21.04 5.91
41 C26H17F3N8O3S 53.98 2.96 19.37 5.54
(578.54) 54.15 3.05 19.21 5.61
4
Beige
70
53
85
85
73
77
44
70
EtOH/Dioxane
192-3
EtOH
259-60
EtOH/DMF
127-8
EtOH
158-9
EtOH/Dioxane
193-5
EtOH/Dioxane
251-2
Dioxane
>300
DMF
131-2
DMF
274-5
DMF/H2O
154-5
DMF/H2O
195-6
Benzene
233-4
Benzene
183-4
DMF/H2O
212-3
DMF/H2O
225-6
EtOH
246-7
EtOH/Dioxane
>300
DMF/H2O
288-9
DMF/H2O
>300
5
Yellow
C
7
Beige
C
8
Yellow
C
C
9
Brown
10
11
12
13
14
15
16
17
18
19
20
21
23a
23b
23c
23d
Deep Red
Purple
Gray
C
C
Brown
Dark brown
Brown
42
Dark brown
Dark brown
Brown
45
64
37
34
Dark brown
Yellow
Yellow
53
Beige
Beige
Brown
DMF/H2O
290-1
DMF/H2O
Beige

2402
N. M. Rateb
TABLE III Spectral data of the newly synthesized compounds
Compound
Spectral data
3
IR: 2220 (CN), 3195 (NH)
1H NMR: 6.67 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.76 (d, 2H,
J = 3.8 Hz, 3-H of two furyl rings), 8.02 (d, 2H, J = 3.8 Hz, 5-H of two
furyl rings), 8.21(s, 1H, 5-H of the pyridinethione ring), 14.10 (b, 1H,
NH)
4
IR: 2209 (CN)
1H NMR: 2.69 (s, 3H, CH3), 6.75 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl
rings), 7.66 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.93 (d, 2H,
J = 3.8 Hz, 5-H of two furyl rings), 8.08(s, 1H, 5-H of the
pyridinethione ring)
5
IR: 2218 (CN)
1H NMR: 3.41 (s, 3H, SCH3), 6.65 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two
furyl rings), 7.73 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.88 (d, 2H,
J = 3.8 Hz, 5-H of two furyl rings), 8.01(s, 1H, 5-H of the
pyridinethione ring)
7
IR: 3496, 3249 (NH2), 2197 (CN)
1H NMR: 6.57 (br, 2H, NH2), 6.75 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two
furyl rings), 7.72 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.92 (d, 2H,
J = 3.8 Hz, 5-H of two furyl rings), 8.31(s, 1H, 5-H of the
thienopyridine ring)
8
IR: 3486, 3352 (NH2), 1744 (CO)
1H NMR: 1.30 (t, 3H, J = 3.7 Hz, CH3), 4.31 (q, 2H, J = 2.5 Hz, CH2),
6.21 (br, 2H, NH2), 6.76 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings),
7.52 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.48 (s, 1H, 5-H of the
thienopyridine ring), 7.99 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings)
IR: 2218 (CN), 1723 (CO)
9
1H NMR: 2.32 (s, 3H, CH3CO), 4.22 (s, 2H, SCH2), 6.69 (dd, 2H, J = 4.0,
4.0 Hz 4-H of two furyl rings), 7.73 (d, 2H, J = 3.8 Hz, 3-H of two furyl
rings), 8.01 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings), 8.17 (s, 1H, 5-H
of the pyridinethione ring)
10
11
12
IR: 3480, 3289 (NH2), 1596 (CO)
1H NMR: 2.38 (s, 3H, CH3CO), 6.85 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two
furyl rings), 7.25 (br, 2H, NH2), 7.50 (d, 2H, J = 3.8 Hz, 3-H of two furyl
rings), 7.73 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings), 7.82 (s, 1H, 5-H
of the thienopyridine ring)
IR: 3374, 3198 (NH2), 2213 (CN)
1H NMR: 2.01 (s, 3H, CH3), 6.43 (br, 2H, NH2), 6.65 (dd, 2H, J = 4.0, 4.0
Hz 4-H of two furyl rings), 7.69 (d, 2H, J = 3.8 Hz, 3-H of two furyl
rings), 7.95 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings), 8.13 (s, 1H, 5-H
of the thienopyridine ring)
IR: 3423 (NH), 1662 (CO)
1H NMR: 6.71 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.72 (d, 2H,
J = 3.8 Hz, 3-H of two furyl rings), 8.02 (d, 2H, J = 3.8 Hz, 5-H of two
furyl rings), 8.25 (s, 1H, 5-H of the thienopyridine ring), 8.57 (s, 1H,
Proton on C-2 of pyrimidine ring), 12.56 (s, 1H, NH of pyrimidine ring)
(Continued on next page)

Multicyclic Thienopyridines
2403
TABLE III Spectral data of the newly synthesized compounds
(Continued)
Compound
Spectral data
13
1H NMR: 6.70 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.75 (d, 2H,
J = 3.8 Hz, 3-H of two furyl rings), 7.99 (d, 2H, J = 3.8 Hz, 5-H of two
furyl rings), 8.17 (s, 1H, 5-H of the thienopyridine ring), 9.66 (s, 1H,
Proton on C-2 of pyrimidine ring)
14
15
16
17
IR: 3349, 3111 (NH2), 1662 (CO)
1H NMR: 6.76 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.41 (br,
2H, NH2), 7.78 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.93 (d, 2H,
J = 3.8 Hz, 5-H of two furyl rings), 8.19 (s, 1H, 5-H of the
thienopyridine ring), 12.97 (s, 1H, NH of pyrimidine ring)
IR: 3308, 3137 (NH2)
1H NMR: 6.75 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.32 (br,
2H, NH2), 7.75 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 8.01 (d, 2H,
J = 3.8 Hz, 5-H of two furyl rings), 8.24 (s, 1H, 5-H of the
thienopyridine ring), 12.89 (s, 1H, NH of pyrimidine ring)
IR: 2248 (CN)
1H NMR: 1.22 (t, 3H, J = 8.2 Hz, CH3), 4.33 (q, 2H, J = 9.6 Hz, CH2),
6.73 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.77 (d, 2H, J = 3.8
Hz, 3-H of two furyl rings), 7.98 (d, 2H, J = 3.8 Hz, 5-H of two furyl
rings), 8.11 (s, 1H, 5-H of the thienopyridine ring), 8.66 (s, 1H, CH-O)
IR: 3542 (NH)
1H NMR: 6.21 (br, 1H, NH), 6.78 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl
rings), 7.01–7.53 (m, 5H, phenyl protons), 7.69 (d, 2H, J = 3.8 Hz, 3-H
of two furyl rings), 7.99 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings), 8.15
(s, 1H, 5-H of the thienopyridine ring), 8.82 (s, 1H, proton on C-2 of
pyrimidine ring)
18
19
20
21
IR: 3430, 3352 (2NH), 1732, 1656 (2CO)
1H NMR: 6.63 (dd, 2H, J = 41.0, 4.0 Hz 4-H of two furyl rings), 7.82 (d,
2H, J = 3.8 Hz, 3-H of two furyl rings), 7.87 (d, 2H, J = 3.8 Hz, 5-H of
two furyl rings), 8.25 (s, 1H, 5-H of the thienopyridine ring), 12.76,
12.83 (2s, 2H, NH protons of pyrimidine ring)
IR: 3378, 3238 (2NH), 1656 (CO)
1H NMR: 6.69 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.79 (d, 2H,
J = 3.8 Hz, 3-H of two furyl rings), 8.22 (d, 2H, J = 3.8 Hz, 5-H of two
furyl rings), 8.31 (s, 1H, 5-H of the thienopyridine ring), 12.25, 12.89
(2s, 2H, NH protons of pyrimidine ring)
IR: 3413 (NH), 1705 (CO)
1H NMR: 6.71 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 7.08-7.62
(m, 5H, phenyl protons), 7.74 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings),
8.19 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings), 8.15 (s, 1H, 5-H of the
thienopyridine ring), 12.19 (s, 1H, NH of pyrimidine ring)
IR: 3414-3199 (NH2, NH), 1650 (CO)
1H NMR: 4.38 (br, 2H, N-NH2), 6.70 (br, 2H, NH2), 6.75 (dd, 2H, J = 4.0,
4.0 Hz 4-H of two furyl rings), 7.55 (d, 2H, J = 3.8 Hz, 3-H of two furyl
rings), 7.38 (s, 1H, 5-H of the thienopyridine ring), 7.89 (d, 2H, J = 3.8
Hz, 5-H of two furyl rings), 9.39 (br, 1H, NH)
(Continued on next page)

2404
N. M. Rateb
TABLE III Spectral data of the newly synthesized compounds
(Continued)
Compound
Spectral data
23a
IR: 3445, 3257 (NH2), 1640 (CO)
1H NMR: 2.80 (s, 6H, 3-,5-CH3 of pyrazol), 6.78 (dd, 2H, J = 4.0, 4.0 Hz
4-H of two furyl rings), 6.81 (br, 2H, NH2), 7.12-7.44 (m, 4H, phenyl
protons), 7.54 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.59 (s, 1H,
5-H of the thienopyridine ring), 7.93 (d, 2H, J = 3.8 Hz, 5-H of two furyl
rings)
23b
IR: 3472, 3238 (NH2) 1665 (CO)
1H NMR: 2.82 (s, 6H, 3-,5-CH3 of pyrazol), 6.79 (dd, 2H, J = 4.0, 4.0 Hz
4-H of two furyl rings), 6.83 (br, 2H, NH2), 7.18-7.51 (m, 4H, phenyl
protons), 7.61 (d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.69 (s, 1H,
5-H of the thienopyridine ring), 7.99 (d, 2H, J = 3.8 Hz, 5-H of two furyl
rings)
23c
23d
IR: 3475–3188 (NH2), 1659 (CO)
1H NMR: 6.75 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 6.81 (br,
2H, NH2), 6.93 (br, 2H, 2 NH2), 7.05–7.47 (m, 4H, phenyl protons), 7.62
(d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.79 (s, 1H, 5-H of the
thienopyridine ring), 8.01 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings)
IR: 3458-3216 (NH2), 1651 (CO)
1H NMR: 6.69 (dd, 2H, J = 4.0, 4.0 Hz 4-H of two furyl rings), 6.79 (br,
2H, NH2), 6.98 (br, 2H, 2 NH2), 7.14–7.53 (m, 4H, phenyl protons), 7.71
(d, 2H, J = 3.8 Hz, 3-H of two furyl rings), 7.85 (s, 1H, 5-H of the
thienopyridine ring), 8.11 (d, 2H, J = 3.8 Hz, 5-H of two furyl rings)
temperature over night. The precipitate was filtered, washed with wa-
ter, and recrystallized from dioxin (Tables II and III).
7,9-Di-2-Furylpyrido[3 ꢀ,2 ꢀ:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (12)
Method A. A mixture of 7 (3.07 g, 10 mmol) and formic acid (20 mL)
was heated under reflux for 7 h. After cooling, the reaction mixture was
poured over ice and the formed solid was collected and recrystallized
form N,N-dimethylformamide (Tables II and III).
Method B. Compound 8 (3.54 g, 10 mmol) was heated with for-
mamide (20 mL) at 180◦C for 2 h. After cooling, the reaction mixture
was poured over ice and the formed solid was collected by filtration and
recrystallized form N,N-dimethylformamide (Tables II and III).
4-Chloro-7,9-di-2-furylpyrido[3ꢀ,2 ꢀ:4,5]thieno[3,2-d]pyrimidine
(13)
Compound 12 reacted with POCl3 (20 mL) under reflux for
1 h. The reaction mixture was poured over ice, and the resulting

Multicyclic Thienopyridines
2405
solid was collected by filtration and recrystallized form dilute N,N-
dimethylformamide (Tables II and III).
Pyrido[3 ꢀ,2 ꢀ:4,5]thieno[3,2-d]pyrimidine derivatives 14, 15, 18
and 19 General Procedure
Two grams of each of compounds 7 and 8 were heated with 5 g each
of urea and thiourea at 160–170◦C for 30 min. The clear solution went
mushy, and heating was continued for another 10 min at 180◦C. The
resulting solid (in each case) was dissolved in dilute sodium hydrox-
ide and then carefully acidified with acetic acid to obtain the corre-
sponding crude products which were recrystallized from dilute N,N-
dimethylformamide (Tables II and III).
Ethyl (2-Cyano-4,6-di-2-furylthieno[2,3-b]-
pyridin-3-yl)imidoformate (16)
A mixture of 7 (3.07 g, 10 mmol) and triethylorthoformate (20 mL)
with catalytic amount of acetic acid were heated under reflux at 140◦C
for 6 hrs. The resulting dark brown solution was allowed to cool to room
temperature and evaporated under vacuum. n-Hexane was added to the
residue and the separated solid was filtered, washed with n-hexane and
recrystallized from benzene (Tables II and III).
7,9-di-2-Furyl-N-phenylpyrido[3 ꢀ,2 ꢀ:4,5]thieno[3,2-
d]pyrimidin-4-amine (17)
Compound 16 (1.82 g, 5 mmol) was dissolved in ethanol (10 mL)
containing aniline (1.5 mL) was heated under reflux at 110◦C for 6 h.
Ethanol and aniline was removed under vacuum. The crude product
residue was triturated with n-hexane and crystallized from benzene
(Tables II and III).
7,9-Di-2-Furyl-3-phenyl-2-thioxo-2,3-dihydropyrido-
[3 ꢀ,2 ꢀ:4,5]thieno[3,2-d]pyrimidin-4(1H)-one (20)
A mixture of compound 8 (3.54 g, 10 mmol) and the phenyl isoth-
iocyanate (1.35 g, 10 mmol) in acetonitrile (30 mL) was heated under
reflux for 15 h in the presence of anhydrous potassium carbonate (1.4 g).
The reaction mixture was then cooled, filtered, diluted with water (10
mL), and neutralized with hydrochloric acid (2M). The resulting solid
was filtered, washed with water, dried, and recrystallized from ethanol
(Tables II and III).

2406
N. M. Rateb
3-Amino-4,6-di-2-furylthieno[2,3-b]pyridine-2-carbohydrazide
(21)
A mixture of compound 8 (3.54 g, 10 mmol) and hydrazine hydrate
(4 ml, 85% solution, 4 mmoles) in absolute ethanol (20 mL) for 24 h was
heated under reflux. The reaction mixture was cooled, and the resulting
solid was collected and washed with ethanol/water and recrystallized
from ethanol/dioxin (Tables II and III).
3-Amino-4,6-di-2-furylthieno[2,3-b]-2-pyridyl-4-arylazo-3,5-
disubstituted-1-pyrazolyl-methanone (23a-d)
A mixture of compound 21 (1.7 g, 5 mmol) and the appropriate of
arylazoacetylacetone 22a, b and arylazomalononitrile 22c, d (5 mmol)
was heated under reflux in glacial acetic acid (10 mL) with stirring
for 6 h. The reaction mixture was cooled to room temperature and the
separated solid was filtered, washed with water, dried, recrystallized
from dilute N,N-dimethylformamide (Tables II and III).
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