Pyridine-2(1H)-thione in heterocyclic synthesis: Synthesis of some new nicotinic acid ester, thieno[2,3-b]pyridine, pyrido[3′,2′:4,5]thieno [3,2-d]pyrimidine, and Thiazolylpyrazolo-[3,4-b]pyridine derivatives

Article abstract of DOI:10.1080/10426500500272152

Nicotinic acid esters 3a-c were prepared by the reaction of pyridine-2(1H)-thione derivative 1 with a-halo-reagents 2a-c. Compounds 3a-c underwent cyclization to the corresponding thieno[2,3-b]pyridines 4a-c via boiling in ethanol/piperidine solution. Com

Full text of DOI:10.1080/10426500500272152

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Phosphorus, Sulfur, and Silicon
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Pyridine-2(1H)-thione in
Heterocyclic Synthesis:
Synthesis of Some New
Nicotinic Acid Ester, Thieno[2,
3-b]pyridine, Pyrido[3′, 2′: 4,
5]thieno [3, 2-d]pyrimidine,
and Thiazolylpyrazolo[3, 4-
b]pyridine Derivatives
Mohamed A. M. Gad-Elkareem a , Azza M. Abdel-
Fattah b & Mohamed A. A. Elneairy b
a Chemistry Department , Al-Azhar University ,
Assïut, Egypt
b Chemistry Department , Cairo University , Giza,
Egypt
Published online: 15 Aug 2006.
To cite this article: Mohamed A. M. Gad-Elkareem , Azza M. Abdel-Fattah &
Mohamed A. A. Elneairy (2006) Pyridine-2(1H)-thione in Heterocyclic Synthesis:
Synthesis of Some New Nicotinic Acid Ester, Thieno[2, 3-b]pyridine, Pyrido[3′, 2′:
4, 5]thieno [3, 2-d]pyrimidine, and Thiazolylpyrazolo[3, 4-b]pyridine Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:4, 891-911, DOI:
10.1080/10426500500272152
To link to this article: http://dx.doi.org/10.1080/10426500500272152
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Phosphorus, Sulfur, and Silicon, 181:891–911, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500272152
Pyridine-2(1H)-thione in Heterocyclic Synthesis:
Synthesis of Some New Nicotinic Acid Ester,
Thieno[2,3-b]pyridine, Pyrido[3ꢀ,2ꢀ:4,5]thieno
[3,2-d]pyrimidine, and Thiazolylpyrazolo-
[3,4-b]pyridine Derivatives
Mohamed A. M. Gad-Elkareem
Chemistry Department, Al-Azhar University, Ass¨ıut, Egypt
Azza M. Abdel-Fattah
Mohamed A. A. Elneairy
Chemistry Department, Cairo University, Giza, Egypt
Nicotinic acid esters 3a–c were prepared by the reaction of pyridine-2(1H)-thione
derivative 1 with α-halo-reagents 2a–c. Compounds 3a–c underwent cyclization to
the corresponding thieno[2,3-b]pyridines 4a–c via boiling in ethanol/piperidine
solution. Compounds 4a–c condensed with dimethylformamide-dimethylacetal
(DMF-DMA) to afford 3-{[(N,N-dimethylamino)methylene]amino}thieno[2,3-b]-
pyridine derivatives 6a–c. Moreover, compounds 4a–c and 6a–c reacted with dif-
ferent reagents and afforded the pyrido[3ꢀ, 2ꢀ : 4, 5]thieno[3,2-d]pyrimidine deriva-
tives 10a–d, 11a–c, 12a,b, 14a,b, 17, and 19. In addition, pyrazolo[3,4-b]pyridine
derivative 20 (formed via the reaction of 1 with hydrazine hydrate) reacted with
ethylisothiocyanate yielded the thiourea derivative 21. Compound 21 reacted
with α-halocarbonyl compounds to give the 3-[(3H-thiazol-2-ylidene)amino]-1H-
pyrazolo[3,4-b]pyridine derivatives 23a–c, 25, and 27a,b.
Keywords Ethyl nicotinates; pyridinethiones; pyridothienopyrimidines; thiazolylpyra-
zolo[3, 4-b]pyridines; thieno[2, 3-b]pyridnes
INTRODUCTION
In the last few years, our research group has devoted much at-
tention to the construction of new pyridine and annelated pyridine
derivatives1−8 of expected biological activities. On account of the re-
ported biological activities of a pyridine ring that can be found in a
Received March 1, 2005; accepted June 10, 2005.
Address correspondence to Mohamed A. M. Gad-Elkareem, Al-Azhar University,
Chemistry Department, Faculty of Science, Ass¨ıut 71524, Egypt. E-mail: m65gad@
yahoo.com
891

892
M. A. M. Gad-Elkareem et al.
broad variety of drugs, such as milirinone, which is useful for treat-
ment of the heart,9 acetylcholine enhancement useful in the treat-
ment of Alzheimer disease10 and substituted pyridine derivatives were
used as antitumer11 and antiamnesic12 agents. Recently, ethyl nicoti-
nate derivatives were reported to be used as agrochemical fungicid13
and anticancer14 agents. Also, S-alkylpyridines posses neurotropic
activity.15 Moreover, thieno[2, 3-b]pyridines are of special importance
due to the reported biological activities such as antibacterial,3,8,16−20
antihypertensive,21 and ganodotropin-releasing hormone antagoniz-
22,23
ing activity
and have neurotropic activity.15 Some thieno[2, 3-b]-
pyridine-2-carboxylate derivatives were reported to be used as
anti-inflammatory.24 (1)Benzothieno[2, 3-b]pyrimidines were used as
phospho diestrase
V
inhibitors.25 In addition, pyridothienopy-
rimidines have found applications as analgesics,26 antipyretics,27
antiflammatories,28 antianaphylactic,29,30 and antimicrobial19,31 activ-
ities. Pyrazolo[3, 4-b]pyridines have been used in treating thrombo-
cytopenia, erythropenia,32 and pemcytopenia;33 they also are useful
for the treatment of depression and obsessive compulsive disorder.34
They have been used as CRF antagonists,35 platelet aggregation
inhibitors,36 and antimicrobial.3,4,37 On the other hand, several substi-
tuted thiazolyl derivatives are reported to possess anti-inflammatory,
antioxidant,38−40 lipoxygenase inhibitors,40 anticancer,41 anti–HIV,41
and antimicrobial3,4,41−43 activities. The previously mentioned findings
stimulated the interest for the synthesis of some new ethyl nicoti-
nate, thieno[2, 3-b]pyridine, pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]pyrimidine,
and thiazolylpyrazolo[3, 4-b]pyridine derivatives of expected biological
activities.
RESULTS AND DISCUSSION
It has been found that pyridine-2(1H)-thione 144 reacted with
ethyl chloroacetate (2a) in KOH/DMF solution under stirring
at r.t. to afford the corresponding ethyl-5-cyano-6-[(2-ethoxy-2-
oxoethyl)thio]nicotinate derivative 3a via dehydrochloronation. The
structure of 3a was confirmed by elemental analysis and spectral data.
The IR spectrum of 3a showed the presence of absorption bands due
to C N at 2224 and two C O at 1750 and 1723 cm−1 function groups.
In a similar manner, compound 1 reacted with each of 2-chloro-N-(4-
methoxyphenyl)acetamide (2b) and chloroacetonitrile (2c) to afford the
corresponding ethyl nicotinate derivatives 3b,c. The 1H NMR spec-
trum of compound 3b exhibited the two singlet signals at δ = 4.03 and
δ = 8.79 ppm assignable for SCH2 and NH. The structure of compounds
3a–c was further elucidated via its cyclization to the corresponding

Pyridine-2(1H)-thione in Heterocyclic Synthesis
893
thieno[2, 3-b]pyridine derivatives 4a–c upon boiling in ethanol contain-
ing a few drops of piperidine as a catalyst. The IR spectra of compounds
4a–c showed the presence of the absorption bands of the newly born
NH2 group (cf, Scheme 1 and Experimental Section).
SCHEME 1
An unequivocal support for the structure 4a–c was achieved via their
synthesis by another route, by the reaction of 1 and each of 2a–c in
ethanolic sodium ethoxide solution to afford the same reaction products
4a–c (cf, Scheme 1 and Experimental Section).
The condensation of 4a with DMF-DMA in dry xylene un-
der reflux yielded the corresponding 3-{[(N, N-dimethylamino)-
methylene]amino}-6-methylthieno[2, 3-b]pyridine derivative 6a rather
than the possible alternative 3-amino-6-[2-(N, N-dimethylamino)-
vinyl]thieno[2, 3-b]pyridine derivative 5a. Compound 5a was ruled
out based on spectral data and chemical transformations; thus,
the IR spectrum of 6a showed the absence of the absorption band
due to the NH2 group while its 1H NMR revealed the signals

894
M. A. M. Gad-Elkareem et al.
at δ = 2.65 ppm for CH3 at δ = 2.80 ppm for N(CH3)2 and ab-
sence of any signals due to NH2 protons. Similarly, compounds
4b,c condensed with DMF-DMA to give the corresponding 3-{[(N,
N-dimethylamino)methylene]amino}-6-methylthieno[2, 3-b]pyridine
derivatives 6b,c rather than 3-amino-6-[2-(N, N-dimethylamino)-
vinyl]thieno[2, 3-b]pyridine derivatives 5b,c (cf, Scheme
1 and
Experimental Section).
The hydrolysis of compound 4a in 10% ethanolic potassium
hydroxide solution afforded after acidification the corresponding
thieno[2, 3-b]pyridine-2-carboxylic acid derivative 7 which, in tern,
reacted with acetic anhydride and afforded the corresponding
2-methylpyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d][1,3]oxazine-4-one derivative 8.
The IR spectrum of compound 8 showed the presence of the absorp-
tion band of the newly C O of oxazinone ring at 1754 cm−1, and the
absence of the absorption band corresponded to NH2 group while its 1H
NMR spectrum indicated the presence of singlet signal due to C(2)-CH3
at δ = 3.59 ppm, and an absence of any signals may be attributed to
NH2 or OH protons (cf, Scheme 2 and Experimental Section).
SCHEME 2
The reaction of the oxazinone derivative 8 with p-anisidine
(9a) in acetic acid afforded the corresponding 2-methyl-3-(4-
methoxyphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d ]pyrimidine derivative
10a. The IR spectrum of 10a showed the absence of the absorption
band of C O of the oxazinone ring while its 1H NMR spectrum re-
vealed the presence of the signals of the additional C6H4-OCH3 pro-
tons. Analogously, compound 8 reacted with p-toluidine (9b), hydrazine
hydrate (9c), and 4-aminopyridine (9d) to give the corresponding

Pyridine-2(1H)-thione in Heterocyclic Synthesis
895
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine derivatives 10b–d in a respec-
tive manner (cf, Scheme 2 and Experimental Section).
The reactivity of the formamidine derivative 6a towards aro-
matic amines was investigated. Thus, 6a reacted with p-anisidine
(9a) in glacial acetic acid to afford the corresponding 3-(4-
methoxyphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d ]pyrimidine derivative
11a via the loss of one molecule of each of dimethylamine and ethanol.
1
The H NMR spectrum of 11a did not reveal any signals attributed
to N(CH3)2, and 2-ethoxycarbonyl protons and revealed the signals of
the new C6H4-OCH3 at δ = 3.88 and 7.31–7.37 ppm. A strong evidence
for the structure 11a came from its synthesis via another route by
heating compound 6b in glacial acetic acid under reflux5 to give the
same reaction product 11a (cf, Scheme 3 and Experimental Section).
SCHEME 3
In the same manner, compound 6a reacted with p-toluidine
(9b) and hydrazine hydrate (9c) to yield the corresponding
pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]pyrimidine derivatives 11b,c. In contrast
behavior, the reaction of 6a with 4-aminopyridine (9d) afforded 3-
aminothieno[2, 3-b]pyridine derivative 4a instead of the expected
3-pyridin-4-ylpyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]pyrimidine derivative 11d.
The formation of 4a in this reaction product proceed via (N, N-
dimethylamino)methylene group exchange.45 The condensation of
3-aminopyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]pyrimidine derivative 11c with
each of DMF-DMA and p-bromobenzaldehyde afforded the correspond-
ing condensation products 12a,b respectively (cf, Scheme 3 and Exper-
imental Section).
The work was extended to study the reactivity of 2-cyano-3-{[(N, N-
dimethylamino)methylene]amino}thieno[2, 3-b]pyridine derivative 6c
towards aromatic amines 9a,b,d. Thus, 6c reacted with p-
anisidine (9a) in glacial acetic acid under reflux to yield the

896
M. A. M. Gad-Elkareem et al.
corresponding 4-[(4-methoxyphenyl)amino]pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-
d]pyrimidine derivative 14a. The IR spectrum of 14a indicated the ab-
sence of CN group and presence of NH at 3209 cm−1, while its 1H NMR
revealed NH at δ = 7.07 ppm, which lost after a D2O-exchange. The
formation of 14a from 6c and p-anisidine (9a) is assumed to procced
through the Dimorth rearrangement45 of the initial cyclization product
13a under the reaction condition to yield 14a.
Similarly, 6c reacted with p-toluidine (9b) under the same reaction
condition to afford 4-[(4-methylphenyl)amino]pyrido[3ꢀ,2ꢀ:4,5]thieno-
[3, 2-d]pyrimidine derivative 14b.
A hard evidence for structure 14a,b came from its synthesis
through another route via the condensation of 4c with triethylortho-
formate and the subsequent condensation of the so formed 2-cyano-
3-[(ethoxymethylene)amino]thieno[2, 3-b]pyridine derivative 15 with
9a,b to afford a product identical in all respect (m.p., mixed m.p., and
spectral data) with 14a,b (cf. Scheme 4 and Experimental Section).
SCHEME 4
In contrast to its behavior towards aromatic amines 9a,b, com-
pound 6c reacted with 4-aminopyridine (9d) afforded 3-amino-2-
cyanothieno[2,3-b]pyridine derivative 4c instead of the expected 4-
(pyridin-4-ylamino)pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine derivative
14d. The formation of 4c in this reaction is assumed to proceed via
the (N, N-di-methylamino)methylene group exchange.45 The same be-
havior was observed in the reaction of compound 15 with 9d to give 4c
instead of 14d (cf. Scheme 4 and Experimental Section).
Work was also extended to study the reactivity of the aminocarbox-
amide system in compound 4b. Thus, the treatment of compound 4b
with chloroacetyl chloride in DMF solution afforded the correspond-
ing 3-[(2-chloroacetyl)amino]thieno[2, 3-b]pyridine derivative 16. The
IR (cm−1) spectrum of compound 16 showed the presence of two NH at

Pyridine-2(1H)-thione in Heterocyclic Synthesis
897
3377 and 3291 and two carbonyl at 1722 and 1647 function groups. The
1H NMR spectrum of 16 revealed signals at δ = 3.50 (s, 2H, COCH2Cl),
8.47 (s, 1H, NH), and 8.70 (s, 1H, NH). The cyclization of compound 16
via heating its solution in a mixture of acetic anhydride and acetic
acid yielded the corresponding 2-chloromethylpyrido[3ꢀ,2ꢀ:4,5]thieno-
[3, 2-d]pyrimidine derivative 17, while the acetylation of 4b using
acetyl chloride in glacial acetic acid afforded compound 10a. The
treatment of 4b with formic acid5 afforded the corresponding 3-
(4-methoxyphenyl)pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]pyrimidine derivative
11a (cf, Scheme 5 and Experimental Section).
SCHEME 5
Diazotization and self coupling of the amino amide system in com-
pound 4b afforded the corresponding pyrido[3ꢀ,2ꢀ:4,5]thieno[3, 2-d]-
[1,2,3]triazinone derivative 18. The reaction of 4b with carbon disul-
fide in pyridine afforded the pyridothienopyrimidine derivative 19. The
structure of compounds 18 and 19 was established based on the el-
emental analyses and spectral data (cf. Scheme 5 and Experimental
Section).
The work was further extended to shed more light on the reactivity of
3-aminopyrazolo[3,4-b]pyridine derivative 20 (prepared by the reaction
of 1 with hydrazine hydrate)44 towards isothiocyanate. Thus, compound
20 reacted with ethyl isothiocyanate in pyridine solution to afford the
thiourea derivative 21. The structure of 21 was infered by elemental
analysis, spectral data, and chemical transformations. The IR spectrum
of 21 showed the absence of the absorption band due to the NH2 group.

898
M. A. M. Gad-Elkareem et al.
1
The H NMR spectrum of 21 revealed 3NH protons at δ = 7.58, 9.96,
and 12.53 ppm, which lost after the D2O-exchange.
The reaction of the thiourea derivative 21 with α-halocarbonyl com-
pounds was investigated. Thus, compound 21 reacted with chloroace-
tone (22a) in an ethanol solution contaning sodium acetate under
reflux to give the corresponding 3-[(3-ethyl-4-methyl-3H-thiazol-2-
ylidene)amino]-1H-pyrazolo[3, 4-b]pyridine derivative 23a via the loss
of one molecule of each of hydrogen chloride and water. The structure
of compound 23a was elucidated by elemental analysis and spectral
data. 1H NMR spectrum of 23a revealed the signal of thiazole-C(5)H at
δ = 5.87 and only one NH at δ = 10.94 ppm (cf. Scheme 6 and Experi-
mental Section).
SCHEME 6
Similarly, compound 21 reacted with ω-bromoacetophenone 22b
and p-methyl-ω-bromoacetophenone 22c under the same reaction
conditions to give the corresponding 3-[(thiazol-2-ylidene)amino]-1H-

Pyridine-2(1H)-thione in Heterocyclic Synthesis
899
pyrazolo[3, 4-b]pyridine derivatives 23b,c respectively. The reaction
of ethyl chloroacetate with 21 gave the corresponding 3-[(3-ethyl-4-
oxothiazolidin-2-ylidene)amino1H-pyrazolo[3, 4-b]pyridine derivative
25 through the intermediate 24 via the loss of ethanol molecule.3,4
The 1H NMR spectrum of 25 indicated the presence of CH2 pro-
tons of the thiazole moiety at δ = 3.96 ppm. Also, compound 21
reacted with ethyl-2-chloro-3-oxobutanoate (26a) and 3-chloropentane-
2,4-dione (26b) to afford the corresponding 3-[(3-ethyl-3H-thiazol-2-
ylidene)amino]-1H-pyrazolo[3, 4-b]pyridine derivatives 27a,b, respec-
tively. The structures of 27a,b were confirmed based on elemen-
tal analyses and spectral data (cf. Scheme 6 and the Experimental
Section).
EXPRIMENTAL
Melting points were measured with a Gallenkamp apparatus and are
uncorrected. IR spectra in KBr discs were recorded on BRUKER Vec-
1
tor 22 FT-IR spectrophotometer. H NMR spectra were determined in
DMSO-D6 and CDCl3 at 300 MHz on Varian Mercury VX spectrometer
using TMS as an internal standared. Chemical shifts are expressed as δ
ppm units and coupling conestant J as Hz. Mass spectra were recorded
on GCMS-QP 1000 EX spectrometer at 70 eV. Elemental analyses were
carried out at the Microanalytical Center of Cairo University, Giza,
Egypt.
Compounds 1 and 20 were prepared according to the literature
procedures.44 * In the 1H NMR data means that these protons are D2O-
exchange.
The Reaction of 1 With α-Halocarbonyl Compounds 2a–c
General Procedure
A mixture of compound 1 (10 mmoles) and each of compounds 2a–c
(10 mmoles) in DMF (30 mL) containing KOH (12 mmoles) was stirred
at r.t. for 2 h then poured onto ice-cold water and acidified with dil. HCl.
The solid products obtained were filtered off, washed with water, and
crystallized from ethanol to give compounds 3a–c, respectively.
Ethyl-5-cyano-6-[(2-ethoxy-2-oxoethyl)thio]-4-
(4-methoxyphenyl)-2-methylnicotinate (3a)
Yellow crystals (68%, ethanol), m.p. 118◦C, IR υ (cm−1): 2224 (CN),
1750 (CO aliph.ester), 1723 (CO arom. ester), 1606 (C N). Anal. for
C21H22N2O5S (414), calcd.: C, 60.86; H, 5.31; N, 6.76; S, 7.72. Found, C,
60.94; H, 5.43; N, 6.68; S, 7.62%.

900
M. A. M. Gad-Elkareem et al.
Ethyl-5-cyano-6-({2-[(4-methoxyphenyl)amino]-2-oxoethyl}-
thio)-4-(4-methoxyphenyl)-2-methylnicotinate (3b)
Pale yellow crystals (64%, ethanol), m.p. 178◦C, IR υ (cm−1): 3323
1
(NH), 2221 (CN), 1724 (CO-ester), 1672 (CO-amide), 1610 (C N). H
NMR (CDCl3), δ 0.96–1.03 (t, J = 7.2 Hz, 3H, CH2 CH3); 2.68 (s, 3H,
CH3); 3.78 (s, 3H, OCH3); 3.85 (s, 3H, OCH3); 4.03 (s, 2H, SCH2CO);
4.06–4.13 (q, J = 7.2 Hz, 2H, CH2CH3); 6.834–6.878 (d, J = 8.8 Hz, 2H,
Ar-H); 6.968–7.012 (d, J = 8.8 Hz, 2H, Ar-H); 7.325–7.408 (m, 4H, Ar-
H)); 8.79 (s, 1H, NH). Anal. for C26H25N3O5S (491) calcd: C, 63.54; H,
5.09; N, 8.55; S, 6.51. Found, C, 63.41; H, 5.19; N, 8.40; S, 6.63%.
Ethyl-5-cyano-6-[(cyanomethyl)thio]-4-(4-methoxyphenyl)-2-
methylnicotinate (3c)
Yellow crystals (70%, ethanol), m.p. 138–140◦C, IR υ (cm−1): 2248
(CN), 2220 (CN), 1727 (CO) 1601 (C N). Analysis for C19H17N3O3S
(367) calcd: C, 62.12; H, 4.63; N, 11.44; S, 8.72. Found, C, 62.00; H, 4.50;
N, 11.68; S, 8.60%.
Synthesis of Compounds 4a–c
Route A: Cyclization of Compounds 3a–c
A solution of compounds 3a–c (10 mmoles) in ethanol (30 mL) con-
taining a catalytic amount of piperidine (0.5 mL) was heated under
reflux for 3 h. The solid products obtained after cooling were filtered off
and crystallized from ethanol to afford compounds 4a–c.
Route B
A mixture of compound 1 (10 mmoles) and compounds 2a–c (10
mmoles) in ethanolic sodium ethoxide (prepared from 0.02 atom sodium
metal and 40 mL ethanol) was heated under reflux for 4 h and then
cooled. The reaction mixtures were then poured onto ice-cold water and
neutralized by diluted HCl. The solid products obtained were filtered
off and crystallized from ethanol to give compounds 4a–c.
Diethyl-3-amino-4-(4-methoxyphenyl)-6-methylthieno[2,3-b]-
pyridine-2,5-dicarboxylate (4a)
Yellow crystals (68%, ethanol), m.p. 164◦C, IR υ (cm−1): 3478, 3367
(NH2), 1725 (CO-pyrid.ester), 1674 (CO-ester in thiophene with H-
1
bond), 1606 (C N). H NMR (CDCl3),: δ 0.99–1.03 (t, J = 7.2 Hz, 3H,
CH2 CH3); 1.34–1.38 (t, J = 7.0 Hz, 3H, CH2 CH3); 2.69 (s, 3H, CH3);
3.86 (s, 3H, OCH3); 4.02–4.09 (q, J = 7.2 Hz, 2H, CH2CH3); 4.24–4.35
(q, J = 7.0 Hz, 2H, CH2CH3); 5.54 (s, 2H, NH2*); 6.98–7.022 (d, 2H,

Pyridine-2(1H)-thione in Heterocyclic Synthesis
901
Ar-H, J = 8.4); 7.268–7.310 (d, 2H, Ar-H, J = 8.4). Anal. for
C21H22N2O5S (414) calcd: C, 60.86; H, 5.31; N, 6.76; S, 7.72. Found,
C, 60.98; H, 5.20; N, 6.65; S, 7.90%.
Ethyl-3-amino-2-{[(4-methoxyphenyl)amino]carbonyl}-4-
(4-methoxyphenyl)-6-methythieno[2,3-b]pyridine-
5-carboxylate (4b)
Yellow crystals (63%, ethanol), m.p. 176–177◦C, IR υ (cm−1): 3477,
3320, 3220 (NH2 and NH), 1725 (CO-ester), 1630 (CO-amide with H-
bond). Anal. for C26H25N3O5S (491) a clcd: C, 63.54; H, 5.09; N, 8.55; S,
6.51. Found, C, 63.66; H, 5.18; N, 8.43; S, 6.63%.
Ethyl-3-amino-2-cyano-4-(4-methoxyphenyl)-6-
methylthieno[2,3-b]pyridine-5-carboxylate (4c)
Yellow crystals (68%, ethanol), m.p. 198–200◦C, IR υ (cm−1): 3475,
3343 (NH2), 2198 (CN), 1728 (CO), 1628 (C N).1H NMR (CDCl3): δ
0.97–1.04 (t, J = 7.4 Hz, 3H, CH2 CH3); 2.67 (s, 3H, CH3); 3.88 (s, 3H,
OCH3); 4.00–4.11 (q, J = 7.4 Hz, 2H, CH2CH3); 4.37 (s, 2H, NH2*);
6.993–7.035 (d, J = 8.4 Hz, 2H, Ar-H); 7.259–7.301 (d, J = 8.4 Hz, 2H,
Ar-H). Anal. for C19H17N3O3S (367) calcd: C, 62.12; H, 4.63; N, 11.44;
S, 8.72. Found, C, 62.25; H, 4.78; N, 11.31; S, 8.87%.
The Reaction of 4a–c with DMF-DMA
A mixture of compounds 4a–c (10 mmoles) and DMF-DMA (13
mmoles) in dry xylene (30 mL) was heated under reflux for 6 h. The
reaction mixture was cooled and triturated with petroleum ether (40-
60). The solid product obtained was filtered off and crystallized from
ethanol to give compounds 6a–c, respectively.
Diethyl-3-{[(N,N-dimethylamino)methylene] amino}-4-
(4-methoxyphenyl)-6-methylthieno[2,3-b]pyridine-2,5-
dicarboxylate (6a)
Yellow crystals (48%), m.p. 130◦C, IR υ (cm−1): 1724 (CO), 1703 (CO),
1632 (C N). 1H NMR (CDCl3): δ 0.95–1.00 (t, J = 7.2 Hz, 6H, two CH2
CH3); 2.65 (s, 3H, CH3), 2.80 (s, 6H, N(CH3)2), 3.81 (s, 3H, OCH3), 3.98–
4.05 (q, J = 7.2 Hz, 4H, two CH2CH3), 6.82–7.10 (m, 4H, Ar-H), 7.13 (s,
1H, N CH). Anal. for C24H27N3O5S (469), calcd.: C, 61.40; H, 5.75; N,
8.95; S, 6.82. Found, C, 61.56; H, 5.61; N, 8.80; S, 6.55%.

902
M. A. M. Gad-Elkareem et al.
Ethyl-3-{[(N,N-dimethylamino)methylene]amino}-2-
{[(4-methoxyphenyl)amino]carbonyl}-4-(4-methoxyphenyl)-6-
methylthieno[2,3-b] pyridine-5-carboxylate (6b)
Yellow crystals (53%,), m.p. 228–229◦C, IR υ (cm−1): 3221 (NH), 1718
(CO-ester), 1657 (CO-amide), 1626 (C N). 1H NMR (DMSO-d6): δ 0.92–
0.97 (t, J = 7.2 Hz, 3H, CH2 CH3); 2.57 (s, 3H, CH3); 2.7 (s, 6H, N(CH3)2);
3.72 (s, 3H, OCH3); 3.83 (s, 3H, OCH3); 4.02–4.05 (q, J = 7.2 Hz, 2H,
CH2CH3); 6.889–6.919 (d, J = 9 Hz, 2H, Ar-H); 6.973 (s, 1H, N CH);
7.002–7.031 (d, J = 8.7 Hz, 2H, Ar-H); 7.146–7.175 (d, J = 8.7 Hz, 2H,
Ar-H); 7.457–7.487 (d, J = 9 Hz, 2H, Ar-H); 10.91 (s, 1H, NH). Anal. for
C29H30N4O5S (546) calcd.: C, 63.73; H, 5.49; N, 10.25; S, 5.86. Found,
C, 63.58; H, 5.32; N, 10.11; S, 5.98%.
Ethyl-2-cyano-3-{[(N,N-dimethylamino)methylene]amino}-4-
(4-methoxyphenyl)-6-methylthieno[2,3-b]pyridine-5-
carboxylate (6c)
Yellow crystals (53%), m.p. 136–138◦C, IR υ (cm−1): 2198 (CN), 1723
(CO), 1627 (C N). Anal. for C22H22N4O3S (422) calcd.: C, 62.56; H, 5.21;
N, 13.27; S, 7.58. Found, C, 62.68; H, 5.10; N, 13.40; S, 7.43%.
3-Amino-5-ethoxycarbonyl-4-(4-methoxyphenyl)-6-
methylthieno[2,3-b]pyridine-2-carboxylic acid (7)
A solution of compound 4a (10 mmoles) in ethanol (30 mL) containing
10% KOH was heated under reflux for 3 h. The reaction mixture was
cooled, poured onto ice-cold water, and neutralized with dilute HCl. The
solid product obtained was filtered off and crystallized from ethanol to
give compound 7 as yellow crysals (61%), m.p. 176◦C, IR υ (cm−1): 3441–
3338 (NH2 and OH), 1728 (CO-ester), 1662 (CO-acid with H-bond), 1606
(C N). 1H NMR (DMSO-d6): δ 1.04–1.11 (t, J = 7.2 Hz, 3H, CH2 CH3);
2.60 (s, 3H, CH3); 3.84 (s, 3H, OCH3); 3.96–4.05 (q, J = 7.2 Hz, 2H,
CH2CH3); 5.65 (hump, 2H, NH2*); 7.094–7.138 (d, J = 8.8 Hz, 2H, Ar-
H); 7.319–7.363(d, J = 8.8 Hz, 2H, Ar-H); 12.75 (hump, 1H, OH*). Anal.
for C19H18N2O5S (386) calcd.: C, 59.06; H, 4.66; N, 7.25; S, 8.29. Found,
C, 59.16; H, 4.54; N, 7.36; S, 8.18%.
Ethyl-9-(4-methoxyphenyl)-2,7-dimethyl-4-oxo-4H-
pyrido[3 ꢀ,2 ꢀ:4,5] thieno[3,2-d][1,3]oxazine-8-carboxylate (8)
A solution of compound 7 (10 mmoles) in acetic anhydride (30 mL)
was heated under reflux for 4 h and then cooled. The solid product
obtained was filtered off and crystallized from ethanol to afford com-
pound 8 as yellow crystals (48%), m.p. 317–318◦C, IR υ (cm−1): 1754
(CO oxazinone), 1721 (CO-ester), 1610 (C N). 1H NMR (DMSO-d6):
δ 0.96–0.99 (s, J = 7.2 Hz, 3H, CH2CH3); 2.61 (s, 3H, CH3-C(7)); 3.59

Pyridine-2(1H)-thione in Heterocyclic Synthesis
903
(s, 3H, CH3-C(2)); 3.96–4.01 (q, J = 7.2 Hz, 2H, CH2CH3); 6.986–7.014
(d, J = 8.4 Hz, 2H, Ar-H); 7.293–7.321 (d, J = 8.4 Hz, 2H, Ar-H). Anal.
for C21H18N2O5S (410) calcd.: C,61.46; H, 4.39; N, 6.82; S, 7.80. Found,
C, 61.32; H, 4.28; N, 6.93; S, 7.69%.
Reaction of 8, 6a, and 6c With Aromatic Amines 9a,b,d
A solution of each of 8, 6a, and 6c (10 mmoles) in glacial acetic acid
(40 mL) was treated with 9a,b,d (12 mmoles). The reaction mixture
was heated under reflux for 3 h and then cooled. The solid product
obtained was filtered off and crystallized from the proper solvent to
give compounds 10a,b,d, 11a,b, 4a, 14a,b, and 4c, respectively.
Ethyl-3,9-bis(4-methoxyphenyl)-2,7-dimethyl-4-oxo-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (10a)
Yellow crystals from toluene/pet. ether (65%), m.p. 156–158◦C, IR υ
(cm−1): 1721 (CO-ester), 1679 (CO C(4)), 1607 (C N), 1H NMR (CDCl3):
δ 1.00–1.07 (t, J = 7.2 Hz, 3H, CH2CH3); 2.2 (s, 3H, CH3-C(2)); 2.73 (s, 3H,
CH3-C(7)); 3.85 (s, 3H, OCH3); 3.91 (s, 3H, OCH3); 4.06–4.16 (q, J = 7.2
Hz, 2H, CH2CH3); 6.93–7.13 (m, 6H, Ar-H); 7.332–7.376 (d, J = 8.8 Hz,
2H, Ar-H). Anal. for C28H25N3O5S (515) calcd.: C, 65.24; H, 4.85; N,
8.15; S, 6.21. Found, C, 65.36; H, 4.71; N, 8.00; S, 6.36%.
Ethyl-9-(4-methoxyphenyl)-2,7-dimethyl-3-(4-methylphenyl)-
4-oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (10b)
Yellow crystals from toluene/pet. ether (58%), m.p. 188–190◦C, IR
υ (cm−1): 1717 (CO-ester), 1660 (CO C(4)), 1605 (C N), Anal. for
28H25N3O4S (499), calcd.: C, 67.33; H, 5.01; N, 8.41; S, 6.41. Found,
C, 67.53; H, 5.20; N, 8.23; S, 6.25%.
Ethyl-9-(4-methoxyphenyl)-2,7-dimethyl-4-oxo-3-(4-pyridinyl)-
3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (10d)
Pale yellow crystals from toluene/pet. ether (55%) m.p. 260–262◦C,
IR υ (cm−1): 1731 (CO-ester), 1657 (CO C(4)), 1610 (C N). Anal. for
C26H22N4O4S (486), calcd.: C, 64.19; H, 4.52; N, 11.52; S, 6.58. Found,
C, 64.31; H, 4.36; N, 11.38; S, 6.72%.
Ethyl-3,9-bis(4-methoxyphenyl)-7-methyl-4-oxo-3,4-
dihydropyrido [3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (11a)
Pale yellow crystals from dioxane (52%), m.p. 207–208◦C. IR υ (cm−1):
1726 (CO-ester), 1682 (C(4) O), 1609 (C N). 1H NMR (CDCl3) δ 1.04–

904
M. A. M. Gad-Elkareem et al.
1.08 (t, J = 7.2 Hz, 3H, CH2CH3); 2.76 (s, 3H, CH3); 3.85 (s, 3H, OCH3);
3.88 (s, 3H, OCH3); 4.06–4.17 (q, J = 7.2 Hz, 2H, CH2CH3); 6.96–7.03
(m, 4H, Ar-H); 7.31–4.37 (m, 4H, Ar-H); 7.96 (s, 1H, C(2)-H). Anal. for
C27H23N3O5S (501), calcd.: C, 64.67; H, 4.59; N, 8.38; S, 6.38. Found, C,
64.78; H, 4.71; N, 8.24; S, 6.22%.
Ethyl-9-(4-methoxyphenyl)-7-methyl-3-(4-methylphenyl)-4-
oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (11b)
Yellow crystals from ethanol (59%), m.p. 252–54◦C. IR υ (cm−1): 1724
(CO-ester), 1681 (C(4) O), 1607 (C N). Anal. for C27H23N3O4S (485),
calcd.: C, 66.80; H, 4.74; N, 8.66; S, 6.60. Found, C, 66.68; H, 4.61; N,
8.82; S, 6.76%.
Ethyl-9-(4-methoxyphenyl)-4-[(4-methoxyphenyl)amino]-7-
methylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (14a)
Pale yellow crystals from ethanol (66%), m.p. 250–52◦C, IR υ (cm−1):
1
3209 (NH); 1719 (CO), 1602 (C N). H NMR (CDCl3): δ 0.99–1.06 (t,
J = 7.0 Hz, 3H, CH2CH3); 2.72 (s, 3H, CH3); 3.86 (s, 3H, OCH3); 3.89 (s,
3H, OCH3); 4.07-4.11 (q, J = 7.0 Hz, 2H, CH2CH3); 6.92–7.00 (m, 4H,
Ar-H), 7.07 (s, 1H, NH*); 7.331–7.374 (d, J = 8.4 Hz, 2H, Ar-H) 7.391–
7.435 (d, J = 8.8 Hz, 2H, Ar-H); 8.46 (s, 1H, C(2)-H). MS, M+, 500 (100%).
Anal. for C27H24N4O4S (500), calcd.: C, 64.80; H, 4.80; N, 11.20; S, 6.40.
Found, C, 64.68; H, 4.61; N, 11.35; S, 6.66%.
Ethyl-9-(4-methoxyphenyl)-4-[(4-methylphenyl)amino]-
7-methylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (14b)
Yellow crystals from ethanol (68%), m.p. 268–70◦C, IR υ (cm−1):
1
3230 (NH); 1718 (CO), 1605 (C N). H NMR (CDCl3): δ 1.00–1.07 (t,
J = 7.2 Hz, 3H, CH2CH3); 2.38 (s, 3H, CH3); 2.73 (s, 3H, CH3); 3.89 (s,
3H, OCH3); 4.08–4.11 (q, J = 7.2 Hz, 2H, CH2CH3); 6.92 (s, 1H, NH*);
6.921–7.012 (d, J = 8.2 Hz, 2H, Ar-H); 7.194–7.236 (d, J = 8.4 Hz, 2H,
Ar-H); 7.340–7.381 (d, J = 8.2 Hz, 2H, Ar-H); 7.401–7.443 (d, J = 8.4 Hz,
2H, Ar-H); 8.50 (s, 1H, C(2)-H). Anal. for C27H24N4O3S (484), calcd.: C,
66.94; H, 4.96; N, 11.57; S, 6.61. Found, C, 66.80; H, 4.75; N, 11.46; S,
6.78%.
Reaction of 8 and 6a With Hydrazine Hydrate
A solution of each of 8 and 6a (10 mmoles) in hydrazine hydrate (40
mL) was heated under reflux for 3 h. The solid products obtained after

Pyridine-2(1H)-thione in Heterocyclic Synthesis
905
cooling were filtered off and crystallized from dioxane to give 10c and
11c, respectively.
Ethyl-3-amino-9-(4-methoxyphenyl)-2,7-dimethyl-4-oxo-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (10c)
Yellow crystals (58%), m.p. 316–317◦C, IR υ (cm−1): 3365, 3267
(NH2), 1716 (CO-ester), 1664 (C(4) O), 1611 (C N). Anal. for
C21H20N4O4S (424), calcd.: C, 59.43; H, 4.71; N, 13.20; S, 7.54. Found,
C, 59.30; H, 4.85; N, 13.38; S, 7.41%.
Ethyl-3-amino-9-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (11c)
Yellow crystals (62%), m.p. 218◦C, IR υ (cm−1): 3298, 3204 (NH2),
1718 (CO-ester), 1669 (C(4) O), 1607 C N). 1H NMR (DMSO-d6): δ
0.92–0.96 (t, J = 7.2 Hz, 3H, CH2CH3); 2.61 (s, 3H, CH3), 3.41 (br,
2H, NH2*); 3.80 (s, 3H, OCH3); 4.02–4.04 (q, J = 7.2 Hz, 2H, CH2CH3);
6.961–6.989 (d, J = 8.4 Hz, 2H, Ar-H); 7.242–7.270 (d, J = 8.4 Hz, 2H,
Ar-H); 8.25 (s, 1H, C(2)-H). MS, M+, 410 (100%), M+1, 411 (26.7%). Anal.
for C20H18N4O4S (410), calcd.: C, 58.53; H, 4.39; N, 13.65; S, 7.80. Found,
C, 58.70; H, 4.50; N, 13.48; S, 7.96%.
Ethyl-3-{[(N,N-dimethylamino)methylene]amino}-9-
(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydropyrido-
[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine-8-caroxylate (12a)
This compound was synthesized from compound 11c (10 m moles)
and DMF-DMA (10 m moles) in a manner similar to that described for
the preparation of compound 6. It was crystallized from dioxane to give
yellow crystals, (58%), m.p. 179–180◦C, IR υ (cm−1): 1724 (CO-ester),
1
1670 (C(4) O), 1620 (C N). H NMR (CDCl3): δ 0.99–1.05 (t, J = 7.0
Hz, 3H, CH2CH3); 2.73 (s, 3H, CH3), 3.03 (s, 6H, N(CH3)2); 3.88 (s, 3H,
OCH3); 4.04-4.14 (q, J = 7.0 Hz, 2H, CH2CH3); 6.939–6.980 (d, J = 8.2
Hz, 2H, Ar-H); 7.26 (s, 1H, N CH); 7.308–7.35 (d, J = 8.2 Hz, 2H, Ar-
H); 8.0 (s, 1H, C(2)-H). Anal. for C23H23N5O4S (465), calcd.: C, 59.35; H,
4.94; N, 15.05; S, 6.88. Found, C, 59.50; H, 4.81; N, 15.21; S, 6.72%.
Ethyl-3-{[(4-bromophenyl)methylene]amino}-9-(4-methoxy-
phenyl)-7-methyl-4-oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno-
[3,2-d]pyrimidine-8-carboxylate (12b)
A suspension of 11c (10 mmoles) and 4-bromobenzaldehyde (10
mmoles) in ethanol (50 mL) was heated under reflux for 3 h in the pres-
ence of piperidine (0.5 mL) as a catalyst. The solid product obtained

906
M. A. M. Gad-Elkareem et al.
during reflux was collected after cooling by filtration and crystallized
from dioxane to give compound 12b as yellow crystals (62%), m.p. 263–
264◦C, IR υ (cm−1): 1716 (CO-ester), 1681 (C(4) O), 1608 (C N). Anal.
for C27H21N4O4SBr (577), calcd.: C, 56.15; H, 3.64; N, 9.70; S, 5.54; Br,
13.86. Found, C, 56.26; H, 3.51; N, 9.87; S, 5.40; Br, 13.71%.
Ethyl-2-cyano-3-[(ethoxymethylene)amino]-4-(4-
methoxyphenyl)-6-methylthieno[2,3-b]pyridine-5-
carnoxylate (15)
A solution of 4c (10 mmoles) in acetic anhydride (30 mL) was
treated with triethylorthoformate (25 mmoles). The reaction mixture
was heated under reflux for 3 h and then cooled. The solid product ob-
tained was filtered off and crystallized from ethanol to give 15 as yellow
crystals (72%), m.p. 160–62◦C, IR υ (cm−1): 2212 (CN); 1730 (CO), 1630
(C N). Anal. for C22H21N3O4S (423), calcd.: C, 62.41; H, 4.96; N, 9.93;
S, 7.56. Found, C, 62.30; H, 4.83; N, 9.78; S, 7.68%.
Ethyl-3-[(2-chloroacetyl)amino]-4-(4-methoxyphenyl)-2-{[(4-
methoxyphenyl)amino]carbonyl}-6-methylthieno[2,3-b]-
pyridine-5-carboxylate (16)
A mixture of compound 4b (10 m moles) and chlorocetylchloride (12
m moles) in dimethylformamide (30 mL) was stirred at r.t. for 3 h. The
reaction mixture was then poured onto ice-cold water. The solid product
thus formed was filtered off and crystallized from ethanol to yield com-
pound 16 as yellow crystals (61%), m.p. 215–216◦C. IR υ (cm−1): 3377,
3291 (2NH), 1722 (CO-ester), 1647 (CO-amides), 1611 (C N). 1H NMR
(CDCl3): δ 0.97–1.05 (t, J = 7.2 Hz, 3H, CH2CH3); 2.68 (s, 3H, CH3); 3.50
(s, 2H, COCH2Cl); 3.78 (s, 3H, OCH3); 3.87 (s, 3H, OCH3); 4.00–4.11 (q,
J = 7.2 Hz, 2H, CH2CH3); 6.77–7.03 (m, 4H, Ar-H), 7.28–7.42 (m, 4H,
Ar-H), 8.47 (s, 1H, NH), 8.70 (s, 1H, NH). Anal. for C28H26N3O6SCl
(567.5), calcd.: C, 59.20; H 4.58; N 7.40; S, 5.63; Cl, 6.25. Found, C,
59.31; H, 4.70; N, 7.25; S, 5.50; Cl, 6.10%.
Ethyl-2-chloromethyl-3,9-bis(4-methoxyphenyl)-7-methyl-4-
oxo-3,4-dihydropyrido[3ꢀ,2ꢀ:4,5]thieno-
[3,2-d]pyrimidine-8-carboxylate (17)
A solution of 16 (10 mmoles) in glacial acetic acid (30 mL) containing 5
mL of acetic anhydride was heated under reflux for 4 h and then cooled.
The solid product obtained was filtered off and crystallized from ethanol
to give 17 as yellow crystals (70%), m.p. 194–96◦C. IR υ (cm−1): 1713
1
(CO-ester), 1677 (C(4) O), 1606 (C N). H NMR (CDCl3): δ 1.00–1.07
(t, J = 7.2 Hz, 3H, CH2CH3); 2.75 (s, 3H, CH3-C(7)); 3.86 (s, 3H, OCH3);
3.87 (s, 3H, OCH3); 3.97 (s, 2H, C(2)-CH2Cl); 4.06–4.17 (q, J = 7.2 Hz, 2H,

Pyridine-2(1H)-thione in Heterocyclic Synthesis
907
CH2CH3); 6.941–6.985 (d, J = 8.8 Hz, 2H, Ar-H); 7.002–7.046 (d, J = 8.8
Hz, 2H, Ar-H); 7.186–7.230 (d, J = 8.8 Hz, 2H, Ar-H); 7.329–7.373 (d,
J = 8.8 Hz, 2H, Ar-H). Anal. for C28H24N3O5SCl (549.5), calcd.: C, 61.14;
H, 4.36; N, 7.64; S, 5.82; Cl, 6.46. Found, C, 61.00; H, 4.23; N, 7.76; S,
5.70; Cl, 6.59%.
Ethyl-3,9-bis(4-methoxyphenyl)-7-methyl-4-oxo-3,4-
dihydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d][1,2,3]triazine-8-
carboxylate (18)
A solution of 4b (10 m moles) in acetic acid (30 mL) containing conc.
HCl (1.0 mL) was treated with a cold saturated solution of sodium ni-
trite (15 m moles). The reaction mixture was stirred in ice bath for 1 h.
The solid product thus formed was filtered off, washed with water, and
crystallized from ethanol to afford 18 as yellow crystals (58%), m.p.
194◦C. IR υ (cm−1): 1724 (CO-ester), 1961 (C(4) O), 1608 (C N). Anal.
for C26H22N4O5S (502), calcd.: C, 62.15; H, 4.38; N, 11.15; S, 6.37. Found
C, 62.30; H, 4.24; N, 11.31; S, 6.20%.
Ethyl-3,9-bis(4-methoxyphenyl)-7-methyl-4-oxo-2-thioxo-
1,2,3,4-tetrahydropyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]
pyrimidine-8-carboxylate (19)
A mixture of compound 4b (10 mmoles) and carbon disulfide (5 mL)
in pyridine (30 mL) was heated under reflux for 8 h and then cooled.
The reaction mixture was poured onto ice-cold water and acidified with
diluted HCl. The solid product obtained was filtered off and crystallized
from ethanol to give compound 19 as yellow crystals (48%), m.p. 198◦C.
IR υ (cm−1): 3224 (NH), 1724 (CO-ester), 1673 (C(4) O), 1611 (C N).
Anal. for C27H23N3O5S2 (533), calc.: C, 60.78; H, 4.31; N, 7.88; S, 12.00.
Found, C, 60.92; H, 4.48; N, 7.73; S, 12.11%.
Ethyl-3-{[(ethylamino)carbonothioyl]amino}-4-(4-
methoxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (21)
A mixture of 20 (10 mmoles) and ethylisothiocyanate (15 mmoles) in
pyridine (30 mL) was heated under reflux for 6 h and then cooled. The re-
action mixture was poured onto ice-cold water and acidified with diluted
HCl. The solid product was filtered off, washed with water, and crystal-
lized from ethanol to afford compound 21 as yellow crystals (69%), m.p.
216–18◦C. IR υ (cm−1): 3404, 3252, 3206 (3NH); 1726 (CO), 1605 (C N).
1H NMR (CDCl3): δ 0.91–1.04 (t, J = 7.0 Hz, 3H, CH2 CH3); 1.22–1.34 (t,
J = 7.4 Hz, 3H, CH2CH3); 2.78 (s, 3H, CH3); 3.64–3.74 (q, J = 7.0 Hz, 2H,
CH2CH3); 3.90 (s, 3H, OCH3); 3.99–4.15 (q, J = 7.4 Hz, 2H, CH2CH3);
7.105–7.148 (d, J = 8.6 Hz, 2H, Ar-H); 7.345–7.388 (d, J = 8.6 Hz, 2H,

908
M. A. M. Gad-Elkareem et al.
Ar-H); 7.58 (s, 1H, NH*); 9.96 (s, 1H, NH*); 12.53 (hump, 1H, NH*).
Anal. for C20H23N5O3S (413), calc.: C, 58.11; H, 5.57; N, 16.95; S, 7.75.
Found, C, 58.28. H, 5.41; N, 16.80; S, 7.87%.
The Reaction of 21 With α-Halocarbonyl Compounds
General Procedure
A mixture of 21 (10 mmoles) and each of 22a–c, ethyl chloroacetate,
and 26a,b (10 mmoles) in ethanol (30 mL) containing 1.0 g of sodium
acetate was heated under reflux for 4 h and then cooled. The reaction
mixture was poured onto cold water. The solid product thus formed was
filtered off, washed with water, and crystallized from the proper solvent
to give 23a–c, 25, and 27a,b, respectively.
Ethyl-3-[(3-ethyl-4-methyl-3H-thiazol-2-ylidene)amino]-4-(4-
methoxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (23a)
Yellow crystals from ethanol (66%), m.p. 256–58◦C. IR υ (cm−1):
1
3188 (NH); 1713 (CO), 1604 (C N). H NMR (CDCl3): δ 0.91–0.97 (t,
J = 7.0 Hz, 3H, CH2CH3); 1.04–1.32 (t, J = 7.2 Hz, 3H, CH2CH3); 2.18
(s, 3H, CH3-C(4)-thiazol.); 2.75 (s, 3H, CH3-C(6)); 3.92–3.96 (q, J = 7.0
Hz, 2H, CH2CH3); 3.86 (s, 3H, OCH3); 4.07–4.09 (q, J = 7.2 Hz, 2H,
CH2CH3); 5.87 (s, 1H, C(5)-H-thiazol.); 6.924–6.966 (d, J = 8.2 Hz, 2H,
Ar-H); 7.413–7.455 (d, J = 8.2 Hz, 2H, Ar-H); 10.94 (hump, 1H, NH*).
Anal. for C23H25N5O3S (451), calc: C, 61.19; H, 5.54; N, 15.52; S, 7.09.
Found, C, 61.32; H, 5.68; N, 15.40; S, 7.25%.
Ethyl-3-[(3-ethyl-4-phenyl-3H-thiazol-2-ylidene)amino]-4-(4-
methoxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (23b)
Yellow crystals from ethanol (63%), m.p. 232–423◦C. IR υ (cm−1):
3192 (NH); 1720 (CO), 1607 (C N). Anal. for C28H27N5O3S (513), calc.:
C, 65.49; H, 5.26; N, 13.64; S, 6.23. Found, C, 65.32; H, 5.39; N, 13.40;
S, 6.45%.
Ethyl-3-{[3-ethyl-4-(4-methylphenyl)-3H-thiazol-2-ylidene]
amino}-4-(4-methoxphenyl)-6-methyl-1H-pyrazolo[3,4-b]
pyridine-5-carboxylate (23c)
Yellow crystals from ethanol (60%), m.p. 266–268◦C. IR υ (cm−1):
1
3193 (NH); 1718 (CO), 1608 (C N). H NMR (CDCl3): δ 0.76–0.82 (t,
J = 7.0 Hz, 3H, CH2CH3); 0.97–1.04 (t, J = 7.2 Hz, 3H, CH2CH3); 2.4
(s, 3H, CH3,p-tolyl); 2.76 (s, 3H, CH3-C(6)); 3.56–3.61 (q, J = 7.0 Hz, 2H,

Pyridine-2(1H)-thione in Heterocyclic Synthesis
909
CH2CH3); 3.81 (s, 3H, OCH3); 4.06–4.10 (q, J = 7.2 Hz, 2H, CH2CH3);
6.07 (s, 1H, C(5)-H-thiazol.); 6.897–6.939 (d, J = 8.4 Hz, 2H, Ar-H); 7.17–
7.27 (m, 4H, Ar-H); 7.427–7.470(d, J = 8.6 Hz, 2H, Ar-H); 11.05 (s, 1H,
NH*). Anal. for C29H29N5O3S (527), calc.: C, 66.03; H, 5.50; N, 13.28; S,
6.07. Found, C, 66.22; H, 5.68; N, 13.40; S, 6.25%.
Ethyl-3-[(3-ethyl-4-oxothiazolidin-2-ylidene)amino]-4-(4-
methoxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-
carboxylate (25)
Yellow crystals from ethanol (68%), m.p. 246–248◦C. IR υ (cm−1):
1
3206 (NH); 1720 (CO), 1605 (C N). H NMR (DMSO-d6): δ 0.69–0.73
(t, J = 6.8 Hz, 3H, CH2CH3); 0.89–0.97 (t, J = 7.0 Hz, 3H, CH2CH3);
2.58 (s, 3H, CH3); 3.37–3.357 (q, J = 6.8 Hz, 2H, CH2CH3); 3.80 (s, 3H,
OCH3); 3.96 (s, 2H, CH2); 3.98–4.05 (q, J = 7.0 Hz, 2H, CH2CH3); 6.97–
7.01 (d, J = 8.0 Hz, 2H, Ar-H); 7.27–7.31 (d, J = 8.0 Hz, 2H, Ar-H); 13.49
(s, 1H. NH*). Anal. for C22H23N5O4S (453), calc.: C, 58.27; H, 5.07; N,
15.45; S, 7.06. Found, C, 58.12; H, 5.20; N, 15.30; S, 7.20%.
Ethyl-3-[(4-ethoxycarbonyl-3-ethyl-5-methyl-3H-thiazol-2-
ylidene) amino]-4-(4-methoxyphenyl)-6-methyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (27a)
Yellow crystals from ethanol (65%), m.p. 280–282◦C. IR υ (cm−1):
3197 (NH); 1729 (CO), 1697 (CO), 1607 (C N). 1H NMR (CDCl3): δ 0.88–
0.96 (t, J = 7.0 Hz, 3H, CH2CH3); 0.99–1.03 (t, J = 7.2 Hz, 3H, CH2CH3);
1.28–1.35 (t, J = 7.4 Hz, 3H, CH2CH3); 2.57 (s, 3H, CH3-C(5)thiazole);
2.76 (s, 3H, CH3-C(6)); 3.69–3.73 (q, J = 7.0 Hz, 2H, CH2CH3); 3.86 (s,
3H, OCH3); 4.05–4.09 (q, J = 7.2 Hz, 2H, CH2CH3); 4.24–4.28 (q, J = 7.4
Hz, 2H, CH2CH3); 6.923–6.961 (d, J = 7.6 Hz, 2H, Ar-H); 7.396–7.434
(d, J = 7.6 Hz, 2H, Ar-H); 11.13 (hump, 1H. NH). Anal. for C26H29N5O5S
(523), calc.: C, 59.65; H, 5.54; N, 13.38; S, 6.12. Found, C, 59.48; H, 5.49;
N, 13.51; S, 6.23%.
Ethyl-3-[(4-acetyl-3-ethyl-5-methyl-3H-thiazol-2-
ylidene)amino]-4-(4-methoxyphenyl)-6-methyl-1H-pyrazolo-
[3,4-b]pyridine-5-carboxylate (27b)
Yellowish brown crystals from ethanol (64%), m.p. 248–50◦C. IR υ
(cm−1): 3191 (NH); 1713 (CO-ester), 1655 (CO-acetyl), 1605 (C N).
Anal. for C25H27N5O4S (493), calc.: C, 60.85; H, 5.47; N, 14.19; S, 6.49.
Found, C, 60.98; H, 5.34; N, 14.31; S, 6.33%.

910
M. A. M. Gad-Elkareem et al.
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