Pyridine-2(1H)-thiones: Versatile Precursors for Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their Fused Azines

Article abstract of DOI:10.1002/jhet.3444

Pyridine-2(1H)-thiones were prepared and reacted with several active halogenated reagents to afford novel thieno[2,3-b]pyridines in excellent yields. Thieno[2,3-b]pyridine-2-carbohydrazide derivative was prepared by the reaction of either ethyl 2-((3-cyanopyridin-2-yl)thio)acetate derivative or thieno[2,3-b]pyridine-2-carboxylate derivative with hydrazine hydrate. On the other hand, the reaction of either pyridine-2(1H)-thione or ethyl 2-((pyridin-2-yl)thio)acetate derivative with hydrazine hydrate afforded the corresponding 1H-pyrazolo[3,4-b]pyridine derivative. Thieno[2,3-b]pyridine derivatives reacted with several reagents to afford the corresponding pyrimidine-4(3H)-ones and [1,2,3]triazin-4-(3H)-one. Moreover, 2-carbohydrazide derivative reacted with β-dicarbonyl reagents to give 2-((3-methyl-1H-pyrazol-1-yl)carbonyl)thienopyridines. The structure of the target molecules is elucidated using elemental analyses and spectral data.

Full text of DOI:10.1002/jhet.3444

Month 2018
Pyridine-2(1H)-thiones: Versatile Precursors for Novel Pyrazolo[3,4-b]
pyridine, Thieno[2,3-b]pyridines, and Their Fused Azines
*
Sherif M. H. Sanad,
Azza M. Abdel-Fattah, Fawzy A. Attaby, and Mohamed A. A. Elneairy
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*E-mail: sherif_hamed1980@yahoo.com
Received August 18, 2018
DOI 10.1002/jhet.3444
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Pyridine-2(1H)-thiones were prepared and reacted with several active halogenated reagents to afford
novel thieno[2,3-b]pyridines in excellent yields. Thieno[2,3-b]pyridine-2-carbohydrazide derivative was
prepared by the reaction of either ethyl 2-((3-cyanopyridin-2-yl)thio)acetate derivative or thieno[2,3-b]pyri-
dine-2-carboxylate derivative with hydrazine hydrate. On the other hand, the reaction of either
pyridine-2(1H)-thione or ethyl 2-((pyridin-2-yl)thio)acetate derivative with hydrazine hydrate afforded the
corresponding 1H-pyrazolo[3,4-b]pyridine derivative. Thieno[2,3-b]pyridine derivatives reacted with
several reagents to afford the corresponding pyrimidine-4(3H)-ones and [1,2,3]triazin-4-(3H)-one.
Moreover, 2-carbohydrazide derivative reacted with β-dicarbonyl reagents to give 2-((3-methyl-1H-
pyrazol-1-yl)carbonyl)thienopyridines. The structure of the target molecules is elucidated using elemental
analyses and spectral data.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antifungal [30], antiprotozals [29], anticancer [31,32], and
antimicrobial agents [33].
It had been reported that dihydropyridines
show important biological activity including anticancer
agents [1–5], antihypertensive and antiarrhythmic [6–9].
Pyridine-2(1H)-thiones exhibit several bioactivities
including antifungal and antibacterial [10]. Also, 2-S-
alkylpyridines exhibit a wide range of bioactivities
as antiradical [11], cardiovascular [12,13], and antioxidant
[14].
In connection with the fascinating biological activities of
the earlier compounds and in continuation of the effort
regarding the synthesis and reactions of pyridines and
their fused heterocyclic derivatives [34–43], this study
was pointed to design facile methods for the preparation
of novel hybrid molecules of pyrimidin-4(3H)-one or
[1,2,3]triazin-4-(3H)-one on the skeleton of thieno[2,3-b]
pyridine of potent bioactivity.
Moreover, thieno[2,3-b]pyridine derivatives have been
included in many medicinal preparations including
anticancer [15–17], antiviral [18], anti-inflammatory [19],
antimicrobial [20], and antihypertensive [21]. Furthermore,
pyrimidines act as antipyretic [22,23], antiallergic [24,25],
antianaphylactic [26,27], antimicrobial [28], and
antiprotozoals agents [29] while [1,2,3]triazines act as
RESULTS AND DISCUSSION
Two synthetic routes were designed to prepare the novel
4-(3,5-dibromo-4-methoxyphenyl)-6-phenyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (6a). Therefore, 3,5-
© 2018 Wiley Periodicals, Inc.

S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
dibromo-4-methoxybenzaldehyde (1a) reacted with
acetophenone (2) in ethanolic potassium hydroxide
solution to afford the corresponding 3-(3,5-dibromo-4-
methoxyphenyl)-1-phenylprop-2-en-1-one (3). Then,
compound 3 reacted with 2-cyanoethanethioamide (4) in
dioxane containing triethylamine at reflux to give 6a in a
good yield (Scheme 1 and Experimental section). The
1H-NMR spectrum of 6a revealed a singlet signal due to
pyridine NH at δ = 14.23 ppm. Moreover, compound 6a
could also be prepared by the reaction of 1a with 4, in
ethanol containing triethylamine under stirring at room
temperature, to give the corresponding 2-cyano-3-(3,5-
thio)acetate (8a) in 89% yield. The 1H-NMR spectrum of
8a revealed a singlet signal due to SCH2 group at
δ = 4.26 ppm. The 2-S-alkyl derivative 8a underwent
intramolecular cyclization via its boiling in ethanolic
sodium ethoxide solution to give 10a in 91% yield. The
1H-NMR spectrum of 10a revealed a singlet signal due
to NH2 group at δ = 6.01 ppm. In a similar manner,
pyridine-2(1H)-thione derivative 6a reacted with each of
chlorocetone (7b), chloroacetonitrile (7c), 2-bromo-1-
phenylethan-1-one (7d), 2-bromo-1-(4-chlorophenyl)
ethan-1-one (7e), and chloroacetamide (7f) in methanolic
solution containing sodium methoxide to afford the
corresponding 2-S-alkylpyridine derivatives 8b–8f,
respectively. Boiling of compounds 8b–8f in ethanolic
solution containing sodium ethoxide gave the
corresponding thieno[2,3-b]pyridine derivatives 10b–
10f, respectively, in excellent yields. The structure of the
latter compounds was confirmed by spectral data
(Scheme 2 and Experimental section).
Moreover, pyridine-2(1H)-thione derivative 6b reacted
with each of 7a–7c in methanolic solution containing
sodium methoxide to afford the corresponding 2-S-
alkylpyridine derivatives 9a–9c, respectively. The latter
compounds were cyclized into the corresponding
thieno[2,3-b]pyridine derivatives 11a–c, respectively,
upon boiling in ethanolic sodium ethoxide solution. On
the other hand, the reaction of 6b with each of 7d or 7e in
methanolic sodium methoxide solution afforded directly
the corresponding thieno[2,3-b]pyridine derivatives 11d
and 11e, respectively, without the isolation of 9d or 9e. It
dibromo-4-methoxyphenyl)prop-2-enethioamide
(5a).
Compound 5a reacted with 4 in ethanolic sodium
ethoxide solution at reflux to give 6a (Scheme 1 and
Experimental section).
On the other hand, the starting material 6-amino-
4-(4-hydroxyphenyl)-2-thioxo-1,2-dihydropyridine-3,5-
dicarbonitrile (6b) [44] was prepared, in a good yield, by
the reaction of 4-hydroxybenzaldehyde (1b) with 4 to
give prop-2-enethioamide derivative 5b. Compound 5b
reacted with 4 in ethanol containing triethylamine at
reflux to give 6b (Scheme 1).
Ethyl
3-amino-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylthieno[2,3-b]pyridine-2-carboxylate (10a) could be
prepared by a two-step synthetic route. Thus, compound
6a reacted with ethyl chloroacetate (7a) in methanolic
sodium methoxide solution under stirring at room
temperature to afford the corresponding ethyl 2-((3-cyano-
4-(3,5-dibromo-4-methoxyphenyl)-6-phenylpyridin-2-yl)
Scheme 1. Synthesis of pyridine-2(1H)-thiones 6a,b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their
Fused Azines Using Pyridine-2(1H)-thiones as Starting Materials
Scheme 2. Synthesis of thieno[2,3-b]pyridines 10a–f and 11a–e.
is worthy to mention that the thin-layer chromatography of
the crude products (obtained from the reaction of
compound 6b with 7d or 7e) indicated the presence of the
main products (compounds 11d and 11e) together with
traces of other products. After crystallization, the thin-
layer chromatography of the pure products indicated the
presence of compounds 11d and 11e only (Scheme 2 and
Experimental section).
group at δ = 4.57 ppm and pyrazole NH group
at δ = 12.05 ppm. Based on the earlier data, compound
13 was formulated as 3,6-diamino-4-(4-hydroxyphenyl)-
1H-pyrazolo[3,4-b]pyridine-5-carbonitrile. Compound 13
could also be prepared by the direct reaction of
pyridine-2(1H)-thione 6b with hydrazine hydrate in
boiling ethanol at reflux (Scheme 3 and Experimental
section).
The
ethyl
2-((3-cyanopyridin-2-yl)thio)acetate
Our
study
included
the
reaction
of
2-
derivative 8a reacted with hydrazine hydrate in
pyridine at reflux to yield 12. The 1H-NMR spectrum
of 12 revealed three singlet signals due to NHNH2
group at δ = 4.47 ppm, NH2 group at δ = 6.05 ppm,
and NH group at δ = 9.27 ppm. Based on the earlier
data, compound 12 was formulated as 3-amino-4-(3,5-
dibromo-4-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-
2-carbohydrazide (12). Compound 12 could also be
prepared by the reaction of ethyl 3-aminothieno[2,3-b]
pyridine-2-carboxylate derivative 10a with hydrazine
hydrate in pyridine at reflux. On the other hand, the
reaction of ethyl 2-((6-amino-3,5-dicyanopyridin-2-yl)
thio)acetate derivative 9a with hydrazine hydrate gave a
carbohydrazide derivative 12 with formic acid to afford
the corresponding 9-(3,5-dibromo-4-methoxyphenyl)-3-
(formylamino)-7-phenylpyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-4(3H)-one (14) in 86% yield. The 1H-NMR
spectrum of 14 revealed a singlet signal due to NH group
at δ = 11.62 ppm (Scheme 4). On the other hand,
compound 12 reacted with boiling acetic anhydride at
reflux to give the corresponding 3-(N,N-diacetylamino)-2-
methylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
derivative 15 in 84% yield. In a similar manner, compound
12 reacted with each of dimethylformamide-dimethylacetal
in dry xylene at reflux and triethylorthoformate at reflux
to give the corresponding pyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-4(3H)-one derivatives 16 and 17, respectively, in
excellent yields (Scheme 4 and Experimental section).
1
sulfur free reaction product 13. The H-NMR spectrum
of 13 revealed two singlet signals due to pyrazole NH2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
Scheme 3. Synthesis of thieno[2,3-b]pyridine-2-carbohydrazide derivative 12 and 3,6-diamino-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 13.
Scheme 4. Synthesis of pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 14–17.
Moreover, compound 12 reacted with β-dicarbonyl
reagents to afford new thienopyridine derivatives
incorporating pyrazole moiety. Thus, 2-carbohydrazide
derivative 12 reacted with boiling acetylacetone at reflux
to give the corresponding 3-amino-2-((3,5-dimethyl-1H-
pyrazol-1-yl)carbonyl)thieno[2,3-b]pyridine derivative 18.
afford the corresponding 2-((5-hydroxy-3-methyl-1H-
pyrazol-1-yl)carbonyl)thieno[2,3-b]pyridine derivative 19
(Scheme 5 and Experimental section).
Moreover, 2-carbohydrazide derivative 12 reacted
with 2-benzylidenemalononitrile (20a) in boiling
pyridine at reflux to give 3-amino-N0-benzylidene-4-(3,5-
dibromo-4-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-
2-carbohydrazide (22a) in 86% yield. The structure of 22a
1
The H-NMR spectrum of 18 revealed the presence of
the signals of two CH3 groups at δ = 2.26 and 2.58 ppm,
respectively. In a similar manner, compound 12 reacted
with ethyl acetoacetate in boiling acetic acid at reflux to
1
was confirmed based on IR, MS, and H-NMR spectra. It
is a noteworthy that the formation of 21a as a product of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their
Fused Azines Using Pyridine-2(1H)-thiones as Starting Materials
Scheme 5. Synthesis of 3-amino-2-((3-methyl-1H-pyrazol-1-yl)carbonyl)thieno[2,3-b]pyridines 18 and 19 and N0-arylidenethieno[2,3-b]pyridine-2-
carbohydrazides 22a,b.
the earlier reaction is excluded and reaction between 12
and 20a most properly proceeded via the nucleophilic
addition of NH2 group on ylidene double bond followed
with ylidene group exchange with the loss of one
molecule of malononitrile to afford 22a. Compound 22a
could also be prepared, in 90% yield, by the reaction of
12 with benzaldehyde (23a). In the same way, 3-
amino-N0-(4-methoxybenzylidene)thieno[2,3-b]pyridine-2-
carbohydrazide derivative 22b could be prepared, in
excellent yield, either by the reaction of 12 with the
appropriate 2-(4-methoxybenzylidene) malononitrile (20b)
or anisaldehyde (23b) (Scheme 5 and Experimental section).
The synthetic utility of thieno[2,3-b]pyridine-2-
carbonitrile derivative 10c and 2-carbamide derivative 10f
as building blocks for the synthesis of novel pyrimidine
derivatives was also investigated. Therefore, the reaction
of either 10c or 10f with formic acid at reflux afforded
the corresponding 9-(3,5-dibromo-4-methoxyphenyl)-7-
phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
(24), in 82% and 87% yields, respectively. The 1H-
NMR spectrum of 24 revealed a singlet signal due to
NH group at δ = 12.92 ppm. It is a noteworthy that
the reaction of 2-carbonitrile derivative 10c with
formic acid proceeds by the initial acid hydrolysis of
nitrile function to give 2-carbamide derivative 10f as
an intermediate followed by reaction with formic
acid to give compound 24. In the same way, the
reaction of either 10c or 10f with acetic anhydride at
reflux afforded 2-methylpyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-4(3H)-one derivative 25 (Scheme 6 and
Experimental section).
Next, the reaction of both 10c and 10f with carbon
disulfide in boiling pyridine at reflux was investigated.
Thus, compound 10c reacted with carbon disulfide
to afford the corresponding pyrido[30,20:4,5]thieno[3,2-d]
pyrimidine-2,4(1H,3H)-dithione
derivative
26a.
Compound 26a reacted with iodomethane in methanolic
solution containing sodium methoxide to afford
2,4-bis(methylsulfanyl)pyridothieno[3,2-d]pyrimidine. In
the same way, compound 10f reacted with carbon
disulfide to afford the corresponding 2-thioxo-2,3-
dihydropyridothieno[3,2-d]pyrimidin-4(1H)-one derivative
26b (Scheme 6 and Experimental section).
Furthermore, the chemical potential of 2-carbamide
derivative 10f to prepare thieno[2,3-b]pyridine derivative
incorporating fused [1,2,3]triazine moiety was also
studied. Therefore, 10f reacted with nitrous acid was
prepared in situ by the addition of sodium nitrite solution
Journal of Heterocyclic Chemistry
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S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
Scheme 6. Reactions of thieno[2,3-b]pyridines 10c and 10f.
to 10f dissolved in a mixture of acetic acid and
hydrochloric acid, with stirring to afford the
corresponding [1,2,3]triazin-4-(3H)-one derivative 28, in
89% yield. The 1H-NMR spectrum of 28 revealed a
singlet signal due to NH group at δ = 15.57 ppm
(Scheme 6 and Experimental section).
KGaA, Darmstadt, Germany) or Aldrich (Sigma-Aldrich
Corporation as a subsidiary of Merck KGaA, St. Louis,
Missouri). These chemicals were used without further puri-
fication. The melting points were measured on a Stuart
melting point apparatus and are uncorrected. IR spectra
were recorded on a Smart iTR, which is an ultra-high-
performance versatile attenuated total reflectance sampling
accessory on the Nicolet iS10 FT-IR spectrometer
manufactured by Thermo Fisher Scientific Inc., Fitchburg,
Dane County, Wisconsin. 1H-NMR and 13C-NMR spectra
were recorded on Varian Mercury at 300 and 75 MHz, re-
spectively, spectrophotometer using tetramethylsilane as
an internal standard and DMSO-d6 as solvent and chemical
shifts were expressed as δ ppm units. The instrument
manufactured by Varian Inc., Palo Alto, California. Ele-
mental analyses were carried out on a EuroVector instru-
ment C, H, N, S analyzer EA3000 Series. Compound 6b
[44] was prepared according to the reported literature.
CONCLUSION
We develop a synthetic pathway for novel pyrazolo[3,4-
b]pyridine, thieno[2,3-b]pyridines, and their fused
pyrimidine-4(3H)-ones and [1,2,3]triazin-4-(3H)-one by
the reaction of pyridine-2(1H)-thiones with available
chemical reagents. The bioactivity of the newly
synthesized compounds still under study.
EXPERIMENTAL
Procedure
for
synthesis
of
3-(3,5-dibromo-4-
methoxyphenyl)-1-phenylprop-2-en-1-one (3).
A solution
All organic solvents were acquired from commercial
sources and used as received unless otherwise stated. All
other chemicals were acquired from Merck (Merck
of 3,5-dibromo-4-methoxybenzaldehyde (1a, 5 mmol) in
10 mL ethanol was added portion wisely with constant
stirring at room temperature to
a
solution of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their
Fused Azines Using Pyridine-2(1H)-thiones as Starting Materials
acetophenone (2, 5 mmol) in 10 mL ethanol containing
potassium hydroxide (5 mmol). After complete addition,
the stirring was continued for 3 h, and the solid that
formed was collected by filtration, washed with cold
ethanol, and recrystallized from ethanol to yield colorless
crystals (96%); m.p. 102–104°C; IR (υ cmꢀ1): 1678
proper solvent to give the final products 8a–f, 9a–c, and
11d,e, respectively.
Ethyl
2-((3-cyano-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylpyridin-2-yl)thio)acetate (8a).
Colorless crystals
(dioxane, 89%); m.p. 184–186°C; IR (υ cmꢀ1): 2208
(CN), 1733 (CO); 1H-NMR (DMSO-d6): δ 1.17 (t,
J = 6.9 Hz, 3H, OCH2CH3), 3.95 (s, 3H, OCH3), 4.11 (q,
J = 6.9 Hz, 2H, OCH2CH3), 4.26 (s, 2H, SCH2), 7.31–
8.27 (m, 8H, ArH’s); Anal. for C23H18Br2N2O3S (562.3):
C, 49.13; H, 3.23; N, 4.98; S, 5.70. Found: C, 48.80; H,
1
(CO); H-NMR (DMSO-d6): δ 3.87 (s, 3H, CH3), 7.52–
8.29 (m, 9H, 7 ArH’s and CH=CH); Ms m/z (%): 398
(36.4, M++4), 396 (73.2, M++2), 394 (35.0, M+), 379
(7.4), 363 (7.0), 317 (16.6), 276 (10.3), 105 (51.8), 77
(100.0); Anal. for C16H12Br2O2 (396.1): C, 48.52; H,
3.05. Found: C, 48.88; H, 2.74%.
3.01; N, 5.32; S, 5.98%.
4-(3,5-Dibromo-4-methoxyphenyl)-2-((2-oxopropyl)thio)-6-
phenylnicotinonitrile (8b).
Colorless crystals (dioxane,
91%); m.p. 188–190°C; IR (υ cmꢀ1): 2207 (CN), 1711
(CO); 1H-NMR (DMSO-d6): δ 2.30 (s, 3H, COCH3),
3.95 (s, 3H, OCH3), 4.37 (s, 2H, SCH2), 7.31–8.21 (m,
8H, ArH’s); Anal. for C22H16Br2N2O2S (532.3): C,
49.65; H, 3.03; N, 5.26; S, 6.02. Found: C, 49.86; H,
Procedure for synthesis of 2-cyano-3-(3,5-dibromo-4-
methoxyphenyl)prop-2-enethioamide (5a).
A mixture of
1a (5 mmol) and 2-cyanoethanethioamide (4, 5 mmol) in
ethanol (25 mL) containing triethylamine (0.2 mL) was
stirred at room temperature for 3 h. The product so
formed was filtrated, washed with cold ethanol, and
recrystallized from ethanol as orange crystals (91%); m.p.
202–204°C; IR (υ cmꢀ1): 3330, 3210 (NH2), 2210 (CN),
2.76; N, 5.02; S, 6.27%.
2-((Cyanomethyl)thio)-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylnicotinonitrile (8c).
Colorless crystals (dioxane,
92%); m.p. 176–178°C; IR (υ cmꢀ1): 2225, 2208 (CN);
1H-NMR (DMSO-d6): δ 3.96 (s, 3H, OCH3), 4.53 (s, 2H,
SCH2), 7.33–8.42 (m, 8H, ArH’s); Anal. for
C21H13Br2N3OS (515.2): C, 48.95; H, 2.54; N, 8.16; S,
1
1550 (CS); H-NMR (DMSO-d6): δ 3.89 (s, 3H, CH3),
8.05 (s, 1H, olefinic-CH), 8.29 (s, 2H, ArH’s), 11.25 (s,
2H, NH2); Ms m/z (%): 378 (22.9, M++4), 376 (43.1,
M++2), 374 (21.1, M+), 343 (22.2), 331 (21.1), 314
(20.0), 290 (21.4), 278 (21.1); Anal. for C11H8Br2N2OS
(376.1): C, 35.13; H, 2.14; N, 7.45; S, 8.53. Found: C,
35.00; H, 2.36; N, 7.69; S, 8.20%.
6.22. Found: C, 48.72; H, 2.30; N, 8.36; S, 6.45%.
4-(3,5-Dibromo-4-methoxyphenyl)-2-((2-oxo-2-phenylethyl)
thio)-6-phenylnicotinonitrile (8d).
Colorless crystals
(dioxane, 90%); m.p. 186–188°C; IR (υ cmꢀ1): 2212
Procedure for synthesis of 6a. Method “A”. A mixture
of 3 (5 mmol) and 4 (5 mmol) in dioxane (25 mL)
containing triethylamine (0.2 mL) was heated at reflux
for 3 h. The reaction mixture was cooled, and the product
so formed was filtrated, washed with cold ethanol, and
recrystallized from dioxane.
Method “B”. A mixture of 5a (5 mmol) and 4 (5 mmol)
in ethanolic sodium ethoxide solution (prepared from
5 mmol of Na in of ethanol 25 mL) was heated at reflux
for 5 h. The reaction mixture was cooled and the product
so formed was filtrated, washed with cold ethanol, and
1
(CN), 1680 (CO); H-NMR (DMSO-d6): δ 3.95 (s, 3H,
OCH3), 5.06 (s, 2H, SCH2), 7.18–8.16 (m, 13H, ArH’s);
Anal. for C27H18Br2N2O2S (594.3): C, 54.57; H, 3.05; N,
4.71; S, 5.39. Found: C, 54.90; H, 2.89; N, 4.52; S, 5.30%.
2-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-4-(3,5-dibromo-4-
methoxyphenyl)-6-phenylnicotinonitrile (8e).
Colorless
crystals (dioxane, 92%); m.p. 196–198°C; IR (υ cmꢀ1):
1
2211 (CN), 1678 (CO); H-NMR (DMSO-d6): δ 3.95 (s,
3H, OCH3), 5.07 (s, 2H, SCH2), 7.15–8.12 (m, 12H,
ArH’s); Anal. for C27H17Br2ClN2O2S (628.8): C, 51.58;
H, 2.73; N, 4.46; S, 5.10. Found: C, 51.33; H, 2.99; N,
4.78; S, 4.89%.
2-((3-Cyano-4-(3,5-dibromo-4-methoxyphenyl)-6-
recrystallized from dioxane.
4-(3,5-Dibromo-4-methoxyphenyl)-6-phenyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (6a). Orange crystals (86%
phenylpyridin-2-yl)thio)acetamide (8f).
Colorless crystals
from A or 80% from B); m.p. 258–260°C; IR (υ cmꢀ1):
(dioxane, 88%); m.p. 246–248°C; IR (υ cmꢀ1): 3378,
1
1
3159 (NH), 2219 (CN), 1550 (CS); H-NMR (DMSO-
3196 (NH2), 2210 (CN), 1668 (CO); H-NMR (DMSO-
d6): δ 3.90 (s, 3H, OCH3), 7.17–8.11 (s, 8H, ArH’s),
14.23 (s, 1H, NH); Anal. for C19H12Br2N2OS (476.2): C,
47.92; H, 2.54; N, 5.88; S, 6.73. Found: C, 47.62; H,
2.78; N, 6.03; S, 7.02%.
d6): δ 3.95 (s, 3H, OCH3), 4.08 (s, 2H, SCH2), 7.28–8.34
(m, 10H, 8 ArH’s and NH2); Anal. for C21H15Br2N3O2S
(533.2): C, 47.30; H, 2.84; N, 7.88; S, 6.01. Found: C,
47.05; H, 2.96; N, 7.99; S, 6.32%.
General procedure for synthesis of 8a–8f, 9a–9c, 11d, and
11e. A mixture of each of 6a,b (5 mmol) and each of
Ethyl 2-((6-amino-3,5-dicyano-4-(4-hydroxyphenyl)pyridin-
2-yl)thio)acetate (9a). Colorless crystals (ethanol, 89%);
7a–f (5 mmol) in methanolic sodium methoxide solution
(10 mmol/20 mL of methanol) was stirred at room
temperature for 2 h, and then, the reaction mixture was
neutralized with diluted HCl. The products were filtrated,
washed with cold water, and then recrystallized from the
m.p. 250–252°C; IR (υ cmꢀ1): 3411 (OH), 3320, 3222
1
(NH2), 2216 (CN), 1736 (CO); H-NMR (DMSO-d6): δ
1.10 (t, 3H, CH2CH3), 3.73 (s, 2H, SCH2), 4.23 (q, 2H,
CH3CH2), 6.96 (d, J = 13.2 Hz, 2H, ArH’s), 7.45 (d,
J = 13.2 Hz, 2H, ArH’s), 7.96 (s, br, 2H, NH2), 10.14 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
br, 1H, OH); Anal. for C17H14N4O3S (354.4): C, 57.62; H,
3.98; N, 15.81; S, 9.05. Found: C, 57.80; H, 4.23; N,
15.55; S, 9.32%.
4.15 (q, J = 7.2 Hz, 2H, CH3CH2), 6.01 (s, br, 2H, NH2),
7.53–8.27 (m, 8H, ArH’s); Ms m/z (%): 564 (35.9,
M++4), 562 (70.2, M++2), 560 (36.9, M+), 535 (53.7),
488 (53.7), 485 (51.8), 468 (66.0), 440 (53.7), 412
(59.4), 77 (100.0); Anal. for C23H18Br2N2O3S (562.3): C,
49.13; H, 3.23; N, 4.98; S, 5.70. Found: C, 49.01; H,
2.99; N, 4.89; S, 5.98%.
2-Amino-4-(4-hydroxyphenyl)-6-((2-oxopropyl)thio)pyridine-
3,5-dicarbonitrile (9b).
Pale yellow crystals (ethanol,
93%); m.p. 220–222°C; IR (υ cmꢀ1): 3415 (OH), 3322,
1
3222 (NH2), 2216 (CN), 1719 (CO); H-NMR (DMSO-
d6): δ 2.33 (s, 3H, CH3), 4.20 (s, 2H, SCH2), 6.90 (d,
J = 13.2 Hz, 2H, ArH’s), 7.36 (d, J = 13.2 Hz, 2H,
ArH’s), 7.87 (s, br, 2H, NH2), 10.05 (s, br, 1H, OH); Anal.
for C16H12N4O2S (324.4): C, 59.25; H, 3.73; N, 17.27; S,
9.89. Found: C, 59.36; H, 3.89; N, 17.36; S, 9.64%.
2-Amino-6-((cyanomethyl)thio)-4-(4-hydroxyphenyl)
2-Acetyl-3-amino-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylthieno[2,3-b]pyridine
(10b).
Orange crystals
(dioxane, 89%); m.p. 262–264°C; IR (υ cmꢀ1): 3448,
3278 (NH2); 1H-NMR (DMSO-d6): δ 3.90 (s, 3H, OCH3),
2.40 (s, 3H, COCH3), 6.75 (s, br, 2H, NH2), 7.51–8.20 (m,
8H, ArH’s); Ms m/z (%): 534 (41.8, M++4), 532 (83.1,
M++2), 530 (42.9, M+), 519 (8.1), 504 (72.4), 485 (67.3),
455 (53.0), 437 (56.1), 410 (56.1), 77 (24.4); Anal. for
C22H16Br2N2O2S (532.3): C, 49.65; H, 3.03; N, 5.26; S,
6.02. Found: C, 49.30; H, 3.21; N, 5.08; S, 5.84%.
pyridine-3,5-dicarbonitrile (9c).
Brown crystals (ethanol,
90%); m.p. 224–226°C; IR (υ cmꢀ1): 3411 (OH), 3322,
1
3222 (NH2), 2215 (CN); H-NMR (DMSO-d6): δ 4.19 (s,
2H, CH2), 6.90 (d, J = 13.2 Hz, 2H, ArH’s), 7.40 (d,
J = 13.2 Hz, 2H, ArH’s), 7.89 (s, br, 2H, NH2), 10.06 (s,
br, 1H, OH); Anal. for C15H9N5OS (307.3): C, 58.62; H,
2.95; N, 22.79; S, 10.43. Found: C, 58.30; H, 2.90; N,
3-Amino-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylthieno[2,3-b]pyridine-2-carbonitrile (10c).
Yellow
crystals (dioxane, 92%); m.p. 240–242°C; IR (υ cmꢀ1):
1
22.98; S, 10.66%.
3466, 3345 (NH2), 2197 (CN); H-NMR (DMSO-d6): δ
3,6-Diamino-4-(4-hydroxyphenyl)-2-(phenylcarbonyl)
thieno[2,3-b]pyridine-5-carbonitrile (11d). Orange crystals
3.95 (s, 3H, OCH3), 5.80 (s, 2H, NH2), 7.28–8.25 (s, 8H,
ArH’s); Ms m/z (%): 517 (31.2, M++4), 515 (63.4,
M++2), 513 (31.8, M+), 487 (12.1), 436 (100.0), 420
(41.5), 410 (25.3), 405 (33.8), 249 (21.1), 77 (38.6);
Anal. for C21H13Br2N3OS (515.2): C, 48.95; H, 2.54; N,
8.16; S, 6.22. Found: C, 49.21; H, 2.77; N, 8.22; S, 6.01%.
3-Amino-2-benzoyl-4-(3,5-dibromo-4-methoxyphenyl)-6-
(ethanol, 91%); m.p. 322–324°C; IR (υ cmꢀ1): 3454
1
(OH), 3285, 3169 (NH2), 2214 (CN); H-NMR (DMSO-
d6): δ 5.72 (s, br, 2H, NH2), 6.92–7.96 (m, 11H, 9 ArH’s
and NH2), 10.05 (s, br, 1H, OH); Ms m/z (%): 387 (6.7,
M++1), 386 (11.1%, M+), 298 (13.3), 265 (13.3), 162
(17.8), 106 (88.9), 92 (13.3), 78 (100.0); Anal. for
C21H14N4O2S (386.4): C, 65.27; H, 3.65; N, 14.50; S,
8.30. Found: C, 65.40; H, 3.49; N, 14.74; S, 8.66%.
3,6-Diamino-2-[(4-chlorophenyl)carbonyl]-4-(4-
hydroxyphenyl)thieno[2,3-b]pyridine-5-carbonitrile (11e).
phenylthieno[2,3-b]pyridine (10d).
Yellow crystals
(dioxane, 90%); m.p. 208–210°C; IR (υ cmꢀ1): 3468,
3318 (NH2); 1H-NMR (DMSO-d6): δ 3.88 (s, 3H,
OCH3), 7.18 (s, br, 2H, NH2), 7.54–8.27 (m, 13H,
ArH’s); Ms m/z (%): 596 (40.7, M++4), 594 (75.7,
M++2), 577 (53.7), 562 (52.7), 519 (50.0), 503 (64.8),
475 (55.5), 410 (56.1), 77 (24.4); Anal. for
Orange crystals (ethanol, 87%); m.p. 324–326°C; IR (υ
1
cmꢀ1): 3449 (OH), 3305, 3168 (NH2), 2214 (CN); H-
NMR (DMSO-d6): δ 5.76 (s, br, 2H, NH2), 6.90–7.95
(m, 10H, 8 ArH’s and NH2), 10.05 (s, br, 1H, OH); Ms
m/z (%): 423 (19.6, M++3), 422 (15.7, M++2), 421 (29.4,
M++1), 420 (43.1, M+), 281 (23.5), 265 (11.8), 139
(76.5), 111 (100.0); Anal. for C21H13ClN4O2S (420.9): C,
59.93; H, 3.11; N, 13.31; S, 7.62. Found: C, 59.69; H,
2.99; N, 13.18; S, 7.86%.
General procedure for synthesis of 10a–10f and 11a–11c.
A mixture of each of 8a–f and 9a–c (5 mmol) in ethanolic
sodium ethoxide solution (10 mmol of sodium in 20 mL of
ethanol) was heated at reflux for 2 h, and then, the reaction
mixture was cooled and neutralized with diluted HCl. The
products were filtrated, washed with cold water, and then
recrystallized from the proper solvent to give the final
products 10a–f and 11a–c, respectively.
C27H18Br2N2O2S (594.3): C, 54.57; H, 3.05; N, 4.71; S,
5.39. Found: C, 54.78; H, 2.92; N, 4.96; S, 5.26%.
3-Amino-2-(4-chlorobenzoyl)-4-(3,5-dibromo-4-
methoxyphenyl)-6-phenylthieno[2,3-b]pyridine
(10e).
Yellow crystals (dioxane, 94%); m.p. 226–228°C; IR (υ
1
cmꢀ1): 3466, 3320 (NH2); H-NMR (DMSO-d6): δ 3.90
(s, 3H, OCH3), 7.22 (s, br, 2H, NH2), 7.56–8.25 (m,
12H, ArH’s); Anal. for C27H17Br2ClN2O2S (628.8): C,
51.58; H, 2.73; N, 4.46; S, 5.10. Found: C, 51.74; H,
2.46; N, 4.68; S, 4.80%.
3-Amino-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylthieno[2,3-b]pyridine-2-carbamide (10f).
Yellow
crystals (dioxane, 91%); m.p. 272–274°C; IR (υ cmꢀ1):
1
3441, 3310, 3142 (NH2), 1651 (CO); H-NMR (DMSO-
d6): δ 3.94 (s, 3H, OCH3), 6.10 (s, br, 2H, NH2), 7.30 (s,
br, 2H, CONH2), 7.48–8.24 (m, 8H, ArH’s); Ms m/z (%):
535 (5.5, M++4), 533 (10.8, M++2), 531 (5.9, M+), 516
(2.0), 515 (8.2), 487 (5.1), 412 (100.0); Anal. for
C21H15Br2N3O2S (533.2): C, 47.30; H, 2.84; N, 7.88; S,
6.01. Found: C, 47.44; H, 3.04; N, 7.62; S, 5.74%.
Ethyl
3-amino-4-(3,5-dibromo-4-methoxyphenyl)-6-
phenylthieno[2,3-b]pyridine-2-carboxylate (10a).
Yellow
crystals (dioxane, 91%); m.p. 236–238°C; IR (υ cmꢀ1):
1
3461, 3359 (NH2), 1681 (CO); H-NMR (DMSO-d6): δ
1.47 (t, J = 7.2 Hz, 3H, CH3CH2), 3.92 (s, 3H, OCH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their
Fused Azines Using Pyridine-2(1H)-thiones as Starting Materials
Ethyl 3,6-diamino-5-cyano-4-(4-hydroxyphenyl)thieno[2,3-b]
pyridine-2-carboxylate (11a).
reflux for 6 h. After cooling the reaction mixture was
diluted with ice-cold water and neutralized with diluted
hydrochloric acid. The product so formed was collected
by filtration, washed with water and then recrystallized
from ethanol/dimethylformamide mixture as pale yellow
crystals (91% from 6b or 85% from 9a); m.p. 340–
342°C; IR (υ cmꢀ1): 3484 (OH), 3346, 3231 (NH2), 2220
(CN); 1H-NMR (DMSO-d6): δ 4.57 (s, br, 2H, NH2),
6.74 (d, J = 13.2 Hz, 2H, ArH’s), 7.39 (d, J = 13.2 Hz,
2H, ArH’s), 7.58 (s, br, 2H, NH2), 10.02 (s, br, 1H, OH),
12.05 (s, br, 1H, NH); Anal. for C13H10N6O (266.3): C,
58.64; H, 3.79; N, 31.56. Found: C, 58.43; H, 3.95; N,
31.38%.
Golden yellow crystals
(ethanol, 90%); m.p. 280–282°C; IR (υ cmꢀ1): 3471
(OH), 3347, 3229 (NH2), 2220 (CN), 1669 (CO); 1H-
NMR (DMSO-d6): δ 1.18 (t, J = 6.9 Hz, 3H, CH2CH3),
4.28 (q, J = 6.9 Hz, 2H, CH3CH2), 5.74 (s, br, 2H, NH2),
6.90 (d, J = 13.2 Hz, 2H, ArH’s), 7.42 (d, J = 13.2 Hz,
2H, ArH’s), 7.91 (s, br, 2H, NH2), 10.10 (s, br, 1H, OH);
Ms m/z (%): 355 (28.5, M++1), 354 (83.7, M+), 326
(17.6), 307 (100.0), 282 (23.1), 251 (9.9); Anal. for
C17H14N4O3S (354.4): C, 57.62; H, 3.98; N, 15.81; S,
9.05. Found: C, 57.30; H, 3.74; N, 15.98; S, 9.23%.
2-Acetyl-3,6-diamino-4-(4-hydroxyphenyl)thieno[2,3-b]
pyridine-5-carbonitrile (11b).
Yellow crystals (ethanol,
General procedure for synthesis of compounds 14 and
24. A solution of each of 12, 10c or 10 f (5 mmol) in
formic acid (20 mL) was heated at reflux for 5 h. The
reaction mixture was cooled and the solid products were
filtrated, washed with cold ethanol and then recrystallized
from the proper solvent to yield 14 and 24, respectively.
9-(3,5-Dibromo-4-methoxyphenyl)-3-(formylamino)-7-
phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
87%); m.p. 330–332°C; IR (υ cmꢀ1): 3472 (OH), 3360,
1
3215 (NH2), 2214 (CN); H-NMR (DMSO-d6): δ 2.26 (s,
3H, CH3), 6.74–6.92 (m, 4H, 2 ArH’s and NH2), 7.41 (d,
J = 13.2 Hz, 2H, ArH’s), 7.96 (s, br, 2H, NH2), 10.09 (s,
br, 1H, OH); Ms m/z (%): 325 (24.7, M++1), 324 (100.0,
M+), 309 (42.3), 281 (47.4), 264 (24.7), 114 (19.6), 87
(39.2) 76 (32.0); Anal. for C16H12N4O2S (324.4): C,
59.25; H, 3.73; N, 17.27; S, 9.89. Found: C, 59.01; H,
(14).
Pale brown crystals (dioxane/ethanol mixture,
86%); m.p. 200–202°C; IR (υ cmꢀ1): 3217 (NH), 1711
3.50; N, 17.55; S, 10.12%.
1
3,6-Diamino-4-(4-hydroxyphenyl)thieno[2,3-b]pyridine-2,5-
dicarbonitrile (11c). Orange crystals (ethanol, 85%); m.p.
(CHO), 1661 (CO); H-NMR (DMSO-d6): δ 3.95 (s, 3H,
OCH3), 7.56–8.37 (m, 9H, 8 ArH’s and pyrimidine CH-
2), 8.60 (s, 1H, CHO), 11.62 (s, 1H, NH); Ms m/z (%):
588 (21.1, M++4), 586 (44.3, M++2), 584 (21.6, M+),
569 (11.7), 555 (11.7), 543 (11.7), 492 (12.4), 479
(17.6), 465 (15.4), 77 (15.0); Anal. for C23H14Br2N4O3S
(586.3): C, 47.12; H, 2.41; N, 9.56; S, 5.47. Found: C,
300–302°C; IR (υ cmꢀ1): 3448 (OH), 3308, 3210 (NH2),
1
2219 (CN); H-NMR (DMSO-d6): δ 5.89 (s, 2H, NH2),
6.92 (d, J = 13.2 Hz, 2H, ArH’s), 7.45 (d, J = 13.2 Hz,
2H, ArH’s), 7.95 (s, br, 2H, NH2), 10.11 (s, br, 1H, OH);
Ms m/z (%): 307 (85.7, M+), 131 (100.0), 75 (57.1), 60
(100.0); Anal. for C15H9N5OS (307.3): C, 58.62; H, 2.95;
N, 22.79; S, 10.43. Found: C, 58.55; H, 3.12; N, 22.46;
S, 10.20%.
47.33; H, 2.24; N, 9.78; S, 5.64%.
9-(3,5-Dibromo-4-methoxyphenyl)-7-phenylpyrido[30,20:4,5]
thieno[3,2-d]pyrimidin-4(3H)-one (24). Pale yellow crystals
Procedure for synthesis of 3-amino-4-(3,5-dibromo-4-
methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-
carbohydrazide (12). A mixture of 8a or 10a (6 mmol)
(glacial acetic acid, 82% from 10c or 87% from 10 f); m.p.
1
>350°C; IR (υ cmꢀ1): 3159 (NH), 1656 (CO); H-NMR
(DMSO-d6): δ 3.95 (s, 3H, OCH3), 7.22–8.35 (m, 9H, 8
ArH’s and pyrimidine CH-2), 12.92 (s, 1H, NH); Anal.
for C22H13Br2N3O2S (541.2): C, 48.64; H, 2.41; N, 7.74;
S, 5.90. Found: C, 48.41; H, 2.65; N, 7.85; S, 5.76%.
General procedure for synthesis of compounds 15 and
25. A solution of each of 12, 10c or 10 f (5 mmol) in
acetic anhydride (20 mL) was heated at reflux for 5 h.
The reaction mixture was cooled and the solid products
were filtrated, washed with cold ethanol and then
recrystallized from the proper solvent to yield 15 and 25,
and hydrazine hydrate (5 mL, 80%) in pyridine (20 mL)
was heated at reflux for 8 h. After cooling, the reaction
mixture was diluted with ice-cold water and neutralized
with diluted hydrochloric acid. The product so formed
was collected by filtration, washed with water and then
recrystallized from dioxane as yellow crystals (79% from
8a or 89% from 10a); m.p. 204–206°C; IR (υ cmꢀ1):
1
3436, 3311, 3156 (NH and NH2); H-NMR (DMSO-d6):
δ 3.87 (s, 3H, OCH3), 4.47 (s, 2H, NHNH2), 6.05 (s, 2H,
NH2), 7.32–8.26 (m, 8H, ArH’s), 9.27 (s, 1H, NH); Ms
m/z (%): 550 (36.1, M++4), 548 (71.4, M++2), 546 (36.5,
M+), 530 (85.7), 517 (59.1), 499 (67.3), 469 (61.2), 453
(55.1); Anal. for C21H16Br2N4O2S (548.3): C, 46.01; H,
2.94; N, 10.22; S, 5.85. Found: C, 46.36; H, 3.25; N,
10.00; S, 5.62%.
respectively.
3-(N,N-Diacetylamino)-9-(3,5-dibromo-4-methoxyphenyl)-2-
methyl-7-phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-
one (15). Pale brown crystals (dioxane/ethanol mixture,
84%); m.p. 142–144°C; IR (υ cmꢀ1): 1722, 1650 (CO);
1H-NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 2.42 (s, 6H, 2
CH3), 3.86 (s, 3H, OCH3), 7.55–8.37 (m, 8H, ArH’s);
Ms m/z (%): 658 (42.4, M++4), 656 (87.5, M++2), 654
(40.3, M+), 623 (50.9), 556 (55.5), 538 (12.9), 458
(58.3), 318 (72.2), 77 (19.4); Anal. for C27H20Br2N4O4S
Procedure
for
synthesis
of
3,6-diamino-4-(4-
hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
(13). A mixture of 6b or 9a (6 mmol) and hydrazine
hydrate (5 mL, 80%) in ethanol (20 mL) was heated at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
(656.4): C, 49.41; H, 3.07; N, 8.54; S, 4.89. Found: C,
49.66; H, 3.32; N, 8.74; S, 5.12%.
dropwisely. The solid product was filtrated and then
recrystallized from dioxane to yield 18 as yellow crystals
(88%); m.p. 238–240°C; IR (υ cmꢀ1): 3325, 3229 (NH2),
9-(3,5-Dibromo-4-methoxyphenyl)-2-methyl-7-
phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
(25). Colorless crystals (glacial acetic acid, 86% from
1
1661 (CO); H-NMR (DMSO-d6): δ 2.26 (s, 3H, CH3),
2.58 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 6.28 (s, 1H,
pyrazole CH-4), 7.03 (s, br, 2H, NH2), 7.50–8.32 (m, 8H,
ArH’s); Ms m/z (%): 614 (16.7, M++4), 612 (32.9,
M++2), 610 (16.2, M+), 584 (10.6), 520 (21.3), 517 (7.9),
489 (8.4), 473 (3.9), 77 (23.2); Anal. for
C26H20Br2N4O2S (612.3); C, 51.00; H, 3.29; N, 9.15; S,
5.24. Found: C, 50.72; H, 2.99; N, 9.33; S, 5.52%.
10c or 90% from 10 f); m.p. >350°C; IR (υ cmꢀ1): 3426
1
(NH), 1651 (CO); H-NMR (δ ppm) (DMSO-d6): δ 2.25
(s, 3H, CH3), 3.89 (s, 3H, OCH3), 7.54–8.32 (m, 8H,
ArH’s), 12.74 (s, 1H, NH); Ms m/z (%): 559 (25.1,
M++4), 557 (52.1, M++2), 555 (24.3, M+), 540 (19.3),
528 (13.2), 509 (12.7), 471 (15.1), 447 (17.8), 432
(18.0); Anal. for C23H15Br2N3O2S (557.3): C, 49.57; H,
2.71; N, 7.54; S, 5.75. Found: C, 49.28; H, 2.93; N, 7.74;
S, 5.41%.
Procedure for synthesis of 3-amino-4-[3,5-dibromo-4-
methoxyphenyl]-2-{(5-hydroxy-3-methyl-1H-pyrazol-1-yl)
carbonyl}-6-phenylthieno[2,3-b]pyridine (19).
A mixture
Procedure for synthesis of 3-[(N,N-dimethylamino)
methyleneamino]-9-(3,5-dibromo-4-methoxyphenyl)-7-
phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
(16). A mixture of 12 (5 mmol) and dimethylformamide-
of 12 (5 mmol) and ethyl acetoacetate (5 mmol) in glacial
acetic acid (15 mL) was heated at reflux for 5 h. The
solid product was filtrated and recrystallized from glacial
acetic acid to yield 19 as yellow crystals (85%); m.p.
332–334°C; IR (υ cmꢀ1): 3584 (OH), 3388, 3314 (NH2),
dimethylacetal (12 mmol) in dry xylene (15 mL) was
heated at reflux for 5 h. The reaction mixture was cooled
and the solid product was collected by filtration and then
recrystallized from dioxane/ethanol mixture to yield 16 as
colorless crystals (90%); m.p. 256–258°C; IR (υ cmꢀ1):
1
1667 (CO); H-NMR (DMSO-d6): δ 2.36 (s, 3H, CH3),
3.88 (s, 3H, OCH3), 6.00 (s, 1H, pyrazole CH-4), 7.56–
8.31 (m, 10H, 8 ArH’s and NH2), 11.88 (s, 1H, OH); Ms
m/z (%): 616 (37.1, M++4), 614 (78.1, M++2), 612 (36.4,
M+), 583 (47.4), 566 (41.6), 537 (41.6), 522 (59.1), 487
(49.6), 471 (40.1), 438 (45.2); Anal. for C25H18Br2N4O3S
(614.3); C, 48.88; H, 2.95; N, 9.12; S, 5.22. Found: C,
49.19; H, 3.22; N, 9.26; S, 5.00%.
1
1677 (CO); H-NMR (DMSO-d6): δ 2.92 (s, 3H, NCH3),
2.99 (s, 3H, NCH3), 3.85 (s, 3H, OCH3), 7.22–8.35 (m,
10H, 8 ArH’s, pyrimidine CH-2 and NCH=N); Ms m/z
(%): 615 (18.2, M++4), 613 (33.2, M++2), 611 (17.56,
M+), 600 (9.6), 585 (16.7), 567 (13.0), 558 (9.6), 540
(12.1), 536 (7.4), 505 (17.1), 471 (11.7), 77 (9.5); Anal.
for C25H19Br2N5O2S (613.3); C, 48.96; H, 3.12; N,
11.42; S, 5.23. Found: C, 49.26; H, 2.90; N, 11.69; S,
5.49%.
General procedure for synthesis of compounds 22a and
22b.
A mixture of 12 (5 mmol) and each of the
appropriate arylidenepropanedinitrile 20a and 20b or
appropriate aldehyde 23a and 23b (5 mmol) in pyridine
(20 mL) was heated at reflux for 6 h. The solid products
were collected by filtration and recrystallized from the
proper solvent to yield 22a and 22b, respectively.
3-Amino-N0-benzylidene-4-(3,5-dibromo-4-methoxyphenyl)-
6-phenylthieno[2,3-b]pyridine-2-carbohydrazide (22a).
Procedure
for
synthesis
of
9-(3,5-dibromo-4-
methoxyphenyl)-3-(ethoxymethyleneamino)-7-
phenylpyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-one
(17). A solution of 12 (5 mmol) in triethylorthoformate
(20 mL) was heated at reflux for 5 h. The reaction
mixture was cooled and the solid product was filtrated,
washed with cold ethanol and then recrystallized from
dioxane to yield 17 as colorless crystals (92%); m.p.
Yellow crystals (dioxane, 86% from 20a or 90% from
23a); m.p. 282–284°C; IR (υ cmꢀ1): 3439, 3330, 3176
(NH and NH2); 1H-NMR (DMSO-d6): δ 3.92 (s, 3H,
OCH3), 6.65 (s, br, 2H, NH2), 7.54–8.30 (m, 14H, 13
ArH’s and CH=N), 11.58 (s, 1H, NH); Ms m/z (%): 638
(41.9, M++4), 636 (84.8, M++2), 634 (42.6, M+), 621
(70.6), 618 (60.3), 548 (22.4), 532 (51.7), 517 (51.7),
489 (49.1), 451 (44.8), 473 (3.9), 77 (3.2); Anal. for
C28H20Br2N4O2S (636.4); C, 52.85; H, 3.17; N, 8.80; S,
1
260–262°C; IR (υ cmꢀ1): 1674 (CO); H-NMR (DMSO-
d6): δ 1.37 (t, J = 7.2 Hz, 3H, CH3CH2), 3.89 (s, 3H,
CH3O), 4.39 (q, J = 7.2 Hz, 2H, CH3CH2), 7.54–8.65
(m, 10H, 8 ArH’s, pyrimidine CH-2 and N=CH); Ms m/z
(%): 616 (11.1, M++4), 614 (22.7, M++2), 612 (11.9,
M+), 597 (22.7), 569 (12.5), 556 (4.6), 537 (29.9), 508
(25.3), 494 (24.4), 475 (27.8); Anal. for C25H18Br2N4O3S
(614.3); C, 48.88; H, 2.95; N, 9.12; S, 5.22. Found: C,
49.13; H, 2.99; N, 9.26; S, 4.96%.
5.04. Found: C, 52.59; H, 2.90; N, 9.02; S, 5.23%.
3-Amino-4-(3,5-dibromo-4-methoxyphenyl)-6-phenyl-N0-(4-
methoxybenzylidene)thieno[2,3-b]pyridine-2-carbohydrazide
(22b). Yellow crystals (dioxane, 89% from 20b or 93%
from 23b); m.p. 300–302°C; IR (υ cmꢀ1): 3427, 3333,
Procedure for synthesis of 3-amino-4-[3,5-dibromo-4-
methoxyphenyl]-2-{(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl}-
1
3189 (NH and NH2); H-NMR (DMSO-d6): δ 3.86 (s,
6-phenylthieno[2,3-b]pyridine (18).
A mixture of 12
3H, OCH3), 3.90 (s, 3H, OCH3), 6.64 (s, br, 2H, NH2),
7.57–8.31 (m, 13H, 12 ArH’s and CH=N), 11.56 (s, 1H,
NH); Ms m/z (%): 668 (19.4, M++4), 666 (39.2, M++2),
664 (18.8, M+), 651 (12.1), 638 (3.3), 635 (13.0), 546
(5 mmol) and acetylacetone (15 mL) was heated at reflux
for 5 h. The reaction mixture was evaporated to its half
volume, cooled and then 5 mL of ethanol was added
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis of Novel Pyrazolo[3,4-b]pyridine, Thieno[2,3-b]pyridines, and Their
Fused Azines Using Pyridine-2(1H)-thiones as Starting Materials
(12.8), 530 (16.4), 519 (6.0), 491 (22.8), 451 (1.1), 77
(3.2); Anal. for C29H22Br2N4O3S (666.4); C, 52.27; H,
3.33; N, 8.41; S, 4.81. Found: C, 52.50; H, 3.08; N, 8.19;
S, 4.88%.
3 h. The solid obtained was filtrated and recrystallized
from dioxane to yield 28 as colorless crystals (89%); m.p.
1
234–236°C; IR (υ cmꢀ1): 3159 (NH), 1657 (CO); H-
NMR (DMSO-d6): δ 3.92 (s, 3H, OCH3), 7.54–8.34 (m,
8H, ArH’s), 15.57 (s, 1H, NH); Ms m/z (%): 546 (15.3,
M++4), 544 (30.8, M++2), 542 (16.3, M+), 503 (14.3),
501 (13.2), 472 (14.3), 458 (13.6), 362 (14.4); Anal. for
C21H12Br2N4O2S (544.2); C, 46.35; H, 2.22; N, 10.29; S,
5.89. Found: C, 46.09; H, 2.54; N, 10.53; S, 5.63%.
General procedure for synthesis of compounds 26a,b.
A
mixture of each of 10c or 10f (5 mmol) and carbon
disulfide (5 mL) in pyridine (25 mL) was heated at reflux
for 12 h. The mixture was cooled, poured onto ice-cold
water, and then neutralized with diluted hydrochloric
acid. The products were collected by filtration, washed
with cold ethanol, and recrystallized from the proper
REFERENCES AND NOTES
solvent to afford the final products 26a,b, respectively.
9-(3,5-Dibromo-4-methoxyphenyl)-7-phenylpyrido[30,20:4,5]
thieno[3,2-d]-pyrimidine-2,4(1H,3H)-dithione (26a). Yellow
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M. M. Eur J Med Chem 2011, 46, 137.
crystals (dioxane, 88%); m.p. 198–200°C; IR (υ cmꢀ1):
1
3374 (NH), 1555 (CS); H-NMR (DMSO-d6): δ 3.98 (s,
3H, OCH3), 7.27–8.24 (m, 9H, 8 ArH’s and NH), 13.05
(s, br, 1H, NH); Ms m/z (%): 593 (26.8, M++4), 591
(53.5, M++2), 589 (27.0, M+), 576 (18.9), 516 (42.5),
485 (8.6), 475 (6.3), 326 (47.2); Anal. for
C22H13Br2N3OS3 (591.4); C, 44.68; H, 2.22; N, 7.11; S,
16.27. Found: C, 44.92; H, 1.99; N, 6.87; S, 16.11%.
9-(3,5-Dibromo-4-methoxyphenyl)-7-phenyl-2-thioxo-2,3-
dihydropyrido-[30,20:4,5]thieno[3,2-d]pyrimidin-4(1H)-one
(26b). Yellow crystals (dioxane, 84%); m.p. 328–330°C;
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IR (υ cmꢀ1): 3173 (NH), 1660 (CO), 1559 (CS); 1H-NMR
(DMSO-d6): δ 3.99 (s, 3H, OCH3), 7.22–8.32 (m, 9H, NH
and 8 ArH’s), 12.95 (s, br, 1H, NH); Ms m/z (%): 577
(42.8, M++4), 575 (82.0, M++2), 573 (41.6, M+), 498
(46.0), 481 (19.0), 471 (4.7), 465 (68.2), 398 (6.3), 365
(57.9); Anal. for C22H13Br2N3O2S2 (575.3); C, 45.93; H,
2.28; N, 7.30; S, 11.15. Found: C, 46.23; H, 2.00; N,
7.09; S, 11.36%.
9-(3,5-Dibromo-4-methoxyphenyl)-2,4-bis(methylsulfanyl)-
7-phenylpyrido-[30,20:-4,5]thieno[3,2-d]pyrimidine (27).
A
mixture of 26a (5 mmol) and iodomethane (10 mmol) in
methanolic sodium methoxide solution (10 mmol/25 mL
of methanol) was stirred at room temperature for 2 h. The
product was filtrated, washed with cold ethanol, and then
recrystallized from dioxane to yield 27 as colorless
1
crystals (95%); m.p. 270–272°C; H-NMR (DMSO-d6): δ
2.15 (s, 3H, SCH3), 2.19 (s, 3H, SCH3), 3.97 (s, 3H,
OCH3), 7.50–8.26 (m, 8H, ArH’s); Ms m/z (%): 621
(32.7, M++4), 619 (65.1, M++2), 617 (31.9, M+), 572
(48.1), 557 (41.6), 540 (10.2), 495 (30.6), 482 (33.4),
471 (54.0), 433 (41.6); Anal. for C24H17Br2N3OS3
(619.4); C, 46.54; H, 2.77; N, 6.78; S, 15.53. Found: C,
46.28; H, 2.99; N, 7.04; S, 15.78%.
Procedure
for
synthesis
of
9-(3,5-dibromo-4-
methoxyphenyl)-7-phenylpyrido[30,20:4,5]thieno[3,2-d][1,2,3]
triazin-4(3H)-one (28). A stirred cold solution (0–5°C) of
each of 10 f (5 mmol) in acetic acid (20 mL) and
concentrated hydrochloric acid (4 mL) was treated drop
wise with cold solution of sodium nitrite (5 mmol in
5 mL of water) with stirring. Stirring was continued for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. H. Sanad, A. M. Abdel-Fattah, F. A. Attaby, and M. A. A. Elneairy
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet