Anti-alzheimer and anti-cox-2 activities of the newly synthesized 2,3′-bipyridine derivatives (I)

Article abstract of DOI:10.1080/10426500902717333

3-Aryl-1-pyridin-3-ylprop-2-en-1-ones 1a,b reacted with 2-cyanoethane-thioamide (2) to afford the corresponding 4-aryl-6-thioxo-1,6- dihydro-2,3′-bipyridine-5-carbonitriles 6a,b. The synthetic potentiality of compounds 6a,b were investigated in the presen

Full text of DOI:10.1080/10426500902717333

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Anti-Alzheimer and Anti-Cox-2 Activities
of the Newly Synthesized 2,3′-Bipyridine
Derivatives (I)
Fawzy A. Attaby a , Azza M. Abdel-Fattah a , Labeeb M. Shaif a &
Mohamed M. Elsayed b
a Chemistry Department, Faculty of Science, Cairo University, Giza,
Egypt
b Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
Published online: 28 Dec 2009.
To cite this article: Fawzy A. Attaby , Azza M. Abdel-Fattah , Labeeb M. Shaif & Mohamed M. Elsayed
(2009) Anti-Alzheimer and Anti-Cox-2 Activities of the Newly Synthesized 2,3′-Bipyridine Derivatives
(I), Phosphorus, Sulfur, and Silicon and the Related Elements, 185:1, 129-139
To link to this article: http://dx.doi.org/10.1080/10426500902717333
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Phosphorus, Sulfur, and Silicon, 185:129–139, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902717333
ANTI-ALZHEIMER AND ANTI-COX-2 ACTIVITIES OF THE
NEWLY SYNTHESIZED 2,3ꢀ-BIPYRIDINE DERIVATIVES (I)
Fawzy A. Attaby,1 Azza M. Abdel-Fattah,1 Labeeb M. Shaif,1
and Mohamed M. Elsayed2
1Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
2Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
3-Aryl-1-pyridin-3-ylprop-2-en-1-ones 1a,b reacted with 2-cyanoethane-thioamide (2) to af-
ford the corresponding 4-aryl-6-thioxo-1,6-dihydro-2,3ꢀ-bipyridine-5-carbonitriles 6a,b. The
synthetic potentiality of compounds 6a,b were investigated in the present study via their reac-
tions with several active-hydrogen containing compounds 8a–g aiming to synthesize 4-aryl-
6-pyridin-3-ylthieno[2,3-b]pyridin-3-amines 10a–n via 6-(alkylthio)-4-aryl-2,3ꢀ-bipyridine-
5-carbonitriles 9a–n. The structures of all newly synthesized heterocyclic compounds were
elucidated by considering the data of IR, 1H NMR, and mass spectra, as well as that of
elemental analyses. Anti-Alzheimer and anti-COX-2 activities for all newly synthesized het-
erocyclic compounds were investigated.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords 6-(Alkylthio)-4-aryl-2, 3ꢁ-bipyridine-5-carbonitriles; 3-aryl-1-pyridin-3-ylprop-2-
en-1-ones; 2-cyanoethanethioamide; 6-pyridin-3-ylthieno-[2,3-b]pyridin-3-amines; 6-thioxo-
1, 6-dihydro-2,3ꢁ-bipyridine-5-carbonitrile
INTRODUCTION
In conjunction with our previous recent work,1–19 and with the aim to investigate and
evaluate the biological activities of the newly synthesized heterocyclic compounds, we here
interested to use 3-aryl-1-pyridin-3-ylprop-2-en-1-ones as key compounds to synthesize
2,3ꢁ-bipyridine-5-carbonitriles required for several chemical transformations, as well as
our medicinal chemistry programs.
RESULTS AND DISCUSSION
3-Phenyl-1-pyridin-3-ylprop-2-en-1-one20 (1a) reacted with 2-cyanoethane-
thioamide (2) in absolute ethanol containing a catalytic amount of piperidine under reflux
to afford a reaction product. The reaction product formed via a Michael addition of CH2
Received 8 July 2008; accepted 31 December 2008.
Address correspondence to Fawzy A. Attaby, Chemistry Department, Faculty of Science, Cairo University,
Giza 12613, Egypt. E-mail: Fattaby@hotmail.com
129

130
F. A. ATTABY ET AL.
in 2 on CH CH of 1a to give the non-isolable products 3a, 4a, and 5a followed
by cyclization via dehydration and dehydrogenation to give 6a. The IR (cm−1) of this
reaction product showed the bands of NH (3169) and CN (2220) groups. Its mass spectrum
gave m/z = 289 (100%), which corresponded to the molecular weight of the formula
C17H11N3S of the assigned structure, as well as m/z = 256 (12.5%), which corresponded to
(M+ - SH).
In a similar manner, 3-(4-methoxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (1b) re-
acted with 2-cyanoethanethioamide (2) under the same above-mentioned experimental
conditions to give the finally isolated 6b via the non-isolable intermediates 3b, 4b, and 5b.
The chemical structure of 6b was elucidated by considering the data of IR, 1H NMR, and
mass spectra, as well as that of elemental analyses (see the Experimental section). A further
confirmation of 6a,b arose from their synthesis through another pathway via the reaction
of each of 1a,b and malononitrile (7) in a dispersed sulfur, morpholine, and ethanol under
reflux for 2 h (Scheme 1).21 It important to note here that 6a,b obtained by the two pathways
are identical in all physical and chemical properties.
The synthetic potentiality of each of 6a,b was investigated through electrophilic sub-
stitution reactions using several electrophilic C-species. Thus, it has been found that 1a
reacted with ethyl chloroacetate (8a) in stirred methanolic solution of sodium methoxide
at room temperature for 15 min to give a reaction product. The IR (cm−1) of this reaction
product showed the bands of CN (2220) and CO (1734) of the newly introduced COOEt
group. Its 1H NMR (δ ppm) spectrum revealed the signals of SCH2
,
COOCH2CH3,
and COOCH2CH3 protons, and this confirm the good nucleophilicity of S in 6a that
facilitates the electrophilic attack of 8a to afford 9a in a very pure form and in a good
yield. Furthermore, the structure of 9a was elucidated through its cyclization in ethanolic
sodium ethoxide under reflux for 30 min to give a reaction product whose IR spectrum
showed no bands of CN group, but instead bands of the newly formed NH2 group were
1
detected. Also, the H NMR spectrum of this reaction product revealed signals of NH2
protons and did not reveal the signals of CH2 protons. Considering the data of both
1
IR and H NMR, we concluded that both SCH2 and CN functional groups in 9a in-
volved in the cyclization step to give the finally isolated 10a. A further confirmation of the
structure of 10a was obtained through its preparation authentically via the reaction of 6a
with 8a in ethanolic sodium ethoxide under reflux for 2 h (see the Experimental section).
Similarly, 6a reacted with each of 8c, 8e, and 8g in stirred methanolic solution of sodium
methoxide at room temperature to give the corresponding 2-alkylthio derivatives 9c, 9e,
and 9g, whose structures were elucidated by considering the data of IR and elemental
analyses. Also, 9c and 9e cyclized in ethanolic sodium ethoxide under reflux for 30 min
and gave the corresponding thieno[2,3-b]pyridine derivatives 10c and 10e respectively,
which were also obtained via refluxing of 6a with each of 8c and 8e in ethanolic sodium
ethoxide for 2 h. Unexpectedly, 9g did not undergo a cyclization reaction under a vari-
ety of experimental conditions to give the corresponding thieno[2,3-b]pyridine derivative
10g.
In contrast to the behavior of 6a towards each of 8a, 8c, 8e, and 8g, it has been
found that 6a reacted with each of 8b, 8d, and 8f either in stirred methanolic sodium
methoxide at room temperature or under reflux in ethanolic sodium ethoxide to give the
corresponding thieno[2,3-b]pyridine derivatives 10b, 10d, and 10f, respectively, whose
1
structures were elucidated by considering the data of IR, H NMR, and mass spec-
tra, as well as that of elemental analyses. It is important to report here that all trials
aimed at isolating compounds 9b, 9d, and 9f failed under a variety of experimental

2,3ꢁ-BIPYRIDINE DERIVATIVES (I)
131
Scheme 1
conditions. The structure of 10d was confirmed via its preparation through another route
by reaction of 6a with or 3-chloropentan-2,4-dione (8dꢁ) in methanolic solution of sodium
methoxide either under stirring at room temperature or under reflux for 2 h. The reac-
tion appears to proceed via the intermediates I and II through removal of the acetic acid
molecule to give 2-acetyl-3-amino-4-phenyl-6-(3-pyridyl)thieno[2,3-b]pyridine (10d) (see
Equation 1).
In continuation to our effort to investigate the electrophilic substitution reaction along
the SH group in each of 6a,b, compound 6b is a key structure for that goal. Thus, it has been
found that 6b reacted with each of 8a, 8b, 8c, 8e, 8f, and 8g in a stirred methanolic solution
of sodium methoxide for 15 min to afford the corresponding 2-alkylthio derivatives 9h, 9i,

132
F. A. ATTABY ET AL.
Equation 1
9j, 9l, 9m, and 8n (Scheme 2). The structures of these reaction products were elucidated
by considering the data of their elemental analyses, IR, and 1H NMR (see the Experimental
section). A further elucidation for these structures arose from their cyclization in methanolic
solution of sodium methoxide under reflux for 30 min to give the corresponding thieno[2,3-
b]pyridine derivatives 10h, 10i, 10j, 10l, 10m, and 10n, respectively. An authentic sample
of each of 10h, 10i, 10j, 10l, 10m, and 10n obtained via a reflux mixture of 6b and each
of 8a, 8b, 8c, 8e, 8f, and 8g in ethanolic solution of sodium ethoxide for 2 h. In contrast
to this behavior, 6b reacted with 1-chloroacetone (8d) or 3-chloropentan-2,4-dione (8dꢁ)
either in a methanolic solution of sodium methoxide at room temperature for 15 min under
stirring or under reflux for 2 h in an ethanolic solution of sodium ethoxide to give directly
the corresponding thieno[2,3-b]pyridine derivative 10k (see Equation 1). The structure of
10n was confirmed further via its preparation authentically through the hydrolysis of 10h
in ethanolic 10% KOH under reflux (see the Experimental section).
Biological Evaluation
Anti-Alzheimer activity. For compounds 1a,b, their potency as anti-Alzheimer
agents relative to Flurbiprofen is high enough, while after their reactions to afford the
corresponding bipyridine-5-carbonitriles 6a,b, their relative potency decreased. (See the
Supplemental Materials online).
Structural activity relationship of anti-Alzheimer activity. Generally for
compounds 9, we note that the phenyl moiety provides the highest anti-Alzheimer activity
compared with phenyl-p-methoxy. Thus, we can conclude that the p-methoxy group has
no effect. The potency as anti-Alzheimer agents for S-substitution in all compounds 9 with

2,3ꢁ-BIPYRIDINE DERIVATIVES (I)
133
phenyl moiety relative to Flurbiprofen is arranged in descending order as follows: acid >
ketone > ester > amide.
Anti-COX-2 activity. For the substituted pyridine derivatives 9, their potency as
anti-COX-2 activities is arranged in descending order as follows: 9h, 9n, 9e, 9i, 9m, 9a,
(9c, 6b), 9j, (9l, 9g). (See Figure 6 in the Supplemental Materials online).
N
H
N
S
EtONa/EtOH/ reflux/2h
NC
Ar
6a,b
X-CH-Y
(8a-g )
MeONa/MeOH stirring
at room T/30 min
(X = Cl , Br)
X-CH2-Y
8a-g
R
Ar
Ar
NH2
N
Z
Y
S
S
N
EtONa/EtOH
N
reflux/30 min
N
N
10a, b, c, d, e, f, g, h, i, j, k, l, m, n
9a, [b], c, [d], e, [f], g, h, i, j, l, m, n
10
a
b
c
d
e
f
h
i
Ar
C6H5
C6H5
C6H5
C6H5
z
9
a
c
e
g
h
i
j
Ar
C6H5
C6H5
C6H5
Y
COOEt
CN
CONH2
COMe
COPh
COPh-p-Cl
COOEt
CN
COOEt
CONH2
COPh
COOH
COOEt
CN
C6H5
C6H5
C6H5
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
CONH2
COPh
l
m
CONH2
C6H4-4-OCH3 COPh-p-Cl
j
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
C6H4-4-OCH3
COMe
COPh
COPh-p-Cl
C6H4-4-OCH3 COOH
k
l
m
n
n
COOH
Scheme 2

134
F. A. ATTABY ET AL.
EXPERIMENTAL
All melting points were uncorrected. IR (KBr discs) spectra were recorded on a
Shimadzu FTIR-8201PC Spectrophotometer. 1H NMR spectra were recorded on a Varian
Mercury 300 MHz, and a Varian Gemini 200 MHz spectrometers using TMS as an internal
standard and CDCl3, DMSO-d6, and (CD3)2CO as solvents. Chemical shifts were expressed
as δ (ppm) units. Mass spectra were recorded on Shimadzu GCMS-QP1000EX using an inlet
type at 70 eV. The Microanalytical Center of Cairo University performed the microanalyses.
Synthesis of 6a,b (General Method)
Method A. A solution of each of 2 (2.60 g, 2.6 mmol) and each of 1a,b (5.43 g and
5.8 g, 2.6 mmol) in absolute ethanol (30 mL) containing a catalytic amount of piperidine
(0.4 mL) was heated under reflux for 5 h. The reaction mixture was evaporated, cooled,
and triturated with ethanol. The products were formed collected by filtration, washed with
cold ethanol, and then crystallized from the proper solvent to give the corresponding 6a,b,
respectively.
Method B. A mixture of dispersed sulfur (0.67 g, 1.9 mmol) and morpholine (1.7
mL, 1.9 mmol) in ethanol (50 mL) was refluxed for 20 min. Malononitrile (7) (1.30 g, 1.9
mmol) was added followed by 1a,b (3.97 g and 4.◦54 g, 1.9 mmol), and the mixture was
refluxed for 2 h. The mixture was cooled to ∼20 C, and 10% HCl was added to reach
pH 5–6. The precipitates that formed were filtered off and washed with water and cooled
ethanol, then crystallized from dioxane to give the corresponding 6a,b respectively.
4-Phenyl-6-thioxo-1,6-dihydro-2,3ꢁ-bipyridine-5-carbonitrile (6a): As orange
◦
crystals, yielded by 71%, mp 240 C, IR (ν cm−1): 3169 (NH), 3053 (aromatic CH)
and 2220 (CN); MS: 289 (M+, 100% which corresponds to the molecular weight of
the molecular formula C17H11N3S of the assigned structure), 287 (M+ 2H, 84%);
1
256 (M+ SH, 12.5%); H NMR (DMSO-D6) (δppm): 7.22–7.82(m, 5H, Ph, protons),
8.19–9.01 (m, 5H, pyridine H,s) and 14.10 (s, br, 1H, SH); Anal. for C17H11N3S (289)
Calcd./Found (%): C(70.56/70.60), H(3.83/3.90), N(14.52/14.58), S(11.08/11.16%).
4-(4-Methoxyphenyl)-6-thioxo-1,6-dihydro-2,3ꢁ-bipyridine-5-carbonitrile (6b):
As orange crystals, yielded by 76%, mp 272 ◦C; IR (ν cm−1): 3174 (NH), 3020 (aromatic-
CH) and 2216 (CN); MS: 319 (M+, 100% which corresponds to the molecular weight of
the molecular formula C18H13N3OS of the assigned structure), 318 (M+-H, 30.6%), 287
1
(M+ S, 4.6%); H NMR (DMSO-D6) (δ ppm): 3.85 (s, 3H, OCH3), 7.11–7.84(m, 4H,
Ar), 8.17–9.22 (m, 5H, pyridine H,s) and 14.2 (s, br, 1H, SH); Anal, for C18H13N3OS (319)
Calcd./Found(%): C(67.69/67.72), H(4.10/4.14), N(13.16/13.19), and S (10.04/10.11%).
Synthesis of 9a, 9c, 9e, 9g–i, 9j, 9l–n: General Procedure
A solution of each of 6a,b (0.29 g and 0.32 g, 1 mmol) and ethyl chloroacetate (8a),
chloroacetonitrile (8b), 2-chloroacetamide (8c), 1-chloroacetone (8d), 3-chloropentane-
2,4-dione (8dꢁ), 2-bromo-1-phenyl-ethanone (8e), 2-bromo-1-p-chlorophenylethanone
(8f), chloroacetic acid (8g) (0.12 g, 0.08 g, 0.09 g, 0.09 g, 0.13 g, 0.2 g, 0.23 g and 0.09 g 1
mmol, respectively) in sodium methoxide (prepared from 0.14 g of sodium and methanol
25 mL) was stirred at room temperature for 15 min. The formed precipitate was collected
by filtration, washed with water, and crystallized from the proper solvent to give 9a, 9c,
9e, 9g, 9h, 9i, 9j, 9l, 9m, and 9n, respectively.

2,3ꢀ-BIPYRIDINE DERIVATIVES (I)
135
Ethyl [(5-cyano-4◦-phenyl-2,3ꢁ-bipyridin-6-yl)thio]acetate (9a): As pale yellow
crystals (87%), mp 196 C; IR υ(cm−1): 3066 (C H, aromatic), 2220 (CN), 1734 (es-
ter CO); 1H NMR (DMSO-D6) (δppm): 1.16 (t, 3H, CH2CH3), 2.49 (s, 2H, SCH2), 4.30
(q, 2H, CH2CH3), 7.56–7.79(m, 5H, phenyl H,s), 8.07–9.40 (m, 5H, pyridine H,s); Anal.,
for C21H17N3O2S (375), Calcd./Found (%): C(67.18/67.23), H(4.56/4.61), N(11.19/11.23),
S(8.54/8.61%).
2-[(5-Cyano-4-phenyl-2,3ꢁ-bipyridin-6-yl)thio]acetamide (9c): As pale yellow
crystals (84%), mp 265 ◦C; IR υ(cm−1): 3432, 3128 (NH2), 2215 (CN), 1684 (CO amide);
Anal., for C19H14N4OS (346), Calcd./Found (%): C(65.88/65.90%), H(4.07/4.11%),
N(16.17/16.22%), S(9.26/9.30%).
6-[(2-Oxo-2-phenylethyl)thio]-4-phenyl-2,3ꢁ-bipyridine-5-carbonitrile (9e): As
◦
orange crystals (91%); mp 210 C; IR υ(cm−1): 3058 (C H, aromatic), 2213 (CN),
1690 (CO); Anal. for C25H17N3OS (407), Calcd./Found(%): C(73.69/73.72), H(4.21/4.26),
N(10.31/10.40), S(7.87/7.90%).
[(5-Cyano-4-phenyl-2,3ꢁ-bipyridin-6-yl)thio]acetic acid (9g): As orange crystals
(80%); mp = 300–302 ◦C; IR υ(cm−1): 2927–3387 acid (OH), 3062 (CH, aromatic), 2214
(CN); Anal. for C19H13N3O2S (347), Calcd./Found (%): C(65.69/65.73), H(3.77/3.85),
N(12.10/1219), S(9.23/9.30).
Ethyl{[5-cyano-4-(4-methoxyphenyl)-2,3ꢁ-bipyridin-6-yl]thio}acetate (9h): As
pale yellow crystals (80%); mp 182 ◦C; IR υ(cm−1): 3045 (C H aromatic), 2214
(CN), 1736 (ester CO). 1H NMR (DMSO-D6) (δppm): 2.50 (s, 2H,
SCH2),
3.18–3.18 (overlapped, 3H, CH2CH3), 3.86 (s, 3H, OCH3), 4.28 (overlapped q,
2H, CH2CH3), 7.79 (m, 4H, Ar H,s), 8.03–9.39 (m, 5H, pyridine); Anal. for
C22H19N3O3S (405), Calcd./Found (%): C(65.17/65.21), H(4.72/4.80), N(10.36/10.43),
S(7.91/8.00).
6-[(Cyanomethyl)thio]-4-(4-metho◦xyphenyl)-2,3ꢁ-bipyridine-5-carbonitrile (9i):
As yellow crystals (84%); mp 185–157 C; IR υ(cm−1): 3051 (C H aromatic), 2214
(CN); Anal. for C20H14N4OS (358) Calcd./Found (%): C(67.02/67.10), H(3.94/4.03),
N(15.63/15.70), S(8.95/9.06).
2-{[5-Cyano-4-(4-methoxyphenyl)-2,3ꢁ-bipyridin-6-yl]thio}acetamide (9j): As
yellow crystals (84%); mp 212 ◦C; IR υ(cm−1): 3391, 3204 (NH2), 3079 (C H aromatic),
2216 (CN), 1666 (CO); Anal. for C20H16N4O2S (376) Calcd./Found(%):C(63.81/63.90),
H(4.28/4.33), N(14.88/14.95), S(8.52/8.61).
6-[(2-Oxo-2-phenylethyl)thio]-4-(4-methoxyphenyl)-2,3ꢁ-bipyridine-5-carbonit
rile (9l): As orange crystals (91%); mp 182 ◦C; IR υ(cm−1): 3046 (C H aromatic), 2213
(CN); Anal. for C26H19N3O2S (437), Calcd./Found (%): C(71.38/71.42), H(4.38/4.44),
N(9.60/9.64), S(7.33/7.41).
6-{[2-(4-Chlorophenyl)-2-oxoethyl]thio}-4-(4-methoxyphenyl)-2,3ꢁ-bipyrid-ine-
◦
5-carbonitrile (9m): As yellow crystals (89%); mp 225 C; IR υ(cm−1): 3064 (C H
aromatic), 2206 (CN), 1697 (CO); Anal. for C26H18ClN3O2S (471), Calcd./Found (%):
C(66.17/66.22), H(3.84/3.90), Cl(7.51/7.60), N(8.90/9.00), S(6.79/6.85).
{[5-Cyano-4-(4-methoxyphenyl)-2,3ꢁ-bipyridin-6-yl]thio}acetic acid (9n): As or-
◦
ange crystals (80%); mp 278 C; IR υ(cm−1): 3336–3529 (acidic OH), 3040 (C H aro-
matic), 2209 (CN), 1653 (CO); 1H NMR (DMSO-D6) (δ ppm): 2.49 (s, 3H, SCH2 ),
3.85 (s, 3H, OCH3), 7.11–7.83 (m, 4H, Ar H,s), 8.16–9.21 (m, 5H, pyridine H,s) and 14.3
(s, br., 1H, COOH); Anal. for C20H15N3O3S (377) Calcd./Found (%): C(63.65/63.70),
H(4.01/4.10), N(11.13/11.20), S(8.50/8.58).

136
F. A. ATTABY ET AL.
The Synthesis of 10a–n
Method A. A solution of each of 9a, 9c, 9e, 9g, 9h, 9i, 9j, 9l, 9m, and 9n (0.38 g,
0.35 g, 0.41 g, 0.35 g, 0.41 g, 0.36 g, 0.38 g, 0.44 g, 0.47 g, and 0.38 g, respectively 1
mmol) in sodium ethoxide solution (prepared from 0.10 g of sodium and 25 mL ethanol)
was heated under reflux for 30 min. The solid that formed after cooling was collected by
filtration, washed with water and ethanol, then crystallized from the proper solvent to afford
10a–n, respectively.
Method B. A solution of each of 6a,b (0.29 g and 0.32 g, respectively, 1 mmole)
and ethyl-chloroacetate (8a), chloroacetonitrile (8b), 2-chloroacetamide (8c), 1-chloro-
acetone (8d), 3-chloropentane-2,4-dione (8dꢁ), 2-bromo-1-phenylethanone (8e), 2-bromo-
1-(4-chlorophenyl)ethanone (8f), and chloroacetic acid (8g) (0.12 g, 0.08 g, 0.09 g, 0.09 g,
0.13 g, 0.20 g, 0.23 g, and 0.09 g, respectively, 1 mmole) in sodium methoxide (prepared
from 0.10 g of sodium and 25 mL ethanol) heated under reflux for 2 h. The solid products
so formed after cooling, collected by filtration, washed with water and ethanol, and dried,
then crystallized from the proper solvent to afford 10a–n, respectively.
Ethyl
3-amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carboxylate
(10a): As yellow crystals crystallized from ethanol (90%); mp 180 ◦C; IR υ(cm−1): 3478,
3333 (NH2), 3057 (C H aromatic), 1666 (CO); 1H NMR (DMSO-D6) (δppm): 1.05 (t,
2H, CH2CH3), 3.44 (q, 2H, CH2CH3), 6.46 (s, 2H, NH2), 7.48–7.89 (m, 5H, phenyl H,s)
and 8.57–9.38 (m, 5H, pyridine H’s); Anal, for C21H17N3O2S (375), Calcd./Found (%):
C(67.18/67.23), H(4.56/4.61), N(11.19/11.23), and S (8.54/8.60).
3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbonitrile (10b): As
◦
yellow crystals crystallized from ethanol (85%); mp 274 C; IR υ(cm−1): 3448, 3298,
3180 (NH2), 3052(C–H aromatic), 2183 (CN); MS (m/z): 328 ( M+, 100% which cor-
responds to the molecular weight of the molecular formula C19H12N4S of the assigned
structure), 254 (M+ Pyridyl, 17%), 166 (Pyridine CN, CN C C NH2, 5.3%), 140
(Pyridine, CN C C NH2, 7.0%), 100 (Pyridine CN, 5.3%) and 66 (CN C C NH2,
10.5%); Anal. for C19H12N4S (328), Calcd./Found (%): C(69.49/69.52), H(3.68/3.72),
N(17.06/17.12), S(9.76/9.82).
3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridine-2◦-carboxamide (10c):
As orange crystals crystallized from dioxane (80%); mp 225 C; IR υ(cm−1): 3475,
3433, 3300, 3119 (NH2 and amidic NH2), 1645 (amidic CO); MS (m/z): 346 (M+,
100% which corresponds the molecular weight of the molecular formula C19H14N4OS
of the assigned structure), 330 (M+ NH2, 7.5%), 329 (M+ NH2 H, 50.7%), 328
(M+ NH2 2H, 11.0%), 300 (M+ CONH2–2H, 84.9%), 256 (M+ PhCN NH2,
35.6%), 228 (M+ PhCN CONH2, 26.0%); Anal. for C19H14N4OS (346), Calcd./Found
(%): C(65.88/65.94), H(4.07/4.11), N(16.17/16.21), S(9.26/9.31%).
1-(3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)ethanone (10d):
◦
As orange crystals crystallized from acetic acid (83%); mp 183 C; IR υ(cm−1): 3485,
3310 (NH2), 3054 (C H aromatic), 1620 (CO); MS (m/z): 345 (M+, 100% which
corresponds to the molecular weight of the molecular formula C20H15N3OS of the assigned
structure), 344 (M+ H, 43.4%), 330 (M+ CH3, 56.2%), 302 (M+ COCH3, 36.9%);1H
NMR (DMSO-D6) (δppm): 2.39 (s, 3H, COCH3), 6.50 (s, br., 2H, NH2) 7.48–7.92 (m,
5H, phenyl H,s) and 8.57–9.39 (m, 5H, pyridine H,s); Anal. for C20H15N3OS (345),
Calcd./Found (%): C(69.54/69.62), H(4.38/4.42), N(12.17/12.22), S(9.28/9.30).
(3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)(phe◦nyl)-methanone
(10e): As orange crystals crystallized from dioxane (79%); mp = 210 C; IR υ(cm−1):

2,3ꢁ-BIPYRIDINE DERIVATIVES (I)
137
3469, 3382, 3305 (NH2), 3057 (C H aromatic), 1678 (CO); MS (m/z): 407 (M+, 84.3%
which corresponds to the molecular weight of the molecular formula C25H17N3OS of
the assigned structure), 406 (M+ H, 100%), 302 (M+ COPh, 28.2%), 105 (PhCO,
68.8%); Anal. for C25H17N3OS (407), Calcd./Found (%): C(73.69/73.75), H(4.21/428),
N(10.31/10.38), S(7.87/7.94).
(3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)(4-chlorophenyl)-
ethanone (10f): As yellow crystals crystallized from dioxane (86%); mp 226 ◦C;
IR υ(cm−1): 3461, 3284 (NH2), 3053 (C H aromatic), 1685 (CO); MS (m/z): 442
(M+, 60.6% which corresponds to the molecular weight of the molecular formula
C25H16ClN3OS of the assigned structure), 443 (M+1, 29.9%), 440 (M+ 2H, 100%),
301 (M+ COC6H4 p Cl, 10.3%); Anal. for C25H16ClN3OS (441.5), Calcd./Found (%):
C(67.94/67.99), H(3.65/3.71), Cl(8.02/8.11), N(9.51/9.59), S(7.26/7.33).
Ethyl
3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyrid◦-ine-2-
carboxylate (10h): As yellow crystals crystallized from ethanol (88%); mp 219 C; IR
υ(cm−1): 3497, 3379 (NH2), 3062 (C H aromatic), 1665 (CO); MS (m/z): 405 (M+,
100% which corresponds to the molecular weight of the molecular formula C22H19N3O3S
of the assigned structure), 358 (M+ C2H5, H, 66.4%), 332 (M+ COOEt, 4.3%), 330
(M+ COOEt, −2H, 27.6%), 139 ( COC6H4Cl 31%); H NMR (DMSO-D6) (δppm):
1
1.28 (t, 3H, CH2CH3), 3.86 (s, 3H, OCH3), 4.27 (q, 2H, CH2CH3), 5.90 (s, 2H, NH2),
7.14–7.48 (m, 4H, Ar H,s) and 8.53–9.35 (m, 5H, pyridine H,s); Anal. for C22H19N3O3S
(405) Calcd./Found (%): C(65.17/65.22), H(4.72/4.80), N(10.36/10.41), S(7.91/7.99).
3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbonit
rile (10i): As orange crystals crystallized from dioxane (90%); mp 210 C; IR υ(cm−1):
◦
3460, 3382, 3296 (NH2), 3065 (C H aromatic), 2188 (CN); MS (m/z): 358 (M+, 100%
which corresponds to the molecular weight of the molecular formula C20H14N4OS of the
assigned structure), 357 (M+ H, 34.6%), 327 (M+ OCH3, 17.4%), 316 (M+ CN NH2,
5.3%), 313 (M+ NH2, CN, 3H 19%); Anal. for C20H14N4OS (358), Calcd./Found (%):
C(67.02/6711), H(3.94/4.00), N(15.63/15.70), S(8.95/9.02).
3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carboxa
mide (10j): As yellow crystals crystallized from acetic acid (81%); mp 268 ◦C; IR
υ(cm−1): 1656 (CO), 3467, 3289 (NH2), 3407, 3126 (NH2); MS (m/z): 376 (M+, 100%
which corresponds to the molecular weight of the molecular formula C20H16N4O2S
of the assigned structure), 360 (M+ NH2, 12%), 358 (M+ NH2, −2H, 80.8%), 332
(M+ CONH2, 5.2%), 330 (M+ CONH2, −2H, 44.3%); Anal. for C20H16N4O2S (376),
Calcd./Found (%): C(63.81/63.90), H(4.28/4.33), N(14.88/1494), S(8.52/8.60).
1-[3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl]etha
none (10k): As yellow crystals crystallized from acetic acid (86%); mp = 233–236 ◦C; IR
υ(cm−1): 3445, 3288 (NH2), 3033 (C H aromatic), 1620 (CO); MS (m/z): 375 (M+, 100%
which corresponds to the molecular weight of the molecular formula C21H17N3O2S of
the assigned structure), 374 (M+ H, 61.7%), 360 (M+ CH3 40.5%), 332 (M+ COCH3
18.8%); Anal. for C21H17N3O2S (375), Calcd./Found (%): C(67.18/67.22), H(4.56/4.62),
N(11.19/11.23), S(8.54/8.62).
(3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)(phen
yl)methanone (10l): As orange crystals crystallized from dioxane (72%); mp 206 ◦C; IR
υ(cm−1): 3481, 3301 (NH2), 3045 (C H aromatic), 1656 (CO); MS (m/z): 437 (M+, 100%
which corresponds to the molecular weight of the molecular formula C26H19N3O2S of
the assigned structure), 436 (M+ H, 93%), 105 (COPh, 20.9%); Anal. for C26H19N3O2S
(437), Calcd./Found (%): C(71.38//71.42), H(4.38/4.42), N(9.60/9.68), S(7.33/7.42).

138
F. A. ATTABY ET AL.
(3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)-(4-chl
orophenyl)methanone (10m): As orange crystals crystallized from dioxane (90%);
◦
mp 205 C; IR υ(cm−1): 3479, 3306 (NH2), 3040 (C H aromatic), 1654 (CO); MS
(m/z): 471 (M+, 100% which corresponds to the molecular weight of the molecular
formula C26H18ClN3O2S of the assigned structure), 473 (M+2, 37.0%), 472 (M+1,
50.3%), 470 (M+-H, 99.2%), 469 (M+ 2H, 11.7%), 139 ( COC6H4Cl, 31%); Anal. for
C26H18ClN3O2S (471), Calcd./Found (%): C(66.17/66.22), H(3.84/3.90), Cl(7.51/7.60),
N(8.90/8.98), S(6.79/6.82).
3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carboxy
lic acid (10n): As orange crystals crystallized from acetic acid (71%), mp 320–322 ◦C; IR
υ(cm−1): 3467 (NH2), 3230–3467 (acid OH); MS (m/z): 332 (M+-COOH, 64.5%), 316
(M+ COOH NH2, 43.5%), 303 (M+ pyridyl, 9.7%), 289 (M+ CO2 CS, 64.5%);1H
NMR (DMSO-D6) (δppm): 3.85 (s, 3H, OCH3), 5.57 (s, 2H, NH2), 7.10–7.68 (m, 4H, Ar
H,s), 8.50–932 (m, 5H, pyridine H,s) and 14.3 (s, br., 1H, COOH); Anal. for C20H15N3O3S
(377), Calcd./Found (%): C(63.65/63.71), H(4.01/4.11), N(11.13/11.19), S(8.50/8.59).
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