Reactions of cyanothioacetamide: Synthesis of several new thioxohydro-pyridine-3-carbonitrile and thieno[2,3-b]pyridine derivatives

Article abstract of DOI:10.1080/10426500490475058

Cyanothioacetamide (1) reacted with α,β-unsaturated carbonyl compounds 2a-d to afford thioxohydropyridine-3-carbonitriles 5a-d, which were used as the starting materials for the preparation of several thienopyridines via their reactions with active halogen-containing compounds, e.g., 2-bromo-1-phenylethanone (7a), 2-bromo-1-p-tolylethanone (7b), chloroacetone (10a), α-chloroacetylacetone (10b), and chloroacetic acid ethyl ester (13). The structure of the newly synthesized heterocyclic compounds were established based on the data of elemental analyses, IR, ¹H NMR, and mass spectra.

Full text of DOI:10.1080/10426500490475058

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Reactions of
Cyanothioacetamide: Synthesis
of Several New Thioxohydro-
pyridine-3-carbonitrile
and Thieno[2,3-b]pyridine
Derivatives
Fawzy A. Attaby a , Sanaa M. Eldin a , Mohamed A.
A. Elneairy a & Ali K. K. El-Louh a
a Department of Pesticidal Chemistry, National
Research Center, Giza, Egypt
Version of record first published: 16 Aug 2010.
To cite this article: Fawzy A. Attaby , Sanaa M. Eldin , Mohamed A. A. Elneairy &
Ali K. K. El-Louh (2004): Reactions of Cyanothioacetamide: Synthesis of Several
New Thioxohydro-pyridine-3-carbonitrile and Thieno[2,3-b]pyridine Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 179:11, 2205-2220
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Phosphorus, Sulfur, and Silicon, 179:2205–2220, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490475058
REACTIONS OF CYANOTHIOACETAMIDE:
SYNTHESIS OF SEVERAL NEW
THIOXOHYDRO-PYRIDINE-3-CARBONITRILE
AND THIENO[2,3-b]PYRIDINE DERIVATIVES
Fawzy A. Attaby, Sanaa M. Eldin, Mohamed A. A. Elneairy,
and Ali K. K. El-Louh
Chemistry Department, Faculty of Science, Cairo University,
Giza, A. R. Egypt; and Department of Pesticidal Chemistry,
National Research Center, Dokki, Giza, A. R. Egypt
(Received February 12, 2004; accepted March 27, 2004)
Cyanothioacetamide (1) reacted with α,β-unsaturated carbonyl com-
pounds 2a–d to afford thioxohydropyridine-3-carbonitriles 5a–d,
which were used as the starting materials for the preparation of sev-
eral thienopyridines via their reactions with active halogen-containing
compounds, e.g., 2-bromo-1-phenylethanone (7a), 2-bromo-1-p-tolyl-
ethanone (7b), chloroacetone (10a), α-chloroacetylacetone (10b), and
chloroacetic acid ethyl ester (13). The structure of the newly synthesized
heterocyclic compounds were established based on the data of elemental
analyses, IR, 1H NMR, and mass spectra.
Keywords: 2-Methylthio-pyridines; 2-oxopropylthiopyridines; 3-
aminothieno[2,3-b]pyridines; cyanothioacetamide; thioxohydropy-
ridines
INTRODUCTION
In the last few years our group has been interested in the synthe-
sis of heterocyclic derivatives with potential biological activity, and
we have published several articles on this subject.1–17 On the other
hand, the reported biological activities of thioxohydropyridines18,19 and
thienopyridines20–22 stimulated our interest for the synthesis of several
derivatives of these ring systems that are required for the medicinal
chemistry program.
Address correspondence to Fawzy A. Attaby, Chemistry Department, Faculty of
Science, Cairo University, Giza, A. R. Egypt. E-mail: Fattaby@hotmail.com
2205

2206
F. A. Attaby et al.
RESULTS AND DISCUSSION
It has been found that the α,β-unsaturated ketones 2a–d reacted with
cyanothioacetamide (1) in ethanol in the presence of catalytic amounts
of piperidine to afford the corresponding 2-thioxohydropyridine-3-
carbonitrile derivatives 5a–d, respectively, via the nonisolable inter-
mediates 3a–d and 4a–d. The structure of 5a–d was established based
on elemental analyses, IR, and 1H NMR spectral data. The mass spec-
trum of 5d, as a typical example, gave m/z = 352, which is the molecular
weight of the molecular formula C23H16N2S of the assigned structure
(cf. Chart 1). Compounds 5a–d were taken as the starting materials for
the present study owing to the presence of more than one active center
in their structure.
Compound 5a reacted with methyl iodide in methanolic sodium
methoxide to give the corresponding 4-(1-naphthyl)-2-methylthio-
6-phenylpyridine-3-carbonitrile 6a, whose structure was elucidated
based on elemental analysis, IR, and 1H NMR spectral data. Other
analogues 5b–d were reacted similarly with methyl iodide to afford the
corresponding 2-methylthiopyridine-3-carbonitrile derivatives 6b–d,
respectively (Chart 1).
Similarly, 5a–d reacted with the ω-bromoacetophenone deriva-
tives 7a, b in methanolic sodium methoxide solution to give the
corresponding 2-aroyl-3-aminothieno[2,3-b]pyridine derivatives 9a–h.
Compounds 9a–h were most probably formed via the nonisolable in-
termediates 8a–h through dehydrobromination. Both the CH2 and the
CN groups were involved in the cyclization step to give the nonisolable
intermediates, which rearranged to give 9a–h (Chart 1).
The work was extended to shed more light on the reactivity of
5a–d towards the active halogen-containing reagents. Thus, 5a, b, d
reacted with chloroacetone (10a) and with α-chloroacetylacetone (10b)
in methanolic sodium methoxide to afford directly the corresponding
3-amino-2-acetylthieno[2,3-b]pyridine derivatives 12a, b, d respec-
tively, via the nonisolable intermediates 11a, b, d, e, f, h. The struc-
tures of 12a, b, d were established based on elemental analyses and
IR spectra. The mass spectrum of 12b as a typical example gave m/z =
408 which agreed with the molecular weight of a molecular formula
C26H20N2OS of the assigned structure (Chart 2). It is notable to re-
port here that all trials to isolate the intermediates 11a, b, d, e, f, h
were unsucessful under a variety of reaction conditions. Moreover,
an additional confirmation of the structures of 12a, b, d was achieved
via their alternative synthesis by the reaction of 5a, b, d with 10a, b
in boiling ethanol containing a catalytic amount of triethylamine
(Scheme 1).

Reactions of Cyanothioacetamide
2207
CHART 1

2208
F. A. Attaby et al.
CHART 2
In contrast to the behavior of 5a, b, d towards the reaction of 10a, b,
it has been found that compound 5c reacted with 10a, b to afford
the corresponding 4-(2-naphthyl)-2-(oxopropylthio)-6-phenylpyridine-
3-carbonitrile (11c) and 2-(1-acetyl-2-oxopropyl-thio)-4-(2-naphtyl)-6-
phenylpyridine-3-carbonitrile (11g), respectively. The IR spectra of
11c, g showed the presence of absorption bands of the nitrile function
1
and the acetyl CO group in their proper positions, while the H NMR

Reactions of Cyanothioacetamide
2209
SCHEME 1
spectrum of 11c revealed the signals of CH3, CH2, and aromatic protons;
the 1H NMR spectrum of 11g revealed the signals of two CH3, CH, and
aromatic protons. More evidence for the structure of 11c, g was obtained
through their cyclization using ethanolic potassium hydroxide solution
to afford the 2-acetyl-3-aminothieno[2,3-b] pyridine derivatives 12c, d.
The IR spectra of 12c, d showed no bands of the CN group, while the
1
bands of the newly born NH2 were detected and the H NMR spectra
revealed the signals of CH3, NH2, and the aromatic protons (Scheme 1).
Compounds 5a–d underwent a nucleophilic substitution reaction
with ethyl chloroacetate (13) in methanolic sodium methoxide to afford
the products corresponding to the dehydrochlorination reactions. The
IR spectra of such products showed the bands corresponding to CN and
ester-CO groups. By considering the above-mentioned data in addition
1
to the H NMR spectra and the chemical analyses data, such reaction
products could be formulated as the ethyl 2-[6-aryl-4-aryl-3-cyano-2-
pyridylthio]acetate derivatives 14a–d, respectively. Further confirma-
tion of the structure of each of 14a–d arose from their cyclization in
ethanolic potassium hydroxide (10% KOH) to give the corresponding

2210
F. A. Attaby et al.
ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate derivatives 15a–d.
The IR spectrum of each of 15a–d showed no bands of the CN func-
tion, while the bands of the newly formed NH2 group were detected. By
1
considering the above-mentioned data in addition to H NMR spectra
it can be proposed that both the CN and SCH2 groups were involved
in the cyclization step. Compounds 15a–d were also synthesized au-
thentically by heating 5a–d with ethyl chloroacetate (13) in ethano-
lic potassium hydroxide (10% KOH). It is remarkable to report here
that the compounds 15a–d obtained by the two pathways are iden-
tical in all physical and chemical properties (m.p., mixed m.p., and
IR).
The position and chemical reactivity of the ethoxycarbonyl group
in 15a–d were confirmed by their reaction with hydrazine hydrate.
Thus, 15a reacted with hydrazine hydrate in boiling ethanol to give a
product of a molecular formula corresponding to simple addition of one
molecule of 15a to one molecule of hydrazine hydrate, followed by loss
of ethanol. An elemental analysis of the reaction product gave the data
corresponding to a molecular formula C24H18N4OS, and its IR spectrum
showed no bands of the ester-CO, group, while the bands related to the
NH, two NH2 and hydrazidic-CO groups were detected. By considering
the above-mentioned data in addition to 1H NMR spectrum, this reac-
tion product could be formulated as N-amino[3-amino-4-(1-naphthyl)-
6-phenylthieno[2,3-b]pyridin-2-yl]carboxamide (16a) (Chart 2).
Similarly, 15b–d reacted with hydrazine hydrate to furnish
the corresponding N-amino(3-amino-4,6-diarylthieno[2,3-b]pyridin-2-
yl]carboxamides 16b–d, whose structures were also confirmed by el-
emental analysis and spectral data studies. The mass spectrum of 16c,
as a typical example, gave m/z = 410, which agreed with the molecular
weight of the molecular formula C24H18N4OS of the assigned structure
(Chart 2).
EXPERIMENTAL
All melting points are uncorrected. IR (KBr discs) were recorded on
Shimadzu FTIR-8201PC Spectrophotometer. 1H NMR spectra were
recorded on Varian Mercury 300 MHz. and Varian Gemini 200
MHz. Spectrometers using TMS as an internal standard and CDCl3,
DMSO-d6 and (CD3)2CO as solvents and chemical shifts are expressed
as δ ppm units. Mass spectra were recorded on Shimadzu GCMS-
QP1000EX using inlet type at 70 eV. Microanalyses were performed
by the Microanalytical Center of Cairo University.

Reactions of Cyanothioacetamide
2211
Synthesis of 5a–d: General Method
A solution of each of 1 (1 g) and 2a–d (2.58 g, 2.72 g, 2.58 g, and 2.72 g,
respectively) 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 then evaporated till dryness and cooled and titurated with
ethanol. The product formed was collected by filtration, washed with
cold ethanol, and then crystallized from the proper solvent to give the
corresponding 5a–d, respectively.
4-(1-Naphthyl)-6-phenyl-2-thioxohydropyridine-3-
carbonitrile (5a)
Crystallized from ethanol as orange crystals (70%), m.p. 264–266◦C.
1
IR (ν cm−1): 3346 (NH), 3051 (aromatic-CH) and 2217 (CN). H NMR
(δ ppm): 5.25 (s, br., 1H, NH) and 7.25–7.99 (m, 13H, ArH’s). Anal. for
C22H14N2S (338.43) Calcd. (%): C, 78.08; H, 4.17; N, 8.28; S, 9.47; Found:
C, 78.3; H, 4.0; N, 8.5; S, 9.3.
6-(4-Methylphenyl)-4-(1-naphthyl)-2-thioxohydropyridine-
3-carbonitrile (5b)
Crystallized from ethanol as yellow crystals (72%), m.p. 258–259◦C.
IR (ν cm−1): 3217 (NH), 3049 (aromatic-CH), 2931 (sat. CH) and
2209(CN). 1H NMR (δppm): 2.83 (s. 3H, CH3), 5.28 (s, br., 1H, NH) and
7.25–7.97 (m, 12H, ArH’s). Anal. for C23H16N2S (352.46): Calcd. (%): C,
78.38; H, 4.58; N, 7.95; S, 9.10. Found: C, 78.1; H, 4.8; N, 7.7; S, 9.4.
4-(2-Naphthyl)-6-phenyl-2-thioxohydropyridine-3-
carbonitrile (5c)
Crystallized from ethanol as yellow crystals (85%), m.p. 252–254◦C.
1
IR (ν cm−1): 3339 (NH), 3051 (aromatic-CH) and 2219 (CN). H NMR
(δ ppm): 5.67 (s, br., 1H, NH) and 7.18–8.08 (m, 13H, ArH’s). Anal.
for C22H14N2S (338.43): Calcd. (%): C, 78.08; H, 4.17; N, 8.28; S, 9.47.
Found: C, 78.4; H, 4.4; N, 8.0; S, 9.1.
6-(4-Methylphenyl)-4-(2-naphthyl)-2-thioxohydropyridine-
3-carbonitrile (5d)
Crystallized from ethanol as orange crystals (87%), m.p. 250–252◦C;
IR (ν cm−1): 3317 (NH), 3056 (aromatic-CH), 2937 (sat. CH) and 2218
1
(CN). H NMR (δ ppm): 2.91 (s. 3H, CH3), 5.56 (s, br., 1H, NH) and
7.23–7.87 (m, 12H, ArH’s). Anal. for C23H16N2S (352.46): Calcd. (%): C,
78.38; H, 4.58; N, 7.95; S, 9.10. Found: C, 78.5; H, 4.3; N, 7.7; S, 9.3.
Synthesis of 9a–h, 12a–d, and 15a–d: General Method
A solution of each of 5a–d (1.69 g, 1.76 g, 1.69 g, and 1.76 g, respectively)
in ethanol and potassium hydroxide solution (10 ml of 10% KOH) was

2212
F. A. Attaby et al.
heated with each of 7a (0.99 g), 7b (1.16 g), 10a (0.46 g), 10b (0.67 g),
and 13 (0.61 g) under reflux for 2–3 h. The reaction mixture was cooled,
poured into ice-cold water, and acidified with hydrochloric acid. The
product formed was collected by filtration, washed with water followed
by cold ethanol, and crystallized from the proper solvent to give 9a–h,
12a–d, and 15a–d, respectively.
3-Amino-2-benzoyl-4-(1-naphthyl)-6-phenylthieno-
[2,3-b]pyridine (9a)
Crystallized from ethanol as yellow crystals (78%); m.p. 174◦C; IR
(ν cm−1): 3446, 3316 (NH2) and 3021 (aromatic-CH); 1H NMR (δ ppm):
6.14 (s, br., 2H, NH2) and 7.29–8.11 (m, ArH’s). Anal. for C30H20N2OS
(456.57): Calcd. (%) C, 78.92; H, 4.42; N, 6.14; S, 7.02. Found: C, 78.7;
H, 4.6; N, 6.5; S, 7.4.
3-Amino-2-benzoyl-6-(4-methylphenyl)-4-(1-naphthyl)-
thieno[2,3-b]pyridine (9b)
Crystallized from ethanol as yellow crystals (79%), m.p. 182◦C; IR
(ν cm−1): 3437, 3306 (NH2), 3042 (aromatic-CH) and 2931 (sat. CH). 1H
NMR (δ ppm): 2.75 (s, 3H, CH3), 6.11 (s, br., 2H, NH2) and 7.26–8.07
(m, 17H, ArH’s). Anal. for C31H22N2OS (470.60): Calcd. (%): C, 79.12;
H, 4.71; N, 5.95; S, 6.81. Found: C, 79.4; H, 4.5; N, 5.8; S, 6.6.
3-Amino-2-benzoyl-4-(2-naphthyl)-6-phenylthieno[2,3-
b]pyridine (9c)
Crystallized from ethanol as yellow crystals (73%), m.p. 198◦C; IR (ν
cm−1) 3443, 3322 (NH2) and 3021 (aromatic-CH). 1H NMR (δ ppm): 6.41
(s, br., 2H, NH2) and 7.23–7.95 (m, 18H, ArH’s). Anal. for C30H20N2OS
(456.57): Calcd. (%): C, 78.92; H, 4.42; N, 6.14; S, 7.02. Found: C, 79.1;
H, 4.2; N, 6.3; S, 7.2.
3-Amino-2-benzoyl-6-(4-methylphenyl)-4-(2-naphthyl)-
thieno[2,3-b]pyridine (9d)
Crystallized from ethanol as yellow crystals (78%), m.p. 182◦C; IR
(ν cm−1): 3431, 3315 (NH2), 3027 (aromatic-CH) and 2924 (sat. CH). 1H
NMR (δ ppm): 3.03 (s, 3H, CH3), 5.88 (s, br., 2H, NH2) and 7.27–7.84
(m, 17H, ArH’s). Anal. for C31H22N2OS (470.60): Calcd. (%): C, 79.12;
H, 4.71; N, 5.95; S, 6.81. Found: C, 79.4; H, 4.9; N, 5.7; S, 7.1.
3-Amino-2-(4-chlorobenzoyl)-4-(1-naphthyl)-6-phenyl-
thieno[2,3-b]pyridine (9e)
Crystallized from ethanol as yellow crystals (75%), m.p. 194◦C; IR
(ν cm−1): 3437, 3332 (NH2), and 3026 (aromatic-CH). 1H NMR (δ
ppm): 6.27 (s, br., 2H, NH2) and 7.27–7.93 (m, 17H, ArH’s). Anal. for
C30H19N2OSCl (491.02): Calcd. (%): C, 73.39; H, 3.90; N, 5.71; S, 6.53;
Cl, 7.22. Found: C, 73.5; H, 3.7; N, 5.9; S, 6.2; Cl, 7.5.

Reactions of Cyanothioacetamide
2213
3-Amino-2-(4-chlorobenzoyl)-4-(1-naphthyl)-6-(4-
methylphenyl)thieno-[2,3-b]-pyridine (9f)
Crystallized from ethanol as yellow crystals (77%), m.p. 186◦C; IR
(ν cm−1): 3446, 3317 (NH2), 3019 (aromatic-CH) and 2927 (sat. CH). 1H
NMR (δ ppm): 2.92 (s, 3H, CH3), 5.78 (s, br., 2H, NH2) and 7.29–7.91
(m, 16H, ArH’s). Anal. for C31H21N2OSCl (505.04): Calcd. (%): C, 73.73;
H, 4.19; N, 5.55; S, 6.35; Cl, 7.02. Found: C, 73.6; H, 4.2; N, 5.7; S, 6.1;
Cl, 7.2.
3-Amino-2-(4-chlorobenzoyl)-4-(2-naphthyl)-6-phenyl-
thieno[2,3-b]pyridine (9g)
Crystallized from ethanol as yellow crystals (76%), m.p. 184◦C; IR
(ν cm−1): 3443, 3322 (NH2) and 3021 (aromatic-CH). 1H NMR (δ
ppm): 6.09 (s, br., H, NH2) and 7.23–7.85 (m, 17H, ArH’s). Anal. for
C30H19N2OSCl (491.02): Calcd. (%): C, 73.39; H, 3.90; N, 5.71; S, 6.53;
Cl, 7.22. Found: C, 73.2; H, 3.6; N, 5.5; S, 6.7; Cl, 7.5.
3-Amino-2-(4-chlorobenzoyl-4-(2-naphthyl)-6-(4-
methylphenyl)thieno[2,3-b]-pyridine (9h)
Crystallized from ethanol as yellow crystals (79%), m.p. 206–208◦C.
IR (ν cm−1): 3431, 3315 (NH2), 3027 (aromatic-CH) and 2924 (sat. CH).
1H NMR (δ ppm): 2.55 (s, 3H, CH3), 6.31 (s, br., 2H, NH2) and 7.23–8.03
(m, 16H, ArH’s). Anal. for C31H21N2OSCl (505.04): Calcd. (%): C, 73.73;
H, 4.19; N, 5.55; S, 6.35; Cl, 7.02. Found: C, 73.9; H, 4.0; N, 5.8; S, 6.0;
Cl, 7.4.
Ethyl 3-Amino-4-(1-naphthyl)-6-phenylthieno[2,3-b]-
pyridine-2-carboxylate (15a)
Crystallized from ethanol as yellow crystals (76%), m.p. 208–210◦C;
IR (ν cm−1): 3446, 3287 (NH2), 3057 (aromatic-CH) and 2931 (sat. CH).
1H NMR (δ ppm): 0.71 (t, 3H, J = 7.2 Hz, CH2CH3), 3.93 (d, 2H, J =
7.2 Hz, CH2CH3) 5.96 (s, br., 2H, NH2) and 7.24–8.04 (m, 12H, ArH’s).
Anal. for C26H20N2O2S (424.53): Calcd. (%): C, 73.56; H, 4.75; N, 6.60;
S, 7.55. Found: C, 73.4; H, 4.9; N, 6.4; S, 7.4.
Ethyl 3-Amino-6-(4-methylphenyl)-4-(1-naphthyl)
thieno[2,3-b]pyridine-2-carboxylate (15b)
Crystallized from ethanol as orange crystals (81%), m.p. 236–238◦C;
IR (ν cm−1): 3446, 3287 (NH2), 3057 (aromatic-CH) and 2931 (sat. CH).
1H NMR (δ ppm): 0.58 (t, 3H, J = 7.1 Hz, CH2CH3), 3.02 (s, 3H, CH3),
3.92 (q, 2H, J = 7.1 Hz, CH2CH3) 5.74 (s, br., 2H, NH2) and 7.22–8.06

2214
F. A. Attaby et al.
(m, 12H, ArH’s). Anal. for C27H22N2O2S (438.55): Calcd. (%): C, 73.95;
H, 5.06; N, 6.39; S, 7.31. Found: C, 73.8; H, 5.2; N, 6.7; S, 7.6.
Ethyl 3-Amino-4-(2-naphthyl)-6-phenylthieno[2,3-b]-
pyridine-2-carboxylate (15c)
Crystallized from ethanol as yellow crystals (86%), m.p. 228–230◦C;
IR (ν cm−1): 3419, 3287 (NH2), 3052 (aromatic-CH) and 2953 (sat.
CH). 1H NMR (δ ppm): 0.61 (t, 3H, J = 7.0 Hz, CH2CH3), 3.84
(q, 2H, J = 7.0 Hz, CH2CH3), 6.17 (s, br., 2H, NH2) and 7.24–
7.83 (m, 12H, ArH’s). Anal. for C26H20N2O2S (424.53): Calcd. (%):
C, 73.56; H, 4.75; N, 6.60; S, 7.55. Found: C, 73.7; H, 4.6; N, 6.9;
S, 7.2.
Ethyl 3-Amino-6-(4-methylphenyl)-4-(2-naphthyl)-
thieno[2,3-b]pyridine-2-carboxylate (15d)
Crystallized from ethanol as orange crystals (78%), m.p. 224–226◦C;
IR (ν cm−1): 3417, 3287 (NH2), 3041 (aromatic-CH) and 2943 (sat. CH).
1H NMR (δ ppm): 0.48 (t, 3H, J = 7.1 Hz, CH2CH3), 2.98 (s, 3H, CH3),
3.71 (q, 2H, J = 7.1 Hz, CH2CH3) 5.42 (s, br., 2H, NH2) and 7.27–7.98
(m, 12H, ArH’s). Anal. for C27H22N2O2S (438.55): Calcd. (%): C, 73.95;
H, 5.06; N, 6.39; S, 7.31. Found: C, 73.7; H, 5.2; N, 6.6; S, 7.1.
Synthesis of 6a–d, 11c, g, 12a, b, d, e, f, h, 14a–d:
General Method
A mixture of each of 5a–d (1.69 g, 1.76 g, 1.69 g, and 1.76 g) in methano-
lic sodium methoxide (prepared from 0.12 g of sodium metal in 10 ml
methanol) and each of methyl iodide (1.4 g), 10a (0.46 g), 10b (0.67 g),
and 13 (0.61 g) was heated under reflux for 2–3 h. The reaction mixture
was evaporated to dryness and then cooled and titurated with ethanol
was collected by filtration. Crystallization from the proper solvent gave
the corresponding products 6a–d, 11c, g, 12a,b, d, e, f, h, and 14a–d,
respectively.
Another Method for Synthesis of 12a, b, d, e, f, h
A mixture of each of 5a (1.69 g), 5b (1.76 g), 5d (1.76 g) and each of
10a (0.46 g), 10b (0.67 g) in methanolic sodium methoxide (prepared
as above) was stirred for 3–4 h. The product formed was collected by
filtration, washed with cold ethanol, and then crystallized from the
proper solvent to give 12a, b, d, e, f, h, respectively.

Reactions of Cyanothioacetamide
2215
2-Methylthio-4-(1-naphthyl)-6-phenylpyridine-3-
carbonitrile (6a)
Crystallized from ethanol as white crystals (91%), m.p. 174◦C; IR
(ν cm−1): 3056 (aromatic-CH), 2963 (sat. CH) and 2212 (CN). 1H NMR
(δ ppm): 2.69 (s, 3H, -S-CH3) and 7.23–7.97 (m, 13H, ArH’s). Anal. for
C23H16N2S (352.45): Calcd. (%): C, 78.38; H, 4.58; N, 7.95; S, 9.10. Found:
C, 78.5; H, 4.4; N, 7.6; S, 9.3.
6-(4-Methylphenyl)-2-methylthio-4-(1-naphthyl)pyridine-3-
carbonitrile (6b)
Crystallized from ethanol as white crystals (87%), m.p. 154◦C. IR
(ν cm−1): 3058 (aromatic-CH); 2964 (sat. CH) and 2212 (CN). 1H NMR
(δ ppm): 2.63 (s, 3H, CH3), 2.85 (s, 3H, S CH3) and 7.31–7.89 (m, 12H,
ArH’s). Anal. for C24H18N2S (366.49): Calcd.: C, 78.66; H, 4.95; N, 7.64;
S, 8.75. Found: C, 78.9; H, 4.7; N, 7.9; S, 8.9.
2-Methylthio-4-(2-naphthyl)-6-phenylpyridine-3-
carbonitrile (6c)
Crystallized from ethanol as white crystals (88%), m.p. 186◦C; IR
1
(ν cm−1): 3051 (aromatic-CH) and 2219 (CN). H NMR (δ ppm): 2.70
(s, 3H, S CH3) and 7.24–7.83 (m, 13H, ArH’s). Anal. for C23H16N2S
(352.46): Calcd. (%): C, 78.38; H, 4.58; N, 7.95; S, 9.10. Found: C, 78.6;
H, 4.4; N, 7.7; S, 8.8.
6-(4-Methylphenyl)-2-methylthio-4-(2-naphthyl)pyridine-3-
carbonitrile (6d)
Crystallized from ethanol as white crystals (82%), m.p. 164◦C; IR
(ν cm−1): 3058 (aromatic-CH), 2964 (sat. CH) and 2212 (CN). 1H NMR
(δ ppm): 2.6 (s, 3H, CH3), 2.7 (s, 3H, S CH3) and 7.2–7.9 (m, 12H,
ArH’s). Anal. for C24H18N2S (366.49): Calcd. (%): C, 78.66; H, 4.95; N,
7.64; S, 8.75. Found: C, 78.5; H, 4.7; N, 7.7; S, 9.0.
2-Acetyl-3-amino-4-(1-naphthyl)-6-phenylthieno[2,3-
b]pyridine (12a)
Crystallized from ethanol as yellow crystals (77%), m.p. 210–212◦C.
IR (ν cm−1): 3447, 3312 (NH2), 3021 (aromatic-CH) and 2923 (sat. CH).
1H NMR (δ ppm): 3.44 (s, 3H, COCH3), 6.42 (s, br., 2H, NH2), and 7.28–
7.97 (m, 13H, ArH’s). Anal. for C25H18N2OS (394.50): Calcd. (%): C,
76.12; H, 4.60; N, 7.10; S, 8.13. Found: C, 76.3; H, 4.9; N, 6.8; S, 8.3.

2216
F. A. Attaby et al.
2-Acetyl-3-amino-6-(4-methylphenyl)-4-(1-naphthyl)-
thieno[2,3-b]pyridine (12b)
Crystallized from ethanol as yellow crystals (86%), m.p. 176◦C; IR
(ν cm−1): 3441, 3315 (NH2), 3019 (aromatic-CH) and 2916 (sat. CH). 1H
NMR (δ ppm): 2.81 (s, 3H, CH3), 3.22 (s, 3H COCH3), 5.63 (s, br., 2H,
NH2) and 7.31–8.06 (m, 12H, ArH’s). Anal. for C26H20N2OS (408.53):
Calcd. (%): C, 76.44; H, 4.93; N, 6.86; S, 7.85. Found: C, 76.1; H, 5.2;
N, 6.6; S, 7.5.
2-Acetyl-3-amino-4-(2-naphthyl)-6-phenylthieno[2,3-b]-
pyridine (12c)
Crystallized from ethanol as yellow crystals (89%); m.p. 244–246◦C;
IR (ν cm−1): 3427, 3297 (NH2), 3024 (aromatic-CH) and 2921 (sat. CH);
1H NMR (δ ppm): 3.37 (s, 3H, COCH3), 6.10 (s, br., 2H, NH2), and 7.36–
8.17 (m, 13H, ArH’s); Anal. for C25H18N2OS (394.50): Calcd. (%): C,
76.12; H, 4.60; N, 7.10; S, 8.13. Found: C, 76.4; H, 4.4; N, 7.4; S, 8.13.
2-Acetyl-3-amino-6-(4-methylphenyl)-4-(2-naphthyl)-
thieno[2,3-b]pyridine (12d)
Crystallized from ethanol as yellow crystals (78%), m.p. 220–222◦C;
IR (ν cm−1): 3446, 3313 (NH2), 3052 (aromatic-CH) and 2926 (sat. CH).
1H NMR (δ ppm): 2.72 (s, 3H, CH3), 3.46 (s, 3H COCH3), 5.91 (s, br., 2H,
NH2) and 7.33–7.90 (m, 12H, ArH’s). Anal. for C26H20N2OS (408.53):
Calcd. (%): C,76.44; H, 4.93; N, 6.86; S, 7.85. Found: C, 76.7; H, 4.6;
N, 6.4; S, 7.5.
Synthesis of 11c, g and 14a–d: General Method
A solution of each of 5c (1.69 g) and 5a–d (1.69 g, 1.76 g, 1.69 g, and
1.76 g, respectively) in sodium methoxide (prepared as above) and 10a
(0.46 g), 10b (0.67 g), and 13 (0.61 g) was stirred for 2–3 h. The product
formed was collected by filtration, washed with cold ethanol, and then
crystallized from the proper solvent to give the products 11c, g and
14a–d, respectively.
4-(2-Naphthyl)-2-(2-oxopropylthio)-6-phenylpyridine-3-
carbonitrile (11c)
Crystallized from ethanol as yellow crystals (77%), m.p. 160◦C; IR
1
(ν cm−1): 3021 (aromatic-CH), 2212 (CN) and 1722 (ketonic-CO). H
NMR (δ ppm): 3.02 (s, 2H, CH2), 3.33 (s, 3H, CH3) and 7.32–8.18 (m,
13H, ArH’s). Anal. for C25H18N2OS (394.50): Calcd. (%): C, 76.12; H,
4.60; N, 7.10; S, 8.13. Found: C, 76.3; H, 4.8; N, 6.9; S, 8.3.

Reactions of Cyanothioacetamide
2217
2-[1-Acetyl-2-(oxopropylthio)]-4-(2-naphthyl)-6-phenyl-
pyridine-3-carbonitrile (11g)
Crystallized from ethanol as brown crystals (81%), m.p. 202–204◦C;
IR (ν cm−1): 3049 (aromatic-CH), 2974 (sat. CH), 2218 (CN) and 1702
(ketonic-CO). 1H NMR (δ ppm): 3.23 (s, 1H, CH), 3.46 (s, 6H, two CH3)
and 7.34–8.11 (m, 13H, ArH’s). Anal. for C27H20N2O2S (436.54): Calcd.
(%): C, 74.29; H, 4.62; N, 6.42; S, 7.35. Found: C, 74.5; H, 4.7; N, 6.1; S,
7.6.
Ethyl 2-[3-Cyano-4-(1-naphthyl)-6-phenylpyrid-2-ylthio]-
acetate (14a)
Crystallized from ethanol as white crystals (91%), m.p. 162◦C; IR
(ν cm−1): 3033 (aromatic-CH), 2929 (sat. CH), 2217 (CN) and 1738
1
(ester-CO). H NMR (δ ppm): 0.91 (t, 3H, J = 7.1 Hz, CH2CH3), 3.42
(s, 2H, CH2), 4.15 (q, 2H, J = 7.1 Hz, CH2CH3) and 7.26–7.99 (m, 13H,
ArH’s). Anal. for C26H20N2O2S (424.53): Calcd. (%): C, 73.56; H, 4.75;
N, 6.60; S, 7.55. Found: C, 73.7; H, 4.4; N, 6.7; S, 7.9.
Ethyl 2-[3-Cyano-6-(4-methylphenyl)-4-(1-naphthyl)pyrid-
2-ylthio]acetate (14b)
Crystallized from ethanol as orange crystals (79%), m.p. 188◦C. IR
(ν cm−1): 3037 (aromatic-CH), 2931 (sat. CH), 2215 (CN) and 1728
1
(ester-CO). H NMR (δ ppm): 1.03 (t, 3H, J = 7.2 Hz, CH2CH3), 2.84
(s, 3H, CH3), 3.22 (s, 2H, CH2), 4.02 (q, 2H, J = 7.2 Hz, CH2CH3)
and 7.23–7.95 (m, 12H, ArH’s). Anal. for C27H22N2O2S (438.55): Calcd.
(%): C, 73.95; H, 5.06; N, 6.39; S, 7.31. Found: C, 74.1; H, 4.8; N, 6.6;
S, 7.1.
Ethyl 2-[3-Cyano-4-(2-naphthyl)-6-phenylpyrid-2-ylthio]-
acetate (14c)
Crystallized from ethanol as white crystals (90%), m.p. 176◦C; IR
(ν cm−1): 3041 (aromatic-CH), 2935 (sat. CH), 2220 (CN) and 1729
1
(ester-CO). H NMR (δ ppm): 0.87 (t, 3H, J = 6.9, Hz, CH2CH3), 3.11
(s, 2H, CH2), 4.20 (q, 2H, J = 6.9 Hz, CH2CH3) and 7.23–7.83 (m, 13H,
ArH’s). Anal. for C26H20N2O2S (424.53): Calcd. (%): C, 73.56; H, 4.75;
N, 6.60; S, 7.55. Found: C, 73.4; H, 4.6; N, 6.5; S, 7.8.
Ethyl 2-[3-Cyano-6-(4-methylphenyl)-4-(2-naphthyl)pyrid-
2-ylthio]acetate (14d)
Crystallized from ethanol as white crystals (87%), m.p. 196◦C; IR
(ν cm−1): 3037 (aromatic-CH), 2946 (sat. CH), 2223 (CN) and 1733
1
(ester-CO). H NMR (δ ppm): 0.91 (t, 3H, J = 7.0 Hz, CH2CH3), 2.79
(s, 3H, CH3), 3.37 (s, 2H, CH2), 4.02 (q, 2H, J = 7.0 Hz, CH2CH3) and

2218
F. A. Attaby et al.
7.23–8.09 (m, 12H, ArH’s). Anal. for C27H22N2O2S (438.55): Calcd. (%):
C, 73.95; H, 5.06; N, 6.39; S, 7.31. Found: C, 74.7; H, 5.1; N, 6.4; S, 7.1.
Synthesis of 16a–d: General Method
A mixture of each of 14a–d (0.01 mole of each) and hydrazine hydrate
(20–25 ml) was heated under reflux for 6–8 h. The product formed after
cooling was filtrated off, washed with cold ethanol and crystallized from
the proper solvent to give the products 16a–d, respectively.
N-Amino-[3-amino-4-(1-naphthyl)-6-phenylthieno[2,3-b]-
pyridin-2-yl]carboxamide (16a)
Crystallized from ethanol as yellow crystals (70%), m.p. 248–250◦C.
IR (ν cm−1): 3451, 3325, 3217, 3161 (two NH2, NH), 3029 (aromatic-CH)
1
and 1687 (amidic-CO). H NMR (δ ppm): 3.82 (s, br., 2H, thiophene-
NH2), 5.84 (s, br., 2H, CONHNH2), 6.27 (s, br., 1H, CONHNH2) and
7.23–7.97 (m, 13H, ArH’s). Anal. for C24H18N4OS (410.50): Calcd. (%):
C, 70.22; H, 4.42; N, 13.65; S, 7.81. Found: C, 70.4; H, 4.2; N, 13.8;
S, 7.7.
N-Amino-[3-amino-6-(4-methylphenyl)-4-(1-naphthyl)-
thieno[2,3-b]pyri-din-2-yl]carboxamide (16b)
Crystallized from ethanol as yellow crystals (79%), m.p. 240–242◦C;
IR (ν cm−1): 3447, 3307, 3231, 3172 (two NH2, NH), 3039 (aromatic-CH),
1
2943 (sat. CH) and 1677 (amidic-CO). H NMR (δ ppm): 2.76 (s, 3H,
CH3), 3.85 (s, br., 2H, thiophene-NH2), 5.84 (s, br., 2H, CONHNH2),
6.21 (s, br., 1H, CONHNH2) and 7.21–7.99 (m, 12H, ArH’s). Anal. for
C25H20N4OS (424.53): Calcd. (%): C, 70.73; H, 4.75; N, 13.20; S, 7.55.
Found: C, 70.9; H, 4.9; N, 13.5; S, 7.3.
N-Amino-[3-amino-4-(2-naphthyl)-6-phenylthieno[2,3-b]-
pyridin-2-yl]carboxamide (16c)
Crystallized from ethanol as yellow crystals (69%), m.p. 244–246◦C;
IR (ν cm−1): 3445, 3323, 3251, 3168 (two NH2, NH), 3037 (aromatic-CH)
1
and 1683 (amidic-CO). H NMR (δ ppm): 3.62 (s, br., 2H, thiophene-
NH2), 5.75 (s, br., 2H, CONHNH2), 6.18 (s, br., 1H, CONHNH2) and
7.33–8.12 (m, 13H, ArH’s). Anal. for C24H18N4OS (410.50): Calcd. (%):
C, 70.22; H, 4.42; N, 13.65; S, 7.81. Found: C, 70.0; H, 4.7; N, 13.4;
S, 8.0.

Reactions of Cyanothioacetamide
2219
N-Amino-[3-amino-6-(4-methylphenyl)-4-(2-naphthyl)-
thieno[2,3-b]pyridin-2-yl]carboxamide (16d)
Crystallized from ethanol as yellow crystals (66%), m.p. 236–823◦C;
IR (ν cm−1): 3443, 3315, 3247, 3168 (two NH2, NH), 3024 (aromatic-
1
CH), 2950 (sat. CH) and 1686 (amidic-CO). H NMR (δ ppm): 2.93 (s,
3H, CH3), 3.71 (s, br., 2H, thiophene-NH2), 5.43 (s, br., 2H, CONHNH2),
7.27–8.03 (m, 12H, ArH’s), and 8.77 (s, br., 1H, CONHNH2); Anal. for
C25H20N4OS (424.53): Calcd. (%): C, 70.73; H, 4.75; N, 13.20; S, 7.55.
Found: C, 70.5; H, 4.4; N, 13.5; S, 7.6.
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