SYNTHESIS OF SOME 2-(SUBSTITUTED THIO)PYRIDINES AND THIENOPYRIDINES

Full text of DOI:10.1135/cccc19940978

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Abdel-Monem:
SYNTHESIS OF SOME 2-(SUBSTITUTED THIO)PYRIDINES
AND THIENO[2,3-b]PYRIDINES
Maisa I. ABDEL-MONEM
Department of Chemistry,
Faculty of Science, Assiut University, Assiut 71516, Egypt
Received April 16, 1993
Accepted September 27, 1993
Pyridine heterocycles occupy a unique position in medicinal chemistry. The naturally
occurring B6 vitamine (pyridoxol, pyridoxal, pyridoxamine), some alkaloids and
coenzymes1 contain pyridine nucleus. Many thienopyridine derivatives have been in-
vestigated because of the various biological activities such as against diabetes mellitus,
as analgetics, anti-inflammatories, sedatives, and anticoagulants2 – 10
.
EXPERIMENTAL
All melting points are uncorrected. IR spectra (KBr, cm−1) were recorded on a Pye–Unicam SP 3-100
1
spectrophotometer. The H NMR spectra (δ, ppm) were recorded on a Varian EM-390 90 MHz NMR
spectrometer using TMS as internal standard. The mass spectra were obtained using an AET MS-9
mass spectrophotometer operating at 70 eV. The yields, melting points and analytical data of all re-
ported compounds are given in Table I.
3-Cyano-6-(4-hydroxyphenyl)-2-mercapto-4-phenylpyridine (IIa)
A mixture of chalcone I (2.91 g, 13 mmol) and cyanothioacetamide (1.3 g, 13 mmol) in sodium
methoxide solution (1 g sodium dissolved in 50 ml absolute methanol) was heated to 50 °C for 48 h.
The reaction mixture was acidified with dilute HCl. The crystalline compound thus formed was col-
lected and recrystallized from ethanol as orange prisms. IR spectrum: 3 450 (OH); 2 200 (C≡N);
1 600 (C=N).
3-Cyano-6-(4-hydroxyphenyl)-2-methylthio-4-phenylpyridine (IIb)
A mixture of IIa (3.04 g, 10 mmol), methyl iodide (0.71 g, 15 mmol) and anhydrous sodium acetate
(2 g) in ethanol (50 ml) was refluxed for 3 h, then allowed to cool and diluted with water. The pre-
cipitated solid was collected and recrystallized from ethanol to form buff needles. IR spectrum: 3 440
(OH); 2 220 (C≡N).
Ethyl-4-(3-cyano-2-methylthio-4-phenyl-2-pyridyl) Phenoxyacetate (IIIa)
To a suspension of IIb (3.18 g, 10 mmol) and anhydrous potassium carbonate (1.51 g, 11 mmol) in
acetone (50 ml), ethyl chloroacetate (1.07 ml, 10 mmol) was added. The mixture was refluxed for
21 h, then allowed to cool and diluted with water. The product thus precipitated was collected by
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filtration and crystallized from ethanol as pale yellow needles. 1H NMR spectrum (CD3SOCD3):
1.4 t, 3 H (C−CH3); 2.6 s, 3 H (SCH3); 4.3 q, 2 H (CH2); 4.7 s, 2 H (OCH2); 7.0 – 8.0 m, 10 H
(arom.). IR spectrum: 2 955 (−CH aliph.); 2 200 (C≡N); 1 740 (C=O).
4-(3-Cyano-2-methylthio-4-phenyl-6-pyridyl)phenoxyacethydrazide (IIIb)
A mixture of ester IIIa (4.04 g, 10 mmol) and 99% hydrazine hydrate (0.5 ml, 10 mmol) in absolute
ethanol (50 ml) was refluxed for 8 h. The solid product was collected and recrystallized from dioxane
as white needles. 1H NMR spectrum (CDCl3): 2.5 s, 3 H (CH3); 4.7 s, 2 H (OCH2); 5.1 s, 2 H
(NH2); 9.3 s, 1 H (NH); 7.3 – 8.7 m, 10 H (arom.). IR spectrum: 3 100, 3 265 (NHNH2); 2 200
(C≡N); 1 710 (C=O).
N1-[4-(3-Cyano-2-methylthio-4-phenyl-6-pyridyl)phenoxyacetyl]-N4-phenyl-
3-thiosemicarbazide (IIIc)
A mixture of IIIb (3.90 g, 10 mmol) and phenylisothiocyanate (1.27 ml, 10 mmol) in absolute ethanol
(40 ml) was refluxed for 3 h. The crystalline product was collected and recrystallized from dioxane
as white crystals. IR spectrum: 3 360, 3 200 (NH); 2 215 (C≡N); 1 720 (C=O).
3-Cyano-6-[4-3′,5′-dimethylpyrazol-1′-yl)carbonylmethoxyphenyl]-2-methylthio-
4-phenylpyridine (IIId)
To a mixture of IIIb (1.95 g, 5 mmol) and acetylacetone (0.5 ml, 5 mmol) in ethanol (30 ml), few
drops of glacial acetic acid was added. The resulting mixture was refluxed for 3 h, concentrated and
allowed to cool. The separated product was collected and recrystallized from ethanol as white
1
needles. H NMR spectrum (CD3SOCD3): 2.4 s, 3 h (CH3); 2.6 s, 3 H (CH3); 2.9 s, 3 H (SCH3); 4.6 s,
2 H (OCH2); 5.7 s, 1 H (CH-pyrazole); 7.1 – 7.7 m, 10 H (arom.). IR spectrum: 2 910 (CH aliph.);
2 220 (C≡N); 1 710 (C=O).
N1-Arylidene-4-(3-cyano-2-methylthio-4-phenyl-6-pyridyl)phenoxyacethydrazides (IVa – IVd)
To a solution of IIIb (3.90 g, 10 mmol) in ethanol (30 ml), an ethanolic solution of appropriate alde-
hyde (10 mmol) was added. The resulting mixture was refluxed for 4 h. On cooling, the product was
collected and recrystallized from dioxane, dioxane–ethanol or ethanol as needle crystals. IR spectra
of compounds IVa – IVd: 3 200 – 3 230 (NH); 2 215 – 2 220 (C≡N); 1 670 – 1680 (C=O).
3-Cyano-2-methylthio-6-[4-(4′-phenyl-5-thioxo-3,4-dihydro-1,2,4-triazol-3-ylmethoxy)phenyl]-
4-phenylpyridine (V)
Compound IIIc (5.25 g, 10 mmol) was dissolved in alcoholic sodium hydroxide solution (8%, 20 ml)
and heated on a water bath for 3 h. The solution was filtered and the clear filtrate was acidified with
dilute HCl. The separated product was collected, dried and crystallized from dioxane as white
needles. 1H NMR spectrum (CD3SOCD3): 2.3 s, 3 H (SCH3); 5.2 s, 2 H (OCH2); 10.5, 1 H (NH);
8.0 – 7.3 m, 15 H (arom.). IR spectrum: 3 450 (NH); 2 210 (C≡N); 1 600 (C=N).
Ethyl[3-Cyano-6-(4-hydroxyphenyl)-4-phenyl-2-pyridylthio]acetate (VIa)
To a suspension of IIa (3.04 g, 10 mmol) and anhydrous sodium acetate (2 g) in ethanol (50 ml),
ethyl chloroacetate (1.07 ml, 10 mmol) was added. The mixture was refluxed for 3 h and allowed to
cool. The precipitated product was filtered, washed with water and recrystallized from ethanol as buff
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1
crystals. H NMR spectrum (CD3SOCD3): 1.5 t, 3 H (CH3); 3.5 s, 2 H (SCH2); 4.3 q, 2 H (C−CH2);
7.7 – 7.4 m, 10 H (arom.); 10.5 s, 1 H (OH). IR spectrum: 3 400 (OH); 2 220 (C≡N); 1 730 (C=O).
[3-Cyano-6-(4-hydroxyphenyl)-4-phenyl-2-pyridylthio]acethydrazide (VIb)
A mixture of VIa (4.78 g, 10 mmol) and 99% hydrazine hydrate (0.5 ml, 10 mmol) in absolute ethanol
(50 ml) was refluxed for 4 h. The precipitated product was collected and recrystallized from ethanol
as white needles. IR spectrum: 3 340 – 3 200 (NHNH2, OH); 2 210 (C≡N); 1 660 (C=O).
N1-[3-Cyano-6-(4-hydroxyphenyl)-4-phenyl-2-pyridylthio]acetyl-N4-phenyl-
3-thiosemicarbazide (VIc)
A mixture of VIb (3.76 g, 5 mmol) and phenyl isothiocyanate (0.64 ml, 5 mmol) in absolute ethanol
(50 ml) was refluxed for 4 h. The product was collected and recrystallized from dioxane as white
needles. IR spectrum: 3 400 – 3 240 (NH, OH); 2 215 (C≡N); 1 680 (C=O).
2-(3,5-Dimethylpyrazol-4-yl)carbonylmethylthio-3-cyano-6-(4-hydroxyphenyl)-
4-phenylpyridine (VId)
A mixture of VIb (1.88 g, 5 mmol) and acetylacetone (0.5 ml, 5 mmol) in absolute ethanol (50 ml)
was refluxed for 5 h. The reaction mixture was concentrated and the precipitated product was fil-
1
tered, dried and recrystallized from ethanol as white needles. H NMR spectrum (CD3SOCD3): 2.4 s,
3 H (CH3); 2.7 s, 3 H (CH3); 5.2 s, 2 H (SCH2); 6.7 s, 1 H (CH-pyrazole); 7.5 – 7.0 m, 10 H
(arom.); 9.7 s, 1 H (OH). IR spectrum: 3 410 (OH); 2 220 (C≡N); 1 675 (C=O).
N1-Arylidene-[3-cyano-6-(4-hydroxyphenyl)-4-phenyl-2-pyridylthio]acethydrazides (VIIa – VIIc)
To a solution of VIb (1.88 g, 10 mmol) in ethanol (40 ml), an ethanolic solution of the appropriate
aldehyde (10 mmol) was added. The resulting mixture was refluxed for 2 – 4 h. The solid product
was collected and recrystallized from the dioxane–water mixture or dioxane to give compounds VIIa – VIIc.
IR spectra: 3 440 – 3 450 (OH); 3 200 – 3 240 (NH); 2 210 – 2 220 (C≡N); 1 660 – 1 665 (C=O).
Cyclization of Compounds VIa, VId and VIIa – VIIc. General Procedure
Compound VIa, VId, VIIa, VIIb or VIIc (10 mmol) was suspended in sodium ethoxide solution
(150 mg sodium dissolved in 50 ml ethanol). The reaction mixture was refluxed for 15 min and
cooled. After acidification of the mixture with diluted HCl, the solid was collected and identified.
Ethyl 3-amino-6-(4-hydroxyphenyl)-4-phenylthieno[2,3-b]pyridine-2-carboxylate (VIIIa). The
compound VIIIa was obtained from VIa and recrystallized from dioxane to form yellow needles.
1H NMR spectrum (CDCl3): 1.4 t, 3 H (CH3); 4.1 q, 2 H (CH2); 5.7 s, 2 H (NH2); 7.2 – 7.9 m, 10 H
(arom.); 9.7 s, 1 H (OH). IR spectrum: 3 480 – 3 400 (NH2, OH); 1 680 (C=O).
3-Amino-2-(3,5-dimethylpyrazol-1-yl)carbonyl-6-(4-hydroxyphenyl)-4-phenylthieno[2,3-b]pyridine
(VIIIc). The compound VIIIc was obtained from VId and recrystallized from ethanol as orange
needles. IR spectrum: 3 480 – 3 410 (NH2, OH); 1 650 (C=O).
N1-Arylidene-2-amino-6-(4-hydroxyphenyl)-4-phenylthieno-[2,3-b]pyridine-2-carbohydrazides
(IXa – IXc). The title compounds were obtained from VIIa – VIIc and recrystallized from ethanol
as yellow needles. IR spectra: 3 410 – 3 140 (NH2, NH, OH); 1 645 – 1 650 (C=O).
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TABLE I
The yields, melting points and analytical data of the synthesized compounds
Calculated/Found
M.p., °C
Yield, %
Formula
(M.w.)
Compound
% C
% H
% N
% S
IIa
271
82
C18H12N2OS
(304.3)
71.03
71.41
3.97
3.73
9.20
8.98
10.53
10.19
IIb
243
67
C19H14N2OS
(318.4)
71.67
71.33
4.42
4.17
8.79
8.58
10.07
10.27
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
V
130
77
C23H20N2O3S
(404.4)
68.30
67.93
4.98
5.38
6.92
6.71
7.92
8.21
215
73
C21H18N4O2S
(390.4)
64.60
64.96
4.64
4.89
14.35
14.23
8.21
8.09
173
75
C28H23N5O2S2
(525.6)
63.97
63.77
4.40
4.27
13.32
13.15
12.19
12.32
184
63
C26H22N4O2S
(454.5)
68.70
68.37
4.87
4.51
12.32
12.68
7.05
7.02
235
91
C28H22N4O2S
(478.5)
70.27
69.98
4.62
4.51
11.71
11.43
6.70
6.50
193
93
C29H24N4O3S
(508.5)
68.49
68.11
4.75
4.32
11.01
11.33
6.30
5.98
210
90
C30H27N5O2S
(521.6)
69.07
69.14
5.21
5.27
13.43
13.25
6.14
6.06
237
91
C28H21ClN4O2S
(512.9)
65.65
65.44
4.12
4.32
10.92
10.75
6.25
6.07
231
61
C28H21N5OS2
(507.8)
66.21
66.33
4.16
4.28
13.84
13.72
12.62
12.37
VIa
VIb
VIc
VId
215
89
C22H18N2O3S
(390.4)
67.68
67.25
4.64
4.53
7.17
7.47
8.20
7.94
273
81
C20H16N4O2S
(376.4)
63.81
64.05
4.28
4.53
14.88
15.00
8.51
8.31
236
83
C27H21N5O2S2
(511.6)
63.38
63.51
4.13
4.33
13.69
13.61
12.53
12.76
210
76
C25H20N4O2S
(440.5)
68.16
67.85
4.57
4.61
12.72
12.32
7.27
7.11
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TABLE I
(Continued)
Calculated/Found
%
M.p., °C
Yield, %
Formula
(M.w.)
Compound
%
C
H%
N
VIIa
VIIb
VIIc
VIIIa
VIIIb
VIIIc
IXa
159
91
C27H20N4O2S
(464.6)
69.79
69.62
4.33
4.53
12.05
12.23
6.90
6.74
267
93
C28H22N4O3S
(494.5)
68.00
67.83
4.47
4.75
11.32
11.04
6.48
6.22
221
89
C27H19ClN4O2S
(499.0)
64.98
64.72
3.83
4.03
11.22
11.52
6.42
6.19
>360
65
C22H18N2O3S
(390.4)
67.68
67.23
4.64
4.30
7.17
7.23
8.21
8.33
>360
67
C27H19N5OS2
(493.6)
65.70
65.33
3.87
3.51
14.19
14.19
12.99
12.70
261
67
C25H20N4O2S
(440.5)
68.16
67.99
4.57
4.31
12.72
12.55
7.27
7.01
267
70
C27H20N4O2S
(464.6)
69.79
69.45
4.33
4.21
12.31
12.52
6.90
6.83
IXb
231
70
C28H22N4O3S
(494.5)
68.00
68.34
4.47
4.45
11.32
11.61
6.48
6.21
IXc
257
73
C27H19ClN4O2S
(499.0)
64.98
64.77
3.83
3.91
11.22
11.53
6.42
6.27
Xa
131
83
C26H24N2O5S
(476.4)
65.54
65.31
5.07
5.34
5.87
5.72
6.72
6.53
Xb
203
77
C22H20N6O3S
(448.4)
58.92
58.71
4.49
4.32
18.73
18.51
7.14
7.32
XI
305
65
C26H24N2O5S
(476.4)
66.54
65.29
5.07
5.31
5.87
5.60
6.72
6.84
XIIa
XIIb
XIIc
243
87
C36H28N6O3S
(624.6)
69.22
69.35
4.51
4.24
13.45
13.21
5.13
5.15
253
91
C38H32N6O5S
(685.0)
66.62
66.71
4.70
4.53
12.31
12.62
4.68
4.73
230
90
C36H26Cl2N6O3S
(693.6)
62.33
62.10
3.77
3.52
12.11
12.35
4.62
4.43
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3-Amino-6-(4-hydroxyphenyl)-4-phenyl-2-(4-phenyl-5-thioxo-2,4-dihydro-1,2,4-triazol-3-yl)-
thieno[2,3-b]pyridine (VIIIb)
Thiosemicarbazide VIc (5.11 g, 10 mmol) was dissolved in alcoholic sodium hydroxide solution (8%,
20 ml) and heated on a water bath for 5 h. The solution was filtered and the clear filtrate was acidi-
fied with diluted HCl. The separated product was collected and recrystallized from ethanol as orange
prisms. IR spectrum: 3 490 – 3 400 (NH2, OH); 3 310 (NH); 1 600 (C=N).
3-Cyano-2-ethoxycarbonylmethylthio-6-(4-ethoxycarbonylmethoxyphenyl)-4-phenylpyridine (Xa)
Method A. A mixture of IIa (3.04 g, 10 mmol) and ethyl chloroacetate (2.14 ml, 20 mmol) was
refluxed in dry acetone (30 ml) and anhydrous K2CO3 (2 g) on a steam bath for 21 h. After cooling,
the precipitated product was filtered, washed with water several times and recrystallized from ethanol
as yellow crystals. IR spectrum: 3 000 (CH aliph.); 2 240 (C≡N); 1 730 (C=O). Mass spectrum, m/z:
476 (M+ 32.79%).
Method B. A mixture of VIa (3.90 g, 10 mmol) and ethyl chloroacetate (1.07 ml, 10 mmol) was
refluxed in dry acetone (30 ml) and anhydrous K2CO3 (2 g) for 21 h. The product obtained after
recrystallization was identical to that reported in method A according to melting point and spectral
data.
[3-Cyano-6-(4-hydrazinocarbonylmethoxyphenyl)-4-phenyl-2-pyridylthio]acethydrazide (Xb)
A mixture of Xa (4.76 g, 10 mmol) and hydrazine hydrate (1 ml, 20 mmol) in absolute ethanol
(40 ml) was refluxed for 5 h. The solid product was filtered off and recrystallized from dioxane as
yellow crystals. IR spectrum: 3 290 – 3 210 (NHNH2); 2 210 (C≡N); 1 740 (C=O).
Ethyl 3-Amino-6-(4-ethoxycarbonylmethoxyphenyl)-4-phenylthieno-[2,3-b]pyridine-
2-carboxylate (XI)
Compound Xa (4.76 g, 10 mmol) was suspended in sodium ethoxide solution (100 mg sodium in
50 ml ethanol). The reaction mixture was refluxed for 15 min and cooled. The solid obtained was
recrystallized from ethanol–chloroform as yellow needles. IR spectrum: 3 370 – 3 290 (NH2); 1 735
(C=O).
N1-Arylidene[3-cyano-6-(4-N1-arylidenephenoxyacethydrazide)-4-phenyl-2-pyridylthio]-
acethydrazide (XIIa – XIIc)
To a solution of compound Xb (4.48 g, 10 mmol) in ethanol (30 ml), an ethanolic solution of the
appropriate aldehyde (20 mmol) was added. The resulting mixture was refluxed for about 4 h. The
solid formed on cooling was collected and recrystallized from ethanol of the dioxane–water mixture.
IR spectra: 3 220 – 3 200 (NH); 2 200 – 2 210 (C≡N); 1 690 – 1 670 (C=O).
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