Enaminones as building blocks in organic synthesis: Synthesis of new polyfunctional pyridines, condensed pyridines, and penta substituted benzene

Article abstract of DOI:10.1081/SCC-120014783

Several new thienopyridine and methylthioether derivatives have been synthesized. New synthesis of pyrido[2,3-b]-thieno[3,2-d]pyrimidine and penta substituted benzene were achieved.

Full text of DOI:10.1081/SCC-120014783

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ENAMINONES AS BUILDING BLOCKS IN ORGANIC
SYNTHESIS: SYNTHESIS OF NEW POLYFUNCTIONAL
PYRIDINES, CONDENSED PYRIDINES, AND PENTA
SUBSTITUTED BENZENE
a
b
c
F. A. Abu-Shanab , Y. M. Elkholy & M. H. Elnagdi
a
Chemistry Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
b
c
Version of record first published: 22 May 2009.
To cite this article: F. A. Abu-Shanab, Y. M. Elkholy & M. H. Elnagdi (2002): ENAMINONES AS BUILDING BLOCKS IN ORGANIC
SYNTHESIS: SYNTHESIS OF NEW POLYFUNCTIONAL PYRIDINES, CONDENSED PYRIDINES, AND PENTA SUBSTITUTED BENZENE,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:22,
3493-3502
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3493–3502, 2002
ENAMINONES AS BUILDING BLOCKS IN
ORGANIC SYNTHESIS: SYNTHESIS OF
NEW POLYFUNCTIONAL PYRIDINES,
CONDENSED PYRIDINES, AND PENTA
SUBSTITUTED BENZENE
1
2,
F. A. Abu-Shanab, Y. M. Elkholy, *
3
and M. H. Elnagdi
1
Chemistry Department, Faculty of Science,
Al-Azhar University, Assiut, Egypt
Chemistry Department, Faculty of Science,
Helwan University, Cairo, Egypt
Chemistry Department, Faculty of Science,
Cairo University, Giza, Egypt
2
3
ABSTRACT
Several new thienopyridine and methylthioether derivatives
have been synthesized. New synthesis of pyrido[2,3-b]-
thieno[3,2-d]pyrimidine and penta substituted benzene were
achieved.
*
Corresponding author. E-mail: y-elkholy@yahoo.com
3
493
DOI: 10.1081/SCC-120014783
Copyright & 2002 by Marcel Dekker, Inc.
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3
494
ABU-SHANAB, ELKHOLY, AND ELNAGDI
[
1–3]
The considerable activity of polyfuctionally substituted pyridines
as calcium channel blockers and as antiviral agent has stimulated consider-
[
4–9]
able interest in developing synthesis of pyridines derivatives.
recently reported
Thus, we
efficient synthesis of 1a–c via reacting 2a–c with
[10,11]
cycanothioacetamide. In this article we report on the utility of these
compounds for synthesis of polyfunctionally condensed pyridines such as
3–10 (Sch. 1). Moreover, results of our effort to extend synthetic approach
for 1 functionally substituted pyridones to enable is also reported.
Thus methylation of 3-cyano-5-carbethoxy-6-methylpyridine-2(1H)-
thione 1b with Dimethylformamidedimethylacetal (DMFDMA) afforded
the corresponding methylthioether 3. Treatment of 3 with DMFDMA in
anhydrous DMF afforded the corresponding N,N-dimethylenamine 4 which
is assigned the configuration based on the presence of two doublet at ꢀ 8.10,
and 6.47 ppm corresponding to the two trans vinyl protons, with coupling
[
12]
constant 12.4 Hz. Treatment of 4 with aromatic amines in glacial acetic
acid gave the corresponding N-arylenamines 5a,b without cyclization
Scheme 1.

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POLYFUNCTIONAL SUBSTITUTED PYRIDINES
3495
1
(
Sch. 1), HNMR of 5a shows triplet at ꢀ 1.38, quartet at ꢀ 4.32 for ethyl
group and doublet at ꢀ 10.97 pm, exchangeable for NHgroup.
The pyridine-2(1H)-thione 1a reacted with phenacyl bromide in the
presence of K CO under reflux in ethanol to give the thieno[2,3-b]pyridine
3
2
derivative 6. Also pyridine-2(1H)-thione derivatives 1a–c reacted with
chloroacetamide in the presence of K CO under reflux in ethanol to give
2
3
thieno[2,3-b]pyridine derivatives 7a–c (Sch. 1). Treatment of 7a,c with
nitrous acid afforded the pyrido[2,3-b]thieno[3,2-b]-1,2,3-triazine derivatives
8a,b in good yield. Also, compound 7a on treatment with DMFDMA
afforded a product that is formulated as pyrido[2,3-b]thieno[3,2-d]pyrim-
idine-4(3H)-one 9 and it’s tautomer 10 (Sch. 1). Tautomer 9 is believed to
1
be the major one as HNMR shows two singlets at ꢀ 8.93 and 8.43 ppm
corresponding to the two ring protons and a broad exchangeable signal at
1
0.75 ppm for the NHof structure 9, whereas the NHof 10 would normally
appear at ꢀ 12 ppm.
The reaction of enamine 2c (prepared via condensation of diethyl-
,3-acetondicarboxylatewithDMFDMA)withmalononitrile,sodiumhydride
1
in DMF produced the pyridone derivative 11a rather than pentasubstituted
benzene derivative 12a, (Sch. 2). When the reaction was reported using
1
pipyridine, ethanol, as medium compound 11b was separated. HNMR
spectrum for compound 11a shows the methylene group (a) at ꢀ 4.03 ppm
as a singlet. IR spectrum for 11b shows the disappearance of the cyano group.
The most likely route to the formation of pyridone derivatives 11a,b is
outlined in (Sch. 2). While the reaction of enamine 2a with malononitrile,
pipyridine in ethanol furnish the pyran derivative 13 but not the pyridone
derivative 14 or tetrasubstituted benzene derivative 15, (Sch. 2), it’s
1
HNMR shows two singlets at ꢀ 2.55 and 2.37 for the two methyls in the
structure 13, NHof pyridone 14 would normally appear at ꢀ 12 ppm in
1
HNMR.
The reaction of 2c with cyanoacetamide afforded the pentasubstituted
[
benzene 16 rather than the expected pyridone derivative 17. The structure
13]
1
of 16 was confirmed by HNMR spectrum which an exchangeable signal for
one proton at ꢀ 12.27 ppm for the intramolecular hydrogen bonded OH, a
broad exchangeable signal at ꢀ 8.22 ppm for two protons of the amide NH2
group, a singlet ꢀ 8.19 ppm for the ring proton and two broad exchangeable
signals at ꢀ 7.82 and 7.02 ppm for two proton of the amino group.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on
1
a Perkin-Elmer 1710 FTIR spectrometer for Nujol mulls. HNMR

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496
ABU-SHANAB, ELKHOLY, AND ELNAGDI
Scheme 2.
spectra were recorded on a Bruker AC 300 spectrometer at 300 MHz
spectrometer with DMSO-d6 and CDCl3 as solvent and TMS as
internal standards. Mass spectra were obtained on a Finnigan 4500
(
low resolution) and Kratos Concept (high resolution, HRMS)

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POLYFUNCTIONAL SUBSTITUTED PYRIDINES
3497
Table 1. Analytical Data and Physical Characteristic of New Compounds
Elemental Analysis (Calcd.)
ꢁ
M.P. ( C)
(solvent)
Yield
(%)
Compound
C
HN
5.09
3
135–137
EtOH(55.93)
97
55.89
11.93
13.96
12.06
11.62
9.25
(5.02)
(5.84)
(5.01)
(5.38)
(4.51)
(4.41)
(4.65)
(5.12)
(30.7)
(3.94)
(3.47)
(5.03)
(5.40)
(4.54)
(5.40)
(11.86)
6.11
(14.43)
5.05
(13.38)
5.59
(11.90)
4.40
(9.70)
4.48
(16.86)
4.80
(15.05)
5.16
(14.33)
2.91
(21.54)
3.85
(18.42)
3.42
(16.21)
5.15
(10.07)
5.80
(9.45)
4.35
(15.90)
5.25
(9.45)
4
172–174
EtOH(57.76)
79
94
96
86
93
95
93
83
82
82
67
59
60
35
57.69
63.17
64.77
65.75
53.25
51.80
53.10
50.69
51.39
55.38
65.01
52.96
61.54
52.90
5
5
6
7
7
7
8
8
9
a
210–211
EtOH(63.71)
b
210–211
EtOH(64.58)
185–186
AcOH(65.80)
a
b
c
270–271
AcOH(53.01)
16.70
15.16
14.31
21.25
18.27
16.42
10.25
9.20
245–247
AcOH(51.61)
210–212
AcOH(53.24)
a
b
210
AcOH(50.77)
178–180
AcOH(51.13)
317–319
AcOH(55.59)
1
1
1
1
1a
1b
3
240
EtOH(56.11)
217
EtOH(52.70)
250
EtOH(61.36)
15.75
9.61
6
221–223
MeOH(52.70)
spectrometers using electron impact (EI) or chemical ionization
with amonia (CI). Microanalyses were carried out in the Micro-
analytical laboratory at the Department of Chemistry, Manchester
University, U.K.

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POLYFUNCTIONAL SUBSTITUTED PYRIDINES
3499

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3
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ABU-SHANAB, ELKHOLY, AND ELNAGDI
Ethyl-5-cyano-2-methyl-6-methylthiopyridine-3-carboxylate (3): Equi-
molar amount of 1b (1.93 g, 10 mmol), and DMFDMA (1.19 g, 10 mmol)
in anhydrous DMF (10 mL) were stirred overnight at room temperature.
The reaction mixture was poured onto ice-water, and the solid obtained was
crystallized from ethanol.
Ethyl-5-cyano-2-[2(N,N-dimethylamino)ethyl]-6-methylthiopyridine-3-
carboxylate (4): A mixture of 3 (2.36 g, 10 mmol) and DMFDMA (1.19 g,
10 mmol) in anhydrous DMF (10 mL) were stirred overnight at
room temperature. Then the reaction was heated at 120–125 C for about
ꢁ
0.5 h. The reaction mixture was poured onto ice-water, and the solid
obtained was recovered by filtration and purified by crystallization from
ethanol.
General method for the reaction of 4 with aniline derivatives to prepare,
Ethyl-5-cyano-2-[2(N-phenylamino)ethyl]-6-methylthiopyridine-3-carboxylate
(
5a) and Ethyl-5-cyano-2-[2(N-p-tolylamino)ethyl]-6-methylthiopyridine-3-
carboxylate (5b): Equimolar amount of 4 (0.3 g, 1 mmol) and aromatic
amine (1 mmol) were dissolved in acetic acid (15 mL). The reaction mixture
was stirred at room temperature overnight. The solid was recovered by
filtration and purified by crystallization from ethanol.
5
-Acetyl-3-amino-2-benzyl-6-methylthieno[2,3-b]pyridine
Equimolar amount of 1a (1.92 g, 10 mmol) and phenacyl bromide (1.99 g,
0 mmol), anhydrous potassium carbonate (2 g, 15 mmol) in absolute etha-
(6):
1
nol (30 mL), were heated under reflux for 3 h. The reacion mixture was
diluted with water, and the product was collected by filtration and recystal-
lized from acetic acid.
General method for the reaction of pyridine-2(1H)-thione derivative
1a–c) with chloroacetamide to prepare, 5-Acetyl-3-amino-6-methyl-
(
thieno[2,3-b]pyridine-2-carboxamide (7a), 3-Amino-5-carbethoxy-6-methyl-
thieno[2,3-b]pyridine-2-carboxamide (7b), and 3-Amino-5-carbethoxy-6-
ethylthieno [2,3-b]pyridine-2-carbox-amide (7c): Equimolar amount of
pyridine-2(1H)-thione (1a–c), chloroacetamide (0.66 g, 10 mmol) and
anhydrous potassium carbonate (2 g, 15 mmol) in absolute ethanol (30 mL),
were heated under reflux for 3 h. The reacion mixture was diluted with water,
and the product was collected by filtration and recrystallized from acetic acid.
General method for the reaction of 3-aminothieno[2,3-b]pyridine-2-
carboxamide derivatives (7a,c) with nitrous acid to prepare, 8-Acetyl-7-
methyl-3,4-dihydropyrido[2,3 : 5,4]thieno[2,3-d]triazine-4-one
(8a)
and
Ethyl-7-ethyl-3,4-dihydropyrido[2,3 : 5,4]thieno[2,3-d]triazine-4-one 8-carbo-
xylate (8b): A solution of 7a or 7c (1 mmol) in acetic acid (25 mL)
was treated with sodium nitrite (0.14 g, 2 mmol) portionwise with stirring
at room temperature for 1 h. The solid was collected and purified by
crystalisation from acetic acid.

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POLYFUNCTIONAL SUBSTITUTED PYRIDINES
3501
8-Acetyl-7-methylpyrido[2,3-b]thieno[3,2-d]pyrimidine-4(3H)-one (9): A
solution of 7a (0.30 g, 1 mmol) in dry DMF (10 mL) was treated with
DMFDMA (0.12 g, 1 mmol) portionwise with stirring at room temperature,
and stirred for a further 12 h. The solid was collected and purified by
recrystallization from acetic acid.
Ethyl-3-cyano-6-(carboxymethyl)pyridine-2(1H)-one-5-carboxylate (11a):
A mixture of diethyl 1,3-acetone dicarboxylate (2.02 g, 10 mmol) and
DMFDMA (1.19 g, 10 mmol) in anhydrous DMF (10 mL) in a dry flask
under argon was stirred at room temperature for 24 h. In a second flask,
a mixture of sodium hydride (0.48 g, 10 mmol) and malononitrile (0.66 g,
10 mmol) in anhydrous DMF (10 mL) was stirred under argon at room
temperature for 10 min. The content of the second flask were transferred
by syringe into the first flask, and the resulting mixture was stirred for 24 h.
A mixture of ethanol (25 mL) and water (25 mL) was added, then
the reaction mixture acidified with conc. HCl to pH 4, and stirring was
continued for 24 h. The product so formed was recovered by filtration and
purified by crystallization from ethanol.
Ethyl-3-carbamoyl-6-(carbethoxymethyl)pyridine-2(1H)-one-5-carboxy-
late (11b): The reaction was carried out as described above using diethyl
1
1
,3-acetone dicarboxylate (2.02 g, 10 mmol) and DMFDMA (1.19 g,
0 mmol) and malononitrile (0.66 g, 10 mmol), pipyridine (1 mL) in absolute
ethanol (30 mL) solvent.
5-Acetyl-3-cyano-6-methyl-2-iminopyran (13): The reaction was carried
out as described above using acetylacetone (1 g, 10 mmol), DMFDMA
(
1.19 g, 10 mmol) and malononitrile (0.66 g, 10 mmol), pipyridine (1 mL) in
absolute ethanol, (30 mL) solvent.
-Amino-2,6-bis(carbethoxy)-4-carbamoylphenol (16): The reaction was
carried out as described above using diethyl 1,3-acetone dicarboxylate
3
(
(
2.02 mL, 10 mmol) and DMFDMA (1.19 g, 10 mmol) and cyanoacetamide
0.84 g, 10 mmol), in anhydrous DMF (10 mL).
ACKNOWLEDGMENTS
We are grateful to Prof. Dr. B. J. Wakefield, University of Salford,
Salford MS 4 WT. U.K. for microanalysis and spectral measurements.
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Received in the UK April 26, 2001