A facile method for the synthesis of novel pyridinone derivatives via ketene N,S-acetals

Article abstract of DOI:10.1081/SCC-100106218

A simple and easy method is provided for the synthesis of the novel pyridinone derivatives (3a-e), (8a-c) and (10a-c) by the reaction of ketene acetals (2a-e), (7a-c) and (9a-c) with ethyl cyanoacetate respectively. Compounds (3b-d) reacted with triethyl

Full text of DOI:10.1081/SCC-100106218

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A FACILE METHOD FOR THE SYNTHESIS OF NOVEL
PYRIDINONE DERIVATIVES VIA KETENE N,S-ACETALS
Eljazi I. Al-Afaleq a
a Chemistry Department, Faculty of Science , (Girls College) , P.O. Box 838, Dammam,
31113, Kingdom Saudi Arabia (K.S.A)
Published online: 22 Aug 2006.
To cite this article: Eljazi I. Al-Afaleq (2001) A FACILE METHOD FOR THE SYNTHESIS OF NOVEL PYRIDINONE DERIVATIVES
VIA KETENE N,S-ACETALS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:22, 3557-3567, DOI: 10.1081/SCC-100106218
To link to this article: http://dx.doi.org/10.1081/SCC-100106218
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SYNTHETIC COMMUNICATIONS, 31(22), 3557–3567 (2001)
A FACILE METHOD FOR THE
SYNTHESIS OF NOVEL PYRIDINONE
DERIVATIVES VIA KETENE N,S-ACETALS
Eljazi I. Al-Afaleq
Chemistry Department, Faculty of Science,
(Girls College) P.O. Box 838, Dammam 31113,
Kingdom Saudi Arabia (K.S.A)
E-mail: Eljazii@yahoo.com
ABSTRACT
A simple and easy method is provided for the synthesis of the
novel pyridinone derivatives (3a–e), (8a–c) and (10a–c) by the
reaction of ketene acetals (2a–e), (7a–c) and (9a–c) with ethyl
cyanoacetate respectively. Compounds (3b–d) reacted with
triethyl orthoformate to afford the pyridinone derivatives
(4–6) respectively. Compound 7a reacted with ethyl acetoace-
tate or diethyl malonate to give thiazolopyridinone derivative
11 or 12 respectively.
Heterocyclic ketene N,S-acetals1–7 or aminals8–14 as well as ketoketene
or cyanoketene S,S-acetals15–20 are important synthons for the synthesis of a
wide variety of new heterocycles and fused heterocycles, therefore, their
synthesis and reactions have given rise to much attention.21,22 As an exten-
sion of our recent studies23,24 in heterocyclic synthesis, we report here the
synthesis of some new pyridine derivatives via ketene N,S-acetals.
3557
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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AL-AFALEQ
Compounds (2a–e) were prepared by the reaction of active methylene
compounds (1a–e) with phenyl isothiocyanate and one equivalent of methyl
iodide in a one-pot reaction using phase transfer catalysis (PTC) conditions
[KOH/DMF/tetrabutyl ammonium bromide TBAB] in almost 100% yield
(Scheme 1).
The formed ketene N,S-acetals 2a–e were then treated with ethyl
cyanoacetate in the presence of ammonium acetate and AcOH at 200ꢀC
for different periods of times to afford 2-oxo-phenylpyridines (3a–e),
(Scheme 2). Presumably, the reaction mechanism involves a nucleophilic
attack of ketene NH group at the ethyl-cyanoacetate carbonyl carbon
atom with subsequent cyclization.
Scheme 1.
In case of compounds (3c–e), the ester group was converted into
the corresponding amide group through the reaction of the evolved
NH3 from AcONH4 during the reaction. Analytical and spectral data
(cf. Table) of the obtained products revealed that the carboxamido group
was formed.
The structure of these compounds were also confirmed by the reaction
of compounds (3b–d) with triethyl orthoformate (Scheme 3) to give phenyl-
pyridine-3,5-dicarbo-nitrile 4, phenylpyrido[4,3-d ]-pyrimidine 5 and phenyl-
pyrido[2,3-d ]-pyrimidine 6.
Moreover, cyclic ketene N,S-, N,O- or N,N-acetals were allowed to
react with ethyl cyanoacetate to afford the corresponding fused pyridone
derivatives. Namely, the reaction of 2-thiazolidinylidenemalononitrile (7a),
2-imidazolidinylidene malono- nitrile (7b) or 2-oxazolidinylidenemalononi-
trile (7c) with ethyl cyanoacetate gave dihydrothiazolo(1,2-a)pyridin-4-one

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3559
Scheme 2.
(8a), dihydroimidazolo(1,2-a)pyridin-4-one (8b) or dihydr- oxazolo(1,2-
a)pyridin-4-one (8c), respectively (Scheme 4).
Under these conditions, 2-thiazolidinylideneacetylacetone (9a), 2-imi-
dazolidinyl-iden e acetylacetone (9b) or 2-oxazolidinylideneacetyl-acetone
(9c) reacted with ethyl cyanoacetate to afford thiazolo[3,2-a]-pyridine
(10a), midazo[1,2-a]-pyridine (10b) or oxazolo[3,2-a]-pyridine (10c), respect-
ively (Scheme 5).
When ketene acetals with two acyl groups, such as (2a) and (9a–c)
react with ethyl cyanoacetate under the above conditions the elimination of
one of the acyl groups takes place due to ammonolysis.

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AL-AFALEQ

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3561

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AL-AFALEQ
Scheme 3.
Scheme 4.
Scheme 5.

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3563
Compound (7a) was also allowed to react with different esters, such as
ethyl acetoacetate or diethyl malonate to give thiazolo[3,2-a]-pyridine (11)
or 12, respectively (Scheme 6).
Scheme 6.
EXPERIMENTAL
All melting points were determined on a Kofler melting points appa-
ratus and were determined. IR spectra were obtained on a Nicolet 710
FT-IR spectrometer. 1H-NMR spectra were recorded on a Varian EM
360 A at 60 MHz using TMS as an internal standard. The elemental analyses
were carried out on an elemental analyzer model 240C. Analytical and
spectral data for compounds (3–6), (8) and (10–12) were tabulated in the
above table.
Synthesis of 1,2-Dihydro-2-oxo-1-phenylpyridine
Derivatives (3a–e)
General Procedure
A stirred mixture of ketene N,S-acetals (2a–e) (0.01 mol), ethyl
cyanoacetate (0.01 mol), ammonium acetate (3.0 g) and acetic acid (0.6 ml)
were heated at 200ꢀC for different period of times, then left to cool and
recrystallized with ethanol.

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AL-AFALEQ
6-Amino-1,2-dihydro-4-methyl-2-oxo-1-phenylpyridine-3-carbonitrile (3a).
The general procedure using heating for 2 h was used to give (3e) as
yellow crystals.
Diamino-1,2-dihydro-2-oxo-1-phenylpyridine-3,5-dicarbonitrile (3b). The
general procedure using heating for 3h was used to give ( 3e) as pale
yellow crystals.
4,6-Diamino-1,2-dihydro-2-oxo-3-cyano-1-phenylpyridine-5-carboxamide.
(3c). The general procedure using heating for 3h was used to give ( 3e) as
white crystals.
6-Amino-1,2-dihydro-3-cyano-4-methyl-2-oxo-1-phenylpyridine-5-carb-
oxamide (3d). The general procedure using heating for 3h was used to give
(3e) as white crystals.
6-Amino-3-cyano-1,2-dihydro-4-hydroxy-1-phenylpyridine-5-carboxamide
(3e). The general procedure using heating for 3h was used to give ( 3e) as
white crystals.
Synthesis of 4,6-Bisethoxymethyleneamino-1,2-
dihydro-2-oxo-1-phenyl-pyridine-3,5-dicarbonitrile (4)
A mixture of (3b) (2.51 g, 0.01 mol) and triethyl orthoformate (2.96 g,
0.02 mol), was refluxed in (20 mL) acetic anhydride for 3h, then concen-
trated to half of its volume and left to cool. The solid product was filtered
off and recrystallized from CHCl3 to give compound (4) as white crystals.
Synthesis of 5-Ethoxymethyleneamino-3,4,6,7-tetrahydr-4,
7-dioxo-6-phenyl-pyrido[4,3-d ]pyrimidine-8-carbonitrile (5)
A mixture of (3c) (2.69 g, 0.01 mol) and triethyl orthoformate (2.96 g,
0.02 mol), was refluxed in (20 mL) acetic anhydride for 3h, then concen-
trated to half of its volume and left to cool. The solid product was filtered
off and recrystallized from dioxan to give compound (5) as white crystals.
Synthesis of 3,4,7,8-Tetrahydro-5-methyl-4,7-
dioxo-8-phenylpyrido[2,3-d ]-pyrimidine-6-carbonitrile (6)
A mixture of (3d) (2.68 g, 0.01 mol) and triethyl orthoformate
(1.48 g, 0.01 mol), was refluxed in (20 mL) acetic anhydride for 3h, then

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3565
concentrated to half of its volume and left to cool. The solid product was
filtered off and recrystallized from dioxan to give (6) as white crystals.
Synthesis of (8a–c)
General Procedure
A mixture of cyanoketene N,S, N,N or N,O-acetal (7a–c) (0.01 mol),
ethyl cyanoacetate (1.13g, 0.01 mol), ammonium acetate (3.0 g) and acetic
acid (0.6 mL) was heated with stirring at 200ꢀC for different period of times,
then left to cool and recrystallized from ethanol.
7-Amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyridine-6,8-dicarboni-
trile (8a). The general procedure using heating for 3h was used to give ( 8a)
as white crystals.
7-Amino-1,2,3,5-tetrahydro-5-oxo-imidazo[1,2-a]pyridine-6,8-dicarboni-
trile (8b). The general procedure using heating for 2 h was used to give (8b)
as colorless crystals.
7-Amino-2,3-dihydro-5-oxo-5H-oxazolo[3,2-a]pyridine-6,8-dicarbonitrile
(8c). The general procedure using heating for 2.5 h was used to give (8c) as
deep yellow crystals.
Synthesis of (10a–c)
General Procedure
A mixture of ketoketene N,S N,N or N,O-acetal (9a–c) (0.01 mol),
ethyl cyanoacetate (0.01 mol), ammonium acetate (3.0 g) and acetic acid
(0.6 ml) was heated with stirring at 200ꢀC for different period of times,
then left to cool and recrystallized from ethanol.
2,3-Dihydro-7-methyl-5-oxo-5H-thiazolo[3,2-a]pyridine-6-carbonitrile (10a).
The general procedure using heating under reflux for 2 h was used to give
(10a) as orange crystals.
1,2,3,5-Tetrahydro-7-methyl-5-oxo-5H-imidazolo[1,2-a]pyridine-6-carbo-
nitrile (10b). The general procedure using heating under reflux for 2 h was
used to give (10b) as pale brown crystals.
2,3-Dihydro-7-methyl-5-oxo-5H-oxazolo[3,2-a]pyridine-6-carbonitrile (10c).
The general procedure using heating under reflux for 2 h was used to give
(10c) as white crystals.

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AL-AFALEQ
Synthesis of (11) and (12)
General Procedure
A mixture of cyanoketene N,S-acetal (7a) (0.01 mol), ethyl acetoace-
tate or diethyl malonate (0.01 mol), ammonium acetate (3.0 g) and acetic
acid (0.6 mL) was heated with stirring at 200ꢀC for different period of times,
then left to cool and recrystallized from ethanol.
7-Amino-6-acetyl-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]-pyridine-8-
carbonitrile (11). The general procedure using heating under reflux for 3h
was used to give (11) as red crystals.
Ethyl-7-amino-8-cyano-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyridine-
6-carbonitrile (12). The general procedure using heating under reflux for 2 h
was used to give (12) as brown crystals.
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Received in the USA January 21, 2001

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