1,4-Diaza-bicyclo[2,2,2]octane as a novel and efficient catalyst for the synthesis of 3,4,6-trisubstituted 2-pyridone derivatives

Article abstract of DOI:10.1002/cjoc.201090130

3,4,6-Trisubstituted 2-pyridone derivatives have been synthesized in good to excellent yields through a condensation reaction of various 1,3-diketones with amides in the presence of 1,4-Diaza-bicyclo[2,2,2]octane (DABCO) at reflux temperature.

Full text of DOI:10.1002/cjoc.201090130

NOTE
1,4-Diaza-bicyclo[2,2,2]octane as a Novel and Efficient Catalyst
for the Synthesis of 3,4,6-Trisubstituted 2-Pyridone Derivatives
Heravi, Majid M.
Tahershamsi, Leili
Oskooie, Hossein A.
Baghernejad, Bita
Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran 19569, Iran
3,4,6-Trisubstituted 2-pyridone derivatives have been synthesized in good to excellent yields through a conden-
sation reaction of various 1,3-diketones with amides in the presence of 1,4-Diaza-bicyclo[2,2,2]octane (DABCO) at
reflux temperature.
Keywords 3,4,6-trisubstituted 2-pyridone derivative, 1,4-diaza-bicyclo[2,2,2]octane, 1,3-diketone
Introduction
Results and discussion
In a typical procedure, cyanoacetamide (1 mmol)
and acetylacetone (1 mmol) in the presence of a
cata-lytic amount of DABCO in ethanol at reflux
temperature afforded the desired 2-pyridones 3a in 90%
yield (Entry 1, Table 1). The reaction was then applied
to a variety of 1,3-diketones and amides in good yields
(Table 1). We performed the effect of various solvents
on the synthesis of 3a. This reaction was carried out in
various solvents and the best results in terms of yield
and time were obtained in ethanol (Table 2). The effect
of temperature was studied by carrying out the reactions
at different temperatures (Table 1). The yields of reac-
tions increased as the reaction temperature was raised.
From these results, it was decided that refluxing tem-
perature would be the best temperature for all reactions.
In each reaction, the yield is a function of the reaction
time and the best time for all reactions was within
1— 1.5 h. The reaction proceeded very cleanly under
reflux condition and without any side products. In the
absence of the catalyst, the reaction did not complete
even after 24 h. The progress of the reaction was moni-
tored by TLC and GC and the results indicate that the
yields were affected by changing the catalyst moles. The
reactions proceeded well with 1 mol% of catalyst and
use of an increased amount of catalyst did not make
much difference. DABCO can act as a base catalyst and
a plausible mechanism for this reaction is suggested in
Scheme 1.
In recent years there has been an increasing interest
in the chemistry of 2-pyridones derivatives because of
their biological significance. 2-Pyridones represent a
unique class of pharmacophore, which has been ob-
served in various therapeutic agents1 and antibiotics.2
They are also versatile precursors for the construction of
complex natural products,3 pyridines.4 3-Cyano-2-
pyridones are important intermediates in the pharma-
ceutical, dye and photo industries.5 There are numerous
methods available for their synthesis,6 but most of these
procedures have significant drawbacks such as long re-
action time, low yields, harsh reaction conditions, diffi-
cult work-up and use of environmentally toxic reagents
or media. Consequently, there is a need to develop new
methods for synthesis of these compounds. 1,4-Diaza-
bicyclo[2,2,2]octane (DABCO) has been widely used as
a catalyst for the Baylis-Hillman reactions,7 a catalyst
for acceleration of benzoylation reactions8 and as a
structure directing agent for the synthesis of zeolite.9 It
can also catalyze the self and cross-condensation of
α-acetylenic ketones,10 the coupling of α-keto-esters
with acrylonitrile11 and the dimerization of α,β-unsatu-
rated ketones and nitriles.12
In our attempts to develop new catalyst systems,13
we selected DABCO as a catalyst to synthesize
3,4,6-trisubstituted 2-pyridones derivatives (Eq. 1).
In order to show the merit of the present work, we
compared the results of the synthesis of these com-
pounds in the presence of various catalysts but the best
result was obtained with DABCO (Table 3).
In conclusion, we have described a highly efficient
procedure for the preparation of 2-pyridones via a con-
* E-mail: mmh1331@yahoo.com; Tel.: 0098-2188041344; Fax: 0098-2188047861
Received December 24, 2008; revised October 16, 2009; accepted November 23, 2009.
670
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Chin. J. Chem. 2010, 28, 670— 672

Catalyst for the Synthesis of 3,4,6-Trisubstituted 2-Pyridone Derivatives
Scheme 1
Table 1 Synthesis of 2-pyridones catalyzed by DABCO
Yielda/%
Entry
1
1
2
Product
Time/h
1
25 ℃ 40 ℃ Reflux
Acetylacetone
Cyanoacetamide
62
60
58
60
59
74
70
70
71
72
90
85
85
90
85
2
3
4
5
1,3-Diphenylpropane-1,3-dione Cyanoacetamide
1
Ethyl acetoacetate
Ethyl benzoylacetate
Methyl acetoacetate
Cyanoacetamide
Cyanoacetamide
Cyanoacetamide
1.30
1.20
1.30
6
Acetyl acetone
1-Naphthylacetamide
1.30
66
78
95
7
8
1,3-Diphenylpropane-1,3-dione 1-Naphthylacetamide
1,3-Diphenylpropane-1,3-dione Thioacetamide
1
62
60
71
71
98
95
1.5
a Yields were analyzed by GC.
densation reaction of various 1,3-diketones with amides
using DABCO as a catalyst. The procedure offers sev-
eral advantages including high yields, operational sim-
plicity, cleaner reaction, minimal environmental impact,
Chin. J. Chem. 2010, 28, 670— 672
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671

Heravi et al.
NOTE
Table 2 Synthesis of 3a in different solvents using DABCO as a
catalyst
was cooled and the precipitate formed was filtered off
and recrystallized from ethanol to give pure product.
1
3a: m.p. 290 ℃ (Lit.14 288—289 ℃); H NMR δ:
Entry
Solvent
THF
Time/h
Yielda/%
2.62 (s, 3H, CH3), 2.68 (s, 3H, CH3), 6.80 (1H,＋5H, Ph);
－1
1
2
3
4
5
6
2
68
75
85
75
81
90
IR (KBr) ν: 2200, 1640 cm ; GC/MS: 148 (M ).
CH3OH
CH3CN
CHCl3
2.20
3
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General procedure for preparation of 3,4,6-tri-
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mmol), cyanoacetamide (1 mmol), and DABCO 1
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Chin. J. Chem. 2010, 28, 670— 672